CEFTRIAXONE COMPOSITIONS FOR INHALATION AND USES

THEREOF

TECHNICAL FIELD

The present disclosure generally relates to ceftriaxone compositions for inhalation, e.g., using a nebulizer, and uses of the compositions for the treatment of bacterial infections diseases or conditions, in particular bacterial infections diseases or conditions associated with the respiratory system, e.g., pneumonia and tuberculosis.

BACKGROUND

Respiratory tract infections are infectious diseases involving the respiratory tract. An infection of this type usually is further classified as an upper respiratory tract infection (URI or URTI), or a lower respiratory tract infection (LRI or LRTI). Lower respiratory infections, such as pneumonia, tend to be far more severe than upper respiratory infections.

Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever and difficulty breathing. Pneumonia is usually caused by infection with viruses or bacteria, and less commonly by other microorganisms. Identifying the responsible pathogen can be difficult. The disease may be classified by where it was acquired, such as community- or hospital-acquired or healthcare- associated pneumonia.

Risk factors for pneumonia include cystic fibrosis, chronic obstructive pulmonary disease (COPD), sickle cell disease, asthma, diabetes, heart failure, a history of smoking, a poor ability to cough (such as following a stroke), and a weak immune system.

Each year, pneumonia affects about 450 million people globally (7% of the population) and results in about 4 million deaths. With the introduction of antibiotics and vaccines in the 20th century, survival has greatly improved. Nevertheless, pneumonia remains a leading cause of death in developing countries, and also among the very old, the very young, and the chronically ill. Pneumonia often shortens the period of suffering among those already close to death.

Treatment depends on the underlying cause. Pneumonia believed to be due to bacteria is treated with antibiotics. If the pneumonia is severe, the affected person is generally hospitalized. Oxygen therapy may be used if oxygen levels are low. Antibiotics by mouth, rest, simple analgesics, and fluids are typically administered to pneumonia patients. However, those with other medical conditions, the elderly, or those with significant trouble breathing may require more advanced care. If the symptoms worsen, the pneumonia does not improve with home treatment, or complications occur, hospitalization may be required. Worldwide, approximately 7-13% of cases in children result in hospitalization, whereas in the developed world between 22 and 42% of adults with community-acquired pneumonia are admitted.

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB) bacteria and other Mycobacterium species, that usually affects the lungs, but can also affect other parts of the body. Tuberculosis is a major disease in developing countries and a growing problem in the world's developed regions. The infection may be asymptomatic for a significant period of time, but most commonly the disease manifests as acute pneumonia resulting in fever and dry cough. If untreated, tuberculosis typically leads to serious complications and death.

Ceftriaxone is an antibiotic used for the treatment of a number of bacterial infections. These include middle ear infections, endocarditis, meningitis, pneumonia, bone and joint infections, intra-abdominal infections, skin infections, urinary tract infections, gonorrhea, and pelvic inflammatory disease. It is also sometimes used before surgery and following a bite wound to try to prevent infection. Ceftriaxone is given by injection into a vein or into a muscle.

Specifically, ceftriaxone is typically provided as a powder, which is solubilized and administered by injection to the subject as an aqueous solution having a concentration of 100-300 mg/ml or 10-40 mg/ml for intramuscular (IM) and intravenous (IV) injection, respectively. The typical doses administered are 1-2 ceftriaxone grams per day.

Such high dosages are undesired, specifically for antibiotics, in which increased systemic consumption contributes to the emergence of antibiotic resistance. Also, adverse effects may occur, especially when the treatment is prolonged and the subject is unhealthy. Common side effects include pain at the site of injection and allergic reactions. Other possible side effects include C. difficile associated diarrhea, hemolytic anemia, gall bladder disease, and seizures. It is not recommended in those who have had anaphylaxis to penicillin but may be used in those who have had milder reactions. WO 2016/059630 discloses a nebulizer comprising a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium and a gas channel configured to introduce pressure gradient to the porous medium.

WO 2017/149534 discloses a method for treating a disease or disorder in a subject in need thereof comprising administering, via inhalation, to the subject an aerosol comprising a nicotine formulation using a nebulizer. The subject may have a respiratory disease affecting the air ways, the alveoli or the interstitium, such as, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, acute bronchitis, cystic fibrosis, pneumonia, tuberculosis, fragile connections between alveoli, pulmonary edema, lung cancer in its many forms, acute respiratory distress syndrome, pneumoconiosis, mouth and pharynx cancer, tracheal tumors and interstitial lung disease among others.

WO 2019/215719 discloses a nebulizer cartridge comprising at least one porous medium having a proximal surface, the at least one porous medium extending between a first position and a second position; at least one reservoir configured to contain a liquid; at least one mobile liquid absorbing element; at least one stationary liquid absorbing element being in contact with the at least one reservoir; at least one conveyer connected to the at least one mobile liquid absorbing element, and configured to be actuated by a motor; and a track operably linked to the at least one conveyer; wherein said at least one conveyer and said at least one mobile liquid absorbing element connected thereto are configured to move along the track; and wherein the at least one mobile liquid absorbing element is configured to be in contact with the at least one stationary liquid absorbing element, and upon movement along the track it is further configured to be in contact with the at least one porous medium.

US 2020/0352953 discloses a method of treating a bacterial infection of a subject, the method comprising: topically administering a topical composition to the subject comprising contacting a tissue surface of the subject to be treated with the topical composition, wherein the tissue surface comprises skin or mucosal tissue, and wherein the topical composition comprises ceftriaxone for injection powder combined with a carrier. US 2020/0352953 further discloses that the topical composition is administered in a dosage amount of between approximately 400 mg and 4 g ceftriaxone and that it is topically administered once or twice daily.

There is an unmet need for compositions, which enable improved treatment of pneumonia as well as other bacterial infections, at low doses that can reduce adverse effects and frequency and severity of adverse events, and can further reduce the development of antibiotic resistance.

SUMMARY

The following embodiments and aspects thereof are described and illustrated in conjunction with compositions and methods which are meant to be exemplary and illustrative, not limiting in scope. In various embodiments, one or more of the above- described problems have been reduced or eliminated, while other embodiments are directed to other advantages or improvements.

The present invention provides pulmonary pharmaceutical compositions comprising ceftriaxone, which are suitable for administration to subjects in need thereof via inhalation. Preferably the compositions are provided as aqueous solutions of ceftriaxone at ceftriaxone concentrations ranging from 10 mg/ml to 250 mg/ml or 20 mg/ml to 200 mg/ml ceftriaxone. The present invention further provides pharmaceutical uses and methods of treatment, which include administering ceftriaxone or said pulmonary pharmaceutical compositions to a subject in need thereof. Specifically, the pharmaceutical uses and methods of treatment are intended to treat bacterial infections associated with the respiratory system, such as bacterial pneumonia.

Advantageously, the compositions of the present invention are effective in the treatment of bacterial infections, in particular bacterial infections associated with the respiratory tract, e.g., pneumonia and tuberculosis, by administering ceftriaxone via inhalation, while delivering significantly lower daily doses compared to the typical doses required to achieve similar treatment with ceftriaxone delivered via injection. Thus, the compositions, uses and methods of treatment of the present invention may provide effective treatment of various bacterial infections, e.g., bacterial pneumonia, employing ceftriaxone, while minimalizing the adverse effects associated with this antibiotic. In particular, it was surprisingly found that effective treatment of pneumonia may be achieved by administering amounts as low as 1 to 250 milligrams/day of ceftriaxone via inhalation.

Furthermore, it is hypothesized that by administering the compositions of the invention through the respiratory system for treatment of bacterial infections associated with the respiratory tract, high local concentration of ceftriaxone may be achieved in the airways, compared to that achieved by intravenous (IV) or intramuscular (IM) injection. Therefore, the compositions, uses and methods of treatment of the present invention may reduce the development and spread of antibiotic resistance (AR) associated with ceftriaxone.

According to some embodiments, there is provided a method of treating a bacterial infectious disease or condition associated with the respiratory tract, the method comprising administering ceftriaxone to a subject in need thereof via inhalation. According to some embodiments, there is provided a method of treating a bacterial infectious disease or condition associated with the respiratory tract, the method comprising administering from 1 to 250 mg/day ceftriaxone to a subject in need thereof via inhalation.

In some embodiments, the bacterial infectious disease or condition is amenable to treatment with injectable ceftriaxone.

According to some embodiments, the bacterial infectious disease or condition is selected from the group consisting of pneumonia, tuberculosis (TB), bacterial meningitis, otitis media, and chronic obstructive pulmonary disease. Each possibility represents a separate embodiment of the invention. In some embodiments, the bacterial infectious disease is selected from pneumonia and tuberculosis (TB). In some embodiments, the bacterial infectious disease is pneumonia. In other embodiments, the bacterial infectious disease is TB.

According to some embodiments, the method comprises administering from 1 to 250 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering from 4 to 200 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering from 4 to 120 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering ceftriaxone to the subject at least two sessions a day via inhalation. According to some embodiments, the method comprises administering ceftriaxone to the subject four times a day via inhalation.

According to some embodiments, each session comprises a continuous inhalation or 5 to 50 discrete inhalations. Each possibility represents a separate embodiment of the invention. According to some embodiments, the period of the administration is in the range of 2-60 minutes. According to some embodiments, each administration comprises a continuous inhalation for the period of 5-15 minutes. According to some embodiments, each administration comprises 10-30 discrete inhalations for the total period of 5-15 minutes. According to some embodiments, each discrete inhalation comprises 50-500 microgram ceftriaxone.

According to some embodiments, the method comprises administering ceftriaxone to the subject four sessions a day via inhalation, wherein each session comprises administration of 1-30 mg ceftriaxone via inhalation.

According to some embodiments, the ceftriaxone is provided as a liquid pharmaceutical composition comprising ceftriaxone and a pharmaceutically acceptable carrier, excipient or diluent. According to some embodiments, the ceftriaxone is provided as a dry powder or as a pharmaceutical composition comprising ceftriaxone and a pharmaceutically acceptable carrier, excipient or diluent.

According to some embodiments, the method comprises administering a pharmaceutical composition comprising ceftriaxone and a pharmaceutically acceptable carrier, excipient or diluent to a subject in need thereof via inhalation.

According to some embodiments, the pharmaceutical composition is liquid. According to some embodiments, the pharmaceutical composition is aqueous.

According to some embodiments, the pharmaceutical composition comprises 20 to 200 mg/ml ceftriaxone. According to some embodiments, the pharmaceutical composition comprises 10 to 100 mg/ml ceftriaxone. According to some embodiments, the pharmaceutical composition comprises 20 to 50 mg/ml ceftriaxone.

According to some embodiments, the ceftriaxone is provided as an aqueous pharmaceutical composition comprising ceftriaxone at a concentration of 20 to 200 mg/ml, and each session comprises administering 25 to 250 microliter of the aqueous pharmaceutical composition. According to some embodiments, each session comprises administering 50 to 150 microliters of the aqueous pharmaceutical composition. According to some embodiments, the ceftriaxone is provided as an aqueous pharmaceutical composition comprising ceftriaxone at a concentration of 20 to 200 mg/ml, and wherein each discrete inhalation delivers 1 to 5 microliters of the aqueous pharmaceutical composition.

According to some embodiments, the pharmaceutical composition comprises at least one additive selected from the group consisting of a propellant, an anti-coughing agent and a flavorant.

According to some embodiments, the pharmaceutical composition comprises a flavorant. According to some embodiments, the flavorant is selected from the group consisting of: peppermint, spearmint, eucalyptol, menthol, eugenol, cocoa, vanilla, cinnamon, licorice, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethylvanillin, methyl salicylate, acesulfame potassium, saccharine, aspartame, dextrose, mannitol, sorbitol, fructose and combinations thereof.

According to some embodiments, the pharmaceutical composition comprises an anti coughing agent. According to some embodiments, the anti-coughing agent is selected from the group consisting of menthol, dextromethorphan, dextromethorphan hydrobromide, hydrocodone, caramiphen dextrorphan, 3-methoxymorphinan or morphinan- 3-ol, carbetapentane, codeine, acetylcysteine and combinations thereof. According to some embodiments, the pharmaceutical composition comprises a propellant.

According to some embodiments, the pharmaceutical composition comprises at least one preservative selected from the group consisting of benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride, phenylethyl alcohol, chlorobutanol, potassium sorbate, phenol, m-cresol, o-cresol, pcresol, chlorocresol and combinations thereof. According to some embodiments, the pharmaceutical composition is substantially devoid of anesthetics.

According to some embodiments, the pharmaceutical composition has pH above 4. According to some embodiments, the pharmaceutical composition has pH above 5.5. According to some embodiments, the method comprises administering ceftriaxone to the subject via inhalation using a nebulizer or an inhaler. According to some embodiments, the method comprises administering ceftriaxone to the subject via inhalation using a nebulizer.

According to some embodiments, the nebulizer comprises a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium and a gas channel configured to introduce pressure gradient to the porous medium. According to some embodiments, the displaceable wetting mechanism comprises a rotatable elongated member. According to some embodiments, the rotatable elongated member is configured to move across the surface of the porous medium, thereby to homogeneously or semi-homogeneously spread the liquid over the surface. According to some embodiments, the rotatable elongated member is axially movable. According to some embodiments, the displaceable wetting mechanism further comprises an actuator configured to displace or induce the displacement of the rotatable elongated member. According to some embodiments, the rotatable elongated member comprises a first magnet, and the actuator comprises a second magnet, magnetically associated with said first magnet, such that by moving the second magnet displacement of the rotatable elongated member is induced.

According to some embodiments, the nebulizer comprises a porous medium configured to produce aerosols, a liquid absorbing material configured to absorb a liquid, a wetting mechanism configured to press the liquid absorbing material against the porous medium, thereby to wet the porous medium with the liquid absorbed in the liquid absorbing material and a gas channel configured to introduce pressure gradient to the porous medium. According to some embodiments, the liquid absorbing material is selected from a sponge, a tissue and foam.

According to some embodiments, the nebulizer comprises a porous medium configured to produce aerosols, the porous medium having a first side and a second side, a liquid absorbing material configured to absorb a liquid, the liquid absorbing material having a first side and a second side, a wetting mechanism configured to press the liquid absorbing material against the porous medium, thereby to wet the porous medium with the liquid absorbed in the liquid absorbing material, an opening configured to deliver aerosols to a subject, and a gas channel configured to introduce a gas pressure gradient, such that the first side of the porous medium and the second side of the porous medium have different gas pressure levels, thereby producing the aerosol, wherein the wetting mechanism is attached to the first side of the liquid absorbing material, wherein the first side of the porous medium is facing the liquid absorbing material and the opening, and the second side of the porous medium is facing the gas channel.

According to some embodiments, the method comprises administering ceftriaxone to the subject via inhalation using a nebulizer, wherein the nebulizer comprises a nebulizer cartridge comprising: at least one porous medium having a proximal surface, the at least one porous medium extending between a first position and a second position; at least one reservoir configured to contain a liquid; at least one mobile liquid absorbing element; at least one stationary liquid absorbing element being in contact with the at least one reservoir; at least one conveyer connected to the at least one mobile liquid absorbing element, and configured to be actuated by a motor; and a track operably linked to the at least one conveyer, wherein said at least one conveyer and said at least one mobile liquid absorbing element connected thereto are configured to move along the track; and wherein the at least one mobile liquid absorbing element is configured to be in contact with the at least one stationary liquid absorbing element, and upon movement along the track it is further configured to be in contact with the at least one porous medium.

According to some embodiments, the method comprises (a) generating an aerosol comprising the ceftriaxone and comprising droplets having a mass median aerodynamic diameter (MMAD) of at most 10 microns; and (b) administering said aerosol to the subject via inhalation.

According to some embodiments, the aerosol droplets have MMAD of at most 5 microns. According to some embodiments, the aerosol droplets have MMAD of at most 3 microns. According to some embodiments, the aerosol droplets have sub-micron MMAD.

According to some embodiments, there is provided ceftriaxone, for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract, via inhalation. According to some embodiments, there is provided ceftriaxone, for use, via inhalation at a daily dose in the range of 1 to 250 mg per day, in the treatment of a bacterial infectious disease or condition associated with the respiratory tract. According to some embodiments, the bacterial infectious disease or condition is amenable to treatment with injectable ceftriaxone.

According to some embodiments, the bacterial infectious disease or condition is selected from the group consisting of pneumonia, tuberculosis (TB), bacterial meningitis, otitis media, and chronic obstructive pulmonary disease. In some embodiments, the bacterial infectious disease is selected from pneumonia and tuberculosis (TB). In some embodiments, the bacterial infectious disease is pneumonia. In some embodiments, the bacterial infectious disease is tuberculosis (TB).

According to some embodiments, the ceftriaxone is used for the treatment described above, via inhalation at a daily dose in the range of 2 to 200 mg ceftriaxone per day. According to some embodiments, the ceftriaxone is used via inhalation at a daily dose in the range of 4 to 120 mg ceftriaxone per day. According to some embodiments, the ceftriaxone is used via inhalation at least twice a day. According to some embodiments, the ceftriaxone is used via inhalation at least two sessions a day.

According to some embodiments, the ceftriaxone is for use in the treatment of pneumonia via inhalation at a daily dose in the range of 2 to 250 mg ceftriaxone per day. According to some embodiments, the ceftriaxone is for use in the treatment of pneumonia via inhalation at a daily dose in the range of 2 to 200 mg ceftriaxone per day. According to some embodiments, the ceftriaxone is for use in the treatment of pneumonia via inhalation at least twice a day. According to some embodiments, the ceftriaxone is for use in the treatment of pneumonia via inhalation four times a day, each time comprises administration of about 1 to 30 mg ceftriaxone.

According to some embodiments, the ceftriaxone is for use in the treatment of tuberculosis via inhalation at a daily dose in the range of 1 to 250 mg ceftriaxone per day. According to some embodiments, the ceftriaxone is for use in the treatment of tuberculosis via inhalation at a daily dose in the range of 2 to 200 mg ceftriaxone per day. According to some embodiments, the ceftriaxone is for use in the treatment of tuberculosis via inhalation at a daily dose in the range of 4 to 120 mg ceftriaxone per day. According to some embodiments, the ceftriaxone is for use in the treatment of tuberculosis via inhalation at least twice a day. According to some embodiments, the ceftriaxone is for use in the treatment of tuberculosis via inhalation four times a day, each time comprises administration of about 1 to 30 mg ceftriaxone.

According to some embodiments, each session comprises a continuous inhalation or 5- 50 discrete inhalations, wherein the period of the administration is in the range of 2-60 minutes. According to some embodiments, the ceftriaxone is for use via inhalation four sessions a day via inhalation, wherein each session comprises administration of 1-30 mg ceftriaxone via inhalation. According to some embodiments, each administration comprises a continuous inhalation for the period of 5-15 minutes. According to some embodiments, each administration comprises 10-30 discrete inhalations for the total period of 5-15 minutes. According to some embodiments, each discrete inhalation comprises 50-500 microgram ceftriaxone.

According to some embodiments, the ceftriaxone is provided as a dry powder or as a pharmaceutical composition comprising ceftriaxone and a pharmaceutically acceptable carrier, excipient or diluent. According to some embodiments the ceftriaxone is provided as an aqueous pharmaceutical composition.

According to some embodiments, the pharmaceutical composition comprises 20 to 200 mg/ml ceftriaxone. According to some embodiments, the ceftriaxone is provided as an aqueous pharmaceutical composition comprising ceftriaxone at a concentration of 20 to 200 mg/ml, and wherein each session comprises administering 50 to 150 microliter of the aqueous pharmaceutical composition. According to some embodiments, the ceftriaxone is provided as an aqueous pharmaceutical composition comprising ceftriaxone at a concentration of 20 to 200 mg/ml, and wherein each discrete inhalation delivers 1 to 5 microliters of the aqueous pharmaceutical composition.

According to some embodiments, there is provided a pulmonary pharmaceutical composition, provided in a dosage form suitable for aerosolization using a nebulizer, wherein the pulmonary composition comprises an aqueous solution of ceftriaxone at a concentration in the range of 20 to 200 mg/ml and a pharmaceutically acceptable carrier, excipient or diluent.

According to some embodiments, the pulmonary pharmaceutical composition is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract. According to some embodiments, the pulmonary pharmaceutical composition is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract, via inhalation.

According to some embodiments, there is provided a pulmonary pharmaceutical composition comprising ceftriaxone and a pharmaceutically acceptable carrier, excipient or diluent, for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation.

In some embodiments, the bacterial infectious disease or condition is amenable to treatment with injectable ceftriaxone.

In some embodiments, the bacterial infectious disease or condition is selected from the group consisting of pneumonia, tuberculosis (TB), bacterial meningitis, otitis media, and chronic obstructive pulmonary disease. In some embodiments, the bacterial infectious disease is selected from pneumonia and tuberculosis (TB). In some embodiments, the bacterial infectious disease is pneumonia. In some embodiments, the bacterial infectious disease is tuberculosis (TB).

According to some embodiments, the pulmonary composition comprises an aqueous solution of ceftriaxone at a concentration in the range of 10 to 250 mg/ml. According to some embodiments, the pulmonary composition comprises an aqueous solution of ceftriaxone at a concentration in the range of 20 to 200 mg/ml.

According to some embodiments, the pulmonary composition is used via inhalation using a nebulizer.

According to some embodiments, the composition is for use via inhalation at a daily dose in the range of 1 to 250 or 4 to 120 mg ceftriaxone per day. Each possibility represents a separate embodiment of the invention. According to some embodiments, the composition is for use via inhalation at least two sessions a day. According to some embodiments, each session comprises a continuous inhalation or 5-50 discrete inhalations, wherein the period of the administration is in the range of 2-60 minutes. According to some embodiments, the composition is for use via inhalation four sessions a day via inhalation, wherein each session comprises administration of 1-30 mg ceftriaxone via inhalation. According to some embodiments, each administration comprises a continuous inhalation for the period of 5-15 minutes or wherein each administration comprises 10-30 discrete inhalations for the total period of 5-15 minutes. According to some embodiments, each administration comprises 10-30 discrete inhalations for the total period of 5-15 minutes, wherein each discrete inhalation comprises 50-500 microgram ceftriaxone.

According to some embodiments, the pulmonary composition is used via inhalation at a daily dose in the range of 1 to 250 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is used via inhalation at a daily dose in the range of 2 to 200 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is used via inhalation at least twice a day. According to some embodiments, the pulmonary composition is used via inhalation four times a day, each time comprises administration of about 1 to 30 mg ceftriaxone.

According to some embodiments, the pulmonary composition is for use in the treatment of pneumonia via inhalation at a daily dose in the range of 1 to 250 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use in the treatment of pneumonia via inhalation at a daily dose in the range of 2 to 200 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use in the treatment of pneumonia via inhalation at least twice a day. According to some embodiments, the pulmonary composition is for use in the treatment of pneumonia via inhalation four times a day, each time comprises administration of about 1 to 30 mg ceftriaxone.

According to some embodiments, the pulmonary composition is for use in the treatment of tuberculosis via inhalation at a daily dose in the range of 1 to 250 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use in the treatment of tuberculosis via inhalation at a daily dose in the range of 2 to 200 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use in the treatment of tuberculosis via inhalation at least twice a day. According to some embodiments, the pulmonary composition is for use in the treatment of tuberculosis via inhalation four times a day, each time comprises administration of about 1 to 30 mg ceftriaxone

According to some embodiments, the pharmaceutical composition comprises 10 to 50 mg/ml ceftriaxone. According to some embodiments, the pharmaceutical composition comprises 20 to 200 mg/ml ceftriaxone.

According to some embodiments, the pharmaceutical composition comprises at least one additive selected from the group consisting of a propellant, an anti-coughing agent and a flavorant. According to some embodiments, the pharmaceutical composition comprises a flavorant. According to some embodiments, the flavorant is selected from the group consisting of: peppermint, spearmint, eucalyptol, menthol, eugenol, cocoa, vanilla, cinnamon, licorice, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethylvanillin, methyl salicylate, acesulfame potassium, saccharine, aspartame, dextrose, mannitol, sorbitol, fructose and combinations thereof. According to some embodiments, the pharmaceutical composition comprises an anti-coughing agent. According to some embodiments, the anti-coughing agent is selected from the group consisting of menthol, dextromethorphan, dextromethorphan hydrobromide, hydrocodone, caramiphen dextrorphan, 3-methoxymorphinan or morphinan- 3-ol, carbetapentane, codeine, acetylcysteine and combinations thereof. According to some embodiments, the pharmaceutical composition comprises a propellant. According to some embodiments, the pharmaceutical composition comprises at least one preservative selected from the group consisting of benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride, phenylethyl alcohol, chlorobutanol, potassium sorbate, phenol, m-cresol, o-cresol, pcresol, chlorocresol and combinations thereof. According to some embodiments, the pharmaceutical composition has pH above 5. According to some embodiments, the pharmaceutical composition is devoid of anesthetics.

According to some embodiments, the pharmaceutical composition is used via inhalation using a nebulizer, wherein the nebulizer comprises a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium and a gas channel configured to introduce pressure gradient to the porous medium. According to some embodiments, the displaceable wetting mechanism comprises a rotatable elongated member. According to some embodiments, the rotatable elongated member is configured to move across the surface of the porous medium, thereby to homogeneously or semi- homogeneously spread the liquid over the surface. According to some embodiments, wherein the rotatable elongated member is axially movable. According to some embodiments, the displaceable wetting mechanism further comprises an actuator configured to displace or induce the displacement of the rotatable elongated member. According to some embodiments, the rotatable elongated member comprises a first magnet, and the actuator comprises a second magnet, magnetically associated with said first magnet, such that by moving the second magnet displacement of the rotatable elongated member is induced.

According to some embodiments, the pharmaceutical composition is used via inhalation using a nebulizer, wherein the nebulizer, wherein the nebulizer comprises a porous medium configured to produce aerosols, a liquid absorbing material configured to absorb a liquid, a wetting mechanism configured to press the liquid absorbing material against the porous medium, thereby to wet the porous medium with the liquid absorbed in the liquid absorbing material and a gas channel configured to introduce pressure gradient to the porous medium. According to some embodiments, the liquid absorbing material is selected from a sponge, a tissue and foam.

According to some embodiments, there is provided a nebulizer cartridge comprising the pharmaceutical composition or pulmonary composition of the present invention. According to some embodiments, there is provided a nebulizer cartridge comprising a liquid reservoir, containing a pharmaceutical composition, wherein the pharmaceutical composition comprises an aqueous solution of ceftriaxone at a concentration in the range of 20 to 200 mg/ml. According to some embodiments, there is provided a nebulizer cartridge comprising a porous medium and a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium, wherein the porous medium comprises a plurality of pores, and wherein at least some of said plurality of pores comprise the liquid, wherein the liquid comprises the pharmaceutical composition of the present invention.

According to some embodiments, the cartridge comprises at least one porous medium having a proximal surface, the at least one porous medium extending between a first position and a second position; at least one reservoir, which contains the pharmaceutical composition; at least one mobile liquid absorbing element; at least one stationary liquid absorbing element being in contact with the at least one reservoir; at least one conveyer connected to the at least one mobile liquid absorbing element, and configured to be actuated by a motor; and a track operably linked to the at least one conveyer, wherein said at least one conveyer and said at least one mobile liquid absorbing element connected thereto are configured to move along the track; and wherein the at least one mobile liquid absorbing element is configured to be in contact with the at least one stationary liquid absorbing element, and upon movement along the track it is further configured to be in contact with the at least one porous medium.

According to some embodiments, the cartridge comprises a porous medium and a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium, wherein the displaceable wetting mechanism comprises a rotatable elongated member, and the liquid reservoir.

According to some embodiments, the cartridge comprises the liquid reservoir containing the pharmaceutical composition, a porous medium, and a liquid absorbing material, configured to be pressed against the porous medium thereby to wet the porous medium with the liquid absorbed in the liquid absorbing material, wherein the liquid absorbing material comprises the pharmaceutical composition absorbed therein. According to some embodiments, the cartridge further comprises a rod and a solid plate connected to the liquid absorbing material.

According to some embodiments, the cartridge is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation. According to some embodiments, the cartridge contains the present pharmaceutical composition.

According to some embodiments, there is provided an aerosolization filling composition comprising ceftriaxone as disclosed herein or the pharmaceutical composition as disclosed herein.

According to some embodiments, the aerosolization filling composition is selected from a nebulizer cartridge filling composition and an inhaler cartridge filling composition.

According to some embodiments, there is provided an aerosol composition comprising ceftriaxone, wherein the aerosol comprising droplets having a mass median aerodynamic diameter (MMAD) of at most 10 microns. According to some embodiments, the aerosol droplets have MMAD of at most 5 microns. According to some embodiments, the aerosol droplets have MMAD of at most 3 microns. According to some embodiments, the aerosol droplets have sub-micron MMAD. According to some embodiments, the aerosol is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation.

In some embodiments, the bacterial infectious disease or condition is amenable to treatment with injectable ceftriaxone.

In some embodiments, the bacterial infectious disease or condition is selected from the group consisting of pneumonia, tuberculosis (TB), bacterial meningitis, otitis media, and chronic obstructive pulmonary disease. In some embodiments, the bacterial infectious disease is selected from pneumonia and tuberculosis (TB). In some embodiments, the bacterial infectious disease is pneumonia. In some embodiments, the bacterial infectious disease is tuberculosis (TB).

According to some embodiments, the aerosol is used via inhalation at a daily dose in the range of 1 to 250 mg ceftriaxone per day. According to some embodiments, the aerosol is used via inhalation four times a day, each time comprises administration of about 1 to 30 mg ceftriaxone.

According to some embodiments, the aerosol is for use in the treatment of pneumonia via inhalation at a daily dose in the range of 1 to 250 mg ceftriaxone per day. According to some embodiments, the aerosol is for use in the treatment of pneumonia via inhalation four times a day, each time comprises administration of about 1 to 30 mg ceftriaxone.

According to some embodiments, the aerosol is for use in the treatment of tuberculosis (TB) via inhalation at a daily dose in the range of 1 to 250 mg ceftriaxone per day. According to some embodiments, the aerosol is for use in the treatment of tuberculosis (TB) via inhalation four times a day, each time comprises administration of about 1 to 30 mg ceftriaxone.

According to some embodiments, the aerosol comprises an aqueous solution of ceftriaxone at a concentration in the range of 10 to 250 mg/ml and a pharmaceutically acceptable carrier, excipient or diluent. According to some embodiments, the aerosol further comprising at least one additive selected from the group consisting of a preservative, a propellant, an anti-coughing agent and a flavorant. According to some embodiments, the aerosol has pH in the range of 5.5 to 8.

According to some embodiments, the aerosol is prepared by aerosolizing the pharmaceutical composition of the present invention using a nebulizer or an inhaler. Certain embodiments of the present disclosure may include some, all, or none of the above advantages. One or more technical advantages may be readily apparent to those skilled in the art from the figures, descriptions and claims included herein. Moreover, while specific advantages have been enumerated above, various embodiments may include all, some or none of the enumerated advantages.

In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the figures and by study of the following detailed descriptions.

BRIEF DESCRIPTION OF THE FIGURES

Examples illustrative of embodiments are described below with reference to figures attached hereto. In the figures, identical structures, elements or parts that appear in more than one figure are generally labeled with a same numeral in all the figures in which they appear. Alternatively, elements or parts that appear in more than one figure may be labeled with different numerals in the different figures in which they appear. Dimensions of components and features shown in the figures are generally chosen for convenience and clarity of presentation and are not necessarily shown in scale. The figures are listed below.

Fig. 1 schematically illustrates a nebulizer with a porous medium, according to some embodiments;

Fig. 2 schematically illustrates a nebulizer with porous medium and medication containers, according to some embodiments;

Fig. 3 schematically illustrates a nebulizer with a sponge pressed against a porous medium, according to some embodiments;

Fig. 4 schematically illustrates generation of aerosol within a nebulizer, according to some embodiments;

Fig. 5 schematically illustrates a nebulizer system, according to some embodiments; Fig. 6a schematically illustrates a nebulizer with a rotatable wetting mechanism and a bottom actuator at side cross section, according to some embodiments;

Fig. 6b schematically illustrates a nebulizer with a rotatable wetting mechanism and a bottom actuator at top cross section, according to some embodiments;

Fig. 6c schematically illustrates a nebulizer with a rotatable wetting mechanism and a peripheral actuator at side cross section, according to some embodiments; Fig. 6d schematically illustrates a nebulizer with a rotatable wetting mechanism and a peripheral actuator at top cross section, according to some embodiments;

Fig. 6e schematically illustrates a nebulizer with a rotatable wetting mechanism and a flexible medication deploying end at side cross section, according to some embodiments;

Fig. 6f schematically illustrates a nebulizer with a rotatable wetting mechanism and a flexible medication deploying end at top cross section, according to some embodiments;

Fig. 6g schematically illustrates a nebulizer with a rotatable wetting mechanism having protruding ends at side cross sections, according to some embodiments;

Fig. 6h schematically illustrates a nebulizer with a rotatable wetting mechanism having protruding ends at top cross section, according to some embodiments;

Fig. 6i schematically illustrates a nebulizer with a rotatable wetting mechanism and a spacer at side cross sections, according to some embodiments;

Fig. 6j schematically illustrates a nebulizer with a rotatable wetting mechanism and a spacer at top cross sections, according to some embodiments;

Fig. 7 schematically illustrates nebulizer with a rotatable wetting mechanism and a liquid deploying structure, according to some embodiments;

Fig. 8 schematically illustrates nebulizer with a rotatable wetting mechanism and a liquid absorbing material, according to some embodiments;

Fig. 9 schematically illustrates a side cross section of a nebulizer assembly including an aerosolizing cartridge comprising a rotatable wetting mechanism, according to some embodiments;

Fig. 10 schematically illustrates a nebulizer system assembly with a rotatable wetting mechanism, according to some embodiments;

Fig. 11 schematically illustrates a nebulizer cartridge, according to some embodiments; Fig. 12 schematically illustrates a nebulizer cartridge, according to some embodiments; Fig. 13 schematically illustrates a nebulizer cartridge, according to some embodiments; Fig. 14 schematically illustrates a nebulizer cartridge, according to some embodiments; Figs. 15A and 15B schematically illustrate a perspective sectional view of nebulizer, according to some embodiments; and Fig. 16 Shows gamma scintigraphy images obtained upon inhalation of a ceftriaxone- radioisotope mixture by human volunteers (left - anterior; right - posterior).

DETAILED DESCRIPTION

In the following description, various aspects of the disclosure will be described. For the purpose of explanation, specific configurations and details are set forth in order to provide a thorough understanding of the different aspects of the disclosure. However, it will also be apparent to one skilled in the art that the disclosure may be practiced without specific details being presented herein. Furthermore, well-known features may be omitted or simplified in order not to obscure the disclosure.

Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, and as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. Provided herein is ceftriaxone, which is administered via inhalation and may be used for pharmaceutical purposes. Specifically, ceftriaxone is shown for the first time to be highly effective in the treatment of pneumonia, when administered via inhalation. Preferably, the administration of the present invention involves creating an aerosol comprising ceftriaxone using a nebulizer and providing the formed aerosol to a subject in need thereof via inhalation.

Specifically, the ceftriaxone of the present invention may be provided in the form of a pulmonary pharmaceutical composition comprising ceftriaxone. More specifically, the pharmaceutical composition of the present invention may be aqueous and may contain about 20 to 200 mg/ml ceftriaxone. Other additives, which are usually relevant to pulmonary pharmaceutical composition (rather than to pharmaceutical composition for injection) may also be contained in the present pulmonary pharmaceutical composition. As shown herein, the daily dosing of ceftriaxone, when provided via inhalation may be advantageously reduced by an order of magnitude, while achieving similar therapeutic results. Indeed, doses as low as about 4 or about 120 mg/day ceftriaxone are shown to be effective in the treatment of pneumonia. Ceftriaxone has the chemical formula shown below. It is an acidic compound, which is commonly provided as a sodium salt. Thus, the term “ceftriaxone”, as used herein, encompasses any form of ceftriaxone, including acidic or basic salts and any hydrate of this compound.

Pharmaceutical compositions

According to some embodiments, there is provided a pulmonary pharmaceutical composition comprising ceftriaxone and a pharmaceutically acceptable carrier, excipient or diluent.

According to some embodiments, the pulmonary pharmaceutical composition is provided in a dosage form suitable for aerosolization. According to some embodiments, the pulmonary pharmaceutical composition is provided in a dosage form suitable for aerosolization using a nebulizer or an inhaler. According to some embodiments, the pulmonary pharmaceutical composition is provided in a dosage form suitable for aerosolization using a nebulizer.

The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" as used herein refers to any and all solvents (including water), dispersion media, preservatives, antioxidants, coatings, isotonic and absorption delaying agents, surfactants, fillers, disintegrants, binders, diluents, lubricants, glidants, pH adjusting agents, buffering agents, enhancers, wetting agents, solubilizing agents, surfactants, antioxidants the like, that are compatible with pharmaceutical administration. Specifically in the context of the present invention the "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" are compatible with pulmonary administration, e.g., via inhalation. The use of such media and agents for pharmaceutically active substances is well known in the art.

According to some embodiments, the pulmonary pharmaceutical composition is for use in the treatment of a bacterial infectious disease or condition. In some embodiments, the bacterial infectious disease or condition is associated with the respiratory tract. According to some embodiments, the pulmonary pharmaceutical composition is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation. According to some embodiments, the pulmonary pharmaceutical composition is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation using an aerosol generating device. According to some embodiments, the pulmonary pharmaceutical composition is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation using a nebulizer.

Specific diseases and conditions associated with the respiratory tract are as detailed herein in breadth. Also, methods of treatment and specific pharmaceutical uses of the present invention are elaborated below.

The phrases "suitable for use in the administration via inhalation", "suitable for administration via inhalation" and "suitable for inhalation" are interchangeable and refer to compositions, that may be administered to a human subject via inhalation without the subject experiencing undue toxicity, strangulation, breathing difficulties and the like, while being effective for the intended use of the administration (e.g., for treating a disease or disorder). According to some embodiments, the pulmonary composition is formulated for inhalation.

According to some embodiments, the ceftriaxone is of pharmaceutical grade.

As used herein the terms "formulation" and "compositions" generally refer to any mixture, solution, suspension or the like that contains an active ingredient, such as ceftriaxone, and, optionally, a carrier. The carrier may be any carrier acceptable for inhalation, that is compatible for delivery with the active agent.

As detailed herein the composition of the current invention is a composition for inhalation. The terms "composition for inhalation" and "pulmonary composition", as used herein, are interchangeable and refer to composition adapted to be delivered to a subject through the respiratory tract. The compositions for inhalation of the current invention may be delivered to the lungs of the subject via a dedicated device, such as an inhaler or a nebulizer.

According to some embodiments, the pulmonary pharmaceutical composition is liquid. According to some embodiments, the pulmonary pharmaceutical composition is aqueous. According to some embodiments, the pulmonary pharmaceutical composition is a liquid solution. According to some embodiments, the pulmonary pharmaceutical composition is an aqueous solution.

The term "solution" as used herein broadly refers to a combination, mixture and/or admixture of ingredients having at least one liquid component. Thus, the term "aqueous solution" refers to any solution, in which at least one of its liquid components is water, wherein at least 50% of its weight is water. Aqueous solutions typically include water in greater quantity or volume than a solute. Typical additional solvents include alcohols, aldehydes, ketones, sulfoxides, sulfones, nitriles and/or any other suitable solubilizing molecule or carrier compound. Preferably, "solution" refers broadly to a mixture of miscible substances, where one substance dissolves in a second substance. More preferably, in a solution the essential components are homogeneously mixed and that the components are subdivided to such an extent that there is no appearance of light scattering visible to the naked eye when a one-inch diameter bottle of the mixture is viewed in sunlight.

According to some embodiments, the pulmonary pharmaceutical composition is in liquid form. According to some embodiments, the pulmonary pharmaceutical composition comprises at least 40% w/w water. According to some embodiments, the pulmonary pharmaceutical composition comprises at least 50% w/w water. According to some embodiments, the pulmonary pharmaceutical composition comprises at least 60% w/w water. According to some embodiments, the pulmonary pharmaceutical composition comprises at least 70% w/w water. According to some embodiments, the pulmonary pharmaceutical composition comprises at least 75% w/w water. According to some embodiments, the pulmonary pharmaceutical composition comprises at least 80% w/w water. According to some embodiments, the pulmonary pharmaceutical composition comprises at least 85% w/w water. According to some embodiments, the pulmonary pharmaceutical composition comprises at least 90% w/w water. It is to be understood that the phrase "pulmonary pharmaceutical composition comprises at least 90% w/w water" means that each gram of the total composition includes at least 900 milligrams of water and at most 100 milligrams of materials other than water. According to some embodiments, the pulmonary pharmaceutical composition comprises more than 90% w/w water.

As the known ceftriaxone formulation are suitable for injection, but not necessarily for inhalation, the present invention is further directed to a reformulation, which resulted in a novel composition of aqueous ceftriaxone, suitable for inhalation.

According to some embodiments, the pulmonary composition comprises ceftriaxone at a concentration in the range of 20 to 200 mg/ml. According to some embodiments, the pulmonary composition comprises ceftriaxone at a concentration in the range of 5 to 100 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration in the range of 100 to 200 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration in the range of 10 to 300 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration in the range of 20 to 150 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration in the range of 75 to 250 mg/ml.

According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 300 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 250 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 200 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 180 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 160 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 150 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 140 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 130 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 120 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 110 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 100 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 90 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 80 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 70 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 60 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of no more than 50 mg/ml.

According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of at least 5 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of at least 7 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of at least 8 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of at least 10 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of at least 12 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of at least 15 mg/ml. According to some embodiments, the pulmonary composition comprises of ceftriaxone at a concentration of at least 20 mg/ml.

According to some embodiments, the pulmonary composition is consisting of the aqueous solution.

According to some embodiments, the composition is provided in a kit, wherein the kit comprises the pharmaceutical composition of the present invention and further comprises instructions for use via inhalation. According to some embodiments, the composition is provided in a kit, wherein the kit comprises ceftriaxone and further comprises instructions for use via inhalation.

According to some embodiments, the pharmaceutical composition comprises at least one additive selected from the group consisting of a propellant, an anti-coughing agent and a flavorant.

According to some embodiments, the additive is suitable for use in inhaling solutions. According to some embodiments, the additive is approved for use in inhaling solutions. Specifically, many additives described herein are beneficial and approved for compositions, which are intended for administration via inhalation. Such additives are either not beneficial or not approved or not relevant to the known ceftriaxone compositions, which are intended for administration via injection.

According to some embodiments, the pulmonary pharmaceutical composition further comprises at least one additive at a concentration of 0.1-5% w/w. According to some embodiments, the pulmonary pharmaceutical composition further comprises at least one additive at a concentration of 0.1-1% w/w. According to some embodiments, the pulmonary pharmaceutical composition further comprises at least one additive at a concentration of 0.1-0.5% w/w. According to some embodiments, the pulmonary pharmaceutical composition further comprises at least one additive at a concentration of 0.1-0.3% w/w.

According to some embodiments, the pharmaceutical composition comprises a flavorant. According to some embodiments, the flavorant is selected from the group consisting of: peppermint, spearmint, eucalyptol, menthol, eugenol, cocoa, vanilla, cinnamon, licorice, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethylvanillin, methyl salicylate, acesulfame potassium, saccharine, aspartame, dextrose, mannitol, sorbitol, fructose and combinations thereof.

According to some embodiments, the flavorant is a sweetener. According to some embodiments, the sweetener is selected from the group of artificial sweeteners including saccharine, aspartame, dextrose and fructose. According to some embodiments, the additive is selected from menthol, eucalyptol, tyloxapol and a combination thereof. According to some embodiments, the additive is selected from menthol, eucalyptol, tyloxapol and a combination thereof, and is present at a concentration of 0.1-0.5% w/w based on the total weight of the pulmonary pharmaceutical composition.

According to some embodiments, the pharmaceutical composition comprises an anti coughing agent. According to some embodiments, the anti-coughing agent is selected from the group consisting of menthol, dextromethorphan, dextromethorphan hydrobromide, hydrocodone, caramiphen dextrorphan, 3-methoxymorphinan or morphinan- 3-ol, carbetapentane, codeine, acetylcysteine and combinations thereof. The term "anti-coughing agent" as used herein refers to an active agent used for the suppression, alleviation or prevention of coughing and irritations and other inconveniencies in the large breathing passages that can, or may, generate coughing. Anti-coughing agent include, but are not limited to antitussives, which are used for which suppress coughing, and expectorants, which alleviate coughing, while enhancing the production of mucus and phlegm. Anti-coughing agents may ease the administration of inhaled aerosols.

According to some embodiments, the at least one anti-coughing agent is selected from expectorants, antitussives or both. According to some embodiments, the at least one anti-coughing agent is an expectorant According to some embodiments, the at least one anti-coughing agent is an antitussive.

According to some embodiments, the pharmaceutical composition comprises a propellant.

A suitable propellant is any fluorocarbon, e.g. a 1-4 hydrogen containing fluorocarbon (such as CHF2CHF2, CF3CH2F, CH2F2CH3 and CF3CHFCF3), a perfluorocarbon, e g. a 1-4 carbon perfluorocarbon, (such as CF3CF3, CF3CF2CF3); or any mixture of the foregoing, having a sufficient vapor pressure to render them effective as propellants. Some typical suitable propellants include conventional chlorofluorocarbon (CFC) propellants such as mixtures of propellants 11, 12 and 114. Non-CFC propellants such as 1,1,1,2-tetrafluoroethane (Propellant 134a), 1,1,1,2,3,3,3-heptafluoropropane (Propellant 227) or mixtures thereof are preferred. According to some embodiments, the pulmonary pharmaceutical composition further comprises at least one preservative. According to some embodiments, the pharmaceutical composition comprises at least one preservative selected from the group consisting of benzyl alcohol, propylparaben, methylparaben, benzalkonium chloride, phenylethyl alcohol, chlorobutanol, potassium sorbate, phenol, m-cresol, o-cresol, pcresol, chlorocresol and combinations thereof.

According to some embodiments, the pharmaceutical composition further comprises a steroid. According to some embodiments, the steroid is an anti-inflammatory steroid. According to some embodiments, the pharmaceutical composition further comprises a corticosteroid.

According to some embodiments, the pharmaceutical composition comprises a bronchodilator.

As used herein, the term "bronchodilator" refers to a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Bronchodilators are typically used in the treatment of lung disorders, including COPD and asthma. According to some embodiments, the bronchodilator is long-acting. According to some embodiments, the bronchodilator is short-acting. Non limiting examples of bronchodilators include albuterol (Proventil HFA®, ProAir®, Ventolin HF A®), levalbuterol (Xopenex®), ipratropium (Atrovent®), indacaterol (Arcapta®), umeciidinium (Incruse®), tiotropium (Spiriva®), olodaterol (Stiverdi®), formoterol (Foradil®), aclidinium (Tudorza®), and salmeterol (Serevent®).

According to some embodiments, the bronchodilator is selected from the group consisting of: albuterol (salbutamol), levalbuterol, ipratropium, indacaterol, umeciidinium, tiotropium, olodaterol, formoterol, aclidinium, and salmeterol. Each possibility represents a separate embodiment of the invention. According to some embodiments, the bronchodilator is a non-volatile compound. According to some embodiments, the bronchodilator has boiling point above 300°C, above 250°C or above 200°C. Each possibility represents a separate embodiment of the invention. According to some embodiments, the bronchodilator is selected from the group consisting of albuterol, salbuterol, terbutaline, metoproperanol, isoproterenol, epinephrine, and isoetharine.

According to some embodiments, the bronchodilator is selected from a long acting beta agonist (LABA), a long acting muscarinic antagonist (LAMA) and a combination thereof. According to some embodiments, the bronchodilator is a long acting beta agonist (LABA). According to some embodiments, the bronchodilator is a long acting muscarinic antagonist (LAMA). According to some embodiments, the bronchodilator is a combination of a long acting beta agonist (LABA) and a long acting muscarinic antagonist (LAMA). According to some embodiments, the bronchodilator is salbutamol.

According to some embodiments, the pulmonary pharmaceutical composition further comprises at least one mucolytic agent. According to some embodiments, the pulmonary pharmaceutical composition further comprises one mucolytic agent.

As used herein, the term "mucolytic agent" refers to an agent (e.g. a pharmaceutical agent) that is used to dissolve or breakdown mucus. According to some embodiments, the mucolytic agent acts to reduce the viscosity of mucus so that it may be cleared from the respiratory tract. According to some embodiments, the mucolytic agent reduces the elasticity of mucus, such that the mucous may more readily be cleared from the respiratory tract. According to some embodiments, the mucolytic agent reduces both the viscosity and the elasticity of mucus. Examples of mucolytic agents include, but are not limited to, thiol-based drugs, recombinant human DNAse, hypertonic saline, ambroxol, or an airway epithelial cell ion channel modulator.

According to some embodiments, the mucolytic agent is selected from the group consisting of sodium 2-sulfanylethanesulfonate; disodium 2,2'- disulfanediyldiethanesulfonate; N-acetylcysteine, ambroxol and bromhexine. Each possibility represents a separate embodiment of the present invention.

According to some embodiments, the pharmaceutical composition is substantially devoid of anesthetics. According to some embodiments, the pulmonary pharmaceutical composition is devoid of anesthetics. According to some embodiments, the pharmaceutical composition is substantially devoid of lidocaine. According to some embodiments, the pulmonary pharmaceutical composition is devoid of lidocaine. Specifically, known pharmaceutical compositions of ceftriaxone are for injection. In the treatment of pneumonia for example, as detailed below, when administered by injection, high doses of ceftriaxone of up to 1-2 grams are required for effective treatment. Thus, often lengthy infusions are required to deliver sufficient amounts of ceftriaxone to pneumonia patients. As a result, anesthetics are often required to induce temporary loss of sensation in the patient, and lidocaine is incorporated into pharmaceutical compositions for injection of ceftriaxone.

According to some embodiments, the pulmonary composition is substantially devoid of organic solvents.

As used herein, “substantially devoid” means that a preparation or composition according to the invention that generally contains less than 3% of the stated substance, such as less than 1% or less than 0.5%.

According to some embodiments, the pulmonary pharmaceutical composition less than 10% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 8% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 6% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 5% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 4% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 3% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 2% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 1% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 0.5% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 0.4% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 0.3% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 0.2% w/w organic solvents. According to some embodiments, the pulmonary pharmaceutical composition less than 0.1% w/w organic solvents. According to some embodiments, the organic solvent is selected from the group consisting of: dichloromethane, chloroform. Benzene, toluene, chlorobenzene, hexane, pentane, hexanes, heptane, dimethylformamide, dimethyl sulfoxide, acetone, methanol and combinations thereof.

According to some embodiments, the pharmaceutical composition has pH in the range of 4-9. According to some embodiments, the pH is in the range of 4-5, 5-6, 6-7, 7-8, or 8-9. Each possibility represents a separate embodiment of the invention. According to some embodiments, the pharmaceutical composition has pH above 5. According to some embodiments, the pharmaceutical composition has pH above 5.5. According to some embodiments, the pharmaceutical composition has pH in the range of 5 to 8. According to some embodiment, the pharmaceutical composition further comprises at least one buffer. The terms "buffer," "buffering system," and/or "buffer solution" refer to compounds which reduce the change of pH upon addition of small amounts of acid or base, or upon dilution. The term "buffering agent" refers to a weak acid or weak base in a buffer solution. According to one embodiment, the buffer is an acetate buffer. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose in the range of 1 to 250 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose in the range of 2 to 150 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose in the range of 4 to 120 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose in the range of 2 to 75 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose in the range of 75 to 150 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose in the range of 2 to 20 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose in the range of 100 to 150 mg ceftriaxone per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose in the range of 2 to 10 mg ceftriaxone per day.

According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of no more than 300 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of no more than 275 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of no more than 250 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of no more than 225 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of no more than 200 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of no more than 175 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of no more than 150 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of no more than 125 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of no more than 120 mg per day.

According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of at least 1 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of at least 2 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of at least 3 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of at least 4 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of at least 5 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of at least 10 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of at least 15 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of at least 20 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of at least 30 mg per day. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose of at least 50 mg per day. Specifically, it was surprisingly found that ceftriaxone at dosages as low as about 4 to 120 mg per day is effective in the treatment of pneumonia, whereas when administered via injection, it is required at daily dosages of 1-2 grams. According to some embodiments, the pulmonary composition is for use via inhalation at least two sessions a day. According to some embodiments, the pulmonary composition is for use via inhalation at least three sessions a day. According to some embodiments, the pulmonary composition is for use via inhalation at least four sessions a day. According to some embodiments, the pulmonary composition is for use via inhalation two sessions a day. According to some embodiments, the pulmonary composition is for use via inhalation three sessions a day. According to some embodiments, the pulmonary composition is for use via inhalation four sessions a day. According to some embodiments, each session comprises administration of 1 mg to 30 mg ceftriaxone. According to some embodiments, each session comprises administration of 1 mg to 50 mg ceftriaxone. According to some embodiments, each session comprises administration of 5 mg to 50 mg ceftriaxone. According to some embodiments, each session comprises administration of 1 mg to 10 mg ceftriaxone. According to some embodiments, each session comprises administration of no more than 150 mg ceftriaxone. According to some embodiments, each session comprises administration of no more than 125 mg ceftriaxone. According to some embodiments, each session comprises administration of no more than 100 mg ceftriaxone. According to some embodiments, each session comprises administration of no more than 90 mg ceftriaxone. According to some embodiments, each session comprises administration of no more than 80 mg ceftriaxone. According to some embodiments, each session comprises administration of no more than 70 mg ceftriaxone. According to some embodiments, each session comprises administration of no more than 60 mg ceftriaxone. According to some embodiments, each session comprises administration of no more than 50 mg ceftriaxone. According to some embodiments, each session comprises administration of no more than 40 mg ceftriaxone. According to some embodiments, each session comprises administration of no more than 30 mg ceftriaxone. According to some embodiments, each session comprises administration of at least 1 mg ceftriaxone. According to some embodiments, each session comprises administration of at least 2 mg ceftriaxone. According to some embodiments, each session comprises administration of at least 3 mg ceftriaxone. According to some embodiments, each session comprises administration of at least 4 mg ceftriaxone. According to some embodiments, each session comprises administration of at least 5 mg ceftriaxone. According to some embodiments, each session comprises administration of at least 10 mg ceftriaxone According to some embodiments, each session comprises administration of at least 15 mg ceftriaxone.

According to some embodiments, each session comprises administration of 10-500 microliters, 20-400 microliters, 25-200 microliters, 30-300 microliters, 40-200 microliters or 50-150 microliters of the composition of the present invention. Each possibility represents a separate embodiment of the invention.

According to some embodiments, each session comprises administration of no more than 400 microliters of the composition of the present invention. According to some embodiments, each session comprises administration of no more than 300 microliters of the composition. According to some embodiments, each session comprises administration of no more than 200 microliters of the composition. According to some embodiments, each session comprises administration of no more than 150 microliters of the composition. According to some embodiments, each session comprises administration of at least 10 microliters of the composition. According to some embodiments, each session comprises administration of at least 20 microliters of the composition. According to some embodiments, each session comprises administration of at least 30 microliters of the composition. According to some embodiments, each session comprises administration of at least 40 microliters of the composition. According to some embodiments, each session comprises administration of at least 50 microliters of the composition.

According to some embodiments, each session comprises a continuous inhalation or a predetermined number of discrete inhalations. According to some embodiments, each session comprises a continuous inhalation. According to some embodiments, each session comprises a predetermined number of discrete inhalations. According to some embodiments, the predetermined number of discrete inhalations is 5-50, 7-40. 10-30, 15-25 or about 20.

As used herein, the term "about" refers to a range of values ± 20%, or ± 10% of a specified value. For example, the phrase "about 20 discrete inhalations" includes ± 20% of 20, i.e., from 16 to 24; or ±10% i.e., from 18 to 22.

According to some embodiments, the period of the administration in each session (either continuous or discrete) is in the range of 2-60 minutes. According to some embodiments, the period of the administration in each session is in the range of 1-60 minutes, 2-45 minutes, 3-30 minutes or 5 to 15 minutes. Each possibility represents a separate embodiment of the invention. According to some embodiments, the period of the administration in each session is about 10 minutes.

According to some embodiments, each session comprises a predetermined number of discrete inhalations as detailed above, wherein each discrete inhalation involves administration of a predetermined amount of ceftriaxone. According to some embodiments, the predetermined amount of ceftriaxone is in the range of 10-1000 micrograms, 20-850 micrograms, 30-750 micrograms, 40-600 micrograms, 50-500 micrograms, 25-75 micrograms, 400-600 micrograms, about 50 micrograms or about 500 micrograms. Each possibility represents a separate embodiment of the invention. According to some embodiments, each session comprises a predetermined number of discrete inhalations as detailed above, wherein each discrete inhalation involves administration of a predetermined volume of the present ceftriaxone composition. According to some embodiments, the predetermined volume of ceftriaxone is in the range of 1-10 microliters, 1-5 microliters, 1.5-4 microliters, or about 2.5 microliters. Each possibility represents a separate embodiment of the invention.

According to some embodiments, the instructions in the kit of the present invention include further specify the dosage amounts as specified above.

According to some embodiments, the ceftriaxone is the sole active ingredient in the pulmonary pharmaceutical composition. According to some embodiments, the composition comprises ceftriaxone as the only active ingredient.

The term "active ingredient" refers to an agent, active ingredient compound or other substance, or compositions and mixture thereof that provide some pharmacological and/or biological, often beneficial, effect.

According to some embodiments, the pulmonary pharmaceutical composition may comprise one or more active agents, other than ceftriaxone. According to some embodiments, the one or more active agents include one or more pharmaceutically active agents. According to some embodiments, the one or more active agents are suitable or may be adjusted for inhalation. According to some embodiments, the one or more pharmaceutically active agents are directed for treatment of a medical condition through inhalation. Methods of treatment and pharmaceutical uses

According to some embodiments, there is provided a method of treating a bacterial infectious disease or condition, the method comprising administering ceftriaxone to a subject in need thereof via inhalation. According to some embodiments, there is provided a method of treating a bacterial infectious disease or condition, the method comprising administering from 1 to 250 mg/day ceftriaxone to a subject in need thereof via inhalation.

According to some embodiments, there is provided a method of treating a bacterial infectious disease or condition, the method comprising administering the present pulmonary pharmaceutical composition to a subject in need thereof via inhalation. According to some embodiments, there is provided a method of treating a bacterial infectious disease or condition, the method comprising administering the pulmonary pharmaceutical composition of the present invention to a subject in need thereof via inhalation. According to some embodiments, there is provided a method of treating a bacterial infectious disease or condition, the method comprising administering the present pulmonary pharmaceutical composition to a subject in need thereof via inhalation at a daily dosage of 1 to 250 mg ceftriaxone per day. According to some embodiments, there is provided a method of treating a bacterial infectious disease or condition, the method comprising administering the pulmonary pharmaceutical composition of the present invention to a subject in need thereof via inhalation at a daily dosage of 1 to 250 mg ceftriaxone per day.

According to some embodiments, there is provided ceftriaxone, for use in the treatment of a bacterial infectious disease or condition via inhalation.

As used herein, the term "bacterial infectious disease or condition" refers to a disease or condition that involves a bacterial infection or caused by a bacterial infection. According to some embodiments, the bacterial infectious disease or condition is amenable to treatment with injectable ceftriaxone. According to some embodiments, there is provided ceftriaxone, for use in the treatment of disease or condition amenable to treatment with injectable ceftriaxone. According to some embodiments, there is provided ceftriaxone, for use in the treatment of disease or condition amenable to treatment with injectable ceftriaxone via inhalation at a daily dosage of 1 to 250 mg ceftriaxone per day. As used herein, the phrase "amenable to treatment with injectable ceftriaxone" refers to a bacterial infectious disease or condition that is susceptible to treatment with ceftriaxone by injection, may be treated with ceftriaxone by injection and/or known to be treated with ceftriaxone by injection (e.g., IV or IM injection). Examples of diseases and conditions amenable to treatment with ceftriaxone are bacterial meningitis, community acquired pneumonia, hospital acquired pneumonia, acute otitis media, intra-abdominal infections, complicated urinary tract infections (including pyelonephritis), infections of bones and joints, complicated skin and soft tissue infections, gonorrhea, syphilis, bacterial endocarditis, acute exacerbations of chronic obstructive pulmonary disease, and disseminated Lyme borreliosis (early (stage II) and late (stage III)). Ceftriaxone may also be used for pre-operative prophylaxis of surgical site infections, and in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.

According to some embodiments, the bacterial infectious disease or condition is selected from the group consisting of bacterial meningitis, community acquired pneumonia, hospital acquired pneumonia, bronchitis, sinusitis, acute otitis media, intra abdominal infections, complicated urinary tract infections (including pyelonephritis), infections of bones and joints, complicated skin and soft tissue infections, gonorrhea, syphilis, bacterial endocarditis, acute exacerbations of chronic obstructive pulmonary disease, and disseminated Lyme borreliosis (early (stage II) and late (stage III)). According to some embodiments, the bacterial infectious disease or condition is caused by a bacteria species selected from the group consisting of staphylococcus aureus, staphylococci coagulase-negative, streptococcus pyogenes (Group A), streptococcus agalactiae (Group B), streptococcus pneumoniae , borrelia burgdorferi , Haemophilus influenzae , Haemophilus parainfluenzae , moraxella catarrhalis, neisseria gonorrhoea, neisseria meningitidis, proteus mirabilis, providencia spp., treponema pallidum, staphylococcus epidermidis, staphylococcus haemolyticus, staphylococcus hominis, citrobacter jreundii, enterobacter aerogenes, enterobacter cloacae, escherichia coli, klebsiella pneumoniae, klebsiella oxytoca, morganella morganii, proteus vulgaris, serratia marcescens, bacteroides spp., fusobacterium spp., peptostreptococcus spp., and clostridium perjringens. Each possibility represents a separate embodiment According to some embodiments, the bacterial infectious disease or condition is caused by a bacteria species selected from the group consisting of staphylococcus aureus, staphylococci coagulase-negative, streptococcus pyogenes (Group A), streptococcus agalactiae (Group B), streptococcus pneumoniae , borrelia burgdorferi , Haemophilus influenzae , Haemophilus parainfluenzae , moraxella catarrhalis, neisseria gonorrhoea, neisseria meningitidis, proteus mirabilis, providencia spp., and treponema pallidum. According to some embodiments, the bacterial infectious disease or condition is associated with the respiratory tract.

The phrase "disease or condition associated with the respiratory tract" as used herein interchangeably with the term "disease or condition associated with the respiratory system" encompass bacterial infectious diseases or conditions that involve or caused by a bacterial infection in the respiratory tract, as well as bacterial infectious diseases or conditions that can cause respiratory symptoms or affect components associated with the respiratory tract. The term "components associated with the respiratory tract" includes components of the respiratory tract (upper and lower), and components that are connected to the respiratory tract.

According to some embodiments, the bacterial infectious disease or condition is selected from the group consisting of pneumonia, tuberculosis (TB), bacterial meningitis, otitis media, and chronic obstructive pulmonary disease. Each possibility represents a separate embodiment of the present invention.

It should be noted that otitis media is considered as an upper respiratory tract infection. Also, it should be understood that bacterial meningitis, although not being directly a respiratory tract infectious disease, can be caused by bacteria that first cause an upper respiratory tract infection and then travel through the blood stream to the brain. According to some embodiments, the bacterial infectious disease or condition is selected from the group consisting of pneumonia, tuberculosis (TB), otitis media, and chronic obstructive pulmonary disease. According to some embodiments, the bacterial infectious disease or condition is selected from the group consisting of pneumonia, tuberculosis (TB), and chronic obstructive pulmonary disease.

In some embodiments, the bacterial infectious disease or condition is a respiratory tract bacterial infection. As used herein, the term "respiratory tract bacterial infection" encompasses bacterial infections of the upper respiratory tract (e.g., nose, sinuses, and throat) and of the lower respiratory tract (e.g., trachea, bronchial tubes, and lungs).

In some embodiments, the respiratory tract bacterial infection is bacterial pneumonia. In some embodiments, the bacterial pneumonia is selected from the group consisting of community acquired pneumonia, hospital acquired pneumonia, healthcare associated pneumonia, and ventilator associated pneumonia. In some embodiments, the bacterial pneumonia is selected from community acquired pneumonia and hospital acquired pneumonia.

In contrast with pneumonia that is known to be treated by injectable ceftriaxone, tuberculosis (TB) is currently not treated with ceftriaxone. In some embodiments, the bacterial infectious disease or condition is tuberculosis.

According to some embodiments, the ceftriaxone is of pharmaceutical grade. According to some embodiments, the ceftriaxone is devoid of anesthetics.

According to some embodiments, the ceftriaxone is provided as a dry powder or as a pharmaceutical composition comprising ceftriaxone and a pharmaceutically acceptable carrier, excipient or diluent.

The term “treating” a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, ameliorating abrogating, substantially inhibiting, slowing or reversing the progression of a disease, condition or disorder, substantially ameliorating or alleviating clinical or esthetical symptoms of a condition, substantially preventing the appearance of clinical or esthetical symptoms of a disease, condition, or disorder, and protecting from harmful or annoying symptoms. Treating further refers to accomplishing one or more of the following: (a) reducing the severity of the disorder;

(b) limiting development of symptoms characteristic of the disorder(s) being treated;

(c) limiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting recurrence of the disorder(s) in patients that have previously had the disorder(s); and/or (e) limiting recurrence of symptoms in patients that were previously asymptomatic for the disorder(s).

The term “patient”, “subject”, or “individual” are used interchangeably and refer to either a human or a non-human animal. According to some embodiments, the subject is human. The term "administering” or “administration of’ a substance, a compound, an agent or a composition, to a subject can be carried out using one of a variety of methods known to those skilled in the art. The compositions for inhalation as disclosed herein are administered to the lungs, for example orally (by inhalation through the trachea) or nasally (by inhalation through the nose). The term "pulmonary administration" is intended to encompass any suitable delivery method by which the composition is delivered to the lungs via the respiratory tract.

According to some embodiments, the compositions for inhalation as disclosed herein are administered to the lungs through the throat of a subject. According to some embodiments, the compositions for inhalation as disclosed herein are administered to the lungs through the pharynx of a subject. According to some embodiments, the compositions for inhalation as disclosed herein are administered to the lungs through the nose of a subject.

Typically, compositions for inhalation are intended to the lungs and are administered through the pharynx and trachea to the lungs. However, compositions for the respiratory system may also be delivered nasally (i.e., through the nose). Nasal administration is less common, but is being developed by means of Orally Inhaled and Nasal Drug Product (OINDP). OINDPs are defined by the International Pharmaceutical Aerosol Consortium on Regulation & Science (IPAC-RS) as providing therapeutic benefit by delivery of a pharmaceutical substance to the lungs or nasal cavity. OINDP is generally characterized by: (a) delivery of the drug at a specific range of particle sizes, which may be the drug particle alone, or bound to a carrier, or dissolved or suspended in a liquid droplet; and (b) targeted deposition to specific membranes.

According to some embodiments, the method comprises administering from 1 to 250 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering from 1 to 230 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering from 2 to 215 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering from 2 to 200 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering from 2 to 190 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering from 3 to 180 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering from 3 to 170 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering from 3 to 170 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering from

4 to 150 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering about 4 to about 120 mg ceftriaxone per day to the subject via inhalation.

Advantageously, the pulmonary compositions and routes of administration provided in the present disclosure are effective even with very low daily dosages (ca. 4 to about 120 mg ceftriaxone per day), which is in contrast with intravenous delivery of ceftriaxone, which requires daily amounts of 1-2 grams. According to some embodiments, this is beneficial to reduce adverse effects associated with high ceftriaxone doses. Furthermore, without wishing to be bound by any theory or mechanism, it is hypothesized that inhaled ceftriaxone, although given at low dosage compared to injected ceftriaxone, can achieve local concentration in the respiratory system which is significantly greater than the minimal inhibitory concentration (MIC) required to prevent visible growth of a given strain of bacteria in the airways, thus enabling a focused and efficient antibiotic treatment in the airways while minimizing the development of bacterial resistance and reducing systemic toxicity. Thus, according to some embodiments, the pulmonary compositions and methods of the present invention are beneficial in reducing the development and spread of antibiotic resistance associated with ceftriaxone.

According to some embodiments, the method comprises administering no more than 250 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 240 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 230 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 220 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 210 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 200 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 190 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 180 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 170 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 160 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 150 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 140 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 130 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 120 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 110 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering no more than 100 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering at least 1 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering at least 2 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering at least 3 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering at least 4 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering at least 5 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering at least 10 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering at least 20 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering at least 30 mg ceftriaxone per day to the subject via inhalation. According to some embodiments, the method comprises administering at least 40 mg ceftriaxone per day to the subj ect via inhalation. According to some embodiments, the method comprises administering at least 50 mg ceftriaxone per day to the subject via inhalation.

The precise dose to be employed also depends on the progression of the disease, and should be decided according to the judgment of the practitioner and each patient's circumstances. The administration schedule can be taken once-daily, twice-daily, thrice-daily, four sessions daily, five sessions daily, five sessions daily, six sessions daily, seven sessions daily, eight sessions daily, nine sessions daily, ten sessions daily, once-weekly, twice-weekly, thrice-weekly, once-monthly, twice-monthly, thrice- monthly, or any other administration schedule known to those of skill in the art. Each possibility represents a separate embodiment of the invention. According to some embodiments, the administration comprises at least one daily session. According to some embodiments, the administration comprises at least 2 daily sessions. According to some embodiments, the administration comprises at least 3 daily sessions. According to some embodiments, the administration comprises at least 4 daily sessions. According to some embodiments, the administration comprises at least 5 daily sessions. According to some embodiments, the administration comprises at least 6 daily sessions. According to some embodiments, the administration comprises at least 7 daily sessions. According to some embodiments, the administration comprises at least 8 daily sessions. According to some embodiments, the administration comprises no more than 10 daily sessions. According to some embodiments, the administration comprises no more than 8 daily sessions. According to some embodiments, the administration comprises no more than 6 daily sessions. According to some embodiments, the administration comprises no more than 5 daily sessions. According to some embodiments, the administration comprises no more than 4 daily sessions. According to some embodiments, the pharmaceutical composition is administered twice a week. The administration may be continuous, i.e., every day, or intermittently. The terms “intermittent” or “intermittently” as used herein means stopping and starting at either regular or irregular intervals. For example, intermittent administration can be administration in one to six days per week or it may mean administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week) or it may mean administration on alternate days. In some embodiments, the overall treatment duration is up to 10 days. According to some embodiments, each session comprises a continuous inhalation or a predetermined number of discrete inhalations. Each possibility represents a separate embodiment of the invention.

According to some embodiments, the period of the administration in each session is in the range of 2-60 minutes. According to some embodiments, the period of the administration in each session is in the range of 3-50 minutes. According to some embodiments, the period of the administration in each session is in the range of 4-40 minutes. According to some embodiments, the period of the administration in each session is in the range of 5-30 minutes. According to some embodiments, the period of the administration in each session is in the range of 5-20 minutes. According to some embodiments, the period of the administration in each session is in the range of 5-15 minutes. According to some embodiments, the period of the administration in each session is at least 1 minute, at least 2 minutes, at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 6 minutes, at least 7 minutes, at least 8 minutes, at least 9 minutes or at least 10 minutes. According to some embodiments, the period of the administration in each session is no more than 120 minutes, no more than 90 minutes, no more than 60 minutes, no more than 50 minutes, no more than 40 minutes, no more than 30 minutes, no more than 20 minutes, no more than 10 minutes. According to some embodiments, the period of the administration in each session is about 10 minutes. According to some embodiments, each administration comprises a continuous inhalation. According to some embodiments, each administration comprises a continuous inhalation for the period specified above.

According to some embodiments, each administration comprises a predetermined number of discrete inhalations. According to some embodiments, each administration comprises a predetermined number of discrete inhalations for the total administration period specified above. According to some embodiments, the predetermined number of discrete inhalations is in the range of 3 to 60, 4 to 50, 5 to 40, 10 to 30, 15 to 25. Each possibility represents a separate embodiment of the invention. According to some embodiments, the predetermined number of discrete inhalations is in at least 5, at least 10, at least 15 or at least 20. Each possibility represents a separate embodiment of the invention. According to some embodiments, the predetermined number of discrete inhalations is in no more than 1000, no more than 500, no more than 200, no more than 100, no more than 50, no more than 30 or no more than 20. Each possibility represents a separate embodiment of the invention. According to some embodiments, each administration comprises about 20 discrete inhalations. According to some embodiments, each discrete inhalation comprises 10-1500, 25-1000 or 50-500 microgram ceftriaxone. Each possibility represents a separate embodiment of the invention. According to some embodiments, each discrete inhalation comprises at least 10, at least 20, at least 30, at least 40, at least 50, at least 75, at least 100, at least 200, at least 300, or at least 400 microgram ceftriaxone. According to some embodiments, each discrete inhalation comprises no more than 2000, no more than 1500, no more than 1000, no more than 750, no more than 500, no more than 400, no more than 300, no more than 200, no more than 100, no more than 75 or no more than 50 microgram ceftriaxone. Each possibility represents a separate embodiment of the invention.

According to some embodiments, the method comprises administering ceftriaxone to the subject four sessions a day via inhalation, wherein each session comprises administration of 1-30 mg ceftriaxone via inhalation.

According to some embodiments, the use comprises co-administration of the pharmaceutical composition of the present invention with an additional active agent. The additional active agent may be any other active pharmaceutical agent, which is effective in treating the specific bacterial infectious disease or condition (e.g., pneumonia). In some embodiments, for example but not limited to cases of polymicrobial infections, the additional active agent is an antibiotic agent. The additional active agent may be delivered by inhalation or by any other administration route. According to some embodiments, the additional active agent is administered in a route other than pulmonary, i.e., orally through ingestion or intravenously.

The term “coadministration” encompasses administration of a first and second agent in an essentially simultaneous manner. The agents can be administered in a sequential manner in either order. When coadministration involves the separate administration of each agent, the agents may be administered sufficiently close in time to have the desired effect (e.g., complex formation). The term “sequential manner” refers to an administration of two compounds at different times, and optionally in different modes of administration. The agents can be administered in a sequential manner in either order. The terms “substantially simultaneous manner” refers to administration of two compounds with only a short time interval between them. According to some embodiments, the time interval is in the range of from 0.5 to 60 minutes.

According to some embodiments, the method comprises administering ceftriaxone to the subject at least twice a day via inhalation. According to some embodiments, the method comprises administering ceftriaxone to the subject at least three times a day via inhalation. According to some embodiments, the method comprises administering ceftriaxone to the at least four times a day via inhalation. According to some embodiments, the method comprises administering ceftriaxone to the subject twice a day via inhalation. According to some embodiments, the method comprises administering ceftriaxone to the subject three times a day via inhalation. According to some embodiments, the method comprises administering ceftriaxone to the four times a day via inhalation.

According to some embodiments, each administration comprises at least 1 mg ceftriaxone. According to some embodiments, each administration comprises at least 2 mg ceftriaxone. According to some embodiments, each administration comprises at least 3 mg ceftriaxone. According to some embodiments, each administration comprises at least 4 mg ceftriaxone. According to some embodiments, each administration comprises at least 5 mg ceftriaxone. According to some embodiments, each administration comprises at least 7 mg ceftriaxone. According to some embodiments, each administration comprises at least 10 mg ceftriaxone. According to some embodiments, each administration comprises at least 15 mg ceftriaxone. According to some embodiments, each administration comprises at least 20 mg ceftriaxone. According to some embodiments, each administration comprises at least 25 mg ceftriaxone. According to some embodiments, each administration comprises at least 30 mg ceftriaxone.

According to some embodiments, each administration comprises no more than 200 mg ceftriaxone. According to some embodiments, each administration comprises no more than 190 mg ceftriaxone. According to some embodiments, each administration comprises no more than 180 mg ceftriaxone. According to some embodiments, each administration comprises no more than 170 mg ceftriaxone. According to some embodiments, each administration comprises no more than 160 mg ceftriaxone. According to some embodiments, each administration comprises no more than 150 mg ceftriaxone. According to some embodiments, each administration comprises no more than 140 mg ceftriaxone. According to some embodiments, each administration comprises no more than 130 mg ceftriaxone. According to some embodiments, each administration comprises no more than 120 mg ceftriaxone. According to some embodiments, each administration comprises no more than 110 mg ceftriaxone. According to some embodiments, each administration comprises no more than 100 mg ceftriaxone. According to some embodiments, each administration comprises no more than 90 mg ceftriaxone. According to some embodiments, each administration comprises no more than 80 mg ceftriaxone. According to some embodiments, each administration comprises no more than 70 mg ceftriaxone. According to some embodiments, each administration comprises no more than 60 mg ceftriaxone. According to some embodiments, each administration comprises no more than 50 mg ceftriaxone. According to some embodiments, each administration comprises no more than 40 mg ceftriaxone. According to some embodiments, each administration comprises no more than 30 mg ceftriaxone.

According to some embodiments, the ceftriaxone is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation at a daily dose in the range of 1 to 250 mg ceftriaxone per day. According to some embodiments, the ceftriaxone is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation at a daily dose in the range of 4 to 120 mg ceftriaxone per day. According to some embodiments, the ceftriaxone is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation at least twice a day. According to some embodiments, the ceftriaxone is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation four times a day, each time comprises administration of about 1-50 mg ceftriaxone. Although in various sections bacterial infectious diseases or conditions are referred generally, it is to be understood that the relevant embodiments are also to be read as referring to each disease or condition (e.g., pneumonia or tuberculosis) individually.

According to some embodiments, the ceftriaxone is provided as a dry powder or as a pharmaceutical composition comprising ceftriaxone and a pharmaceutically acceptable carrier, excipient or diluent. According to some embodiments, the ceftriaxone is provided as a dry powder. According to some embodiments, the ceftriaxone is provided as a pharmaceutical composition comprising ceftriaxone and a pharmaceutically acceptable carrier, excipient or diluent. According to some embodiments, the ceftriaxone is provided as the pharmaceutical composition of the present invention. According to some embodiments, the method comprises administering a pharmaceutical composition comprising ceftriaxone and a pharmaceutically acceptable carrier, excipient or diluent to a subject in need thereof via inhalation. According to some embodiments, the method comprises administering the pulmonary pharmaceutical composition as disclosed herein.

According to some embodiments, the administering of the ceftriaxone to a subject comprises delivering of the ceftriaxone to the respiratory system of the subject.

As used herein, "respiratory system" refers to the system of organs in the body responsible for the intake of oxygen and the expiration of carbon dioxide. The system generally includes all the air passages from the nose to the pulmonary alveoli. In mammals it is generally considered to include the lungs, bronchi, bronchioles, trachea, nasal passages, and diaphragm. For purposes of the present disclosure, delivery of a drug to the "respiratory system" indicates that a drug is delivered to one or more of the air passages of the respiratory system, in particular to the lungs.

It is to be understood that any embodiment related to pulmonary pharmaceutical composition above, may apply for any of the methods disclosed herein. Specifically, wherein the method is for treatment of a subject, the pulmonary pharmaceutical composition may be used for the specified treatment, according to some embodiments. According to some embodiments, the method comprises

(a) generating an aerosol comprising the ceftriaxone and comprising droplets having a mass median aerodynamic diameter (MMAD) of at most 10 microns; and

(b) administering said aerosol to the subject via inhalation. According to some embodiments, the method comprises

(a) providing ceftriaxone in an aerosolizable dosage form;

(b) providing an aerosol generating device;

(c) generating an aerosol from the aerosolizable dosage form using the aerosol generating device, wherein the aerosol comprises the ceftriaxone and has droplets having a mass median aerodynamic diameter (MMAD) of at most 10 microns; and

(d) administering said aerosol to the subject via inhalation, thereby treating the treating the bacterial infectious disease or condition.

According to some embodiments, the bacterial infectious disease or condition is pneumonia or tuberculosis.

According to some embodiments, there is provided a method for treating a bacterial infectious disease or condition in a subject, the method comprising:

(a) providing ceftriaxone in an aerosolizable dosage form;

(b) providing an aerosol generating device;

(c) generating an aerosol from the aerosolizable dosage form using the aerosol generating device, wherein the aerosol comprises the ceftriaxone and has droplets having a mass median aerodynamic diameter (MMAD) of at most 10 microns; and

(d) administering said aerosol to the subject via inhalation, thereby treating the bacterial infectious disease or condition.

According to some embodiments, there is provided a method for treating a disease or condition associated with the respiratory tract, the method comprising:

(a) providing ceftriaxone in an aerosolizable dosage form;

(b) providing an aerosol generating device;

(c) generating an aerosol from the aerosolizable dosage form using the aerosol generating device, wherein the aerosol comprises the ceftriaxone and has droplets having a mass median aerodynamic diameter (MMAD) of at most 10 microns; and

(d) administering said aerosol to a subject in need thereof via inhalation, thereby treating the disease or condition. According to some embodiments, there is provided a method for treating pneumonia in a subject, the method comprising:

(a) providing ceftriaxone in an aerosolizable dosage form;

(b) providing an aerosol generating device;

(c) generating an aerosol from the aerosolizable dosage form using the aerosol generating device, wherein the aerosol comprises the ceftriaxone and has droplets having a mass median aerodynamic diameter (MMAD) of at most 10 microns; and

(d) administering said aerosol to the subject via inhalation, thereby treating the pneumonia.

According to some embodiments, there is provided a method for treating tuberculosis in a subject, the method comprising:

(a) providing ceftriaxone in an aerosolizable dosage form;

(b) providing an aerosol generating device;

(c) generating an aerosol from the aerosolizable dosage form using the aerosol generating device, wherein the aerosol comprises the ceftriaxone and has droplets having a mass median aerodynamic diameter (MMAD) of at most 10 microns; and

(d) administering said aerosol to the subject via inhalation, thereby treating the tuberculosis.

According to some embodiments, the aerosolizable dosage form is the pulmonary pharmaceutical composition of the present invention. According to some embodiments, the aerosolizable dosage form is a ceftriaxone dry powder.

According to some embodiments, the aerosol droplets have MMAD of at most 5 microns. According to some embodiments, the aerosol droplets have MMAD of at most 3 microns. According to some embodiments, the aerosol droplets have MMAD of at most 2 microns. According to some embodiments, the aerosol droplets have MMAD of at most 1 micron. According to some embodiments, the aerosol droplets have sub micron MMAD.

According to some embodiments, the aerosol is an aqueous aerosol.

According to some embodiments, the aerosol is as detailed hereinbelow. According to some embodiments, the aerosol generating device is as detailed hereinbelow.

According to some embodiments, the method comprises the steps of:

(a) providing a nebulizer;

(b) providing a liquid composition comprising ceftriaxone; and

(c) operating the nebulizer to produce an aerosol comprising droplets of said liquid, wherein said aerosol is administered to the lungs of a subject in need thereof, thereby treating the bacterial infectious disease or condition.

According to some embodiments, the method comprises the steps of:

(i) providing a nebulizer comprising a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread the liquid over the porous medium thereby to wet the porous medium and a gas channel, wherein said porous medium is having two sides, wherein a first side is facing the displaceable wetting mechanism;

(ii) providing a liquid composition comprising at least one anti-infective agent;

(iii)operating the displaceable wetting mechanism thereby spreading the liquid onto said first side of the porous medium; and

(iv) connecting the gas channel to a pressure source and introducing pressure gradient to the porous medium thereby producing aerosol at the first side of the porous medium, wherein the aerosol comprises droplets of the liquid, wherein said aerosol is administered to the subject in need thereof.

According to some embodiments, the nebulizer is as detailed hereinbelow.

Aerosol generating devices cartridges and fillings

The term "aerosol generating device" refer to a device configured to produce a vapor or aerosol from a liquid or solid composition aerosol generating devices are typically used to deliver a solid or liquid (including semi liquid) composition to a subject in need thereof in an inhalable form (i.e. in a substantially gaseous form). Aerosol generating devices include nebulizers and inhalers, which typically produce aerosols by application of mechanical force on the compositions (e.g., by gas flow or vacuum), and to vaporizers and electronic cigarettes, which typically heating unit(s) and produce aerosols by vaporizing the composition. In both instances, the composition is delivered through an outlet, wherein in the latter instances (i.e., vaporizers and electronic cigarettes) the vapor is usually at least partially being condensed to form droplets of the composition, through the delivery.

According to some embodiments, the method comprises administering ceftriaxone to the subject via inhalation using a nebulizer or an inhaler. According to some embodiments, the method comprises administering ceftriaxone to the subject via inhalation using an inhaler. According to some embodiments, the method comprises administering ceftriaxone to the subject via inhalation using a nebulizer.

According to some embodiments, the nebulizer comprises a nebulizer cartridge comprising a porous medium and a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium, wherein the porous medium comprises a plurality of pores, and wherein at least some of said plurality of pores comprise the liquid, wherein the liquid comprises ceftriaxone. According to some embodiments, the nebulizer comprises a nebulizer cartridge comprising a porous medium and a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium, wherein the porous medium comprises a plurality of pores, and wherein at least some of said plurality of pores comprise the liquid, wherein the liquid comprises the pharmaceutical composition of the present invention. According to some embodiments, the nebulizer comprises a nebulizer cartridge comprising a porous medium and a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium, wherein the porous medium comprises a plurality of pores, and wherein at least some of said plurality of pores comprise the liquid, wherein the liquid is the pharmaceutical composition of the present invention.

According to some embodiments, the nebulizer comprises a porous medium and a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium, wherein the porous medium comprises a plurality of pores, and wherein at least some of said plurality of pores comprise the liquid, wherein the liquid comprises ceftriaxone. According to some embodiments, the nebulizer comprises a porous medium and a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium, wherein the porous medium comprises a plurality of pores, and wherein at least some of said plurality of pores comprise the liquid, wherein the liquid comprises the pharmaceutical composition of the present invention. According to some embodiments, the nebulizer comprises a porous medium and a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium, wherein the porous medium comprises a plurality of pores, and wherein at least some of said plurality of pores comprise the liquid, wherein the liquid is the pharmaceutical composition of the present invention.

There are described below devices and systems for generating the aerosol described herein from the composition of the current invention, according to some embodiments. Said devices and systems, specifically, nebulizers and nebulizer systems, are also configured to carry out the method of the present invention. The nebulizers are configured for delivery of compositions using a porous medium and a displaceable spreading mechanism or liquid absorbing material. The aerosol may be generated by wetting the porous medium. Wetting may include applying the displaceable spreading mechanism thereby spreading liquid on the surface of the porous medium. Alternatively, wetting may include wetting the liquid absorbing material, then pressing it against the porous medium, or a surface thereof, resulting in a relatively uniform wetting of the porous medium. Once the porous medium, or a surface thereof, is wet, applying pressure gradient upon the porous medium results in the generation of aerosol. Advantageously, the nebulizers are configured to provide the aerosol by implementing pressure differentials, rather than heating/vaporization. Thus, according to some embodiments, the dosage form described herein is suitable for aerosolization using the type of nebulizers, which do not include a heating unit. According to some embodiments, the nebulizer is devoid from a heating unit. According to some embodiments, the method of the current invention is devoid from heating the composition.

According to some embodiments, the nebulizer referred herein above comprises a porous medium that is configured to produce aerosol, a liquid absorbing material configured to absorb a liquid, a wetting mechanism configured to press the liquid absorbing material against the porous medium or a first surface of the porous medium, thereby to wet the porous medium with the liquid absorbed in the liquid absorbing material and a gas channel configured to introduce pressure gradient to the porous medium. The nebulizers elaborated herein below provide aerosols having small droplet size, which was found to be specifically beneficial for treatment of bacterial respiratory diseases (e.g. pneumonia) with ceftriaxone.

According to some embodiments, applying pressure gradient entails introducing pressurized air to one side of the porous medium. According to some embodiments, applying pressure gradient entails introducing vacuum or sub-atmospheric pressure near one side of the porous medium. According to some embodiments, applying pressure gradient upon the porous medium entails having different pressure levels between two sides or surfaces of the porous medium.

Advantageously, the devices, systems and methods disclosed herein provide a relatively uniform or homogeneous wetting of the porous surface that may result in small diameter aerosol droplets, and confer the ability to yield such small diameter aerosol drops with high efficiency.

According to some embodiments, the nebulizer comprises a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread the composition for inhalation over the porous medium thereby to wet the porous medium and a gas channel configured to introduce pressure gradient to the porous medium. According to some embodiments, the displaceable wetting mechanism may include a rotatable elongated member. According to some embodiments, the rotatable elongated member is configured to move across the surface of the porous medium, thereby to homogeneously or semi-homogeneously spread the composition for inhalation on the surface. According to some embodiments, the elongated member is axially movable. According to some embodiments, the elongated member is movable to cover approximately all the surface of the porous medium.

The term "approximately" as used herein may refer to the percentage of surface of the porous medium that may be coated with liquid by the spreading movement of the elongated member. Approximately may refer to more than 50% coverage, more than 60% coverage, at least 70% coverage, at least 80% coverage, at least 90% coverage or at least 95% coverage. According to some embodiments, the wetting mechanism further includes an actuator, configured to displace or induce the displacement of the elongated member. The term "displacement" as used herein may be interchangeable with any one or more of the terms movement, movement across. This term may refer to the motion of the wetting mechanism across, or along, at least one surface of the porous medium. According to some embodiments, the elongated member comprises a first magnet, and the actuator comprises a second magnet, magnetically associated with the first magnet of the elongated member, such that by moving/displacing the second magnet of the actuator, a displacing of the elongated member is induced. According to some embodiments, said first magnet may comprise a plurality of magnets. According to some embodiments, said second magnet may comprise a plurality of magnets. According to some embodiments, one or more of the plurality of magnets includes an electromagnet. According to some embodiments, the actuator comprises a motor configured to displace the elongated member. According to some embodiments, the elongated member is at least partially covered with polytetrafluoroethylene (PTFE), commercially knowns as Teflon®, or any other appropriate coating materials. According to some embodiments, the elongated member is an elongated tubular member. According to some embodiments, the elongated member is movable by an actuator, mechanically connected thereto. According to some embodiments, the elongated member is movable by the air-flow within the nebulizer and/or through the porous material. According to some embodiments, the elongated member is a roller. According to some embodiments, the elongated member is a smearing device. According to some embodiments, the elongated member is a spreading device. According to some embodiments, the elongated member is configured to force at least portions of the liquid to at least some of the pores of the porous medium.

According to some embodiments, the nebulizer further comprises a spacer configured to elevate said displaceable wetting mechanism from the surface of said porous medium. According to some embodiments, said spacer is integrally formed with said displaceable wetting mechanism. According to some embodiments, said spacer comprises a protrusion in said displaceable wetting mechanism. According to some embodiments, said spacer is configured to be placed between said displaceable wetting mechanism and the surface of said porous medium. According to some embodiments, said pacer comprises a ring-shaped configured to facilitate low-friction displacement of said displaceable wetting mechanism. According to some embodiments, the nebulizer further comprises a liquid deploying mechanism configured to controllably deploy a liquid (such as a liquid comprising the composition for inhalation) on the surface of said porous medium for being spread by said displaceable wetting mechanism. According to some embodiments, said liquid deploying mechanism comprises a conduit. According to some embodiments, said conduit has a receiving end, configured to obtain a liquid from a liquid source, and a deploying end, configured to deploy the liquid on the surface of said porous medium. According to some embodiments, said deploying end of said conduit is flexible and configured to flexibly move by the displacement of said displaceable wetting mechanism, thereby deploy the liquid at more than one location on the surface of said porous medium.

According to some embodiments, the nebulizer further comprises an opening configured to deliver the aerosols to a respiratory system of a subject.

According to some embodiments, there is provided a method for producing an aerosol as described hereinbelow, the method comprising producing an aerosol by performing the step described hereinafter. According to some embodiments, there is provided a method for treating an infective disease, the method comprising producing an aerosol by performing the steps described hereinafter.

According to some embodiments, the steps for carrying out said methods includes:

(a) providing a nebulizer comprising a porous medium configured to produce aerosols, a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium and a gas channel, wherein said porous medium is having two sides, a first side facing the displaceable wetting mechanism;

(b) providing a liquid pulmonary composition comprising ceftriaxone, in a dosage form suitable for aerosolization using a nebulizer;

(c) operating the displaceable wetting mechanism thereby spreading the liquid pulmonary composition onto said first side of the porous medium; and

(d) connecting the gas channel to a pressure source and introducing pressure gradient to the porous medium thereby producing aerosol at the first side of the porous medium, the aerosol comprises droplets of the composition.

According to some embodiments, the steps for carrying out said methods includes: (a) Providing a nebulizer comprising a porous medium configured to produce aerosols, a liquid absorbing material configured to absorb a liquid, a wetting mechanism configured to press the liquid absorbing material against the porous medium, and a gas channel configured to introduce pressure gradient to the porous medium, wherein the porous medium is having two sides wherein a first side is facing the liquid absorbing material;

(b) providing a liquid pulmonary composition comprising ceftriaxone, provided in a dosage form suitable for aerosolization using a nebulizer;

(c) wetting the liquid absorbing material with the liquid composition;

(d) pressing the liquid absorbing material against the porous medium; and

(e) introducing pressure gradient to the porous medium thereby producing aerosol at the first side of the porous medium, the aerosol comprises droplets of the liquid composition.

According to some embodiments, the method further comprises delivering the aerosols to a respiratory system of a subject in need thereof.

According to some embodiments, the liquid absorbing material comprises the pulmonary composition for inhalation disclosed herein.

According to some embodiments, the method further comprises iterating the following steps at least one more time: pressing the liquid absorbing material against the porous medium, introducing pressure gradient to the porous medium and producing aerosol at the first side of the porous medium, the aerosol comprises droplets of the liquid composition.

The nebulizer disclosed herein may function as an inhaler under some circumstances. Thus, the terms ‘nebulizer’ and ‘inhaler’ as used herein may be interchangeable.

The terms 'medium' and 'material' as used herein are interchangeable.

Reference is now made to Fig. 1, which schematically illustrates a nebulizer 100 comprising a porous medium 104, according to some embodiments. Nebulizer 100 further comprises a sponge 102, a wetting mechanism 106, a gas channel 110 and an outlet 112. Wetting mechanism 106 comprises a rod and a solid plate connected to sponge 102.

The terms 'nozzle' and 'outlet' as used herein are interchangeable. According to some embodiments, the liquid absorbing material is a sponge, a tissue, a foam material, a fabric or any other material capable of fully or partially retrievably absorbing liquids. Each possibility is a separate embodiment of the invention. According to some embodiments, the liquid absorbing material is configured to enable small diameter droplets to pass through the structure thereof and to obstruct large diameter droplets from passing through the material thereof.

According to some embodiments, the liquid absorbing material is configured to filter the passage of droplets depending on their diameter, such that large diameter droplets are obstructed by the liquid absorbing material.

The terms ‘sponge’ and ‘liquid absorbing material’ as used herein refer to any material that is capable of incorporating, taking in, drawing in or soaking liquids, and upon applying physical pressure thereto, release a portion or the entire amount/volume of the absorbed liquid. The physical pressure may be achieved for example by pressing the material against a solid structure.

According to some embodiments, the liquid absorbing material is having two sides, wherein a first side is facing the wetting mechanism and a second side is facing the porous medium. According to some embodiments, the wetting mechanism is a movable solid medium facing the first side of the liquid absorbing material. According to some embodiments, the wetting mechanism is in close proximity to the first side of the liquid absorbing material. According to some embodiments, the wetting mechanism is attached to the first side of the liquid absorbing material.

The term 'attached to' as used herein includes, but is not limited to, linked, bonded, glued, fastened and the like.

According to some embodiments, the porous medium is having two sides, wherein a first side is facing the liquid absorbing material and a second side is facing the gas channel. According to some embodiments, the first side of the porous medium is facing the liquid absorbing material and the gas channel. According to some embodiments, the liquid absorbing material and the porous medium are in close proximity. According to some embodiments, the first side of the liquid absorbing material and the first side of the porous medium are in close proximity.

Without being bound by any theory or mechanism, a pressure gradient at the porous medium reflects the presence of value difference between the pressure at the first side of the porous material and the pressure at the second side of the porous material, such that pressure values vary inside the volume of the porous medium. These values range from the pressure value at the first side to the pressure value at the second side of the porous medium.

According to some embodiments, the gas channel is a gas delivery channel configured to introduce pressure gradient to the porous medium. According to some embodiments, the gas channel is a gas delivery channel configured to introduce pressurized gas to the porous medium. According to some embodiments, the gas channel is a gas suction channel configured to introduce sub-pressurized gas to the porous medium.

The term 'channel' as used herein is interchangeable with any one or more of the terms port, passage, opening, orifice, pipe and the like.

According to some embodiments, a pressurized gas container is configured to deliver pressurized gas through the gas channel to the porous medium and create an ultra- atmospheric pressure on one side of the porous medium, thereby induce a pressure gradient at the porous medium.

The term 'pressurized gas' as used herein is interchangeable with the term 'compressed gas' and refers to gas under pressure above atmospheric pressure.

According to some embodiments, a vacuum container or sub-atmospheric pressure container is configured to suck gas through the gas channel and create a sub- atmospheric pressure on one side of the porous medium, thereby induce a pressure gradient within the porous medium.

According to some embodiments, the gas channel is connected to a gas source. According to some embodiments, the gas source is a mobile gas source, such as, a gas container. According to some embodiments, the gas source is a gas pump, configured to introduce pressure gradient in the porous medium by pumping gas to or from the gas delivery channel. According to some embodiments, the gas source is a pressurized gas container, configured to contain pressurized gas and to induce a pressure gradient in the porous medium by releasing pressurized gas to the pressurized-gas delivery channel. According to some embodiments, the nebulizer further comprises an opening configured to deliver the aerosols to a respiratory system of a subject. According to some embodiments, the opening is connected to a nozzle. According to some embodiments, the opening is mechanically connected to a nozzle. According to some embodiments, the nozzle is detachable.

The correlation between droplet size and deposition thereof in the respiratory tract has been established. Droplets around 10 micron in diameter are suitable for deposition in the oropharynx and the nasal area; droplets around 3-5 micron in diameter are suitable for deposition in the central airways and droplets between 1-3 microns are suitable for delivery to the alveoli (droplets substantially smaller than 1 micron will also target the alveolar region) and may be useful for delivering pharmaceuticals to the systemic circulation). The therapy provided by the present invention is directed to the latter, and indeed it was found that the upon aerosolization of the composition of the present invention with the nebulizer disclosed herein, an aerosol comprising droplet in the range of 0.5-3 microns is formed. In some embodiments, the aerosol comprises droplet in the range of 1-3 microns. According to some embodiments, the aerosol droplets have MMAD of at most 3 microns. According to some embodiments, the aerosol droplets have MMAD of at most 2 microns. According to some embodiments, the aerosol droplets have MMAD of at most 1 micron. According to some embodiments, the aerosol droplets have sub-micron MMAD.

According to some embodiments, the liquid absorbing material comprises the composition for inhalation of the current invention.

According to some embodiments, the nebulizer further comprises a first container, configured to contain liquids to be delivered to the liquid absorbing material. According to some embodiments, the liquids comprise the composition for inhalation of the current invention.

According to some embodiments, the nebulizer further comprises a second container configured to contain a composition comprising the additional active agent, as disclosed herein above.

According to some embodiments, the nebulizer provides an aerosol containing a therapeutically effective amount of the composition for inhalation of the present invention. As used herein, the term “therapeutically effective amount” refers to a pharmaceutically acceptable amount of a pharmaceutical composition which prevents or ameliorates at least partially, the symptoms signs of a particular disease, for example, pneumonia. The term “pharmaceutically acceptable” as used herein means approved by a regulatory agency of the Federal or a state government or listed in the U. S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and, more particularly, in humans.

Useful pharmaceutically acceptable carriers are well known in the art, and include, for example, lactose, glucose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water and methylcellulose. Other pharmaceutical carriers can be sterile liquids, such as water, alcohols (e.g., ethanol) and lipid carriers such as oils (including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like), phospholipids (e.g., lecithin), polyethylene glycols, glycerin, propylene glycol or other synthetic solvents. Each possibility represents as separate embodiment of the present invention.

Pharmaceutical acceptable diluents include, but are not limited to, sterile water, phosphate saline, buffered saline, aqueous dextrose and glycerol solutions, and the like. Each possibility is a separate embodiment of the invention.

According to some embodiments, the wetting mechanism is a mechanic mechanism configured to apply pressure onto the liquid absorbing medium. According to some embodiments, the wetting mechanism is a pneumatic mechanism configured to apply pressure onto the liquid absorbing medium. In some embodiment the wetting mechanism is coupled with an actuator. According to some embodiments, the wetting mechanism comprises a metering pump adapted to delivering a pre-determined volume of liquid at desired pressure(s) directly to the surface of the porous medium.

According to some embodiments, the nebulizer is mobile. According to some embodiments, the nebulizer is handheld. According to some embodiments, the nebulizer is powered by a mobile power source.

There is provided, according to some embodiments, a nebulizer housing configured to host at least one cartridge having a liquid absorbing material. The housing may further include any one or more of a porous medium, an opening, a nozzle connected to the opening, one or more container for containing the composition for inhalation, and a combination thereof. According to some embodiments, the nebulizer housing is mobile. According to some embodiments, the housing is handheld. According to some embodiments, the nebulizer is powered by a mobile power source. According to some embodiments, the cartridge is disposable. According to some embodiments, the cartridge is recyclable. According to some embodiments, the liquid absorbing material is disposable. According to some embodiments, the cartridge is reusable.

According to some embodiments, the nebulizer is configured to communicate wirelessly with servers, databases, personal devices (computers, mobile phones) among others.

According to some embodiments, the nebulizer is assembled by introducing a cartridge into the housing.

According to some embodiments, the nebulizer is provided as part of a nebulizer system comprising a housing, an opening in the housing configured to deliver an aerosols to a subject, a receptacle configured to receive a cartridge (the cartridge comprises a liquid absorbing material, and a porous medium, having at least one porous surface, configured to produce aerosols and a wetting mechanism configured to press the liquid absorbing material against the porous medium or against a surface of the porous medium), an actuator configured to control the wetting mechanism and a gas channel, to introduce a pressure gradient to the porous medium.

According to some embodiments, the liquid absorbing material is presoaked with the composition for inhalation. According to some embodiments, the presoaked liquid absorbing material is hermetically or semi hermetically sealed. According to some embodiments, the seal is configured to be disrupted or otherwise removed upon usage. According to some embodiments, the seal is configured to be automatically disrupted or otherwise removed, for example, by an actuator in the nebulizer system. According to some embodiments, the seal is configured to be manually removed or disrupted by a user prior to use thereof.

According to some embodiments, the nebulizer system further comprises control mechanism configured to control the release of the liquid from the container containing same, into the liquid absorbing material. According to some embodiments, the control mechanism is configured to control the release of the liquid in a slow and/or gradual release manner. According to some embodiments, the nebulizer system further comprises deployment mechanism configured to deploy the medication or liquid from the container containing same and into the liquid absorbing material.

According to some embodiments, the nebulizer system or cartridge comprises a medication preparation mechanism for mixing the composition for inhalation with a liquid to enable reconstitution of the medication, or dilution thereof, prior to aerosolization of the composition.

According to some embodiments, some mechanisms of the nebulizer system are configured to provide homogeneous or semi homogeneous wetting of the porous medium. According to some embodiments, the mechanisms are other than the liquid absorbing material and the wetting mechanism. Examples for such mechanisms include, but are not limited to, spray mechanism, wiping mechanisms and the like. Reference is now made to Fig. 2, which schematically illustrates a nebulizer 200 comprising a porous medium 204 and a sponge 202, according to some embodiments. Nebulizer 200 further comprises a liquid container 214 and a medication container 216. Liquid container 214 and medication container 216 are configured to enable deployment of their possibly contained contents to sponge 202 to be pressed against porous medium 204.

Reference is now made to Fig. 3 which schematically illustrates a nebulizer 300 comprising a porous medium 304 and a sponge 302, according to some embodiments. As illustrated, a liquid container 314 and a medication container 316 have had their content deployed to sponge 302, and sponge 302 is pressed against porous medium 304 by a wetting mechanism 306. A pressurized gas 318 is delivered to porous medium 304 via a gas channel 310.

Reference is now made to Fig. 4 which schematically illustrates generation of aerosol within a nebulizer, according to some embodiments. A nebulizer 400 is introduced comprising a porous medium 404, a sponge 402 and a nozzle 412, according to some embodiments. Sponge 402 is released from its previous press and wetting position (press and wetting of porous medium 404). A pressurized gas 418 delivered to porous medium 404 via a gas channel 410 introduces a pressure gradient to porous medium 404. The pressure gradient results in the production of an aerosol having large droplets 422 and small droplets 420. Large droplets 422 are impacted by sponge 402 which obstructs their path towards nozzle 412. Small droplets 420, are lighter than large droplets 422, and are mostly drifted away from impacting sponge 402, thus they are not obstructed and may flow towards nozzle 412. Large droplets 422 are impacted and obstructed by sponge 402, advantageously resulting in a delivery of aerosol characterized with small diameter/size droplets.

The terms 'droplet size' and 'mass median aerodynamic diameter', also known as MMAD, as used herein are interchangeable. MMAD is commonly considered as the median particle diameter by mass.

According to some embodiments, control over droplet size and modality of generated aerosol is achieved by controlling physical properties of the porous medium. According to some embodiments, the physical properties of the porous medium are adjusted based on the desired droplet size. The physical properties of the porous medium, may include, but are not limited to, physical dimensions of the porous medium as a whole, pore count, pore density, pore distribution, pore shape, homogeneity of the aforementioned pore features, hydrophobicity of the porous material, and electromagnetic affinity among other properties. Each possibility is a separate embodiment of the invention.

The term "modality" as used herein refers to the modality of size distributions and includes, but is not limited to, uni-modal, bi-modal and tri-modal size distributions. According to some embodiments, control over droplet size and modality of generated aerosol is achieved by controlling the physical properties of the liquid absorbing material.

According to some embodiments, control over droplet size and modality of generated aerosol is achieved by controlling the pressure gradient on the porous medium. According to some embodiments, control over droplet size and modality of generated aerosol is achieved by controlling the properties of the medication and/or liquid and/or composition. The properties of the medication and/or liquid and/or composition which may be adjusted to achieve the desired aerosol, include, but are not limited to, viscosity, surface tension, pH, electrolyte concentration, solid content and polarity.

According to some embodiments, control over droplet size and modality of generated aerosol is achieved by introducing an impactor. According to some embodiments, the liquid absorbing material is configured to act as an impactor. According to some embodiments, the liquid absorbing material is the impactor. According to some embodiments, control over droplet size of generated aerosol is achieved by introducing a filter. According to some embodiments, the liquid absorbing material is configured to act as a filter. According to some embodiments, the liquid absorbing material is the filter. According to some embodiments, the impactor is an independent structure, different from the liquid absorbing material. According to some embodiments, the filter is an independent structure, different from the liquid absorbing material.

Reference is now made to Fig. 5 which schematically illustrates a nebulizer system 500, according to some embodiments. Nebulizer system 500 comprises a gas pump 528 an actuator 530 a first deployment controller 524, a second deployment controller 526, a wetting mechanism 506, a sponge 502, a porous medium 504, a gas channel 510, a liquid container 514, a medication container 516 and a nozzle 512.

According to some embodiments, pump 528 is configured to deliver compressed gas to porous medium 504 via gas channel 510. Actuator 530 is configured to control the movement and function of wetting mechanism 506 for pressing sponge 502 against porous medium 504. First deployment controller 524 is configured to control the deployment of contained liquid in liquid container 514 to sponge 502, and second deployment controller 526 is configured to control the deployment of medication in medication container 516 to sponge 502.

According to some embodiments, the actuator is configured to control the pressure applied onto the liquid absorbing material. According to some embodiments, the actuator is configured to control the movement of the wetting mechanism. According to some embodiments, the actuator operates through mechanic, electro mechanic, electromagnetic, electro thermal, hydraulic, pneumatic or electronic mechanism. Each possibility is a separate embodiment of the invention.

There is provided, according to some embodiments, a method for treating an infective disease, the method comprising the steps of providing a liquid absorbing material, a porous medium having two sides in which the first side is facing the liquid absorbing material and further providing a composition as described herein is the form of a liquid, wetting the liquid absorbing material with the composition, pressing liquid absorbing material against the porous medium, introducing pressure gradient to the porous medium and producing aerosol at the first side of the porous medium, the produced aerosol comprises droplets of the composition. According to some embodiments, the composition is provided in a container. According to some embodiments, the method further comprises controlling the release of the liquid from the container into the liquid absorbing material. According to some embodiments, the method further comprises releasing the liquid in a slow and/or gradual release manner. According to some embodiments, the method further comprises deploying the medication or liquid from the container and into the liquid absorbing material. According to some embodiments, the method further comprises providing a first container with a liquid and a second container with medication, and mixing the medication with the liquid to form the composition disclosed herein, prior to aerosolization.

The term 'wetting' as used herein refers to homogenous or pseudo homogenous wetting of one side of the porous medium.

According to some embodiments, the method further comprises wetting the porous medium homogenously.

According to some embodiments, the method further comprises providing the composition for inhalation disclosed herein and mixing the composition for inhalation with the liquid, prior to wetting the liquid absorbing agent.

According to some embodiments, the liquid absorbing material already includes the composition for inhalation. The composition for inhalation within the liquid absorbing material may be in a solid form, e.g., a powder, or otherwise concentrated, such that upon wetting the liquid absorbing material, the composition for inhalation is reconstituted, or otherwise diluted, thereby resulting with the required pharmaceutically acceptable form suitable for inhalation following the conversion thereof into aerosols. The terms “composition for inhalation” and “pulmonary composition” as used herein are interchangeable.

According to some embodiments, the liquid absorbing material comprises at least one composition for inhalation at least partially absorbed therein.

The term "partially absorbed therein" as used herein refers to the percentage of liquid absorbed in the pores of the porous material, wherein 0% refers to a porous material where all of its pores are vacant of liquid. Thus, the term "partially absorbed therein" may refer to a porous material wherein at least 0.005% of the pores contain liquid, or wherein the overall contents of the vacant space within the porous material occupied with liquid is 0.005%. According to some embodiments, partially absorbed therein refers to at least 0.001% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 0.05% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 0.01% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 0.5% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 0.1% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 1% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 5% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 10% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 20% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 30% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 40% liquid contents within the porous material. According to some embodiments, partially absorbed therein refers to at least 50% liquid contents within the porous material.

According to some embodiments, the term "partially absorbed therein" may refer to the content of liquid within the volume of pores located on the surface and in the immediate vicinity of the surface (sub surface) of a porous medium. According to some embodiments, the volume of the sub-surface may extend from the surface to a depth of about 50 micron from the surface.

According to some embodiments, partially absorbed therein refers to a porous material wherein at least 0.5% of the surface and sub-surface pores contain liquid. According to some embodiments, partially absorbed therein refers to at least 1% liquid contents within the surface and sub-surface pores. According to some embodiments, partially absorbed therein refers to at least 10% liquid contents within the surface and sub surface pores. According to some embodiments, partially absorbed therein refers to at least 20% liquid contents within the surface and sub-surface pores. According to some embodiments, partially absorbed therein refers to at least 30% liquid contents within the surface and sub-surface pores. According to some embodiments, partially absorbed therein refers to at least 40% liquid contents within the surface and sub-surface pores. According to some embodiments, partially absorbed therein refers to at least 50% liquid contents within the surface and sub-surface pores. According to some embodiments, partially absorbed therein refers to at least 60% liquid contents within the surface and sub-surface pores.

According to some embodiments, the pressing of the liquid absorbing material upon the porous medium is iterated a plurality of times. According to some embodiments, the pressing is executed while applying a non-constant pressing force/pressure across iterations. According to some embodiments, after deploying a content of the composition for inhalation into the liquid absorbing material, a first pressing of the liquid absorbing material against the porous medium is carried out utilizing a first pressing force (pressure), a second pressing of the liquid absorbing material against the porous medium is executed utilizing a second pressing force, and so on. According to some embodiments, the first pressing force is lower than the second pressing force, advantageously resulting in a more unified wetting of the porous surface of the porous medium.

According to some embodiments, a deployment of the composition for inhalation into the liquid absorbing material is performed, then the liquid absorbing material is pressed against the porous medium, wetting the porous surface of the porous medium for generating aerosol, and then a deployment of a second liquid into the liquid absorbing material is performed. According to some embodiments, the second liquid is sterile. According to some embodiments, the second liquid is saline, water, carrier, cleansing liquid and the like, the deployment of which may be performed for diluting the composition for inhalation content in the liquid absorbing material. According to some embodiments, the deployment of the second liquid is performed for cleansing the liquid absorbing material and releasing the residues that may accumulate in the liquid absorbing material to achieve better delivery of further composition for inhalation to the subject, or for cleansing the liquid absorbing material, the porous medium or both. According to some embodiments, by cleansing the liquid absorbing material, the porous medium or both, the components may be reused. Advantageously, the cleansing may prevent accumulation of medication residue in the nebulizer or some components thereof.

According to some embodiments, the droplets of the aerosol produced from the composition of the present invention are having an MMAD within the range of 0.3 to 7 microns. According to some embodiments, the MMAD is within the range of 2 to 10 microns. According to some embodiments, the MMAD is less than 5 microns. According to some embodiments, the droplets of the aerosol produced by the method and nebulizers disclosed herein are having an MMAD within the range of 0.3 to 7 microns. According to some embodiments, the MMAD is within the range of 2 to 10 microns. According to some embodiments, the MMAD is less than 5 microns. According to some embodiments, the MMAD is in the range of 1 to 3 microns. According to some embodiments, the aerosol droplets have MMAD of at most 3 microns. According to some embodiments, the aerosol droplets have MMAD of at most 2 microns. According to some embodiments, the aerosol droplets have MMAD of at most 1 micron. According to some embodiments, the aerosol droplets have sub-micron MMAD.

According to some embodiments, the wetting mechanism includes a rotatable/displaceable elongated member, configured to be movably placed on the surface of the porous medium, or in close proximity thereto, or placed on the liquid absorbing material. According to some embodiments, the wetting mechanism includes a rotatable/displaceable elongated member (e.g. a spinning magnet) configured to be placed on the liquid absorbing material, such that liquid is extracted from the liquid absorbing material by the wetting mechanism. According to some embodiments, the rotatable elongated member is configured to move across the surface of the porous medium, thereby to homogeneously or semi-homogeneously spread the liquid on the surface of the porous medium.

According to some embodiments, the elongated member is axially movable. According to some embodiments, the elongated member is movable to cover the entire surface of the porous medium or substantial portions thereof. According to some embodiments, the wetting mechanism further includes an actuator, configured to displace/move or induce the displacement/movement of the elongated member. The term "substantial portions" as used herein commonly refers to at least 30% coverage of the surface of the porous medium. According to some embodiments, the substantial portions include at least 50% coverage of the surface of the porous medium, at least 60% coverage of the surface of the porous medium, at least 70% coverage of the surface of the porous medium, at least 80% coverage of the surface of the porous medium or at least 90% coverage of the surface of the porous medium.

According to some embodiments, the elongated member may include a magnet, and the actuator may also include a magnet, magnetically associated with the magnet of the elongated member, such that by moving/displacing the magnet/electromagnet of the actuator, a moving/displacing of the elongated member may be induced.

According to some embodiments, one or more of the magnets includes an electromagnet. According to some embodiments, the actuator may include a motor configured to move/displace the actuating magnet.

According to some embodiments, the elongated member may be coated by a hydrophobic coating. According to some embodiments, the elongated member may be at least partially coated by a hydrophobic coating. According to some embodiments, the coating may be smooth, non-corrosive, non-toxic, non-evaporative or a combination thereof. According to some embodiments, the coating may include polytetrafluoroethylene (e.g., Teflon®).

The term "at least partially" as used herein may include at least 50% coating of the elongated member, at least 60% coating of the elongated member, at least 70% coating of the elongated member, at least 80% coating of the elongated member or at least 90% coating of the elongated member.

According to some embodiments, the elongated member is an elongated tubular member. According to some embodiments, the elongated member may be movable by an actuator, mechanically connected thereto. According to some embodiments, the elongated member may be movable by an air-flow within the nebulizer and/or through the porous material.

According to some embodiments, the elongated member may be a roller. According to some embodiments, the elongated member may be a smearing device. According to some embodiments, the elongated member may be a spreading device. According to some embodiments, the elongated member may be configured to force at least portions of the liquid to at least some of the pores of the porous medium.

Reference is now made to Fig. 6a, which schematically illustrates a side cross section of a nebulizer 900 with a rotatable wetting mechanism, according to some embodiments. Said nebulizer 900 is adapted to aerosolize the composition for inhalation of the present invention and to produce the aerosol of the present invention, according to some embodiments. According to some embodiments, the wetting mechanism of nebulizer 900 includes a rotatable elongated member, such as movable magnet 940, which is placed on, or in close proximity to a surface of a porous medium, such as porous disc 904, within a nebulizer housing, such as housing 902. Movable magnet 940 is configured to rotate on porous disc 904, thereby homogeneously or semi- homogeneously spread a liquid (such as a liquid comprising the composition for inhalation of the current invention) on porous disc 904 and/or at least partially force the liquid within the pores of porous disc 904. According to some embodiments, nebulizer 900 further includes a liquid deploying mechanism, such as medication conduit 946, configured to provide liquids and/or composition(s) (such as the composition for inhalation of the current invention) to movable magnet 940 and/or porous disc 904. According to some embodiments, nebulizer 900 further includes an actuator configured to directly or indirectly move or induce the displacement of movable magnet 940. According to some embodiments, the actuator includes a motor 944, mechanically or electromechanically connected to an actuator-magnet, such as motor-magnet 942 being associated with movable magnet 940, such that a displacement of motor-magnet 942 induces a displacement of movable magnet 940. Motor 944 is configured to axially rotate motor-magnet 942, thereby induce an axial rotation of movable magnet 940 over/on the surface of porous medium 904.

In operation, according to some embodiments, pressurized gas/air is provided to housing 902, for example through pressurized-gas conduit 910, and introduced to one side of porous disc 904 which interrupts the flow of gasses therethrough, thereby a pressure gradient occurs across porous disc 904. The composition for inhalation may be provided through medication conduit 946 and introduced to the surface of porous disc 904, and then movable magnet 940 spreads the composition homogeneously or semi-homogeneously on the surface and at least partially forced through the pores of porous disc 904 by the axial rotation thereof, induced by the rotation of motor magnet 942 and motor 944. According to some embodiments, the pressure gradient on porous disc 904 generates a mist of multiple droplets as the gas passes through the pores, the mist is then delivered through an outlet, such as mouthpiece 912. According to some embodiments, the outlet comprises an adapter for nasal delivery.

Reference is now made to Fig. 6b, which schematically illustrates a top cross section view of a nebulizer 901 with a rotatable wetting mechanism, according to some embodiments. The rotatable wetting mechanism includes a displaceable/movable elongated member, such as a movable magnet 940, which is placed on, or in close proximity to a surface of a porous medium, such as a porous disc 904 held within a nebulizer housing 902. Movable magnet 940 is configured to be rotatable (arrows 950) and to spread/smear/distribute the composition for inhalation on the surface of porous disc 904, the liquids may be provided onto the surface of porous disc 904, and According to some embodiments, the composition for inhalation may be provided to rotatable magnet 940.

Reference is now made to Fig. 6c, which schematically illustrates a side cross section of a nebulizer 900 with a rotatable wetting mechanism and a peripheral actuator, according to some embodiments. According to some embodiments, the wetting mechanism of nebulizer 900 includes a rotatable elongated member, such as movable magnet 940, which is placed on, or in close proximity to a surface of a porous medium, such as porous disc 904, within a nebulizer housing, such as housing 902. Movable magnet 940 is configured to rotate on porous disc 904, thereby homogeneously or semi- homogeneously spread the composition for inhalation on porous disc 904 and/or at least partially force a liquid into the pores of porous disc 904. According to some embodiments, nebulizer 900 further includes a liquid deploying mechanism, such as medication conduit 946, configured to provide liquids and/or composition(s) (such as the composition for inhalation) to movable magnet 940 and/or porous disc 904. According to some embodiments, nebulizer 900 further includes a peripheral actuator configured to directly or indirectly move or induce the displacement of movable magnet 940. According to some embodiments, the peripheral actuator included is configured to be placed over, or to surround, movable magnet 940 and to fluctuate the magnetic field flux near movable magnet 940, thereby induce a mechanical movement thereof (rotation). According to some embodiments, the peripheral actuator may be a ring actuator such as controllable electromagnet-ring 960 which may include a plurality of controllable electro-magnets (not shown) which are electrically controlled for inducing a gradient in the electromagnetic field flux in the environment of movable magnet 940, thereby induce an axial rotation of movable magnet 940 over/on the surface of porous medium 904.

Reference is now made to Fig. 6d, which schematically illustrates a top cross section view of a nebulizer 901 with a rotatable wetting mechanism, according to some embodiments. The rotatable wetting mechanism includes a displaceable/movable elongated member, such as a movable magnet 940, which is placed on, or in close proximity to a surface of a porous medium, such as a porous disc 904 held within a nebulizer housing 902. According to some embodiments, nebulizer 901 may also include a peripheral actuator configured to induce a change in the magnetic field flux in the environment of movable magnet 940 thereby induce a rotatable movement thereof 950. According to some embodiments, peripheral actuator may be a ring actuator such as controllable electromagnet-ring 960. According to some embodiments, movable magnet 940 is configured to be rotatable (arrows 950) and to spread/smear/distribute the composition for inhalation on the surface of porous disc 904, the liquids may be provided onto the surface of porous disc 904, and According to some embodiments, the composition for inhalation may be provided to rotatable magnet 940

Reference is now made to Fig. 6e, which schematically illustrates a side cross section of a nebulizer 900 with a rotatable wetting mechanism, according to some embodiments. According to some embodiments, nebulizer 900 is essentially similar to the nebulizer of Fig. 6a, and further includes a flexible medication deploying end, such as flexible-conduit 948 which is connected to medication conduit 946 and is configured to provide/deploy the composition for inhalation on porous disc 904. According to some embodiments, flexible-conduit 948 is configured to reach near the surface of porous disc 904, and to be flexibly movable by the rotation of movable magnet 940 for deploying the composition for inhalation at close proximity to the surface of porous disc 904 without obstructing the rotation/axial-movement thereof. According to some embodiments, deploying medication near the surface of porous disc 904 via a flexible member, such as flexible-conduit 948, may provide a homogeneous spreading of the composition for inhalation on the surface of porous disc 904. Reference is now made to Fig. 6f, which schematically illustrates a top cross section view of a nebulizer 901 with a rotatable wetting mechanism, according to some embodiments. The rotatable wetting mechanism includes a displaceable/movable elongated member, such as a movable magnet 940, which is placed on, or in close proximity to a surface of a porous medium, such as a porous disc 904 held within a nebulizer housing 902. Movable magnet 940 is configured to be rotatable (arrows 950) and to spread/smear/distribute the composition for inhalation on the surface of porous disc 904, the composition for inhalation may be provided onto the surface of porous disc 904, and, according to some embodiments, the composition for inhalation may be provided to rotatable by a flexible medication deploying member, such as flexible- conduit 948 shown at a first location, and is flexibly movable (arrow 951) to a second location 949 by the rotation of movable magnet 940.

Reference is now made to Fig. 6g, which schematically illustrates a side cross section of a nebulizer 900 with a rotatable wetting mechanism, essentially as described in Fig. 6a, according to some embodiments. According to some embodiments, nebulizer 900 further includes two spacers mounter/fastened on movable magnet 940, such as a first Teflon™ ball 962 and second Teflon™ ball 964, each being mechanically connected to one end of movable magnet 940 for elevating it from the surface of porous disc 904 and thereby improve the homogeneous spreading of the composition for inhalation and lead to production of controllable aerosol droplet size.

According to some embodiments, the two spacers may be integrally formed with the movable magnet. According to some embodiments, the two spacers are protrusions at the two ends of the movable magnet.

Reference is now made to Fig. 6h, which schematically illustrates a top cross section of a nebulizer 900 with a rotatable wetting mechanism, essentially as described in Fig. 6b, according to some embodiments. Depicted in Fig. 6h are first Teflon™ ball 962 and second Teflon™ ball 964, each being mechanically connected to one end of movable magnet 940 to prevent direct contact thereof with the surface of porous disc 904 Reference is now made to Fig. 6i, which schematically illustrates a side cross section of a nebulizer 900 with a rotatable wetting mechanism, essentially as described in Fig. 6a, according to some embodiments. According to some embodiments, nebulizer 900 further includes a spacer placed/mounted/integrated on the surface of porous disc 904, such as a Teflon-ring 970 which is configured to elevate movable magnet 940 above the surface of porous medium 904 for providing spacing and preventing a direct contact therebetween. According to some embodiments, movable magnet 940 is tightened to Teflon-ring 970, and is pulled towards porous disc by the magnetic field applied by motor magnet 942. According to some embodiments, Teflon-ring 970 is configured to facilitate low-friction movement of movable magnet 940 thereon.

Reference is now made to Fig. 6j, which schematically illustrates a top cross section of a nebulizer 900 with a rotatable wetting mechanism, essentially as described in Fig. 6b, according to some embodiments. Depicted in Fig. 6j is Teflon-ring 970 placed on the surface of porous disc 904, to prevent direct contact thereof with the movable magnet 940

According to some embodiments, the spacing/distance/elevation between the surface of the porous medium and the movable magnet is approximately 100 micron (0.1 pm). According to some embodiments, the spacing/distance/elevation between the surface of the porous medium and the movable magnet is in the range of 50 micron (0.05 pm) to 150 micron (0.15 pm). According to some embodiments, the spacing/distance/elevation between the surface of the porous medium and the movable magnet is in the range of 20 micron (0.02 pm) to 200 micron (0.2 pm).

According to some embodiments, the term "approximately" may refer to the distance between the surface of the porous medium and the movable magnet, and thus may refer to values within the range of 20% or less from the value indicated. For example, a spacing/distance/elevation of approximately 100 micron (0.1 pm) includes values within the range of 80-100 micron.

Without being bound by any theory or mechanism of action, the distance between the surface of the porous medium and the movable magnet seems to result with advantageous droplet size distribution, possible due to an improved wetting mechanism. Reference is now made to Fig. 7, which schematically illustrates nebulizer 1000 with a rotatable wetting mechanism and a liquid deploying structure 1046, according to some embodiments. Liquid deploying mechanism, such as liquid conduit 1046 is configured to deploy/provide liquids to the surface of a porous medium 1004 and a rotatable magnet 1040 is placed on the surface of porous medium 1004 and is configured to be movable thereon and to homogeneously or semi-homogeneously spread the liquids provided by liquid conduit 1046 on the surface of porous medium 1004. The wetting mechanism further comprises an actuator having, according to some embodiments, a control-magnet 1042 magnetically/mechanically associated with rotatable magnet 1040 and rotated by a motor 1044.

When a pressure gradient is applied on porous medium 1004, a mist/aerosol of multiple droplets is released from the wetted/damped/moistened surface of porous medium

1004

According to some embodiments, motor 1044 may comprise a brushed or brushless DC motor, for example a steppe moto or the like. According to some embodiments, motor 1044 may comprise an AC motor, such as an induction motor or the like.

Reference is now made to Fig. 8, which schematically illustrates a nebulizer 1100 with a rotatable wetting mechanism and a liquid absorbing material, such as sponge 1102, according to some embodiments. Liquid absorbing material is placed on a surface of a porous medium 1104 and configured to reversibly contain/absorb liquids, and release the liquids with changed physical conditions such as pressing. A movable elongated spreader/presser, such as rotating rod 1140, is placed on sponge 1102 and is configured to press at least some portions thereof against the surface of porous medium 1104, thereby force the release of absorbed liquids from sponge 1102. The moving of rotating rod 1140 is induced/caused by the rotating displacement of an actuator that is mechanically and/or magnetically associated with rotating rod 1140. According to some embodiments, rotating rod 1140 may be movable/rotatable by inducing magnetic field changes in the environment thereof, and the actuator includes a magnetic-field inducer 1142 rotatable by a motor 1144 and configured to induce the rotation/displacement of rotating rod 1140 on sponge 1102 thereby pressing against various areas thereon and controllably releasing liquid to the surface of porous medium 1104. When a pressure gradient is applied on porous medium 1104, a mist/aerosol of multiple droplets is released from the wetted/damped/moistened surface of porous medium

1104

Reference is now made to Fig. 9, which schematically illustrates a side cross section of a nebulizer assembly 1300 with a rotatable wetting mechanism, according to some embodiments. Nebulizer 1300 includes a housing 1302 with an inlet orifice 1310, an outlet orifice 1312, a liquid conduit 1346 and a pressure-sensor conduit 1348. Nebulizer 1300 further includes a rotatable spreading mechanism, such as spreading elongated magnet 1340 placed on a surface of a porous disc 1304 for spreading liquids thereon, an actuator within housing 1302 is associated with spreading elongated magnet 1340, the actuator includes a motor 1344 mechanically connected to a motor-magnet 1342 and is configured to rotate spreading elongated magnet 1340 for spreading liquids (such as the composition disclosed herein) on the surface and/or through the pores of porous disc 1304. According to some embodiments, liquid conduit 1346 is configured to provide the composition for inhalation to a central section of spreading elongated magnet 1340.

Reference is now made to Fig. 10, which schematically illustrates a nebulizer system assembly 1700 with a rotatable wetting mechanism, according to some embodiments. Nebulizer system assembly 1700 includes various functional, control and/or indicatory components. For exemplary purposes, system assembly 1700 includes a nebulizer, a gas pump for providing pressurized gas to the nebulizer, a pressure sensor, control gauges and buttons and others.

According to some embodiments, there is provided a nebulizer cartridge comprising a porous medium and a displaceable wetting mechanism configured to spread a liquid over the porous medium thereby to wet the porous medium, wherein the porous medium comprises a plurality of pores, and wherein at least some of said plurality of pores comprise the liquid, wherein the liquid comprises the pulmonary pharmaceutical composition of the present invention. Any one of the embodiments above may refer to the present cartridge, which comprises the pulmonary pharmaceutical composition of the present invention.

According to some embodiments, there is provided a nebulizer cartridge comprising at least one porous medium; at least one reservoir containing the pharmaceutical composition of the present invention; at least one mobile liquid absorbing element; at least one stationary liquid absorbing element; and at least one conveyer configured to be actuated by a motor; wherein said at least one mobile liquid absorbing element is movable by the conveyer on a track; wherein said at least one stationary liquid absorbing element extends from the at least one reservoir to the track; and is in contact with the liquid, when contained in the reservoir, such that upon moving the at least one mobile liquid absorbing element on the track, the at least one mobile liquid absorbing element is at least temporarily in contact with the at least one stationary liquid absorbing element and at least temporarily in contact with the at least one porous medium. Reference is now made to Figs. 11-14, which schematically illustrate a nebulizer cartridge. Fig. 11 schematically illustrate a nebulizer cartridge 100 comprising a porous medium 102, reservoir 104, a stationary liquid absorbing element 106, a mobile liquid absorbing element 108 at position 134, a conveyer 110, a pressurized air inlet 112 and a snap-fit 114, according to some embodiments.

According to some embodiments, the at least one reservoir contains the present pulmonary composition. According to some embodiments, the at least one stationary liquid absorbing element is having a proximal surface facing the at least one reservoir and is in contact with the liquid contained in the reservoir, thereby absorbed with a first amount of the liquid. According to some embodiments, the at least one stationary liquid absorbing element is having an upper surface facing the at least one mobile liquid absorbing element at position 134. At this configuration, the mobile liquid absorbing element absorbs from the at least one stationary liquid absorbing element a portion of the first amount of the liquid.

According to some embodiments, reservoir 104 is a container for holding liquid. According to some embodiments, reservoir 104 contains a first amount of aqueous ceftriaxone composition 116. According to some embodiments, reservoir 104 is having a distal surface 104a facing a first surface 106a of stationary liquid absorbing element 106, and being in contact with ceftriaxone composition 116. According to some embodiments, stationary liquid absorbing element 106 includes a first portion of the first amount of ceftriaxone composition 116 absorbed therein.

According to some embodiments, stationary liquid absorbing element 106 is a sponge. According to some embodiments, stationary liquid absorbing element 106 is a hydrophilic sponge. According to some embodiments, mobile liquid absorbing element 108 is a sponge. According to some embodiments, mobile liquid absorbing element 108 is a hydrophilic sponge. It is to be understood that a hydrophilic sponge has high tendency to absorb aqueous solutions.

The terms "liquid absorbing material", "liquid absorbing element" and "liquid absorbent material" as used herein are interchangeable and refer to any material, or element comprising a material that is capable of incorporating, taking in, drawing in or soaking liquids, and upon applying physical pressure thereto or being in contact with another material, release a portion or the entire amount/volume of the absorbed liquid. According to some embodiments, the at least one stationary liquid absorbing element is configured to absorb water in an amount which is at least 100% of its weight. According to some embodiments, the at least one mobile liquid absorbing element is configured to absorb water in an amount which is at least 100% of its weight. According to some embodiments, the at least one stationary liquid absorbing element comprises cloth, wool, felt, sponge, foam, cellulose, yam, microfiber or a combination thereof. Each possibility represents a separate embodiment. According to some embodiments, the at least one mobile liquid absorbing element comprises cloth, wool, felt, sponge, foam, cellulose, yarn, microfiber or a combination thereof. Each possibility represents a separate embodiment.

Without wishing to be bound by any theory or mechanism of action, when the liquid is a water-based pharmaceutical composition, hydrophilic mobile- and/or stationary liquid absorbing element(s) are preferred. In this situation, the aqueous composition in the reservoir(s) is efficiently absorbed in the stationary liquid absorbing element(s); and therefrom it absorbs in the mobile liquid absorbing element(s) to create equilibrium. Consequently, the absorbed mobile liquid absorbing element(s) delivers the aqueous composition to the at least one porous medium to produce the desired aerosol. In addition, when the at least one stationary liquid absorbing element comprises a hydrophilic sponge, as it comes in contact with the aqueous pharmaceutical composition in the reservoir, capillary action within and among the pores of the sponge lead to absorption of the ceftriaxone composition therein. The same capillary action results with the absorption of the aqueous pharmaceutical composition by the at least one mobile liquid absorbing element. According to some embodiments, the at least one mobile liquid absorbing element is hydrophilic. According to some embodiments, the at least one mobile liquid absorbing element is a hydrophilic sponge. Likewise, according to some embodiments, the at least one stationary liquid absorbing element is hydrophilic, for example, a hydrophilic sponge. According to some embodiments, the at least one mobile liquid absorbing element and the at least one stationary liquid absorbing element are composed of the same material.

Referring again to Fig. 11, this figure illustrates a configuration where stationary liquid absorbing element 106 is in contact with mobile liquid absorbing element 108 which is in position 134 (hereinafter, "Configuration A"). As stationary liquid absorbing element 106 is in a fixed position and is in contact with the liquid contained in reservoir 104, it absorbs a portion of ceftriaxone composition 116 therefrom. Thus, stationary liquid absorbing element 106 is being absorbed with a portion of ceftriaxone composition 116. Furthermore, when mobile liquid absorbing element 108 is in position 134, as illustrated in Fig. 11, mobile liquid absorbing element 108 absorbs a portion of ceftriaxone composition 116 absorbed in stationary liquid absorbing element 106. According to some embodiments, while the cartridge is disconnected (i.e. it is not connected to a nebulizer control unit, as depicted in Fig. 11) liquid absorbing element 108 is in position 134. According to some embodiments, while liquid absorbing element 108 is in position 134 the amount ceftriaxone composition 116 in reservoir 104 is remained substantially constant.

Specifically, according to some embodiments, stationary liquid absorbing element 106 comprises a first surface 106a, and second surface 106b. According to some embodiments, first surface 106a is facing reservoir 104. According to some embodiments, first surface 106a is protruding into reservoir 104. According to some embodiments, stationary liquid absorbing element 106 is absorbing a portion of ceftriaxone composition 116 from reservoir 104 through first surface 106a. Thus, according to some embodiments, a portion of ceftriaxone composition 116 is absorbed into stationary liquid absorbing element 106. Thus, according to some embodiments, the amount of ceftriaxone composition 116 in reservoir 104 and the amount of ceftriaxone composition 116 in stationary liquid absorbing element 106 is in equilibrium. According to some embodiments, the amount of ceftriaxone composition 116 in reservoir 104 and the amount of ceftriaxone composition 116 in stationary liquid absorbing element 106 is in equilibrium, such that the amount of amount ceftriaxone composition 116 in each of reservoir 104 and liquid absorbing element 106 is substantially constant, when nebulizer cartridge 100 is in Configuration A.

According to some embodiments, second surface 106b is facing mobile liquid absorbing element 108 where mobile liquid absorbing element 108 is nested within conveyer 110.

Each one of first surface 106a and second surface 106b may be substantially flat, or curved, according to some embodiments. Fig. 11 refers to the former option, while, due to an amorphous shape, which sponges tend to have while soaked and/or squeezed, the latter option is contemplated. According to some embodiments, first surface 106a and second surface 106b may be a continuation of one another. For, example according to some embodiments, the surface of stationary liquid absorbing element 106 may be round, such that first surface 106a and second surface 106b partially overlaps at the convex surface of liquid absorbing element 106.

According to some embodiments, conveyer 110 comprises a retaining unit 118 and track 120. According to some embodiments, retaining unit 118 and track 120 are physically connected to each other. According to some embodiments, conveyer 110 is retaining, encompassing, housing or nesting mobile liquid absorbing element 108. According to some embodiments, conveyer 110 comprises a retaining unit, configured to retain therein mobile liquid absorbing element 108, such that conveyer 110 and the at least one mobile liquid absorbing element 108 are moving together, as one unit. According to some embodiments, conveyer 110 comprises at least one rack-like element and at least one cogwheel. According to some embodiments, the at least one rack-like element is located along track 120. According to some embodiments, each of the at least one rack-like element and the at least one cogwheel comprises serrated teeth. According to some embodiments, the at least one cogwheel comprises an external cogwheel having serrated teeth. According to some embodiments, the serrated teeth of the at least one rack-like element are interlocking with the serrated teeth of the external cogwheel, such that upon rotating said interlocking external cogwheel, its teeth are rotating a radial direction, and pushing the interlocked teeth of the at least one rack-like element, such that the at least one rack-like element is moved at a tangential direction in a rack and pinion mechanism. According to some embodiments, rotating said external cogwheel in the opposite direction entails moving the at least one rack-like element in the opposite direction. According to some embodiments, the at least one retaining unit and the at least one rack-like element are physically connected, such that upon rotating the at least one cogwheel, the at least one liquid absorbing element is being moved along the track.

According to some embodiments, conveyer 110 is configured to move mobile liquid absorbing element 108 along the course of track 120. According to some embodiments, the motion along track 120 is enabled by an operating motor, which is located in a control unit, connectable to nebulizer cartridge 100 (not shown) as discussed with reference to Figs 15A and 15B.

According to some embodiments, track 120 extends from conveyer 110 to end point 124. Accordingly, and according to some embodiments, the course of track 120 extends from position 134 to end point 124. According to some embodiments, end point 124 is distal from stationary liquid absorbing element 106. According to some embodiments, upon operation of a nebulizer comprising nebulizer cartridge 100 liquid absorbing element 106 travels between position 134 and end point 124, as discussed when referring to Figs 15A and 15B. According to some embodiments, upon operation of a nebulizer comprising nebulizer cartridge 100, retaining unit 118 is shifted from position 134 to end point 124, as discussed when referring to Figs 15A and 15B.

According to some embodiments, mobile liquid absorbing element 108 is shifted, by the movement of conveyer 110 on track 120 in parallel to surface 130 of porous medium 102

According to some embodiments, upon moving along track 120 the at least one mobile liquid absorbing element 108 spreads the first liquid on surface 130 of porous medium 102. According to some embodiments, track 120 is adapted and positioned, such that, when mobile liquid absorbing element 108 travels from position 134 it covers approximately the entire surface of porous medium 102 (not shown).

According to some embodiments, porous medium 102 has two flat surfaces, one of which is surface 130 which faces mouthpiece and the other is surface 132, which faces pressurized air inlet 112 and/or the control unit (not shown).

According to some embodiments, track 120 extends across the surface of at least one porous medium 102. According to some embodiments, nebulizer cartridge 100 further comprises a pressurized air inlet 112, configured to enable transfer of pressurized air from the pressurized air source in the control unit to nebulizer cartridge 100. According to some embodiments, pressurized air inlet 112 is configured to allow passage of pressurized air from a nebulizer pump to (and through) porous medium 102. According to some embodiments, pressurized air inlet 112 is located proximally to porous medium 102, such that it faces surface 132. Reference to the flow of pressurized air is discussed in greater detail, when referring to Figs. 15A and 15B.

According to some embodiments, flat surface 130 is facing track 120. According to some embodiments, surface 132 is facing pressurized air inlet 112. According to some embodiments, porous medium 102 includes a plurality of pores 126.

According to some embodiments, the at least one mobile liquid absorbing element 108 is configured to discharge at least portions of the liquid absorbed therein into, and onto, at least some of the plurality of pores 126.

According to some embodiments, when mobile liquid absorbing element 108 is in position 134 before the first action of nebulizer cartridge 100, porous medium 102 is dry.

According to some embodiments, upon connecting a control unit to cartridge 100, and following its operation (e.g., by pressing a button), mobile liquid absorbing element 108 is moved along track 120 between starting point 122 and end point 124, and spreads ceftriaxone composition 116 thereon. According to some embodiments, upon connecting a control unit to cartridge 100, and following its operation (e.g., by pressing a button), mobile liquid absorbing element 108 is moved along track 120 between position 134 and end point 124, and spreads ceftriaxone composition 116 over surface 130. According to some embodiments, during the move, an amount of ceftriaxone composition 116 is penetrating pores 126 of porous medium 102. According to some embodiments, the penetrating entails wetting porous medium 102.

According to some embodiments, upon operation of a nebulizer comprising nebulizer cartridge 100, pressurized air may enter through pressurized air inlet 112 as further detailed with reference to Figs. 15A and 15B. According to some embodiments, during operation of a nebulizer, the pressurized air entering nebulizer cartridge 100 from pressurized air inlet 112 is hitting surface 132 of porous medium 102, wherein porous medium 102 includes therein a portion of ceftriaxone composition 116, leading to aerosol formation (as further discussed in reference to Fig. 12). According to some embodiments, the pressurize air is hitting flat surface 132 when porous medium 102 is wet, thereby leading to formation of aerosol. According to some embodiments, the aerosol comprises droplets of ceftriaxone composition 116. According to some embodiments, the formation of aerosol leaves porous medium 102 substantially dry. According to some embodiments, the at least one mobile liquid absorbing element is in contact with the at least one stationary liquid absorbing element, for a first time period, which is the time period from the contact and until operating the conveyer. Thus, according to some embodiments, the at least one mobile liquid absorbing element is absorbed with liquid, which is maintained therein until the conveyer is operated, thereafter some of the liquid is discharged onto the porous medium during the traveling of the mobile liquid absorbing element 108 along track 120. As a result, according to some embodiments, at least one porous medium 102 remains dry, or substantially dry, in cartridge 100 until its intended use, i.e., until a user connects the cartridge to the hand-held control unit and operates its conveyer motor. According to some embodiments, the at least one porous medium is dried upon application of pressurized air from the control unit, therethrough.

According to some embodiments, snap-fit 114 is located at the edge of nebulizer cartridge 100, such that it faces flat surface 132. According to some embodiments, snap- fit 114 is configured to connect to matching snap-fit, located at the edge of a complementary nebulizer control unit.

Reference is now made to Fig. 12, which schematically illustrates a nebulizer cartridge 200, according to some embodiments. According to some embodiments, nebulizer cartridge 200 is similar to nebulizer cartridge 100. According to some embodiments, nebulizer cartridge 200 includes elements similar to those of nebulizer cartridge 100: at least one porous medium 202 having a plurality of pores; at least one reservoir 204 containing an aqueous pharmaceutical composition; at least one stationary liquid absorbing element 206; at least one mobile liquid absorbing element 208; a conveyer 210 comprising retaining unit 218, and track 220 having starting point and end point; pressurized air inlet 212; and a snap-fit (not indicated in Fig. 12). According to some embodiments, nebulizer cartridge 200 further includes a mouthpiece 228 configured to enable a user to inhale aerosol 230 formed by a nebulizer having nebulizer cartridge 200.

According to some embodiments, when the pressurized air flows from pressurized air inlet 212 and hits wet porous medium 202, aerosol 230 forms and proceeds through mouthpiece 228 into the respiratory tract of a nebulizer user.

Reference is now made to Fig. 13, which schematically illustrates a nebulizer cartridge 300 comprising a first porous medium 302, a first reservoir 304, a first stationary liquid absorbing element 306, a first mobile liquid absorbing element 308, a conveyer 310, a second porous medium 352 having plurality of pores 326, a second reservoir 354 having plurality of pores 376, a second stationary liquid absorbing element 356, a second mobile liquid absorbing element 358 and a snap-fit 314, according to some embodiments.

According to some embodiments, nebulizer cartridge, e.g., any of nebulizer cartridge 100, 200 or 300 comprises a plurality of porous media.

According to some embodiments, the first stationary liquid absorbing element extends from the first reservoir to the first track, and is in contact with the first liquid contained in the first reservoir, such that upon moving along the first track, the first mobile liquid absorbing element is at least temporarily in contact with the first stationary liquid absorbing element and at least temporarily in contact with the first porous medium. According to some embodiments, the second stationary liquid absorbing element extends from the second reservoir to the second track; and is in contact with the second liquid contained in the second reservoir, such that upon sliding the second mobile liquid absorbing element on the second track, the second mobile liquid absorbing element is at least temporarily in contact with the second stationary liquid absorbing element and at least temporarily in contact with the second porous medium.

According to some embodiments, each of the first and the second conveyers separately comprises a rack and pinion mechanism.

It is to be understood that the cartridge may include more than two reservoirs, each containing a different liquid. In such cases, as explained with respect to the two- reservoir system, the cartridge may include a respective number of mobile- and stationary liquid absorbing elements and conveyers. Accordingly, the hand-held control unit may include the same number of conveyer motors. It is further to be understood that the inclusion of more than one reservoir (together with matching number of the remaining elements) allows tailor-made nebulizer-based combination therapy. Today, in conventional nebulizer-based combination therapies a number of medications are delivered to the respiratory tract at once. In such cases, both compounds will be delivered to the same region in the respiratory tract depending on the average size of the droplets. However, it may be beneficial to target different active compounds to different locations in the respiratory tract. Duplication of all nebulizer/cartridge element, as portrayed herein, allows to control the droplet sized of each aerosolized composition separately, thus to target different regions in the respiratory tract based on the desired location of each API (e.g., ceftriaxone). According to some embodiments, each of first stationary liquid absorbing element 306, second stationary liquid absorbing element 356, first mobile liquid absorbing element 308 and second mobile liquid absorbing element 358 is individually, a sponge, e.g. a hydrophilic sponge. According to some embodiments, first stationary liquid absorbing element 306, second stationary liquid absorbing element 356, first mobile liquid absorbing element 308 and second mobile liquid absorbing element 358 are made of the same material.

Fig. 13 illustrates a configuration where first mobile liquid absorbing element 308 is not in contact with first stationary liquid absorbing element 306 (as in Fig. 11, with parallel elements), but rather it is in contact with first porous medium 302 as the former is in position 335 (hereinafter, "Configuration B"). Similarly, Fig. 13 illustrates a configuration where the second side of the system is in Configuration B, as second mobile liquid absorbing element 358 is not in contact with second stationary liquid absorbing element 356, but rather it is also in contact with first porous medium 302 as the former is in position 335. According to some embodiments, a configuration, where first mobile liquid absorbing element 308 is in contact with first stationary liquid absorbing element 306 (and second mobile liquid absorbing element 358 is in contact with second stationary liquid absorbing element 356), i.e. Configuration A, precedes Configuration B. Thus, according to some embodiments, in Configuration A, first mobile liquid absorbing element 308 and second mobile liquid absorbing element 358 are contacting first porous medium 302 and second porous medium 352 respectively, when each one of them is wet (i.e. first mobile liquid absorbing element 308 is absorbed with portion of first ceftriaxone composition 316; and second mobile liquid absorbing element 358 is absorbed with portion of second aqueous pharmaceutical composition 366). According to some embodiments, when first mobile liquid absorbing element 308 and second mobile liquid absorbing element 358 shift from position 334 to position 335, Configuration A shifts to Configuration B. At Configuration B, first mobile liquid absorbing element 308 and second mobile liquid absorbing element 358 transfer portions of ceftriaxone composition 316 and second aqueous pharmaceutical composition 366 to first mobile liquid absorbing element 308 and second mobile liquid absorbing element 358, respectively.

According to some embodiments, each of first reservoir 304 and second reservoir 354 acts as a container for holding liquid. According to some embodiments, first reservoir 304 contains first ceftriaxone composition 316. According to some embodiments, first reservoir 304 is in contact with first stationary liquid absorbing element 306. According to some embodiments, second reservoir 354 contains second aqueous pharmaceutical composition 366. According to some embodiments, second reservoir 354 is in contact with second stationary liquid absorbing element 366. According to some embodiments, each one of ceftriaxone 316 and second aqueous pharmaceutical composition 366, separately comprises a therapeutically effective amount of medication for treating one or more medical conditions, which affect the respiratory system Fig. 13 illustrates Configuration B, where first mobile liquid absorbing element 308 is in contact with first porous medium 302; and second mobile liquid absorbing element 358 is in contact with second porous medium 352, as first mobile liquid absorbing element 308 and second mobile liquid absorbing element 358 are position 335. As a result, when Configuration B is applied, a portion of ceftriaxone composition 316 is spread on first porous medium 302 and a portion of second aqueous pharmaceutical composition 366 is spread on second porous medium 352.

As detailed above, when referring to first surface 106a and second surface 106b of stationary liquid absorbing element 106, Configuration A, where a mobile liquid absorbing element is in prolonged contact with a stationary liquid absorbing element leads to an equilibrium, where the absorbing elements and the reservoir, each separately contains a constant amount of liquid, according to some embodiments. According to some embodiments, a transition to position 335, as shown in Fig. 13, leads to a spreading of a portion of ceftriaxone composition 316 and second aqueous pharmaceutical composition 366 over first porous medium 302 and second porous medium 352, respectively, in Configuration B. According to some embodiments, the spreading draws out portion of ceftriaxone composition 316 and second aqueous pharmaceutical composition 366 from first mobile liquid absorbing element 308 and second mobile liquid absorbing element 358, such that upon their return to their original position (i.e., position parallel to position 135), they may absorb further liquids to reach a new equilibrium. According to some embodiments, conveyer 310 acts in the similar manner to the action of conveyer 110, but while moving two mobile liquid absorbing elements (first mobile liquid absorbing element 308 and second mobile liquid absorbing element 358). According to some embodiments, conveyer 310 comprises first track 320, second track 370, external cogwheel 340, internal cogwheel 342 and serrated teeth 344

According to some embodiments, conveyer 310 is configured to move first mobile liquid absorbing element 308 on the course of first track 320 upon operation from a motor. Conveyer motors and their actions are detailed when referring to Figs 15A-B. According to some embodiments, conveyer 310 is also configured to move second mobile liquid absorbing element 358 on the course of second track 320 upon operation of the same motor or other motor.

All or some of the transitions and manipulations, which take place during the shifting of first mobile liquid absorbing element 308 and second mobile liquid absorbing element 308 over track 320 and track 370 respectively, are similar to those depicted when referring to track 120, starting point 122 (parallel to starting point 322 and starting point 372 in Fig. 13) and end point 124 (parallel to end point 324 and end point 374 in Fig. 13) above.

According to some embodiments, first porous medium 302 and second porous medium 352 are substantially similar to porous medium 102.

According to some embodiments, the at least one mobile liquid absorbing element (e.g. at least one mobile liquid absorbing element 108) is configured to homogeneously or semi-homogeneously spread the liquid across the surface of the at least one porous medium (e.g. at least one porous medium 102) upon moving on the track (e.g. track 12). According to some embodiments, the spreading is homogeneous. According to some embodiments, Snap-fit 314 is located at the edge of nebulizer cartridge 300 and is configured to connect to another (matching) snap-fit mechanism, located at the edge of a complementary nebulizer control unit.

Reference is now made to Fig. 14, which schematically illustrates a nebulizer cartridge 400, according to some embodiments. According to some embodiments, nebulizer cartridge 400 is similar to nebulizer cartridge 300. According to some embodiments, nebulizer cartridge 400 includes elements similar to those of nebulizer cartridge 300: a first porous medium 402, a second porous medium 452, a first reservoir 404, a first stationary liquid absorbing element (not shown), a first mobile liquid absorbing element (not shown), a conveyer, a second reservoir 454, a second stationary liquid absorbing element (not shown), a second mobile liquid absorbing element (not shown) and a snap- fit 414. According to some embodiments, nebulizer cartridge 400 further comprises a mouthpiece 428 for enabling a user to inhale an aerosol(s) formed by a nebulizer having nebulizer cartridge 400. Specifically, when pressurized air flows from a pressurized air source in a nebulizer control unit and hits wet first porous medium 402 and/or second porous medium 452, the aerosol(s) form and proceed through mouthpiece 428 into the respiratory tract of a nebulizer user, according to some embodiments.

Reference is now made to Figs. 15A and 15B, each schematically illustrate a perspective sectional view of nebulizer 500, according to some embodiments. Nebulizer 500 comprises a nebulizer cartridge 580, which may be similar to any one of nebulizer cartridges 100, 200, 300 or 400; and a nebulizer control unit 582.

According to some embodiments, nebulizer cartridge 580, and nebulizer control unit 582 may be provided as separate units. Preferably, nebulizer cartridge 580, and nebulizer control unit 582 are interconnectable. According to some embodiments, nebulizer control unit 582 is a hand-held unit, which is operated by a nebulizer user in need for inhaling an aerosolized pharmaceutical composition. According to some embodiments, nebulizer control unit 582 comprises a conveyer motor 586, a computing unit 588, electric power source 590 and pressurized air source 592.

According to some embodiments, conveyer motor 586 is located in nebulizer control unit 582. According to some embodiments, conveyer motor 586 is powered by electric power source 590. According to some embodiments, conveyer motor 586 is operated by computing unit 588. According to some embodiments, conveyer motor 586 comprises a set of conveyer motor of cogwheels 596.

According to some embodiments, set of conveyer motor of cogwheels 596 includes an external conveyer motor cogwheel 598. According to some embodiments, external conveyer motor cogwheel 598 is rotating together with set of conveyer motor of cogwheels 596 by conveyer motor 586 as a result from instruction(s) from computing unit 588. According to some embodiments, external conveyer motor cogwheel 598 is interlocking with an external cogwheel of the conveyer of nebulizer cartridge 580, such that upon rotation of external conveyer motor cogwheel 598, a rack and pinion mechanism operates to affect the movement of a mobile sponge(s) as detailed above with reference to Fig. 13.

According to some embodiments, pressurized air source 592 is located in nebulizer control unit 582. According to some embodiments, pressurized air source 592 is an air pump, configured to produce pressurized gas. Specifically, pressurized air source 592 is configured to produce pressurized air from atmospheric air, according to some embodiments. Pressurized air source 592 comprises air pump motor 594, which is powered by electric power source 590 and operated by computing unit 588, according to some embodiments. According to some embodiments, air pump motor 594 affects the formation of pressurized air in pressurized air source 592.

According to some embodiments, computing unit 588 is located in nebulizer control unit 582. According to some embodiments, computing unit 588 is powered by electric power source 590. According to some embodiments, computing unit 588 is operated by a nebulizer user according to some embodiments, upon receiving an instruction(s) from the nebulizer user, computing unit 588 instructs conveyer motor to affect the rotation of set of conveyer motor of cogwheels 596, which eventually, as described above results in the movement of a wet mobile sponge(s) towards a porous medium or media. As detailed herein, the process is resulting in the wetting of the porous medium/ media. According to some embodiments, upon receiving an instruction(s) from the nebulizer user, computing unit 588 instructs air pump motor 594 to affect to operation of pressurized air source 592 and thereby create pressurized air. The formed pressurized air exists nebulizer control unit 582 and enters nebulizer cartridge 580, through an air inlet located in nebulizer cartridge 580 in proximity to its connection surface with nebulizer control unit 582, according to some embodiments. According to some embodiments, after entering nebulizer control unit 582 pressure difference therein results in the pressurized air proceeding towards and hitting the porous medium/ media thereby forming an aerosol, upon instruction of the nebulizer user.

According to some embodiments, electric power source 590 is located in nebulizer control unit 582 and may include rechargeable batteries, where it is configured to power air pump motor 594 and computing unit 588.

According to some embodiments, nebulizer cartridge 580 has a similar configuration to that of any one nebulizer cartridge 100, nebulizer cartridge 200, nebulizer cartridge 300, or nebulizer cartridge 400. According to some embodiments, nebulizer cartridge 580 includes elements similar to those of the above nebulizer cartridges: one or more porous media, one or more reservoirs, one or more stationary sponges, one or more mobile sponges, one or more conveyers and a snap-fit.

According to some embodiments, there is provided a method for producing aerosols, the method comprises: providing the nebulizer disclosed herein; obtaining instructions from a user to operate the conveyer motor(s); operating the conveyer motor(s) thereby spreading the ceftriaxone composition of the present invention onto the surface of the at least one porous medium; and operating the pressurized air source thereby introducing pressure gradient to the at least one porous medium and thereby producing aerosol, wherein the aerosol comprises droplets of the ceftriaxone composition. According to some embodiments, the method comprises connecting the control unit and the nebulizer cartridge, such that upon their connection, the serrated teeth of the external conveyer motor cogwheel are interlocked with the serrated teeth of the external cogwheel of the at least one rack-like element of the conveyer.

According to some embodiments, obtaining instructions from a user comprises obtaining instructions to the computing unit. According to some embodiments, upon receiving instructions in the computing unit, the computing unit sends a signal to the conveyer motor to turn on and operate. According to some embodiments, upon operation of the conveyer motor, it rotates the at least one conveyer motor cogwheel. According to some embodiments, rotating the at least one conveyer motor cogwheel by the motor entails rotating the serrated teeth of the external conveyer motor cogwheel. According to some embodiments, upon rotating said external conveyer motor cogwheel, its teeth are rotating in a radial direction, and pushing the interlocked teeth of the external cogwheel of the at least one rack-like element, such that the external cogwheel of the at least one rack-like element are rotated in the same direction. According to some embodiments, the serrated teeth of the at least one rack-like element are interlocking with the serrated teeth of the external cogwheel, such that upon rotating said interlocking external cogwheel, its teeth are rotating a radial direction, and pushing the interlocked teeth of the at least one rack-like element, such that the at least one rack like element is moved at a tangential direction in a rack and pinion mechanism. According to some embodiments, rotating said external cogwheel in the opposite direction entails moving the at least one rack-like element in the opposite direction. According to some embodiments, the at least one retaining unit and the at least one rack-like element are physically connected, such that upon rotating the at least one cogwheel, the at least one liquid absorbing element is being moved along the track. According to some embodiments, upon receiving instructions the computing unit sends a signal to the conveyer motor to rotate the at least one conveyer motor cogwheel in the opposite direction, thereby inverting of the process and moving the at least one rack like element in the opposite direction. As a result, obtaining instructions from a user entails affecting the movement or sliding of the at least one mobile liquid absorbing element along the track at any desired direction. According to some embodiments, upon receiving instructions in the computing unit, the computing unit sends a signal to the pressurized air source to turn on and operate. According to some embodiments, the pressurized air source is an air pump having an air pump motor. According to some embodiments, upon receiving instructions, the computing unit sends a signal to the air pump motor to turn on and operate.

According to some embodiments, the air pump comprises blades. According to some embodiments, upon operation of the air pump motor, the air pump motor rotates the blades. According to some embodiments, the rotating of the blades creates pressurized air (i.e. positive air pressure). According to some embodiments, the pressurized air exits the control unit and enters the nebulizer cartridge, through the air inlet. According to some embodiments, the entering of the pressurized air to the nebulizer cartridge results in the pressurized air hitting the at least one porous medium, thereby creating aerosol. According to some embodiments, the aerosol exits the nebulizer cartridge through the mouthpiece. As a result, operating the pressurized air source and conveyer motor through instructions from the user to the computing unit, results in the wetting of the at least one porous medium and hitting it with pressurized air, such that the wetting liquid is aerosolized and the aerosol exits the nebulizer through the mouthpiece.

According to some embodiments, operating the conveyer motor(s) comprises instructing the computing unit to operate the conveyer motor. According to some embodiments, the instructing is performed by a user. According to some embodiments, instructing the computing unit entails determining a desired amount of aerosol to be produced; wherein operating the conveyer motor(s) is repeated for a number of times in response to the desired amount of aerosol. According to some embodiments, the method further comprises delivering the aerosols to the respiratory system of a subject in need thereof.

The nebulizer disclosed herein may function as an inhaler under some circumstances. Thus, the terms ‘nebulizer’ and ‘inhaler’ as used herein may be interchangeable. According to some embodiments, there is provided an aerosol generating device cartridge comprising a liquid container, wherein the liquid container contains pharmaceutical composition as disclosed herein. According to some embodiments, the aerosol generating device cartridge is any one of the cartridges disclose hereinabove (e.g., in any one of Figs. 1-15).

According to some embodiments, the cartridge is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract. Specifically, the present cartridge may be specified or approved by the relevant authorities to be used for the treatment of bacterial infectious diseases or conditions associated with the respiratory tract, such as pneumonia and tuberculosis.

According to some embodiments, there is provided an aerosolization filling composition comprising ceftriaxone as disclosed herein or the pharmaceutical composition as disclosed herein. According to some embodiments, the filling is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract. Specifically, the present filling may be specified or approved by the relevant authorities to be used for the treatment of bacterial infectious diseases or conditions associated with the respiratory tract, such as pneumonia and tuberculosis. According to some embodiments, the aerosolization filling composition is selected from a nebulizer cartridge filling composition and an inhaler cartridge filling composition.

Aerosol compositions

According to some embodiments, there is provided an aerosol composition comprising ceftriaxone, wherein the aerosol comprising droplets having a mass median aerodynamic diameter (MMAD) of at most 10 microns. According to some embodiments, the aerosol droplets have MMAD of at most 5 microns.

As used herein the term "aerosol" refers to a suspension of solid or liquid particles in a gas. As used herein "aerosol" may be used generally to refer to a drug that has been vaporized, nebulized, or otherwise converted from a solid or liquid form to an inhalable form including suspended solid or liquid drug particles. According to some embodiments, the drug particles include ceftriaxone particles.

Another requirement from the generated aerosol is to have droplets having the required size so as to reach the lungs of the aerosol generating device and/or pulmonary composition user. These requirements are detailed below. According to some embodiments, the aerosol has droplets having a mass median aerodynamic diameter (MMAD) of at most 5 microns.

As shown herein the composition of the invention provide an effective dose of ceftriaxone, which is comparable in effectivity to a much higher amount of ceftriaxone delivered via injection. Without wishing to be bound by any theory or mechanism of action, the high effectivity of ceftriaxone that reaches the lungs by inhaling the ceftriaxone composition using an aerosol generating device is, in part, attributed to the small aerosol droplets, having MMAD within the range of about 0.2 to 4 microns.

The correlation between droplet size and deposition thereof in the respiratory tract has been established. Droplets around 10 micron in diameter are suitable for deposition in the oropharynx and the nasal area; droplets below around 4 micron in diameter are suitable for deposition in the central airways and may be especially beneficial for delivery of ceftriaxone the subjects in a need thereof. The droplets formed by aerosolizing the pulmonary pharmaceutical composition of the current invention are small, having droplet size in the range of 0.1 to 5 micron, according to some embodiments. According to some embodiments, the aerosol composition comprises droplets having a mass median aerodynamic diameter (MMAD) of at most 5 microns. According to some embodiments, the aerosol composition comprises droplets having a mass median aerodynamic diameter (MMAD) of at most 4 microns. According to some embodiments, the aerosol composition comprises droplets having a mass median aerodynamic diameter (MMAD) of at most 3 microns. According to some embodiments, the aerosol composition comprises droplets having a mass median aerodynamic diameter (MMAD) of at most 2 microns. According to some embodiments, the aerosol composition comprises droplets having a mass median aerodynamic diameter (MMAD) of at most 1 microns. According to some embodiments, the aerosol composition comprises droplets having a mass median aerodynamic diameter (MMAD) of at most 0.8 microns. According to some embodiments, the aerosol composition comprises droplets having a mass median aerodynamic diameter (MMAD) of at most 0.6 microns. According to some embodiments, the aerosol composition comprises droplets having a mass median aerodynamic diameter (MMAD) of at most 0.5 microns. According to some embodiments, the aerosol droplets have sub-micron MMAD.

It was surprisingly found that aerosolization of a formulation as disclosed herein, results in droplets having a mass median aerodynamic diameter (MMAD) sufficiently small so as to reach the lungs, rather than precipitate on their way thereto. The small droplets reaching the lungs enable efficient respiratory delivery of the ceftriaxone. This is an overall advantage as maximizing the delivery of ceftriaxone to the lungs, while minimizing its deposition in the mouth and throat are considered highly beneficial.

The terms 'droplet size' and 'mass median aerodynamic diameter', also known as MMAD, as used herein are interchangeable. MMAD is commonly considered as the median particle diameter by mass. MMAD may be evaluated by plotting droplet size vs. the cumulative mass fraction (%) in the aerosol. MMAD may then be determined according to the interpolated droplet size corresponding to the point, where the cumulative mass fraction is 50%. This points represent the estimated values of particle sizes, above which the droplets are responsible to half to masses and below which the droplets are responsible to the other halves, in each solution. According to some embodiments, the aerosol comprises droplets having a Geometric Standard Diameter (GSD) within the range of about 0.2-7 micron. According to some embodiments, the aerosol comprises droplets having a GSD within the range of about 0.2-5 micron. According to some embodiments, the aerosol droplets have GSD of at most 3 microns. According to some embodiments, the aerosol droplets have GSD of at most 2 microns. According to some embodiments, the aerosol droplets have GSD of at most 1 micron. According to some embodiments, the aerosol droplets have sub-micron GSD.

According to some embodiments, the aerosol is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation. According to some embodiments, the aerosol is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation using an aerosol generating device. According to some embodiments, the aerosol is suitable for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation. According to some embodiments, the aerosol is suitable for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation using an aerosol generating device the aerosol is for use in the treatment of pneumonia via inhalation. According to some embodiments, the aerosol is for use in the treatment of a pneumonia via inhalation using an aerosol generating device. According to some embodiments, the aerosol is suitable for use in the treatment of pneumonia via inhalation. According to some embodiments, the aerosol is suitable for use in the treatment of pneumonia via inhalation using an aerosol generating device the aerosol is for use in the treatment of TB via inhalation. According to some embodiments, the aerosol is for use in the treatment of TB via inhalation using an aerosol generating device. According to some embodiments, the aerosol is suitable for use in the treatment of a TB via inhalation. According to some embodiments, the aerosol is suitable for use in the treatment of TB via inhalation using an aerosol generating device.

According to some embodiments, the aerosol generating device is a nebulizer. According to some embodiments, the aerosol generating device is a nebulizer as disclosed herein. According to some embodiments, the aerosol comprises ceftriaxone at a concentration as detailed above in any one of the embodiments, which relate to the pulmonary composition of the present invention. According to some embodiments, the aerosol comprises ceftriaxone at a concentration in the range of 20 to 200 mg/ml, 5 to 100 mg/ml, 100 to 200 mg/ml, 10 to 300 mg/ml, 20 to 150 mg/ml or 75 to 250 mg/ml. Each possibility represents a separate embodiment of the invention.

According to some embodiments, the aerosol is for use in the treatment of a bacterial infectious disease or condition associated with the respiratory tract via inhalation at a daily dose in any one of the amounts specified in the corresponding embodiments, which relate to the pulmonary composition of the present invention. According to some embodiments, the pulmonary composition is for use via inhalation at a daily dose in the range of 1 to 250 mg, 2 to 150 mg, 4 to 120 mg, 2 to 75 mg, 75 to 150 mg, 2 to 20 mg, 100 to 150 mg or 2 to 10 mg ceftriaxone per day. Each possibility represents a separate embodiment of the invention.

According to some embodiments, the pulmonary composition is for use via inhalation at a number of sessions/times a day, as detailed above for the present pulmonary composition. In addition, according to some embodiments, each session comprises administration of an amount of ceftriaxone (i.e., mass of ceftriaxone and/or volume of ceftriaxone composition), as detailed above for the present pulmonary composition. According to some embodiments, each session comprises a continuous inhalation or a predetermined number of discrete inhalations, as detailed for the present ceftriaxone pulmonary composition above. Also, the duration of each session is as respectively disclosed above.

According to some embodiments, each session comprises a predetermined number of discrete inhalations as detailed above, wherein each discrete inhalation involves administration of a predetermined amount of ceftriaxone. Also, it is to be understood by the person having ordinary skill in the art that the amount of ceftriaxone in each inhalation roughly equals to the amount of ceftriaxone in individual aerosol.

Thus, according to some embodiments, the aerosol comprises a predetermined amount of ceftriaxone. According to some embodiments, the predetermined amount of ceftriaxone is in the range of 10-1000 micrograms, 20-850 micrograms, 30-750 micrograms, 40-600 micrograms, 50-500 micrograms, 25-75 micrograms, 400-600 micrograms, about 50 micrograms or about 500 micrograms. Each possibility represents a separate embodiment of the invention.

Furthermore, according to some embodiments, each session comprises a predetermined number of discrete inhalations as detailed above, wherein each discrete inhalation involves administration of a predetermined liquid volume of the present aerosol. According to some embodiments, the predetermined liquid volume of aerosol is in the range of 1-10 microliters, 1-5 microliters, 1.5-4 microliters, or about 2.5 microliters. Each possibility represents a separate embodiment of the invention.

The term “liquid volume” refers to the total volume of the liquids within an aerosol. Specifically, it is understood that aerosols are gas-liquid mixtures, wherein the total visible volume of the aerosol is roughly the volume of gas (e.g., air). The liquid volume, however, refers to the liquid content only.

According to some embodiments, the aerosol further comprising at least one additive selected from the group consisting of a preservative, a propellant, an anti-coughing agent and a flavorant.

It is to be understood that the additive(s) specified above as part of the present pharmaceutical composition similarly apply for the present aerosol.

According to some embodiments, the aerosol is devoid of anesthetics.

According to some embodiments, the aerosol composition further comprises at least one carrier acceptable for inhalation (also preservative etc.).

According to some embodiments, the aerosol composition further comprises at least one additive at a concentration of 0.1-1% w/w. According to some embodiments, the additive is approved for use in inhaling solutions.

According to some embodiments, the aerosol is prepared by aerosolizing the pharmaceutical composition of the present invention using a nebulizer or an inhaler. According to some embodiments, the nebulizer is any one of the nebulizers disclosed herein above or a nebulizer comprising a nebulizer cartridge as any one of the cartridges disclosed above.

According to some embodiments, the inhalable aerosol is inhaled by the user of the nebulizer. According to some embodiments, the inhalable aerosol is inhaled by the subject. According to some embodiments, the method further comprises the step of inhaling the inhalable aerosol by the subject.

The terms “comprising”, "comprise(s)", "include(s)", "having", "has" and "contain(s)," are used herein interchangeably and have the meaning of “consisting at least in part of’. When interpreting each statement in this specification that includes the term “comprising”, features other than that or those prefaced by the term may also be present. Related terms such as “comprise” and “comprises” are to be interpreted in the same manner. The terms “have”, “has”, having” and “comprising” may also encompass the meaning of “consisting of’ and “consisting essentially of’, and may be substituted by these terms. The term “consisting of’ excludes any component, step or procedure not specifically delineated or listed. The term “consisting essentially of’ means that the composition or component may include additional ingredients, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed compositions or methods.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” or “comprising,” when used in this specification, specify the presence of stated features, integers, steps, operations, elements, or components, but do not preclude or rule out the presence or addition of one or more other features, integers, steps, operations, elements, components, or groups thereof. While a number of exemplary aspects and embodiments have been discussed above, those of skill in the art will recognize certain modifications, additions and sub combinations thereof. It is therefore intended that the following appended claims and claims hereafter introduced be interpreted to include all such modifications, additions and sub-combinations as are within their true spirit and scope.

Having now generally described the invention, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.

EXAMPLES

Example 1: Inhaled Ceftriaxone for treating pneumonia

In order to assess the efficacy of inhaled ceftriaxone for treating pneumonia, a comparative clinical trial is performed.

Patients who had clinical and radiographic documentation of community acquired pneumonia are divided into the following treatment groups:

Group 1 : Administration of ceftriaxone via inhalation, for 5-10 days at a total daily dose of 75-100 mg given in four divided doses (four times a day).

Group 2: Intravenous administration of ceftriaxone for 5-10 days, at a single daily dose of 1-2 gr.

Group 3 : Intravenous administration of ceftriaxone for 2-3 days at a single daily dose of 1-2 gr ceftriaxone, followed by administration of ceftriaxone via inhalation for 3-7 days at a total daily dose of 75-100 mg given in four divided doses (four times a day). For intravenous administration (Groups 2 and 3), the ceftriaxone is given in a form of an aqueous solution having a concentration of ~20 mg/ml.

For inhalation (Groups 1 and 3), the ceftriaxone is given in a form of an aqueous solution having a concentration of ~50 mg/ml, and is administered using a nebulizer as described hereinabove.

Clinical evaluation of response is based on resolution or improvement of clinical and laboratory signs of infection including:

• Defervescence

• Normalization of leukocytosis

• Disappearance of or diminution in the level of purulent sputum production

• Stabilization of general physical condition • Radiographic resolution of lung infiltrates.

Patients are assessed at the baseline (day 0), in several time points during treatment period, 10 to 14 days post-therapy, and 4 to 6 weeks post-therapy. A chest X ray is obtained at the baseline and at the main clinical evaluation time points. The location and extent of lung involvement (e.g., segmental or lobar) and the presence of pleural effusion are recorded.

For microbiological assessments, cultures of respiratory tract secretions are done at the baseline, in several time points during treatment period, and 10 to 14 days and 4 to 6 weeks post-therapy, as well as when clinically indicated.

The primary efficacy measure is the clinical outcome, which is determined 10 to 14 days post-therapy. The clinical responses at this time are classified as follows:

Cure: complete resolution of all signs and symptoms of pneumonia and improvement or resolution of chest X-ray findings.

Improvement: Improvement or resolution of all radiographic findings with incomplete resolution of all signs and symptoms of pneumonia.

Failure: Persistence or progression of signs and symptoms after 3 days of therapy, development of new findings consistent with active infection, persistence or progression of radiographic findings, death due to pneumonia, or inability to complete the study because of pneumonia-related adverse events.

At 4 to 6 weeks post-therapy, response is classified as cure or failure.

The results of the trial show that administration of ceftriaxone via inhalation, either alone or in combination with short IV treatment, is non-inferior to prolonged IV treatment. Advantageously, the inhaled ceftriaxone is given at significantly lower doses than the injected ceftriaxone, thus may be beneficial for reducing undesirable effects associated with this antibiotic.

Example 2: Assessment of deep lung deposition of orally inhaled Ceftriaxone

Aim

To assess in-vivo aerosol deposition of orally inhaled ceftriaxone.

Method

A clinical study using aerosol generating device disclosed herein.

Participants: 6 healthy volunteers. Design

Single center, non-randomized, open-label.

The study is carried out in Rambam Medical Center, Israel.

Aerosol deposition quantified by aerosol radiolabeling and SPECT/CT imaging.

Assessment Parameters

Aerosol deposition pattern in lungs and regions of interest

Aerosol deposition in mouth, throat, pharynx, trachea and GI tract

Aerosol Lung Penetration Index (ratio of deposition in peripheral lung versus central lung)

The volunteers were administered 10 inhalations of an aqueous ceftriaxone aerosol during a 10-20-minute dosing session. The aerosol was produced from aerosolization of an aqueous composition containing 20 mg/ml ceftriaxone and labeled technetium- DTPA (diethylenetriamine pentaacetate). At total the volunteers were administered 250 micrograms of ceftriaxone via inhalation.

SPECT/CT (Single-photon emission computed tomography) imaging with dual head gamma camera was performed after completion of the 10-min or 20 min dosing sessions of inhaled labeled composition. Both 3D SPECT/CT images as well as planar 2D radiographs were obtained. The planar radiographs cover most of the upper body and enable quantification of aerosol deposition in the head, throat, conducting airways, lungs and gastrointestinal tract. The planar images can also be used to calculate the penetration index which is defined as the ratio of aerosol deposited in the periphery of the lungs and the aerosol deposited in the central lung area.

The SPECT/CT can provide regional analysis based on slices through different areas of the lungs and can also be used to calculate the penetration index.

Study Results:

Preliminary results show:

Extraordinary aerosol deposition achieved with the aerosol generating device of the present invention:

No deposition in mouth, pharynx and trachea No deposition in GI tract

Uniform deposition in lungs (gas-like deposition pattern) The penetration index is defined as the ratio of aerosol deposited in the lung periphery (P) versus the central lung (C), as known in the art. The measured results are provided in Table 1:

Table 1: P/C ratio achieved with different aerosol generating devices

Figure 16 shows gamma scintigraphy images (left - anterior; right - posterior) obtained at the present experiment.

The planar images show that there is virtually no deposition of aerosol in the mouth, throat, conducting airways and GI tract. The images show that the aerosol penetrates the lungs very well and reaches the peripheral parts of the lungs very effectively.

The penetration index calculated based on the planar images is over 4. Penetration indexes obtained for nebulizer are typically smaller than 0.5 and the highest penetration indexes obtained for soft mist inhalers are below 1.5.

Penetration indexes calculated from various slices of the SPECT/CT images also give results that are significantly higher than those obtained for any other reported aerosol generating device.

Efficient delivery of aerosol to the alveolar region (deep-lung) holds great clinical benefits and opens many opportunities:

For lung conditions, targeted drug delivery directly to the site of action enables high local concentration, increased efficacy and rapid onset, while reducing unwanted systemic exposure and adverse effects.

Without wishing to be bound by any theory of mechanism of action, the efficient delivery of ceftriaxone aerosol to the alveolar region (deep-lung), even at low dosages, is a result of the small aerosol droplet size. The small droplet size was produced from the present ceftriaxone composition using the present aerosol generating device. The present results indicate that small-droplet aerosol is the administration route of choice for a variety of infectious diseases or conditions associated with the respiratory tract, including pneumonia. Whereas the encouraging results were achieved by the present nebulizer, they can be generalized to indicate that any small-droplet ceftriaxone aerosol can be successfully used to treat the relevant diseases or conditions even at very low dosages.

Although the invention is described in conjunction with specific embodiments thereof, it is evident that numerous alternatives, modifications and variations that are apparent to those skilled in the art may exist. It is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of the components and/or methods set forth herein. Other embodiments may be practiced, and an embodiment may be carried out in various ways. Accordingly, the invention embraces all such alternatives, modifications and variations that fall within the scope of the appended claims.