Field of Invention

This invention is about a packaging technique for dry powder inhaler comprising a blister having a layer of polymeric materials in a thickness range of 10 to 60 pm and an aluminum folio layer in a thickness range of 5 to 40 pm superposed to the layer of the polymeric material and having at least one cavity that is used for storing an inhalable formulation is in the volume range of 32 to 60 mm ³ and the cavity is filled up to 25-100% wherein the inhalable composition is comprising one or more active agent, which is selected from the group consisting of short-acting p2 agonists (SABAs), long-acting p2 agonists (LABAs), ultralong acting p2 agonists, long-acting muscarinic antagonists (LAMAs), non-selective dopamine agonist and corticosteroids or a pharmaceutically acceptable salt thereof, in characterizing that a pouch is surrounding an inhaler device equipped with the blister in a vacuum-sealed manner.

Background of Invention

Asthma and chronic obstructive pulmonary disease (COPD) affect more than 30 million people in the United States. More than 100,000 deaths each year are attributable to these conditions. Obstruction to airflow through the lungs is the characteristic feature in each of these airway diseases, and the medications utilized in treatment are often similar. Chronic obstructive pulmonary disease (COPD) is a widespread chronic lung disorder encompassing chronic bronchitis and emphysema. The causes of COPD are not fully understood. Experience shows that the most important cause of chronic bronchitis and emphysema is cigarette smoking. Air pollution and occupational exposures may also play a role, especially when combined with cigarette smoking.

Obstructive lung disease is a significant public health problem. Asthma, chronic obstructive pulmonary disease (COPD) and other obstructive airway diseases are highly prevalent chronic diseases in the general population. These obstructive airway illnesses are manifested with chronic inflammation affecting the whole respiratory tract. Obstruction is usually intermittent and reversible in asthma but is progressive and irreversible in COPD. Drugs combines pharmacologic activity with pharmaceutical properties. Desirable performance characteristics expected form them are physical and chemical stability, ease of processing, accurate and reproducible delivery to the target organ, and availability at the site of action. For the dry powder inhalers (DPIs), these goals can be met with a suitable powder formulation, an efficient metering system, and a carefully selected device. Dry powder inhalers are well known devices for administering pharmaceutically active agents to the respiratory tract to treat respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

Pharmaceutical compositions for inhalation used in the treatment of obstructive airway diseases can comprise various active agents such as long acting muscarinic antagonists (LAMA), long acting beta agonists (LABA), short acting beta-2 agonists (SABA) and corticosteroids.

Inhaled corticosteroids are medications used to treat chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases. Inhaled corticosteroids reduce inflammation in the airways that carry air to the lungs (bronchial tubes) and reduce the mucus made by the bronchial tubes which makes easier to breathe. They are taken by using an inhaler. This medication should be taken consistently so that it decreases inflammation in the airways of your lungs and prevents chronic obstructive pulmonary disease (COPD), asthma and other obstructive airway diseases flare-ups. Inhaled corticosteroids are considered the most effective long-term usage medication for control and management of asthma.

The clinical benefits of inhaled corticosteroids in other obstructive airway diseases include a decrease in airway hyperresponsiveness, an improvement in lung function and a reduction in severity of symptoms, frequency of exacerbations, the need for rescue medication, and an increase in symptom-free days.

Fluticasone is the most commonly used corticosteroid in the dry powder formulations for inhalation. Fluticasone furoate, which is a salt of fluticasone, is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. Fluticasone furoate is available as a combination product with vilanterol, under the tradename Breo Ellipta®. Its use is indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. Long-acting p adrenoceptor agonists (LABAs, more specifically, long-acting 2 adrenergic receptor agonists) are usually prescribed for moderate-to-severe persistent asthma patients or patients with chronic obstructive pulmonary disease (COPD).

On the other hand, long-acting p2-adrenergic agonists are bronchodilators taken routinely in order to control and prevent bronchoconstriction. They are not intended for fast relief. These medications may take longer to begin working but relieve airway constriction for up to 12 hours. They are used in combination with a corticosteroid to treat asthma in a metered-dose or dry powder inhaler. They relax the smooth muscles lining the airways that carry air to the lungs (bronchial tubes). This allows the tubes to stay open longer and makes breathing easier.

Salmeterol is a selective long-acting beta2-adrenergic agonist (LABA) used in the maintenance and prevention of asthma symptoms and maintenance of chronic obstructive pulmonary disease (COPD) symptoms. Symptoms of bronchospasm include shortness of breath, wheezing, coughing and chest tightness. It is also used to prevent breathing difficulties during exercise.

The combination of a long-acting p2-agonist (LABA) and an inhaled corticosteroid is more efficacious in asthma and chronic obstructive pulmonary disease (COPD) than other combination therapies or than either alone.

Inhalers are well known devices for administering pharmaceutically active materials to the respiratory tract by inhalation. Such active materials commonly delivered by inhalation include bronchodilators such as p ₂ agonists and anticholinergics, corticosteroids, antiallergies and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.

Administration of asthma drugs by an oral inhalation route is very much in focus today, because of advantages offered like rapid and predictable onset of action, cost effectiveness and high level of comfort for the user. Dry powder inhalers (DPI) are especially interesting as an administration tool, compared to other inhalers, because of the flexibility they offer in terms of nominal dose range, i.e. the amount of active agent that can be administered in a single inhalation.

Dry powder inhalers (DPI) are becoming more and more popular because of their ease of use and medical efficacy. DPI's can be divided into two major categories: bulk and pre- metered devices. Pre-metered devices are gaining more and more market share due to the ability to control the product and process of metering a correct dose to the user. DPIs with pre-metered doses are, because of this, more reliable than bulk inhalers that meter the powder dose inside the inhaler. A pre-metered DPI moves the critical step of metering a dose to a pharmaceutical production process.

Patients often rely on medication delivered by dry powder inhalers for rapid treatment of respiratory disorders that are debilitating and sometimes life-threatening. It is, therefore, essential that the prescribed dose of the drug is delivered accurately and consistently to meet the patient's needs and comply with the requirements of regulatory authorities.

However, in the active agents and excipients administered via inhalation, one encounters certain stability related problems due to environmental and physical conditions. Mentioned active agents and excipients are influenced substantially by the temperature, air and humidity conditions. Exposure to air and moisture causes structural destruction of said active agents and excipients and leads them to build up a change in chemical behavior. Stability of the developed products is not in desired levels and shelf - life thereof are getting shorter. In addition, these active agents may react with excipients used along with them in the step of developing formulation. This, on the other hand, leads to impurities in the formulations and undesired compositions to get involved in the formulations. It is of critical importance for the formulation, to employ excipients, packaging materials, production and packaging methods not bringing along to mentioned problems. Moisture and air content of the active agents, excipients kept in the blister or capsule, packaging materials or medical devices used may be determinative for the stability. That is, the air and the moisture content within the finished product including the foil blister or capsule, medical device and the packaging materials such as pouch foil is quite important for these kinds of pharmaceutical forms. A build-up of moisture can prevent the administration of an effective dose of medicament by causing an increase in particle size and/or adherence of hygroscopic particles to the walls of the carrier or device, thereby leading to reduced uptake via inhalation by the patient. In extreme cases, depending upon the chemical nature of the medicament, moisture build-up may lead to degradation of the drug. Another problem can be microbial contamination, which is often assisted by the undesirable presence of excess moisture.

It has been observed that high temperature increases the effect of relative humidity and causes agglomeration. Due to the agglomeration of particles with a size of 5 pm, it affects the reduction of fine particle dose (FPD) results. Accordingly it has an unfavorable effect on the stability of the products in terms of the quality aspects including the FPD and impurity profiles.

The formulations of dry powder Inhaler final products are packaged with different techniques. One of these techniques is the preservation technique in primary packaging only. Examples of this are products stored in medical devices including blisters as primary packaging.

Blisters consist of 2 layers, the bottom foil and the top foil. The desired amount of product is filled between the lower and upper foil layer. After filling, the bottom foil and the top foil are pressed with the appropriate temperature, pressure and time to ensure that they stick together. These foils used in primary packaging are composite materials in sheet form.

The first layer is a metal foil/ aluminum foil is often used. The polymeric material is used as the second layer. Commonly used polymeric materials can be listed as Polypropylene (PP), Polyamide (PA), Polyethylene (PE), polyethylene terephthalate (PET), Polyvinyl chloride (PVC), Polyvinylidene chloride (PVDC). Polymer material thickness is 10-60 pm and 20-30 pm thickness with low moisture permeability is preferred. Moisture permeability is 0.6 g/100 inch at 25°C in 24 hours, but 0.3 g/100 inch is preferred.

Materials with adhesive properties such as polyurethane are used between the metal foil and polymeric dishes. Finally, for the heat bonding of these composite materials (bottom foil and top foil), Vinychloride/vinylacetate; A heat seal lacquer material such as polybutylmetacrylate is also used.

In addition to primary packaging, there are secondary packaging applications. Secondary packaging is carried out by placing the primary packaged product (blister) inside the medical device in an additional pouch. The packaging material generally used here is also a composite material consisting of polymer and metal layers. The difference from the primary packaging material is the layer thickness. Composite materials with lower water vapor and oxygen permeability and thicker layers are chosen due to their high strength. Thus, better preservation of product quality and performance throughout the shelf life is ensured. However, the secondary packaging pouch may be insufficient in the quality and performance of dry powder inhaler products.

The maximum amount of moisture (water) in 1 m ³ of 20°C air is 17 g. Relative humidity is the ratio of the amount of moisture in the air to the maximum humidity that the air can hold. When the temperature is 20°C and the relative humidity is 40%, the amount of water in the air is 6.8 g/m ³ . In the light of this information, the product is trapped by air (oxygen + water vapor/moisture) during the secondary packaging process and comes into contact with the product in the secondary packaging throughout its shelf life.

In order to provide the proper conditions, desiccant (silica gel, zeolite, alumina, anhydrous calcium sulfate, etc.) is put into the pouch together with the product. Or, there is information in the literature about creating a layer from materials with moisture-retaining properties in the secondary packaging material pouch. In this way, it is aimed to prevent or reduce the moisture that may come into contact with the product. However, the amount of the desiccant should be determined carefully in order to be sure to prevent the existing moisture, if the required dessiccant is too much, this can cause some technical problems in the packaging machine when putting it into the pouch, a microbiological contamination risk can occur, desiccant amount can vary according to different formulations/ products and also additional costs occur with the use of desiccant .

In the prior art, W02001098174A1 numbered patent application relates to containers and dispensers for medicament powders. In particular, the mentioned invention relates to dry powder inhalation dispensers and components thereof which substantially alleviate or reduce moisture build-up therein. The mentioned invention also relates to a method for reducing moisture ingress inside a dry powder inhaler.

Thanks to the absence of the need for desiccants, there is a need for packaging for dry powder inhalers that is more economical, has a longer shelf life, has reduced economic losses, and offers higher quality products.

In this present invention, vacuum technology for processes in the secondary packaging is used for a dry powder inhaler. For this dry powder inhaler (DPI) which comprises one or more active agent selected from the group consisting of a non-selective dopamine agonist, Long-acting, p2 agonist, corticosteroid, long-acting, muscarinic antagonists, vacuum technology for processes in the secondary packaging is used.

With the present invention, the increase in the amount of impurities of the active agents slowed down the increase during the shelf life. In addition, the decrease in the amount of Fine Particle Dose (FPD) was slowed down, the possibility of microbial growth was eliminated as a result of the intake of air and moisture in the secondary packaging, and additional costs were avoided by eliminating the need for desiccant in the secondary packaging.

Description of the invention

This invention is about a packaging technique for dry powder inhaler comprising a blister having a layer of polymeric materials in a thickness range of 10 to 50 pm and an aluminum folio layer in a thickness range of 5 to 40 pm superposed to the layer of the polymeric material and having at least one cavity that is used for storing an inhalable formulation is in the volume range of 32 to 60 mm ³ and the cavity is filled up to 25-100% wherein the inhalable composition is comprising one or more active agent, which is selected from the group consisting of short-acting p2 agonists (SABAs), long-acting p2 agonists (LABAs), ultralong acting p2 agonists, long-acting muscarinic antagonists (LAMAs), non-selective dopamine agonist and corticosteroids or a pharmaceutically acceptable salt thereof, in characterizing that a pouch is surrounding an inhaler device equipped with the blister in a vacuum-sealed manner.

According to the preferred embodiment, said pouch is in a thickness range of 10 to 120 pm. If the thickness is below 10 pm, the pouch will not be resistant to outside impacts and also it can cause tearings. If the thickness is above 120 pm, this can harden the vacuum process technically and can increase the cost of the process.

According to the present invention, the polymeric materials are preferred because the polymeric materials have low melting temperature, low thermal conductivity and heat resistant, low odor, gas and water vapor permeability and chemical resistant. The polymeric materials are resistant to tearing, to pulling and to impact.

According to the present invention, the polymeric materials are selected from the group consisting of polyethylene, polypropylene, polystyrene, polyolefin, polyamide, polyvinyl chloride, polyurethane, vinyl acetate, polybutylmethacrylate, copolymer of vinyl chloride, polyethylene terephthalate (PET), polyvinyl chloride (PVC), ortho-phthalic aldehyde (OPA) or mixtures thereof.

According to the preferred embodiment, the polymeric material is preferably polyethylene terephthalate (PET) according to its low melting point and the plastic properties.

In one aspect, the present invention provides the dry powder formulation which contain active agents which is selected from the group consisting of short-acting p2 agonists (SABAs), long-acting p2 agonists (LABAs), ultra-long acting p2 agonists, long-acting muscarinic antagonists (LAMAs), non-selective dopamine agonist and corticosteroids or pharmaceutically acceptable salt thereof and is inhaled from the blisters. In another aspect, the present invention provides the dry powder formulation which contains active agent and inhaled by providing controlled dosing of the dry powder formulation in an effective and stable way.

In another aspect, the present invention provides the dry powder formulation which contains active agents and is inhaled in an effective, hygienic, user-friendly way.

According to the preferred embodiment, the said active agents is selected from a group comprising short-acting p2 agonists (SABAs), long-acting p2 agonists (LABAs), ultra-long acting p2 agonists, long-acting muscarinic antagonists (LAMAs), non-selective dopamine agonist and corticosteroids or pharmaceutically acceptable salt thereof in combination.

According to the preferred embodiment, said short-acting p2 agonists (SABAs) is selected from the group comprising bitolterol, fenoterol, isoprenaline, levosalbutamol, orciprenaline, pirbuterol, procaterol, ritodrine, salbutamol, terbutaline, albuterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

According to the preferred embodiment, said long-acting p2 agonists (LABAs) is selected from the group comprising arformoterol, bambuterol, clenbuterol, formoterol, salmeterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

According to the preferred embodiment, said ultra long-acting p2 agonists is selected from the group comprising abediterol, carmoterol, indacaterol, olodaterol, vilanterol or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

According to the preferred embodiment, said long-acting muscarinic antagonists (LAMAs) is selected from the group comprising aclidinium, glycopyrronium, tiotropium, umeclidinium or a pharmaceutically acceptable salt or ester thereof, or an enantiomerically pure form thereof, or a racemic mixture thereof, or a combination of two or more thereof.

According to the preferred embodiment, said non-selective dopamine agonist is apomorfin or a pharmaceutically acceptable salt or ester thereof.

According to the preferred embodiment, said corticosteroid is selected from the group comprising ciclesonide, budesonide, fluticasone, aldosterone, beklometazone, betametazone, chloprednol, cortisone, cortivasole, deoxycortone, desonide, desoxymetasone, dexametasone, difluorocortolone, fluchlorolone, flumetasone, flunisolide, fluquinolone, fluquinonide, flurocortisone, fluorocortolone, flurometolone, flurandrenolone, halcynonide, hydrocortisone, icometasone, meprednisone, methylprednisolone, mometasone, paramethasone, prednisolone, prednisone, tixocortole, triamcynolondane or mixtures thereof.

According to this invention, a packaging technique for dry powder inhaler wherein contains an inhalable composition comprising long-acting p2 agonists (LABAs), corticosteroid and at least one pharmaceutically acceptable excipient.

According to this preferred embodiment, said long-acting p2 agonists (LABAs) is salmeterol salt. According to this preferred embodiment, said salmeterol salt is salmeterol xinafoate.

According to the preferred embodiment, said corticosteroid is fluticasone. According to this preferred embodiment, said fluticasone salt is fluticasone propionate.

In a preferred embodiment, the package for dry powder inhaler wherein contains an inhalable composition comprising salmeterol xinafoate, fluticasone propionate and at least one pharmaceutically acceptable excipient.

According to one embodiment, the amount of salmeterol xinafoate is between 0.02-4%, preferably 0.04-3%, more preferably 0.06-2% by weight of the total composition.

According to this embodiment, the amount of fluticasone propionate is between 0.4-14%, preferably 0.6-12%, more preferably 0.8-10% by weight of the total composition.

According to one embodiment, salmeterol xinafoate and fluticasone propionate have a d90 particle size less than 15 pm, preferably less than 12 pm, more preferably less than 10 pm.

With active agents which have particularly high efficacy, only small amounts of the active agent are needed per single dose to achieve the desired therapeutic effect. In such cases, the active agent has to be diluted with suitable excipients in order to prepare the inhalable powder.

According to this invention, the inhalable formulation comprising salmeterol xinafoate and fluticasone propionate includes at least one pharmaceutically acceptable excipient is selected from the group consisting of monosaccarides, disaccarides, polylactides, oligo-and polysaccarides, polyalcohols, glucose, arabinose, lactose, lactose monohydrate, lactose anhydrous, saccharose, maltose, dextrane, sorbitol, mannitol, xylitol, sodium chloride, calcium carbonate or mixtures thereof.

In a preferred embodiment, at least one pharmaceutically acceptable excipient is lactose monohydrate. The said lactose monohydrate is present in the composition in two parts. One of these parts is lactose monohydrate having fine particle size which means the mean particle size (D50 value) is in the range of 0.01-25 pm, preferably 0.01-20 pm. The other part is lactose monohydrate having coarse particle size which means the mean particle size (D50 value) is in the range of 25-250 pm, preferably 35-100 pm.

According to the preferred embodiment, the total amount of total lactose is between 82- 99.58%, preferably 85-99.36%, more preferably 88-99.14% by weight of the total composition.

The most important feature of the invention is related to a pouch is surrounding an inhaler device equipped with the blister in a vacuum-sealed manner. One of the most important features here is that a pouch which surrounding an inhaler device equipped with the blister in a vacuum-sealed manner is applied to dry powder inhaler devices. Here, a blister has a layer of polymeric materials in a thickness range of 10 to 50 pm and an aluminum folio layer in a thickness range of 5 to 40 pm superposed to the layer of the polymeric material and has at least one cavity for storing an inhalable formulation is in the volume range of 32 to 60 mm ³ and the cavity is filled up to 25-100%.

The vacuuming process mentioned in the invention is carried out with a vacuum device. Parameters of vacuum device for processes in the secondary packaging are approximately;

• Max. Vacuum pressure: 0.5-2 mBar

• Vacuum Pump: 10-155 m ³ /h

• Electrical Power: 4000 w

• Sealing Type: Double

• Electric Supply: 230-400V 150-60 H

Vacuum packaging efficiency depends on the tight combination of the pouch with low gas and moisture permeability and the entire product surface. The method of vacuum packaging is an easily controllable process. Any error that may occur during production can be easily detected due to the air mass that will occur in the pouch. The inventors surprisingly found that the amount of decrease in the amount of Fine Particle Dose (FPD) decreased as a result of removing the existing moisture (water vapor) from the environment when the air in the secondary packaging was removed by vacuuming technique. Therefore, it contributed to the preservation of the FPD amount of the product throughout its shelf life.

Another important advantage of the invention is that it prevents decomposition reactions due to oxidation in active agents due to the presence of oxygen next to the moisture removed from the environment. In other words, it is to prevent the increase in the amount of impurities that may occur during the shelf life of the final product.

Another advantage of the invention is that it prevents microbial growth that may occur due to oxygen and humidity.

In the inventors' study with serial number 215510328, as a result of 3-month stability followup of only pouch and vacuum sealed manner samples at 25°C/60% RH, 30°C/65% RH, 30°C/75% RH and 40°C/75% RH. The obtained FPD amount results are given in the table below.

In the 3rd month stability study showed that the minimum decrease in fine particle dose amount of the Salmeterol and Fluticasone P. in the product was at the 25°C-60% RH stability condition, the maximum decrease was at 40°C-75R RH stability condition.

High temperature and humidity increased the agglomeration, cohesive and adhesive forces and turned small particles into large particles. Therefore, the amount of FPD decreased. This decrease in the amount of FPD slowed down with the vacuum packaging technique.

Accordingly, better FPD results were obtained compared to only pouch packaging.

The moisture content affect the formulation, by hydrolysis. The common moisture interactions which occur are water-solid interactions, water-amorphous solid interactions, drug-excipient interactions and the change in the crystal habit of the solids.

The science behind the hydrolysis is due to the moisture sensitive functional group of the ingredient, and the other freely moveable living groups.

As can be seen from the results obtained from the study, especially the total impurity and impurity H amount increased in the product under the 6-month accelerated stability condition. The total impurity increased from 0.37% to 4.24%, and the impurity H increased from 0.01% to 1.39% in the product packaged only in pouch.

The impurity amount of the product in the vacuum sealed pouch was found to be relatively low. At the end of the 6-month accelerated stability study, the total impurity amount was 2.33%, the impurity H amount was 0.58%.

According to the results, when the trials using only pouch were compared with the vacuum- sealed manner, the increase in the amount of impurities of the active agent of salmeterol slowed down with the vacuum-sealed manner. In other words, it was beneficial to control the humidity in the secondary packaging with the vacuum-sealed manner. With the invention, the packaging process of dry powder inhalers has been developed, which is more economical, has a longer shelf life, has reduced economic losses and offers better quality products, thanks to the elimination of the need for a desiccant. As mentioned in the field of invention part, using desiccants as desiccants have some disadvantages when compared to usage of vacuum. In terms of technical aspects, it is easier and more cheaper to use vacuum instead of using desiccants. It is proved with the above experimental data that using vacuum encourages the increase in FPD values, stability of the product and minimizes the microbial contamination. Example 1 : Salmeterol xinaofoate- Fluticasone propionate inhalable formulation

Example 2: Salmeterol xinaofoate- Fluticasone propionate inhalable formulation

Example 3: Salmeterol xinaofoate- Fluticasone propionate inhalable formulation