Field of invention

The present invention relates to the preperation of pharmaceutical compositions comprising azelastine hydrochloride and beclomethasone dipropionate in the treatment of seasonal and perenial allergic rhinitis, having a specific weight for suspension agent and surfactant.

Background of the invention

Azelastine is a selective antihistamine, and Azelastine HCI has a chemical name as (±)-l- (2H)-phthalazinone, 4-[(4-chlorophenyl) methyl] -2-(hexahydro- 1-methyl- lH-azepin-4-yl)- monohydrochloride and its chemical structure is shown in the Figure I.

Figure 1

Azelastine HCI is indicated for the relief of the symptoms of allergic rhinitis including seasonal allergic rhinitis and perennial allergic rhinitis for single therapy use.

Beclomethasone is a synthetic glucocorticoid with anti-inflammatory and immunomodulating properties, generally administered as an intranasal spray with dipropionate form.

Beclomethasone dipropionate has a chemical name as [2-[ (8S, 9R, 10S, 1 IS, 13S, 14S, 16S, 17R)-9-chloro- 11 -hydroxy- 10, 13, 16-trimethyl-3-oxo-17-propanoyloxy - 6, 7, 8, 11, 12, 14, 15, 16 - octahydrocyclopenta[a]phenanthren-17-yl]-2-oxoethyl] propanoate and its chemical structure is shown in the Figure 2. Beclomethasone dipropionate has molecular weight of 521 g/mol, white to almost white crystalline powder.

Figure 2 Beclomethasone dipropionate is indicated for the prophylaxis and treatment of perennial and seasonal allergic rhinitis including hayfever, and vasomotor rhinitis. Beclometasone dipropionate has a potent anti-inflammatory effect within the respiratory tract, with a lower incidence and severity of adverse events than those observed when corticosteroids are administered systemically.

Beclomethasone dipropionate is available as an inhaler, cream, tablets, and nasal spray. The inhaled form can be used in the long-term management of asthma. The cream may be used for dermatitis and psoriasis. The tablets have been used to treat ulcerative colitis. The nasal spray dosage form is used to treat allergic rhinitis and nasal polyps.

Allergic rhinitis, also known as “hay fever” is an inflammation in the nose which occurs when the immune system overreacts to allergens in the air. Generally, there are two kinds of allergic rhinitis: seasonal allergic rhinitis and perennial allergic rhinitis.

Seasonal allergic rhinitis: Symptoms of seasonal allergic rhinitis can ocur on specific seasons; mainly in the spring and fall. It is an allergic reaction to pollen from trees which is common in early spring, grasses which is common in late spring and summer and weeds which is common in fall.

Perennial allergic rhinitis: People with perennial allergic rhinitis experience symptoms in all year. It is generally caused by dust mites, cockroaches and dander from pets. Symptoms caused by dander might worsen in winter, when houses are closed up. Spores from indoor and outdoor fungi and molds are considered both seasonal and perennial.

Sensitive person inhales an allergen, shows following symptoms in generally: runny nose, itchy eyes, sneezing, stuffy nose due to blockage or congestion, and fatigue (often reported due to poor quality sleep as a result of nasal obstruction).

Complications that may be associated with Allergic rhinitis include reduced quality of life, decreased concentration and focus problem, problems remembering things, sleep disorders, worsening asthma, more motor vehicle accidents, sinusitis and ear infection.

Many excipients can be used for nasal spray dosage forms. It argued that a certain amount is well tolerated by patients, whereas others state that they might increase the risk of adverse events for patients.

Alternative to oral and intarvascular route, nasal administration is an effective way of systemic delivery. Some of the crirical points to nasal formulation process: high water solubility, sufficient chemical stability, pleasant smell or taste, favourable nasal absorption parameters, minimum nasal irritation, low dose and non toxic metabolites.

Aqueous nasal preparations may comprise excipients; to adjust the viscosity or to adjust stabilise the pH value or to increase the solubility of active ingredient or to stabilise the preparation. Administration device for nasal route should be designed without contamination. Specific properties of product development process for liquid preparations such as nasal spray are phyicochemical properties of active ingredient, vehicle, pH and buffer capacity, osmotic value, viscosity and appearance/smell/taste.

Summary of the invention

The present invention relates to the preparation of pharmaceutical compositions comprising azelastin or pharmaceutically acceptable salts or esters thereof, beclomethasone or pharmaceutically acceptable salts or esters thereof and one or more pharmaceutically acceptable excipients including suspending agent and surfactant in a specific weight in the formulation.

The present invention relates to the preperation of pharmaceutical compositions comprising azelastine HCI and beclomethasone dipropionate in the treatment of seasonal and perenial allergic rhinitis, having a specific weight for suspension agent and surfactant in the formulation.

Detailed description of the invention

The present invention relates to the preparation of pharmaceutical compositions comprising azelastin or pharmaceutically acceptable salts or esters thereof, beclomethasone or pharmaceutically acceptable salts or esters thereof and, and one or more pharmaceutically acceptable carriers or excipients.

The present invention provides compositions, particularly pharmaceutical compositions, comprising azelastine and/or one or more of its pharmacologically acceptable salts or esters thereof, particularly azelastine hydrochloride, and one or more pharmaceutically acceptable carriers or excipients.

The present invention provides compositions, particularly pharmaceutical compositions, comprising beclomethasone and/or one or more of its pharmacologically acceptable salts or esters thereof, particularly beclomethasone dipropionate, and one or more pharmaceutically acceptable carriers or excipients.

In this invention, a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt or ester thereof, beclomethasone or a pharmaceutically acceptable salt or ester thereof, suspending agent, surfactant and at least one further pharmaceutically acceptable excipient, wherein said suspending agent is present at a concentration of from 1.20% to 1.40% (w/v), the surfactant is present at a concentration of not more than 0.01% (w/v) and the composition is administered intranasally. In this invention, a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt or ester thereof, beclomethasone or a pharmaceutically acceptable salt or ester thereof, suspending agent, surfactant and at least one further pharmaceutically acceptable excipient, wherein said suspending agent is microcrystalline cellulose, present at a concentration of from 1.20 % to 1.40 % (w/v), wherein said surfactant is Polysorbate 20, present at a concentration of not more than 0.01% (w/v), and the composition is administered intranasally.

Azelastine is often preferred in the treatment of allergic rhinitis due to its rapid onset of action. Sprays containing azelastine hydrochloride alone can be used in combination with nasal steroids or other treatments in patients with persistent allergic rhinitis symptoms, while they can be used alone to relieve allergic rhinitis symptoms in patients with intermittent symptoms.

Nasal antihistamines such as azelastine are much less involved in the systemic circulation than oral antihistamines. Because of their local action, nasal antihistamines have more reliable side effect profile than oral antihistamines. It begins to relieve the nasal symptoms, which are the most disturbing symptoms for allergic rhinitis patients, in approximately 15-30 minutes. The onset of action of oral antihistamines and nasal steroids is much longer than this period.

Beclomethasone, an intranasal steroid, is still the most powerful drug used in the treatment of both allergic and nonallergic rhinitis. Nasal corticosteroids effectively reduce nasal symptoms such as sneezing, itching, discharge and congestion.

Nasal corticosteroids such as beclomethasone are currently used as the first choice for most patients with allergic rhinitis, especially those with persistent or severe symptoms. The most important reason for the use of nasal corticosteroids in the treatment of allergic rhinitis is that it can create a high drug concentration in the receptor area and the risk of systemic side effects is at the lowest level.

Microcrystalline cellulose, also known as MCC or cellulose gel, is commonly used in the food industry to enhance the properties or attributes of a final food product. It has also been used as a binder and disintegrant in pharmaceutical tablets, as a suspending agent in liquid pharmaceutical formulations, and as binders, disintegrants, and processing aids in industrial applications.

In the pharmaceutical excipient market, there are many co-process products of MCC. One of the mentioned product is MCC RC591, is also called Avicel RC591. MCC RC591 is coprocessed product of Microcrystalline Cellulose (MCC) and Sodium Carboxymethylcellulose (CMC). This product has advantages for liquid, suspension and solution products. Some advantages are improved suspension power, higher thixotropy and gel strength and improved stabilization.

Polyoxyethylene sorbitan fatty acid esters (Polysorbates) are a class of emulsifiers used in pharmaceuticals and food industry. Polysorbates are used in wide variety of pharmaceutical formulations including oral, otic, ophtalmic, topical, parenteral and nasal spray preparations. Polysorbates occur as viscous, oily liquids or waxy solids, and have characteristic odor and bitter taste. Polysorbates should be stored in a well-closed container, protected from light, in a cool, dry place.

Examples of polysorbates: Polysorbate 20 (polyoxyethylene (20) sor bitan monolaurate), Polysorbate 40 (polyoxyethylene (20) sorbitan monopalmitate), Polysorbate 60 (polyoxyethylene (20) sorbitan monostearate), Polysorbate 80 (polyoxyethylene (20) sorbitan monooleate)

Polysorbate 20 is used as an excipient in pharmaceutical applications to stabilize emulsions and suspensions. Its color and form at 25 °C: yellow oily or brownish yellow liquid.

The present invention provides pharmaceutical compositions comprising azelastine hydrochloride and beclomethasone dipropionate formulated for use as nasal sprays.

Nasal spray formulations are categorized as solutions and suspensions. pH, buffer capacity, osmolarity, antimicrobial level and viscosity properties are critical points for development of nasal spray products.

Generally, excipients that is used in nasal sprays are suspending agent, surfactant, antimicrobial preservatives, osmolarity agent, viscosity agent, chelating agent, tonicity agent, sweetening agent and solvent except active ingredient.

Dosage form of nasal spray is known a cost-effective pharmaceutical form with easy to use and self-administrable.

In one embodiment, MCC is used as suspending agent in this invention.

In one embodiment, MCC RC591 is used as a suspending agent for pharmaceutical nasal spray composition comprising azelastin HCI and beclomethasone dipropionate.

In one embodiment, MCC RC-591 contains sodium carboxymethyl cellulose between the weight ratio of 8.3-15.0%.

In one embodiment, MCC RC-591 contains 11.0% of sodium carboxymethyl cellulose.

MCC RC591 has high wettability characteristic and it is well known in the pharmaceutical art for its usage in the preparation of pharmaceutical suspensions and emulsions to give thickness to obtain the suspension.

MCC RC591 is a dispersible, colloidal MCC comprising medium viscosity. It is used in food and pharmaceutical suspensions to regulate and modify viscosity and for its thixotropic characteristics, manufactured by FMC Corporation. It has long shelf-life stability, is stable at pH range 4-11, and is odorless/tasteless. In one embodiment, the ratio of MCC used to the total weight is between 1.20% -1.40%. The composition comprises MCC at the concentration of 1.20, 1.25, 1.30, 1.35 or 1.40 (w/v). The most preferred amount in this range is 1.30%.

In one embodiment, polysorbate is used as surfactant. Polysorbates with different properties are available in the market. The most wellknown polysorbates are polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80.

In one embodiment, polysorbate 20 is used as surfactant in this invention.

In one embodiment, polysorbate 40 is used as surfactant in this invention.

In one embodiment, polysorbate 60 is used as surfactant in this invention.

In one embodiment, polysorbate 80 is used as surfactant in this invention.

In one embodiment, the ratio of polysorbate used to the total weight is not more than 0.01%.

Nasal preparations may comprise excipients; to adjust the viscosity or to adjust stabilise the pH value or to increase the solubility of active ingredient or to stabilise the preparation.

In this invention, the formulations preferably contain osmolarity agent, suspending agent, antimicrobial preservative, surfactant, pH agent and solvent.

The present invention provides a pharmaceutical composition for use in a method of treating allergic rhinitis in a patient in need thereof, including seasonal allergic rhinitis and/or perenial allergic rhinitis.

In one embodiment, the present invention relates to a pharmaceutical composition comprising azelastine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The present invention provides compositions, particularly pharmaceutical compositions, comprising azelastine and/or one or more of its pharmacologically acceptable salts or esters thereof, particularly azelastine hydrochloride.

In one embodiment, the present invention relates to a pharmaceutical composition comprising beclomethasone or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

The present invention provides compositions, particularly pharmaceutical compositions, comprising beclomethasone and/or one or more of its pharmacologically acceptable salts or esters thereof, particularly beclomethasone dipropionate. Advantages

The nasal spray product containing azelastin HCI and beclomethasone dipropionate active ingredients will be the first commercially available product in the world.

Instead of using two separate products of azelastin and beclomethasone for use in the treatment, it is provided patient compliance who received the required amount pharmaceutically with single azelastin and beclomethasone combination product.

Although nasal corticosteroids such as beclomethasone are effective in all symptoms of allergic rhinitis, their maximum efficacy begins in about 2 weeks. A combination of nasal corticosteroid such as beclomethasone and antihistamine such as azelastine is preferred to relieve the patient in a short time.

For the treatment of allergic rhinitis, a synergistic effect is expected for a more effective treatment in short time using with the combination of azelastine and beclomethasone active ingredients, which were previously used in mono form in the treatment of allergic rhinitis.

The present invention provides pharmaceutical composition comprising azelastin HCI, beclomethasone dipropionate and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation

In this invention, a nasal spray product with optimum characteristics about stability, pH, assay was obtained by using minimum excipient in the formulation.

Nasal spray dosage form is cost-effective, easy to use and self-administrable, so it has high patient compliance.

The term "treatment" or "treating" means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and/or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.

The compositions of the present invention can be administered via intranasal administration to a patient. The compositions are administered directly to the nasal mucosa (i.e., intranasally, e.g., in the form of a nasal spray or drops).

In this invention, the term "allergic rhinitis" will be understood to include “allergic” irritation and/or inflammation, including seasonal rhinitis ( e.g. caused by outdoor agents such as pollen; hay fever) and/or perennial rhinitis ( e.g. caused by house dust mites, indoor mold etc), as well as the symptoms thereof. Pharmaceutical composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, preservatives, viscosity modifiers, emulsifiers, buffering agents, and the mixtures thereof, to facilitate the physical formulation of various dosage forms for intranasal administration like nasal sprays.

Suspending agents, which may be used according to the present invention, include, but are not limited to, xanthan gum, guar gum and microcrystalline cellulose. Preferably, the suspending agent is microcrystalline cellulose.

The osmolarity agent can be selected from the group, but not limited to, sodium chloride, potassium chloride, and sugars, e.g., mannitol, dextrose, sorbitol and a mixture thereof. The preferred osmolarity agent is dextrose.

Suitable surfactants and wetting agents according to the present invention include, but are not limited to, heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, polyoxyethylene stearate, polyoxyethylen sorbitan monolaurate, benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbates, for example polysorbate 20, polysorbate 40, polysorbate 60 or polysorbate 80, sorbitan monopalmitate, sodium salts of fatty alcoholsulfates such as sodium lauryl sulfate, sodium dodecylsulfate, sodium salts of sulfosuccinates such as sodium dioctylsulfosuccinate, partially esters of fatty acids with alcohols such as glycerine monostearate, partially esters of fatty acids with sorbitans such as sorbitan monolaurate, partially esters of fatty acids with polyhydroxyethylene sorbitans such as polyethyleneglycol sorbitan monolaurate, - monostearate or -monooleate, ethers of fatty alcohols with polyhydroxyethylene, esters of fatty acids with polyhydroxyethylene, copolymers of ethylenoxide and propylenoxide (Pluronic®) and ethoxylated triglycerides. The preferred surfactants is polysorbate 20.

Preservatives can be selected from the group, but not limited to, benzalkonium chloride, acetone sodium bisulfite, benzethonium chloride, benzoic acid, benzyl alcohol, boric acid, butylated hydroxyanisole, butylene glycol, calcium acetate, cetylpyridinium chloride, chlorhexidine, glycerin, potassium metabisulfite, potassium nitrate, potassium sorbate, propionic acid, propylene glycol, propylparaben sodium, sodium acetate, sodium benzoate, sodium borate, sodium lactate, sodium metabisulfite, sodium propionate, sodium sulfite, sorbic acid, zinc oxide, and N-acetylcysteine, and a mixture thereof. The preferred preservative is Benzalkonium Chloride and/or Phenylethyl Alcohol and mixtures thereof. pH agents can be selected from the group, but not limited to, sodium citrate, citric acid, sodium phosphate (dibasic, heptahydrate form), and boric acid or equivalent conventional buffers, or combinations thereof. The preferred pH agents is Citric Acid.

Solvents/cosolvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, distilled water and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred solvent is distilled water. Example 1: Azelastin HCI - Beclomethasone dipropionate Nasal Spray

Procedure for composition comprising Azelastin HCI-Beclomethasone dipropionate Nasal Spray;

1. Stage 1 Dissolving and Mixing

Purified water, dextrose, MCC RC591, Azelastin HCI, Phenylethyl Alcohol, Benzalkonium Chloride, Polysorbate 20, Beclomethasone Dipropionate. Mix them after each addition.

2. Stage 2 pH Adjustment and Volume make-up

Adding citric acid and making up the final volume using purified water.

3. Stage 3 Packaging

Nasal spray preparations are packed in spray bottles.

Droplet size of Allergodil, Rinoclenil, Dymista and present invention are shown in table 1.

Table 1: Initial results of droplet size for Azelastin HCI - Beclomethasone dipropionate Nasal Spray and the other products

According to table 2, viscosity results for present invention are close to viscosity result of Dymista product.

Table 2: Analysis results of viscosity for Azelastin HCI - Beclomethasone dipropionate Nasal Spray and the other products

According to table 3, the assay results of the present invention were found within the determined limits. Test results are within specified limits.

There is no significient changes were observed for pH values of the present invention under different temperatures; 25°C, 30°C and 40°C. (Table 3) According to table 3, there is no changes were observed for density values of the present invention.

Table 3: Assay, pH and density results of present invention for Azelastin HCI and Beclomethasone dipropionate (after 3 months) According to table 4, there was no increase in impurity values for Azelastine HCI. There is no significant change in impurity values for Beclomethasone dipropionate for all temperature.

Table 4: Impurity results of present invention for Azelastin HCI and Beclomethasone dipropionate (3 months)