FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION: ""NASAL SPRAY"
2. APPLICANT
(a) NAME: CIPLA LTD.
(b)NATIONALITY: Indian Company incorporated under the Indian
Companies ACT, 1956
(c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India
3.PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention in which it is to be performed:

Technical field:
The present invention relates to a pharmaceutical composition useful for preventing or minimizing allergic reactions. More particularly, the invention relates to a stable pharmaceutical composition comprising anhydrous mometasone furoate, which may be administered in the form of a nasal spray. The invention also relates to a process for the preparation of such a composition and to a method of treatment of a subject in need thereof.
Background and prior art:
Many people suffer from seasonal and perennial allergic rhinitis worldwide. Symptoms of seasonal and perennial allergic rhinitis include nasal itch, congestion, runny nose, sneezing and watery eyes. Seasonal allergic rhinitis is commonly known as "hay fever". It is caused by allergens which are present in the air at specific times of the year. Perennial allergic rhinitis is caused by allergens which are present in the environment year-round. Examples of such allergens are dust mites, mold, mildew, and pet dander.
Such forms of rhinitis are treated with medicaments such as, for example, steroidal antiinflammatory agents. Mometasone furoate is an example of a widely used steroidal antiinflammatory agent. Such an agent is generally used by spraying it into the nasal passages of the human patient where it deposits on surfaces of the mucosa which line the nasal cavities. In this position, the medicament exerts its pharmacological action as it is in contact with bodily tissues and interacts with steroid receptors.
For maximum effectiveness, the nature of the pharmaceutical composition containing the medicament should be such that the medicament is delivered readily to all portions of the nasal cavities (the target tissues) where it performs its pharmacological function. In addition, the medicament should remain in contact with the target tissues for relatively long periods of time. The longer the medicament remains in contact with the target tissues, the greater the opportunity for the medicament to perform its function. In order to remain in contact with the target tissues, the medicament must be capable of resisting those forces in the nasal passages that function to remove
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particles from the nose. Such forces, referred to as "mucociliary clearance", are recognized as being extremely effective in removing particles from the nose in a rapid manner, for example, within 10-30 minutes .from the time the particles enter the nose.
It is particularly important that such pharmaceutical compositions have satisfactory stability and shelf-life properties, such that they remain stable and active for as long as possible.
Other desired characteristics of the pharmaceutical composition are that it should not contain ingredients which cause the user discomfort, and that it not include constituents that are considered to be detrimental to the environment, for example, ozone depletors.
US 2005/0186144 describes methods for treating rhinosinusitis of the upper airway passages in patients afflicted with said disease, which comprises administering at least once a day to the surfaces of said passages of said patients an amount of aerosolized particles of mometasone furoate as a monotherapy for treating said disease.
WO 2004/020289 describes methods of introducing a non-aqueous suspension or solution of a medicament, such as mometasone furoate anhydrous into a metered dose inhaler for administration to the lungs. The medicament is introduced as an alcoholic solution, typically together with a surfactant.
US 6,127,353 describes an aqueous composition comprising a stable crystalline form of mometasone, namely mometasone furoate monohydrate. The inventors of US 6,127,353 found that a composition containing anhydrous mometasone furoate in aqueous solution was unstable, and converted to a different crystalline form after storage at 35°C.
Therefore, it is an object of the present invention to provide stable compositions containing anhydrous mometasone furoate. In particular it is an object of the present invention to provide a mometasone furoate composition that does not change its crystalline form. It is also an object of
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the invention to provide an aqueous composition of anhydrous mometasone furoate which can be administered to the nasal mucosa.
Disclosure of the invention:
In accordance with the above objects, the present inventors have developed aqueous mometasone furoate anhydrous compositions, which are stable and maintain the same crystalline form in solution for long periods of time. These compositions can be formed as nasal sprays.
In a first aspect, the present invention provides a stable aqueous pharmaceutical composition comprising anhydrous mometasone furoate in a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier preferably comprises water.
The composition is preferably in the form of a suspension. The suspension is preferably an aqueous suspension. The composition is preferably in the form of a nasal spray.
The pharmaceutical compositions of the present invention are stable. The anhydrous form of anhydrous mometasone furoate in the pharmaceutical compositions according to the invention does not change its crystallinity during storage, and has a long shelf-life.
The pharmaceutical composition of the present invention may comprise from 0.1 to 10.0 mg of anhydrous mometasone furoate per gram of suspension.
The anhydrous mometasone furoate can be manufactured by known methods, such as those described in US 4,472,393.
The pharmaceutically acceptable carrier of the present invention may further comprise, inter alia, suitable excipients and auxiliaries, such as preservatives, suspending agents, viscosifiers, isotonicity agents, buffering agents, humectants, etc.
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The pharmaceutical composition may further comprise one or more preservative. It is preferred that the preservative comprises one or more substance selected from the group consisting of benzalkonium chloride, benzethonium chloride, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, butyl p-hydroxybenzoate, propyl p-hydroxybenzoate, thimerosal, sodium dehydroacetate and myristyl-gamma-picolinium chloride, sodium benzoate, potassium benzoate, potassium sorbate. Preferably the preservative is benzalkonium chloride.
The pharmaceutical composition may further comprise one or more buffering agents. The buffering agent may comprise one or more substance selected from the group consisting of sodium hydrogenphosphate, potassium dihydrogenphosphate, dipotassium phosphate, anhydrous sodium dihydrogenphosphate, crystalline sodium dihydrogenphosphate, boric acid, borax, sodium acetate, citric acid, citric anhydride, sodium citrate, sodium glutamate and creatinine. Preferably the buffering agent is citric acid and sodium citrate. The citric acid may be anhydrous.
The pharmaceutical composition may further comprise one or more humectants. The humectants may be selected from one or more substance selected from the group consisting of glycerol, propylene glycol, sorbitol, carboxyvinyl polymer, polyethylene glycol.
The composition may further comprise one or more suspending agents. The suspending agents may be selected from one or more of sodium carboxymethyl cellulose, xanthan gum, microcrystalline cellulose, carragenan, veegum, tragacanth, bentonite, methylcellulose, and polyethylene glycols. A preferred suspending agent is a mixture of microcrystalline cellulose and carboxymethylcellulose.
The pharmaceutical composition may further comprise one or more wetting agents. Since mometasone furoate is hydrophobic it is preferable to include a pharmaceutically acceptable dispersing agent which functions to wet the particles of medicament to facilitate dispersion thereof in the aqueous phase of the composition. The present invention may comprise suitable dispersing agents selected from the group consisting of one or more of fatty alcohols, esters, and ethers, including, for example, those sold under the trademarks Pluronic, Tergitol, Span, and Tween. It is preferred to use a hydrophilic, non-ionic surfactant, like Polysorbate 80.
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For the purpose of nasal administration a mildly acidic pH is generally preferred. Preferably the compositions of the present invention have a pH in the range of 3 to 6, more preferably in the range of3.5to5.
The compositions of the present invention also possess appropriate isotonicity and viscosity. Preferably compositions according to the present invention have an osmotic pressure of 270 to 350 mOsm/liter. Any suitable isotonic agent and/or thickening agent may be used to achieve appropriate isotonicity and/or viscosity.
In an embodiment, the composition comprises from 0.01 and 0.10 wt% anhydrous mometasone furoate, based on the weight of the composition. Preferably the composition comprises from 0.1 to 10 wt% anhydrous mometasone furoate. In a preferred embodiment, the composition comprises 0.05 wt% anhydrous mometasone furoate.
In an embodiment, the composition comprises 0.001 to 0.05 wt% of a preservative. In a preferred embodiment, the composition comprises 0.01 wt% preservative.
In an embodiment, the composition comprises 0.01 to 1.0 wt% of a buffering agent. In a preferred embodiment, the composition comprises approximately 0.475 wt% buffering agent. The buffering agent may be a mixture of buffering agents. In a particularly preferred embodiment, the buffering agent comprise 0.195 wt% citric acid and 0.277 wt% sodium citrate.
In an embodiment, the composition comprises 0.05 to 5 wt% of a humectant. Preferably the composition comprises 0.1 to 5 wt% humectant. More preferably, the composition comprises approximately 2.0 wt% humectant.
In an embodiment, the composition comprises 0.1 to 4 wt% of a suspending agent. Preferably the composition comprises 1.0 to 5 wt% of a suspending agent. More preferably the composition comprises 1.0 to 3 wt% of a suspending agent. More preferably still, the composition comprises 2 wt% of a suspending agent.
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In an embodiment, the composition comprises 0.001 to 0.2 wt% of a wetting/dispersing agent. Preferably, the composition comprises 0.01 wt% of a wetting/dispersing agent.
The remainder of the composition may comprise water.
The composition according to the invention may be alcohol-free. In particular, the composition may be free from ethanol, ethyl alcohol, phenylethyl alcohol and the like.
For the purpose of nasal application a composition according to the present invention is preferably included in a suitable container. The container is preferably provided with means enabling the application of the contained composition to the nasal mucosa. Suitable applicators are known in the art and include those aiding the administration of liquid nasal compositions in a solution or spray form. Since the dosing should be done as accurately as possible, spray form is a more suitable medium. Spray form administrators suitable for use include atomizers, pump-atomizers, aerosols and the like.
It will be appreciated, therefore, that the present invention further provides a pharmaceutical product comprising (i) a housing containing a composition comprising mometasone furoate anhydrous in a pharmaceutically acceptable liquid carrier; and (ii) means enabling the application of the composition from within the housing to the nasal mucosa.
The stability of the compositions in accordance with the present invention may be defined by standard methods. The anhydrous crystalline form is stable at room temperature. In particular, when subjected to temperatures of 25° for a period of three months and at 40°C for a period of three months, the formulation was stable, in that the crystalline form of the anhydrous mometasone furoate in the composition described herein does not change.
In another method, when rotated for five days at 35°C and an additional four weeks at room temperature (typically approximately 20 to 25°C, more typically 22 to 25°C, and most typically
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25°C) the crystalline form of the anhydrous mometasone furoate in the composition described herein does not change.
The crystalline form may be assessed using X-ray diffraction methods.
The present invention also provides, a process for preparing a pharmaceutical composition substantially as hereinbefore described, which process comprises combining anhydrous mometasone furoate with a pharmaceutically acceptable carrier.
The present invention also provides a method of administering mometasone furoate anhydrous to a subject requiring mometasone treatment, which method comprises administering via the nasal route to said subject a pharmaceutical composition as described herein. In particular, the treatment is of allergic rhinitis, and optionally disorders associated with allergic rhinitis.
The present invention also provides, for use in the manufacture of a medicament for the treatment of a disease state requiring mometasone treatment, especially allergic rhinitis, mometasone furoate anhydrous in a pharmaceutically acceptable liquid carrier.
The present invention will now be described further with reference to the XRD spectra of Figure 1, and the following Example, which do not limit the scope of the invention in any way.
Stability of the mometasone furoate anhydrous API was confirmed by boiling in water (with and without the surfactant Tween 80) for two hours whilst stirring at 70 deg in a water bath, followed by 2 hours at 70 deg on a magnetic stirrer. The solution was cooled to room temperature, filtered and the residue containing the API was dried at 25 °C under vacuum. The dried sample was tested by X-ray diffraction, and the XRD pattern was found to be concordant with that of mometasone furoate anhydrous.
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Example 1

Sr.No. Ingredients Qty.(%w/w)
1. Mometasone Furoate anhydrous 0.050
2. Benzalkonium ChlorideAs Benzalkonium chloride solution 10%w/v 0.01%w/w 0.1%v/w
3. Anhydrous citric acid 0.195
4. Glycerol 2.0
5. Dispersible cellulose 2.0
6. Polysorbate 80 0.01
7. Sodium Citrate 0.277
8. Water for injection qs
1. Dispersible cellulose was dissolved in water to obtain a lump-free suspension.
2. To this was added glycerol under stirring.
3. A separate solution of citric acid was made and added to the main bulk.
4. This was followed by the addition of a separate solution of sodium citrate to the main bulk.
5. Polysorbate was dissolved in water, to this the mometasone furoate anhydrous was added to get a uniform slurry.
6. Benzalkonium chloride (as 10%w/v solution) was added to the above slurry.
7. This drug slurry was added to the main bulk of cellulose dispersion under continuous stirring.
8. The pH was adjusted and the volume was made up.
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Description of drawing:
Figure 1 shows XRD spectra for mometasone furoate monohydrate (BX 2029), mometasone furoate anhydrous API (BX 3039), and mometasone furoate anhydrous formulation (160606). The monohydrate peak is clearly visible in the BX 2029 trace, and is absent in the remaining pattern, indicating the presence of anhydrous form in the formulation.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Dated this 19th day of October 2006
Dr. Gopakumar G. Nair
Agent for the Applicant Gopakumar Nair Associates
To
The Controller of Patents
The Patent Office, at Mumbai. 10

Name of the Applicant: M/s. CIPLA Limited Application Number: /MUM/2006

Total No of Sheets 1 Sheet No 1

BX2K9J/ rrri^
MOMETASONt

Figl

Dr. Gopakumar G. Nair
Agent for the Applicant Gopakumar Nair Associates

To
The Controller of Patents
The Patent Office, at Mumbai.

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