Title of Invention	A TOPICAL AEROSOL DOSE COMPOSITION AND METHOD OF MAKING THEREOF
Abstract	A topical medicinal aerosol compositions and preparations thereof as sprays, especially wherein the topical medicament is drug which may be anti-emetic, anti-anginal, anti-inflammatory, steroid or hormonal steroid.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See Section 10) A TOPICAL AEROSOL DOSE COMPOSITION AND METHOD OF MAKING THEREOF M/S. CIPLA LIMITED, MUMBAI CENTRAL, MUMBAI-400 008, MAHARASHTRA, India, an Indian Company incorporated under the Companies Act, 1956. The following specification particularly describes and ascertains the nature of this invention, and the manner in which it is to be performed. GRANTED 26-7-2007 ORIGINAL 26-7-2007 FIELD OF INVENTION This invention relates to topical medicinal aerosol compositions and the preparations thereof, as sprays, especially wherein the topical medicament is a drug which may be anti-emetic, anti-anginal, anti-inflammatory, steroid or hormonal steroid. BACKGROUND AND PRIOR ART Many delivery systems for topical applications are available in the market like lotions, creams, gels, ointments, transdermal patches and sprays. Any one of the above can be used for delivering medication depending upon the kind of release profile which is desired, viz. Immediate release or sustained release. For hormonal drugs, transdermal patches consisting of an occlusive backing membrane have been conventionally used. However, there is a problem of localized skin irritation. Metered-dose topical aerosol (MDTA) formulations can overcome this problem. They are novel, quick-drying, non-occlusive formulations which cause marked enhancement of the skin permeation of the drug both invitro and invivo. A MDTA can offer advantages of lower skin irritation, greater ease of use, increased dosage flexibility, and a simple manufacturing method when compared to existing transdermal patch devices. British Pat. 1,372,721 describes a container of antiseptic for the treatment of burns and scalds by topical application, containing a topically acceptable antiseptic active agent against Pseudomonas aeruginosa, a pressuring agent and atleast one surfactant admixed with water, said container comprising an outlet, and valve means operable to allow discharge of the contents of the container through said outlet in the form of a foam which is effective in the control of Pseudomonas aeruginosa at the site of a burn or scald. US Pat 4,534,958 describes and claims "a sprayable aerosol foam treatment composition which is a liquid in the aerosol container and forms a gel upon application to the skin" comprising water, propellant, volatile solvent, and a polyoxyethylene-polyoxypropylene copolymer whose function is not described and optionally also including a burn treatment agent and one or more adjuvants and method of use thereof "for treating living skin". DEFINITION OF THE INVENTION The present invention is a topical medicinal aerosol composition consisting of weight/weight from about 0.1 % to 5 % of a topical medicament or a mixture of two or more topical medicaments, from about 10% to 50% of an aqueous or non¬aqueous vehicle from about 0.1 % to 5% of film-former, from about 0.1 % to 5% of solubilizers, from about 0.1% to 8% of permeation enhancers, from about 1% to 10% of plasticisers, from about 10% to 90% of liquefied propellant, the said composition being dischargeable from an aerosol dispenser as a spray on the application site. The above-mentioned composition is prepared by mixing the ingredients like the drug, the solubilizers, the plasticisers, the permeation enhancers and the film-formers alongwith the aqueous or non-aqueous vehicle and then charging the same with liquified propellant into an aerosol metered valve dispenser. Alternatively, the above-mentioned composition can be prepared by dispensing the ingredients like the drug, the solubilizers, the plasticisers, the permeation enhancers and the film-formers alongwith the aqueous or non-aqueous vehicle in to an aerosol metered dose pump dispenser. Liquefied propellant may or may not be used where the composition consists of metered dose pumps. The composition so prepared is used as a spray by discharging the same from the aerosol dispenser on the application site. An Aerosol Dispenser is a device fitted with a metering assembly comprising either a metered valve or a metered pump. Metered valves function with the aid of liquefied propellant, while Metered pumps function on the principle of hydraulic pressure. The topical medicament can be any medicinal compound which is stable on admixture with the other ingredients of the pressurized aerosol composition and effective on topical administration or a combination of any two or more such compounds, and is preferably a drug which can be anti-emetic, anti-anginal, anti¬inflammatory, steroids, or hormonal steroids. The preferred anti-emetic is scopolamine. The preferred anti-anginals are nitroglycerine, clonidine, isosorbide dinitrate, propanolol HCI, timolol maleate, clonazepam or verapamil. The preferred anti-inflammatory drugs are diclofenac sodium, ibuprofen, ketoprofen, indomethacin piroxicam, ketorolac or tromethamine. The preferred steroids are hydrocortisone and esters thereof, dexamethasone, fluocinolone acetonide or betamethasone and salts thereof. The preferred hormonal steroids are estradiol, or norethisterone or a combination thereof, testosterone or progesterone. The liquefied propellant, where used in the composition, can be any pharmaceutically acceptable liquefied propellant having a vapor pressure alone or in mixture of from about 20 p.s.i.g. to about 130 p.s.i.g. and is preferably hydrocarbons (propane, butane, isobutane, or dimethylether), hydroflurocarbons and hydrochloroflurocarbons (dichlorodifluromethane (P12), trichloromonofluromethane (P11), dichlorofluroethane, monochlorodifluromethane (P22), dichlorotetrafluroethane (P114), difluroethane (P152 A), Tetrafluoroethane (P134 A), heptafluoropropane (P227B) or compressed gases (nitrogen or carbon dioxide). The aqueous or non-aqueous vehicle is mostly about 80% or more weight/weight but may contain weight/weight from about 1 % to 20% of a humectant or a mixture of two or more humectants selected which are polyhydric alcohol"s or polyvinylpyrrolidone. The polyhydric alcohol"s are preferably propylene glycol, butylene glycol, a polyethylene glycols, glycerol or sorbitol. The non-aqueous vehicle/solvents can be acetone, isopropyl alcohol, methylene chloride, methyl-ethyl-ketone, absolute alcohol or ethyl acetate. These are solvents which remain liquid at ambient conditions (15-30°C). The film-formers can be any acrylic acid polymers or co-polymers, and is preferably Plastoid B, Eudragit E100, Eudragit RS, Eudragit RL, Eudragit 100 or Eudragit S 100, poly vinyl acetate or cellulose acetate. The solubilizers can be Eudragit E100, surfactants (Polysorbates, Polyvinyl alcohol, Polaxamers, Polyoxyl 35 castor oil, Polyoxyl 40 hydrogenated castor oil, Cetomacragol, Glyceryl monostearate, Nonoxinols, Octoxinols, Polyoxyl stearate, sucrose esters, Sodium lauryl sulphate) or polyhydric alcohols (propylene glycols or polyethylene glycols, transcutol). The plasticisers can be triethyl citrate, acetyltributyl citrate, castor oil or polyethylene glycol. The permeation enhancers can be lyophllic solvents (dimethyl sulfoxide, dimethyl formamide) surfactants (Tween 80, sodium lauryl sulfate), two-component systems (oleic acid, octyl dimethyl paraamino benzoic acid (Padimate O)), or polyhydric alcohols (propylene glycol, transcutol). DISCLOSURE OF INVENTION The compositions are generally prepared by mixing the ingredients without the liquefied propellant at a temperature in the range of 0-100°C and ambient pressure and then charging the resulting mixture together with the liquefied propellant into an aerosol metered valve dispenser to achieve the final composition. Mixing is preferably carried out at a temperature in the range of 10-25°C. Alternatively, the compositions can be prepared by dispensing the ingredients in an aerosol metered dose pumps which deliver the aerosol. Liquefied propellants may or may not be used where the composition consists of metered dose pumps. The aerosol dispenser can be a conventional aerosol can or bottle having a conventional metered spray aerosol valve or pump. A desirable feature of the dispenser is an all position valve having a shroud that permits spraying when the dispenser is held at any angle so that horizontal bottom surfaces as well as horizontal top surfaces and vertical surfaces can be sprayed. The valve actuator must be one which produces a spray and not a foam at the nozzle. A preferred valve actuator is a mechanical breakup actuator which employs mechanical forces rather than expansion and evaporation of the propellant to produce a spray. A typical mechanical breakup actuator has a conical or cylindrical swirl chamber with an inlet channel oriented perpendicular to the axis thereof. This structure imparts a swirling motion to the aerosol mixture upon discharge. The . swirling motion occurs around the axis of the swirl chamber forming thin conical film of discharged mixture, which breaks into droplets as it leaves the swirl chamber and travels in the direction of the axis thereof. The result is a fine, soft, dispersed spray which can be easily controlled to produce a stable thin film of even thickness completely contacting the application site. In dispensing a composition of the invention the aerosol dispenser can typically be held about 1 to 2 inches (2 to 4 cm) from the application site and produces a film of even thickness. PROCESS FOR THE MANUFACTURE OF METERED-DOSE TOPICAL AEROSOL DISPENSER AS SPRAY The composition as per the invention can be prepared as follows:- 1. By dissolving the film-former(s) in aqueous or non-aqueous vehicle under stirring to form a clear solution. 2. Then by dissolving the drug and the solubilizer(s) alongwith the permeation enhancer(s), if required, in the solution so formed under stirring. 3. Then by adding plasticiser(s) in the solution so prepared and filling the same in the conventional aerosol cans. 4. Finally, by charging these filled cans with liquefied propellant to give a fine spray with the help of metered valves. The sequence of the steps of the process can be altered as required. Example (composition consisting of metered valve as an aerosol dispenser) Ingredients Percent w/w The drug 0.5%-10% Plastoid B 2.25% Eudragit E100 0.25% Propylene glycol 3% Sodium lauryl sulfate 3.5% Acetone 20% Propellant 70% Alternatively, the composition as per the invention can be prepared as follows : • By dissolving the film-former(s) in aqueous or non-aqueous vehicle under stirring to form a clear solution. • Then by dissolving the drug and the solubilizer(s) alongwith the permeation enhancer(s), if required, in the solution so formed under stirring and adding plasticiser(s) to the same. • Then by combining the solution so formed with liquefied propellant(s), if required, which evaporate rapidly after it is aerosolized. • Finally, by filling the solution so formed in conventional aerosol cans to be dispensed with the help of metered pumps. The sequence of the steps of the process can be altered as required. Example (composition consisting of metered pump as an aerosol dispenser) Ingredients Percent w/w The drug Plastoid B 0.5%-10% 2.25% Eudragit E 100 Propylene glycol Sodium lauryl sulfate Acetone 0.25% 3% 3.5% 20% Solvent/propellant 60-70% The above process can be used for preparing the MDTA with any of the drugs which are anti-emetic, anti-anginal, anti-inflammatory, steroids or hormonal steroids as mentioned above. Eudragit E 100 used in the examples cited above, as a film-former, is a self-adhesive, hydrophilic matrix system. Also it acts as a solubilizer for the drug . Plastoid B used in the examples cited above, is a film-former. Eudragit E 100 and Plastoid B together when used gives a better peelability and water washability. Acetone used in the examples cited above, as a non-aqueous vehicle is volatile, quick-drying and non-occlusive. Also it helps in dispensing the contents of the spray over a greater surface area. Propylene glycol used in the examples cited above, as a plasticiser for the film so formed after application, acts as a humectant which prevents the excessive drying of the application site after application of the medicament. Propylene glycol is also a solubilizer for the drug and a permeation enhancer. Propellant used in the example(s) cited above, is responsible for developing proper pressure within the container and for expulsion of the product when the valve is open. It is also responsible (together) with the valve, for dispensing the product as a fine spray. Only propellants which are very stable compounds and relatively non-toxic, inert and non-flammable like those listed above can be used in the composition. Sodium lauryl sulfate used in the examples cited above, acts as a solubiliser for the drug. Solvents, used in the example cited above, act as a vehicle for the aerosol. Liquefied propellants may or may not be used alongwith the solvents to obtain the desirable aerosol characteristics in MDTA consisting of Aerosol Metered Dose Pump Dispensers. This composition can be discharged from the aerosol dispenser as a fine, soft, dispersed spray which can easily be controlled to produce a stable thin film of even thickness on a target surface. This film has been observed to last for at least 24 hours on human skin. The concentrations of the film-formers in the composition can be varied as required to obtain a patch which can deliver the drug for a period of upto 2 to 5 days. The result with this composition can be considered to be a significant advance in the art of medicinal aerosol compositions, because it permits application of a treatment medicament by a method whereby no physical contact on the area of application is required except by the film-forming spray itself. The film is easily removable from the application site by water in preparation for reapplication of the film or other treatment. Moreover, the use of MDTA increases percutaneous penetration and overcomes the problems of poor drug availability to the application site and skin irritation experienced with the transdermal patches. It therefore offers the advantages of lower skin, irritation, greater ease of use, increased dosage flexibility, and a simple manufacturing method when compared to existing transdermal patch devices. Further, it is a compact unit which can be conveniently used for easy and quick application of the drug over a greater surface area which is usually limited to 50 cm2, preferably from 10 cm2 to 25 cm2. We Claim: 1. A topical aerosol dose composition and method of making thereof, comprising 0.1% to 5% of topical medicaments and an aqueous / non - aqueous vehicle in the range of 10% to 50% by weight, a film former 0.1% to 5%, solubilisers 0.1% to 5% and a permeation enhancers 0.1% to 8%, plasticizers 1% to 10%,liquefied propellant 10% to 90%, 2. A composition as claimed in claim 1, wherein a topical medicament is selected from anti-emetic, anti-anginal, anti-inflammatory, steroid or hormonal steroid, 3. A composition as claimed in claim 2, wherein the anti-emetic is a scopolamine, 4. A composition as claimed in claims 1 and 2, wherein an anti-anginal drug is selected from nitroglycerine, clomidone, sosorbide dintrate, propanl Hcl, timolol maleate, clonazepam or verapamil, 5. A composition as claimed in claims 1 and 2, wherein an anti-inflammatory drug is selected from diclofenac sodium, ibuprofen, ketoprofen, indomethacin, piroxican, ketorolac, tromethamine, 6. A composition as claimed in claim 1 and 2 wherein steroid is hydrocortisome or esters thereof, dexamethasone, thiocinolone acetonide or betamethsone and salts thereof, 7. A composition as claimed in claims 1 and 2, wherein the hormonal steroid is selected from estradiol, noethisterone or combination thereof, testosterone, progesterone, 8. A composition as claimed in claim 1, wherein the liquefied propellant used in the composition, is a vapor or pressure alone or mixture from 20 p.s.i.g to 130 p.s.i.g and preferably hydrocarbons such as propane, butane, isobutene or dimethylether (P 12), trichloromonofluromethane (P 11), dichloroterafluroethane, monochloerodifluromethane (p 22), tetrafluoroethane (P134A), hepatafluoropropane (P227B) or compressed gases (nitrogen or carbon dioxide), 9. A composition as claimed in any proceeding claims, where in the aqueous or non¬aqueous vehicle contains from 1% to 20% or a humectant or a mixture of two or more humectants which are polyhydric alcohols or polyvinylpyrrolidone, the polyhydric alcohols are preferably propylene glycol, bytylene glycol, a polyethylene glycols, glycerols or sorbitol, and the non aqueous vehicles, isopropyl alcohol, methylne chloride, methyl-ethyl-ketone, and absolute alcohol or ethyl alcohol, methylene chloride, methyl-ethyl-ketone, absolute alcohol or ethyl acetate, these are solvents which remain liquid at ambient conditions, 10. A composition as claimed in claim 1, where in the film formers are selected from the group of acrylic acid polymers or copolymers preferably plastoid, Eudragit, Eudragit, Eudrait, Eudragit, Eudragit, polyvinyl acetate or cellulose acetate, 11. A composition as claimed in claim 1, wherein solubilizers are selected from the group of eudragit, surfactants (polysorbates, polyvinyl alcohol, poaxamers, polyoxl, caster of polyoxyl hydrogenated castor oil, cetomacragol, glyceryl monosterate, nonoxinols, octoxinols, polyoxyl sterarate, sucrose esters, sodium lauryl sulphate) or polyhydric alcohols (propylene glycols or polyethylene glycols, transcutol), 12. A composition as claimed in claim 1, wherein plasticizers are selected from triethyl citrate, acetyltributyl citrate, castor oil, polyethylene glycol, 13. A composition as claimed in claim 1, wherein permeation enhancers are selected from the group consisting of lyophillic solvents (dimethyl sulfoxide, dimethyl formamide) surfactants (sodium laurl sulfate), two - component systems (oleic acid, octl dimethyl paraamino benzoic acid (padimate O), or polyhydric alcohols (propylene glycol, transcutol), 14. A method of making a tropical aerosol composition comprising the following steps, mixing an ingredients of the composition, without the liquefied propellant into an aerosol metered valve dispenser, the said dispenser, having a mechanical actuator, 15. A method as claimed in claim 15, wherein mixing of ingredients is carried out at a temperature in the range of 5 degrees C to 100 degree C, preferable 10- 25degreeC, 16. A composition according to any of the proceeding claims consisting an aerosol dispenser fitted with a metering assembly comprising either a metered valve or a metered pump, metered valves function with the aid of liquefied propellant, while metered pumps function on the principle of hydraulic pressure, 17. A method according to any of the preceding claims, further comprising by dissolving the film - former in aqueous or non aqueous vehicle under stirring to form a clear solution, dissolving the drug and the solubilizers along with the permeation enhancers, if required in the solution so formed under stirring, adding plasticizers in the solution so prepared and filling the same in the conventional aerosol cans, charging these filled cans with liquefied propellant to give a fine spra with the help of pf metered valves, 18. A method according to any of the preceding claims, which can alternatively be prepared as follows, By dissolving the film formers in aqueous or non aqueous vehicle under Stirring to form a clear solution, Dissolving the drug and the solubilizer along with permeation enhancers, If required in the solution so formed under stirring and adding Plasticizers to the same, By combining the solution so formed with liquefied propellant, if Required, which evaporate rapid after it is aerosolized, Finally by filling the solutions so formed in conventional aerosol cans To be dispensed with the help of metered pumps, The sequence of the steps of the process can be alteres as required, 19. A method according to claim 17 and 18 wherein eudrgit, used as a film former, is used as a self adhesive, hydrophilic matrix stem, 20. A method according to claims 17 and 18, wherein plastoid used as a film former, 21. A method according to claim 17 or 18 wherein eudrgit and plastitoid used together give a better reliability and water wash ability, 22. A method according to claim 19 and 21 wherein acetone used as non aqueous vehicle is volatile, quick - drying, and non occlusive. 23. A method as claimed in above claims, wherein propylene glycol used a plasticizer for the film so formed after application is used as a humectants which prevents the excessive drying also propylene glycol is a solubolizer for the drug and permeations enhancer, 24. A method as claimed in above claims, wherein propellant used in the composition is responsible for developing proper pressure within the container, 25. A method according to claim 19, wherein solvent acts as vehicle for the aerosol, 26. A topical aerosol dose composition and method of making thereof, such as herein described with reference to foregoing examples. Dated this 3rd day of February 1999 V.Ramu Agent for the Applicant

Documents:

92-bom-1999-abstract(26-07-2007).doc

92-bom-1999-abstract(26-07-2007).pdf

92-bom-1999-cancelled page(26-07-2007).pdf

92-bom-1999-claim( granted)-(26-07-2007).pdf

92-bom-1999-claim(26-07-2007).doc

92-bom-1999-correspondence(26-07-2007).pdf

92-bom-1999-correspondence(ipo)-(05-03-2008).pdf

92-bom-1999-form 1(05-02-1999).pdf

92-bom-1999-form 18(29-12-2005).pdf

92-bom-1999-form 2(granted)(26-07-2007).doc

92-bom-1999-form 2(granted)(26-07-2007).pdf

92-bom-1999-other document(05-02-1999).pdf

92-bom-1999-power of attorney(11-07-2001).pdf