(12) United States Patent
` Lulla et al.
` USOO6962.691B1
` (10) Patent No.: US 6,962,691 B1
` (54) TOPICAL SPRAY COMPOSITIONS
` (75) Inventors: Amar Lulla, Colaba (IN); Geena Malhotra, Mazgaon (IN); Preeti Raut,
` Vile Paele (IN)
` (73) Assignee: U & I Pharmaceuticals Ltd., Long Island City, NY (US)
` (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35
` U.S.C. 154(b) by 0 days.
` (21) Appl. No.: 09/503,843
` (22) Filed: Feb. 15, 2000
` (30) Foreign Application Priority Data
` May 20, 1999 (IN) ............................. 382/BOM/99 Aug. 17, 1999 (IN) ......................... 582/BOM/2000
` Jan. 13, 2000 (IN) ........................... 43/BOM/2000 Jan. 13, 2000 (IN) ........................... 44/BOM/2000
` (51) Int. CI.7. A61L 9/04
` (52) U.S. Cl. .......................... 424/45; 424/81; 424/448;
` 424/434
` (58) Field of Search ............................ 424/45, 81, 448,
` 424/434
` (56) References Cited
` U.S. PATENT DOCUMENTS
` 3,476,853 A 11/1969 Jatul et al.
` 3,932,602 A * 1/1976 Sweger ........................ 424/45
` 4.293,542 A 10/1981 Lang et al.
` 4,316,887 A 2/1982 Kamishita et al. ............ 424/81
` 4,534,958 A 8/1985 Adams et al.
` 4,704,406 A 11/1987 Stanislaus et al.
` 4,826,677 A 5/1989 Mueller et al.
` 5,413,792 A 5/1995 Ninomiya et al.
` 5,474,783 A 12/1995 Miranda et al.
` 5,725,491 A 3/1998 Tipton et al.
` 5,980,921 A 11/1999 Biedermann et al.
` FOREIGN PATENT DOCUMENTS
` CA 1175355 4/1981
` EP O OSS 396 7/1982
` EP OO55397 7/1982
` (45) Date of Patent: Nov. 8, 2005
` EP OOSS397 A1 7/1982
` EP O356.196 A2 2/1990
` EP 390 541 10/1990
` EP O 521 4S5 1/1993
` EP O 617 972 10/1994
` EP O619115 A1 12/1994
` EP O679.390 A2 2/1995
` EP O6793.90 11/1995
` EP T13 708 5/1996
` EP O761.095 A2 12/1997
` GB 1372721 11/1974
` WO WO 88/09 185 12/1988
` WO WO 96/30000 10/1996
` WO WO 96/33689 * 10/1996
` WO WO 97/O1327 1/1997
` WO WOO 756 870 5/1997
` WO WO 98/23291 6/1998
` WO WOOO 10540 3/2000
` OTHER PUBLICATIONS
` Jenny McElroy, “Victorian School of Pharmacy develops
` spray-on drugs,” New Zealand Pharmacy, p. 3, Nov. 1999.
` “Isocard Transdermal Spray”, ABPI Compendium of Data
` Sheets and Summaries of Product Characteristics p. 306.
` * cited by examiner
` Primary Examiner-Christopher S. F. Low
` Assistant Examiner-Amy Lewis
` (74) Attorney, Agent, or Firm-Venable LLP; Julie A. Petruzzelli; Keith G. Haddaway
` (57) ABSTRACT
` A topical, medicinal Spray composition is provided com
` prising a drug or combination of drugs in a carrier which, when sprayed on a Surface, forms a film. The composition
` comprises at least one medicament, at least one film former
` and at least one vehicle. The composition of the invention may further comprise at least one permeation enhancer, at
` least one Solubilizer, at least one plasticizer, and at least one water Soluble additive. A metered dose of the composition
` can be sprayed on a topical Site to form a stable, breathable
` film, preferably over a fixed Surface area. A wide range of medicaments for human and Veterinary use may be present that act locally or transdermally.
` 3 Claims, No Drawings
`
`Padagis US LLC, EX1074
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`US 6,962,691 B1
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` TOPCAL SPRAY COMPOSITIONS
` BACKGROUND OF THE INVENTION
` 1. Field of the Invention
` This invention relates to compositions for topical appli cation of pharmaceutical compounds. Specifically, the
` invention relates to topical medicinal Spray compositions,
` their use and films formed upon use. The compositions may
` be used to treat a variety of disorders. 2. Background of the Invention Many delivery Systems for the topical application of
` pharmaceutical compounds are currently available and
` include lotions, creams, gels, ointments, transdermal patches and SprayS. The choice of delivery System usually depends
` upon the desired pharmacokinetic profile of the drug, for
` example, whether immediate or Sustained release is required. Many of these Systems Suffer from occlusion problems and may cause skin irritation. For example, many compounds, including hormonal drugs, are conventionally
` delivered using a transdermal patch. These patches comprise
` an occlusive backing membrane which often results in local skin irritation. A further disadvantage of transdermal patches is that percutaneous penetration of the drug is often poor.
` The problem of skin irritation associated with transdermal patches is not as pronounced when topical Spray formula
` tions are used. For example, British Patent Specification No.
` 1,372,721 discloses a container of antiseptic for the topical treatment of burns and Scalds, containing a topically accept able antiseptic active agent against Pseudomonas aerugi
` nosa, a preSSuring agent and at least one Surfactant admixed
` with water. The container comprises an outlet, and valve means operable to allow discharge of the contents of the
` container through the outlet in the form of a foam which is effective in the control of Pseudomonas aeruginosa at the
` site of a burn or Scald. U.S. Pat. No. 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'. The composition in U.S. Pat.
` No. 4,534,958 comprises water, propellant, volatile solvent, a polyoxyethylene copolymer whose function is not
` described, and optionally a burn treatment agent and one or more adjuvants. The composition is used “for treating living
` skin'.
` However, conventional topical Spray formulations tend to
` remain at the application Site for only a short time. For example, they are easily rubbed off. As a result, the medi
` cament to be absorbed through the skin is only available transiently. By contrast, medicament in a transdermal patch
` is potentially available for as long as the patch remains in place.
` This invention provides advantages not previously real
` ized. Specifically, the invention provides a composition for the topical application of pharmaceutical compounds with
` out causing occlusion problems or skin irritation. Moreover,
` the inventive compositions remove the need for an adhesive patch. The invention further provides a topically applied
` composition that may remain as a breathable film on the skin
` for an extended period of time.
` SUMMARY OF THE INVENTION
` Through this invention, the advantages offered by trans
` dermal patches and topical sprays have been combined,
` while the disadvantages associated with each have been
` minimized. This invention relates to a topical Spray com
` position which can be sprayed onto the skin to form a
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` breathable film or patch, which remains Stable and in place over a period of days. In this way, a medicament can be
` delivered transdermally over a period of time. Since the film
` is non-occlusive, the problem of local skin irritation asso ciated with transdermal patches is Substantially reduced.
` The invention provides a composition for topical appli
` cation of one or more medicaments, comprising at least one medicament for Systemic or topical availability, at least one
` film former, and one or more vehicles. The composition contains preferably up to about 30% of the at least one
` medicament, more preferably up to about 10% of the at least one medicament and most preferably up to about 5% of the
` at least one medicament. The composition may further comprise one or more additional components Selected from
` the group consisting of permeation enhancers, Solubilizers,
` plasticizers, and water Soluble additives, including humec tants. Medicaments in the composition may be present in a
` form that is Solubilized or Suspended. After application, the medicaments may be locally or transdermally available and
` may be released from the composition. A wide range of
` medicaments for human or Veterinary use may be used in the composition and the medicament may be present in chiral
` form. The compositions are preferably in a form suitable for application by Spraying from an aerosol or pump Spray
` container.
` The invention further provides a stable, breathable film formed by applying the inventive compositions. The film is
` preferably formed over a fixed surface area. The fixed surface area is preferably less than about 50 cm and more preferably from about 10 cm to about 25 cm. Medicaments of the composition may be locally or transdermally available
` for release from the film.
` Moreover, the invention comprises a method of using the inventive compositions pursuant to which a metered dose of the composition is dispensed onto an intended application
` Site. The intended application site is preferably Skin, and the
` metered dose is preferably applied over a fixed Surface area.
` The fixed surface area is preferably less than about 50 cm and more preferably from about 10 cm to about 25 cm°. The metered dose of the composition is preferably dispensed by Spraying the composition from a pump or aeroSol Spray
` dispenser. In one embodiment, the composition forms a
` Stable, breathable film on the intended application site after dispensing.
` The above objectives and advantages of the invention are
` illustrative, and not exhaustive, of those which can be
` achieved by the invention. The examples presented herein are non-limiting.
` DETAILED DESCRIPTION OF THE
` INVENTION
` In describing the invention, the following definitions are applicable throughout.
` “Breathable film” refers to a film formed on the Surface of
` the skin that does not interfere with perspiration, respiration
` and other metabolic activities of the skin.
` “Film-formers' refers to compounds, preferably poly
` mers, that form Stable films on a Surface when applied. Within the meaning of the present invention, a film is stable
` if it is resistant to removal by rubbing for an extended period of time. The extended period of time is preferably at least
` about 24 hours and most preferably from about 1 day to about 5 days.
` “Topical application” refers to being applied to a Surface
` Such as skin.
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`US 6,962,691 B1
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` “Topically active” refers to the composition or medica ment for topical application which treats predominately the
` Surface on which it is applied.
` “Percutaneous penetration” or “transdermally available”
` means that the medicament of the composition is absorbed through skin when applied topically. Typically, although not
` necessarily, the medicament will then be distributed throughout the body resulting in Systemic action as opposed
` to being only locally active.
` “Permeation Enhancer” refers to a component used to enhance the penetration rate of drugs through the skin, preferably by temporarily diminishing the impermeability of
` the skin. Permeation enhancers have also been called
` “accelerants' and "Sorption promoters.” Examples of per
` meation enhancers include lipophilic Solvents, Surfactants, menthol, fatty acid esters and polyhydric alcohols.
` "Plasticizer” refers to a component that aids a composi
` tion in forming a flexible, adherent film on the skin. Examples of plasticizers include citrate esters, dimethyl
` isosorbide, castor oil, propylene glycol and polyethylene glycol.
` “Solubilizer” refers to components that aid in the disso lution or dispersement of the drug in the formulation. Examples of Solubilizers include acrylate and methacrylate
` ester polymers and copolymers, Surfactants, polyhydric
` alcohols, Vitamin E, Vitamin E TPGS and labrasol.
` The present invention includes a topical, medicinal Spray composition comprising a drug or combination of drugs as
` a Solution or Suspension in a vehicle optionally containing a
` polymer or combination of polymers which, when sprayed
` on the Surface of the skin, forms a film on the skin. The compositions of the invention preferably comprise up to
` about 30% of at least one medicament (e.g., 0.0001% to about 30%), more preferably up to about 10% of at least one medicament (e.g., 0.0001% to about 10%) and most pref erably up to about 5% of at least one medicament (e.g., 0.0001% to about 5%) dissolved or suspended in one or more vehicles which comprise up to 90% of the composition
` (e.g., 0.0001% to about 90%). The composition may further
` contain one or more film former, Solubilizer, permeation enhancer and plasticizer. The composition may contain one
` or more of these additives in amounts of up to about 10%
` film-former (e.g., 0.0001% to about 10%), up to about 10% solubilizer (e.g., 0.0001% to about 10%), up to about 8% permeation enhancer (e.g., 0.0001% to about 8%), and up to about 10% plasticizer (e.g., 0.0001% to about 10%). The inventive composition may be sprayed on a topical Site to
` form a stable, breathable film on the site, from which film
` the medicaments act locally on the Surface or are transder mally available. Preferably, the composition further com
` prises up to about 7% (w/w) of one or more water-soluble additives (e.g., 0.0001% to about 7%). The drug or combi nation of drugs. So deposited in the matrix of the film-former
` may remain Solubilized or Suspended. The exact formulation of the composition may vary depending on the nature of the
` particular medicament used (for example, the Solubility profile) and the release profile desired. The compositions can be dispensed from any dispenser, preferably a dispenser
` which provides the composition as a spray, and may be used
` for Systemic action or topical action. The drug from the
` composition may be released over a period of time or immediately.
` The compositions of the present invention are preferably
` applied in a metered dose over a predetermined Surface area. Accordingly, the present invention may also provide for the
` administration of the composition by Spraying the compo
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` Sition from a dispenser. The invention further provides a method for applying the composition and the resultant film. Preferably, the composition is dispensed from a pump
` dispenser or from an aerosol dispenser. In the latter case, the composition additionally comprises from about 10% to 90%
` of propellant in order to provide a Suitable pressure within the aeroSol dispenser. Generally, propellant is not required
` for compositions dispensed from a pump dispenser. How
` ever, if desired, Such compositions may also comprise from
` about 10% to 90% of a propellant which is liquid at room
` temperature, for example, trichloromonofluoromethane
` (P11). The invention also provides a method of preparing a pump dispenser containing the Spray composition of the
` invention comprising mixing the ingredients of the compo
` Sition with or without liquid propellant and placing the mixed ingredients in a pump dispenser.
` In addition, the invention provides a method of preparing an aerosol dispenser containing the Spray composition of the
` invention comprising mixing the ingredients of the compo
` Sition without propellant and charging the mixture together
` with propellant into an aeroSol dispenser. The composition is
` preferably dispensed from the chosen dispenser in a metered
` dose.
` The medicament can be any medicinal compound in the
` Salt or base form or a combination of compounds which is Stable on mixing with the other ingredients of the compo
` Sition and effective on topical administration. The medica ment is preferably a drug which is an anti-emetic, an anti-anginal, an anti-inflammatory, a Steroid, a Steroid hor
` mone, a bronchodilator or a drug used to treat Osteoporosis.
` Additional preferred medicaments include drugs used to treat incontinence, antidepressants/anxiolytics, antimigraine
` agents, agents used in Smoking cessation therapy, antidiar
` rheals, anticholinergics, anticonvulsants, drugs for mood
` disorders/obsessive compulsive disorder, ACE inhibitors, calcium channel blockers, antihypertensives/diuretics, anti obesity drugs, hormonal peptides and analogues, drugs for
` benign prostatic hyperplasia/urinary retention and erectile dysfunctions, antiparkinson agents Such as dopamine ago
` nists and MAO inhibitors, drugs for sleep disorders and antidiabetic agents.
` One preferred anti-emetic is Scopolamine. Preferred anti
` anginals include nitroglycerine, clonidine, isosorbide dini trate, propanolol HCl, timolol maleate, clonazepam and Verapamil. Preferred anti-inflammatory drugs include
` diclofenac Sodium, naproxen Sodium, ibuprofen, ketoprofen,
` indomethacin, piroXicam, ketorolac, tromethamine and nimeSulide. Preferred steroids include hydrocortisone and
` esters thereof, dexamethasone, fluocinolone acetonide and
` betamethasone and salts thereof. Preferred hormonal ste
` roids include estradiol or noethisterone and their pharma ceutically acceptable Salts or a combination thereof, test
` osterone or progesterone. Preferred bronchodilators include
` Salbutamol and Salts thereof, bambuterol, Salmeterol Xin
` afoate, fluticasone propionate, mometasone furoate, budes onide, beclomethasone dipropionate, Sodium cromoglycate
` and isoprenaline Sulphate. Preferred drugs used in case of
` Osteoporosis include alendronic acid, pamidronic acid,
` etidronic acid and their pharmaceutically acceptable Salts.
` Preferred drugs used to treat incontinence include vaso pressin and oxybutynin. Preferred antidepressants/anxiolyt
` ics include imipramine, mirtazapine and desipramine. Pre
` ferred antimigraine agents include naratriptan, Zolmitriptan
` and Sumatriptan. One preferred antidiarrheal is loperamide.
` One preferred antiulcerant is misoprostol. Preferred anticho linergics include hyoscyamine, atropine and trihex
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` yphenidyl. Preferred anticonvulsants include lorazepam, diazepam and tiagabine. Preferred drugs for antimood dis
` orderS/obsessive compulsive disorder include fluoxetine and paroxetine. Preferred ACE inhibitors include lisinopril, tran
` dollapril and captopril. Preferred calcium channel blockers include amlodipine and felodipine. Preferred antihyperten
` Sives/diuretics include praZOsin and amiloride. Preferred antiobesity drugs include methamphetamine and Sibutra
` mine hydrochloride. Preferred hormonal peptides and ana
` logues include GnRH analogues Such as nafarelin, leupro
` lide acetate, insulin and growth hormone and analogues thereof. Preferred drugs for benign prostatic hyperplasia/
` urinary retention include doxazosin, tamsulosin, teraZoSin and finasteride. Preferred drugs for erectile dysfunction
` include alprostadil and Sildenafil citrate. Preferred antipar kinson agents include dopamine agonists Such as bromocrip
` tine and cabergoline and MAO inhibitorS Such as Selegiline
` HCl. One preferred agent for Sleep disorders is melatonin.
` Preferred antidiabetic agents include first and Second gen eration Sulphonyl ureas Such as glimepiride, rosiglitaZone,
` glyburide and glipizide. The chiral forms of all the drugs
` mentioned above, as well as achiral forms, can be used to make the topical Spray composition of the present invention.
` The film-formers preferably include acrylic polymers or copolymers, including methacrylic polymers and copoly
` merS. Preferred film-formers include a non-ionic copolymer of methyl methacrylate and butyl methacrylate (Plastoid B(R), a copolymer of dimethylamine ethyl methacrylate and
` a neutral methacrylic acid ester (Eudragit E1000R), ammonio methacrylate copolymer type B (Eudragit RS(R), USP/NF), ammonio methacrylate copolymer type A (Eudragit RLE), USP/NF), methacrylic acid copolymer type A (Eudragit L1000R, USP/NF), methacrylic acid copolymer type B (Eudragit S100R USP/NF), polyvinyl acetate, cellulose acetate, polyvinyl alcohol, povidone, povidone vinyl
` acetate, hydroxypropyl methyl cellulose, hydroxy ethyl cel
` lulose, methyl cellulose and ethyl cellulose. The breathability of the film is achieved by the absence of any occlusive backing membrane together with the generally hydrophilic properties of the film-forming polymer(s).
` These polymers can partially dissolve on exposure to mois
` ture (from the skin or air), the dissolution resulting in the formation of a porous film. This porosity can be enhanced by
` including additional water-Soluble additives, Such as those
` detailed below.
` Preferred solubilizers include a copolymer of dimethy lamine ethyl methacrylate and a neutral methacrylic acid
` ester (Eudragit E100(R), USP/NF); surfactants, for example, Sodium lauryl Sulphate, polyhydric alcohols, for example,
` propylene glycol or polyethylene glycol, Vitamin E, Vitamin
` E TPGS (tocopheryl polyethylene glycol 1000 succinate)
` and labrasol, or any two or more of the above in combina tion. Preferably, the solubilizer is a copolymer of dimethy lamine ethyl methacrylate and a neutral methacrylic acid
` ester (Eudragit E100(R) in combination with, a non-ionic copolymer of methyl methacrylate and butyl methacrylate
` (Plastoid B(R). The solubilizers serve to dissolve the drug in the chosen vehicle. Many of the solubilizers also enhance percutaneous penetration of drug and/or act as humectants.
` Preferred plasticizers include triethyl citrate, dimethyl
` isosorbide, acetyltributyl citrate, castor oil, propylene gly
` col, and polyethylene glycol, or any two or more of the
` above in combination.
` The permeation enhancer is preferably a lipophilic Sol
` vent, for example, dimethyl Sulfoxide, dimethyl formamide or isopropyl myristate; a Surfactant, for example, Tweens or
` Sodium lauryl Sulfate; menthol, oleic acid, octyl dimethyl
` 1O
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` para-amino benzoic acid (Padimate 0); mixed esters of capric and caprylic acid, or a polyhydric alcohol, for example, propylene glycol or diethylene glycol monoethyl
` ether EP (transcutol); or any two or more of the above in
` combination.
` The vehicle can be water or a non-aqueous Solvent. Preferred nonaqueous vehicles include acetone, isopropyl alcohol, methylene chloride, methyl-ethyl-ketone, absolute
` alcohol, ethyl acetate and trichloromonofluoromethane (P11), methylene dimethyl ether or any two or more of the
` above in combination.
` The aqueous or non-aqueous vehicle may additionally
` comprise (weight/weight of vehicle) up to 20% of one or
` more humectants. Preferred humectants include polyhydric alcohols and polyvinyl pyrrolidone. Preferred polyhydric alcohols are propylene glycol, butylene glycol, polyethylene
` glycol, glycerol and Sorbitol.
` The water-Soluble additive is preferably propylene glycol, Sodium lauryl Sulphate, one or more polaxomers, polyoxyl
` 35 castor oil, polyoxyl 40 hydrogenated castor oil, cetomac rogol, polyethylene glycol or transcutol, or any two or more
` of the above in combination.
` When the composition is dispensed as an aerosol, the
` vehicle partly comprises a propellant in an amount to
` provide from about 10% to about 90% (w/w) of the com position. The propellant can be any pharmaceutically
` acceptable propellant which provides a Suitable pressure
` within an aerosol dispenser, preferably a pressure of from
` about 20 p.S.i.g. to about 130 p.S.i.g. Preferred propellants include hydrocarbons, for example, propane, butane, isobu tane, or dimethylether; hydrofluorocarbons and hydrochlo
` rofluorocarbons, for example, dichlorodifluoromethane
` (P12), trichloromonofluoromethane (P11), dichlorofluoroet hane, monochlorodifluoromethane (P22), dichlorotetrafluo roethane (P114), difluoroethane (P152a), tetrafluoroethane (134a), heptafluoropropane (P227b); or compressed gases,
` for example, nitrogen or carbon dioxide.
` The topical compositions of the present invention are
` quick drying, non-occlusive formulations which cause marked enhancement of the skin permeation of the drug both
` in vitro and in Vivo when compared with existing transder mal patches. They offer the advantages of lower Skin irri
` tation, greater ease of use, increased dosage flexibility and a
` Simpler method of manufacture when compared to existing
` transdermal patches.
` The present compositions are a significant advance over
` conventional medicinal aerosol compositions, Since they permit the application of a medicament by a method whereby no physical contact on the area of application is required, except by the film-forming Spray itself. The topical
` films formed by the present compositions Show excellent stability and peelability and can be easily removed from the Site of application by Washing with water.
` The compositions are generally prepared by mixing the
` ingredients, without liquefied propellant, at a temperature of
` from O C. to 100° C. and at ambient pressure. If propellant
` is to be added, the resulting mixture is then charged with the liquefied propellant into an aeroSol dispenser to achieve the
` final composition. Mixing is preferably carried out at a
` temperature of from 10 C. to 25 C. Alternatively, the mixed composition is placed in a pump dispenser, for
` example, a metered dose pump, which dispenses the com position typically without liquefied propellant Since a pres
` Surized atmosphere is not required. Propellant which is
` liquid at room temperature may, however, be included in a pump dispenser composition as part of the aqueous vehicle.
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` The composition So prepared is sprayed from the dispenser
` onto a topical Site, at which site it forms a Stable, plastic film or patch.
` The aerosol dispenser is preferably a conventional aeroSol
` can having a conventional metered spray aeroSol valve. The pump dispenser is preferably a conventional can or bottle having a conventional metered Spray pump. Preferably, the
` aeroSol dispenser has an all position valve having a shroud that permits spraying when the dispenser is held at any
` angle. In this way, horizontal bottom Surfaces, as well as
` horizontal top Surfaces and Vertical Surfaces, can be sprayed. The valve actuator can be any actuator 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 a 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 dispenser is
` typically held about 1 to 2 inches (2.5 to 5 cm) from the application site and produces a film of even thickness. The dispensers used in the present invention are preferably
` compact units. They can be conveniently used for quick and
` easy application of a medicament over a large Surface area. The composition is preferably applied over a fixed Surface
` area. Typically, the fixed Surface area is not more than 50 cm, and is more preferably from 10 cm to 25 cm’. In general, a composition according to the present inven
` tion Suitable for use in an aerosol dispenser can be prepared
` as follows:
` 1. Dissolve the film former in the chosen vehicle with
` Stirring to form a clear Solution; 2. Dissolve or Suspend the active ingredient and Solubi lizer(s) along with the permeation enhancer, together
` with any water-Soluble additives required, in the Solu
` tion formed in Step 1, 3. Add the plasticizer to the solution and fill a conven
` tional aerosol can with the mixture; and 4. Charge the filled can with liquefied propellant.
` The following examples illustrate the preparation of com positions according to the present invention.
` Examples 1 and 2 below represent partly generalized
` formulas which can be used with any Suitable medicament to prepare compositions according to the present invention
` for use in an aeroSol dispenser.
` EXAMPLE 1.
` Ingredients Percent wifw
` Active ingredient 0.5-10.0
` Plastoid B 2.25
` Eudragit E 100 O.25
` Propylene glycol 3.0
` Sodium lauryl sulfate 3.5
` Acetone 2O
` Propellant C.S.
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` -continued
` Ingredients Percent wifw
` Vitamin E O1
` Transcutol 1.O
` EXAMPLE 2
` Ingredients Percent wifw
` Active ingredient 15
` Povidone 3
` Powidone VA-64 2
` Vitamin E 0.5
` PEG 4OO 1.O
` Propylene glycol 1.5
` Ethanol 15
` Acetone 15
` Propellant C.S.
` More Specific examples of compositions for use in an
` aeroSol dispenser are Set forth in Examples 3 through 5.
` EXAMPLE 3
` Ingredients Percent wifw
` Estradiol 1.
` PVP-K-30 6
` PVPVA 4
` Vitamin E 1.
` PEG 6OOO 2
` Propylene glycol 3
` P12 58.1
` P11 24.9
` EXAMPLE 4
` Ingredients Percent wifw
` Estradiol 2
` PVP K-30 6
` PVPVA 4
` Vitamin E 1.
` PEG 6OOO 2
` Propylene glycol 3
` P12 24.9
` P11 57.1
` EXAMPLE 5
` Ingredients Percent wifw
` Alendronate sodium 1.
` PVP K-30 6
` PVPVA 4
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`US 6,962,691 B1
` 9
` -continued
` Ingredients Percent wifw
` Vitamin E 0.5
` Menthol O.OS
` Dimethyl isosorbide 3.0
` Acetone 1O
` Ethanol 1O
` Tetrafluoroethane (P134) 25.45
` Dichlorodifluoromethane 40
` (P12)
` To prepare a composition according to the present inven
` tion Suitable for use in a pump dispenser, the general method
` Set forth above for an aerosol dispenser can be used, except that it is not necessary to charge the pump dispenser with liquefied propellant to provide a pressurized atmosphere.
` The mixture itself may contain propellant which is liquid at
` room temperature as part of the vehicle.
` Examples 6 through 9 represent partly generalized for
` mulas which can be used with any Suitable medicament to prepare compositions according to the present invention for use in a pump dispenser.
` EXAMPLE 6
` Ingredients Percent wifw
` Active ingredient 0.5-10.0
` Plastoid B 5.6
` Eudragit E 100 O.6
` Propylene glycol 4.0
` Sodium lauryl sulfate 3.0
` Acetone 2O
` Isopropyl alcohol C.S.
` Vitamin E O.2
` Transcutol 2.O
` EXAMPLE 7
` Ingredients Percent wifw
` Active ingredient 25
` Povidone 6
` Powidone VA-64 4
` Vitamin-E 1.O
` Propylene glycol 3
` Ethanol 27
` Acetone C.S.
` Methylene chloride 27
` EXAMPLE 8
` Ingredients Percent wifw
` Active ingredient 15
` PVPK30 6
` PVPVA 4
` Vitamin-E TPGS 0.5
` Dimethyl isosorbide 5
` 1O
` 15
` 25
` 35
` 40
` 45
` 50
` 55
` 60
` 65
` 10
` -continued
` Ingredients
` Ethanol
` Trichloromonofluoromethane
` (P11)
` EXAMPLE 9
` Ingredients
` Active ingredient
` PVPVA
` Vitamin E
` Propylene glycol
` Ethanol
` Trichloromonofluoromethane
` (P11)
` Percent wifw
` 2O
` C.S.
` Percent wifw
` 0.5-10
` 1O
` 0.5
` 3
` 25
` C.S.
` More Specific examples of compositions which can be used
` in a pump dispenser are set forth in Examples 10 through 12.
` EXAMPLE 10
` Ingredients
` Estradiol
` PVP K-30
` PVPVA
` Vitamin E
` PEG 6OOO
` Propylene glycol
` Acetone
` Methylene chloride
` Ethanol
` Dichlorodifluoromethane
` (P12)
` EXAMPLE 11
` Ingredients
` Estradiol
` PVP K-30
` PVPVA
` Vitamin E
` PEG 6OOO
` Polyethylene glycol
` Acetone
` Methylene chloride
` Ethanol
` Percent wifw
` Percent wifw
`6
`
`
`
`
`
`
`
`US 6,962,691 B1
` 11
` EXAMPLE 12
` Ingredients Percent wifw
` Estradiol 1.
` PVP K-30 6
` PVPVA 4
` Vitamin E 1.
` Menthol O.OS
` Dimethyl isosorbide 5
` Acetone 27.48
` Ethanol 27.48
` P11 27.48
` The following further explanation is given of the above
` examples. Eudragit E 100 is a self-adhesive, hydrophilic
` matrix System. It also acts as a Solubilizer for the drug
` Estradiol. Plastoid B is a film-former. When used together, Eudragit E 100 and Plastoid B give better peelability and
` water washability than when either is used alone. Acetone is a volatile, quick-drying, non-occlusive vehicle which helps to dispense the contents of the Spray over a large Surface
` area. Propylene glycol acts as a humectant to prevent the excessive drying of the application site after application of
` the medicament. It also acts as a plasticizer for the film formed after application. Propylene glycol additionally acts
` as a Solubilizer for the drug and a permeation enhancer.
` Sodium lauryl Sulfate acts as a Solubilizer for the drug. Propellant is necessary for developing proper pressure
` within an aerosol container and for expulsion of the com position when the valve is open. It is also responsible,
` together with the valve, for dispensing the product as a fine Spray. The preferred propellants are very Stable com