WO2009101412A1

WO2009101412A1 - Topical pharmaceutical composition

Info

Publication number: WO2009101412A1
Application number: PCT/GB2009/000397
Authority: WO
Inventors: Amar Lulla; Geena Malhotra; Philip Anthony Curtis
Original assignee: Cipla Limited
Priority date: 2008-02-13
Filing date: 2009-02-13
Publication date: 2009-08-20

Abstract

A transdermal pharmaceutical composition for spraying comprising: a. pharmaceutically active agent, b. at least one penetration enhancing agents, comprising a phospholipid, a lipid or a combination thereof, c. film forming polymer, such as a copolymer of polyvinyl alcohol and polyvinylpyrrolidone d.vehicle e. optionally, a propellant and/or other pharmaceutically acceptable excipients and a volatile silicone as emollient.

Description

Topical Pharmaceutical Composition

Technical field

The present invention relates to a pharmaceutical composition suitable for topical delivery of drugs. More specifically, the invention relates to a pharmaceutical compositions having better penetration enhancing ability for use in the delivery of a physiologically active agent to an animal, including a human. Any drug suitable for transdermal, transcutaneous or topical administration, including local and systemic active agents, can be used in the present formulations.

Background of the Invention

Transdermal drug delivery is the non-invasive delivery of medications from the surface of the skin - the largest and most accessible organ of the human body - through its layers, to the circulatory system. It provides a convenient, pain-free, and non-invasive method of administering active agents to a subject. Additionally, the administration of active agents, such as drugs, through the skin or mucosal surface avoids the well-documented problems associated with the "first pass effect" encountered by oral administration of active agents. As known in the art, orally administered drugs are absorbed and enter the bloodstream where they are transported by the portal vein directly to the liver before entering the general circulation of the body. If the drug is subject to a high hepatic clearance, i.e., it is rapidly metabolized by the liver, then a substantial fraction of the absorbed dose is extracted from the blood and metabolized before it ever reaches the systemic circulation. The consequence of this "first pass effect" phenomenon is a significant reduction in the bioavailability of the drug. In some instances, the first pass effect is so large as to render oral administration of a drug ineffective.

The application of transdermal delivery to a wider range of drugs is limited due to the significant barrier to penetration across the skin which is associated primarily with the outermost stratum corneum layer of the epidermis. Consequently the daily dose of drug that can be delivered from a transdermal formulation is relatively low, effectively limiting this route of administration to potent drugs. Reduction of the skin barrier function is predicted to increase the therapeutic efficacy of dermatological formulation and transdermal devices, by obtaining significant improvements in the kinetics and/or extent of percutaneous absorption. Significant efforts have been made in the art to develop strategies to overcome the impermeability of intact human skin. One of the methods involves the use of microneedles to breach the stratum corneum, resulting in the formation of micropores in the skin. The micropores facilitate the delivery of a therapeutic composition directly to the viable epidermis. Another method that has been used to improve the rate of transdermal delivery is sonophoresis. Using this technique, cavitation is produced when ultrasound induced pressure variation is applied to the skin. Ionotophoresis has also been used to assist in transdermal delivery of a physiologically active agent. This method involves the application of galvanic or direct electrical current, which then gives rise to charged ions of an active agent, which are propelled through the skin. The application of heat to the area of skin application of a transdermal composition using heated bandages or the like has also been reported. The rate of transdermal administration can also be assisted by the use of dermal penetration enhancers, which provide a non-invasive yet effective method of improving drug delivery across the skin.

For example, U. S. Pat. No. 5,891,462 teaches the use of lauryl alcohol as a permeation enhancer for estradiol and norethindrone acetate. Such formulations are not appealing to the user or to anyone else in close proximity to the user.

U.S. Patent 4,751,087 discloses the use of butyl stearate, ethyl oleate and equivalent fatty acid esters containing 14 to 20 carbon atoms in combination with glyceryl monolaurate as penetration enhancers in the transdermal delivery of nitroglycerin.

U.S. Patent 20080233183 discloses the use of propylene glycol in combination with ethoxydiglycol as a permeation enhancer for various pharmaceutically active agents.

European Patent Application 123,948 published on November 7, 1984 discloses the use of pyroglutamyloxy-2, 3-dihydroxypropane as a penetration enhancer for the transdermal delivery of nitroglycerin. U.S. patent 3,711,602 discloses the use of dimethyl sulfoxide (DMSO) as a penetration enhancer for numerous medicaments.

Although permeation enhancers have become widely used in transdermal or topical delivery of drugs, there is no specific permeation enhancer that can be considered as suitable for all drugs, as demonstrated above.

Also the prior art chemical penetration enhancers increase skin permeability by irreversibly damaging or altering the physicochemical nature of the stratum corneum to reduce its diffusional resistance. One of the problems associated with many chemical penetration enhancers is that they cause irritancy in the skin. The toxicity associated with many chemical penetration enhancers has limited their usefulness for clinical application, hi recent years there has been a move towards investigation of potential penetration enhancers classified as GRAS (Generally Regarded as Safe) by the FDA.

Thus there is a need to provide a transdermal formulation comprising safe, non-irritating and effective penetration enhancers.

Object of the Invention

It is an object of the present invention is to improve the penetration of the active ingredient across the stratum corneum by the use of a safe, non-irritating and effective penetration enhancing agent.

Another object of the present invention is to provide a transdermal formulation so as to bypass the first pass metabolism of pharmaceutically active ingredient.

Another object of the present invention is to provide a topical composition whereby there are reduced or no side effects associated with the use of such penetration enhancing agent.

Another object of the present invention is to provide the compositions that may incorporate a wide variety of pharmacologically active compounds or prodrugs thereof. Another object of the present invention is to provide a transdermal pharmaceutical composition that is easy to use, stable and non- irritating, non-odorous and with cosmeticity.

Summary of the Invention

The present invention provides a penetration enhancing pharmaceutical composition comprising a pharmaceutically active agent, one or more penetration enhancing agents, a film forming polymer, a vehicle and optionally a propellant.

Another aspect of the present invention is to provide a method of administration of the pharmaceutical composition to a subject in need thereof.

In yet another aspect of the present invention there is provided a process of manufacture of the pharmaceutical composition.

Detailed description

The topical drug delivery route is associated with several advantages apart from bypassing the first pass metabolism. However due to poor permeability of drugs across the stratum corneum, this route has limited applicability. Thus there is a need to provide a transdermal formulation that effectively penetrates the skin through the use of safe and effective penetration enhancing agents.

The inventors have surprisingly found that a composition comprising phospholipids, lipids or combinations thereof enhances the permeation of the drug across the several layers of the skin thereby enhancing the therapeutic effect of the drug. Also these phospholipids/lipids have higher affinity for the naturally found phospholipids/lipids on the skin. Thus, they enhance the permeation of drug across the skin without any harmful effects on the skin.

Phospholipids/lipids are amphoteric in nature and this permits them to associate with lipophilic or hydrophobic active compounds and at the same time to be dispersed in aqueous media. Therefore, they can be associated with any of the pharmaceutically active agents for which the topical administration is a viable approach. Phospholipids/lipids can keep the drug in a folly solύbilized form on the surface of the skin and can thereby assist the permeation of the drug into the deeper layers of the epidermis. This is a significant improvement over many topical formulations, especially where the micronised drug is suspended in a viscous carrier.

5 Also the use of phospholipids/lipids in the topical formulation according to present invention provides a composition that is free of any side effects, irritation to the skin and malodor.

Non-limiting examples of phospholipids/lipids that may be used in the present invention may be selected from the group consisting of lecithin, a lecithin derived from egg or soybean, PHOSPHOLIPON.RTM. 85G, PHOSPHOLIP ON.RTM. 90G^® and PHOSPHOLIPON.RTM.

10 90H^® (the fully hydrogenated version of PHOSPHOLIPON.RTM. 90G^®), LECINOL S- 10.RTM^®, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-

15 phosphatidylethanolamine, steroids and terpenes, stearylamine, dodecylamine, hexadecylamine, acetylpalmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate, dioctadecylammonium bromide, amphoteric polymers, triethanolamine lauryl sulfate, cationic lipids, dioleylphosphatidylcholine (DOPC), sphingomyelin, cephalin, cardiolipin, phosphatic acid, cerebrosides, dicetylphosphate, and combinations thereof. 0 In a preferred embodiment, the lecithin is phospholipon G.

In a preferred embodiment, the composition contains one or more of: lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, 5 lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, steroids and terpenes, stearylamine, dodecylamine, hexadecylamine, acetylpalmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate, dioctadecylammonium bromide, amphoteric polymers, triethanolamine lauryl sulfate, cationic lipids, dioleylphosphatidylcholine (DOPC), sphingomyelin, cephalin, cardiolipin, phosphatic acid, 0 cerebrosides, dicetylphosphate. The penetration enhancing agents of the present invention may be present in an amount ranging from 0.5% to 30% weight of the formulation. Preferably the penetration enhancing agents may be present in an amount ranging from 5%-25% weight of the formulation.

As used herein, a "pharmaceutically active agent" refers to an agent that produces a biological effect in in-vitro or in vivo systems. The term is intended to include compounds affecting at least one of any therapeutic, prophylactic, pharmacological or physiological response in a subject. More specifically, any active agent that is capable of producing a pharmacological response, either localized or systemic, is within the contemplation of the invention. It should be noted that the active agents might be used singularly or as a mixture of two or more agents or drugs.

As will be understood by those of skill in the art, suitability for transdermal administration of a particular pharmaceutically active agent requires consideration of several factors. For example, prior to incorporating a pharmaceutically active agent in the present formulations, the agent should be evaluated with respect to its permeability through the skin, potential for skin irritation or allergic reaction, pharmacokinetic properties, pharmacodynamic properties, therapeutic window and whether metabolic responses in vivo are consistent with continuous administration.

Non-limiting examples of suitable pharmaceutically active agents that may be used in the composition according to the invention include, but are not limited to, anti-inflammatory drugs, analgesics, antiarthritic drugs, antispasmodics, antidepressants, antipsychotics, tranquilizers, antianxiety drugs, narcotic antagonists, antiparkinsonism agents, cholinergic agonists, chemotherapeutic drugs, immunosuppressive agents, antiviral agents, antibiotic agents, appetite suppressants, antiemetics, anticholinergics, antihistamines, antimigraine agents, coronary, cerebral or peripheral vasodilators, hormonal agents, contraceptives, antithrombotic agents, diuretics, antihypertensive agents, cardiovascular drugs and opioids. Suitable pharmaceutically active agents include both those that are soluble in aqueous media as well as those soluble in non-aqueous media. Such active agents are preferably used in transdermal spray compositions. In accordance with the present invention, the hormonal agent is suitably selected from one or more of the group consisting of testosterone, estradiol, ethinylestradiol, progesterone, norethisterone acetate, gestodene, oestriol, oestrone, mestranol, stilbestrol, dienestrol, epiestriol, estropipate, zeranol, allylestrenol, dydrogesterone, lynoestrenol, nestorone, norgestrel, norethyndrel, norethisterone, gestodene, levonorgestrel, medroxyprogesterone, megestrol and MENT (7-methyl-19-testosterone). Particularly preferred among the suitable compounds is estradiol.

The pharmaceutically active agents of the present invention may be present in an amount up to about 40% by weight of the formulation. Estradiol formulations suitably comprise about 0.1 % to about 10 % of estradiol by weight of the formulation.

The pharmaceutically active agents contained in the present formulation may suitably be included in a variety of forms, depending on the solubility and release characteristics desired. Non-limiting examples of suitable forms include neutral molecules, components of molecular complexes, and pharmaceutically acceptable salts, free acids or bases, or quaternary salts of the same, or as combinations of these. Simple derivatives of drugs such as pharmaceutically acceptable ethers, esters, amides which have desirable retention and release characteristics, and which are easily metabolized at body pH and temperature, may be employed. Enzymes, pro-active forms or pro-drugs are also suitable for use in the present invention.

The formulations of the present invention further comprise of film forming polymers that can be natural, synthetic polymers, or polymers that have both natural and synthetic portions.

Suitable film-forming polymers include both synthetic and natural polymers such as methyl cellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, pullulan, carboxymethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, sodium alginate,

Pectin, gelatin polyvinylpyrrolidone, polyvinyl alcohol, partially hydrolysed polyvinyl acetate, modified polyvinylpyrrolidone such as a polyvinylpyrrolidone/vinyl acetate copolymer, polyethylene oxides, ethylene/maleic anhydride copolymer, methyl vinyl ether- maleic anhydride copolymer, starch or modified starches such as hydroxy propyl starch

[Zeina^®], water-soluble polyamides or polyesters, copolymers and homopolymers of acrylic acids, natural gums such as alginates, dextrins and proteins such as gelatins and caseins. Mixtures of such film-forming polymers may also be used.

In a preferred embodiment, the film forming polymer is preferably polyvinylpyrrolidone such as polyvinylpyrrolidone/vinyl acetate copolymer [VP/VA copolymer], VP/VA copolymers are particularly useful as film forming agents. Their hygroscopicity decreases with an increase of the proportion of vinyl acetate in the molecule. This property of VPfYA copolymers is extremely useful, as it works in sprays and lotions. Also, VP/VA copolymers are primary film formers for a variety of products which demand different degrees of water resistance including aerosol, aqueous, and organic solvent systems. These polymers exhibit film flexibility, good adhesion, luster, water remoisten ability, and hardness.

The film forming polymer, especially the VP /VA copolymer, may be present in an amount between about 0.1% to about 20% by weight of the formulation. More preferably, the film forming polymer, especially the VP/VA copolymer, is present in an amount between about 0.1% by weight to about 10% by weight of the formulation. Most preferably, film forming polymer, especially the VP/VA copolymer is present in an amount between about 0.1% by weight to about 5% by weight of the formulation.

The VP/VA copolymer may comprise any suitable proportion of vinylpyrrolidone to vinyl acetate. Preferably the VP/VA copolymer may comprise from 50 to 70 weight % vinylpyrrolidone. hi one embodiment, the VP/VA copolymer comprises 60 weight % vinylpyrrolidone.

The pharmaceutically acceptable vehicle according to the invention should be chosen such that the advantageous properties intrinsically associated with the present invention are not, or are not substantially, altered by the envisaged addition.

Preferably, the vehicle used according to the invention is chosen so as to be an agent that solubilizes the active agent. The vehicle may be a volatile solvent or a non-volatile solvent.

Accordingly the vehicle can be, for example, water, one or more alcohol, one or more polyols, one or more ethers, one or more esters, one or more aldehydes, one or more ketones, one or more fatty acids, fatty alcohols, or fatty esters, or a mixture thereof. More preferably, the vehicle used is a volatile solvent. In a preferred embodiment, the volatile solvent is an alcohol. According to the invention, the term "alcohol" is intended to mean linear or branched aliphatic alcohols such as ethanol, propanol or isopropanol.

According to the invention, the term "alcoholic vehicle" is intended to mean a vehicle comprising at least 15 wt% alcohol, and preferably at least 25 wt% alcohol; the preferred alcohol is ethanol.

The formulation of present invention may also comprise emollient such as silicone, particularly volatile silicone. According to the invention, the term "volatile silicone" is intended to mean polyorgano-siloxane compounds, which may be cyclic or linear. It is a particular feature of the invention to provide a transdermal pharmaceutical composition comprising a silicone, especially a volatile silicone. The composition may include one or more of the other components described above, and one or more of the active ingredients described above. The silicone containing composition is preferably a spray composition. The silicone is useful as an emollient in the composition.

The cyclic volatile silicones according to the invention are preferably polydimethylcyclosiloxanes.

The linear volatile silicones according to the invention are linear polysiloxanes such as hexamethyldisiloxane. The linear volatile silicones generally have a viscosity of less than approximately 5 centistokes at 25° Celsius, whereas the cyclic volatile silicones generally have a viscosity of less than approximately 10 centistokes at 25° Celsius.

Preferred volatile silicones according to the invention are the linear siloxanes, and more preferably hexamethyldisiloxane. By way of example, mention may be made of the product sold by the company DOW CORNING, DC Fluid 0.65cSt.

Dow Corning provides a commercial product sold under the name DC Silmogen Carrier, which is made up of 99% of hexamethyldisiloxane and 1% of silicone gum, which product may advantageously be used in one of the compositions according to the invention.

The volatile silicone of the present invention may be present in an amount ranging from 5%-30% weight of the formulation. Preferably the volatile silicone may be present in an amount ranging from 10%-25% weight of the formulation.

The formulations of the present invention may also comprise additional components, such as anti-nucleating agents. As used herein, the term "anti-nucleating agent" refers to any material included in the formulation to prevent crystallization of the pharmaceutically active agent from the nonaqueous vehicle. Suitably, the anti-nucleating agent should be present in an amount from about 1% to about 10% of the formulation by weight. In a preferred embodiment, the anti-nucleating agent comprises about 5% of the formulation by weight. A suitable anti-nucleating agent useful in the present invention is a polyvinylpyrrolidone (PVP). The term "polyvinylpyrrolidone" or "PVP" refers to a polymer, either a homopolymer or copolymer, containing vinylpyrrolidone (also referred to as N-vinylpyrrolidone, N-vinyl- 2-pyrrolidone and N-vinyl-2-pyrrolidinone) as a monomeric unit. PVP polymers include soluble and insoluble homopolymeric PVPs, and copolymers such as vinylpyrrolidone/vinyl acetate and vinylpyrrolidone/dimethylamino-ethylmethacrylate. The cross-linked homopolymer is insoluble and is generally known in the pharmaceutical industry under the designations polyvinylpolypyrrolidone, crospovidone and PVP.

A suitable PVP for use in the present invention as an anti-nucleating agent is known in the art as PVP K-30. Suitably, PVP K-30 is included in an amount from about 1 % to 10 % of the formulation by weight.

In an embodiment, the VP/VA copolymer may act as an anti-nucleating agent, in which case an additional anti-nucleating agent may be unnecessary.

The pharmaceutical composition according to the invention may also contain inert additives or combinations of these additives, such as: wetting agents; emollients such as volatile silicon oil, hydrogenated castor oil, surfactants; humectants; flavor enhancers; preserving agents; stabilizers; moisture regulators; pH regulators; osmotic pressure modifiers; emulsifiers; UV- A and UV-B screening agents; antioxidants, excipients which can be used for the formulation of a gel, an ointment, or of a foaming composition and synthetic polymers.

Of course, those skilled in the art will appreciate that while selecting the compound (s) to be added to these compositions, the advantageous properties intrinsically associated with the present invention are not, or are not substantially, altered by the envisaged addition.

The composition according to the invention is more particularly intended for treating the skin and the mucous membranes, and may be provided in the form of ointments, creams, milks, powders, impregnated pads, syndets, solutions, gels, sprays, spot-on, foams, suspensions, lotions, sticks, shampoos, pledgets or washing bases. It may also be provided in the form of suspensions of lipid or polymer vesicles or nanospheres or microspheres or polymer patches and hydrogels to allow controlled release. This topical-application composition may be provided in anhydrous form, in aqueous form or in the form of an emulsion.

The composition according to the invention showing improved penetration is preferably administered in the form of a sprayable composition.

The sprayable form, or spray, can be obtained by conventional formulation means known to those skilled in the art. For example, the composition may be sprayed by means of a mechanical spraying device which pumps the composition from a container, bottle or equivalent. The composition passes through a nozzle which can be aimed directly at the desired site of application. The nozzle can be chosen so as to apply the composition in the form of vaporization or of a jet of droplets, according to techniques known to those skilled in the art. According to the pharmaceutical active agent chosen, the spraying mechanism must be capable of always delivering the same amount of active agent. The mechanisms for controlling the amount of composition to be delivered by the spray are also known to those skilled in the art.

Alternatively, the topical formulation according to the present invention may further comprise use of propellants (e.g. CFC or HFA) which may be administered in a suitable metered dose spray device. The following examples are for the purpose of illustration of the invention only and are not intended in any way to limit the scope of the present invention.

Example 1

Process

(1) Kollidon VA64 was dissolved in ethanol.

(2) To the above solution, Lecithin was added and mixed. (3) Finally, estradiol was dissolved in the solution obtained in step (2) under stirring to get a clear solution.

Example 2

According to the preferred embodiment, the pharmaceutical composition may be processed by conventional methods as known to a person skilled in the art:

(1) Kollidon VA64 was dissolved in ethanol.

(2) To the above solution, Lecithin was added and mixed. (3) Finally, estradiol was dissolved in the solution obtained in step (2) under stirring to get a clear solution. (4) Solution of step (3) was added to canister. Crimped it and filled the propellant.

Example 3

(1) Kollidon VA64 was dissolved in ethanol.

(2) To the above solution, Q7-9180 silicone fluid was added and mixed.

(3) Finally, estradiol was dissolved in the solution obtained in step (2) to get a clear solution.

Example 4

(1) Kollidon VA64 was dissolved in ethanol.

(2) To the above solution, Q7-9180 silicone fluid was added and mixed. (3) Finally, estradiol was dissolved in the solution obtained in step (2) to get a clear solution. (4) Solution of step (3) was added to canister. Crimped it and filled the propellant

Claims

CLAIMS:

1. A transdermal pharmaceutical composition comprising: a. pharmaceutically active agent, b. at least one penetration enhancing agents, comprising a phospholipid, a lipid or a combination thereof, c. film forming polymer, d. vehicle e. optionally, a propellant and/or other pharmaceutically acceptable excipients.

2. A composition according to claim 1, wherein the penetration enhancing agent is a lecithin.

3. A composition according to claim 2, wherein the lecithin is selected from lecithin, a lecithin derived from egg or soybean, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP -phosphatidylethanolamine,

4. A composition according to claim 1, wherein the lipid is a steroid, a terpene, stearylamine, dodecylamine, hexadecylamine, acetylpalmitate, glycerol ricinoleate, hexadecyl stearate, isopropyl myristate, dioctadecylammonium bromide, an amphoteric polymer, triethanolamine lauryl sulfate, a cationic lipid, dioleylphosphatidylcholine (DOPC)₅ sphingomyelin, cephalin, cardiolipin, phosphatic acid, a cerebroside, dicetylphosphate, polydimethylcyclosiloxanes, a polysiloxane such as hexamethyldisiloxane, and combinations thereof.

5. A composition according to any preceding claim, further comprising a silicone.

6. A transdermal pharmaceutical composition comprising: a. pharmaceutically active agent, b. at least one penetration enhancing agents, c. film forming polymer, d. vehicle e. a silicone f. optionally, a propellant and/or other pharmaceutically acceptable excipients.

7. A composition according to claim 5 or 6, wherein the silicone is a polydimethylcyclosiloxane.

8. A composition according to claim 5 or 6, wherein the silicone is a linear polysiloxane.

9. A composition according to claim 8, wherein the silicones is hexamethyldisiloxane.

10. A composition according to any one of claims 5 to 9, wherein the silicone comprises from about 5% to 30 wt% of the composition.

11. A composition according to any preceding claim, wherein the pharmaceutically active agent is selected from the group consisting of anti-inflammatory drugs, analgesics, antiarthritic drugs, antispasmodics, antidepressants, antipsychotics, tranquilizers, antianxiety drugs, narcotic antagonists, antiparkinsonism agents, cholinergic agonists, chemotherapeutic drugs, immunosuppressive agents, antiviral agents, antibiotic agents, appetite suppressants, antiemetics, anticholinergics, antihistaminics, antimigraine agents, coronary, cerebral or peripheral vasodilators, hormonal agents, contraceptives, antithrombotic agents, diuretics, antihypertensive agents, cardiovascular drugs and opioids.

12. A composition according to any preceding claim, wherein the pharmaceutically active is a hormonal agent selected from one or more of the group consisting of testosterone, estradiol, ethinylestradiol, progesterone, norethisterone acetate, gestodene, oestriol, oestrone, mestranol, stilbestrol, dienestrol, epiestriol, estropipate, zeranol, allylestrenol, dydrogesterone, lynoestrenol, nestorone, norgestrel, norethyndrel, norethisterone, gestodene, levonorgestrel, medroxyprogesterone, megestrol and MENT (7-methyl-19-testosterone.

13. A composition according to any preceding claim, wherein the pharmaceutically active agent is an estradiol.

14. A composition according to any preceding claim, wherein the penetration enhancer comprises from about 0.5% to 30% by weight of the composition.

15. A composition according to any preceding claim, wherein the film forming polymer is selected from methyl cellulose, hydroxy propyl cellulose, hydroxy propyl methyl cellulose, pullulan, carboxymethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidone, sodium alginate, Pectin, gelatin polyvinylpyrrolidone (VP), polyvinyl alcohol (VA), partially hydrolysed polyvinyl acetate, modified polyvinylpyrrolidone such as a polyvinylpyrrolidone/vinyl acetate copolymer, polyethylene oxides, ethylene/maleic anhydride copolymer, methyl vinyl ether-maleic anhydride copolymer, starch or modified starches, water-soluble polyamides or polyesters, copolymers and homopolymers of acrylic acids, natural gums such as alginates, dextrins and proteins such as gelatins and caseins .

16. A composition according to any preceding claim, wherein the film forming polymer is a VAATP copolymer.

17. A composition according to any preceding claim, wherein the film forming polymer is present in an amount from about 0.1% to about 20% by weight of the composition.

18. A composition according to any preceding claim, wherein the vehicle is a volatile solvent.

19. A composition according to claim 18, wherein the volatile solvent is an alcohol .

20. A transdermal composition according to any preceding claim, which is in the form of a spray, spot-on foam, patch, gel, cream or ointment

21. A method of administering a pharmaceutically active agent, comprising spraying a therapeutically effective amount of a composition according to any one of claims 1 to 20 onto the skin of a subject in need thereof.

22. The use of a phospholipid, lipid or a combination thereof as a penetration enhancer in a transdermal pharmaceutical composition.

23. The use of a volatile silicone as an emollient in a transdermal pharmaceutical composition.

24. The use according to claim 22 or 23, wherein the transdermal pharmaceutical composition is as defined in any one of claims 1 to 20.