AU2003240299B2 - Metastable pharmaceutical compositions - Google Patents

Description

00 0 METASTABLE PHARMACEUTICAL

COMPOSITIONS

Field of the Invention ct The present invention relates to compositions for the transdermal delivery of physiologically active agents, to uses of those compositions, and to methods for the transdermal delivery of physiologically active agents.

C Backgcround of the Invention N There is a constant need for methods for the safe and effective administration of physiologically active agents. For many medications it is important that the administration regime is as simple and non-invasive as possible in order to maintain a high level of compliance by a patient. Oral administration is one administration regime that is commonly used because it is a relatively simple regime to follow. However, the oral administration route is also complicated because of complications associated with gastrointestinal irritation and with drug metabolism in the liver.

Administration of physiologically active agents through the skin ('transdermal drug delivery') has received increased attention because it not only provides a relatively simple dosage regime but it also provides a relatively slow and controlled route for release of a physiologically active agent into the systemic circulation. However, transdermal drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is a complex mechanism.

Structurally, the skin consists of two principal parts, a relatively thin outermost layer (the 'epidermis') and a thicker inner region (the 'dermis'). The outermost layer of the epidermis (the 'stratum corneum') consists of flattened dead cells which are filled with keratin. The region between the flattened dead cells of the stratum corneum is filled with lipids which form lamellar phases that are responsible for the natural barrier properties of the skin.

Y\ LouisAcux\Spece\735417 _speci 00108doc 1 2 0 For effective transdermal delivery of a physiologically active agent that is applied Sto the surface of the skin ('topical application'), the agent must be partitioned F firstly from the vehicle into the stratum corneum, it must typically then be diffused within the stratum corneum before being partitioned from the stratum corneum to the viable epidermis and dermis and then into the bloodstream.

To maximise the concentration (thermodynamic activity) of the physiologically 0active agent in the vehicle it is common for the physiologically active agent to be c present as a saturated solution or solid.

N To overcome some of the problems with transdermal delivery that are associated with transport across the dermal layers ('percutaneous absorption'), physiologically active agents are commonly formulated with incorporation of one or more drug penetration enhancers. For example, aqueous ethanol is commonly used as a vehicle in formulations for topical application and it is known that ethanol can act as a penetration enhancer that can increase the flux of an active agent across the skin because of a solvent drag effect (Berner et al., 1989, J.

Pharm. Sci, 78(5), 402-406. Penetration enhancers are known to cause skin irritation in some individuals. In the present invention, ethanol is unlikely to act as a penetration enhancer since, due to the small quantity applied to the skin, the ethanol acts as an intermediary solvent which spreads the drug and enhancer over the skin. Since the drying time of the compositions in question is less than 2 minutes, and in vitro weight loss measurements have previously confirmed that the ethanol evaporates off pig skin with a surface temperature of 32 0C within 1 minute all that remains is the drug. The short exposure time, less than 2 minutes, of ethanol or similar lipid extracting solvents to the skin is unlikely to alter the barrier function of the skin (Abrams et al., 1993, J. Invest. Dermatol, 101, 609- 613).

U.S. Patent Number 6444234 combines particular solvents and solute modifiers with skin stabilisers in a transdermal delivery system to form a true solution and thus minimizing irritation to the skin. US Patent Number 6299900 describes the non-occlusive delivery of a physiologically active agent across the skin however, this composition relies on a penetration enhancer to achieve an increased flux.

V uie\Ac\Speciel73417Ispc 090108 doc 0 Compositions formulated without the use of a penetration enhancer are generally not effective enough to deliver significant amounts of the physiological active Sthrough the skin. Compositions containing alcohol and acetone vehicles have been used for topical delivery of antibiotics, as seen in U.S. Patent Number 6017912, which describes the use of fluoroquinolone in the topical treatment of skin infections and inflammatory conditions. However, such compositions have inherently low permeabilities of the physiological active.

N In order to overcome the low permeability, the physiological active must have a maximised thermodynamic activity. According to U.S. Patent Number 6528094, (Ni the use of stable shaped particles is particularly well-suited to the fabrication of pharmaceutical formulations, particularly where sustained release and uniform bioavailability are desired. It has been shown that to achieve high permeation rates across the skin, the concentrations of the drug dissolved may need to be high such that it possess a high tendency to crystallise. As a result transdermal patches are often thermodynamically unstable because the drug shows a tendency to recrystallise during storage (Xinghang et al., 1996, Int. J. Pharm., 142(1), 115-119 and Latsch et al., 2003, Eur. J. Pharm. Biopharm., In Press, Corrected Proof).

The use of testosterone in a volatile solvent has been previously disclosed (Wester et al., 1976). However, these compositions which consisted of testosterone dissolved in neat acetone have a propensity to de-fat (remove lipid) the skin under the chronic exposure conditions and therefore suffer from the disadvantage of causing skin irritation as opposed to the compositions that are the subject of this invention.

The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known or part of the common general knowledge in Australia or any other country as at the priority date of any of the claims.

Throughout the description and claims of the specification, the word "comprise" Y: Louise AcnakSS ae~k73541-SpeCs 090108 doc 00 0 and variations of the word, such as "comprising" and "comprises", is not intended Sto exclude other additives, components, integers or steps.

IND Summary of the Invention The present invention arises from the inventor's studies of volatile sprays and aerosols and in particular from the realisation that, for finite dose formulations, appreciable enhancement of percutaneous absorption can be attained from the (Ni in situ formation of a metastable deposit within the skin using a volatile vehicle, 0 10 such as a spray or aerosol.

Previous studies with these type of pharmaceutical compositions have indicated that the rate and extent of partitioning into the skin is already quite efficient with or without added penetration enhancer (Morgan et al., 1998, J. Pharm. Sci, 87(10), 1213-1218. The present invention arises, at least in part, from the realisation that an increase in the percutaneous absorption of the physiologically active agent may be achieved by the deliberate formation of a metastable drug in situ that has a lower melting point than would be otherwise achieved from the range of crystalline polymorph(s) routinely supplied by the commercial manufacturer. This reduction in melting point translates to an increase in the diffusion of the drug across the epidermis and dermis and into the bloodstream. To put the invention into practice the present inventor's have found that some combinations of physiologically active agent and volatile solvent form a metastable solid in situ when they are applied topically.

Accordingly, the present invention provides a composition including: one or more physiologically active agents; and a volatile pharmaceutically acceptable solvent wherein the physiologically active agent forms a metastable deposit upon evaporation of the volatile solvent. The lower melting point metastable deposit arises, at least in part, from either a metastable pseudopolymorph such as an alcohol solvate, a metastable polymorph, a metastable amorphous solid, or a mixture of these. Typically the reduction in melting point (at atmospheric Y: Loose Ac %Sp oes%7 17_speci 090108doc 4A 0 pressure) provided by the metastable deposit will be in the range of from 1 to and preferably from 2 to In one aspect, the present invention provides a pharmaceutical composition for transdermal delivery comprising; 0 from about 0.1% to about 10% by weight of one or more physiologically active agents; and 9 from about 85% to 99.8% by weight of the total composition of a volatile N carrier comprising a volatile pharmaceutically acceptable solvent selected from the group consisting of ethanol, isopropanol, chloroform, acetone and mixtures thereof, and optionally, a propellant; wherein the composition is free of non-volatile penetration enhancers, and wherein the physiological active agent is formulated with the volatile carrier so that the composition forms a metastable deposit comprising the active agent upon evaporation of the volatile solvent as determined by melting point and DSC analysis.

In another aspect, the present invention provides use of a volatile solvent and a physiologically active agent in the preparation of a spray on transdermal pharmaceutical composition of the active by formulating with the volatile solvent so that the composition when applied to the skin of a subject forms a metastable deposit of the active agent upon evaporation of the volatile solvent whereby partitioning of the physiologically active agent from the stratum corneum to the viable epidermis is enhanced.

In a further aspect, the present invention provides a method for the transdermal delivery of a physiologically active agent to a subject in need thereof, comprising applying to the skin of the subject a pharmaceutical composition comprising: from about 0.1% to about 10% by weight of one or more physiologically active agents; and (ii) from about 85% to about 99.8% by weight of a volatile carrier comprising one or more volatile pharmaceutically acceptable solvents selected from the group consisting of ethanol, isopropanol, chloroform and acetone, and mixtures thereof, and optionally, a propellant; Y k1ouiseAcnSpecies\735417_speci 090108 Coc 00 0 wherein the composition is free of non-volatile penetration enhancers and wherein, upon application and evaporation of the volatile solvent, the composition forms a metastable deposit comprising the active agent.

In yet a further aspect, the present invention provides a method of treatment or \prophylaxis of disease in a subject in need thereof by transdermal administration of a physiologically active agent, comprising applying to the skin of the subject a c(i topical pharmaceutical composition comprising: 0 10 from about 0.1% to about 10% by weight of one or more N physiologically active agents; and (ii) from about 85% to about 99.8% by weight of a volatile carrier comprising one or more volatile pharmaceutically acceptable solvents selected from the group consisting of ethanol, isopropanol, chloroform and acetone, and mixtures thereof, and optionally a propellant; wherein the composition is free of non-volatile penetration enhancers and wherein, upon application and evaporation of the volatile solvent, the composition forms a metastable deposit comprising the active agent.

Unlike a solid precipitate salt derivative of a drug) or a high melting point crystalline polymorph, the metastable deposit is readily partitioned into the skin Y:LouiseAcr'Speoes'35417_spec 090108 dOc WO 2004/000361 PCTiAU20031000785 upon evaporation of the volatile solvent and rapidly diffuses across the stratum corneum. The formation of the higher melting point crystalline deposits in the skin leads to a higher propensity toward skin irritation and a decrease in percutaneous absorption efficiency (due to the need for greater energy to dissolve the crystal prior to diffusional transport).

The metastable deposit also has excellent skin feel and touch when in some instances it may be desirable to rub the metastable deposit into the skin of a human.

The composition of the invention is essentially free of penetration enhancers.

Penetration enhancers have the effect of increasing skin permeability by reversibly damaging or altering the physiochemical nature of the stratum corneum to reduce its diffusion resistance. Penetration enhancers are generally lipophilic, non-volatile compounds with a molecular weight greater than 100 and a vapour pressure below 10mm Hg at atmospheric pressure and normal skin temperature of 32-C.

In addition to providing improved percutaneous absorption efficiency, the composition of the invention may also provide lower irritancy than some other delivery systems such as benzyl alcohol sprays, because the irritating penetration enhancer is removed. Also, the composition of the present invention may avoid problems with crystallisation and/or supersaturation that are encountered with storage of existing type transdermal patches because the pharmaceutical compositions of this invention exist as stable, single phase solutions and hence have no crystalline nature (or polymorphic memory) during their pharmaceutical shelf life. Another advantage of the present invention is the rapid partitioning into the skin from these in-situ forming metastable compositions which means the skin can act as a natural crystalline inhibitor for the physiologically active agent, further improving the stability of the metastable deposit within the skin. This leads to consistent and reliable delivery profile of the physiologically active agent over the desired dosage interval, which is typically once every 24 hours.

WO 2004/000361 PCTiAU20031000785 6 The present invention also provides a method of delivering a metastable drug formulation to a host, the method including the steps of applying a topical spray composition containing one or more physiologically active agents, and a volatile pharmaceutically acceptable solvent to the skin of the host so that the volatile solvent evaporates to form a metastable deposit containing the active agent.

The present invention further provides a composition for spray application to the skin of a subject for transdermal administration of a physiologically active agent, the composition comprising: a physiologically active agent; (ii) a volatile pharmaceutically acceptable solvent; and (iii) a propellant, preferably a fluoro hydrocarbon; wherein the composition when applied to the skin as a spray forms a metastable deposit in the skin of the subject.

The invention also provides a spray device for transdermal administration of a physiologically active agent comprising a chamber for maintaining the composition under pressure, a mixture contained within the chamber comprising the physiologically active agent, a pharmaceutically acceptable solvent which is volatile when applied to skin and a propellant which is preferably maintained at least partially in liquid form under pressure within the chamber and valve means for providing delivery of the mixture and wherein the mixture provides a metastable deposit of physiologically active agent on the skin. The propellant is preferably a hydrofluorocarbon such as HFC-134a or HFC-227. HFC-134a is the most preferred propellant. The hydrofluorocarbon propellant is preferably from 15 to 50% by volume of the total pharmaceutical composition and more preferably from 20 to 40% by volume of the total composition.

The invention further provides the use of an active agent for manufacture of a medicament for treatment or prophylaxis disease in a subject wherein the composition includes a physiologically active agent and a volatile carrier and is topically applied to the skin of the subject for transdermal administration WO 2004/000361 PCTiAU2003/000785 7 wherein the volatile solvent evaporates to form a metastable deposit containing the active agent.

In addition the metastable composition avoids the disadvantage of spray nozzle blockage seen with existing film-forming sprays or aerosols.

The invention also provides a composition as described above contained in a chamber wherein the propellent is HFC-134a. The volatile solvent and active will preferably provide a single phase solution of the active.

As used herein the term 'amorphous' means substantially non-crystalline. It will be appreciated that, unless specified otherwise, the term amorphous includes within its scope a phase that does display some crystallinity.

The combination of physiologically active agent and volatile solvent of the present invention is limited functionally to those that together form a metastable deposit with a melting point lower than that seen from the range of crystalline polymorph(s) routinely supplied by the commercial manufacturer or obtained from crystallisation from methanol or chloroform. For this reason it is preferred that the active agent is relatively non-volatile relative to the volatile solvent so that upon application of the composition to the skin of the host, only the volatile solvent evaporates at physiological temperatures.

In practice, it has been found that the physiologically active agent may selected from a range of potent, lipophilc, physiologically active agents with a molecular weight less than 600 Daltons and a melting point less than 200°C with the list including apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, anticholinergics such as oxybutynin, tolterodine and darifenacin, testosterone, MENT (7-methyl-19-testosterone), ethyinyl estradiol, or an pharmaceutically acceptable salt or derivative of any one of the aforementioned.

The drug and solvent generally have the ability to intimately mix, such that the solvent will interact with the crystal face of the drug. Therefore, the drug will WO 2004/000361 PCTiAU20031000785 8 typically have a saturated solubility in the solvent of greater than or equal to 0.05% w/w, more preferably greater than or equal to 0.1% w/w.

Preferably the volatile solvent has a vapour pressure is above 35mm Hg at atmospheric pressure and normal skin temperature of 320C. The volatile solvent will preferably comprise a lower alcohol. More preferably the volatile solvent will comprise at least 60% by weight of the total volatile solvent component of lower alcohol.

Most preferably the volatile solvent component will consist essentially of one or more lower alcohols. The preferred lower alcohols are ethanol, isopropanol and mixture thereof.

Conveniently, the composition is a topical spray composition that contains the physiologically active agent and the volatile solvent and the method includes the step of spraying the composition onto the skin of the host to form the metastable deposit containing the physiologically active substance.

In each of the above cases the metastable deposit is preferably formed in the epidermis of the host.

Brief Description of the Figures In the accompanying figures: Figure 1 shows a plot of the cumulative amount of drug penetrating across the skin from the metastable composition compared to a saturated solution of drug.

Figure 2 gives an example of base DSC profiles before and after evaporation from ethanol.

0 Figure 3 shows a plot of the melting point of each model drug, before and after evaporation from a volatile solvent after a time period of 24 hours.

SFigure 4 shows a plot of the diffusion profile for fentanyl through human epidermis, after evaporation from ethanol and isopropyl alcohol.

Detailed Description of the Invention

C

A benefit of the present invention is that the composition is stable, which means that it is not prone to supersaturation or crystallisation during its pharmaceutical shelf life.

S 10 This may be contrasted with transdermal patches in which crystallisation of the active Sagent has presented a problem in the past. Thus the composition of the present invention can be held in a primary container during the shelf life without encountering shelf-life problems of the prior art transdermal patches.

The composition of the present invention may contain from about 0.1% to about of the physiologically active agent, and from about 85% to about 99.8% of the volatile solvent.

Optionally, the vehicle may have additional pharmaceutical excipients, for example gelling agents, such as CARBOPOL T M (an acrylic acid polymer) and cellulose derivatives.

The invention will now be described with reference to the following examples. It is to be understood that the examples are provided by way of illustration of the invention and that they are in no way limiting to the scope of the invention.

Example 1 In situ formation of metastable drug deposits The formation of a metastable deposit of drug within the stratum corneum can be expected to increase the penetration of a drug across the skin relative to a Y.\Louise Acru Species\735AI17spe 090108doc WO 2004/000361 PCTiAU2003/000785 saturated solution of a drug or a simple dispersion of the solid drug on the surface of the skin as shown in figure 1 (levels not detected).

Example 2 Melting point reduction for various active agents mixed with volatile solvent The ability to form a metastable deposit of the drug after evaporation of a volatile solvent can be determined by the reduction in melting point achieved 24 hours after solvent evaporation, as shown in figures 2 and 3.

Materials Fentanyl Buspirone Testosterone Ethinyl Estradiol (EE2) EtOH Isopropyl alcohol (IPA) Chloroform Acetone The active agents chosen represent a diverse range of physicochemical properties as shown in the following table: Drugs of Choice physiocochemical properties MW Daltons LogP MP Fentanyl 336.48 3.79 84.0°C Buspirone 385.51 2.63 103.5°C Testosterone 288.4 3.01 156,0°C

EE

2 296.4 3.91 180,8°C Method Various w/v mixtures of active agent and volatile solvent were prepared. A microlitre aluminium micro-DSC pan was then placed in a 50 microlitre aluminium DSC pan, and 5 microlitre aliquots of each formulation were pipetted WO 2004/000361 PCT/AU2003/000785 11 into the 10 microlitre DSC pan. The volatile solvent was allowed to evaporate and further aliquots were re-applied until sufficient residue remained.

The pans were maintained at ambient temperature and 33% relative humidity for 24 hours. After this time the pans were covered and hermetically sealed.

DSC was then performed under a stream of nitrogen and at 10 2 C/minute and within a temperature range that depended on the drug.

Results Evaporation by each solvent resulted in melting point modulation (Figure 2).

DSC analysis of buspirone after solvent evaporation demonstrated the steadier melting point reduction (Figure In contrast, fentanyl, testosterone and EE2 showed very solvent dependent melting point reductions. In each case, isopropyl alcohol demonstrated the most significant difference in melting point change when compared to the compound base. Melting point depression is, we have found, an indication that the composition will have an increase in percutaneous absorption. In addition, the stratum corneum may prevent crystallisation, resulting in a solvent deposited metastable solid within the stratum corneum.

Example 3 Effect of metastable compositions on percutaneous penetration The choice of solvent used in a composition can be selected on the basis of the desired transdermal delivery profile as measured by percutaneous penetration (an example of which is shown in figure 4) in order to achieve the desired pharmacological effect.

The aforementioned examples are not meant to be limiting and it is envisaged that combinations of volatile solvents could also be used to obtain the desired pharmacological effect; for example on a weight basis.

Ethanol IPA 20-80 20-80 Ethanol :Acetone or IPA or Chloroform 60-90 :10-40; WO 2004/000361 PCTiAU2003/000785 12 or a mixture thereof.

Diffusion Studies Diffusion studies were conducted to determine the delivery profile of metastable compositions across skin.

Formulations Fentanyl in ethanol (1 mole) Fentanyl in isopropyl alcohol (1 mole) All formulations were prepared by accurately weighing the appropriate amount of physiological active into a volumetric flask and made up to volume with appropriate volatile solvent.

Method In vitro diffusion experiments were performed using stainless steel flow-through diffusion cells, using human epidermis maintained at 32°C. The receptor solution consisted of either 10% EtOH in 0.002% NaN3 or 20% EtOH in 0.002% NaN3, Eight cells for each condition were treated with 5pl of appropriate donor phase, each a finite dose that was formulation dependent. Samples were collected at appropriate time points and analysed by high performance liquid chromatography (HPLC).

WO 2004/000361 PCT/AU2003/000785 13 Table 1. HPLC conditions for receptor solution analysis.

Parameters Method Buspirone Fentanyl Column Symmetry C18 (3.9*150mm) 5pm Symmetry C18 (3.9*150mm) Line A: 20% AcN in 0.01M Mobile Line A: 5nM TEA (milli-Q), pH 10.9 KH2P04 pH 2.85nM Phase Line B: 100% AcN Line B: 90 AcN pH 2.8 Gradient: Time %A %B Isocratic: 0 80 Pump 70% A 63 37

B

9 80 11 80 Flow rate 1.0 ml/min 1.0 ml/min Absorbance 239 nm 210 nm Injection pl 50 pl volume Column

°C

Temp.

Results Diffusion experiments were performed using fentanyl as a model compound, after ethanol and isopropyl alcohol evaporation.

Fentanyl diffusion profile, through human epidermis, demonstrates a change in delivery profile which is solvent dependent (Figure After evaporation from ethanol, fentanyl showed a sigmoidal, first order diffusion profile indicating that the initial burst across the skin is limited. However, after evaporation from isopropyl alcohol, fentanyl shows a zero order release rate profile. Therefore, the leaving tendency may be modified to suit the desired delivery rate by altering the volatile solvent vehicle.

Claims (23)

1. A pharmaceutical composition for transdermal delivery comprising; from about 0.1% to about 10% by weight of one or more physiologically active agents; and from about 85% to 99.8% by weight of the total composition of a volatile carrier comprising a volatile pharmaceutically acceptable solvent selected from the group consisting of ethanol, isopropanol, chloroform, acetone and mixtures thereof, and optionally, a propellant; wherein the composition is free of non-volatile penetration enhancers, and wherein the physiological active agent is formulated with the volatile carrier so that the composition forms a metastable deposit comprising the active agent upon evaporation of the volatile solvent as determined by melting point and DSC analysis.

2. A pharmaceutical composition according to claim 1 wherein the composition comprises a physiologically active agent selected from the group consisting of apomorphine, fentanyl, ropinirole, rivastigmine, buspirone, rizatriptan, anticholinergics, ethynyl estradiol or a pharmaceutically acceptable salt or derivatives thereof.

3. A pharmaceutical composition according to claim 1 or claim 2 wherein the composition comprises a hydrofluorocarbon propellant and is formulated for application as an aerosol.

4. A pharmaceutical composition according to claim 3 wherein the propellent is HFC-134a.

A pharmaceutical composition according to claim 3 or claim 4 wherein the hydrofluorocarbon propellant is from 15 to 50% by volume of the total pharmaceutical composition.

6. A pharmaceutical composition according to claim 1 or claim 2 wherein the metastable deposit has a melting point that is from 1 to 50 0 C lower than the Y:Louise\Acrx\Species\735417_spe 090108 doc oO melting point of the active agent at atmospheric pressure.

S7. A pharmaceuticcal composition according to claim 1 or claim 2 wherein the metastable deposit has a melting point that is from 2 to 300C lower than the melting point of the active agent at atmospheric pressure.

8. A pharmaceutical composition according to any one of claims 3 to Swherein the composition is contained in a chamber of a spray applicator device N comprising a valve for delivering the composition from the chamber, a nozzle for dispersing the composition as an aerosol and means for providing a metered dose of aerosol from the nozzle said composition being retained under pressure within the chamber so as to maintain said propellent in a liquid form.

9. A pharmaceutical composition according to any one of claims 1 to 8 wherein the composition comprises a volatile solvent and propellant and provides a single phase solution of the active agent.

A pharmaceutical composition according to claim 1 or claim 2 wherein the composition contains no propellant.

11 A pharmaceutical composition according to claim 1 wherein composition comprises a physiologically active agent with a saturated solubility in the volatile solvent of not less than 0.05% w/w.

12. A pharmaceutical composition according to claim 1 wherein the composition comprises a physiologically active agent with a molecular weight of less than 600 Daltons and a melting point less than 2000C.

13. A pharmaceutical composition according to claim 1 wherein the composition comprises a physiologically active agent selected from the group consisting of testosterone, MENT (7-methy-19-testosterone), or a pharmaceutically acceptable salt or derivative thereof. Y:.ouisec\Sp:ees735417_spea 090108 doC 00 0

14. A pharmaceutical composition according to any one of claims 1 to 13 N wherein the composition comprises a volatile solvent selected from the group Sconsisting of ethanol and isopropanol.

15. A pharmaceutical composition according to any one of claims 1 to 14 further comprising a gelling agent in an amount of from 0.1% to 20% by weight of the total pharmaceutical composition.

16. A pharmaceutical composition according to claim 15 wherein the gelling agent is a cellulose derivative.

17. A pharmaceutical composition according to claim 16 wherein the gelling agent is selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl-methyl cellulose, hydroxyethyl cellulose, and mixtures thereof.

18. A pharmaceutical composition according to claim 15 wherein the gelling agent is an acrylic acid polymer.

19. Use of a volatile solvent and a physiologically active agent in the preparation of a spray on transdermal pharmaceutical composition of the active by formulating with the volatile solvent so that the composition when applied to the skin of a subject forms a metastable deposit of the active agent upon evaporation of the volatile solvent whereby partitioning of the physiologically active agent from the stratum corneum to the viable epidermis is enhanced.

A method for the transdermal delivery of a physiologically active agent to a subject in need thereof, comprising applying to the skin of the subject a pharmaceutical composition comprising: from about 0.1% to about 10% by weight of one or more physiologically active agents; and (ii) from about 85% to about 99.8% by weight of a volatile carrier comprising one or more volatile pharmaceutically acceptable solvents selected from the group consisting of ethanol, isopropanol, chloroform and acetone, and mixtures thereof, and optionally, a propellant; Y LouisAC\Spedes\735417_spee 090108 doc 00 wherein the composition is free of non-volatile penetration enhancers 0 and F wherein, upon application and evaporation of the volatile solvent, the composition forms a metastable deposit comprising the active agent. \O

21. A method of treatment or prophylaxis of disease in a subject in need thereof by transdermal administration of a physiologically active agent, (Ni comprising applying to the skin of the subject a topical pharmaceutical C composition comprising: t'q from about 0.1% to about 10% by weight of one or more N physiologically active agents; and (ii) from about 85% to about 99.8% by weight of a volatile carrier comprising one or more volatile pharmaceutically acceptable solvents selected from the group consisting of ethanol, isopropanol, chloroform and acetone, and mixtures thereof, and optionally a propellant; wherein the composition is free of non-volatile penetration enhancers and wherein, upon application and evaporation of the volatile solvent, the composition forms a metastable deposit comprising the active agent.

22. A pharmaceutical composition according to claim 1 substantially as hereinbefore described.

23. A method according to claim 20 or claim 21 substantially as hereinbefore described. Y:\Louise Acw\Sf e es%\735417_speci 090108.0oc