WO1997006788A1

WO1997006788A1 - Transdermal administration of vorozole

Info

Publication number: WO1997006788A1
Application number: PCT/EP1996/003558
Authority: WO
Inventors: Marcus Joannes Maria Noppe; Theo Cesar Garrevoet; Jozef Peeters; Jean-Louis Mesens
Original assignee: Janssen Pharmaceutica N.V.
Priority date: 1995-08-14
Filing date: 1996-08-08
Publication date: 1997-02-27
Also published as: AR003979A1; ZA966842B; AU6821196A

Abstract

Medical patches for the transdermal administration of vorozole through intact skin for an extended period of time which comprise: (a) a drug reservoir (1) comprising vorozole (I) and preferably a skin permeation enhancer (II) for vorozole in amounts sufficient to deliver (I) at a therapeutically effective rate for said extended period of time, and (b) a drug-impermeable backing (2); methods of treating patients with such patches; process of manufacturing such patches.

Description

TRANSDERMAL ADMINISTRAΗON OF VOROZOLE

This invention relates to a medical patch for the transdermal administration of vorozole and to a method of treating a subject by administering vorozole thereto with said medical patch.

Vorozole is generic to the (+)-(S)-6-[(4-chlorophenyl)(lH-l,2,4-triazol-l-yl)methyl]- 1 -methyl- lH-benztriazole. The E.P. Application 0,293,978, published on December 7, 1988 specifically describes racemic (±)-6-[(4-chlorophenyl)(lH-l,2,4-triazol-l-yl)- methylj-1-methyl-lH-benztriazole and its ethanedioate salt, its preparation and pharmacological activity as aromatase inhibitor. E.P. Application 0,371,559, published on June 6, 1990, describes the use of benzimidazoles and of benzotriazoles, amongst which (±)-6-[(4-chlorophenyl)( IH- 1 ,2,4-triazol- 1 -yl)methyl ]- 1 -methyl- lH-benztriazole, in the treatment of epithelial disorders, by suppressing the metabolism of endogenous or exogenously administered retinoic acid. Most of the pharmacological activity originates from the dextrorotatory (S)-(+)-enantiomer. WO 94/1 1364, published on May 26,

1994, describes a process of preparing enantiomerically pure 6-[(4-chlorophenyl)

( IH- 1 ,2,4-triazol- 1 -yl)methyl]- 1 -methyl- 1 H-benztriazole.

Various conventional pharmaceutical dosage forms, including tablets, capsules, drops, suppositories, oral solutions and injectable solutions are exemplified in the above¬ mentioned patents and patent applications. In practice, vorozole will normally be administered in the base form (i.e. not as a salt) in a tablet or in a buffered, oral or intramuscular solution for the purposes of producing an antitumor effect. For a number of reasons, it is desirable to administer vorozole using a non-invasive route, in particular using transdermal delivery, especially in a rate-controlled manner.

The main patient target group for treatment with vorozole are post-menopausal women under treatment for breast cancer. Vorozole inhibits the formation of oestrogens which have a trophic effect on breast cancer tumor cells. The administration of vorozole is required during weeks, sometimes even months. The conventional administration is, of course, oral administration. However, the prolonged and continous therapy requiring a constant plasma level of vorozole forces the patient into a rigid scheme of daily intake. In other words, successful therapy requires a high degree of patient compliance.

Vorozole may be used in combination with other therapies, for example, radiotherapy or chemotherapy, which therapies may impede convenient oral intake of vorozole because of, for instance, nausea or gastroparesis. Some patients may even be in such a bad condition that oral intake as such becomes a major problem. Patients with declining or already declined mental capacities, e.g. elderly patients, often forget or refuse to take necessary daily medication.

While some generically related compounds are not prone for transdermal delivery, it was found that it was possible to deliver vorozole in a transdermal manner.

Hence, the present invention provides a means for administrating vorozole via a non- invasive non-oral route, i.e. a means for administrating vorozole via a transdermal route. The present invention provides for a device for the transdermal administration of vorozole, i.e. a medical transdermal patch.

The application of transdermal drug delivery technology to the administration of a wide variety of drugs has been proposed and various systems for accomplishing this are disclosed in numerous technical journals, handbooks and patents. These systems can deliver controlled amounts of drugs to patients for extended periods of time ranging in duration from several hours to several days. So far there are no patents nor is there any other prior art that describes a transdermal delivery system which is intended to deliver vorozole. Nor are there data on skin permeability or therapeutic transdermal delivery rates of vorozole adequate to design such a system. In addition, vorozole has characteristics which impose a combination of restraints on a transdermal delivery system which have hitherto not been addressed in other systems.

It would be desirable that the device delivers the drug at a substantially constant rate for at least about 24 hours while at the same time keeping the amount of drug within both the unused and depleted systems to a minimum. Also, the degree to which the system controls the release rate should be relatively high in order to assure that excessive amounts of the drug are not delivered in the event that the skin of a patient has been damaged and has an abnormally high permeability. In addition to these general design criteria, properties of vorozole such as skin permeability and drug absorption in the skin may impose additional conflicting design constraints.

Interestingly, it has now been found that vorozole preferably in the presence of a suitable skin permeation enhancer (SPE) can be administered through intact skin at a rate which is sufficient to attain therapeutically meaningful plasma levels. Consequently, the present invention concerns a medical patch for the transdermal administration, especially the rate- controlled transdermal administration, of vorozole through intact skin for an extended period of time which comprises : (a) a drug reservoir (1) comprising vorozole (I) in amounts sufficient to deliver (I) at a therapeutically effective rate for said extended period of time, and

(b) a drug-impermeable backing (2).

In particular, the present invention concerns a medical patch for the transdermal administration, especially the rate-controlled transdermal administration, of vorozole through intact skin for an extended period of time which comprises : a) a drug reservoir (1) comprising vorozole (I) and a skin permeation enhancer (II) for vorozole in amounts sufficient to deliver (I) at a therapeutically effective rate for said extended period of time, and

(b) a drug-impermeable backing (2).

The invention also concerns a process for inducing and maintaining an antitumor effect, which comprises administering vorozole through an area of intact skin at a therapeutically effective rate for an extended period of time with a medical patch as described herein.

There is a relatively wide range of permeability of normal human skin to drug molecules and this permeability not only varies from individual to individual and site to site but is also highly dependent on the chemical form of the drug. We have discovered that, in order to obtain the delivery rates noted above, the drug should be incorporated in the transdermal therapeutic system in the uncharged form of the base. Consequently, the term vorozole as used hereinafter comprises the base form and other uncharged forms such as its solvates, e.g. its hydrates.

The permeability of normal skin to vorozole base, when for instance dissolved in polyethylene glycol e.g. PEG 400, is rather low. Although the penetration of vorozole through the skin is already appreciable when dissolved in, for instance, 50% (v/v) ethanol in water, still it is preferred that an amount of permeation enhancer should be provided in a system (preferably rate-controlled) sufficient to increase the flux of drug through the skin to a value no less than the flux of drug from the system. Thus, sufficient permeation enhancer should be delivered to increase the permeability of even the most impermeable skin to a value at least equal to that of the patch. This will produce a patch in which at least 50% of the flux is controlled by the patch. It is preferable that the patch be at least 70% controlling and this objective can be obtained if the permeability of skin for the drug is increased to at least 2.4 times the steady state flux from the patch.

Suitable skin penetration enhancers induce a temporary, reversible increase in skin permeability. The skin permeation enhancer (II) to be used in the vorozole patches according to the present invention is selected from the group consisting of fatty acids, monoglyceride esters of such fatty acids, C8-18 alkylsaccharides, C8-18 acyl carnitines, azone (l-dodecylazacycloheptan-2-one) and C1-14 alkyl methylsulfoxides.

Fatty acids are saturated and unsaturated C8-20 alkanoic acids such as caprylic (C8:θ)_. capric (Ci0:0). lauric (Ci2:0), myristic (C]4_:o), palmitic (Ci6:0)_> palmitoleic (C ^_:\), stearic (Ci8_:o), oleic (Cig.j), linoleic (C18_.2 linolenic (Cι g_:3), and arachidonic (^c20:4) ^acid-

Cδ-18 alkylsaccharides are for example n-octyl-beta-D-glucopyranoside and n-lauryl- beta-D-glycopyranoside.

Ci-14 alkyl methylsulfoxides are for example dimethylsulfoxide and decyl methysulfoxide.

Preferred are the saturated Cδ- 14 alkanoic acids and the unsaturated C 16-20 alkanoic acids having cis double bonds, especially lauric acid and oleic acid.

The skin permeation enhancer (II) should be used in an amount that does not damage the skin of the subject to be treated; in practice this means that the weight-by-weight ratio (I) : (II) (w/w) ranges from 1 : 1 to 1 : 10 and in particular is about 1 :5 in the case of the especially preferred lauric acid and oleic acid.

Vorozole in the presence of a skin permeation enhancer may be administered to the human body via the transdermal route at a therapeutically effective rate for an extended period of time : a rate in the range of 10 to 500 μg/h for a substantial portion of said extended period of time is feasible. Steady-state administration rates obtainable range from about 10-300 μg/h and preferably from about 25-150 μg/h.

When transdermal systems according to this invention are applied to the skin, vorozole will be transferred from the system into the skin where it is absorbed into the blood¬ stream. The skin absorbs a certain amount of vorozole before any significant absoφtion into the bloodstream occurs. Since most transdermal therapeutic systems exhibit an initial transitory, increased release of drug which occurs at a significantly higher rate than the steady-state rate later obtained, inclusion of additional amounts of the drug at the skin contacting surface of the device is not an absolute requirement.

Having described the requirements imposed on transdermal therapeutic systems for administering vorozole and methods for its transdermal administration, the following description concerns various specific rate-controlled transdermal patch designs. Figures 1 to 5 are all cross-sectional views of such patches. A first type of rate-controlled transdermal patch is shown in Figure 1 : a polymer membrane permeation-controlled patch wherein the drug reservoir (1) is sandwiched between the drug-impermeable backing (2) and a rate-controlling polymeric membrane (4) on the external surface of which a layer (3) of an adhesive polymer is applied. The rate-controlling polymeric membrane (4) has a specific permeability and may be made of a nonporous (homogeneous or heterogeneous) polymeric material or of a porous (semipermeable) membrane.

The drug reservoir (1) may exist in solid, suspension or solution form. Preferably, the drug reservoir (1) contains : (i) a suspension comprising (I) and (II) dispersed homogeneously in a solid polymer matrix suspended in a liquid medium, [e.g. polisobutylene in silicone fluid] or (ii) a drug solution comprising (I) and (II) in a releasable solvent [e.g. alkyl alcohols and diols such as ethanol, 1 -propanol, 1 -butanol, 1 -octanol, lauryl alcohol, linolenyl alcohol, and propylene glycol possibly in admixture with water]. The releasable solvents may have skin permeation enhancing properties for vorozole by themselves, e.g. propylene glycol or 50 % (v/v) ethanol/water. Therefore, the drug solution comprises in particular propylene glycol or 50 % (v/v) ethanol/water as a releasable solvent.

A patch wherein the drug reservoir (1) contains a solution comprising 0.1 to 10% by weight of (I), 0.1 to 10% by weight of (II), and 50 % (v/v) ethanol/water as 100% or propylene glycol ad 100 % is presently considered the formula of choice for insertion in a transdermal delivery system.

The drug-impermeable backing (2) is preferably a plastic laminate, e.g. a polyester film laminate or a polyester-polyurethane film (which is air and water permeable). The puφose of the backing is to prevent passage of the drug through the surface of the reservoir distant from the adhesive layer. In order to obtain a system wherein the flux is controlled by the system itself and not just by the permeability of the skin, the rate- controlling polymeric membrane (4) limits the flux of (I) and (II) from the drug reservoir to a level less than the flux of (I) and (II) through the skin to which it is applied.

In order to minimize the amount of skin permeation enhancer delivered to the patient, it is advantageous that patch has a polymeric membrane (4) which restricts the flux of (II) from the drug reservoir (1) substantially more than the flux of (I) from the drug reservoir

(D- The rate-controlling membrane can be from about 0.5-5 mm thick and preferably about

1-3 mm thick. It can be conveniently made of ethylene-vinyl acetate copolymer (e.g. 9%

VA). To provide adequate system life, the loading will be from about 5-50 mg/cm^ yielding a dry loading of from about 0.01-5 mg/cm^.

The adhesive layer (3) comprises a drug-compatible, hypoallergenic pressure-sensitive adhesive polymer and may be disposed in the flow path of (I) and (II) from the drug reservoir (1) to the skin. Silicone adhesive, polyacrylate, are considered particularly useful. However, other means for maintaining this system (and the following designs) on the skin can be employed. Such means include a peripheral ring of adhesive outside the path of drug from the system to the skin, in which case the adhesive need not be drug compatible. The use of adhesive overlays or other fastening means such as buckles, belts, and elastic arm bands is also contemplated.

The drug formulation inside the reservoir can be introduced by injection molding, spray coating, microencapsulation and other techniques known in the art. The rate of drug release from the polymer membrane permeation-controlled system should be constant. The release of drug from this type of rate-controlled drug delivery system is controlled by appropriately choosing the partition coefficient and diffusivity of the drug and the thickness and nature of the rate-controlling polymeric membrane (4).

A second type of rate-controlled patch is shown in Figure 2 : a polymer matrix dif¬ fusion-controlled patch wherein the drug reservoir (1) comprises a matrix of a hydro¬ philic or lipophilic polymer wherein (I) and (II) are homogeneously dispersed, said drug reservoir (1) being mounted onto an occlusive baseplate (5) in a compartment fabricated from the drug-impermeable backing (2), and wherein the adhesive layer (3) is applied along the circumference of the patch to form a strip of adhesive rim sur-rounding the drug reservoir (1). The medicated polymer is formed by homogeneously dispersing (I), (II) and polymer. It is then shaped into a form having a defined surface area and controlled thickness, which form is then mounted onto the occlusive baseplate (5). At steady state the release is continuous, but not constant as the amount of drug delivered is proportional with the square root of the period of time. In this type of patch, the release of drug is controlled by appropriately choosing the loading dose and the polymer. An absorbent pad (6) can be sandwiched between (2) and (5).

The drug reservoir can also be formulated by directly dispersing the drug in a pressure- sensitive adhesive polymer such as poly(isobutylene)-based or a poly(acrylate)-based adhesive polymer. The medicated adhesive polymer is then attached to the drug- impermeable backing to form a single layer or multiple layers of drug reservoir. A patch design of this type is shown in Figure 3 : a polymer matrix diffusion-controlled patch wherein the drug reservoir (1) comprises a pressure-sensitive adhesive polymer wherein (I) and (II) are homogeneously dispersed. A strippable backing member (7) or release liner adapted to be removed prior to use is advantageously used to cover the drug reservoir prior to use.

Figure 4 shows a modification of the previous design : a polymer matrix gradient- controlled patch wherein the drug reservoir (1) comprises multilaminate adhesive layers of a pressure-sensitive adhesive polymer wherein (I) and (II) are dispersed in a proportional manner thus forming a concentration gradient which raises from the skin contacting surface towards the drug-impermeable layer (2). The increasing drug loading level of the layers compensates for the increase in diffusional path and under appropriate circumstances a constant drug release profile can be obtained. Alternatives to this approach consist of varying the polymer solubility of the impregnated drug or varying the particle size distribution of drug crystals in the various laminates of the adhesive matrix.

Figure 5 shows a fourth type of design : a microreservoir partition-controlled patch wherein the drug reservoir (1) comprises a matrix of a hydrophilic or lipophilic polymer wherein many discrete, unleachable, microscopic drug reservoirs comprising (I) and (II) are homogeneously dispersed, said drug reservoir (1) being mounted onto an occlusive baseplate (5) in a compartment fabricated from the drug-impermeable backing (2), and wherein the adhesive layer (3) is applied along the circumference of the patch to form a strip of adhesive rim surrounding the drug reservoir (1). The drug reservoir is formed by first suspending the drug solids in an aqueous solution of a water-miscible drug solubilizer, and then homogeneously dispersing the drug suspension in a lipophilic polymer by high shear mechanical force to form a multitude of unleachable, microscopic drug reservoirs. The thermodynamically unstable dispersion is fixed by immediately crosslinking the polymer chains in situ. In this type of patch, the release of drug can follow either a partition-controlled or matrix diffusion-controlled process depending on the solubilities of the drug in the liquid compartments and in the polymer matrix.

Such a system has the advantage of being easily fabricated, but in the absence of a rate controlling membrane, delivers drug at a rate which is determined primilarily by the permeability of the skin at the site of application on the particular individual. Thus, while this system can be employed to provide drug delivery rates within the ranges described herein, the actual delivery rate cannot be as precisely controlled as would be with the systems described generally in Fig. 1. Suitable materials for fabricating the contact adhesive/reservoir layer include EVA polymers having approximately 0 to 18% vinylacetate content and polyisobutylene/mineral oil containing from 15 to 25% high molecular weight polyisobutylene (an average molecular weight 1,200,000) 20 to 30% low molecular weight polyisobutylene (average molecular weight 35,000) and balance of light mineral oil having a viscosity at 38°C. of approximately 10 mPa.s (centipoise). In addition to the drug, the drug reservoir-contact adhesive layer can also contain additives, permeation enhancers and other materials as are generally known to the art.

The drug reservoirs described above may comprise further ingredients. In order to prevent the growth of micro-organisms such as bacteria, yeasts and fungi in the patches, a preservative agent may be added. Suitable preservatives should be physicochemically stable and effective in the circumstances mentioned above. They comprise benzoic acid, sorbic acid, methylparaben, propylparaben, imidazohdinyl urea (= Germall 115®) and diazolidinyl urea (= Germall II®), phenoxetol, benzyl alcohol, quaternary compounds, e.g. benzylalkonium chloride, and the like. The concentration of the preservatives may range from 0.05% to 1%, particularly from 0.1% to 0.5%, and most particularly is about 0.2%.

The drug reservoir may also be sterilized following art-known procedures. Drug reservoirs may be sterilized by irradiation with gamma rays. Drug solutions can be filtered aseptically and then sterilized by autoclaving.

The patches optionally may include additional ingredients known in the art of formulation such as stabilizers (EDTA) , antioxidants (BHT, BHA), solubility enhancers (cyclo- dextrins), viscosity regulating agents, surfactants (especially non-ionic), hydrating agents (urea), plasticizers (isopropyl myristate) and the like ingredients.

Several patents describe a wide variety of materials which can be used for fabricating the various layers of the transdermal vorozole delivery systems according to this invention. This invention therefore contemplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions.

The following examples are intended to illustrate the scope of the present invention in all its aspects; all percentages are by weight unless otherwise noted. Experimental part

Example 1 In vitro model Human skin was obtained from cosmetic surgical correction. The skin was stored less than 24 hours at 4 °C before it was used in a permeation study. Nude mice were sacrificed and the skin was removed and used within 2 hours.

Modified Franz cells (Novel Drug Delivery Systems, second edition, Yie W. Chien, volume 50 of the Drugs and the Pharmaceutical Sciences edited by J. Swarbrick) with an orifice diameter of 17.0 mm were used. The cells were kept at 32 °C in a circulated water bath. Auto sampling was done with a Gilson auto sampler (model 222). One ml samples were withdrawn after various time intervals. After sampling, 1.0 ml fresh receptor solution was pumped into the receptor compartment. The receptor compartment was filled with 15.0 ml of Eurand buffer pH 7.2 ( mixture of 0.87 g potassium phosphate-monobasic with 190.0 ml 0.2 M sodium hydroxide, diluted to 1000 ml with water, with addition of 1 M HCl to correct the pH to 7.2 if needed) containing 0.25% l,l,l-trichloro-2-methyl-2-propanol hemihydrate as an antibacterial agent. Caps were placed over the side arms in order to reduce evaporation. The dose (500 μl) was applied through the open top of the cells.

Detection of vorozole

The concentration of vorozole in the receptor fluid was determined by HPLC. Samples were injected by completely filling a 30μl loop injection valve (Valco valve). A RP 18 Hypersil ODS column (lenght 10 cm, particle size 3 μm) was eluted at ambient temperature with a mobile phase consisting of 0.015M tetrabutylammoniumhydrogen- sulfate (A) and acetonitrile (B). An isocratic elution (68% A and 32% B) at a flow rate of 1.5 ml/min was performed. The absorbance of the column effluent was monitored at 220 nm (Varian UV 200 detector). The retention time of vorozole was 3.6 minutes.

Evaluation of transdermal permeation of vorozole.

In a first experiment, the donor phase (500μl) consisted of :

1° 6% (w/v) vorozole in PEG 400,

2° 1% (w/v) vorozole in 50% (v/v) ethanol/water, 3° 1% (w/v) vorozole, 5% (w/v) oleic acid in 50% (v/v) ethanol/water,

4° 1% (w/v) vorozole, 5% (w/v) lauric acid in 50% (v/v) ethanol/water.

Human skin was used as barrier in the device. The results of the experiment are summarized in table 1 : the accumulated amount of vorozole (μg/cm²) in the receptor phase was calculated. The permeation of vorozole was followed for 56 hours.

Table 1

Time (hours) Formulation number :

1 2 3 4

(μg/cm²⁾ (μg/cm²⁾ (μg/cm²⁾ (μg/cm²⁾

0 0.0 0.0 0.0 0.0

2 0.0 0.0 0.0 0.0

4 0.0 0.0 0.0 0.0

6 0.0 0.0 0.0 0.0

8 0.0 0.0 0.0 0.0

10 0.0 0.0 0.0 0.0

12 0.0 0.0 0.0 0.0

16 0.0 0.0 0.0 0.0

20 7.5 7.3 100.3 1 10.6

24 9.1 11.7 146.5 153.1

28 10.6 20.3 155.1 198.2

32 1 1.9 32.1 167.2 228.9

36 12.8 44.6 179.3 258.6

40 14.2 58.5 185.4 281.4

44 14.9 68.9 180.8 304.2

48 14.7 * * *

52 18.5 84.7 184.7 333.8

56 21.1 95.4 198.7 345.3

(*sample broke n)

Example 2 1 g of vorozole and g of 5 g oleic acid are dissolved in 100 ml of a 50% (v/v) ethanol/water mixture. This solution is added to an aqueous acrylate adhesive dispersion while mixing. An adhesive thickener is added and the resulting mixture is stirred until homogenous. Then, the mixture is coated on an impermeable backing such as a polyester film laminate and dried. A release liner (e.g. siliconized plastic sheet) is laminated to the adhesive layer. The final sheet is cut to form transdemal devices of comprising about 10 mg of vorozole. Example 3

1 g of vorozole and 5 g of lauric acid are dissolved in 100 ml of a 50% (v/v) ethanol/ water mixture. This solution is added to an aqueous acrylate adhesive dispersion while mixing. An adhesive thickener is added and the resulting mixture is stirred until homogenous. Then, the mixture is coated on an impermeable backing such as a polyester film laminate and dried. A release liner (e.g. siliconized plastic sheet) is laminated to the adhesive layer. The final sheet is cut to form transdermal devices of comprising about 10 mg of vorozole.

Claims

1. A medical patch for the transdermal administration of vorozole through intact skin for an extended period of time which comprises : (a) a drug reservoir (1) comprising vorozole (I) in amounts sufficient to deliver (I) at a therapeutically effective rate for said extended period of time, and (b) a drug-impermeable backing (2).

2. A medical patch according to claim 1 which comprises : (a) a drug reservoir (1) comprising vorozole (I) and a skin permeation enhancer (II) for vorozole in amounts sufficient to deliver (I) at a therapeutically effective rate for said extended period of time, and (b) a drug-impermeable backing (2).

3. A patch according to claim 2 wherein the skin permeation enhancer (LT) is selected from the group consisting of fatty acids, monoglyceride esters of fatty acids, Cδ-18 alkylsaccharides, Cδ-18 acylcarnitines, azone and Ci-14 alkyl methylsulfoxides.

4. A patch according to claim 2 wherein (I) is delivered through intact skin at a rate in the range of 10 to 500 μg/h for a substantial portion of said extended period of time.

5. A patch according to claim 2 wherein the area of said intact skin is within the range of 5 to 100 cm².

6. A patch according to claim 2 wherein (I) is delivered through intact skin at a rate in the range of 0.5 to 20 μg/h.cm².

7. A patch according to claim 2 comprising sufficient (I) and (II) to allow administration of (I) for up to 4 days.

8. A polymer membrane permeation-controlled patch according to claim 2 wherein the drug reservoir (1) is sandwiched between the drug-impermeable backing (2) and a rate-controlling polymeric membrane (4) on the external surface of which a layer (3) of an adhesive polymer is applied.

9. A patch according to claim 8 wherein the drug reservoir (1) contains (i) a suspension comprising (I) and (II) dispersed homogeneously in a solid polymer matrix suspended in a liquid medium, or (ii) a drug solution comprising (I) and (II) in a releasable solvent.

10. A patch according to claim 9 wherein the drug solution comprises propylene glycol or 50 % (v/v) ethanol/water as a releasable solvent.

11. A patch according to claim 10 wherein the drug reservoir (1) contains a solution comprising 0.1 to 10% by weight of (I), 0.1 to 10% by weight of (II), and 50 % (v/v) ethanol/water ad 100 % or propylene glycol ad 100 %.

12. A patch according to claim 8 wherein the rate-controlling polymeric membrane (4) is either a porous polymeric membrane or a nonporous polymeric membrane.

13. A patch according to claim 12 wherein the rate-controlling polymeric membrane (4) limits the flux of (I) and (II) from the drug reservoir to a level less than the flux of (I) and (II) through the skin to which it is applied.

14. A patch according to claim 12 wherein the polymeric membrane (4) restricts the flux of (I) from the drug reservoir (1) substantially more than the flux of (II) from the drug reservoir (1).

15. A patch according to claim 8 wherein the adhesive layer (3) is disposed in the flow path of (I) and (II) from the drug reservoir (1) to the skin.

16. A polymer matrix diffusion-controlled patch according to claim 2 wherein the drug reservoir (1) comprises a matrix of a hydrophilic or lipophilic polymer wherein (I) and (II) are homogeneously dispersed, said drug reservoir (1) being mounted onto an occlusive baseplate (5) in a compartment fabricated from the drug-impermeable backing (2), and wherein the adhesive layer (3) is applied along the circumference of the patch to form a strip of adhesive rim surrounding the drug reservoir (1).

17. A polymer matrix diffusion-controlled patch according to claim 2 wherein the drug reservoir (1) comprises a pressure-sensitive adhesive polymer wherein (I) and (II) are homogeneously dispersed. ,„„„ 97/06788

-14-

18. A polymer matrix gradient-controlled patch according to claim 2 wherein the drug reservoir (1) comprises multilaminate adhesive layers of a pressure-sensitive adhesive polymer wherein (I) and (II) are dispersed in a proportional manner thus forming a concentration gradient which raises from the skin contacting surface towards the drug-impermeable layer (2).

19. A microreservoir partition-controlled patch according to claim 2 wherein the drug reservoir (1) comprises a matrix of a hydrophilic or lipophilic polymer wherein many discrete, unleachable, microscopic drug reservoirs comprising (I) and (H) are homogeneously dispersed, said drug reservoir (1) being mounted onto an occlusive baseplate (5) in a compartment fabricated from the drug-impermeable backing (2), and wherein the adhesive layer (3) is applied along the circumference of the patch to form a strip of adhesive rim surrounding the drug reservoir (1).

20. A process for inducing and maintaining an antitumour effect, which comprises administering vorozole through an area of intact skin at a therapeutically effective rate for an extended period of time with a medical patch as claimed in any one of the claims 1 to 16.