AU633207B2 - Compositions comprising cytotoxic agent and permeation enhancers - Google Patents

Description

OPI DATE 30/10/91 AOJP DATE 05/12/91 APPLN. TP 75620 91 PCT NUMBER PCT/US91/01987 Pcr INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 5 (11) International Publication Number: WO 91/15210 A61K 31/505, 47/10, 47/22 Al A61K 47/26 (43) International Publication Date: 17 October 1991 (17.10.91) (21) International Application Number: PCT/US91/01987 (74) Agents: LARSON, Jacqueline, S. et al.; Alza Corporation, P.O. Box 10950, Palo Alto, CA 94303-0802 (US).

(22) International Filing Date: 25 March 1991 (25.03.91) (81) Designated States: AT (European patent), AU, BE (Euro- Priority data: pean patent), CH (European patent), DE (European pa- 502,488 30 March 1990 (30.03.90) US tent), DK (European patent), ES (European patent), FI, FR (European patent), GB (European patent), GR (European patent), IT (European patent), JP, KR, LU (Eu- (71)Applicant: ALZA CORPORATION [US/US]; 950 Page ropean patent), NL (European patent), NO, SE (Euro- Mill Road, Palo Alto, CA 94303-0802 pean patent).

(72) Inventors: CORMIER, Michel, N. 1240 Dale Avenue, #42, Mountain View, CA 94040 TASKOVICH, Li- Published na, T. 751 Gailen Avenue, Palo Alto. CA 94303 With international search report.

YUM, Su, II 1021 Runnymead Court, Los Altos, CA Before the expiration of the time limit for amending the 94022 claims and to be republished in the event of 4te receipt of amendments.

(54)Title: COMPOSITIONS COMPRISING CYTOTOXIC AGENT AND PERMEATION ENHANCERS (57) Abstract The present invention is directed to a composition of matter for the percutaneous administration of a cytotoxic agent, and particularly to the percutaneous administration of 5-fluorouracil. The composition comprises, in combination, the cytotoxic agent to be administered and a permeation-enhancing mixture that includes a lower alkanol, propylene glycol or a mixture of polyethylene glycols, a third permeation enhancer and, optionally, a covehicle. The invention is also directed to a method for treating malignant and non-malignant skin disorders and comprises applying to an area of skin affected by a skin disorder, a therapeutically effective amount of the composition of this invention.

I I r I WO 91/15210 PCT/US91/01987 1 COMPOSITIONS COMPRISING CYTOTOXIC AGENT AND PERMEATION ENHANCERS FIELD OF THE INVENTION This invention relates to the delivery of cytotoxic agents.

More particularly, this invention relates to novel compositions for enhancing the percutaneous absorption of cytotoxic agents. Still more particularly, but without limitation thereto, this invention 1o relates to the delivery of a cytotoxic agent such as to the skin utilizing a permeation-enhancing mixture of a lower alkanol, propylene glycol or a mixture of polyethylene glycols, and a third permeation enhancer.

:s BACKGROUND OF THE INVENTION Traditional treatments of malignant tumors of the skin such as actinic keratosis and superficial basal cell carcinoma and nonmalignant skin disorders such as psoriasis have included daily or more frequent application of cytotoxic agents such as fluorouracil with or without an occlusive dressing to the affected area.

Penetrating solvents have been investigated for enhancing percutaneous absorption of certain cytotoxic agents in an effort to more successfully treat more resistive conditions. Severe skin inflammation from damage to treated tissue by the cytotoxic agent typically occurs with this treatment, severely limiting its usefulness.

A method based on the timing of administration of a cytotoxic agent in a penetrating solvent, preferably without occlusion, is disclosed in U.S. Pat. Nos. 4,820,711, 4,849,426 and 4,853,388 for the treatment of actinic keratosis or psoriasis with less damage to treated tissue.

Fluorouracil (5-fluorouracil or 5-FU) is a fluorinated pyrimidine antineoplastic agent that acts as an antimetabolite to uracil. It interferes with DNA synthesis by inhibiting thymidylate a WO 91/15210 PCT/US91/01987 2 synthetase activity. Thymidylate synthetase catalyzes the methylation of deoxyuridylic acid to thymidylic acid, a DNA precursor. It also inhibits, to a lesser extent, the formation of RNA. The effects of DNA and RNA deprivation are most marked on those s cells which grow more rapidly and which take up fluorouracil at a more raDid pace.

Fluorouracil is used topically for the treatment of actinic or solar keratosis and also for the treatment of other tumors of the skin such as Bowen's disease and superficial basal cell carcinoma Pat. No. 4,849,426; Physicians Desk Reference, 43rd Ed., Medical Economics Company (1989) p 1729; Martindale, The Extra Pharmacopoeia, 28th Ed., The Pharmaceutical Press, (1982) pp 210-211]. It has also been reported to be useful in the treatment of psoriasis and other non-malignant skin disorders Pat. No.

4,853,388; Pearlman et al. (1986) J. Am. Acad. Dermatol. 15:1247; Martindale, supra, p 211].

Fluorouracil is available commercially as a 1% topical solution in propylene glycol under the name FLUOROPLEX® (Herbert Laboratories division, Allergan Pharmaceuticals). It is also available as a 2% or topical solution in propylene glycol or as a 5% cream under the name EFUDEX® (Roche Laboratories division, Hoffmann-La Roche Inc.).

The principal barrier to topical delivery of drugs to the skin is the stratum corneum, the outermost layer of the skin comprising keratin-rich cells embedded in multiple lipid bilayers, which presents a highly impermeable barrier. Such impermeability of the skin is essential to the well-being of a living organism, preventing ingress of mest materials including pharmaceutical agents. Because of the advantages of dermal application of pharmaceutically active agents, methods of increasing skin permeability have been sought. In an effort to increase skin permeability, it has been proposed to usp various penetrating solvents with cytotoxic agents such as fluorouracil, as described in, for example, U.S. 4,820,711, 4,849,426 and 4,853,388, which also cite several other references on the subject. Examples of such penetration enhancers include, for L~ 1 ~a~--p-eccl I~B i 3 ARC 1800 example, certain essential oils such as eucalyptus and chenopodium, substituted azacycloalkan-2-ones such as Azone® (1-dodecylazacycloheptan-2-one), bis-azacyclopentanonyl alkanes, dimethylsulfoxide (DMSO), lower alkyl amides, dimethylacetamide (DMA), dimethyl s formamide (DMF), 1-methyl-2-pyrrolidone, n-decylmethyl sulfoxide, propylene glycol, and tertiary amine oxides.

The present invention greatly increases drug permeability through the skin. While it is known in the art to use permeation io enhancers singly or together in a binary system in combination with pharmaceutical agents, this invention utilizes a novel combination of three enhancers in a permeation-enhancing mixture with a cytotoxic agent such as 5-fluorouracil. The combined effect produces a significant improvement.

SUMMARY OF THE INVENTION The present invention is directed to a composition of matter for the percutaneous administration of a cytotoxic agent, and particularly to the percutaneous administration of The composition comprises, in combination, the cytotoxic agent to be administered and a permeation-enhancing mixture that includes a lower alkanol, propylene glycol or a mixture of polyethylene glycols, a third permeation enhancer and, optionally, a covehicle.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the distribution of 5-fluorouracil in epidermis and dermis of the hairless guinea pig after 24 h permeation from various permeation-enhancing mixtures.

FIG. 2 presents a comparison of 5-fluorouracil distribution between stratum corneum epidermis and dermis in -(SUBSTITUTE

SS-EET

r i ARC 1800 hairless guinea pig after 24 h permeation from various permeationenhancing mixtures.

DETAILED DESCRIPTION OF THE INVENTION This invention codelivers a lower alkanol, propylene glycol and/or a mixture of polyethylene glycols, and a third permeation enhancer to aid in delivery of cytotoxic agents such as 5-fluorouracil across the skin. Their combined effect according to this invention has been shown to produce dramatic increases in the permeation of together with a significant reduction on lag time. Improved enhancement of permeation according to this invention can be obtained over a relatively wide range of weight ratios.

According to one aspect of the present invention, therefore, there is provided a composition of matter for percutaneous administration of a cytotoxic agent, which composition comprises a cytotoxic agent to be administered and a permeation-enhancing mixture; characterized in that the said mixture comprises:i) a lower alkanol, ii) propylene glycol and/or a mixture of polyethylene glycols, and iii) a third permeation enhancer selected from lactones; butyrolactone; substituted azacycloalkan-2-ones; azacycloalkan-2-ones having 5 to 7 carbons in the cycloalkyl group; Azone®; amides; dimethylacetamide (DMA); dimethyl formamide (DMF); dimethyl lauramide; propylcne carbonate; polyethylene glycol monolaurate; sorbitan monolaurate; sucrose monolaurate; sucrose monncocoate; pyrrolidones; octyl pyrrolidone; dimethylbutylurea; methyl glycerol monooleate; oleic acid; and propionic acid.

Suitable concentrations of the cytotoxic agent in the composition will depend upon the choice of agent. When the cytooxic Vt SUBSTITUlTEiS L- 4 a ARC 1800 agent is 5-fluorouracil, it may be present in the composition in an amount ranging from about 0.001 to about 10% by weight, preferably from about 0.1 to about 5% by weight, and more preferably from about to about 3% by weight. The permeation-enhancing mixture may be present in an amount ranging from about 90 to about 99.999% by weight, preferably from about 95 to about 99.9% by weight, and more preferably from about 97 to about 99.5% by weight.

The permeation-enhancing mixture may include a covehicle.

o Suitable cytotoxic agents for use in this invention include '4' SU62iT!.s' 5 JT'

I

ARC 1800 colchicine, vinblastine sulfate, cyclophosphamide, azathioprine, cyclocytidine, azocytidine, azaserine, cisplatin, cycloheximide, mechlorethamine, cycloleucine, cytarabine, dacarbazine, dactinomycin, dichloromethotrexate, emetrine hydrochloride, etoposide, quanazole, hydroxyurea, idoxuridine, mercaptopurine, methotrexate, methyl GAG (methylglyoxal bis(guanylhydrazone)), metoprine, pyrimethamine, thioguanine, thiotepa, vincristine sulfate, and cyclosporin A. 5-Fluorouracil is preferred.

The term, "lower alkanol," as used herein, refers to an alkanol of two to four carbon atoms. An alkanol of two or three carbons is preferred, and ethanol is more preferred. The lower alkanol is present in the permeation-enhancing mixture in an amount of between about 5% and about 75% by weight, preferably between about 10% and about 50% by weight.

The propylene glycol in the permeation-enhancing mixture may be partially or totally replaced by a mixture of polyethylene glycols of different molecular weight (from 100 to 10,000) in order to modify the rheology of the formulation. The total amount of propylene glycol and/or polyethylene glycols present in the permeationenhancing mixture is between about 5% and about 75% by weight, preferably between about 10% and about 50% by weight.

The third permeation enhancer may be compatible in the mixture with the lower alkanol and propylene glycol or polyethylene glycols and in combination will enhance percutaneous penetration of the cytotoxic agent such that the drug delivery rate is at therapeutic levels. Additionally, the enhancer, when applied to the skin surface, may be non-toxic, non-irritating on' prolonged exposure and under occlusion, non-sensitizing on repeated exposure and essentially free from other adverse side effects.

1*j L -i C lllrs n 6 ARC 1800 Preferably, the third permeation enhancer is selected from propylene carbonate, butyrolactone, sucrose monolaurate and sucrose monococoate. The third permeation enhancer is present in the permeation-enhancing mixture in an amount between about I% and about 75% by weight, typically between about 10% and about 40% by weight.

The covehicle, when present in the permeation-enhancing mixture, may be chosen to be soluble within the enhancer composition.

Representative covehicles include water, mineral oil, silicone oil, ethylene-vinyl acetate polymers or other low molecular weight polymers soluble in water, lower alcohols or suitable oils.

Preferred are water and mineral oil, with water more preferred. The covehicle is generally present in the permeation-enhancing mixture in an amount from 0% to about 60% by weight.

The pH of the formulation may be conveniently in the range of 2 to 10 and is preferably in the range of 4 to 8. The pH of the formulation may be adjusted with sodium hydroxide or hydrochloric acid and/or a buffering agent such as, for example, phosphate, TRIS, HEPES, or EPPS. Thus, where it is necessary to adjust the pH of the formulation, it is preferred to use an aqueous buffer as the covehicle.

The present invention greatly increases drug permeability through the skin. It also significantly reduces the lag time between application of the drug to the skin and delivery of the drug through the stratum corneum. These are very desirable attributes because many cytotoxic agents, such as 5-fluorouracil, are toxic if allowed to remain on the skin surface. Therefore, a short surface exposure time is better. To obtain a short exposure time while delivering a therapeutically useful amount of agent, a high flux rate is need; a SUBSTITtUTE SE T ~I WO 91/15210 PCT/US91/01987 7 short lag time is also helpful. As a result, less of the cytotoxic agent is required to be applied to the treated sites to deliver equal or greater amounts of drug through the stratum corneum into the epidermis and especially into the dermis. At the same time, the Sagent is removed quickly from the surface of the skin into the epidermis and dermis. This, in turn, provides greater efficiency by using less of the toxic material and also results in less irritation and other dermatological side effects to the skin during relatively short exposure about one to 24 hours).

According to the invention, the cytotoxic agent and the permeation-enhancing mixture are placed in transmitting relationship to the skin area having the skin disorder, preferably in a pharmaceutically acceptable carrier therefor. The drug and the :s permeation-enhancing mixture are typically dispersed within a physiologically compatible matrix or carrier which may be applied directly to the body as a lotion, cream, ointment, gel or solution, preferably a lotion, cream or solution. Such compositions can also contain stabilizers, dyes, diluents, pigments, vehicles, inert fillers, excipients, gelling agents, buffers and otner components of topical compositions as is known to the art.

When the composition is applied to the skin, it may be desirable to occlude the site of administration. Occlusion has been found, in treatment of psoriasis with corticosteroids for example, to increase the effectiveness of the treatment. However, occlusion of prior art topical solutions of 5-FU has resulted in reported serious local toxicities such as erosions and even severe burns. But because the present invention gives greatly enhanced permeability, less is required in a topical comosition, resulting in a much lower and acceptable degree of local toxicity to the treated site during relatively short exposure about one to 24 hours), whether the site is occluded or not.

3s In other embodiments, the cytotoxic agent and the permeationenhancing mixture would be administered from a transdermal delivery Lc- WO 91/15210 PCT/US91/0198 8 device, such as those described in, for example, U.S. Pat. Nos.

3,598,122, 3,598,123, 4,379,454, 4,286,592, 4,314,557 and 4,568.343.

In the practice of the present invention, the composition containing the cytotoxic agent and the permeation-enhancing mixture is applied to an area of skin having the skin disorder in a quantity sufficient to wet or cover the surface and to provide a therapeutically effective amount of the cytotoxic agent to the skin.

By "therapeutically effective amount" is meant an amount of cytotoxic io agent that provides a desired effective therapeutic treatment of the targeted skin disorder. The treated area may or may not be occluded.

In a preferred embodiment, the treated area is not occluded.

The following examples are offered to illustrate the practice of the present invention and are not intended to limit the invention in any manner.

The permeation enhancer/vehicle mixtures used in the following examples were chosen from those listed in Table A below, to which was added an amount of 5-fluorouracil and trace amounts of radiolabelled (available from New England Nuclear), to 80% of saturation.

z 1 L_ _C~eq_ I WO 91/15210 PCT/US91/0198- 9 TABLE A wt/wt Composition No. Permeation Enhancer PE EtOH Propylene Glycol HEPPS* Control 100 s I Sucrose Monococoate 30 20 20

(SMC)

II Sucrose Monococoate 30 20

(SMC)

III Propylene Carbonate 30 20 20

(PC)

IV Butyrolactone (BL) 30 20 20 V Efudex® (absent) (present) VI 5FU/TEA 22.22 22.22 55.55 ic buffer, 0.05 M to pH 6.2 TRIS buffer to pH 8.9 molar ratio of 5-FU to triethanolamine The Efudex® used in the following examples was a commercial preparation from Roche consisting of 5% wt/wt fluorouracil compounded with propylene glycol, tris(hydroxymethyl) aminomethane, hydroxypropyl cellulose, parabens (methyl and propyl) and disodium edetate. The Efudex was labelled with a tracer amount of 3 EXAMPLE 1 To determine the in vitro permeation of 5-fluorouracil through human epidermis using various permeation-enhancing mixtures (selected from Table circular pieces (1.63 cm 2 of human breast epidermis were mounted on horizontal permeation cells with the stratum corneum facing the donor compartment of the cell. A known volume (20-23 ml) of water (receptor solution) was placed in the receptor compartment.

The cells were then placed in a water bath-shaker at 37'C and allowed to come to temperature. 0.2 mL of the donor solution (containing FU at 80% of saturation in the permrction-enhancing mixture) was transferred to the donor compartment. At 5, 24 and 48 hours, the receptor solutions were removed and replaced with equal volumes of fresh receptor solution previously equilibrated to 37°C. To determine the drug concentration in the removed receptor solutions, s~- WO 91/15210 PCT/US91/01987 aliquots of the receptor solutions were filtered and weighed in scintillation vials and counted with Aquassure® scintillation fluor (New England Nuclear).

At the end of'the permeation tests, the pieces of epidermis were removed and rinsed once with the corresponding permeationenhancing mixture, followed by a rinse in 25% EtOH and two rinses in water. The epidermis was then blotted between two pieces of filter paper and weighed in a scintillation vial, digested with NCS solubilizer and counted with toluene fluor to determine the drug concentration in the epidermis.

The counts of all the samples and the corresponding specific activity standards were corrected to disintegrations per minute (DPM) :s by means of established quench curve programs.

The in vitro flux of 5-FU through human epidermis from each of formulations I, II, IV and VI was higher than the flux of the drug from Efudex or from the control. The highest permeation of through human epidermis, and also with the shortest lag time, was obtained from formulation I with a drug flux of 11.9 gg/cm 2 -hr at the sampling and 14.2 pg/cm 2 -hr at the 24-hr sampling. The complete results are presented in Table B below.

1 -e i -3 1 L~-II i WO 91/15210 PCT/US91/0198" 11 TABLE B Donor Soln. Flux Epidermal Conc.* (uq/cm 2 -hr) Drug Content No. (mq/q) 5 hr 24 hr (uq/cm 2 (uq/cm 2 Control 15.6 0.16 0.30 0.82 15.4 I 15.6 11.9 14.2 332 16.4 13 II 14.6 0.90 5.73 114 11.2 IV 28.4 1.53 12.28 242 69.3 VI 25.2 5.15 4.11 107 35.7 V Efudex 50.0 0.77 1.75 38 25.2 at 80% of saturation cumulative amount of drug permeated through epidermis at 24 hours EXAMPLE 2 The in vivo permeation of 5-fluorouracil through hairless guinea pig skin using various permeation-enhancing mixtures (chosen from Table A) was determined following the procedure described by Schalla and Schaefer [Localization of compounds in different skin layers and its use as an indicator of percutaneous absorption. In: 3o Percutaneous absorption: mechanisms, methodology, drug delivery.

R.L. Bronaugh and H.I. Maibach, eds., New York: Marcel Dekker Inc., (1985)]. Hairless guinea pigs (IAS/HA-HO, Charles River) weighing 450 to 700 g were anesthetized, and the dorsal skin of each animal was washed with a soap solution, rinsed thoroughly with water and dried. 100 uL of each drug donor solution was applied to 3.63 cm 2 sites within glass rings cemented to the dorsal skin. The open 2nd of the glass ring was sealed with a plastic disc, and the animals were wrapped with gauze and placed in individual cages with food and water ad libitum. After 24 hr, the glass ring was removed, the excess donor solution was wiped off the skin, and the sites were washed three times with a soap solution. The sites were then rinsed with water and examined for erythema. The guinea pigs were sacrificed, and a large piece of skin including the application site was excised from each guinea pig for stripping and sectioning.

I

~I WO 91/15210 PCT/US91/01987 12 To remove the stratum corneum by stripping, a piece of adhesive tape larger than the application site was placed on the skin and a pressure of 40 g/cm 2 was applied over the entire site. The tape was then "stripped" off with a swift motion. The skin was stripped in this way 20 to 25 times to remove as much stratum corneum as possible. Each piece of tape was incubated 24 h at room temperature in 15 ml of Aquassure and the radioactive content was measured by scintillation counting. The full thickness of remaining skin was then inverted and frozen at -80°C. Three punch biopsies 6 mm in diameter were cut out from each site and each biopsy was frozen and sectioned parallel to the surface of the epidermis in a cryostat.

Each section was then incubated 24 h in 15 ml of Aquassure and the radioactive content was measured.

1s During the above procedure, representative samples of skin (stripped and normal) were removed and fixed for histology processing (staining with Kasson's trichrome).

Results of 5-FU distribution in tape strips of the stratum corneum are expressed as Ag/cm 2 calculated from its known specific activity. Drug concentrations were not calculated, as the volume of stratum corneum recovered on each tape could not be determined. In the epidermis and dermis, 5-FU distribution is expressed as pg/cm' of tissue. Finally, the total quantities of the drug in the stratum 2z corneum, epidermis and dermis are expressed in gg/cm 2 For each experimental condition, two animals were used (one site per animal).

The stripping was performed on the entire site and the sectioning on three biopsies. of 0.28 cm 2 After tape stripping, the guinea pig skin presented only a few remaining cornified layers at the surface of the epidermis. The epidermis was 30 to 40 im thick. The total thickness of the skin was about 1200 gm.

The distribution profile of 5-FU in the stratum corneum was similar with all formulations, although the total amount of recovered in the stratum corneum varied from 2.2 0.7 pg/cm 2 (formulation II) to 11.7 4.1 gg/cm 2 (formulation IV) (Table C).

Differences in the distribution profile were apparent in the L l lbll II~C1 Cql~-: WO 91/15210 PCT/US91/01987 13 epidermis, but these were not statistically significant. In the dermis, 5-FU concentrations were consistently higher after permeation from formulation I than from the four other formulations. The total amount of 5-FU recovered in the dermis ranged from 0.9 0.1 g/cm 2 (formulation V) to 2.9 0.8 gg/cm' (formulation I) (Table See, also, FIGS. 1 and 2.

TABLE C Donor Soln. Total Amount 5-FU Recovered (uq/cm 2 Conc. Stratum No. wt/wt) Corneum Epidermis Dermis I 1.6 7.6 0.1 1.3 0.4 2.9 0.8 II 1.6 2.2 0.7 0.7 0.2 0.9 0.2 III 2.9 10.6 2.1 0.9 0.2 1.4 0.4 IV 3.1 11.7 4.1 1.5 0.5 2.1 0.7 V Efudex 5.0 3.3 1.0 0.6 0.2 0.9 0.1 While the present invention has been described and illustrated with reference to certain preferred embodiments thereof, it should not be construed as being limited thereto. Various modifications, changes, omissions, and substitutions that are obvious to those of skill in the art can be effected within the spirit and scope of the invention and are intended to be within the scope of the following claims.

Claims (9)

1. A composition of matter for the treatment of a skin disorder, which composition comprises a cytotoxic agent to be administered and a permeation-enhancing mixture; characterized in that the said permeation-enhancing mixture comprises:- i) 5-75% by weight of a lower alkanol, ii) 5-75% by weight of propylene glycol and/or a mixture of polyethylene glycols, and iii) 1-75% by weight of a third permeation enhancer selected from lactones; butyrolactone; substituted azacycloalkan-2-ones; azacycloalkan-2-ones having to 7 carbons in the cycloalkyl group; Azone@; amides; dimethylacetamide (DMA); dimethyl formamide (DMF); dimethyl lauramide; propylene carbonate; polyethylene glycol monolaurate; sorbitan monolaurate; sucrose monolaurate; sucrose monococoate; pyrrolidones; octyl pyrrolidone; dimethylbutylurea; methyl gluceth-10; glycerol monooleate; oleic acid; and propionic acid.

2. A composition as claimed in claim 1, wherein the cytotoxic agent is

3. A composition as claimed in claim 1 and claim 2 wherein the said permeation-enhancing mixture also comprises a covehicle.

4. A composition as claimed in claim 3, wherein the permeation-enhancing mixture includes up to 60% by weight of covehicle.

A composition as claimed in claim 3 or claim 4 wherein the covehicle is water or an aqueous buffer. ^s kiJ',Tn Br:?I ARC 1800

6. A composition as claimed in any preceding claim,wherein the composition comprises about 0.001 to about 10% by weight cytotoxic agent and about 90 to about 99.999% by weight permeation- enhancing mixture.

7. A composition as claimed in any preceding claim,wherein the composition comprises about 0.1 to about 5% by weight cytotoxic agent and about 95 to about 99.9% by weight permeation-enhancing mixture.

8. A composition as claimed in any preceding claim wherein the lower alkanol is present in an amount between 10 and 50% by weight, propylene glycol and/or mixture of polyethylene glycols is present in an amount between 10 and 50% by weight, and the third permeation enhancer is present in an amount between 10 and 40% by weight.

9. A composition as claimed in any preceding claim wherein the lower alkanol is ethanol. j"''i