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(11) EP 2 214 643 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 9/00 (2006.01) A61K 47/32 (2006.01) 02.04.2014 Bulletin 2014/14 A61K 31/56 (2006.01) A61K 31/57 (2006.01) A61K 47/14 (2006.01) A61K 9/12 (2006.01) (2006.01) (21) Application number: 08845547.2 A61K 47/10

(22) Date of filing: 31.10.2008 (86) International application number: PCT/AU2008/001613

(87) International publication number: WO 2009/055859 (07.05.2009 Gazette 2009/19)

(54) DELIVERY SYSTEM FOR AND TRANSDERMALES FREISETZUNGSSYSTEM FÜR UND STEROIDE SYSTÈME D’ADMINISTRATION TRANSDERMIQUE POUR HORMONES ET STÉROÏDES

(84) Designated Contracting States: (56) References cited: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR EP-A2- 0 328 806 EP-A2- 0 409 383 HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT WO-A1-00/44347 WO-A1-93/10201 RO SE SI SK TR WO-A1-94/06452 WO-A1-94/07478 WO-A1-03/039597 WO-A1-2007/016766 (30) Priority: 02.11.2007 US 984787 P WO-A2-00/45795 US-A1- 2006 275 218 US-B2- 6 818 226 (43) Date of publication of application: 11.08.2010 Bulletin 2010/32 • MORGAN, T.M. ET AL.: ’Transdermal delivery of in postmenopausal women with a novel (73) Proprietor: Acrux DDS Pty Ltd topical aerosol’ J. PHARMA. SCI. vol. 87, no. 10, West Melbourne, Victoria 3003 (AU) 1998, pages 1226 - 1228, XP000777994 • MORGAN, T.M. ET AL.: ’Enhanced Transdermal (72) Inventors: delivery of sex hormones in swine with a novel • SETIAWAN, Kerrie topical aerosol.’ J. PHARMA. SCI. vol. 87, no. 10, West Melbourne, Victoria 3003 (AU) 1998, pages 1219 - 1225, XP000777993 • WATKINSON, Adam • OSBOURNE, DW ET AL.: ’ penetration West Melbourne, Victoria 3003 (AU) Enhancers cited in the technical literature’ PHARMACEUTICAL TECHNOLOGY. November (74) Representative: Schnappauf, Georg et al 1997, pages 58 - 66, XP008134247 ZSP Patentanwälte • H.-Y. THONG ET AL.: ’Percutaneous Penetration Partnerschaftsgesellschaft Enhancers: An Overview.’ SKIN PHARMACOL Radlkoferstrasse 2 PHYSIOL. vol. 20, 2007, pages 272 - 282, 81373 München (DE) XP009139652

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 214 643 B1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 214 643 B1 2

Description (’topical application’), the agent must partition firstly from the vehicle into the stratum corneum, it must typically Field then diffuse within the stratum corneum before partition- ing from the stratum corneum to the viable epidermis. [0001] This invention relates to a transdermal delivery 5 [0007] A transdermal "patch" typically consists of a ma- system and to a transdermal delivery of hormones and trix or reservoir containing the to be administered, steroids. together with a backing layer, an adhesive and a protec- tive release liner. Release membranes may also be in- Background corporated. The delivery of through these systems 10 is either through passive diffusion, controlled by a semi- [0002] Steroids and hormones include sex hormones permeable release membrane, or is controlled by the ad- and certain adrenocortical hormones (). hesive/adhesive matrix. The system may also incorpo- The corticosteroids have numerous and diversified phys- rate drug penetration enhancers to increase the flux of iological functions and pharmacological effects. They in- the drug through the skin. fluence carbohydrate, , , and purine metabo- 15 [0008] Oneof the drawbacks ofthe current approaches lism; electrolyte and water balance; and the functions of to administering hormones and steroids is that the for- the cardiovascular system, the kidney, , mulations are typically in continuous contact with the nervous system, and other organs and tissues. Thera- skin. Creams and ointments or adhesives used in patch- peutically, the corticosteroids are used for treating hor- es can cause skin irritation and sensitisation. A significant monal insufficiencies, inflammation, and other condi-20 proportion of patch users suffer from skin irritation and tions, whereas the sex hormones are widely used for sensitisationdue to adhesives usedin the patch. Steroids contraception and hormonal insufficiencies, as well as and hormones, particularly the sex steroidal hormones for treating other conditions. have a relatively poor skin permeation and many patches [0003] The two main classes of sex steroids are an- require high loads of drug or large a surface area in order drogens and , of which the most important hu- 25 to provide effective levels. man derivatives are and estradiol (17p-es- [0009] The rate of drug delivery across a dermal sur- tradiol), respectively. Other contexts will Include pro- face can be increased by dermal penetration enhancers. gestagen as a third class of sex steroids, distinct from The problem with most known dermal penetration en- and estrogens. is the only nat- hancers is that they are often toxic, irritating or allergenic. urally-occurring human progestagen. Progestins are30 These enhancers tend to be proton accepting solvents synthetic sex hormones used in contraception either such as dimethylsulfoxide and dimethylacetamide. More alone or with estradiol. Androgens are often referred to recently, 2-pyrrolidine, N,N-diethyl-m-toluamide (Deet), as "male sex hormones", since they have masculinizing 1-dodecal-azacycloheptane-2-one (Azone), N, N effects, while estrogens and progestagens are consid- dimethylformamide, N-methyl-2-pyrrolidine and ered "female sex hormones" although all types are35 thioglycolate have been reported as effective enhancers. present in each gender, albeit at different levels. Andro- However, difficulties remain with because the problem gens may be used in treatment of reduced or in of irritation at the site of application. and/or difficulty in treatment of depression in both men and women. providing sufficient enhancement of transdermel absorp- [0004] Administration of hormones and steroids tion. through the skin (’transdermal delivery’) has received in- 40 [0010] WO 94/06452 discloses a of protein creased attention because it not only provides a poten- or peptide in triacetin or polyethylene glycol. tially simple dosage regime but it also provides a rela- [0011] WO 93/10201 discloses a pressure-sensitive tively controlled route for release of a hormone into the poly(N-vinyl lactam) adhesive composition. systemic circulation. However, transdermal drug delivery [0012] EP 0 409 383 discloses estradiol or other es- is complicated by the fact that the skin behaves as a45 trogen composition for topical application. natural barrier and therefore transport of agents through [0013] EP 0 328 806 describes a transdermal delivery the skin is a complex mechanism. system for or its derivatives. [0005] Structurally, the skin consists of two principle [0014] WO 2007/016766 discloses a transdermal de- parts, a relatively thin outermost layer (the ’epidermis’) livery formulation which includes an organic sulfoxide and a thicker inner region (the ’dermis’). The outermost 50 and a further compound selected from , layer of the epidermis (the ’stratum corneum’) consists fatty acid, azone-related compound and mixtures there- of flattened dead cells which are filled with . The of. region between the flattened dead cells of the stratum [0015] WO 00/44347 relates to a pharmaceutical com- corneum is filled with which form lamellar phases position for topical administration in the form of a medi- that are responsible for the natural barrier properties of 55 cated stick. the skin. [0016] The discussion of documents, acts, materials, [0006] For effective transdermal delivery of a pharma- devices, articles and the like is included in this specifica- cological agent that is applied to the surface of the skin tion solely for the purpose of providing a context for the

2 3 EP 2 214 643 B1 4 present invention. It is not suggested or represented that in to refer to a broad class of useful chemical and thera- any or all of these matters formed part of the prior art peutic agents. base or were common general knowledge in the field [0023] The term "pharmacological" in describing the relevant to the present invention as it existed before the agents contemplated herein is used in a broad sense to priority date of each claim of this application. 5 comprehend not only agents having a direct pharmaco- logical effect on the host, but also those having an indirect Summary or observable effect which is useful in the medical arts. The term pharmacological agent includes of [0017] The invention provides a transdermal delivery the agent which in vivo exerts the physiological effect. system comprising a composition comprising at least one 10 Steroids encompass compounds having the general cy- agent selected from hormones and steroids, a penetra- clopentanoperhydrophenanthrene ring system of formu- tion enhancer comprising a polyethylene glycol of aver- la: age molecular weight no more than 300, and a solvent selected from C2 to C4 alkanol and mixtures thereof in an amount in the range of from 70% to 95%, by weight 15 of the total composition. [0018] In a further aspect the invention provides a method of preparing a transdermal delivery system com- prising a composition for administration to an area of der- mal surface of a subject, the method comprising combin- 20 ing at least one pharmacological agent selected from hor- mones and steroids, a penetration enhancer comprising polyethylene glycol of average molecular weight no more [0024] Steroids vary by the functional groups attached than 300 and 70% to 95% by weight of the composition to these rings and the oxidation tate of the rings. The 25 of solvent selected from C2 to C4 alkanols and mixtures may be in the form of the active drug or may be thereof. a steroid which in vivo provides a more active [0019] The transdermal delivery system w ill preferably form of the steroid. The steroids include drugs and pro- be applied In a dose sufficient to provide an effective drugs which provide eutrogenic, androgenic glucocorti- amount of at least one pharmacological agent in the coid, adrenocortoid, anabolic or activity. Ex- bloodstream of an animal. 30 amples of steroids include, for example, dexametha- [0020] Preferably the animal is a human but the inven- sone, , dexamethasone tion also extends to the treatment of non-human animals. phosphate, , , , , , hy- Definitions drocortisone sodium phosphate, hydrocortisone sodium 35 succinate, , , prednisolone ace- [0021] It will be understood by those skilled in the art tate, prednisolone sodium phosphate, prednisolone teb- that the term polyethylene glycol does not include dieth- utate, prednisolone pivalate, , triamcinolo- ylene glycol (although diethylene glycol may if desired ne acetonide,triamcinolone hexacetonide, triamcinolone be present as an additional component). Polyethylene diacetate, , methylprednisolone ac- glycol of average molecular weight no more than 300 40 etate, methylprednisolone sodium succinate, flunsolide, includes polyethylene glycol of nominal average molec- beclomethasone dipropionate, sodium ular weight 200 and 300 wherein the average molecular phosphate, betamethasone, vetamethasone disodium weight is not more than 110% and not less than 90% phosphate, vetamethasone sodium phosphate, betam- (preferably not more than 105% and not less than 95%) ethasone acetate, betamethasone disodium phosphate, of the nominated value. Polyethylene glycol is of formula 45 acetate, , desoxycorti- H-[OCH2CH2]n-OH. An average molecular weight of no costerone, desoxycorticosterone acetate, desoxycorti- more than 300 means the average value of n is at least costerone pivalate, desoximethasone, estradiol, fludro- 3 and is generally from 3 to 6 such as 3, 4, 5 or 6 (although cortisone, acetate, acetate, the average need not be an integer) and more preferably fluorohydrocortisone, , , 3 to 5. Polyethylene glycol (PEG) is widely available from 50 , , , commercial suppliers in pharmaceutical grades and is , , methandrostenolone, sold in specified nominal molecular weights which gen- methylandrostenediol, methyl testosterone, erally signify that the average molecular weight is not , testosterone, , more than 105% and not less than 95% of the nominated testosteronepropionate, ,, estradiol ben- value. The viscosities and methods for molecular weight 55 zoate, , , , estrone determination are disclosed in USP NF Official Compen- benzoate, acetoxypregnenolone, acetate, dium of Standards Volume 11180-1182 [2007 Edition]. acetate, flurogestone acetate, hy- [0022] The term "pharmacological agent" is used here- droxymethylprogesterone, hydroxymethylprogesterone

3 5 EP 2 214 643 B1 6 acetate, hydroxyprogesterone,hydroxyprogesterone ac- drone acetate. The permeation rate of norethindrone rap- etate, hydroxyprogesterone caproate, ac- idly peaks after application, whereas norethindrone ac- etate, normethisterone, , progesterone, etate having a higher molecular weight reaches a maxi- ethynyl estradiol, , , ethister- mum after the norethindrone permeation rate begins to one, ethynodiol diacetate, norethindrone, norethindrone 5 decline, steroids having a free at a position acetate, , acetonide, fluran- on the steroid ring, such as the 17- position, the 3-posi- drenolone, hydrocortisone sodium succinate, methyl- tion, or at the 11-position on the fused ring. Particularly prednisolone sodium succinate, prednisolone phosphate preferred are steroidal hormones such as estrogens, pro- sodium, , sodium, gestins, and androgens. The corresponding steroid pro- , , , prometh- 10 drug (prosteroid) is defined as a corresponding structure olone, , testosterone phenylace- to the steroid where the free hydroxy at the 3,11 or 17 tate, , and norethynodrel. position has been reacted with an reactive moi- [0025] A "prodrug" is a pharmacological drug which is ety.Particularly preferred aresteroid derivatives acylated administered in an inactive or less active form and is me- at the 17 position hydroxyl for example by a C1-C12 al- tabilised into an active form. The prodrug itself may have 15 kanoyl group. Regardless of whether the steroid or the little or none of the desired activity until it interacts with corresponding prosteroid derivative is incorporated in the the systems of the body such as the skin or circulatory carrier composition as the dominant drug, each provides systems. Nonetheless hormones and steroids used in a source of steroid in the bloodstream to achieve the the transdermal delivery system of the invention include intended physiological effect which, in the case of the hormones and steroids which are prodrugs which on ad- 20 corresponding prosteroid, occurs through metabolic con- ministration form a more active hormone or steroid in vivo version of the derivative. A is the corre- during or after the process of transdermal administration. sponding structure to the steroid where the free hydroxy [0026] In yet another preferred embodiment, a prodrug group on the ring has been esterified. Examples of a ster- or a composition of prodrug mixed with the parent com- oid and its corresponding ester include estradiol and es- position has a permeation rate that is faster or slower 25 tradiol benzoate, estradiol 17-beta cypionate, estradiol thanan identicalcomposition havinga pharmacologically 17 propionate, estradiol hemisuccinate (eutocol), estra- equivalent amount of the parent drug. In still another pre- diol enanthate, , , ferred embodiment, the composition has a duration of and estradiol proprionate, etc. Another example is testo- the therapeutic effect that is longer or shorter than a com- sterone and its corresponding ester of testosterone such position having a pharmacologically equivalent amount 30 as 17 betacypionate, testosterone enanthate, testoster- of the parent drug alone. In another preferred embodi- one nicotinate, testosterone phenylacetate, testosterone ment, the prodrug is more lipophilic than the parent drug proprionate, etc. Also included are non- that have and the prodrug has a greater permeation rate through groups on the 17 position such as testosterone 17- the skin. Generally the Prohormones and prosteroids are hemiacetal, or that have groups on the 3-position variations or derivatives of the parent hormones or ster- 35 such as estradiol 3-methyl . oids which have groups cleavable under metabolic con- [0027] The terms "percutaneous" and "transdermal" ditions. Prodrugs become the parent drugs which are are used herein in the broadest sense to refer to being pharmaceutically active in vivo, when they undergo sol- able to pass through unbroken skin. volysis under physiological conditions or undergo enzy- [0028] Theterm "dermalpenetration enhancer" is used matic degradation. Prodrugs commonly known in the art 40 herein in its broadest sense to refer to an agent which include acid esters prepared by reaction of the parent improves the rate of percutaneous transport of active acids or alcohol with a suitable alcohol or acid respec- agents across the skin for use and delivery of active ctively, or amides prepared by reaction of the parent acid agents to organisms such as animals, whether it be for or amine compound with an amine or acid respectively, local application or systemic delivery. or basic groups reacted to form an acylated base deriv- 45 [0029] The term "non-occlusive" is used herein in its ative. Examples of prodrugs are discussed in, Bundgard, broadest sense to refer to not trapping or closing the skin Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam to the atmosphere by means of a patch device, fixed res- 1985; Silverman, The Organic Chemistry of Drug Design ervoir, application chamber, tape, bandage, sticking and Drug Action, pp. 352-401, Academic Press, San Di- plaster, or the like which remains on the skin at the site ego, Calif., 1992 and Burger’s Medicinal Chemistry and 50 of application for a prolonged length of time. It is partic- Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178,949-982 ularly preferred that the transdermal delivery system of (1995).The other methodfor controlling the blood plasma the invention is non-occlusive. profile of subject is in the selection of the prodrug, such [0030] The term "stratum corneum" is used herein in as based on its molecular weight or polarity. By increas- its broadest sense to refer to the outer layer of the skin, ing the molecular weight of the prodrug, the time to the 55 which is comprised of (approximately 15) layers of ter- onset of permeation of effective amounts of the prodrug minally differentiated keratinocytes made primarily of the will increase relatives to the parent drug. One example proteinaceous material keratin arranged in a ’brick and of this effect is in the use of norethindrone and norethin- mortar’ fashion with the mortar being comprised of a

4 7 EP 2 214 643 B1 8 matrix made primarily from , ceramides and agent. long chain fatty acids. The stratum corneum creates the [0038] Typically the PEG of average molecular weight rate limiting barrier for diffusion of the active agent across less than 300 will be present in an amount in the range the skin. of from 0.5 to 20% such as 1%, 1.5%, 2%, 2.5%, 3%, [0031] The term "skin-depot" is used herein in its5 3.5%, 4%. 4.5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, broadest sense to refer to a reservoir or deposit of active 14%, 15%, 16%, 17%, 18%, 19%, or 20%. Preferably agent and dermal penetration enhancer within the stra- the PEG of average molecular weight less than 300 is tum corneum, whether it be intra-cellular (within kerati- present in an amount in the range of from 0.5 to 15% and nocytes) or intercellular. most preferably from 0.5 to 10% by weight of the com- [0032] The term "volatile:non-volatile liquid vehicle" is 10 position. used in the art to refer to a liquid pharmaceutical vehicle [0039] The composition of the invention preferably comprising a volatile liquid mixed with a non-volatile liquid comprises PEG 200 in an amount in the range of from vehicle, such as a dermal penetration enhancer. A sys- 0.1 to 40% by weight of the total composition and pref- tem or vehicle comprising a volatile liquid mixed with a erably from 0.5 to 20% such as 1%, 1.5%, 2%, 2.5%, non-volatile dermal penetration enhancer when de-15 3%, 3.5%, 4%, 4.5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, scribed herein is used in its broadest sense to include 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%. those systems known as volatile: non-volatile liquid ve- [0040] Preferably the volatile solvent has a vapour hicles. pressure above 35 mm Hg at atmospheric pressure and [0033] The term "aliphatic" includes straight chain, normal skin temperature of 32 degrees Celsius. In a par- branched chain and cyclic aliphatic and may be saturated 20 ticularly preferred form of the invention the solvent pref- alkyl groups or unsaturated aliphatic containing from 1 erably is or isopropanol, or a mixture thereof. to 3 unsaturated groups particularly 1 to 3 double bonds. [0041] The volatile solvent is preferably present in the [0034] The transdermal drug delivery system of the composition of the invention in an amount in the range present invention enables a wide range of pharmacolog- of 70 to 90% or 75 to 90% by weight of the total compo- ical agents selected from hormones and steroids to be 25 sition. delivered through the skin to achieve a desired systemic [0042] The composition of the invention may if desired effect. The drug delivery system preferably comprises at contain one or more additional adjuvants such as those least one active agent intimately mixed with a non-volatile selected from the group consisting of penetration en- dermal penetration enhancer and a volatile liquid. Where hancers, surfactants, thickeners and solvents. Examples the drug delivery system is applied to the skin, at least 30 ofsuitable thickeners include polyacrylic acids; andacylic one active agent selected from hormones and steroids acid copolymers, agor, carrageenan, food starch, gelat- and non-volatile liquid are thermodynamically driven into ins, germ Arabic, guorgem, hydroxyethyl cellulose hy- the skin as the volatile liquid evaporates. Once within the droxypropymethyl cellulose, protein and polyvinyl pyrro- skin the non-volatile liquid may either disrupt the lipid lidone. The content of thickener may be from 0 to 5%. matrix and/or act as a solubilizer to allow an enhanced 35 [0043] In one embodiment the penetration enhancer penetration rate of the at least one active agent through component of the composition may comprise one or more the skin and into the subject being treated. In this way, additional penetration enhancers. Of particular note are the dermal penetration enhancer acts as a vehicle and esters of preferably selected from the Ce manysystemic active agentsare ableto be transdermally to C30 aliphatic ester of salicylic acid and more preferably 40 administered to an animal. C8 to C12 alkyl salicylate and most preferably octyl sali- [0035] The subject to be treated with the transdermal cylate particularly 2-ethylhexyl saliclate. When an ester delivery system is generally a , preferably a hu- of salicyclic acid is present in combination with polyeth- man being, male or female. The term "therapeutically ylene glycol, the weight ratio of the ester of salicylic add effective amount" means the amount of the subject com- to the polyethylene glycol (of average molecular weight pound that will elicit the biological or medical response 45 no more than 300) is preferably in the range of from 95:5 of a tissue, system, animal or human that is being sought. to 5:95 and preferably from to 1:10 to 10:1 such as 1:10 [0036] Throughout the description and the claims of to 5:1 and 1:5 to 2:1. The optimal ratio may vary depend- this specification the word "comprise" and variations of ing on the nature and concentration of the active agent the word, such as "comprising" and "comprises" is not and the concentration of the penetration enhancer com- intended to exclude other additives, components, inte- 50 bination. gers or steps. [0044] Known dermal penetration enhancers may be included in addition to PEG of molecular weight no more Detailed Description than 300. Examples of known penetration enhancers are laurocapram and laurocapram derivatives, such as those [0037] The present inventors have found that the use 55 1-alkylazacycloheptan-2-ones specified in U.S. Pat. No. of polyethylene glycol (of molecular weight no more than 5,196,410, and oleic acid and its ester derivatives, such 300) as a penetration enhancer shows a significant im- as methyl, ethyl, propyl, isopropyl, butyl, vinyl and glyc- provement in penetration enhancement of the active erylmonooleate, and those given in U.S. Pat. No.

5 9 EP 2 214 643 B1 10

5,082,866, particularly dodecyl (N,N-dimethylamino) ac- , conjugated estrogenic hormones, Pol- etate and dodecyl (N,N-dimethylamino) propionate and yestradiol phosphate and and mixtures thereof; in U.S. Pat. No. 4,861,764, particularly 2-n-nonyl-1-3-di- [0052] Progesterone and progestins such as norethis- oxolane. Most preferred known dermal penetration en- terone, , , levonorg- hancers are oleic acid and its ester derivatives, such as 5 estrel, , anagestone, , dimethis- methyl, ethyl, propyl, isopropyl, butyl, vinyl and glyceryl- terone, , , ethynodiol, Ethyn- monooleate, and those given in U.S. Pat. No. 5,082,866, odiol diacetate, , gestodene, ethinylestradi- particulary dodecyl (N,N-dimethylamino) acetate and do- ol, , 17-hydroxy-16-methylene-pro- decyl (N,N-dimethylamino) propionate and in U.S. Pat. gesterone, 17. alpha.- hydroxyprogesterone, lynestre- No. 4,861,764, particularly 2-n-nonyl-1-3-dioxolane. 10 nol, , melengestrol, norethin- [0045] Preferably the composition will comprise no drone, norethynodrel, , Gestonorone, more than 5% by weight of the other non-volatile pene- Norethisterone, , , Levonorg- tration enhancer more preferably no more than 1% and estrel, , , , most preferably no more than 0.5%by weight of the com- MENT (7-methyl-19-testosterone); , and position of non-volatile penetration enhancers other than 15 trimigestone , , and and PEG of molecular weight of no more than 300. mixtures thereof; [0046] In a preferred embodiment of the invention the [0053] Selective progesterone modulators composition consists essentially of: such as , CDB-4124 and mixtures thereof; [0054] Selective estrogen receptormodulators such as (i) at least one active selected from hormones and 20 , , , , steroids and more preferably steroidal sex hor- , , and mixtures there- mones; of; (ii) a penetration enhancer component consisting es- [0055] such as and mix- sentially of a polyethylene glycol of average molec- tures thereof. ular weight no more than 300; 25 [0056] such as and Gestri- (iii) a volatile solvent consisting of one or more of none and mixtures thereof; ethanol and isopropanol; [0057] such as acetate (iv) optionally a propellant. and danazol and mixtures thereof; [0058] such as tamoxifen and epitiosta- [0047] It will be understood by those skilled in the art 30 nol and the inhibitors, and 4-hy- that and polyols contain a certain amount of wa- droxy- and its derivatives and mixtures ter. Typically the total water content of the composition thereof. is less than 20% by weight and preferably less than 10% [0059] Androgens and anabolic agents such as andr- by weight of the total composition. oisoxazole, , , , [0048] The composition of the invention may be in a 35 , . formyldienolone, 4-hydroxy-19- range of forms such as a liquid, cream, paste, , lotion, nortestosterone, , methenolone, methyl- patch (matrix and reservoir), tape, plaster or film former. trienolone, , norbolethone, , In the more preferred embodiment the transdermal de- and . Androgenic steroids can in- livery system is in the form of a liquid for application to a clude , fluoxymesterone, , mes- defined area of skin. 40 terolone, methandrostenolone, 17-, [0049] The compositions of the present invention may 17. alpha.- methyltestosterone 3-cyclopentyl enol ether, be in any form suitable for topical application to the skin. norethandrolone, , oxandrolone, Suitable forms include sprayable liquids; ; liquids that oxymesterone, oxymetholone, , stanlolone, may be applied using a roll-on device; lacquers; and sus- , testosterone, testosterone 17-chloral hemia- tained release matrices of transdermal delivery devices 45 cetal, testosterone proprionate, testosterone enanthate such as patches. The compositions are usually adminis- (DHEA), andros- tered alone but, under some circumstances, administra- tenedione (Andro): an androstenediol, androsterone, di- tion may be further modified by using other delivery hydrotestosterone (DHT) and and deriv- mechanisms such as iontophoresism, ultrasound and atives thereof; microneedles to enhance penetration. Non-occlusive ap- 50 [0060] 5-alpha reductase inhibitors such as finas- plication and in particular spray application is preferred. teride, , LY-191704 and MK-306 and mixtures [0050] Suitable pharmacologically active hormones thereof; and steroids may be selected from: [0061] Corticosteroids such as betamethasone, beta- [0051] Estrogens such as estradiol, estriol, estradiol valerate, cortisone, dexamethasone, dexam- benzoate, estradiol 17. beta.-cypionate, estradiol enan- 55 ethasone 21-phosphate, fludrocortisone, flumethasone, thate, estradiol propionate, estrone, , , fluocinonide , fluocinolone, fluoc- , mestranol, stilboestrol, di-inolone acetonide, , , halopre- enoestrol, epioestriol, , done, hydrocortisone, hydrocortisone 17-valerate, hy-

6 11 EP 2 214 643 B1 12 drocortisone 17-butyrate, hydrocortisone 21-acetate [0072] Compositions of the invention may include a methylprednisolone, prednisolone, prednisolone 21- plurality of hormones from one or more of these groups. phosphate, prednisone, triamcinolone, triamcinolone ac- For example it may be desirable for contraceptive formu- etonide and mixtures thereof; lations to comprise one or more estrogens and one or [0062] Further examples of steroidal antiinflammatory 5 more progestins. agents for use in the instant compositions include include [0073] The transdermal delivery system may be used cortodoxone, fluoracetonide, fludrocortisone, difluor- to deliver a therapeutically effective amount of the hor- sone diacetate, flurandrenolone acetonide, , mone and/or steroid to a local area or to the systemic amcinafel, , betamethasone and its other es- circulation. In one embodiment the system provides a ters, chloroprednisone, clorcortelone, , des- 10 pharmaceutically effective level of the pharmacological onide, dichlorisone, , flucloronide, flumeth- agent in the systemic circulation, for example a pharma- asone, , flucortolone, fluoromethalone, fluper- ceutically effective blood level. In one preferred form of olone, fluprednisolone, , methylmepred- the invention the drug delivery system comprises on a nisolone, paramethasone, cortisone acetate, hydrocorti- weight basis from about 0.1 to about 10% of at least one sone cyclopentylpropionate, cortodoxone, flucetonide, 15 pharmacological agent selected from hormone and ster- fludrocortisone acetate, flurandrenolone acetonide, me- oids in an amount of from about 0.1 to 12% of the dermal drysone, , amcinafide, betamethasone, beta- penetration enhancer and from about 78 to 95% ethanol, methasone benzoate, chloroprednisone acetate, cloco- isopropanol or mixture thereof. rtolone acetate, descinolone acetonide, desoximeta- [0074] or conditions that may be treated by sone,dichlorisone acetate, difluprednate, flucloronide, 20 using the drug delivery system and methods of the flumethasone pivalate, flunisolide acetate, present invention include, but are not limited to, male acetate, fluprednisolone valerate,paramethasone ace- hormone replacement in testosterone deficient hypogo- tate, , prednival, triamdnolone hexaceto- nadal men, female hormone replacement therapy for nide, , and nivazol and mixtures postmenopausal women using for example estradiol, an- thereof; 25 drogen replacement therapy for females lacking libido [0063] such as Aminogluthetim- using an such as testosterone, male contra- ide, , Exemestane, , ception (for example using a progestin such etonogestrel and Vorozole; optionally with testosterone) and female contraception [0064] such as Clomifene and Urofoll- (for example using a progestin optionally in combination itropin; 30 with an estrogen). [0065] GnRH:(receptor) such as , [0075] In one embodiment the transdermal delivery , , , and Triptore- system further comprises a spray apparatus comprising lin; a container for a transdermal composition, a spray nozzle [0066] GnRHantagonist: , Cetrorelixand Gan- and an actuator for delivering a metered dose of spray lrelix; 35 from the container via the nozzle. [0067] Pituitary hormones and their active derivatives [0076] The transdermal delivery system will preferably or analogs such as corticotrophin, thyrotropin, follicle be applied in a dose sufficient to provide an effective stimulating hormone (FSH), luteinising hormone (LH) amount of the at least one pharmacological agent in the and gonadotrophin releasing hormone (GnRH); bloodstream of the animal. [0068] Thyroid hormones such as calcitonin, thyroxine 40 [0077] Preferably, the applicator provides a metered and liothyronine and antithyroid agents such as carbim- dose application such as a metered dose aerosol, a and propylthiouracil; and stored-energy metered dose pump or a manual metered [0069] Other miscellaneous hormone agents such dose pump. Preferably the drug delivery system is ap- asoctreotide; and mixtures from two or more of the plied to the skin of the animal covering a delivery surface groups. 45 area between about 10 and 800 cm2, more preferably [0070] The optimal ratio of penetration enhancer to ac- between about 10 and 400 cm 2, and most preferably be- tive will differ depending on the nature of the active and tween about 10 and 200 cm2. The application is most the penetration enhancer. Typically the weight ratio of preferably performed by means of a topical metered dose penetration enhancer to active will be in the range of from spray combined with an actuator nozzle shroud which 1000:1 to 1:1000 and preferably from 500:1 to 1:10 and 50 together accurately control the amount and/or uniformity most preferably from 20:1 to 1:1. of the dose applied. One function of the shroud is to keep [0071] The penetration enhancer used according to the nozzle at a pro-determined height above, and per- the invention is particularly useful in transdermal admin- pendicular to, the skin to which the drug delivery system istration of hormones. Hormones that may be used in the is being applied. This function may also be achieved by drug delivery system of the present invention include sys- 55 means of a spacer-bar or the like. Another function of the temically active hormones which can be delivered shroud is to enclose the area above the skin in order to through the skin with the assistance of the dermal pen- prevent or limit bounce-back and/or loss of the drug de- etration enhancer to achieve a desired effect. livery system to the surrounding environment. Preferably

7 13 EP 2 214 643 B1 14 the area of application defined by the shroud is substan- Example 1 tially circular in shape. [0078] The invention will now be described with refer- Investigation of the Effect of PEG200 on Cumulative ence to the following examples. It is to be understood Permeation of the progestin Norethisterone Acetate that the examples are provided by way of illustration of 5 and the Estrogen Estradiol Through In the invention and that they are in no way limiting to the Vitro. scope of the invention. Methods: Examples 10 Finite-dose diffusion studies were undertaken us- [0079] The compositions of the Examples and their ing dermatomed human female abdominal skin (500 performance are compared with reference to the draw- mm). ings. [0081] These experiments were performed over 24 Brief Description of Drawings 15 hours using Franz-type cells. Pre-cut skin membranes were mounted as a barrier between the halves of greased [0080] In the drawings: (high vacuum grease, BDH) horizontal Franz-type per- meation cells in the middle of the receptor chamber of Figure 1 is a column chart comparing the permeation the cell with the stratum corneum facing the donor cham- of a progestin + an estrogen from a control with pro- 20 ber. The area available for permeation was approximate- gestintransdermal delivery compositionof theinven- ly 0.925 cm2. The receptor chambers of the permeation tion containing PEG-200 pursuant to Example 1. cells were filled with the receptor phase (Phosphate Buff- ered Saline pH 7.4) and capped. The permeation cells Figures 2a and 2b are column charts showing the were immersed in a constant temperature water bath effect on progestin permeation of comparative25 such that the receptor chambers were maintained at transdermal compositions containing different pro- 35°C. Receptor chamber contents were continuously ag- gestins and PEG400 rather than PEG 200 as de- itated by small PTFE-coated magnetic stirrer bars driven scribed in Example 2. by submersible magnetic stirrers. The skin was allowed to equilibrate to temperature with receptor for 1 Figure 3 is a column chart which shows the effect of 30 h in the water bath prior to dosing. PEG 200 on the permeation of an androgen from [0082] The formulations were applied to the skin at a transdermal delivery compositions described in Ex- dose of 3.6 mL/cm2. The applied formulation was spread ample 3. over the skin area using an Eppendorf positive displace- ment pipette tip without breaking the skin membrane. Figure 4 and Figure 5 are column charts which com- 35 [0083] The formulations consisted of:- pare the effect of PEG 200 and PEG 400 respectively on permeation of an androgen from transdermal de- s Comparison composition 1: 2.8% Norethisterone livery compositions described in Example 4. Acetate (NETA), 0.55% Estradiol (E2), 5% Octyl Sal- icylate (OS) Figure 6 is a column chart examining the effect of 40 PEG 200 on permeation of an androgen from com- s Composition 2: 2.8% NETA, 0.55% E2, 5% Poly- positions of Example 5. Glycol 200 (PEG200)

Figure 7 is a column chart examining the effect of s Composition 3: 2.8% NETA, 0.55% E2, 5% OS, PEG 200 on the permeation of an estrogen from45 5% PEG200 transdermal delivery compositions described in Ex- ample 6. s Composition 4: 2.8% NETA, 0.55% E2, 10% PEG200 Figure 8 is a column chart showing the effect of PEG 200 on the permeation of the androgen testosterone 50 s Composition 5: 2.8% NETA, 0.55% E2, 5% OS, in the presence of another permeation enhancer as 10% PEG200 described in Example 7. [0084] The amount of active that permeated the skin was quantified using validated HPLC methods 55 [0085] Figure 1 compares the penetration of compar- ative composition 1 with compositions 2-5 relating to in- vention. PEG200 in combination with OS was found to significantly enhance the permeation of both Norethis-

8 15 EP 2 214 643 B1 16 terone Acetate and estradiol through human epidermis in vitro. PEG400 was found to inhibit the permeation of in vitro. Permeation of NETA is compared in Figure 1. ethinylestradiol through human epidermis in vitro.

Example 2 Example 3 5 Investigation Into the Effect of PEG200 and PEG400 Investigation Into the Effect of PEG200 on Cumula- on Cumulative Nestorone & Ethinylestradiol Perme- tive Testosterone Permeation Through Human Skin ation Through Human Skin In Vitro In Vitro

Methods: 10 Methods:

[0086] Finite-dose in vitro diffusion studies were un- [0093] Finite-dose in vitro diffusion studies were un- dertaken using dermatomed human female abdominal dertaken using dermatomed human female abdominal skin(500 mm). skin (500 mm). [0087] These experiments were performed over 24 15 [0094] These experiments were performed over 24 hours using stainless steel, flow through diffusion cells hours using stainless steel, flow through diffusion cells based on those described previously (Cooper, E.R. J. based on those described previously (Cooper, E.R. J. Pharm. Sci. 1984, 73, 1153-1156) except that the cell Pharm. Sci. 1984, 73, 1153-1156) except that the cell was modified to increase the diffusion area to 1.0cm2. was modified to increase the diffusion area to 1.0cm2. The formulations were applied using a finite dose tech- 20 The formulations were applied using a finite dose tech- nique (Franz, T.J. Curr. Probl. Dermatol., 1978, 7, 58-68) nique (Franz, T.J. Curr. Probl. Dermatol., 1978, 7, 58-68) to mimic clinical dosing conditions at an applied dose to mimic clinical dosing conditions at an applied dose volume of 3.6 mL /cm2. A piece of stainless steel wire volume of 3.6 mL /cm2. A piece of stainless steel wire mesh was placed directly below the skin in the receptor mesh was placed directly below the skin in the receptor chamber of the of the diffusion cell to maintain a turbulent 25 chamber of the of the diffusion cell to maintain a turbulent flow of receptor solution below the skin. The diffusion flow of receptor solution below the skin. The diffusion cells were maintained at a flow rate of approximately 0.5 cells were maintained at a flow rate of approximately 1.0 mL/hr by a microcassette peristaltic pump (Watson Mar- mL/hr by a microcassette peristaltic pump (Watson Mar- low 505S UK). The cells were kept at 32 6 0.5°C by a low 505S UK). The cells were kept at 32 6 0.5°C by a heater bar and the samples were collected into appro- 30 heater bar and the samples were collected into appro- priatelysized glassvials fora periodof 24 hr. The receptor priately sizedglass vials for a period of 24 hr. The receptor (Phosphate Buffered Saline pH7.4) maintained solutions (0.002%w/v NaN3) maintained sink conditions sink conditions below the skin. below the skin. [0088] The formulations consisted of:- [0095] The formulations consisted of:- 35 s Composition (Comp) 1 (Control): 1.35% Nestor- s Comp 1: 5% Testosterone (TES), in ethanol (95%) one (NES), 0.35% Ethinylestradiol (EE) in Isopropyl s Comp 2: 5% TES, 1.0% polyethylene glycol 200 Alcohol (IPA) (PEG200) in ethanol (95%) s Comp 3: 5% TES, 2.5% PEG200 in ethanol (95%) s Comp 2: 1.35% NES, 0.35% EE, 5% Polyethylene 40 glycol 400 (PEG400) in IPA Comp 3: 1.35% NES, [0096] The amount of active that permeated the skin 0.35% EE, 0.5% Polyethylene glycol (PEG200) in was quantified using validated HPLC methods. IPA [0097] The effect of the combination of PEG200 in Compositions 2 and 3 is compared with a control Com- [0089] The amount of active that permeated the skin 45 position 1 in Figure 3 As shown in Figure 3, PEG200 in was quantified using validated HPLC methods. was found to significantly enhance the permeation of [0090] The effect of PEG400 on permeation of NES Testosterone through human epidermis in vitro. and EE is shown in Figures 2a and 2b respectively. Fig- ures 2a and 2b: thus show Nestorone and Ethinylestra- Example 4 diol permeation respectively obtained from the applica- 50 tion of Composition 2 (not of the invention) compared Investigation into the Effect of PEG200 and PEG 400 against application of a control composition 1. on Cumulative Permeation of the AndrogenTesto- [0091] PEG200 in combination with OS was found to sterone from a lotion through Human Skin In Vitro. enhance the permeation of both Nestorone and Ethi- nylestradiol through human epidermis in vitro. 55 Methods: [0092] The addition of PEG400 to the formulation did not have a significant effect (enhancing or inhibitory) on [0098] Finite-dose in vitro permeation studies were un- the permeation of Nestorone through human epidermis dertaken using dermatomed skin (Padgett Model B or S

9 17 EP 2 214 643 B1 18 electricdermatome setat 500 mm) preparedfrom excised was placed in the receptor chamber of the of each per- female, abdominal tissue. meation cell to support the skin and to maintain a turbu- [0099] These experiments were conducted over 24 lent flow of receptor solution below the skin. The receptor hours (h) using flow-through systems with a 1-cm2 ad- solution was maintained at a nominal flow rate of 0.5 ministration area. A piece of stainless steel wire mesh 5 mL/h by a peristaltic pump (Watson Marlow 520S Peri- was placed in the receptor chamber of each permeation staltic Pump with313A adaptor and 308MC 8 roller pump- cell to support the skin and to maintain a turbulent flow head; Stauff Corporation, ). The cells were of receptor solution below the skin. The receptor solution placed on a heater bar to keep the temperature of the was maintained at a flow rate of approximately 0.5 mL/hr skin at 32 6 1°C. by a peristaltic pump (Watson Marlow 520S Peristaltic 10 [0106] Following a 2-h equilibration of the skin with the Pump with 313A adaptor and 308MC 8 roller pump-head; receptorsolution (RS; 0.002%sodium azide), thestratum Stauff Corporation, Australia). The cells were placed on corneum surface was dosed with 3.6 mL/cm2of a Metered a heater bar to keep the temperature of the skin at 32 6 Dose Transdermal Spray (MDTS) formulation using a 1°C. positive displacement pipette. The formulation was [0100] Following a 2-h equilibration of the skin with the 15 spread evenly over the skin area using the pipette tip. receptor solution (RS; 0.002% sodium azide), the stratum Permeation samples were collected into appropriately corneum surface was dosed with either 15 or 30 mL/cm2 sized glass vials for a period of 24 h. of an MD-Lotion formulation using a positive displace- [0107] The Metered Dose Transdermal Spray formu- ment pipette. The formulation was spread evenly over lations contained: the skin area using the pipette tip. Permeation samples 20 were collected into appropriately sized glass vials for a • Testosterone (TES), Polyethylene glycol 200 (PEG period of 24 h. 200) or Polyethylene glycol 400 (PEG 400) isopropyl [0101] The effect of the addition of Polyethylene glycol alcohol (IPA). 200 (PEG200) or Polyethylene glycol 400 (PEG 400) on the permeation of testosterone was investigated.25 [0108] The amount of active that permeated the skin 0.5-5%w/v PEG200 or PEG 400 was added to the fol- was quantified using validated HPLC methods and the lowing Testosterone (TES) Lotion formulation:-• Formu- results for PEG 200 are shown in Figure 6. lation: 2%w/v TES, 2%w/v polyvinylpyrrolidone (PVP) in (IPA). Results: [0102] The amount of active that permeated the skin 30 was quantified using validated HPLC methods. Results [0109] PEG200 increased the permeation of TES for PEG 200 are shown in Figure 4 and results for PEG through human skin in vitro. The addition of Adding PEG 400 are shown in Figure 5. 400 to the formulation did not result in any significant difference in the permeation of TES when compared with Results: 35 the control formulation.

[0103] PEG200 significantly enhanced the permeation Example 6 of TES through human skin in vitro. PEG400 did not have any effect on the permeation of TES through human skin Estradiol Spray: Investigation Into the Effect of in vitro. 40 PEG200 and PEG 400 on Estradiol Permeation Through Human Skin In Vitro Example 5 Methods: Investigation Into the Effect of PEG200 and PEG 400 on Cumulative Permeation of the Androgen Testo- 45 [0110] Finite-dose in vitro permeation studies were un- sterone Through Human Skin From a Transdermal dertaken using dermatomed skin (Padgett Model B or S Testosterone Composition Applied as a Spray In Vit- electric dermatome set at 500 mm)prepared fromexcised ro female, abdominal skin. [0111] These experiments were conducted over 24 Methods: 50 hours (h) using flow-through systems with a 1-cm2 ad- ministration area. A piece of stainless steel wire mesh [0104] Finite-dose in vitro permeation studies were un- was placed in the receptor chamber of the of each per- dertaken using dermatomed skin (Padgett Model B or S meation cell to support the skin and to maintain a turbu- electricdermatome setat 500 mm) preparedfrom excised lent flow of receptor solution below the skin. The receptor female, abdominal skin. 55 solution was maintained at a nominal flow rate of 0.5 [0105] These experiments were conducted over 24 mL/h by a peristaltic pump (Watson Marlow 520S Peri- hours (h) using flow-through systems with a 1-cm2 ad- staltic Pump with313A adaptor and 308MC 8 roller pump- ministration area. A piece of stainless steel wire mesh head; Stauff Corporation, Australia). The cells were

10 19 EP 2 214 643 B1 20 placed on a heater bar to keep the temperature of the s Comp 1: 2% Testosterone (TES), 5% Octyl Sali- skin at 32 6 1°C. cylate (OS), 2% polyvinyl pyrrolidine (PVP), 30% iso- [0112] Following a 2-h equilibration of the skin with the propyl alcohol (IPA) in ethanol (95%) receptor solution (RS; 0.002% sodium azide), the stratum s Comp 2: 2% TES, 5% OS, 2% PVP, 30% IPA, corneum surface was dosed with 3.6 mL/cm2 of an Es- 5 0.5% polyethylene glycol 200 (PEG200) in ethanol tradiol Transdermal Spray formulation using a positive (95%) displacementpipette. The formulation was spread evenly s Comp 3: 2% TES, 5% OS, 2% PVP, 30% IPA, over the skin area using the pipette tip. Permeation sam- 1.0% PEG200 in ethanol (95%) ples were collected into appropriately sized glass vials s Comp 4: 2% TES, 5% OS, 2% PVP, 30% IPA, for a period of 24 h. 10 2.5% PEG200 in ethanol (95%) [0113] The Estradiol Transdermal Spray formulations contained:- [0119] The amount of active that permeated the skin was quantified using validated HPLC methods • Testosterone (TES), Polyethylene glycol 200 (PEG [0120] The effect on permeation of TES from using the 200) or Polyethylene glycol 400 (PEG 400) isopropyl 15 composition as shown in Figure 8. PEG200 was found alcohol (IPA) to significantly enhance the permeation of Testosterone in combination with the permeation enhancer octyl sali- [0114] The amount of active that permeated the skin cylate (OS) through human epidermis in vitro. was quantified using validated HPLC methods and the results are depicted in Figure 7.. 20 Claims Results: 1. A transdermal delivery system comprising a compo- [0115] In both the 0.25% and the 0.50% formulations sition comprising at least one pharmacological agent PEG200 was found to enhance the permeation of Estra- 25 selected from hormones and steroids; a penetration diol through human skin in vitro. enhancer comprising a polyethylene glycol (PEG) of average molecular weight no more than 300; and a Example 7 solvent selected from C 2 to C4 alkanol and mixtures thereof in an amount in the range of from 70% to Investigation Into the Effect of PEG200 on Cumulative 30 95%, by weight of the total composition. Testosterone Permeation Through Human Skin In Vitro 2. A transdermal delivery system according to claim 1 Methods: wherein the PEG of average molecular weight of no more than 300 is present in an amount of at least [0116] Finite-dose in vitro diffusion studies were un- 35 0.1% by weight of the total composition. dertaken using dermatomed human female abdominal skin (500 mm). 3. A transdermal delivery system according to any one [0117] These experiments were performed over 24 of the previous claims wherein the polyethylene gly- hours using stainless steel, flow through diffusion cells col of average weight no more than 300 is present based on those described previously (Cooper, E.R. J. 40 in an amount in the range of from 0.5% to 20% by Pharm. Sci. 1984, 73, 1153-1156) except that the cell weight of the total composition. was modified to increase the diffusion area to 1.0cm2. The formulations were applied using a finite dose tech- 4. A transdermal delivery system according to any one nique (Franz, T.J. Curr. Probl. Dermatol., 1978, 7, 58-68) of the previous claims wherein the composition con- to mimic clinical dosing conditions at an applied dose 45 sists essentially of: volume of 15 mL /cm2. A piece of stainless steel wire mesh was placed directly below the skin in the receptor (i) the at least one pharmacological agent se- chamber of the of the diffusion cell to maintain a turbulent lected from hormones and steroids; flow of receptor solution below the skin. The diffusion (ii) the penetration enhancer component con- cells were maintained at a flow rate of approximately 1.0 50 sisting of a polyethylene glycol of average mo- mL/hr by a microcassette peristaltic pump (Watson Mar- lecular weight no more than 300; low 505S UK). The cells were kept at 32 6 0.5°C by a (iii) a volatile solvent consisting of one or more heater bar and the samples were collected into appro- of ethanol and isopropanol; and priatelysized glassvials fora periodof 24 hr. The receptor (iv) optionally a propellant. 55 solutions (0.002%w/v NaN3) maintained sink conditions below the skin. 5. A transdermal delivery system according to any one [0118] The formulations consisted of:- of the previous claims wherein the total water content of the composition is less than 10% by weight of the

11 21 EP 2 214 643 B1 22

total composition. ne, progesterone, ethynyl estradiol, mestranol, dimethisterone, ethisterone, ethynodiol diacetate, 6. A transdermal delivery system according to any one norethindrone, norethindrone acetate, norethister- of the previous claims which is non-occlusive. one, , flurandrenolone, hydro- 5 cortisone sodium succinate, methylprednisolone so- 7. A transdermal delivery system according to any one dium succinate, prednisolone phosphate sodium, tri- of the previous claims wherein the weight ratio of amcinolone acetonide, hydroxydione sodium, penetration enhancer to pharmacological agent is in spironolactone, oxandrolone, oxymetholone, pro- the range of from 20:1 to 1:1. metholone, testosterone cypionate, testosterone 10 phenylacetate, estradiol cypionate, and norethyno- 8. A transdermal delivery system according to any one drel and the salts and prodrugs thereof. of the previous claims wherein at least one pharma- cological agent comprises one or more selected from 11. A transdermal delivery system according to any one the group consisting of steroidal hormones. of the previous claims for female contraception com- 15 prising one or more estrogens and one or more pro- 9. A transdermal delivery system according to any one gestins. of the previous claims wherein at least one pharma- cological agent comprises one or more steroids 12. A transdermal delivery system according to any one which provide eutrogenic, androgenic, glucocorti- of the previous claims wherein the drug delivery sys- coid, adrenocortoid, anabolic or birth control activity. 20 tem comprises on a weight basis from about 0.1 to about 10% of the steroid or hormone, from about 0.1 10. A transdermal delivery system according to claim 9 to 12% of the penetration enhancer and from about wherein the pharmacological agent comprises one 70 to 95% ethanol, isopropanol or mixture thereof. or more steroids selected from the group consisting of dexamethasone, , dex- 25 13. A transdermal delivery system according to claim 1 amethasone sodium phosphate, cortisone, corti- further comprising a spray apparatus comprising a sone acetate, hydrocortisone, hydrocortisone ace- container containing the transdermal composition, a tate, hydrocortisone cypionate, hydrocortisone sodi- spraynozzle and anactuator for deliveringa metered um phosphate, hydrocortisone sodium succinate, doseof spray fromthe containervia thespray nozzle. prednisone, prednisolone, ,30 prednisolone sodium phosphate, prednisolone teb- 14. A transdermal delivery system according to any one utate, prednisolone pivalate, triamcinolone, triamci- of claims 1 to 13 for transdermal administration of at nolone acetonide, triamcinolone hexacetonide, tri- least one pharmacological agent selected from hor- amcinolone diacetate, methylprednisolone, methyl- mones and steroids. prednisolone acetate, methylprednisolone sodium 35 succinate,flunsolide, beclomethasonedipropionate, 15. The transdermal delivery system according to claim betamethasone sodium phosphate, betametha- 14, wherein the transdermal administration is by ap- sone, vetamethasone disodium phosphate, vetam- plication of the medicament to an area of dermal sur- ethasone sodium phosphate, betamethasone ace- face of a subject. tate, betamethasone disodium phosphate, chloro- 40 prednisone acetate, corticosterone, desoxycorticos- 16. The transdermal delivery system according to claim terone, desoxycorticosterone acetate, desoxycorti- 15 wherein the subject is in need of male hormone costerone pivalate, desoximethasone, estradiol, replacement in testosterone deficient hypogonadal fludrocortisone, fludrocortisone acetate, dichlori- men, female hormone replacement therapy for post- sone acetate, fluorohydrocortisone, fluorometholo- 45 menopausal women, or androgen replacement ther- ne, fluprednisolone, paramethasone, parametha- apy for females lacking libido or suffering depression sone acetate, androsterone, fluoxymesterone, al- using an androgen, male contraception or female dosterone, methandrostenolone, methylandrosten- contraception. ediol, methyl testosterone, norethandrolone, testo- sterone, testosterone enanthate, testosterone pro- 50 17. A methodof preparing atransdermal deliverysystem pionate, equilenin, equilin, , estra- comprising a composition for administration to an diol dipropionate, estriol, estrone, , area of dermal surface of a subject, the method com- acetoxypregnenolone, anagestone acetate, chlo- prising combining at least one pharmacological rmadinone acetate, flurogestone acetate, hy- agent selected from hormones and steroids, a pen- droxymethylprogesterone, hydroxymethylproges- 55 etration enhancer comprising polyethylene glycol of terone acetate, hydroxyprogesterone, hydroxypro- average molecular weight no more than 300 and gesterone acetate, hydroxyprogesterone caproate, 70% to 95% by weight of the composition of solvent , normethisterone, pregnenolo- selectedfrom C 2 to C 4 alkanols and mixtures thereof.

12 23 EP 2 214 643 B1 24

18. A transdermal delivery system according to claim 1 6. Transdermales Zuführsystem gemäß einem der vor- wherein the PEG of average molecular weight no hergehenden Ansprüche, das nicht-okklusiv ist. more than 300 is PEG 200 in an amount of from 0.1 to 40% by weight of the total composition. 7. Transdermales Zuführsystem gemäß einem der vor- 5 hergehenden Ansprüche, wobei das Gewichtsver- 19. A transdermal delivery system according to claim 1 hältnis von Penetrationsverstärker zu pharmakolo- wherein the PEG of average molecular weight no gischem Mittel 20:1 bis 1:1 beträgt. more than 300 is of formula H-[OCH2 CH2)n-OH where n is 4. 8. Transdermales Zuführsystem gemäß einem der vor- 10 hergehenden Ansprüche, wobei mindestens ein pharmakologisches Mittel eines oder mehreres aus Patentansprüche der Gruppe, bestehend aus Steroidhormonen, um- fasst. 1. Transdermales Zuführsystem, das eine Zusammen- setzung umfasst, die mindestens ein pharmakologi- 15 9. Transdermales Zuführsystem gemäß einem der vor- sches Mittel, das aus Hormonen und Steroiden aus- hergehenden Ansprüche, wobei mindestens ein gewählt ist, einen Penetrationsverstärker, der ein pharmakologisches Mittel ein oder mehrere Steroide Polyethylenglykol (PEG) eines durchschnittlichen umfasst, die eutrogene, androgene, glukokortikale, Molekulargewichts von nicht mehr als 300 umfasst, adrenokortikale, anabole Aktivität oder Geburtskon- 20 und ein Lösungsmittel, das aus C2 bis C4-Alkanol trollaktivität bereitstellen. und Gemischen davon ausgewählt ist, in einer Men- ge von 70% bis 95% nach Gewicht der Gesamtzu- 10. Transdermales Zuführsystem gemäß Anspruch 9, sammensetzung umfasst. wobei das pharmakologische Mittel ein oder mehre- re Steroide umfasst, die ausgewählt sind aus der 2. Transdermales Zuführsystem gemäß Anspruch 1, 25 Gruppe, bestehend aus Dexamethason, Dexame- wobei das PEG eines durchschnittlichen Molekular- thasonacetat, Dexamethasonnatriumphosphat, gewichts von nicht mehr als 300 in einer Menge von Cortison, Cortisonacetat, Hydrocortison, Hydrocor- mindestens 0,1% nach Gewicht der Gesamtzusam- tisonacetat, Hydrocortisoncypionat, Hydrocortison- mensetzung vorliegt. natriumphosphat, Hydrocortisonnatriumsuccinat, 30 Prednison, Prednisolon, Prednisolonacetat, Predni- 3. Transdermales Zuführsystem gemäß einem der vor- solonnatriumphosphat, Prednisolontebutat, Predni- hergehenden Ansprüche, wobei das Polyethyleng- solonpivalat, Triamcinolon, Triamcinolonacetonid, lykol eines durchschnittlichen Molekulargewichts Triamcinolonhexacetonid, Triamcinolondiacetat, von nicht mehr als 300 in einer Menge von 0,5% bis Methylprednisolon, Methylprednisolonacetat, Me- 20% nach Gewicht der Gesamtzusammensetzung 35 thylprednisolonnatriumsuccinat, Flunsolid, Be- vorliegt. clomethasondipropionat, Betamethasonnatrium- phosphat, Betamethason, Vetamethasondinatrium- 4. Transdermales Zuführsystem gemäß einem der vor- phosphat, Vetamethasonnatriumphosphat, Beta- hergehenden Ansprüche, wobei die Zusammenset- methasonacetat, Betamethasondinatriumphosphat, zung im Wesentlichen besteht aus: 40 Chlorprednisonacetat, Corticosteron, Desoxycorti- costeron, Desoxycorticosteronacetat, Desoxycorti- (i) dem mindestens einen pharmakologischen costeronpivalat, Desoximethason, Estradiol, Fludro- Mittel, das aus Hormonen und Steroiden aus- cortison, Fludrocortisonacetat, Dichlorisonacetat, gewählt ist, Fluorhydrocortison, Fluormetholon, Fluprednisolon, (ii) der Penetrationsverstärkerkomponente, die 45 Paramethason, Paramethasonacetat, Androsteron, aus einem Polyethylenglykol eines durch- Fluoxymesteron, Aldosteron, Methandrostenolon, schnittlichen Molekulargewichts von nicht mehr Methylandrostendiol, Methyltestosteron, Noret- als 300 besteht, handrolon, Testosteron, Testosteronenanthat, Tes- (iii) einem flüchtigen Lösungsmittel, das aus ei- tosteronpropionat, Equilenin, Equilin, Estradiolben- nem oder mehreren von Ethanol und Isopropa- 50 zoat, Estradioldiproprionat, Estriol, Estron, Estron- nol besteht, und benzoat, Acetoxypregnenolon, Anagestonacetat, (iv) gegebenenfalls einem Treibmittel. Chlormadinonacetat, Flurogestonacetat, Hydroxy- methylprogesteron, Hydroxymethylprogestero- 5. Transdermales Zuführsystem gemäß einem der vor- nacetat, Hydroxyprogesteron, Hydroxyprogestero- hergehenden Ansprüche, wobei der gesamte Was- 55 nacetat, Hydroxyprogesteroncaproat, Melenge- sergehalt der Zusammensetzung weniger als 10% strolacetat, Normethisteron, Pregnenolon, Proges- nach Gewicht der Gesamtzusammensetzung be- teron, Ethinylestradiol, Mestranol, Dimethisteron, trägt. Ethisteron, Ethinodioldiacetat, Norethindron, Nore-

13 25 EP 2 214 643 B1 26

thindronacetat, Norethisteron, Fluocinolonacetonid, gewählt ist, eines Penetrationsverstärkers, der Po- Flurandrenolon, Hydrocortisonnatriumsuccinat, Me- lyethylenglykol eines durchschnittlichen Molekular- thylprednisolonnatriumsuccinat, Prednisolonphos- gewichts von nicht mehr als 300 umfasst, und 70% phatnatrium, Triamcinolonacetonid, Hydroxydi- bis 95% nach Gewicht der Zusammensetzung eines 5 onnatrium, Spironolacton, Oxandrolon, Oxymetho- Lösungsmittels, dass aus C2 bis C4-Alkanolen und lon, Prometholon, Testosteroncypionat, Testoste- Gemischen davon ausgewählt ist, umfasst. ronphenylacetat, Estradiolcypionat und Norethinod- rel und den Salzen und Arzneimittelvorläufern da- 18. Transdermales Zuführsystem gemäß Anspruch 1, von. wobei das PEG eines durchschnittlichen Molekular- 10 gewicht von nicht mehr als 300 PEG 200 in einer 11. Transdermales Zuführsystem gemäß einem der vor- Menge von 0,1 bis 40% nach Gewicht der Gesamt- hergehenden Ansprüche für eine weibliche Emp- zusammensetzung ist. fängnisverhütung, das ein oder mehrere Estrogene und ein oder mehrere Progestine umfasst. 19. Transdermales Zuführsystem gemäß Anspruch 1, 15 wobei das PEG eines durchschnittlichen Molekular- 12. Transdermales Zuführsystem gemäß einem der vor- gewichts von nicht mehr als 300 der Formel

hergehenden Ansprüche, wobei das Arzneimittelzu- H-[OCH2 CH2]n-OH entspricht, wobei n 4 beträgt. führsystem auf einer Gewichtsbasis etwa 0,1 bis et- wa 10% des Steroids oder Hormons, etwa 0,1 bis 12% des Penetrationsverstärkers und etwa 70 bis 20 Revendications 95% Ethanol, Isopropanol oder ein Gemisch davon umfasst. 1. Système de délivrance transdermique comprenant une composition comprenant au moins un agent 13. Transdermales Zuführsystem gemäß Anspruch 1, pharmacologique choisi parmi les hormones et les das ferner eine Sprühvorrichtung umfasst, die einen 25 stéroïdes; un renforçateur de pénétration compre- Behälter, der die transdermale Zusammensetzung nant un polyéthylène glycol (PEG) ayant une masse enthält, eine Sprühdüse und ein Bedienelement zum moléculaire moyenne ne dépassant pas 300; et un Zuführen einer gemessenen Dosis des Sprays von solvant choisi parmi un alcool en C2 à C4 et leurs dem Behälter über die Sprühdüse umfasst. mélanges en une quantité dans l’intervalle de 70% 30 à 95%, en poids de la composition totale. 14. Transdermales Zuführsystem gemäß einem der An- sprüche 1 bis 13 für eine transdermale Verabrei- 2. Système de délivrance transdermique selon la re- chung mindestens eines pharmakologischen Mit- vendication 1, dans lequel le PEG ayant une masse tels, das aus Hormonen und Steroiden ausgewählt moléculaire moyenne ne dépassant pas 300 est pré- ist. 35 sent en une quantité d’au moins 0,1 % en poids de la composition totale. 15. Transdermales Zuführsystem gemäß Anspruch 14, wobei die transdermale Verabreichung durch Appli- 3. Système de délivrance transdermique selon l’une zieren des Medikaments an einen Hautoberflächen- quelconque des revendications précédentes, dans bereich eines Lebewesens erfolgt. 40 lequel le polyéthylène glycol ayant une masse mo- léculaire moyenne ne dépassant pas 300 est présent 16. Transdermales Zuführsystem gemäß Anspruch 15, en une quantité dans l’intervalle de 0,5% à 20% en wobei das Lebewesen einen Bedarf für einen männ- poids de la composition totale. lichen Hormonaustausch in testosterondefizitären hypogonadalen Männern, eine weibliche Hormon- 45 4. Système de délivrance transdermique selon l’une austauschtherapie für postmenopausale Frauen quelconque des revendications précédentes, dans oder eine Androgenaustauschtherapie für Frauen, lequel la composition consiste essentiellement en: denen Libido fehlt oder die an Depression leiden, unter Verwendung eines Androgens, männliche (i) le au moins un agent pharmacologique choisi Empfängnisverhütung oder weibliche Empfängnis- 50 parmi les hormones et les stéroïdes; verhütung hat. (ii) le composant renforçateur de pénétration consistant en un polyéthylène glycol ayant une 17. Verfahren zum Herstellen eines transdermalen Zu- masse moléculaire moyenne ne dépassant pas führsystems, das eine Zusammensetzung für eine 300; Verabreichung an einen Hautoberflächenbereich ei- 55 (iii) un solvant volatil consistant en un ou plu- nes Lebewesens umfasst, wobei das Verfahren ein sieurs parmi l’éthanol et l’isopropanol; et Vereinigen von mindestens einem pharmakologi- (iv) en option un agent propulseur. schen Mittel, das aus Hormonen und Steroiden aus-

14 27 EP 2 214 643 B1 28

5. Système de délivrance transdermique selon l’une testostérone, noréthandrolone, testostérone, enan- quelconque des revendications précédentes, dans thate de testostérone, propionate de testostérone, lequel la teneur totale en eau de la composition est équilénine,équiline, benzoate d’oestradiol,dipropio- inférieure à 10% en poids de la composition totale. nate d’oestradiol, oestriol, oestrone, benzoate d’oes- 5 trone, acétoxypregnénolone, acétate d’anagestone, 6. Système de délivrance transdermique selon l’une acétate de chlormadinone, acétate de flurogestone, quelconque des revendications précédentes, qui est hydroxyméthylprogestérone, acétate d’ hydroxymé- non-occlusif. thylprogestérone, hydroxyprogestérone, acétate d’hydroxyprogestérone, caproate d’hydroxyproges- 7. Système de délivrance transdermique selon l’une 10 térone, acétate de mélengestrol, norméthistérone, quelconque des revendications précédentes, dans pregnénolone, progestérone, éthynyl oestradiol, lequel le rapport en poids du renforçateur de péné- mestranol, diméthistérone, éthistérone, diacétate tration à l’agent pharmacologique est dans l’interval- d’éthynodiol, noréthindrone, acétate de noréthindro- le de 20:1 à 1:1. ne, norethistérone, acétonide de fluocinolone, flu- 15 randrénolone, succinate sodique d’hydrocortisone, 8. Système de délivrance transdermique selon l’une succinatesodique deméthylprednisolone, phospha- quelconque des revendications précédentes, dans te sodique de prednisolone, acétonide de triamcino- lequel au moins un agent pharmacologique com- lone, hydroxydione sodique, spironolactone, oxan- prend un ou plusieurs choisis dans le groupe con- drolone, oxymétholone, prométholone, cypionate de sistant en hormones stéroïdiennes. 20 testostérone, phénylacétate de testostérone, cypio- nate d’oestradiol, et noréthynodrel, et leurs sels et 9. Système de délivrance transdermique selon l’une promédicaments. quelconque des revendications précédentes, dans lequel au moins un agent pharmacologique com- 11. Système de délivrance transdermique selon l’une prend un ou plusieurs stéroïdes qui procurent une 25 quelconque des revendications précédentes pour activité eutrogénique, androgénique, de glucocorti- contraception féminine, comprenant un ou plusieurs coïde, d’adrénocorticoïde, anabolisante ou de régu- oestrogènes et un ou plusieurs progestatifs. lation des naissances. 12. Système de délivrance transdermique selon l’une 10. Système de délivrance transdermique selon la re- 30 quelconque des revendications précédentes, dans vendication 9, dans lequel l’agent pharmacologique lequel le système de délivrance de médicament comprend un ou plusieurs stéroïdes choisis dans le comprend sur une base pondérale d’environ 0,1 à groupe consistant en dexaméthasone, acétate de environ 10% du stéroïde ou de l’hormone, d’environ dexaméthasone,phosphate sodiquede dexamétha- 0,1 à 12% du renforçateur de pénétration et d’envi- sone, cortisone, acétate de cortisone, hydrocortiso- 35 ron 70 à 95% d’éthanol, d’isopropanol ou de leur ne, acétate d’hydrocortisone, cypionate d’hydrocor- mélange. tisone, phosphate sodique d’hydrocortisone, succi- nate sodique d’hydrocortisone, prednisone, predni- 13. Système de délivrance transdermique selon la re- solone,acétate deprednisolone, phosphatesodique vendication 1, comprenant en outre un appareil de de prednisolone, tébutate de prednisolone, pivalate 40 pulvérisation comprenant un récipient contenant la de predsinolone, triamcinolone, acétonide de triam- composition transdermique, une buse de pulvérisa- cinolone, hexacétonide de triamcinolone, diacétate tion et un actionneur pour délivrer une dose mesurée de triamcinolone, méthylprednisolone, acétate de de pulvérisation venant du récipient via la buse de méthylprednisolone, succinate sodique de méthyl- pulvérisation. prednisolone, flunsolide, dipropionate de béclomé- 45 thasone, phosphate sodique de bétaméthasone, bé- 14. Système de délivrance transdermique selon l’une taméthasone, phosphate disodique de vétamétha- quelconque des revendications 1 à 13 pour adminis- sone, phosphate sodique de vétaméthasone, acé- tration transdermique d’au moins un agent pharma- tate de bétaméthasone, phosphate disodique de bé- cologiquechoisi parmi les hormones et les stéroïdes. taméthasone, acétate de chloroprednisone, corti- 50 costérone, désoxycorticostérone, acétate de dé- 15. Système de délivrance transdermique selon la re- soxycorticostérone, pivalate de désoxycorticostéro- vendication 14, dans lequel l’administration trans- ne, désoxyméthasone, oestradiol, fludrocortisone, dermique s’effectue par application du médicament acétate de fludrocortisone, acétate de dichlorisone, à une aire de surface dermique d’un sujet. fluorohydrocortisone, fluorométholone, flupredniso- 55 lone, paraméthasone, acétate de paraméthasone, 16. Système de délivrance transdermique selon la re- androstérone, fluoxymestérone, aldostérone, mé- vendication 15, dans lequel le sujet a besoin du rem- thandrosténolone, méthylandrostènediol, méthyl placement d’hormone mâle chez les hommes hypo-

15 29 EP 2 214 643 B1 30

gonodiques déficients en testostérone, d’une théra- pie de remplacement d’hormone femelle pour les femmes post-ménopausées, ou d’une thérapie de remplacement d’androgène pour les femmes dé- nuées de libido ou souffrant de dépression utilisant 5 un androgène, une contraception masculine ou une contraception féminine.

17. Procédé pour la préparation d’un système de déli- vrance transdermique comprenant une composition 10 pour administration à une aire de surface dermique d’un sujet, le procédé comprenant la combinaison d’au moins un agent pharmacologique choisi parmi les hormones et les stéroïdes, un renforçateur de pénétration comprenant du polyéthylène glycol15 ayant une masse moléculaire moyenne ne dépas- sant pas 300 et 70% à 95% en poids de la compo-

sition d’un solvant choisi par les alcanols en C 2 à C 4 et leurs mélanges. 20 18. Système de délivrance transdermique selon la re- vendication 1, dans lequel le PEG ayant une masse moléculaire moyenne ne dépassant pas 300 est le PEG 200 en une quantité allant de 0,1 à 40% en poids de la composition totale. 25

19. Système de délivrance transdermique selon la re- vendication 1, dans lequel le PEG ayant une masse moléculaire moyenne ne dépassant pas 300 est de 30 formule H-[OCH2CH2]n-OH où n est 4.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 9406452 A [0010] • WO 0044347 A [0015] • WO 9310201 A [0011] • US 5196410 A [0044] • EP 0409383 A [0012] • US 5082866 A [0044] • EP 0328806 A [0013] • US 4861764 A [0044] • WO 2007016766 A [0014]

Non-patent literature cited in the description

• USP NF Official Compendium of Standards. 2007, • Burger’s Medicinal Chemistry and Drug Chemistry. vol. 11180-11 [0021] 1995, vol. 1, 172-178949-982 [0026] • BUNDGARD. Design of Prodrugs. Elsevier, 1985, • COOPER, E.R. J. Pharm. Sci., 1984, vol. 73, 7-921-24 [0026] 1153-1156 [0087] [0094] [0117] • SILVERMAN.The Organic Chemistry ofDrug Design • FRANZ, T.J. Curr. Probl. Dermatol., 1978, vol. 7, and Drug Action. Academic Press, 1992, 352-401 58-68 [0087] [0094] [0117] [0026]

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