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Transdermal Delivery System for Hormones and Steroids

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(19) TZZ _¥_T (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) TRANSDERMAL DELIVERY SYSTEM FOR HORMONES AND STEROIDS TRANSDERMALES FREISETZUNGSSYSTEM FÜR HORMONE 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 estradiol 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.: ’Skin 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 drug 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 drugs 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 (corticosteroids). 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, protein, fat, 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, skeletal muscle, 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 estrogens, of which the most important hu- 25 to provide effective blood levels. man derivatives are testosterone 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- androgens and estrogens. Progesterone 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 calcium 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 libido 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 suspension 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 estrogen 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 fatty acid ester, layer of the epidermis (the ’stratum corneum’) consists fatty acid, azone-related compound and mixtures there- of flattened dead cells which are filled with keratin. The of. region between the flattened dead cells of the stratum [0015] WO 00/44347 relates to a pharmaceutical com- corneum is filled with lipids 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 prodrugs 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.
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  • Us Anti-Doping Agency

    Us Anti-Doping Agency

    2019U.S. ANTI-DOPING AGENCY WALLET CARDEXAMPLES OF PROHIBITED AND PERMITTED SUBSTANCES AND METHODS Effective Jan. 1 – Dec. 31, 2019 CATEGORIES OF SUBSTANCES PROHIBITED AT ALL TIMES (IN AND OUT-OF-COMPETITION) • Non-Approved Substances: investigational drugs and pharmaceuticals with no approval by a governmental regulatory health authority for human therapeutic use. • Anabolic Agents: androstenediol, androstenedione, bolasterone, boldenone, clenbuterol, danazol, desoxymethyltestosterone (madol), dehydrochlormethyltestosterone (DHCMT), Prasterone (dehydroepiandrosterone, DHEA , Intrarosa) and its prohormones, drostanolone, epitestosterone, methasterone, methyl-1-testosterone, methyltestosterone (Covaryx, EEMT, Est Estrogens-methyltest DS, Methitest), nandrolone, oxandrolone, prostanozol, Selective Androgen Receptor Modulators (enobosarm, (ostarine, MK-2866), andarine, LGD-4033, RAD-140). stanozolol, testosterone and its metabolites or isomers (Androgel), THG, tibolone, trenbolone, zeranol, zilpaterol, and similar substances. • Beta-2 Agonists: All selective and non-selective beta-2 agonists, including all optical isomers, are prohibited. Most inhaled beta-2 agonists are prohibited, including arformoterol (Brovana), fenoterol, higenamine (norcoclaurine, Tinospora crispa), indacaterol (Arcapta), levalbuterol (Xopenex), metaproternol (Alupent), orciprenaline, olodaterol (Striverdi), pirbuterol (Maxair), terbutaline (Brethaire), vilanterol (Breo). The only exceptions are albuterol, formoterol, and salmeterol by a metered-dose inhaler when used