(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/020527 Al 14 February 2013 (14.02.2013) P O P C T (51) International Patent Classification: (74) Common Representative: UNIVERSITY OF VETER¬ A61K 9/06 (2006.01) A61K 47/32 (2006.01) INARY AND PHARMACEUTICAL SCIENCES A61K 9/14 (2006.01) A61K 47/38 (2006.01) BRNO FACULTY OF PHARMACY; University of A61K 47/10 (2006.01) A61K 9/00 (2006.01) Veterinary and Pharmaceutical Sciences Brno Faculty Of A61K 47/18 (2006.01) Pharmacy, Palackeho 1/3, CZ-61242 Brno (CZ). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/CZ20 12/000073 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (22) Date: International Filing BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, 2 August 2012 (02.08.2012) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (25) Filing Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (26) Publication Language: English ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (30) Priority Data: NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, 201 1-495 11 August 201 1 ( 11.08.201 1) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, 2012- 72 1 February 2012 (01.02.2012) TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 2012-5 11 26 July 2012 (26.07.2012) ZW. (71) Applicant (for all designated States except US): UNIVER¬ (84) Designated States (unless otherwise indicated, for every SITY OF VETERINARY AND PHARMACEUTICAL kind of regional protection available): ARIPO (BW, GH, SCIENCES BRNO FACULTY OF PHARMACY GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, [CZ/CZ]; Palackeho 1/3, CZ-61242 Brno (CZ). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, FT, LT, LU, LV, (71) Applicants : JAMPILEK, Josef [CZ/CZ]; Husova MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, 202/17, CZ-29301 Mlada Boleslav (CZ). OPATRILOVA, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Radka [CZ/CZ]; Ukrajinska 25, CZ-62500 Brno - Bohu- ML, MR, NE, SN, TD, TG). nice (CZ). COUFALOVA, Lenka [CZ/CZ]; Sladkova Declarations under Rule 4.17: 439/11, CZ-37701 JindficMv Hradec (CZ). CERNIKOVA, Aneta [CZ/CZ]; CZ-5695 1 Morasice 152 (CZ). — of inventorship (Rule 4.17(iv)) DOHNAL, Jiff [CZ/CZ]; Detska 2506/42, CZ-10000 Published: Praha 10 - Strasnice (CZ). — with international search report (Art. 21(3)) o (54) Title: UTILIZATION OF ALAPTIDE AS TRANSDERMAL PENETRATION MODIFIER FN PHARMACEUTICAL COMPOSITIONS FOR HUMAN AND VETERINARY APPLICATIONS CONTAFNING ANTI-FNFLAMMATORY DRUGS AND/OR ANTIMICROBIAL CHEMO- © THERAPEUTICS (57) Abstract: The invention deals with the way of utilization of micronized, nanonized and/or surface-modified alaptide, which af o fects penetration of other pharmaceutically active compounds through the skin as a pharmaceutical adjuvant (excipient). These phar maceutical compositions composed of alaptide as the excipient, pharmaceutical active ingredients (non-steroidal anti-inflammatory drugs and/or antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics, i.e. antibacterials, o antimycotics, antivirotics) and other pharmaceutical excipients can be used for preparation of drug formulations, which can influence the drug level in the body in time and can be used for both local and systemic administration. TITLE: Utilization of Alaptide as Transdermal Penetration Modifier in Pharmaceutical Compositions for Human and Veterinary Applications Containing Anti-inflammatory Drugs and/or Antimicrobial Chemotherapeutics. TECHNICAL FIELD: The invention deals with utilization of (¾-8-methyl-6,9-diazaspiro[4.5]decan-7,10-dione, known by the international non-proprietary name of "alaptide", as a pharmaceutical adjuvant (excipient) for modification of transdermal penetration of drugs in pharmaceutical formulations convenient for transdermal application, i.e. for preparation of human and/or veterinary drug formulations, which can influence the drug level in the body in time and can be used for both local and systemic administration of non-steroidal anti-inflammatory drugs (otherwise non-steroidal antiphlogistics or NSAIDs) and/or antipyretics/non-opiate analgesics and/or glucocorticoids and/or antimicrobial chemotherapeutics (antibacterials/ antimycobacterials, antimycotics, antivirotics). STATE OF THE ART: Background The recent development in the field of pharmaceutical dosage forms results in the discovery of additional highly sophisticated drug delivery systems that allow maintaining a stationary level of the active substance in an organism. Transdermal therapeutic systems represent an excellent alternative to conventional pharmaceutical dosage forms. However, the application of transdermal drug delivery faces the problem of insufficient or no penetration of active pharmaceutical substances through the skin. To solve this critical issue some physical or chemical possibilities/approaches for overcoming the skin barrier were developed. The idea of percutaneous drug absorption appeared long ago; the Ebers papyrus mentioned it as early as the 16th century B.C. In 1975 Idson stated that the epidermic barrier was a limiting factor for percutaneous absorption and that once the drug passed through stratum rne m (SC) of the epidermis, its absorption was guaranteed. A significant search for chemical substances improving skin permeability has been the subject of extensive studies during the last decades. More than 350 different compounds are known as chemical penetration enhancers perturbing the SC barrier to facilitate drug delivery. The largest increase in the number of enhancers was noted in the 80s of the last century. At present it can be said that the active pool of such substances is rather stable. At the time when new chemical entities are being discovered with exponential speed (which is evident from the Chemical Abstract Service lists), the retention of the number of chemical penetration enhancers is quite surprising. The source of this anomaly is an apparent insufficient understanding of mechanistic principles determining the power of enhancers, low efficiency of experimental effect determination and the fact that the enhancers have not reached their full potential in transdermal or topical systems so far (Prausniiz, M.R. et al. Nature Rev. Drug Discov. 2004, 3, 115; Rabiskovd M. et al. Technology of Pharmaceutics, 3rd ed., Galen Prague, 2006; Idson, B. J. Pharm. Sci. 1975, 64, 901; Pfister, W.R. et al. Pharm. Tech. 1990, 14, 132; Finnin, B.C.; et al. J. Pharm. Sci. 1999, 88, 955; Karande, P. et al. Proc. Natl. Acad. Sci. USA 2005, 102, 4688; Williams, A.C. & Barry, B.W. Chemical permeation enhancement, In: Enhancement in Drug Delivery E., Touitou B.W., Barry (Eds.), CRC Press, Boca Raton, 2007, pp.233-254; Jampilek, J. et al. Med. Res. Rev., in press, DOI 10.1002/med.20227). Transdermal therapeutic systems (TTSs) or transdermal drug delivery systems are topical dosage forms intended to deliver a drug substance at a controlled rate through the intact skin into the systemic circulation and to maintain efficacious plasma levels during prolonged time. A characteristic feature of TTSs in comparison with other topical dosage forms (ointments, creams) is the transport of defined and precise drug dosages through the healthy skin per defined time. The area-dosage-time relationships are determined as a crucial factor. Predecessors of TTSs were semi-solid topical dosage forms, mostly ointments, with the expected systemic effect. For some indications TTSs have already been used in clinical practice for the treatment of a variety of systemic diseases, for certain drugs they are tested or clinical trials are performed nowadays. At present transdermally applicable drugs include glycerol trinitrate, scopolamine, nicotine, oxybutynin, contraceptives, anodynes (e.g., fentanyl, buprenorphine), antihypertensive or antiarythmic drugs (e.g., clonidine, propranolol), drugs against pain/inflammatory or antiparkinsonics (rotigotine). A number of new pharmaceuticals are developed or even under clinical evaluation, for example antipsychotics, non-steroidal hormones or antineoplastics (e.g., physostigmine, selegiline, insulin or 5-fluorouracil). However, the number of drugs that can be delivered transdermally is more limited than it was originally expected (Jampilek, J. et al. Med. Res. Rev., in press, DOI 10.1002/med.20227; Bos, J.D. et al. Exp. Dermatol. 2000, 9, 165; Benson, H.A.E. Curr. Drug Deliv. 2005, 2, 23; Delgado-Charro, M.B. & Guy, R.H. Transdermal drug delivery, In: Drug Delivery and Targeting, Hillery A.M., Lloyd A.W., Swarbrick J. (Eds.), Taylor & Francis, London, pp.207-236; Swart, P.J. et al. Int. J. Pharm. 1992, 88, 165; Muller, W. et al. U.S. Patent 7,413,747, 2008; Moller, H.J. et al. Pharmacopsychiatry 1999, 32, 99; Lee, K.C. et al. Neuropsychiatr. Dis. Treat. 2007, 3, 527; Wong, T.W. Recent Pat. Drug Deliv. Formul. 2009, 3, 8; Chandrashekar, N.S. et al. Asian Pac. J. Cancer Prev. 2008, 9, 437). The advantages of transdermal administration include, above all, good pharmacokinetic properties of application systems, the ability to maintain long-lasted stationary plasma levels of active substances, including drugs with short biological half-lives, which reduces undesirable side effects occurring as a result of considerable fluctuations of drug plasma levels. In contrast, the plasma levels achieved with the use of conventional dosage forms exhibit peaks and may even reach a toxic level leading to complications. Presystemic elimination of the applied dosage (hepatic first-pass effect) and such effects as pH change in the GIT or interactions with simultaneously applied preparations or food are also prevented effectively.