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(12) United States Patent (10) Patent No.: US 8,980,308 B2 Horstmann Et Al

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(12) United States Patent (10) Patent No.: US 8,980,308 B2 Horstmann Et Al (12) United States Patent (10) Patent No.: US 8,980,308 B2 Horstmann et al. (45) Date of Patent: Mar. 17, 2015 (54) TRANSDERMAL PHARMACEUTICAL 5,877,173 A * 3/1999 Olney et al. ................... 514,217 PREPARATION CONTAINING ACTIVE 5,902,601 A 5/1999 Horstmann 6,193.992 B1* 2/2001 El-Rashidy et al. .......... 424/430 SUBSTANCE COMBINATIONS, FOR 2003, OO82214 A1 5, 2003 Williams TREATING PARKINSONS DISEASE 2003/01 19884 A1 6/2003 Epstein et al. 2004/OO13620 A1* 1/2004 Klose et al. ..................... 424,59 (75) Inventors: Michael Horstmann, Neuwied (DE); 2007/0225.379 A1* 9/2007 Carrara et al. ................ 514,756 Frank Theobald, Bad Breisig (DE) FOREIGN PATENT DOCUMENTS (73) Assignee: LTS Lohmann Therapie-Systeme AG, CA 2 383 509 3, 2001 Andernach (DE) DE 3710966 12/1987 EP O241809 B1 8, 1990 (*) Notice: Subject to any disclaimer, the term of this EP B-04O4807 6, 1993 patent is extended or adjusted under 35 EP 1254 661 11, 2002 EP A-1 256339 10, 2003 U.S.C. 154(b) by 1785 days. FR 2788.982 8, 2000 JP S611451 12 T 1986 (21) Appl. No.: 10/568,941 JP S61186.317 8, 1986 JP A S62-249923 10, 1987 (22) PCT Filed: Aug. 14, 2004 JP A HO2-503677 11, 1990 JP AH11-506744 6, 1999 PCT/EP2004/OO9136 JP H11506462 6, 1999 (86). PCT No.: JP AH11-209271 8, 1999 JP A 2000-514053 10, 2000 S371 (c)(1), JP A 2001-398.65 2, 2001 (2), (4) Date: Feb. 21, 2006 JP 2001518058 10, 2001 JP A 2002-97137 4/2002 (87) PCT Pub. No.: WO2005/018619 JP 2003513014 4/2003 JP 2OO75O2795 2, 2007 PCT Pub. Date: Mar. 3, 2005 WO WO 89,09051 10, 1989 WO WO 9600062 A1 1, 1996 (65) Prior Publication Data WO WOOOf 45795 8, 2000 WO WOOOf74661 12, 2000 US 2007/OO26054A1 Feb. 1, 2007 WO WO O2, 15889 2, 2002 WO WO O2/47666 6, 2002 (30) Foreign Application Priority Data WO WO O2/O89777 11, 2002 Aug. 20, 2003 (DE) .................................. 10338 174 OTHER PUBLICATIONS Korczyn, et al., Emerging Therapies in the Pharmacological Treat (51) Int. Cl. ment of Parkinson's Disease, Drugs, 2002, 62(5) 775-786.* A 6LX 9/70 (2006.01) Korczyn et al. Emerging Therapies in the Pharmcological Treatment A6 IK3I/3 (2006.01) of Parkinsons Disease, Drugs, 2002, 62(5) 775-786.* A6 IK3I/38 (2006.01) Schneider, E.; “Kominierte Therapien.” Neuro-Psychopharmaka; A6 IK3I/428 (2006.01) vol. 5: Parkinsonmittel und Nootropika, pp. 131-133; ed. P. Riederer, A6 IK 45/06 (2006.01) et al., Springer Verlag, Vienna (1992). (52) U.S. Cl. (Continued) CPC ............... A61K 9/7092 (2013.01); A61 K3I/13 (2013.01); A61 K3I/381 (2013.01); A61 K Primary Examiner — Anand Desai 3 1/428 (2013.01); A61K 45/06 (2013.01) Assistant Examiner — Melissa Mercier USPC .......................................................... 424/449 (74) Attorney, Agent, or Firm — D. Peter Hochberg: Sean F. (58) Field of Classification Search Mellino None See application file for complete search history. (57) ABSTRACT (56) References Cited The transdermal pharmaceutical preparations for the treat ment of Parkinson's disease contain a combination of at least U.S. PATENT DOCUMENTS two active Substances selected from the following groups of active Substances: dopamine agonists and L-dopa, monoam 4,666.441. A * 5/1987 Andriola et al. .............. 424/448 ine oxidase inhibitors, anticholinergics, NMDA-receptor 4,812,481 A 3/1989 Reisching antagonists, sympathomimetics; at least two of the said active 4,877,618 A * 10/1989 Reed, Jr. ....................... 424/448 4,963,568 A * 10/1990 Schoenleber et al. ........ 514,320 substances being members of different active substance 5,462,746 A 10, 1995 Wolter et al. groups. 5,614, 178 A * 3/1997 Bloom et al. ................... 424,60 5,807,570 A * 9/1998 Chen et al. .................... 424/449 11 Claims, No Drawings US 8,980,308 B2 Page 2 (56) References Cited Iravani, Mahmoud, M. et al.; “3,4- Methylenedioxymethamphetamine (Ecstasy) Inhibits Dyskinesia OTHER PUBLICATIONS Expression and Normalized Motor Activity in 1-methyl-4-phenyl 1,2,3,6 tetrahydropyridine-treated primates;” Journal of Sudo, et al.; Transdermal Absorption of L-dopa from Hydrogel in Neuroscience; vol. 23, No. 27; Oct. 8, 2003; pp. 9107-9115. Rats; Eur: J. Pharm. Sci.; 7 (1998), pp. 67-71. Rupniak, Therapeutic efficacy of a novel transdermal delivery system Reiderer, P. et al., “Neuro-Psychopharmaka, Bd5:” (1992), Springer for (+)-PHNO in parkinsonian squirrel monkeys; JNeurolNeurosurg Verlag, Wien. Psychiatry (1989) V. 52, No. 2, p. 289-90. Mucke, H.A.M.; “Rotigotine Schwarz Pharma.” Idrugs, Current "Amitriptyline” in:National Library of Medicine, Specialized Infor Drugs Ltd., GB; vol. 6, No. 9 (2003), pp. 894-899. mation Services. Im Internet ( http://chem2.sis.nlm.nih.gov/ Tuite, P. et al.: “Recent Developments in the Pharmacological Treat chemidplus/jsp/chemidlite/ChemFull.jsp >, 2004. ment of Parkinson's Disease.” Expert Opinion on Investigational Potential of Transdermal Drug Delivery in Parkinson's Disease Drugs, Ashley Publications Ltd., London, GB, vol. 12, No. 8; Aug. 1, Drugs Aging, 2002, 19 (8), 561-570. 2003; pp. 1335-1352. "Dopamine agonists and neuroprotection in Parkinson's disease: Abramsky, O., et al.; "Combined Treatment of Parkinsonian Tremor European Journal of Neurology (2002); vol. 9, suppl. 3, pp. 7-14. with Propranolol and Levodopa.” Journam of The Neurological Sci Naohide Inoue, et al.; A new idea of a drug therapy in Parkinson's ences; Dec. 1971; vol. 14, No. 4; pp. 491-494. disease—MAO-B inhibitor selegiline hydrochloride therapy; J. of Charles, P.D.. et al.: "Classification of Tremor and Update on Treat Progress of Medicine; vol. 199, No. 4, pp. 289-292 (Oct. 27, 2001). ment.” American Family Physician, American Academy of Family Physicians (U.S.); vol. 59, No. 6; Mar. 15, 1999: pp. 1565-1572. * cited by examiner US 8,980,308 B2 1. 2 TRANSIDERMAL PHARMACEUTICAL An important role in the accompanying therapy of Parkin PREPARATION CONTAINING ACTIVE son's disease is played by the treatment with anticholinergi SUBSTANCE COMBINATIONS, FOR cally active Substances (muscarine receptor antagonists), TREATING PARKINSONS DISEASE which particularly enables the suppression of the tremor. Substances of this group which are of therapeutical impor CROSS-REFERENCE TO RELATED tance are, for example, bipreriden, trihexyphenidyl, procycli APPLICATIONS dine, bornaprine, metixene, orphenadrine, Scopolamine, atro pine and other belladonna alkaloids, benzatropine and This application is a National Stage application of Interna nicotine. tional Application No. PCT/EP2004/009136, filed on Aug. 10 Also suitable for the Parkinson therapy is a further group of active substances which are NMDA (N-methyl-D-aspartate) 14, 2004, which claims priority of German application num receptor antagonists; these include, for example, memantine ber 10338 174.0, filed on Aug. 20, 2003. and amantadine. These Substances act synergistically with BACKGROUND OF THE INVENTION L-dopa and, in the case of a combination therapy, enable a 15 reduction of the L-dopa dose. Akinesia in Parkinson patients, in particular, can be advantageously affected by additional Field of the Invention administration of NMDA receptor antagonists. The combination therapy of parkinsonism has been gener The invention relates to transdermally administrable phar ally established, and the resultant advantageous effects are maceutical preparations for treating Parkinson's syndrome, known (e.g. E. Schneider, “Kombinierte Therapien'; in: said preparations containing a combination of at least two “Neuro-Psychopharmaka', Vol. 5: Parkinsonmittel and Noot active substances which are suitable for use in the therapy of ropika, pp. 131-144. ed. P. Riederer et al.; Springer Verlag, Parkinson's syndrome. The invention further relates to the Vienna, 1992). In principle, the combination of oral medica use of such an active Substance combination for the manufac ments is of disadvantage, however, since the effect obtained at ture of a transdermally administrable medicament for treating 25 a certain point in time is dependent on the, if anything, hap Parkinson's disease, as well as to the therapeutic treatment of hazard intrinsic kinetics of the active substance following oral Parkinson patients by transdermally administering one of the absorption as a single dose. Since the individual active Sub said pharmaceutical preparations. stances contained in an active Substance combination differin Active Substances from the following groups are currently terms of their half-lives and oral dosage intervals, a uniform being utilised in the drug therapy of Parkinson's disease: 30 exposition of the patient to the different active substances anti-Parkinson agents having dopaminergic effect, especially does not result, rather there are wild fluctuations in the rela L-dopa and dopamine receptor antagonists; centrally active tive effects of each active substance component, depending anti-cholinergic agents (muscarine receptor antagonists); on the changes occurring in the active Substance levels over monoamine oxidase inhibitors; NMDA antagonists; beta the course of the day. sympatholytics. 35 Because of these known pharmacokinetic particularities, Apart from the above, administration of sympathomimet “fixed' active substance combinations within an oral admin ics from the group of the phenylethylamine derivatives (e.g. istration form (e.g. tablets containing combined active Sub Ecstasy=MDMA) is being taken into consideration, as in stances) are regarded by the drug approval authorities as very Some patients who are suffering from dyskinesias after long problematic and are approved only in exceptional cases. term use of L-dopa, an improvement of the symptoms has 40 Therefore, a combination therapy is generally carried through been observed. by separate administration of two or more mono-Substance The most potent and most important Parkinson medica preparations. This, however, requires dosage intervals which ment is L-dopa (Levodopa), which is almost exclusively are accurately adapted to the individual half-lives of these administered orally, preferably in combination with decar individual Substances.
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