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(12) United States Patent (10) Patent No.: US 6,916,487 B2 Klose Et Al

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(12) United States Patent (10) Patent No.: US 6,916,487 B2 Klose Et Al USOO69 16487B2 (12) United States Patent (10) Patent No.: US 6,916,487 B2 Klose et al. (45) Date of Patent: *Jul. 12, 2005 (54) TRANSDERMAL DELIVERY OF 4.299.826 11/1981 Luedders ANTIEMETCS 4,440,777 4/1984 Zupan 4,557,934 12/1985 Cooper (75) Inventors: Kathryn Traci-Jane Klose, Chelsea 4,704,406 11/1987 Stanislaus 4.820,724 4/1989 Nimni (AU); Jianwen Zhou, Ivanhoe (AU); 4.954,487 9/1990 Cooper et al. Timothy Matthias Morgan, Carlton 5,034,386 7/1991 Peck et al. North (AU); Barrie Charles Finnin, 5,036,100 7/1991. Deboeck et al. Glen Iris (AU); Barry Leonard Reed, 5,082,656 1/1992 Hui et al. ..................... 514/24 Strathmore (AU) 5,082,866 1/1992 Wong et al. (73) Assignee: Acrux DDS PTY LTD, Victoria (AU) (Continued) (*) Notice: Subject to any disclaimer, the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 AU 30258/89 9/1989 U.S.C. 154(b) by 62 days. AU 49984/1990 9/1989 AU 91413/91 6/1992 DE 4334. 553 4/1995 This patent is Subject to a terminal dis EP 189 861 8/1986 claimer. JP 61-268631 11/1986 WO 92/19271 11/1992 (21) Appl. No.: 10/428,019 WO 96/30000 10/1996 (22) Filed: May 2, 2003 OTHER PUBLICATIONS (65) Prior Publication Data R.J. Feldmann et al., “Arch Derm', vol. 94, Percutaneous Penetration of 14C Hydrocortisone in Man, pp. 649–651 US 2004/0013621 A1 Jan. 22, 2004 (Nov. 1966). Related U.S. Application Data (Continued) (60) Continuation-in-part of application No. 09/910,780, filed on Primary Examiner. Shelley A. Dodson Jul. 24, 2001, which is a division of application No. 09/125, 436, filed as application No. PCT/AU97/00091 on Feb. 19, Assistant Examiner-Konata M. George 1997, now Pat. No. 6,299,900. (74) Attorney, Agent, or Firm-Foley & Lardner LLP (30) Foreign Application Priority Data (57) ABSTRACT Feb. 19, 1996 (AU) ............................................ PN 8411 The present invention provides a transdermal drug delivery System which comprises: a therapeutically effective amount (51) Int. Cl. ................................................. A61F 13/02 of an antiemetic; at least one dermal penetration enhancer, (52) U.S. Cl. ........................ 424/448; 424/449; 514/974 which is a Safe skin-tolerant ester Sunscreen ester; and at (58) Field of Search ................................. 424/448, 449; least one volatile liquid. The invention also provides a 514/974 method for administering at least one Systemic acting anti emetic thereof to an animal which comprises applying an (56) References Cited effective amount of the antiemetic in the form of the drug delivery System of the present invention. U.S. PATENT DOCUMENTS 3,989.816 A 11/1976 Rajadhyaksha 19 Claims, 1 Drawing Sheet O - -0-2.5% Granisetron (control) n=7 -O- 5% Granisetron, 8% Octy Salicylate n=5 60 - 50 - 40 Time (h) US 6,916.487 B2 Page 2 U.S. PATENT DOCUMENTS Nimni, U.S. Patent No. 4,820,742, Internet: www.paten 5,122,519 A 6/1992 Ritter ts.ibm.com/fegi-bin/any2htm Document, Dual Phase Sol 5,256,647 A 10/1993 Minaskanian et al. vent Carrier System, pp.3, 4 and 6 out of 7 pages. 5.487,898 A 1/1996 Lu et al. 6,299,900 B1 * 10/2001 Reed et al. ................. 424/449 Journal Of Toxicology and Environmental Health, Bucks, OTHER PUBLICATIONS D.A., et al., Percutaneous Absorption of Hydroquinone in Humans: Effect of 1-Dodecylazacycloheptan-2-One M. F. Coldman et al., “Journal of Pharmaceutical Sciences', (AZone) and the 2-Ethylhexyl Ester of 4-(Dimethylamino) vol. 58, No. 9, Enhancement of Percutaneous Absorption by the Use of Volatile. Nonvolatile Systems and Vehicles, pp. Benzoic Acid (Escalol 507), vol. 24, pp. 27-289 (1988). 1098–1102 (Sep. 1969). Physicians’ Desk Reference, PDR 51 Ed., 1997, pp. P.P. Bhatt et al., “International Journal of Pharmaceutics' 50, Finite dose transport of drugs in liquid formulations through 1299-1300. Stratum corneum. analytical Solution to a diffusion model, pp. 197–203 (1989). * cited by examiner U.S. Patent Jul. 12, 2005 US 6,916,487 B2 -0-2.5% Granisetron (control) n=7 -O- 5% Granisetron, 8% Octyl Salicylate n=6 Time (h) FIGURE 1 US 6,916,487 B2 1 2 TRANSIDERMAL IDELIVERY OF or more dermal penetration enhancers (Finnin and Morgan, ANTIEMETCS J. Pharm. Sci., Vol 88, No. 10, October 1999, pp. 955–958) which are often lipophilic chemicals that readily partition This application is a continuation-in-part of U.S. patent into the Stratum corneum whereupon they exert their effects application Ser. No. 09/910,780, filed Jul. 24, 2001, which on improving the transport of drugs across the skin barrier. is a divisional of application Ser. No 09/125,436 now U.S. There is a need for improvements in the transdermal Pat. No. 6,299,900, filed Dec. 18, 1998 as the U.S. national delivery of antiemetics. stage application of PCT application PCT/AU97/00091, filed Feb. 19, 1997. The entire contents of each of U.S. SUMMARY OF THE INVENTION patent application Ser. No. 09/910,780, U.S. Pat. No. 6,299, According to the present invention there is provided a 900, and PCT application PCT/AU97/00091 are incorpo transdermal drug delivery System comprising: rated herein by reference, and priority to each is claimed (a) a therapeutically effective amount of an antiemetic under 35 U.S.C. S 119 and/or S120. agent, FIELD OF THE INVENTION 15 (b) at least one dermal penetration enhancer, which is a The present invention relates to transdermal drug deliv Safe skin-tolerant ester Sunscreen of formula (I): ery. More Specifically, the invention relates to a topical absorption/penetration enhancing agent for use in the deliv (I) ery of antiemetics and antiemetic derivatives to an animal, N (CH=CH)-COR including a human. The invention also relates to a System for the non-occlusive delivery to an animal of antiemetics and 21 antiemetic derivatives acroSS a dermal Surface of the animal. Transdermal drug formulations of the present invention may be used for systemic delivery. wherein 25 R" is hydrogen, lower alkyl, lower alkoxy, halide, BACKGROUND OF THE INVENTION hydroxy or NR There is a constant need for methods for the safe and R; effective administration of physiologically active agents, R is a Cs to Cls alkyl; Such as antiemetics. For many medications it is important R and R" are each independently hydrogen, lower alkyl that the administration regime is as Simple and non-invasive or R and R together with the nitrogen atom to which as possible in order to maintain a high level of compliance they are attached form a 5- or 6-membered heterocyclic by a patient. Oral administration is one administration ring, regime that is commonly used because it is a relatively n is 0 or 1, and Simple regime to follow. However, the oral administration 35 q is 1 or 2, route is also complicated because of complications associ wherein, when n is 0 and R is NRR", then NR'R' is ated with gastrointestinal irritation, drug metabolism in the para-Substituted, and wherein Said dermal penetration liver and is often impractical if a patient is vomiting or enhancer is present in an amount of from about 10 to USCOUS. about 10,000 wt % based on the weight of the an Administration of physiologically active agents through 40 antiemetic agent, and the skin (transdermal drug delivery) has received increased (c) at least one volatile liquid. attention because it not only provides a relatively simple In addition to providing improved percutaneous absorp dosage regime but it also provides a relatively slow and tion efficiency, the composition of the invention may also controlled route for release of a physiologically active agent provide lower irritancy than Some other more occlusive into the Systemic circulation. However, transdermal drug 45 delivery Systems. Such as transdermal patches, because the delivery is complicated by the fact that the skin behaves as composition is non-occlusive to the skin. a natural barrier and therefore transport of agents through More preferably the dermal penetration enhancer is the skin is a complex mechanism. Selected from the group consisting of a Cs to Cs alkyl Structurally, the skin consists of two principle parts, a para-aminobenzoate, Cs to Cs alkyl dimethyl-para relatively thin outermost layer (the 'epidermis) and a 50 aminobenzoate, Cs to Cs alkyl cinnamate, Cs to Cs alkyl thicker inner region (the dermis). The outermost layer of methoxycinnamate or Cs to Cs alkyl Salicylate. Most pref the epidermis (the stratum corneum) consists of flattened erably the dermal penetration enhancer is octyl Salicylate dead cells which are filled with keratin. The region between (2-ethylhexyl Salicylate, octisalate), octyl dimethyl para the flattened dead cells of the stratum corneum are filled with aminobenzoate or octyl para-methoxycinnamate (Padimate lipids which form lamellar phases that are responsible for 55 O). the natural barrier properties of the skin. The drug delivery Systems according to the invention may For effective transdermal delivery of a physiologically comprise one or more antiemetics together with the pen active agent that is applied to the Surface of the skin (topical etration enhancer incorporated into a dosage form for topical application), the agent must be partitioned firstly from the application to the skin of animals. Suitable dosage forms vehicle into the Stratum corneum, it must typically then be 60 include creams, lotions, gels, ointments, mousses, SprayS, diffused within the stratum corneum before being partitioned aeroSols, or any one of a variety of transdermal devices for from the Stratum corneum to the viable epidermis and then use in the continuous administration of Systematically active into the dermal circulation.
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