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(12) Patent Application Publication (10) Pub. No.: US 2010/0297032 A1 Setiawan Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0297032 A1 Setiawan Et Al US 2010O297.032A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0297032 A1 Setiawan et al. (43) Pub. Date: Nov. 25, 2010 (54) TRANSDERMAL DELIVERY SYSTEM Publication Classification (75) Inventors: Kerrie Setiawan, Victoria (AU); (51) Eiki/12 2006.O1 Adam Watkinson, Victoria (AU) A6II 3/5685 (2006.01)( .01) Correspondence Address: A6II 3/566 (2006.01) FOLEY AND LARDNER LLP A63L/92 (2006.01) SUTESOO A 6LX 3/57 (2006.01) 3OOOK STREET NW A6II 3/196 (2006.01) WASHINGTON, DC 20007 US A6II 3/55 (2006.01) 9 (US) A6IP 25/24 (2006.01) A6IP5/00 (2006.01) (73)73) AssigneeA A X DDS Ptvy Ltd. A6IP 5/8 (2006.01) (21) Appl. No.: 12/740,663 A6M 35/00 (2006.01) (52) U.S. Cl. ........... 424/43; 514/170; 514/179; 514/182: (22) PCT Filed: Oct. 31, 2008 514/570; 514/567; 514/214.02: 604/310 (86). PCT No.: PCT/AUO8/O1614 (57) ABSTRACT S371 (c)(1) A transdermal delivery system comprising a composition (2), (4) Date. Aug. 9, 2010 comprising a physiologically active agent and a penetration s e 19 enhancer wherein the penetration enhancer comprises a com bination of (i) an ester of salicylic acid, preferably selected Related U.S. Application Data from the C to Coaliphatic ester of Salicylic acid and (ii) (60) Provisional application No. 60/984,787, filed on Nov. polyethylene glycol (PEG) of average molecular weight no 2, 2007. more than 300. Patent Application Publication Nov. 25, 2010 Sheet 1 of 10 US 2010/0297.032 A1 Formulations Contain 4.0 - 2.8% NETA, 0.55% E2, (O or 5)% OS, (0-10)% PEG200 in IPA With Out OS E. With 5% OS 2 (?o 3.0 s E S. N 8 O 2.0 - cus as Old C. S. > d - it P 1.0 - c) O Cl O. O O 5 1 O PEG200 Concentration (% w/v) Figure 1: Norethisterone Acetate permeation obtained from the application of Compositions 2-5 compared against application of a control. Patent Application Publication Nov. 25, 2010 Sheet 2 of 10 US 2010/0297.032 A1 Formulations contain 2.8% NETA, O.55% E2, (O or 5)9% OS, (O-10)% PEG200 in IPA 1.5 - Without OS With 5% OS GN to 1.0 N. d) &us 5d 2 g 3 E O 5 O d O OO - O 5 1 O PEG200 concentration (% w/v) Figure 2: Estradiol permeation obtained from the application of Compositions 2-5 in accordance with the invention compared with application of control Composition 1. Patent Application Publication Nov. 25, 2010 Sheet 3 of 10 US 2010/0297.032 A1 3.0 - 2.5 - 2.0 - 15 - 10 OO 1.35% NES, 0.35% EE, 1.35% NES, 0.35% EE, 5%. OS in PA 5% OS, 5% PEG400 in PA (a) Figure 3a: Ethinylestradiol permeation obtained from the application of Composition 2 (not of the invention) compared against application of a control composition 1. 0.3 1.35% NES, 0.35% EE, 1.35% NES, 0.35% EE, 5% OS in IPA 5% OS, 5% PEG400 in IPA (b) Figure 3b: Nestorone permeation obtained from the application of Example 2 compared against application of a control. Patent Application Publication Nov. 25, 2010 Sheet 4 of 10 US 2010/0297.032 A1 Formulations Contain 1.35% NES, 0.35% EE, (O or 5)% OS, (O - 10)% PEG200 in IPA 4.0 - without OS With 5% OS O O.5 l 2.5 5 1O PEG200 concentration (% w/v) Figure 4: Nestorone permeation obtained from the application of Compositions 3 12 compared against application of the Composition 1 control. Patent Application Publication Nov. 25, 2010 Sheet S of 10 US 2010/0297.032 A1 Formulations CO ntain 1.35% NES, 0.35% EE, (O or 5)% OS, (O - 10% PEG200 in IPA PEG200 concentration (% w/v) Figure 5: Ethinylestradiol permeation obtained from the application of Compositions 3-12 compared against application of the Composition 1 control. Patent Application Publication Nov. 25, 2010 Sheet 6 of 10 US 2010/0297.032 A1 Formulations Contain 2% TES, 5% OS, (O-2.5)% PEG200, 2% PVP, 30% IPA in 95% ethanol 25. O - 1 5. O 1O.O - 5. O O.O - O O.5 l 2.5 PEG200 concentration (% w/v) Figure 6 (Comp 1): Testosterone permeation obtained from the application of Compositions 2-4 Compared against application of a control. Patent Application Publication Nov. 25, 2010 Sheet 7 of 10 US 2010/0297.032 A1 Formulations Contain 2.0 - 5% TES, 5% OS, (O-2.5)% PEG200 in 95% ethanol 1 5 1.0 - O 5 O.O - O 2.5 PEG200 concentration (% w/v) Figure 7: Testosterone permeation obtained from the application of Compositions 2-3 Compared against application of a control. Patent Application Publication Nov. 25, 2010 Sheet 8 of 10 US 2010/0297.032 A1 Figure8: Permeation of KETO transdermal spray in comparison with a commercially available gel. Formulations contain 5% KETO, 0 or 5% OS, O or 2.5% PEG 2 OO in PA. 25 - TNO Enhancer 2O OS PEG 200 15 - SOS - PEG 200 1 O Commercially Available Gel 5%. KETO Figure9: 2.5% KETO, 0 or 5% OS, 2.5% PEG 200 or PEG 4 OO in IPA 2 5 PEG 200 PEG 4OO 2 O 1 5 1 O 5 PEG PEG - OS Patent Application Publication Nov. 25, 2010 Sheet 9 of 10 US 2010/0297.032 A1 Figure10: Permeation of Diclofenac transdermal spray (2% DIC diethylamine, 0 or 5% OS, 0 or 2.5% PEG200 in IPA) vs. a commercially available gel 16 - 14 - No Enhancer OS 1O - PEG 200 8 - SOS - PEG 200 Commercially available gel 2%DC Patent Application Publication Nov. 25, 2010 Sheet 10 of 10 US 2010/0297.032 A1 Figure 11: DIC diethylamine from a transdermal spray formulation (1%DIC, O or 5%OS, O or 2.5% PEG400 in IPA) No Enhancer OS PEG 4OO OS-PEG 4OO Figure12: Effect of PEG200 or PEG 400 on Estradiol permeation. Formulations contain - - 0.25%E2, (O or 5)% OS, (O or 5)% (PEG200 or PEG400) in IPA 1.0 - O. 6 - O. 4 - 0.2 - S S S S O.O - S O.25% E2 in IPA O.25% E2, 5% OS 0.25% E2, 5% OS, 0.25% E2, 5% O.25%, 5% OS, (no enhancer) in IPA 5% PEG2OO in IPA PEG 4OO in IPA 5% PEG 4OO in IPA US 2010/0297.032 A1 Nov. 25, 2010 TRANSIDERMAL DELVERY SYSTEM dine and calcium thioglycolate have been reported as effec tive enhancers. However, difficulties remain with such dermal FIELD enhancers because the problem of irritation at the site of application has not been overcome. 0001. This invention relates to a transdermal delivery sys tem and to a method of transdermal delivery of a physiologi 0009. The most critical problem with these compounds cally active agent. however is their toxicity. If a compound when used as a dermal enhancer is toxic, irritating or allergenic, then that compound is unsuitable for application to the animal body. BACKGROUND Dimethyl acetamide is not clinically acceptable for these 0002 Administration of physiologically active agents reasons. Although Deet and AZones have lower reported tox through the skin (transdermal delivery) has received icities, their toxicity is still such that they are not widely used. increased attention because it not only provides a relatively It is possible that AZone and dimethyl sulfoxide may be simple dosage regime but it also provides a relatively slow employed as a dermal penetration enhancer if the amount and controlled route for release of a physiologically active applied is Sufficiently small so as not to be appreciably toxic, agent into the systemic circulation. However, transdermal irritating or allergenic to the animal. drug delivery is complicated by the fact that the skin behaves 0010. The compositions of the present invention are suit as a natural barrier and therefore transport of agents through able for use as vehicles for the topical application of specific the skin is a complex mechanism. compounds to the skin using pharmaceutical, nutraceutical, 0003 Structurally, the skin consists of two principle parts, cosmetic or veterinary preparations. Such topical application a relatively thin outermost layer (the epidermis) and a enables the specific compounds to penetrate the skin and thicker inner region (the dermis). The outermost layer of the enter the circulatory system thereby enabling the active com epidermis (the stratum corneum) consists of flattened dead pound (s) to have a systemic effect. The at least one active cells which are filled with keratin. The region between the compound may be a pharmacologically active compound. A flattened dead cells of the stratum corneum is filled with lipids “pharmacologically active compound is a compound that which form lamellar phases that are responsible for the natu has a therapeutic effect on the human or animal body in the ral barrier properties of the skin. treatment or prevention of a condition. 0004 For effective transdermal delivery of a physiologi 0011. The discussion of documents, acts, materials, cally active agent that is applied to the Surface of the skin devices, articles and the like is included in this specification (topical application), the agent must partition firstly from solely for the purpose of providing a context for the present the vehicle into the stratum corneum, it must typically then invention. It is not suggested or represented that any or all of diffuse within the stratum corneum before partitioning from these matters formed part of the prior art base or were com the stratum corneum to the viable epidermis.
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