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(12) Patent Application Publication (10) Pub. No.: US 2007/0077288A1 Klose Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2007/0077288A1 Klose Et Al US 20070077288A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0077288A1 Klose et al. (43) Pub. Date: Apr. 5, 2007 (54) TRANSDERMAL DELIVERY OF now Pat. No. 6,299,900, filed as 371 of international NON-STEROIDAL ANTI-NFLAMMATORY application No. PCT/AU97/00091, filed on Feb. 19, DRUGS 1997. (75) Inventors: Kathryn Traci-Jane Klose, Bonbeach (30) Foreign Application Priority Data (AU); Margarita Vladislavova Bakalova, Bundoora (AU); Timothy Feb. 19, 1996 (AU)........................................ PN8144796 Matthias Morgan, Carlton North (AU); Berrie Charles Finnin, Glen Iris (AU); Publication Classification Barry Leonard Reed, Strathmore (AU) (51) Int. Cl. Correspondence Address: A6IR 8/37 (2006.01) FOLEY AND LARDNER LLP A6IR 8/49 (2006.01) SUTE SOO A6II 3 L/60 (2006.01) 3OOOK STREET NW (52) U.S. Cl. ............................. 424/449; 514/159: 424/59 WASHINGTON, DC 20007 (US) (57) ABSTRACT (73) Assignee: Acrux DDS Pty Ltd. The present invention provides a transdermal drug delivery (21) Appl. No.: 11/517,575 system which comprises: a therapeutically effective amount (22) Filed: Sep. 8, 2006 of a non-steroidal anti-inflammatory drug; at least one dermal penetration enhancer, which is a safe skin-tolerant Related U.S. Application Data ester Sunscreen ester, and at least one volatile liquid. The invention also provides a method for administering at least (60) Continuation-in-part of application No. 10/759,303, one systemic or locally acting non-steroidal anti-inflamma filed on Jan. 20, 2004, which is a continuation-in-part tory drug to an animal which comprises applying an effec of application No. 09/910,780, filed on Jul. 24, 2001, tive amount of the non-steroidal anti-inflammatory drug in now Pat. No. 6,818,226, which is a division of the form of the drug delivery system of the present inven application No. 09/125,436, filed on Dec. 18, 1998, tion. -O- 5% whw ibuprofen, 5% wiv Padimate On=3 8 -O- 5% w/w ibuprofen n=3 O C4 O 0 1 2 3 4 5 6 7 8 g 101112131415 1617 18192021222324 Time (hours) Patent Application Publication Apr. 5, 2007 Sheet 1 of 2 US 2007/0077288A1 9 -O- 5% w/w Ibuprofen, 5% w/w Padimate On=3 -O- 5% whv ibuprofen n=3 0 1 2 3 4 5 6 7 8 9 10 1112131415 161718 192021222324 Time (hours) FIGURE 1 Patent Application Publication Apr. 5, 2007 Sheet 2 of 2 US 2007/0077288A1 ld O S. S g g S N LD CN O n ON s U C2 O CN co 2 aC. sC. ses o A. C. s e-M E 2 S. o 5 ae is Sn Fmam - C - 9 S &SS 2 s 5 CO SS e --Sn O 33a iSSS w O ld Co Lo o ld O O ld O on O N. L CN O N Ld on CN CN v vm v wn (u06)N3OldNSOLNNOWV3NIVANNO FIGURE 2 US 2007/0077288 A1 Apr. 5, 2007 TRANSIDERMAL DELVERY OF NON-STEROIDAL partitioned from the stratum corneum to the viable epidermis ANTI-NFLAMMATORY DRUGS and then into the dermal circulation. 0001. This application is a continuation-in-part of U.S. 0007 To overcome some of the problems with transder patent application Ser. No. 10/759,303 filed Jan. 20, 2004, mal delivery that are associated with transport across the which is a continuation-in-part of U.S. Pat. No. 6,818,226, dermal layers (percutaneous absorption), physiologically filed Jul. 24, 2001, which is a divisional of U.S. Pat. No. active agents are commonly formulated with incorporation 6,299,900, filed Dec. 18, 1998 as the U.S. national stage of one or more dermal penetration enhancers (Finnin and application of PCT application PCT/AU97/00091, filed Feb. Morgan, J. Pharm. Sci., Vol 88, No. 10, October 1999, pp. 19, 1997. The entire contents of each of U.S. patent appli 955-958) which are often lipophilic chemicals that readily cation Ser. No. 10/759,303, U.S. Pat. No. 6,818,226, U.S. partition into the stratum corneum whereupon they exert Pat. No. 6,299,900, and PCT application PCT/AU97/00091 their effects on improving the transport of drugs across the are incorporated herein by reference, and priority to each is skin barrier. claimed under 35 U.S.C. S 119 and/or S120. 0008. There is a need for improvements in the transder mal delivery of non-steroidal anti-inflammatory drugs. FIELD OF THE INVENTION 0002 The present invention relates to transdermal drug SUMMARY OF THE INVENTION delivery. More specifically, the invention relates to a topical 0009. According to the present invention there is pro absorption/penetration enhancing agent for use in the deliv vided a transdermal drug delivery system comprising: ery of non-steroidal anti-inflammatory drugs and non-ste roidal anti-inflammatory drug derivatives to an animal, 0010 (a) a therapeutically effective amount of a non including a human. The invention also relates to a system for steroidal anti-inflammatory drug; the non-occlusive delivery to an animal of non-steroidal 0011 (b) at least one dermal penetration enhancer, anti-inflammatory drugs and non-steroidal anti-inflamma which is a safe skin-tolerant ester Sunscreen of formula tory drug derivatives across a dermal Surface of the animal. (I): Transdermal drug formulations of the present invention may be used for local application or systemic delivery. (I) BACKGROUND OF THE INVENTION N (CH=CH)-COR2 0003. There is a constant need for methods for the safe (R)- and effective administration of physiologically active 21 agents, such as non-steroidal anti-inflammatory drugs. For many medications it is important that the administration regime is as simple and non-invasive as possible in order to 0012 wherein maintain a high level of compliance by a patient. Oral 0013) R' is hydrogen, lower alkyl, lower alkoxy, administration is one administration regime that is com halide, hydroxy or NR R: monly used because it is a relatively simple regime to follow. However, the oral administration route is also com 0014) R is a Cls to Cls alkyl: plicated because of complications associated with gas 0015 R and R are each independently hydrogen, trointestinal irritation and with drug metabolism in the liver. lower alkyl or R and R together with the nitrogen 0004 Administration of physiologically active agents atom to which they are attached form a 5- or 6-mem through the skin (transdermal drug delivery) has received bered heterocyclic ring; increased attention because it not only provides a relatively simple dosage regime but it also provides a relatively slow 0016 n is 0 or 1, and and controlled route for release of a physiologically active 0017 q is 1 or 2, agent into the systemic circulation. However, transdermal 0018 wherein, when n is 0 and R' is NR'R'', then NR drug delivery is complicated by the fact that the skin behaves R" is para-substituted, and wherein said dermal pen as a natural barrier and therefore transport of agents through etration enhancer is present in an amount of from about the skin is a complex mechanism. 10 to about 10,000 wt % based on the weight of the 0005 Structurally, the skin consists of two principle non-steroidal anti-inflammatory drug; and parts, a relatively thin outermost layer (the epidermis) and a thicker inner region (the dermis). The outermost layer of 0019 (c) at least one volatile liquid. the epidermis (the stratum corneum) consists of flattened 0020. In addition to providing improved percutaneous dead cells which are filled with keratin. The region between absorption efficiency, the composition of the invention may the flattened dead cells of the stratum corneumare filled with also provide lower irritancy than Some other more occlusive lipids which form lamellar phases that are responsible for delivery systems such as transdermal patches, because the the natural barrier properties of the skin. composition is non-occlusive to the skin. 0006 For effective transdermal delivery of a physiologi 0021 More preferably the dermal penetration enhancer is cally active agent that is applied to the Surface of the skin selected from the group consisting of a Cs to Cs alkyl (topical application), the agent must be partitioned firstly para-aminobenzoate, Cs to Cs alkyl dimethyl-para-ami from the vehicle into the stratum corneum, it must typically nobenzoate, Cs to Cs alkyl cinnamate, Cs to Cs alkyl then be diffused within the stratum corneum before being methoxycinnamate or Cs to Cs alkyl salicylate. Most pref US 2007/0077288 A1 Apr. 5, 2007 erably the dermal penetration enhancer is octyl salicylate from about 1 to 10% of the at least one dermal penetration (2-ethylhexyl salicylate, octisalate), octyl dimethyl para enhancer and from about 75 to 98% ethanol, isopropanol or aminobenzoate or octyl para-methoxycinnamate (Padimate mixture thereof. O). 0026. In another preferred form of the invention the drug 0022. The drug delivery systems according to the inven delivery system comprises, on a weight basis, from about 1 to 5% of an non-steroidal anti-inflammatory drug, from tion may comprise one or more non-steroidal anti-inflam about 1 to 5% of at least one dermal penetration enhancer, matory drugs together with the penetration enhancer incor which is a safe skin-tolerant ester Sunscreen, from about 45 porated into a dosage form for topical application to the skin to 90% ethanol, isopropanol or mixture thereof, 5 to 45% of animals. Suitable dosage forms include creams, lotions, water; and optionally 0.5 to 5% of a thickening agent. gels, ointments, mousses, sprays, aerosols, or any one of a variety of transdermal devices for use in the continuous 0027.
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