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

(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.

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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

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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 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 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 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. Whilst it is preferred that the non-steroidal anti administration of systematically active drugs by absorption inflammatory drug and penetration enhancer be delivered by through the skin, underlying soft tissue or joints. Some simultaneous administration, the penetration enhancer may examples of suitable vehicles are given in U.S. Pat. Nos. be applied before or after the application of the non-steroidal 3,598,122, 3,598,123, 3,742,951, 3,814,097, 3,921,636, anti-inflammatory drug, if desired. 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 0028. The present invention also provides a method for 4,069,307, 4,201,211, 4,230,105, 4,292,299, 4,292,303, administering at least one systemic or locally acting non 5,323,769, 5,023,085, 5,474,783, 4,941,880 and 4,077,407. steroidal anti-inflammatory drug to an animal which com These disclosures are thus hereby incorporated herein by prises applying an effective amount of the non-steroidal reference. anti-inflammatory drug in the form of the drug delivery system of the present invention. 0023 Optionally the drug delivery system may contain pharmaceutical compounding agents, such as one or more 0029 Preferably the animal is a human but the invention thickening agents such as cellulosic thickening agents, eth also extends to the treatment of non-human animals. ylcellulose, hydroxypropyl cellulose, hydroxypropyl meth 0030 Preferably the drug delivery system is not super ylcellulose, povidone, polyacrylic acids such as carbopol, saturated with respect to the non-steroidal anti-inflammatory Sepigel R (polyacrylamidefisoparaffin/laureth-7), the Gan drug. As the Volatile liquid of the drug delivery system trezR series of polymethyl vinyl ether/maleic anhydride evaporates, the resulting non-volatile composition is rapidly copolymers such as the butyl ester of PVM/MA copolymer driven into the dermal surface. It is possible that as the GantreZ(RA-425, and any thickening agent known in the art Volatile liquid evaporates, the non-volatile dermal penetra that has good compatibility with the volatile liquid and tion enhancer becomes Supersaturated with respect to the enhancers of the present invention. non-steroidal anti-inflammatory drug. However, it is pre 0024 Non-steroidal anti-inflammatory drugs that may be ferred that any Supersaturation does not occur before trans used in the composition of the present invention include any port of the resulting non-volatile composition across the locally or systemically active non-steroidal anti-inflamma epidermal Surface has occurred. tory drugs which are compatible with the dermal penetration 0031. It is most desirable that, after application of the enhancers of the present invention and which can be deliv drug delivery system, the volatile component of the delivery ered through the skin with the assistance of the dermal system evaporates and the area of skin to which the drug penetration enhancer to achieve a desired effect. Suitable delivery system was applied becomes touch-dry. Preferably non-steroidal anti-inflammatory drugs include ibuprofen, said area of skin becomes touch-dry within 10 minutes, more , , aclofenac, , , preferably within 3 minutes, most preferably within 1 aproxen, , , , indomethacin, minute. , , , , Sali cylamide, , , desoxysulindac, tenoxi 0032. The group of dermal penetration enhancing ester cam, , ketoralac, , amtolimetin, aza Sunscreen compounds of the present invention are particu propaZone, , , larly suitable for transdermal delivery non-steroidal anti hydrochloride, bromfenal, , butibufen, , inflammatory drugs through the skin of an animal. These , choline Salicylate, , dipyone, , dermal penetration enhancing compounds are of low toxicity , , , , , fen to the skin and are excellent promoters of percutaneous tiazac, , , , , absorption. , , , fepradinol, magnesium 0033 Preferred volatile liquids of the present invention salicylate, , , , include safe skin-tolerant solvents such as ethanol and , , oxaproZen, , priaz isopropanol. An aerosol propellant, Such as dimethyl ether, olac, , , produaZone, , may constitute a volatile liquid for the purpose of the present Salalate, , sodium thiosalicylate, , invention. , , , , and The non-steroidal anti-inflammatory agent may 0034 Surprisingly the group of dermal penetration com be a racemic mixture or individual enantiomers where pounds identified enhance the absorption of non-steroidal applicable. anti-inflammatory drugs through the skin while avoiding the significant pharmacological disadvantages and toxicities of 0025. In one preferred form of the invention the drug prior art enhancers. Additionally, the group of compounds of delivery system comprises on a weight basis from about 1 to the invention Surprisingly exhibit appreciable penetration about 15% of the non-steroidal anti-inflammatory drug, into and substantivity for the outer layers of the skin, namely US 2007/0077288 A1 Apr. 5, 2007 the stratum corneum which has previously presented a preferred that the penetration enhancer and non-steroidal formidable barrier to percutaneous drug absorption. anti-inflammatory drug are in approximately equal propor 0035) In drug delivery systems according to the present tions. invention a pharmaceutical compounding agent, co-solvent, 0041 A particular advantage of the drug delivery system Surfactant, emulsifier, antioxidant, preservative, stabiliser, of the present invention is that patient compliance is diluent or a mixture of two or more of said components may improved as the system does not occlude the skin. As a result be incorporated in these systems as is appropriate to the local irritation and allergic sensitisation problems arising particular route of administration and dosage form. The from prolonged exposure of the skin to both the delivery amount and type of components used should be compatible system of occlusive transdermal patch devices and the with the dermal penetration enhancers of this invention as adhesive used to affix these patches to the skin are reduced. well as with the non-steroidal anti-inflammatory drug. A 0042. The following definitions apply through this co-solvent or other standard adjuvant, such as a surfactant, may be required to maintain the non-steroidal anti-inflam description and the claims which follow. matory drug in Solution or Suspension at the desired con 0043. The terms “percutaneous” and “transdermal are centration. used herein in the broadest sense to refer to being able to 0036). The pharmaceutical compounding agents can pass through unbroken skin. include paraffin oils, esters such as isopropyl myristate, 0044) The term “dermal penetration enhancer is used ethanol, silicone oils and vegetable oils. These are prefer herein in its broadest sense to refer to an agent which ably used in the range 1 to 50%. Surfactants such as improves the rate of percutaneous transport of active agents ethoxylated fatty alcohols, glycerol mono Stearate, phos across the skin or use and delivery of active agents to phate esters, and other commonly used emulsifiers and organisms such as animals, whether it be for local applica surfactants preferably in the range of 0.1 to 10% may be tion or systemic delivery. used, as may be preservatives such as hydroxybenzoate 0045. The term “non-occlusive' is used herein in its esters for preservation of the compound preferably in broadest sense to refer to not trapping or closing the skin to amounts of 0.01% to 0.5%. Typical co-solvents and adju the atmosphere by means of a patch device, fixed reservoir, vants may be ethyl , isopropyl alcohol, acetone, application chamber, tape, bandage, Sticking plaster, or the dimethyl ether and glycol ethers such as diethylene glycol like which remains on the skin at the site of application for mono ethyl ether. These may be used in amounts of 1 to a prolonged length of time. 50%. 0046) The term “stratum corneum is used herein in its 0037 Because of the effect of the penetration enhancer of broadest sense to refer to the outer layer of the skin, which the invention, the dosage of the non-steroidal anti-inflam is comprised of (approximately 15) layers of terminally matory drug may often be less than that conventionally used. differentiated keratinocytes made primarily of the proteina It is proposed that, a dosage near the lower end of the useful ceous material keratin arranged in a brick and mortar range of the particular non-steroidal anti-inflammatory drug fashion with the mortar being comprised of a lipid matrix may be employed initially and increased as indicated from made primarily from cholesterol, ceramides and long chain the observed response if necessary. fatty acids. The stratum corneum creates the rate-limiting 0038. The concentration of non-steroidal anti-inflamma barrier for diffusion of the active agent across the skin. tory drug used in the drug delivery system will depend on its 0047 The term “skin-depot' is used herein in its broadest properties and may be equivalent to that normally utilised sense to refer to a reservoir or deposit of active agent and for the particular non-steroidal anti-inflammatory drug in dermal penetration enhancer within the stratum corneum, conventional formulations. Both the amount non-steroidal whether it be intra-cellular (within keratinocytes) or inter anti-inflammatory drug and the amount of penetration cellular. enhancer will be influenced by the type of effect desired. 0048. The term “volatile:non-volatile liquid vehicle' is 0.039 Where it is desired to achieve higher systemic used in the art to refer to a liquid pharmaceutical vehicle concentration of a non-steroidal anti-inflammatory drug, comprising a volatile liquid mixed with a non-volatile liquid proportionately higher concentrations of the enhancer of the vehicle. Such as a dermal penetration enhancer. A system or invention may be required in the transdermal drug delivery vehicle comprising a volatile liquid mixed with a non system of the present invention, and the amount of non volatile dermal penetration enhancer when described herein steroidal anti-inflammatory drug included in the composi is used in its broadest sense to include those systems known tion should be sufficient to provide the blood level desired. as volatile:non-volatile liquid vehicles. 0040. The concentration of absorption/penetration 0049 Alkyl and alkoxy groups referred to herein may be enhancer may be in the range from 10-10,000 weight percent either straight chain or branched. The term “lower alkyl of absorption/penetration enhancer based upon the weight of means alkyl groups containing from 1 to 5 carbon atoms. non-steroidal anti-inflammatory drug. The ratio of penetra The term lower alkoxy has a similar meaning. The term tion enhancer to non-steroidal anti-inflammatory drug may “long chain alkyl means alkyl groups containing from 5 to vary considerably and will be governed as much as anything, 18 carbon atoms, more preferably 6 to 18 carbonatoms. The by the pharmacological results that are required to be term “halide” means fluoride, chloride, bromide or iodide. achieved. In principle, it is desirable that as little absorption The term "heterocyclic ring is herein defined to mean a ring enhancer as possible is used. On the other hand, for some of carbon atoms containing at least one hetero atom, and non-steroidal anti-inflammatory drugs, it may well be that further the ring may be saturated or unsaturated to any the upper range of 10,000% by weight will be required. It is allowable degree. US 2007/0077288 A1 Apr. 5, 2007

0050. The term "sunscreen” is used herein in its broadest inflammatory drug varies with differences in both the nature sense to refer to a chemical agent capable of filtering out of the dermal penetration enhancer and the non-steroidal ultraviolet light. anti-inflammatory drug. It is understood that different der mal penetration enhancers may need to be selected to be 0051. The drug delivery system of the present invention appropriate for delivery of various non-steroidal anti-in enables a wide range of non-steroidal anti-inflammatory flammatory drugs. drugs to be delivered through the skin to achieve a desired systemic effect. The drug delivery system preferably com 0056 Diseases or conditions that may be treated by using prises the non-steroidal anti-inflammatory drug intimately the drug delivery system and methods of the present inven mixed with a non-volatile dermal penetration enhancer and tion include, but are not limited to pain associated with a volatile liquid. Where the drug delivery system is applied musckuloskeletal disorders, arthritic pain, and other inflam to the skin, the non-steroidal anti-inflammatory drug and matory conditions of joints and soft-tissue (e.g. muscle non-volatile liquid are thermodynamically driven into the tissue). skin as the volatile liquid evaporates. Once within the skin 0057 The drug delivery system of the present invention the non-volatile liquid may either disrupt the lipid matrix may be applied to the skin by means of an aerosol, spray, and/or act as a solubilizer to allow an enhanced penetration pump-pack, brush, Swab, or other applicator. Preferably, the rate of the non-steroidal anti-inflammatory drug through the applicator provides either a fixed or variable metered dose skin and into the Subject being treated. In this way, the application Such as a metered dose aerosol, a stored-energy dermal penetration enhancer acts as a vehicle and many metered dose pump or a manual metered dose pump. Pref systemic active non-steroidal anti-inflammatory drugs are erably the drug delivery system is applied to the skin of the able to be transdermally administered to an animal. animal covering a delivery surface area between about 10 0.052 It is believed that the non-volatile dermal penetra and 2000 cm, more preferably between about 10 and 400 tion enhancer is readily absorbed into the stratum corneum cm, and most preferably between about 10 and 200 cm. in sufficient quantities to form a reservoir or depot of the The application is most preferably performed by means of a dermal penetration enhancer within the stratum corneum. topical metered dose spray combined with an actuator The dermal penetration enhancer also contains the non nozzle shroud which together accurately control the amount steroidal anti-inflammatory drug to be administered and as and/or uniformity of the dose applied. One function of the the dermal penetration enhancer crosses through the skin to shroud is to keep the nozzle at a pre-determined height form the skin-depot, the non-steroidal anti-inflammatory above, and perpendicular to, the skin to which the drug drug contained therein is transported through the skin and delivery system is being applied. This function may also be contained within the depot. These depots are believed to achieved by means of a spacer-bar or the like. Another form within the lipid matrix of the stratum corneum wherein function of the shroud is to enclose the area above the skin the lipid matrix creates a rate-limiting barrier for diffusion of in order to prevent or limit bounce-back and/or loss of the the non-steroidal anti-inflammatory drug across the skin and drug delivery system to the Surrounding environment. Pref allows the dermally administered non-steroidal anti-inflam erably the area of application defined by the shroud is matory drug to be systemically released over a period of Substantially circular in shape. time, usually up to 24 hours. 0058. The drug delivery system may be propelled by 0053) Once the volatile liquid of the drug delivery system either pump pack or by the use of propellants such as has evaporated, driving the mixture of non-volatile dermal hydrocarbons, hydro fluorocarbons, nitrogen, , penetration enhancer and non-steroidal anti-inflammatory carbon dioxide or ethers, preferably dimethyl ether. The drug into the stratum corneum, the outer Surface of the skin drug delivery system is preferably in a single phase system is then substantially free of non-steroidal anti-inflammatory as this allows less complicated manufacture and ease of dose drug and non-volatile dermal penetration enhancer. Normal uniformity. It may also be necessary to apply a number of touching, wearing of clothes, rinsing or even washing of the dosages on untreated skin to obtain the desired result. skin will not, to any significant extent, affect delivery of the non-steroidal anti-inflammatory drug or displace either the DETAILED DESCRIPTION OF THE non-steroidal anti-inflammatory drug or the non-volatile INVENTION dermal penetration enhancer, once the Volatile liquid has 0059) The invention will now be described with reference evaporated. to the following examples and accompanying figure. The 0054) This is in contrast to prior-art systems where super examples and figure are not to be construed as limiting the saturated solutions are used to increase the rate of drug invention in any way. They are included to further illustrate permeation across the skin. Such Supersaturated Solutions the present invention and advantages thereof. are susceptible of ready precipitation and require stabiliza 0060) In the accompanying figure: tion, such as with polymers, or protection from external 0061 FIG. 1 Shows the cumulative amount of ibuprofen Surfaces or objects which may effect nucleation. penetrating into the microdialysis probe, adjusted for indi 0.055 The rate of absorption of the non-steroidal anti vidual probe recovery over a 24 hour period. inflammatory drug via the stratum corneum is increased by the non-volatile dermal penetration enhancer. The non 0062 FIG. 2 Shows the cumulative amount of ibuprofen steroidal anti-inflammatory drug may be dissolved or Sus transferring across shed Snake skin versus time for gel pended in the dermal penetration enhancer at the time when formulations of ibuprofen (5 mg of each gel was applied to it is being transported from the Surface of the skin and into the skin). the stratum corneum. The performance of the dermal pen 0063. In the examples, the effectiveness of the penetra etration enhancer to deliver a desired non-steroidal anti tion enhancers are illustrated by measuring the skin pen US 2007/0077288 A1 Apr. 5, 2007

etration of formulations of a number of representative non from the torso, the Subcutaneous fat and connective tissue is steroidal anti-inflammatory drugs with the dermal removed and the skin is cut into circles of 2.0 cm, and then penetration enhancers. Also, the skin penetration of non is placed into diffusion cells for flux measurements. steroidal anti-inflammatory drugs are measured with other prior art penetration enhancers as well as formulations of the In vitro Skin Diffusion Experiments in Horizontal Diffusion non-steroidal anti-inflammatory drugs with common adju Cells vants, which serve as control formulations. The comparisons generally consist of measuring the relative penetration 0071. A modified stainless steel flow-through diffusion through shed Snake skin of the various formulations. In cell assembly based on that first shown by Cooper in J. every case, those formulations which contain the dermal Pharm. Sci. 73(8), 1984, is used to perform the experiments penetration enhancers deliver more of the non-steroidal on diffusion of the drugs from various donor compositions anti-inflammatory drug through the skin than the corre through the skin (either snake or hairless mouse). The cell sponding control formulation or commercial preparation. consists of an upper section and a lower section. A stainless steel wire mesh Support is housed in a recess in the lower EXAMPLE 1. section of the cell. The skin Sample, cut into a circle, is 0064. Enhanced skin penetration of ibuprofen using Padi gently placed over the Support and the two sections of the mate O in a transdermal gel composition (Composition 3B). cells are secured together by Screws, using the locating FIG. 1 shows the cumulative amount of ibuprofen penetrat holes, to form a tight seal. An aperture in the upper section ing into the microdialysis probe, adjusted for individual of the cell, which has an area of 0.79 cm (0.5 cm in probe recovery over a 24 hour period. diameter), forms a well above the skin into which the topical formulation is applied. In most cases 400 microL of formu 0065. As shown in FIG. 1, the addition of the safe lation, Solution or Suspension containing the drug Substance Sunscreen ester dermal penetration enhancer, Padimate O. to be tested is applied evenly over the skin. The bottom causes a marked 3.5-fold increase in the in vivo transdermal section of the cell is provided with inlet and outlet tubes delivery of ibuprofen across the skin (p<0.05). which connect to the bottom of the recess and through which 0.066 The diffusion of ibuprofen from the gel formula a Solution is pumped by a microcassette peristaltic tions is measured in vivo in conscious rats. Briefly, linear pump (Watson Marlow, UK) (not shown) at a constant flow microdialysis probes are inserted in the Subcutaneous region rate to maintain sink conditions. The receptor Solution on the dorsum of Sprague Dawley rats. These probes allow consists of 50% propylene glycol in water, is made isotonic sampling of the extracellular fluid for exogenous or endog with 0-9% sodium chloride and is preserved with 0-1% enous substances (Ungerstedt 1991: Microdilysis prin sodium azide or 0.1% sodium fluoride. To prevent air ciples and applications for studies in animals and man. bubbles forming under the skin, the wire mesh ensures Journal of Internal Medicine 230: 365-373 Ungerstedt turbulent receptor flow. The recess is filled with receptor 1991) and thus once the ibuprofen penetrates the skin it is Solution prior to placing the skin in the cell. The receptor collected in the dialysate flowing through the probe. The Solution is degassed by spraying the solution into fine dialysate is collected in hourly intervals for 24 hours and droplets under vacuum while stirring at 40 degrees C. analysed directly by RP-HPLC. Degassing is repeated three times. These precautions elimi nate the need for a bubble chamber in the diffusion cell. The 0067 Samples are analysed for ibuprofen directly by diffusion cells are set on a hollow metal heater bar which RP-HPLC using the following conditions: Column Waters maintains normal skin temperature of 32 degrees C. (+0.5 Spherisorb Cs column (4.6 mmx250 mm); Mobile phase— degrees C.) by means of heated, circulating water (Thermo 55% Acetonitrile, 45% water made to pH 3.5 with ortho mix, Braun, Germany). Each diffusion cell has its receptor phosphoric acid; Flow rate 1.5 mL/min: Absorbance 210 solution collected via tube into polyethylene vials (6 ml nm, and Injection Volume—20 uL. liquid scintillation vials, Packard instruments, Netherlands) In vitro Skin Diffusion Measurements Shed Snake Skin at two or four hour intervals for 24 hours, by means of an automated rotating fraction collector (Retriever II, ISCO, 0068 The Children’s python shed snake skin is obtained Australia). The amount of drug in each vial containing during natural shedding and the dorsal skin is used. Shed receptor solution is determined by reverse phase HPLC. Snake skin has been shown to be a Suitable model membrane Prior to analysis each vial is weighed with an analytical for human skin by Itoh, et al., “Use of Shed Snake Skin as balance (Mettler AT261, Australia) and the volume is cal a Model Membrane for In Vitro Percutaneous Penetration culated from the density of the receptor solution which is Studies: Comparison with Human Skin’. Pharm. Res., 1.0554 g/cm at 22 degrees C. 7(10), 1042-1047, 1990; and Rigg, et al., “Shed Snake Skin and Hairless Mouse Skin as Model Membranes for Human 0072 The concentration of applied drug in each diffusion Skin During Permeation Studies”. J. Invest. Dermatol. 94; cell sample is measured using high pressure liquid chroma 235-240,1990. tography (HPLC). The receptor solution is assayed neat, with 20 microL injected (WISP 712 autoinjector, Waters, Full Thickness Skin Australia) into a freshly prepared and degassed (by filtering) 0069. The animals for these investigations are obtained mobile phase. Each drug is separated using a pre column from the animal house at the Victorian College of Pharmacy, fitted with a C18 insert and a mu. Bondapak C18 (30 Monash University, Parkville, Australia. cm.times.3.9 mm) HPLC column (Waters). Absorbance is measured at the appropriate wavelength using a Waters Hairless Mouse Skin tuneable absorbance detector and peak area is plotted and 0070 Hairless mice of 4-8 weeks of age are used. The integrated using a Shimadzu C-R3A chromatic integrator. mouse skin is excised and full-thickness skin is isolated The results for each experiment are the average values of US 2007/0077288 A1 Apr. 5, 2007

four replicate diffusion cells unless stated otherwise. The steroidal anti-inflammatory drug within the same formula assay conditions for each different drug are given in each tion to achieve percutaneous absorption enhancement. example. EXAMPLE 4 EXAMPLE 2 0078 Table 3 shows the median amount (Og/cm) of 0073. The in vitro diffusion cell method described above ibuprofen penetrating across full-thickness hairless mouse is used to compare the penetration of 400 microL of 2% w/v. skin in vitro when 400 microL of a 2% w/v ibuprofen and ketoprofen in 70% v/v aqueous ethanol applied to the shed 2% v/v dermal penetration enhancer in 70% v/v aqueous snake skin following the application of 400 microL of the ethanol is applied. Again, AZone is selected as the standard different dermal penetration enhancers in a 2% v/v solution for comparison and the control formulation contains no in 70% ethanol, 2 hours prior to the application of the penetration enhancer. The detection wavelength is 210 nm ketoprofen. The control experiment involves application of and the mobile phase consists of acetonitrile:water (55:45) 400 microL of 70% aqueous ethanol alone for 2 hours, made to pH 3.0 with orthophosphoric acid. followed by application of 400 microL of the 2% ketoprofen Solution. Samples are assayed according to the method TABLE 3 described previously. The detection wavelength is 255 nm. and the mobile phase consists of acetonitrile: water (55:45) Enhancer type after 12 hours after 24 hours made to pH 3.0 with orthophosphoric acid (BDH, Australia). Octyl methoxycinnamate 2% viv 1099* 2458: Table 1 shows the mean flux of ketoprofen across the snake Octyl dimethyl PABA 2% viv 1123% 2981: skin over 24 hours as determined by the linear regression of Azone 2% viv 1036* 2684: the cumulative amount of ketoprofen crossing the skin Control (no enhancer) 474 1819 versus time (Units=microg/cmh). n = 8, *statistically significantly different from control, p < 0.05 following ANOVA on Ranks. TABLE 1. EXAMPLE 5 Mean flux +/- p value Enhance std error (micro relative ment 0079 FIG. 2 shows the cumulative amount of ibuprofen Enhancer type g/cm h) to control ratio transferring across shed Snake skin versus time for gel Control - no enhancer, n = 9 0.96 - 0.18 formulations of ibuprofen. 5 mg of each gel is applied to the AZone, n = 2 2.58 - 0.23 O.OO29 2.7 skin. Samples are assayed by the HPLC method mentioned Octyl dimethyl PABA, n = 3 2.25 + 0.14 O.OO68 2.3 Octylmethoxy cinnamate, n = 3 3.22 - 0.28 O.OOO3 3.35 in Example 4. The gels are made to a final concentration of Octyl salicylate, n = 2 27.66 - 5.26 &O.OO70 28.81 5% w/w ibuprofen and 2% w/w dermal penetration enhancer by first dissolving them in 50% v/v aqueous ethanol then NB. Enhancement ratio = mean flux enhancerimean flux control adding 2% w/w Sepigel 305TM (SEPPIC, Paris, France) as a gelling agent and stirring at room temperature until a gel is 0074 Statistical significance is determined by means of a formed. This formulation is compared with the commercial Student's t-test. AZone is selected as the standard penetra IBUGELTM (Dermal Laboratories, UK) formulation which tion enhancer for comparison since it has been widely used contains 5% w/w ibuprofen in an ethanolic gel base formed in previous percutaneous penetration experiments. with carbopol. As well, 2% w/w dermal penetration enhancer is added to the IBUGEL by simple mixing. The EXAMPLE 3 ibuprofen contents of each gel are determined by HPLC and are found to be 5.02, 5.75 and 5.43 mg/g for the gel using 0075. The same protocol as Example 2 is repeated, Sepigel-305TM and enhancer, the IBUGEL and the IBUGEL except the dermal penetration enhancers are included in the with enhancer, respectively. ketoprofen formulation, such that 400 microL of 2% w/v. ketoprofen and 2% v/v dermal penetration enhancer in 70% 0080 Both the cumulative amounts at 12 an 24 h and the V/V aqueous ethanol is applied to the skin from the start of mean flux over 24 h are significantly greater (p<0.05) for the diffusion experiment. both the enhanced gel formulations when compared to the commercial IBUGEL formulation. The flux enhancement 0.076 Table 2 shows the mean flux of ketoprofen across ratios are 6.15 and 2.61 for the gel using Sepigel-305TM and the Snake skin over 24 hours. enhancer and the IBUGEL with enhancer (n=3) respectively when compared to the IBUGEL (p<0.05). TABLE 2 EXAMPLE 6 Mean flux +/- p value Enhance std error (micro relative ment 0081 Table 4 shows the mean flux over 24 h of ketopro Enhancer type g/cm h) to control ratio fen from a transdermal patch using the enhancer octyl Control - no enhancer, n = 10 O.78 O.O7 salicylate compared with a control without enhancer. The AZone, n = 2 2.84 - 0.11 &OOOO1 3.6 patches are prepared by dissolving 300 mg of ketoprofen, Octyl dimethyl PABA, n = 2 2.71 - 0.18 &OOOO1 3.5 Octylmethoxy cinnamate, n = 2 2.08 - 0.39 O.O413 2.7 400 mg of penetration enhancer, 300 mg of polyethylene Octyl salicylate, n = 4 61.68 - 14.89 &O.OO59 79.1 glycol 400 and 800 mg of hydroxypropylcellulose in 20 mL of ethanol and stirring until Viscous. This is then poured onto a clean glass plate and dried at 40 degrees Celsius for 1 h. 0077. These results demonstrate the ability of the dermal The thickness of this film is approximately 1 mm. Circles of penetration enhancers to be applied together with the non 0.8 cm are cut out of this matrix and are stuck onto the US 2007/0077288 A1 Apr. 5, 2007 middle of 2.0 cm circles of OPSITETM adhesive bandage. This patch is stuck onto 2.0 cm pieces of snake skin and is -continued placed in the diffusion cell. The ketoprofen content of each patch formulation is determined by HPLC in triplicate and Topical lotion compositions is found to be 6.99+0.30 mg/cm and 6.76+0.24 mg/cm, for Composition 9A Composition 9B the control and octyl salicylate patches respectively (mean contentistd error, n=4). Component Amount Component Amount Aqueous ethanol to 100 mL Aqueous ethanol to 100 mL. TABLE 4 (90% w/v) (90% w/v) Mean flux +f- p value Std error (micro relative Enhancement Enhancer type g/cm h) to control ratio We claim: Control - no enhancer O.47 O.04 1. A transdermal drug delivery system comprising: Octyl salicylate 11.70 - 0.65 &O.OOO1 25.2 (a) a therapeutically effective amount of a non-steroidal anti-inflammatory drug; (b) at least one dermal penetration enhancer, which is a EXAMPLE 7 safe skin-tolerant ester Sunscreen of formula (I): 0082 (I) (CH=CH)-COR2 Topical Spray compositions N Composition 7A Composition 7B 2 Component Amount Component Amount Ibuprofen 4% ww. Ibuprofen 4% wiv wherein Octyl salicylate 5% wiv Padimate O 6% ww. Aqueous ethanol to 100 mL Aqueous ethanol to 100 mL. R" is hydrogen, lower alkyl, lower alkoxy, halide, (95% w/v) (95% w/v) hydroxy or NR R: R is a Cs to Cls alkyl; R and R are each independently hydrogen, lower EXAMPLE 8 alkyl or RandR together with the nitrogenatom to 0083) which they are attached form a 5- or 6-membered heterocyclic ring; n is 0 or 1, and Topical gel compositions q is 1 or 2, Composition 8A Composition 8B wherein, when n is 0 and R' is NR R, then NR'R' is Component Amount Component Amount para-Substituted, and wherein said dermal penetration Ibuprofen 2% Wiv Ibuprofen 2% Wiw enhancer is present in an amount of from about 10 to Octyl salicylate 1% Wiv Padimate O 2% Wiw about 10,000 wt % based on the weight of the non Carbopol 0.9% wiv Carbopol 0.9% wiv steroidal anti-inflammatory drug; and O.1N NaOH 4.72% Wiv O.1N NaOH 4.92% Wiv Aqueous ethanol to 100 mL Aqueous ethanol to 100 mL. (c) at least one volatile liquid. (70% w/v) (70% w/v) 2. The transdermal drug delivery system according to claim 1, wherein the dermal penetration enhancer is octyl salicylate. EXAMPLE 9 3. The transdermal drug delivery system according to claim 1, wherein the volatile liquid selected from the group 0084) consisting of ethanol, isopropanol, and a mixture thereof. 4. The transdermal drug delivery system according to claim 1, comprising on a weight basis: Topical lotion compositions (a) from about 1 to about 15% of said non-steroidal anti-inflammatory drug; Composition 9A Composition 9B (b) from about 1 to about 10% of said at least one dermal Component Amount Component Amount penetration enhancer; and Ibuprofen 2% Wiv Ibuprofen 2% Wiv Octyl salicylate 2% Wiv Padimate O 3% Wiv (c) from about 75 to about 98% of said volatile liquid. Hydroxy propyl 1.5% ww. Ethyl cellulose 1.5% ww. 5. The transdermal drug delivery system according to cellulose claim 1, wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of acemetacin, amtol US 2007/0077288 A1 Apr. 5, 2007

metin, , benorilate, benoxaprofen, benzy animal which comprises applying an effective amount of the damine hydrochloride, bromfenal, bufexamac, butibufen, non-steroidal anti-inflammatory drug in the form of the drug carprofen, celecoxib, choline Salicylate, dipyone, droxicam, delivery system according to claim 1. etodolac, etofenamate, etoricoxib, felbinac, , floc 12. The method according to claim 11, wherein the tafenine, indoprofen, isoxicam, lomoxicam, loxoprofen, non-steroidal anti-inflammatory drug is selected from the licofelone, fepradinol, , meclofenamic group consisting of acemetacin, amtolimetin, azapropaZone, acid, meloxicam, morniflumate, niflumic acid, nimeSulide, benorilate, benoxaprofen, benzydamine hydrochlorie, bro oxaproZen, piketoprofen, priazolac, pirprofen, propy mfenal, bufexamac, butibufen, carprofen, celecoxib, choline , produaZone, rofecoxib, Salalate, sodium salicy salicylate, dipyone, droxicam, etodolac, etofenamate, etori late, sodium thiosalicylate, Suprofen, tenidap, tiaprofenic coxib, felbinac, fentiazac, floctafenine, indoprofen, isoxi acid, trolamine salicylate, and Zomepirac. cam, lomoxicam, loxoprofen, licofelone, fepradinol, mag 6. The transdermal drug delivery system according to nesium salicylate, meclofenamic acid, meloxicam, claim 1, wherein the non-steroidal anti-inflammatory drug is morniflumate, niflumic acid, nimeSulide, oxaproZen, pike selected from the group consisting of aclofenac, aloxiprin, toprofen, priazolac, pirprofen, propyphenaZone, produa aproxen, aspirin, diflunisal, fenoprofen, indomethacin, Zone, rofecoxib, Salalate, sodium salicylate, sodium thiosali mefenamic acid, piroxicam, phenylbutaZone, , cylate, Suprofen, tenidap, tiaprofenic acid, trolamine salicylic acid, Sulindac, desoxysulindac, , trama salicylate, and Zomepirac. dol, ketoralac, clonixin, fenbufen, benzydamine hydrochlo ride, meclofenamic acid, flufenamic acid and tolmetin. 13. The method according to claim 12, wherein the 7. The transdermal drug delivery system according to non-steroidal anti-inflammatory drug is piroxicam. claim 1, wherein the non-steroidal anti-inflammatory drug is 14. The method according to claim 11, wherein the piroXicam. non-steroidal anti-inflammatory drug is selected from the 8. The transdermal drug delivery system according to group consisting of aclofenac, aloxiprin, aproxen, aspirin, claim 1, wherein the non-steroidal anti-inflammatory drug is diflunisal, fenoprofen, indomethacin, mefenamic acid, selected from the group consisting of ibuprofen, naproxen, piroXicam, phenylbutaZone, Salicylamide, Salicylic acid, flurbiprofen, diclofenac, and ketoprofen. Sulindac, desoxysulindac, tenoxicam, tramadol, ketoralac, 9. The transdermal drug delivery system according to clonixin, fenbufen, benzydamine hydrochloride, meclofe claim 8, comprising on a weight basis: namic acid, flufenamic acid and tolmetin. 15. The method according to claim 11, wherein the (a) from about 1 to about 15% ibuprofen; non-steroidal anti-inflammatory drug is selected from the (b) from about 1 to about 10% octyl salicylate; and group consisting of ibuprofen, naproxen, flurbiprofen, (c) from about 75 to about 98% Alcohol USP (95% diclofenac, and ketoprofen. ethanol). 16. The method according to claim 11, wherein the drug 10. The transdermal drug delivery system according to delivery system is applied to the skin of the animal covering claim 8, comprising on a weight basis: a delivery surface area between about 10 and 2000 cm. 17. The method according to claim 11, wherein the drug (a) from about 1 to about 5% ibuprofen; delivery system is applied to the skin of the animal covering (b) from about 1 to about 5% octyl salicylate; and a delivery surface area between about 10 and 400 cm. (c) from about 45 to about 90% of a volataile liquid 18. The method according to claim 11, wherein the drug Selected from the group consisting of ethanol, isopro delivery system is applied to the skin of the animal covering panol, and a mixture thereof; a delivery surface area between about 10 and 200 cm. 19. The method according to claim 11, wherein the drug (d) from about 5 to about 45% water; and delivery system is applied using a fixed or variable metered (e) from about 0.5 to about 5% of a thickening agent. dose applicator. 11. A method for administering at least one systemic or locally acting non-steroidal anti-inflammatory drug to an

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