EP2485730A1 - Topical formulation comprising etoricoxib and a zwitterionic surfactant - Google Patents

Abstract

The present invention provides topical pharmaceutical compositions, methods for preparation, and methods of treatment comprising a selective COX-2 inhibitor and useful for the treatment of pain, particularly pain associated with osteoarthritis. The compositions can provide good selective COX-2 inhibitor permeability and bioavailability at the target site. In certain preferred embodiments, the invention provides a pharmaceutical composition comprising etoricoxib, a zwitterionic surfactant or charged derivative thereof, an alpha-hydroxy acid, at least one molecular penetration enhancer, at least one lower alcohol, and water.

Description

TOPICAL FORMULATION COMPRISING ETORICOXIB AND A ZWITTERIONIC SURFACTANT

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present invention claims priority to U.S. Provisional Patent Application No. 61/250,452, filed October 9, 2009, the teaching of which is hereby incorporated by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

[0002] Osteoarthritis (OA) is a chronic joint disease characterized by progressive degeneration of articular cartilage. Symptoms include joint pain and impaired movement. OA is one of the leading causes of disability worldwide and a major financial burden to health care systems. It is estimated to affect over 15 million adults in the United States alone. See Boh, L.E.; Osteoarthritis. In: DiPiro, J.T.; Talbert, R.L.; Yee, G.C. et al. editors.

Pharmacotherapy: a pathophysiological approach. 4th ed. Norwalk (CT): Appleton & Lange, pp. 1441-59 (1999). [0003] An OA treatment's efficacy is generally assessed by three outcome measures: pain, physical function, and a patient global assessment. See Bellamy, N.; Kirwan, J.; Boers, M.; Brooks, P.; Strand, V.; Tugwell, P. et al. Recommendations for a core set of outcome measures for future Phase III clinical trials in knee, hip and hand osteoarthritis. Consensus development at OMERACT III., J Rheumatol, 24:799-802 (1997). To be suitable for chronic use, a therapy must generally show efficacy on these three variables over a sustained period of time. In the U.S., the Food and Drug Administration (FDA) has required OA therapies to show superiority over placebo over a twelve-week period before approval of a new drug application.

[0004] Oral non-steroidal anti-inflammatory drugs (NS AIDs) are a mainstay in the management of OA. These drugs are thought to exert their analgesic effect by impeding the production of signaling molecules called prostaglandins through inhibition of the

cyclooxygenase ("COX") enzyme. The COX enzyme has two isoforms, COX-1 and COX-2. Traditional NSAIDs inhibit both isoforms of the COX enzyme, while the selective COX-2 (coxib) class of NSAIDs preferentially inhibits COX-2. [0005] NSAIDs have analgesic, anti-inflammatory, and antipyretic effects and are useful in reducing pain and inflammation. They are, however, associated with serious potential side effects including nausea, vomiting, peptic ulcer disease, and gastrointestinal (GI)

hemorrhage. Although selective COX-2 inhibitors produce fewer gastrointestinal side effects, they may increase the risk of thrombotic events (e.g., stroke or heart attack). Because of this potential side effect, most of the selective COX-2 inhibitors have been withdrawn from the U.S. market.

[0006] Topical NS AIDs offer the possibility of achieving local therapeutic benefit while reducing or eliminating the risk of systemic side effects. There has been widespread interest in this approach to treating OA, but data supporting the efficacy of topical NSAIDs in the treatment of OA is limited. For instance, a study of thirteen randomized placebo controlled trials (RCT's) of various topical NSAIDs tested specifically for use in the treatment of OA concluded that they were not generally efficacious for chronic use in OA. (Lin et al. , Efficacy of topical non-steroidal anti-inflammatory drugs in the treatment of osteoarthritis: meta-analysis of randomized controlled trials, BMJ, doi:10.1136/bmj.38159.639028.7C (2004)). [0007] Pennsaid Gel™ is a topical formulation comprising diclofenac sodium that overcomes disadvantages of prior art NSAID formulations. U.S. Patent Publication No. 2008/030031 1. Pennsaid™ solution has been shown in clinical trials to be effective for treating the pain and symptoms of osteoarthritis, and it has been approved for use in Canada, the U.S., and several European countries. [0008] A topical formulation containing a COX-2 selective inhibitor would offer patients an attractive new treatment modality. Such a formulation could minimize systemic exposure to the active pharmaceutical ingredient by localizing the drug at the site of action. At the same time a topical coxib might have even better GI safety profile than topical formulations containing traditional NSAIDs, making it particularly suitable for patients at risk of GI bleeds.

[0009] The dearth of options for topical NSAID treatment of OA with robust efficacy data partially arises from the difficulty associated with delivering a molecule through the skin both in a sufficient quantity to exert a therapeutic effect and in a manner that makes the treatment itself tolerable. It is generally believed that clinical efficacy of topical treatments in the treatment of OA requires absorption of the active ingredient and its penetration in sufficient quantities into underlying inflamed tissues including the synovium and synovial fluid of joints. See Rosenstein, Topical agents in the treatment of rheumatic disorders, Rheum. Dis. Clin North Am., 25: 899-918 (1999). [0010] Various factors can affect the absorption rates and penetration depth of topical pharmaceutical preparations, including the nature of the active ingredient, the nature of the vehicle, the pH, and the relative solubility of the active in the vehicle versus the skin

(Ostrenga J. et al, Significance of vehicle composition I: relationship between topical vehicle composition, skin penetrability, and clinical efficacy, Journal of Pharmaceutical Sciences, 60: 1175-1179 (1971)). More specifically, drug attributes such as solubility, size and charge, as well as vehicle attributes such as the drug dissolution rate, spreadability, adhesion, and ability to alter the membrane permeability can each have significant effects on permeability.

[0011] Seemingly minor variations in formulations can produce significant changes in their performance. For instance, Naito demonstrates significant variability in penetration among topical NSADD formulations simply by changing the gelling agent used in the compositions (Naito et al. , Percutaneous absorption of diclofenac sodium ointment, Int. Jour, of

Pharmaceutics, 24: 115-124 (1985)). Similarly, Ho noted significant variability in penetration by changing the proportions of alcohol, propylene glycol, and water (Ho et al, The influence of cosolvents on the in- vitro percutaneous penetration of diclofenac sodium from a gel system, J. Pharm. Pharmacol, 46:636-642 (1994)). It was noted that the changes affected three distinct variables: (i) the solubility of the drug in the vehicle, (ii) the partition coefficient of the drug between the vehicle and the skin, and (iii) alteration of skin structure.

[0012] Ho et al. (Id.) also noted that (i) the pH of the vehicle, (ii) the drug solubility, and (iii) the viscosity of a gel matrix can influence penetration from a gel dosage form. The pH value affects the balance between ionized and non-ionized forms of the drug, which have different permeation properties (Obata, International Journal of Pharmaceutics, 89: 191-198 (1993)). The viscosity can affect diffusion of the drug through the gel matrix and release of the drug from the vehicle into the skin. The solubility of the drug in the vehicle will affect the partition coefficient of the drug between the composition and the recipient membrane or tissue (Ho, Id.).

[0013] The skin barrier can be compromised by several physical methods, such as iontophoresis, ultrasound, electroporation, heat, and microneedles. Molecular penetration enhancers (MPE™s) are a preferred means for reversibly lowering the skin barrier. At least 400 chemicals have been identified as skin permeability enhancers. General categories of MPE™s include pyrrolidones, fatty acids, fatty acid esters, fatty acid alcohols, sulfoxides, essential oils, terpenes, oxazoldines, surfactants, polyols, azone and derivatives, and epidermal enzymes. [0014] The mechanisms by which MPE™s reduce the skin barrier function are not well understood (see Williams and Barry "Penetration Enhancers" Advanced Drug Delivery Reviews 56: 603-618 (2004)), although it has been proposed that the mechanisms can be grouped into three broad categories: lipid disruption, increasing corneocyte permeability, and promoting partitioning of the drug into the tissue.

[0015] The challenge with use of MPE™s is that few seem to induce a significant or therapeutic enhancement of drug transport at tolerable levels. This is because an MPE™'s disruption of the skin barrier can potentially cause skin irritation. With increased disruption, skin irritation is expected to become a greater issue. This is particularly problematic with topical OA treatments where the goal is to have the active penetrate deeply into joint tissue and where the drug must be used on a long-term basis due to the nature of the disease.

[0016] In light of the foregoing, there is a considerable need for the development of topical NSAED formulations suitable for long-term use in the treatment of OA, and especially for formulations containing coxibs. The challenge has been to develop an optimal composition which will deliver the active agent to the underlying tissue in sufficient concentration to treat OA on a long-term basis, while reducing or minimizing the incidence of intolerable skin irritation caused by disrupting the skin barrier and while providing a composition and dosage that leads to and encourages patient compliance. The present invention satisfies these and other needs. BRIEF SUMMARY OF THE INVENTION

[0017] The present invention provides pharmaceutical compositions, methods for preparation, and methods of treatment comprising a selective COX-2 inhibitor, a zwitterionic surfactant or charged derivative thereof, a hydroxy acid, at least one molecular penetration enhancer (MPE™), at least one lower alcohol, and water. In a preferred embodiment, the selective COX-2 inhibitor is etoricoxib. In a preferred embodiment, the hydroxyl acid is an alpha-hydroxy acid. The compositions enhance permeability and bioavailability of the selective COX-2 inhibitor, and they are useful for topical treatment of pain and/or inflammation. In a preferred embodiment, the method of treatment is directed to pain associated with OA.

[0018] In an alternative embodiment, the hydroxy acid or alpha-hydroxy acid is optional, and the composition further comprises an acid that is not a hydroxyl acid, such as caprylic acid or hydrochloric acid. [0019] As such, in one embodiment, the present invention provides a pharmaceutical composition for topical administration, the composition consisting of, consisting essentially of, or comprising a selective COX-2 inhibitor (e.g., etoricoxib), a zwitterionic surfactant or charged derivative thereof, a hydroxy acid (e.g., an alpha-hydroxy acid), a lower alcohol, and water. In a preferred aspect, the composition comprises 0.1% to 5% (w/w) of the selective COX-2 inhibitor, 0.5% to 10% of a zwitterionic surfactant or charged derivative thereof, 0.5% to 5% of a hydroxy acid, a lower alcohol, and water. More preferably, the composition is a solution. In a preferred aspect, the selective COX-2 inhibitor is etoricoxib. In another aspect or preferred aspect of the embodiment, the lower alcohol is a monohydric alcohol. [0020] In a more preferred aspect, the composition comprises about 1% to 3% (w/w) of a selective COX-2 inhibitor. Still more preferably, the composition comprises about 1 or 2% (w/w) of a selective COX-2 inhibitor. Yet still more preferably, the selective COX-2 inhibitor is etoricoxib.

[0021] In yet another more preferred aspect, the zwitterionic surfactant or charged derivative thereof is derived from coconut oil. Still more preferably, the zwitterionic surfactant or charged derivative thereof is a member selected from the group of disodium cocoamphodiacetate (DCAM), sodium cocoamphodiacetate, and cocoamidopropyl betaine. Alternatively, the composition comprises about 5% (w/w) of the zwitterionic surfactant or charged derivative thereof. [0022] In another more preferred aspect, the composition comprises about 1.5 or 2.5% (w/w) of the hydroxy acid. More preferably, the hydroxy acid is an alpha-hydroxy acid. Alternatively or still more preferably, the alpha-hydroxy acid is lactic acid.

[0023] In certain aspects, the lactic acid is racemic (i.e., racemic lactic acid). Alternatively, the lactic acid is enantiomerically enriched or is substantially a single enantiomer (e.g., (S)- lactic acid, also termed L-laciic acid). Preferably, the lactic acid is L-iactic acid.

[0024] In another aspect of the embodiment, the composition comprises at least one molecular penetration enhancer (MPE™). More preferably, the molecular penetration enhancer is a fatty acid ester. Still more preferably, the composition comprises about 1% to 5% (w/w) of the fatty acid ester. Yet still more preferably, the fatty acid ester is selected from the group of glycerol monolaurate (GML) and isopropyl myristate (IPM).

Alternatively, the molecular penetration enhancer is a terpene. More preferably, the terpene is selected from the group consisting of limonene and geraniol. Still more preferably, the composition comprises about 3% (w/w) terpene. Alternatively and yet still more preferably, the composition comprises about 1% to 5% of a second molecular penetration enhancer.

[0025] In certain alternative embodiments, the MPE™ is optional.

[0026] In yet another preferred aspect of the embodiment, the composition comprises ethanol and at least a second lower alcohol. More preferably, the second lower alcohol is a monohydric alcohol, and still more preferably, the second lower alcohol is a member selected from the group of isopropanol and 2-(2-ethoxyethoxy)ethanol. Alternatively, the

composition comprises 3% to 10% of the second lower alcohol. In an alternative aspect or preferred aspect, the composition comprises 3% to 10% of a third lower alcohol, and more preferably, the third lower alcohol is a monohydric alcohol.

[0027] In another embodiment, the present invention provides a pharmaceutical composition for topical administration, the composition consisting of, consisting essentially of, or comprising 1% to 3% (w/w) etoricoxib, 1.5 to 2.5% lactic acid, 5% disodium dicocoamphodiacetate or cocoamidopropyl betaine, at least 1% of at least one molecular penetration enhancer, 10% isopropanol, and water.

[0028] In yet another embodiment, the present invention provides a method for topically treating pain in a subject, the method comprising topically applying a pharmaceutical composition to treat pain in the subject; the composition consisting of, consisting essentially of, or comprising 0.1% to 5% (w/w) etoricoxib, 0.5% to 10% of a zwitterionic surfactant or charged derivative thereof, 0.5% to 5% of a hydroxy acid, a lower alcohol, and water. More preferably, the pain is associated with OA. In an alternative aspect or preferred aspect, the lower alcohol is a monohydric alcohol.

[0029] In still yet another embodiment, the present invention provides a use of a pharmaceutical composition as described herein for the manufacture of a medicament for the topical treatment of osteoarthritis or pain associated therewith.

[0030] These and other objects, aspects and embodiments and will become more apparent when read with the following detailed description and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG. 1 illustrates etoricoxib permeation through porcine skin from a first series of topical formulations (Table 1) at 4, 21, and 24 hours after application. [0032] FIG. 2 illustrates etoricoxib permeation through porcine skin from a second series of topical formulations (Table 2) at 4, 20, and 24 hours after application.

[0033] FIG. 3 illustrates etoricoxib permeation through porcine skin from a third series of topical formulations (Table 3) at 4, 20, and 24 hours after application. [0034] FIG. 4 illustrates etoricoxib permeation through porcine skin from a fourth series of topical formulations (Table 4) at 4, 20, and 24 hours after application.

[0035] FIG. 5 illustrates etoricoxib permeation through porcine skin from a fifth series of topical formulations (Table 5) at 4, 20, and 24 hours after application.

[0036] FIG. 6 illustrates etoricoxib permeation through porcine skin from a sixth series of topical formulations (Table 6) at 4, 20, and 24 hours after application..

[0037] FIG. 7 illustrates etoricoxib permeation through porcine skin from a seventh series of topical formulations (Table 7) at 4, 21, and 24 hours after application.

[0038] FIG. 8 illustrates etoricoxib permeation through porcine skin from a eighth series of topical formulations (Table 8) at 4, 21, and 24 hours after application. [0039] FIG. 9 illustrates etoricoxib permeation through porcine skin from a ninth series of topical formulations (Table 9) at 4, 21, and 26 hours after application.

[0040] FIG. 10 illustrates etoricoxib permeation through porcine skin from a tenth series of topical formulations (Table 10) at 4, 21, and 26 hours after application.

[0041] FIG. 11 illustrates etoricoxib permeation through porcine skin from a eleventh series of topical formulations (Table 11) at 4, 21, and 26 hours after application.

[0042] FIG. 12 illustrates etoricoxib permeation through porcine skin from a twelfth series of topical formulations (Table 12) at 4, 21, and 26 hours after application.

[0043] FIG. 13 illustrates etoricoxib permeation through porcine skin from a thirteenth series of topical formulations (Table 13) at 4, 21, and 26 hours after application. [0044] FIG. 14A illustrates etoricoxib permeation through porcine skin of a 25 μΐ sample from the fourteenth series of topical formulations (Table 14) at 4, 21 , and 26 hours after application.

[0045] FIG. 14B illustrates etoricoxib permeation through porcine skin of a 10 μΐ sample from the fourteenth series of topical formulations (Table 14) at 4, 21 , and 26 hours after application. [0046] FIG. 15 A illustrates etoricoxib permeation through porcine skin from a fifteenth series of topical formulations (Table 15) at 4, 8, and 24 hours after application.

[0047] FIG. 15B illustrates the etoricoxib skin retention in porcine skin from the fifteenth series of topical formulations (Table 15) at 24 hours after application. [0048] FIG 16A illustrates etoricoxib permeation through porcine skin from a sixteenth series of topical formulations (Table 16) at 4, 21 and 26 hours after application.

[0049] FIG 16B illustrates etoricoxib skin retention in porcine skin from the sixteenth series of topical formulations (Table 16) at 26 hours after application.

[0050] FIG 17A illustrates etoricoxib permeation through porcine skin from a seventeenth series of topical formulations (Table 17) at 4, 21 and 24 hours after application.

[0051] FIG 17B illustrates etoricoxib skin retention in porcine skin from the seventeenth series of topical formulations (Table 17) at 24 hours after application.

[0052] FIG. 18 illustrates etoricoxib permeation through porcine skin from an eighteenth series of topical formulations (Table 18B) at 4, 21, and 24 hours after application. [0053] FIG. 19 illustrates etoricoxib permeation through porcine skin from a nineteenth series of topical formulations (Table 19) at 4, 21, and 24 hours after application.

[0054] FIG. 20 illustrates etoricoxib permeation through porcine skin from a twentieth series of topical formulations (Table 20) at 4, 21, and 24 hours after application.

[0055] FIG. 21 illustrates etoricoxib permeation through, and retention in, porcine skin from a twenty- first series of topical formulations (Table 21) at 4, 21, and 24 hours after application.

[0056] FIG. 22 illustrates etoricoxib permeation through porcine skin from a twenty- second series of topical formulations (Table 22) at 4, 21 and 24 hours after application.

[0057] FIG. 23 illustrates etoricoxib permeation through human cadaver skin from a twenty-third series of topical formulations (Table 23) at 4, 8, 12, 16, 20 and 24 hours after application.

[0058] FIG. 24 illustrates etoricoxib skin retention in human cadaver skin from a twenty- fourth series of topical formulations (Table 24) at 4, 8, 12, 16, and 20 hours after application. [0059] FIG. 25 illustrates etoricoxib permeation through human cadaver skin from a twenty-fifth series of topical formulations (Table 25) at 4, 8, 14, 24, 36 and 48 hours after application.

[0060] FIG. 26 illustrates etoricoxib permeation through human cadaver skin from a twenty-six series of topical formulations (Table 26) at 4, 8, 14, 24, 42 and 48 hours after application.

[0061] FIG. 27 illustrates etoricoxib permeation through human cadaver skin from a twenty-seventh series of topical formulations (Table 27) at 4, 8, 14, 24, 36 and 48 hours after application. [0062] FIG. 28 illustrates etoricoxib permeation through human cadaver skin from a twenty-eighth series of topical formulations (Table 28) at 4, 8, 14, 24, 36 and 48 hours after application.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions [0063] The terms "a," "an," or "the" as used herein not only includes aspects with one member, but also includes aspects with more than one member. For example, an

embodiment including "a cellulosic thickening agent and a lower monohydric alcohol" should be understood to present certain aspects with at least a second cellulosic thickening agents, at least a second lower monohydric alcohol, or both. [0064] The term "about" as used herein includes a close (i.e., narrow) range around the explicit value for a variable. For example, in certain instances the term "about" includes 5%- 10% higher or 5-10% lower than the value given. For example, "about 10" includes the range of values from 9.5 to 10.5 or from 9 to 11.

[0065] When "about" is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, "from about 5 to 20%" is equivalent to "from about 5% to about 20%." When "about" is applied to the first value of a set of values, it applies to all values in that set. Thus, "about 7, 9, or 11%" is equivalent to "about 7%, about 9%, or about 11%."

[0066] In compositions comprising an "additional" or "second" component, the second component as used herein is chemically different from the other components or first component. A "third" component is different from the other, first , and second components, and further enumerated or "additional" components are similarly different. [0067] The term "agent" as used herein indicates a compound or mixture of compounds that, when added to a pharmaceutical composition, tend to produce a particular effect on the composition's properties. For example, a composition comprising a thickening agent is likely to be more viscous than an otherwise identical comparative composition that lacks the thickening agent.

[0068] "Alpha-hydroxy acid" as used herein indicates an organic compound comprising at least one carbon substituted with a hydroxy! group and a carboxylic acid group (i.e., a C(OH)(C0₂H) group). It also indicates the salts thereof (i.e., a carboxylate group and its associated counterion rather than a carboxylic acid). Examples of alpha-hydroxy acids include citric acid, glycolic acid, aldonic acids (e.g. , gluconic acid), 2-hydroxycaproic acid, 2-hydroxycaprylic acid, 2-hydroxypropionic acid, lactic acid, malic acid, mandelic acid, tartaric acid, and the like, as well as mixtures thereof.

[0069] "Cellulosic thickening agent" as used herein includes a thickening agent that is a natural or synthetic polymeric carbohydrate (e.g., cellulose, pharmaceutically acceptable vegetable gums) or a polymeric or oligomeric derivative of a polymeric carbohydrate that is produced by chemical modification (e.g. , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose). Representative cellulosic thickening agents include cellulose, hydroxypropyl cellulose ("HPC"), hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, and the like. [0070] In general, the "error bars" on the graphs provided in the figures represent the standard error of the mean value, whereas the top of the solid, shaded bar represents a single data value, which is the mean value of the distribution of data values.

[0071] "Finite dosing" as used herein generally includes an application of a limited reservoir of an active agent. The active agent in the reservoir is depleted with time, leading to a tapering off of the absorption rate of the active agent after a maximum absorption rate is reached.

[0072] "Formulation," "pharmaceutical composition," and "composition" as used herein are equivalent terms referring to a composition of matter suitable for pharmaceutical use.

[0073] "Infinite dosing" as used herein generally includes an application of a large reservoir of an active agent. The active agent in the reservoir is not significantly depleted with time, thereby providing protracted, continuous, steady-state absorption of the active. [0074] "Lower alcohol" as used herein includes straight- or branched-chain alkyl alcohols of 1 to 6 carbon atoms. Representative lower monohydric alcohols include methanol, ethanol, n-propanol, isopropanol (also known as isopropyl alcohol (IP A)), n-butanol, t- butanol, n-pentanol, 3-pentanol, 2-methoxyethanol, propylene glycol, and the like. [0075] "Monohydric alcohol" as used herein includes includes straight- or branched-chain alkyl alcohols with a single hydroxyl group. Representative monohydric alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-pentanol, 3-pentanol, 2- methoxyethanol, 2-(2-ethoxyethoxy)ethanol, olelyl alcohol, and the like.

[0076] The term "or" as used herein should in general be construed non- exclusively. For example, an embodiment of "a composition comprising A or B" would typically present an aspect with a composition comprising both A and B. "Or" should, however, be construed to exclude those aspects presented that cannot be combined without contradiction (e.g. , a composition pH that is between 9 and 10 or between 7 and 8).

[0077] Generally, when a percentage range is taught, it incorporates all full or partial percentages in between (i.e. , within the bounds of the range). For example, a percentage range of 15 to 25% would also teach the specific values of 17.36% and 21%. A percentage range of about 13% to 17% would also teach the specific values of 12.97%, 16%, and 17.1%.

[0078] "Penetration enhancer", "molecular penetration enhancer" or "MPE™" as used herein includes an agent or a combination of agents that improves the transport of molecules such as a pharmaceutically or cosmetically active agent into or through a natural membrane such as skin or nail. Various conditions may occur at different sites in the body, either in the skin or below the skin, creating a need to target delivery of compounds. For example, in a treatment for osteoarthritis, delivery of the active agent to the underlying tissues surrounding the joint may be necessary to achieve therapeutic benefit. A molecular penetration enhancer may be used to assist in the delivery of an active agent i) directly into the skin or nail; ii) locally, or regionally, into tissue(s) underlying the skin or nail; or iii) indirectly via systemic distribution to the site of the disease. If systemic distribution of an active agent (e.g., etoricoxib) would be likely to produce side effects, a molecular penetration enhancer is preferably selected to maximize direct delivery and to minimize systemic distribution. A molecular penetration enhancer may be a pure substance or may comprise, consist essentially of, or consist of a mixture of different chemical entities.

[0079] "Selective COX-2 inhibitor" as used herein should in general be construed to mean the selective COX-2 (coxib) class of NSAIDs that preferentially inhibits COX-2, as well as the pharmaceutically acceptable derivatives or salts thereof. By extension, the term

"etoricoxib" as used herein, includes pharmaceutically acceptable derivatives or salts thereof.

[0080] "Thickening agent" as used herein includes an agent or combination of agents that increases the viscosity of a composition. A thickening agent may be a pure substance, or it may comprise, consist essentially of, or consist of a mixture of different chemical entities. Exemplary thickening agents include cellulose polymers, carbomer polymers, carbomer derivatives, cellulose derivatives, polyvinyl alcohol, poloxamers, polysaccharides, and the like, as well as mixtures thereof.

[0081] "Topical formulation" as used herein includes a composition that is suitable for topical application to the skin, a nail, or a mucosa. A topical formulation may, for example, be used to confer a therapeutic or cosmetic benefit to its user. Specific topical formulations can be used for topical, local, regional, or transdermal application of substances.

[0082] "Transdermal" as used herein includes a process that occurs through the skin. The terms "transdermal," "percutaneous," and "transcutaneous" can be used interchangeably. In certain embodiments, "transdermal" may also include epicutaneous.

[0083] "Transdermal application" as used herein includes administration through the skin. Transdermal application can be used for systemic delivery of an active agent; however, it is also useful for delivery of an active agent to tissues underlying the skin with minimal systemic absorption. In certain embodiments, "transdermal application" may also include epicutaneous application.

[0084] In general, the unit prefix "u" as used herein is equivalent to "μ" or "micro." For example, "ul" is equivalent to "μΐ" or "microliters."

[0085] "Zwitterionic surfactant" as used herein includes a surface-active agent that comprises atoms bearing a formal charge other than zero, but in which the agent has a net charge of zero. Examples include sodium cocoamphoacetate (i.e., cocoamphoglycinate), cocoamidopropyl betaine, cocoamidopropyl hydroxysultaine, potassium cocoamphodiacetate, dodecyl betaine, phospholipids such as lecithin, alkyl or acyl amphopropionates or sulfobetaines (i.e., sulfonic acid analogs to carboxylic acid betaines), sodium

lauroamphoacetate, and the like, as well as mixtures and poly(ethylene glycol) derivatives thereof.

[0086] A "zwitterionic surfactant charged derivative" as used herein indicates a cationic or anionic surfactant that is a salt of a zwitterionic surfactant. Examples include disodium dicocoamphodicetate, disodium dicocoamphodipropionate, and the like, as well as mixtures thereof.

II. Selective COX-2 Inhibitor

[0087] The present invention provides a pharmaceutical composition comprising, consisting essentially of, or consisting of a selective COX-2 inhibitor. In a preferred aspect, the selective COX-2 inhibitor is selected from the group of celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, valdecoxib, and a combination thereof. More preferably, the selective COX-2 inhibitor is selected from the group of celecoxib, etoricoxib, and rofecoxib. Still more preferably, the selective COX-2 inhibitor is etoricoxib. In another preferred aspect, the pharmaceutical composition comprises 0.1% to 5% (w/w) of etoricoxib, preferably 1%> to 3%, and more preferably about 1 or 2%.

[0088] In one aspect, a composition permits delivery of a selective COX-2 inhibitor daily dosage of about 0.01 mg to about 120 mg, preferably about 0.1 mg to 60 mg, preferably about 1 mg to about 30 mg, and most preferably about 1 mg to about 10 mg. Yet still more preferably, the formulation permits delivery of a daily dosage of about 3 mg. Preferably the concentration is such that this dosage amount can be provided by application of the composition from one to four times a day, preferably one to two times a day, to a skin area of up to about 2500 cm², preferably about 1200 to 1800 cm² (750 cm²/knee). Alternatively, the

2 2

composition can be applied to a skin area of about 1 to 50 cm , about 50 to 250 cm , about 100 to 500 cm², about 200 to 800 cm², or about 800 to 1200 cm².

[0089] A person skilled in the art will appreciate that the dosage and application area will vary on and can be tailored to the area being treated (e.g., knees, fingers, toes, back, and the like). In one preferred aspect, a single knee is treated and the application area is about 750 cm². In another preferred aspect, both knees of an individual are treated and the application area is about 1500 cm² (about 750 cm² per knee).

[0090] In another aspect, the formulation of the present invention provides a total or a systemic dose that is less than 50%> of the systemic daily dose of the maximum approved oral dose; preferably less than 25%>, more preferably less than 10%>, and most preferably less than 5%, yet provides local or regional delivery levels sufficient for therapeutic benefit.

Preferably the concentration is such that this dosage amount can be provided by application of the composition from one to four times a day, preferably one to two times a day, to a skin area of up to about 2500 cm², preferably about 1200 to 1800 cm² (750 cm²/knee). Alternatively, the composition can be applied to a skin area of about 1 to 50 cm², about 50 to 250 cm², about 100 to 500 cm², about 200 to 800 cm², or about 800 to 1200 cm².

[0091] In still another aspect, the pharmaceutical composition comprising etoricoxib provides better flux (as determined by the Franz cell procedure of Example 2) than an analogous comparative formulation comprising a selective COX-2 inhibitor. Preferably, this comparative formulation comprises etoricoxib. More preferably, the flux of etoricoxib is at least 1.5 times greater than the flux of the comparative formulation's active. In other words, the ratio of (i) the composition's etoricoxib flux to (ii) the comparative formulation's coxib flux is preferably greater than 1.0, and more preferably at least about 1.5. [0092] Still more preferably, the composition has an etoricoxib flux that is at least 2.0 times greater than the comparative formulation's coxib flux. Yet still more preferably, the composition has an etoricoxib flux that is at least 4.0 times greater than the comparative formulation's coxib flux.

[0093] In an alternative aspect, the composition has a selective COX-2 inhibitor flux equal to or greater than the selective COX-2 inhibitor flux from a known comparative formulation with the same selective COX-2 inhibitor. Preferably, the selective COX-2 inhibitor flux is greater than the flux of the comparative formulation with the same selective COX-2 inhibitor.

More preferably, the selective COX-2 inhibitor flux is at least 1.5 times greater than the flux of a comparative formulation with the same selective COX-2 inhibitor. In other words, the ratio of (i) the selective COX-2 inhibitor flux of the composition to (ii) the selective COX-2 inhibitor flux from a comparative formulation with the same selective COX-2 inhibitor is preferably greater than 1.0, and more preferably at least about 1.5.

[0094] Still more preferably, the composition has a selective COX-2 inhibitor flux that is at least 2.0 times greater than the selective COX-2 inhibitor flux from a known comparative formulation with the same selective COX-2 inhibitor. Yet still more preferably, the composition has a selective COX-2 inhibitor flux that is at least 4.0 times greater than the selective COX-2 inhibitor flux from a comparative formulation with the same selective COX- 2 inhibitor.

[0095] In another alternative aspect, the present invention provides a composition comprising etoricoxib and having an etoricoxib flux (as determined by the Franz cell procedure of Example 2) of at least 0.1 μg/hr cm² at 24 hours, preferably at least 0.2 μg/hr/cm² at 24 hours. [0096] Still more preferably, the composition comprising etoncoxib has an enhancement ratio (ER) of at least 2. Yet still more preferably, the composition comprising etoricoxib has an ER of at least 5.0. Yet still more preferably, the composition comprising etoricoxib has an ER that is at least 10.0. As indicated in the example section, ER is the ratio of a test formulation comprising etoricoxib versus a hydroalcoholic control solution comprising the same selective COX-2 inhibitor.

III. Zwitterionic Surfactant and Hydroxy Acid

[0097] In a preferred aspect, the composition comprises a zwitterionic surfactant. More preferably, the zwitterionic surfactant is derived from coconut oil. Still more preferably, the zwitterionic surfactant is a member selected from the group of disodium cocoamphodiacetate, sodium cocoamphodiacetate, cocoamidopropyl betaine, and mixtures thereof. In an aspect or preferred aspect, the composition comprises 0.5% to 10% (w/w) of the zwitterionic surfactant. More preferably, the composition comprises 5% (w/w) of the zwitterionic surfactant. [0098] In another preferred aspect, the composition comprises a hydroxy acid such as citric acid, salicylic acid, malic acid, tropic acid, or a derivative or salt thereof. More preferably, the composition comprises an alpha-hydroxy acid. Still more preferably, the alpha-hydroxy acid is lactic acid. Yet still more preferably, the alpha-hydroxy acid is L-lactic acid.

Alternatively, the composition comprises about 0.5% to 5% (w/w) of the hydroxy acid, such as about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5%, and more preferably, about 1.5 to 2.5% (w/w) (e.g., about 1.5%; about 2.5%>). Alternatively and more preferably, the composition comprises about 0.5% to 5% (w/w) of the alpha-hydroxy acid, and still more preferably about 1.5 to 2.5% (w/w) (e.g., about 1.5%; about 2.5%).

[0099] In an alternative embodiment, the hydroxy acid or alpha-hydroxy acid is optional, and the composition comprises an acid such as caprylic acid, hydrochloric acid,

dehydroacetic acid, or a derivative or salt thereof. Alternatively, the composition comprises about 0.5% to 5% (w/w) of the acid, such as about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5%, and more preferably, about 1.5 to 2.5% (w/w) (e.g., about 1.5%; about 2.5%).

IV. Other Components [0100] In a preferred aspect, at least one molecular penetration enhancer is present in the carrier. In certain aspects, the MPE™ is selected from the group of terpenes, fatty acid esters, and fatty acid alcohols. More preferably, the MPE™is a terpene. Examples include d- limonene, limonene oxide, geraniol, -pinene, a-pinene oxide, thymol, menthone, menthol, neomenthol, 3-carene, /-carvol, carvone, carveol, 1,8-cineole (eucalyptol), citral,

dihydrocarveol, dihydrocarvone, 4-terpinenol, fenthone, menthone, pulegone, pulegol, isopulegol, piperitone, camphor, terpineol, a-terpineol, terpinen-4-ol, linalool, carvacrol, trans-anethole, ascaridole, safrole, racemic mixtures thereof (e.g., DL-limonene), and pharmaceutically acceptable isomers thereof. In certain preferred aspects, a second MPE™ is present (e.g., a fatty acid ester and a terpene).

[0101] In one specific embodiment, the composition of the present invention comprises limonene or geraniol. In one aspect, the composition comprises about 0.1% to 5% (w/w) of limonene or geraniol, such as about 0.1, 1, 2, 3, 4 or 5%, and more preferably about 3% to 5% (w/w).

[0102] In certain aspects, the terpene MPE™ can be included within an essential oil.

Essential oils that include a substantial proportion of at least one terpene MPE™ include oils of peppermint, eucalyptus, chenopodium, anise, and yling-yling. Preferably, the essential oil is eucalyptus oil.

[0103] Alternatively, a fatty acid ester or fatty alcohol ester is used as an MPE™.

Examples of preferred fatty acid ester MPE™s are glyceryl monoesters. More preferably, the MPE™ is glyceryl monolaurate. In one aspect, the composition comprises about 0.5% to 5% (w/w) of glyceryl monolaurate, such as about 0.5, 1, 2, 3, 4 or 5%, and preferably about 1 to 3% (w/w) (e.g. about 1%; about 3%).

[0104] In another aspect, a fatty acid ester or a fatty alcohol ester is used as an MPE™ in the composition. Examples of fatty acid ester and fatty alcohol esters include butyl acetate, caproyl glycolate, cetyl lactate, cocoyl glycolate, decyl N,N-dimethylamino acetate, decyl N,N-dimethylamino isopropionate, diethyleneglycol oleate, diethyl sebacate, diisopropyl sebacate, dodecyl N,N-dimethylamino acetate, dodecyl N,N-dimethylamino butyrate, dodecyl N,N-dimethylamino isopropionate, dodecyl 2-(N,N-dimethylamino)propionate, EQ-5-oleyl ester, ethyl acetate, ethyl acetoacetate, ethyl propionate, glyceryl dilaurate, glyceryl dioleate, glycerol monoethers, glycerol monooleate, glycerol monolinoleate, isopropyl isostearate, isopropyl laurate, isopropyl linoleate, isopropyl myristate, isopropyl palmitate, isostearoyl glycolate, lauroyl glycolate, methyl acetate, methyl caprate, methyl laurate, methyl oleate, methyl propionate, methyl valerate, 1-monocaproyl glycerol, medium-chain-length monoglycerides, benzyl or substituted benzyl nicotinate, octyl acetate, octyl N.N- dimethylamino acetate, oleyl oleate, n-pentyl N-acelylprolinate, propylene glycol monolaurate, sodium lauroyl glycolate, tetradecyl 7Y,N-dimethylamino acetate, tromethamine lauroyl glycolate and the like. Still other examples include sunscreens such as Padimate-O, homosalate, cinnamate esters, octocrylene, and the like.

[0105] Other MPE™s include fatty acids, lactic acid, fatty alcohols (e.g., oleyl alcohol, stearyl alcohol, decanol), fatty alcohol ethers, hexahydro-l-dodecyl-2H-azepin-2-one (e.g., laurocapram, Azone™) and derivatives thereof, dimethylsulfoxide (DMSO) and related sulfoxides (e.g., n-decyl methylsulfoxide), salicylic acid and alkyl esters thereof (e.g., methyl salicylate), N,N-dimethylacetamide, dimethylformamide, N,N-dimethyltoluamide, 2- pyrrolidinone and N-alkyl derivatives thereof (e.g., N-methyl-2-pyrrolidone (NMP) and N- octyl-2-pyrrolidinone), and 2-nonyl-l,3-dioxolane. See Osborne, D.W.; Henke, J. J. "Skin Penetration Enhancers Cited in the Technical Literature," Pharmaceut. Tech. 58-66 (Nov. 1997).

[0106] In one preferred aspect, the composition comprises a mixture of a lower alcohol and water. More preferably, the lower alcohol is a monohydric lower alcohol, and still more preferably, the lower alcohol is ethanol, isopropanol, or diethylene glycol monoethyl ether. In certain aspects, the composition comprises a second lower alcohol. In certain other aspects, the composition comprises a third lower alcohol.

[0107] In another aspect, the composition comprises at least about 3, 5, 7, 9.5, 10, 10.5, 11, 11.5, 12, 14, 15, 20, 25, 30, 31, 31.5, 32, 32.5, 33, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 44.5, 45, 46, 46.5, 47, 47.5, 48, 48.5, 49, 49.5, 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 56.5, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75% (w/w) of a lower alcohol. More preferably, the composition comprises at least about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 44.5, 45, 46, 46.5, 47, 47.5, 48, 48.5, 49, 49.5, 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 56.5, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, or 75% (w/w) of a lower alcohol. Still more preferably, the composition comprises at least about 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 56.5, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75% (w/w) of a lower alcohol.

[0108] In other aspects, the composition comprises at most about 3, 5, 7, 9.5, 10, 10.5, 1 1, 11.5, 12, 14, 15, 20, 25, 30, 31, 31.5, 32, 32.5, 33, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 44.5, 45, 46, 46.5, 47, 47.5, 48, 48.5, 49, 49.5, 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 56.5, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75% (w/w) of a lower alcohol. More preferably, the composition comprises at most about 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 44.5, 45, 46, 46.5, 47, 47.5, 48, 48.5, 49, 49.5, 50, 50.5, 51 , 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 56.5, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75% (w/w) of a lower alcohol. Still more preferably, the composition comprises at most about 50, 50.5, 51, 51.5, 52, 52.5, 53, 53.5, 54, 54.5, 55, 55.5, 56, 56.5, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, or 75% (w/w) of a lower alcohol.

[0109] In another aspect, the composition comprises 35 to 75% of a lower alcohol. In still another aspect, the composition comprises the same or differing amounts of a first and at least one additional alcohol. More preferably, the composition comprises 40% to 65% (w/w) of ethanol and 10% (w/w) of isopropanol. In another more preferred aspect, the composition comprises 40% to 65% (w/w) of ethanol, 10% (w/w) of isopropanol, and 3% to 10% (w/w) of 2-(2-ethoxyethoxy)ethanol. In certain instances, the first alcohol is about 35 to 75% (w/w), the at least one additional alcohol is between about 0.1 to 10% more (w/w) (e.g., about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10%) and the at least one more additional alcohol is between about 0.1 to 10 % more (w/w) (e.g., about 0.1, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10%; about 35% to 95% total alcohol). In one aspect, the first alcohol is about 35 to 75%, and the second lower alcohol is about 3% to 10%. In certain aspects, the composition further comprises about 3 to 10% of a third lower alcohol.

[0110] In another aspect, the lower alcohol is a diol. Alternatively, the composition additionally comprises a diol. Suitable diols include, but are not limited to, propylene glycol, butanediol, butynediol, pentanediol, hexanediol, octanediol, neopentyl glycol, 2 -methyl- 1,3- propanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, dibutylene glycol, propylene glycol, and a combination thereof. In one aspect, the

formulation comprises about 0.1% to 15% of propylene glycol, such as about 0.1 , 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15%, and preferably about 0.1 to 5%.

[0111] In yet another aspect, the composition comprises at least one additional

pharmaceutically acceptable surfactant. Preferably, the surfactant is a nonionic surfactant. More preferably, the surfactant is a polysorbate surfactant. Still more preferably, the surfactant is polysorbate 20. [0112] Other nonionic surfactants include (but are not limited to) cetomacrogol 1000, cetostearyl alcohol, cetyl alcohol, cocoamide diethanolamine, cocoamide monoethanolamine, decyl glucoside, glyceryl laurate, lauryl glucoside, polyoxyethylene ethers of fatty acids such as cetyl alcohol or stearyl alcohol, narrow-range ethoxylates, octyl glucoside, oleyl alcohol, poloxamers, polyethylene glycol, sorbitan monolaurate, polyoxyethylene sorbitan

monolaurate, sorbitan dioleate, sorbitan trilaurate, sorbitan monopalmitate, polyoxyethylene (20) sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, polyoxyethylene (20) sorbitan monostearate, sorbitan monooleate, sorbitan trioleate, polyoxyethylene (20) sorbitan monooleate, stearyl alcohol, sucrose coconut fatty ester mixtures, and sucrose monolaurate.

[0113] In still yet another aspect, the composition comprises at least one additional thickening agent, preferably a cellulosic thickening agent. Suitable cellulosic thickening agents include, but are not limited to, hydroxypropyl cellulose (HPC) of various grades, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, dextran, guar gum, pectin, starch, cellulose, and the like. More preferably, the cellulosic thickening agent is HPC.

[0114] In an alternative or preferred aspect, the composition comprises about 1% to 5% of a cellulosic thickening agent, such as about 1, 2, 3, 4, or 5%. More preferably, the composition comprises from 1% to 2% of a cellulosic thickening agent. Still more preferably, the composition comprises 1% of a cellulosic thickening agent. Alternatively, the composition comprises 2% of a cellulosic thickening agent.

[0115] In one aspect, the composition additionally comprises urea. More preferably, the composition comprises about 0.5% to 10% (w/w) urea such as about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%. Still more preferably, the composition comprises 2% to 10% urea. Yet still more preferably, the composition comprises 5% urea. Alternatively, the composition comprises 2.5% urea, or the composition comprises 10% urea.

[0116] In another aspect, the composition additionally comprises an anti-oxidant. Preferred anti-oxidants for use in the present invention include butylated hydroxytoluene, butylated hydroxyanisole, ascorbyl linoleate, ascorbyl dipalmitate, ascorbyl tocopherol maleate, calcium ascorbate, carotenoids, kojic acid and its pharmaceutically acceptable salts, thioglycolic acid and its pharmaceutically acceptable salts (e.g., ammonium), tocopherol, tocopherol acetate, tocophereth-5, tocophereth-12, tocophereth-18, tocophereth-80, and the like. [0117] In another aspect, the composition additionally comprises a chelating agent.

Preferred chelating agents include ethylenediamine tetraacetic acid (EDTA), diammonium EDTA, dipotassium EDTA, calcium disodium EDTA, HEDTA, tetraethylammonium (TEA) EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium phosphate, diammonium citrate, galactaric acid, galacturonic acid, gluconic acid, glucuronic acid, humic acid, cyclodextrin, sodium citrate, potassium citrate, the sodium salt of ethylenediamine-tetra (methylene phosphonic acid) (EDTMP), and potassium EDTMP.

[0118] In certain preferred aspects, the compositions of the invention optionally include a buffer or a pH-adjusting agent (e.g., in addition, the topical formulations of the present invention can also comprise a pH-adjusting agent). In one particular embodiment, the pH- adjusting agent is a base. Suitable pH-adjusting bases include bicarbonates, carbonates, hydroxides (such as alkali or alkaline earth metal hydroxide as well as transition metal hydroxides), and the like. In an alternative aspect, suitable pH-adjusting bases include amines, such as diethanolamine, triethanolamine, or aminopropanol; bicarbonates;

carbonates; and hydroxides, such as ammonium hydroxide, alkali or alkaline earth metal hydroxide, or transition metal hydroxides. Alternatively, the pH-adjusting agent can also be an acid, an acid salt, or mixtures thereof.

[0119] The pH-adjusting agent can be present in an amount sufficient to adjust the pH of the composition to between about pH 4.0 to 10.0; more preferably, between about pH 7.0 to 9.5. In certain embodiments, the unadjusted pH of the admixed components is between about 8 and 10, such as about 9, without the need for the addition of any pH-adjusting agents.

[0120] Preferably, the pH-adjusting agent is sodium hydroxide, hydrochloric acid, or a combination of both, and is present in an amount sufficient to adjust the pH of the

composition to between about pH 4.0 to 8.5, more preferably, to between about pH 5.5 to 7.0, such as about 6.0 or 6.5. Even more preferably, the pH is adjusted to about 4.0, 4.2, 4.4, 4.6, 4.8, 5.0, 5.2, 5.4, 5.6, 5.8, 6.0, 6.2, 6.3, 6.4, 6.6, 6.8, 7.0, 7.2, 7.4, 7.6, 7.8, 8.0, 8.4, 8.5, or any fraction in-between.

[0121] In certain preferred aspects, a small amount of acid or base is included in the formulation. Non-limiting examples of amounts of acid or base that may be included in the formulation are about 0.000001%, 0.00001%, 0.0001%, 0.001%, 0.0012%, 0.01%, 0.012%, 0.1%, or 1.0%. Preferably, this amount is about 0.0001%. 0.0002%, 0.0003%, 0.0004%, 0.0005%, 0.0006%, 0.0007%, 0.0008%, 0.0009%, 0.0010%, 0.0011%, 0.0012%, 0.0015%, 0.0016%, 0.0017%, 0.0018%, 0.0019%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.01%, 0.012%, or 0.02%. More preferably, this amount is about 0.001%. 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%, 0.008%, 0.009%, 0.010%, 0.011%, 0.012%, 0.015%, 0.016%, 0.017%, 0.018%, 0.019%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%), 0.08%., 0.09%, 0.1%, or as needed to adjust the formulation to the desired pH. [0122] Further, the pH-adjusting agent can also be a buffer. Preferably, the pH of the composition of the invention can be adjusted or stabilized with a buffer. Suitable buffers include citrate/citric acid buffers, acetate/acetic acid buffers, phosphate/phosphoric acid buffers, formate/formic acid buffers, propionate/propionic acid buffers, lactate/lactic acid buffers, carbonate/carbonic acid buffers, ammonium/ammonia buffers, and the like. In certain instances, the buffer is an acidic buffer system such as, for example, benzocaine. In more preferred instances, the acidic acid buffer system is citric acid or a citric acid salt.

[0123] In certain preferred aspects, the buffer is present at a concentration of about 0.000001 M, 0.00001 M, 0.0001 M, 0.001 M, 0.0012 M, 0.01 M, 0.012 M, 0.1 M, or 1.0 M. Preferably, this amount is about 0.0010 M, 0.0015 M, 0.002 M, 0.003 M, 0.004 M, 0.005 M, 0.006 M, 0.007 M, 0.008 M, 0.009 M, 0.01 M. 0.012 M, or 0.02 M. Alternatively and preferably, this amount is about 0.001 M. 0.002 M, 0.003 M, 0.004 M, 0.005 M, 0.006 M, 0.007 M, 0.008 M, 0.009 M, 0.010 M, 0.011 M, 0.012 M, 0.015 M, 0.016 M, 0.017 M, 0.018 M, 0.019 M, 0.02 M, 0.025 M, 0.03 M, 0.035 M, 0.04 M, 0.045 M, 0.05 M, 0.055 M, 0.06 M, 0.065 M, 0.07 M, 0.075 M, 0.08 M, 0.085 M, 0.09 M, 0.095 M, or 0.1 M. Alternatively and preferably, this amount is about 0.10 M, 0.1 1 M, 0.12 M, 0.13 M, 0.14 M, 0.15 M, 0.16 M, 0.17 M, 0.18 M, 0.19 M, 0.20 M, 0.21 M, 0.22 M, 0.23 M, 0.24 M, 0.25 M, 0.26 M, 0.27 M, 0.28 M, 0.29 M, 0.30 M, 0.31 M, 0.32 M, 0.33 M, 0.34 M, 0.35 M, 0.36 M, 0.37 M, 0.38 M, 0.39 M, 0.40 M, 0.41 M, 0.42 M, 0.43 M, 0.44 M, 0.45 M, 0.46 M, 0.47 M, 0.48 M, 0.49 M, 0.50 M, 0.55 M, 0.60 M, 0.65 M, 0.7 M, 0.75 M, 0.8 M, 0.85 M, 0.9 M, 0.95 M, or 1.0 M.

[0124] In certain preferred aspects, the inventive formulation includes a buffer, and a second pH-adjusting agent {e.g., sodium hydroxide or hydrochloric acid) to adjust the pH of the composition to a desired pH. More preferably, the second pH-adjusting agent comprises two agents (e.g., sodium hydroxide and hydrochloric acid) that are included as needed to adjust the pH of the composition to a desired pH.

[0125] In certain aspects, the composition of the present invention comprises a

preservative, such as propyl paraben or methyl paraben, or combinations thereof. The formulation may be made bacteriostatic by the addition of preservatives. For example, a composition can contain about 0.001 to 8%; preferably, about 0.01 to 6%; and more preferably, about 0.05 to 5% (w/w) of a preservative or a combination of preservatives. A variety of preservatives are suitable, including, but not limited to, benzoic acid, benzyl alcohol, benzylhemiformal, benzylparaben, 5-bromo-5-nitro-l,3-dioxane, 2-bromo-2- nitropropane-1 ,3-diol, butyl paraben, phenoxyethanol, methyl paraben, propyl paraben, diazolidinyl urea, calcium benzoate, calcium propionate, captan, chlorhexidine diacetate, chlorhexidine digluconate, chlorhexidine dihydrochloride, chloroacetamide, chlorobutanol, p- chloro-m-cresol, chlorophene, chlorothymol, chloroxylenol, m-cresol, o-cresol, diethylene glycol dimethyl ether ("DEDM") hydantoin, DEDM hydantoin dilaurate, dehydroacetic acid, dibromopropamidine diisethionate, and l,3-bis(hydroxymethyl)-5,5-dimethylimidazolidine- 2,4-dione ("DMDM") hydantoin. In certain aspects, the formulations herein may be (i) sterile or essentially free from microorganisms such as bacteria and viruses that can cause infection and (ii) optionally preservative-free.

V. Other Properties

[0126] In still yet another aspect, the composition is selected from the group of a gel, a foam, a cream, an emulsion, a lotion, an organogel, an o ntment, a solution, and a transdermal patch. More preferably, the composition is a solution. Alternatively, the composition is a gel.

[0127] In yet another alternative aspect, the composition is more viscous than water at standard temperature and pressure (STP). Alternatively, the composition has a kinematic viscosity of more than about 1 centistokes (cSt) or a dynamic viscosity of more than about 1 centipoise (cP). In certain aspects, the dynamic viscosity of the composition is at least about 2, 3, 4, 5, 7, 10, 12, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80, 90, 100, 150, 200, 250, 500, 1000, 2000, 3000, 5000, 10,000 cP at STP. In yet other aspects, the composition is thixotropic (i.e., it decreases in viscosity upon being stirred or shaken). The composition's viscosity can be adjusted by the addition of a cellulosic thickening agent, such as

hydroxypropyl cellulose, or other thickening agents.

[0128] In another aspect, the composition is acidic. In certain aspects, the composition has a pH of below 7.5, of below 6.5, of below 5.5, of below 4.5, of below 3.5, or of below 2.5. In certain other aspects, the pH of the composition may range from about 1.5 to about 7, about 2 to about 7, about 3 to about 7, about 4 to about 7, or about 5 to about 7. In still other aspects, the pH of the composition may range from about 1.5 to about 5.5, about 2.5 to about 5.5, about 3.5 to about 5.5, or about 4.5 to about 5.5.

[0129] In yet another aspect, the composition is basic. In certain aspects, the composition has a pH of above 7, of above 8, of above 9, of above 10, of above 1 1, or of above 12. In certain other aspects, the pH of the composition may range from about 7 to about 12.5, about 7 to about 11.5, about 7 to about 10.5, about 7 to about 9.5, or about 7 to about 8.5. In still other aspects, the pH of the composition may range from about 9 to about 12.5, about 9 to about 11.5, about 9 to about 1 .5, or about 8.5 to about 10. [0130] In still yet another aspect, the composition is neutral. In certain aspects, the composition has a pH of about 7. In certain other aspects, the composition has a pH from about 6 to about 8.5, from about 5.5 to about 8, about 6 to about 8, about 6.5 to about 8.5, or from about 6.5 to about 7.5. [0131] In certain other aspects, a composition is designed for high penetration, for high retention in the skin, or for both high penetration and high retention. The optimal composition will have a balance between penetration and retention, enabling an effective amount of the active ingredient to pass through the skin, but also enabling it to stay in the target area for a sufficient duration to alleviate the patient's pain or other symptoms. [0132] In another aspect, a composition is designed for topical efficacy with minimal systemic distribution of the coxib through the body by the circulatory system ( e.g., the cardiovascular system). Without being bound by theory, it is believed that minimization of systemic distribution would decrease the side effects of the composition, especially the side effect of adverse cardiovascular events. The optimal composition will have low systemic bioavailability, but will effectively treat pain or other symptoms associated with the site of application.

[0133] In a preferred aspect, a formulation provides the advantage of favorable stability at six months, as reflected in the lack of any substantial changes in viscosity, the absence of phase separation and crystallization at low temperatures, and a low level of impurities. [0134] In another preferred aspect, a formulation comprising etoricoxib provides additional advantages in comparison to previously described etoricoxib compositions. Such advantages may include one or more of the following: adhering well to the skin, spreading easily, drying more quickly, and showing greater in vivo absorption. In some more preferred aspects, the drying rate results in a residue of at most 50% of the starting amount after 24 hours. In other more preferred aspects, the transdermal selective COX-2 inhibitor (e.g., and still more preferably, etoricoxib) flux as determined by Franz cell procedure at finite dosing or at infinite dosing is at least 1.5 times that of a comparative formulation.

[0135] In still yet another preferred aspect, the composition remains stable for an acceptable time period between preparation and use when stored in a closed container at normal ambient temperature. Preferably, an "acceptable time period" is at least about 30 days, more preferably at least about six months, still more preferably at least about one year, and yet still more preferably at least about two years. [0136] In an alternative aspect, the present invention provides a formulation that degrades by less than 1% over the course of 6 months at room temperature. More preferably, the rate of degradation is less than about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or less than 0.1 %, and all fractions in between, over the course of six months at room temperature. VI. Methods of Preparation

[0137] In one aspect, the pharmaceutical composition is formulated as a cream, an emulsion, a gel (e.g., a hydrogel, an organogel, or an inorganic or silica gel), a lotion, a lacquer, an ointment, a solution (e.g. , a highly viscous solution), or a transdermal patch. The pharmaceutical composition may also be prepared so that it may be applied to the skin as a foam. In a preferred aspect, the composition is a solution. Alternatively, the composition is a transdermal patch.

VII. Methods of Treatment

[0138] In certain embodiments, the invention describes a method for treating pain comprising the step of applying a topical, selective COX-2 inhibitor composition to a subject. In one aspect, the pharmaceutical composition is applied to the skin of the subject.

[0139] In another aspect, the selective COX-2 inhibitor is delivered locally to the skin with minimal systemic absorption. In yet another aspect, the selective COX-2 inhibitor is delivered to and through the skin with minimal systemic absorption. In a still yet another aspect, the selective COX-2 inhibitor is delivered to the tissue surrounding or under the area of skin application with minimal systemic absorption.

[0140] In other aspects, the subject is a human. Alternatively, the subject is a non-human mammal.

[0141] In still other aspects, the treatment is continued for at least 12 weeks. More preferably, the treatment is continued for at least six months. [0142] The compositions of the invention may be useful to alleviate acute pain, chronic pain, or both. Compositions of the invention are particularly suited for use in treating OA chronically. They may also be useful for the treatment of other chronic joint diseases characterized by joint pain, degeneration of articular cartilage, impaired movement, and stiffness. Suitable joints include the knee, elbow, hand, wrist and hip. The compositions of the invention may also be useful for the treatment of other pain-associated disorders, including (but not limited to) muscle pain, lower back pain, neck pain, rheumatoid arthritis, fibromyalgia, myofascial pain, gout, sprains, strains, contusions, and neuropathic pain conditions.

[0143] Due to the properties of higher flux and greater in vivo absorption, it is believed that the formulations of the present invention can be administered at lower dosing than previously described etoricoxib formulations. In particular, it is expected that the compositions of the invention can be used at twice-a-day or once-a-day dosing in the treatment of OA. This would represent a significant improvement as lower dosing is associated with better patient compliance, an important factor in treating chronic conditions.

[0144] Compositions of the present invention may, if desired, be presented in a bottle, jar, or other container-closure system approved by the FDA or other regulatory authority, which may provide one or more unit dosages containing the active ingredient. The package or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of

pharmaceuticals, the notice indicating approval by the agency. VIII. Examples

[0145] Below, the present invention will be described by way of examples, which are provided for illustrative purposes only. Accordingly, they are not to be construed as limiting the scope of the present invention as defined by the appended claims.

[0146] Example 1: General Procedure for Composition Preparation [0147] For a typical zwitterionic surfactant/alpha-hydroxy acid composition, the surfactant (e.g., disodium dicocoamphodiacetate) was combined with solid etoricoxib. About half of the monohydric alcohol (e.g., ethanol) and water was added. The resulting suspension or solution was thoroughly mixed by vortexing until a clear solution was obtained.

[0148] The terpene (e.g., geraniol) and additional monohydric alcohols (e.g., 2-(2- ethoxyethoxy)ethanol, isopropanol) were optionally added. All other components except for the alpha-hydroxy acid were then added. The resulting suspension or solution was thoroughly mixed by vortexing until a clear solution was obtained. If any solids precipitate or failed to dissolve, more of the first monohydric alcohol and water were added.

[0149] Finally, the alpha-hydroxy acid (e.g., lactic acid) was added, followed by the remaining monohydric alcohol and water. The resulting suspension or solution was thoroughly mixed by vortexing for about 30 min or until a clear and homogeneous solution was obtained.

[0150] Example 2: Exemplary Procedure for Skin Permeation Measurement:

[0151] Comparisons were mainly performed using porcine skin, but in some cases, human cadaver skin was used (i.e., Tables 23 to 28). The permeation of etoricoxib through human cadaver skin or porcine skin from each of the present formulations was measured using Franz diffusion cells ("FDC's).

[0152] Porcine skin pieces were obtained from Lampire Biological Laboratories, Inc., Pipersville, PA. Porcine skins were collected immediately following animal sacrifice, and the hairs were trimmed with clippers. Larger pieces of excess fat were removed with a filet knife. The skin was then trimmed to a set thickness of some 2 mm, cut into individual pieces, wrapped in aluminum foil, frozen, shipped, and stored at -78 °C.

[0153] Prior to use, the skin pieces were dermatomed to a thickness of 0.5 to 1mm and were allowed to thaw, in air, to room temperature. Skin pieces were cut into circular pieces of an appropriate size for mounting in the FDC. The FDCs had a 3 ml receptor well volume, that was filled with isotonic phosphate buffered saline solution ("PBS") doped with 0.01% sodium azide. The flanges of the FDCs were coated with vacuum grease to ensure a complete seal and were clamped together with uniform pressure using a pinch clamp (SS #18 VWR 80073-350 from VWR Scientific, West Chester PA). After the FDCs were assembled, the porcine skin was allowed to pre-hydrate for 45 min with isotonic PBS. Isotonic PBS was then removed and formulation was applied to the donor well or directly to the skin surface, depending on the amount of formulation applied. The receptor wells were maintained at 37 °C (temperature on the surface of the skin is about 30 °C) in a stirring block with continual agitation via a stir bar. During exploratory studies, the initial applied dose was 100 ul, but this application dose was gradually reduced to 50 ul, 25 ul, 10 ul and 5 ul levels.

[0154] The flux rates were calculated using the fact that the donor well of each cell had an approximate area of 0.55 cm². Samples were drawn from the receptor wells at various times, as provided in the examples that follow. Franz diffusion cell measurements were typically made in six-fold replicates for each formulation. The concentration of etoricoxib in the samples was measured using HPLC analysis using a CI 8 column and acetonitrile and water as the mobile phase. Flux rates, F, were calculated based on the total transference of etoricoxib across the skin after time, t, according to t * A where D is the concentration of the drug in the receptor well after incubation time t, V is the volume of the receptor well and A is the surface area of skin.

[0155] Example 3: General Method for Skin Retention Studies [0156] At the end of the permeation study, skin samples were removed from the Franz cells for skin retention studies. Any excess of formulation was carefully wiped away, first with cotton swabs and then with lint-free paper. The skin samples were quickly washed with cold water and ethanol, and the skin samples were then dried for 1 h at room temperature. After being cut into small pieces with a pair of stainless steel scissors, the samples were transferred into 5 mL scintillation vials, and 2 mL of absolute ethanol was added. The liquid phase was filtered through 9 mm diameter disposable syringe filters (0.45 μιη, Acrodisc®). The filtrate, after appropriate dilution, was assayed by HPLC.

[0157] Example 4: Etoricoxib Formulations 1

[0158] Table 1: Etoricoxib Formulations 1 (FIG. 1)

[0159] This experiment was a test of sunscreens as enhancers for the delivery of NSAIDs (e.g., US 2007/0077288 Al). However, no significant permeation of etoricoxib was obtained. [0160] In composition F8, a combination of the terpene limonene and the zwitterionic surfactant disodium cocoamphodiacetate were used, and the amount of ethanol was reduced. This composition showed significant penetration of etoricoxib.

[0161] Example 5: Etoricoxib Formulations 2

[0162] Table 2: Etoricoxib Formulations 2 (FIG. 2)

F20 = 3 μΐ application instead of 100 μΐ as with others

[0163] To show the value of disodium cocoamphodiacetate for penetration enhancement, a control formulation without disodium cocoamphodiacetate was prepared. Removal of this ingredient reduced the penetration (cf. F15, F16, and F17).

[0164] Removal of urea from the formulation did not significantly reduce penetration. The formulations containing cocoamidopropyl betaine (F13) or ammonium lauryl sulfate (F14) exhibited penetration enhancement.

Example 6: Etoricoxib Formulations 3

[0166] Table 3: Etoricoxib Formulations 3 (FIG. 3)

[0167] In this experiment, the addition of urea to the chassis modified the permeation (cf. F21 and F22).

[0168] Example 7: Etoricoxib Formulations 4

[0169] Table 4: Etoricoxib Formulations 4 (FIG. 4)

[0170] The zwitterionic surfactant cocoamidopropyl betaine provided similar behavior to disodium dicocoamphodiacetate. The formulations comprising triethyl citrate (F36 to F39) provided significantly less permeation of etoricoxib than formulations comprising isopropanol and zwitterionic surfactants (F31 to F35).

[0171] Example 8: Etoricoxib Formulations 5

[0172] Table 5: Etoricoxib Formulations 5 (FIG. 5)

[0173] Etoricoxib analogs to valdecoxib formulations from US 2003/0161867 and US 2005/0096371 (F48-F50) were prepared. F48 and F49 produced a dramatic reduction in the delivery of etoricoxib. F50 was included in the skin permeation study, but it was not physically stable. Therefore, permeation data is not reported in FIG. 5.

[0174] Example 9: Etoricoxib Formulations 6

[0175] Table 6: Etoricoxib Formulations 6 (FIG. 6)

[0176] Formulation F60 (cf. US 2005/0096371 ) showed very low penetration when compared to other formulations.

[0177] Example 10: Etoricoxib Formulations 7

[0178] Table 7: Etoricoxib Formulations 7 (FIG. 7)

[0179] A variation of the chassis containing lactic acid and disodium cocoamphodiacetate (F61) produced good results. Other chassis (F64, F65) produced lower permeation.

[0180] Example 11: Etoricoxib Formulations 8

[0181] Table 8: Etoricoxib Formulations 8 (FIG. 8)

[0182] The terpene geraniol enhanced penetration (F75).

[0183] Example 12: Etoricoxib Formulations 9

[0184] Table 9: Etoricoxib Formulations 9 (FIG. 9)

[0185] The penetration-enhancing activity of geraniol was further confirmed (F85). The activity was enhanced by addition of isopropyl myristate (F86). [0186] Example 13: Etoricoxib Formulations 10

[0187] Table 10: Etoricoxib Formulations 10 (FIG. 10)

[0188] In this chassis, the removal of lactic acid (cf. F91 and F94) modified the delivery of etoricoxib.

[0189] Example 14: Etoricoxib Formulations 11

[0190] Table 11: Etoricoxib Formulations 11 (FIG. 11)

Application:

A= 10 μΐ

B= 25 μΐ

[0191] Dosing studies proved that permeation is proportional to the applied amount. The studies also suggested a possible change in permeation in the formulation containing polysorbate 20. [0192] Example 15: Etoricoxib Formulations 12

[0193] Table 12: Etoricoxib Formulations 12 (FIG. 12)

[0194] Geraniol together with isopropyl myristate and optionally propylene glycol increased the penetration (cf. Fl 11 , Fl 12 and Fl 18). Glycerin monolaurate also enhanced penetration (Fl 17).

[0195] Example 16: Etoricoxib Formulations 13

[0196] Table 13: Etoricoxib Formulations 13 (FIG. 13)

[0197] The results support that etoncoxib permeation is dependent upon the components used. The results suggest that the inclusion of alpha-hydroxy acids provides better permeation (F123).

[0198] Example 17: Etoricoxib Formulations 14

[0199] Table 14: Etoricoxib Formulations 14 (FIGS. 14A, 14B)

[0200] This study further confirmed the importance of lactic acid in penetration enhancement. In a dosing study with 10 μΐ (Figure 14B) and 25 μΐ (Figure 14A). The penetration appeared to increase with the amount of drug applied.

[0201] Example 18: Etoricoxib Formulations 15

[0202] Table 15: Etoricoxib Formulations 15 (FIGS. 15A. 15B)

[0203] This study further confirms the delivery of etoricoxib from the chassis. After 24 h, retention of etoricoxib from developed formulations appeared at least 2-3 times higher than control. This study suggested that permeation starts to level off around 8-12 hours. Figure 15A illustrates permeation results, and Figure 15B illustrates skin retention results.

[0204] Example 19: Etoricoxib Formulations 16

[0205] Table 16: Etoricoxib Formulations 16 (FIGS. 16A, 16B)

[0206] Cellulosic thickening agents were incorporated in the compositions. Reduction permeation was observed for some hydroxypropyl cellulose formulations. Figurel6A illustrates skin permeation and Figure 16B illustrates skin retention of the formulations.

[0207] Example 20: Etoricoxib Formulations 17

[0208] Table 17: Etoricoxib Formulations 17 (FIGS. 17A, 17B)

[0209] Formulations with various concentrations of etoricoxib were prepared. Figure 17A illustrates skin permeation and Figure 17B illustrates skin retention of the formulations.

[0210] Example 21: Selected Etoricoxib Formulations

[0211] Table 18A: Selected Etoricoxib Formulations

Unless otherwise stated, the application amount of formulation to each donor cell was 25 μΐ.

[0212] These formulations contain zwitterionic detergent and an alpha-hydroxy acid. They also contain molecular penetration enhancers such as isopropyl myristate, geraniol or limonene, either alone or in combination. Formulations I and I-E contain geraniol, while I-D contains limonene. The formulations are contained in monohydric alcohol/water with glycerin monolaurate as an additional optional enhancer or emulsifier.

[0213] In certain instances below (i.e., some subsequent examples), formulations were prepared having lower amounts of disodium cocoamphodiacetate ("DCAM") and/or glycerine monolaurate ("GML"). In addition, other glycerine monoesters were used in lieu of glycerine monolaurate or in combination. Moreover, in certain aspects, other acids were used. In other instances, formulations were prepared with thickeners.

[0214] In certain studies below, the Enhancement Ratio (ER) of the test formulation is provided. A formulation's ER is the ratio of a test formulation versus a hydroalcoholic solution as control. In transdermal studies, it is common practice to use a hydroalcoholic control, since this combination appears to provide optimal dissolution for various drug compounds. [0215] In certain embodiments below, the etoricoxib concentrations used were 0.5, 1.0, 2.0, 3.0, and 5.0%. The etoricoxib studies included 48-hour, two dose studies: dosing at 0 and 8 hours; 48-hour, four-dose studies: dosing at 0, 9, 21 and 29 hours; and 48-hour studies with 1 and 2 % actives after pretreatment w/placebo and with dosing at 0, 21 and 29 hours. In the latter study, the placebo plays a role of a conditioning agent and also may behave as permeation enhancer.

[0216] Example 22: Etoricoxib Formulations 18

[0217] Table 18B: Etoricoxib Formulations 18 (FIG. 18)

Table 18B

Ingredients F170-con F171 F172 F173 F174

Percentage in wt/wt% wt/wt% wt/wt% wt/wt% wt/wt%

Etoricoxib 2 2 2 2 2

Ethanol 48 39.5 41.5 42.5 44.5

DCAM 5 5 5 3

ΓΡΑ 10 10 10 10

Transcutol 10 10 10 10

L-Lactic acid 2.5 2.5 1.5 1.5

IPM 3 3 3 3

GML 3 1 1 1

Water 50 25 25 25 25

24hrs ER 1.00 6.06 6.36 5.94 10.12

Dosing (ul) 5.00 5.00 5.00 5.00 5.00

[0218] In Example 22, DCAM chassis formulations were prepared with lower levels of GML and DCAM. In DCAM chassis formulations, the reduction of the DCAM amount to 3% slightly increases the cumulative amount of etoricoxib. No difference in permeation was observed when the GML level was decreased from 3 to 1%. The results are shown in FIG. 18B. [0219] Example 23: Etoricoxib Formulations 19 [0220] Table 19: Etoricoxib Formulations 19 (FIG. 19)

Table 19

Ingredients F180- F181 F182 F183 F184 F185 F186 F187 con

Percentage in wt wt% wt/wt% wt/wt% wt/wt% wt/wt% wt/wt% wt/wt% wt/wt%

Etoricoxib 2 2 2 2 2 2 2 2

Ethanol 48 44 45 45 45 45 44 45

DCAM 5 5 5 5 5 5 5

IPA 10 10 10 10 10 10 10

Transcutol 10 10 10 10 10 10 10

L-Lactic acid 2.5 1.5 1.5 1.5 1.5 1.5 1.5

DPM 3 3 3 3 3 3 3

GML 1 1

Water 50 22.5 22.5 22.5 22.5 22.5 22.5 22.5

Glycerin 1

monostearate

Glycerin 1

monooleate

Glycerin 1 2

monoricinoleate

Glycerin 1 monopalmitate

24hrs ER 1.00 10.00 8.95 9.06 10.26 4.94 8.17 7.45

Dosing (ul) 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 [0221] In Example 23, other glycerin monoesters in a DCAM chassis were evaluated. The results show that addition of other glycerin esters does not significantly influence the cumulative amount of etoricoxib delivered by the formulation.

[0222] Example 24: Etoricoxib Formulations 20

[0223] Table 20: Etoricoxib Formulations 20 (FIG. 20)

Table 20

Ingredients F190 F191 F192 F193 F194 F195 F196 F197 F198 F199-con

Percentage wt/wt% wt/wt% wt/wt% wt/wt% wt wt% wt/wt% wt/wt% wt/wt% wt/wt% Wt/wt% in

Etoricoxib 2 2 2 2 2 2 2 2 2 2

Ethanol 44 45.5 45.5 46 45 44 44 41.5 44 48

Water 22.₅ 24 23 23 23 22.5 22.5 25 22.5 50

DC AM 5 3 3 5 5 5 5 5 5

IPA 10 10 10 10 10 10 10 10 10

Transcutol 10 10 10 10 10 10 10 10 10

L-Lactic 2.5 1.5 2.5 2.5 acid

IPM 3 3 3 3 3 3 3 3 3

GML 1 1 1 1 1 1 1 1 1

Hydrochlori 1

c acid (1:1)*

Citric Acid 2.5

Dehydroacet 2.5

ic acid

Caprylic 2.5

acid

24hrs ER 2.62 4.30 3.54 1.78 3.48 2.65 2.19 2.95 3.53 1.0

Dosing (ul) 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00

*This is a 1 to 1 mixture of concentrated hydrochloric acid (37.5 % in water) with water

[0224] In Example 24, the use of various other acids instead of lactic acid were evaluated. At the 1.5% level, lactic acid provided better permeation than other acids.

[0225] Example 25: Etoricoxib Formulations 21 [0226] Table 21: Etoricoxib Formulations 21 (FIG. 21) Table 21 A

Ingredients F200* F201 F202* F203 F204 F205 F206

Percentage wt/wt% wt/wt wt/wt wt/wt% wt/wt wt/wt t/wt

in % % % % %

Etoricoxib 2 2 2 2 2 2 2

EtOH 44.5 44.5 44.5 44.5 44.5 44.5 44.5

DCAM 3 0 6 1.5 3 3 1.5

IPA 10 10 10 10 10 10 10

L-Lactic 1.5 1.5 1.5 1.5 0 3 3

acid

IPM 3 3 3 3 3 3 3

GML 1 1 1 1 1 1 1

Transcutol 10 10 10 10 10 10 10

Water 25 28 22 26.5 26.5 23.5 25

24hrs ER 8.14 N/A 3.83 N/A N/A N/A N/A

Dosing (ul) ₅.00 N/A S.00 N/A N/A N/A N/A

* Formulations 200 and 202 were homogeneous. Homogeneous = monophasic with no particles, droplets are suspended or precipitated.

Table 21B

Ingredients F207* F208* F209 F210* F21 1 F212 con

Percentage wt/wt wt wt wt/wt wt/wt wt/wt wt/wt wt/wt

in % % % % % % %

Etoricoxib 2 2 2 2 2 2 2

EtOH 44.5 44.5 44.5 44.5 44.5 44.5 48

DCAM 6 3 3 3 3 3

IPA 10 10 10 10 10 10

L-Lactic 3 1.5 1.5 1.5 1.5 1.5

acid

IPM 3 0 6 1.5 3 3

GML 1 1 1 1 1 1

Transcutol 10 10 10 10 0 5

Water 20.5 28 22 26.5 35 30 50

24hrs ER 7.(59 4.54 N/A 5.79 N/A N/A 1.00

Dosing (ul) 5.00 5.00 N/A 5.00 N/A N/A 5.00

* Formulations 207, 208, and 210 were homogeneous. Homogeneous = monophasic with no particles, droplets are suspended or precipitated.

[0227] Example 25 evaluated the role of the DCAM amount, lactic acid, IPM, and transcutol levels. Removal of DCAM reduces permeation. However, doubling the level does not increase the delivery over the 3 % level. Permeation is not enhanced by removing ΓΡΜ or reducing the amount of IPM to 1.5%. The permeation and skin retention results are shown Fig. 20. Only homogeneous formulations were tested.

[0228] Example 26: Etoricoxib Formulation 22

[0229] Table 22: Etoricoxib Formulation 22 (FIG. 22)

Table 22

Ingredients F220- F221 F222 F223 F224 F225 F226 F227 F228 con

Percentage in wt/wt% wt/wt% wt/wt% wt/wt% wt/wt% wt/wt% wt/wt% wt wt% wt/wt%

Etoricoxib 2 1 1 1 1 1 1 1 1

DCAM 3 3 3 3 3 3 3 3

Ethanol 48 48.5 48.5 47.5 46.5 48.5 47.5 46.5 47.5

IPA 10 10 10 10 10 10 10 10

L-Lactic acid 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5

IPM 3 3 3 3 3 3 3 3

GML 1 1 1 1 1 1 1 1

Transcutol 10 10 10 10 10 10 10 10

Water 50 20 20 20 20 20 20 20 20

HPC (HY 117) 2

HPC (HY 121) 2 2 2

Methocel 2 2 2

PVP90 1 2 1 2 3

24hrs ER 1.00 5.47 5.08 7.48 6.79 7.41 5.35 4.10 5.62

Dosing (ul) 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00

[0230] Example 26 evaluated the effects of different thickening agents. All formulations with thickening agents showed nearly similar permeation behaviors. However, formulations containing HPC 121 together with PVP90 showed somewhat higher permeation than those with HPC 121 alone.

[0231] Example 27: Etoricoxib Formulation 23

[0232] Table 23A: Etoricoxib Formulation 23 (FIG. 23)

Table 23A

Ingredients F230 F231 F232 F233 F234 F235-con

Percentage in wt/wt% wt/wt% wt/wt% wt/wt% wt/wt% wt/wt%

Etoricoxib 0.5 1 2 3 5 2

Etanol 47 47.5 46.5 48 48 48

DCAM 3 3 3 3 3

ΓΡΑ 10 10 10 10 10

L-Lactic acid 1.5 1.5 1.5 1.5 1.5

EPM 3 3 3 3 3

GML 1 1 1 1 1

Transcutol 10 10 10 10 10

HPC HY117 2 2 2 2 2

Water 22 21 21 18.5 16.5 50

Dosing (ul) 5.00 5.00 5.00 5.00 5.00 5.00

Table 23B

Accumulated dose in (ug/cm2)

[0233] Example 27 evaluated the concentration variations of etoricoxib in the formulations. [0234] Example 28: Etoricoxib Formulation 24

[0235] Table 24A: Etoricoxib Formulation 24 (FIG. 24)

Table 24A

Ingredients F240 F241 F242 F243-con

Percentage in wt/wt% wt/wt% wt/wt% wt/wt%

Etoricoxib 0.5 1 2 2

Ethanol 47 47.5 45.5 48

DCAM 3 3 3

IPA 10 10 10

L-Lactic acid 1.5 1.5 1.5

ΓΡΜ 3 3 3

GML 1 1 1

Transcutol 10 10 10

HPC HY117 2 2 2 50

Water 22 21 22

Dosing (ul) 5.00 5.00 5.00 5.00

Table 24B

Accumulated dose in (ug/cm2)

Formula F240 F241 F242 F243-con

Time

4hrs 0.35 1.19 0.98 0.08

8hrs 0.80 2.02 1.86 0.14

12hrs 1.24 2.85 2.81 0.17

16hrs 1.56 3.52 3.46 0.22

20hrs 2.30 4.95 4.73 0.54

StdErr StdErr StdErr StdErr

4hrs 0.13 0.33 0.35 0.04

8hrs 0.20 0.45 0.43 0.05

12hrs 0.30 0.55 0.62 0.06

16hrs 0.35 0.65 0.63 0.07

20hrs 0.47 0.78 0.80 0.05

20hrs ER 4.30 9.23 8.82 1.00

[0236] Example 28 evaluated the concentration variations of etoricoxib in the formulations. [0237] Example 29: Etoricoxib Formulation 25

[0238] Table 25A: Etoricoxib Formulation 25 (FIG. 25)

Table 25A

Ingredients F250 F251 F252 F253 F254-con

Percentage in wt/wt% wt/wt% wt/wt% wt/wt% wt/wt%

Etoricoxib 1 1 5 5 2

DC AM 3 3 3 3

Etanol 47.5 47.5 47.5 47.5 48

IPA 10 10 10 10

L-Lactic Acid 1.5 1.5 1.5 1.5

IPM 3 3 3 3

GML 1 1 1 1

Transcutol 10 10 10 10

HPC (HY117) 2 2 2 2

Water 21 21 17 17 50

Dosing (ul) 5.00 5.00x2 5.00 5.00x2 5.00

Table 25B

Accumulated dose in (ug/cm2)

[0239] Example 29 evaluated 48 hour BID two dose studies with dosing at 0 and 8 hours. [0240] Example 30: Etoricoxib Formulation 26

[0241] Table 26A: Etoricoxib Formulation 26 (FIG. 26)

Table 26A

Ingredients F260 F261 F262 F263 F264-con

Percentage in wt/wt% wt/wt% wt/wt% wt/wt% wt/wt%

Etoricoxib 1 1 2 2 2

DC AM 3 3 3 3

Ethanol 47.5 47.5 47.5 47.5 48

IPA 10 10 10 10

L-Lactic Acid 1.5 1.5 1.5 1.5

IPM 3 3 3 3

GML 1 1 1 1

Transcutol 10 10 10 10

HPC (HY117) 2 2 2 2

Water 21 21 20 20 50

Dosing (ul) 5.00 5.00x2 5.00 5.00x2 5.00

Table 26B

Accumulated dose in (ug/cm2)

Formula F260 F261 F262 F263 F264-con

Time

4hrs 0.55 0.67 1.75 0.51 0.21

8hrs 1.30 1.45 1.87 1.22 0.37

14hrs 2.09 3.32 2.97 2.47 0.46

24hrs 3.54 5.90 4.85 4.67 0.58

36hrs 5.39 8.43 6.46 8.31 0.65

48hrs 5.35 9.10 6.95 9.16 0.85

StdErr StdErr StdErr StdErr StdErr

4hrs 0.07 0.20 0.89 0.06 0.07

8hrs 0.16 0.36 0.58 0.19 0.10

14hrs 0.29 0.91 0.69 0.42 0.13

24hrs 0.50 1.58 1.12 0.85 0.16

36hrs 0.69 2.24 1.11 1.44 0.20

48hrs 0.66 2.35 1.19 1.59 0.20

48hrs ER 6.32 10.74 8.21 10.81 1.00

[0242] Example 30 evaluated 48 hour BID studies with dosing at 0 and 8 hours. [0243] Example 31: Etoricoxib Formulation 27

[0244] Table 27A: Etoricoxib Formulation 27 (FIG. 27)

Table 27A

Ingredients F270-con F271 F272 F273 F274

Percentage in wt/wt% wt/wt% wt/wt% wt/wt% wt/wt%

Etoricoxib 2 1 1 2 2

DCAM 3 3 3 3

Ethanol 48 47.5 47.5 47.5 47.5

JPA 10 10 10 10

L-Lactic Acid 1.5 1.5 1.5 1.5

IPM 3 3 3 3

GML 1 1 1 1

Transcutol 10 10 10 10

HPC (HY117) 2 2 2 2

Water 50 21 21 20 20

Dosing (ul) 5.00 5.00 5.00x4 5.00 5.00x4

Table 27B

Accumulated dose in u /cm2

Example 31 evaluated 48 hour four dose studies with dosing at 0 and 9, 21 and 29 [0246] Example 32: Etoricoxib Formulation 28

[0247] Table 28A: Etoricoxib Formulation 28 (FIG. 28)

Table 28A

Ingredients Placebo/ Placebo/ F282 F283 F284-con

F280 F281

Percentage in wt/wt% wt/wt% wt/wt% wt/wt% wt/wt%

Etoricoxib 0 0 1 2 2

DCAM 3 3 3 3

Ethanol 48.5 48.5 47.5 47.5 48

IPA 10 10 10 10

L-Lactic Acid 1.5 1.5 1.5 1.5

IPM 3 3 3 3

GML 1 1 1 1

Transcutol 10 10 10 10

HPC (HY117) 2 2 2 2

Water 21 21 21 20 50

Dosing (ul) 5.00x3 5.00x3 5.00x3 5.00x3 5.00x3

Table 28B

Accumulated dose in u /cm2)

[0248] Example 32 evaluates 48 hour studies after a single pretreatment w/placebo with 1 and 2% active agents and with dosing at 0, 21, and 29 hours. In this study, the placebo plays a role of a conditioning agent and also may behave as permeation enhancer. [0249] General Results and Comment for Dosing Regimen and Two- and Four-Dose Studies (Examples 27 Through 32: Tables 23-28, FIGS. 23-28):

[0250] Using a single dosing regimen, there was an increase of the etoricoxib delivery observed from increasing the etoricoxib concentrations from 0.5% to 1%. The maximum etoricoxib delivery across intact human skin was observed at 1% etoricoxib concentration. There was no further increase of etoricoxib delivery at higher etoricoxib concentrations, i. e. , 2%, 3% or 5%.

[0251] In two-dose studies, once-daily and twice-daily dosing regimen were evaluated with both 1% and 2% etoricoxib formulations. For twice-daily application, the respective test formulation was applied at 0 and 8 hours on Day 1 , while the control formulation was applied once at 0 hours. The amount of etoricoxib delivered across intact human skin was followed over a 24-hour and 48-hour period and compared among the various dosing regimens.

[0252] The results showed that: (i) similar quantities of etoricoxib were delivered from the 1% and the 2% formulations; (ii) twice-daily application of the 1% formulation appears to further increase the etoricoxib delivery, but not from the 2% formulation; (iii) based on the total etoricoxib delivery over the first 24 hours, twice daily application of the 1% formulation appears to deliver equivalent quantity of etoricoxib as the once daily 2% application; and (iv) based on the total etoricoxib delivery over the entire 48-hour study period, the maximum etoricoxib delivery appeared to be reached using the 1% etoricoxib formulation applied twice daily, and there was no increase in the etoricoxib delivery with twice daily application of the 2% formulation.

[0253] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.

Claims

WHAT IS CLAIMED IS: 1. A pharmaceutical composition for topical administration, the composition comprising:

0.1 % to 5% (w/w) of etoricoxib;

0.5% to 10% of a zwitterionic surfactant or charged derivative thereof;

0.5% to 5% of a hydroxy acid;

optionally at least one molecular penetration enhancer;

at least one lower alcohol; and

water.

2. The pharmaceutical composition of claim 1, wherein the composition comprises about 1% to about 3% (w/w) etoricoxib.

3. The pharmaceutical composition of claim 2, wherein the composition comprises about 1 or 2% (w/w) etoricoxib.

4. The pharmaceutical composition of claim 1, wherein the zwitterionic surfactant or charged derivative thereof is derived from coconut oil.

5. The pharmaceutical composition of claim 4, wherein the zwitterionic surfactant or charged derivative thereof is a member selected from the group consisting of disodium cocoamphodiacetate, sodium cocoamphoacetate, and cocamidopropyl betaine.

6. The pharmaceutical composition of any one of claims 1, 4, or 5, wherein the composition comprises about 5% (w/w) of the zwitterionic surfactant or charged derivative thereof.

7. The pharmaceutical composition of claim 1, wherein the hydroxy acid is an alpha-hydroxy acid.

8. The pharmaceutical composition of claim 7, wherein the alpha- hydroxy acid is lactic acid.

9. The pharmaceutical composition of claim 8, wherein lactic acid is L- lactic acid.

10. The pharmaceutical composition of any one of claims 1-9 wherein the composition comprises 1.5% (w/w) of the hydroxy acid.

11. The pharmaceutical composition of claim 1 , wherein the composition further comprises the molecular penetration enhancer.

12. The pharmaceutical composition of claim 11, wherein the molecular penetration enhancer is a member selected from the group consisting of a fatty acid ester and a terpene.

13. The pharmaceutical composition of claim 12, wherein the composition comprises 1% to 5% (w/w) of the fatty acid ester.

14. The pharmaceutical composition of claim 13, wherein the fatty acid ester is a member selected from the group consisting of glycerol monolaurate and isopropyl myristate.

15. The pharmaceutical composition of claim 11, wherein the composition comprises 3% to 5% (w/w) of the terpene.

16. The pharmaceutical composition of claim 15, wherein the terpene is a member selected from the group consisting of geraniol and limonene.

17. The pharmaceutical composition of any one of claims 1-16, wherein the composition comprises 1% to 5% (w/w) of a second molecular penetration enhancer.

18. The pharmaceutical composition of claim 1, wherein the lower alcohol is a monohydric alcohol.

19. The pharmaceutical composition of claim 18, wherein the lower monohydric alcohol is ethanol.

20. The pharmaceutical composition of any one of claims 1- 19, wherein the composition comprises at least a second lower alcohol.

21. The pharmaceutical composition of claim 20, wherein the second lower alcohol is a monohydric alcohol.

22. The pharmaceutical composition of claim 21 , wherein the second lower alcohol is a member selected from the group consisting of isopropanol and 2-(2- ethoxyethoxy)ethanol.

23. The pharmaceutical composition of any one of claims 20-22, wherein the composition comprises 3% to 10% of the second lower alcohol.

24. The pharmaceutical composition of claim 23, wherein the composition further comprises 3 to 10% of a third lower alcohol.

25. The pharmaceutical composition of claim 1, wherein the composition is a solution or a gel.

26. A pharmaceutical solution for topical administration, the composition comprising:

1 % to 2% (w/w) of etoricoxib ;

5% disodium dicocoamphodiacetate or cocoamidopropyl betaine; 1.5% lactic acid;

at least 1% of at least one molecular penetration enhancer;

10% isopropanol; and

water.

27. A method for topically treating pain in a subject, the method comprising:

topically applying a pharmaceutical composition comprising:

0.1 % to 5% (w/w) of etoricoxib;

0.5% to 10% of a zwitterionic surfactant or charged derivative thereof;

0.5% to 5% of a hydroxy acid;

at least one molecular penetration enhancer;

at least one lower alcohol; and

water.

28. The method of claim 27, wherein said composition comprises 35% to 65% of the lower alcohol and 10% to 30% water.

29. The method of any of claims 27-28, wherein the pain is associated with osteoarthritis.

30. Use of a pharmaceutical composition according to any one of claims 1 - 26 for the manufacture of a medicament for the topical treatment of osteoarthritis or pain associated therewith.