EP2485730A1 - Formulation topique comprenant de l'étoricoxib et tensio-actif zwitterionique - Google Patents

Formulation topique comprenant de l'étoricoxib et tensio-actif zwitterionique

Info

Publication number
EP2485730A1
EP2485730A1 EP10766200A EP10766200A EP2485730A1 EP 2485730 A1 EP2485730 A1 EP 2485730A1 EP 10766200 A EP10766200 A EP 10766200A EP 10766200 A EP10766200 A EP 10766200A EP 2485730 A1 EP2485730 A1 EP 2485730A1
Authority
EP
European Patent Office
Prior art keywords
etoricoxib
composition
pharmaceutical composition
acid
formulations
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10766200A
Other languages
German (de)
English (en)
Inventor
Servet Buyuktimkin
Nadir Buyuktimkin
Jagat Singh
John M. Newsam
Dominic King-Smith
Edward T. Kisak
Bradley S. Galer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nuvo Research Inc
Original Assignee
Nuvo Research Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nuvo Research Inc filed Critical Nuvo Research Inc
Publication of EP2485730A1 publication Critical patent/EP2485730A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • Osteoarthritis 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.
  • a therapy must generally show efficacy on these three variables over a sustained period of time.
  • Food and Drug Administration has required OA therapies to show superiority over placebo over a twelve-week period before approval of a new drug application.
  • NS AIDs Oral non-steroidal anti-inflammatory drugs
  • COX cyclooxygenase
  • 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.
  • COX-1 COX-1
  • COX-2 COX-2
  • 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)
  • 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.
  • Topical NS AIDs offer the possibility of achieving local therapeutic benefit while reducing or eliminating the risk of systemic side effects.
  • data supporting the efficacy of topical NSAIDs in the treatment of OA is limited.
  • RCT's placebo controlled trials
  • 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)).
  • Pennsaid GelTM is a topical formulation comprising diclofenac sodium that overcomes disadvantages of prior art NSAID formulations.
  • PennsaidTM 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.
  • 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.
  • 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.
  • 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
  • the skin barrier can be compromised by several physical methods, such as iontophoresis, ultrasound, electroporation, heat, and microneedles.
  • MPETMs Molecular penetration enhancers
  • Molecular penetration enhancers are a preferred means for reversibly lowering the skin barrier. At least 400 chemicals have been identified as skin permeability enhancers.
  • General categories of MPETMs include pyrrolidones, fatty acids, fatty acid esters, fatty acid alcohols, sulfoxides, essential oils, terpenes, oxazoldines, surfactants, polyols, azone and derivatives, and epidermal enzymes.
  • MPETMs have the challenge with use of MPETMs. This is because an MPETM'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.
  • 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 (MPETM), at least one lower alcohol, and water.
  • the selective COX-2 inhibitor is etoricoxib.
  • 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.
  • the method of treatment is directed to pain associated with OA.
  • 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.
  • 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.
  • 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.
  • the selective COX-2 inhibitor is etoricoxib.
  • the lower alcohol is a monohydric alcohol.
  • 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.
  • 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.
  • the lactic acid is racemic (i.e., racemic lactic acid).
  • the lactic acid is enantiomerically enriched or is substantially a single enantiomer (e.g., (S)- lactic acid, also termed L-laciic acid).
  • the lactic acid is L-iactic acid.
  • the composition comprises at least one molecular penetration enhancer (MPETM). 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).
  • MPETM molecular penetration enhancer
  • 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).
  • GML glycerol monolaurate
  • IPM isopropyl myristate
  • 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.
  • the MPETM is optional.
  • 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 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.
  • the second lower alcohol is a monohydric alcohol
  • the second lower alcohol is a member selected from the group of isopropanol and 2-(2-ethoxyethoxy)ethanol.
  • composition comprises 3% to 10% of the second lower alcohol.
  • composition comprises 3% to 10% of a third lower alcohol, and more preferably, the third lower alcohol is a monohydric alcohol.
  • 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.
  • 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.
  • the lower alcohol is a monohydric alcohol.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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..
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FIG. 14A illustrates etoricoxib permeation through porcine skin of a 25 ⁇ sample from the fourteenth series of topical formulations (Table 14) at 4, 21 , and 26 hours after application.
  • FIG. 14B illustrates etoricoxib permeation through porcine skin of a 10 ⁇ sample from the fourteenth series of topical formulations (Table 14) at 4, 21 , and 26 hours after application.
  • 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.
  • FIG. 15B illustrates the etoricoxib skin retention in porcine skin from the fifteenth series of topical formulations (Table 15) at 24 hours after application.
  • 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.
  • FIG 16B illustrates etoricoxib skin retention in porcine skin from the sixteenth series of topical formulations (Table 16) at 26 hours after application.
  • 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.
  • FIG 17B illustrates etoricoxib skin retention in porcine skin from the seventeenth series of topical formulations (Table 17) at 24 hours after application.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • agent 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.
  • Alpha-hydroxy acid indicates an organic compound comprising at least one carbon substituted with a hydroxy! group and a carboxylic acid group (i.e., a C(OH)(C0 2 H) group). It also indicates the salts thereof (i.e., a carboxylate group and its associated counterion rather than a carboxylic acid).
  • 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.
  • Cellulosic thickening agent 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.
  • Finite dosing 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.
  • composition as used herein are equivalent terms referring to a composition of matter suitable for pharmaceutical use.
  • “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.
  • “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.
  • “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.
  • compositions 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).
  • Penetration enhancer 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.
  • 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.
  • 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.
  • etoricoxib as used herein, includes pharmaceutically acceptable derivatives or salts thereof.
  • Thickening agent 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.
  • Topical formulation 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.
  • Transdermal as used herein includes a process that occurs through the skin.
  • the terms “transdermal,” “percutaneous,” and “transcutaneous” can be used interchangeably.
  • “transdermal” may also include epicutaneous.
  • 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.
  • Zwitterionic surfactant 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 cocoamphoacetate (i.e., cocoamphoglycinate), cocoamidopropyl betaine, cocoamidopropyl hydroxysultaine, potassium cocoamphodiacetate, dodecyl betaine, phospholipids such as lecithin, alkyl or acyl amphopropionates or sulfobetaines (i.e.,
  • lauroamphoacetate and the like, as well as mixtures and poly(ethylene glycol) derivatives thereof.
  • 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.
  • the present invention provides a pharmaceutical composition comprising, consisting essentially of, or consisting of a selective COX-2 inhibitor.
  • 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.
  • the pharmaceutical composition comprises 0.1% to 5% (w/w) of etoricoxib, preferably 1%> to 3%, and more preferably about 1 or 2%.
  • 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.
  • 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 cm 2 , preferably about 1200 to 1800 cm 2 (750 cm 2 /knee).
  • 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 cm 2 , preferably about 1200 to 1800 cm 2 (750 cm 2 /knee).
  • 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
  • composition can be applied to a skin area of about 1 to 50 cm , about 50 to 250 cm , about 100 to 500 cm 2 , about 200 to 800 cm 2 , or about 800 to 1200 cm 2 .
  • 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).
  • a single knee is treated and the application area is about 750 cm 2 .
  • both knees of an individual are treated and the application area is about 1500 cm 2 (about 750 cm 2 per knee).
  • 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.
  • 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 cm 2 , preferably about 1200 to 1800 cm 2 (750 cm 2 /knee).
  • the composition can be applied to a skin area of about 1 to 50 cm 2 , about 50 to 250 cm 2 , about 100 to 500 cm 2 , about 200 to 800 cm 2 , or about 800 to 1200 cm 2 .
  • 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.
  • this comparative formulation comprises etoricoxib.
  • the flux of etoricoxib is at least 1.5 times greater than the flux of the comparative formulation's active.
  • 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.
  • 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.
  • 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.
  • the selective COX-2 inhibitor flux is greater than the flux of the comparative formulation with the same selective COX-2 inhibitor.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ g/hr cm 2 at 24 hours, preferably at least 0.2 ⁇ g/hr/cm 2 at 24 hours.
  • the composition comprising etoncoxib has an enhancement ratio (ER) of at least 2.
  • the composition comprising etoricoxib has an ER of at least 5.0.
  • the composition comprising etoricoxib has an ER that is at least 10.0.
  • ER is the ratio of a test formulation comprising etoricoxib versus a hydroalcoholic control solution comprising the same selective COX-2 inhibitor.
  • 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.
  • 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.
  • 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%>).
  • 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%).
  • the hydroxy acid or alpha-hydroxy acid is optional, and the composition comprises an acid such as caprylic acid, hydrochloric acid,
  • 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%).
  • the MPETM is selected from the group of terpenes, fatty acid esters, and fatty acid alcohols. More preferably, the MPETMis 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,
  • a second MPETM is present (e.g., a fatty acid ester and a terpene).
  • the composition of the present invention comprises limonene or geraniol.
  • 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).
  • the terpene MPETM can be included within an essential oil.
  • Essential oils that include a substantial proportion of at least one terpene MPETM include oils of peppermint, eucalyptus, chenopodium, anise, and yling-yling.
  • the essential oil is eucalyptus oil.
  • a fatty acid ester or fatty alcohol ester is used as an MPETM.
  • fatty acid ester MPETMs are glyceryl monoesters. More preferably, the MPETM 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%).
  • a fatty acid ester or a fatty alcohol ester is used as an MPETM in the composition.
  • 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
  • MPETMs 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, AzoneTM) 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition comprises 35 to 75% of a lower alcohol.
  • 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.
  • 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).
  • the first alcohol is about 35 to 75%
  • the second lower alcohol is about 3% to 10%.
  • the composition further comprises about 3 to 10% of a third lower alcohol.
  • the lower alcohol is a diol.
  • 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.
  • the Suitable diols include, but are not limited to, propylene glycol, butanediol, butynediol, pentanediol, hexanediol, octanediol, neopentyl glycol, 2 -methyl- 1,3- propanediol, di
  • 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%.
  • composition comprises at least one additional
  • the surfactant is a nonionic surfactant. More preferably, the surfactant is a polysorbate surfactant. Still more preferably, the surfactant is polysorbate 20.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • EDTA ethylenediamine tetraacetic acid
  • diammonium EDTA diammonium EDTA
  • dipotassium EDTA calcium disodium EDTA
  • HEDTA tetraethylammonium
  • TAA t
  • 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).
  • 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.
  • suitable pH-adjusting bases include amines, such as diethanolamine, triethanolamine, or aminopropanol; bicarbonates;
  • the pH-adjusting agent can also be an acid, an acid salt, or mixtures thereof.
  • 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.
  • 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.
  • 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.
  • a small amount of acid or base is included in the formulation.
  • 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%.
  • the pH-adjusting agent can also be a buffer.
  • 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.
  • the buffer is an acidic buffer system such as, for example, benzocaine.
  • the acidic acid buffer system is citric acid or a citric acid salt.
  • 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.
  • 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.
  • this amount is about 0.001 M.
  • 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.
  • 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.
  • a second pH-adjusting agent e.g., sodium hydroxide or hydrochloric acid
  • 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.
  • 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.
  • 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.
  • preservatives include, 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,
  • DEDM di
  • 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.
  • the composition is more viscous than water at standard temperature and pressure (STP).
  • STP standard temperature and pressure
  • the composition has a kinematic viscosity of more than about 1 centistokes (cSt) or a dynamic viscosity of more than about 1 centipoise (cP).
  • 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.
  • 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.
  • the composition is acidic.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the composition remains stable for an acceptable time period between preparation and use when stored in a closed container at normal ambient temperature.
  • 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.
  • 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
  • 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.
  • a gel e.g., a hydrogel, an organogel, or an inorganic or silica gel
  • a lotion e.g., a hydrogel, an organogel, or an inorganic or silica gel
  • a solution e.g. , a highly viscous solution
  • transdermal patch e.g., a transdermal patch.
  • the invention describes a method for treating pain comprising the step of applying a topical, selective COX-2 inhibitor composition to a subject.
  • the pharmaceutical composition is applied to the skin of the subject.
  • the selective COX-2 inhibitor is delivered locally to the skin with minimal systemic absorption.
  • the selective COX-2 inhibitor is delivered to and through the skin with minimal systemic absorption.
  • the selective COX-2 inhibitor is delivered to the tissue surrounding or under the area of skin application with minimal systemic absorption.
  • the subject is a human.
  • the subject is a non-human mammal.
  • the treatment is continued for at least 12 weeks. More preferably, the treatment is continued for at least six months.
  • 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.
  • 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.
  • 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.
  • compositions of the present invention can be administered at lower dosing than previously described etoricoxib formulations.
  • 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.
  • 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
  • Example 1 General Procedure for Composition Preparation
  • the surfactant e.g., disodium dicocoamphodiacetate
  • solid etoricoxib e.g., ethanol
  • the resulting suspension or solution was thoroughly mixed by vortexing until a clear solution was obtained.
  • terpene e.g., geraniol
  • additional monohydric alcohols e.g., 2-(2- ethoxyethoxy)ethanol, isopropanol
  • 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.
  • alpha-hydroxy acid e.g., lactic acid
  • monohydric alcohol e.g., ethanol
  • the resulting suspension or solution was thoroughly mixed by vortexing for about 30 min or until a clear and homogeneous solution was obtained.
  • Example 2 Exemplary Procedure for Skin Permeation Measurement:
  • 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.
  • the skin pieces 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.
  • PBS isotonic phosphate buffered saline solution
  • 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.
  • 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.
  • the flux rates were calculated using the fact that the donor well of each cell had an approximate area of 0.55 cm 2 .
  • 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.
  • Example 3 General Method for Skin Retention Studies
  • 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 ⁇ , Acrodisc®). The filtrate, after appropriate dilution, was assayed by HPLC.
  • 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.
  • 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).
  • Etoricoxib analogs to valdecoxib formulations from US 2003/0161867 and US 2005/0096371 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.
  • Formulation F60 (cf. US 2005/0096371 ) showed very low penetration when compared to other formulations.
  • 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).
  • Example 21 Selected Etoricoxib Formulations
  • the application amount of formulation to each donor cell was 25 ⁇ .
  • 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.
  • 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.
  • formulations were prepared having lower amounts of disodium cocoamphodiacetate (“DCAM”) and/or glycerine monolaurate (“GML”).
  • DCAM disodium cocoamphodiacetate
  • GML glycerine monolaurate
  • other glycerine monoesters were used in lieu of glycerine monolaurate or in combination.
  • other acids were used.
  • formulations were prepared with thickeners.
  • 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.
  • it is common practice to use a hydroalcoholic control since this combination appears to provide optimal dissolution for various drug compounds.
  • 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.
  • the placebo plays a role of a conditioning agent and also may behave as permeation enhancer.
  • 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)
  • Example 23 Dosing (ul) 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 10.00 [0221]
  • 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.
  • 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.
  • Example 25 Etoricoxib Formulations 21 [0226] Table 21: Etoricoxib Formulations 21 (FIG. 21) Table 21 A
  • 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 ⁇ or reducing the amount of IPM to 1.5%. The permeation and skin retention results are shown Fig. 20. Only homogeneous formulations were tested.
  • 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.
  • Example 27 evaluated the concentration variations of etoricoxib in the formulations.
  • Example 28 Etoricoxib Formulation 24
  • Example 28 evaluated the concentration variations of etoricoxib in the formulations. [0237]
  • Example 29 Etoricoxib Formulation 25
  • Example 29 evaluated 48 hour BID two dose studies with dosing at 0 and 8 hours.
  • Example 30 Etoricoxib Formulation 26
  • Example 30 evaluated 48 hour BID studies with dosing at 0 and 8 hours. [0243]
  • Example 31 Etoricoxib Formulation 27
  • Example 31 evaluated 48 hour four dose studies with dosing at 0 and 9, 21 and 29 [0246]
  • Example 32 Etoricoxib Formulation 28
  • 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):

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Abstract

L'invention concerne des compositions pharmaceutiques topiques, des procédés de préparation et des procédés de traitement comprenant un inhibiteur sélectif de COX-2 et utilisés pour traiter une douleur, en particulier une douleur associée à l'ostéoarthrite. Les compositions peuvent produire une bonne perméabilité d'inhibiteur sélectif de COX-2 et une biodisponibilité sur un site cible. Dans certains modes de réalisation préférés, l'invention concerne une composition pharmaceutique comprenant de l'étoricoxib, un tensio-actif zwittérionique ou des dérivés chargés de ce dernier, un acide alpha-hydroxy, au moins un promoteur de pénétration moléculaire, au moins un alcool faible et de l'eau.
EP10766200A 2009-10-09 2010-10-08 Formulation topique comprenant de l'étoricoxib et tensio-actif zwitterionique Withdrawn EP2485730A1 (fr)

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EP2575813A1 (fr) * 2010-05-28 2013-04-10 Nuvo Research Inc. Formulation topique d'étoricoxib
EA030797B1 (ru) 2012-12-21 2018-09-28 ТЕЙКОКУ ФАРМА ЮЭсЭй, ИНК. Система трансдермальной доставки гормонов (варианты) и способы ее применения

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AUPN814496A0 (en) 1996-02-19 1996-03-14 Monash University Dermal penetration enhancer
SK14762003A3 (sk) 2001-05-31 2004-08-03 Pharmacia Corporation Kožou prestupujúci prípravok obsahujúci selektívne inhibujúcu cyklooxygenázu-2 a jednosýtny alkohol
WO2005044227A1 (fr) 2003-11-05 2005-05-19 Glenmark Pharmaceuticals Limited Compositions pharmaceutiques topiques
MX2009004038A (es) 2006-10-17 2009-08-24 Nuvo Res Gel de diclofenaco.

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