EP2482850A2 - Topische formulierungen - Google Patents

Topische formulierungen

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Publication number
EP2482850A2
EP2482850A2 EP10762838A EP10762838A EP2482850A2 EP 2482850 A2 EP2482850 A2 EP 2482850A2 EP 10762838 A EP10762838 A EP 10762838A EP 10762838 A EP10762838 A EP 10762838A EP 2482850 A2 EP2482850 A2 EP 2482850A2
Authority
EP
European Patent Office
Prior art keywords
composition
etoricoxib
pharmaceutical composition
formulation
urea
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Withdrawn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
EP10762838A
Other languages
English (en)
French (fr)
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 EP2482850A2 publication Critical patent/EP2482850A2/de
Withdrawn legal-status Critical Current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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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.
  • 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) requires OA therapies to show superiority over placebo over a twelve-week period.
  • FDA Food and Drug Administration
  • NSAIDs 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.
  • 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 GI 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.
  • Topical NSAIDs 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 metaanalysis 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.
  • U.S. Patent Publication No. 2008/0300311 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 drug containing a COX-2 selective inhibitor would offer patients an attractive new treatment modality. Such a drug 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.
  • the skin barrier can be compromised by several physical methods, such as iontophoresis, ultrasound, electroporation, heat, and microneedles.
  • 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, oxazolidines, surfactants, polyols, azone and derivatives, and epidermal enzymes.
  • MPETMs The challenge with use of MPETMs is that few seem to induce a significant or therapeutic enhancement of drug transport at tolerable levels. This is because a 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.
  • the present invention provides pharmaceutical compositions, methods for preparation, and methods of treatment comprising a selective COX-2 inhibitor, a lower amino alcohol, a cellulosic thickening agent, and urea.
  • the selective COX-2 inhibitor is etoricoxib.
  • the formulations enhance permeability and bioavailability, and they are useful for topical treatment of pain and/or inflammation.
  • the method of treatment is directed to pain associated with OA.
  • 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 lower amino alcohol, a cellulosic thickening agent, urea, a lower alcohol, and water.
  • a selective COX-2 inhibitor e.g. , etoricoxib
  • the composition comprises 0.1% to 5% (w/w) etoricoxib, 0.5% to 5% of a lower amino alcohol, 0.5% to 5% of a cellulosic thickening agent, 0.5% to 10% urea, 35% to 65% of a lower alcohol, and 15% to 30% of water.
  • the composition comprises 1% to 3% (w/w) of a selective COX-2 inhibitor. Still more preferably, the composition comprises 1% (w/w) of a selective COX-2 inhibitor. Alternatively, the composition comprises 2% (w/w) of a selective COX-2 inhibitor. Alternatively or yet still more preferably, the selective COX-2 inhibitor is etoricoxib.
  • the lower amino alcohol is 2-amino-2-methylpropanol ("AMP")-
  • AMP 2-amino-2-methylpropanol
  • the lower alcohol is a monohydric alcohol.
  • the composition further comprises an additional molecular penetration enhancer (MPE ). More preferably, the MPETM is the lower alcohol 2-(2-ethoxyethoxy)ethanol (Transcutol ® ). Still more preferably, the composition comprises 5% to 25% (w/w) 2-(2-ethoxyethoxy)ethanol, and yet still more preferably, 10% 2-(2-ethoxyethoxy)ethanol.
  • MPETM is the lower alcohol 2-(2-ethoxyethoxy)ethanol
  • Transcutol ® the lower alcohol 2-(2-ethoxyethoxy)ethanol
  • the composition comprises 5% to 25% (w/w) 2-(2-ethoxyethoxy)ethanol, and yet still more preferably, 10% 2-(2-ethoxyethoxy)ethanol.
  • the MPETM is a terpene. More preferably, the terpene is selected from the group consisting of limonene, geraniol and mixtures thereof. Still more preferably, the composition comprises 0.1% to 5% (w/w) terpene, and yet still more preferably, 3% terpene. [0023] In yet still another aspect of the embodiment or preferred aspect, the composition further comprises a nonionic surfactant. More preferably, the nonionic surfactant is a polysorbitan ester. Still more preferably, the polysorbitan ester is polysorbate 20 (Tween ® 20).
  • the composition comprises from 0.5% to 15% (w/w) nonionic surfactant, and yet still more preferably, 2% to 10% nonionic surfactant.
  • 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, 0.5% to 3% AMP, 1% to 3% hydroxypropyl cellulose, 2% to 10% urea, 10% 2-(2-ethoxyethoxy)ethanol, a lower monohydric alcohol, and water.
  • said composition consists of, consists essentially of, or comprises 2% to 5% urea.
  • said composition consists of, consists essentially of, or comprises about 7.5% urea.
  • 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 a selective COX-2 inhibitor (e.g., etoricoxib), a lower amino alcohol, a cellulosic thickening agent, urea, a lower alcohol, and water.
  • a selective COX-2 inhibitor e.g., etoricoxib
  • the composition comprises 0.1% to 5% (w/w) etoricoxib, 0.5% to 5% of a lower amino alcohol, 0.5% to 5% of a cellulosic thickening agent, 0.5% to 10% urea, a lower alcohol, and water.
  • the composition comprises 35% to 65% of a lower alcohol and 15% to 30% water.
  • the lower amino alcohol is 2- amino-2-methylpropanol.
  • the lower alcohol is a monohydric alcohol.
  • the pain is associated with OA.
  • FIG. 1 describes etoricoxib permeation through porcine skin from a first series of topical formulations (Table 1) at 4, 21, and 26 hours after application.
  • FIG. 2 describes etoricoxib permeation through porcine skin from a second series of topical formulations (Table 2) at 4, 21, and 26 hours after application.
  • FIG. 3 describes etoricoxib permeation through porcine skin from a third series of topical formulations (Table 3) at 4 and 20 hours after application at two different dosing levels.
  • FIG. 4 describes etoricoxib permeation through porcine skin from a fourth series of topical formulations (Table 4) at 4, 20, and 24 hours after application.
  • FIG. 5 describes etoricoxib permeation through porcine skin from a fifth series of topical formulations (Table 5) at 4, 21, and 24 hours after application.
  • FIG. 6 describes etoricoxib permeation through porcine skin from a sixth series of topical formulations (Table 6) at 4, 21, and 26 hours after application.
  • FIG. 7 describes etoricoxib permeation through porcine skin from a further series of topical formulations (Table 8) at 4, 21, and 26 hours after application.
  • FIG. 8 describes etoricoxib permeation through porcine skin from a further series of topical formulations (Table 9) at 4, 21, and 26 hours after application.
  • FIG. 9 describes etoricoxib permeation through porcine skin from a further series of topical formulations (Table 10) at 4, 21, and 26 hours after application. DETAILED DESCRIPTION OF THE INVENTION I. Definitions
  • a not only include aspects with one member, but also include aspects with more than one member.
  • 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 agent, 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.
  • 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 formulation, tend to produce a particular effect on the formulation's properties. For example, a formulation comprising a thickening agent is likely to be more viscous than an otherwise identical comparative formulation that lacks the thickening agent.
  • 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 amino alcohol” as used herein includes straight- or branched-chain alkyl compounds of 2 to 8 carbon atoms, and preferably, of 2 to 6 carbon atoms.
  • Representative lower amino alcohols include 2-amino-2-methylpropanol, meglumine, serine methyl ester, serine ethyl ester, threonine ethyl ester, and the like.
  • “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, n-butanol, t-butanol, n-pentanol, 3-pentanol, 2- methoxyethanol, propylene glycol, and the like.
  • “Monohydric alcohol” as used herein 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, oleyl alcohol, and the like.
  • “Nonionic surfactant” as used herein indicates a surface-active agent that is uncharged under the conditions of the formulation.
  • Representative nonionic surfactants include the polysorbitans (e.g., polysorbitan 20), fatty acid esters (e.g., isopropyl myristate), 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 formulation 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.
  • An MPETM 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 underlying or near to the skin or nail; or iii) indirectly via systemic distribution to the site of the disease. If systemic distribution of an active agent would be likely to produce side effects (e.g., etoricoxib), an MPETM is preferably selected to maximize direct delivery and to minimize systemic distribution.
  • An MPETM may be a pure substance or may comprise, consist essentially of, or consist of a mixture of different chemical entities. [0053] "Thickening agent" as used herein includes an agent or combination of agents that increases the viscosity of a formulation.
  • 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 cellulosic thickening agents, carbomer polymers, carbomer derivatives, cellulose derivatives, polyvinyl alcohol, poloxamers, polysaccharides, and mixtures thereof.
  • Topical formulation includes a formulation 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.
  • 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. In certain embodiments, “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.
  • 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 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, more preferably about 1 mg to about 30 mg, and still more preferably about 1 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 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 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 , 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 .
  • 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.
  • 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. 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.
  • 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 ⁇ /1 ⁇ / ⁇ 2 at 24 hours.
  • the composition comprises 2-amino-2-methylpropanol ("AMP"). More preferably, the composition comprises 0.5% to 5% AMP. Still more preferably, the composition comprises from 0.5% to 2% AMP. Yet still more preferably, the composition comprises 1% AMP. Alternatively, the composition comprises 1.5% AMP.
  • AMP 2-amino-2-methylpropanol
  • the composition comprises a cellulosic thickening agent.
  • suitable cellulosic thickening agents include, but are not limited to, 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.
  • the cellulosic thickening agent is HPC.
  • the composition comprises 0.5% to 5 % of a cellulosic thickening agent. 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 comprises urea. More preferably, the composition comprises 0.5% to 10% urea. Still more preferably, the composition comprises 2% to 10% urea. Alternatively, the composition comprises 2% to 5% urea. Yet still more preferably, the composition comprises about 5%» urea. Alternatively, the composition comprises about 2.5% urea, the composition comprises about 7.5% urea, or the composition comprises about 10% urea.
  • the composition comprises a mixture of AMP and a cellulosic thickening agent.
  • the composition comprises a mixture of AMP and urea, or the composition comprises a mixture of a cellulosic thickening agent and urea.
  • the composition comprises a mixture of AMP, a cellulosic thickening agent, and urea.
  • urea may function as an MPETM to assist in the delivery of a selective COX-2 inhibitor.
  • AMP may function as an MPETM to assist in the delivery of a selective COX-2 inhibitor.
  • urea and AMP may function as MPETMs to assist in the delivery of a selective COX-2 inhibitor.
  • the composition comprises a mixture of a lower monohydric alcohol and water. More preferably, the lower monohydric alcohol is ethanol or 2-(2- ethoxyethoxy)ethanol. In certain aspects, the composition comprises a second lower monohydric alcohol. In certain other aspects, the composition comprises a third lower monohydric alcohol. In one aspect, the formulation does not include isopropanol. In certain aspects, the lower monohydnc alcohol may function as a MPE .
  • 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, 63, or 65% (w/w) of a lower monohydric alcohol.
  • the composition comprises at most 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, 63, or 65% (w/w) of a lower monohydric alcohol.
  • the composition comprises 35% to 65% of a lower monohydric alcohol.
  • the composition comprises the same or differing amounts of a first and at least one additional monohydric alcohol.
  • the composition can include 44% to 54% of ethanol and 10% of 2-(2-ethoxyethoxy)ethanol.
  • 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 mixtures thereof.
  • the formulation comprises 0.1% to 15% (w/w) of propylene glycol; more preferably, the formulation comprises 0.1% to 5% (w/w) of propylene glycol.
  • an additional MPE is present m the carrier.
  • the MPETM is selected the group consisting of terpenes, fatty acid esters, and fatty acid alcohols. More preferably, the MPE is a terpene. Examples include iMimonene, limonene oxide, geraniol, cc-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, a-terpineol, terpinen-4-ol, linalool, carvacrol, trans-anethole, ascaridole, safrole, racemic mixtures thereof (e.g., dl-limonene), and pharmaceutically acceptable isomers thereof.
  • a second MPETM can be present (e.g. , a fatty acid ester and a terpene).
  • the composition of the present invention comprises limonene or geraniol.
  • the composition comprises 0.1% to 5% (w/w) of limonene or geraniol.
  • the composition comprises 3% (w/w) of limonene or geraniol.
  • the formulation does not include menthol or a-terpineol.
  • 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.
  • a fatty acid ester is used as an MPETM in the composition.
  • MPETM glyceryl monoesters. More preferably, the MPETM is glyceryl monolaurate.
  • a fatty acid ester or a fatty alcohol ester is used as an MPE in the composition.
  • fatty acid 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-dimefhylamino butyrate, dodecyl N,N- dimethylamino isopropionate, dodecyl 2-(N,N-dimethylamino)propionate, ethylene oxide (EO)-5-oleyl ester, ethyl acetate, ethyl acetoacetate, ethy
  • sunscreens such as Padimate-O, homosalate, cinnamate esters, octocrylene, and the like.
  • Other 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 (i.e., laurocapram or AzoneTM) and derivatives thereof, dimethylsulfoxide (DMSO) and related sulfoxides (e.g., n-decyl methylsulfoxide), salicylic acid and alkyl esters thereof (e.g., methyl salicylate), ⁇ , ⁇ -dimethyl acetamide, dimethyl formamide, 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.
  • DMSO dimethylsulfoxide
  • related sulfoxides e.g.
  • the composition additionally comprises at least one pharmaceutically acceptable surfactant.
  • the surfactant is a nonionic surfactant. More preferably, the surfactant is a polysorbate surfactant. Still more preferably, the surfactant is polysorbitan 20.
  • the composition comprises 0.5% to 15% (w/w) of a nonionic surfactant, preferably 2 to 10%.
  • 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 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 about 10.0, more preferably about pH 7.0 to about 9.5.
  • the unadjusted pH of the admixed components is between 8 and 10, such as 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 about 8.5, more preferably to between about pH 5.5 to about 7.0, such as 6.0 or 6.5. Even more preferably, the pH is adjusted to about 4.0, 4.2,
  • 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. More preferably, this amount is about 0.001 M.
  • this amount is about 0.10 M, 0.11 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.
  • 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.
  • a composition can contain 0.001-8%, preferably 0.01-6%, more preferably 0.05-5% by weight of the total composition 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, di
  • the present invention provides a pharmaceutical composition for topical administration, said composition comprising, consisting essentially of, or consisting of: 0.1% to 5% (w/w) of a selective COX-2 inhibitor; 0.5% to 5% of a lower amino alcohol; 0.5% to 5% of a cellulosic thickening agent; 0.5% to 10% urea; at least one lower alcohol; and water.
  • a selective COX-2 inhibitor is etoricoxib.
  • the present invention provides a pharmaceutical composition for topical administration, said composition comprising, consisting essentially of, or consisting of: 2% (w/w) of a selective COX-2 inhibitor; 0.5% to 3% 2-amino-2- methylpropanol; 1% to 3% of hydroxypropyl cellulose; 2% to 5% urea; 10% 2-(2- ethoxyethoxy)ethanol; a lower monohydric alcohol; and water. More preferably, the selective COX-2 inhibitor is etoricoxib.
  • the composition is selected from the group of a gel, a cream, an emulsion, a foam, a lotion, an organogel, an ointment, and a transdermal patch. More preferably, 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, or 10,000 cP at STP.
  • the dynamic viscosity is from 100 to 1000 cP, from 250 to 2000 cP, from 500 to 5000 cP, or from 500 to 20,000 cP.
  • the dynamic viscosity of the composition is at least about 10 4 , 5 x 10 4 , 10 5 , 5 x 10 5 , 10 6 , 5 x 10 6 , 10 7 or 10 8 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 addition of a cellulosic thickening agent 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.
  • the composition has a pH of above 7, of above 8, of above 9, of above 10, of above 11, or of above 12.
  • 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.
  • the pH of the composition may range from about 9 to about 12.5, about 9 to about 11.5, about 9 to about 10.5, or about 8.5 to about 10.
  • the composition is neutral.
  • 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 composition 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 composition 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., 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 composition.
  • the transdermal selective COX-2 inhibitor e.g., etoricoxib
  • 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 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.
  • the pharmaceutical composition is formulated as a cream, an emulsion, a foam, 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 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.
  • the composition is a gel.
  • the composition is a gel.
  • composition is a 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 compositions.
  • the compositions of the invention can be used at twice-a-day dosing 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
  • etoricoxib and urea were combined. The mixture was dissolved in a portion of the ethanol and water components.
  • the cellulosic thickening agent was then added with the remainder, if any, of the ethanol and water components.
  • the composition was thoroughly mixed by vortexing for about 30 min or until a clear and homogenous system formed.
  • the skin pieces Prior to use, the skin pieces were dermatoned to a thickness of 0.5 to 1 mm and were allowed to thaw, in air, to room temperature.
  • 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 the composition was applied to the donor well or directly to the skin surface, depending on the amount of the composition applied.
  • the receptor wells were maintained at 37°C (the temperature on the surface of the skin is about 30 °C) in a stirring block with continual agitation via a stir bar.
  • the flux rates were calculated by assuming a radius of 0.42 cm in the donor well (i.e., an 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 6-fold replicates for each composition. 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
  • D is the concentration of the drug in the receptor well after incubation time t
  • V is the volume of the receptor well
  • A is the surface area of skin
  • the objective for the preparation of F9 was to evaluate whether the delivery of etoricoxib would be increased in the presence of AMP together with other ingredients as MPETMs.
  • the formulation including AMP in combination with urea and HPC (F9) showed significantly enhanced delivery of etoricoxib relative to the control (F10).
  • Example 5 Etoricoxib Composition Investigation III [0131] Table 3: Etoricoxib Composition Investigation III
  • Example 8 Etoricoxib Composition Investigation VI [0140] Table 6: Etoricoxib Composition Investigation VI
  • Ctl-2 is a control
  • compositions contain AMP, cellulosic thickener, urea, and a terpene (i.e., limonene, geraniol) at different levels.
  • the amount of formulation applied to each donor cell was 25 ⁇ , except for IIIA and IIIB (50 ⁇ ).
  • Various alcohol mixtures were used as solvents.
  • Polysorbitans (especially polysorbate 20) were added at different levels as non-ionic surfactants.
  • the etoricoxib concentration was maintained at 2% for all formulations; a formulation containing 2% etoricoxib, 48% ethanol and 50% water was included as a control.
  • the etoricoxib-delivery enhancement ratios were calculated as the ratios of etoricoxib delivery from test formulations to those from the control formulation.
  • AMP The optimal concentration of AMP appears to be at 3.0% (F75, F76, and F77); excluding AMP from the formulation led to unstable formulation (E091027- 08).
  • DL-Limonene The optimal concentration of DL-limonene appears to be at 3% since the reduction of limonene levels to 0 and 1.5 % led to diminished etoricoxib delivery (F71 vs. F78, and F79).
  • Transcutol ® The absence of Transcutol ® or at a lower (5%) level impacted negatively on the physical stability of the formulation (E091027- 12 and E091027-
  • Transcutol ® may be important for stability.
  • AMP The incorporation of AMP enhanced the etoricoxib delivery (F80 vs. F86).
  • DL-Limonene The optimal DL-limonene concentration in enhancing etoricoxib delivery across intact pig skin appears to be 3%. Reducing the DL-limonene levels to 0 or 1.5% led to reduced etoricoxib delivery (F80 vs. F87 and F88).
  • Transcutol ® Transcutol ® at 10% concentration is optimal. Removing Transcutol ® from the formulation or reducing the Transcutol ® concentration to a lower level (i.e., 5%) led to reduction of the etoricoxib delivery (F80 vs. F90 and F89).
  • HY121 a second HPC gelling agent
  • HY121 a second HPC gelling agent
  • both water and HY121 concentrations were maintained as constants while varying the concentrations of other excipients.
  • Visual inspection of formulations incorporating either HY117 or HY121 as the gelling agent indicated that HY121 is a more effective gelling agent for this particular formulation and produces the desired formulation viscosity of the final formulation.
  • AMP Increasing the AMP concentration beyond the 1.5% level led to formulation instability (F95 and F96) in this study.
  • Transcutol ® Removing Transcutol ® from the formulation or reducing to a 5% level led to reduction of the etoricoxib permeation (F100 and F101).

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EA030797B1 (ru) 2012-12-21 2018-09-28 ТЕЙКОКУ ФАРМА ЮЭсЭй, ИНК. Система трансдермальной доставки гормонов (варианты) и способы ее применения
WO2016105499A1 (en) 2014-12-23 2016-06-30 Intellectual Property Associates, Llc Methods and formulations for transdermal administration
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US20050020658A1 (en) * 2002-11-21 2005-01-27 Katsuyuki Inoo Selective cyclooxygenase-2 inhibitor patch
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