WO2011149645A1 - Topical etoricoxib formulation - Google Patents
Topical etoricoxib formulation Download PDFInfo
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- WO2011149645A1 WO2011149645A1 PCT/US2011/035788 US2011035788W WO2011149645A1 WO 2011149645 A1 WO2011149645 A1 WO 2011149645A1 US 2011035788 W US2011035788 W US 2011035788W WO 2011149645 A1 WO2011149645 A1 WO 2011149645A1
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- etoricoxib
- pharmaceutical formulation
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- 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
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- 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
-
- 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
- A61K47/14—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
- 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
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- 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
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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) has required OA therapies to show superiority over placebo over a twelve-week period before approval of a new drug application.
- 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)
- 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 NSAIDs offer the possibility of achieving local therapeutic benefit while reducing or eliminating the risk of systemic side effects.
- 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.
- Pennsaid Gel TM is a topical formulation comprising diclofenac sodium that overcomes disadvantages of prior art NSAID formulations.
- U.S. Patent Publication No. 2008/0300311 Pennsaid TM 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.
- Naito demonstrates significant variability in penetration among topical NSAID formulations simply by changing the gelling agent used in the formulations (Naito et al, Percutaneous absorption of diclofenac sodium ointment, Int. Jour, of
- Ho et al also noted that (i) the pH of the vehicle, (ii) the drug solubility, and (iii) the viscosity of a gel matrix can influence penetration from a gel dosage form.
- the pH value affects the balance between ionized and non-ionized forms of the drug, which have different permeation properties (Obata, InternationalJournal of Pharmaceutics, 89: 191-198 (1993)).
- the viscosity can affect diffusion of the drug through the gel matrix and release of the drug from the vehicle into the skin.
- the solubility of the drug in the vehicle will affect the partition coefficient of the drug between the formulation and the recipient membrane or tissue (Ho, Id.).
- 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 reduce the skin barrier function
- Williams and Barry “Penetration Enhancers” Advanced Drug Delivery Reviews 56: 603-618 (2004) although it has been proposed that the mechanisms can be grouped into three broad categories: lipid disruption, increasing corneocyte permeability, and promoting partitioning of the drug into the tissue.
- the challenge with use of MPETMs is that few seem to induce a significant or
- the present invention provides inter alia pharmaceutical formulations, methods for preparation, and methods of treatment comprising a selective COX-2 inhibitor, a thickening agent, at least one lower alcohol, and water, wherein the formulation comprises about 50% to 80% (w/w) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1 (or, alternatively, 65% to 85% (w/w) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1).
- the selective COX-2 inhibitor is etoricoxib.
- the formulations enhance permeability and bioavailability of the selective COX-2 inhibitor, and preferably, they are useful for topical treatment of pain or inflammation. In a more preferred
- the method of treatment is directed to pain associated with OA.
- the present invention provides a pharmaceutical formulation for topical administration, the formulation consisting of, consisting essentially of, or comprising etoricoxib, a thickening agent, a lower alcohol, and water, wherein the formulation comprises about 50% to 80% (w/w) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1. Alternatively, the formulation comprises about 65% to 85% (w/w) of the lower alcohol and water in a ratio of about 2: 1 to 8:1.
- the formulation comprises about 0.1 % to 5% (w/w) of etoricoxib. In a more preferred aspect, the formulation comprises about 1% to 5% (w/w) of a etoricoxib. Alternatively, and still more preferably, the formulation comprises about 0.5% to 5% (w/w) of a etoricoxib. Yet still more preferably, the formulation comprises about 1% or 2%) (w/w) of etoricoxib.
- the formulation further comprises about 1% to 10% (w/w) urea.
- the formulation comprises about 2.5% to 5% (w/w) urea, about 5% to 7.5% (w/w) urea, or about 5% to 10% (w/w) urea.
- the formulation comprises about 5% (w/w) urea.
- the formulation comprises about 0.1% to 5% (w/w) of the thickening agent. In a more preferred aspect, the formulation comprises about 2% (w/w) of the thickening agent. In a preferred aspect, the thickening agent is
- the lower alcohol is ethanol
- the lower alcohol is a mixture of ethanol and isopropanol in a ratio of about 4: 1 to 12: 1; more preferably, 4.5: 1 to 12: 1; and still more preferably, about 5: 1 to 12: 1.
- the formulation comprises about 60% to 75% (w/w) lower alcohol. More preferably, the formulation comprises about 65% to 70% (w/w) lower alcohol. Even more preferably, the formulation comprises about 65% to 85% (w/w) lower alcohol.
- the formulation comprises about 55 to 85% (w/w) of a lower alcohol; more preferably, about 55% to 80% (w/w), about 55% to 75% (w/w), or about 65% to 80% (w/w); and still more preferably, 58.5% to 67.5% (w/w).
- the formulation further comprises 2-(2- ethoxyethoxy)ethanol (Transcutol ® ). More preferably, the formulation comprises about 5% to 15% (w/w) Transcutol ® . Still more preferably, the formulation comprises about 5% or about 10%) (w/w) Transcutol ® .
- the formulation is a low-viscosity gel.
- the formulation is a high-viscosity gel or a semi-solid formulation.
- the gel is a pourable gel.
- the gel is a non-pourable gel.
- the formulation further comprises an alkyl ester.
- the alkyl ester is selected from the group consisting of isopropyl myristate (IPM), diisopropyl adipate, ethyl oleate, ethyl laurate, isopropyl palmitate, diethyl sebacate, monolaurin, glycerin ricinolate and combinations thereof.
- the formulation comprises about 1 to 15% (w/w) of the alkyl ester.
- the alkyl ester is isopropyl myristate. Still more preferably, the formulation comprises about 2.5% to 15% (w/w) isopropyl myristate. Yet more preferably, the formulation comprises about 2.5% to 10%> (w/w) isopropyl myristate. Yet still more preferably, the formulation comprises about 5% (w/w) isopropyl myristate.
- the stability of the formulation is based on the ratio of the alkyl ester to water.
- the stability of the formulation is based on the ratio of isopropyl myristate (IPM) to water.
- IPM isopropyl myristate
- the IPM:water ratio is preferably less than about 1 :4.7, and more preferably, less than about 1 :3.7.
- the IPM: water ratio is preferably less than about 1 :3.1, and more preferably, about 1 :2.
- the IPM:water ratio is preferably less than about 1 :4.2 and greater than about 1 : 1.19 (i.e., between about 1 : 1.2 and 1 :4.2).
- the IPM: water ratio is preferably greater than about 1 :2.7.
- the IPM: water ratio is preferably about 1 :3.0.
- the present invention provides a gel formulation for topical administration, the formulation comprising about 1% to 5% (w/w) etoricoxib (or, alternatively and preferably, about 0.5%> to 5% (w/w) etoricoxib), about 2.5% to 10%> urea (w/w); about 2% (w/w) thickening agent; about 45% to 63% (w/w) ethanol; about 5% to 10% (w/w) isopropanol; and water.
- the gel formulation further comprises about 5% to 15% (w/w) 2-(2-ethoxyethoxy)ethanol; and more preferably, the gel formulation further comprises about 2.5% to 10% (w/w) isopropyl myristate.
- the present invention provides a method for topically treating pain in a subject, the method comprising topically applying a pharmaceutical formulation comprising about 0.1% to 5% (w/w) etoricoxib (or, preferably, about 0.5% to 5% (w/w) etoricoxib), a thickening agent, a lower alcohol, and water; wherein the formulation comprises about 65% to 85% (w/w) (or, alternatively and preferably, about 50% to 80% (w/w)) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1.
- the present invention provides a method for topical administration of a gel formulation, the method comprising topically applying a pharmaceutical formulation to a subject, wherein the formulation comprises about 0.1% to 5%) (w/w) etoricoxib (or, preferably, about 0.5%> to 5% (w/w) etoricoxib), about 2.5% to 5% urea (w/w), a thickening agent, a lower alcohol, and water.
- the method is for topically treating pain in the subject.
- the formulation comprises about 65% to 85%o (w/w) (or, alternatively and preferably, about 50%> to 80%> (w/w)) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1 (i.e., the formulation comprises about 50 to 80% (w/w) of the water-alcohol mixture).
- the method comprises topically applying a pharmaceutical formulation comprising about 1% to 5% (w/w) etoricoxib (or, alternatively and preferably, about 0.5%) to 5% (w/w) etoricoxib), about 2.5% to 5% urea (w/w), about 2% (w/w) thickening agent, about 45% to 63% (w/w) ethanol, about 5% to 10% (w/w) isopropanol; and water.
- a pharmaceutical formulation comprising about 1% to 5% (w/w) etoricoxib (or, alternatively and preferably, about 0.5%) to 5% (w/w) etoricoxib), about 2.5% to 5% urea (w/w), about 2% (w/w) thickening agent, about 45% to 63% (w/w) ethanol, about 5% to 10% (w/w) isopropanol; and water.
- the pain is associated with osteoarthritis.
- the present invention provides a use of any of the formulations described herein in the manufacture of a medicament for the 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 26 hours after application. 10 ⁇ formulations were applied to each donor cell compartment.
- FIG. 2 illustrates etoricoxib permeation through porcine skin from a second series of topical formulations (Table 2) at 4, 21, and 26 hours after application. 10 ⁇ formulations were applied to each donor cell compartment.
- FIG. 3 illustrates etoricoxib permeation through human cadaver skin from a third series of topical formulations (Table 3) at 4, 8, 12, 16, and 20 hours after application. 5 ⁇ formulations were applied to each donor cell compartment.
- FIG. 4 illustrates etoricoxib permeation through porcine skin from a fourth series of topical formulations (Table 4) at 4, 21 , and 24 hours after application. 5 ⁇ formulations were applied to each donor cell compartment.
- FIG. 5 illustrates etoricoxib permeation through human cadaver skin from a fifth series of topical formulations (Table 5) at 4, 8, 12, 16, 20, and 24 hours after application. 5 ⁇ formulations were applied to each donor cell compartment.
- FIG. 6 illustrates etoricoxib permeation through porcine skin from a sixth series of topical formulations (Table 6) at 4, 21 and 24 hours after application. 10 ⁇ formulations were applied to each donor cell compartment.
- 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. 10 ⁇ formulations were applied to each donor cell compartment.
- FIG. 8 illustrates etoricoxib permeation through porcine skin from an eighth series of topical formulations (Table 8) at 4, 21 and 24 hours after application. 10 ⁇ formulations were applied to each donor cell compartment.
- FIG. 9 illustrates etoricoxib permeation through human cadaver skin from once- daily and twice-daily administration of 1% and 2% etoricoxib formulations (Table 11) at 4, 8, 14, 24, 36, and 48 hours after application. 5 ⁇ formulations were applied to each donor cell compartment.
- FIG. 10 illustrates the effects of two cumulative days of once- or twice-daily dosing of 1% and 2% etoricoxib formulations across human cadaver skin (Table 12). 5 ⁇ formulations were applied to each donor cell compartment.
- FIG. 11 illustrates the effects of four dosing regimens, including 1% and 2% etoricoxib formulations (Table 13), across human cadaver skin. 5 ⁇ formulations were applied to each donor cell compartment.
- the terms “a,” “an,” or “the” as used herein not only includes aspects with one member, but also aspects with more than one member.
- an embodiment including “a thickening agent and a lower alcohol” should be understood to present aspects with at least a second thickening agent, at least a second lower alcohol, or both.
- the term “about” as used herein to modify a numerical value indicates a defined range around that value. If “X” were the value, “about X” would generally indicate a value from 0.95X to 1.05X.
- any reference to “about X” specifically indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.0 IX, 1.02X, 1.03X, 1.04X, and 1.05X.
- “about X” is intended to teach and provide written description support for a claim limitation of, e.g., "0.98X.”
- "about X” indicates from (X-l) to (X+l).
- "about X” as used herein specifically indicates at least the values X, X-l , and X+l .
- 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
- Cellulosic thickening agent includes a thickening agent that is 1) a natural or synthetic polymeric carbohydrate (e.g., cellulose, pharmaceutically acceptable vegetable gums); 2) a polymeric or oligomeric derivative of a polymeric carbohydrate that is produced by chemical modification (e.g., hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose); or 3) mixtures thereof.
- Representative cellulosic thickening agents include cellulose, hydroxypropyl cellulose ("HPC"), hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, carboxymethyl cellulose, and the like.
- embodiments described herein that include chiral compounds may include embodiments with the racemic form or embodiments enriched in the D- or L- enantiomer thereof (up to and including pure or essentially pure D-lactic acid or L-lactic acid).
- the phrase "effective amount” or “effective dose” means an amount sufficient to achieve the desired result and accordingly will depend on the ingredient and its desired result. Nonetheless, once the desired effect is known, determining the effective amount is within the skill of a person skilled in the art.
- ER Enhancement ratio
- a test result e.g., ug/cm 2 accumulated dose of product
- a control composition comprising the same active at the same concentration, but a different vehicle (e.g., the active ingredient in an alcohol-water mixture with no other components).
- the "error bars" on the graphs provided in the figures represent the standard error of the mean value, whereas the top of the solid, shaded, or patterned bar represents a single data value, which is the mean value of the distribution of data values.
- Finite dosing as used herein generally includes an application of a limited reservoir of an active agent.
- the active agent in the reservoir is depleted with time, leading to a tapering off of the absorption rate of the active agent after a maximum absorption rate is reached.
- "Formulation,” “pharmaceutical composition,” and “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 about 6 carbon atoms. Representative lower alcohols include methanol, ethanol, n- propanol, isopropanol (also known as isopropyl alcohol or IPA), 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, olelyl alcohol, and the like.
- 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.
- a percentage range when a percentage range is taught, it incorporates all full or partial percentages in between (i.e., within the bounds of the range). For example, a percentage range of 15 to 25% would also teach inter alia the specific values of 17.36% and 21%. A percentage range of about 13 to 17% would also teach inter alia the specific values of 12.97%, 16%, and 17.1%.
- pH refers to the apparent pH of the formulation as determined by methods standard in the art.
- pH adjusting agent refers to a compound added to the compositions of the present application for the purpose of changing the pH of the
- compositions examples include pharmaceutically acceptable acids, pharmaceutically acceptable bases, and pharmaceutically acceptable buffers.
- pharmaceutically acceptable means compatible with the treatment of animals, and in particular, humans.
- pharmaceutically acceptable salt means a
- a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable basic addition salt is achieved using standard techniques. For example, the neutral compound is treated with an acid or base in a suitable solvent and the formed salt is isolated by filtration, extraction, or any other suitable method.
- a ratio iscalculated based on the cumulative amount of active (e.g. etoricoxib) delivered through the skin over the period of the experiment (i.e., from 4 to 60 h, and preferably, over 24 h).
- active e.g. etoricoxib
- 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 pharmaceutically acceptable derivatives or salts thereof.
- etoricoxib includes pharmaceutically acceptable derivatives or salts thereof.
- subject as used herein includes all members of the animal kingdom, preferably mammals, and most preferably, humans.
- Surfactant as used herein includes a surface-active agent. Surfactants reduce the surface tension of a solvent in which they are dissolved.
- Thickening agent 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 carbomer polymers, carbomer derivatives, cellulose polymers, cellulose derivatives, polyvinyl alcohol, poloxamers, polysaccharides, and the like, as well as mixtures thereof.
- Non-limiting examples of formulations containing a thickening agent include gel and semi-solid formulations.
- Topical formulation includes the administration of a composition (e.g. , a formulation containing a pharmaceutically or cosmetically active agent) to the skin, nail, mucosa, or other localized region of the body. Topical application may result in the delivery of an active agent to the skin, a localized region of the body, a localized volume of the body, or the systemic circulation.
- a composition e.g. , a formulation containing a pharmaceutically or cosmetically active agent
- Topical application may result in the delivery of an active agent to the skin, a localized region of the body, a localized volume of the body, or the systemic circulation.
- 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.
- 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. In certain embodiments, "transdermal” may also include epicutaneous.
- Treatment includes any cure, amelioration, or prevention of a disease in a mammal, particularly a human. Treatment may prevent the disease from occurring; inhibit the disease's spread; relieve the disease's symptoms (e.g., fully or partially alleviate pain from osteoarthritis), fully or partially remove the disease's underlying cause, shorten a disease's duration, or do a combination of these things.
- Treatment may prevent the disease from occurring; inhibit the disease's spread; relieve the disease's symptoms (e.g., fully or partially alleviate pain from osteoarthritis), fully or partially remove the disease's underlying cause, shorten a disease's duration, or do a combination of these things.
- Treating” or “treatment” as used herein also broadly includes any approach for obtaining beneficial or desired results in a subject's condition, including clinical results.
- beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable.
- Treating” and “treatment” as used herein include prophylactic treatment.
- Treatment methods comprise administering to a subject a therapeutically effective amount of an active agent.
- the administering step may consist of a single administration or may comprise a series of administrations.
- the length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof.
- the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
- the compositions are administered to the subject in an amount and for a duration sufficient to treat the patient.
- 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 cocoamidopropyl betaine, cocoamphoacetate (i.e., cocoamphoglycinate), cocoamidopropyl hydroxysultaine, dodecyl betaine, phospholipids (e.g., lecithin), alkyl or acyl amphopropionates or sulfobetaines (i.e., sulfonic acid analogs to carboxylic acid betaines), and the like, as well as mixtures and poly(ethylene glycol) derivatives thereof.
- a "charged derivative of a zwitterionic surfactant” or “charged derivative thereof as used herein indicates a cationic or anionic surfactant that is a salt of a zwitterionic surfactant produced by either protonation or deprotonation (e.g., by reaction of
- cocoamphodiacetate with sodium hydride or hydroxide to produce disodium
- cocoamphodiacetate examples include sodium cocoamphoacetate, sodium
- lauroamphoacetate disodium dicocoamphodicetate, potassium cocoamphodiacetate, dipotassium cocoamphodiacetate, disodium dicocoamphodipropionate, and the like (e.g., metal salts of alkyl or acyl amphopropionates or sulfobetaines), as well as mixtures and poly(ethylene glycol) derivatives thereof.
- micro as used herein can be alternatively abbreviated as “ ⁇ ” or “u.”
- micrograms are typically abbreviated as g, but can alternatively be abbreviated as “ug.”
- w/w or "wt/wt” means a percentage expressed in terms of the weight of the ingredient or agent over the total weight of the composition multiplied by 100.
- the active agent is an anti-inflammatory agent. More preferably, the agent is a non-steroidal anti-inflammatory drug. Preferably, the agent is a coxib. More preferably, the coxib is etoricoxib. In other instances, the active ingredient is a combination or mixture of active agents, such as at least two active agents.
- Non-limiting examples of NSAIDs include acetic acid derivatives such as indomethacin, sulindac, etodolac, and diclofenac; propionic acid derivatives such as ibuprofen, naproxen, fenoprofen, ketoprofen, fluriprofen, and oxaprozin; coxibs such as celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, and etoricoxib; fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, and tolfenamic acid; enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, and isoxicam; and the compounds' pharmaceutically acceptable salts such as diclofenac sodium, naproxen sodium, and diclofenac potassium.
- acetic acid derivatives such as indom
- Acetic acid derivatives, coxibs, and their pharmaceutically acceptable salts are preferred.
- Other NSAIDs include aspirin, salicylic acid, diflunisal, etodolac, meclofenamate, nabumetone, salsalate, and their pharmaceutically acceptable salts.
- 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 formulation comprises about 0.05% to 10% (w/w) of a coxib. More preferably, the formulation comprises about 0.1 % to 5% (w/w) of a coxib, preferably etoricoxib. Still more preferably, the formulation comprises about 0.5% to 5%, 0.1% to 3%, 1% to 3%, 1% to 5%, 2% to 4%, or 2% to 5% (w/w) of a coxib, preferably etoricoxib. Yet still more preferably, the formulation comprises about 1 , 2, 3, 4, or 5% (w/w) of a coxib, preferably etoricoxib. In another preferred aspect, the pharmaceutical
- composition comprises about 0.1 % to 5% (w/w) of etoricoxib, preferably about 1% to 3% (w/w) or about 0.5 to 5% (w/w), and more preferably about 1 or 2% (w/w).
- a formulation enables delivery of a therapeutically effective amount of a selective COX-2 inhibitor.
- a formulation enables delivery of a selective COX-2 inhibitor daily dosage of about 0.01 mg to about 120 mg; more preferably, about 0.1 mg to 60 mg; still more preferably, about 1 mg to about 30 mg; and yet more preferably, about 1 to about 10 mg. Yet still more preferably, the formulation enables delivery of a daily dosage of about 3 mg.
- the selective COX-2 inhibitor concentration of the formulation 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 (e.g., both knees at about 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 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 still more preferably, less than 5%, yet provides local or regional delivery levels sufficient for therapeutic benefit or treatment.
- the concentration is such that this dosage amount can be provided by application of the composition from one to four times a day; more preferably, one to two times a day; to a skin area of up to about 2500 cm 2 and preferably about 1200 to 1800 cm 2 (e.g., both knees at about 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 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 pharmaceutical formulation comprising a selective COX- 2 inhibitor has a flux value (as determined, e.g., by the Franz cell procedure of Example 10) at least equal to the flux of 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 as great as 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 flux of 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 formulation has a selective COX-2 inhibitor flux that is at least 2.0 times as great as the flux of a comparative formulation with the same selective COX-2 inhibitor. Yet still more preferably, the formulation has a selective COX-2 inhibitor flux that is at least 4.0 times as great as the flux of a comparative formulation with the same selective COX-2 inhibitor.
- the present invention provides a formulation comprising etoricoxib, wherein the formulation provides an etoricoxib flux 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 pharmaceutical formulation comprising etoricoxib provides greater flux (as determined, e.g., by the Franz cell procedure of Example 10) than an analogous comparative formulation comprising a selective COX-2 inhibitor.
- this comparative formulation comprises etoricoxib. More preferably, the flux of etoricoxib is at least 1.5 times as great as the flux of the comparative hydroalcoholic formulation's active agent.
- the ratio of: (i) the formulation'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 formulation has an etoricoxib flux that is at least 2.0 times as great as the comparative formulation's coxib flux. Yet still more preferably, the formulation has an etoricoxib flux that is at least 4.0 times as great as the comparative formulation's coxib flux.
- the composition comprising etoricoxib has an enhancement ratio (ER) of at least 2. Yet still more preferably, the composition comprising etoricoxib has an ER of at least 5.0. Yet still more preferably, the composition comprising etoricoxib has an ER that is at least 10.0.
- ER enhancement ratio
- the formulation further comprises about 0.1% to 25% (w/w) urea.
- the formulation comprises about 1% to 10%> (w/w) urea.
- the formulation comprises about 2% to 5%, about 2.5% to 5%, about 3% to 6%, about 5% to 7.5%, about 5% to 10%, or about 7.5% to 10% (w/w) urea.
- the formulation comprises about 1, 2, 3, 4, 5, 6, 7, or 8% (w/w) urea; more preferably, about 5% (w/w) urea.
- the formulations herein comprise at least one thickening agent, such as a cellulose polymer, a carbomer, a polyvinyl pyrrolidone, a polyvinyl alcohol, a poloxamer, a xanthan gum, a locus bean gum, a guar gum and mixtures thereof.
- the formulation includes a cellulosic thickening agent.
- Suitable cellulosic thickening agents include, but are not limited to, hydroxypropyl cellulose (HPC) of various grades,
- the cellulosic thickening agent is HPC.
- the formulation comprises about 0.5% to 5% (w/w) of the thickening agent, such as about 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 2, 3, 4, or 5% (w/w).
- the formulation comprises from about 0.5% to 1% (w/w) of a thickening agent or about 0.5 to 2% (w/w) of a thickening agent. Still more preferably, the formulation comprises about 2% (w/w) of a thickening agent. Alternatively, the formulation comprises about 1%) (w/w) of a thickening agent.
- the formulation has a viscosity of at least 100 centipoise (cP).
- the formulation has a viscosity of at least 500 cP. More preferably, the formulation has a viscosity of at least 1000 cP. Still more preferably, the viscosity is 5000- 10,000, 10,000-15,000, 15,000-25,000 or 25,000-50,000 cP. Alternatively, the viscosity is more than 50,000 cP or more than 100,000 cP.
- the formulations include a lower alcohol. More preferably, the lower alcohol is a monohydric lower alcohol, and still more preferably, the lower alcohol is selected from a C l to C g alkanol, such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, pentanol, and the like, as well as a mixture thereof. Ethanol is preferred. A combination of ethanol and isopropanol is especially preferred.
- the formulation includes about 50%> to 80%> (w/w) of the lower alcohol (preferably, ethanol or a mixture of ethanol and isopropanol).
- the formulations include about 50, 53, 55, 56, 57, 58, 58.5, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 67.5, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, or 79% (w/w) of a lower alcohol. More preferably, the formulation comprises from about 55% to 75% (w/w) of a lower alcohol.
- the formulation comprises from about 60 to 75%, about 63 to 75%, about 65 to 75%), about 65 to 70%, about 68 to 75%, or about 70 to 75% (w/w) of a lower alcohol.
- the formulation comprises from about 50% to 75% (w/w), about 55% to 70%, about 57% to 75%, about 58.5% to 70%, 58.5% to 67.5%, about 60 to 70%, about 65% to 85%, or about 70 to 85% (w/w) of a lower alcohol.
- the formulation comprises about 56.5, 57, 57.5, 58, 58.5, 59, 59.5, 60, 60.5, 61 , 61.5, 62, 62.5, 63, 64.5, 65, 65.5, 66, 66.5, 67, 67.5, 68, 68.5, 69, 69.5, 70, 70.5, or 71% (w/w) of a lower alcohol such as ethanol or a mixture of ethanol and isopropanol.
- a lower alcohol such as ethanol or a mixture of ethanol and isopropanol.
- the lower alcohol is a mixture of ethanol and isopropanol in a ratio of about 4.5 : 1 to 12: 1 , and preferably, about 5 : 1 to 12: 1 , or even about 4: 1 to about 12: 1 or 4: 1 to 12: 1.
- the formulations can include a diol.
- Suitable diols include, but are not limited to, propylene glycol, butanediol, butynediol, pentanediol, hexanediol, octanediol, neopentyl glycol, 2-methyl-l,3-propanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol, dibutylene glycol, propylene glycol, and the like, as well as a mixture thereof.
- the formulation comprises about 0% to 15% (w/w) of propylene glycol, and preferably, about 0 to 5% (w/w).
- the diol is a glycol, such as ethylene glycol, propylene glycol, and a mixture thereof.
- the formulations include water.
- water is present from about 5% to 35% (w/w) such as about 5, 6, 7, 8, 9, 10, 11, 12, 12.5, 13, 14, 15, 16, 16.6, 17, 17.5, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 33, or 35% by weight (w/w).
- the formulation includes from about 5 to 10%>, about 10 to 20%>, about 10 to 15%, about 15 to 20%, about 20 to 25%, about 25 to 30%, about 30 to 35% (w/w), or about 10 to 35%) (w/w) water.
- the mixture includes about 8, 10, 12, 12.5, 13, 16, 16.6, 17, 18, 19, or 20%> (w/w) water.
- the ratio of lower alcohol and water is about 2 : 1 to 8 : 1.
- the formulation further comprises at least one alkyl ester.
- the alkyl ester is a penetration enhancer. More preferably, the alkyl ester is selected from the group consisting of isopropyl myristate, diisopropyl adipate, ethyl oleate, ethyl laurate, isopropyl palmitate, diethyl sebacate, monolaurin, glycerin ricinolate and combinations thereof. Still more preferably, the formulation comprises from about 1% to about 15%) (w/w) alkyl ester.
- the alkyl ester is isopropyl myristate.
- the formulation comprises about 1% to 15% (w/w) isopropyl myristate, such as about 1, 2, 2.5, 3, 4, 5, 6, 7, 7.5, 8, 9, 10, 11, 12, 13, 14, or 15% (w/w).
- the formulation comprises about 2.5% to 10%, about 5% to 10%, about 5% to 15%, or about 10% to 15% (w/w) isopropyl myristate.
- the formulation comprises about 5, 7.5, or 10% (w/w) isopropyl myristate.
- the formulation may comprise at least one pharmaceutically acceptable surfactant.
- the surfactant may be a nonionic, cationic, anionic, or zwitterionic surfactant or a charged derivative thereof.
- the surfactant or derivative may be present at about 1% to 10% (w/w), such as about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10%> (w/w).
- the formulation is free or substantially free of surfactants, such as polysorbates, zwitterionic surfactants; or molecular penetration enhancers like limonene, lower amino alcohols, hydroxy acids or non-hydroxy acids.
- surfactants such as polysorbates, zwitterionic surfactants; or molecular penetration enhancers like limonene, lower amino alcohols, hydroxy acids or non-hydroxy acids.
- minimizing components such as surfactants and penetration enhancers in topical formulations can decrease the chance of skin irritation and other side-effects. This is especially relevant when treating diseases such as osteoarthritis, where long term treatment is required.
- the formulations of the present invention have the added advantage of enhanced penetration of active agents in the absence of additional components, thereby improving patient tolerance of topical formulations.
- certain embodiments of the present invention's topical formulations have good stability and provide properties of higher flux and greater in vivo absorption. 1.
- composition comprises or may comprise at least one
- nonionic surfactants include polysorbates, such as polysorbate 20 (Tween 20), Tween 40, Tween 60, and Tween 80; poly(oxyethylene) (POE) fatty acid esters, such as Myrj 45, Myrj 49, Myrj 52 and Myrj 59; poly(oxyethylene) alkyl ethers, such as poly(oxyethylene) cetyl ether, poly(oxyethylene) palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, Brij 38, Brij 52, Brij 56 and Brij Wl; sucrose esters; partial esters of sorbitol and its anhydrides, such as sorbitan monolaurate; mono or diglycerides and isoceteth-20.
- 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
- non-ionic surfactants include, but are not limited to, fatty acid diesters, polyethylene glycol glycerol fatty acid esters, alcohol-oil transesterification products, polyglycerized fatty acids, sterol and sterol derivatives, polyethylene glycol alkyl ethers, sugar esters, polyethylene glycol alkyl phenols, polyoxyethylene- polyoxypropylene block copolymers, sorbitan fatty acid esters and lower alcohol fatty acid esters.
- the composition comprises or may comprise at least one pharmaceutically acceptable cationic surfactant.
- cationic surfactants include octyl trimethylammonium salts, cetyl trimethyl ammonium salts, stearyl trimethyl ammonium salts, benzyl trimethyl ammonium salts, alkylamines, alkylimidazoles, ethoxylated amines, non-amphoteric quaternary surfactants, esterquats, and mixtures thereof.
- Quaternary surfactants contain at least one nitrogen atom, which is covalently bonded to four alkyl or aryl groups.
- Cationic surfactants include, but are not limited to, non-amphoteric quaternary ammonium compounds, in particular benzyltrialkyl ammonium chlorides or bromides, e.g., benzyl dimethylstearyl ammonium chloride; alkyl trialkyl ammonium salts, e.g., cetyl trimethyl ammonium chloride or bromide, alkyl dimethylhydroxy ethyl ammonium chloride or bromide, dialkyl dimethyl ammonium chloride or bromide, and alkylamide ethyltrimethyl ammonium ether sulfates; alkylpyridinium salts, e.g., lauryl or cetyl pyrimidinium chloride; N,N'-dialkylimidazoline derivatives; compounds having cationic character, such as amine oxides, e.g., alkyl dimethylamine oxides or alkylaminoethyl dimethylamine oxides
- the formulations comprises or may comprise an anionic surfactant, such as an alkyl sulfate, e.g., sodium, ammonium, or triethylammonium (TEA) lauryl sulfate.
- an anionic surfactant such as an alkyl sulfate, e.g., sodium, ammonium, or triethylammonium (TEA) lauryl sulfate.
- acylamino acids include acyl glutamates, e.g., sodium acyl glutamate, di-TEA palmitoyl aspartate, and sodium caprylic/capric glutamate; acyl peptides, e.g., palmitoyl-hydrolyzed milk protein, sodium cocoyl-hydrolyzed soya protein and sodium/potassium cocoyl-hydrolyzed collagen;
- sarcosinates e.g., myristoyl sarcosin, TEA-lauroyl sarcosinate, sodium lauroyl sarcosinate and sodium cocoyl sarcosinate
- taurates e.g., sodium lauroyl taurate and sodium
- methylcocoyl taurate acyl lactylates, lauroyl lactylate, caproyl lactylate; and alaninates; and the like.
- anionic surfactants include carboxylic acids and derivatives, such as carboxylic acids, e.g. , lauric acid, aluminum stearate, magnesium alkanolate, and zinc undecylenate; ester carboxylic acids, e.g., calcium and sodium stearoyl lactylates, laureth-6 citrate, and sodium PEG-4 lauramide carboxylate; ether carboxylic acids, e.g., sodium laureth-13 carboxylate, and sodium PEG-6 cocoamide carboxylate; and the like.
- carboxylic acids e.g. , lauric acid, aluminum stearate, magnesium alkanolate, and zinc undecylenate
- ester carboxylic acids e.g., calcium and sodium stearoyl lactylates, laureth-6 citrate, and sodium PEG-4 lauramide carboxylate
- ether carboxylic acids e.g., sodium laureth-13 carboxylate, and sodium PEG-6 cocoamide carboxylate
- anionic surfactants include esters of phosphoric acid and salts, e.g., dilaureth- 4 phosphate.
- Other anionic surfactants include sulfonic acids and salts, such as acyl isethionate, e.g., sodium ammonium cocoyl isethionate; alkylaryl sulfonates; alkyl sulfonates, e.g., sodium coco monoglyceride sulfate, sodium C 12 _ 14 olefin-sulfonate, sodium lauryl sulfoacetate and magnesium PEG-3 cocamide sulfate; sulfosuccinates, e.g., dioctyl sodium sulfosuccinate, disodium laureth sulfosuccinate, disodium lauryl sulfosuccinate, disodium undecylenamido-MEA-sulfosuccin
- the formulation comprises or may comprise a zwitterionic surfactant or a charged derivative thereof.
- the zwitterionic surfactant or charged derivative thereof is selected from the group of disodium cocoamphodiacetate, sodium cocoamphodiacetate, cocoamidopropyl betaine, and a mixture thereof.
- zwitterionic surfactants or charged derivatives thereof include, but are not limited to, amino acids such as ⁇ -N-alkylaminopropionic acids, aminopropyl alkylglutamide, alkylaminopropionic acid, sodium alkylimidodipropionate, dihydroxyethyl alkyl glycinate, and lauroamphocarboxyglycinate; imino acids such as N-alkyl- -iminodipropionic acids; imidazoline derivatives that are not N,N'-dialkylated; quaternary ammonium amino acid sulfobetaines such as alkyl amidopropyl hydroxysultaines, cocoamidopropyl hydroxysultaine, sodium cocoamphohydroxypropyl sulfonate, or sodium capryloamphohydroxypropyl sulfonate; quaternary ammonium amino acid betaines, e.g., dodecyl
- amidopropyl betaines such as cocoamidopropyl betaine; alkyl dimethyl betaines;
- phospholipids such as lecithin; acyl dialkyl ethylenediamines, e.g., sodium acyl
- Emollients can optionally be added to the formulations of the invention so that the formulations can maintain or increase the moisture content of the stratum corneum when the formulation is applied (e.g., to the skin of the knee). Emollients may be added to the formulations in addition to the components already described, which may also aid in maintaining or improving the skin condition of the user.
- the use of emollients in a foamable formulation is discussed in U.S. Patent No. 7,651,990, incorporated herein by reference in its entirety for all purposes.
- added emollients are included in the formulations of the invention at a concentration between about 0.1 and 30% (w/w).
- the added emollient can be present in the formulation at a concentration between about 0.5% and 10% (w/w).
- the emollient concentration can be between about 1% and 5% (w/w).
- Emollients are generally separated into two broad classes based on their function.
- the first class of emollients functions by forming an occlusive barrier to prevent water evaporation from the stratum corneum.
- the second class of emollients penetrate into the stratum corneum and physically bind water to prevent evaporation.
- the first class of emollients is subdivided into compounds which are waxes at room temperature and compounds which are liquid oils.
- the second class of emollients includes those which are water soluble and are often referred to as humectants.
- Suitable emollients may be selected from any of the classes known in the art.
- a general list of useful emollients appears, for example, in U.S. Pat. No. 4,478,853 and in EPO patent application 0 522 624A1 as well as in the CTFA Cosmetic Ingredient Handbook published by The Cosmetic, Toiletry, and Fragrance Association, Wash. D.C. (1992) under the listings "Skin Conditioning agents,” “emollients,” “humectants,” “miscellaneous” and “occlusive” (incorporated herein by reference in its entirety for all purposes).
- emollients may be chosen from the following non-limiting list of general emollients, occlusive emollients, and humectants.
- general emollients include short-chain alkyl or aryl esters (C 1 -C 6 ) of long-chain straight- or branched-chain alkyl or alkenyl alcohols or acids (C 8 -C 32 ) and their polyethoxylated derivatives; short-chain alkyl or aryl esters (C 1 -C 6 ) of C 4 -C 12 diacids or diols optionally substituted with one or more hydroxyl groups; alkyl or aryl C 1 -C w esters of glycerol, pentaerythritol, ethylene glycol, propylene glycol, as well as polyethoxylated derivatives of these with polyethylene glycol; C 12 -C 22 alkyl esters or ethers
- Non-limiting examples of occlusive emollients include cyclic and linear
- dimethicones polydialkylsiloxanes; polyarylalkylsiloxanes; long chain (C 8 -C 3g ) alkyl and alkenyl esters of long straight- or branched-chain alkyl or alkenyl alcohols or acids; long chain (C 8 -C 3g ) alkyl and alkenyl amides of long straight- or branched-chain (C 8 -C 3g ) alkyl or alkenyl amines or acids; hydrocarbons including straight and branched chain alkanes and alkenes such as squalene, squalane and mineral oil; jojoba oil; polysiloxane polyalkylene copolymers; short-chain alkyl or aryl esters (C 1 -C 3g ) of C 12 -C 22 diacids or diols optionally substituted with one or more hydroxyl groups such as diisopropyl dimer dilinoleate; and
- Non-limiting examples of humectant-type emollients include glycerol,
- polyglycerols e.g., diglycerol, triglycerol, polyglycerin-3, tetraglycerol, hexaglycerol, decaglycerols
- propylene glycol dipropylene glycol, polypropylene glycol, polyethylene glycol (PEG-2 to PEG-45M, preferably a molecular weight between about 300 and 1 ,000)
- sorbitol polyhydric alcohol ethoxylates (e.g., sorbeth-6, sorbeth-30, glycereth-1 to glycereth- 31), methoxy ethers of polyethylene glycol (methoxy-PEG-2 to methoxy-PEG-100) methoxy ethers of polyhydric alcohol ethoxylates (e.g., glycereth-7 methoxide), pantothenol, gluconic acid salts and the like.
- polyhydric alcohol ethoxylates
- humectant-type agents like that could also be employed include: 1 ,2,6- hexanetriol, acetamide mea, aluminum hydroxide, arginine pea, butoxypropanol, butylene glycol, dimethyl imidazolidinone, dimethylsilanol hyaluronate, dipotassium glycyrrhizate, erythritol, ethoxy-diglycol, fructose, glucamine, gluconic acid, glucose, glucose glutamate, glucuronic acid, glutamic acid, glycogen, glycyrrhizic acid, heilmoor clay, hexacosyl glycol, histidine, hyaluronic acid, hydrogenated honey, hydrogenated starch, hydrolysate, hydrolyzed collagen, hydrolyzed elastin, hydrolyzed glycosaminoglycans, hydrolyzed keratin, hydrolyzed silk,
- emollients may affect the viscosity and stability of the formulations of the present invention.
- a single emollient may be added to the formulation.
- two or more emollients may be added to the formulation. While any of a variety of emollients may be added to the formulations of the present invention, some embodiments will include wax and oil type emollients either alone or combined with water-soluble emollients.
- emollient systems can be comprised of humectants in addition to occlusive wax and oil emollients in concentrations that achieve a moisturizing effect and which maintains and improves the condition of the skin upon repeated use.
- Emollients may be non-comedogenic and chosen to avoid skin irritation or sensitization reactions.
- the formulation 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, or tocophereth-80.
- 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
- the formulation is basic. In certain aspects, the formulation has a pH of above about 7, 8, 9, 10, 11, or 12. In certain other aspects, the pH of the formulation may range from about 7 to 12.5, about 7 to 11.5, about 7 to 10.5, about 7 to 9.5, or about 7 to 8.5. In still other aspects, the pH of the formulation may range from about 9 to 12.5, about 9 to 11.5, about 9 to 10.5, or about 8.5 to 10.
- the formulation may include a buffering or pH-adjusting agent to maintain its basic pH. Preferably, the formulation has a pH value between about 7 and 10 and fractional values between 7 and 10. [0138] In still yet another aspect, the formulation is neutral. In certain aspects, the formulation has a pH of about 7.
- the formulation has a pH from about 6 to about 8.5, from about 5.5 to 8, about 6 to 8, about 6.5 to 8.5, or from about 6.5 to 7.5.
- the formulation may include a buffering or pH-adjusting agent to maintain its neutral pH.
- the formulation has a pH value between about 6 and 8.5 and fractional values between 6 and 8.5.
- the formulation is a cream, lotion, gel, or foam.
- the formulation is a high-viscosity gel.
- the formulation is a low-viscosity gel.
- the gel is a pourable gel.
- the gel is a non-pourable gel.
- the composition is more viscous than water at standard temperature and pressure (STP).
- 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 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 stability of the formulation is based on the ratio of the alkyl ester to water. More preferably, the stability of the formulation is based on the ratio of isopropyl myristate (IPM) to water.
- IPM isopropyl myristate
- the IPM:water ratio is preferably less than about 1 :4.7, and more preferably, less than about 1 :3.7.
- the IPM : water ratio is preferably less than about 1 :3.1, and more preferably, about 1 :2.
- the IPM:water ratio is preferably less than about 1 :4.2 and greater than about 1 : 1.19. In a more preferred aspect, when the urea:IPM ratio is 2: 1 in the absence of Transcutol ® , the IPM: water ratio is preferably greater than about 1 :2.7. In an even more preferred aspect, when the ureaTPM ratio is 1 : 1 in presence of Transcutol ® , the IPM:water ratio is preferably about 1 :3.0.
- 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 via the blood through the body. 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 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.
- compositions of the 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.
- the invention describes a method for treating pain comprising the step of applying a topical formulation to a subject to treat the pain.
- the pain is caused by osteoarthritis.
- the topical formation is a gel or semi-solid formulation.
- the invention provides a gel formulation for topical
- the formulation comprising a selective COX-2 inhibitor, a thickening agent, at least one lower alcohol, and water, wherein the formulation comprises about 50% to 80% (w/w) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1. Alternatively, the formulation comprises about 65% to 85% (w/w) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1.
- the present invention presents a method for topically treating pain in a subject, the method comprising topically applying a pharmaceutical formulation comprising a selective COX-2 inhibitor, a thickening agent, at least one lower alcohol, and water, wherein the formulation comprises about 50% to 80% (w/w) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1. Alternatively, the formulation comprises about 65% to 85% (w/w) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1.
- the method comprises topically applying a pharmaceutical formulation comprising a selective COX-2 inhibitor, a thickening agent, at least one lower alcohol, and water, wherein the formulation comprises about 50%> to 80%> (w/w) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1. Alternatively, the formulation comprises about 65% to 85% (w/w) of the lower alcohol and water in a ratio of about 2: 1 to 8: 1.
- the pharmaceutical formulation is applied to the skin of the subject. In another aspect, the pharmaceutical formulation is applied to a joint of the subject.
- the pharmaceutical formulation is applied to the skin covering the joint or near to the joint.
- the active agent is delivered locally to the joint with minimal systemic absorption. In yet another aspect, the active agent is delivered to the tissue surrounding the joint with minimal systemic absorption. [0157] In still other aspects, the subject is a human. Alternatively, the subject is a non- human mammal. [0158] In yet still other aspects, the treatment is continued for at least 12 weeks. More preferably, the treatment is continued for at least six months.
- compositions of the invention may be useful to alleviate acute pain, chronic pain, or both.
- Compositions of the invention are particularly suited for use in treating OA chronically. They may also be useful for the treatment of other chronic joint diseases characterized by joint pain, degeneration of articular cartilage, impaired movement, and stiffness. Suitable joints include the knee, elbow, hand, wrist and hip.
- the compositions of the invention may also be useful for the treatment of other pain-associated disorders, including (but not limited to) muscle pain, lower back pain, neck pain, rheumatoid arthritis, fibromyalgia, myofascial pain, gout, sprains, strains, contusions, and neuropathic pain conditions.
- the treatment may be administered once a day.
- the treatment may be administered twice a day.
- the treatment may be administered three times a day.
- the treatment may be administered four times a day. More preferably, the treatment is administered one to two times a day.
- Formulations of the present invention may, if desired, be presented in a bottle, jar, or other container-closure system approved by the Food and Drug Administration or other regulatory body, which may provide one or more dosages containing the active ingredient.
- the package or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, the notice indicating approval by the agency.
- the present invention includes a kit containing, consisting essentially of, or comprising a coxib formulation as taught herein, a container closure system comprising the formulation, and a notice describing a method of use for the formulation.
- Formulations of the present invention are useful and effective when applied topically to treat a pain.
- the amount of the active agent present in the formulation will be the amount that is therapeutically effective, i.e., an amount that will result in the effective treatment of the pain (preferably, a pain from osteoarthritis) when applied.
- the formulation may be applied directly to the skin or applied in an absorbent pad.
- the therapeutically effective amount will vary depending on the subject and the severity of the affliction and can be determined routinely by one of ordinary skill in the art.
- the formulation is a liquid or semisolid, such as a cream, ointment, lotion, lacquer, or gel (preferably, a gel) having a solvent in which the active agent or its pharmaceutically acceptable salt is dissolved.
- the formulation can be any of the inventive formulations disclosed in the claims or specification of this application. VI. EXAMPLES
- each homogeneous formulation was applied to each donor cell compartment.
- Formulations applied to each donor cell compartment were those described as physically stable (Y) or physically unstable (N). Comparisons were mainly performed using human cadaver skin, but in some cases, porcine skin was used (i.e., Figures 1, 2, 4, and 6-8).
- the compositions were prepared by first weighing etoricoxib and urea into a container and mixing the ingredients for ⁇ 2-3 min. Then, a portion of the ethanol and water was added to the mixture. Next, the following ingredients, if included, were added: isopropyl myristate, isopropanol and Transcutol ® . The mixture was then topped up with the remaining ethanol and water. While vortexing, the cellulose thickener (e.g., HY121 or HY117) was slowly added to the mixture, followed by vortexing for ⁇ 30 min or until a clear and homogenous system formed.
- the cellulose thickener e.g., HY121 or HY117
- urea and Transcutol ® were important for maintaining physical stability (Table 1).
- Trials were performed on porcine skin ( Figure 1) using the general procedure described in Example 10 with a finite dosing regimen of 10 ⁇ /cell. Concentrations of urea at 5% provided best physical stability for the formulation (e.g. Fl vs. F2, F3, F4). The proportion of isopropanol to ethanol was also important for physical stability. For this series, the best physical stability and permeation were observed when the amount of ethanol and isopropanol was 67.5% (e.g., F10 vs. Fl 1).
- Isopropyl myristate seemed to increase permeation.
- best results were observed from formulations containing at least 67.5% lower alcohol and from an ethanol/isopropanol ratio higher than 5: 1 but less than 12:1.
- the formulation with 1% active agent had the highest permeation ( Figure 5). In one aspect of the invention, these formulations are preferred.
- IPM isopropyl myristate
- Figure 6 isopropyl myristate
- ester/hydro xyester combinations achieved the same or reduced permeation compared to IPM ( Figure7).
- diesters e.g., diisopropyl adipate, diethyl sebacate
- IPM Figure 8
- Table 9 sets forth a preferred aspect of the formulation (F91). [0189] Table 9. Composition of a Preferred Aspect of the Formulation
- the flanges of the Franz cells 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). After Franz cells were assembled, the skin was allowed to pre-hydrate for 45 minutes with PBS. The PBS was then removed and an appropriate amount of formulation was added to the skin. Dosing level was 5-10 ⁇ per cell (-9-18 ⁇ /cm 2 ) except as otherwise indicated herein.
- Receptor wells of the Franz cells were maintained at 37°C (temperature on the surface of the skin is about 32°C) in a stirring dry block with continual agitation via a stir bar. Samples were drawn from the receptor wells at varying time points. Measurements were made in five- or six-fold replicates. The concentration of etoricoxib in the samples was analyzed using high-performance liquid chromatography.
- Example 11 The Effect of Increasing Etoricoxib Concentration on Delivery [0192] A prototype formulation chassis containing a specific penetration enhancer combination of isopropyl myristate, urea and Transcutol ® was used in this study to explore the optimal dosing regimen for etoricoxib.
- ETO etoricoxib
- Table 11 Effects of Once- and Twice-Daily Dosing (Time 0 and 8 h) Frequencies for 1% and 2% Etoricoxib Formulations' Transdermal Delivery Across Intact Human Skin
- ETO etoricoxib
- Enhancement ratio over control [0202] Based on the cumulative etoricoxib delivery during the first 24 hours of the study (Table 12, Figure 10), twice-daily application of 1% etoricoxib formulation was effective in increasing the amount of etoricoxib delivered across skin over the once-daily dosing regimen. However, there was no difference in the etoricoxib delivery between once-daily to twice- daily application of the 2% formulation. [0203] Based on the cumulative etoricoxib delivered during the first 24 hours and the entire 48-hour study (Table 12, Figure 10), 1% formulation applied twice daily was the most effective dosing regimen in delivering etoricoxib transdermally.
- the residual etoricoxib in the skin from Day 1 dosing contributes to the continuous etoricoxib delivery following consecutive dosing over multiple days.
- etoricoxib deliveries from four different dosing regimens two treatment regimens each for the 1% and 2% formulations were evaluated.
- the four dosing regimens were the following:
- compositions of formulations used in the study are listed in Table 13.
- the cumulative etoricoxib delivered across intact human skin at the end of the 24 hours and 48 hours studies are summarized in Table 14 ( Figure 11).
- the etoricoxib delivered during the second 24 hours of the study was calculated manually by subtracting the amount delivered during the first 24 hours from cumulative amount over the entire 48 hours.
- Table 14 Amount of Etoricoxib (ETO) Delivered Across Intact Human Skin over 24-hour and 48-hour Periods: A Mechanistic Study of a Sample
- Example 15 Stability of Etoricoxib Formulations [0213] Table 17A: Urea:Transcutol ® :IPM:Water Ratio Effect (F1-F14) Urea:Transcutol ® :IPM:Water Ratio Stability IPM:Water
- the IPM:water ratio preferably is less than 1 :4.7, and more preferably 1 :3.7 and below (Table 17A).
- the IPM:water ratio preferably is less than 1 :3.7, and more preferably, less than 1 :2.7.
- the IPM:water ratio is preferably greater than 1 :2.7.
- the IPM:water ratio is preferably less than 1 :4.2.
- the IPM:water ratio is preferably less than 1 :4.7, and more preferably 1 :3.7 and below.
- the IPM : water ratio is preferably less than 1 :3.1, and more preferably 1 :2.7.
- the ureaTPM ratio is 1 :2 in the absence of Transcutol ® , the
- IPM: water ratio is preferably less than 1 :4.2 and greater than 1 : 1.19.
- the IPM: water ratio is preferably greater than 1 :2.7.
- the IPM:water ratio is preferably less than 1 :4.7, and more preferably 1 :3.7 and below.
- the IPM : water ratio is preferably less than 1 :3.1, and more preferably 1 :2.
- the IPM:water ratio is preferably less than 1 :4.2 and greater than 1 : 1.19.
- the IPM:water ratio is preferably greater than 1 :2.7.
- a desirable ratio of ureaTPM is 1 : 1 in presence of Transcutol ®
- a preferable IPM:water ratio is 1 :3.0
- the IPM: water ratio is preferably 1 :3.
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Cited By (5)
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WO2014020366A1 (en) * | 2012-07-31 | 2014-02-06 | Egis Pharmaceuticals Public Limited Company | Transdermal formulation containing cox inhibitors |
US9144553B2 (en) | 2012-12-21 | 2015-09-29 | Teikoku Pharma Usa, Inc. | Compositions and methods for transdermal delivery of hormones and other medicinal agents |
JP2016515609A (ja) * | 2013-04-02 | 2016-05-30 | テミス メディケア リミティド | ジエチレングリコールモノエチルエーテル又は他のアルキル誘導体を含む医薬活性成分の組成物 |
CN111419815A (zh) * | 2020-04-23 | 2020-07-17 | 永信药品工业(昆山)股份有限公司 | 依托考昔片及其优化方法 |
CN112870156A (zh) * | 2021-03-25 | 2021-06-01 | 深圳前海九华国际投资控股有限公司 | 依托考昔散原位凝胶及其制备方法 |
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WO2014020366A1 (en) * | 2012-07-31 | 2014-02-06 | Egis Pharmaceuticals Public Limited Company | Transdermal formulation containing cox inhibitors |
EA033950B1 (ru) * | 2012-07-31 | 2019-12-12 | Эгиш Дьёдьсердьяр Зрт. | Трансдермальный препарат, содержащий ингибиторы cox |
AU2018202875B2 (en) * | 2012-07-31 | 2019-12-12 | Egis Gyógyszergyár Zrt. | Transdermal formulation containing COX inhibitors |
US9144553B2 (en) | 2012-12-21 | 2015-09-29 | Teikoku Pharma Usa, Inc. | Compositions and methods for transdermal delivery of hormones and other medicinal agents |
US9579296B2 (en) | 2012-12-21 | 2017-02-28 | Teikoku Pharma Usa, Inc. | Compositions and methods for transdermal delivery of hormones and other medicinal agents |
JP2016515609A (ja) * | 2013-04-02 | 2016-05-30 | テミス メディケア リミティド | ジエチレングリコールモノエチルエーテル又は他のアルキル誘導体を含む医薬活性成分の組成物 |
KR101875263B1 (ko) * | 2013-04-02 | 2018-07-05 | 테미스 메디케어 리미티드 | 디에틸렌 글리콜 모노에틸에테르 또는 다른 알킬 유도체를 포함하는 약학적 활성제의 조성물 |
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