Classifications

• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • 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
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • 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
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • 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]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to topical compositions, particularly topical compositions, which are used for applying pharmaceutical agents to the skin.
• the invention also relates to compositions for treating pain resulting from local stimulation of nociceptors in skin, bones, joints, and muscles and in skin disorders wherein inflammation is a component of the pathogenesis.
• An example of such an inflammatory skin disorder that relates to the present invention is pseudofolliculitis barbae.
• inflammatory skin conditions involve an inflammatory process. Often, such disorders involve inflammatory cells (e.g., polymorphonuclear neutrophils and lymphocytes) infiltrating the skin with no overt or known infectious etiology. Symptoms of inflammatory skin conditions generally include erythema (redness), edema (swelling), pain, pruritus, increased surface temperature and loss of function.
• inflammatory cells e.g., polymorphonuclear neutrophils and lymphocytes
• Symptoms of inflammatory skin conditions generally include erythema (redness), edema (swelling), pain, pruritus, increased surface temperature and loss of function.
• Treatments for different inflammatory skin conditions typically include topical or oral steroids (e.g., for various types of eczema, acne, and erythema multiforme); ultraviolet light (e.g., for nummular eczema and mycosis fungoides); antibiotics, and other antiinflammatory therapies.
• Topical or oral steroids e.g., for various types of eczema, acne, and erythema multiforme
• ultraviolet light e.g., for nummular eczema and mycosis fungoides
• antibiotics e.g., for nummular eczema and mycosis fungoides
• Corticosteroids have the greatest importance for the treatment of inflammatory skin disorders. Weak to medium strong corticosteroids (e.g., nonfluorinated derivatives of hydrocortisone) are mainly employed for the therapy of inflammatory, allergic and pruritic skin disorders.
• NSAIDs consists of propionic acid derivatives (the so-called "profens,” e.g., ibuprofen), and another group of NSAIDs consists of acetic acid derivatives (e.g., indomethacin).
• NSAIDs can cause gastric ulcers and bleeding on long-term oral use.
• a goal of topical administration of NSAIDs is to deliver therapeutically effective levels of drug to the local target (e.g., nociceptors and inflammatory cells in the skin) while bypassing the stomach and preventing systemic delivery.
• the local target e.g., nociceptors and inflammatory cells in the skin
• NSAIDs are often not well absorbed when administered topically. Those topical formulations that do provide some absorption through the skin can result in substantial systemic delivery and often fail to provide therapeutic levels in the skin.
• methyl salicylate which is often applied to the skin in the form of an ointment or cream and which elicits a soothing, mildly analgesic effect.
• methyl salicylate suffers from the disadvantage that it possesses an odor, which under certain circumstances, and to certain individuals, can be regarded as unpleasant.
• U.S. Patent 4,185,100 entitled, “Topical Anti-Inflammatory Drag Therapy” describes a method of topical treatment of an inflammatory condition of the skin comprising applying to the affected area a nonsteroidal anti-inflammatory agent and concurrently a topically active anti-inflammatory corticosteroid.
• These agents are applied in a dermatologically-acceptable, topical vehicle selected from the group consisting of creams, gels, ointments, powders, aerosols and solutions suitable for topical administration.
• CARBOPOL ® gel system containing ibuprofen, propylene glycol, water, CARBOPOL ® 940 (polyacrylic acid polymer) and diisopropanolamine, as an illustrative example of a pharmaceutical composition for percutaneous absorption by topical application made in two liquid drag-containing phases, which are to be mixed together in situ just before use to form a supersaturated drag-containing gel.
• the EPO application discloses a nonalcoholic gel system for delivering ibuprofen topically.
• Ibuprofen Using Hydroalcoholic Gel describes a hydroalcoholic gel comprising ibuprofen, a hydroxypropylcellulose or polyacrylic acid polymer, with propylene glycol being an optional but preferred ingredient.
• the patent further teaches the desirability of adding alkalinizing agent to the formulation to increase percutaneous absorption, the desirability of water, and the use of the S-enantiomer.
• Kishi et al. discloses NSAID-containing (e.g., ibuprofen) hydroalcoholic gels having a pH in the range of 7.0 to 9.0.
• the gel ointment comprises a phenylacetic acid anti-inflammatory compound, a carboxyvinyl polymer, a water-soluble organic amine (e.g., triethanolamine), and water wherein the amount of organic amine is such that the gel ointment has a pH in the range of 7.0 to 9.0, and preferably 7.3 to 7.8.
• Topical gels containing ibuprofen have been described in U.S. Patent
• Pseudofolliculitis barbae is a skin disorder primarily affecting subjects who shave curly hairs. A coiled hair tends to grow by curving backward toward the skin. Over the course of a single day's growth, the tip of the hair shaft may press back into the skin. Since the razor leaves a sharp sheared edge on the hair tip, the hair may actually penetrate the skin and continue proceeding inward.
• the epidermis i.e., the outermost layer of the skin
• the epidermis contains keratinocytes.
• keratinocytes and other nonhematopoi- eticallyderived resident cells produce various cytokines which stimulate migration of T cells and expression of adhesion molecules.
• inflammatory cells e.g., polymorphonuclear neutrophils and lymphocytes
• infiltrate the skin from the dermis
• Full-blown PFB is typically characterized by irritating bumps, itchiness, and discoloration of the affected areas. PFB becomes part of an accelerating cycle. The bumps are present the next time shaving takes place, resulting in a cut of the raised area and further irritation. Additionally, complications of PFB include cellulitis, furunculosis, and hypertrophic or keloid scars. Secondary bacterial infection can also result from PFB.
• topical formulations and particularly gel formulations are thickened using well-known polymeric thickeners, such as the CARBOPOL ® materials which are copolymers or polymers of polyacrylic acids.
• polymeric thickeners such as the CARBOPOL ® materials which are copolymers or polymers of polyacrylic acids.
• CARBOPOL ® materials which are copolymers or polymers of polyacrylic acids.
• Conventional use of such polymers as thickeners in topical formulations requires that the polymers be neutralized in order to get the appropriate thickening performance.
• compositions have been discovered that, when topically applied, deliver therapeutic levels of an NSAID to an individual with a local inflammatory disorder
• compositions of the present invention have one or more advantageous pharmacodynamic properties and provide therapeutic levels of NSAID for a diverse range of local inflammatory disorders. Moreover, therapeutic levels of an NSAID are attained with minimal systemic delivery.
• the present invention provides a composition comprising an NSAID prodrug, a solvent, and a thickening agent wherein the NSAID prodrug is a phenylacetic acid-type NSAID unsubstituted alkyl ester wherein the thickening agent is optionally a polymeric thickening agent.
• the present invention provides a composition comprising a composition comprising an NSAID, an NSAID prodrug, a solvent, and at least one excipient selected from thickeners, humectants, keratolytics, oils, emollients, surfactants, preservatives, colorants, UV blockers, antioxidants, and perfumes.
• the present invention provides a method of treating an inflammatory skin disorder comprising topically administering to a subject in need thereof, an NSAID prodrug , wherein the NSAID prodrug is a phenylacetic acid-type NSAID alkyl ester and wherein the subject is a human, a livestock animal (e.g., beef and dairy cattle, sheep, poultry, and swine, etc.), or a companion animal (dogs, cats, horses, etc).
• livestock animal e.g., beef and dairy cattle, sheep, poultry, and swine, etc.
• a companion animal e.g., cats, horses, etc.
• an alcoholic gel composition comprising: one or more alcoholic solvents in an amount of about 10% to about 90%, one or more NSAIDs in a total amount of about 0.001% to about 25%, a polymeric thickener in an amount of about 0.05% to about 5%, and one or more keratolytic agents are present in a total keratolytic agent concentration amount of about 0.015% to about 25, and wherein the NSAID is substantially dissolved in the one or more alcoholic solvents.
• a composition comprises; one or more alcoholic solvents in an amount of about 50% to about 70%, an NSAID in a total amount of about 5% to no more than about 25%, and a polymeric thickener in an amount of about 0.05% to about 2%, and water in an amount from 0 to about 20%.
• a composition comprises: one or more alcoholic solvents in an amount of about 10% to about 90%, one or more topically active drugs in a total amount of about 0.001% to about 25%, and a polymeric thickener in an amount of about 0.05% to about 5%, wherein the topically active drug is substantially dissolved in the one or more alcoholic solvents, wherein the composition has a viscosity of about 2,000 cps to about 50,000 cps without the addition of an alkalinizing agent.
• an alcoholic gel composition comprises at least one alcoholic solvent present in a total amount from about 30% to about 90%, at least one NSAID having a carboxylic acid group, and at least one polymeric thickener selected from the group consisting of polyacrylic acid thickeners and alkylhydroxycellulose thickeners present in a total thickener amount of about 0.1% to about 5%, wherein upon storage of the composition, ester formation between the at least one alcoholic solvent and the carboxylic acid group is less than about 0.03% per day.
• Also provided in another embodiment is a method of treating a local inflammatory disorder comprising applying to the skin of a subject in need thereof any topically acceptable composition of the present invention.
• delivery systems including a storage devices
• delivery systems useful for delivering any of the compositions of the present invention.
• the inflammatory skin disorder is pseudofolliculitis barbae.
• Figure 1 shows the viscosity-stabilizing effects of salicylic acid with storage.
• Figure 2 shows the pH-stabilizing effects of salicylic acid with storage.
• Figure 3 shows the stabilizing effects of salicylic acid with storage as a pH vs. viscosity plot.
• Figure 4 shows plots of loglOP vs. viscosity change upon addition of various active drugs,
• Figure 5 shows percutaneous absorption of present compositions.
• Figure 6 shows the UV chromatogram (220 nm) of HPLC following injection of Formula I a stored 3 months ⁇ 25 0 C.
• Figure 7a shows the positive ESI mass spectrum for the ibuprofen peak.
• Figure 7b shows the UV spectrum for the ibuprofen.
• Figure 8a shows the positive ESI mass spectrum obtained from the prodrug.
• Figure 8b shows the UV spectrum obtained from the prodrug
• Figure 9 shows prodrug generation with time of storage and the positive effect of salicylic acid.
• Figure 10 shows prodrug generation with time of storage and the negative effect of alkalinizing agent addition.
• Figure 11 shows prodrug generation with time of storage and the negative effect of alkalinizing agent addition - longer study.
• Figure 12 shows prodrug generation with time of storage and the effect of alkalinizing agent addition and NSAID concentration.
• Figure 13 shows the effect of the keratolytic agent salicylic acid on prodrug formation upon storage of composition 1 a.
• % in reference to a concentration of a component of a composition, means the ratio of weight of a component to total weight expressed as a percent, unless otherwise stated.
• solvent means a solvent or solvent system, wherein, a substantial portion of a topically active drug may be solubilized therein, in compositions of the present invention.
• Alkalinizing agent means an agent known in the art to be usefully added to a composition in order to increase the pH of the composition.
• alkalinizing agents include ammonium hydroxide, alkaline earth metal salts such as magnesium oxide, magnesium hydroxide, calcium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, aluminum hydroxide, potassium carbonate, sodium bicarbonate, and the like,
• organic basic salts such as alkanolamines such as methanolamine, ethanolamine, propanolamine, butanolamine, dimethanolamine diethanolamine, dipropanolamine, dibutanolamine, diisopropanolamine, trimethanolamine triethanolamine, tripropanolamine, diisopropanolamine, tributanolamine, aminomethylpropanol, N-methyl glucamine, tetrahydroxypropyl ethylene diamine, and the like; alkylamines such as methylamine, e
• disorder means any abnormal pathology.
• a disorder can be inherited, infectious, acquired, induced (e.g., contact dermatitis or inflammation following surgical incision), chronic, or acute.
• Excipients means any material that is combined with a drug in order to produce a drug dosage form.
• Nonlimiting examples of excipients include, for example, thickeners, humectants, keratolyses, oils, emollients, surfactants, preservatives, colorants, UV blockers, antioxidants, perfumes, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol .
• Thickening agent means any agent useful as an aid to thicken or add structure to a topical formulations. These agents impart physical stability and increased viscosity.
• thickening agents are gums and natural polysaccharides, mineral thickeners, oils, and synthetic polymeric thickeners. Additionally, a thickening agent refers to one or more agents that, in combination, result in a viscosity suitable for dermatologic applications.
• Topicically active drug means a pharmaceutical or botanical compound that can be applied to the skin in a useful composition with an activity that has therapeutic efficacy against a local target.
• Topically active drugs include all drug polymorphs, crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers), enantiomers. salts, solvates and complexes thereof and solvates and complexes of salts thereof.
• “Local Targets” means, by way of example, skin, joints, muscle, and ligaments.
• “Local Inflammatory disorder” means a disorder wherein an inflammatory process is a component of a disorder of a local target.
• Prodrug means a pharmacologically inactive or less active chemical derivative of a topically active drug can be converted to the more active form (“parent drug") by an enzymatic or chemical hydrolysis in vivo.
• the prodrug consists of the parent drug covalently linked to another compound (the "pro-moiety").
• prodrug does not include an NSAID derivative formed by esterification at an NSAID carboxylic acid functionality with an acyloxyalkyl radical.
• Prodrug ester denotes a prodrug wherein the pro-moiety is in ester linkage to the parent drug.
• Safe and effective amount means an amount of the composition which is sufficient to provide adequate treatment of the condition being treated, but is not so great as to provide undesirable side effects to the user.
• Substantially alkalinizing agent-free means that the composition comprises no alkalinizing agent other than an alkalinizing agent that is present as a contaminant of another component used in preparing such a composition.
• Treatment means curative, palliative and/or prophylactic treatment.
• prophylactic treatment is not meant to indicate a quantitative effect, but rather that there has been a clinically observable beneficial effect,
• prophylactic treatment includes a situation where a composition of the present invention is administered to a subject before symptoms are observable and symptoms subsequently occur, but to a lesser degree than without administration.
• Topicically acceptable and “dermatologically acceptable” composition means that, when applied to the skin, there is no significant skin irritation under normal usage circumstances with typical patients.
• Viscosity means liquid fluidity as measured by a Brookfield DV-III Ultra
• compositions according to the present invention have one or more superior feature desired in a topical formulation, namely (1) pH stability; (2) viscosity stability; (3) minimal systemic delivery; (4) rapid delivery of therapeutic levels of a topically active drug to the skin; (5) delivery of high levels of a topically active drug to the skin; (6) delivery of sustained therapeutic levels of a topically active drug for an extended period of time; (7) rheologic properties that increase skin exposure to the topically active drug; (8) prodrug generating; and (9) prodrug formation inhibition.
• Prodrug Compositions namely (1) pH stability; (2) viscosity stability; (3) minimal systemic delivery; (4) rapid delivery of therapeutic levels of a topically active drug to the skin; (5) delivery of high levels of a topically active drug to the skin; (6) delivery of sustained therapeutic levels of a topically active drug for an extended period of time; (7) rheologic properties that increase skin exposure to the topically active drug; (8) prodrug generating; and (9) prodrug formation inhibition.
• NSAID prodrugs can be formulated into compositions of the present invention such that there is superior drug delivery to local targets yet systemic delivery remains minimal. Without being bound by theory, it is believed that the hydrophobic nature of the NSAID prodrugs allows for superior dermal delivery. Such delivery is followed by release of the pro-moiety by resident enzymes in the skin (e.g., esterases), converting the prodrug to the less hydrophobic, parent drug. This less hydrophobic drug has reduced ability to diffuse further to the more vascularized regions.
• a prodrug of a topically active drug has reduced or no pharmacological activity, but when administered topically, the drug is converted into a drug having the desired activity (the parent drug).
• exemplary prodrugs of the present invention include NSAID prodrugs, for example, NSAID prodrugs of the phenylacetic acid type.
• Other exemplary NSAIDs and NSAID classes useful in the present invention are disclosed elsewhere herein. Those skilled in the art will readily recognize a functionality on a topically active drug that is useful for derivitization to add the promoiety through a bond to the NSAID that can be processed in local tissues to form the parent drug.
• Prodrugs can be formed from a parent drug, for example, by adding a promoiety through esterification of a carboxylic acid functionality (for example, aryl carboxylic acid derivative NSAIDs).
• a carboxylic acid functionality for example, aryl carboxylic acid derivative NSAIDs.
• the hydrogen of the hydroxyl group of the carboxylic acid is replaced, for example, by alky or aryl or carbonyl.
• An alkyl can be unsubstituted or substituted, for example, such as alkyloxyalkyl, alkoxycarbonylalkyl, alkoxycarbonylaminoalkyl, aminoalkyl, or alkylcarbonylaminoalkyl.
• pro-moieties are methyl, ethyl, isopropyl, n-propyl, tert- butyl, butyl, pentyl, methoxy, tert-butoxy, methoxyethyl, ethoxymethyl, methoxy- methyl, phenyl, carboxyethyl, methoxycarbonylmethyl, methoxycarbonylethyl, tert- butoxycarbonylaminomethyl, methoxycarbonyl, aminomethyl, and methylcarbonyl- aminomethyl; or a pharmaceutically acceptable salt thereof.
• a prodrug can also be produced to form an amide ester or a thioester.
• a prodrug can be formed in an NSAID by, for example, adding a pro-moiety to the NSAID through ether formation at a hydroxyl functionality wherein the hydrogen of the hydroxyl functionality is replaced by an alkanoyloxyalkyl.
• a pro-moiety can also be linked to an NSAID through formation of carbonates, carbamates, and amides covalently bonded through the carbonyl carbon.
• Topically active drugs useful as prodrugs in the present invention, are optionally poorly soluble, practically water insoluble, or water insoluble.
• topically active drugs contain a carboxylic acid functionality and/or a hydroxyl functionality.
• topically active drugs contain a carboxylic acid functionality and/or a hydroxyl functionality and are water insoluble or practically water insoluble.
• compositions of the present invention additionally provide one or more superior topical formulation features when compared to the corresponding parent NSAID (e.g., ketoprofen is the corresponding parent NSAID of ketoprofen isobutyl ester): (1) higher levels of drug in the skin or deeper tissue (e.g., joints or muscles); (2) more sustained level of an NSAID in the skin or deeper tissue (e.g., joints or muscles); and/or (3) more rapid delivery of an NSAID in the skin or deeper tissue (e.g., joints or muscles).
• NSAID e.g., ketoprofen is the corresponding parent NSAID of ketoprofen isobutyl ester
• NSAID prodrug esters can be topically applied in a variety of compositions.
• Compositions comprising such prodrugs can generally be made to contain greater amounts of such prodrug when compared to the corresponding parent NSAID.
• Compositions comprising NSAID prodrugs are especially useful for conditions where it is desirable to rapidly produce levels of an NSAID at a target site.
• compositions comprising NSAID prodrugs are especially useful for conditions where it is desirable to achieve penetration.
• compositions comprising such prodrugs can have reduced alcohol at a given concentration of prodrug when compared to the corresponding NSAID.
• reduced alcohol compositions are useful for local inflammatory disorders where alcohol is undesirable (e.g., conditions where drying agents are contraindicated). Such undesirable conditions include conditions where it is undesirable to dry or further dry the skin. Examples of such disorders especially useful for treatment with a reduced alcohol compositions of NSAID prodrug esters are psoriasis and dermatitis.
• NSAID prodrug compositions of the present invention can be gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages, microemulsions, and/or liposomes.
• Optional carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated.
• NSAID prodrug compositions can be prepared by dissolving all or substantially all of an NSAID prodrug in a solvent.
• useful solvents or solvent systems are alcohols, organogels, complexing agents, cyclodextrins, liposomes, microsomes, phospholipids/copolymers, and oil-in-water emulsions.
• NSAID prodrug compositions can also be prepared without any significant addition of solvent.
• Solvents in compositions of the present invention, have surprising effect on drug delivery of compositions of the present invention. Without being bound by . theory, the inventors believe that NSAIDs are absorbed into the skin by two different mechanisms: diffusion from the solvent and transport concurrently with the solvent. Both mechanisms are competed with by evaporation of the solvent, especially in the case of volatile solvents. However, in high NSAID compositions (e.g., about 5% or greater), NSAID absorption through both mechanisms can be substantially accelerated. This is believed to result in faster drug delivery, high drug levels at target sites, and deeper penetration. Nevertheless, the more hydrophilic nature of the dermis can result in the surprisingly minimal systemic delivery of NSAIDs in compositions containing an alcohol solvent.
• NSAID prodrugs generally have increased alcohol solubility when compared to the corresponding NSAIDs, it is now possible to prepare a dermatologically acceptable composition with reduced content of an alcohol solvent (or other organic solvent).
• the present invention provides a composition comprising an NSAID prodrug, a solvent, and a thickening agent wherein the NSAID prodrug is a phenylacetic acid-type NSAID unsubstituted alkyl ester wherein the thickening agent is optionally a polymeric thickening agent (such agents described elsewhere herein).
• the thickening agent is present in an amount of about 0.05% to about 5%.
• the present invention provides a composition comprising an NSAID prodrug, a solvent, and a thickening agent wherein the NSAID prodrug is an unsubstituted alkyl ester of an NSAID other than naproxen wherein the thickening agent is optionally a polymeric thickening agent (such agents described elsewhere herein).
• the present invention provides a composition comprising an NSAID prodrug, a solvent, and a thickening agent wherein the NSAID prodrug is of the NSAID type selected from the group consisting of phenyl acetic-type NSAID, mefanamic-type NSAID, oxicam-type NSAID, and indomethacin type NSAID, and wherein the NSAID prodrug is an unsubstituted alkyl ester.
• the present invention provides a composition comprising an Ci-C 3 carbon unsubstituted alkyl ester NSAID prodrug, a solvent, and a thickening agent.
• the present invention provides a composition comprising an ester NSAID prodrug, a solvent, and a thickening agent, wherein the NSAID prodrug is an ibuprofen prodrug, and wherein the promoiety is an ester linkage (i.e., ester-linked) to the NSAID and wherein the promoiety is an amidyl, a thio, and/or an unsubstituted alkyl.
• the NSAID prodrug is an ibuprofen prodrug
• the promoiety is an ester linkage (i.e., ester-linked) to the NSAID and wherein the promoiety is an amidyl, a thio, and/or an unsubstituted alkyl.
• the thickening agent is optionally a polymeric thickening agent (such agents described elsewhere herein).
• the thickening agent is present in an amount of about 0.05% to about 10%.
• the percentage is about 0.05% to about 5%; optionally, about 0.05% to about 2%.
• the present invention provides a composition
• a composition comprising an NSAID, an NSAID prodrug, a solvent, and at least one excipient such as a thickener, a humectant, a keratolytic, an oil, an emollient, a surfactant, a preservative, a colorant, a UV blocker, an antioxidant, or a perfume.
• the NSAID prodrug can be metabolized to form the NSAID (e.g., coformulation of flurbiprofen and flurbiprofen ethyl ester).
• compositions of the present invention comprising an NSAID and a NSAID prodrug have surprisingly beneficial effects on local inflammatory disorders.
• the NSAID prodrug results in more rapid diffusion and greater localization than the corresponding parent NSAID.
• the prodrug after being delivered to the target tissue, is converted to the parent NSAID. It is believed that the 100% conversion to the parent NSAID is not instantaneous upon absorption into the skin. It believed that the NSAID prodrug is not as active as the parent drug at the site of action.
• the NSAID in the composition generally provides a slower drug delivery as a result of the NSAID 's lower hydrophobicity but provides for higher activity once at a local site. Regardless of the mechanism, the NSAID prodrug/NSAID combination results in compositions with not only rapid and sustained delivery, but higher local concentration of active drug to target tissues.
• the coformulation of an NSAID and NSAID prodrug according to the present invention can be manufactured by a step of combining an NSAID, an NSAID prodrug, a solvent, and optionally one or more excipients to form a dermatologically acceptable composition.
• the solvent in an NSAID prodrug composition of the present invention can be an alcoholic solvent or a nonalcoholic solvent.
• the present invention provides a method of treating a epidermal inflammatory disorder comprising topically administering to a subject in need thereof, an ibuprofen prodrug, wherein the epidermal inflammatory is selected from the group consisting of psoriasis, folliculitis, PFB, and/or dermatitis.
• Dermatitis can, for example, be contact dermatitis, occupationally acquired dermatitis, and the like.
• the aforementioned NSAID prodrug compositions of the present invention can be gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages, microemulsions, and/or liposomes.
• Optional carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated.
• the NSAID prodrug compositions of the present invention can be an organogel composition and are particularly useful for topical administration of NSAID prodrugs.
• organogel useful herein is a lecithin organogel obtained by adding small amounts of water to a solution of lecithin in organic solvents.
• lecithin organogels are prepared at room temperature by, for example, dissolving lecithin in an organic solvent and adding enough water while stirring to obtain the a gel with a desired viscosity.
• One or more NSAID prodrugs can be dissolved in the organic solvent prior to the addition of lecithin.
• Organic solvents useful herein include, as nonlimiting examples, hydrocarbons, ethers, amines, and esters.
• the organic solvent is a fatty acid ester such as isopropyl palmitate or isopropyl myristate.
• the organogel of the present invention is a pluronic organogel.
• the pluronic surfactant is a block copolymers of ethylene oxide and propylene oxide.
• the pluronic can be added to the water (which can optionally have a drug dissolved in it) solution prior to its addition to the organic solvent/lecithin solution.
• pluronics are typically incorporated in organogels to stabilize the gel matrix wherein the lecithin ingredient is not of high purity.
• the organic solvent can be reduced or replaced by an NSAID prodrug ester. This allows compositions to be prepared at a higher total NSAID concentration. Such compositions are also useful to solubilize an additional drug of poor water solubility.
• NSAID prodrugs of the present invention can be formulated in to an alcohol-free composition of the phospholipids/ polyoxy- ethylenepolyoxypropylene copolymer type. Moreover, the phospholipid concentration can be reduced or replaced by the NSAID prodrug. This provides for a composition with a useful concentration of NSAID prodrug, a useful viscosity, yet does not deposit substantial amounts of inert ingredient on the skin. Moreover, for some local inflammatory disorders, phospholipids deposited on the skin can have a soothing or even therapeutic effect (e.g., burn from UV exposure).
• Oil-in-water (o/w) emulsions are useful compositions for NSAID prodrugs of the present invention.
• Such compositions are made of an oil phase, a water phase, and an emulsif ⁇ er.
• the oil phase is a useful solvent for the NSAID prodrug as well as other hydrophobic drugs and/or excipients.
• the water phase can usefully solubilize hydrophilic drugs and/or excipients.
• the solvent for the NSAID prodrug is reduced or replaced by the NSAID prodrug if it is a liquid NSAID prodrug.
• typical emulsifiers are nonionic or anionic surfactants as polyoxyethylene 20 sorbitan trioleate (polysorbate 85), sorbitan monolaurate, polyoxyethylene 4 lauryl ether sodium stearate, and the like.
• Oil-in-water emulsions are especially beneficial for NSAID prodrugs of the present invention because one skilled in the art is able to adjust the oil/water ratio to provide sufficient drug solubilization and, at the same time, optimal drug delivery (i.e., movement of the drug from the formulation into the skin).
• the present invention provides a method of treating a local inflammatory disorder comprising topically administering to a subject in need thereof an NSAID alkyl ester wherein the NSAID is other than naproxen, and wherein the subject is a mammal other than a rodent.
• the present invention provides a method of treating a local inflammatory disorder comprising topically administering to a subject in need thereof an NSAID alkyl ester wherein the NSAID is other than naproxen, and wherein the subject is a human, a livestock animal, or a companion animal
• the present invention provides a method of treating an inflammatory epidermal disorder comprising topically administering to a subject in need thereof, an NSAID prodrug , wherein the NSAID prodrug is a phenylacetic acid- type NSAID alkyl ester.
• the present invention provides a method of treating an inflammatory skin disorder comprising topically administering to a subject in need thereof, an NSAID prodrug, wherein the NSAID prodrug is a phenylacetic acid-type NSAID alkyl ester and wherein the subject is a human, a livestock animal, or a companion animal
• the present invention provides a method of treating a local inflammatory disorder comprising topically administering to a subject in need thereof an NSAID prodrug, wherein the NSAID prodrug is an NSAID 1-3 carbon alkyl ester and wherein the subject is a human, a livestock animal, or a companion animal.
• the local inflammatory disorder is a skin disorder or optionally, an epidermal skin disorder.
• the local inflammatory disorder is psoriasis, folliculitis, PFB, and/or dermatitis.
• alcoholic gel compositions useful for administering a topically active drug.
• the topically active drug is an NSAID.
• a composition comprises:
• a polymeric thickener in an amount of about 0.05% to about 5%, wherein the topically active drug is substantially dissolved in the one or more alcoholic solvents.
• one or more keratolytic agents are present in the present compositions at a total keratolytic agent concentration amount of about 0.015% to about 25%, or about 0.05% to about 10%, or about 0.05% to about 5%, or about 0.05% to about 2%. Keratolytic agents useful in alcoholic gel compositions of the present invention are described further herein below.
• a keratolytic agent can optionally be used in the present invention at a concentration effective to stabilize the composition with regards to pH and viscosity.
• a stabilizing keratolytic agent is salicylic acid, and an exemplary viscosity- and/or pH-stabilizing amount is about 0.05% to about 25%, or about 0.05% to about 10%, or about 0.05% to about 5%, or about 0.05% to about 2%.
• the keratolytic agent is present in a pH-stabilizing amount.
• the keratolytic agent is present in a viscosity-stabilizing amount.
• the keratolytic agent is selected from the group consisting of ⁇ - and ⁇ -hydroxycarboxylic and ⁇ -ketocarboxylic acids and salts, amides or esters thereof.
• the keratolytic agent is a salicylate.
• the polymeric thickener is a polyacrylic thickener. It is surprisingly now discovered that alcoholic gels of the present invention that comprise a polyacrylic thickener provide a therapeutically beneficial pH and viscosity, with a reduced requirement for added alkalinizing agent or without requiring any neutralization step in the process of making the composition. This is contrary to conventional teachings in the art of polyacrylic acid polymeric thickeners. For example, see Noveon technical bulletin which states “target a pH range between 7,3 - 7.7.” and "The key to formulating a hydroalcoholic gel with CARBOPOL® polymers is choosing the correct neutralizing agent. Because the solubility of the CARBOPOL® salt changes with increased alcohol levels, it is necessary to use specific neutralizing agents for specific hydroalcoholic blends.” (See Noveon TDS 255 Revised 12/99.)
• compositions are now provided herein with therapeutically beneficial pH and viscosity values, yet having reduced or no alkalinizing agent by selection of alcoholic solvent and concentration, active drug and concentration, polyacrylic thickener and concentration, and water concentration.
• alcoholic solvent and concentration e.g., acetate
• active drug and concentration e.g., sodium EDTA
• polyacrylic thickener and concentration e.g., sodium EDTA
• water concentration e.g., sodium sulfate
• compositions of the present invention are generally acidic and have a pH of from about 3.0 to about 6.5, optionally from about 4.0 to about 5.5, or optionally from about 4,3 to about 5,0.
• a composition comprises:
• a composition comprises:
• one or more alcoholic solvents in an amount of about 50% to about 70%
• a polymeric thickener in an amount of about 0.05% to about 2%, wherein the composition has a viscosity of about 2,000 to about 50,000 cps without the addition of an alkalinizing agent.
• a composition comprises:
• a polymeric thickener in an amount of about 0.05% to about 5%, wherein the topically active drug is substantially dissolved in the one or more alcoholic solvents, wherein the composition has a viscosity of about 2,000 to about 50,000, and wherein the compositions contains no alkalinizing agent in an amount more than required to raise the pH of the composition about 2 pH units, or optionally no more than about 1 pH unit, or about 0.5 pH unit.
• a composition comprises an alkalinizing agent at a concentration less than 0.5%. In one embodiment, no alkalinizing agent is added.
• compositions are substantially free of alkalinizing agent.
• the drug is optionally an NSAID and optionally of the phenylacetic acid-type NSAID.
• a composition comprising an active drag useful in the present invention, about 25% water, 50% isopropanol, and a polymeric thickener has a viscosity unsuitable for effective therapeutic delivery of an active drag.
• a composition comprising an active drag useful in the present invention, less than about 24% water and more than about 40% ethanol which have a suitable viscosity.
• gel compositions of the present invention comprise less than about 24% water and about 40% alcoholic solvent or more (e.g., about 40% to about 80%).
• Such compositions, applied once or twice a day to PFB patients demonstrated efficacy. This is especially remarkable because the study subjects included those that had chronic symptoms unresponsive to other treatments.
• a composition comprises:
• a composition comprises:
• a composition comprises: a phenylacetic-type NSAID prodrug ester, a solvent, and a thickening agent wherein promoiety is an amidyl, a thio, or unsubstituted alkyl.
• a composition comprises an NSAID prodrug, a solvent, and at least one excipient that is a thickener, a humectant, a keratolytic, an oil, an emollient, a surfactant, a preservative, a colorant, a UV blocker, an antioxidant, or a perfume wherein the NSAID prodrug is an unsubstituted alkyl ester of an NSAID other than naproxen.
• compositions contain a humectant.
• an alcoholic gel composition comprises one or more alcoholic solvents in an amount of about 10% to about 90%, an NSAID in a total amount of about .001% to about 25%, and a polyacrylic thickener in an amount of about 0.05% to about 5%, wherein the one or more keratolytic agents are present in a total keratolytic agent concentration amount of about 0.015% to about 25%, and wherein the NSAID is substantially dissolved in the one or more alcoholic solvents.
• a composition comprises an alcoholic gel composition comprising at least one alcoholic solvent present in a total amount from about 30% to about 90%, at least one NSAID having a carboxylic acid group, and at least one polymeric thickener selected from the group consisting of polyacrylic acid thickeners and alkylhydroxycellulose thickeners present in a total thickener amount of about 0.1% to about 5%, wherein upon storage of the composition, ester formation between the at least one alcoholic solvent and the carboxylic acid group is less than about 0.03% per day.
• the pH of the composition is greater than 5.0.
• the composition further comprises a keratolytic agent (e.g., a salicylate) in an amount that inhibits ester formation (i.e., prodrug formation).
• a keratolytic agent e.g., a salicylate
• the alcoholic solvent is a branched alcohol or an alcohol with four or more carbons.
• an alcoholic gel composition comprises at least one alcoholic solvent present in a total amount from about 30% to about 90%, at least one NSAID having a carboxylic acid group, and at least one polymeric thickener selected from the group consisting of polyacrylic acid thickeners and alkylhydroxycellulose thickeners present in a total thickener amount of about 0.1% to about 5%, wherein upon storage of the composition, ester formation between the at least one alcoholic solvent and the carboxylic acid group is greater than about 0.03% per day.
• the composition has a pH of less than about 5.
• the alcoholic solvent is a straight chain with three or fewer carbons.
• the active drug has a carboxylic acid group and when the alcoholic solvent is a Ci -C 3 straight alcohol (e.g., methanol, ethanol, or propanol), the alcoholic solvent and the carboxylic acid group react at an accelerated rate to form an ester upon storage of the composition.
• the alcoholic solvent and the carboxylic acid group react at an accelerated rate to form an ester upon storage of the composition.
• the active drug has a carboxylic acid and when the alcoholic solvent is a branched alcohol or an alcohol with four or more carbons, the rate of ester formation between the alcoholic solvent and the carboxylic acids group upon storage is inhibited compared to a CpC 3 straight chain alcohol.
• a keratolytic agent can optionally be used in the present invention at a concentration effective to increase the rate of esterification of the active drug.
• An exemplary keratolytic agent is salicylic acid at a concentration of about 0.05% to about 5%, or about 0.05% to about 2.5%, or about 0.1% to about 1.5%, or about 0.1% to about 1%.
• decreasing water concentration results in an increase in prodrug formation upon storage of a gel composition of the present invention when the active drug has a carboxylic acid group and the alcoholic solvent is a Ci-C 3 straight chain alcohol.
• An esterification rate- stimulating water concentration is below about 24%, or below about 20%, or below about 17%.
• An esterification rate-inhibiting concentration of water is at or above about 24%, or above about 30%, or above about 40%.
• compositions can now be prepared to comprise a topically acceptable alcoholic solvent, a topically active drug having a carboxylic acid group, a prodrug with the chemical structure equivalent to that formed by esterification of the active drug with the alcoholic solvent, and a polymeric thickener, wherein the drug and the prodrug are at concentrations such that upon storage for six months at room temperature, said concentrations are each maintained within about 80% or about 90%.
• Alcoholic gel compositions disclosed herein above optionally further comprise one, two, three, or four of the following:
• Glycerine about 0.1% to 15%
• Panthenol about 0.1% to 15%
• Polysorbate about 0.1% to 15%
• Humectant about 0.1% to about 20%
• compositions provide an especially effective treatment for local inflammatory disorders because of the coactions of a topically active drug, a polymeric thickener, an alcoholic solvent and, optionally, one or more excipients.
• the active drug is solubilized in the alcoholic solvent and is able to partially diffuse through the hydrophobic epidermis.
• Evidence for diffusion is not only demonstrated by diffusion assays disclosed herein, but by a visual absence of drug on the surface of the skin after the gel has penetrated the skin and/or dried (i.e., absence of "ashing").
• a prodrug is used with increased hydrophobicity (over its active metabolite). The inventors have discovered that such increased hydrophobicity enables increased direct delivery of drug through the follicle opening to a specific therapeutic target (i.e., the epidermal lining of the follicular pore). In some inflammatory skin disorders such as PFB, this is a common site of injury.
• the gel properties of the composition allows administration of an increased volume of composition (i.e., more thickly applied), especially when compared to liquid formulations. This provides higher doses of the topically active drug.
• Each component of the composition retards evaporation of the alcohol, allowing extended time for the NSAID to be absorbed into the skin after application. This is an improvement over formulations that evaporate quickly leaving greater amounts of the NSAID dried on the surface of the skin.
• a composition contains a relatively high concentration of at least one NSAID ("high NSAID compositions").
• high NSAID compositions can comprise about 1% to about 20%, such as about 2% or about 5%, or about 10%, or about 15%.
• a high NSAID composition when the NSAID is practically insoluble or poorly soluble in water, contains a high concentration of alcohol, for example, about 10% to about 90% or, for example, more than about 20%, or more than about 40%, or more than about 60%.
• a 15% concentration of an NSAID of the propionic acid derivative type can be formulated in a 60% alcohol composition.
• compositions comprising about 5% to about 20% concentration of an NSAID of the propionic acid derivative type and alcohol at a concentration of about 20% to about 60% have an unexpectedly useful pharmacodynamic profile.
• the optional keratolytic agent removes the dead cells from the epidermis including regions around the hair follicles, sebaceous glands, and sweat glands, further enhancing diffusion of the active drug carried in the alcoholic solvent.
• the optional humectant draws water into the epidermis, follicles, and glands and causes them to open up. This coaction facilitates diffusion of the active drug to the therapeutic targets in skin.
• compositions of the present invention are especially beneficial in PFB, where the hair follicle is the site of the skin injury and, therefore, a therapeutic target.
• compositions of the present invention are useful for treating subjects affected by a local inflammatory disorder by topical application.
• a local inflammatory disorder can be, for example, a skin disorder.
• Other examples of disorders that can be usefully treated with compositions of the present invention are set forth below herein.
• a subject with PFB is treated by topical application of an alcoholic gel comprising an NSAID, an alcoholic solvent, and a polymeric thickener.
• One embodiment provides a method of treating a subject comprising topically administering to a subject in need thereof a composition comprising a phenylacetic- type NSAID prodrug ester, a solvent, and a thickening agent wherein promoiety is an amidyl, a thio, or an unsubstituted alkyl and whereiri the subject has a condition selected from psoriasis, folliculitis, eczema and dermatitis.
• the present invention comprises, inter alia, one or more topically active drugs useful according to the present invention.
• topically active drugs include antiinflammatories (NSAIDs) and salicylates. While some skilled artisans may classify salicylates as NSAIDs, as used herein, the term NSAID does not include salicylates.
• NSAID antiinflammatories
• salicylate means a non-NSAID salicylic acid or a derivative of salicylic acid, such as methyl salicylate, sodium salicylate, trifluoroethyl salicylate, diflunisal, etc.
• Topically active drugs useful in the present invention can also be selected from analgesics, antibacterial agents, antiwrinkle agents, antihistamines, antifungal agents, anesthetics, corticosteroids, glucocorticoids, antivirals (for example, anti- herpetics), and antiallergic compounds.
• analgesics for example, amitriptamine, amitriptamine, amitriptamine, amitriptamines, piroxicam, and azathiophen, piroxicam, and azathione, fenofibuprofen, fenofe, fenofe, fenofe, fenofe, fenofe, fenofe, fenofepine, corticosteroids, glucocorticoids, antivirals (for example, anti- herpetics), and antiallergic compounds.
• the phrase "the active drug” and the like are use to mean the more awkward phrase "the one or more active drugs.”
• the active drug is provided as a free acid or a free base.
• the active drug has a pK a from about 3.0 to about 6.5, optionally from about 4.5 to about 7, optionally from about 4 to about 5, and optionally from about 4.3 to about 4.7.
• the active drug has a has a 1Og 1O P value of about 2 to about 5, optionally of about 3 to about 5, optionally of about 3 to about 4, optionally of about 2 to about 3, and optionally of about 2.3 to about 2.7.
• the active drug is an NSAID of the phenylacetic acid type such as those below. Phenylacetic acid-type NSAIDs are distinguished herein from ' phenylacetic acids that are di-substituted to form fused phenyl rings, such as the naphthylene of naproxen.
• an NSAID prodrug of the phenylacetic acid type is formed by an ester linkage to a pro-moiety at the hydroxyl group of the carboxylic acid.
• the active drug is an NSAID of the N-Arylanthranilic acid types such as the nonlimiting examples mefanamic.
• an NSAID prodrug of the iV-Arylanthranilic acid type is formed by an ester linkage to a promoiety at the hydroxyl group of the carboxylic acid.
• the active drug is an NSAID of the oxicam type, such as the nonlimiting examples piroxicam and meloxicam.
• an NSAID prodrug of the oxicam type is formed by an ether linkage to a promoiety at the hydroxyl group of the fused ring heterocycle.
• the NSAID is diclofenac, indomethacin, and/or sulindac.
• an NSAID prodrug is formed by an ester linkage to a promoiety at the hydroxyl group of the carboxylic acid.
• the NSAID prodrug is an NSAID of the naphthalene- acetic acid type exemplified by naproxen.
• the naphthalene-acetic acid-type NSAID prodrug is a Ci-C 3 alkyl ester.
• an NSAID prodrug of the naphthalene-acetic acid type is formed by an ester linkage to a promoiety at the hydroxyl group of the carboxylic acid.
• one or more active drugs are selected from ibuprofen salt, ibuprofen free acid, and esters thereof.
• the NSAID is a selective or preferential COX-2 inhibitor.
• the NSAID is a macrolid such as tacrolimus and pimecrolimus.
• the NSAID is a bufexamac, dicoflenac, etofenamate, felbinac, entiazac, fepradinol, flufenamic, lunoxaprofen, flubiprofen, ibuprofen, indomethacin, sonixin, ketoprofen, ketorolac, niflumic, oxyphenbutazone, piketoprofen, piroxicam, pranoprofen, or suxibuzone.
• the NSAID is a prodrug.
• the prodrug has an ester that can be formed by derivatizing a carboxylic acid.
• the active drug is a naturally-occurring herbal compound containing an anti-inflammatory component.
• the weight percent of the selected drug is adjusted according to the relative amount of anti-inflammatory component in the compound.
• Such ingredients may include, but are not limited to, willow bark, turmeric root, licorice root and ginger root.
• the ester is formed by reaction of an active drug of the present invention and the alcoholic solvent.
• the active drug is present in compositions of the present invention at a total active drug amount of about 0.001% to about 20% of the total composition, optionally 0.5% to about 20%, or from about 5% to about 20%, or from about 10% to about 20%.
• the active drug is substantially dissolved in the alcoholic solvent, by way of example, about 90% dissolved.
• Alcoholic gel compositions of the present invention and, optionally, NSAID prodrug compositions of the present invention comprise, inter alia, one or more alcoholic solvents.
• Alcoholic solvents of the present invention are selected from topically acceptable, monohydric or polyhydric alcohols. Alcoholic solvents of the present invention are present in a total alcohol amount of about 30% to about 80%, optionally from about 40% to about 70%, or optionally from about 50% to about 65%.
• Such alcoholic solvents are well known in the art. They may be straight or branched chain and may contain from one to about 14 carbons. They may be unsubstituted or substituted alkyl alcohols. They include, for example, ethanol, isopropyl alcohol, myristoyl alcohol, propylene glycol, glycerin and alkyl glycerol derivatives.
• the alcoholic solvent is ethanol, isopropyl alcohol, propylene glycol, glycerin, myristoyl alcohol, and mixtures thereof.
• the alcoholic solvent is ethanol.
• the present invention comprises, inter alia, one or more polymeric thickener.
• the phrase "the polymeric thickener” and the like are use to mean the more awkward phrase "the one or more polymeric thickeners.”
• the polymeric thickener comprises a homo- or copolymer having dissociable side groups on the polymer, such as acetic acid groups.
• the polymer is a polymer (or copolymer) of polyacrylic acids, such as those sold under the trade name CARBOPOL® (Noveon); polyoxyethylene- polyoxypropylene copolymers (poloxamer), such as available as LUTROL®, and the like.
• CARBOPOL®-ty ⁇ e resins such as CARBOPOL® and PEMULEN® (Noveon) are polymers of acrylic acid, crosslinked with polyalkenyl ethers or divinyl glycol.
• CARBOPOL®-type polymers are flocculated powders of particles averaging about 0.2 micron in diameter.
• Nonlimiting examples of CARBOPOL® polymers are CARBOPOL® ULTREZTM 10, CARBOPOL® ULTREZTM 20, CARBOPOL® ETDTM 2020 and CARBOPOL® ETDTM 2001
• polymers useful according to the present invention are carboxyvinyl, polyacrylamides, polysaccharides, natural gums (for example, xanthan gum), polyvinlsulfonates, polyalkylsulfones and polyvinylalcohols, or mixtures thereof.
• alkylhydroxycellulose materials such as KLUCEL®, commercially available from Hercules (Wilmington, DE).
• Nonlimiting examples of alkylhydroxycelluloses useful in the present invention include sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, and methylcellulose.
• Nonlimiting examples of gums useful in the present invention include xanthan gum, sodium carrageenan, sodium alginate, hydroxypropyl guar, gum Arabic (acacia), and gum tragacanth.
• the polymeric thickener is present in compositions of the present invention at a total thickener amount of about 0.1% to about 5% of the total composition, optionally 0.5% to about 5%, or from about 1.5% to about 3% of the thickener component.
• compositions of the present invention include one or more keratolytic agents.
• Keratolytic agents used according to the invention may be chosen from ⁇ - and ⁇ -hydroxycarboxylic or ⁇ -ketocarboxylic acids, salts, amides or esters thereof. More particularly, nonlimiting examples of ⁇ -hydroxy acids are glycolic acid, lactic acid, tartaric acid, malic acid, citric acid, mandelic acid and, in general, fruit acids.
• Nonlimiting examples of ⁇ -hydroxy acids are salicylic acid and derivatives thereof, in particular alkyl derivatives, such as 5-n-octanoylsalicylic acid.
• Keratolytic agent used according to the invention may also be chosen from retinoids (retinoic acid or retinol) and derivatives thereof, benzoyl peroxide, urea, boric acid, allantoin (e.g. glyoxyldiureide or 5-ureidohydantoin) sulfur, resorcinol, and hexachlorophene.
• retinoids retinoic acid or retinol
• benzoyl peroxide e.g. glyoxyldiureide or 5-ureidohydantoin
• allantoin e.g. glyoxyldiureide or 5-ureidohydantoin
• compositions of the present invention comprise at least one humectant.
• Humectants useful according to the present invention are hygroscopic compounds that promote retention of water.
• Nonlimiting examples of such are polyhydric alcohols (e.g., glycerin, propylene glycol, polypropylene glycol, mannitol and sorbitol, and the like) and polyols, such as the polyethylene glycols, fructose, glucose, lactic acid, 1,3 butylene glycol, wheat gluten; macrocytis yyrifera; ceratonia silaqual; hespridin methyl chalocone; dipeptide-2; palmitoyl tetrpeptide-3; palmitoyl pentapeptides, and panthenols.
• polyhydric alcohols e.g., glycerin, propylene glycol, polypropylene glycol, mannitol and sorbitol, and the like
• One or more humectants can optionally be included in the composition in total humectant amount of about 0.1 % to about 20%, or about 0.5% to about 10%, or about 1% to about 5%.
• Viscosity values that are useful and desirable according to the present invention vary as a function of the indication being treated. For example, where broad coverage (i.e., large areas of skin) or lower levels of drug application are desired, a less viscous composition is advantageous. Examples of less viscous compositions are about 2,000 cps to about 50,000 cps, or about 2,000 cps to about 25,000 cps, or 2,000 cps to about 10,000 cps, or about 5,000 cps to about 15,000 cps. Such less viscous compositions facilitate spreading of applied composition.
• a more viscous composition is advantageous.
• examples of more viscous compositions are about 20,000 cps to about 200,000 cps or about 50,000 cps to about 100,000 cps.
• One skilled in the art will readily be able to increase the viscosity of the present compositions by, for example, increasing the polymeric thickener concentration.
• compositions are relatively resistant to viscosity changes upon addition of alkalinizing agent; for example, less than about 50% viscosity change per pH unit that the composition is alkalinized, or less than about 25%, or less than about 15%.
• compositions of the present invention may also contain optional components which are typically used in topical pharmaceutical and/or cosmetic formulations. These materials, such as solvents, oils, emollients, surfactants, preservatives, colorants, UV blockers, and perfumes are well known in the art and they are used in the present compositions at their conventional art-established levels for their art-established effects. [00204] Optionally, in other embodiments, it is advantageous to add antioxidants to the compositions of the invention.
• the antioxidants are advantageously selected from the group consisting of amino acids (e.g., glycine, histidine, tyrosine, tryptophan) and their derivatives; imidazoles, (e.g., urocanic acid) and their derivatives; peptides, such as D,L-carnosine, D-carnosine, L-carnosine and their derivatives (e.g., anserine); carotenoids; carotenes (e.g., alpha-carotene, beta-carotene, lycopene) and their derivatives; chlorogenic acid and derivatives thereof; lipoic acid and its derivatives (e.g., dihydrolipoic acid); aurothioglucose, propylthiouracil and other thiols (e.g., thioredoxin, glutathione, cysteine, cystine, cystamine and their glycosyl, N-acetyl, methyl, ethyl,
• vitamin E and/or its derivatives are used as the antioxidant or antioxidants, their respective concentrations are advantageously chosen from the range of about 0.001% to about 10%.
• vitamin A or vitamin A derivatives, or carotenes or their derivatives are used as the antioxidant or antioxidants, their respective concentrations are advantageously chosen from the range of about 0.001% to about 10%.
• compositions may also contain oils, generally at levels of from about 0% to about 5% of the composition.
• the oils may be present for their emollient effects or can be used as part of an oil/water emulsion composition.
• the oils which may be used in the present invention are generally partially or poorly soluble in C 8 or greater alcohols. Examples of such oils include mineral oils, safflower oil, castor oil, sunflower oil, silicone oil, olive oil, dimethicone, cyclomethicone, triglycerides. Particularly preferred is dimethicone.
• Emollients may be included in the compositions of the present invention, generally at levels of from about 0% to about 5%, for the purpose of enhancing both the formulation properties of the compositions (for example, the ability to apply the composition to the skin smoothly), as well as to provide desirable skin feel.
• emollients include silicone materials, such as dimethi cones (both cyclic and linear), pantethine derivatives (such as panthenol, pantothenic acid, pantetheine, and pantethine), and allantoin.
• compositions of the present invention may also contain surfactants which generally act to improve the formulation properties of the compositions.
• surfactants are included at a concentration of about 0% to about 5% of the composition.
• Nonionic surfactants are generally the ones used in the present invention, with sorbitol fatty acid esters and alkyl polyethoxylates (for example, Cg-C] 8 (EO) 4-5 o) being preferred.
• Examples of surfactants which may be utilized in the present invention include polysorbate 20 and polysorbate 80, both of which have commercial availability.
• embodiments of the present invention further comprise a UV- absorbing agent such as singular (monomeric) aromatic compounds and/or reflecting pigments such as octyl methoxycinnamate (PARSOL® MCX), benzophenone- 3(oxybenzone) and octyl dimethyl PABA.
• a UV- absorbing agent such as singular (monomeric) aromatic compounds and/or reflecting pigments such as octyl methoxycinnamate (PARSOL® MCX), benzophenone- 3(oxybenzone) and octyl dimethyl PABA.
• the composition of the invention may further comprise penetration enhancers for improved transepidermal or percutaneous delivery of drug.
• the penetration enhancers suitable for the present invention include terpenes, terpene alcohols, essential oils, surfactants, and the like. Some such examples include d-limonene, terpinen-4-ol, menthone, 1,8-cineole, 1-pinene, alpha-terpineol, carveol, carvone, pulegone, eucalyptol, peppermint oil, sorbitan esters, polysorbates, sodium lauryl sulfate, and the like.
• a composition comprises a poorly water-soluble or practically water-insoluble NSAID formulated in the absence of alcohol.
• NSAID a poorly water-soluble or practically water-insoluble NSAID formulated in the absence of alcohol.
• One such composition is an organogel, for example, a lecithin organogel obtained by adding small amounts of water to a solution of lecithin in organic solvents.
• One or more NSAIDs can be dissolved in the organic solvent.
• Organic solvents useful herein include, as nonlimiting examples, hydrocarbons, ethers, amines, and esters.
• the organic solvent is a fatty acid ester such as isopropyl palmitate or isopropyl myristate.
• the organogel of the present invention is a pluronic organogel. It has further been discovered that NSAIDs of the present invention can be formulated in to an alcohol- free composition in a phospholipids/ polyoxyethylenepolyoxypropylene copolymer composition. This provides for a composition with a useful concentration of an NSAID, a useful viscosity, yet does not deposit substantial amounts of inert ingredient on the skin. Moreover, in for some local inflammatory disorders, phospholipids deposited on the skin can have a soothing or even therapeutic effect (e.g., burn from UV exposure).
• Oil-in-water (o/w) emulsions are useful compositions for NSAIDs of the present invention.
• the oil phase is a useful solvent for the NSAID as well as other hydrophobic drugs and/or excipients.
• the water phase can usefully solubilize hydrophilic drugs and/or excipients.
• Oil-in-water emulsions are especially beneficial for NSAIDs of the present invention because one skilled in the art is able to adjust the oil/water ratio to provide sufficient drug solubilization and, at the same time, optimal drug delivery (i.e., movement of the drug from the formulation into the skin).
• One embodiment of the present invention provides a method of treating PFB comprising applying to the skin of a subject in need thereof, a composition comprising one or more alcoholic solvents in an amount of about 10% to about 90%, one or more NSAIDs in a total amount of about 0.001% to about 25%, and a polymeric thickener in an amount of about 0.05% to about 5%.
• Another embodiment provides a method of treating PFB comprising applying to the skin of a subject in need thereof a composition comprising one or more alcoholic solvents in an amount of about 30% to about 70%, one or more NSAIDs in a total amount of about 1 % to less than about 25%, and a polymeric thickener in an amount of about 0.05% to about 5%.
• Another embodiment provides a method of treating PFB comprising applying to the skin of a subject in need thereof, a composition comprising one or more alcoholic solvents in an amount of about 30% to about 70%, one or more NSAIDs in a total amount of about 5% to less than about 25%, a polymeric thickener in an amount of about 0.05% to about 5%, and one or more keratolytic agents are present in a total keratolytic agent concentration amount of about 0.015% to about 25%, and wherein the NSAID is substantially dissolved in the one or more alcoholic solvents.
• Another embodiment provides a method of treating PFB comprising applying to the skin of a subject in need thereof a composition comprising an NSAID prodrug,
• a composition comprising an NSAID prodrug
• Such a composition can be prepared by combining the NSAID prodrug with a dermatologically acceptable excipient.
• the present invention is useful for treating a subject with a local inflammatory disorder such as skin, joints, muscle, and ligaments.
• a local inflammatory disorder such as skin, joints, muscle, and ligaments.
• Examples of inflammatory skin disorders that can be effectively treated according to the present invention are disorders of the epidermis and dermis.
• Nonlimiting examples of such a disorders include eczema and related conditions; insect bites; erythroderma; mycosis fungoides and related conditions; pyoderma gangrenosum; erythema multiforme; rosacea; onychomycosis; acne, boils, and related conditions; UV damage; psoriasis; folliculitis and related conditions such as in-grown toe and finger nails; acne keloidalis, and boils.
• Nonlimiting examples of eczemas useful for treatment according to the present invention are atopic eczema, acrodermatitis continua, contact allergic dermatitis, contact irritant dermatitis, dyshydrotic eczema or pompholyx, lichen simplex chronicus, nummular eczema, seborrheic dermatitis, and stasis eczema.
• Nonlimiting examples of folliculitis useful for treatment according to the present invention are pseudomonas folliculitis (hot tub folliculitis), barber's itch, tinea barbae, pseudofolliculitis barbae, pityrosporum folliculitis, and herpetic folliculitis.
• pseudofolliculitis barbae includes pseudofolliculitis of areas other that the beard (barbae).
• PFB signifies a condition of the skin (or area of the skin) wherein inflammation results from physical trauma caused, at least in part, from hair growth.
• PFB can affect men with curly hair who shave their faces; women with hirsutism who shave or wax their faces; subjects with curly or sharp-tipped hair who shave their legs, arm pits, and the so-called bikini areas (i.e., pubic region, upper thighs, etc.); as well as individual who develop hair-induced skin inflammation even in the absence of shaving (e.g., ingrown hairs).
• PFB subjects that can also be treated with compositions of the present invention in combination with other treatments or activities such as shaving, laser treatment, waxing (for hair removal), or depilatory treatment.
• the present invention is useful for treating a subject with local pain, for example pain resulting from stimulation of nociceptors in the skin, bones, joints, and muscles.
• local pain for example pain resulting from stimulation of nociceptors in the skin, bones, joints, and muscles.
• many or most of the aforementioned local inflammatory disorders further comprise a pain component resulting from stimulation of nociceptors in the skin.
• Nonlimiting examples of such pain that result from stimulation of nociceptors in bones, joints, and muscles usefully treated by compositions of the present invention are arthritis, muscle damage, surgery of bones, joints, and muscles, fibromyalgia, neuropathy, and muscle cramps.
• embodiments of the present invention also reduce the inflammatory response associated with arthritis.
• Delivery Systems and Storage Vessels also provided is a delivery system (including a storage device) useful for delivering any of the compositions of the present invention.
• Delivery system useful for compositions of the present invention include a pump dispenser, jar, spray bottle, wipes, shaving razors adapted for gel delivery, pouch, tube, roll-on, squeeze bottles, aerosol containers, flexible articles intended to be worn on the skin (impregnating said composition into a fibrous or nonfibrous matrix, dermal patch, adhesive tape, etc.).
• Suitable propellants for compositions in an aerosol container are the customary known readily-volatile liquefied propellants, for example, hydrocarbons
• compositions of the present invention are made in a conventional manner as exemplified herein. Moreover, one skilled in the art can readily understand that the scope of the invention includes other compositions that follow the teaching herein.
• compositions of the present invention are used for the topical delivery of topically active drug to the skin of a human or animal patient in need of such treatment. Specifically, a safe and effective amount of the composition is applied to the skin at the site where treatment is required.
• the compositions of the present invention can be used to provide an analgesic or antiinflammatory effect to the patient by applying a safe and effective amount (e.g., from about 0.002 to about O.Olg/cm 2 ) of a composition of the present invention wherein the pharmaceutical active is an nonsteroidal anti-inflammatory material, such as ibuprofen.
• composition having the following components and properties is made using conventional techniques:
• the pH of the final gel is from 3,5 to 4.8.
• the viscosity of the gel is from 1 ,200 cps to 75,000 cps.
• composition is made in the following manner: a) dissolve all alcohol soluble ingredients in the ethanol; b) add optional liquid components; c) in a separate vessel, optionally add water and water soluble components and stir until dissolved; d) combine the optional water/water soluble components to the alcohol solution; e) add the CARBOMER® slowly with agitation and allow CARBOMER® to hydrate for 18 hours.
• Another formulational example is a composition comprising: a) about 1 to about 40% isopropyl alcohol b) about 20 to about 50% ethanol c) 0.01 to about 0.05% saffiower oil d) 5 to about 10% of anesthetic agent e) 1 to 1.5% thickening agent such as KLUCEL® f) water qs to 100% [00237]
• Example 3
• Another formulational example is a composition comprising: a) about 49 to 73% ethanol b) about 1 to 4% glycerin c) about 1 to 3% polysorbate 80 d) about 1 to 10% acetaminophen e) about 0.01 to 0.1% oleyl alcohol f) 2 to 4% CARBOPOL® 981 g) water qs to 100% [00238]
• Example 4 is a composition comprising: a) about 49 to 73% ethanol b) about 1 to 4% glycerin c) about 1 to 3% polysorbate 80 d) about 1 to 10% acetaminophen e) about 0.01 to 0.1% oleyl alcohol f) 2 to 4% CARBOPOL® 981 g) water qs to 100% [00238]
• compositions were prepared as shown in Table 1 , with and without the active drug ibuprofen ("IBU").
• IBU active drug
• polymeric thickeners namely ULTREZTM 10, ULTREZTM 20, 980 (Noveon), and 981 (Noveon).
• Table 2 compositions with 15% ibuprofen show a substantially lower viscosity than the similar composition without an active drug. This was the similar finding for compositions made with each of the polyacrylic polymeric thickeners.
• hydro alcoholic gels of the present invention when containing a substantial amount of an active ingredient (e.g., 5-20%) and a polyacrylic thickener, have superior viscosity for dermatalogic application without the need of added alkalinizing agent (neutralization).
• an active ingredient e.g., 5-20%
• a polyacrylic thickener e.g., polyacrylic thickener
• compositions were prepared as shown in Table 3. As is shown in Table 4, the compositions comprising 15% ibuprofen and 2.5% polymeric thickener show a substantially lower viscosity than the similar composition without an active drug and comparable to the composition with no active drug and 1.5% polymeric thickener.
• compositions were prepared according to Table 5 and viscosity was measured. As shown in Table 6, decreasing the amounts of water resulted in an increase in viscosity, Unexpectedly, a further decrease in water from 25% to 18%, when combined with the addition of 15% ibuprofen (free acid) resulted in a desirable viscosity of 11,300 cps. Thus, a dermatologic composition can be prepared according to the present invention with low water content (e.g., about 5% to about 20%) and no additional alkalinizing agent, [00245] Table 5.
• compositions were prepared according to Table 7, [00248] Table 7.
• compositions were prepared according to Table 8. As shown in Table 9, viscosity in the compositions is greater with the ethanol solvent than with the isopropanol solvent. Moreover, addition of 15% active results in a marked decrease in viscosity. [00251] Table 8.
• compositions prepared according to Table 12 Hydroalcoholic gel compositions comprising salicylic acid and ethanol attain a higher viscosity than a similar composition comprising salicylic acid and isopropyl alcohol. Moreover, the ethanol/salicylic acid composition showed negligible viscosity change following the addition of alkalinizing agent, When the pH is adjusted one unit for the isopropanol composition, there is a surprising decrease in viscosity. [00257] Table 12. Compositions and Viscosity
• hydroalcoholic gels of the present invention when containing a substantial amount of an active ingredient (e.g., 5-20%), an amount of isopropanol sufficient to dissolve the dermatologic active ingredient, and a polyacrylic thickener, have a useful viscosity for dermatologic application without the need of added alkalinizing agent (neutralization).
• an active ingredient e.g., 5-20%
• an amount of isopropanol sufficient to dissolve the dermatologic active ingredient
• a polyacrylic thickener have a useful viscosity for dermatologic application without the need of added alkalinizing agent (neutralization).
• Such compositions when water content is greater than about 50%, can be pH adjusted to 5.0 and maintain superior viscosity for dermatologic compositions.
• Composition Ia was prepared with or without 0.15% salicylic acid (SA) (with the difference made up with water addition) and tested for stability of pH and viscosity with storage time.
• SA salicylic acid
• the salicylic acid-containing composition showed better stability of viscosity within 15% of initial values ( Figure 1) and pH ( Figure 2).
• the initial phase shows about 10% greater variations of pH when no salicylic acid present. From day 28 through 78, while the means for compositions with and without salicylic acid were similar (3.96 vs. 3.90, respectively), the standard deviations for the salicylic acid-containing composition was half that of compositions in the absence of salicylic acid (0.08 vs. 0.16, respectively).
• Figure 3 shows a plot of pH vs. viscosity for each of the samples from Figures
• compositions of the present invention were prepared according to Table 14 and viscosity quantified. [00264] Table 14. Viscosity
• Table 14 also shows that addition of an active drug NSAID to a composition of the present invention can cause a positive or a negative effect on viscosity. Addition of ibuprofen had the most marked viscosity-lowering effect.
• Figure 4 shows the normalized change in viscosity plotted against the logio P value.
• compositions were spiked with tracer levels ( ⁇ 1.0 ⁇ Ci/3.2 mg composition dosed per diffusion cell) of [ 3 H] -ibuprofen.
• tracer levels ⁇ 1.0 ⁇ Ci/3.2 mg composition dosed per diffusion cell
• a single, clinically-relevant, finite dose ( ⁇ 5 mg composition/cm 1 ) was applied to dermatomed human abdominal skin from elective surgery.
• Percutaneous absorption was evaluated using this skin mounted on Bronaugh flow-through diffusion cells maintained at a constant temperature of 32 0 C by use of recirculating water baths. These cells have an opening with a nominal area of 0.64 cm 2
• Fresh receptor fluid, PBS containing 0.1% sodium azide and 1.5% Oleth 20 was continuously pumped under the dermis at a flow rate of 1 ml/hr and collected in 6-hour intervals.
• composition residing on the skin surface was removed by wiping with two, dry, cotton swabs.
• the upper layers of the stratum corneum were removed from the epidermis with a single cellophane tape-strip.
• the remaining epidermis was then physically separated from the dermis and processed for analysis separately. Quantity of radioactivity in the wipes, tape-strip, epidermis, dermis, and receptor fluid samples was determined using liquid scintillation counting techniques.
• compositions 16a-d have desirable percutaneous absorption. It should be noted that percutaneous absorption demonstrated in this ex vivo assay is but one factor contributing to delivery of therapeutically effective drug to target areas.
• compositions of the present invention upon storage, result in the generation of a prodrug form of the active ingredient.
• prodrug formation results from reaction of a carboxylic acid group of the active drug with the alcoholic solvent to form an ester linkage.
• composition Ia stored for 3 months at 25 0 C.
• a new peak (i.e., the prodrug) distinct from the ibuprofen peak was detected within the chromatographic profile.
• the peak showed an elution position considerably later than Ibuprofen and a UV response at 220 nm.
• composition 1 a was diluted in twenty- five milliliters of
• Solvent A Water Solvent B: Acetonitrile Gradient: Start 40 % B
• Sequential detection was performed by UV absorbance using an HP diode array detector followed by ESI-MS followed by ESI-MS using a Sciex QSTAR®/Pulsar quadrupole-TOF mass spectrometer operating in either the positive and negative ion modes.
• Figure 6 illustrates the UV chromatogram (220 nm) following injection of
• Composition Ia stored 3 months at 25 0 C using the chromatographic conditions • described above. Ibuprofen showed a peak at about 14 minutes and the prodrug showed a peak at about 32 minutes.
• Figure 7a shows the positive ESI mass spectrum for the Ibuprofen peak.
• the expected (M+H)+ pseudomolecular ion is observed at m/z 207,13 with corresponding (M+NH 4 ) + and (M+Na) + pseudomolecular ions at m/z 224.15 and 229.10 respectively.
• Dimeric cluster ions may be assigned to signals at m/z 430.27 and m/z 435.22.
• a notable, possible fragment ion also appears at m/z 161.12 consistent with decarboxylation as illustrated below:
• Figure 7b shows the UV spectrum for the Ibuprofen which demonstrates maxima at approximately 220 nm and 265 ran.
• Figure 8a shows the positive ESI mass spectrum obtained from the prodrug.
• a possible (M+H) + is observed at m/z 235.15 and, as in the Ibuprofen data, corresponding (M+NH 4 ) + and (M+Na) + pseudomolecular ions may be assigned at mlz 254,13 and m/z 257.13 respectively.
• the signal at m/z 161.12 consistent with the same fragment ion described for Ibuprofen.
• Figure 8b shows the UV spectrum obtained from the prodrug and is very similar to that obtained for Ibuprofen with maxima at approximately 220 nm and 265 nm.
• prodrug has (1) a neutral mass of 234.15 Da; (2) a UV spectrum very similar to that of Ibuprofen; (3) retention behavior that suggests it to be considerably more hydrophobic than ibuprofen; (4) no significant negative ion MS response; and (5) a positive ion MS spectrum indicating a shared fragment with ibuprofen.
• composition 1 a The effect of alkalinizing agent ("neutralization") on the generation of prodrug was examined in Composition 1 a. As shown in Figure 10, prodrug generation is linear for at least the first 26 days. In the composition without alkalinizing agent, that rate was approximately 0.05% per day as compared to the lower rate of about 0.025% per day in the neutralized samples.
• compositions were prepared according to Table 7. As can be seen in Figure 12, alkalinizing agent substantially decrease the rate of prodrug formation. Moreover, decreasing the concentration of active drug in neutralized compositions substantially decrease the rate of prodrug formation. Linear extrapolation of the data indicate that at an initial concentration of 14.8% ibuprofen in neutralized compositions would prevent the formation of the prodrug.
• composition substantially similar to Composition Ia is made to contain 24% water and -50% ethanol, there is a further reduction in the prodrug formation rate.
• adjusting the pH to 5.5 through addition of diisopropylamine results in a substantial increase in prodrug formation rate when compared to a similar composition adjust to pH 5.0 with diethylamine.
• compositions similar to Ia were prepared and tested for prodrug formation in the presence or absence of salicylic acid. As shown in Figure 13, salicylic acid increases the rate of prodrug formation. [00293] Example 21
• compositions containing stabilized concentrations of topically active drug and a prodrug are prepared according to Table 18. [00294] These compositions are prepared according to equilibrium equation of the esterification process, namely:
• the initial concentrations and final concentrations are within 10% of the initial concentrations.
• PFB efficacy is examined by a 10-week double blind, placebo-controlled, cross-over clinical trial, The investigator performs a quantitative assessment of PFB lesions at the baseline at weekly thereafter. Papules, pustules, and ingrown hairs as defined below are counted and recorded.
• Papule A small solid elevation less than 1.0 cm in diameter
• Pustule A small, circumscribed elevation of the skin which contains yellowwhite exudates.
• Ingrown Hair A hair that has exited the skin, curved around and reentered the skin, or a hair that has pierced the follicle and is growing under or in the skin.
• Lesions are counted on the neck, lower left and right cheeks, and jaw line
• alcoholic gels contain an NSAID of the phenylacetic acid type are effective to reduce severity of PFB in mild, moderate, and severe PFB.
• organogels containing high concentrations of NSAID of the phenylacetic acid type are effective in treatment of PFB with an "every-other-day" application regimen.
• Test subjects with acne or dermatitis e.g., contact dermatitis also report therapeutic efficacy against there indications.
• organogel containing 10% NSAID of the phenylacetic acid type reports efficacy similar to subjects treated with an alcoholic composition (10% NSAID of the phenylacetic acid type) but report that the organogels have less of a drying effect and cause less stinging of razor cuts.
• Radioactive (Ci 4 ) and nonradioactive ethyl esters and isopropyl esters of ibuprofen and of ketoprofen are synthesized.
• the esters are made between the hydroxyl group of the carboxylic acid using synthesis of NSAID alkyl ester.
• radiolabel ibuprofen ethyl ester is synthesized as above, only the starting material 2-[4-(2-methylpropyl)phenyl]propanoic acid, is Ci 4 labeled.
• the other NSAID alkyl esters are similarly made. Each is formulated separately at 15% prodrug in 60% alcohol corresponding to the promoiety (i.e., reactant), 1% ULTREZTM 10, and 24% water. A comparator composition is also prepared with ketoprofen. A placebo is prepared with no active. [00316] The prodrug compositions are tested on PFB subjects according to
• Example 22 including pharmacokinetic analysis.
• 0.2 gm of the C ⁇ -labeled compositions are applied per cm 2 of skin of minipigs, and punch biopsies of skin are taken from multiple sites at intervals from 30 seconds to 24 hours after application. Serum samples are also taken at intervals, Results are shown in Table 19. [00318] Table 19
• Oil in water NSAID prodrug compositions are formulated as illustrated in Table 20.
• compositions are formulated according to Table 20.
• Each NSAID or NSAID prodrug is formulated four different ways: as an organogel ("A"), as an oil-in-water (“B”), as an alcoholic gel (“C”), and as a phospholipids/polyoxyethylenepolyoxypropylene copolymer composition.
• the compositions are formulated according to the teaching in the present invention and by consideration of the physicochemical properties of each drug. Each composition is prepared at three pHs: 4.0, 5.0, and 6.0.
• Drug concentrations are 15% (if soluble) or at an empirically-determined saturation concentration. Drug absorption, distribution, metabolism and elimination is determined in ex vivo and in vivo animal models.
• Efficacy is measured in the contact dermatitis model in the hairless guinea pig
• Models are generated to aid in the selection and optimization of NSAID (and/or NSAID prodrug) and formulation for various inflammatory skin disorders.

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