CN101151028A

CN101151028A - Topical gels compositions

Info

Publication number: CN101151028A
Application number: CNA2006800100569A
Authority: CN
Inventors: M·斯潘-韦德; A·J·沃德
Original assignee: ISW Group Inc
Current assignee: ISW Group Inc
Priority date: 2005-03-03
Filing date: 2006-02-27
Publication date: 2008-03-26
Also published as: ZA200707375B

Abstract

Topical alcoholic gel compositions are disclosed that are useful for delivering therapeutic levels of an NSAID to target in and below the skin. The compositions comprise a topically active drug, an alcoholic solvent, a polymeric thickener, and optionally a keratolytic agent. In one embodiment, excellent viscosity for dermal application is attained without the need of a step for neutralizing the pH of the composition. Alcoholic and alcohol-free topical compositions comprising an NSAID prodrug are also disclosed. The compositions are particularly useful for the treatment of pseudo folliculitis barbae.

Description

Topical gels compositions

The cross reference of related application

The application requires the priority of following application: the U.S. Provisional Patent Application US60/658 that on March 3rd, 2005 submitted to, 084; The U.S. Provisional Patent Application US60/681 that on May 13rd, 2005 submitted to, 102; With the U.S. Provisional Patent Application US60/690 that submitted on June 14th, 2005,201, these documents intactly are incorporated herein by reference separately.

Technical field

The present invention relates to topical compositions, especially for the topical compositions that pharmaceutically active agents is applied to skin.The invention still further relates to the pain that treatment causes because of the local excitation of nociceptor in skin, bone, joint and muscle and the compositions of the pain in the skin disorder, wherein inflammation is pathogenetic factor.The example of this class inflammatory dermatosis related to the present invention is a pseudofolliculitis barbae.

Invention field

The pathogeny of various skin disorders comprises inflammatory process.Usually this class disease relates to the inflammatory cell (for example polymorphonuclear neutrophil leukocyte and lymphocyte) that is impregnated into skin, but does not have the obvious or known infection cause of disease.The symptom of inflammatory dermatosis generally comprises erythema (rubescent), edema (swelling), pain, pruritus, surface temperature rising and afunction.

Although researched and developed the method for the treatment inflammatory dermatosis of certain limit, none is in full force and effect or do not have an adverse side effect.Treat different inflammatory dermatosiss and generally comprise local or oral steroid (for example being used for various types of eczemas, acne and erythema multiforme); Ultraviolet light (for example being used for nummular eczema and mycosis fungoides); Antibiotic and other anti-inflammatory therapy.

Corticosteroid has maximum importance to treatment inflammatory dermatosis disease.Corticosteroid from weak to moderate strength (for example nonfluorinated derivant of hydrocortisone) is mainly used in inflammation, anaphylaxis and itching skin disease therapy.Although use oral steroid short term therapy (several days or a few week) comparatively safe, long-term treatment (above 3 months) may cause unwanted side effect, comprises Cushing's syndrome, skin graph thinning and the sensitivity increase to infecting.In addition, may delay, continue some months such as the improvement that makes various acne treatments.

Have the various activating agents that are usually used in belonging to non-narcotic class and nonsteroidal medical practice, and they still can be used for anti-inflammatory and pain.They are salicylate and the activating agent that also has so-called on-steroidal AID (NSAIDs).

There are the various newer medicines of buying at present.Although the chemical constitution of these new activating agents changes quite widely, the many common architectural features in these chemical compounds are to exist hydroxy-acid group (COOH).For example, one group of NSAIDs form, and another group of NSAIDs is formed (for example indomethacin) by acetogenin by propanoic derivatives (so-called " the fragrant class in Lip river ", for example ibuprofen).

When orally using for a long time, NSAIDs can cause gastric ulcer and hemorrhage.The purpose of topical administration NSAIDs is the medicine of treatment effect level is delivered to local target (for example nociceptor in the skin and inflammatory cell), shunts and prevent systemic delivery from stomach simultaneously.

Regrettably, NSAIDs can't fully be absorbed when topical usually.Those provide the topical preparation of percutaneous certain absorption can cause actual systemic delivery really and can not provide treatment level usually in skin.

In addition, usually by topical administration counter-stimulus treatment acute inflammation and pain.In this respect, widely used activating agent is a methyl salicylate, usually its form with ointment or cream is applied to skin and causes the analgesic activity that appropriateness is soft.Yet there is defective in methyl salicylate, and promptly it has abnormal smells from the patient in some cases and may be regarded as discomfort to some individuality.

Title is a method of having described the topical therapeutic inflammatory dermatosis in the U.S. Pat 4,185,100 of " local anti-inflammatory medication ", comprises Zoned application anti-inflammatory agent of being encroached on and the antiphlogistic corticoid of using Topically active simultaneously.Use these activating agents in the mode of the acceptable topical vehicle of dermatological, described topical vehicle is selected from cream, gel, ointment, powder, aerosol and the solution that is suitable for topical.

Kyuki etc. at " Anti-Inflammatory Effect of Diclofenac-SodiumOintment (Cream) in Topical Application; " Japan J.Pharmacol.33 has described the antiinflammatory action of diclofenac sodium among the 121-132 (1983).Use three types substrate to prepare ointment: to compare lithology, Emulsion (cream) and gel-type vehicle and antiinflammatory action thereof.Cream base is reported to by Kyaki etc. has effective function.

Title comprises ibuprofen, propylene glycol, water, CARBOPOL for the disclosed patent application EP0151953 of EP of " topical drug's delivery system " has described on the 10-11 page or leaf ^The ibuprofen CARBOPOL of 940 (acrylic acid polymers) and diisopropanolamine (DIPA) ^Gel systems is as the illustrative example of pharmaceutical composition, and said composition is used for absorbing by the local application percutaneous, and it is made by two liquid phases that comprise medicine, in position they is mixed together before use, so that form the gel that comprises oversaturated medicine.Disclosed the gel systems that does not contain alcohol that is used for the local delivery ibuprofen in the EPO application.

Title is the U.S. Pat 5 of " method of using aqueous alcohol gel dermal delivery ibuprofen ", 093, described the aqueous alcohol gel that comprises ibuprofen, hydroxypropyl cellulose or acrylic acid polymer in 133, wherein propylene glycol is optional, but preferred ingredients.Further instructed in this patent basifier has been joined in the preparation so that increase the benefit that percutaneous absorbs, the application of the benefit of water and S-enantiomer.

The title of Kishi etc. is to have disclosed the aqueous alcohol gel with 7.0-9.0 scope pH that comprises NSAID (for example ibuprofen) in the U.S. Pat 4,533,546 of " anti-inflammatory analgesic gelation ointment ".The gel ointment agent comprises phenylacetic acid anti-inflammatory compound, CVP Carbopol ETD2050, water solublity organic amine (for example triethanolamine) and water, and wherein the consumption of organic amine makes the gel ointment agent have the pH of 7.0-9.0 and preferred 7.3-7.8 scope.

The U.S. Pat 6,277,362 that authorize August 21 calendar year 2001 has been described the topical gels that comprises ibuprofen that is used for the treatment of pseudofolliculitis barbae (PFB) among the Ita.Pseudofolliculitis barbae is the skin disorder that mainly influences the experimenter of the curling chaeta of shaving.Curly hair is tended to by growing towards the skin bending.In single day growth course, the tip of hair shaft can be squeezed into skin to returning.Because razor has been left over sharp-pointed trim edge making a start, so hair in fact can transdermal and continued to enter to inside.

Epidermis (being the outermost layer of skin) comprises keratinocyte.As to penetrating the reaction of (for example hair), the deutero-residual cell of keratinocyte and other non-hematopoietic cell produces the cytokines that various stimulation T cell migration and adhesion molecule are expressed.As a result of, inflammatory cell (for example polymorphonuclear neutrophil leukocyte and lymphocyte) soaks into skin (from corium), causes the local swelling speckle.

The general features of full-blown PFB is zest speckle, pruritus and involved area decolouring.PFB becomes the ingredient of acceleration cycle.Speckle appears at next shaving when taking place, and produces the bulge area scratch and further stimulates.In addition, the complication of PFB comprises cellulitis, furunculosis and hypertrophic scar or keloid.The Secondary cases bacterial infection also can cause because of PFB.

Prior art for the known PFB of the relating to experimenter of present inventor comprises following list of references: U.S. Pat 3,981, and JIUYUE licensed to Mario de laGuarida on the 21st in 681,1976 years; U.S. Pat 4,228 licensed to WilliamE.Bliss on October 14th, 163,1980; U.S. Pat 4,525 licensed to Ronald J.Tutsky on June 25th, 344,1985; U.S. Pat 4,775 licensed to Nicholas V.Perricone on October 4th, 530,1988; With U.S. Pat 5,034, licensed to StevenE.Rosen etc. on July 23rd, 221,1991.

Generally speaking, use well-known polymer viscosifier, such as the CARBOPOL that is acrylic copolymer or polymer ^Material thickening topical preparation and particularly gel preparation.This base polymer neutralizes these polymer so that obtain suitable thickening characteristic as the conventional application need of thickening agent in topical preparation.Therefore, for example Fresno etc. is described below in Eur.J.Pharm.Biopharm.:54:329-335 (2002): " as to other CARBOPOL ^TMResin, in and ULTREZ ^TM10 dispersions are for the essential and mechanical property of polymer thus of research and development rheology .... ".The topical preparation that need to use neutral polymer viscosifier also is disclosed in the FIP World Congress Proceedings of the U.S. Pat 5,976,566 that licensed to Samour etc. on November 2nd, 1999 and Akbari etc., and Nice is among the France (2002).

The active drug delivery that provides valid density that needs in this area is so that the topical preparation of treatment inflammatory dermatosis, and they have favourable rheological properties, minimum systemic delivery and epidermis and corium are sent fast.

Summary of the invention

Had been found that new compositions, when used the part, they can be delivered to the NSAID of treatment level the individuality of suffering from the local inflammation disease.

Surprisingly, have been found that compositions of the present invention has one or more good pharmacodynamic profiles and is provided for the NSAID of various local inflammation treatment of conditions levels.In addition, the NSAID of treatment level and minimum systemic delivery have been obtained.

In one embodiment, the invention provides the compositions that comprises NSAID prodrug, solvent and thickening agent, wherein said NSAID prodrug is the unsubstituted Arrcostab of phenylacetic acid type NSAID, and wherein said thickening agent is optional to be polymer viscosifier.

In another embodiment, the invention provides the compositions that comprises NSAID, NSAID prodrug, solvent and at least a excipient, described excipient is selected from thickening agent, wetting agent, keratolytic agent, oil, softening agent, surfactant, antiseptic, coloring agent, UV blocker, antioxidant and spice.

In another embodiment, the invention provides the method for treatment inflammatory dermatosis disease, comprise experimenter's topical administration NSAID prodrug of these needs is arranged, wherein said NSAID prodrug is a phenylacetic acid type NSAID Arrcostab, and wherein said experimenter behaviour, livestock animals (for example calf and milch cow, sheep, poultry and pig etc.) or companion animals (Canis familiaris L., cat, horse etc.).

In another embodiment, the alcogel compositions comprises: one or more alcoholic solvents of the about 10%-of consumption about 90%; One or more NSAIDs of the about 0.001%-of total amount about 25%; The polymer viscosifier of the about 0.05%-of consumption about 5%; Have one or more keratolytic agents of the about 0.015%-of concentration about 25 with total keratolytic agent, and wherein NSAID is dissolved in one or more alcoholic solvents basically.

In one embodiment, compositions comprises: one or more alcoholic solvents of the about 50%-of consumption about 70%; The about 5%-of total amount is no more than about 25% NSAID; Polymer viscosifier with the about 0.05%-of consumption about 2%; Water with consumption 0-about 20%.

In one embodiment, compositions comprises: one or more alcoholic solvents of the about 10%-of consumption about 90%; One or more Topically active medicines of the about 0.001%-of total amount about 25%; With the polymer viscosifier of the about 0.05%-of consumption about 5%, wherein said Topically active medicine is dissolved in one or more alcoholic solvents basically, and wherein said composition has approximately 2 under the situation of not adding basifier, and 000cps-is about 50, the viscosity of 000cps.

In one embodiment, the alcogel compositions comprises at least a alcoholic solvent that exists with the about 30%-of total amount about 90%, at least a NSAID that has hydroxy-acid group and at least a polymer viscosifier, it is selected from Polyacrylate thickeners and alkyl hydroxy cellulose thickener, wherein total amount of thickening agent is about 0.1%-about 5%, wherein when storing said composition, the ester between described at least a alcoholic solvent and the hydroxy-acid group forms and is lower than about 0.03% every day.

The method of treatment local inflammation disease also is provided in another embodiment, has comprised any local acceptable composition of experimenter's dermal administration the present invention of these needs is arranged.

The delivery system that is used to send arbitrary composition of the present invention (comprising storage device) also is provided in another embodiment.

Optional described inflammatory dermatosis disease is a pseudofolliculitis barbae.

The accompanying drawing summary

The salicylic viscosity stabilization effect of accompanying drawing 1 expression is with the variation that stores.

The salicylic pH-Stabilization of accompanying drawing 2 expressions is with the variation that stores.

Accompanying drawing 3 expression is as the variation with storage of the salicylic Stabilization of pH and viscosity relationship figure.

The figure of viscosity variation relation when accompanying drawing 4 expression log10P and interpolation different activities medicine.

The percutaneous of the accompanying drawing 5 expression present compositions absorbs.

The UV chromatogram (220nm) of HPLC under accompanying drawing 6 expressions are injected～25 ℃ behind 3 months the formula 1a of storage.

Accompanying drawing 7a represents the positive ESI mass spectrum at ibuprofen peak.

Accompanying drawing 7b represents the UV spectrum of ibuprofen.

Accompanying drawing 8a represents the positive ESI mass spectrum available from prodrug.

Accompanying drawing 8b represents the UV spectrum available from prodrug.

Accompanying drawing 9 expressions produce with the prodrug that salicylic acid storage time and positive acting change.

The prodrug that the negative role that accompanying drawing 10 expressions are added with storage time and basifier changes produces.

The prodrug that the negative role that accompanying drawing 11 expressions are added with storage time and basifier changes produces-studies for a long period of time.

Accompanying drawing 12 expressions produce with the effect of storage time and basifier interpolation and the prodrug of NSAID concentration change.

The effect that prodrug formed when accompanying drawing 13 was represented the keratolytic agent salicylic acid to storage composition 1a.

Detailed Description Of The Invention

Use used herein as giving a definition:

Definition

Unless otherwise stated, otherwise " % " intention that relates to constituent concentration in the composition is expressed as the composition of percentage and the ratio of gross weight.

Solvent or solvent system in " solvent " intention present composition, wherein the Topically active medicine can be dissolved in wherein basically.

Known can be used for adding in the composition in order to increase the reagent of composition pH in " basifier " intention this area. The limiting examples of this class basifier comprises ammonium hydroxide; Alkali salt, such as magnesia, magnesium hydroxide, calcium hydroxide, NaOH, potassium hydroxide, lithium hydroxide, aluminium hydroxide, potash, sodium acid carbonate etc. Other example comprises: organic basic salt, such as alkanolamine, such as carbinolamine, monoethanolamine, butanolamine, dimethanolamine, diethanol amine, dipropanolamine, two butanolamines, diisopropanolamine (DIPA), trimethanolamine, triethanolamine, tripropanol amine, diisopropanolamine (DIPA), three butanolamines, aminomethyl propanol, N-METHYL-ALPHA-L-GLUCOSAMINE, tetrahydroxypropyl ethylenediamine etc.; Alkyl amine, such as methylamine, ethamine, propylamine, butylamine, diethylamine, di-n-propylamine, isopropylamine etc.

The arbitrarily unusual pathologic condition of " illness " intention. Illness can be (for example inflammation behind contact dermatitis or the surgical incision) genetic, infective, acquired, bringing out property, chronic or acute.

" excipient " intention is mixed with medicine in order to produce the arbitrary substance of pharmaceutical dosage form. The limiting examples of excipient comprises: for example thickener, NMF, keratolytic, oil, emulsifying agent, surfactant, anticorrisive agent, colouring agent, UV retarding agent, antioxidant, spices, mineral oil, atoleine, albolene, glycerine, polyethylene glycol and propane diols.

Any agent that " thickener " intention is used as thickening or structure is added to the auxiliary agent in the topical preparation. These reagent are given physical stability and are increased viscosity. The limiting examples of thickener is natural gum and natural polysaecharides, mineral thickener, oil and synthetic polymer thickener. In addition, the generation of thickener intention combining form is suitable for one or more reagent of the viscosity that dermic uses.

" the local active medicine of using " intention can be applied to medicine or the plant compound in the useful composition that local target is had therapeutic efficiency of skin. The typical activity medicine comprises solvate and the compound of all medicine polymorphs, its crystal habit, its pro-drug and isomers (comprising optically-active, geometry and dynamic isomer), enantiomer, salt, solvate and compound and salt thereof.

" local target " be intention skin, joint, muscle and ligament as an example.

" local inflammation illness " intention inflammatory process is the illness of the part of local target.

" pro-drug " intention can change into the active form (" parent drug ") that has more with the Topically active medicine without pharmacological activity or active lower chemical derivative by enzymatic in the body or chemical hydrolysis. Pro-drug is by forming (" front-part ") with the covalently bound parent drug of another kind of compound. Pro-drug used herein does not comprise by the NSAID derivative with the esterification formation on NSAID carboxylic-acid functional base of acyloxy alkyl. Before " pro-drug ester " expression-part is the pro-drug that ester bond is connected with parent drug.

The compositions consumption that " safety and effective dose " intention is enough to the treatment disease is provided abundant treatment, but this therapeutical effect is not big to user is produced unwanted side effect.

" be substantially free of basifier " unless the intention compositions does not conform to the basifier basifier exists as the pollutant of the another kind of composition that is used to prepare this based composition.

" treatment " intention is cured, and takes stopgap measures and/or prophylactic treatment." treatment " is not to mean the quantitative effect of expression, but has observable clinically beneficial effect.For example, prophylactic treatment is included in to be observed before the symptom and symptom takes place subsequently, but degree gives compositions of the present invention when being lower than not administration experimenter's situation.

" local acceptable " and " dermatological is acceptable " compositions intention are when being applied to skin, and the skin to general patient under normal operating position does not have the obvious stimulation effect.

" viscosity " intention is as passing through the flow graph of Brookfield DV-III Ultra program controlled, spindle (spindle) #LV4, the liquid fluidity that 10rpm measures.

Compositions of the present invention has one or more required in topical preparation advantageous feature, that is: (1) pH stability; (2) viscosity stability; (3) minimum systemic delivery; (4) part of treatment level is delivered to skin fast with active medicine; (5) high-caliber part with active drug delivery to skin; (6) send the part active medicine of continued treatment level in long-time; (7) increase the local rheological behavior of contact skin with active medicine; (8) prodrug produces; (9) prodrug forms and suppresses.

The prodrug compositions

Find unexpectedly and NSAID prodrug preparation cost inventive compositions make to exist good medicine to be delivered to local target, and the systemic delivery maintenance is can minimum.Bound by theory does not think that NSAID prodrug hydrophilic can carry out good dermal delivery.Before this class is sent and is discharged by the residence enzyme in the skin (for example esterase) subsequently-and part, thus prodrug is changed into the lower parent drug of hydrophilic.This low hydrophilic medicine has the more ability in vascularization zone that further diffuses to of reduction.

According to the present invention, local prodrug with active medicine has reduction or does not have pharmacological activity.But when topical, this medicine can be converted to has required active medicine (parent drug).Typical prodrug of the present invention comprises the NSAID prodrug, for example phenylacetic acid type NSAID prodrug.Disclosed in the other parts of this paper and to be used for other typical NSAIDs of the present invention and NSAID class.Those skilled in the art be easy to discern be used to derive in case the part of adding forward part by the key that is connected with NSAID with the functional group on the active medicine, described precursor portions can be processed to parent drug in local organization.

Select precursor-part can regulate the speed that dipole moment, electric charge, diffusion rate and hydrolytic rupture become " parent " medicine.

Prodrug can for example be formed by parent drug by adding precursor-part through esterification carboxylic-acid functional base (for example arylcarboxylic acid derivative NSAIDs).For example, the hydrogen of carboxylic acid hydroxyl is by alkyl or aryl or carbonyl substituted.Alkyl can not be substituted or be substituted, for example alkoxyalkyl, alkoxycarbonyl alkyl, alkoxycarbonyl amido alkyl, aminoalkyl or alkyl-carbonyl-amino alkyl.

Other example of precursor-part be methyl, ethyl, isopropyl, n-pro-pyl, the tert-butyl group, butyl, amyl group, methoxyl group, tert-butoxy, methoxy ethyl, ethoxyl methyl, methoxy, phenyl, carboxyethyl, methoxycarbonyl group methyl, methoxycarbonyl group ethyl, tertbutyloxycarbonyl aminomethyl, methoxycarbonyl group, aminomethyl and methyl carbonyl aminomethyl; Or its pharmaceutically acceptable salt.

Prodrug can also be produced so that form carboxylic acid amide esters or thioesters.

For example, can precursor-part be added to by formation ether on the hydroxyl-functional base and form prodrug on the NSAID in NSAID, wherein the hydrogen of hydroxyl-functional base is replaced by the alkanoyloxy alkyl.

Precursor-part can also be connected with NSAID by carbonates, carbamates or the amide-type that forms by the carbonyl carbon covalent bonding.

The method for preparing prodrug is as described herein.Other method is described in the following document: for example U.S. Pat 5,073, and 641; U.S. Pat 5,998,465; U.S. Pat 5,811,438; U.S. Pat 6,730,696; U.S. Pat 6,620,813; U.S. Pat 6,143,734; U.S. Pat 5,750,564; U.S. Pat 5,484,833; U.S. Pat 5,315,027; U.S. Pat 4,990,658; U.S. Pat 4,851,426; U.S. Pat 4,049,700; With U.S. Pat 3,228,831.

The patent of above-mentioned citation intactly is incorporated herein by reference.

Optional for slightly solubility as the part of prodrug of the present invention with active medicine, be actually water-fast or water-insoluble.

Local with optional carboxylic-acid functional base and/or the hydroxyl-functional base of containing of active medicine.

Local contain carboxylic-acid functional base and/or hydroxyl-functional base and for water-insoluble or in fact water-fast with active medicine is optional.

Excellent specific property

Use the present invention at present, can prepare compositions with solvent with different pharmacodynamic profiles by selecting NSAID, precursor-part.Compositions of the present invention also provides one or more topical preparation's features that are better than corresponding parent NSAID (for example ketoprofen is the corresponding parent NSAID of ketoprofen isobutyl ester): (1) is higher levels of drugs in skin or deep tissue (for example joint or muscle); (2) more lasting NSAID level in skin or deep tissue (for example joint or muscle); And/or (3) in skin or deep tissue (for example joint or muscle) more fast NSAID send.

In addition, can use NSAID prodrug esters of the present invention with the form of various compositionss.Generally can prepare the compositions that comprises this class prodrug so that contain more substantial this class prodrug than corresponding parent NSAID.

The compositions that comprises the NSAID prodrug especially is applied to produce fast the situation of NSAID level on target spot.

The compositions that comprises the NSAID prodrug especially is applied to the situation that the needs realization penetrates.

The compositions that comprises this class prodrug is compared the alcohol that can have minimizing under the prodrug concentration specifying with corresponding NSAID.The compositions that this class alcohol reduces can be used for the local inflammation disease, and wherein alcohol is unwanted (for example avoiding the situation of desiccant).The unwanted situation of this class comprises drying or the further disadvantageous situation of dry skin.Especially can be used for using the example of this class disease of the NSAID prodrug esters combination treatment that alcohol reduces to be psoriasis and dermatitis.

NSAID prodrug compositions of the present invention can be gel, hydrogel, lotion, solution, cream, ointment, dusting, dressing, foam, thin film, skin patch, wafer, implant, sponge, fiber, binder, microemulsion and/or liposome.Optional carrier comprises alcohol, water, mineral oil, liquid paraffin, white vaseline, glycerol, Polyethylene Glycol and propylene glycol.Can mix penetration enhancer.

Can by will be all or whole basically NSAID prodrug be dissolved in solvent and prepare NSAID prodrug compositions.The useful solvent or the limiting examples of solvent system are alcohols, organogel, chelating agent, cyclodextrin, liposome, microsome, phospholipid/copolymer and oil-in-water emulsion.Can also under the situation of not adding any a large amount of solvents, prepare NSAID prodrug compositions.

In compositions of the present invention, solvent is sent the medicine of the present composition has unexpected effect.Bound by theory not, the present inventor thinks that NSAIDs is absorbed into skin by two kinds of different mechanism: diffusion and transport simultaneously with solvent from solvent.Two kinds of mechanism are all competed with evaporating solvent, especially with regard to volatile solvent.Yet when high NSAID compositions (more than for example about 5% or 5%), NSAID can be quickened in fact by the absorption of two kinds of mechanism.Think that this can cause medicine to be sent more fast, the levels of drugs on target spot is higher and penetrate darker.However, however unexpected minimum of the systemic delivery that has more the NSAIDs in the compositions that hydrophilic can cause wrapping alcoholic solvent of corium.

Because the NSAID prodrug is compared the pure dissolubility that generally has increase with corresponding N SAIDs, so can prepare the dermatological acceptable composition of alcoholic solvent content (or other organic solvent) at present with reduction.

Preparation

In one embodiment, the invention provides the compositions that comprises NSAID prodrug, solvent and thickening agent, wherein the NSAID prodrug is the unsubstituted Arrcostab of phenylacetic acid type NSAID, and wherein thickening agent is optional is polymer viscosifier (this class reagent is described in the other part of this paper).The about 0.05%-of the amount of described optional thickeners about 5%.

In one embodiment, the invention provides the compositions that comprises NSAID prodrug, solvent and thickening agent, wherein the NSAID prodrug is the unsubstituted Arrcostab of the NSAID of non-naproxen, and wherein thickening agent is optional is polymer viscosifier (this class reagent is described in the other part of this paper).

In one embodiment, the invention provides the compositions that comprises NSAID prodrug, solvent and thickening agent, wherein the NSAID prodrug belongs to the NSAID class, it is selected from phenylacetic acid type NSAID, mefenamic acid (mefanamic)-class NSAID, former times health-class NSAID and indomethacin class NSAID, and wherein said NSAID prodrug is unsubstituted Arrcostab.

In one embodiment, the invention provides and comprise C ₁-C ₃The compositions of unsubstituted Arrcostab NSAID prodrug, solvent and the thickening agent of carbon.

In one embodiment, the invention provides the compositions that comprises ester NSAID prodrug, solvent and thickening agent, wherein the NSAID prodrug is the ibuprofen prodrug, and wherein precursor portions (promoiety) for the ester bond that is connected with NSAID (being ester-connection) and wherein precursor portions be amide groups, sulfenyl and/or unsubstituted alkyl.

In the embodiment of prodrug of the present invention, thickening agent is optional to be polymer viscosifier (this class reagent is described in the other part of this paper).The about 0.05%-of the amount of described optional thickeners about 10%.The optional about 0.05%-of percentage ratio about 5%; Optional about 0.05%-about 2%.

In another embodiment, the invention provides a kind of compositions, it comprises NSAID, NSAID prodrug, solvent and at least a excipient, such as thickening agent, wetting agent, keratolytic agent, oil, softening agent, surfactant, antiseptic, coloring agent, UV blocker, antioxidant or spice.Randomly, described NSAID prodrug can be metabolised to NSAID (for example common preparation of flurbiprofen and flurbiprofen ethyl ester).

The compositions of the present invention that comprises NSAID and NSAID prodrug has unexpected beneficial effect to local inflammatory disease.Bound by theory does not think that the NSAID prodrug causes spreading more fast and bigger localization than corresponding parent NSAID.After being delivered to target tissue, prodrug is converted to parent NSAID.Believe that 100% changes into parent NSAID and takes place simultaneously when being absorbed into skin.Think that the NSAID prodrug is not to have same activity with parent drug on site of action.NSAID in the compositions generally provides comparatively slowly medicine to send, because the NSAID hydrophobicity is lower, and in case arrive part, just provides higher activity.No matter mechanism how, NSAID prodrug/NSAID combination makes that compositions is not only quick and continues to send, and the local concentration of the active medicine of arrival target tissue is higher.

Can be by becoming the step of dermatological acceptable composition to prepare NSAID of the present invention and the common preparation of NSAID prodrug NSAID, NSAID prodrug, solvent and one or more optional mixed with excipients.

Randomly, the solvent in the NSAID prodrug compositions of the present invention can be alcohol (alcoholic) solvent or Non-alchoholic solvents.

In another embodiment, the invention provides the method for treatment epidermis inflammatory disease, comprise and give the ibuprofen prodrug to the experimenter that these needs are arranged, wherein the epidermis inflammation is selected from psoriasis, folliculitis, PFB and/or dermatitis.For example, dermatitis can be contact dermatitis, professional acquired dermatitis etc.

The NSAID prodrug compositions of the invention described above can be gel, hydrogel, lotion, solution, cream, ointment, dusting, dressing, foam, thin film, skin patch, wafer, implant, sponge, fiber, binder, microemulsion and/or liposome.Optional carrier comprises alcohol, water, mineral oil, liquid paraffin, white vaseline, glycerol, Polyethylene Glycol and propylene glycol.Can mix penetration enhancer.

Have been found that NSAID prodrug compositions of the present invention can and be particularly useful for the topical of NSAID prodrug for organogel composition.The useful organogel of a kind of this class is by low amounts of water being joined the lecithin organogel that obtains in the lecithin in organic solvent among the present invention.Generally speaking, for example, at room temperature prepare the lecithin organogel by lecithin being dissolved in organic solvent and adding enough water, be stirred to simultaneously the gel that obtains to have required viscosity.One or more NSAID prodrug can be dissolved in organic solvent, add lecithin afterwards.

Can be used for organic solvent of the present invention as limiting examples and comprise hydro carbons, ethers, amine and esters.Optional organic solvent is a fatty acid ester, such as isopropyl palmitate or isopropyl myristate.

Optional organogel of the present invention is Pluronic (pluronic) organogel.Optional Pluronic surfactant is the block copolymer of oxirane and expoxy propane.Pluronic can be joined in water (can choose wantonly medicine the is dissolved in wherein) solution, after this it be added in organic solvent/lecithin soln.As an example, generally Pluronic is mixed organogel so that stable gel substrate, wherein lecithin fraction is not to have high-purity.

In addition, have been found that in organogel of the present invention that organic solvent can reduce or be replaced by NSAID prodrug ester.This makes it possible to prepare the compositions of higher total NSAID concentration.This based composition also is used to dissolve the other medicine that is refractory to water.

Further discovery can be mixed with NSAID prodrug of the present invention phospholipid/poloxalkol the based composition that does not contain alcohol.In addition, phospholipid concentration can reduce or be replaced by the NSAID prodrug.This just provides the compositions of NSAID prodrug with useful concentration, useful viscosity, but said composition can not make a large amount of inert components be deposited on the skin.In addition, with regard to some local inflammation disease, the phospholipid that is deposited on the skin has the effect (for example burning from the UV irradiation) of alleviating and even treating.

Oil-in-water type (o/w) Emulsion is the useful compositions of NSAID prodrug of the present invention.This based composition is made of oil phase, water and emulsifying agent.Oil phase is the useful solvent that is used for NSAID prodrug and other hydrophobic drug and/or excipient.Water can usefully dissolve hydrophilic medicament and/or excipient.Randomly, the solvent that is used for the NSAID prodrug can be reduced or be replaced by the NSAID prodrug, as long as it is a liquid NSAID prodrug.As an example, typical emulsifying agent is nonionic or anionic surfactant, as polyoxyethylene 20 sorbitan trioleate (polysorbate85), sorbitan laurate, polyoxyethylene 4 lauryl ether sodium stearates etc.Oil-in-water emulsion is especially useful to NSAID prodrug of the present invention, because those skilled in the art can adjust oil/water than so that enough medicament solubilizations are provided, and provides best medicine to send (be medicine move go into skin) simultaneously from preparation.

Therapeutic Method

In one embodiment, the invention provides the method for treatment local inflammation disease, comprise experimenter's topical administration NSAID Arrcostab of these needs is arranged, wherein NSAID is not a naproxen, and wherein the experimenter is non-rodentine mammal.

In one embodiment, the invention provides the method for treatment local inflammation disease, comprise experimenter's topical administration NSAID Arrcostab of these needs is arranged, wherein NSAID is not a naproxen, and wherein experimenter's behaviour, livestock animals or companion animals.

In another embodiment, the invention provides the method for treatment inflammatory epidermis disease, comprise experimenter's topical administration NSAID prodrug of these needs is arranged, wherein the NSAID prodrug is a phenylacetic acid type NSAID Arrcostab.

In another embodiment, the invention provides the method for treatment inflammatory dermatosis disease, comprise experimenter's topical administration NSAID prodrug of these needs is arranged, wherein the NSAID prodrug is phenylacetic acid type NSAID Arrcostab and wherein experimenter's behaviour, livestock animals or companion animals.

In another embodiment, the invention provides the method for treatment local inflammation disease, comprise experimenter's topical administration NSAID prodrug of these needs is arranged, wherein the NSAID prodrug is Arrcostab and wherein experimenter's behaviour, livestock animals or the companion animals of a NSAID 1-3 carbon.

Randomly, described local inflammation disease is skin disorder or optional is the epidermis skin disorder.Optional local inflammation disease is psoriasis, folliculitis, PFB and/or dermatitis.

Contain alcogel

The invention provides in addition and be used to give locally contain the alcogel compositions with active medicine.Optional part is NSAID with active medicine.

In one embodiment, compositions comprises:

(1) one or more alcoholic solvents of the about 10%-of consumption about 90%;

(2) the local active medicine of using of one or more of the about 0.001%-of total amount about 25%; With

(3) polymer viscosifier of the about 0.05%-of consumption about 5%, wherein the part is dissolved in described one or more alcoholic solvents basically with active medicine.

It is about 5% that optional one or more keratolytic agents that exist in the present composition, its total keratolytic agent concentration amounts are about 0.015%-about 25% or about 0.05%-about 10% or about 0.05%-, or about 0.05%-about 2%.Further describe hereinafter and be used for the keratolytic agent that the present invention contains the alcogel compositions.

Observed as being easy to from the application's embodiment, find can choose wantonly unexpectedly keratolytic agent is used for the present invention with concentration at effective stable composition aspect pH and the viscosity.The keratolytic agent that this class is stable be salicylic acid and typical viscosities-and/or pH-stablize consumption and be about 0.05%-about 25% or about 0.05%-about 10% or about 0.05%-about 5% or about 0.05%-about 2%.

Optional keratolytic agent exists with the amount of stablizing pH.

Optional keratolytic agent exists with the amount of stable viscosity.

Optional keratolytic agent is selected from α-and beta-hydroxycarboxylic acids and beta-keto carboxylic acid and salt, amide-type or esters.

Optional keratolytic agent is a salicylate.

In one embodiment, polymer viscosifier is a Polyacrylate thickeners.Find that unexpectedly the alcogel that contains that the present invention comprises Polyacrylate thickeners provides and treats useful pH and viscosity, and the demand of adding basifier is reduced or need not any neutralization procedure in preparation compositions process.This with this area in the routine instruction of relevant acrylic acid polymer thickening agent opposite.For example, referring to the Noveon technical bulletin, wherein described: " target is pH scope 7.3-7.7 " and " use the key of CARBOPOL  polymer formulation aqueous gel to be to select correct nertralizer.Because the dissolubility of CARBOPOL  salt changes with the increase of pure level, so must will use specific nertralizer for concrete aqueous alcohol admixture " (referring to NoveonTDS 255,12/99 revisions).

As conspicuous in the embodiment of the present application, the compositions that present the application provides has treatment useful pH and viscosity number, and by selecting alcoholic solvent and concentration, active medicine and concentration, Polyacrylate thickeners and concentration and water concentration can have minimizing or not having basifier.Bound by theory not, the present inventor supports its theory on evidence, i.e. new interaction between the carboxylic acid of active medicine, polymer viscosifier (for example acetas) electric charge and alcoholic solvent and the water concentration has caused obtaining being suitable for the rheological properties of topical.

Compositions of the present invention is generally tart and to have about 3.0-about 6.5, optional about 4.0-about 5.5 or choose the pH of about 4.3-about 5.0 wantonly.

In one embodiment, compositions comprises:

(1) one or more alcoholic solvents of the about 10%-of consumption about 90%;

(2) one or more part active medicine of the about 0.001%-of total amount about 25%; With

(3) polymer viscosifier of the about 0.05%-of consumption about 5%, wherein the part is dissolved in described one or more alcoholic solvents basically with active medicine, wherein the part is dissolved in described one or more alcoholic solvents basically with active medicine, wherein said composition has about 2 under the situation of not adding basifier, 000-is about 50, the viscosity of 000cps.

In one embodiment, compositions comprises:

(1) one or more alcoholic solvents of the about 50%-of consumption about 70%;

(2) the about 5%-of total amount is no more than about 25% NSAID; With

(3) polymer viscosifier of the about 0.05%-of consumption about 2%, wherein said composition has approximately 2 under the situation of not adding basifier, and 000-is about 50, the viscosity of 000cps.

In one embodiment, compositions comprises:

(1) one or more alcoholic solvents of the about 10%-of consumption about 90%;

(3) polymer viscosifier of the about 0.05%-of consumption about 5%, wherein the part is dissolved in described one or more alcoholic solvents basically with active medicine, wherein said composition has about 2,000-about 50,000 viscosity, and wherein said composition does not contain above compositions pH being increased about 2 pH units or the optional basifier that is no more than about 1 pH unit or about 0.5 institute of pH unit expense.

In one embodiment, compositions comprises concentration and is lower than 0.5% basifier.In one embodiment, do not add basifier.

In another embodiment, compositions is substantially free of basifier.Described medicine is optional to be NSAID and optional benzene acetic acid-type NSAID.

Find that unexpectedly the water concentration (having in the presence of the active medicine) that increases in the present composition causes viscosity obviously to descend.This is opposite with the preparation that does not contain active medicine, wherein increases water and causes viscosity to increase.

For example, as can be observed from one or more embodiment of the application, comprise the compositions that is used for active medicine of the present invention, about 25% water, 50% isopropyl alcohol and polymer viscosifier and have and be not suitable for the effectively treatment viscosity of sending of active medicine.This is opposite with the analogous composition of the present invention with suitable viscosity, and analogous composition of the present invention comprises and is used for active medicine of the present invention, is lower than about 24% water and is higher than about 40% ethanol.

Also find to comprise and be lower than about 24% water and about 40% or during more alcoholic solvent (for example about 40%-about 80%), can obtain the therapeutic efficiency of excellence at gel combination of the present invention.This based composition shows effect when using every day once or twice to PFB patient.This result is uncommon, because the experimenter of research comprises that those have the experimenter who other is treated unresponsive chronic sympton.

In one embodiment, compositions comprises:

(1) one or more alcoholic solvents of the about 10%-of consumption about 90%;

(2) total about 0.001%-of NSAID consumption is no more than one or more NSAIDs of about 25%;

(3) polymer viscosifier of the about 0.05%-of consumption about 5%; With

(4) water of consumption 0-about 30%.The optional water yield is about 0%-about 20%.

In one embodiment, compositions comprises:

(1) one or more alcoholic solvents of the about 20%-of consumption about 95%;

(2) total about 1%-of NSAID consumption is no more than one or more NSAIDs of about 25%;

(3) polymer viscosifier of the about 0.05%-of consumption about 5%; With

(4) water of consumption 0%-about 20%.

In one embodiment, compositions comprises phenylacetic acid type NSAID prodrug ester, solvent and thickening agent, and wherein precursor portions is amide groups, sulfenyl or unsubstituted alkyl.

In one embodiment, compositions comprises NSAID prodrug, solvent and at least a excipient, described excipient is thickening agent, wetting agent, keratolytic agent, oil, softening agent, surfactant, antiseptic, coloring agent, UV blocker, antioxidant or spice, and wherein the NSAID prodrug is the unsubstituted Arrcostab of the NSAID of non-naproxen.

Optional above-mentioned composition comprises wetting agent.

In one embodiment, contain the alcogel compositions and comprise the NSAID of the about .001%-of one or more alcoholic solvents, total amount about 25% of the about 10%-of consumption about 90% and the Polyacrylate thickeners of the about 0.05%-of consumption about 5%, wherein to exist concentration amounts to be about 0.015%-about 25% for total keratolytic agent of one or more keratolytic agents, and wherein NSAID is dissolved in described one or more alcoholic solvents basically.

In one embodiment, compositions comprises and contains the alcogel compositions, said composition comprises at least a alcoholic solvent of the about 30%-of total amount about 90%, at least a NSAID that has hydroxy-acid group and at least a polymer viscosifier, it is selected from Polyacrylate thickeners and alkyl hydroxy cellulose thickener, the total amount of thickening agent is about 0.1%-about 5%, wherein when said composition stored, the ester that forms between at least a described alcoholic solvent and hydroxy-acid group was lower than about 0.03% every day.The pH of optional said composition is greater than 5.0.Optional said composition further comprises can suppress the keratolytic agent (for example salicylate) that ester forms (being that prodrug forms) consumption.Optional alcoholic solvent is branched-chain alcoho or the alcohol that contains 4 or 4 above carbon.

In one embodiment, contain at least a alcoholic solvent, at least a NSAID that has hydroxy-acid group and at least a polymer viscosifier that the alcogel compositions comprises the about 30%-of total amount about 90%, it is selected from Polyacrylate thickeners and alkyl hydroxy cellulose thickener, the total amount of thickening agent is about 0.1%-about 5%, wherein when said composition stored, the ester that forms between described at least a alcoholic solvent and hydroxy-acid group was lower than about 0.03% every day.Optional said composition has the pH less than about 5.Optional alcoholic solvent is the direct-connected alcohol that contains 3 or 3 following carbon.

As conspicuous from the application's embodiment, when active medicine has hydroxy-acid group and is C at alcoholic solvent ₁-C ₃During straight chain alcohol (for example methanol, ethanol or propanol), described alcoholic solvent and hydroxy-acid group form ester with the accelerated speed reaction when composition stores.

When active medicine has carboxylic acid and is branched-chain alcoho or when having 4 or 4 above carbon at described alcoholic solvent, when storing, form the speed and the C of ester between alcoholic solvent and the hydroxy-acid group ₁-C ₃Straight chain alcohol is compared and is inhibited.

The concentration that keratolytic agent can be chosen wantonly with effective increase active medicine esterification ratio is used for the present invention.Typical keratolytic agent is the salicylic acid of about 0.05%-about 5% or about 0.05%-about 2.5% or about 0.1%-about 1.5% or about 1% concentration of about 0.1%-.

In addition, when active medicine had hydroxy-acid group, alcoholic solvent and hydroxy-acid group formed the speed of ester when the pH of increase compositions can reduce storage.Reduce pH and can increase esterification rate.The pH that quickens esterification is about 3.5-about 5.0.The pH that suppresses the esterification ratio is higher than about 5 or about 6 or about 7.

In addition, conspicuous as being easy to from the embodiment of the present application, when active medicine has hydroxy-acid group and alcoholic solvent is C ₁-C ₃During straight chain alcohol, the prodrug when the reduction water concentration causes gel combination of the present invention to store forms and increases.The water concentration that quickens esterification rate is lower than about 24% or be lower than about 20% or be lower than about 17%.The water concentration that suppresses esterification rate is about 24% or be higher than 24% or be about 30% or be higher than about 40%.

In addition, conspicuous as being easy to from the embodiment of the present application, the part that can prepare and comprise local acceptable alcoholic solvent, have hydroxy-acid group now with active medicine, have and by the chemical constitution prodrug of the medicine equivalence that forms with alcoholic solvent esterification activity medicine and the compositions of polymer viscosifier, the concentration of wherein said medicine and described prodrug makes that described concentration maintains in about 80% or about 90% separately when at room temperature storing 6 months.

Above disclose contain the alcogel compositions optional further comprise in the following composition a kind of, two kinds, three kinds or four kinds:

Glycerol (about 0.1%-15%)

Pantothenylol (about 0.1%-15%)

Polysorbate (about 0.1%-15%)

Wetting agent (about 0.1%-about 20%)

Excellent specific property

Bound by theory not, the present inventor think the present composition because of the part with active medicine, polymer viscosifier, alcoholic solvent and choose any one kind of them or the interaction of multiple excipient provides local inflammatory disease is especially effectively treated.

Active medicine in alcoholic solvent solubilising and can be partly by the diffusion of hydrophobicity epidermis.The evidence of diffusion not only obtains the confirmation of the diffusion test of this paper disclosure, and does not exist medicine to be confirmed (promptly do not have " ashing ") on the skin surface by visual observation after gel penetrates skin and/or drying.In addition, in certain embodiments of the invention, use to have the hydrophobic prodrug of increasing (surpassing its active metabolite).The present inventor has been found that the hydrophobicity that this class increases can directly be delivered to concrete treatment target increase (being the epidermis internal layer in folliculus hole) by the folliculus perforate by the messenger drug thing.In such as some inflammatory dermatosis disease of this class of FEB, it is common damage location.

The gel characteristic of compositions makes it possible to increase the compositions (promptly using more densely) of volume, especially compares with liquid preparation.This just provides the part active medicine of higher dosage.

Each composition in the compositions delays the evaporation of alcohol, thereby makes NSAID go into the time lengthening of skin using post-absorption.Here it is to rapid evaporation and dry on skin surface, leave over the improvement of the preparation of NSAID in a large number.

In one embodiment of the invention, compositions comprises at least a NSAID (" high NSAID compositions ") of relative high concentration.For example, it is about 20% that compositions can comprise about 1%-, and all according to appointment 2% or about 5% or about 10% or about 15%.

In fact insoluble or when being insoluble in water, high NSAID compositions comprises the alcohol of high concentration as NSAID, for example about 10%-is about 90%, or for example surpasses about 20% or surpass about 40% or surpass about 60%.

As an example, can in 60% alcohol composition, prepare the propanoic derivatives class NSAID of 15% concentration.

The present inventor has been found that the compositions % of the alcohol of the propanoic derivatives class NSAID that comprises about 20% concentration of about 5%-and about 60% concentration of about 20%-has unexpected useful pharmacodynamic profiles.

Optional keratolytic agent has been removed dead cell from epidermis, comprise hair follicle, sebaceous gland and sweat gland district on every side, thereby has further strengthened the diffusion of the active medicine that carries in the alcoholic solvent.

Optional wetting agent sucks epidermis, folliculus and body of gland with water and makes it open.This interaction favorable activity drug diffusion is to skin treatment target extremely.

Acting among the PFB of present composition mesocuticle separating medium and/or wetting agent is especially useful, and wherein hair follicle is the position of skin injury and is the treatment target thus.

Therapeutic Method

The above-mentioned alcogel compositions that contains is used for treating the experimenter who is subjected to the infringement of local inflammation disease by local application.The local inflammation disease can be dermatosis for example.Can use other example of disease of present composition treatment as described below.

In one embodiment, the experimenter that the alcogel treatment suffers from PFB that contains who comprises NSAID, alcoholic solvent and polymer viscosifier by local application.

An embodiment provides treatment experimenter's method, comprise the compositions that experimenter's topical administration that these needs are arranged is comprised phenylacetic acid type NSAID prodrug ester, solvent and thickening agent, wherein precursor portions is amide groups, sulfenyl or unsubstituted alkyl, and wherein the experimenter suffers from the disease that is selected from psoriasis, folliculitis, eczema and dermatitis.

The part active medicine

The present invention comprises one or more especially and can be used for part of the present invention active medicine.Typical part comprises anti-inflammatory agent (NSAIDs) and salicylic acid esters with active medicine.Although those skilled in the art can be categorized as the salicylic acid esters NSAIDs as used herein, term NSAID does not comprise the salicylic acid esters.Therefore, the used salicylate intention of the application is non--NSAID salicylic acid or salicyclic acid derivatives, such as methyl salicylate, sodium salicylate, salicylic acid trifluoro ethyl ester, diflunisal etc.

Be used for part of the present invention and can also be selected from analgesic, antibacterial, anti-wrinkle medicine, antihistaminic, antifungal, anesthetics, steroid, corticosteroid, glucocorticoid, antiviral agents (for example antiherpetic) and antiallergic chemical compound with active medicine.In the application's description, for for purpose of brevity, term " active medicine " etc. are in order to refer to term " one or more active medicines ".

In one embodiment, provide active medicine as free acid or free alkali form.

In one embodiment, it is about 6.5 that active medicine has about 3.0-, and optional about 4.5-is about 7, optional about 4-about 5 and choose the pKa of about 4.3-about 4.7 wantonly.

In one embodiment, it is about 5 that active medicine has about 2-, and optional about 3-is about 5, and optional about 3-is about 4, optional about 2-about 3 and choose the log of about 2.3-about 2.7 wantonly ₁₀The P value.

In one embodiment, active medicine is those phenylacetic acid types NSAID as described below.Phenylacetic acid type NSAIDs is in this application with two to be replaced to the phenylacetic acid class (such as the naphthalene of naproxen) of fused phenyl ring different.

The 4-biphenyl acetic acid

Ibufenac

Ibuprofen

Ketoprofen

Fenoprofen

Flurbiprofen

In one embodiment, phenylacetic acid type NSAID prodrug forms by ester bond is connected on precursor-part on the carboxylic acid hydroxyl.

In one embodiment, active medicine is N-aryl-anthranilic acid type NSAID, such as the limiting examples mefenamic acid.

Mefenamic acid

In one embodiment, N-aryl-anthranilic acid type NSAID prodrug forms by ester bond is connected on precursor-part on the carboxylic acid hydroxyl.

In one embodiment, active medicine is former times health class NSAID, such as limiting examples piroxicam and meloxicam.

Piroxicam

Meloxicam

In one embodiment, former times health class NSAID prodrug forms by ehter bond is connected on precursor-part on the heterocyclic hydroxyl of fused rings.

In one embodiment, NSAID is diclofenac, indomethacin and/or sulindac.

Diclofenac

Indomethacin

In one embodiment, the NSAID prodrug forms by ester bond is connected on precursor-part on the carboxylic acid hydroxyl.

In one embodiment, the NSAID prodrug is naphthalene-acetic acid type NSAID, is the typical case with the naproxen.It is optional that naphthalene-acetic acid type NSAID prodrug is C ₁-C ₃Arrcostab.

Naproxen

In one embodiment, naphthalene-acetic acid type NSAID prodrug forms by ester bond is connected on precursor-part on the carboxylic acid hydroxyl.

In one embodiment, one or more active medicines are selected from ibuprofen salt, ibuprofen free acid and esters thereof.

In one embodiment, NSAID is selectivity or preferred cox 2 inhibitor.Advantageously the example of the COX-2 enzyme inhibitor that gives by the present invention comprises specific inhibitor, such as celecoxib, valdecoxib, rofecoxib, varecoxib, parecoxib etc., or preferred inhibitors, such as meloxicam, nimesulide, etodolac etc.

In one embodiment, NSAID is a macrolide, such as tacrolimus and pimecrolimus.

In one embodiment, NSAID is bufexamac, diclofenac (dicoflenac), etofenamate, felbinac, entiazac, fepradinol, flufenamic acid, lunoxaprofen, Flurbiprofen, ibuprofen, indomethacin, sonixin,, ketoprofen, ketorolac, niflumic acid, oxyphenbutazone, piketoprofen, piroxicam, pranoprofen or suxibuzone.

In one embodiment, NSAID is a prodrug.

In one embodiment, prodrug has the ester that can form by the carboxylic acid of deriving.

In one embodiment, active medicine is the naturally occurring medical herbs complex that comprises anti-inflammatory component.The percentage by weight of selected medicine is according to the relative quantity adjustment of anti-inflammatory component in the complex.This class component can include, but are not limited to bark of willow, goldenseal, licorice and race.

In one embodiment, by making the reaction of active medicine of the present invention and alcoholic solvent form ester.

In one embodiment, active medicine is present in the present composition with the active medicine total amount that accounts for the about 0.001%-of total composition about 20%, optional 0.5%-about 20% or about 5%-about 20% or about 10%-about 20%.

Optional active medicine is dissolved in alcoholic solvent basically, as an example, dissolves about 90%.

Alcoholic solvent

The alcogel compositions that contains of the present invention, and optional NSAID prodrug compositions of the present invention comprises one or more alcoholic solvents especially.

Alcoholic solvent of the present invention is selected from local acceptable monohydric alcohol or polyalcohols.The total about 30%-of amount of alcohol of alcoholic solvent of the present invention is about 80%, optional about 40%-about 70% or choose about 50%-about 65% wantonly.

This class alcoholic solvent is well-known in the art.They can be for direct-connected or side chain and can comprise about 14 carbon of 1-.They can be the alkyl alcohols that is not substituted or replaces.For example, they comprise ethanol, isopropyl alcohol, myristyl alcohol, propylene glycol, glycerol and alkyl glycerol derivant.

Optional alcoholic solvent is ethanol, isopropyl alcohol, propylene glycol, glycerol, myristyl alcohol and composition thereof.Optional alcoholic solvent is an ethanol.The present invention comprises one or more polymer viscosifiers especially.In the application's description, for for purpose of brevity, term " polymer " thickening agent " etc. be used for also referring to term " one or more polymer viscosifiers ".

Polymer viscosifier

In one embodiment of the invention, polymer viscosifier is included in that have on the polymer can dissociated side group, such as the homopolymer or the copolymer of aceticoceptor.

Randomly, described polymer is acrylic acid polymer (or copolymer), such as product sold (Noveon) under trade name CARBOPOL ; Polyoxyethylene-polyoxypropylene copolymer (poloxamer) is such as being purchased as LUTROL  etc.CARBOPOL -resinoid is in polyalkenyl ether or the crosslinked acrylate copolymer of DIETHYLENE GLYCOL such as CARBOPOL  and PEMULEN  (Noveon).CARBOPOL -base polymer is on average having the particulate flocculation powder of about 0.2 micron diameter.The limiting examples of CARBOPOL  polymer is CARBOPOL  ULTREZ ^TM10, CARBOPOL  ULTREZ ^TM20, CARBOPOL  ETD ^TM2020 and CARBOPOL  ETD ^TM2001.

Being used for other base polymer of the present invention is carboxyl vinyl (carboxyvinyl), polyacrylamide, polysaccharide, natural gum (for example xanthan gum), polyvinylsulfonic acid esters (polyvinlsulfonates), polyalkylsulfone class and polyvinyl alcohol or its mixture.

Can be used for other base polymer of the present invention is the alkyl hydroxy cellulosic material, such as can be available from Hercules (Wilmington, KLUCEL  DE).

Can be used for the cellulosic limiting examples of alkyl hydroxy of the present invention and comprise sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose and methylcellulose.

The limiting examples that can be used for natural gum of the present invention comprises xanthan gum, carrageenan sodium, sodium alginate, hydroxypropyl guar gum, Radix Acaciae senegalis (arabic gum) and tragakanta.

In one embodiment, polymer viscosifier is present in the present composition with such amount, and it is about 5% that thickening agent accounts for about 0.1%-of described whole compositions, the thickening agent composition of optional 0.5%-about 5% or about 1.5%-about 3%.

Keratolytic agent

Compositions of the present invention comprises one or more keratolytic agents.The keratolytic agent that the present invention uses can be selected from α-and beta-hydroxycarboxylic acids or beta-keto carboxylic acid, its salt, amide-type or esters.More particularly, the limiting examples of 'alpha '-hydroxy acids is glycolic, lactic acid, tartaric acid, malic acid, citric acid, mandelic acid, and is generally fruit acid.The limiting examples of beta-hydroxy acid is salicylic acid and derivant thereof, particularly alkyl derivative, such as 5-just-MEXORYL SAM.

The keratolytic agent that the present invention uses can also be selected from retinoid (retinoic acid or retinol) and derivant, benzoyl peroxide, urea, boric acid, allantoin (for example allantoin or 5-ureido-hydantoin urea) sulfur, resorcinol and hexachlorophene.

Wetting agent

Optional compositions of the present invention comprises at least a wetting agent.The hygroscopic compound of the wetting agent that the present invention uses for promoting that water keeps.The limiting examples of this class material is polyalcohols (for example glycerol, propylene glycol, polypropylene glycol, mannitol and sorbitol etc.) and polyalcohols, such as polyethylene glycols, fructose, glucose, lactic acid, 1,3 butanediol, wheat gluten; Macrocystis pyrifera (L.) Ag. (macrocytis yyrifera); Algaroba (ceratonia silaqual); Hesperidin methyl chalcone derivative (hespridin methyl chalocone); Dipeptides-2; Palmitoyl Tetrapeptide (palmitoyl tetrpeptide)-3; Matrixyl class (palmitoylpentapeptides); With the pantothenylol class.

Optional one or more the wetting agent total amount that can be included in the compositions is about 0.1%-about 20% or about 0.5%-about 10% or about 1%-about 5%.

Viscosity and pH

Useful and the ideal viscosity number of the present invention changes with the indication of being treated.For example, the medicament administration of broad coverage (promptly comparatively big skin area) or reduced levels if desired, the compositions that viscosity is lower is favourable so.The example of low cementitious compositions is about 2, and 000cps-is about 50,000cps or about 2, and 000cps-is about 25,000cps or 2,000cps-is about 10,000cps or about 5,000cps-is about 15,000cps.The exhibition that is coated with of the compositions that the more low-viscosity compositions of this class helps using.

The more limited if desired covering or the medicament administration of higher level, so more the compositions of viscosity is favourable.More the example of cementitious compositions is about 20, and 000cps-is about 200,000cps or about 50, and 000cps-is about 100,000cps.Those skilled in the art are easy to for example to increase by the concentration that increases polymer viscosifier the viscosity of the present composition.

Find that also this based composition has relative toleration to viscosity-modifying when adding basifier; For example, it is about 50% that the change of each pH unit's viscosity of alkalization compositions is lower than, or be lower than about 25% or be lower than about 15%.

Optional ingredients

Compositions of the present invention can also comprise the optional member that generally is used for topical drug and/or cosmetic formulations.These materials are well-known in the art and they usually generally acknowledge that with it level of establishing is used for the present composition such as solvent, oil, softening agent, surfactant, antiseptic, coloring agent, UV blocker and spice.

In other embodiments, optionally advantageously antioxidant is joined in the present composition.Antioxidant advantageously is selected from: aminoacid (for example glycine, histidine, tyrosine, tryptophan) and its derivant; Imidazoles (for example urocanic acid) and its derivant; The peptide class, such as D, L-carnosine, D-carnosine, L-carnosine and derivant thereof (for example anserine); Carotenoid; Carotene (for example alpha-carotene, beta-carotene, lycopene) and derivant thereof; Chlorogenic acid and derivant thereof; Thioctic acid and derivant thereof (for example dihydrolipoic acid); Aurothioglucose, propylthiouracil and other thio-alcohol (for example thioredoxin, glutathion, cysteine, cystine, cystamine and glycosyl thereof, N-acetyl group, methyl, ethyl, propyl group, amyl group, butyl and lauryl, palmityl, oleoyl, γ-Ya oleoyl, cholesteryl and glyceride type) and salt thereof; Dilauryl thiodipropionate, distearyl thiodipropionate, thiodipropionic acid and derivant thereof (esters, ethers, peptide class, lipid, nucleotide, nucleoside and salt); The sulfo group oxime compound of extremely low tolerance dose (for example S-(3-amino-3-carboxylic propyl group)-S-butyl sulfur oxygen imido, homocysteine sulfo group oxime, buthionine sulfones, five-, six-, seven thionine sulfo group oximes) (for example pmol-.mu.mol/kg); And also have (metal) chelating agen (for example alpha-hydroxy fatty acid, Palmic acid, phytic acid, lactoferrin), 'alpha '-hydroxy acids (for example citric acid, lactic acid, malic acid), humic acid, bile acid, bile extract, bilirubin, biliverdin, EDTA, EGTA and derivant thereof; Unsaturated fatty acid and derivant thereof (for example gamma-Linolenic acid, linoleic acid, oleic acid); Folic acid and derivant thereof, ubiquinone and pantothenylol and derivant thereof; Vitamin C and derivant (for example ascorbic palmitate, phosphoric acid ascorbic acid Mg, acetic acid acid ascorbyl ester); Tocopherols and derivant (for example alpha-tocopherol acetate); Vitamin A and derivant (Palimitate-A); Coniferyl benzoate with benzoin resin; Rutinic acid and derivant thereof; Alpha-glycosyl rutin, ferulic acid, furfurylidene glucitol, carnosine, butylated hydroxytolyene, Butylated hydroxyanisole, nordihydroguaiacic acid, nordihydroguaiaretic acid, THBP 2,4,5 trihydroxybutyrophenone, uric acid and derivant thereof; Mannose and derivant thereof; Zinc and derivant thereof (ZnO for example, ZnSO ₄); Selenium and derivant thereof (for example selenomethionine); Stilbene class and its derivant; (for example stilbene oxide, trans stilbene oxide); Derivant (salt, esters, ethers, saccharide, nucleotide, nucleoside, peptide class and lipid) with the suitable described active component of the present invention.

The amount of antioxidant (one or more chemical compounds) in compositions is about 0.001%-about 30% or about 0.05%-about 20% or about 1%-about 10%.

If vitamin E and/or its derivant are as antioxidant or multiple antioxidant, its corresponding concentration advantageously is selected from about 0.001%-about 10% so.

If vitamin A or vitamin A derivative or carotene or derivatives thereof are multiple as antioxidant or antioxidant, its corresponding concentration advantageously is selected from about 0.001%-about 10% so.

Compositions can also comprise oil, and mean level accounts for about 0%-about 5% of compositions.Having oil is the ingredient that maybe can be used as oil/water emulsion composition because of its softening agent effect.Can be used for the general part of oil of the present invention or be insoluble in C ₈Or C ₈Above alcohols.The example of this class oil comprises mineral oil, safflower oil, Oleum Ricini, Oleum helianthi, silicone oil, olive oil, simethicone, cyclomethicone, triglyceride.Preferred especially simethicone.

For fortified compositions preparation characteristic (for example smoothly compositions being applied to the ability of skin) and purpose that ideal dermal sensation is provided, can comprise softening agent in the present composition, the about 0%-of mean level about 5%.The example of this class softening agent comprises silicone material, such as simethicone (ring-type and linearity), pantethine derivant (such as pantothenylol, pantothenic acid, Pantetheine and pantethine) and allantoin.

Compositions of the present invention can also comprise the general surfactant that improves the composite preparation characteristic that rises.Generally speaking, the surfactant concentration that comprises in the compositions is about 0%-about 5%.The general nonionic surfactant that uses among the present invention, wherein preferred Span class and alkyl polyethoxylate (C for example ₈-C ₁₈(EO) _4-50).The example that can be used for surfactant of the present invention comprises polysorbate20 and polysorbate80, and both are all commercially available.

Embodiment of the present invention are optional further to comprise the UV-absorbent, such as single (monomer) aromatic compounds and/or reflexive pigment, such as octyl methoxycinnamate (PARSOL  MCX), benzophenone-3 (oxybenzone) and octyldimethyl PABA.

Compositions of the present invention can further comprise and be used to improve the penetration enhancer of medicine through epidermis or dermal delivery.Be suitable for penetration enhancer of the present invention and comprise terpenoid, terpene alcohols, quintessence oil, surfactant etc.Some this class example comprises d-limonene, terpinene-4-alcohol, menthone, 1,8-cineole, 1-pinene, α-terpinol, carveol, carvone, pulegone, cineole, Oleum menthae, sorbitan ester class, polysorbate esters, sodium lauryl sulphate etc.

Compositions with other solvent

The present invention also provides and has not contained alcohol or the low compositions that is used for the treatment of inflammatory dermatosis of pure content.In one embodiment, compositions comprises be insoluble in water or the in fact water-fast NSAID for preparing under no pure situation.A kind of this based composition is an organogel, for example by low amounts of water being joined the lecithin organogel that obtains in the solution of lecithin in organic solvent.One or more NSAIDs can be dissolved in organic solvent.

The organic solvent that is used for here as limiting examples comprises hydro carbons, ethers, amine and esters.Optional organic solvent is a fatty acid ester, such as isopropyl palmitate or isopropyl myristate.Optional organogel of the present invention is the Pluronic organogel.Further discovery can be mixed with NSAIDs of the present invention the compositions that does not contain alcohol in phospholipid/poloxalkol compositions.This just provides the NSAID with useful concentration, useful viscosity, but can not make inert component be deposited on compositions on the skin surface in a large number.In addition, in some local inflammation disease, phospholipid is deposited on can have on the skin to be alleviated and even therapeutical effect (for example because of burning that the UV irradiation causes).

Oil-in-water type (o/w) Emulsion is used for NSAIDs compositions of the present invention.Oil phase is the useful solvent that is used for NSAID prodrug and other hydrophobic drug and/or excipient.Water can usefully dissolve hydrophilic medicament and/or excipient.Oil-in-water emulsion is especially useful to NSAID of the present invention, because those skilled in the art can adjust oil/water than so that enough medicament solubilizations are provided, and provides best medicine to send (be medicine move go into skin) simultaneously from preparation.

The PFB preparation

One embodiment of the invention provide the method for treatment PFB, the experimenter who comprises these needs are arranged is applied to compositions on the skin, and said composition comprises one or more NSAIDs of the about 0.001%-of one or more alcoholic solvents, total amount about 25% of the about 10%-of consumption about 90% and the polymer viscosifier of the about 0.05%-of consumption about 5%.

Another embodiment provides the method for treatment PFB, the experimenter who comprises these needs are arranged is applied to compositions on the skin, and the about 1%-of one or more alcoholic solvents, total amount that said composition comprises the about 30%-of consumption about 70% is lower than about 25% one or more NSAIDs and the polymer viscosifier of the about 0.05%-of consumption about 5%.

Another embodiment provides the method for treatment PFB, the experimenter who comprises these needs are arranged is applied to compositions on the skin, the about 5%-of one or more alcoholic solvents, total amount that said composition comprises the about 30%-of consumption about 70% is lower than the polymer viscosifier of about 25% the about 0.05%-of one or more NSAIDs, consumption about 5% and one or more keratolytic agents that there is the about 0.015%-of concentration about 25% in total keratolytic agent, and wherein NSAID is dissolved in described one or more alcoholic solvents basically.

Another embodiment provides the method for treatment PFB, comprises the compositions that will comprise the NSAID prodrug to experimenter that these needs are arranged and is applied on the skin.Can be by NSAID prodrug and the acceptable mixed with excipients of dermatological be prepared this based composition.

The local inflammation disease

The present invention is used for the treatment of and suffers from the local inflammation disease, such as the experimenter of skin, joint, muscle and disorder of ligament.

Can be epidermis and corium disease according to the example of the effective inflammatory dermatosis disease for the treatment of of the present invention.The limiting examples of this class disease comprises: eczema and relevant disease; Insect bite; Erythroderma; Mycosis fungoides and relevant disease; Pyoderma gangrenosum; Erythema multiforme; Rosacea; Tinea unguium; Acne, furuncle and relevant disease; The UV infringement; Psoriasis; Folliculitis and relevant disease are inwardly grown such as toe and fingernail; Acne keloid and furuncle.

The limiting examples of the eczema that can be used for treating according to the present invention is atopic eczema, intensive acrodermatitis, contact allergic dermatitis, contact irritant dermatitis, pompholyx eczema or pompholyx, lichen chronicus simplex, nummular eczema, seborrheic dermatitis and stasis eczema.

The limiting examples that can be used for treating folliculitis according to the present invention is pseudomonas folliculitis (heat pipe folliculitis (hot tub folliculitis)), tinea barbae, tinea barbae, pseudofolliculitis barbae, pityrosporum folliculitis and herpetic folliculitis.

The used pseudofolliculitis barbae of the application comprises the barbers' itch in non-palpus portion (other that) (palpus) zone.Therefore, PFB represents the inflammation result's that causes because of hair growth to small part skin (or skin area) disease.Therefore, PFB can influence the male of the facial chaeta that curls of shaving; Its women who has hirsutism facial or waxing of shaving; The existence in its shank of shaving, arm depression and so-called bikini district is curled or the experimenter of sharp end chaeta (be the share, go up shank etc.); And even the individuality (for example chaeta is inwardly grown) of the scytitis that chaeta brings out takes place under shaving not.

Can also use the present composition and other treatment or activity, such as shaving, laser therapy, waxing (being used to remove chaeta) or depilation therapy coupling treatment PFB experimenter.

The present invention is used for the treatment of the experimenter who suffers from local pain, for example the pain example that causes because of the stimulation of nociceptor in skin, bone, joint and muscle.Those skilled in the art are easy to recognize that many or most of above-mentioned local inflammation disease further comprises the pain factor that causes because of the stimulation of nociceptor in skin.Because of the stimulation of nociceptor in bone, joint and muscle cause can be by present composition treatment the limiting examples of this class pain be arthritis, muscle damage, bone, joint and muscle operation, fibromyalgia, neuropathy and muscle spasm.Optional embodiment of the present invention can also alleviate the inflammatory reaction relevant with arthritis.

Delivery system and storage capsule

The delivery system that is used to send any present composition (comprising storage device) also is provided.

The delivery system that is used for the present composition comprises pump-type distributor, cylinder, spray bottle, cleaning piece (wipes), be suitable for that gel sends scrape razor, sachet, pipe, roller coating device (roll-on), squeeze bottle, aerosol container, be attached to flexible products on the skin (described compositions is impregnated into fiber or non-fibre substrate, skin patch, adhesive tape etc.).

The suitable propellant that is used for the compositions of aerosol container is the propellant of common known effumability, for example hydro carbons (propane, butane, iso-butane) or gas-pressurized.

Embodiment

As the application's example, prepare dermatological acceptable composition of the present invention in a conventional manner.In addition, those skilled in the art's easy to understand scope of the present invention comprises other compositions that the application instructs.

Compositions of the present invention be used for local with the part with the active medicine local delivery to there being this class to treat the human or animal patient of needs.Especially, the compositions of safety and effective dose is applied to needs the position for the treatment of on the skin.In specific embodiment, compositions of the present invention is used for by using safety and effective dose (the about 0.01g/cm of for example about 0.002- ²) the present composition provide pain relieving or antiinflammatory action to the patient, wherein pharmaceutically active agents is the non-steroid anti-inflammatory substance, such as ibuprofen.

The following example is intended to illustrate compositions of the present invention and preparation and application.These embodiment are used for limiting scope of the present invention.

Embodiment 1

Use the routine techniques preparation to have the compositions of following ingredients and characteristic:

Composition	Amount
Composition	Amount	CARBOMERULTREZ ^TM10	2.5％
Ethanol	55-65％	CARBOMERULTREZ ^TM10	2.5％
Ethanol	55-65％	Ibuprofen	5-18％

The pH of final gel is 3.5-4.8.The viscosity of gel is 1,200cps-75,000cps.

Prepare compositions according to following manner:

A) all pure soluble components are dissolved in ethanol;

B) add the optional liquid composition;

C) optionally in independent container add entry and water soluble ingredient and tip to dissolving;

D) merge optional water/water soluble ingredient and alcoholic solution;

E) add CARBOMER  and make CARBOMER  aquation 18 hours by slow stirring.

When said composition being applied to the PFB damage, the consumption of observing effective treatment PFB in several days time limits is about 0.005g/cm ²

Embodiment 2

Another preparation embodiment is the compositions that comprises following component:

A) about 40% isopropyl alcohol of about 1-

B) about 50% ethanol of about 20-

C) about 0.05% safflower oil of 0.01-

D) about 10% anesthetics of 5-

E) 1-1.5% thickening agent is such as KLUCEL 

F) water is in right amount to 100%

Embodiment 3

A) about 49-73% ethanol

B) about 1-4% glycerol

C) about 1-3% polysorbate80 (polysorbate 80)

D) about 1-10% acetaminophen

E) about 0.01-0.1% oleyl alcohol

f)2-4％CARBOPOL981

G) water is in right amount to 100%

Embodiment 4

Preparation compositions as shown in table 1 wherein comprises and does not comprise active medicine ibuprofen (" IBU ").Use 4 kinds of different polymer viscosifiers, i.e. ULTREZ ^TM10, ULTREZ ^TM20,980 (Noveon) and 981 (Noveon).Just as shown in table 2, the compositions table that contains 15% ibuprofen reveals and is lower than the viscosity that does not similarly contain the compositions of active medicine basically.This result is similar with the result that the compositions of using every kind of Polyacrylate thickeners preparation is found.We have the excellent viscosity that is used for dermal administration and need not to add basifier (neutralization) at the aqueous alcohol gel of the present invention of reaching a conclusion thus when comprising a large amount of active components (for example 5-20%) and Polyacrylate thickeners.

Table 1a. forms

	Compositions 1a (+IBU)	Compositions 1b (IBU)
	Compositions 1a (+IBU)	Compositions 1b (IBU)	Composition	％W/W	％W/W
Ibuprofen			Composition	％W/W	％W/W
Ibuprofen		15	0
Ethanol		15	0	57.33	57.33
Ethanol	Glycerol	3	3	57.33	57.33
D-panthenol	Glycerol	3	3	0.15	0.15
D-panthenol	Polysorbate20	2	2	0.15	0.15
Propylene glycol	Polysorbate20	2	2	2	2
Propylene glycol	Salicylic acid	0.15	0.15	2	2
Polymer viscosifier	Salicylic acid	0.15	0.15	2.5	2.5
Polymer viscosifier	Water	17.87	32.87	2.5	2.5

Table 2. viscosity

	Viscosity (cps)
	Viscosity (cps)		Thickening agent	No IBU		15％ IBU
ULTREZ			Thickening agent	No IBU		15％ IBU
ULTREZ	^TM10	37,500	11300
ULTREZ ^TM20	^TM10	37,500	11300	42,300	20000
ULTREZ ^TM20	980 ^TM(Noveon)	31,900	10700	42,300	20000
981 ^TM(Noveon	980 ^TM(Noveon)	31,900	10700	23,800	11590

Embodiment 5

Preparation compositions as shown in table 3.As shown in table 4, the viscosity gauge that comprises the compositions of 15% ibuprofen and 2.5% polymer viscosifier reveal be lower than basically the compositions that similarly do not contain active medicine and with do not contain active medicine and contain the compositions of 1.5% polymer viscosifier suitable.

Table 3. is formed

	Compositions 3a	Compositions 3b	Compositions 3c
	Compositions 3a	Compositions 3b	Compositions 3c	Composition	％W/W	％W/W	％W/W
Ibuprofen				Composition	％W/W	％W/W	％W/W
Ibuprofen		0	0	15
Ethanol		0	0	15	60.35	71.85	57.33
Ethanol	Glycerol	3	3.57	3	60.35	71.85	57.33
D-panthenol	Glycerol	3	3.57	3	0.15	0.18	0.15
D-panthenol	Polysorbate20	2	2.38	2	0.15	0.18	0.15
Propylene glycol	Polysorbate20	2	2.38	2	2	2.38	2
Propylene glycol	Salicylic acid	0.15	0.18	0.15	2	2.38	2
ULTREZ ^TM10	Salicylic acid	0.15	0.18	0.15	2.5	1.78	2.5
ULTREZ ^TM10	Water	29.85	17.68	17.87	2.5	1.78	2.5

Table 4: viscosity

Compositions	Ibuprofen %	ULTREZ ^TM10％	Average viscosity (cps)
Compositions	Ibuprofen %	ULTREZ ^TM10％	Average viscosity (cps)	3a	0	2.5	22900
3b	0	1.78	7600	3a	0	2.5	22900
3b	0	1.78	7600	3c	15	2.5	7600

Embodiment 6

According to table 5 preparation compositions and mensuration viscosity.As shown in table 6, reduce the water yield and cause viscosity to increase.Surprisingly, when merge adding 15% ibuprofen (free acid), water further is reduced to 18% from 25%, and to cause ideal viscosity be 11,300cps.Therefore, can prepare low water content (for example about 5%-about 20%) and not add the dermatological compositions of other basifier according to the present invention.

Table 5. is formed

	Compositions 5a	Compositions 5b	Compositions 5c	Compositions 5d
	Compositions 5a	Compositions 5b	Compositions 5c	Compositions 5d	Component	％W/W	％W/W	％W/W	％W/W
EtOH	57.33	63.71	59.11	57.33	Component	％W/W	％W/W	％W/W	％W/W
EtOH	57.33	63.71	59.11	57.33	Active component	15.00	0.00	0.00	0.00
Glycerol	3.00	3.32	3.10	3.00	Active component	15.00	0.00	0.00	0.00
Glycerol	3.00	3.32	3.10	3.00	D-panthenol	0.15	0.17	0.15	0.15
Salicylic acid	0.15	0.17	0.15	0.15	D-panthenol	0.15	0.17	0.15	0.15
Salicylic acid	0.15	0.17	0.15	0.15	Polysorbate20	2.00	2.22	2.06	2.00
Propylene glycol	2.00	2.22	2.06	2.00	Polysorbate20	2.00	2.22	2.06	2.00
Propylene glycol	2.00	2.22	2.06	2.00	Total Water	17.87	25.41	30.79	32.87
ULTREZ ^TM10	2.50	2.78	2.58	2.50	Total Water	17.87	25.41	30.79	32.87
ULTREZ ^TM10	2.50	2.78	2.58	2.50	Water/EtOH	31.2	40.0	52.1	57.3

Table 6. viscosity

Compositions	% active medicine (ibuprofen)	% water	pH	Average viscosity (cps)
Compositions	% active medicine (ibuprofen)	% water	pH	Average viscosity (cps)	5a	15	18	3.68	11300
5b	0	25	3.83	43800	5a	15	18	3.68	11300
5b	0	25	3.83	43800	5c	0	31	3.60	37900
5d	0	33	3.39	37500	5c	0	31	3.60	37900

Embodiment 7

Different water in the check present composition ConcentrationWith the effect of pH to viscosity.According to table 7 preparation compositions.

Table 7. is formed

Component	7a		7b	7c	7d
Component	7a		7b	7c	7d	EtOH	57.33	57.33	50.75	50.35
Active component	15.00	15.00	15.00	15.00		EtOH	57.33	57.33	50.75	50.35
Active component	15.00	15.00	15.00	15.00	Glycerol	3.00	3.00	3.00	3.00
D-panthenol	0.15	0.15	0.15	0.15	Glycerol	3.00	3.00	3.00	3.00
D-panthenol	0.15	0.15	0.15	0.15	Salicylic acid	0.15	0.15	0.15	0.15
Tween 20	2.00	2.00	2.00	2.00	Salicylic acid	0.15	0.15	0.15	0.15
Tween 20	2.00	2.00	2.00	2.00	Propylene glycol	2.00	2.00	2.00	2.00
Water	17.87	17.87	24.45	24.85	Propylene glycol	2.00	2.00	2.00	2.00
Water	17.87	17.87	24.45	24.85	ULTREZ ^TM10	2.50	2.50	2.50	2.50
Water/alcohol	31.2	31.2	48.2	49.4	ULTREZ ^TM10	2.50	2.50	2.50	2.50
Water/alcohol	31.2	31.2	48.2	49.4	pH	3.68	5	5	5
The basifier that adds	Do not have	Diisopropylamine	Diethylamine	Diisopropylamine	pH	3.68	5	5	5
The basifier that adds	Do not have	Diisopropylamine	Diethylamine	Diisopropylamine	Viscosity (cps)	11600	12700	7500	4000

Observed as being easy in the table 7, similar with compositions 1a basically, but contain in 18% water and the 57% alcoholic acid compositions, cause the viscosity appropriateness to increase by adding diisopropylamine adjustment pH.Yet, similar with compositions 1a basically, but contain in 24% water and～50% alcoholic acid compositions, by the interpolation diisopropylamine pH is adjusted to 5.5 viscosity that cause ratio of viscosities to use diethylamine to be adjusted to the analogous composition of pH5.0 unexpectedly and reduces significantly.Therefore, in compositions of the present invention, reduce water and the ratio (for example being lower than 50%) of ethanol and stablized viscosity (promptly cause pH lower) unexpectedly the influence of viscosity.

Embodiment 8

Have with do not have the active component ibuprofen in the presence of two kinds of different alcoholic solvents of test to the effect of viscosity.According to table 8 preparation compositions.Just as shown in table 9, use ethanol as the viscosity of the compositions of solvent greater than the viscosity of using isopropyl alcohol as the compositions of solvent.In addition, the active component of interpolation 15% causes viscosity significantly to reduce.

Table 8. is formed

	Compositions 8a	Compositions 8b	Compositions 8c	Compositions 8d
	Compositions 8a	Compositions 8b	Compositions 8c	Compositions 8d	Component	57％EtOH， ULTREZ ^TM10	60％IPA， ULTREZ ^TM10	57％EtOH， ULTREZ ^TM20	60％IPA， ULTREZ ^TM20
EtOH	57.33	0.00	57.33	0.00	Component	57％EtOH， ULTREZ ^TM10	60％IPA， ULTREZ ^TM10	57％EtOH， ULTREZ ^TM20	60％IPA， ULTREZ ^TM20
EtOH	57.33	0.00	57.33	0.00	Isopropyl alcohol	0.00	60.00	0.00	60.35
Active component	0.00	0.00	15.00	15.00	Isopropyl alcohol	0.00	60.00	0.00	60.35
Active component	0.00	0.00	15.00	15.00	Glycerol	3.00	3.00	3.00	3.00
D-panthenol	0.15	0.15	0.15	0.15	Glycerol	3.00	3.00	3.00	3.00
D-panthenol	0.15	0.15	0.15	0.15	Salicylic acid	0.15	0.15	0.15	0.15
TWEEN20	2.00	2.00	2.00	2.00	Salicylic acid	0.15	0.15	0.15	0.15
TWEEN20	2.00	2.00	2.00	2.00	Propylene glycol	2.00	2.00	2.00	2.00
Water	17.87	15.20	17.87	14.85	Propylene glycol	2.00	2.00	2.00	2.00
Water	17.87	15.20	17.87	14.85	ULTREZ ^TM	2.50	2.50	2.50	2.50

Table 9. viscosity

Compositions	% active medicine (ibuprofen)	Average viscosity (cps)
Compositions	% active medicine (ibuprofen)	Average viscosity (cps)	8a	0	37500
8b	0	27000	8a	0	37500
8b	0	27000	8c	15	11600
8d	15	3200	8c	15	11600

Embodiment 9

Use is according to the effect to viscosity of the compositions test different solvents of preparation in the table 10 and polymer viscosifier.

Table 10. is formed

Component	10a	10b	10c	10d
Component	10a	10b	10c	10d	EtOH	57.33	0.00	57.33	0.00
Isopropyl alcohol	0.00	60.00	0.00	60.35	EtOH	57.33	0.00	57.33	0.00
Isopropyl alcohol	0.00	60.00	0.00	60.35	Active component	15.00	15.00	15.00	15.00
Glycerol	3.00	3.00	3.00	3.00	Active component	15.00	15.00	15.00	15.00
Glycerol	3.00	3.00	3.00	3.00	D-panthenol	0.15	0.15	0.15	0.15
Salicylic acid	0.15	0.15	0.15	0.15	D-panthenol	0.15	0.15	0.15	0.15
Salicylic acid	0.15	0.15	0.15	0.15	TWEEN ^TM20	2.00	2.00	2.00	2.00
Propylene glycol	2.00	2.00	2.00	2.00	TWEEN ^TM20	2.00	2.00	2.00	2.00
Propylene glycol	2.00	2.00	2.00	2.00	Water	17.87	15.20	17.87	14.85
ULTREZ ^TM 10	2.50	2.50	0	0	Water	17.87	15.20	17.87	14.85
ULTREZ ^TM 10	2.50	2.50	0	0	ULTREZ ^TM 20	0	0	2.50	2.50

Table 11. viscosity

Alcohol content, CARBOPOL ^TM	Average viscosity (cps)
Alcohol content, CARBOPOL ^TM	Average viscosity (cps)	57％EtOH，Ultrez ^TM10	11600
60％IPA，Ultrez ^TM10	3200	57％EtOH，Ultrez ^TM10	11600
60％IPA，Ultrez ^TM10	3200	57％EtOH，Ultrez ^TM20	20000
57％IPA，Ultrez ^TM20	16200	57％EtOH，Ultrez ^TM20	20000

Embodiment 10

Use is according to the compositions test different solvents and the effect of interpolation basifier to viscosity of table 12 preparation.Comprise salicylic acid and alcoholic acid aqueous alcohol gel combination has obtained to be higher than the similar viscosity that comprises the compositions of salicylic acid and isopropyl alcohol.In addition, ethanol/water poplar acid composition shows negligible viscosity-modifying after adding basifier.When the pH with the isopropyl alcohol compositions adjusts a unit, there is unexpected viscosity degradation.

Table 12. is formed and viscosity

Component	12a	12b	12c	12d
Component	12a	12b	12c	12d	EtOH	57.33	0.00	57.33	0.00
Isopropyl alcohol	0.00	60.00	0.00	60.35	EtOH	57.33	0.00	57.33	0.00
Isopropyl alcohol	0.00	60.00	0.00	60.35	Active component	15.00	15.00	15.00	15.00
Glycerol	3.00	3.00	3.00	3.00	Active component	15.00	15.00	15.00	15.00
Glycerol	3.00	3.00	3.00	3.00	D-panthenol	0.15	0.15	0.15	0.15
Salicylic acid	0.15	0.15	0.15	0.15	D-panthenol	0.15	0.15	0.15	0.15
Salicylic acid	0.15	0.15	0.15	0.15	TWEEN ^TM20	2.00	2.00	2.00	2.00
Propylene glycol	2.00	2.00	2.00	2.00	TWEEN ^TM20	2.00	2.00	2.00	2.00
Propylene glycol	2.00	2.00	2.00	2.00	Water	17.87	15.20	17.87	14.85
ULTREZ ^TM10	2.50	2.50	2.50	2.50	Water	17.87	15.20	17.87	14.85
ULTREZ ^TM10	2.50	2.50	2.50	2.50
pH	3.68	4.07	5.0	5.0
pH	3.68	4.07	5.0	5.0	Viscosity	11600	3200	11700	2700
					Viscosity	11600	3200	11700	2700

Embodiment 11

Use is according to the compositions test different solvents concentration of table 13 preparation and the pH effect to viscosity.We reach a conclusion aqueous alcohol gel of the present invention comprise a large amount of active components (for example 5-20%), when being enough to dissolve dermatosis with the isopropyl alcohol of active component consumption and Polyacrylate thickeners, have and can be used for the viscosity that dermatosis is used, and need not to add basifier (neutralization).This based composition is lower than at about 50% o'clock and pH can be adjusted to 5.0 and keep the good viscosity that can be used for dermatological composition in water content.

Table 13. is formed

Component	13a	13b	13c
Component	13a	13b	13c	pH	pH4.07	pH5.0	pH5.0
Isopropyl alcohol	60.00	60.00	50.35	pH	pH4.07	pH5.0	pH5.0
Isopropyl alcohol	60.00	60.00	50.35	Ibuprofen	15.00	15.00	15.00
Glycerol	3.00	3.00	3.00	Ibuprofen	15.00	15.00	15.00
Glycerol	3.00	3.00	3.00	D-panthenol	0.15	0.15	0.15
Salicylic acid	0.15	0.15	0.15	D-panthenol	0.15	0.15	0.15
Salicylic acid	0.15	0.15	0.15	Tween 20	2.00	2.00	2.00
Propylene glycol	2.00	2.00	2.00	Tween 20	2.00	2.00	2.00
Propylene glycol	2.00	2.00	2.00	Water	15.20	15.20	24.85
Ultrez ^TM10	2.50	2.50	2.50	Water	15.20	15.20	24.85
Ultrez ^TM10	2.50	2.50	2.50	Viscosity (cps)	3159	2699	120

Embodiment 12

Preparation contains or does not contain the stability that the compositions 1a (wherein forming difference by adding water) of 0.15% salicylic acid (SA) and test pH and viscosity changed with the storage time.Comprise salicylic compositions table reveal initial value 15% in good viscosity stability (accompanying drawing 1) and good pH (accompanying drawing 2) stability.

Initial stage when not containing salicylic acid (4 weeks at the most) shows about pH more than 10% and changes.From the 28th day to the 78th day, although contain and the meansigma methods similar (being respectively 3.96 and 3.90) of salicylated compositions not, the standard deviation that comprises salicylic compositions was half (being respectively 0.08 and 0.16) that does not have salicylic compositions.

Accompanying drawing 3 expressions are from the sample pH separately and the sketch map of viscosity relationship of attached Fig. 1 and 2.This drawings clear ground shows that in comprising salicylic compositions viscosity is more stable as the function of pH.Therefore, 0.15% is the stable salicylic acid concentration of viscosity and pH.

Embodiment 13

Checked of the effect of different activities medicine to present composition viscosity.According to table 14 preparation compositions and quantitative to viscosity.

Table 14. viscosity

Active medicine	Viscosity average cps	δ viscosity	δ viscosity to the calibration of % active medicine
Active medicine	Viscosity average cps	δ viscosity	δ viscosity to the calibration of % active medicine	Placebo	42300	0	0
10% ibuprofen	32500	-9844	-984	Placebo	42300	0	0
10% ibuprofen	32500	-9844	-984	10% acetaminophen	53000	10656	1066
10% ketoprofen	52000	9656	966	10% acetaminophen	53000	10656	1066
10% ketoprofen	52000	9656	966	10% aspirin	40000	-2344	-234
10% flufenamic acid	31400	-10944	-1094	10% aspirin	40000	-2344	-234
10% flufenamic acid	31400	-10944	-1094	2.5% sulindac	40600	-1744	-174
2.5% Phenylbutazone	40300	-2044	-818	2.5% sulindac	40600	-1744	-174
2.5% Phenylbutazone	40300	-2044	-818	2.5% furosemide	38100	-4244	-1698
3% naproxen	38500	-3844	-1538	2.5% furosemide	38100	-4244	-1698
3% naproxen	38500	-3844	-1538	2.5% phenacetin	41000	-1344	-448

Table 14 is also represented to add active medicine NSAID to can produce in the present composition viscosity front or negative effect.Add ibuprofen and have the effect that reduces viscosity the most significantly.

Accompanying drawing 4 expressions are to log ₁₀Normalized (normalized) viscosity-modifying that the P value is drawn.These data show viscosity-modifying and the log that has one group of active medicine of similar acidic-group in use ₁₀There is linear dependence between the P.

Embodiment 14

Use the absorption and the penetrance of active medicine ibuprofen in the human body skin research topical compositions that the elective surgery operation is downcut described in FDA and AAPS Report of the Workshop on Principles andPractices of In Vitro Percutaneous Penetration Studies:Relevance to Bioavailability and Bioequivalence (Pharm.Res.4:265,87).

Use tracer level (each diffusion cell is used～1.0 μ Ci/3.2mg compositionss) [ ³H]-ibuprofen makes all compositionss produce spikings.With single clinical relevant limited dosage (～5mg compositions/cm ¹) be applied to human abdomen's skin from the skin graftization of elective surgery.The skin evaluation percutaneous that use is fixed on the Bronaugh flow type diffusion cell absorbs, and described diffusion cell maintains under 32 ℃ the constant temperature by using the recirculation water-bath.These ponds have 0.64cm ²The opening of nominal area.Comprise the fresh accepter fluid PBS of 0.1% Hydrazoic acid,sodium salt and 1.5%Oleth 20 and collection in 6-hour at interval with 1ml/ hour flow velocity uninterrupted pumping.Contact skin after 24-hour time limit, in compositions by removing compositions residual on the skin surface with two exsiccant cotton swab wipings.In order to remove any residual compositions that remains on the skin surface, remove the destratum corneum upper strata from epidermis with the single-glass strip of paper.Remove remaining epidermis and processing so that analyze respectively by physics mode from corium then.Use radioactive amount in liquid scintillation counting technical measurement cleaning piece, tape, epidermis, corium and the accepter fluid sample.

As shown in table 15, through revising preparation and the similar gel combination of compositions 1a; Be purchased other gel commodity preparation.

Table 15. is formed

	15a	15b	15c	15d
	15a	15b	15c	15d	IBU
	15	10	15	15	IBU
	15	10	15	15	EtOH	60.2	60.2	60.2	60.2
D-panthenol	0.15	0.15	-	0.15	EtOH	60.2	60.2	60.2	60.2
D-panthenol	0.15	0.15	-	0.15	Pantethine			0.15
EDTA	0.05	0.05	-	0.05	Pantethine			0.15
EDTA	0.05	0.05	-	0.05	Salicylic acid	0.15	0.15	0.15	0.15
ULTREZ ^TM10	2.5	2.5	2.5	-	Salicylic acid	0.15	0.15	0.15	0.15
ULTREZ ^TM10	2.5	2.5	2.5	-	KLUCEL				2.5

Table 16: result

			The monolayer tape	Accepter
			The monolayer tape	Accepter	10％Boot’s Gel		Meansigma methods	3.87	3.90
SD	2.88	2.25					Meansigma methods	3.87	3.90
SD	2.88	2.25	％CV	74.22			57.62
5％Ibuleve Gel		Meansigma methods	％CV	74.22			57.62	18.42	11.53
		Meansigma methods	SD	2.36	4.62			18.42	11.53
		％CV	SD	2.36	4.62	12.80	40.06
		％CV	10％Ibuleve Gel		Meansigma methods	12.80	40.06	20.71	8.15
SD	2.62	3.80			Meansigma methods			20.71	8.15
SD	2.62	3.80			％CV	12.64	46.65
15a		Meansigma methods			％CV	12.64	46.65	13.38	5.98
		Meansigma methods	SD	11.12	2.82			13.38	5.98
		％CV	SD	11.12	2.82	83.09	47.22
		％CV	15b		Meansigma methods	83.09	47.22	17.57	13.30
SD	9.15	1.99			Meansigma methods			17.57	13.30
SD	9.15	1.99			％CV	52.06	14.99
					％CV	52.06	14.99
					15c		Meansigma methods	8.77	5.89
SD	7.22	1.69					Meansigma methods	8.77	5.89
SD	7.22	1.69	％CV	82.36			28.70
15d		Meansigma methods	％CV	82.36			28.70	67.40	6.59
		Meansigma methods	SD	6.90	3.04			67.40	6.59
		％CV	SD	6.90	3.04	10.23	46.15

Shown in table 16 and accompanying drawing 5, compositions 16a-d has ideal percutaneous and absorbs.Should notice that it only is to promote the factor of treatment active drug delivery to target region that the percutaneous that confirms absorbs in this isolated measuring.

Embodiment 15

In one embodiment, have been found that compositions of the present invention causes the prodrug form of active component to produce when storing.This class prodrug forms because of the hydroxy-acid group of active medicine and alcoholic solvent react and forms due to the ester bond.

The compositions 1a that stores 3 months down at 25 ℃ is carried out the HPLC analysis.In chromatogram, detected the new peak (being prodrug) that is different from the ibuprofen peak.This peak shows eluting position and the UV response under 220nm that quite lags than ibuprofen.

Next, the peak is characterised in that retention position, UV spectrum and mass spectrum response.In addition, collect the separator at peak from being used for liquid chromatography-mass spectral chromatographic system.

Next step is with 25 milliliters of (50: 50) water: dilution in acetonitrile 2 gram compositions 1a.Centrifugal solution and collection supernatant are used for analyzing.

The following chromatograph of carrying out:

Pump: Hewlett Packard Model 1100 binary systems

Solvent orange 2 A: water

Solvent B: acetonitrile

Gradient: initial 40%B

In the time of 20 minutes, rise to 60%B

In the time of 40 minutes, rise to 90%B

Flow velocity: 1.0ml/ minute

Immobile phase ZORBAX  CS (4.6 * 150mm)

Column temperature: 25C

Sampling volume 25L

Absorb by the UV that uses the HP diode array detector, use ESI-MS subsequently, use the Sciex QSTAR /mass spectral ESI-MS of Pulsar quadripolar plate-TOF that is applied in operation under the positive and negative ion mode to carry out continuous detecting subsequently.

Accompanying drawing 6 illustrations use UV chromatogram (220nm) above-mentioned chromatographic condition stores 3 months compositions 1a at 25 ℃ of following sample introductions after.Ibuprofen in the time of about 14 minutes, go out the peak and and prodrug in the time of about 32 minutes, go out the peak.

Accompanying drawing 7a represents the positive ESI mass spectrum at ibuprofen peak.Observe (the M+H)+false molecular ion of expectation at m/z 207.13 places, and observe (M+NH at m/z 224.15 and 229.10 places respectively ₄) ⁺(M+Na) ⁺False molecular ion.Dimerization cluster ion can be classified as the signal at m/z430.27 and m/z 435.22 places.Noticeable possible fragment ion also appears at m/z 161.12, and is consistent with decarboxylation as shown below:

Accompanying drawing 7b is illustrated in about 220nm and the 265nm place shows peaked ibuprofen UV spectrum.

Accompanying drawing 8a represents the positive ESI mass spectrum available from prodrug.Observe possible (M+H) at m/z 235.15 places ⁺, as in the data of ibuprofen, can be with corresponding (M+NH ₄) ⁺(M+Na) ⁺False molecular ion can be classified as mlz 254.13 and m/z 257.13.Attention occurs at the m/z161.12 place and signal to the described identical fragment ion unanimity of ibuprofen.

Accompanying drawing 8b represent available from the UV spectrum of prodrug and with have very similar that peaked ibuprofen obtains at about 220nm and 265nm place.

The data that obtain in this research show that prodrug has: the neutral quality of (1) 234.15Da; (2) with the very similar UV spectrum of ibuprofen; (3) point out its obviously more hydrophobic retention property than ibuprofen; (4) no significance anion MS reaction; (5) show the cation MS spectrum that has fragment with ibuprofen.

These data have supported that prodrug is the evaluation of isobutyl phenenyl ethyl propionate.

Embodiment 16

The effect (" neutralization ") that basifier produces prodrug among the check compositions 1a.Shown in accompanying drawing 10, prodrug produces pro-at least 26 days for linear.In the compositions of alkali-free agent, with in sample in about 0.025%/day compare than low rate, this speed is about 0.05%/day.

Embodiment 17

The effect (" neutralization ") that basifier produces prodrug among the check compositions 1a in the experiment of longer-term limit.Accompanying drawing 11 is illustrated in does not have basifier to exist following prodrug to produce at least 100 days with stable state.

Embodiment 18

The effect (or medicine stability) that the application of initial activity drug level and different basifiers produces prodrug.According to table 7 preparation compositions.As observed in accompanying drawing 12, basifier has reduced prodrug basically and has formed speed.In addition, the concentration that reduces active medicine in the neutral compositions has reduced prodrug formation speed basically.The linear extrapolation of data is illustrated in the neutral compositions 14.8% ibuprofen initial concentration can prevent that prodrug from forming.

Embodiment 19

Checked different water concentrations and pH in the present composition prodrug to be formed the effect of speed.Observed as being used at table 17, similar with compositions 1a basically, but contain in 18% water and the 57% alcoholic acid compositions, cause prodrug formation speed significantly to descend by adding diisopropylamine increase pH.

When make basically with compositions 1a similar compositions in when comprising 24% water and～50% ethanol, prodrug forms speed and further reduces.Surprisingly, by add diisopropylamine with pH be adjusted to 5.5 with use diethylamine that analogous composition is adjusted to pH5.0 to compare the remarkable prodrug that increased and form speed.

Table 17:

% water	% ethanol	pH	Add basifier	% prodrug/sky
% water	% ethanol	pH	Add basifier	% prodrug/sky	18	57	3.68	Do not have	0.0516
18	57	5.0	Diisopropylamine	0.0262	18	57	3.68	Do not have	0.0516
18	57	5.0	Diisopropylamine	0.0262	24	51	5.0	Diethylamine	0.0078
24	50	5.5	Diisopropylamine	0.0200	24	51	5.0	Diethylamine	0.0078

Embodiment 19

Preparation is with the 1a similar compositions and be with or without test prodrug formation in the presence of the salicylic acid.Shown in accompanying drawing 13, salicylic acid has increased prodrug and has formed speed.

Embodiment 21

Comprise the compositions of the part of steady concentration according to table 18 preparation with active medicine and prodrug.

Balance equation according to esterification process prepares these compositionss, that is:

Acid+alcohol=ester+water

The equilibrium constant K that describes poised state is:

The K=[ester] [water]/[acid] [alcohol]

Wherein [] expression " concentration ".

With these composition stores at room temperature 6 months and mensuration active medicine and prodrug concentration.In all situations, initial concentration and final concentration initial concentration 10% in.

Also according to the fresh compositions of table 18 preparation and be stored in 40 ℃ following 30 days and measure active medicine and prodrug concentration.In all situations, initial concentration and final concentration initial concentration 10% in.

Table 18

	Alcohol (%)	Water (%)	Temperature	pH	Active medicine (%)	Prodrug (%)
	Alcohol (%)	Water (%)	Temperature	pH	Active medicine (%)	Prodrug (%)	18a	60 ethanol	15	25	4.0 do not add basifier	12 ibuprofen	3 ibuprofen ethyl esters
18b							18a	60 ethanol	15	25	4.0 do not add basifier	12 ibuprofen	3 ibuprofen ethyl esters
18b		50 ethanol	24	25	4.0 do not add basifier	13.5 ibuprofen	1.5 ibuprofen ethyl ester
18c		50 ethanol	24	25	4.0 do not add basifier	13.5 ibuprofen	1.5 ibuprofen ethyl ester
18c		70 ethanol	5	25	4.0 do not add basifier	6 ibuprofen	9 ibuprofen ethyl esters
18d		70 ethanol	5	25	4.0 do not add basifier	6 ibuprofen	9 ibuprofen ethyl esters
18d		80 ethanol	5	25	4.0 do not add basifier	4.5 ibuprofen	10.5 ibuprofen ethyl ester
18e		80 ethanol	5	25	4.0 do not add basifier	4.5 ibuprofen	10.5 ibuprofen ethyl ester
18e		60 ethanol	15	40	4.0 do not add basifier	3 ibuprofen	12 ibuprofen ethyl esters
18f		60 ethanol	15	40	4.0 do not add basifier	3 ibuprofen	12 ibuprofen ethyl esters	50 ethanol	24	40	4.0 do not add basifier	9 ibuprofen	6 ibuprofen ethyl esters
18f	18g	60 ethanol	15	25	5.0 interpolation diisopropanol	13.2 ibuprofen	1.8 ibuprofen ethyl ester	50 ethanol	24	40	4.0 do not add basifier	9 ibuprofen	6 ibuprofen ethyl esters

Embodiment 22

Intersection clinical trial check PFB effect by 10-week double blinding placebo.Research worker is damaged baseline PFB weekly after this and is carried out qualitative assessment.Counting and record as pimple, pustule and the ingrown chaeta of giving a definition.

The main purpose of this research is:

● measure once to continue the effect of different interval different N SAID compositions in alleviating PFB disease and symptom in 5 weeks every other day for twice to every day; With

● measure the safety and the toleration of different N SAID compositions.

Counting and record as pimple, pustule and the ingrown chaeta of giving a definition.

Pimple: diameter is lower than the little solid protuberances of 1.0cm.

Pustule: the little limitation cutaneous protuberance that comprises the yellow-white exudate.

Ingrown chaeta: deviate from skin, around crooked and enter the chaeta of skin again or penetrate hair follicle and under skin or the chaeta of middle growth.

Infringement on cervical region, bottom left and right side buccal and Hubei Province line (beard district) is counted.Identical titular clinicist finishes the evaluation of at every turn following up a case by regular visits to.The each evaluation all with evaluation last time independently carried out.The experimenter amounts to when baseline is followed up a case by regular visits to have at least 10 (moderate)-(of) 2 (slightly) hair follicle pimples, pustule or ingrown chaeta and allows carry out this research.

According to 6-point Likert (category) grade evaluation inflammation and/or the infringement of tuberosity cyst, erythema and hyperpigmentation:

0 does not have: the evidence of no active disease.

1 minimum: there be (infringement must be disappeared and hyperpigmentation, but is not to be pink/rubescent) in the infringement of rare non-inflammation.Rare can perceptiblely protuberance the (only can recognize) by sense of touch.

2 is slight: the non-inflammation infringement is preponderated, and does not wherein almost have inflammatory pimple/pustule.Slight red.But slight protuberance as seen.The infringement of no tuberosity cyst.

3 moderates: have some non-inflammation infringement, have a plurality of tangible struvite infringements simultaneously.Determine that infringement is rubescent and protuberance is arranged.Can exist, also can not have a kind of little tuberosity cyst infringement.

4 severes: highly struvite infringement is preponderated.Strong peony.The long-pending lasting time limit of skin turgor and general fermentation is obvious.Can exist, also can not have the infringement of a small amount of tuberosity cyst.

5 is very serious: the infringement of many tuberosity cysts.In source file and on the suitable CRF, write down the result.Identical titular clinicist finishes evaluation at every turn when following up a case by regular visits to.Each assessment should independently be carried out with last time estimating.The experimenter must have at least when baseline is followed up a case by regular visits to, and the grade of moderate (3) could allow carry out this research.

Require all experimenters to estimate the concrete PFB symptom of pruritus, pain and shaving sense of discomfort and PFB thereof weekly general status (" experimenter ' symptom evaluation ") when baseline and afterwards.

The experimenter finishes evaluation to each symptom and general status according to 5-point Likert (category) grade:

0 does not have: symptom/overall PFB situation does not exist.

1 is slight: symptom/overall PFB situation exists, but is not irksome especially.

2 moderates: symptom/overall PFB situation is deposited and is irksome, but the activity that can not disturb every day.

3 severes: symptom/overall PFB situation exists and is irksome and disturbed certain activity every day.

4 is very serious: symptom/overall PFB situation exists and is irksome and hindered many normal activities every day.Each evaluation should independently be carried out with last time estimating.

The overall improvement estimated.The general status of its PFB and the preceding general status of the treatment of using following 5-point Likert (category) grade when requiring the experimenter relatively to follow up a case by regular visits in the 2nd, 4 and 6 weeks:

Before 2 general statuses and shaving sense of discomfort are much better than treatment.

Before 1 general status and shaving sense of discomfort slightly are better than treatment.

0 general status and shaving sense of discomfort change far away, with identical before the treatment.

-1 general status and shaving sense of discomfort slightly increase the weight of before treating.

Before 2 general statuses and shaving sense of discomfort far overweight treatment.

Each evaluation should independently be carried out with last time estimating.

After finishing, evaluation study and showing comprise phenylacetic acid type NSAID contain that alcogel can effectively alleviate slightly, the PFB seriousness among moderate and the severe PFB.In addition, the organogel that comprises high concentration phenylacetic acid type NSAID can effectively use " next day " application program treatment PFB.Test subject with acne or dermatitis (for example contact dermatitis) has also been reported there being the therapeutic efficiency of indication.

Use comprises the alcogel that contains of 5%NSAID prodrug (for example phenylacetic acid type NSAID ethyl ester) and treats some experimenter and report that effect is higher than the experimenter who is equal to combination treatment that use comprises NSAID parent drug (rather than prodrug).

The organogel that use comprises 10% phenylacetic acid type NSAID is treated some experimenter and report effect and use, and to contain alcohol composition (10% phenylacetic acid type NSAID) similar, cuts thorn but report that organogel has lower desiccation and produces less razor.

Inflammation, the infringement of tuberosity cyst, erythema and hyperpigmentation near some experimenter razor touching that experience is more serious usually in the normal phase of its disease.This class pathologic condition of this class subjects reported is improved.

Embodiment 23

Synthesized radioactivity (C ₁₄) and on-radiation ibuprofen and ketoprofen ethyl ester class and isopropyl ester class.Use the method for synthetic NSAID Arrcostab between the carboxylic acid hydroxyl, to prepare esters.

In N2 compression ring border, use Dean Rodney Stark device with 2-[4-(2-methyl-propyl) phenyl] propanoic acid (9.6gm; 465mmol) and right-toluenesulfonic acid (1.52gm, 7.9mmol) solution in toluene (100ml) and ethanol (75ml) was heated under the reflux state 4 hours.Under reduced pressure except that desolvating and residue being dissolved in ethanol (100ml).Use saturated NaHCO ₃Aqueous solution (2 * 100ml) and water (2 * 100ml) extract this solution.Use anhydrous Na ₂SO ₄Dry organic layer filters and concentrates, and obtains 10.4 grams, is clarification grease.Similarly, synthesizing radioactive labelling ibuprofen ethyl ester as mentioned above, but raw material 2-[4-(2-methyl-propyl) phenyl only] propanoic acid is C ₁₄Labelling.

Prepare other NSAID alkyl esters similarly.With they 15% prodrug that is equivalent to precursor portions (being reactant), 1%ULTREZ in 60% alcohol respectively separately ^TM10 and 24% preparation under water.Also use ketoprofen to prepare the comparison compositions.Preparation does not contain the placebo of active component.

Test the prodrug compositions according to 22 couples of FEB experimenters of embodiment, comprise pharmacokinetic analysis.

In addition, every cm ²Small test is used 0.2gm C with the Corii Sus domestica skin ₁₄The compositions of-labelling and using the bark fetching skin perforation biopsy at interval from a plurality of positions in back 30 seconds to 24 hours.Also get blood serum sample at interval.The result is as shown in Table 19.

Table 19

Raw material	Reactant	Product	Whole body level (1=height, 5=is low)	Diffusion rate (1=height, 5=is low)	Effect (1=height, 5=is low)
Raw material	Reactant	Product	Whole body level (1=height, 5=is low)	Diffusion rate (1=height, 5=is low)	Effect (1=height, 5=is low)	2-(3-benzoyl phenyl) propanoic acid	Ethanol	The ibuprofen ethyl ester	4	2	2
2-(3-benzoyl phenyl) propanoic acid	Isopropyl alcohol	The ibuprofen isopropyl ester	5	1	1	2-(3-benzoyl phenyl) propanoic acid	Ethanol	The ibuprofen ethyl ester	4	2	2
2-(3-benzoyl phenyl) propanoic acid	Isopropyl alcohol	The ibuprofen isopropyl ester	5	1	1	2-[4-(2-methyl-propyl phenyl] propanoic acid	Ethanol	The ketoprofen ethyl ester	3	3	3
2-[4-(2-methyl-propyl phenyl] propanoic acid	Isopropyl alcohol	The ketoprofen isopropyl ester	3	3	3	2-[4-(2-methyl-propyl phenyl] propanoic acid	Ethanol	The ketoprofen ethyl ester	3	3	3
2-[4-(2-methyl-propyl phenyl] propanoic acid	Isopropyl alcohol	The ketoprofen isopropyl ester	3	3	3			Ketoprofen	2	5	5
		Placebo						Ketoprofen	2	5	5

Embodiment 24

Preparation oil-in-water type NSAID prodrug compositions as shown in Table 20.

Table 20

	A	B	C
	A	B	C	Water：
Water	10％-45％	25％-35％	20％	Water：
Water	10％-45％	25％-35％	20％	Alcohol
	10％-30％	0％-10％	0％-10％	Alcohol
	10％-30％	0％-10％	0％-10％	The water-soluble active agent	Have	Have	Have
Thickening agent	＜10％	＜10％	＜10％	The water-soluble active agent	Have	Have	Have
Thickening agent	＜10％	＜10％	＜10％	Oil phase：
Oil	30％-90％	0％-30％	0％	Oil phase：
Oil	30％-90％	0％-30％	0％	NSAID prodrug (for example ibuprofen ethyl ester)	10％-90％	45％-90％	50％
Fatty acid				NSAID prodrug (for example ibuprofen ethyl ester)	10％-90％	45％-90％	50％
Fatty acid		30％-90％	0％-30％	0％
Surfactant		30％-90％	0％-30％	0％	＜15％	＜15％	＜15％
Surfactant	Ibuprofen	-	Have	Have	＜15％	＜15％	＜15％
Salicylic acid	Ibuprofen	-	Have	Have	Have	--	Have
Salicylic acid					Have	--	Have
					D	E	F
	Water：				D	E	F
Water	Water：				45％-70％	30％-70％	53％
Water	Alcohol				45％-70％	30％-70％	53％
	Alcohol	0％-10％	5％-15％	5％
	The water-soluble active agent	0％-10％	5％-15％	5％	Have	Have	0％
Thickening agent	The water-soluble active agent	＜10％	＜10％	＜5％	Have	Have	0％
Thickening agent	Oil phase：	＜10％	＜10％	＜5％
Oil	Oil phase：	10％-35％	15％-35％	0％
Oil	NSAID prodrug ester (for example ibuprofen ethyl ester)	10％-35％	15％-35％	0％	10％-40％	25％-50％	30％
Fatty acid	NSAID prodrug ester (for example ibuprofen ethyl ester)				10％-40％	25％-50％	30％
Fatty acid		10％-35％	15％-35％	0％
Surfactant		10％-35％	15％-35％	0％	＜15％	＜10％	＜5％
Surfactant	NSAID	Have	Have	5％	＜15％	＜10％	＜5％
Salicylic acid	NSAID	Have	Have	5％	Have	Have	2％

Embodiment 25

According to table 20 compositions formulated.Prepare each NSAID or NSAID prodrug according to 4 kinds of different modes: as organogel (" A "); As oil-in-water type (" B "); As containing alcogel (" C "); With as phospholipid/poloxalkol compositions.In accordance with the teachings of the present invention and by considering the physicochemical characteristic compositions formulated of each medicine.Each compositions of preparation under three kinds of pHs: 4.0,5.0 and 6.0.

Drug level is 15% (if solvable) or the saturated concentration rule of thumb measured.In stripped and body, measure drug absorption, distribution, metabolism and elimination in the animal model.

In not having the hair Cavia porcellus, measure model of contact dermatitis (J Dermatol.1992Mar for example; 19 (3): 140-5.), psoriasis, (Journal ofInvestigative Dermatology Volume 117 Issue 4 of the atopic dermatitis in the epidermis interleukin 4 transgene mouse model in the mouse model of overexpression amphiregulin, 977 pages, October calendar year 2001) and the effect of other model.

Use the nonparametric variable analysis to analyze all data.Generation model is so that help to select and optimize NSAID (and/or NSAID prodrug) and the preparation that is used for various inflammatory dermatosis diseases.

NSAID	Prodrug ester/ether	Preparation
NSAID	Prodrug ester/ether	Preparation	Bufexamac	Methyl	A，B，C，D
Diclofenac (dicoflenac)	Ethyl	A，B，C，D	Bufexamac	Methyl	A，B，C，D
Diclofenac (dicoflenac)	Ethyl	A，B，C，D	Etofenamate	Isopropyl	A，B，C，D
Felbinac	Normal-butyl	A，B，C，D	Etofenamate	Isopropyl	A，B，C，D
Felbinac	Normal-butyl	A，B，C，D	entiazac	Palmityl	A，B，C，D
Fepradinol	4-(nitrooxy) butyl	A，B，C，D	entiazac	Palmityl	A，B，C，D
Fepradinol	4-(nitrooxy) butyl	A，B，C，D	Flufenamic acid	The dimethyl formamide base	A，B，C，D
lunoxaprofen	alcoholic xyethyl	A，B，C，D	Flufenamic acid	The dimethyl formamide base	A，B，C，D
lunoxaprofen	alcoholic xyethyl	A，B，C，D	Flurbiprofen	Isopropoxy	A，B，C，D
Ibuprofen	Lauryl	A，B，C，D	Flurbiprofen	Isopropoxy	A，B，C，D
Ibuprofen	Lauryl	A，B，C，D	Indomethacin	Isopropyl	A，B，C，D
sonixin	Isopropoxy	A，B，C，D	Indomethacin	Isopropyl	A，B，C，D
sonixin	Isopropoxy	A，B，C，D	Ketoprofen	Lauryl	A，B，C，D
Ketorolac	N-ethyoxyl N-propyl group N-ethylamino	A，B，C，D	Ketoprofen	Lauryl	A，B，C，D
Ketorolac	N-ethyoxyl N-propyl group N-ethylamino	A，B，C，D	Niflumic acid	p-alcoholic xyphenylurea	A，B，C，D
Oxyphenbutazone	The polyethylene glycyl	A，B，C，D	Niflumic acid	p-alcoholic xyphenylurea	A，B，C，D
Oxyphenbutazone	The polyethylene glycyl	A，B，C，D	Piketoprofen	Polyvinyl	A，B，C，D

Piroxicam	propylene glycoxymercaptoethyl	A，B，C，D
Piroxicam	propylene glycoxymercaptoethyl	A，B，C，D	Pranoprofen	The triithylamine base	A，B，C，D
Suxibuzone	The N-ethyoxyl, N-propyl group, N-ethyl, aminoethyl	A，B，C，D	Pranoprofen	The triithylamine base	A，B，C，D
Suxibuzone	The N-ethyoxyl, N-propyl group, N-ethyl, aminoethyl	A，B，C，D	Ufenamate	Ethyl	A，B，C，D
Bufexamac	---	A，B，C，D	Ufenamate	Ethyl	A，B，C，D
Bufexamac	---	A，B，C，D	dicoflenac	---	A，B，C，D
Etofenamate	---	A，B，C，D	dicoflenac	---	A，B，C，D
Etofenamate	---	A，B，C，D	Felbinac	---	A，B，C，D
entiazac	---	A，B，C，D	Felbinac	---	A，B，C，D
entiazac	---	A，B，C，D	Fepradinol	---	A，B，C，D
Flufenamic acid	---	A，B，C，D	Fepradinol	---	A，B，C，D
Flufenamic acid	---	A，B，C，D	lunoxaprofen	---	A，B，C，D
Flurbiprofen	---	A，B，C，D	lunoxaprofen	---	A，B，C，D
Flurbiprofen	---	A，B，C，D	Ibuprofen	---	A，B，C，D
Indomethacin	---	A，B，C，D	Ibuprofen	---	A，B，C，D
Indomethacin	---	A，B，C，D	sonixin	---	A，B，C，D
Ketoprofen	---	A，B，C，D	sonixin	---	A，B，C，D
Ketoprofen	---	A，B，C，D	Ketorolac	---	A，B，C，D
Niflumic	---	A，B，C，D	Ketorolac	---	A，B，C，D
Niflumic	---	A，B，C，D	Oxyphenbutazone	---	A，B，C，D
Piketoprofen	---	A，B，C，D	Oxyphenbutazone	---	A，B，C，D
Piketoprofen	---	A，B，C，D	Piroxicam	---	A，B，C，D
Pranoprofen	---	A，B，C，D	Piroxicam	---	A，B，C，D
Pranoprofen	---	A，B，C，D	Suxibuzone	---	A，B，C，D
Ufenamate	---	A，B，C，D	Suxibuzone	---	A，B，C，D

Claims

1. a dermatological acceptable composition comprises NSAID prodrug, solvent and thickening agent, and wherein NSAID belongs to phenylacetic acid type and the unsubstituted alkyl of precursor portions for being connected with NSAID with ester bond.

2. the described compositions of claim 1, wherein (a) described solvent is an organic solvent; (b) said composition further comprises lecithin and water; (c) said composition is an organogel.

3. a dermatological acceptable composition comprises NSAID prodrug ester, solvent and thickening agent, and wherein the NSAID prodrug is the ibuprofen prodrug, and wherein precursor portions is amide groups, sulfenyl or unsubstituted alkyl.

4. dermatological acceptable composition, comprise NSAID, NSAID prodrug, solvent and at least a excipient, this excipient is thickening agent, cosolvent, wetting agent, keratolytic agent, oil, softening agent, surfactant, antiseptic, coloring agent, UV blocker, antioxidant or spice.

5. the described compositions of claim 4, wherein the NSAID prodrug can be metabolized to NSAID.

6. a preparation method comprises the following step: the excipient of NSAID, NSAID prodrug, solvent and non-solvent is merged into a kind of dermatological acceptable composition.

7. a method for the treatment of inflammatory dermatosis comprises experimenter's topical administration NSAID prodrug of these needs is arranged, and wherein the NSAID prodrug is a phenylacetic acid type NSAID Arrcostab, and wherein said experimenter's behaviour, farm-animals or companion animals.

8. a method for the treatment of inflammatory epidermis disease comprises the dermatological acceptable composition that experimenter's topical administration that these needs are arranged is comprised the ibuprofen prodrug, and wherein said inflammatory epidermis disease is psoriasis, folliculitis, eczema or dermatitis.

9. method for the treatment of the experimenter, comprise the dermatological acceptable composition that this experimenter's topical administration is comprised phenylacetic acid type NSAID prodrug ester, solvent and thickening agent, wherein precursor portions is amide groups, sulfenyl or unsubstituted alkyl, and wherein said experimenter has the disease that is selected from psoriasis, folliculitis, eczema and dermatitis.

10. method for the treatment of PFB, comprise a kind of compositions of experimenter's dermal administration of these needs is arranged, the about 5%-of one or more alcoholic solvents, total amount that said composition comprises about 70% consumption of about 30%-is no more than the polymer viscosifier of one or more NSAIDs of about 25%, about 5% consumption of about 0.05%-and one or more keratolytic agents of total about 0.015%-of keratolytic agent amount about 25%, and wherein NSAID is dissolved in described one or more alcoholic solvents basically.

11. a method for the treatment of PFB comprises the dermatological acceptable composition that experimenter's topical administration that these needs are arranged is comprised the NSAID prodrug.

12. the described method of claim 11 is wherein by merging the described compositions of preparation with NSAID prodrug and the acceptable excipient of dermatological.

13. acceptable alcogel compositions that contains of dermatological, comprise one or more NSAIDs of the about 0.001%-of one or more alcoholic solvents, total amount about 25% of about 90% consumption of about 10%-, the polymer viscosifier of about 5% consumption of about 0.05%-and one or more keratolytic agents that there is the about 0.015%-of concentration about 25% in total keratolytic agent, and wherein NSAID is dissolved in described one or more alcoholic solvents basically.

14. the described compositions of claim 13, wherein one or more keratolytic agents exist with the consumption of effectively stablizing said composition pH and viscosity, and wherein one or more keratolytic agents are salicylate.

15. a compositions comprises phenylacetic acid type NSAID prodrug ester, solvent and thickening agent, wherein precursor portions is amide groups, sulfenyl or unsubstituted alkyl.

16. compositions, comprise NSAID prodrug, solvent and at least a excipient, described excipient is thickening agent, cosolvent, wetting agent, keratolytic agent, oil, softening agent, surfactant, antiseptic, coloring agent, UV blocker, antioxidant or spice, and wherein the NSAID prodrug is the unsubstituted Arrcostab of the NSAID of non-naproxen.

17. the acceptable alcogel compositions that contains of dermatological comprises at least a alcoholic solvent of the about 10%-of (a) total solvent amount about 90%; (b) the phenylacetic acid type NSAID of the about 1%-of total amount about 25%; (c) Polyacrylate thickeners of the about 0.05%-of consumption about 5%; (d) one or more keratolytic agents of total about 0.015%-of keratolytic agent amount about 25%, and wherein NSAID is dissolved in described at least a alcoholic solvent basically.

18. the acceptable alcogel compositions that contains of dermatological comprises at least a alcoholic solvent of the about 50%-of (a) total solvent amount about 70%; (b) the phenylacetic acid type NSAID of the about 5%-of total amount about 25%; (c) Polyacrylate thickeners of the about 0.05%-of consumption about 2%; Wherein said composition has approximately 2 under the situation of not adding basifier, and 000-is about 50, the viscosity of 000cps.

19. the acceptable alcogel compositions that contains of dermatological comprises at least a alcoholic solvent of the about 10%-of (a) total solvent amount about 90%; (b) one or more NSAID of the about 0.001%-of total amount about 25%; (c) polymer viscosifier of the about 0.05%-of consumption about 5%; (d) consumption is the water of 0%-about 20%, and wherein the viscosity of said composition is about 2, and 000cps-is about 50,000cps.

20. the acceptable alcogel compositions that contains of dermatological comprises at least a alcoholic solvent of the about 30%-of (a) total solvent amount about 90%; (b) have at least a NSAID of hydroxy-acid group; (c) at least a polymer viscosifier, it is Polyacrylate thickeners or alkyl hydroxy cellulose thickener, total about 0.1%-of thickening agent amount about 5%, wherein when storing said composition, the prodrug ester between described at least a alcoholic solvent and hydroxy-acid group forms and is lower than about 0.03% every day.

21. the described compositions of claim 20 further comprises and suppress the keratolytic agent that the prodrug ester forms consumption, and wherein said at least a alcoholic solvent is branched-chain alcoho or the alcohol that has 4 or 4 above carbon.

22. the acceptable alcogel compositions that contains of dermatological comprises (a) at least a alcoholic solvent of the about 30%-of amount about 90% always; (b) have at least a NSAID of hydroxy-acid group; (c) can be by the prodrug that forms with at least a alcoholic solvent esterification NSAID; (d) at least a polymer viscosifier, it is selected from Polyacrylate thickeners and alkyl hydroxy cellulose thickener, total thickening agent amount is about 0.1%-about 5%, wherein said medicine and described prodrug exist with such concentration at first, promptly at room temperature store 6 months, described concentration maintain separately initial concentration 80% in.

23. the acceptable alcogel compositions that contains of dermatological comprises at least a alcoholic solvent of the about 20%-of (a) total amount about 95%; (b) at least a NSAID of total NSAID amount about 1%-about 25%; (c) polymer viscosifier of the about 0.05%-of consumption about 5%; (d) consumption is the water of 0%-about 20%.

24. claim 7 or 10 described methods, wherein use a kind of device that described compositions is applied on the skin, described device is selected from roll-on device, is suitable for sending the razor of dermatological acceptable composition, has flooded fiber or non-fibre substrate, transdermal patches, adhesive tape and the aerosol container of described compositions.

25. a dermatological acceptable composition comprises at least a phenylacetic acid type NSAID, organic solvent, wherein said composition further comprises lecithin and water, and wherein said composition is an organogel.

26. claim 1 or 25 described compositionss, wherein at least a NSAID is bufexamac, diclofenac (dicoflenac), etofenamate, felbinac, entiazac, fepradinol, flufenamic acid, lunoxaprofen, Flurbiprofen, ibuprofen, indomethacin, sonixin, ketoprofen, ketorolac, niflumic acid (niflumic), oxyphenbutazone, piketoprofen, piroxicam, pranoprofen or suxibuzone.

27. the described compositions of claim 1, wherein said composition is gel, lotion, organogel, softening agent, solution, cream, ointment, dressing, foam, thin film, microemulsion or liposome.

28. claim 1 or 18 described compositionss, wherein said NSAID has the pH of hydroxy-acid group and said composition in the 0.5pH unit of described hydroxy-acid group pKa.

29. claim 1 or 18 described compositionss, wherein said composition have be selected from that about 3.0-is about 6.5, the pH of the scope of about 4.0-about 5.5 and 4.3-about 5.0.

30. claim 1 or 18 described compositionss have the viscosity that is selected from following scope: about 2000cps-is about 200,000cps; About 50,000cps-is about 200,000cps; About 50,000cps-is about 100,000cps; About 2,000cps-is about 50,000cps; About 2,000cps-is about 25,000cps; About 2,000cps-is about 10,000cps; With about 2,000cps-is about 5,000cps.

31. claim 1 or 18 described compositionss wherein use human body skin to measure in Bronaugh flow type diffusion cell, per hour percutaneous absorbs NSAID at least about 0.1% under 32 ℃.