CN104069060A

CN104069060A - Surface composition containing ibuprofen

Info

Publication number: CN104069060A
Application number: CN201410301673.0A
Authority: CN
Inventors: 埃里克·索尔·福塞尔
Original assignee: Strategic Science and Technologies LLC
Current assignee: Strategic Science and Technologies LLC
Priority date: 2009-06-24
Filing date: 2009-06-24
Publication date: 2014-10-01
Also published as: HK1202263A1

Abstract

The invention generally relates to the transdermal delivery of multiple compositions. In certain respects, the transdermal delivery can be promoted by utilizing an adverse biophysics environment. One set of embodiments of the invention provides a surface delivery composition containing ibuprofen and/or ibuprofen salts, a nitric oxide donor and an optionally selected adverse biophysics environment. In some situations, the composition can be stabilized by using stabilized polymers (such as xanthan gum, BT and/or RD, propylene glycol and a polysorbate surfactant such as polysorbate 20). Compared with the composition lack of one or more than one stabilized polymer, the temperature stability of the composition provided by the invention is unexpectedly realized by virtue of the stabilized polymers, for example: the temperature stability of the composition at a rising temperature (such as at least 40 DEG C (at least about 104 DEG F)) is ensured.

Description

The surface composition that contains ibuprofen

The application is to be the divisional application that on June 24th, 2009, application number are the Chinese patent application of " surface composition that contains ibuprofen " for " 200980161065.1 ", denomination of invention the applying date, and original application is the China national phase application of International Application PCT/US2009/003749.

Invention field

Generality of the present invention relates to the transdermal delivery of compositions.

Background technology

The topical transdermal of medicine is sent, although be desired, is subject to the restriction of prior art.Seldom there is medicine entity with successfully transdermal delivery of effective dose.For example, the medicine of limited kinds (for example neutral and do not form steroid, nicotine and the nitroglycerine of hydrogen bond) is successfully sent by passive diffusion, and passive diffusion is to rely on the Concentraton gradient delivering drugs between outside in skin according to Fick ' s the first diffusion law.The amount of the medicament that can send by simple diffusion is also limited.For example, equate once the concentration of horny layer inner side becomes with outside, flowing of medicament just can stop.Therefore, need to improve part or the whole body transdermal delivery of compositions.

Invention summary

Generality of the present invention relates to part or the whole body transdermal delivery of compositions, in certain embodiments, relates to and utilizes disadvantageous biophysics's environment to carry out transdermal delivery to compositions.Example comprises ibuprofen or other medicament.In some cases, theme of the present invention relates to the optional solution of Related product, particular problem and/or the multiple different purposes of one or more systems and/or goods.

In one group of embodiment, provide the compositions with relatively high temperature stability.In certain embodiments, for example, compositions of the present invention can comprise stabilization of polymers, propylene glycol and Polysorbate surfactant.The limiting examples of stabilization of polymers comprise xanthan gum, bT and/or rD; An example of Polysorbate surfactant is polysorbate 20.The high temperature stability that such combination of components is brought is unexpected, comprises that the compositions of any two kinds (and not comprising the third) in these components does not have the character of this high temperature stabilization because find.Also do not know at present why described combination of components is effective especially aspect the relatively high temperature stability of promotion compositions described herein, because known these components do not participate in any significant chemical reaction each other, and high temperature stability will reduce greatly in the time reducing any in described component.In addition, propylene glycol works and is not known as stabilizing agent at pharmaceutical composition.

Therefore, in one aspect, the present invention relates to send (topical delivery) compositions to subject's skin for surface.In one group of embodiment, described compositions comprises nitric oxide donors, disadvantageous biophysics's environment, stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt.

Another group embodiment in, described compositions comprise water, at least one hydrochlorate (chloride salt), nitric oxide donors, stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt at least about 80% (weight).

In another group of embodiment, described compositions comprises water, sodium chloride, nitric oxide donors, tristerin, spermol, potassium chloride, squalane, stabilization of polymers, isopropyl myristate, oleic acid, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt.

In another group embodiment, described compositions comprise concentration be no more than following concentration ± every kind of following compound of 20%: concentration is the water of approximately 44.2% (weight), concentration is the sodium chloride of approximately 10% (weight), concentration is the nitric oxide donors of approximately 7.5% (weight), concentration is the tristerin of approximately 7% (weight), concentration is the spermol of approximately 7% (weight), concentration is the potassium chloride of approximately 5.5% (weight), concentration is the propylene glycol of approximately 5% (weight), concentration is the squalane of approximately 4% (weight), concentration is that Polysorbate surfactant and the concentration of approximately 2% (weight) is the isopropyl myristate of approximately 1% (weight), concentration is the oleic acid of approximately 1% (weight), concentration is the stabilization of polymers of approximately 0.8% (weight), concentration is ibuprofen and/or the ibuprofen salt of approximately 5.0% (weight).

In another group embodiment, described compositions comprises nitric oxide donors, disadvantageous biophysics's environment, stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt.In another group of embodiment, described compositions comprises stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt.Another group embodiment in, described compositions comprise water, at least one hydrochlorate, stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt at least about 80% (weight).

In yet another aspect, the present invention relates to the purposes of compositions in the medicine for the preparation for the treatment of disease as described herein or disease.In one group of embodiment, the described compositions for medicine comprises nitric oxide donors, disadvantageous biophysics's environment, stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt.

Another group embodiment in, the described compositions for medicine comprise water, at least one hydrochlorate, nitric oxide donors, stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt at least about 80% (weight).

In another group of embodiment, the described compositions for medicine comprises water, sodium chloride, nitric oxide donors, tristerin, spermol, potassium chloride, squalane, stabilization of polymers, isopropyl myristate, oleic acid, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt.

In another group of embodiment, the described compositions for medicine comprise concentration be no more than following concentration ± every kind of following compound of 20%: concentration is the water of approximately 44.2% (weight), concentration is the sodium chloride of approximately 10% (weight), concentration is the nitric oxide donors of approximately 7.5% (weight), concentration is the tristerin of approximately 7% (weight), concentration is the spermol of approximately 7% (weight), concentration is the potassium chloride of approximately 5.5% (weight), concentration is the propylene glycol of approximately 5% (weight), concentration is the squalane of approximately 4% (weight), concentration is that Polysorbate surfactant and the concentration of approximately 2% (weight) is the isopropyl myristate of approximately 1% (weight), concentration is the oleic acid of approximately 1% (weight), concentration is the stabilization of polymers of approximately 0.8% (weight), concentration is ibuprofen and/or the ibuprofen salt of approximately 5.0% (weight).

In another group embodiment, the described compositions for medicine comprises nitric oxide donors, disadvantageous biophysics's environment, stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt.In another group of embodiment, the described compositions for medicine comprises stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt.Another group embodiment in, the described compositions for medicine comprise water, at least one hydrochlorate, stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt at least about 80% (weight).

In yet another aspect, the present invention relates to prepare the method for one or more of embodiments as herein described.In yet another aspect, the present invention relates to use the method for one or more of embodiments as herein described.In yet another aspect, the present invention relates to promote the method for one or more of embodiments as herein described.

According to the following detailed description to various indefiniteness embodiments of the present invention, other advantage of the present invention and new feature will become apparent.In the case of description of the present invention and as a reference and introduce file including contradict and/or inconsistent content, be as the criterion with the present invention.If the as a reference two or more and file including introduced is each other when contradiction and/or inconsistent content, the file leaning backward with the effective date is as the criterion.

Describe in detail

Generality of the present invention relates to the transdermal delivery of multiple combination thing.In some aspects, transdermal delivery can be by promoting with disadvantageous biophysics's environment.One group of embodiment provides and has comprised ibuprofen and/or ibuprofen salt and the surperficial delivering compositions of disadvantageous biophysics's environment and/or nitric oxide donors optionally.In some cases, described compositions can use stabilization of polymers (for example xanthan gum, bT and/or rD), the combination of propylene glycol and Polysorbate surfactant (for example polysorbate 20) carrys out stabilisation, compared with the one or more of compositions lacking in these materials, described combination provides temperature stability for described compositions unexpectedly, for example for example, temperature stability at the temperature (at least 40 DEG C (at least about 104 °F)) raising.

One aspect of the present invention provides such as, compositions for surperficial delivered substance (medicament (as medicine, biological compound etc.)).Described medicament can be applied to object (for example people's) skin, to help to treat medical conditions or disease, and/or its relevant symptoms.In certain embodiments, the invention provides and (for example use pharmaceutical treatment medical conditions or disease and/or slight illness, suffers from the object of medical conditions as described herein or disease with treatment diagnosis), in some cases, the present invention sends the medicament of minimum flow to provide the medicine of effect level to local affected areas, and limits side effect simultaneously.In some cases, the effective dose of described medicament can be when oral the effective dose of medicament.

For example, in one group of embodiment, described medicament is ibuprofen and/or ibuprofen salt.Although ibuprofen is the medicament that effectively resists pain in the time of oral administration, it can stimulate gastric mucosa, the provocable people of ulcer or upper gastrointestinal easily occurs and be conventionally warned and avoid using ibuprofen.Therefore,, in one group of embodiment, the present invention allows ibuprofen surface applied to inflammation or painful area, and avoids all the other positions, particularly stomach of health.Described compositions also can comprise nitric oxide donors, and as L-arginine, it may be useful for the regional flow that for example increases site of delivery, thereby can increase send (for example part or the systemic delivery) of medicament.In some cases, described enhancing can exist by maintain suitable Concentraton gradient in site of delivery.

In addition, in some cases, described compositions can also be mixed with it is for example produced, for the disadvantageous biophysics's environment of medicament (ibuprofen).In disadvantageous biophysics's environment, described medicament environment around can make this medicament in respect to skin (particularly horny layer) and on opinion on public affairs and/or energy in hostile environment (for example, chemical potential and/or the free energy of medicament in described disadvantageous biophysics's environment is significantly greater than chemical potential and/or the free energy of this medicament in skin, transports thereby energetically favor in skin).

The example of such compositions be described in E.Fossel on April 19th, 2005 submit to, name be called in the international patent application No.PCT/US2005/013228 of " Transdermal Delivery of Beneficial Substances Effected by a Hostile Biophysical Environment ", it was announced with WO2005/102282 on November 3rd, 2005, was introduced into herein as a reference.Other technology about disadvantageous biophysics's environment describes in detail in this article.For example, for example, but at relatively high temperature, (at elevated temperatures (at least 40 DEG C (at least about 104 °F)) are unsettled at least about the time period of one day to such compositions conventionally.Therefore,, in one group of embodiment, provide the compositions with relatively high temperature stability herein.For example, in certain embodiments, compositions of the present invention also can comprise stabilization of polymers, propylene glycol and Polysorbate surfactant.The non-limiting example of stabilization of polymers comprise xanthan gum, bT and/or rD; An example of Polysorbate surfactant is polysorbate 20.Other examples as described herein.

The high temperature stability that such combination of components causes is unexpected, because find that the compositions that comprises any two kinds (and not comprising the third) in these components does not have this high temperature stabilization character.Also do not know at present why this combination of components is effective especially aspect the relatively high temperature stability of promotion compositions described herein, because known these components do not participate in mutual any significant chemical reaction, and high temperature stability reduces greatly in the time one of removing in described component.In addition, propylene glycol works and is not known as stabilizing agent in pharmaceutical composition.

For example, in one group of embodiment, can by measure compositions through relatively long-time (for example at least 1 hour, at least about 2 hours, at least 1 day, at least about 1 week, at least about 4 weeks etc.) whether demonstrate to be separated and determine whether described compositions has high temperature stability.For example, in certain embodiments, compositions is exposed under ambient temperature and pressure at least 1 hour, then analyzes said composition and be separated or phase change to determine whether said composition demonstrates.Stable compound is not show the compound being separated, and unstable compound can demonstrate and be separated.Such stability can be used for the storage of such as compositions, transport, the shelf life etc. of compositions.

Medicament (for example ibuprofen and/or ibuprofen salt) can exist with any suitable concentration.For example, in some cases, described medicament exist concentration can be described composition weight at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 7.5%, at least about 8%, at least about 9% or at least about 10%.In addition, described medicament can exist with native form and/or salt.For example, if there is ibuprofen, it can use by its native form, and/or uses lysinate, the arginine salt of ibuprofen etc. of the sodium salt of such as ibuprofen of described ibuprofen salt, the potassium salt of ibuprofen, ibuprofen as one or more of ibuprofen salts.Ibuprofen is easy to commercially available.

" stabilization of polymers " used herein is the polymer that comprises xanthan gum, xanthan derivatives and/or xanthan gum equivalent, for example bT and/or rD, xC, xCD, d, cC, 180, 75 etc., all these can be buied from different suppliers.In certain embodiments, the combination of these and/or other polymer is also available.In some cases, stabilization of polymers is chosen as and conventionally at least thinks that in people, using is safe those.In addition, in certain embodiments, described stabilization of polymers makes by synthetic, and/or through purification to a certain degree.Described stabilization of polymers can have any suitable molecular weight, for example at least about 1,000,000, at least about 2,000,000, at least about 5,000,000, at least about 10,000,000, at least about 25,000,000 or at least about 50,000,000.

Within described stabilization of polymers can be present in described compositions with any suitable concentration.For example, described stabilization of polymers exist concentration can be described composition weight at least about 0.1%, at least about 0.2%, at least about 0.3%, at least about 0.4%, at least about 0.5%, at least about 0.6%, at least about 0.7%, at least about 0.8%, at least about 0.9% or at least about 1%.In some cases, can exist more than a kind of stabilization of polymers, every kind of stabilization of polymers can exist with any suitable amount.As a concrete example, in certain embodiments, described stabilization of polymers substantially by bT and/or rD composition.In some cases, described stabilization of polymers can have fixed proportion bT and/or rD, for example by weight 1: 1 or 3: 5.In another example, the concentration that exists of BT can be approximately 0.3% of described composition weight, the concentration that exists of RD can be 0.5% of described composition weight, or one or both in these two kinds can exist with described above one of other concentration.In other embodiments, also comprise the combination of these and/or other stabilization of polymers, for example bT and xanthan gum, rD and xanthan gum etc.In some cases, can use thickening agent replace stabilization of polymers, or with stabilization of polymers coupling.Multiple thickening agent is commercially available.Thickening agent comprises those that use in food industry, or GRAS reagent (being conventionally considered to safe), for example algin (alginin), guar gum, locust bean gum, collagen, Ovum Gallus domesticus album, Furcellaran (furcellaran), gelatin, agar and/or carrageenin, and the combination of these and/or other stabilization of polymers.Therefore, should be appreciated that mention stabilization of polymers in other embodiments in this paper description time, it should be understood to also to comprise with stabilization of polymers coupling or replaces the thickening agent of stabilization of polymers.

Propylene glycol is commercially available, and can exist with the racemic mixture of any stereoisomer or isomer.It also can exist with any suitable concentration.For example, propylene glycol exist concentration can for described composition weight at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9% or at least about 10%.In some cases, other glycols (as butanediol) can or replace propylene glycol with propylene glycol coupling.Therefore, should be appreciated that in this manual, while mentioning propylene glycol in other embodiments, it should be understood to also to comprise with propylene glycol coupling or replaces other glycol of propylene glycol.

In addition, Polysorbate surfactant also can be present in described compositions with any suitable concentration.For example, in some cases, described Polysorbate surfactant exist concentration can for described composition weight at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, at least about 9% or at least about 10%." Polysorbate surfactant " used herein is the surfactant that comprises Polysorbate.For example, described surfactant can comprise sorbitan mono-laurate, anhydrous sorbitol monopalmitate, sorbitan monostearate, sorbitan monooleate or other anhydrous sorbitol salt.In some cases, described Polysorbate surfactant has following molecular formula:

Wherein w, x, y and z are any suitable positive integer.W, x, y and z also can be identical or different independently of one another.In one group of embodiment, w+x+y+z is 20 (for example,, in polysorbate 20s).In some cases, can use other polymerization sugar to replace Polysorbate surfactant, or with the coupling of Polysorbate surfactant.Therefore, should be appreciated that in this manual, in other embodiments, while mentioning Polysorbate surfactant as an example, the Polysorbate surfactant of mentioning can comprise other polymerization sugar with the coupling of Polysorbate surfactant or replacement Polysorbate surfactant.

In some cases, described compositions can have stabilization of polymers and propylene glycol and the Polysorbate surfactant of fixed proportion.For example, the ratio of these components can be approximately 1: 1: 1, approximately 1: 6: 3, approximately 1: 6: 2, approximately 1: 7: 2, approximately 1: 7: 3, approximately 1.5: 1: 1, approximately 1.5: 6: 3, approximately 1.5: 6: 4, approximately 1: 6: 2.5, approximately 1: 6.25: 2.5, approximately 1: 6.25: 2.5 etc.As mentioned above, in certain embodiments of the invention, these ratios can be used for providing temperature stability for described compositions.

As described in, described compositions also can comprise nitric oxide donors, for example L-arginine and/or L-arginine hydrochlorate.In some cases, such nitric oxide donors can be used for increasing the regional flow of described compositions site of administration, and this can increase sending of medicament.Described nitric oxide donors can be present in described compositions with any suitable concentration.For example, in some cases, described nitric oxide donors exist concentration can be described composition weight at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 7.5%, at least about 8%, at least about 9% or at least about 10%.In some cases, can use one or more of nitric oxide donors (for example 2,3,4,5,6,7,8,9,10 kind etc. nitric oxide donors).

" nitric oxide donors " used herein is the compound that can discharge nitric oxide and/or for example, directly or indirectly nitric oxide part is transferred to another molecule by chemical mode (, passing through biological process).Described nitric oxide donors can discharge into skin by nitric oxide, and/or for example, in tissue (muscle and/or be in close proximity to the member of the blood circulation of skin surface).The non-limiting example of nitric oxide donors comprises arginine (for example L-arginine and/or D-Arg), arginine derivative (for example L-arginine hydrochlorate and/or D-Arg hydrochlorate), nitroglycerine, the nitric oxide-nucleopilic reagent adduct in conjunction with polysaccharide, the azanol, 1 that N-nitroso-group-N-replaces, 3-(nitrooxy methyl) phenyl-2 hydroxybenzoic acid ester/salt etc., and/or any combination of these and/or other compound.

Except L-arginine and L-arginine hydrochlorate, other non-limiting example of nitric oxide donors comprises D, alkyl (such as ethyl, methyl, propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group etc.) ester (such as methyl ester, ethyl ester, propyl ester, butyl ester etc.) and/or its salt of L-arginine, D-Arg or L-arginine and/or D-Arg, and arginic other derivant and other nitric oxide donors.For example, the non-limiting example of officinal salt comprises hydrochlorate, glutamate, Glu, butyrate or oxyacetate (for example, obtaining L-arginine glutamate, Glu, L-arginine butyrate, L-arginine oxyacetate, D-Arg hydrochlorate, D-Arg glutamate, Glu etc.).Other examples of nitric oxide donors comprise the compound based on L-arginine; such as but not limited to the N-hydroxyl-L-arginine of the N-hydroxyl-L-arginine of the L-arginine of the L-arginine of L-homoarginine, N-hydroxyl-L-arginine, nitrous acidylate, nitrous acidylate, nitrous acidylate, nitrous acidylate, citrulline, ornithine, linsidomine (linsidomine), sodium nitroprusside, glutamine etc., and the combination in any of salt (such as hydrochlorate, glutamate, Glu, butyrate, oxyacetate etc.) and/or these and/or other compound.Other non-limiting examples of nitric oxide donors comprise the substrate of S-nitrosothiol, nitrite, 2-hydroxyl-2-nitroso-group hydrazine or various forms of nitricoxide synthases.In some cases, described nitric oxide donors can be the compound that stimulates in vivo nitric oxide endogenous to generate.The example of such compound includes but not limited to the combination in any of substrate, some cytokine, adenosine, Kallidin I, calreticulin (calreticulin), bisacodyl, phenolphthalein, OH-arginine or Endothelin (endothelein) and/or these and/or other compound of L-arginine, various forms of nitricoxide synthases.

Therefore, be to be understood that, in any one embodiment of description L-arginine as herein described and/or L-arginine hydrochlorate, also can replace L_ arginine and/or L-arginine hydrochlorate with other nitric oxide donors, or, in other embodiments of the present invention, can use other nitric oxide donors and L_ arginine and/or L-arginine hydrochlorate to be used in combination.

In some cases, can regulate the concentration of nitric oxide donors in described compositions, make effectively to treat the duration be at least about 3 hours, at least about 5 hours, or in some cases at least about 8 hours or longer.Can also control the duration by the concentration of for example controlling the penetrating agent of use together with nitric oxide donors.Penetrating agent discusses in detail herein.The actual concentrations of concrete application can only be determined with conventional experiment by those of ordinary skill in the art, for example, determine across the transhipment amount of the nitric oxide donors of the function of the external concentration of cadaver skin or suitable animal model, skin graft, synthetic model film, human model etc. by measuring conduct.

As a specific non-limiting example, in certain embodiments, nitric oxide uses L-arginine to provide, and for example concentration is at least about the L-arginine (optionally with one or more of penetrating agent as herein described (for example can produce the penetrating agent of disadvantageous biophysics's environment) combination) of 0.5% weight (wt% or w/v), at least about 0.75wt%, at least about 1wt%, at least about 2wt%, at least about 3wt%, at least about 5wt%, at least about 7wt%, at least about 10wt% or at least about the L-arginine of 15wt%.L-arginine for example may reside in, in suitable delivery vector (ointment or lotion).Because its toxicity is low, dissolubility is high and/or cost is low, L-arginine in some cases can be particularly useful.Other example of nitric oxide donors be described in E.T.Fossel on February 23rd, 2005 submit to, name be called in the international patent application No.PCT/US2005/005726 of " Transdermal Delivery of Nitric Oxide Donor to Improve Body and Skin Appearance ", it announces with WO2005/081964 JIUYUE in 2005 on the 9th, is introduced into herein as a reference.

Do not wish to be bound by any theory, it has been generally acknowledged that medicament flows through skin and can slow down, because it accumulates in tissue.Fick ' s the first diffusion law shows, in the time that inner concentration is substantially equal to outside concentration, passive flowing stops.Regional flow increases and can prevent or at least reduce the mobile stagnation of medicament.Therefore, in the time that said composition is applied to skin, described medicament more easily discharges in tissue from carrier, because this medicament is by flow dispersion, and concentration in tissue can not be gathered.Therefore, in certain embodiments, medicament (for example ibuprofen and/or ibuprofen salt) can be incorporated in skin.

In multiple embodiments, disadvantageous biophysics's environment of the present invention can comprise high ionic strength, high penetrating agent (for example urea, sugar or carbohydrate) concentration, high pH environment (is for example greater than approximately 9, be greater than approximately 10, be greater than approximately 11, be greater than approximately 12, or be greater than approximately 13), low pH environment (is less than approximately 5, be less than approximately 4, be less than approximately 3 or be less than approximately 2), high hydrophobicity component, or high-hydrophilic component or cause the chemical potential of medicament and/or other material that free energy improves, or the combination in any of two or more in these and/or other compound.In certain embodiments, the octanol-water partition coefficient that hydrophobic components can have is at least about 100, at least about 1000, at least about 104, at least about 10 ⁵, or higher in some cases.Similarly, the octanol-water partition coefficient that hydrophilic component can have is for being less than approximately 0.01, being less than approximately 10 ^-3, be less than approximately 10 ^-4, or be less than in some cases approximately 10 ^-5.

In some cases, described compositions defines biophysics's adverse environment.In other cases, medicament can be packaged into make it be transported in tissue and/or its electric charge by derivatization (derivitization) and/or form neutral salt be neutralized.The example of biophysics's adverse environment (for example includes but not limited to high ionic strength environment, by adding urea, sugar, carbohydrate and/or ion salt are as lithium chloride, sodium chloride, potassium chloride, calcium chloride, magnesium chloride, choline chloride, sodium fluoride, lithium bromide etc.), and at high ionic strength for example (for example, be greater than about 0.25M, be greater than about 1M, be greater than about 2M, be greater than about 3M, be greater than about 5M, be greater than about 10M, be greater than about 15M, be greater than about 20M, be greater than about 25M etc., or in some cases, about 0.25M is to about 15M, about 5M is to about 15M, about 10M is to about 15M, Deng) combination of lower these and/or other reagent, high or low pH environment (for example, by adding pharmaceutically acceptable acid or alkali, for example making pH is approximately 3 to approximately 7, approximately 3 to approximately 6, approximately 3 to approximately 5, approximately 7 to approximately 11, approximately 8 to approximately 11, approximately 9 to approximately 11, etc.), or high hydrophobicity environment (for example,, by reducing the water content of environment and increasing lipid, oil and/or wax content).In certain embodiments, described ionic strength is any amount that is greater than haemophysiology ionic strength twice.

In certain embodiments, can also use other high electric charge molecule (as polylysine, polyglutamine, poly-aspartate etc., or the amino acid whose copolymer of these high electric charges) to produce described disadvantageous biophysics's environment.The non-limiting example that is transported to the delivery vector in tissue comprises the component of liposome or collagen Emulsion, collagen peptide or other skin or basement membrane.In and the non-limiting example of electric charge comprise the medicament of sending electroneutral ester or salt form.In certain embodiments, described disadvantageous biophysics's environment can comprise in these conditions any two or more.For example, described disadvantageous biophysics's environment can comprise high ionic strength and high pH or low pH, high hydrophobicity environment and high pH or low pH, comprise high hydrophobicity environment of liposome etc.

In certain embodiments, disadvantageous biophysics's environment can also produce by relatively high electric charge medicament being put into hydrophobicity oiliness environment (for example, containing little water or water-free oil-based cream or washing liquid).Can be by will further assisting absorption with combining with penetrating agent with disadvantageous biophysics's environment, as described further herein.

In one group of embodiment, described compositions can be used as Emulsion and exists.Those of ordinary skill in the art are known, and Emulsion comprises for example, first-phase (for example discontinuous phase) within second fluid phase (continuous phase) conventionally.Described medicament (for example ibuprofen) may reside in arbitrary phase or biphase in.In addition, other material (as described herein those) can with described medicament be present in same mutually in.For example, in the time existing, nitric oxide donors, stabilization of polymers, propylene glycol and/or Polysorbate surfactant all can with described medicament be present in same mutually in, be for example present in discontinuous phase and/or continuous phase.

The compositions that another aspect of the present invention is usually directed to send for surface, it contains by weight at least about 50%, at least about 70%, at least about 80%, at least about 85%, at least about 90%, at least about 95% or substantially whole described in comprise water, at least one hydrochlorate, nitric oxide donors, stabilization of polymers, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt compositions.Described compositions also can comprise other component, for example tristerin, spermol, squalane, isopropyl myristate and/or oleic acid, its can form measure after described compositions partly or entirely.The example of these and/or other component is described in this article to some extent.

Water can exist with any suitable concentration, for example exist concentration be described composition weight at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45% or at least about 50%.In certain embodiments, water exist concentration be described composition weight at least about 40.9%.

The non-limiting example of hydrochlorate comprises sodium chloride, potassium chloride, calcium chloride, magnesium chloride, choline chloride etc.In some cases, can there is more than a kind of hydrochlorate for example sodium chloride and potassium chloride.Described hydrochlorate can exist with any suitable concentration, and in some cases, described hydrochlorate can produce disadvantageous biophysics's environment.For example, described hydrochlorate exist concentration can for described composition weight at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 7.5%, at least about 8%, at least about 9%, at least about 10%, at least about 12%, at least about 15%, at least about 17% or at least about 20%.

As limiting examples, in one group of embodiment, described compositions can be made up of water, sodium chloride, nitric oxide donors, tristerin, spermol, potassium chloride, squalane, stabilization of polymers, isopropyl myristate, oleic acid, propylene glycol, Polysorbate surfactant and ibuprofen and/or ibuprofen salt substantially.

As concrete non-limiting example, in some cases, the concentration that exists of tristerin is approximately 7% of described composition weight.In some cases, the concentration that exists of spermol is approximately 7% of described composition weight.In one group of embodiment, the concentration that exists of Squalene is approximately 4% of described composition weight.In some cases, the concentration that exists of potassium chloride is approximately 5% of described composition weight.In one group of embodiment, the concentration that exists of isopropyl myristate is approximately 1% of described composition weight.In some cases, the concentration that exists of oleic acid is approximately 1% of described composition weight.

In certain embodiments, the present invention relates to a kind of compositions, its comprise concentration be no more than following concentration ± every kind of following compound of 20%: concentration is the water of approximately 40.9% (weight), concentration is the sodium chloride of approximately 10% (weight), concentration is the nitric oxide donors of approximately 7.5% (weight), concentration is the tristerin of approximately 7% (weight), concentration is the spermol of approximately 7% (weight), concentration is the potassium chloride of approximately 5% (weight), concentration is the squalane of approximately 4% (weight), concentration is the stabilization of polymers of approximately 0.8% (weight), concentration is that the isopropyl myristate of approximately 1% (weight), the oleic acid that concentration is approximately 1% (weight), propylene glycol, the concentration that concentration is approximately 5% (weight) are the Polysorbate surfactant of approximately 2% (weight), with concentration be ibuprofen and/or the ibuprofen salt of approximately 7.5% (weight).

Aspect some, use delivery vector (for example emulsifiable paste, gel, liquid, washing liquid, spray, aerosol or transdermal patch) that compositions of the present invention is administered to object of the present invention.In one group of embodiment, compositions of the present invention can be applying or be dipped in the binder or patch that is applied to subject's skin." object " used herein refers to people or non-human animal.The example of object includes but not limited to that mammal such as, such as, such as, as Canis familiaris L., cat, horse, donkey, rabbit, cattle, pig, sheep, goat, rat (Rattus norvegicus (Rattus Norvegicus)), mice (house mouse (Mus musculus)), Cavia porcellus, hamster, primates (monkey, chimpanzee, baboon, ape, gorilla etc.) etc.Such delivery vector can be applied to object (for example people's object) skin.The example of delivery vector as described herein.Delivery vector can promote the nitric oxide donors of valid density and/or medicament to be transported to directly or indirectly in skin.For example, described delivery vector can comprise one or more of penetrating agent, as further described herein.Those of ordinary skill in the art will recognize that nitric oxide donors and/or medicament are joined to system and the technology in delivery vector, described delivery vector is emulsifiable paste, gel, liquid, washing liquid, spray, aerosol or transdermal patch for example.In some cases, can reduce by including the penetrating agent of relatively large or concentration in the concentration of nitric oxide donors in delivery vector and/or medicament, or improve the dense to extend advantageous effects of nitric oxide donors in delivery vector and/or medicament.In one group of embodiment, described nitric oxide donors and/or medicament can with additive (for example theophylline (for example,, with 10% weight/volume)) coupling.

In delivery vector, can there is other material, such as buffer agent, antiseptic, surfactant etc.For example, emulsifiable paste can comprise one or more of in water, mineral oil, tristerin, Squalene, propylene glycol stearate, Semen Tritici aestivi germ oil, tristerin, isopropyl myristate, stearic acid sterol ester, polysorbate 60, propylene glycol, oleic acid, Tocopherol acetate ester, collagen, sorbitan monostearate, vitamin A and D, triethanolamine, methyl hydroxybenzoate, Aloe vulgaris (aloe vera) extract, imidazolidinyl urea, propylparaben, PND and/or BHA.

As concrete non-limiting example, emulsifiable paste can contain one or more of (w/v) in following component: water (20-80%), white oil (3-18%), tristerin (0.25-12%), Squalene (0.25-12%), spermol (0.1-11%), propylene glycol stearate (0.1-11%), Semen Tritici aestivi germ oil (0.1-6%), polysorbate 60 (0.1-5%), propylene glycol (0.05-5%), collagen (0.05-5%), sorbitan monostearate (0.05-5%), vitamin A (0.02-4%), vitamin D (0.02-4%), vitamin E (0.02-4%), triethanolamine (0.01_4%), methyl hydroxybenzoate (0.01-4%), Aloe extract (0.01_4%), imidazolidinyl urea (0.01-4%), propylparaben (0.01-4%), BHA (0.01_4%), L-arginine hydrochlorate (0.25-25%), sodium chloride (0.25-25%), magnesium chloride (0.25-25%) and/or choline chloride (0.25-25%).The percent of every kind of compound can change (or in some cases, described compound can not exist), for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.

In another embodiment, ointment can comprise medicament (for example ibuprofen), and the following component of one or more of any appropriate amount: water (for example 20-80%), L-arginine hydrochlorate (for example 0-25%), sodium chloride (for example 0-25%), potassium chloride (for example 0-25%), tristerin (for example 0-15%), spermol (for example 0-15%), Squalene (for example 0-15%), isopropyl myristate (for example 0-15%), oleic acid (for example 0-15%), polysorbas20 (for example 0-10%) and/or butanediol (for example 0-10%).The percent of every kind of compound can change (or in some cases, described compound can not exist), for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.

In certain embodiments, ointment can comprise medicament and one or more of ion salt, and the concentration of described ion salt is to be at least enough to produce the disadvantageous biophysics's environment for this medicament.For example, described ointment can comprise one or more of (w/v) in following component: charged and/or hydrogen bonding entity (0.001-30%), choline chloride (1-30%), sodium chloride (2-30%) and/or magnesium chloride (1-20%w/v).In another example, described ointment can comprise one or more of (w/v) in following component: L-arginine hydrochlorate (2.5-25%), choline chloride (10-30%), sodium chloride (5-20%) and/or magnesium chloride (5-20%).In another example, described ointment can comprise one or more of (w/v) in following component: creatine (0.001-30%), inosine (0.001-30%), choline chloride (1-30%), sodium chloride (2-30%), magnesium chloride (1-20%), L-arginine (0.1-25%) and/or theophylline (0.1-20%).In some cases, described ointment also can comprise L-arginine hydrochlorate (0-12.5%w/v) and/or theophylline (0-10%w/v).The percent of every kind of compound can change (or in some cases, described compound can not exist), for example 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 20%, etc.In these examples, can provide high ionic strength environment with choline chloride, sodium chloride and/or magnesium chloride.

Although this paper describes ibuprofen and/or ibuprofen salt, but should be appreciated that this is only for example, in other embodiments, can use other medicament to replace ibuprofen and/or ibuprofen salt, or except ibuprofen and/or ibuprofen salt, also use other medicament.The non-limiting example of medicament comprises that micromolecule (for example, molecular weight is less than approximately 2,000Da, be less than approximately 1,500Da or be less than approximately 1,000Da), peptide (for example have be less than approximately 10, be less than approximately 15, be less than approximately 20 or be less than approximately 25 aminoacid), protein (conventionally large than peptide), hormone, vitamin, nucleic acid etc.Other example for suitable medicament of the present invention includes but not limited to that NSAID (nonsteroidal anti-inflammatory drugs, NSAID (non-steroidal anti-inflammatory drug)) is as aspirin, naproxen, celecoxib, rofecoxib (refecoxib) etc.; The anesthesiophore medicament of tool is as morphine, codeine, the third oxygen sweet smell, oxycodone, hydrocodone or other similar anesthetics; For erect or the medicament of sexual dysfunction as Yohimbine, Alprostadil, sldenafil, Tadalafil (cialis), A Buma (uprima), Vardenafil (vardenaifl) etc.; Be used for migrainous medicament as dihydroergotamine and salt, Ergotamine and salt thereof, sumatriptan (surnatripan) and salt, rizatriptan and salt thereof, Zomitriptan and salt thereof etc.; Be used for the medicament of hair-care as Tamsulosin, eflornithine, minoxidil etc.; Or other medicament is as nicotinic acid, lignocaine, benzocaine, naproxen etc.Other example comprises muscle improving agent (muscle improving agent), for example creatine or creatine precursor (for example phosphagen), arginine and/or other nitric oxide donors, and/or ATP precursor is such as, as inosine, adenosine, inosine, adenine, hypoxanthine, ribose, phosphate (sodium dihydrogen phosphate) etc., and/or short synthesizing steroid reagent is as androstene, DHEA, androstenediol, androstenedione etc.Another example is Herba Ephedrae or its component, as ephedrine and pseudoephedrine.Another example is chemotherapeutics or is used for the treatment of cancer and/or the reagent of viral infection, comprises taxol, acyclovir etc. such as but not limited to tamoxifen (for example, for breast cancer treatment), cisplatin, carboplatin and correlation molecule, cyclophosphamide and correlation molecule, vinca alkaloids, epipodophyllotoxin.For example, described cancer and/or viral infection can be skin carcinoma, breast carcinoma, carcinoma of penis, carcinoma of testis or other localized cancer or viral infection (as herpes).

Of the present invention aspect some in, medicament can with penetrating agent (for the transhipment not existing under this penetrating agent, increasing medicament to the reagent of transporting in skin) coupling.In certain embodiments, penetrating agent can limit disadvantageous biophysics's environment and/or with its coupling.The example of penetrating agent comprises capsicum oleoresin or its ingredient, or some molecule that comprises the heterocycle being connected with hydrocarbon chain.

The non-limiting example of penetrating agent includes but not limited to cationic surfactant, anion surfactant or non-ionic surface active agent (such as sodium lauryl sulphate, poloxamer etc.); Fatty acid and alcohols (such as ethanol, oleic acid, lauric acid, liposome etc.); Anticholinergic agent (for example benzilonium bromide, antrenyl); Alkane ketone (for example normal heptane); Amide (for example urea, N, N-dimethyl-m-toluamide); Fatty acid ester (for example n-butyric acie ester); Organic acid (for example citric acid); Polyhydric alcohol (for example ethylene glycol, glycerol); Sulfoxide (for example dimethyl sulfoxine); Terpenes (for example cyclohexene); Urea; Sugar; Carbohydrate or other reagent.In certain embodiments, described penetrating agent comprises salt, for example as described herein.

Therefore, another aspect of the present invention provides medicament (medicine, biologic artifact etc.) to sending in body, such treatment can be general or local (for example relating to the concrete position of body, as head, one or more specific muscle, genitals etc.); This depends on concrete application.

In one group of embodiment, introduce medicament with auxiliary treatment medical conditions or disease, and relevant symptoms.In certain embodiments, the invention provides and (for example use pharmaceutical treatment medical conditions or disease and/or slight illness, treatment diagnosis suffers from the object of medical conditions or disease), in some cases, send on the surface that the invention provides the medicament of low as far as possible amount, to provide the medicine of effect level to affected areas, limited side effect simultaneously.In some cases, the effective dose when effective dose of described medicament can be lower than oral this medicament.Other embodiments of the present invention provide the method for the treatment of pain, and described pain is migrainous pain, arthritic pain, other headache, arthralgia, myalgia and other types of pain for example.Therefore, in certain embodiments, compositions can surface applied in particular body portion, be for example applied to painful area.Meanwhile, in some cases, compositions described herein can be used for the medicine for the preparation for the treatment of pain or Other diseases as described herein or disease.

In yet another aspect, the present invention relates to the medicine box that comprises one or more of compositionss described herein." medicine box " used herein defined the packaging or the suit that comprise the one or more of present compositions and/or other compositions related to the present invention (for example as described in this article those) conventionally.Every kind of component of medicine box can for example, for example, provide with liquid form (, solution) or solid form (, dry powder).In some cases, some compositions can be (constituable) that can build or otherwise machinable (for example, form activity form), for example, by adding suitable solvent or other material (it can provide or not provide together with described test kit) to realize.Other compositions related to the present invention or the example of component include but not limited to solvent, surfactant, diluent, salt, buffer agent, emulsifying agent, chelating agen, filler, antioxidant, binding agent, filler, antiseptic, desiccant, antimicrobial drug, pin, syringe, packaging material, pipe, bottle, flask, beaker, ware, frit, filter, ring, clamp, packaging material (wrap), paster, container etc., for example, for using, use, modify, assembling, storage, packaging, preparation, mix, the composition component (for example, for sample and/or object) of dilution and/or preservation special-purpose.

In some cases, medicine box of the present invention can comprise any type of description, and it provides together with compositions of the present invention, so that those of ordinary skill in the art are familiar with this description is relevant to compositions of the present invention.For example, described description can comprise for using, modify, mix, dilute, preserve, use, assemble, store, pack and/or compositions that preparation is relevant to test kit and/or the explanation of other compositions.In some cases, described description also can comprise sends and/or the explanation of applying said compositions (for example, for special-purpose), for example, for sample and/or object.Any form that described description can be generally acknowledged using those of ordinary skill in the art provides as the suitable carrier that comprises this explanation, (for example the using transtelephonic) of written or disclosed, oral, the audio frequency that for example provides by any way, numeral, (for example video recording, DVD etc.) optics, vision or (comprising the communication based on the Internet or network) form of electronic communication.

In certain embodiments, the present invention relates to promote (promoting) method of one or more embodiment of the present invention as described herein, for example promote preparation or use the method for those compositionss as mentioned above, promoting the method for above-mentioned medicine box, etc." popularization " used herein comprises the method for all doing businesses, include but not limited to sale, advertisement, transfer, license, contract, instruction, cultivation, research, import, outlet, negotiation, financing, loan, trade, sell, resell, distribute, keep in repair, give back, insure, the method for complaint, patent etc., it is relevant to system of the present invention as herein described, unit, goods, method, compositions, medicine box etc.Promotion method can be undertaken by either party, includes but not limited to that individual side, commercial party (public's or individual's), partner, company, trust, agreement or sub-protocol agency, educational institution are as institution of higher learning, research institution, hospital or other Clinical Institutions, government organs etc.Promotion activity can comprise and obviously relevant any type of interchange of the present invention (for example, written, oral and/or electronic communication, such as but not limited to Email, transtelephonic, the Internet, interchange based on Web etc.).

In one group of embodiment, described promotion method can comprise one or more explanations." explanation " used herein can define a kind of assembly (such as guidance, guide, warning, label, points for attention, FAQs or " problem of often asking " etc.) that instructs function, generally includes the written explanation relevant to the present invention and/or packaging of the present invention.Explanation can also comprise that any type of theory directiveness (for example exchanges, oral, electronics, video, numeral, optics, vision etc., provide by any way and make user can clearly realize that this explanation is relevant to the present invention's (example is as described herein).

By following file by reference also herein: E.Fossel was called the international patent application No.PCT/US98/19429 of " Delivery of Arginine to Cause Beneficial Effects " in the name of JIUYUE in 1998 submission on the 17th, it is published as WO99/13717 on March 25th, 1999; The name that the people such as E.Fossel submitted on February 23rd, 2005 is called the international patent application No.PCT/US2005/005726 of " Topical Delivery of a Nitric Oxide Donor to Improve Body and Skin Appearance ", and it is published as WO2005/081964 on the 9th in JIUYUE in 2005; The name that the people such as E.Fossel submitted on April 19th, 2005 was called the international patent application No.PCT/US2005/013228 of " Transdermal Delivery of Beneficial Substances Effected by a Hostile Biophysical Environment ", and it is published as WO2005/102282 on November 3rd, 2005; The international patent application No.PCT/US2005/013230 that is called " Beneficial Effects of Increasing Local Blood Flow " with E.Fossel in the name of submission on April 19th, 2005, it was published as WO2005/102307 on November 3rd, 2005.

What be also incorporated to this paper by introducing is that E.T.Fossel is called the U.S. Patent application No.08/932 of " Topical Delivery of Arginine of Cause Beneficial Effects " in the name of JIUYUE in 1997 submission on the 17th, 227, it is published as 2002/0041903 on April 11st, 2002; The name that E.T.Fossel submitted on July 22nd, 2002 is called the U.S. Patent application No.10/201 of " Topical Delivery of L-Arginine to Cause Beneficial Effects ", 635, it is published as 2003/0028169 on February 6th, 2003; The name that E.T.Fossel submitted on August 5th, 2002 is called the U.S. Patent application No.10/213 of " Topical and Oral Arginine to Cause Beneficial Effects ", and 286, it is published as 2003/0018076 on January 23rd, 2003; The name of the E.T.Fossel issuing on April 20th, 1999 is called the U.S. Patent No. 5,895,658 of " Topical Delivery of L-Arginine to Cause Tissue Warming "; The name of the E.T.Fossel issuing on July 13rd, 1999 is called the U.S. Patent No. 5,922,332 of " Topical Delivery of Arginine to Overcome Pain "; The name of the E.T.Fossel issuing March 27 calendar year 2001 is called the U.S. Patent No. 6 of " Topical and Oral Delivery of Arginine to Cause Beneffcial Effects ", 207,713, be called the U.S. Patent No. 6 of " Topical and Oral Delivery of Arginine to Cause Beneficial Effects " with the name of the E.T.Fossel issuing on October 1st, 2002,458,841.

Following embodiment is intended to illustrate certain embodiments of the present invention, but is not to illustrate four corner of the present invention.

Embodiment 1

The present embodiment for example understands a kind of method of preparing the transdermal prescription of the present invention that comprises ibuprofen.Final composition is presented in table 1.Certainly, it will be appreciated by the skilled addressee that according to other embodiments of the present invention, it is also possible being different from following percent.

table 1

For preparing the preparation of the present embodiment, sodium chloride, potassium chloride, L-arginine and ibuprofen are blended in water, then under rapid mixing, be heated to 74 DEG C.In an independent container, remaining composition is mixed, and be heated to 74 DEG C.Then, at 74 DEG C, under rapid mixing, other composition is joined in water.Then, this mixture is cooled to room temperature, continues to mix simultaneously.Now, form the emulsion with relatively rare denseness.Afterwards, at room temperature by this emulsion with high-speed homogenization so that denseness increase.

Although described herein and for example understood embodiments more of the present invention, but those of ordinary skill in the art should easily predict multiple other method and/or structure for implementing function and/or acquisition result and/or one or more advantage as herein described, each in these variations and/or modification is all thought within the scope of the present invention.More generally, those skilled in the art will easily understand, it is exemplary that all parameters described herein, size, material and structure are all intended to, and actual parameter, size, material and/or structure all will depend on concrete application, or the application used of training centre of the present invention.Those skilled in the art will generally acknowledge or only use normal experiment just can determine multiple embodiments that are equal to of specific embodiment of the invention scheme described herein.Therefore, should be appreciated that foregoing embodiments is as just proposing for example, and all within the scope of claims and equivalent thereof, the present invention can with is specifically described and claimed different schemes is implemented.The present invention relates to each independent characteristic described herein, system, goods, material, medicine box and/or method.In addition, if do not have conflictingly between such feature, system, goods, material, medicine box and/or method, any combination of two or more such features, system, goods, material, medicine box and/or method all comprises within the scope of the present invention.

Definition in the file that all should be understood to have precedence over the definition of dictionary with all definition that use as defined herein, is incorporated to by introducing and/or the common implication of the term that defines.

Unless have obviously contrary instruction, otherwise the singulative using should be understood to comprise plural form in this paper description and claims.

The phrase "and/or" using in description and claims herein should be understood to mean so " any or both " of the key element of combination, and described key element combines existence, in other cases individualism in some cases.Multiple key elements of listing by "and/or" should be explained in an identical manner, are interpreted as so " one or more " of the key element of combination.Different from the key element specifically indicating with "and/or" subordinate sentence, other key element can optionally exist, relevant to those key elements that specifically indicate or irrelevant.Therefore, as a non-limiting example, in the time being combined with as " comprising " with open-ended term, mention " A and/or B ", can only refer in one embodiment A (optionally comprising the key element that is different from B); In another embodiment, it can only refer to that B (optionally comprises the key element that is different from A; In another embodiment, it can refer to A and B (optionally comprising other key element); Deng.

Should be understood to the "or" using in claims the implication having with "and/or" is identical as defined above in description herein.For example, when separating in inventory when every, "or" or "and/or" should be interpreted as comprising, comprise at least one, but also can comprise and exceed a quantity or key element list, and optionally comprise unlisted project.While only having term to represent contrary significantly, for example, when using " only one " or " just what a " or ought using in the claims " by ... composition ", it refers to the key element or the key element list that comprise a lucky quantity.Conventionally, as used herein term "or" in the time being placed on before proprietary term, only should be construed as denoting exclusiveness options (" one or other; but be not both "), when use for example " any ", " one " or " just what a ", " substantially by ... composition " in claims time, should there is it as the general sense using in Patent Law field.

As description and the phrase " at least one " relevant to one or more key element lists using in claims herein, should be understood to refer to be selected from any or at least one key element of multiple key elements in described key element list, but not to be included at least each key element of listing especially in this key element list, and do not get rid of any combination of key element in described key element list.This definition also allows optionally to exist the key element different from the key element of specifically noting in the key element list of term " at least one " indication, and no matter whether it is relevant to those key elements of specifically noting or irrelevant.Thereby, as a non-limiting example, " at least one in A and B " (or, equivalence statement " at least one of A or B ", or equivalence statement " at least one in A and/or B "), in one embodiment, can refer at least one, optionally comprise and exceed an A, and do not have B (with optionally comprising the key element that is different from B); In another embodiment, it refers at least one (optionally comprise and exceed one) B, and does not have A (with optionally comprising the key element that is different from A); In another embodiment, it refers at least one (optionally comprise and exceed one) A, and at least one (optionally comprise and exceed one) B (with optionally comprising other key element); Deng.

Unless had obviously contrary explanation, otherwise it is also understood that in claimed comprising herein and exceed in any method of a step or behavior, the step of the method that the step of described method or the order of behavior are not necessarily limited to wherein recorded or the order of behavior.

In claims and above-mentioned description, all transitive verb terms, as " comprising ", " comprising ", " being loaded with ", " having ", " containing ", " relating to ", " maintenance ", " composition " etc. are all interpreted as it is open, refer to include but not limited to.As for transitive verb term " by ... composition " and " substantially by ... form " should be respectively closed or semienclosed transitive verb term, as what set forth in USPO's patent examination workbook the 2111.03rd part (the United States Patent Office Manual of Patent Examining Procedures, Section2111.03).

Following embodiment content is corresponding to claims of original application:

1. a compositions that is delivered to subject's skin for surface, described compositions comprises:

Nitric oxide donors;

Disadvantageous biophysics's environment;

Stabilization of polymers;

Propylene glycol;

Polysorbate surfactant; With

Ibuprofen and/or ibuprofen salt.

2. the compositions of embodiment 1, each in wherein said nitric oxide donors, disadvantageous biophysics's environment, xanthan gum, propylene glycol, polysorbate 20 and ibuprofen and/or ibuprofen salt is included in delivery vector.

3. the compositions of any one in embodiment 1 or 2, wherein, when being exposed at the temperature of 40 DEG C at least about one time, described compositions is stable.

4. the compositions of any one in embodiment 1-3, wherein, in the time being exposed at the temperature of 40 DEG C at least about one week, described compositions is stable.

5. the compositions of any one in embodiment 1-4, wherein, in the time being exposed at the temperature of 40 DEG C at least about 4 weeks, described compositions is stable.

6. the compositions of any one in embodiment 1-5, wherein said compositions is ointment.

7. the compositions of any one in embodiment 1-6, wherein said compositions is gel.

8. the compositions of any one in embodiment 1-7, wherein said compositions is lotion.

9. the compositions of any one in embodiment 1-8, wherein said compositions is included in transdermal patch.

10. the compositions of any one in embodiment 1-9, wherein said nitric oxide donors comprises L-arginine.

The compositions of any one in 11. embodiment 1-10, wherein said nitric oxide donors comprises L-arginine salt.

The compositions of any one in 12. embodiment 1-11, wherein said nitric oxide donors comprises L-arginine hydrochlorate.

The compositions of any one in 13. embodiment 1-12, wherein said nitric oxide donors exist concentration be described composition weight at least about 0.5%.

The compositions of any one in 14. embodiment 1-13, wherein said nitric oxide donors exist concentration be described composition weight at least about 5%.

The compositions of any one in 15. embodiment 1-14, wherein said nitric oxide donors exist concentration be described composition weight at least about 7%.

The compositions of any one in 16. embodiment 1-15, wherein said disadvantageous biophysics's environment can drive ibuprofen and/or ibuprofen salt to pass through horny layer.

The compositions of any one in 17. embodiment 1-16, wherein said disadvantageous biophysics's environment comprises ion salt.

The compositions of 18. embodiments 17, wherein said ion salt exist concentration be described composition weight at least about 5%.

The compositions of any one in 19. embodiments 17 or 18, wherein said ion salt exist concentration be described composition weight at least about 7%.

The compositions of any one in 20. embodiment 17-19, wherein said ion salt exist concentration be described composition weight at least about 10%.

The compositions of any one in 21. embodiment 1-20, wherein said disadvantageous biophysics's environment comprises choline chloride.

The compositions of any one in 22. embodiment 1-21, wherein said disadvantageous biophysics's environment comprises magnesium chloride.

The compositions of any one in 23. embodiment 1-22, wherein said disadvantageous biophysics's environment comprises calcium chloride.

The compositions of any one in 24. embodiment 1-23, wherein said disadvantageous biophysics's environment has the ionic strength at least about 0.25M.

The compositions of any one in 25. embodiment 1-24, wherein said disadvantageous biophysics's environment has the ionic strength at least about 1M.

The compositions of any one in 26. embodiment 1-25, wherein said disadvantageous biophysics's environment has the pH at least about 9.

The compositions of any one in 27. embodiment 1-25, wherein said disadvantageous biophysics's environment has the pH that is less than approximately 5.

The compositions of any one in 28. embodiment 1-27, wherein said disadvantageous biophysics's environment comprises octanol-water partition coefficient and is at least about 1000 component.

The compositions of any one in 29. embodiment 1-28, wherein, in the time that described compositions is applied to object, described disadvantageous biophysics's environment can make described nitric oxide donors transfer to the skin of described object from described compositions.

The compositions of 30. embodiments 29, wherein said object is behaved.

The compositions of any one in 3L embodiment 1-30, wherein said compositions also comprises the packaging that contains nitric oxide donors, described packaging is selected from liposome, collagen Emulsion, collagen peptide and combination thereof.

The compositions of any one in 32. embodiment 1-31, wherein said stabilization of polymers comprises xanthan gum.

The compositions of any one in 33. embodiment 1-32, wherein said stabilization of polymers comprises bT.

The compositions of any one in 34. embodiment 1-33, wherein said stabilization of polymers substantially by bT and/or rD composition.

The compositions of 35. embodiments 34, in wherein said compositions bT with the ratio of RD is 3: 5.

In 36. embodiments 34 or 35, the compositions of any one, wherein said the concentration that exists of BT is approximately 0.3% of described composition weight, described in the concentration that exists of RD is 0.5% of described composition weight.

The compositions of any one in 37. embodiment 1-36, wherein said stabilization of polymers exist concentration be described composition weight at least about 0.5%.

The compositions of any one in 38. embodiment 1-37, wherein said stabilization of polymers exist concentration be described composition weight at least about 0.8%.

The compositions of any one in 39. embodiment 1-38, wherein propylene glycol exist concentration be described composition weight at least about 3%.

The compositions of any one in 40. embodiment 1-39, wherein propylene glycol exist concentration be described composition weight at least about 5%.

The compositions of any one in 41. embodiment 1_40, wherein said Polysorbate surfactant is polysorbate 20.

The compositions of any one in 42. embodiment 1_41, wherein said Polysorbate surfactant is the Polysorbate that comprises sorbitan mono-laurate part.

The compositions of any one in 43. embodiment 1_42, wherein said Polysorbate surfactant exist concentration be described composition weight at least about 1%.

The compositions of any one in 44. embodiment 1_43, wherein said Polysorbate surfactant exist concentration be described composition weight at least about 2%.

The compositions of any one in 45. embodiment 1_44, wherein said Polysorbate surfactant has following formula:

The compositions of 46. embodiments 45, wherein w+x+y+z is 20.

The compositions of any one in 47. embodiment 1_46, the ratio of the stabilization of polymers that wherein said compositions has and propylene glycol and Polysorbate surfactant is approximately 1: 6.25: 2.5.

The compositions of any one in 48. embodiment 1_47, wherein said compositions comprises ibuprofen.

The compositions of any one in 49. embodiment 1_48, wherein said compositions comprises ibuprofen salt.

The compositions of 50. embodiments 49, the sodium salt that wherein said compositions comprises ibuprofen.

The compositions of any one in 51. embodiment 1-50, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 1%.

The compositions of any one in 52. embodiment 1-51, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 3%.

The compositions of any one in 53. embodiment 1-52, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 5%.

The compositions of any one in 54. embodiment 1-53, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 7%.

55. 1 kinds of methods, comprise compositions from any one in embodiment 1-54 to object that use.

56. 1 kinds are delivered to the compositions of subject's skin for surface, the containing at least about 80% weight package of wherein said compositions:

Water;

At least one hydrochlorate;

Nitric oxide donors;

Stabilization of polymers;

Propylene glycol;

Polysorbate surfactant;

Ibuprofen and/or ibuprofen salt.

The compositions of 57. embodiments 56, wherein said compositions also comprises tristerin.

The compositions of any one in 58. embodiments 56 or 57, wherein said compositions also comprises spermol.

The compositions of any one in 59. embodiment 56-58, wherein said compositions also comprises squalane.

The compositions of any one in 60. embodiment 56-59, wherein said compositions also comprises isopropyl myristate.

The compositions of any one in 61. embodiment 56-60, wherein said compositions also comprises oleic acid.

The compositions of any one in 62. embodiment 56-61, wherein water exist concentration be described composition weight at least about 35%.

The compositions of any one in 63. embodiment 56-62, wherein water exist concentration be described composition weight at least about 40%.

The compositions of any one in 64. embodiment 56-63, wherein said at least one hydrochlorate produces disadvantageous biophysics's environment.

The compositions of any one in 65. embodiment 56-64, wherein said salt is sodium chloride.

The compositions of any one in 66. embodiment 56-65, wherein sodium chloride exist concentration be described composition weight at least about 5%.

The compositions of any one in 67. embodiment 56-66, wherein sodium chloride exist concentration be described composition weight at least about 10%.

The compositions of any one in 68. embodiment 56-67, wherein sodium chloride exist concentration be described composition weight at least about 15%.

The compositions of any one in 69. embodiment 56-68, wherein said nitric oxide donors comprises L-arginine.

The compositions of any one in 70. embodiment 56-69, wherein said nitric oxide donors comprises L-arginine salt.

The compositions of any one in 71. embodiment 56-70, wherein said nitric oxide donors exist concentration be described composition weight at least about 3%.

The compositions of any one in 72. embodiment 56-71, wherein said nitric oxide donors exist concentration be described composition weight at least about 7%.

The compositions of any one in 73. embodiment 56-72, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 3%.

The compositions of any one in 74. embodiment 56-73, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 7%.

The compositions of any one in 75. embodiment 56-74, the sodium salt that wherein said compositions comprises ibuprofen.

The compositions of any one in 76. embodiment 56-75, wherein said stabilization of polymers substantially by bT and/or rD composition.

The compositions of any one in 77. embodiment 56-76, the concentration that exists of wherein said stabilization of polymers is at least about 0.5%.

The compositions of any one in 78. embodiment 56-77, the concentration that exists of wherein said stabilization of polymers is at least about 0.8%.

The compositions of any one in 79. embodiment 56-78, the concentration that exists of wherein said propylene glycol is at least about 3%.

The compositions of any one in 80. embodiment 56-79, the concentration that exists of wherein said propylene glycol is at least about 5%.

The compositions of any one in 81. embodiment 56-80, wherein said Polysorbate surfactant exist concentration be described composition weight at least about 1%.

The compositions of any one in 82. embodiment 56-81, wherein said Polysorbate surfactant exist concentration be described composition weight at least about 2%.

The compositions of any one in 83. embodiment 56-82, wherein said Polysorbate surfactant is polysorbate 20.

84. 1 kinds of methods, comprise compositions from any one in embodiment 56-83 to object that use.

85. 1 kinds are delivered to the compositions of subject's skin for surface, described compositions is made up of following substances substantially:

Water;

Sodium chloride;

Nitric oxide donors;

Tristerin;

Spermol;

Potassium chloride;

Squalane;

Stabilization of polymers;

Isopropyl myristate;

Oleic acid;

Propylene glycol;

Polysorbate surfactant; With

Ibuprofen and/or ibuprofen salt.

The compositions of 86. embodiments 85, the concentration that exists of wherein said water is approximately 40.9% of described composition weight.

The compositions of any one in 87. embodiments 85 or 86, the concentration that exists of wherein said sodium chloride is approximately 10% of described composition weight.

The compositions of any one in 88. embodiment 85-87, wherein said nitric oxide donors is L-arginine hydrochlorate.

The compositions of any one in 89. embodiment 85-88, the concentration that exists of wherein said nitric oxide donors is approximately 7.5% of described composition weight.

The compositions of any one in 90. embodiment 85-89, the sodium salt that wherein said compositions comprises ibuprofen.

The compositions of any one in 91. embodiment 85-90, the concentration that exists of wherein said ibuprofen and/or ibuprofen salt is approximately 7.5% of described composition weight.

The compositions of any one in 92. embodiment 85-91, the concentration that exists of wherein said tristerin is approximately 7% of described composition weight.

The compositions of any one in 93. embodiment 85-92, the concentration that exists of wherein said spermol is approximately 7% of described composition weight.

The compositions of any one in 94. embodiment 85-93, the concentration that exists of wherein said potassium chloride is approximately 5% of described composition weight.

The compositions of any one in 95. embodiment 85-94, the concentration that exists of wherein said Squalene is approximately 4% of described composition weight.

The compositions of any one in 96. embodiment 85-95, wherein said stabilization of polymers comprises xanthan gum.

The compositions of any one in 97. embodiment 85-96, wherein said stabilization of polymers substantially by bT and/or rD composition.

The compositions of any one in 98. embodiment 85-97, the concentration that exists of wherein said stabilization of polymers is approximately 0.8% of described composition weight.

The compositions of any one in 99. embodiment 85-98, the concentration that exists of wherein said isopropyl myristate is approximately 1% of described composition weight.

The compositions of any one in 100. embodiment 85-99, the concentration that exists of wherein said oleic acid is approximately 1% of described composition weight.

The compositions of any one in 101. embodiment 85-100, the concentration that exists of wherein said propylene glycol is 5%.

The compositions of any one in 102. embodiment 85-101, wherein said Polysorbate surfactant is polysorbate 20.

103. one kinds of methods, comprise compositions from any one in embodiment 85-102 to object that use.

104. one kinds are delivered to the compositions of subject's skin for surface, described compositions comprise concentration be no more than shown in concentration ± every kind of following compound of 20%:

Concentration is the water of approximately 44.2% weight;

Concentration is the sodium chloride of approximately 10% weight;

Concentration is the nitric oxide donors of approximately 7.5% weight;

Concentration is the tristerin of approximately 7% weight;

Concentration is the spermol of approximately 7% weight;

Concentration is the potassium chloride of approximately 5.5% weight;

Concentration is the propylene glycol of approximately 5% weight;

Concentration is the squalane of approximately 4% weight;

Concentration is the Polysorbate surfactant of approximately 2% weight; With

Concentration is the isopropyl myristate of approximately 1% weight;

Concentration is the oleic acid of approximately 1% weight;

Concentration is the stabilization of polymers of approximately 0.8% weight;

Concentration is ibuprofen and/or the ibuprofen salt of approximately 5.0% weight.

The compositions of 105. embodiments 104, wherein said stabilization of polymers is xanthan gum.

The compositions of any one in 106. embodiments 104 or 105, wherein said stabilization of polymers substantially by bT and/or rD composition.

The compositions of any one in 107. embodiment 104-106, wherein said Polysorbate surfactant is Polysorbate glucose.

The compositions of any one in 108. embodiment 104-107, wherein said compositions comprises the described compound of recording in described embodiment, concentration shown in its concentration does not exceed+10%.

109. one kinds of methods, comprise compositions from any one in embodiment 104-108 to object that use.

110. one kinds of methods, comprise the compositions that comprises following component at least a portion dermal administration of object:

Nitric oxide donors;

Disadvantageous biophysics's environment;

Stabilization of polymers;

Propylene glycol;

Polysorbate surfactant; With

Ibuprofen and/or ibuprofen salt.

111. one kinds are delivered to the compositions of subject's skin for surface, described compositions comprises:

Stabilization of polymers;

Propylene glycol;

Polysorbate surfactant; With

Ibuprofen and/or ibuprofen salt.

112. one kinds are delivered to the compositions of subject's skin for surface, the containing at least about 80% weight package of wherein said compositions:

Water;

At least one hydrochlorate;

Stabilization of polymers;

Propylene glycol;

Polysorbate surfactant; With

Ibuprofen and/or ibuprofen salt.

Claims

Nitric oxide donors;

Disadvantageous biophysics's environment, it comprises ion salt;

Stabilization of polymers, it comprises xanthan gum;

Propylene glycol;

Polysorbate surfactant; With

Ibuprofen and/or ibuprofen salt.

2. the compositions of claim 1, each in wherein said nitric oxide donors, disadvantageous biophysics's environment, xanthan gum, propylene glycol, Polysorbate and ibuprofen and/or ibuprofen salt is included in delivery vector.

3. the compositions of any one in claim 1 or 2, wherein, when being exposed at the temperature of 40 DEG C at least about one time, described compositions is stable.

4. the compositions of any one in claim 1-3, wherein, in the time being exposed at the temperature of 40 DEG C at least about one week, described compositions is stable.

5. the compositions of any one in claim 1_4, wherein, in the time being exposed at the temperature of 40 DEG C at least about 4 weeks, described compositions is stable.

6. the compositions of any one in claim 1-5, wherein said compositions is ointment.

7. the compositions of any one in claim 1-6, wherein said compositions is gel.

8. the compositions of any one in claim 1-7, wherein said compositions is lotion.

9. the compositions of any one in claim 1-8, wherein said compositions is included in transdermal patch.

10. the compositions of any one in claim 1-9, wherein said nitric oxide donors comprises L-arginine.

The compositions of any one in 11. claim 1-10, wherein said nitric oxide donors comprises L-arginine salt.

The compositions of any one in 12. claim 1-11, wherein said nitric oxide donors comprises L-arginine hydrochlorate.

The compositions of any one in 13. claim 1-12, wherein said nitric oxide donors exist concentration be described composition weight at least about 0.5%.

The compositions of any one in 14. claim 1-13, wherein said nitric oxide donors exist concentration be described composition weight at least about 5%.

The compositions of any one in 15. claim 1-14, wherein said nitric oxide donors exist concentration be described composition weight at least about 7%.

The compositions of any one in 16. claim 1-15, wherein said disadvantageous biophysics's environment can drive ibuprofen and/or ibuprofen salt to pass through horny layer.

The compositions of any one in 17. claim 1-16, wherein said ion salt exist concentration be described composition weight at least about 5%.

The compositions of 18. claim 17, wherein said ion salt exist concentration be described composition weight at least about 7%.

The compositions of any one in 19. claim 17 or 18, wherein said ion salt exist concentration be described composition weight at least about 10%.

The compositions of any one in 20. claim 1-19, wherein said disadvantageous biophysics's environment comprises choline chloride.

The compositions of any one in 21. claim 1-20, wherein said disadvantageous biophysics's environment comprises magnesium chloride.

The compositions of any one in 22. claim 1-21, wherein said disadvantageous biophysics's environment comprises calcium chloride.

The compositions of any one in 23. claim 1-22, wherein said disadvantageous biophysics's environment has the ionic strength at least about 0.25M.

The compositions of any one in 24. claim 1-23, wherein said disadvantageous biophysics's environment has the ionic strength at least about 1M.

The compositions of any one in 25. claim 1-24, wherein said disadvantageous biophysics's environment has the pH at least about 9.

The compositions of any one in 26. claim 1-24, wherein said disadvantageous biophysics's environment has the pH that is less than approximately 5.

The compositions of any one in 27. claim 1-26, wherein said disadvantageous biophysics's environment comprises octanol-water partition coefficient and is at least about 1000 component.

The compositions of any one in 28. claim 1-27, wherein, in the time that described compositions is applied to object, described disadvantageous biophysics's environment can make described nitric oxide donors transfer to the skin of described object from described compositions.

The compositions of 29. claim 28, wherein said object is behaved.

The compositions of any one in 30. claim 1-29, wherein said compositions also comprises the packaging that contains nitric oxide donors, described packaging is selected from liposome, collagen Emulsion, collagen peptide and combination thereof.

The compositions of any one in 31. claim 1-30, wherein said stabilization of polymers comprises bT.

The compositions of any one in 32. claim 1-31, wherein said stabilization of polymers substantially by bT and/or rD composition.

The compositions of 33. claim 32, in wherein said compositions bT with the ratio of RD is 3: 5.

In 34. claim 32 or 33, the compositions of any one, wherein said the concentration that exists of BT is approximately 0.3% of described composition weight, described in the concentration that exists of RD is 0.5% of described composition weight.

The compositions of any one in 35. claim 1-34, wherein said stabilization of polymers exist concentration be described composition weight at least about 0.5%.

The compositions of any one in 36. claim 1-35, wherein said stabilization of polymers exist concentration be described composition weight at least about 0.8%.

The compositions of any one in 37. claim 1-36, wherein propylene glycol exist concentration be described composition weight at least about 3%.

The compositions of any one in 38. claim 1-37, wherein propylene glycol exist concentration be described composition weight at least about 5%.

The compositions of any one in 39. claim 1-38, wherein said Polysorbate surfactant is polysorbate 20.

The compositions of any one in 40. claim 1-39, wherein said Polysorbate surfactant is the Polysorbate that comprises sorbitan mono-laurate part.

The compositions of any one in 41. claim 1_40, wherein said Polysorbate surfactant exist concentration be described composition weight at least about 1%.

The compositions of any one in 42. claim 1_41, wherein said Polysorbate surfactant exist concentration be described composition weight at least about 2%.

The compositions of any one in 43. claim 1_42, wherein said Polysorbate surfactant has following formula:

The compositions of 44. claim 43, wherein w+x+y+z is 20.

The compositions of any one in 45. claim 1_44, the ratio of the stabilization of polymers that wherein said compositions has and propylene glycol and Polysorbate surfactant is approximately 1: 6.25: 2.5.

The compositions of any one in 46. claim 1_45, wherein said compositions comprises ibuprofen.

The compositions of any one in 47. claim 1-46, wherein said compositions comprises ibuprofen salt.

The compositions of 48. claim 47, the sodium salt that wherein said compositions comprises ibuprofen.

The compositions of any one in 49. claim 1_48, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 1%.

The compositions of any one in 50. claim 1_49, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 3%.

The compositions of any one in 51. claim 1-50, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 5%.

The compositions of any one in 52. claim 1-51, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 7%.

Purposes in 53. claim 1-52 in the medicine of compositions disease in for the preparation for the treatment of target of any one.

54. 1 kinds are delivered to the compositions of subject's skin for surface, the containing at least about 80% weight package of wherein said compositions:

Water;

At least one hydrochlorate;

Nitric oxide donors;

Stabilization of polymers, it comprises xanthan gum;

Propylene glycol;

Polysorbate surfactant;

Ibuprofen and/or ibuprofen salt.

The compositions of 55. claim 54, wherein said compositions also comprises tristerin.

The compositions of any one in 56. claim 54 or 55, wherein said compositions also comprises spermol.

The compositions of any one in 57. claim 54-56, wherein said compositions also comprises squalane.

The compositions of any one in 58. claim 54-57, wherein said compositions also comprises isopropyl myristate.

The compositions of any one in 59. claim 54-58, wherein said compositions also comprises oleic acid.

The compositions of any one in 60. claim 54-59, wherein water exist concentration be described composition weight at least about 35%.

The compositions of any one in 61. claim 54-60, wherein water exist concentration be described composition weight at least about 40%.

The compositions of any one in 62. claim 54-61, wherein said at least one hydrochlorate produces disadvantageous biophysics's environment.

The compositions of any one in 63. claim 54-62, wherein said salt is sodium chloride.

The compositions of any one in 64. claim 54-63, wherein sodium chloride exist concentration be described composition weight at least about 5%.

The compositions of any one in 65. claim 54-64, wherein sodium chloride exist concentration be described composition weight at least about 10%.

The compositions of any one in 66. claim 54-65, wherein sodium chloride exist concentration be described composition weight at least about 15%.

The compositions of any one in 67. claim 54-66, wherein said nitric oxide donors comprises L-arginine.

The compositions of any one in 68. claim 54-67, wherein said nitric oxide donors comprises L-arginine salt.

The compositions of any one in 69. claim 54-68, wherein said nitric oxide donors exist concentration be described composition weight at least about 3%.

The compositions of any one in 70. claim 54-69, wherein said nitric oxide donors exist concentration be described composition weight at least about 7%.

The compositions of any one in 71. claim 54-70, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 3%.

The compositions of any one in 72. claim 54-71, wherein said ibuprofen and/or ibuprofen salt exist concentration be described composition weight at least about 7%.

The compositions of any one in 73. claim 54-72, the sodium salt that wherein said compositions comprises ibuprofen.

The compositions of any one in 74. claim 54-73, wherein said stabilization of polymers substantially by bT and/or rD composition.

The compositions of any one in 75. claim 54-74, the concentration that exists of wherein said stabilization of polymers is at least about 0.5%.

The compositions of any one in 76. claim 54-75, the concentration that exists of wherein said stabilization of polymers is at least about 0.8%.

The compositions of any one in 77. claim 54-76, the concentration that exists of wherein said propylene glycol is at least about 3%.

The compositions of any one in 78. claim 54-77, the concentration that exists of wherein said propylene glycol is at least about 5%.

The compositions of any one in 79. claim 54-78, wherein said Polysorbate surfactant exist concentration be described composition weight at least about 1%.

The compositions of any one in 80. claim 54-79, wherein said Polysorbate surfactant exist concentration be described composition weight at least about 2%.

The compositions of any one in 81. claim 54-80, wherein said Polysorbate surfactant is polysorbate 20.

Purposes in 82. claim 54-81 in the medicine of compositions disease in for the preparation for the treatment of target of any one.

83. 1 kinds are delivered to the compositions of subject's skin for surface, described compositions is made up of following substances substantially:

Water;

Sodium chloride;

Nitric oxide donors;

Tristerin;

Spermol;

Potassium chloride;

Squalane;

Stabilization of polymers, it comprises xanthan gum;

Isopropyl myristate;

Oleic acid;

Propylene glycol;

Polysorbate surfactant; With

Ibuprofen and/or ibuprofen salt.

The compositions of 84. claim 83, the concentration that exists of wherein said water is approximately 40.9% of described composition weight.

The compositions of any one in 85. claim 83 or 84, the concentration that exists of wherein said sodium chloride is approximately 10% of described composition weight.

The compositions of any one in 86. claim 83-85, wherein said nitric oxide donors is L-arginine hydrochlorate.

The compositions of any one in 87. claim 83-86, the concentration that exists of wherein said nitric oxide donors is approximately 7.5% of described composition weight.

The compositions of any one in 88. claim 83-87, the sodium salt that wherein said compositions comprises ibuprofen.

The compositions of any one in 89. claim 83-88, the concentration that exists of wherein said ibuprofen and/or ibuprofen salt is approximately 7.5% of described composition weight.

The compositions of any one in 90. claim 83-89, the concentration that exists of wherein said tristerin is approximately 7% of described composition weight.

The compositions of any one in 91. claim 83-90, the concentration that exists of wherein said spermol is approximately 7% of described composition weight.

The compositions of any one in 92. claim 83-91, the concentration that exists of wherein said potassium chloride is approximately 5% of described composition weight.

The compositions of any one in 93. claim 83-92, the concentration that exists of wherein said Squalene is approximately 4% of described composition weight.

The compositions of any one in 94. claim 83-93, wherein said stabilization of polymers substantially by bT and/or rD composition.

The compositions of any one in 95. claim 83-94, the concentration that exists of wherein said stabilization of polymers is approximately 0.8% of described composition weight.

The compositions of any one in 96. claim 83-95, the concentration that exists of wherein said isopropyl myristate is approximately 1% of described composition weight.

The compositions of any one in 97. claim 83-96, the concentration that exists of wherein said oleic acid is approximately 1% of described composition weight.

The compositions of any one in 98. claim 83-97, the concentration that exists of wherein said propylene glycol is 5%.

The compositions of any one in 99. claim 83-98, wherein said Polysorbate surfactant is polysorbate 20.

Purposes in 100. claim 83-99 in the medicine of compositions disease in for the preparation for the treatment of target of any one.

101. one kinds are delivered to the compositions of subject's skin for surface, described compositions comprise concentration be no more than shown in concentration ± every kind of following compound of 20%:

Concentration is the water of approximately 44.2% weight;

Concentration is the sodium chloride of approximately 10% weight;

Concentration is the nitric oxide donors of approximately 7.5% weight;

Concentration is the tristerin of approximately 7% weight;

Concentration is the spermol of approximately 7% weight;

Concentration is the potassium chloride of approximately 5.5% weight;

Concentration is the propylene glycol of approximately 5% weight;

Concentration is the squalane of approximately 4% weight;

Concentration is the Polysorbate surfactant of approximately 2% weight; With

Concentration is the isopropyl myristate of approximately 1% weight;

Concentration is the oleic acid of approximately 1% weight;

Concentration is the stabilization of polymers of approximately 0.8% weight, and it comprises xanthan gum;

The compositions of 102. claim 101, wherein said stabilization of polymers substantially by bT and/or rD composition.

The compositions of any one in 103. claim 101-102, wherein said Polysorbate surfactant is Polysorbate glucose.

The compositions of any one in 104. claim 101-103, wherein said compositions comprises the described compound of recording in described claim, concentration shown in its concentration does not exceed+10%.

Purposes in 105. claim 101-104 in the medicine of compositions disease in for the preparation for the treatment of target of any one.

Purposes in the medicine of 106. one kinds of compositionss disease in for the preparation for the treatment of target, described compositions comprises:

Nitric oxide donors;

Disadvantageous biophysics's environment;

Stabilization of polymers, it comprises xanthan gum;

Propylene glycol;

Polysorbate surfactant; With

Ibuprofen and/or ibuprofen salt.

107. one kinds are delivered to the compositions of subject's skin for surface, described compositions comprises:

Stabilization of polymers, it comprises xanthan gum;

Propylene glycol;

Polysorbate surfactant; With

Ibuprofen and/or ibuprofen salt.

108. one kinds are delivered to the compositions of subject's skin for surface, the containing at least about 80% weight package of wherein said compositions:

Water;

At least one hydrochlorate;

Stabilization of polymers, it comprises xanthan gum;

Propylene glycol;

Polysorbate surfactant; With

Ibuprofen and/or ibuprofen salt.