CN103458928A

CN103458928A - (R)-1,2-propanediol for use as solvent in therapeutic cooling agent compositions

Info

Publication number: CN103458928A
Application number: CN2011800690976A
Authority: CN
Inventors: 魏德烽
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-01-18
Filing date: 2011-06-22
Publication date: 2013-12-18
Anticipated expiration: 2031-06-22
Also published as: JP2014508740A; EP2665492A1; WO2012098342A1; SG192014A1; WO2012098342A8; CA2824827A1; CN103458928B

Abstract

The present invention relates generally to the field of topical medical therapy, cosmetics, and toiletries. More specifically, the invention relates to the use of a solvent comprising (R)-1,2-propanediol for cooling agents, for example, (R)-2-[((1fl,2S,5R)-2-isopropyl- 5-methyl-cyclohexanecarbonyl)-arnino]-propionic acid n-propyl ester (CPS-410). The invention also relates to cooling agent compositions comprising a cooling agent and, 2-propanediol, and methods for their preparation. The invention also relates to the use of such cooling agent compositions in therapy, for example, in the treatment of sensory discomfort, especially sensory discomfort of the skin (e.g., itch). The invention also relates to the use of such cooling agent compositions in cosmetics (e.g., eye make-up products) and toiletries (e.g., after-shave lotion).

Description

(R)-1,2-PD is as the solvent in the therapeutic coolant composition

Related application

The application is involved in the Application No. US12/930 submitted on January 18th, 2011, and 794, its full content is incorporated herein by reference.

Technical field

The present invention relates in general to the field of topical medications, cosmetics and washing product.More specifically, the solvent that the present invention relates to comprise (R)-1,2-PD is for the purposes of coolant, for example, (R)-2-[((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-propanoic acid n-pro-pyl ester (CPS-410).The invention still further relates to the coolant composition that comprises coolant and (R)-1,2-PD, and their preparation method.The invention still further relates to above-mentioned coolant composition in treatment, for example, do not feel like oneself in treatment, especially for example, purposes in do not feel like oneself (, the pruritus) of skin.The invention still further relates to for example, for example, purposes in cosmetics (, eye cosmetic product) and washing product (, (shaving) the rear emulsion of palpus) of above-mentioned coolant composition.

Background technology

Some publications have been quoted herein more fully to describe and to disclose the present invention and prior art state involved in the present invention.By these lists of references, full content separately is incorporated herein by reference.

Outside unless context refers else, in whole the description that comprises the claim of enclosing, wording " is comprised " and its variant as " comprising " and " containing ", be understood to mean and comprise stated integer or step, or the group of integer or step, but do not get rid of the group of any other integer or step or integer or step.

It must be noted that, as used in this description and claims, unless context separately has clear, singulative " ", " a kind of " and " being somebody's turn to do " comprise the plural number denotion.Therefore, for example, mention that " a kind of pharmaceutical carrier " comprises the mixture of two or more these carriers etc.

In this article scope is expressed as from " approximately " particular value, and/or to " approximately " another particular value.When explaining such scope, another embodiment comprises from a particular value and/or to other particular value.Similarly, when by using antecedent " approximately " when value is expressed as to approximation, be to be understood that this particular value forms another embodiment.

This disclosure comprises can be conducive to understand information of the present invention.It is not to admit that any information provided herein is prior art or related to the present invention, or admits that clearly or impliedly any publication is prior art.

Before about 30 years, one group of scientist has synthesized the compound more than 1200 kinds, to attempt finding performance to be better than the coolant of menthol.At Watson et al., summed up their result in 1978.According to this research, some compounds, that is, WS-3((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid acetamide), WS-5([((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-ethyl acetate) and WS-23(2-isopropyl-2,3, N-trimethyl-butyramide) come into the market and be used as the additive of sweet food, food (for example, confection, chewing gum), cosmetics and washing product.

Commercial in other menthol sample coolant of skin and mucosa is, for example, lactic acid menthyl ester (Frescolat ML), TK-10 (coolant 10) and 2-isopropyl-5-methylcyclohexyl 4-(dimethylamino)-4-oxobutanoic acid esters (4-(dimethylamino)-4-ketobutyric acid 2-isopropyl-5-methylcyclohexyl ester).Summarized current information about the coolant for local application (referring to, for example, Leffingwell, 2009).

In for example Wei, 2005 ^a; Wei, 2005b; Wei, 2005c; And Wei, in 2006, other coolant has been described.

The subset detection of skin of the elementary Sensory conduction thing by thering is sensor at teleneuron and mucosa cooling.Under the thermoneutrality that reduces (from 33 ℃ to 23 ℃) with the response skin temperature and suppress by intensification that raises, these sensory fibers show rhythmical, lasting electric discharge.Multidate information is with the form of peak shape string, propagate into axoneuron with the about speed of 20 to 40 pulse/sec along aixs cylinder, causes the people to feel slight chill in the air.Simulate such sensation by the room temperature that for example skin of face is exposed to 15 ℃ to 22 ℃.

For food, sweet food, spice, chewing gum, oral cleansing lotion, lip pomade, with other food (for example, put into the article of mouth), beverage, tobacco product, washing product (for example, emulsion after palpus), for nasal cavity and respiratory symptom, poverty-stricken for gastrointestinal tract, for suppressing the nonprescription drugs compositions (over-the-counter pharmaceutical compositions) of melanocyte activity, and utilized the multiple action to sensory process of (-)-menthol and relevant coolant as the compositions of counterirritant of the discomfort for releive skin and muscle.The menthol sweet food also has to the central nervous system effect of prompting also can appetite-suppressing.

Transient receptor potential cationic channel subfamily M member 8(TRPM8), also be called cold-and menthol receptor 1(CMR1) be the protein of expressing in sensory neuron, and activated as menthol and icilin by low temperature and coolant.Compound WS-12 and CPS-369 are the high selectivity agonist of TRPM8.

Transient receptor potential cationic channel subfamily A member 1(TRPMA1) be the protein of expressing on plasma membrane perhaps many humans and animals cell, and to know most be for environmental stimulus agent, pain, flu and the sensor that stretches.Menthol is the known agonist of TRPA1.

Weil et al., 2005 have reported that 0.5% ethanol can suppress the TRPM8 receptor response of (-)-menthol is reached to 50% in medium, and, under the concentration of 3% ethanol, response is almost completely lost.Benedikt et al., 2007 have confirmed Weil et al., and 2005 result also notices, and the vitro inhibition activity is methanol<ethanol<isopropyl alcohol<butanols.Dimethyl sulfoxine, a kind of solvent had with the similar dielectric constant of water, be considered to hang down inhibition.Benedikt et al., 2007 possible mechanism of action and the suggestion low-molecular-weight alcohols (1) that the ethanol interfere with receptor active has been discussed are absorbed and enter lipid bilayer, and can have a strong impact on the mechanical performance of cell membrane, and/or (2) affect the interior courier (secondary intracellular messengers) of the second cell as receptor activation is transduced into to the phosphatidylinositols-4 of nerve signal, 5-diphosphonic acid.At Weil et al., these researchs of report show that the biological activity solvent medium for coolant is important in 2005 and Benedikt et al., 2007.

It has been generally acknowledged that short chain alcohol interacts as the mechanical compressibility of interfacial tension, every area/molecule and biomembrane by non-specific physical force, and affect the fluid lipid bilayer permeability parameter (referring to, for example, Ly and Longo, 2004).Yet, Harris et al., 2008 have summed up the evidence of another kind of viewpoint recently, that is and, ethanol acts at protein acceptor lip-deep specific " pocket (pocket) " with regulatory function.

Animal can not directly be expressed alleviation, pruritus and the pain of psychological event as cooling, frankness, stimulation.Cell based on using for the gene transfection of the protein relevant to hotness, receptor detects (for example, TRPM8 or TRPA1) can be as the alternative model of sensory process.Receptor detect to produce quantitative data, but these detect that the initial sum do not produced about effect departs from or about the information of people's sensation amount of being brought out by chemicals.Therefore, about the best information of the cooling performance of chemicals from the direct test to the mankind.

Rowsell et al., 1979 filter paper (1x1cm) of having reported the test compounds by being impregnated with known quantity are placed on the test to the menthane carboxamides performance in the volunteer, N-replaced on experimenter's the dorsal surface of tongue.After 30 seconds, require the experimenter to report and whether have cooling effect.By these data reports, be " threshold value, μ g " and the threshold quantity that refers to later produce the test substances of cooling sensation on the tongue of the group that is applied to human volunteer.For 6 experimenters, the average threshold of (-)-menthol is 0.25 μ g, but has 100 times of variations aspect individual sensitivity.In these researchs about menthol sample coolant, the frequent variation that is placed on filter paper on help by coolant as solvent by ethanol and may causes individual sensitivity (because, the refrigerant sense of the at present known meeting Interference Detection of the ethanol as primary solvent).

At coolant in the sending of desired biological target, its be liquid or partially liq the dosage form for skin (for example, emulsion, emulsifiable paste, ointment) and for example, need the solvent for active cooling composition for the dosage form (, aerosol, spray) in respiratory trees (respiratory tree) or oral cavity.Due to known or potential harm, chemicals does not have for local (skin) dosage form as methanol, 1，2-ethandiol, 1,3-PD, dimethyl sulfoxine and butanols.Instead, often use two or three carbon alcoholic solvent as ethanol, isopropyl alcohol and raceme 1,2-PD.

As described herein, the present inventor has obtained wondrous and beyond thought discovery: with other alcoholic solvent, compare, (R)-1,2-PD is less inhibition effectively, is therefore for sending the ideal carrier of chemical coolant.With the raceme 1,2-PD, compare, (R)-1,2-PD has advantages of the frequent twice at least of effect that improves most of coolants.

Summary of the invention

One aspect of the present invention relates to and comprises the compositions (for example, coolant composition) that is dissolved in the coolant in the solvent that contains (R)-1,2-PD.

Another aspect of the present invention for example relates to, for the preparation of the method for compositions (, coolant composition) as described herein, and wherein the method comprises coolant is dissolved in to the step in solvent.

Another aspect of the present invention relates to carries cloth for cleaning, mat or the wet tissue of compositions (for example, coolant composition) as described herein.

Another aspect of the present invention relates to and comprises the storage of compositions (for example, coolant composition) as described herein and stay container.

Another aspect of the present invention relates to and comprises the make-up preparation (for example, eye cosmetic) of compositions (for example, coolant composition) as described herein.

Another aspect of the present invention relates to and comprises washing of compositions (for example, coolant composition) as described herein and protect preparation (for example, must after emulsion).

Another aspect of the present invention relates to the compositions (for example, coolant composition) for come human body or animal body by treatment as described herein.

Another aspect of the present invention relates to as described herein and is used for the treatment of and does not feel like oneself, especially the compositions (for example, coolant composition) of do not feel like oneself (for example, the pruritus) of skin.

Another aspect of the present invention relates to being used for the treatment of as described herein and does not feel like oneself, the method for do not feel like oneself (for example, pruritus) of skin especially, and the method comprises the compositions as described herein (for example, coolant composition) for the treatment of effective dose.

Another aspect of the present invention relates to as described herein (R)-1, the 2-propylene glycol is doing not feel like oneself as described herein for the preparation for the treatment of, especially for example, for example, purposes in the compositions (, coolant composition) of do not feel like oneself (, the pruritus) of skin.

Another aspect of the present invention relates to use (R)-1,2-PD and improves the cooling activity of coolant in fluid composition.

Another aspect of the present invention relates to use (R)-1,2-PD and improves the effect of coolant composition.

As those skilled in the art will understand, characteristics of one aspect of the present invention and preferred embodiment also will relate to other side of the present invention.

The accompanying drawing explanation

Fig. 1 be use intensity of cooling (unit) after coolant as the time (hour) the curve chart of function, wherein used 5 kinds of coolants: the CPS-410(filled circles), the CPS-412(square), CPS-369(points to the triangle of below), the CPS-368(open circles) and the triangle of CPS-411(points upwards), all with the concentration of the 5mg/mL in the solvent mixture at 1% ethanol/99% (R)-1,2-PD (v/v).

Fig. 2 be use cooling effect (unit) after coolant as the time (hour) the curve chart of function, wherein to comprise 0%(v/v) (rhombus), 10%(v/v) (square), 20%(v/v) and (triangle) or 40%(v/v) concentration of the 10mg/mL in the ethanol of (the R)-1,2-PD of (circle) used coolant WS-5(v/v).

The specific embodiment

(R)-1,2-PD

For example, if send the Local cooling agent in the medium for liquid or partially liq, it is desirable to have and will can not disturb the solvent for coolant of biological activity (, its cooling activity).

It has been observed by the present inventors that can for example, by being dissolved in test solvent by test substances and utilizing cotton-tipped applicator (,

) 0.10 to 0.25mL solution is put on separately on skin surface, test the cooling and organoleptic attribute of material to be tested in various solvents.For the reliable position of topical application be in the top of upper lip (higher than the vermilion border of lip), the people, transverse to the people in until nasolabial fold and the skin of (subnasale) under nostril.Known this part face is subject to the intensive domination of cold receptor, and it is only second to eyeball and cloudy anus section (anus genitals, anogenital) surface.Twinge from skin, nice and cool and cold sensation can be experienced and time started and intensity can be evaluated.

As described herein, the inventor has studied a series of alcohols solvent (that is radical of saturated aliphatic C that, has one or two hydroxyl for a series of coolant ₁-C ₄alkane).

Surprisingly and unexpectedly, have been found that other alcoholic solvent (comprising (S)-1,2-PD) of blocking cooling effect fully than many, the cooling effect of the various coolants of the remarkable less interference of (R)-1,2-PD.Do not wish to be limited to any particular theory, the inventor thinks, the stereospecificity (stereospecific nature) of this effect and (R)-1,2-PD.

1,2-PD is the photolytic activity molecule and has a chiral centre, particularly, and the carbon atom in the 2-position.Chiral centre can have (R) or (S) configuration, thereby produces two kinds of enantiomers that are called (R)-1,2-PD and (S)-1,2-PD.

Can be described the mixture of enantiomer by its enantiomeric excess (EE), enantiomeric excess is defined as to the molar fraction (f of most of enantiomers _mAJ) deduct the molar fraction (f of minority enantiomer _mIN):

EE=f _MAJ-f _MIN

It is zero enantiomeric excess (EE) that the molar mixture such as grade (being called racemic mixture or racemate) of enantiomer has.It is 1 enantiomeric excess (EE) that pure enantiomer has.

Therefore, can be by the sample description of 1,2-PD:

● " raceme 1,2-PD ": having is the molar mixture that waits of (the R)-1,2-PD of zero enantiomeric excess and (S)-1,2-PD;

● " (R)-1,2-PD ": having is pure (the R)-1,2-PD of 1 enantiomeric excess; Or have for being greater than zero and be less than (the R)-1,2-PD of (R)-1,2-PD enantiomeric excess of 1 and the mixture of (S)-1,2-PD; Or

● " (S)-1,2-PD ": having is pure (the S)-1,2-PD of 1 enantiomeric excess; Or have for being greater than zero and be less than (the S)-1,2-PD of (S)-1,2-PD enantiomeric excess of 1 and the mixture of (R)-1,2-PD;

In addition, (R)-1,2-PD is the comparatively safe compound that the people uses because racemate be accepted as solvent for cosmetics and medicine (referring to, for example, Lakind et al., 1999).In rodent, the half lethal dose of raceme 1,2-PD is about 25mg/kg body weight, and this shows orally to give larger dose and not instant danger.Intravenous drip based on raceme 1,2-PD research, for " safety " dosage of the mankind's estimation be the 1g/kg body weight/day (referring to, for example, Wilson et al., 2005).In addition, the metabolic pathway of two kinds of enantiomers of 1,2-PD produces Pfansteihl and D-ALPHA-Hydroxypropionic acid, its then by natural endogenous mammalian enzyme, be converted into acetone acid and then be converted into acetic acid (referring to, for example, Ewaschuk et al., 2005).

Although some alcohols of TRPM8 receptor research prediction may disturb receptor activation as ethanol, this paper shows to have blocked the nice and cool sensation from chemical coolant by some alcohols solvent first in the mankind.

The inventor has obtained wondrous and beyond thought discovery: with other alcohols solvent, compare, (R)-1,2-PD be effectively less inhibition and therefore be for sending the ideal carrier of chemical coolant.(R)-1,2-PD has with the raceme 1,2-PD to be compared, and improves the advantage of the effect of (often at least twice) most of coolants.

Identify that (R)-1,2-PD allows design and prepares new liquid and partially liq formula as the ideal solvent for coolant, for use as topical agent.

For example, experimentation described herein shows, the 5mg/mL CPS-410 solution in 1% ethanol/99% (R)-1,2-PD (v/v) is significantly strong and effectively, be used for the treatment of the skin discomfort, especially pruritus on the keratinized skin surface.

Therefore, the present invention relates to comprise the compositions (for example, coolant composition) of the coolant (as described herein) be dissolved in (R)-1,2-PD.

The invention still further relates to the purposes for preparing above-mentioned composition and above-mentioned composition, for example, in treatment, for example, do not feel like oneself in treatment, especially for example, in do not feel like oneself (, the pruritus) of skin.

coolant composition

One aspect of the present invention is to comprise the compositions (for example, coolant composition) that is dissolved in the coolant in the solvent that contains (R)-1,2-PD.

fluid composition

In one embodiment, compositions is fluid composition (for example, liquid coolant compositions).

Use in this article term " liquid " to be used to refer to the material that there is the physical property (as the physical property than solid or gas) of liquid under standard temperature and pressure (STP) (that is, 20 ℃ and 101.325kPa) on conventional meaning.

solvent

In one embodiment, solvent is fully or is mainly (R)-1,2-PD.

In one embodiment, solvent comprises 100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises 95-100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises 90-100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises 85-100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises 80-100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises 75-100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises 70-100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises 65-100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises 60-100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises 55-100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises 50-100%(v/v) (R)-1,2-PD.

In one embodiment, solvent comprises the C of ratio less in addition ₁-C ₃alkanol, for example, to improve the dissolubility of coolant.

In one embodiment, solvent comprises 0-1%(v/v in addition) C ₁-C ₃alkanol.

In one embodiment, solvent comprises 0-2%(v/v in addition) C ₁-C ₃alkanol.

In one embodiment, solvent comprises 0-3%(v/v in addition) C ₁-C ₃alkanol.

In one embodiment, solvent comprises 0-4%(v/v in addition) C ₁-C ₃alkanol.

In one embodiment, solvent comprises 0-5%(v/v in addition) C ₁-C ₃alkanol.

Term " C ₁-C ₃alkanol " be intended to refer to the compound of formula R-OH, wherein R is radical of saturated aliphatic C ₁-C ₃alkyl.C ₁-C ₃alkanol is methanol, ethanol, normal propyl alcohol and isopropyl alcohol.

In one embodiment, solvent comprises 0-1%(v/v in addition) ethanol.

In one embodiment, solvent comprises 0-2%(v/v in addition) ethanol.

In one embodiment, solvent comprises 0-3%(v/v in addition) ethanol.

In one embodiment, solvent comprises 0-4%(v/v in addition) ethanol.

In one embodiment, solvent comprises 0-5%(v/v in addition) ethanol.

For example, in one embodiment, solvent is:

95-100% (R)-1,2-PD/0-5% ethanol (v/v).

For example, in one embodiment, solvent is:

97-100% (R)-1,2-PD/0-3% ethanol (v/v).

For example, in one embodiment, solvent is:

98-100% (R)-1,2-PD/0-2% ethanol (v/v).

For example, in one embodiment, solvent is:

99-100% (R)-1,2-PD/0-1% ethanol (v/v).

The example of suitable solvent comprises:

99% (R)-1,2-PD/1% ethanol (v/v);

98% (R)-1,2-PD/2% ethanol (v/v);

97% (R)-1,2-PD/3% ethanol (v/v);

96% (R)-1,2-PD/4% ethanol (v/v); And

95% (R)-1,2-PD/5% ethanol (v/v).

In one embodiment, solvent additionally comprises water.Can comprise the water of relatively large ratio and can not reduce significantly the cooling activity of coolant and can not cause significantly the precipitation of coolant.

In one embodiment, solvent comprises 0-5%(v/v in addition) water.

In one embodiment, solvent comprises 0-10%(v/v in addition) water.

In one embodiment, solvent comprises 0-15%(v/v in addition) water.

In one embodiment, solvent comprises 0-20%(v/v in addition) water.

In one embodiment, solvent comprises 0-25%(v/v in addition) water.

In one embodiment, solvent comprises 0-30%(v/v in addition) water.

For example, in one embodiment, solvent is:

90-100% (R)-1,2-PD/0-5% ethanol/0-5% water (v/v).

For example, in one embodiment, solvent is:

85-100% (R)-1,2-PD/0-5% ethanol/0-10% water (v/v).

For example, in one embodiment, solvent is:

75-100% (R)-1,2-PD/0-5% ethanol/0-20% water (v/v).

For example, in one embodiment, solvent is:

65-100% (R)-1,2-PD/0-5% ethanol/0-30% water (v/v).

The other example of suitable solvent comprises:

95% (R)-1,2-PD/5% water (v/v);

94% (R)-1,2-PD/1% ethanol/5% water (v/v);

93% (R)-1,2-PD/2% ethanol/5% water (v/v);

92% (R)-1,2-PD/3% ethanol/5% water (v/v);

91% (R)-1,2-PD/4% ethanol/5% water (v/v); With

90% (R)-1,2-PD/5% ethanol/5% water (v/v).

90% (R)-1,2-PD/10% water (v/v);

89% (R)-1,2-PD/1% ethanol/10% water (v/v);

88% (R)-1,2-PD/2% ethanol/10% water (v/v);

87% (R)-1,2-PD/3% ethanol/10% water (v/v);

86% (R)-1,2-PD/4% ethanol/10% water (v/v); With

85% (R)-1,2-PD/5% ethanol/10% water (v/v).

80% (R)-1,2-PD/20% water (v/v);

79% (R)-1,2-PD/1% ethanol/20% water (v/v);

78% (R)-1,2-PD/2% ethanol/20% water (v/v);

77% (R)-1,2-PD/3% ethanol/20% water (v/v);

76% (R)-1,2-PD/4% ethanol/20% water (v/v); With

75% (R)-1,2-PD/5% ethanol/20% water (v/v).

70% (R)-1,2-PD/30% water (v/v);

69% (R)-1,2-PD/1% ethanol/30% water (v/v);

68% (R)-1,2-PD/2% ethanol/30% water (v/v);

67% (R)-1,2-PD/3% ethanol/30% water (v/v);

66% (R)-1,2-PD/4% ethanol/30% water (v/v); With

65% (R)-1,2-PD/5% ethanol/30% water (v/v).

Alternatively, solvent can further comprise other liquid component, for example, and as allowed by percentage ratio discussed above.That is, the percentage ratio of the composition of enumerating (for example, (R)-1,2-PD, ethanol, He Shui) can add up the number that is less than 100, and forms remainder by other liquid component, for example, and other cosolvent (cosolvent).

For example, the embodiment that is described as " 90-100% (R)-1; 2-propylene glycol/0-5% ethanol/0-5% water (v/v) " can also be described to " 90-100% (R)-1; 2-propylene glycol/0-5% ethanol/other liquid component of 0-5% water/0-10% (v/v) " and comprise mixture, its, for example, be 90% (R)-1,2-PD/2% ethanol/other liquid component of 3% water/5% (v/v).

Preferably, any above-mentioned other liquid component (for example, other cosolvent) does not significantly disturb the cooling activity of coolant, and can significantly not reduce the dissolubility (for example, significantly do not induce coolant precipitation from solvent) of coolant in solvent.

Yet in one embodiment, solvent (as described herein) does not comprise other liquid component; That is, solvent only comprises those compositions of enumerating and as liquid component (is respectively for example: (R)-1,2-PD only; Only (R)-1,2-PD and ethanol; Only (R)-1,2-PD and water; Only (R)-1,2-PD, ethanol, He Shui) (for example, respectively, basically by (R)-1,2-PD, formed; Basically by (R)-1,2-PD and ethanol, formed; Basically by (R)-1,2-PD and water, formed; Basically by (R)-1,2-PD, ethanol and water, formed).In this case, the percentage ratio of enumerating composition (for example, (R)-1,2-PD, ethanol, He Shui) must amount up to 100 number.

For avoiding query, use in this article term " (v/v) " to refer to volume fraction on conventional meaning, its mixing front volume based on recording under standard temperature and pressure (STP) (that is, 20 ℃ and 101.325kPa).By mixed volume V _acomposition A and volume V _bthe prepared liquid of composition B can be described to the mixture of " X%A/Y%B(v/v) ", wherein:

X={V _A/(V _A+V _B)}×100

Y={V _B/(V _A+V _B)}×100

For example, can be described to the mixture of " 99% (R)-1,2-PD/1% ethanol (v/v) " by (R)-1,2-PD and the prepared liquid of 1mL ethanol that mixes 99mL.

Unless otherwise prescribed, for example, in the scope of the solvent used in the compositions of the present invention (, coolant composition), (the R)-1,2-PD with enantiomeric excess of 0.50 to 1.00 of mentioning in this article that " (R)-1; the 2-propylene glycol " (as described herein) be used to refer to.

For example, " 95% (R)-1,2-PD/5% ethanol (v/v) " for example refers to, the liquid mixture obtained when the 1,2-PD that mixes 95mL and 5mL ethanol, wherein 1, the 2-propylene glycol is that enantiomeric excess is 0.50 to 1.00 (R)-1,2-PD.

In one embodiment, (R)-1,2-PD has 0.50 to 1.00 enantiomeric excess.

In one embodiment, (R)-1,2-PD has 0.55 to 1.00 enantiomeric excess.

In one embodiment, (R)-1,2-PD has 0.60 to 1.00 enantiomeric excess.

In one embodiment, (R)-1,2-PD has 0.65 to 1.00 enantiomeric excess.

In one embodiment, (R)-1,2-PD has 0.70 to 1.00 enantiomeric excess.

In one embodiment, (R)-1,2-PD has 0.75 to 1.00 enantiomeric excess.

In one embodiment, (R)-1,2-PD has 0.80 to 1.00 enantiomeric excess.

In one embodiment, (R)-1,2-PD has 0.85 to 1.00 enantiomeric excess.

In one embodiment, (R)-1,2-PD has 0.90 to 1.00 enantiomeric excess.

In one embodiment, (R)-1,2-PD has 0.95 to 1.00 enantiomeric excess.

In one embodiment, (R)-1,2-PD has 1.00 enantiomeric excess.

coolant

In one embodiment, coolant is (R)-2-[((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-propanoic acid C ₁-C ₄arrcostab.

In one embodiment, coolant is CPS-368, CPS-369, CPS-410, CPS-411 or CPS-412.

In one embodiment, coolant is CPS-368.

In one embodiment, coolant is CPS-369.

In one embodiment, coolant is CPS-410.

In one embodiment, coolant is CPS-411.

In one embodiment, coolant is CPS-412.

In one embodiment, coolant is [((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-acetic acid C ₁-C ₄arrcostab.

In one embodiment, coolant is WS-5.

In one embodiment, coolant is (1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid C ₁-C ₄alkylamide.

In one embodiment, coolant is WS-3.

In one embodiment, coolant is WS-23(2-isopropyl-2,3, N-trimethyl-butyramide).

In one embodiment, coolant is trialkyl phosphine.

In one embodiment, coolant is CPS-147 or CPS-148.

In one embodiment, coolant is that lactic acid is to menthol ester.

In one embodiment, coolant is (-)-menthol.

In one embodiment, coolant is (or or) TRPM8 agonist.

coolant content

In one embodiment, coolant is dissolved in solvent with the concentration of 0.5-20mg/mL; In other words, compositions comprises with the concentration of 0.5-20mg/mL the coolant be dissolved in solvent.

In one embodiment, concentration is 1-15mg/mL.

In one embodiment, concentration is 2-10mg/mL.

In one embodiment, concentration is 3-8mg/mL.

In one embodiment, concentration is 3mg/mL.

In one embodiment, concentration is 4mg/mL.

In one embodiment, concentration is 5mg/mL.

In one embodiment, concentration is 6mg/mL.

In one embodiment, concentration is 7mg/mL.

In one embodiment, concentration is 8mg/mL.

For avoiding query, in the lower concentration of measuring of standard temperature and pressure (STP) (that is, 20 ℃ and 101.325kPa).

some preferred compositionss

The preferred composition that is suitable as the formula that is locally applied to skin comprises solvent, it is 95-100% (R)-1, the mixture of 2-propylene glycol/0-5% ethanol (v/v), have the 2-10mg/mL coolant (for example, CPS-410 or CPS-412) be dissolved in wherein.

The preferred compositions that is suitable as the formula that is applied topically to skin comprises solvent, it is 97-100% (R)-1, the mixture of 2-propylene glycol/0-3% ethanol (v/v), have the 2-10mg/mL coolant (for example, CPS-410 or CPS-412) be dissolved in wherein.

The most preferred compositions that is suitable as the formula that is applied topically to skin comprises solvent, and it is the mixture of 99% (R)-1,2-PD/1% ethanol (v/v), has the CPS-410 that is dissolved in 5mg/mL wherein.

As described above, purified water can be added to above-mentioned solution and not lose significantly cooling activity, and not inducing significantly the precipitation of coolant.

Such preparation has advantages of the manufacture of being easy to, is convenient to packing and less delivery volume.

Such preparation makes it possible to active component is evenly distributed on skin and does not give skin " greasy feeling " or viscosity sense (a kind of worthless effect, its topical vehicle through being common in standard is as vaseline and mineral oil).

combination

It should be understood that for clarity sake, also can provide a description with the combination of single embodiment some characteristic of the present invention in embodiment independently.Conversely, for simplicity, also can provide a description the of the present invention various characteristics in single embodiment dividually or with any suitable sub-combination.For example, the present invention comprises all combinations with solvent, solvent composition and their amount/ratio, coolant and the concentration dependent embodiment of coolant clearly, and just as being disclosed in this article with disclosing clearly each such combination being the same separately.

other composition

Although above-described relatively simple compositions (comprises coolant, (R)-1,2-propylene glycol, ethanol and optional water) be useful and effective, comprise other conventional formulation but can be desirably in compositions, for example, as other pharmaceutical carrier, diluent, excipient, adjuvant, filler, buffer agent, antiseptic, antioxidant, lubricant, stabilizing agent, solubilizing agent, surfactant (, wetting agent), screening agent, coloring agent, fumet and sweeting agent.

As used herein, term " medicinal " relates to compound, component, material, compositions, dosage form etc., in the scope of rational medical judgment, it is suitable for contacting with in question experimenter's tissue, and there is no excessive toxicity, stimulation, allergy or other problem or complication, and match with rational benefit/risk ratio.Be on the meaning of other component compatibility of formula, every kind of carrier, diluent, excipient etc. must be also " acceptable ".

Suitable carrier, diluent, excipient etc. can be referring to the medical textbooks of standard, for example, remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990; With handbook of Pharmaceutical Excipients, 5th edition, 2005.

Can prepare preparation by well-known any method in pharmaceutical field.Usually, by evenly also closely combining various components prepares preparation, then, if necessary, product is shaped.

For example, preparation can be suitably following liquid form: solution (for example, aqueous, non-aqueous), suspension (for example, aqueous, non-aqueous), Emulsion (for example, oil-in-water, Water-In-Oil), elixir (elixir), syrup, electuary, collutory, drop, capsule, gel, paste, ointment, liniment, emulsifiable paste, emulsion, oil, foam, spray, aerosol (mist) or aerosol (aerosol).

Lozenge (lozenge) is generally comprised within the key component in the flavouring substrate that is generally sucrose and arabic gum or tragacanth.Pastille (pastille) is generally comprised within inert base as the key component in gelatin and glycerol or sucrose and arabic gum.Collutory is generally comprised within the key component in the suitable liquid carrier.Usually prepared from key component and paraffin substrate or water-miscible ointment base by ointment.Usually prepared from key component and oil-in-water emulsifiable paste base by emulsifiable paste.Usually prepared from key component and oil phase by Emulsion, it can only comprise emulsifying agent (emulsifier) (also becoming in addition emulgent (emulgent)) alternatively, or it can comprise at least one emulsifying agent and fat or oily mixture or with fat and both mixture of oil.

Be suitable for the preparation that part (intranasal) gives and comprise, for example, nasal mist, nasal drop and aerosol (for example, by nebulizer (nebuliser), giving).Be suitable for the dosage form that part (eye) gives and comprise eye drop.Being suitable for part (pulmonary) (for example gives, by the treatment of inhalation or insufflation) dosage form comprise those of the aerosol spray that is provided as by pressurized package, wherein used suitable propellant (propellant), as dichlorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbon dioxide or other suitable gas.

Preparation can further comprise other active agents, for example, and other coolant etc.

be suitable for giving

In one embodiment, compositions is suitable for part and gives.

In one embodiment, compositions is suitable for part and gives to skin, for example, and the mankind's skin.

In one embodiment, compositions is suitable for part and gives to scalp, for example the mankind's scalp.

In one embodiment, compositions is suitable for part and gives to mucosa, for example, and the mankind's mucosa.

In one embodiment, compositions is suitable for topical ophthalmic and gives, and for example, gives the mankind.

In one embodiment, compositions is suitable for local intranasal and gives, and for example, gives the mankind.

In one embodiment, compositions is suitable for local oral cavity and gives, and for example, gives the mankind.

In one embodiment, compositions is suitable for local esophagus and gives, and for example, gives the mankind.

In one embodiment, compositions is suitable for local pharyngeal giving, and for example, gives the mankind.

In one embodiment, compositions is suitable for local cloudy anus section (anogenital section) and gives, and for example, gives the mankind.

the method for preparing compositions

Another aspect of the present invention (for example relates to the preparation compositions, coolant composition, method as described herein), the method comprises dissolves coolant (as described herein) in comprising (R)-1,2-PD solvent of (as described herein).

medical usage

Coolant composition, can be used for for example treating doing not feel like oneself of the mankind as described herein as described herein.

purposes in Therapeutic Method

Another aspect of the present invention relates to the purposes of coolant composition in the method by treatment human body or animal body as described herein.

purposes in manufacturing medicine

Another aspect of the present invention relates in the medicament that comprises the coolant composition be used for the treatment of in manufacture uses (R)-1,2-PD.

therapeutic Method

Another aspect of the present invention relates to Therapeutic Method, and the method comprises the coolant composition as described herein of the patient treatment effective dose that needs treatment.

indication

(for example, be applied to Therapeutic Method, be applied to manufacture medicine, be applied to Therapeutic Method) in one embodiment, treatment is that treatment or prevention do not feel like oneself.

(for example, be applied to Therapeutic Method, be applied to manufacture medicine, be applied to Therapeutic Method) in one embodiment, treatment is doing not feel like oneself for the treatment of or prevention skin.

(for example, be applied to Therapeutic Method, be applied to manufacture medicine, be applied to Therapeutic Method) in one embodiment, treatment is treatment or following the doing not feel like oneself of prevention:

(a) stimulation, pruritus and/or the pain for example, with dermatitis (, atopic dermatitis (atopic dermatitis), contact dermatitis, irritant dermatitis, allergic dermatitis (allergic dermatitis (allergic dermatitis)), seborrheic dermatitis) relevant;

(b) for example, with the pain of the skin of burned skin, the skin that is subject to wound, affected skin, anoxia skin and/or irriate the skin of laser surgery, during as angioplasty XRF of intensive step, Enforcement surgery, diabetic ulcer, sunburn, radiation and/or the operation damage relevant to wound debridement in imaging (, by);

(c) to skin infection, insect bite, tan severely, shave, defeathering and/or relevant pruritus and/or the discomfort (for example, actinic keratosis, basal cell carcinoma) of optical dynamic therapy skin;

(d) pruritus relevant to xerosis (often appearing in the old people) and/or psoriasis;

(e) mucositis, stomatitis, cheilitis and/or lip pruritus are for example, relevant to cold sore and/or gingivitis;

(f) pruritus ani, hemorrhoid discomfort, the pain relevant to anal fissure; The pain relevant to anal fistula and/or pruritus; The pain relevant to hemorrhoidectomy; The perineum inflammation; Cloudy anus section (anus genitals) scytitis and/or the discomfort as relevant as incontinence, diaper rash and/or perineum inflammation to local cause;

(g) pudendal pruritus, vulvodynia are (for example, for example, to following relevant: the viral infection (especially weakening in the patient in immunity) of candidiasis, vulvar vestibulitis, vulvodynia, dyspareunia, cloudy anus section's infection (, wart and/or sexually transmitted disease), skin); Or

(h) nostril for example, with respiratory disorder (, hyperemia, rhinitis, asthma, bronchitis, edema due to disorder of QI, chronic obstructive pulmonary disease, dyspnea, sleep apnea and/or snoring) relevant is uncomfortable, intranasal is uncomfortable and/or the upper respiratory tract discomfort.

(for example, the embodiment of the purposes in Therapeutic Method, the embodiment of the purposes in manufacturing medicine, the embodiment of Therapeutic Method) in one embodiment, treatment is the pruritus for the treatment of or preventing canine class.

treatment

As what used in the scope for the treatment of imbalance herein, term " treatment " relates generally to process and the treatment mankind, wherein, realized the therapeutic effect that some are desired, for example, the progression of disease suppressed, and comprise reduction, the tempo aspect of tempo aspect interruption, alleviate disease symptom, improve disease and cure diseases.Also comprise the treatment (that is, prophylactic treatment) as preventive measure.For example, the patient who is applied to not yet develop disease but has the risk of development disease contained in term " treatment ".

For example, treatment comprises the prophylactic treatment of pruritus, reduces the incidence rate of pruritus, the symptom of relieving itch etc.

As used herein, term " treatment effective dose " (for example relates to compositions, coolant composition as described herein) or dosage form (for example, comprise coolant composition as described herein) amount, when the therapeutic scheme according to desired gives, it can produce some desired therapeutic effect effectively, and matches with rational benefit/risk ratio.

experimenter/patient

In one embodiment, experimenter/patient is the mankind.

In one embodiment, experimenter/patient is mammal (for example, the dog class, for example,, in the veterinary treatment of dog class dermatitis).

give approach

In one embodiment, be that part gives the position of desired effect (that is).

In one embodiment, be that part gives to skin, the mankind's skin for example.

For example, can preferably the coolant composition part be given to the surface to one or two ancon and/or one or two knee (for example,, in the treatment of atopic eczema and psoriatic pruritus).

In one embodiment, be that part gives to scalp, the mankind's scalp for example.

For example, can for example preferably the coolant composition part be given, to some or all scalps (, in the treatment of psoriasis and contact dermatitis).

In one embodiment, be that part gives to mucosa, for example, the mankind's mucosa.

In one embodiment, be that topical ophthalmic gives, for example, give the mankind.

In one embodiment, be that local intranasal gives, for example, give the mankind.

In one embodiment, be that local oral cavity gives, for example, give the mankind.

In one embodiment, be that local esophagus gives, for example, give the mankind.

In one embodiment, be local pharyngeal giving, for example, give the mankind.

In one embodiment, be that local cloudy anus section gives, for example, give the mankind.

send-from the liquid of device for storing

Can be with the liquid delivery cooling compositions, for example, from storage, stay container, for example, and bottle or pipe, for example, it is furnished with suitable distribution tip or nozzle.

Therefore, another aspect of the present invention is to comprise the storage of coolant composition as described herein to stay container.

send-cloth for cleaning, mat or wet tissue

Can send cooling compositions via cloth for cleaning, mat or wet tissue cloth for cleaning, mat or wet tissue, for example, as use many business cleaning products (for example, Cottony Cloths, Supreme and Soft Cloths, Supreme, from CVS Pharmacy) to complete.

Therefore, another aspect of the present invention is to carry cloth for cleaning, mat or the wet tissue of coolant composition as described herein.

In one embodiment, cloth for cleaning, mat or wet tissue are suitable for coolant composition is applied topically to the mankind.

conjoint therapy

Term " treatment " comprises therapeutic alliance and therapy, has wherein combined two or more treatments or therapy, for example, and successively or side by side.For example, can also use coolant composition described herein in conjoint therapy, for example, together with other medicament.

One aspect of the present invention relates to and further comprising as described herein or for example, together with one or more (, 1,2,3, the 4 kind etc.) coolant composition of other therapeutic agent.

Will be by the doctor's particular combination at discretion that can utilize the known dosage of its common general knowledge selective dose and skilled practitioner.

Can simultaneously or in turn give medicament (that is, coolant composition, add one or more other medicaments as described herein), and can be to change separately dosage and to give via different approach.

Can be in the one-pack type form by medicament (, coolant composition, add one or more other medicaments as described herein) formulated together, or replacedly, can prepare dividually and provide together single medicament with the form of test kit, alternatively together with their operation instruction.

test kit

One aspect of the present invention relates to test kit, and it comprises: (a) coolant composition as described herein, for example, preferably in suitable container, provide and/or there is suitable packing; (b) operation instruction, for example, about how giving the written explanation of coolant composition.

Written explanation can also comprise that coolant composition is suitable for a series of indication for the treatment of.

other purposes

Another aspect of the present invention relates to the cooling activity that use (R)-1,2-PD improves coolant in fluid composition.

For example, in comprising the fluid composition of coolant, can improve or greatly improve the cooling activity of coolant in obtained compositions for the replacement of (the R)-1,2-PD of some or all of existing solvents.

By this way, can improve the some or all of solvents of prescription to adopt the replacement of (R)-1,2-PD to write out a prescription for preparation, to improve the cooling activity of coolant in the compositions obtained.

Similarly, for example, for the compositions that comprises 1,2-PD (, as the raceme 1,2-PD), add the cooling activity that (R)-1,2-PD can improve or greatly improve coolant in obtained compositions.

By this way, can improve prescription for preparation also to comprise (R)-1,2-PD the solvent except comprising prescription, to improve the cooling activity of coolant in the compositions obtained.

Another aspect of the present invention relates to use (R)-1,2-PD and strengthens the effect of coolant composition.

For example, in comprising the fluid composition of coolant, substitute some or all of existing solvents with (R)-1,2-PD and can allow the compositions of smaller size smaller to there is identical cooling effect.

By this way, can improve for the prescription of preparation to comprise (R)-1,2-PD and/or to substitute some or all of existing solvents with (R)-1,2-PD, to strengthen the effect (and allowing to give smaller size smaller) of the compositions obtained.

Also can use coolant composition as described herein in preparing cosmetics and washing product.Can comprise (R)-1,2-PD with the cooling activity that strengthens coolant wherein and/or the cooling effect that strengthens formula in preparation.By this way, can strengthen the cooling and salubrious effect relevant to these preparations.

For example, can improve for must after the prescription of emulsion to comprise (R)-1,2-propylene glycol and/or substitute some or all of existing solvents with (R)-1,2-PD, with the cooling activity that strengthens coolant wherein and/or strengthen must after the cooling effect of emulsion.By this way, can strengthen the cooling and salubrious effect relevant to emulsion after palpus.

For example, can improve prescription for remove the preparation of cosmetics from eyelid, be used for application and there is the preparation of irritating eye cosmetic and/or be used for applying and make eyelashes (for example, grow faster material

preparation to comprise (R)-1,2-PD and/or to substitute some or all of existing solvents with (R)-1,2-PD, thereby strengthen the cooling activity of coolant wherein and/or strengthen the cooling effect of preparation.By this way, can strengthen the cooling and salubrious effect relevant to preparation.

research and embodiment

material

(R)-1,2-PD (EE at least 0.98), (S)-1,2-PD (EE at least 0.98), 1,3-PD and raceme 1,3 butylene glycol have been bought from Sigma-Aldrich Co.Obtain ethanol, normal propyl alcohol, isopropyl alcohol and raceme 1,2-PD from source, this locality.

Select following coolant for testing:

At US2008/0227857A1 (Sept.18,2008) and coolant and the synthetic method of these coolants, other structural similarity have been further described in 2007.

the toxicology screening

In preliminary study, estimate the toxicity of some crucial coolants in the male adult rat of youth.Coolant is dissolved in 3% ethanol/97% raceme 1,2-PD (v/v) and subcutaneous injection 30mg/kg every day continues 5 days.The monitoring body weight, and, at the 6th day, use excessive pentobarbital sodium by animal euthanasia, then determine the weight of liver and heart.During treating, the animal dead be not treated.The results are summarized in following table." N " is number of repetition.

Do not have significant change aspect the organ weight, except the possible liver weight about CPS-412.The test dose of measuring for the people is 1 to 2mg/ test/experimenter.The test dose of studying in toxicologic study is the 30mg/kg body weight, and the time is 5 days.Determined in the people and measured and do not cause significant security risk.

skin is measured

For the mensuration on skin, coolant is dissolved in to the test solution that there is the coolant concentration of 2mg/mL, 2.5mg/mL, 3mg/mL, 5mg/mL, 10mg/mL or 20mg/mL in alcohols solvent with generation.

(for example, use cotton-tipped applicator

), by the test solution of 0.10mL to 0.25mL be applied to above upper lip, be arranged on the people, and transverse in the people until on the skin of nasolabial fold, and beginning and the persistent period of recording cooling sensation.

The intensity of subjective dermal sensation is rated to 0,1,2 or 3, and wherein 0 is: do not change; 1 is: slight slight chill in the air, cold or tingling; 2 are: the clear and definite signal of nice and cool, cold or tingling; And 3 be: strong is cooling or cold.For the interval of recording sensation, be 5 to 10 minutes intervals, until obtain at least two continuous zero.Result is the meansigma methods for 3 to 6 routine tests of same individual." beginning " is the needed time of nice and cool intensity level for reaching 2.If test solution does not reach numerical value 2, it is considered to invalid so." interruption " is that nice and cool intensity decreases arrives the time lower than 2, and " persistent period " is the time of interrupting deducting the time started.Area under curve (AUC) give pharmaceutically-active intensity and persistent period estimated value and can be from utilizing SigmaPlot(Systat Software, Point Richmond CA) drawing data obtain this value.Provide AUC with meansigma methods ± S.E.M. unit, its be intensity of cooling and time (minute) product.Therefore, if obtain 180 AUC value, it means, 3 intensity of cooling accumulation has continued at least 60 minutes, even the total duration of effect will be longer, for example, 75 minutes, this was due to nice and cool beginning and interrupts the needed time.

skin research 1

Utilize above-described skin to measure, for some different alcohols solvents, studied two kinds of strong coolants, CPS-410 and CPS-369.Concentration is 5mg/mL CPS-410 and 10mg/mLCPS-369.The results are summarized in following table.

Data show, use the alcohol (that is, ethanol, normal propyl alcohol and isopropyl alcohol) with a hydroxyl to cause the loss of the cooling activity of CPS-410 and CPS-369.

Use some dihydroxylic alcohols (that is, 1,3-PD and raceme 1,3 butylene glycol) also to cause the remarkable loss of cooling activity.

In various 1,2-PDs, surprisingly and unexpectedly, (R)-1,2-PD is the optimum solvent of the cooling effect for keeping CPS-410 and CPS-369.According to AUC, (S)-1,2-PD solution only has active and 47% the CPS-369 activity of 27% CPS-410 of corresponding (R)-1,2-PD solution.

skin research 2

For many cosmetics and dermatological preparation, raceme 1,2-PD (propylene glycol) is standard solvent.Compared the activity of some coolants in raceme 1,2-PD and (R)-1,2-PD and the results are summarized in following table.Comprised the ethanol of small scale to promote the dissolving of coolant in solvent mixture.(with term AUC, measure active and report ± S.E.M.; P<0.01t-detects.）

Data show, in each case, with use raceme 1,2-PD, compare, and by (the R)-enantiomer of 1,2-PD, as solvent, can provide higher cooling activity.For 6 kinds in 7 kinds of tested compounds, the cooling activity in (R)-1,2-PD is higher than the about twice of the activity in the raceme 1,2-PD.

Do not recognize in the past, " a large amount of (bulk) " solvent can have such strong effect to the coolant activity in vivo.(R)-1,2-PD is beyond thought, surprising and has practicality as the good performance of solvent.For example, in the design of preparation, the coolant that (R)-1,2-PD solvent will need to few 50% than the raceme 1,2-PD, realize equivalent cooling effect.Conversely, in the situation that expectation reduce preparation in solvent volume, use (R)-1,2-PD can reduce needed volume and reach approximately 50%, still realize the cooling of same degree.

Be dissolved in 1,2-PD and compare, many coolants more are soluble in ethanol.For example, WS-3 and CPS-369 respectively with 300mg/mL and 500mg/mL dissolves in dehydrated alcohol.These compounds are not soluble in 1,2-PD: under standard conditions, dissolubility is about 10mg/mL.

In order to prepare the fluid composition of coolant, using (R)-1,2-PD and above reach to 5%(v/v) solvent mixture of ethanol is very convenient.The ethanol of this tittle can be comprised and cooling activity can be significantly do not lost.

Experimentally, have been found that, add (R)-1, the 2-propylene glycol is to form solvent mixture (from 1% ethanol/99% (R)-1,2-propylene glycol (v/v) is to 3% ethanol/97% (R)-1,2-propylene glycol (v/v)) not appreciable impact of ethanol is dissolved in intensity or the persistent period of the cooling effect of coolant wherein, even experiment in vitro shows the ethanol of low concentration like this, can disturb receptor activation.

In measuring in the people, with at 1% ethanol/99% (R)-1,106 ± the 12(AUC of 2.5mg/mL CPS-369 in the solvent mixture of 2-propylene glycol (v/v)) compare, 2.5-mg/mLCPS-369 solution in 100% (R)-1,2-PD provides 107 ± 13(AUC) activity.Therefore, 1% ethanol (v/v) does not affect the cooling effect of CPS-369.

Fig. 1 be apply intensity of cooling (unit) after 5 kinds of coolants its be as the time (hour) the curve chart of function: the CPS-410(filled circles), the CPS-412(square), CPS-369(points to the triangle of below), the CPS-368(open circles) and the triangle of CPS-411(points upwards), all with the concentration of 5mg/mL in the solvent mixture at 1% ethanol/99% (R)-1,2-PD (v/v).

skin research 3

(-)-menthol is the most widely used coolant in the business application.It is present in various liquid or semi-liquid preparations as

ointment,

the liquid medicine of the steams such as medical patch and Vicks Vaposteam Liquid Medication(eucalyptus oil, Camphora, Mentholum and ethanol) in.(-)-menthol is complicated on the impact of sensory system, but thinks that one of target receptor is the TRP-M8 receptor.Compared (-)-menthol (10mg/mL) in measuring and be dissolved in 1,3-PD or be dissolved in the cooling effect of (-)-menthol in (R)-1,2-PD in the people.For 1,3-PD, cool and add temperature-sensitive ingredients is 13 ± 1 minutes and is 21 ± 2 minutes (P<0.001) for (R)-1,2-PD, shown significant difference.Obviously, be dissolved in 1,3-PD in compare, in the time of in being dissolved in (R)-1,2-PD, (-)-menthol has stronger cooling activity.

skin research 4

May ask: (R)-1 for where, can when existing, the 2-propylene glycol improve or maximize the activity of chemical coolant? that is: (R)-1, what is the mechanism of action of the difference between 2-propylene glycol and other two to three carbon alcohol? do not wish to be limited to any particular theory, the inventor thinks, the most simply explain and be, the activation of TRP-M8 receptor is subject to the inhibition of ethanol and other alcohols, but be not subject to (R)-1, the inhibition of 2-propylene glycol, this is because its stereotaxis orientation and/or (R)-1,2-PD are the antagonisies at the alcohols binding site place on the TRP-M8 receptor.

In pharmacology's term, antagonist is the effect of blocking-up agonist and the chemicals that do not exert an influence itself.Therefore, for example, ethanol suppresses TRP-M8 as agonist and activates, and the agonist effect of antagonist blocking-up ethanol and itself does not produce any change aspect function of receptors.The antagonist of blocking-up inhibition agonist also will have the nice and cool net effect of enhancing.(R)-1,2-PD can antagonism/blocking-up TRP-M8 the ethanol binding site.In health, feeling cold teleneuron level, may there is the endogenous alcohols, for example, and ethanol or glycerol, it suppresses cold receptor, and such inhibition is subject to the antagonism of (R)-1,2-PD.

In order to check this antagonism hypothesis, with 0%, 10%, 20% and 40%(v/v), (R)-1,2-PD is added to the WS-5(known coolant that comprises 10mg/mL) alcoholic solution in.In the time of in being applied to the people, the WS-5 of the 10mg/mL in 100% ethanol does not produce any cooling effect.Yet (R)-1,2-PD reverses ethanol and suppresses to show dose-dependence.Data are shown in Fig. 2.These data provide strong evidence: at the ethanol binding site place of TRP-M8, (R)-1,2-PD is antagonist.

Fig. 2 be cooling effect after using (unit) conduct time (hour) the curve chart of function, for coolant WS-5 to comprise 0%(v/v) (rhombus), 10%(v/v) (square), 20%(v/v) (triangle) or the 40%(v/v) concentration of 10mg/mL in the ethanol of (the R)-1,2-PD of (circle).

Another kind of coolant, WS-3, be widely used in cosmetics, toothpaste and food.In the time of in being applied in the people, the WS-3 be dissolved in dehydrated alcohol with 20mg/mL does not produce cooling significantly.Yet, when using the WS-3 of the 20mg/mL that is dissolved in 3% ethanol/97% (R)-1,2-PD (v/v), its produce to continue 38 ± 3 minutes strong cooling, and together with twinge and sting sense.As bright as above-mentioned tables of data, and be dissolved in (R)-1,2-PD and compare, when being dissolved in the raceme 1,2-PD, the activity of WS-3 is much lower.Therefore, solvent carrier is bioactive crucial determiner.

skin research 5

Rowsell et al., 1978 have described the cooling performance of some trialkyl phosphine first.Referring to, for example, listed compound in tables defined in the 2nd special column the 25th row and the 3rd and 4 special columns therein is walked in the 1st special column the 58th therein.

Coolant CPS-147 and CPS-148 are the members of this compounds (trialkyl phosphine).CPS-147 and CPS-148 chemically are different from (-)-menthol derivative, and it, for example, meaned by WS-3, WS-5, CPS-368, CPS-369, CPS-410, CPS-411 and CPS-412.The binding site of trialkyl phosphine on the TRP-M8 receptor is unknown.According to data discussed above, can find out, with the raceme 1,2-PD, compare, in the time of in being formulated in (R)-1,2-PD, CPS-147 and CPS-148 are all more activated.This is new and beyond thought observed result.

the patient studies 1

There is the plaque psoriasis of 8 years history and 34 years old male of the skin of axillary fossa pathological changes that complaint is itched, there is burn feeling, and allow him lie awake all night.His situation is serious and chronic.His mother complaint, she must dust suction every day sweeps his bedroom to remove exuviae skin bits.After checking, this individuality he ancon and the knee surface on there is pathological changes some silver color, lamellar, but this also like that seriously bothers him not as the dermatosis under his right axillary fossa, and wherein above-mentioned dermatosis shows as the rectangular area of about 2cm * 4cm and has the rubescent and moistening outward appearance of diffusivity.He volunteers to attempt CPS-148 solution (2%CPS-148(w/w), in 1% ethanol/99% (R)-1,2-PD (v/v)) and given how by means of swab (Q-tip ^tM) solution is applied to the indication at his pruritus position.He claims, after using first night, burn feeling and pruritus disappeared in 5 to 10 minutes and he can have good nighttime sleep." as required ", he continues to use solution 1 month and claims and sleep more much betterly than in the past.Subsequently, use course for the treatment of

treat this individuality, and his psoriasis state of an illness significantly improves, so that no longer need local antipruritic.

the patient studies 2

Just suffers from the women of 21 years old of atopic eczema in the time of 4 years old from her.In these years, by using the steroid medicine of emollient cream/ointment and low effect, she learned how to control this disease (be mainly she knee and the elbow bight portion on the skin of pruritus) symptom.Because she says that these medicines make her thinning of skin easily damaged, she is careful especially to the steroid of efficient more, and to suffering from rash and acne sample pimple susceptible.She has busy social schedule and is subjected to especially around nape and the worry of scratching where it itches below ear-lobe at her, and this is because she goes party, cinema, drama institute, concert and wedding, and scratch at full tilt in public, is indecency.She agrees to attempt wet tissue (the cotton towel of 0.4g rectangle; CS-being, Daisan Cotton, Japan), it is added to the CPS-410 solution (CPS-410 of 5mg/mL, in 1% ethanol/99% (R)-1,2-PD (v/v)) of 2mL.Use vacuum equipment to seal individually wet tissue and be stored in refrigerator (

jarden Corp.) in.For this experimenter, use this pastille wet tissue successfully to control pruritus.She means, can " as required " careful use wet tissue, and solvent does not stay shinny residue on her skin.She says: she feels more confident in public now.

the patient studies 3

The people from California of 60 years old visited the botanical garden in Hong Kong in July.His American dietary habit may cause the body odour of attract insect, and this is because he is covered with bite mark and 4 bite mark/cm of bite mark average out on arms and legs ²and cover he the limbs surface at least 8%.This individual agreement is attempted CPS-410 solution (5mg/mL CPS-410, in 1% ethanol/99% (R)-1,2-PD (v/v)) to control stimulation, pruritus and the pain from his bite mark.He immerses solution with plastic chopstick and solution evenly is applied on his skin.Surprisingly, after using in three minutes pruritus significantly alleviate.Still scratch his skin of this individuality, but milder, and there is the intensity of reduction.By means of test solution and, later by means of 1% hydrocortisone emulsifiable paste, he has controlled his pruritus.

the patient studies 4

After using hair dye, within 64 years old, the male has been developed strong pruritus (contact dermatitis) on the scalp at head base portion place.Use cotton head rod to use the CPS-410 solution (CPS-410 of 5mg/mL at the pruritus place, at 1% ethanol/99% (R)-1, in 2-propylene glycol (v/v)) or CPS-412 solution (CPS-412 of 5mg/mL, in 1% ethanol/99% (R)-1,2-PD (v/v)).In using 5 minutes of any solution, scratchiness is suppressed, and this effect continues at least 8 hours.In second experiment, utilize the plastic bottle with taper Yorker nozzle to use solution.This sends solution to the pruritus position with making it possible to more accurate droplet.After using, CPS-410 solution produces cooling feeling, but not as using CPS-412 obvious.After using and within two days, being separated by about 10 hours, pruritus no longer occurs.These results are surprising, and this is because (with respect to the skin in the people) scalp is thick and the receptor of hotness is considered to be positioned at below epidermis at least 1mm place, at epidermis and hypodermic joint.For processing the scalp psoriasis, these results have potential importance, and wherein the pruritus in the scalp pathological changes and burn feeling are worried and uncomfortable source sometimes.

the patient studies 5

Stay in 87 years old male in the pub suite in Hong Kong.He he back and lower limb on suffer from the dried bark pruritus.Air-conditioning during summer in his room is the variation of unpredictable and room temperature while causing excessive perspiration sometimes, and this disease increases the weight of.Skin becomes to stimulate and pruritus.When scratching, the impregnated and pain of the speckle of skin.His dermatologist has opened the prescription of fluocinonide (fluocinolide) 0.05% emulsifiable paste, but this causes infected ulcer sexually transmitted disease (STD) to become, and it must be treated by topical antibiotics.He has attempted 0.5% (w/w) CPS-410 in ointment, and feels some alleviation; Yet he complains " greasy feeling " of ointment, especially when he perspires.He agrees to attempt CPS-410 solution (CPS-410 of 5mg/mL, in 1% ethanol/99% (R)-1,2-PD (v/v)).Use solution and his with a cotton rod and find not have " greasy feeling " relieving itch rapidly simultaneously.He can obtain good nighttime sleep.He regularly uses this solution now.Due to less pathological changes of scratching him, so improved the integrity of his skin and he is happier.

the patient studies 6

Within 45 years old, the women is just cooking fish soup.When the content by hot is transferred to another container from a container, she has unexpectedly splashed the soup of boiling the palm surface of her forearm.After with the cold water flush arm, she complains sharp pain and inquires whether she can test CPS-410 solution (CPS-410 of 5mg/mL, in 1% ethanol/99% (R)-1,2-PD (v/v)).Suppressed pain in 3 minutes after using, but the recurrence later at 2 hours.She uses solution again, but is applied to specifically wider zone, to cover the dermatotome (ermatome) of forearm; Pain is weakened fully, and she " has forgotten " discomfort there.Scalded spontaneous recovery in 24 hours.Be also noted that the solution by applying has reduced by the degree of scalding the redness produced.

Although should be appreciated that above and together with the preferred specific embodiment, described the present invention, the scope that description and embodiment are intended to be illustrative of the invention rather than limiting, it is limited by claims.

list of references

Above quoted some publications with more fully describe and disclose the present invention and with the present invention under prior art.Below provide the whole of these lists of references to quote.

The full content separately of these lists of references is incorporated into to this paper by reference, reaches by reference as every piece of independent list of references that will be combined by particularly and the identical degree of pointing out individually.

Benedikt?et?al.,2007,“Ethanol?inhibits?cold-menthol?receptor?TRPM8by?modulating?its?interaction?with?membrane?phosphatidylinositol4,5-bisphosphate”, J.Neurochemistry,Vol.100,pp.211-224。

et?al.,2007,“Characterisation?of?TRPM8as?a?pharmacophore?receptor”, Cell?Calcium,Vol.42,No.6,pp.618-628。

Ewaschuk?et?al.,2005,“D-Lactate?in?human?and?ruminant?metabolism”, J.Nutrition,Vol.135,pp.1619-1625。

Harris?et?al.,“Ethanol’s?molecular?targets”, Science?Signaling,July15,2008。

Lakind?et?al.,1999,“A?review?of?the?comparative?mammalian?toxicity?of?ethylene?glycol?and?propylene?glycol”, Critical?Reviews?in?Toxicology,Vol.29,pp.331-365。

Leffingwell,2009,“Cooling?Ingredients?and?Their?Mechanism?of?Action”in? Handbook?of?Cosmetic?Science?and?Technology,3rd?ed.,Barel?et?al.,Eds.,Informa?Healthcare(Publisher),New?York)。

Ly and Longo, 2004, " Under the influence of alcohol:the effect of ethanol and methanol on lipid bilayers ", biophysical J., Vol.87, pp.1013-1033.

Rowsell?et?al.,1978,“Phosphine?oxides?having?a?physiological?cooling?effect,”US?Patent?No4,070,496granted?January24,1978。

Rowsell?et?al.,1979,“N-Substituted?paramenthane?carboxamides”,US?Patent?No4,178,459granted11December1979。

Watson?et?al.,1978,“New?compounds?with?the?menthol?cooling?effect”, J. Soc.Cosmet.Chem.,Vol.29,pp.185-200。

Wei,2005a,“Therapeutic1,2,3,6-tetrahydropyrimidine-2-one?compositions?and?methods?therewith”,US?patent?number6,919,348granted19July2005。

Wei,2005b,“Aryl-Substituted?Derivatives?of?Cycloalkyl?and?Branched?Chain?Alkyl?Carboxamides?and?Carboxylic?Acids?Useful?as?Antinociceptive?Drugs?For?Peripheral?Targets”,US?patent?publication?number?US2005/0159394A1published21July2005。

Wei,2005c,“N-Aryl _s-Carboxamide?Compositions?and?Methods”,US?patent?publication?number?US2005/0187211A1published25August2005。

Wei,2006,“N-Alkylcarbonyl-Amino?Acid?Ester?and?N-Alkylcarbonyl-Amino?Lactone?Compounds?and?Their?Use”,international?patent?publication?number?WO2006/103401A2published05October2006。

Wei,2008,“N-Alkylcarbonyl-amino?acid?ester?and?N-alkylcarbonyl-amino?lactone?compounds?and?their?use”,US?patent?publication?number?US2008/0227857A1published18September2008。

Weil?et?al.,2005,“Conservation?of?functional?and?pharmacological?properties?in?the?distantly?related?temperature?sensors?TRP-V1and?TRP-M8”, Molecular?Pharmacology,Vol.68,pp.518-527。

Wilson?et?al.2005,“Propylene?glycol?toxicity:a?severe?iatrogenic?illness?in?ICU?patients?receiving?IV?benzodiazepines:a?case?series?and?prospective,observational?pilot?study”, Chest,Vol.128,pp.1674-1681。

Claims

1. a compositions, comprise the coolant be dissolved in the solvent that contains (R)-1,2-PD.

2. compositions according to claim 1, wherein, described solvent comprises:

95-100%(v/v) (R)-1,2-PD; With

0-5%(v/v) C ₁-C ₃alkanol.

3. compositions according to claim 1, wherein, described solvent comprises:

95-100%(v/v) (R)-1,2-PD; With

0-5%(v/v) ethanol.

4. compositions according to claim 1, wherein, described solvent comprises:

97-100%(v/v) (R)-1,2-PD; With

0-3%(v/v) ethanol.

5. compositions according to claim 1, wherein, described solvent comprises:

99-100%(v/v) (R)-1,2-PD; And

0-1%(v/v) ethanol.

6. compositions according to claim 1, wherein, described solvent comprises:

65-100%(v/v) (R)-1,2-PD;

0-5%(v/v) C ₁-C ₃alkanol; With

0-30%(v/v) water.

7. compositions according to claim 1, wherein, described solvent comprises:

65-100%(v/v) (R)-1,2-PD;

0-5%(v/v) ethanol; With

0-30%(v/v) water.

8. compositions according to claim 1, wherein, described solvent comprises:

75-100%(v/v) (R)-1,2-PD;

0-5%(v/v) ethanol; With

0-20%(v/v) water.

9. compositions according to claim 1, wherein, described solvent comprises:

85-100%(v/v) (R)-1,2-PD;

0-5%(v/v) ethanol; With

0-10%(v/v) water.

10. compositions according to claim 1, wherein, described solvent comprises:

90-100%(v/v) (R)-1,2-PD;

0-5%(v/v) ethanol; With

0-5%(v/v) water.

11., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is (R)-2-[((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-propanoic acid C ₁-C ₄arrcostab.

12., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is:

(R)-2-[((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-methyl propionate (CPS-368);

(R)-2-[((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-ethyl propionate (CPS-369);

(R)-2-[((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-n propyl propionate (CPS-410);

(R)-2-[((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-isopropyl propionate (CPS-411); Or

(R)-2-[((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-n-butyl propionate (CPS-412).

13., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is:

(R)-2-[((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-n propyl propionate (CPS-410).

14., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is:

15., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is [((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-acetic acid C ₁-C ₄arrcostab.

16., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is [((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-ethyl acetate (WS-5).

17., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is (1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid C ₁-C ₄alkylamide.

18., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is (1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkane carboxylic acid acetamide (WS-3).

19., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is 2-isopropyl-2,3, N-trimethyl-butyramide (WS-23).

20., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is trialkyl phosphine.

21., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is:

1-(di-sec-butyl-phosphono)-hexane (CPS-147); Or

1-(di-sec-butyl-phosphono)-heptane (CPS-148).

22., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is that lactic acid is to menthol ester.

23., according to the described compositions of any one in claim 1 to 10, wherein, described coolant is (-)-menthol.

24., according to the described compositions of any one in claim 1 to 23, wherein, described coolant is dissolved in described solvent with the concentration of 0.5mg/mL-20mg/mL.

25., according to the described compositions of any one in claim 1 to 23, wherein, described coolant is dissolved in described solvent with the concentration of 1mg/mL-15mg/mL.

26., according to the described compositions of any one in claim 1 to 23, wherein, described coolant is dissolved in described solvent with the concentration of 2mg/mL-10mg/mL.

27., according to the described compositions of any one in claim 1 to 23, wherein, described coolant is dissolved in described solvent with the concentration of 3mg/mL-8mg/mL.

28. compositions according to claim 1, comprise the coolant be dissolved in solvent, wherein, described solvent comprises:

97%(v/v) (R)-1,2-PD; With

3%(v/v) ethanol;

Wherein said coolant is (R)-2-[((1R, 2S, 5R)-2-isopropyl-5-methyl-cyclohexyl alkyl carbonyl)-amino]-n propyl propionate (CPS-410); And

Wherein said coolant is dissolved in described solvent with the concentration of 5mg/mL.

29. compositions according to claim 1, comprise the coolant be dissolved in solvent, wherein, described solvent comprises:

99%(v/v) (R)-1,2-PD; With

1%(v/v) ethanol;

30., according to the described compositions of any one in claim 1 to 29, described compositions is fluid composition.

31., according to the described compositions of any one in claims 1 to 30, described compositions is suitable for part and gives.

32. one kind for the preparation of the method according to the described compositions of any one in claims 1 to 31, wherein, described method comprises the step that described coolant is dissolved in to described solvent.

33. cloth for cleaning, mat or wet tissue containing the described compositions of any one in good grounds claims 1 to 31.

34. cloth for cleaning according to claim 33, mat or wet tissue, described cloth for cleaning, mat or wet tissue are suitable for giving the people by described compositions part.

35. container is stayed in a storage, comprises according to the described compositions of any one in claims 1 to 31.

For example, 36. a make-up preparation (, eye cosmetic), comprise according to the described compositions of any one in claims 1 to 31.

For example, 37. wash and protect preparation (, latex emulsion after shaving) for one kind, comprise according to the described compositions of any one in claims 1 to 31.

38. according to the described compositions of any one in claims 1 to 31, for come human body or animal body by treatment.

39., according to the described compositions of any one in claims 1 to 31, be used for the treatment of and do not feel like oneself.

40., according to the described compositions of any one in claims 1 to 31, be used for the treatment of doing not feel like oneself of skin.

41., according to the described compositions of any one in claims 1 to 31, be used for the treatment of pruritus.

42., according to the described compositions of any one in claims 1 to 31, be used for the treatment of:

(a) stimulation, pruritus and/or the pain for example, with dermatitis (, atopic dermatitis, contact dermatitis, irritant dermatitis, allergic dermatitis, seborrheic dermatitis) relevant;

(b) pain for example, with the skin of burned skin, the skin that is subject to wound, affected skin, anoxia skin and/or irriate (, be subject to laser surgery, the skin of XRF during as angioplasty of intensive step, diabetic ulcer, sunburn, radiation and/or the operation damage relevant to wound debridement in imaging) relevant;

(c) with skin infection, insect bite, tan severely, shave, relevant pruritus and/or the discomfort of photodynamic therapy (for example, actinic keratosis, basal cell carcinoma) of defeathering and/or skin;

(f) pruritus ani, hemorrhoid discomfort, the pain relevant to anal fissure, the pain relevant to anal fistula and/or pruritus, the pain relevant to hemorrhoidectomy, perineum inflammation, cloudy anus section scytitis and/or the discomfort as relevant as incontinence, diaper rash and/or perineum inflammation to local cause;

(g) pudendal pruritus, vulvodynia (for example, for example, to following relevant: the viral infection (especially weakening in the patient in immunity) of candidiasis, vulvar vestibulitis, vulvodynia, dyspareunia, cloudy anus section's infection (, wart and/or sexually transmitted disease), skin); Or

(h) nostril for example, with respiratory disorder (, congestion, rhinitis, asthma, bronchitis, edema due to disorder of QI, chronic obstructive pulmonary disease, dyspnea, sleep apnea and/or snoring) relevant is uncomfortable, intranasal is uncomfortable and/or the upper respiratory tract discomfort.

43., according to the described compositions of any one in claim 39 to 42, wherein, described treatment is to give by part.

44. one kind is used for the treatment of the method done not feel like oneself, comprise treat effective dose according to the described compositions of any one in claims 1 to 31.

45. a method that is used for the treatment of the dermal sensation discomfort, comprise treat effective dose according to the described compositions of any one in claims 1 to 31.

46. a method that is used for the treatment of pruritus, comprise treat effective dose according to the described compositions of any one in claims 1 to 31.

47. a Therapeutic Method is used for the treatment of:

(h) nostril for example, with respiratory disorder (, congestion, rhinitis, asthma, bronchitis, edema due to disorder of QI, chronic obstructive pulmonary disease, dyspnea, sleep apnea and/or snoring) relevant is uncomfortable, intranasal is uncomfortable and/or the upper respiratory tract discomfort;

Comprise treat effective dose according to the described compositions of any one in claims 1 to 31.

48., according to the described method of any one in claim 44 to 47, wherein, described is that part gives.

49. be used for the treatment of the purposes in the medicine done not feel like oneself according to the described compositions of any one in claims 1 to 31 in manufacture.

50. be used for the treatment of the purposes in the medicine of dermal sensation discomfort according to the described compositions of any one in claims 1 to 31 in manufacture.

51. be used for the treatment of the purposes in the medicine of pruritus according to the described compositions of any one in claims 1 to 31 in manufacture.

52. be used for the treatment of the purposes in the medicine of following disease according to the described compositions of any one in claims 1 to 31 in manufacture:

53., according to the described method of any one in claim 49 to 52, wherein, described medicine is suitable for part and gives.