JP2014508740A - (R) -1,2-propanediol for use as a solvent in a therapeutic coolant composition - Google Patents

Abstract

The present invention relates generally to the fields of topical medication, cosmetics and toiletries. More specifically, the present invention relates to coolants such as n-propyl (R) -2-[((1fl, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionate. It relates to the use of a solvent comprising (R) -1,2-propanediol for the ester (CPS-410). The invention also relates to a coolant and a coolant composition comprising 2-propanediol and a method for its preparation. The invention also relates to the use of such coolant compositions in therapy, for example in the treatment of sensory discomfort, in particular skin sensory discomfort (eg pruritus). The invention also relates to the use of such coolant compositions in cosmetics (eg eye makeup products) and toiletries (eg after shave lotions).
[Selection figure] None

Description

This application is related to US patent application Ser. No. 12 / 930,794, filed Jan. 18, 2011, the contents of which are hereby incorporated by reference in their entirety.

  The present invention relates generally to the fields of topical medication, cosmetics and toiletries. More specifically, the present invention relates to coolants such as n-propyl (R) -2-[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionate. It relates to the use of a solvent comprising (R) -1,2-propanediol for the ester (CPS-410). The invention also relates to a coolant composition comprising a coolant and (R) -1,2-propanediol, and a method for its preparation. The invention also relates to the use of such coolant compositions in therapy, for example in the treatment of sensory discomfort, in particular skin sensory discomfort (eg pruritus). The invention also relates to the use of such coolant compositions in cosmetics (eg eye makeup products) and toiletries (eg after shave lotions).

  Several articles are cited herein to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is hereby incorporated herein by reference in its entirety to the same extent as each individual reference is specifically and individually indicated and incorporated by reference.

  Throughout the specification, including the claims that follow, unless otherwise required, the terms `` comprise '' and variations such as `` comprises '' and `` comprising '' Will be understood to mean including the stated integers or steps, or groups of integers or steps, but not excluding any other integers or steps, or groups of integers or steps.

  As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” may include multiple referents unless the content clearly dictates otherwise. , Should be noted. Thus, for example, reference to “a pharmaceutical carrier” includes a mixture of two or more such carriers, and the like.

  Ranges are expressed herein as “about” one particular value and / or “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the preceding word “about,” it will be understood that the particular value forms another embodiment.

  This disclosure includes information that may be useful in understanding the present invention. That is, any of the information provided herein is either prior art of the presently claimed invention or related to the presently claimed invention, or is explicitly or implicitly referenced The paper is also not approved as prior art.

  About 30 years ago, a group of scientists synthesized over 1200 compounds in an effort to find a coolant with better properties than menthol. The results are summarized in Watson et al., 1978. From this study, several compounds were identified: WS-3 ((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarboxylic acid ethylamide), WS-5 ([((1R, 2S, 5R) -2-Isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -acetic acid ethyl ester) and WS-23 (2-isopropyl-2,3, N-trimethyl-butyramide) reach the market, confectionery, food ( For example, it is used as an additive to sugar confectionery, chewing gum), cosmetics, and toiletries.

  Other menthol-like coolants in commercial use for application to the skin and mucosa are, for example, menthyl lactate (Frescolat ML), menthoxypropanediol (coolant 10), and 2-isopropyl-5-methyl. Cyclohexyl 4- (dimethylamino) -4-oxobutanoate. Current information about coolants used for topical applications has been reviewed (see, eg, Leffingwell, 2009).

  Additional coolants are described, for example, in Wei, 2005a, Wei, 2005b, Wei, 2005c, and Wei, 2006.

  Skin and mucosal cooling is sensed by a subset of primary sensory afferent fibers that have receptors on nerve endings. These sensory fibers show a rhythmic, ongoing discharge at neutral temperature that increases in response to a decrease in skin temperature (33 ° C-23 ° C) and is suppressed by warming. The mechanical information is propagated along the axons in the spike train at about 20-40 impulses / second to the central neuron, with the result that humans perceive coolness. This type of sensation is reproduced, for example, by exposure of the facial skin to an outside temperature of 15 ° C to 22 ° C.

  The multiple effects of (-)-menthol and related coolants on sensory processes include foods, confectionery, flavorings, chewing gums, mouth-freshing agents, lipsticks, and other foods (e.g., mouthpieces), beverages , Compositions for tobacco products, toiletries (e.g. after shave lotions), for nasal and respiratory tract symptoms, for gastrointestinal tract compression, for inhibiting the activity of melanocytes, and for skin and muscle discomfort Used in over-the-counter pharmaceutical compositions as counter-irritants to alleviate. Menthol confectionery can also have a wakefulness effect on the central nervous system and suppress appetite.

  Transient receptor potential cation channel subfamily M member 8 (TRPM8), also known as cold menthol receptor 1 (CMR1), is a protein expressed in sensory neurons, low temperature, and menthol and icilin Activated by a coolant such as Compounds WS-12 and CPS-369 are highly selective agonists of TRPM8.

  Transient receptor potential cation channel subfamily A member 1 (TRPMA1) is a protein expressed on cell membranes or many human and animal cells and is the most sensitive sensor for environmental stimulants, pain, coldness, and elongation. well known. Menthol is a known agonist of TRPA1.

  Weil et al., 2005 show that 0.5% ethanol in the medium inhibits the TRPM8 receptor's response to (-)-menthol by 50%, and that response is almost completely lost at a concentration of 3% ethanol. Reported. Benedikt et al., 2007 confirmed the results of Weil et al., 2005 and pointed out that the activity against in vitro inhibition was methanol <ethanol <isopropanol <butanol. Dimethyl sulfoxide, a solvent with a dielectric constant close to water, was claimed to be less inhibitory. Benedikt et al., 2007, discusses the possible mechanism of ethanol interference with receptor activity, with low molecular weight alcohol being (1) absorbed into the lipid bilayer and severely affecting the mechanical properties of cell membranes. And / or (2) it affects intracellular second messengers such as phosphatidylinositol-4,5-biphosphate, which transmits receptor activation to neuronal signals. These studies are reported in Weil et al., 2005, and Benedikt et al., 2007, show that the solvent medium is important for the biological activity of the coolant.

  Short chain alcohols interact with biological membranes by non-specific physical forces such as interfacial tension, area / molecule mechanical compressibility, and affect the permeability parameters of fluid lipid bilayers. (See, for example, Ly and Longo, 2004). Harris et al., 2008, however, recently compiled evidence for an alternative view, namely the view that ethanol acts on specific “pockets” on the surface of protein receptors to regulate function.

  Animals cannot directly express mental phenomena such as cooling, refreshment, irritation reduction, pruritus, and pain. Receptor assays based on cells that have been transfected with genes for proteins associated with thermoreception (eg, TRPM8 or TRPA1) may be used as surrogate models for sensory processes. Receptor assays provide quantitative data, but these assays do not give information about the onset and cessation of action or the quality of human sensation induced by chemicals. Therefore, the best information regarding the cooling properties of chemicals is derived from direct testing on humans.

  Rowsell et al., 1979 report characterization of N-substituted p-menthane carboxamide on volunteers by placing a filter paper (1 x 1 cm) impregnated with a known amount of the test compound on the dorsal surface of the subject. did. After 30 seconds, subjects were required to report the presence or absence of a cooling effect. These data are reported as “threshold, μg” and refer to the threshold amount of test substance that provides a cooling sensation when applied to the tongue of a group of human volunteers. The average threshold of (-)-menthol for 6 subjects was 0.25 μg, but there was a 100-fold variation in individual sensitivity. Ethanol is frequently used as a solvent in these studies on menthol-like coolants, helping to place the coolant on the filter paper and possibly contributing to variations in individual sensitivity (primary It is now known that ethanol as a solvent interferes with the sense of cooling.

  In the delivery of a coolant to a desired biological target, liquid or partially liquid dermatological preparations (e.g. lotions, creams, ointments) and respiratory tree or oral preparations (e.g. vapors, Spray) requires a solvent for the effective cooling component. Chemicals such as methanol, 1,2-ethanediol, 1,3-propanediol, dimethyl sulfoxide, and butanol are not used in topical (skin) formulations because they are known or potentially harmful. Instead, two or three carbon alcohol solvents such as ethanol, isopropyl alcohol, and racemic 1,2-propanediol are frequently used.

  As described herein, the inventors have found that (R) -1,2-propanediol is not as strongly inhibitory as other alcohol solvents and is therefore ideal for the delivery of chemical coolants. Made a surprising and unexpected discovery that it was an ideal medium. (R) -1,2-propanediol has the advantage of often improving the effectiveness of most coolants by at least a factor of two compared to racemic 1,2-propanediol.

  One embodiment of the present invention relates to a composition (eg, a coolant composition) that includes a coolant dissolved in a solvent that includes (R) -1,2-propanediol.

  Another aspect of the invention relates to a method of preparing a composition (eg, a coolant composition) described herein, the method comprising dissolving the coolant in a solvent.

  Another aspect of the invention relates to a wipe, pad, or wet tissue carrying a composition (eg, a coolant composition) described herein.

  Another aspect of the invention pertains to a reservoir containing a composition (eg, a coolant composition) described herein.

  Another aspect of the invention pertains to cosmetic preparations (eg, eye makeup products) comprising the compositions (eg, coolant compositions) described herein.

  Another aspect of the invention relates to a wash preparation (eg, after shave lotion) comprising a composition described herein (eg, a coolant composition).

  Another aspect of the invention pertains to compositions described herein (eg, coolant compositions) for the treatment of the human or animal body by therapy.

  Another aspect of the present invention relates to a composition (e.g., a coolant composition) described herein for the treatment of sensory discomfort, particularly skin sensory discomfort (e.g. pruritus). To do.

  Another aspect of the present invention includes sensory discomfort described herein, particularly skin, comprising administration of a therapeutically effective amount of a composition described herein (e.g., a coolant composition). Related to methods of treatment of sensory discomfort (eg pruritus).

  Another aspect of the present invention is in the manufacture of a composition (e.g., a coolant composition) for the treatment of sensory discomfort described herein, particularly sensory discomfort (e.g., pruritus) of the skin. Relates to the use of (R) -1,2-propanediol as described herein.

  Another aspect of the invention relates to the use of (R) -1,2-propanediol to improve the cooling activity of a coolant in a liquid composition.

  Another aspect of the invention relates to the use of (R) -1,2-propanediol to improve the effectiveness of the coolant composition.

  Another aspect of the invention pertains to cosmetic preparations (eg, eye makeup products) comprising the compositions (eg, coolant compositions) described herein.

  Another aspect of the invention relates to a wash preparation (eg, after shave lotion) comprising a composition described herein (eg, a coolant composition).

  As will be appreciated by those skilled in the art, the features and preferred embodiments of one aspect of the invention will also relate to other aspects of the invention.

5 coolants, CPS-410 (black circle), CPS-412, all in a solvent mixture of ethanol 1% / (R) -1,2-propanediol 99% (v / v), concentration 5 mg / mL It is a graph of the cooling intensity (unit) according to time (h) after application about (rectangle), CPS-369 (inverted triangle), CPS-368 (white circle), and CPS-411 (triangle). (R) -1,2-propanediol is 0% (v / v) (diamond), 10% (v / v) (square), 20% (v / v) (triangle), or 40% (v / It is a graph of the cooling effect (unit) according to the time (h) after application about the coolant WS-5 with a density | concentration of 10 mg / mL in ethanol which contains v) (circle).

For coolants that do not interfere with biological activity (e.g., their cooling activity) when the (R) -1,2-propanediol topical coolant is to be delivered in a liquid or partially liquid medium It is desirable to have a solvent of

  The inventor has shown that the cooling and sensory properties of the test substance in various solvents can be obtained by dissolving the test substance in the test solvent and using a cotton swab (e.g. Q-tips®) onto the skin surface. It was found that the test can be performed by applying 0.10 to 0.25 mL of the solution one by one. Reliable locations for topical application are above the upper lip (above the lip of the lip), above the person, to the side of the person up to the nasal lip, and below the nose (under the nose) It is skin. This part of the face is known to be innervated densely with cold receptors, second only to the eyeball and anogenital surface. A tingling, cool and cold sensation from the skin can be experienced and graded for onset time and intensity.

As described herein, the present inventors have, for the wide range of coolant, a wide range of alcoholic solvent (i.e., a saturated aliphatic C ₁ -C ₄ alkanes with 1 or 2 hydroxy groups) Studied.

  Surprisingly and unexpectedly, (R) -1,2-propanediol has a variety of coolants compared to other alcohol solvents (including (S) -1,2-propanediol). It has been found that there is virtually no interference with the cooling action, and many other alcohol solvents completely blocked the cooling action. Without wishing to be bound by any particular theory, the inventor believes that this effect is related to the stereospecificity of (R) -1,2-propanediol.

1,2-propanediol is an optically active molecule and has one chiral center, specifically a carbon atom at the 2-position. This chiral center may be in the (R) or (S) configuration, thus giving rise to two enantiomers called (R) -1,2-propanediol and (S) -1,2-propanediol .

A mixture of enantiomers is defined as the molar fraction of the majority enantiomer (f _MAJ ) minus the mole fraction of the minor enantiomer (f _MIN ), the enantiomeric excess (EE). May be described by:

EE = f _MAJ -f _MIN
An equimolar mixture of enantiomers (called a racemic mixture or racemate) has an enantiomeric excess (EE) of zero. Pure enantiomers have an enantiomeric excess (EE) of 1.

As a result, a sample of 1,2-propanediol is
`` Racemic 1,2-propanediol '': an equimolar mixture of (R) -1,2-propanediol and (S) -1,2-propanediol with an enantiomeric excess of 0,
`` (R) -1,2-propanediol '': pure (R) -1,2-propanediol with an enantiomeric excess of 1; or an enantiomeric excess of greater than 0 and less than 1 (R ) -1,2-propanediol, a mixture of (R) -1,2-propanediol and (S) -1,2-propanediol; or `` (S) -1,2-propanediol '': Pure (S) -1,2-propanediol with an enantiomeric excess of 1; or (S) -1,2-propanediol with an enantiomeric excess of greater than 0 and less than 1. It may be described as a mixture of) -1,2-propanediol and (R) -1,2-propanediol.

  In addition, (R) -1,2-propanediol is a relatively safe compound for human use because its racemate is already acceptable as a cosmetic and pharmaceutical solvent (see, eg, Lakind et al., 1999). ) In rodents, the semi-lethal dose of racemic 1,2-propanediol is about 25 mg / kg (body weight), indicating that large doses can be administered orally without imminent risk. Based on studies of intravenous infusion of racemic 1,2-propanediol, the estimated “safe” dose for humans is 1 g / kg (body weight) per day (see, eg, Wilson et al., 2005). In addition, the metabolic pathway of the two enantiomers of 1,2-propanediol produces L- and D-lactic acid, which is then converted to pyruvate and then to acetic acid by natural endogenous mammalian enzymes. (See, for example, Ewaschuk et al., 2005).

  TRPM8 receptor studies predicted that certain alcohols (such as ethanol) could interfere with receptor activation, but the sensation of coolness in humans from chemical coolants Is shown here for the first time.

  The inventors have surprisingly anticipated that (R) -1,2-propanediol is not as strong as other alcohol solvents and is therefore an ideal vehicle for the delivery of chemical coolants. I made a discovery outside. (R) -1,2-propanediol has the advantage of often improving the effectiveness of most coolants by at least a factor of two compared to racemic 1,2-propanediol.

  By specifying (R) -1,2-propanediol as an ideal solvent for coolants, the design and preparation of new liquid and partially liquid formulations for use as topical drugs is possible. It becomes possible.

  For example, experimental studies described herein have shown that a solution of 5 mg / mL CPS-410 in ethanol 1% / (R) -1,2-propanediol 99% (v / v) It is demonstrated to be remarkably powerful and effective on keratinized skin surfaces for the treatment of discomfort, especially pruritus.

  Accordingly, the present invention relates to compositions (eg, coolant compositions) comprising a coolant dissolved in (R) -1,2-propanediol as described herein.

  The invention also relates to the preparation of such compositions and the use of such compositions, for example in therapy, for example in the treatment of sensory discomfort, in particular the sensory discomfort of the skin (eg pruritus).

Coolant Composition One embodiment of the present invention is a composition (eg, a coolant composition) comprising a coolant dissolved in a solvent comprising (R) -1,2-propanediol.

Liquid composition In one embodiment, the composition is a liquid composition (eg, a liquid coolant composition).

  The term `` liquid '' in the conventional sense means a material that has the physical properties of a liquid (compared to the physical properties of a solid or gas) at standard temperature and pressure (i.e., 20 ° C. and 101.325 kPa). Used for writing.

Solvent In one embodiment, the solvent is wholly or mostly (R) -1,2-propanediol.

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

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

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

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

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

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

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

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

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

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

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

In one embodiment, the solvent additionally includes, for example, a relatively small proportion of C ₁ -C ₃ alkanol to improve the solubility of the coolant.

In one embodiment, the solvent is, C ₁ -C ₃ alkanol 0 to 1% (v / v), containing additionally.

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

In one embodiment, the solvent is, C ₁ -C ₃ alkanol 0 to 3% (v / v), containing additionally.

In one embodiment, the solvent is, C ₁ -C ₃ alkanol 0 to 4% (v / v), containing additionally.

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

The term “C ₁ -C ₃ alkanol” is intended to mean a compound of formula R—OH, wherein R is a saturated aliphatic C ₁ -C ₃ alkyl group. C ₁ -C ₃ alkanol is methanol, ethanol, n- propanol, and isopropanol.

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

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

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

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

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

For example, in one embodiment, the solvent is
(R) -1,2-propanediol 95-100% / ethanol 0-5% (v / v)
It is.

For example, in one embodiment, the solvent is
(R) -1,2-propanediol 97-100% / ethanol 0-3% (v / v)
It is.

For example, in one embodiment, the solvent is
(R) -1,2-propanediol 98-100% / ethanol 0-2% (v / v)
It is.

For example, in one embodiment, the solvent is
(R) -1,2-propanediol 99-100% / ethanol 0-1% (v / v)
It is.

Examples of suitable solvents include
(R) -1,2-propanediol 99% / ethanol 1% (v / v),
(R) -1,2-propanediol 98% / ethanol 2% (v / v),
(R) -1,2-propanediol 97% / ethanol 3% (v / v),
(R) -1,2-propanediol 96% / ethanol 4% (v / v), and
(R) -1,2-propanediol 95% / ethanol 5% (v / v),
Is mentioned.

  In one embodiment, the solvent additionally comprises water. A relatively large proportion of water can be included without substantially reducing the cooling activity of the coolant and without substantially inducing precipitation of the coolant.

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

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

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

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

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

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

For example, in one embodiment, the solvent is
(R) -1,2-propanediol 90-100% / ethanol 0-5% / water 0-5% (v / v)
It is.

For example, in one embodiment, the solvent is
(R) -1,2-propanediol 85-100% / ethanol 0-5% / water 0-10% (v / v)
It is.

For example, in one embodiment, the solvent is
(R) -1,2-propanediol 75-100% / ethanol 0-5% / water 0-20% (v / v)
It is.

For example, in one embodiment, the solvent is
(R) -1,2-propanediol 65-100% / ethanol 0-5% / water 0-30% (v / v)
It is.

Further examples of suitable solvents include
(R) -1,2-propanediol 95% / water 5% (v / v),
(R) -1,2-propanediol 94% / ethanol 1% / water 5% (v / v),
(R) -1,2-propanediol 93% / ethanol 2% / water 5% (v / v),
(R) -1,2-propanediol 92% / ethanol 3% / water 5% (v / v),
(R) -1,2-propanediol 91% / ethanol 4% / water 5% (v / v), and
(R) -1,2-propanediol 90% / ethanol 5% / water 5% (v / v),
Is mentioned.

(R) -1,2-propanediol 90% / water 10% (v / v),
(R) -1,2-propanediol 89% / ethanol 1% / water 10% (v / v),
(R) -1,2-propanediol 88% / ethanol 2% / water 10% (v / v),
(R) -1,2-propanediol 87% / ethanol 3% / water 10% (v / v),
(R) -1,2-propanediol 86% / ethanol 4% / water 10% (v / v), and
(R) -1,2-propanediol 85% / ethanol 5% / water 10% (v / v),
Is mentioned.

(R) -1,2-propanediol 80% / water 20% (v / v),
(R) -1,2-propanediol 79% / ethanol 1% / water 20% (v / v),
(R) -1,2-propanediol 78% / ethanol 2% / water 20% (v / v),
(R) -1,2-propanediol 77% / ethanol 3% / water 20% (v / v),
(R) -1,2-propanediol 76% / ethanol 4% / water 20% (v / v), and
(R) -1,2-propanediol 75% / ethanol 5% / water 20% (v / v),
Is mentioned.

(R) -1,2-propanediol 70% / water 30% (v / v),
(R) -1,2-propanediol 69% / ethanol 1% / water 30% (v / v),
(R) -1,2-propanediol 68% / ethanol 2% / water 30% (v / v),
(R) -1,2-propanediol 67% / ethanol 3% / water 30% (v / v),
(R) -1,2-propanediol 66% / ethanol 4% / water 30% (v / v), and
(R) -1,2-propanediol 65% / ethanol 5% / water 30% (v / v),
Is mentioned.

  Optionally, the solvent may further include other liquid components that are possible, for example, in the percentages discussed above. That is, the percentages of the listed components (e.g., (R) -1,2-propanediol, ethanol, and water) may be a total number of less than 100, the remainder being other liquid components, For example, other co-solvents.

  For example, embodiments described as `` (R) -1,2-propanediol 90-100% / ethanol 0-5% / water 0-5% (v / v) '' are also described as `` (R) -1 , 2-propanediol 90-100% / ethanol 0-5% / water 0-5% / other liquid components 0-10% (v / v) '', for example, (R) -1 , 2-propanediol 90% / ethanol 2% / water 3% / other liquid components 5% (v / v).

  Preferably, any such additional liquid components (e.g., other co-solvents) do not substantially interfere with the cooling activity of the coolant and do not substantially reduce the solubility of the coolant in the solvent (e.g., Does not substantially induce precipitation of the coolant from the solvent).

  However, in one embodiment, the solvent (as described herein) does not include other liquid components. That is, the solvent includes only those listed as liquid components (e.g., (R) -1,2-propanediol only; (R) -1,2-propanediol and ethanol only, respectively; ) -1,2-propanediol and water only; (R) -1,2-propanediol, ethanol and water only) (e.g., each consisting essentially of (R) -1,2-propanediol; Consisting essentially of (R) -1,2-propanediol and ethanol; consisting essentially of (R) -1,2-propanediol and water; consisting essentially of (R) -1,2-propanediol, Ethanol and water). In this case, the percentages of the listed components (eg (R) -1,2-propanediol, ethanol, and water) must total a number of 100.

For the avoidance of doubt, the term `` (v / v) '' is a conventional means of volume fraction based on the volume before mixing, measured at standard temperature and standard pressure (i.e. 20 ° C and 101.325 kPa). In the sense, it is used herein. Fluid prepared by mixing volume V _A of the component A and the volume V _B of component B may be described as a mixture of "AX% / BY% (v / v) ",
X = {V _A / (V _A + V _B )} × 100
Y = {V _B / (V _A + V _B )} × 100
It is.

  For example, a liquid prepared by mixing 99 mL of (R) -1,2-propanediol with 1 mL of ethanol is `` (R) -1,2-propanediol 99% / ethanol 1% (v / v) '' May be described as a mixture of

  Unless otherwise specified, in the context of the solvents used in the compositions of the invention described herein (e.g., coolant compositions), `` (R) -1,2-propanediol '' References herein to are intended to mean (R) -1,2-propanediol with an enantiomeric excess of 0.50 to 1.00.

  For example, “(R) -1,2-propanediol 95% / ethanol 5% (v / v)” means, for example, a liquid mixture obtained when 95 mL of 1,2-propanediol is mixed with 5 mL of ethanol. Meaning, this 1,2-propanediol is (R) -1,2-propanediol with an enantiomeric excess of 0.50 to 1.00.

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

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

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

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

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

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

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

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

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

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

  In one embodiment, (R) -1,2-propanediol has an enantiomeric excess of 1.00.

Coolant In one embodiment, the coolant is (R) -2-[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid C ₁ -C _4. It is an alkyl ester.

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

  In one embodiment, the coolant is CPS-368.

  In one embodiment, the coolant is CPS-369.

  In one embodiment, the coolant is CPS-410.

  In one embodiment, the coolant is CPS-411.

  In one embodiment, the coolant is CPS-412.

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

  In one embodiment, the coolant is WS-5.

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

  In one embodiment, the coolant is WS-3.

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

  In one embodiment, the coolant is trialkylphosphine oxide.

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

  In one embodiment, the coolant is p-menthyl lactate.

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

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

Coolant Content In one embodiment, the coolant is dissolved in the solvent at a concentration of 0.5-20 mg / mL. In other words, the composition comprises a coolant dissolved in a solvent at a concentration of 0.5-20 mg / mL.

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

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

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

  In one embodiment, the concentration is 3 mg / mL.

  In one embodiment, the concentration is 4 mg / mL.

  In one embodiment, the concentration is 5 mg / mL.

  In one embodiment, the concentration is 6 mg / mL.

  In one embodiment, the concentration is 7 mg / mL.

  In one embodiment, the concentration is 8 mg / mL.

  For the avoidance of doubt, the concentration is measured at standard temperature and standard pressure (ie 20 ° C. and 101.325 kPa).

Some preferred compositions As a formulation for topical administration to the skin, suitable, preferred compositions have 2-10 mg / mL of a coolant (e.g., CPS-410 or CPS-412) dissolved (R ) -1,2-propanediol 95% to 100% / ethanol 0-5% (v / v).

  As a formulation for topical administration to the skin, suitable and more preferred compositions are those in which 2 to 10 mg / mL of a cooling agent (e.g. CPS-410 or CPS-412) is dissolved (R) -1,2 -Contains a solvent that is a mixture of propanediol 97-100% / ethanol 0-3% (v / v).

  Suitable as a formulation for topical administration to the skin, the most preferred composition is (R) -1,2-propanediol 99% / ethanol 1% (v / v) with 5 mg / mL CPS-410 dissolved. v) containing a solvent that is a mixture.

  Purified water can be added to such a solution discussed above without substantial loss of cooling activity and without substantially inducing precipitation of the coolant.

  Such formulations have the advantage of being easy to manufacture, easy to package, and deliverable in smaller volumes.

  Such a formulation distributes the active ingredient evenly on the skin, but the sensation of “greasy” or sticking to the skin (unusual effects often seen with standard topical excipients such as petrolatum and mineral oil) ) Is not given.

Combinations Certain features of the invention have been described in the context of separate embodiments for clarity, but it will be understood that they may be provided in combination in a single embodiment. On the contrary, the various features of the invention have been described in the context of a single embodiment for the sake of brevity, but may also be provided separately or in any suitable subcombination. . For example, all combinations of embodiments relating to solvents, solvent constituents and their amounts / proportions, coolants, and coolant concentrations are specifically included by the present invention, and each and every such combination is specifically included. , As disclosed individually and explicitly.

The relatively simple composition described above with additional components (including coolant, (R) -1,2-propanediol, ethanol, and optionally water) is useful and effective, but others Pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, antioxidants, lubricants, stabilizers, solubilizers, surfactants (e.g., wetting agents) It may be desirable to include other conventional agents in the composition, such as masking agents, coloring agents, flavoring agents, and sweetening agents.

  As used herein, the term “pharmaceutically acceptable” refers to the subject in question within the scope of sound medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications. Related to compounds, ingredients, materials, compositions, dosage forms, etc. that are appropriate for use in contact with other tissues and that have a reasonable proportion of benefit / risk. Each carrier, diluent, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.

  Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts such as Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990 and Handbook of Pharmaceutical Excipients, 5th edition, 2005. Can be found in

  The formulation may be prepared by any method well known in the pharmaceutical art. In general, formulations are prepared by uniformly and intimately bringing into association the various ingredients and then, if necessary, shaping the product.

  The formulation is suitably, for example, a solution, solution (e.g., aqueous, non-aqueous), suspension (e.g., aqueous, non-aqueous), emulsion (e.g., oil-in-water, water-in-oil), elixir, Syrup, electuary, mouthwash, drop, capsule, gel, paste, ointment, liniment, cream, lotion, oil, foam, spray, mist, or aerosol It may be in form.

  Lozenges typically contain the main ingredients in a flavored base, usually sucrose and acacia or tragacanth. Pastel agents typically include the major components in an inert matrix such as gelatin and glycerin, or sucrose and acacia. Oral cleansers typically contain the major components in a suitable liquid carrier. Ointments are typically prepared from the main ingredients and a paraffinic or water-miscible ointment base. Creams are typically prepared from the main ingredients and an oil-in-water cream base. Emulsions are typically prepared from the main ingredients and an oily phase and may contain only emulsifiers (also known as emulgents), or the emulsions may be fats or oils, or A mixture of both fat and oil and at least one emulsifier may be included.

  Formulations suitable for topical (intranasal) administration include, for example, nasal sprays, nasal drops, and aerosols (eg, administered by nebulizer). Formulations suitable for topical (ocular) administration include eye drops. Suitable formulations for topical (pulmonary) administration (e.g., by inhalation or insufflation therapy) include suitable high pressure gases such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. Can be provided as aerosol sprays from pressurized packs.

  The formulation may further include other active agents, such as other cooling agents.

In one embodiment suitable for administration , the composition is suitable for topical administration.

  In one embodiment, the composition is suitable for topical administration to the skin, eg, topical administration to human skin.

  In one embodiment, the composition is suitable for topical administration to the scalp, eg, topical administration to a human scalp.

  In one embodiment, the composition is suitable for topical administration to the mucosa, eg, topical administration to the human mucosa.

  In one embodiment, the composition is suitable for topical administration to the eye, eg, topical administration to the human eye.

  In one embodiment, the composition is suitable for topical administration to the nose, eg, to the human nose.

  In one embodiment, the composition is suitable for topical administration in the mouth, eg, topical administration in the human mouth.

  In one embodiment, the composition is suitable for topical administration to the esophagus, eg, topical administration to the human esophagus.

  In one embodiment, the composition is suitable for topical administration to the pharynx, eg, topical administration to the human pharynx.

  In one embodiment, the composition is suitable for topical administration to the anal genitalia, for example, topical administration to the human anal genitalia.

Method of Preparing the CompositionAnother aspect of the present invention is that a solvent comprising (R) -1,2-propanediol (as described herein) contains a coolant (described herein). A method of preparing a composition (e.g., a coolant composition as described herein).

Medical Use The coolant compositions described herein are useful, for example, in the treatment of sensory discomfort in humans, as described herein.

Uses in Methods of Therapy Another aspect of the present invention relates to the coolant compositions described herein for use in methods of treatment of the human or animal body by therapy.

Uses in the manufacture of drugs Another aspect of the present invention relates to the use of (R) -1,2-propanediol in the manufacture of a medicament comprising a coolant composition for use in therapy.

Method of Treatment Another aspect of the present invention relates to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a coolant composition described herein.

In one embodiment of the indication (eg, an embodiment of a method of treatment, of use in a method of therapy, of use in the manufacture of a drug), the treatment is treatment or prevention of sensory discomfort.

  In one embodiment (eg, an embodiment of a method of treatment, of use in a method of therapy, of use in the manufacture of a drug), the treatment is treatment or prevention of sensory discomfort in the skin.

In one embodiment (e.g., a therapeutic method embodiment, for use in a method of therapy, for use in the manufacture of a drug), the treatment comprises
(a) irritation, pruritus and / or pain associated with dermatitis (e.g., atopic dermatitis, contact dermatitis, irritant dermatitis, allergic dermatitis, seborrheic dermatitis),
(b) Burned, traumatic, diseased, anoxic and / or irritated skin (e.g., fluoroscopy during image intensive procedures such as laser surgery, angioplasty, diabetic ulcers) , Pain associated with sunburn, radiation, and / or skin damaged by treatment on wound debridement),
(c) pruritus and / or discomfort associated with skin infections, insect bites, sunburns, shavings, hair loss, and / or photodynamic treatment of the skin (e.g., sun keratosis, basal cell carcinoma),
(d) Psoriasis (frequently seen in the elderly) and / or pruritus associated with psoriasis,
(e) mucositis, stomatitis, cheilitis and / or itching of the lips associated with, for example, cold sores and / or gingivitis,
(f) Perianal pruritus, hemorrhoid discomfort, pain associated with anal tears, pain and / or pruritus associated with hemorrhoids, pain associated with hemorrhoidectomy, perineal inflammation, anogenital dermatitis And / or discomfort associated with local causes such as incontinence, diaper rash, and / or perineal inflammation,
(g) vulvar pruritus, vulvar pain (e.g. candidiasis, vulvar vestibular inflammation, vulvar pain, sexual pain, anogenital infection (e.g. warts and / or sexually transmitted diseases), Associated with viral infections of the skin (especially in immunocompromised patients), or
(h) nose discomfort, nasal discomfort associated with respiratory obstruction (e.g., congestion, rhinitis, asthma, bronchitis, emphysema, chronic obstructive pulmonary disease, dyspnea, sleep apnea, and / or snoring), And / or sensory discomfort of upper airway discomfort,
Treatment or prevention.

  In one embodiment (eg, a therapeutic method embodiment, for use in a method of therapy, for use in the manufacture of a drug), the treatment is treatment or prevention of pruritus in a dog.

The term “treatment” as used herein in the context of treating a therapeutic disorder generally relates to human therapy and therapy, in which some desired therapeutic effect, eg, of the disorder, Progression inhibition is achieved and the desired therapeutic effect includes a decrease in the rate of progression, cessation of progression rate, alleviation of the symptoms of the disorder, amelioration of the disorder, and healing of the disorder. Treatment as a preventive measure (ie, prophylaxis) is also mentioned. For example, use of a patient who has not yet suffered a disorder but is at risk of having a disorder is included in the term “treatment”.

  For example, treatment includes prevention of pruritus, reducing the incidence of pruritus, alleviating pruritus symptoms and the like.

  As used herein, the term “therapeutically effective amount” is intended to provide some desired therapeutic effect that is balanced by a reasonable proportion of benefit / risk when administered in accordance with the desired therapeutic regimen. Related to the amount of a composition (e.g., a coolant composition described herein) or a dosage form (e.g., including a coolant composition described herein) that is effective for To do.

Subject / Patient In one embodiment, the subject / patient is a human.

  In one embodiment, the subject / patient is a mammal (eg, in a veterinary treatment of a dog, eg, canine dermatitis).

Route of administration In one embodiment, administration is topical administration (ie, at the site of desired action).

  In one embodiment, administration is topical administration to the skin, eg, to human skin.

  For example, the coolant composition is preferably administered topically on the surface of one or both elbows and / or one or both knees (e.g. in the treatment of pruritus for eczema and psoriasis). Good.

  In one embodiment, the administration is topical administration to the scalp, for example to the human scalp.

  For example, the coolant composition may preferably be administered topically to some or all of the scalp (eg, in the treatment of psoriasis and contact dermatitis).

  In one embodiment, administration is topical administration to the mucosa, eg, to the human mucosa.

  In one embodiment, administration is topical administration to the eye, eg, to the human eye.

  In one embodiment, administration is topical administration to the nose, eg, to the human nose.

  In one embodiment, administration is topical administration to the mouth, eg, to the human mouth.

  In one embodiment, administration is topical administration to the esophagus, eg, to the human esophagus.

  In one embodiment, administration is topical administration to the pharynx, eg, to the pharynx of a human.

  In one embodiment, the administration is topical administration to the anogenital organ, eg, to the human anogenital organ.

The liquid cooling composition from the delivery-reservoir may be delivered as liquid, for example from a reservoir, such as a bottle or tube, fitted with a suitable dispensing tip or nozzle.

  Accordingly, another aspect of the present invention is a storage container comprising a coolant composition as described herein.

Delivery-wipes, pads, and wet tissue cooling compositions are, for example, wipes, pads, as delivered in many commercially available cleaning products (e.g., Cottony Cloths, Supreme and Soft Cloths, Supreme from CVS Pharmacy) Or it may be delivered by wet tissue.

  Accordingly, another aspect of the present invention is a wipe, pad, or wet tissue that carries a coolant composition as described herein.

  In one embodiment, a wipe, pad, or wet tissue is suitable for use in topical administration of a coolant composition to a human.

The term combination therapy “treatment” includes combination therapy and combination therapy, where two or more therapies or therapies are combined, for example, sequentially or simultaneously. For example, the coolant compositions described herein may also be used in combination therapy, for example, in conjunction with other agents.

  One aspect of the present invention is a coolant as described herein further comprising or in combination with one or more (eg, one, two, three, four, etc.) additional therapeutic agents. Related to the composition.

  The particular combination will be at the discretion of the physician selecting a dosage using common general knowledge and dosing regimens known to those skilled in the art.

  The drugs (i.e., one or more other drugs in addition to the coolant composition described herein) may be administered simultaneously or sequentially, individually administered by a variety of administration schedules and various routes. May be.

  The drugs (ie, one or more other drugs in addition to the coolant composition described herein) may be formulated together in a single dosage form, or individual drugs may be separated And may be provided together in the form of a kit, optionally with instructions for use.

One embodiment of the kit the present invention, (a) for example, in a suitable container and / or suitable packaging, preferably provided, the cooling compositions described herein, and (b) the use For the kit, including written instructions on how to administer the coolant composition.

  The written instructions may also include a list of indications for which the coolant composition is an appropriate treatment.

Further Uses Another aspect of the invention relates to the use of (R) -1,2-propanediol to improve the cooling activity of the coolant in the liquid composition.

  For example, replacing (R) -1,2-propanediol with some or all of the solvent present in a liquid composition comprising a coolant can reduce the cooling activity of the resulting coolant in the composition. It can be improved or greatly improved.

  In this way, the recipe for the formulation can be replaced with (R) -1,2-in place of some or all of the solvents in the recipe to improve the cooling activity of the coolant in the resulting composition. It may be modified to use propanediol.

  Similarly, for compositions that already contain 1,2-propanediol (e.g., racemic 1,2-propanediol), the addition of (R) -1,2-propanediol results in the resulting composition The cooling activity of the coolant in it can be improved or greatly improved.

  Thus, the recipe for the formulation should contain (R) -1,2-propanediol in addition to the solvent in the recipe to improve the cooling activity of the coolant in the resulting composition. It may be modified.

  Another aspect of the invention relates to the use of (R) -1,2-propanediol to improve the effectiveness of the coolant composition.

  For example, by replacing (R) -1,2-propanediol with some or all of the solvent present in a liquid composition containing a coolant, the volume of the composition having the same cooling effect is reduced. It may be possible to do.

  Thus, the recipe for the formulation should include (R) -1,2-propanediol to improve the efficacy of the resulting composition (and allow for smaller volume administration). And / or (R) -1,2-propanediol may be modified to replace some or all of the solvent present.

  The coolant compositions described herein may also be used in the preparation of cosmetics and toiletries. (R) -1,2-propanediol may be included in the formulation to improve the cooling activity of the coolant therein and / or improve the cooling efficacy of the formulation. In this way, the cooling and refreshing effects associated with these formulations are enhanced.

  Another aspect of the invention relates to a wash preparation (eg, after shave lotion) comprising a composition described herein (eg, a coolant composition).

  For example, the recipe for after shave lotion may include (R) -1,2-propanediol to improve the cooling activity of the coolant therein and / or improve the cooling effectiveness of the after shave lotion. And / or (R) -1,2-propanediol may be modified to replace some or all of the solvent present. In this way, the cooling and refreshing effects associated with aftershave lotion are enhanced.

  Another aspect of the invention pertains to cosmetic preparations (eg, eye makeup products) comprising the compositions (eg, coolant compositions) described herein.

  For example, preparations for removing cosmetics from the eyelids, preparations for applying eye makeup with irritating properties, and / or preparations for applying substances that extend eyelashes faster (e.g. Latisse®) The recipe includes (R) -1,2-propanediol and / or (R) to improve the cooling activity of the coolant therein and / or to improve the cooling efficacy of the preparation. Modifications may be made to replace 1,2-propanediol with some or all of the solvent present. In this way, the cooling and refreshing effects associated with the preparation are enhanced.

Research and examples
material
(R) -1,2-propanediol (EE, at least 0.98), (S) -1,2-propanediol (EE, at least 0.98), 1,3-propanediol, and racemic 1,3-butane The diol was purchased from Sigma-Aldrich Co. Ethanol, n-propanol, isopropanol, and racemic 1,2-propanediol were obtained from local vendors.

The following coolants were selected for testing.

  These coolants, other structurally similar coolants, and methods for synthesis are further described in U.S. Patent Application Publication No. 2008/0227857 A1 (September 18, 2008) and Bodding et al., 2007. Have been described.

In a toxicological screening preliminary study, several major cooling agents were evaluated for toxicity in young adult male rats. The coolant was dissolved in ethanol 3% / racemic 1,2-propanediol 97% (v / v) and injected subcutaneously at 30 mg / kg daily for 5 days. Body weight was monitored and on day 6, animals were euthanized by pentobarbital sodium overdose and liver and heart weights were measured. None of the treated animals died during the treatment. The results are summarized in the following table. “N” is the number of reproductions.

  For CPS-412, there was no significant change in organ weights, except perhaps liver weight. Test doses in the human assay ranged from 1-2 mg for one subject, one test. The test dose studied in the toxicological study was 30 mg / kg (body weight) for 5 days. It was determined that the human assay did not cause a significant safety risk.

Skin Assay For the assay on skin, the coolant was dissolved in an alcohol solvent to produce a test solution with a coolant concentration of 2, 2.5, 3, 5, 10, or 20 mg / mL.

  Using a cotton swab (e.g., Q-tips®), place 0.10-0.25 mL of test solution on the skin above the upper lip, the skin above the person, the side of the person up to the nasal lip Applied to the skin and noted the onset and duration of the cooling sensation.

  The intensity of the subjective skin sensation was divided into 0, 1, 2, or 3 grades. 0 is no change, 1 is slight cool, cold, or tingling, 2 is a clear signal of cool, cold, or tingling, and 3 is strong cooling or cold. The interval for recording sensations was 5 to 10 minutes unless zero was obtained at least twice in succession. The result was the average of 3-6 separate trials on the same individual. “Start” is the time taken to reach the cooling intensity value of 2. If the test solution did not reach the value of 2, it was considered inert. “Stop” is when the cooling intensity drops below 2, and “duration” is the time obtained by subtracting the start time from the stop time. The area under the curve (AUC) can also be obtained from the plot data using SigmaPlot (Systat Software, Point Richmond CA), assessing the intensity and duration of drug action. AUC is, on average, expressed in ± S.E.M. Units and is the product of cooling intensity and time (minutes). Thus, if an AUC value of 180 is obtained, even if the overall duration of the effect is longer, e.g. 75 minutes, due to the time taken to start and stop the coolness, Means accumulated for at least 60 minutes.

Skin research 1
Two powerful coolants, CPS-410 and CPS-369, were studied for several different alcohol solvents using the skin assay described above. Concentrations were 5 mg / mL for CPS-410 and 10 mg / mL for CPS-369. The results are summarized in the following table.

  The data demonstrate that the use of alcohols with one hydroxyl group (i.e., ethanol, n-propanol, and isopropanol) resulted in a loss of cooling activity for CPS-410 and CPS-369. ing.

  Also, the use of certain dihydroxy alcohols (ie 1,3-propanediol and racemic 1,3-butanediol) resulted in a significant loss of cooling activity.

  Among the 1,2-propanediols, (R) -1,2-propanediol is surprisingly and unexpectedly the best for retaining the cooling action of CPS-410 and CPS-369. It was a solvent. Based on AUC, the (S) -1,2-propanediol solution is only 27% of the CPS-410 activity and only 47% of the CPS-69 activity of the corresponding (R) -1,2-propanediol solution. There wasn't.

Skin research 2
Racemic 1,2-propanediol (propylene glycol) is the standard solvent for many cosmetic and dermatological formulations. The activity of several coolants in racemic 1,2-propanediol was compared to (R) -1,2-propanediol and the results are summarized in the following table. A small proportion of ethanol was included in the solvent mixture to facilitate dissolution of the coolant. (Activity was measured in terms of AUC and reported ± SEM; P <0.01 t-test.)

  The data demonstrate that in each case, the use of the (R) enantiomer of 1,2-propanediol as a solvent provides higher cooling activity than the use of racemic 1,2-propanediol. ing. For 6 of the 7 compounds tested, the cooling activity was about twice as high in (R) -1,2-propanediol than in racemic 1,2-propanediol.

  It has not previously been recognized that “bulk” solvents can have such a strong effect on the activity of a coolant in vivo. The preferred properties of (R) -1,2-propanediol as a solvent are unexpected, surprising and practical. For example, in formulation design, (R) -1,2-propanediol solvent requires 50% less coolant than racemic 1,2-propanediol to achieve the same cooling effect. become. Conversely, in situations where it is desirable to reduce the volume of solvent in the formulation, the use of (R) -1,2-propanediol can reduce the required volume by about 50%, but to the same extent Cooling can be achieved.

  Many coolants are more soluble in ethanol than in 1,2-propanediol. For example, WS-3 and CPS-369 are soluble in absolute ethanol at> 300 mg / mL and> 500 mg / mL, respectively. These compounds are difficult to dissolve in 1,2-propanediol and have a solubility of about 10 mg / mL under standard conditions.

  It is advantageous to use a solvent mixture of (R) -1,2-propanediol with up to 5% ethanol (v / v) to formulate a liquid composition of coolant. These amounts of ethanol can be included without significant loss of cooling activity.

  Even though in vitro experiments suggest that such low concentrations of ethanol interfere with receptor activation, based on the experiments, solvent mixtures (ethanol 1% / (R) -1,2-propanediol 99% (v / v) to ethanol 3% / (R) -1,2-propanediol 97% (v / v)), the ethanol added to (R) -1,2-propanediol is It has been found that it does not significantly affect the strength or duration of the cooling action of the coolant dissolved therein.

  Compared to 2.5 mg / mL 106 ± 12 (AUC) CPS-369 in a solvent mixture of ethanol 1% / (R) -1,2-propanediol 99% (v / v) in human assays, A solution of 2.5 mg / mL CPS-369 in 100% (R) -1,2-propanediol showed an activity of 107 ± 13 (AUC). Therefore, ethanol 1% (v / v) did not affect the cooling effect of CPS-369.

  Figure 1 shows five coolants, CPS-410 (black circles), all having a concentration of 5 mg / mL in a solvent mixture of ethanol 1% / (R) -1,2-propanediol 99% (v / v). , CPS-412 (rectangle), CPS-369 (inverted triangle), CPS-368 (white circle), and CPS-411 (triangle) for the cooling intensity (unit) according to the time (h) after application is there.

Skin research 3
(-)-Menthol is the most widely used coolant in commercial use. (-)-Menthol is present in various numbers of liquid or semi-liquid preparations such as Ben-Gay® ointment, IcyHot® medicated patch, and Vicks Vaposteam Liquid Medicaiton. Although the effect of (-)-menthol on the sensory system is complex, one of the target receptors is thought to be the TRP-M8 receptor. The cooling effect of (−)-menthol (10 mg / mL) in the human assay was compared to (−)-menthol dissolved in 1,3-propanediol or (R) -1,2-propanediol. The cooling duration was 13 ± 1 minutes for 1,3-propanediol and 21 ± 2 minutes for (R) -1,2-propanediol (P <0.001), showing a significant difference. Apparently, (−)-menthol has a higher cooling activity when dissolved in (R) -1,2-propanediol than with 1,3-propanediol.

Skin research 4
You may be asked why the activity of the chemical coolant is improved or maximized in the presence of (R) -1,2-propanediol. That is, what is the mechanism of action that explains the difference between (R) -1,2-propanediol and other 2 or 3 carbon alcohols? Without wishing to be bound by any particular theory, the inventor suggested that the simplest explanation is that activation of the TRP-M8 receptor is inhibited by ethanol and other alcohols because of its stereospecific orientation. Is not inhibited by (R) -1,2-propanediol and / or (R) -1,2-propanediol is an antagonist at the alcohol binding site on the TRP-M8 receptor I believe that.

  In pharmacological terms, an antagonist is a chemical that blocks the action of an agonist without itself producing an effect. Thus, ethanol, for example, acts as an agonist to inhibit activation of TRP-M8, and the antagonist itself blocks the agonistic effect of ethanol without producing any alternative in receptor function . Antagonists that block inhibitory agonists will also have a net effect of enhancing coolness. (R) -1,2-propanediol can antagonize / block the ethanol binding site of TRP-M8. The level of nerve endings that feel cold in the body can be an endogenous alcohol that inhibits the coolness receptor, such as ethanol or glycerol, and such inhibition is then (R) -1,2 -Antagonized by propanediol.

  To test this hypothesis of antagonism, (R) -1,2-propanediol was added at 0%, 10%, 20%, and 40% (v / v) with WS-5 (known coolant ) To an ethanol solution containing 10 mg / mL. WS-5 at 10 mg / mL in 100% ethanol did not produce any cooling effect when applied in humans. However, (R) -1,2-propanediol reversed ethanol inhibition in a dose-dependent relationship. The data is illustrated in FIG. These data provide strong evidence that (R) -1,2-propanediol is an antagonist at the ethanol binding site of TRP-M8.

  FIG. 2 shows that (R) -1,2-propanediol is 0% (v / v) (diamond), 10% (v / v) (square), 20% (v / v) (triangle), or 40 It is a graph of the cooling effect (unit) according to time (h) after application about refrigerant | coolant WS-5 with a density | concentration of 10 mg / mL in ethanol containing% (v / v) (circle).

  Another coolant, WS-3, is widely used in cosmetics, toothpaste, and food. WS-3 dissolved in absolute ethanol at 20 mg / mL did not produce significant cooling when applied in humans. However, when WS-3 dissolved in ethanol 3% / (R) -1,2-propanediol 97% (v / v) at 20 mg / mL, it is tingling, stinging with a needle Along with the sensation, it produced a strong cooling lasting 38 ± 3 minutes. As shown in the data discussed above, WS-3 is much less active when dissolved in racemic 1,2-propanediol than (R) -1,2-propanediol. Thus, the solvent carrier is a major determinant of biological activity.

Skin research 5
The cooling properties of certain trialkylphosphine oxides were first described by Rowsell et al., 1978. For example, see the compounds defined in columns 1 and 58 to column 25 and listed in the tables in columns 3 and 4.

  The coolants CPS-147 and CPS-148 are members of this class of compounds (trialkylphosphine oxides). CPS-147 and CPS-148 include, for example, (−)-menthol derivatives represented by WS-3, WS-5, CPS-368, CPS-369, CPS-410, CPS-411, and CPS-412. Chemically different. The binding site of trialkylphosphine oxide on the TRP-M8 receptor is not known. From the data discussed above, both CPS-147 and CPS-148, when formulated in (R) -1,2-propanediol, compared to racemic 1,2-propanediol, It can be understood that there is more activity. This is a new and unexpected finding.

Patient study 1
A 34-year-old man with 8 years of psoriasis vulgaris complained of some skin lesions that were itchy and burning and would not let him sleep at night. His condition was severe and chronic. His mother complained that the bedroom had to be vacuumed every day to get rid of the exfoliated skin necrotic tissue. Upon examination, this individual had several silvery, scaly lesions on the elbow and knee surfaces, which were a rectangular area of about 2 cm x 4 cm with diffuse redness and wet appearance. He did not bother him as much as the skin lesion on the right. He volunteered to try a CPS-148 solution (CPS-148 (w / w) 2% in ethanol 1% / (R) -1,2-propanediol 99% (v / v)) and swab With a swab stick (Q-tip ™), instructions were given on how to apply the solution to the site of pruritus. He declared that after the first application at night, the burning sensation and pruritus disappeared within 5-10 minutes and he was able to sleep well. He kept using the solution “as needed” for a month and asserted that he slept better. Subsequently, this individual was treated with Enbrel®, and his psoriasis condition improved considerably and there was no longer a need for topical antipruritic drugs.

Patient study 2
A 21-year-old woman had atopic eczema since she was 4 years old. Over the years, she has controlled the symptoms of this condition (mainly skin pruritus on the knee and elbow curvature) through the use of emollient creams / ointments and less potent steroidal drugs. I knew how to do it. She was particularly wary of more potent steroids because these drugs made the skin thinner, more easily destroyed, and more likely to develop rashes and acne-like papules. She has a busy social schedule, and going to parties, movies, plays, concerts, and weddings, and violently scratching in public is not socially elegant, so around the nape and under the earlobe. I was particularly worried by my niece. She added 2mL of CPS-410 solution (ethanol 1% / (R) -1,2-propanediol 99% (v / v) CPS-410 5mg / mL) wet tissue (rectangular cotton 0.4 g, CS-being, Daizo Corporation, Japan). The wet tissue was individually sealed with a vacuum apparatus and stored in a refrigerator (Foodsaver®, Jarden Corp.). By using this medicated wet tissue for this subject, the pruritus was successfully controlled. She stated that wet tissue could be used sparingly "as needed" and that the solvent did not leave a glowing residue on the skin. She said she now feels more confident in public places.

Patient study 3
A 60-year-old from California visited a botanical garden in Hong Kong in July. His American-style eating habits may have caused a body odor that attracted insects. Because he was stabbed everywhere in his arms and legs, and after the stab, he averaged 4 points per cm ² , covering at least 8% of the limb surface. This individual is able to control CPS-410 solution (ethanol 1% / (R) -1,2-propanediol 99% (v / v) in CPS-410 solution to control irritation, itch and pain from insect bites. -410 agreed to try 5mg / mL). He dipped into the solution using a plastic chopstick and applied the solution evenly on the skin. Surprisingly, pruritus was significantly reduced within 3 minutes after application. This individual was still scratching the skin, but he was scratching more gently and gradually. He controlled pruritus with the test solution followed by 1% hydrocortisone cream.

Patient study 4
A 64-year-old man developed severe itching (contact dermatitis) on the scalp of the skull base after using a hair dye. Using a cotton swab, apply CPS-410 solution (5 mg / mL CPS-410 in ethanol 1% / (R) -1,2-propanediol 99% (v / v)) or CPS- 412 solution (ethanol 1% / (R) -1,2-propanediol 99% (v / v) in CPS-412 5 mg / mL) was applied. Itching was suppressed within 5 minutes of application of both solutions, and this effect lasted for at least 8 hours. In a second experiment, the solution was applied using a plastic bottle with a conical Yorker spout. This bottle provided more accurate droplet delivery of the solution to the site of pruritus. The CPS-410 solution provided a sensation of coolness after application, which was not as pronounced as with CPS-412. After 2 days of application, spaced approximately 10 hours apart, pruritus no longer existed. These results are surprising because the scalp is thick (compared to human skin) and the receptor for temperature reception is located at the junction of the epidermis and subcutaneous tissue, at least 1 mm below the skin surface. Met. These results are potentially important for the management of scalp psoriasis, and pruritus and burning sensation during scalp lesions is sometimes a source of tightness and discomfort.

Patient study 5
An 87-year-old man lived in a small hotel suite in Hong Kong. He suffered from pruritus of dry skin on the back and legs. This condition worsened during the summer, when the air conditioning in his room was sometimes unpredictable and room temperature fluctuations caused excessive sweating. The skin was irritated and itchy. The skin patch was sore when macerated and scratched. His dermatologist prescribed a fluocinolide 0.05% cream, which caused infectious ulcerative lesions that had to be treated with topical antibiotics. He tried 0.5% (w / w) CPS-410 of the ointment and felt some relief. However, he complained about the “greasy” feel of the ointment, especially when sweating. He agreed to try a CPS-410 solution (5 mg / mL CPS-410 in 99% (v / v) ethanol 1% / (R) -1,2-propanediol). The solution was applied with a cotton swab and he was found to have no “greasy” sensation, and the pruritus was quickly relieved. He was able to sleep well. He currently uses this solution regularly. By not scratching the lesion too much, the integrity of the skin has improved and he is much more satisfied.

Patient study 6
A 45-year-old woman was cooking fish soup. When moving the hot contents from pan to pan, she accidentally sprinkled boiled soup on the palmar surface of the forearm. After rinsing her arms with cold water, she complained of sharp pain and CPS-410 solution (ethanol 1% / (R) -1,2-propanediol 99% (v / v) CPS-410 5mg / mL) could be tested. Pain was suppressed within 3 minutes after application, but returned after 2 hours. She applied the solution again, but this time over a wider area spanning the dermis of the forearm. The pain was completely attenuated and she “forgot” that she was uncomfortable. The burn itself recovered in 24 hours. It was also observed that the degree of redness and swelling caused by the burn was reduced by the applied solution.

  While the invention has been described above in conjunction with the preferred specific embodiments, the description and examples are intended to illustrate the invention and are defined by the appended claims. It should be understood that it is not intended to limit the scope of the invention.

(Reference)
Several articles are cited above to more fully describe and disclose the present invention and the state of the art to which the present invention pertains. Each of these references is hereby incorporated herein by reference in its entirety to the same extent as each individual reference is specifically and individually indicated and incorporated by reference.

Claims (53)

  A composition comprising a cooling agent dissolved in a solvent containing (R) -1,2-propanediol. The solvent is
(R) -1,2-propanediol 95-100% (v / v), and
C ₁ -C ₃ alkanol 0~5% (v / v)
The composition of claim 1 comprising: The solvent is
(R) -1,2-propanediol 95-100% (v / v) and ethanol 0-5% (v / v)
The composition of claim 1 comprising: The solvent is
(R) -1,2-propanediol 97-100% (v / v) and ethanol 0-3% (v / v)
The composition of claim 1 comprising: The solvent is
(R) -1,2-propanediol 99-100% (v / v) and ethanol 0-1% (v / v)
The composition of claim 1 comprising: The solvent is
(R) -1,2-propanediol 65-100% (v / v)
C ₁ -C ₃ alkanol 0 to 5% (v / v), and 0-30% water (v / v)
The composition of claim 1 comprising: The solvent is
(R) -1,2-propanediol 65-100% (v / v)
Ethanol 0-5% (v / v) and water 0-30% (v / v)
The composition of claim 1 comprising: The solvent is
(R) -1,2-propanediol 75-100% (v / v)
Ethanol 0-5% (v / v) and water 0-20% (v / v)
The composition of claim 1 comprising: The solvent is
(R) -1,2-propanediol 85-100% (v / v)
Ethanol 0-5% (v / v) and water 0-10% (v / v)
The composition of claim 1 comprising: The solvent is
(R) -1,2-propanediol 90-100% (v / v)
Ethanol 0-5% (v / v) and water 0-5% (v / v)
The composition of claim 1 comprising: The coolant is (R) -2-[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid C ₁ -C ₄ alkyl ester. The composition according to any one of 1 to 10. The coolant is
(R) -2-[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid methyl ester (CPS-368),
(R) -2-[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid ethyl ester (CPS-369),
(R) -2-[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid n-propyl ester (CPS-410),
(R) -2-[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid i-propyl ester (CPS-411), or
(R) -2-[((1R, 2S, 5R) -2-Isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid n-butyl ester (CPS-412)
The composition according to any one of claims 1 to 10, wherein The coolant is
(R) -2-[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid n-propyl ester (CPS-410)
The composition according to any one of claims 1 to 10, wherein The coolant is
(R) -2-[((1R, 2S, 5R) -2-Isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid n-butyl ester (CPS-412)
The composition according to any one of claims 1 to 10, wherein The coolant is
[((1R, 2S, 5R ) -2- isopropyl-5-methyl - cyclohexanecarbonyl) - amino] - acetic acid C ₁ -C ₄ alkyl esters, the composition according to any one of claims 1 to 10 object. The coolant is
[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -acetic acid ethyl ester (WS-5)
The composition according to any one of claims 1 to 10, wherein The coolant is
(1R, 2S, 5R) -2- isopropyl-5-methyl - cyclohexane carboxylic acid C ₁ -C ₄ alkyl amide composition according to any one of claims 1 to 10. The coolant is
(1R, 2S, 5R) -2-Isopropyl-5-methyl-cyclohexanecarboxylic acid ethylamide (WS-3)
The composition according to any one of claims 1 to 10, wherein The coolant is
2-Isopropyl-2,3, N-trimethyl-butyramide (WS-23)
The composition according to any one of claims 1 to 10, wherein The coolant is
The composition according to any one of claims 1 to 10, which is a trialkylphosphine oxide. The coolant is
1- (di-sec-butyl-phosphinoyl) -hexane (CPS-147), or
1- (Di-sec-butyl-phosphinoyl) -heptane (CPS-148)
The composition according to any one of claims 1 to 10, wherein   The composition according to any one of claims 1 to 10, wherein the coolant is p-lactate.   The composition according to any one of claims 1 to 10, wherein the coolant is (-)-menthol.   The composition according to any one of claims 1 to 23, wherein the coolant is dissolved in the solvent at a concentration of 0.5 to 20 mg / mL.   24. The composition according to any one of claims 1 to 23, wherein the coolant is dissolved in the solvent at a concentration of 1 to 15 mg / mL.   24. The composition according to any one of claims 1 to 23, wherein the coolant is dissolved in the solvent at a concentration of 2 to 10 mg / mL.   24. The composition according to any one of claims 1 to 23, wherein the coolant is dissolved in the solvent at a concentration of 3 to 8 mg / mL. The composition of claim 1, comprising a coolant dissolved in a solvent, wherein the solvent is
(R) -1,2-propanediol 97% (v / v), and ethanol 3% (v / v),
The coolant is (R) -2-[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid n-propyl ester (CPS-410);
The coolant is dissolved in the solvent at a concentration of 5 mg / mL;
Composition. The composition of claim 1, comprising a coolant dissolved in a solvent, wherein the solvent is
(R) -1,2-propanediol 99% (v / v), and ethanol 1% (v / v),
The coolant is (R) -2-[((1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexanecarbonyl) -amino] -propionic acid n-propyl ester (CPS-410);
The coolant is dissolved in the solvent at a concentration of 5 mg / mL;
Composition.   30. The composition according to any one of claims 1 to 29, which is a liquid composition.   31. A composition according to any one of claims 1 to 30, which is suitable for topical administration.   32. A method for preparing a composition according to any one of claims 1-31, comprising dissolving the coolant in the solvent.   32. A wipe, pad, or wet tissue comprising the composition according to any one of claims 1-31.   34. A wipe, pad, or wet tissue according to claim 33, suitable for use in topical administration of the composition to a human.   A storage container comprising the composition according to any one of claims 1-31.   A cosmetic preparation (e.g. an eye makeup product) comprising the composition according to any one of claims 1-31.   A face wash preparation (eg, after shave lotion) comprising the composition according to any one of claims 1-31.   32. A composition according to any one of claims 1-31, for the treatment of the human or animal body by therapy.   32. A composition according to any one of claims 1-31, for the treatment of sensory discomfort.   32. A composition according to any one of claims 1 to 31 for the treatment of sensory discomfort in the skin.   32. A composition according to any one of claims 1 to 31 for the treatment of pruritus. (a) irritation, pruritus and / or pain associated with dermatitis (e.g., atopic dermatitis, contact dermatitis, irritant dermatitis, allergic dermatitis, seborrheic dermatitis),
(b) Burned, traumatic, diseased, anoxic and / or stimulated skin (e.g., fluoroscopy during image intensive procedures such as laser surgery, angioplasty, diabetic ulcers) , Pain associated with sunburn, radiation, and / or skin damaged by treatment on wound debridement),
(c) pruritus and / or discomfort associated with skin infections, insect bites, sunburns, shavings, hair loss, and / or photodynamic treatment of the skin (e.g., sun keratosis, basal cell carcinoma),
(d) Psoriasis (frequently seen in the elderly) and / or pruritus associated with psoriasis,
(e) mucositis, stomatitis, cheilitis and / or itching of the lips associated with, for example, cold sores and / or gingivitis,
(f) Perianal pruritus, hemorrhoid discomfort, pain associated with anal tears, pain and / or pruritus associated with hemorrhoids, pain associated with hemorrhoidectomy, perineal inflammation, anogenital dermatitis And / or discomfort associated with local causes such as incontinence, diaper rash, and / or perineal inflammation,
(g) vulvar pruritus, vulvar pain (e.g. candidiasis, vulvar vestibular inflammation, vulvar pain, sexual pain, anogenital infection (e.g. warts and / or sexually transmitted diseases), Associated with viral infections of the skin (especially in immunocompromised patients), or
(h) nose discomfort, nasal discomfort associated with respiratory obstruction (e.g., congestion, rhinitis, asthma, bronchitis, emphysema, chronic obstructive pulmonary disease, dyspnea, sleep apnea, and / or snoring), 32. A composition according to any one of claims 1 to 31 for the treatment of and / or upper airway discomfort.   43. A composition for use according to any one of claims 39 to 42, wherein the treatment is by topical administration.   32. A method of treating sensory discomfort comprising the administration of a therapeutically effective amount of the composition of any one of claims 1-31.   32. A method of treating cutaneous sensory discomfort comprising administration of a therapeutically effective amount of a composition according to any one of claims 1-31.   32. A method of treating pruritus comprising administration of a therapeutically effective amount of a composition according to any one of claims 1-31. Comprising administration of a therapeutically effective amount of the composition of any one of claims 1-31.
(a) irritation, pruritus and / or pain associated with dermatitis (e.g., atopic dermatitis, contact dermatitis, irritant dermatitis, allergic dermatitis, seborrheic dermatitis),
(b) Burned, traumatic, diseased, anoxic and / or irritated skin (e.g., fluoroscopy during image intensive procedures such as laser surgery, angioplasty, diabetic ulcers) , Pain associated with sunburn, radiation, and / or skin damaged by treatment on wound debridement),
(c) pruritus and / or discomfort associated with skin infections, insect bites, sunburns, shavings, hair loss, and / or photodynamic treatment of the skin (e.g., sun keratosis, basal cell carcinoma),
(d) Psoriasis (frequently seen in the elderly) and / or pruritus associated with psoriasis,
(e) mucositis, stomatitis, cheilitis and / or itching of the lips associated with, for example, cold sores and / or gingivitis,
(f) Perianal pruritus, hemorrhoid discomfort, pain associated with anal tears, pain and / or pruritus associated with hemorrhoids, pain associated with hemorrhoidectomy, perineal inflammation, anogenital dermatitis And / or discomfort associated with local causes such as incontinence, diaper rash, and / or perineal inflammation,
(g) vulvar pruritus, vulvar pain (e.g. candidiasis, vulvar vestibular inflammation, vulvar pain, sexual pain, anogenital infection (e.g. warts and / or sexually transmitted diseases), Associated with viral infections of the skin (especially in immunocompromised patients), or
(h) nose discomfort, nasal discomfort associated with respiratory obstruction (e.g., congestion, rhinitis, asthma, bronchitis, emphysema, chronic obstructive pulmonary disease, dyspnea, sleep apnea, and / or snoring), And / or methods of treating upper airway discomfort.   48. The method of any one of claims 44 to 47, wherein the administration is topical administration.   32. Use of a composition according to any one of claims 1 to 31 in the manufacture of a medicament for the treatment of sensory discomfort.   32. Use of a composition according to any one of claims 1 to 31 in the manufacture of a medicament for the treatment of sensory discomfort in the skin.   Use of a composition according to any one of claims 1 to 31 in the manufacture of a medicament for the treatment of pruritus. (a) irritation, pruritus and / or pain associated with dermatitis (e.g., atopic dermatitis, contact dermatitis, irritant dermatitis, allergic dermatitis, seborrheic dermatitis),
(b) Burned, traumatic, diseased, anoxic and / or irritated skin (e.g., fluoroscopy during image intensive procedures such as laser surgery, angioplasty, diabetic ulcers) , Pain associated with sunburn, radiation, and / or skin damaged by treatment on wound debridement),
(c) pruritus and / or discomfort associated with skin infections, insect bites, sunburns, shavings, hair loss, and / or photodynamic treatment of the skin (e.g., sun keratosis, basal cell carcinoma),
(d) Psoriasis (frequently seen in the elderly) and / or pruritus associated with psoriasis,
(e) mucositis, stomatitis, cheilitis and / or itching of the lips associated with, for example, cold sores and / or gingivitis,
(f) Perianal pruritus, hemorrhoid discomfort, pain associated with anal tears, pain and / or pruritus associated with hemorrhoids, pain associated with hemorrhoidectomy, perineal inflammation, anogenital dermatitis And / or discomfort associated with local causes such as incontinence, diaper rash, and / or perineal inflammation,
(g) vulvar pruritus, vulvar pain (e.g. candidiasis, vulvar vestibular inflammation, vulvar pain, sexual pain, anogenital infection (e.g. warts and / or sexually transmitted diseases), Associated with viral infections of the skin (especially in immunocompromised patients), or
(h) nose discomfort, nasal discomfort associated with respiratory obstruction (e.g., congestion, rhinitis, asthma, bronchitis, emphysema, chronic obstructive pulmonary disease, dyspnea, sleep apnea, and / or snoring), 32. Use of a composition according to any one of claims 1 to 31 in the manufacture of a medicament for the treatment of and / or upper airway discomfort.   53. The method according to any one of claims 49 to 52, wherein the drug is suitable for topical administration.

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