WO2012098342A1 - (r)-1,2-propanediol destiné à être utilisé comme solvant dans des compositions d'agent rafraîchissant thérapeutique - Google Patents

(r)-1,2-propanediol destiné à être utilisé comme solvant dans des compositions d'agent rafraîchissant thérapeutique Download PDF

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Publication number
WO2012098342A1
WO2012098342A1 PCT/GB2011/000938 GB2011000938W WO2012098342A1 WO 2012098342 A1 WO2012098342 A1 WO 2012098342A1 GB 2011000938 W GB2011000938 W GB 2011000938W WO 2012098342 A1 WO2012098342 A1 WO 2012098342A1
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Prior art keywords
composition according
propanediol
cooling agent
skin
solvent
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PCT/GB2011/000938
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English (en)
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WO2012098342A8 (fr
Inventor
Edward Tak Wei
Original Assignee
Paget, Hugh, Charles, Edward
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Priority claimed from US12/930,794 external-priority patent/US8853267B2/en
Application filed by Paget, Hugh, Charles, Edward filed Critical Paget, Hugh, Charles, Edward
Priority to SG2013054747A priority Critical patent/SG192014A1/en
Priority to JP2013548879A priority patent/JP2014508740A/ja
Priority to EP11729441.3A priority patent/EP2665492A1/fr
Priority to KR1020137021407A priority patent/KR20140037045A/ko
Priority to CN201180069097.6A priority patent/CN103458928B/zh
Priority to CA2824827A priority patent/CA2824827A1/fr
Publication of WO2012098342A1 publication Critical patent/WO2012098342A1/fr
Publication of WO2012098342A8 publication Critical patent/WO2012098342A8/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A61K8/345—Alcohols containing more than one hydroxy group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/002—Aftershave preparations

Definitions

  • the present invention pertains 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-[((1 f?,2S,5R)-2-isopropyl- 5-methyl-cyclohexanecarbonyl)-amino]-propionic acid n-propyl ester (CPS-410).
  • the invention also relates to cooling agent compositions comprising a cooling agent and (f?)-1 ,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).
  • menthol-like cooling agents in commercial use for applications to skin and mucous membranes are, for example, menthyl lactate (Frescolat ML), menthoxypropanediol (Cooling Agent 10), and 2-isopropyl-5-methylcyclohexyl 4-(dimethylamino)-4- oxobutanoate.
  • Current information on cooling agents used for topical applications has been reviewed (see, e.g., Leffingwell, 2009).
  • Cooling of the skin and mucous membranes is detected by a subset of primary sensory afferents that have receptors on nerve endings. These sensory fibers exhibit a rhythmic, ongoing discharge at neutral temperatures that increases in response to skin temperature reductions (from 33°C to 23°C) and is suppressed by warming.
  • the dynamic information is propagated along axons in spike trains, at about 20 to 40 impulses/sec, to central neurons, leading in humans to perceive coolness. This type of sensation is mimicked, for example, by facial skin exposure to ambient temperatures of 15°C to 22°C.
  • Menthol confectionery also has alerting effects on the central nervous system and may suppress appetite.
  • TRPM8 Transient receptor potential cation channel subfamily M member 8
  • CMR1 cold and menthol receptor 1
  • Compounds WS-12 and CPS-369 are highly selective agonists of TRPM8.
  • TRPMA1 Transient receptor potential cation channel subfamily A member 1
  • Menthol is a known agonist of TRPA1.
  • Benedikt et al., 2007 discussed the possible mechanisms of ethanol interference with receptor activity and suggested that low molecular weight alcohols (1 ) are absorbed into lipid bilayers, and may seriously affect the mechanical properties of cell membranes and/or (2) affect secondary intracellular messengers such as phosphatidylinositol-4,5-biphosphate that transduce the receptor activation to neuronal signals. These studies reported in Weil et al., 2005 and Benedikt et al., 2007 show that the solvent medium is important for the bioactivity of cooling agents.
  • Short-chain alcohols are generally thought to interact with biological membranes by non-specific physical forces such as interfacial tension, mechanical compressibility per area/molecule, and affecting the permeability parameters of fluid lipid bilayers (see, e.g., Ly and Longo, 2004).
  • Harris et al., 2008 recently summarized evidence for an alternative view, namely, that ethanol acts on specific "pockets" on protein receptor surfaces to modulate function.
  • Receptor assays based on cells transfected with the genes for proteins associated with thermosensation (e.g., TRPM8 or TRPA1 ) may be used as a substitute model of sensory processes.
  • TRPM8 or TRPA1 The receptor assays yield quantitative data, but these assays give no information on onset and offset of action, or on the quality of human sensations evoked by the chemicals. Thus, the best information on the cooling properties of chemicals is derived from direct tests on humans.
  • Ethanol was frequently used as a solvent in these studies on menthol-like cooling agents to help to place the cooling agent on the filter paper and may have contributed to the variation in individual sensitivity (as it is now known that that ethanol as the primary solvent interferes with the detection of cooling sensations).
  • formulations for the skin e.g., lotions, creams, ointments
  • formulations for the respiratory tree or oral cavity e.g., vapors, sprays
  • a solvent for the active cooling ingredient e.g., methanol, 1 ,2-ethanediol, 1 ,3-propanediol, dimethylsulfoxide, and butanols are not used in topical (skin) formulations because of known or potential hazards. Instead, two or three carbon alcohol solvents such as ethanol, isopropyl alcohol, and racemic 1 ,2-propanediol are frequently used.
  • (R)-1 ,2-propanediol is potently less inhibitory than other alcoholic solvents and thus is an ideal vehicle for the delivery of chemical coolants.
  • (R)-1 ,2-propanediol has the advantage of increasing, often by at least two-fold, the potency of most coolants, as compared to racemic 1 ,2-propanediol.
  • compositions e.g., a cooling agent composition
  • a cooling agent composition comprising a cooling agent dissolved in a solvent comprising (R)-1 ,2-propanediol.
  • Another aspect of the invention pertains to a method of preparing a composition (e.g., a cooling agent composition), as described herein, wherein the method includes a step of dissolving the cooling agent in the solvent.
  • a composition e.g., a cooling agent composition
  • Another aspect of the invention pertains to a wipe, pad, or towelette carrying a
  • composition e.g., a cooling agent composition
  • a cooling agent composition as described herein.
  • Another aspect of the invention pertains to a reservoir container containing a composition (e.g., a cooling agent composition), as described herein.
  • a composition e.g., a cooling agent composition
  • Another aspect of the invention pertains to a cosmetic preparation (e.g., an eye make-up product) comprising a composition (e.g., a cooling agent composition), as described herein.
  • a toiletry preparation e.g., after-shave lotion
  • a composition e.g., a cooling agent composition
  • compositions e.g., a cooling agent composition
  • a composition for treatment of the human or animal body by therapy.
  • Another aspect of the invention pertains to a composition (e.g., a cooling agent composition), as described herein, for treatment of in the treatment of sensory discomfort, especially sensory discomfort of the skin (e.g., itch).
  • a composition e.g., a cooling agent composition
  • Another aspect of the invention pertains to a method of treatment of sensory discomfort, especially sensory discomfort of the skin (e.g., itch), as described herein, comprising administration of a therapeutically effective amount of a composition (e.g., a cooling agent composition), as described herein.
  • Another aspect of the invention pertains to use of ( )-1 ,2-propanediol, as described herein, in the manufacture of a composition (e.g., a cooling agent composition) for the treatment of sensory discomfort, especially sensory discomfort of the skin (e.g., itch), as described herein.
  • a composition e.g., a cooling agent composition
  • Another aspect of the invention pertains to use of ( )-1 ,2-propanediol to improve the cooling activity of a cooling agent in a liquid composition.
  • Another aspect of the invention pertains to use of (f?)-1 ,2-propanediol to increase the potency of a cooling agent composition.
  • a cosmetic preparation e.g., an eye make-up product
  • a composition e.g., a cooling agent composition
  • a toiletry preparation e.g., after-shave lotion
  • a composition e.g., a cooling agent composition
  • Figure 1 is a graph of cooling intensity (units) as a function of time (hours) after application for five cooling agents, CPS-410 (filled circles), CPS-412 (squares), CPS-369 (triangles pointing down), CPS-368 (open circles), and CPS-411 (triangles pointing up), all at a concentration of 5 mg/mL in a solvent mixture of 1 % ethanol / 99%
  • Figure 2 is a graph of cooling effect (units) as a function of time (hours) after application, for the cooling agent WS-5 at a concentration of 10 mg/mL in ethanol containing 0% (v/v) (diamonds), 10% (v/v) (squares), 20% (v/v) (triangles), or 40% (v/v) (circles) of
  • a topical cooling agent is to be delivered in a medium that is liquid or partially liquid, it is desirable to have a solvent for the cooling agent that will not interfere with bioactivity (e.g. , its cooling activity).
  • the Inventor has found that the cooling and sensory properties of a test substance in various solvents can be tested by dissolving the test substance in a test solvent and singly applying 0.10 to 0.25 mL of the solution onto the skin surface using a cotton-tipped applicator (e.g., Q-tips®).
  • a cotton-tipped applicator e.g., Q-tips®
  • a reliable place for topical application is the skin above the upper lip (above the vermilion border of the lips), on the philtrum, lateral to the philtrum until the nasolabial folds, and on the lower nostrils (subnasale).
  • This part of the face is known to be densely innervated with cold receptors, second only to the surfaces of the eyeball and anogenitalia. Tingling, cool and cold sensations from the skin may be experienced and rated for time of onset and intensity.
  • alcoholic solvents i.e., saturated aliphatic Ci-C 4 alkanes having one or two hydroxy groups
  • (f?)-1 ,2-propanediol was found to cause substantially less interference with the cooling actions of various cooling agents, as compared to the other alcoholic solvents (including (S)-1 ,2-propanediol), many of which completely blocked cooling action. Without wishing to be bound by any particular theory, the inventor believes that this effect is related to the stereospecific nature of (f?)-1 ,2-propanediol.
  • 1 ,2-Propanediol is an optically active molecule and has one chiral centre, specifically, the carbon atom at the 2-position. This chiral center may be in the (R) or (S) configuration, and so gives rise to two enantiomers referred to as (R)-1 ,2-propanediol and
  • EE enantiomeric excess
  • An equimolar mixture of enantiomers (referred to as a racemic mixture or a racemate) has an enantiomeric excess (EE) of zero.
  • a pure enantiomer has an enantiomeric excess (EE) of one.
  • (S)-1 ,2-propanediol pure (S)-1 ,2-propanediol having an enantiomeric excess of one; or a mixture of (S)-1 ,2-propanediol and (R)-1 ,2-propanediol having an (S)-1 ,2-propanediol enantiomeric excess of greater than zero and less one).
  • (R)-1 ,2-propanediol is a relatively safe compound for human use because the racemate is already accepted as a solvent for cosmetics and pharmaceuticals (see, e.g., Lakind et al., 1999).
  • the median lethal dose of racemic 1 ,2-propanediol is about 25 mg/kg of body weight, indicating that large doses can be administered orally without immediate danger.
  • An estimated "safe" dose for humans, based on intravenous infusion studies of racemic 1 ,2-propanediol, is 1 g/kg body weight per day (see, e.g., Wilson et al., 2005).
  • (f?)-1 ,2-propanediol is potently less inhibitory than other alcoholic solvents and thus is an ideal vehicle for the delivery of chemical coolants.
  • (R)-1 ,2-propanediol has the advantage of increasing, often by at least two-fold, the potency of most coolants, as compared to racemic
  • compositions e.g., cooling agent compositions
  • a cooling agent dissolved in (R)-1 ,2-propanediol, as described herein.
  • the present 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, especially sensory discomfort of the skin (e.g., itch).
  • composition e.g., a cooling agent composition
  • a cooling agent composition comprising a cooling agent dissolved in a solvent comprising (R)-1 ,2-propanediol.
  • the composition is a liquid composition (e.g., a liquid cooling agent composition).
  • liquid is used herein in the conventional sense to mean a material that has the physical properties of a liquid (as compared to the physical properties of a solid or gas) at standard temperature and pressure (i.e., 20°C and 101.325 kPa).
  • the solvent is entirely or predominantly (R)-1 ,2-propanediol.
  • the solvent comprises 100% (v/v) (R) -1 ,2-propanediol.
  • the solvent comprises 95-100% (v/v (R)-1 ,2-propanediol.
  • the solvent comprises 90-100% (v/v (R)-1 ,2-propanediol.
  • the solvent comprises 85-100% (v/ (R)-1 ,2-propanediol.
  • the solvent comprises 80-100% (v/v (R)-1 ,2-propanediol.
  • the solvent comprises 75-100% (v/v (R)-1 ,2-propanediol.
  • the solvent comprises 70-100% (v/v (R)-1 ,2-propanediol.
  • the solvent comprises 65-100% (v/v (R)-1 ,2-propanediol.
  • the solvent comprises 60-100% (v/v (R)-1 ,2-propanediol.
  • the solvent comprises 55-100% (v/v (R)-1 ,2-propanediol.
  • the solvent comprises 50-100% (v/ (R)-1 ,2-propanediol.
  • the solvent additionally comprises a relatively small proportion of C C 3 alkanol, for example, to improve the solubility of the cooling agent. In one embodiment, the solvent additionally comprises 0-1% (v/v) C r C 3 alkanol.
  • the solvent additionally comprises 0-2% (v/v) C C 3 alkanol.
  • the solvent additionally comprises 0-3% (v/v) C C 3 alkanol.
  • the solvent additionally comprises 0-4% (v/v) C C 3 alkanol.
  • the solvent additionally comprises 0-5% (v/v) C C 3 alkanol.
  • Ci-C 3 alkanol is intended to refer to compounds of the formula R-OH, where R is a saturated aliphatic C C 3 alkyl group.
  • the C C 3 alkanols are methanol, ethanol, n-propanol, and isopropanol.
  • the solvent additionally comprises 0-1% (v/v) ethanol.
  • the solvent additionally comprises 0-2% (v/v) ethanol.
  • the solvent additionally comprises 0-3% (v/v) ethanol.
  • the solvent additionally comprises 0-4% (v/v) ethanol.
  • the solvent additionally comprises 0-5% (v/v) ethanol.
  • the solvent is:
  • the solvent is:
  • the solvent is:
  • the solvent is:
  • Suitable solvents include:
  • the solvent additionally comprises water.
  • a relatively large proportion of water can be included without substantially reducing cooling activity of the cooling agent and without substantially inducing precipitation of the cooling agent.
  • the solvent additionally comprises 0-5% (v/v) water.
  • the solvent additionally comprises 0-10% (v/v) water.
  • the solvent additionally comprises 0-15% (v/v) water.
  • the solvent additionally comprises 0-20% (v/v) water.
  • the solvent additionally comprises 0-25% (v/v) water.
  • the solvent additionally comprises 0-30% (v/v) water.
  • the solvent is:
  • the solvent is:
  • the solvent is:
  • the solvent is:
  • suitable solvents include: 95% (j )-1 ,2-propanediol / 5% water (v/v);
  • the solvent may further comprise other liquid components, for example, as permitted by the percentages discussed above. That is, the percentages of the recited components (e.g., (R)-1 ,2-propanediol, ethanol, and water) may add up to a number less than 100, with the balance made up of other liquid components, for example, other co-solvents.
  • the percentages of the recited components e.g., (R)-1 ,2-propanediol, ethanol, and water
  • the balance made up of other liquid components, for example, other co-solvents.
  • the embodiment described as "90-100% (f?)-1 ,2-propanediol / 0-5% ethanol / 0-5% water (v/v)" may also be described as "90-100% (ft)-1 ,2-propanediol / 0-5% ethanol / 0-5% water / 0-10% other liquid components (v/v)" and encompasses a mixture which is, for example, 90% ( ?)-1 ,2-propanediol / 2% ethanol / 3% water / 5% other liquid components (v/v).
  • any such additional liquid components do not substantially interfere with the cooling activity of the cooling agent, and do not substantially reduce the solubility of the cooling agent in the solvent (e.g., do not substantially induce precipitation of the cooling agent from the solvent).
  • the solvent comprises no other liquid components; that is, the solvent comprises, as liquid components, only those recited (e.g., only (R)-1 ,2-propanediol; only (R)-1 ,2-propanediol and ethanol; only (f?)-1 ,2-propanediol and water; only (f?)-1 ,2-propanediol, ethanol, and water; respectively) (e.g., consists essentially of (R)-1 ,2-propanediol; consists essentially of (f?)-1 ,2-propanediol and ethanol; consists essentially of (R)-1 ,2-propanediol and water; consists essentially of
  • volume fraction is based on volume prior to mixing, measured at standard temperature and pressure (i.e. 20°C and 101.325 kPa).
  • a liquid prepared by mixing 99 mL of (R)-1 ,2-propanediol with 1 mL ethanol may be described as a mixture of "99% (f?)-1 ,2-propanediol / 1% ethanol (v/v)".
  • 95% (R)-1 ,2-propanediol / 5% ethanol (v/v) refers to the liquid mixture that is obtained when, for example, 95 mL of 1 ,2-propanediol is mixed with 5 mL ethanol, wherein the 1 ,2-propanediol is ( )-1 ,2-propanediol with an enantiomeric excess of 0.50 to 1.00.
  • the ( ?)-1 ,2-propanediol has an enantiomeric excess of 0.50 to 1.00. In one embodiment, the (fl)-1 ,2-propanediol has an enantiomeric excess of 0.55 to 1.00. In one embodiment, the (f?)-1 ,2-propanediol has an enantiomeric excess of 0.60 to 1.00. In one embodiment, the ( )-1 ,2-propanediol has an enantiomeric excess of 0.65 to 1.00. In one embodiment, the ( ?)-1 ,2-propanediol has an enantiomeric excess of 0.70 to 1.00.
  • the (ft)-1 ,2-propanediol has an enantiomeric excess of 0.75 to 1.00. ln one embodiment, the (R)-1 ,2-propanediol has an enantiomeric excess of 0.80 to 1 .00. In one embodiment, the ,2-propanediol has an enantiomeric excess of 0.85 to 1 .00. In one embodiment, the (R)-1 ,2-propanediol has an enantiomeric excess of 0.90 to 1 .00. In one embodiment, the (R)-1 ,2-propanediol has an enantiomeric excess of 0.95 to 1 .00. In one embodiment, the (R)- ,2-propanediol has an enantiomeric excess of 1 .00.
  • the cooling agent is an ( )-2-[((1 ?,2S,5/?)-2-isopropyl-5-methyl- cyclohexanecarbonyl)-amino]-propionic acid C C 4 alkyl ester.
  • the cooling agent is CPS-368, CPS-369, CPS-410, CPS-41 1 , or CPS-412. In one embodiment, the cooling agent is CPS-368. In one embodiment, the cooling agent is CPS-369. In one embodiment, the cooling agent is CPS-410.
  • the cooling agent is CPS-41 1.
  • the cooling agent is CPS-412. In one embodiment, the cooling agent is a [((1 f?,2S,5R)-2-isopropyl-5-methyl- cyclohexanecarbonyl)-amino]-acetic acid ester.
  • the cooling agent is WS-5. In one embodiment, the cooling agent is a (1 R,2S,5R)-2-isopropyl-5-methyl- cyclohexanecarboxylic acid C 1 -C 4 alkyl amide.
  • the cooling agent is WS-3. In one embodiment, the cooling agent is WS-23 (2-isopropyl-2,3, N-trimethyl-butyramide).
  • the cooling agent is a trialkylphosphine oxide.
  • the cooling agent is CPS-147 or CPS-148.
  • the cooling agent is p-menthyl lactate. In one embodiment, the cooling agent is (-)-menthol.
  • the cooling agent is (or is also) a TRPM8 agonist. Cooling Agent Content
  • the cooling agent is dissolved in the solvent at a concentration of 0.5-20 mg/mL; in other words, the composition comprises the cooling agent dissolved in the solvent at a concentration of 0.5-20 mg/mL
  • the concentration is 1-15 mg/mL.
  • the concentration is 2-10 mg/mL.
  • the concentration is 3-8 mg/mL.
  • the concentration is 3 mg/mL.
  • the concentration is 4 mg/mL.
  • the concentration is 5 mg/mL.
  • the concentration is 6 mg/mL.
  • the concentration is 7 mg/mL.
  • the concentration is 8 mg/mL.
  • the concentration is measured at standard temperature and pressure (i.e., 20°C and 101.325 kPa).
  • a preferred composition suitable as a formulation for topical administration to the skin comprises a solvent which is a mixture of 95-100% ff? -1 ,2-propanediol / 0-5% ethanol (v/v) with 2-10 mg/mL of a cooling agent (e.g., CPS-410 or CPS-412) dissolved therein.
  • a cooling agent e.g., CPS-410 or CPS-412
  • a more preferred composition suitable as a formulation for topical administration to the skin comprises a solvent which is a mixture of 97-100% (ft -1,2-propanediol / 0-3% ethanol (v/v) with 2-10 mg/mL of a cooling agent (e.g., CPS-410 or CPS-412) dissolved therein.
  • a cooling agent e.g., CPS-410 or CPS-412
  • a most preferred composition suitable as a formulation for topical administration to the skin comprises a solvent which is a mixture of 99% ( j- ,2-propanediol / 1% ethanol (v/v) with 5 mg/mL of CPS-410 dissolved therein.
  • Purified water can be added to such solutions, as discussed above, without substantial loss of cooling activity, and without substantially inducing precipitation of the cooling agent.
  • Such formulations have the advantages of ease of manufacture, ease of packaging, and a smaller volume of delivery.
  • Such formulations allow the active ingredient to be evenly distributed on the skin but do not impart a "greasy” or sticky feel to the skin (an undesirable effect which is often seen with standard topical excipients such as petrolatum and mineral oil).
  • compositions described above comprising cooling agent, (f?)-1 ,2-propanediol, ethanol, and optionally water
  • other conventional agents such as other pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents.
  • pharmaceutically acceptable pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • 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, for example, Remington's Pharmaceutical Sciences. 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 5th edition, 2005.
  • formulations may be prepared by any methods well known in the art of pharmacy. In general, the formulations are prepared by uniformly and intimately bringing into association the various ingredients, and then shaping the product, if necessary.
  • Formulations may suitably be, for example, in the form of liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions
  • elixirs e.g., oil-in-water, water-in-oil
  • syrups electuaries, mouthwashes, drops, capsules, gels, pastes, ointments, liniments, creams, lotions, oils, foams, sprays, mists, or aerosols.
  • Lozenges typically comprise the key ingredients in a flavored basis, usually sucrose and acacia or tragacanth.
  • Pastilles typically comprise the key ingredients in an inert matrix, such as gelatin and glycerin, or sucrose and acacia.
  • Mouthwashes typically comprise the key ingredients in a suitable liquid carrier.
  • Ointments are typically prepared from the key ingredients and a paraffinic or a water-miscible ointment base.
  • Creams are typically prepared from the key ingredients and an oil-in-water cream base.
  • Emulsions are typically prepared from the key ingredients and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier otherwise known as an emulgent
  • Emulsions are typically prepared from the key ingredients and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprise a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • Formulations suitable for topical (intranasal) administration include, for example, nasal spray, nasal drops, and aerosols (e.g., administered by nebuliser).
  • Formulations suitable for topical (ocular) administration include eye drops.
  • Formulations suitable for topical (pulmonary) administration include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro- tetrafluoroethane, carbon dioxide, or other suitable gases.
  • the formulation may further comprise other active agents, for example, other cooling agents, etc.
  • the composition is suitable for topical administration. ln one embodiment, the composition is suitable for topical administration to the skin, e.g., of a human.
  • the composition is suitable for topical administration to the scalp, e.g., of a human.
  • the composition is suitable for topical administration to a mucous membrane, e.g., of a human. In one embodiment, the composition is suitable for topical ocular administration, e.g., to a human.
  • the composition is suitable for topical nasal administration, e.g., to a human.
  • the composition is suitable for topical oral administration, e.g., to a human.
  • the composition is suitable for topical esophageal administration, e.g., to a human.
  • the composition is suitable for topical pharyngeal administration, e.g., to a human. In one embodiment, the composition is suitable for topical anogenital administration, e.g., to a human.
  • compositions e.g., a cooling agent composition, as described herein
  • a composition comprising dissolving a cooling agent (as described herein) in a solvent comprising (f?)-1 ,2-propanediol (as described herein).
  • cooling agent compositions as described herein, are useful, for example, in the treatment of sensory discomfort in a human, as described herein. Use in Methods of Therapy
  • Another aspect of the present invention pertains to a cooling agent composition, as described herein, for use in a method of treatment of the human or animal body by therapy.
  • Another aspect of the present invention pertains to use of ( ?)-1 ,2-propandiol in the manufacture of a medicament comprising a cooling agent composition for use in treatment.
  • Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a cooling agent composition, as described herein.
  • the treatment is treatment or prevention of sensory discomfort.
  • the treatment is treatment or prevention of sensory discomfort of the skin.
  • the treatment is treatment or prevention of sensory discomfort of:
  • irritation, itch and/or pain associated with dermatitis e.g., atopic dermatitis, contact dermatitis, irritant dermatitis, allergic dermatitis, seborrheic dermatitis
  • dermatitis e.g., atopic dermatitis, contact dermatitis, irritant dermatitis, allergic dermatitis, seborrheic dermatitis
  • nostril discomfort, nasal discomfort, and/or upper airway discomfort associated with breathing obstruction e.g., congestion, rhinitis, asthma, bronchitis, emphysema, chronic obstructive pulmonary disease, dyspnea, sleep apnea, and/or snoring.
  • breathing obstruction e.g., congestion, rhinitis, asthma, bronchitis, emphysema, chronic obstructive pulmonary disease, dyspnea, sleep apnea, and/or snoring.
  • the treatment is treatment or prevention of canine pruritus.
  • treatment pertains generally to treatment and therapy, of a human, in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disorder, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the disorder, amelioration of the disorder, and cure of the disorder.
  • Treatment as a prophylactic measure i.e., prophylaxis
  • use with patients who have not yet developed the disorder, but who are at risk of developing the disorder is encompassed by the term "treatment.”
  • treatment includes the prophylaxis of itch, reducing the incidence of itch, alleviating the symptoms of itch, etc.
  • therapeutically-effective amount pertains to that amount of a a composition (e.g., a cooling agent composition, as described herein) or dosage form (e.g., comprising a cooling agent composition, as described herein), which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • the subject/patient is a human.
  • the subject/patient is a mammal (e.g., canine, for example, in the veterinary treatment of canine dermatitis).
  • a mammal e.g., canine, for example, in the veterinary treatment of canine dermatitis.
  • the administration is topical administration (i.e., at the site of desired action).
  • the administration is topical administration to the skin, e.g., of a human.
  • the cooling agent composition may preferably be administered topically to the surfaces of one or both of the elbows and/or one or both of the knees (e.g., in the treatment of the pruritus of atopic eczema and psoriasis).
  • the administration is topical administration to the scalp, e.g., of a human.
  • the cooling agent composition may preferably be administered topically to part of, or all of, the scalp (e.g., in the treatment of psoriasis and contact dermatitis).
  • the administration is topical administration to a mucous membrane, e.g., of a human.
  • the administration is topical ocular administration, e.g., to a human.
  • the administration is topical nasal administration, e.g., to a human.
  • the administration is topical oral administration, e.g., to a human.
  • the administration is topical esophageal administration, e.g., to a human.
  • the administration is topical pharyngeal administration, e.g., to a human.
  • the administration is topical anogenital administration, e.g., to a human. Delivery - Liquid from a Reservoir
  • the cooling composition may be delivered as a liquid, for example, from a reservoir container, for example, a bottle or tube, for example, fitted with a suitable dispensing tip or nozzle.
  • another aspect of the invention is a reservoir container containing a cooling agent composition, as described herein.
  • the cooling composition may be delivered via a wipe, pad, or towellette, for example, as is done with many commercial cleansing products (e.g., Cottony Cloths, Supreme and Soft Cloths, Supreme, from CVS Pharmacy).
  • a wipe, pad, or towelette carrying a cooling agent composition, as described herein.
  • the wipe, pad, or towelette is suitable for use in the topical administration of cooling agent composition to a human.
  • treatment includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously.
  • cooling agent compositions described herein may also be used in combination therapies, e.g., in conjunction with other agents.
  • One aspect of the present invention pertains to a cooling agent composition as described herein, further comprising, or in combination with, one or more (e.g., 1 , 2, 3, 4, etc.) additional therapeutic agents.
  • the particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.
  • the agents i.e., the cooling agent composition as described herein, plus one or more other agents
  • agents i.e., the cooling agent composition as described here, plus one or more other agents
  • the agents may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.
  • One aspect of the invention pertains to a kit comprising (a) a cooling agent composition as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the cooling agent composition.
  • the written instructions may also include a list of indications for which the cooling agent composition is a suitable treatment.
  • Another aspect of the invention pertains to use of (R)-1 ,2-propanediol to improve the cooling activity of a cooling agent in a liquid composition.
  • substitution of (fi)-1 ,2-propanediol for some or all of the existing solvent in a liquid composition comprising a cooling agent may improve, or greatly improve, the cooling activity of the cooling agent in the resulting composition.
  • a recipe for formulation may be modified so as to employ (R)-1 ,2-propanediol instead of some or all of the solvent in the recipe, so as to improve the cooling activity of the cooling agent in the resulting composition.
  • compositions already comprising 1 ,2-propanediol e.g., as racemic
  • the addition of (R)-1 ,2-propanediol may improve, or greatly improve, the cooling activity of the cooling agent in the resulting composition.
  • a recipe for formulation may be modified so as to include (R)-1 ,2-propanediol in addition to the solvent in the recipe, so as to improve the cooling activity of the cooling agent in the resulting composition.
  • Another aspect of the invention pertains to use of ,2-propanediol to increase the potency of a cooling agent composition.
  • substitution of (R)-1 ,2-propanediol for some or all of the existing solvent in a liquid composition comprising a cooling agent may permit a smaller volume of composition to have the same cooling effect.
  • a recipe for formulation may be modified so as to include (f?)-1 ,2-propanediol and/or to substitute (R)-1 ,2-propanediol for some or all of the existing solvent, so as to increase the potency of the resulting composition (and allow a smaller volume to be administered).
  • the cooling agent compositions may also be used in the preparation of cosmetics and toiletries.
  • (f?)-1 ,2-propanediol may be included in the formulations so as to increase the cooling activity of cooling agents therein and/or increase the cooling potency of the formulations. In this way, the cooling and refreshing effects associated with these formulations are enhanced.
  • a toiletry preparation e.g., after-shave lotion
  • a composition e.g., a cooling agent composition
  • a recipe for after-shave lotion may be modified so as to include
  • a cosmetic preparation e.g., an eye make-up product
  • a composition e.g., a cooling agent composition
  • a recipe for a preparation to remove cosmetics from the eyelids, a preparation to apply eye make-up that has irritant properties, and/or a preparation to apply substances that make eyelashes grow faster may be modified so as to include (R)-1 ,2-propanediol and/or to substitute (R)-1 ,2-propanediol for some or all of the existing solvent, so as to increase the cooling activity of cooling agents therein and/or increase the cooling potency of the preparation. In this way, the cooling and refreshing effects associated with the preparation are enhanced.
  • Cooling agents were evaluated for toxicity in young male adult rats. Cooling agents were dissolved in 3%-ethanol / 97% racemic 1 ,2-propanediol (v/v) and injected subcutaneously at 30 mg/kg daily for five days. Body weights were monitored, and on the sixth day, animals were euthanized with an overdose of sodium pentobarbital and liver and heart weights were determined. None of the treated animals died during treatment. The results are summarized in the following table. "N" is the number of replicates.
  • the test doses on the philtrum assay were in the range of 1 to 2 mg per trial per subject.
  • the test doses studied in the toxicological study were 30 mg/kg of body weight for 5 days. It was decided that the philtrum assays did not pose significant safety risks.
  • the cooling agent was dissolved in an alcoholic solvent to yield test solutions with cooling agent concentrations of 2, 2.5, 3, 5, 10, or 20 mg/mL.
  • a cotton-tipped applicator e.g., Q-tips®
  • 0.10 to 0.25 mL of the test solution was applied to the skin above the upper lip, on the philtrum, and lateral to the philtrum up to the nasolabial folds, and the onset and duration of cooling sensations noted.
  • the intensity of the subjective skin sensation was rated as 0, 1 , 2 or 3, with 0 as: no change; 1 as: slight coolness, cold, or tingling; 2 as: clear cut signal of coolness, cold, or tingling; and 3 as: robust cooling or cold.
  • the interval for recording sensations was at 5 to 10 minute intervals, until at least two successive zeroes were obtained. The results were averaged values of 3 to 6 separate trials on the same individual.
  • the "onset” is the time taken to reach a coolness intensity value of 2. If the test solution did not reach a value of 2, then it was considered to be inactive.
  • the "off-set” is when the coolness intensity drops below 2, and the “duration” is the time of off-set minus the time of onset.
  • the area under the curve also gives an estimate of the intensity and duration of drug action and can be obtained from the plotted data using SigmaPlot (Systat Software, Point Richmond CA).
  • the AUC is given in average ⁇ S.E. . units, which is the product of cooling intensity and time (minutes).
  • ⁇ S.E. . units which is the product of cooling intensity and time (minutes).
  • CPS-410 and CPS-369 Two potent cooling agents, CPS-410 and CPS-369, were studied using the skin assay described above, for several different alcoholic solvents.
  • the concentrations were 5 mg/mL CPS-410 and 10 mg/mL CPS-369. The results are summarized in the following table.
  • (R)-1 ,2-propanediol was surprisingly and unexpectedly the best solvent for retaining the cooling action of CPS-410 and CPS-369. Based on AUC, the (S)-1 ,2-propanediol solution had only 27% of the CPS-410 activity and 47% of the CPS-369 activity of the corresponding (R)-1 ,2-propanediol solution.
  • Racemic 1 ,2-propanediol is a standard solvent for many cosmetic and dermatological formulations.
  • cooling agents are more soluble in ethanol than in 1 ,2-propanediol.
  • WS-3 and CPS-369 are soluble in absolute ethanol at > 300 mg/mL and > 500 mg/mL, respectively. These compounds are less soluble in 1 ,2-propanediol, with solubilities of about 10 mg/mL at standard conditions.
  • Figure 1 is a graph of cooling intensity (units) as a function of time (hours) after application for five cooling agents, CPS-410 (filled circles), CPS-412 (squares), CPS-369 (triangles pointing down), CPS-368 (open circles), and CPS-41 1 (triangles pointing up), all at a concentration of 5 mg/mL in a solvent mixture of 1 % ethanol / 99% (7?>1 ,2-propanediol
  • (-)-Menthol is the most widely used cooling agent in commercial applications. It is present in a diverse number of liquid or semi-liquid preparations such as in Ben-Gay® ointment, IcyHot® medicated patch, and in Vicks Vaposteam Liquid Medication.
  • the effects of (-)-menthol on sensory systems are complex, but one of the target receptors is thought to be the TRP-M8 receptor.
  • the cooling effect of (-)-menthol (at 10 mg/mL) in the philtrum assay was compared with (-)-menthol dissolved in 1 ,3-propanediol or in
  • an antagonist is a chemical that blocks the actions of an agonist, without itself producing an effect.
  • ethanol acts as an agonist to inhibit TRP- 8 activation, and an antagonist blocks the ethanol's agonist effect without itself producing any alterations in receptor function.
  • An antagonist that blocks an inhibitory agonist will also have the net effect of enhancing coolness.
  • (R)-1 ,2-propanediol may antagonize/block the ethanol binding site of TRP-M8.
  • endogenous alcohols e.g., ethanol or glycerol
  • (f?)-1 ,2-propanediol was added at 0%, 10%, 20% and 40% (v/v) to an ethanolic solution containing 10 mg/mL of WS-5 (a known cooling agent).
  • WS-5 at 10 mg/mL in 100% ethanol did not produce any cooling effect when applied to the philtrum.
  • (R)-1 ,2-propanediol reversed the ethanol inhibition in a dose-dependent relationship.
  • the data are illustrated in Figure 2. These data provide strong evidence that (f?)-1 ,2-propanediol is an antagonist at the ethanol binding site of TRP-M8.
  • Figure 2 is a graph of cooling effect (units) as a function of time (hours) after application, for the cooling agent WS-5 at a concentration of 10 mg/mL in ethanol containing 0% (v/v) (diamonds), 10% (v/v) (squares), 20% (v/v) (triangles), or 40% (v/v) (circles) of
  • (f?)-1 ,2-propanediol Another cooling agent, WS-3, is widely used is cosmetics, toothpastes and comestibles.
  • WS-3 dissolved in absolute ethanol at 20 mg/mL did not produce significant cooling when it was applied to the philtrum.
  • WS-3 dissolved in 3% ethanol / 97 % (f?J-1 ,2-propanediol (v/v) at 20 mg/mL was applied, it produced robust cooling lasting 38 ⁇ 3 minutes, together with prickling and stinging sensations.
  • WS-3 is much less active when dissolved in racemic 1 ,2-propanediol than in (R)-1 ,2-propanediol.
  • the solvent carrier is a critical determinant of biological activity.
  • the cooling agents CPS-147 and CPS-148 are members of this class of compounds (trialkylphosphine oxides).
  • CPS-147 and CPS-148 are chemically distinct from the (-)-menthol derivatives represented, for example, by WS-3, WS-5, CPS-368, CPS-369, CPS-410, CPS-41 1 , and CPS-412.
  • the binding site of the trialkylphosphine oxides on the TRP- 8 receptor is not known.
  • Patient Study 1 A 34-year old male with an eight-year history of plaque psoriasis complained of an axillary skin lesion that itched, had burning sensations, and kept him awake at night. His condition was severe and chronic. His mother complained that she had to vacuum his bedroom every day in order to remove flaking skin debris. Upon examination, the individual had some silvery, flaky lesions on his elbow and knee surfaces, but this did not bother him as much as the skin lesion under his right axilla, which was manifested as a rectangular area of about 2 cm x 4 cm, with diffuse redness and a moist appearance.
  • a cotton-tipped stick was used to apply CPS-410 solution (5 mg/mL CPS-410 in 1 % ethanol / 99% (RJ-1 ,2-propanediol (v/v)) or CPS-412 solution (5 mg/mL CPS-412 in 1 % ethanol / 99% (ftj-1 ,2-propanediol (v/v)) at the site of itch.
  • the itch sensations were suppressed within 5 minutes of application of either solution, and this effect lasted for at least 8 hours.

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Abstract

La présente invention concerne d'une façon générale le domaine de la thérapie médicale topique, des produits cosmétiques et des articles de toilette. Plus précisément, l'invention porte sur l'utilisation d'un solvant comprenant du (R)-1,2-propanediol pour des agents rafraîchissants, par exemple de l'ester n-propylique de l'acide (R)-2-[((1R,2S,5R)-2-isopropyl-5-méthylcyclohexanecarbonyl)amino]propionique (CPS-410). L'invention porte également sur des compositions d'agent rafraîchissant comprenant un agent rafraîchissant et du 1,2-propanediol et sur des procédés pour leur préparation. L'invention porte également sur l'utilisation de telles compositions d'agent rafraîchissant en thérapie, par exemple dans le traitement d'une gêne sensorielle, en particulier d'une gêne sensorielle de la peau (par exemple des démangeaisons). L'invention porte également sur l'utilisation de telles compositions d'agent rafraîchissant dans des produits cosmétiques (par exemple des produits de maquillage des yeux) et des articles de toilette (par exemple des lotions après rasage).
PCT/GB2011/000938 2011-01-18 2011-06-22 (r)-1,2-propanediol destiné à être utilisé comme solvant dans des compositions d'agent rafraîchissant thérapeutique WO2012098342A1 (fr)

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SG2013054747A SG192014A1 (en) 2011-01-18 2011-06-22 (r)-1,2-propanediol for use as a solvent in therapeutic cooling agent compositions
JP2013548879A JP2014508740A (ja) 2011-01-18 2011-06-22 治療用冷却剤組成物における溶媒としての使用のための（ｒ）−１，２−プロパンジオール
EP11729441.3A EP2665492A1 (fr) 2011-01-18 2011-06-22 (r)-1,2-propanediol destiné à être utilisé comme solvant dans des compositions d'agent rafraîchissant thérapeutique
KR1020137021407A KR20140037045A (ko) 2011-01-18 2011-06-22 치료적 쿨링제 조성물에서 용매로서 사용하기 위한 (r)-1,2-프로판디올
CN201180069097.6A CN103458928B (zh) 2011-01-18 2011-06-22 (r)-1,2-丙二醇用作治疗性冷却剂组合物中的溶剂
CA2824827A CA2824827A1 (fr) 2011-01-18 2011-06-22 (r)-1,2-propanediol destine a etre utilise comme solvant dans des compositions d'agent rafraichissant therapeutique

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US12/930,794 US8853267B2 (en) 2005-03-29 2011-01-18 N-alkylcarbonyl-amino acid ester compounds and their use for skin irritation, itch, and pain
US12/930,794 2011-01-18

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WO2019197789A1 (fr) * 2018-04-13 2019-10-17 Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic Utilisation d'une nouvelle composition pour empêcher ou ralentir l'apparition de signes d'inflammation

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Publication number Priority date Publication date Assignee Title
CN104840642A (zh) * 2015-05-16 2015-08-19 臧海阳 一种治疗风热犯表型感冒的中药组合物及其制备方法
WO2019197789A1 (fr) * 2018-04-13 2019-10-17 Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic Utilisation d'une nouvelle composition pour empêcher ou ralentir l'apparition de signes d'inflammation
FR3080032A1 (fr) * 2018-04-13 2019-10-18 Societe D'exploitation De Produits Pour Les Industries Chimiques Seppic Utilisation d'une nouvelle composition pour empecher ou ralentir l'apparition de signes d'inflammation

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CN103458928B (zh) 2015-09-30
SG192014A1 (en) 2013-08-30
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