Classifications

• • 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
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  • 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
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  • 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

• alcoholic solvents i.e., saturated aliphatic Ci-C 4 alkanes having one or two hydroxy groups
• 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).
• the solvent comprises 95-100% (v/v (R)-1 ,2-propanediol.
• the solvent comprises 85-100% (v/ (R)-1 ,2-propanediol.
• the solvent comprises 75-100% (v/v (R)-1 ,2-propanediol.
• the solvent comprises 65-100% (v/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 0-2% (v/v) ethanol.
• the solvent additionally comprises 0-4% (v/v) ethanol.
• 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);
• 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 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 3-8 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 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.
• 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
• 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.
• 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.
• 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 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.
• Racemic 1 ,2-propanediol is a standard solvent for many cosmetic and dermatological formulations.
• (-)-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
• (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.
• (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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