Classifications

• • 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
• • 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
  • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
• • 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
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
• • 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
  • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
  • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
  • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
• • 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
  • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
• • 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
  • A61P11/16—Central respiratory analeptics
• • 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
  • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric 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
  • A61P17/16—Emollients or protectives, e.g. against radiation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • 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
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/30—Oestrogens
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
  • A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
  • A61K2800/24—Thermal properties
  • A61K2800/244—Endothermic; Cooling; Cooling sensation

Definitions

• the present invention relates to a method of alleviating discomfort experienced by a woman during a hot flash.
• the present invention also relates to the method of use of topical compositions that may be used to alleviate such discomfort. More particularly, the present invention relates to a method of alleviating discomfort, especially the feeling of intense heat, experienced by a woman during a hot flash and the topical application of a composition having cooling ingredients in order to alleviate such discomfort.
• a hot flash is marked by an increase in body temperature accompanied by an intense feeling of unbearable heat, particularly internally radiating body heat.
• a hot flash may also be accompanied by an increase in heart rate, dizziness, anxiety, faintness, a sense of unease, tingling sensations, pressure in the head, nausea, perspiration, and feelings of breathlessness.
• the feeling of heat is often concentrated in the area of the face and neck, and sometimes spreads to the area of the upper chest.
• a hot flash may last for as short as a minute, a hot flash usually lasts as long as two to three minutes, and may last as long as an hour. Regardless of the duration of the hot flash, the discomfort due to the intense feeling of heat is extremely uncomfortable and disconcerting to a woman experiencing the hot flash.
• HRT Estrogen Replacement Therapy
• ERT Estrogen Replacement Therapy
• vitamin supplements such as vitamin E and bioflavonoids
• U.S. Patent No. 5,730,957 to Rizk describes the use of a cooling composition having dimethyl ether and water to alleviate the discomfort associated with heat.
• This cooling composition utilizes the latent heat of vaporization to provide its cooling action and also requires that the cooling composition be at a temperature below ambient temperature and higher than the freezing point of water.
• This patent also provides a method of maintaining the cooling composition at such a temperature that requires a pressurized dispensing container.
• the sole embodiment described in the Rizk patent is a water-dimethyl ether composition contained within an aerosol dispenser (col. 3, line 51 et seq.).
• the use of dimethyl ether has known safety issues.
• U.S. Patent No. 5,703,123 to Pelzer et al. describes the use of compositions having asymmetric carbonates, thiocarbonates and/or carbonates to create a physiologic cooling effect on the skin and on mucosae in compositions such as food stuffs (e.g. beverages, jams,), cosmetic agents (e.g. shaving products, skin care products, etc.), household products (e.g. fabric softeners) and pharmaceutical preparations (e.g. antiseptic ointments, cough mixtures).
• food stuffs e.g. beverages, jams,
• cosmetic agents e.g. shaving products, skin care products, etc.
• household products e.g. fabric softeners
• pharmaceutical preparations e.g. antiseptic ointments, cough mixtures.
• ketals such as 1-methone glycerol ketal or 3,3,5- trimethylcyclohexanone glycerol ketal
• ketals such as 1-methone glycerol ketal or 3,3,5- trimethylcyclohexanone glycerol ketal
• U.S. Patent No. 5,688,497 to Lozeau et al. discloses shaving aids that provide a physiological cooling effect.
• U.S. Patent No. 5,451 ,404 to Furman provides coolant compositions that may be administered topically.
• U.S. Patent No. 4,661 ,476 to Lane et al. describes a method of cooling skin overheated by exposure to heat, sun or wind that is the topical application of an aqueous gel having a starch- polyacrylamide graft copolymer.
• U.S. Patent No. 5,595,970 to Garfield et al. describes the use of a nitric oxide substrate and/or nitric acid donor, either alone or in combination with a progestin or estrogen to alleviate climacterium symptoms such as hot flashes.
• a progestin or estrogen to alleviate climacterium symptoms such as hot flashes.
• the compositions disclosed in Garfield et al. require systemic administration.
• the present invention in brief summary, is a method of alleviating the discomfort associated with hot flashes that comprises the step of applying to the body, particularly to the chest, face and neck area and/or to the wrist and arm area, a topical cooling composition having at least one cooling agent.
• Hot flashes are most commonly associated with the discomforting symptom of an intense feeling of heat that begins in the face, neck, or chest regions and then radiates to other parts of the body.
• many women experience a premonition of an impending hot flash that is accompanied by symptoms, such as a feeling of unease or anxiety, a feeling of pressure in the head, or tingling sensations.
• symptoms such as a feeling of unease or anxiety, a feeling of pressure in the head, or tingling sensations.
• heart rate digital blood flow, and vasodilation of blood vessels of the skin.
• women will experience an intense feeling of heat and which may further be accompanied by feelings of dizziness, nausea and breathlessness.
• the first detectable change is an increase in finger blood flow with a concomitant enhancement of skin conductance, as well as a change in temperature of the skin of the face and neck.
• the increase in skin conductance is followed rapidly by a sharp rise (1-7°C) in finger temperature.
• the degree to which finger temperature rises during a hot flash is inversely proportional to the base-line finger temperature before the flash.
• a 0.5°C increase in finger temperature in a woman with a base-line finger temperature of 35°C may be as good a measure of the occurrence of a hot flash as a 5°C increase in finger temperature in a woman with base-line finger temperature of 29°C, because of the non- linear relationship between skin temperature and blood flow.
• a hot flash is the inverse of a fever.
• the control of body temperature resembles a negative feedback system in which a set point temperature serves as reference for the themoregulatory mechanism.
• a fever can be understood as the upward adjustment of this temperature set point.
• the set point In a febrile episode, the set point is first elevated, initiating vasoconstruction, shivering and behavorial modifications, such as the addition of blankets. This results in an elevation of body temperature to a level that is maintained for a period of time.
• a hot flash is a transient downward adjustment of the set point, which results in the sensation of heat. At the end of a hot flash, the set point returns to normal.
• the trigger for a change in set point may be a series of nerve impulses.
• a fever, even with a rapid onset may last for hours, days or even weeks. In contrast, the duration of a hot flash is in the order of minutes.
• the present invention provides a method of alleviating discomfort experienced by a woman during a hot flash that occurs during menopause including alleviating the feeling of intense heat.
• the present invention further provides a method of alleviating symptoms of physical discomfort resulting from increased heart rate and digital blood flow associated with hot flashes.
• the method of the present invention includes the step of applying topically to the woman a cooling composition having at least one cooling agent.
• a woman experiencing a hot flash may apply the topical cooling composition to any part of her body that feels overheated, it is preferred that the cooling composition is applied topically to the head and/or neck areas. It is more preferred that the cooling composition is applied topically to the face and neck areas. It is most preferred that the cooling composition is applied topically to the temples.
• the cooling composition which is considered a topical composition
• the topical cooling composition may be any form that may be quickly and easily applied to the head and neck areas.
• the topical composition must have at least one cooling agent.
• the cooling agent must be suitable for topical application.
• U.S. Patent No. 5,730,957 to Rizk discloses a cooling mixture of water and dimethyl ether.
• the cooling agents of the present invention are not a mixture of dimethyl ether and water.
• the cooling mixture of the Rizk patent must be delivered at a temperature less than ambient temperature and higher than the freezing point of water.
• the cooling agents suitable and contemplated for use in the present invention do not have any such temperature requirements.
• the cooling mixtures of the Rizk patent achieve their cooling effect through the latent heat of transformation, or evaporation, of both the dimethyl ether and the water components.
• the cooling agents of the present invention in contrast, stimulate the cold receptors of the nervous system, and, thus, achieve a cooling effect that is not dependent upon the temperature of the cooling agent relative to ambient temperature.
• Cooling agents that may be used in the present invention include menthol, and the alkyl-substituted methanols disclosed in U.S. Patent No. 4,069,345 to Gascoyne et al.
• the cooling agent may also be acyclic sulphones or acyclic sulphoxides, phoshine oxides, alkyl-substituted alicyclic carboxylic acids, esters and amides, cyclohexan-amides, cyclic and acyclic amides, substituted ureas and sulphonamides. Examples of the foregoing are disclosed in U.S. Patent Nos. 4,318,900; 4,296,093;
• the cooling agent may also be N-hetero substituted-p-menthane-3-carboxamides as disclosed in U.S. Patent No. 4,190,643 to Watson et al.
• the cooling agent may be monomenthyl succinates, alkali metal salts of monomenthyl succinate, alkaline earth metal salts of monomenthyl succinate, and mixtures thereof. Examples of the foregoing are disclosed in U.S. Patent Nos. 5,725,865 and 5,843,466 to Mane et al.
• the cooling agent can be an asymmetric carbonate, thiocarbonate or urethate as disclosed in U.S. Patent No. 5,703,123 to Pelzer et al.
• the cooling agent can also be a 2-(2-alkoxy-1-methylethyl)-5-methyl cyclohexanol derivative as disclosed in U.S. Patent No. 5,756,857 to Kuribayashi et al.
• Each patent cited in this paragraph is incorporated herein by reference.
• the cooling agent is a ketal, such as menthone glycerin acetal and the ketals disclosed in U.S. Patent No. 5,266,692 to Grub et al., which is incorporated herein by reference, the onset and duration of the effect of the cooling agent may be affected by manipulating the substituents on the ketal.
• the topical cooling composition preferably comprises an alkali metal carbonate and/or bicarbonate and/or alkaline earth metal carbonate as set forth in U.S. Patent No. 5,783,725 to Kuhn et al., which is also incorporated herein by reference, to improve stability of the topical cooling composition.
• cooling composition comprises two or more of the cooling agents, the cooling effect achieved by the cooling composition is enhanced.
• U.S. Patent No. 5,451 ,404 to Furman discloses cooling compositions that are suitable for use in practicing the present invention.
• One example of a topical cooling composition of the Furman '404 patent comprises an effective amount of a first cooling component that is a ketal of the formula
• R 1 represents a C 2 -C 6 -alkylene radical having at least 1 , but not more than 3, hydroxyl group(s) and either R 2 and R 3 independently of one another represent C ⁇ -C ⁇ 0 -alkyl which is optionally substituted by 1 to 3 radicals selected from the group comprising hydroxyl, amino and halogen, or Cs-Cy-cycloalkyl, or C 6 -C ⁇ 2 -aryl, with the proviso that the total of the C atoms of R 2 and R 3 is not less than 3, or R 2 and R 3 together represent an alkylene radical which, together with the carbon atom which carries the radicals R 2 and R 3 , forms a 5-7-membered ring, and a second coolant component selected from the group consisting of menthol, carboxamides and mixtures thereof.
• the preferred cooling agents for the present invention include menthol, menthone glycerin acetal (a non-limiting example of the foregoing is available from Haarmann & Reimer GmbH under the trademark FRESCOLAT ® MGA), menthyl lactate (a non-limiting example of the foregoing is available from Haarmann & Reimer GmbH under the trademark FRESCOLAT ® ML), menthyl pyrrolidane carboxylic acid (PCA) (a non-limiting example of the foregoing is available from Quest International under the tradename QUESTICE L), N-2,3,-Trimethyl-2- isopropyl butanamide (a non-limiting example of the foregoing is available from ChiRex, Inc.
• menthol menthone glycerin acetal
• menthyl lactate a non-limiting example of the foregoing is available from Haarmann & Reimer GmbH under the trademark FRESCOLAT ® ML
• PCA menthyl pyrrolidane carboxylic
• the cooling composition of the present invention comprises from about 0.01 wt% to about 10 wt% of the cooling agent, preferably from about 0.01 wt% to about 5 wt%, more preferably from about 0.1 wt% to about 2 wt%, even more preferably from about 0.1 wt% to about 1 wt%, and most preferably from about 0.2 wt% to about 0.8 wt%.
• the cooling composition is preferably a stick, spray or towelette. It is preferred that the cooling composition is a water-based system. In addition, it is preferred that the when the cooling composition is a water-based composition, the cooling composition further comprises an alcohol, such as ethanol, isopropyl alcohol and propanol. Alcohols act as a solvent and also exert a cooling effect that enhances the benefits of the present invention. When the cooling composition is a water-based system, it is preferred that the cooling composition comprises from about 5 wt% to about 15 wt% of an alcohol. The remainder of the cooling composition may be water. When a water-based system is used, it is preferred that the cooling composition comprises from about 0.01 wt% to about 5 wt% of the cooling agent.
• the cooling composition may also be an anhydrous system.
• an anhydrous system comprising alcohol, such as ethanol, isopropyl alcohol or propanol
• the alcohol comprises the majority of the cooling composition other than the cooling agent.
• an anhydrous, alcohol-free system such as a cosmetic stick
• the composition is comprised of esters, waxes and/or oils in place of the water and alcohol.
• the cooling composition may comprise up to 10 wt% of the cooling agent. It is more preferred that the cooling composition comprises from about 0.1 wt% to about 1 wt% of the cooling agent.
• the natural/botanical extract comprises a soy extract, a black cohosh extract, or a ginseng extract, or mixtures thereof. More preferably, the natural/botanical extract will be a mixture of all three of the foregoing extracts.
• the cooling composition comprises a fragrant component, which is preferably a natural extract
• the alleviation of the discomfort associated with hot flashes is augmented.
• the aromatherapeutic benefits of the fragrant component will provide a calming effect, and thus synergistically enhance the cooling composition's effect on relieving the discomfort, both emotional as well as physiological, associated with hot flashes.
• the cooling composition may also include emulsifiers, thickeners and preservatives.
• Emulsifiers (solubilizers) that can be used in the cooling compositions of the present invention can be cationic, anionic, non-ionic, amphoteric, zwitterionic, or combinations thereof.
• the emulsifier is a polysorbate emulsifier.
• polysorbate emulsifiers are Polysorbate 20 and Polysorbate 80.
• thickeners that can be used are, xanthan gum, magnesium aluminum silicate (a non-limiting example of the foregoing is available under the tradename Veegum), cellulosic thickeners, and polymeric thickeners, such as CARBOPOL, PEMULENTM copolymers and acrylate copolymers.
• a non-limiting example of an acrylate copolymer that may be used in the present invention is an acrylate/Cio to C30 alkyl acrylate copolymer.
• the cooling composition also includes a neutralizer to adjust pH.
• the preferred neutralizer is sodium hydroxide.
• the pH of the cooling composition should be adjusted according to the cooling agent used. For example, it is preferred that when the cooling agent comprises menthone glycerin acetal that the pH of the cooling composition is greater than 7. In contrast, when the cooling agent comprises menthyl lactate, it is preferred that the pH of the cooling composition is less than 7.
• the cooling composition of the present invention described above is used to alleviate the physical symptoms experienced by a woman during a hot flash. It is contemplated that when the cooling composition may be applied immediately when the woman either senses a hot flash about to occur or after a hot flash begins. Although a woman may apply the cooling composition to any surface area of her body that requires relief, it is contemplated that the most useful areas for application will be the chest, face and neck areas, particularly the areas around the temple and at the base of the neck adjacent the spine. In addition, it is also believed that topically applying the cooling composition to the wrist and arm areas will be particularly useful in alleviating discomfort associated with a hot flash.
• the method of the present invention will be used most often to alleviate the discomfort of a hot flash on an as needed basis, it is believed that the method of the present invention may be extended to prophylaxis.
• many women have their slumber disturbed by "night time" hot flashes.
• the onset and duration of action of the cooling agent may be manipulated via changes in chemical structure. Accordingly, women who frequently experience such night time hot flashes may apply, just prior to sleep, topical cooling compositions having cooling agents with either delayed onset or prolonged effect.
• cooling spray When the topical cooling composition is a spray (hereinafter "cooling spray"), it is believed that the optimum benefits of the present invention are achieved in the following manner.
• the user will spray the cooling spray onto the palm(s) of the hand(s) or onto the fingertips.
• the user will then transfer the cooling spray onto the skin.
• the cooling composition should never be directly sprayed onto or near the face area.
• non-spray cooling composition(s) When the topical cooling composition is a stick, towelette, lotion, cream or gel, (hereinafter collectively referred to as "non-spray cooling composition(s)"), the consumer may also manually apply the non-spray cooling composition to the area of skin that feels uncomfortably warm or hot due to the hot flash. It is preferred that the non-spray cooling composition is spread over the surface of the skin, but not rubbed deeply into the skin. Extensive rubbing of the skin may intensify the feeling of heat experienced by the consumer, and is preferably to be avoided.
• Sample A comprised 0.65 wt% menthone glycerin acetal in a compatible vehicle made according to Example 1 above.
• the participants applied Sample A to various parts of their body when experiencing a hot flash.
• Those parts of the body to which the participants applied Sample A included the face, chest, neck/throat, shoulders, back, stomach, legs, arms, wrists and hands.

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  • 2000-02-02 EP EP00905910A patent/EP1171120A4/de not_active Withdrawn
  • 2000-02-02 CA CA002361046A patent/CA2361046A1/en not_active Abandoned
  • 2000-02-02 JP JP2000596935A patent/JP2002536069A/ja active Pending
  • 2000-02-02 AU AU27510/00A patent/AU2751000A/en not_active Abandoned
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