WO2019052303A1 - 含有大麻二酚和/或次大麻二酚的组合物及其在治疗痛经中的应用 - Google Patents

含有大麻二酚和/或次大麻二酚的组合物及其在治疗痛经中的应用 Download PDF

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Publication number
WO2019052303A1
WO2019052303A1 PCT/CN2018/100835 CN2018100835W WO2019052303A1 WO 2019052303 A1 WO2019052303 A1 WO 2019052303A1 CN 2018100835 W CN2018100835 W CN 2018100835W WO 2019052303 A1 WO2019052303 A1 WO 2019052303A1
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Prior art keywords
cannabidiol
composition
dysmenorrhea
preventing
cannabinol
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PCT/CN2018/100835
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English (en)
French (fr)
Inventor
于朝晖
张可
谭昕
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汉义生物科技（北京）有限公司
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Priority to AU2018331073A priority Critical patent/AU2018331073B2/en
Priority to JP2020535286A priority patent/JP6942916B2/ja
Priority to US16/646,533 priority patent/US11123308B2/en
Priority to CA3075668A priority patent/CA3075668C/en
Priority to EP18855825.8A priority patent/EP3673905B1/en
Publication of WO2019052303A1 publication Critical patent/WO2019052303A1/zh

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    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/15—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators
    • A61F13/45—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators characterised by the shape
    • A61F13/47—Sanitary towels, incontinence pads or napkins
    • A61F13/472—Sanitary towels, incontinence pads or napkins specially adapted for female use
    • 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
    • A61K31/05—Phenols
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/20—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing organic materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
    • A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
    • A61L15/42—Use of materials characterised by their function or physical properties
    • A61L15/44—Medicaments
    • 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
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F13/00—Bandages or dressings; Absorbent pads
    • A61F13/15—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators
    • A61F13/45—Absorbent pads, e.g. sanitary towels, swabs or tampons for external or internal application to the body; Supporting or fastening means therefor; Tampon applicators characterised by the shape
    • A61F13/47—Sanitary towels, incontinence pads or napkins
    • A61F2013/4708—Panty-liner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/216—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/402—Anaestetics, analgesics, e.g. lidocaine

Definitions

  • the present invention relates to a composition comprising cannabidiol and/or secondary cannabinol, in particular to a composition comprising cannabidiol and/or cannabinol in the preparation of a medicament for the prevention and/or treatment of topical dysmenorrhea in women And the application of feminine hygiene products.
  • Dysmenorrhea is a common and frequently-occurring disease in gynecology. It has many causes, complicated pathogenesis, large repeatability, and difficult treatment. Especially unmarried women and girls in early menstruation are more common. It is characterized by periodic abdominal pain before and after menstruation or menstruation. Cold pain, burning pain, tingling, dull pain, falling pain, colic, sputum pain, tearing pain, pain extending to the back of the back, even involving the thighs and feet, and even with systemic symptoms, seriously affecting women Work and study reduce the quality of life.
  • Cannabidiol is extracted from natural plant cannabis and has anti-convulsant, sedative, hypnotic, anti-anxiety, anti-psychotic, anti-inflammatory and neuroprotective effects, no psychoactive effect, low binding ability of CBD to CB1 and CB2 receptors.
  • THC tetrahydrocannabinol
  • GW Pharmaceuticals Inc. of the United States developed an intravenous injection using the CBD, which has been approved by the US Food and Drug Administration (FDA) for the treatment of neonatal hypoxic ischemic encephalopathy (NHIE). ).
  • Patent CN103025325A discloses the use of plant cannabinoid cannabinol (CBDV) for the treatment of epilepsy, which discloses that the component containing cannabinoids in the cannabis plant extract for treating seizures constitutes at least 50% ( w/w), and contains CBDV as the main plant cannabinoid and CBD as the secondary cannabinoid.
  • CBDV cannabinoid cannabinol
  • Patent CN1976690A discloses a pharmaceutical composition for treating diseases and/or symptoms of arthritis, wherein the ratio of CBD or CBDV to THC or THCV is less than or equal to 19:1.
  • Patent CN103826621A discloses a pharmaceutical composition comprising plant cannabinoid cannabinol (CBDV) and cannabidiol (CBD), wherein the mass ratio of CBDV to CBD is 7:1 to 1:2, and the composition is used for the composition.
  • CBDV cannabinoid cannabinol
  • CBD cannabidiol
  • a neurological condition characterized by excessive excitement, convulsions, or epilepsy in the central nervous system.
  • Patent CN106074496A discloses the use of a cannabinoid compound in the preparation of a medicament for treating gout.
  • the prior art discloses the application of a cannabinoid compound in the preparation of a medicament for treating gout, lowering blood uric acid and treating hyperuricemia, wherein cannabinol
  • cannabinol The content is 0.3% to 99.7%, and other components are tetrahydrocannabinol, cannabinol, cannabinol, hemp cyclophenol, cannabinoid acid, tetrahydrocannabinol, cannabinol acid, cannabinoid acid, hexahydrogen
  • a cannabinoid compound for the treatment of neuropathic pain is disclosed in the patent CN103533930A, which discloses the treatment of neuropathic pain with cannabinoids, cannabinol, cannabinol and/or tetrahydrocannabinol. application.
  • a film-form mucoadhesive administration form for administering a cannabis preparation is disclosed in the patent CN038137291, which mentions that the preparation can treat and improve dysmenorrhea.
  • the formulation comprises at least one selected from the group consisting of tetrahydrocannabinol, cannabidiol, cannabinol, and cannabinoid pigments.
  • a composition comprising tetrahydrocannabinol (THC) and cannabidiol (CBD) is disclosed in the patent CN028059956, wherein the total weight of cannabinoid is at least 80% by weight and the weight ratio of THC/CBD is 75:25-20: 80, preferably 3:1 to 1:2, particularly preferably 2:1.
  • the analgesic effect of the composition can also be used to treat chronic pain other than diseases such as dysmenorrhea other than advanced cancer or neurological diseases.
  • US20160256411 A1 discloses a method for treating a human disease state or condition by administering a cannabinoid drug to the back of a neck of a human patient, including the treatment of dysmenorrhea.
  • Patent CN105031563A discloses a liquefied alcoholic beverage, and 240 parts of cannabis powder is added to 5000 parts of white wine to prepare medicinal liquor for the treatment of dysmenorrhea.
  • CBD cannabidiol and/or dronabinol
  • sprays or aerosols often contain irritating excipients that do not achieve the goal of continuous administration
  • alcohol in traditional Chinese medicines stimulates the stomach. Mucous membranes, which harm the central nervous system of the human body, especially for underage women and women at the student level, alcohol can affect physical development and learning status.
  • the present invention provides a composition and a feminine hygiene product which can prevent and/or treat dysmenorrhea in women.
  • the present invention addresses the deficiencies of the prior art lack of cannabinol and/or secondary cannabisdiol compositions effective in preventing and/or treating dysmenorrhea in women by administering to the composition the content of cannabidiol and/or secondary cannabisdiol. Adjustments and selection of penetration enhancers provide a topical composition containing fetadiol and/or dronabinol and feminine hygiene products.
  • a first aspect of the invention provides a composition for preventing and/or treating dysmenorrhea in a female, the composition comprising a cannabidiol and/or a secondary cannabinol, a penetration enhancer, and a carrier.
  • the composition of the present invention may contain only cannabinol or only cannabinol, or may contain both cannabidiol and cannabisdiol. It will be understood by those skilled in the art that when the composition contains cannabidiol And the ratio of the mass ratio of the cannabinol to the cannabisdiol may be arbitrary.
  • the mass ratio of the cannabidiol to the cannabinol is 0.1 to 10:1, more preferably The mass ratio of the cannabidiol to the cannabinol is from 2 to 8:1.
  • the mass ratio of the cannabidiol to the cannabinol is from 3 to 7:1, most preferably The mass ratio of the cannabidiol to the cannabinol is 4-6:1.
  • the activator of the present invention is selected from the group consisting of azone, volatile oil, 1,3-dimethyl-2-imidazolidinone (DMI), propylene glycol, ethanol, oleic acid, or a combination of two or more thereof, preferably Azone.
  • the volatile oil of the present invention is an aromatic oil obtained by distillation, pressing or solvent extraction of plants, animals, microorganisms and derivatives thereof.
  • the volatile oil of the present invention refers to an aromatic oil obtained by extracting plant raw materials, more preferably
  • the volatile oil of the present invention is from the family Lamiaceae, such as peppermint, perilla, musk, etc.; Umbelliferae, such as fennel, angelica, medlar, white peony, Chuanxiong, etc.; Asteraceae, such as Ai Ye, Yin Chen, Atractylodes, Atractylodes, Woody, etc.; Rutaceae, such as orange, orange, pepper, etc.; Polygonaceae, such as medlar, cinnamon, etc.; gingeraceae, such as ginger, turmeric, turmeric, etc. extracted.
  • the volatile oil of the present invention is ginger volatile oil or peppermint volatile oil.
  • the mass ratio of the cannabidiol and/or the cannabinol to the penetration enhancer of the present invention is 1:0.1-0.8, more preferably, the cannabidiol and/or the cannabisdiol are promoted.
  • the mass ratio of the penetrant is 1:0.1-0.5, and most preferably, the mass ratio of the cannabidiol and/or the cannabinol to the penetration enhancer is 1:0.2-0.4.
  • cannabinol and/or secondary cannabisdiol improve dysmenorrhea when in a specific range of ratios.
  • the effect is more excellent, possibly due to an improvement in the penetration effect of the penetration enhancer on the absorption of the skin drug, while the penetration enhancer affects the cannabinoid receptor distributed in the absorbent tissue.
  • different types of penetration enhancers can also affect the therapeutic effects of cannabidiol and/or secondary cannabisdiol.
  • azone can further enhance cannabisdiol and/or secondary cannabisdiol. The role.
  • the cannabidiol and/or the cannabinol of the present invention may be extracted or artificially synthesized.
  • the cannabinol and/or the cannabinol of the present invention are extracted from a cannabis plant, and the cannabis plant extracting site may be hemp seeds, hemp leaves, hemp flowers, hemp stalk cores, and hemp roots.
  • the cannabidiol and/or the cannabinol are extracted from the cannabis flower and the leaves.
  • the cannabidiol and/or the cannabinol may be obtained by separately extracting different parts of the cannabis plant, such as cannabis resin extracted from cannabis flower and/or cannabis resin and cannabis leaf extract. a combination of diphenol and/or secondary cannabinol; cannabis resin extracted from hemp stalk core and/or secondary cannabis resin, cannabis resin extracted from cannabis flower and/or cannabis resin and cannabis leaf extract A combination of cannabidiol and/or secondary cannabinol.
  • the cannabidiol and/or the cannabinol may also be obtained by combining different plant parts of the cannabis plant, such as cannabis resin and/or cannabis resin obtained from the extraction of cannabis flowers and leaves; Cannabinol and/or secondary cannabisdiol obtained from the extraction of flowers and leaves; cannabisdiol and/or secondary cannabisdiol obtained from the extraction of hemp stalk cores and flowers; cannabis obtained from the extraction of cannabis stalk cores and leaves Phenol and/or secondary cannabinol; combination of cannabis flower, leaf extract of cannabinol and/or secondary cannabisdiol with cannabis leaf, stalk core extract of cannabidiol and/or cannabinol.
  • cannabis resin and/or cannabis resin obtained from the extraction of cannabis flowers and leaves
  • Cannabinol and/or secondary cannabisdiol obtained from the extraction of flowers and leaves
  • cannabisdiol and/or secondary cannabisdiol obtained from the extraction of hemp stalk cores and flowers
  • the cannabidiol and/or the cannabisdiol according to the present invention can be prepared by a conventional plant extraction method in the prior art, such as solvent extraction, steam distillation, sublimation, supercritical fluid extraction, membrane extraction and separation. Techniques and the like; preferably, a solvent extraction method may be employed, and the extraction solvent may be: a low molecular alcohol (such as methanol, ethanol, butanol or propanol), an acetate (such as methyl acetate or ethyl acetate), a ketone ( Such as acetone), ether (such as methyl ether or ether), low-boiling aliphatic hydrocarbons or aromatic hydrocarbons or chlorinated hydrocarbons; the extraction process can be heated reflux, and can also be combined with other extraction methods such as extraction, distillation, crystallization, chromatography The extract is further purified and separated by a combination of one or more of separations and the like.
  • a solvent extraction method may be employed, and the extraction solvent may
  • composition of the present invention may be in the form of a liquid, a gel, a paste or a patch.
  • the carrier of the present invention can be any carrier suitable for the composition.
  • the carrier is selected from the group consisting of cetyl alcohol, petrolatum, liquid paraffin, glyceryl monostearate, glycerol, hydroxyethyl ester, triethanolamine, ethylparaben, lanolin.
  • cetyl alcohol petrolatum
  • liquid paraffin liquid paraffin
  • glyceryl monostearate liquid paraffin
  • glycerol hydroxyethyl ester
  • triethanolamine ethylparaben
  • lanolin lanolin.
  • One or a combination of two or more of stearic acid is selected from the group consisting of cetyl alcohol, petrolatum, liquid paraffin, glyceryl monostearate, glycerol, hydroxyethyl ester, triethanolamine, ethylparaben, lanolin.
  • stearic acid one or a combination of two or more of stearic acid.
  • the carrier is selected from the group consisting of carbomer, polyvinyl alcohol, carboxymethylcellulose and sodium salts thereof, and one or a combination of two or more of polyacrylic acid and its sodium salt.
  • the carrier is selected from one or a combination of two or more of a hot melt pressure sensitive adhesive, a rubber, a polymer hydrogel, a medical tape, and an acrylate pressure sensitive adhesive.
  • the carrier may be one of a yarn, a cotton thread, a hemp fiber, or a combination of two or more.
  • the carrier is selected from the group consisting of an alcohol solution such as an ethanol solution, glycerin or the like, an ether such as a polyoxyethylene alkyl ether, etc., an ester such as a dibasic acid diester, a vegetable oil such as Castor oil, one or a combination of two or more of corn oil.
  • the carrier may further contain an adhesive, a filler, a humectant, a crosslinking agent, a colorant, a pH adjuster, a tackifier, a preservative, and the like.
  • the adhesive may be selected from the group consisting of gelatin, sodium alginate, gum arabic, starch, methyl cellulose, carboxymethyl cellulose and sodium salts thereof, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, and Kappa.
  • the filler may be selected from one or more of zinc oxide, micronized silica gel, calcium carbonate, diatomaceous earth, and titanium dioxide. Any combination of the above; the humectant may be selected from any one or a combination of two or more of glycerin, propylene glycol, sorbitol, polyethylene glycol; the crosslinking agent may be selected from calcium hydroxide, trichlorination Any one or a combination of two or more of aluminum, aluminum glycinate, and disodium edetate.
  • the ratio of cannabidiol and/or secondary cannabisdiol to carrier described in the compositions of the present invention can be selected depending on the particular formulation form.
  • the mass ratio of the cannabidiol and/or the cannabinol to the carrier is 1:4-50.
  • the mass ratio of the cannabidiol and/or the cannabinol to the carrier is 1:10-40, more preferably, the mass ratio of the cannabidiol and/or the cannabinol to the carrier is 1:20-30.
  • the present invention also provides a feminine hygiene product, the feminine hygiene product comprising the composition of the present invention, the composition comprising an active substance, a carrier and a penetration enhancer, the active substance and the carrier
  • the mass ratio is 1:4 to 50, the mass ratio of the active substance to the penetration enhancer is 1:0.1-0.8, and the active substance is cannabinol and/or secondary cannabisdiol, the cannabidiol
  • the mass ratio to the cancaria diphenol is from 0.1 to 10:1.
  • the mass ratio of the cannabidiol to the cannabinol is from 2 to 8:1, and more preferably, the cannabidiol is The mass ratio of the cannabinol is from 3 to 7:1.
  • the mass ratio of the cannabidiol to the cannabinol is from 4 to 6:1.
  • the carrier is one or a combination of two or more of a yarn, a cotton thread or a hemp fiber.
  • the carrier in the composition is hemp fiber, and the hemp fiber is sprayed or impregnated with an active substance and a penetration enhancer.
  • the feminine hygiene product is a sanitary napkin, a sanitary napkin or a sanitary pad.
  • the present invention also provides the use of a composition comprising cannabidiol and/or secondary cannabinol for the preparation of a medicament for preventing and/or treating dysmenorrhea, which comprises cannabinol and/or secondary cannabisdiol
  • the drug is a gelatinous, creamy or patch-like external drug, and more preferably, the drug is a paste or patch-like external drug, particularly preferably, The drug described is a patch-like external drug.
  • the dysmenorrhea according to the invention is selected from the group consisting of primary dysmenorrhea and secondary dysmenorrhea.
  • the prevention and/or treatment of dysmenorrhea includes prevention and/or treatment of dysmenorrhea caused by swelling of the lower abdomen, nausea, vomiting, headache, diarrhea, somnolence, loss of appetite, irritability, low back pain, lower limb pain, anemia, menstruation At least one or two or more symptoms of excessive and tiredness.
  • the present invention also provides a method of preventing and/or treating dysmenorrhea, the method comprising administering a composition comprising a cannabidiol and/or a secondary cannabinol, a penetration enhancer, and a carrier.
  • the composition comprises cannabidiol and cannabisdiol, and the mass ratio of the cannabidiol to the cannabisdiol is 0.1 to 10:1.
  • the mass ratio of the cannabidiol and/or the secondary cannabinol to the penetration enhancer is 1:0.1-0.8.
  • treating includes inhibiting, delaying, alleviating, attenuating, limiting, alleviating or ameliorating a disease, disorder, condition or condition, its occurrence and/or progression, and/or its symptoms.
  • prevention includes reducing the risk of having, infecting or experiencing a disease, disorder, condition or condition, its occurrence and/or progression, and/or its symptoms.
  • the cannabisdiol extract is obtained, wherein the cannabidiol content is 99.5% by mass.
  • the description of "8 times the amount” and the like in the present invention means that the volume of the extraction solvent used is 8 times the mass of the extraction site, for example, 1 g of the cannabis extraction site and 8 ml of the extraction solvent.
  • the obtained powder is extracted by adding 10 times of absolute ethanol in a mass-to-volume ratio for 3 times, each time for 1 hour;
  • Example 3 Preparation of a topical patch for preventing and/or treating female dysmenorrhea
  • the invention relates to a topical medicine for preventing and/or treating dysmenorrhea in a female, wherein the external medicine is a patch-like external medicine, the backing layer is a non-woven fabric, the protective layer is a release paper, and the cannuladiol is promoted in the drug storage layer.
  • the mass ratio of the penetrant is 1:0.5
  • the penetration enhancer is ginger volatile oil
  • the carrier of the drug storage layer is a polymer hydrogel
  • the mass ratio of the cannabidiol to the carrier is 1:4, the high
  • the molecular hydrogel is prepared by mixing carboxymethylcellulose sodium, glycerin, water and alumina in a mass ratio of 10:30:40:0.1.
  • the cannabisdiol and the ginger volatile oil After mixing the cannabisdiol and the ginger volatile oil, it is mixed with the polymer hydrogel, and then the mixture is poured into a coater, uniformly coated onto the nonwoven fabric of the backing layer, and then covered with a protective layer.
  • Anti-adhesive paper that is, a patch is prepared.
  • Example 4 Preparation of a topical patch for preventing and/or treating female dysmenorrhea
  • the invention relates to a topical medicine for preventing and/or treating dysmenorrhea in a female, wherein the external medicine is a patch-like external medicine, the backing layer is a non-woven fabric, the protective layer is a release paper, and the cannabisdiol in the drug storage layer is
  • the mass ratio of the penetration enhancer is 1:0.1
  • the penetration enhancer is peppermint volatile oil
  • the carrier of the drug reservoir layer is a polymer hydrogel
  • the mass ratio of the cannabisdiol to the carrier is 1:9.
  • the polymer hydrogel is prepared by mixing carboxymethylcellulose sodium, propylene glycol, water and calcium hydroxide in a mass ratio of 7:25:30:0.2.
  • the cannabisdiol and the mint volatile oil After mixing the cannabisdiol and the mint volatile oil, it is mixed with the polymer hydrogel, and then the mixture is poured into a coater, uniformly coated on the nonwoven fabric of the backing layer, and then covered with a protective coating.
  • a layer of anti-adhesive paper, that is, a patch is prepared.
  • Example 5 Preparation of a topical patch for preventing and/or treating female dysmenorrhea
  • the invention relates to a topical medicine for preventing and/or treating dysmenorrhea in a female, wherein the external medicine is a patch-like external medicine, the backing layer is a non-woven fabric, the protective layer is a release paper, and the cannuladiol and the drug in the drug storage layer are
  • the mass ratio of cannabidiol is 5:1
  • the mass ratio of the mixture of cannabidiol and cancariadiol to the penetration enhancer is 1:0.8
  • the penetration enhancer is propylene glycol
  • the carrier of the drug reservoir layer is high.
  • the molecular hydrogel, the mass ratio of the mixture of cannabidiol and the cannabinol to the carrier is 1:15, and the polymer hydrogel is a carboxymethyl fiber having a mass ratio of 8:40:55:0.3.
  • cannabinol and cannabisdiol After mixing cannabinol and cannabisdiol, it is added to propylene glycol, stirred and mixed, and then mixed with the polymer hydrogel, and then the mixture is poured into a coater and uniformly coated onto the backing. On the non-woven fabric of the layer, a protective layer release paper is further coated, that is, a patch is prepared.
  • Example 6 Preparation of a topical patch for preventing and/or treating female dysmenorrhea
  • the invention relates to a topical medicine for preventing and/or treating dysmenorrhea in a female, wherein the external medicine is a patch-like external medicine, the backing layer is a non-woven fabric, the protective layer is a release paper, and the cannabisdiol in the drug storage layer is
  • the mass ratio of the penetration enhancer is 1:0.5
  • the penetration enhancer is azone
  • the carrier of the drug reservoir layer is a hot melt pressure sensitive adhesive
  • the mass ratio of the subcannabinol to the carrier is 1:20.
  • the hot melt pressure sensitive adhesive is styrene-butadiene rubber and tackifier according to the mass ratio of 2.8:3.3:2.1 (the tackifier is a hydrogenated rosin glyceride with a mass ratio of 1:1, and a pentaerythritol ester of rosin). It is heated and melted with squalane and mixed uniformly.
  • the mixture After mixing the cannabinol and the azone, the mixture is mixed with the hot melt pressure sensitive adhesive, and then the mixture is poured into a coater, uniformly coated on the nonwoven fabric of the backing layer, and then covered with a protective coating.
  • a layer of anti-adhesive paper, that is, a patch is prepared.
  • Example 7 Preparation of a topical patch for preventing and/or treating female dysmenorrhea
  • the invention relates to a topical medicine for preventing and/or treating dysmenorrhea in a female, wherein the external medicine is a patch-like external medicine, the backing layer is a non-woven fabric, the protective layer is a release paper, and the cannuladiol is promoted in the drug storage layer.
  • the mass ratio of the penetrant is 1:0.1
  • the penetration enhancer is azone
  • the carrier of the drug reservoir layer is a hot melt pressure sensitive adhesive
  • the mass ratio of the cannabidiol to the carrier is 1:25.
  • Melt pressure sensitive adhesive is weighed styrene-butadiene rubber and tackifier according to mass ratio of 3.9:3.3:2.4 (tackifier is hydrogenated rosin glyceride with mass ratio of 1:1, pentaerythritol ester of rosin) and corner
  • tackifier is hydrogenated rosin glyceride with mass ratio of 1:1, pentaerythritol ester of rosin
  • the cannabidiol After mixing the cannabidiol with the azone, it is mixed with the hot melt pressure sensitive adhesive, and then the mixture is poured into a coater, uniformly applied to the nonwoven fabric of the backing layer, and then covered with a protective layer.
  • Anti-adhesive paper that is, a patch is prepared.
  • Example 8 Preparation of a topical patch for preventing and/or treating female dysmenorrhea
  • the invention relates to a topical medicine for preventing and/or treating dysmenorrhea in a female, wherein the external medicine is a patch-like external medicine, the backing layer is a non-woven fabric, the protective layer is a release paper, and the drug cannabisdiol in the drug storage layer
  • the mass ratio of the penetration enhancer is 1:0.8, the penetration enhancer is azone, the carrier of the drug reservoir layer is a hot melt pressure sensitive adhesive, and the mass ratio of the cannabidiol to the carrier is 1:30.
  • the hot melt pressure sensitive adhesive is weighed into a styrene-butadiene rubber and a tackifier at a mass ratio of 3.5:4.7:3.5 (the tackifier is a hydrogenated rosin glyceride having a mass ratio of 1:1, and a pentaerythritol ester of rosin). It is heated and melted with squalane and mixed uniformly.
  • the cannabidiol After mixing the cannabidiol with the azone, it is mixed with the hot melt pressure sensitive adhesive, and then the mixture is poured into a coater, uniformly applied to the nonwoven fabric of the backing layer, and then covered with a protective layer.
  • Anti-adhesive paper that is, a patch is prepared.
  • Example 9 Preparation of a composition for preventing and/or treating female dysmenorrhea as a composition of hemp fibers
  • a preparation for preventing and/or treating a dysmenorrhea in a female wherein the carrier of the composition is hemp fiber, and the mass ratio of the cannabidiol to the carrier in the composition is 1:50, and the composition promotes
  • the penetrant is azone, and the mass ratio of cannabidiol to azone is 1:0.8.
  • the medium penetration enhancer is azone, and the mass ratio of cannabidiol to azone is 1:0.7.
  • the sanitary napkin comprising an outer layer, an inner layer and a lower layer, the outer layer comprising the hemp-containing fiber prepared in the step 1)
  • the composition is made of textile, the inner layer of the sanitary napkin is a cotton material, and the lower layer is a film material.
  • Example 11 Preparation of a topical cream for preventing and/or treating female dysmenorrhea
  • a topical medicine for preventing and/or treating dysmenorrhea in a female wherein the topical medicine is a cream, wherein the mass ratio of the cannabidiol to the penetration enhancer is 1:0.3, and the penetration enhancer is ginger volatile oil
  • the oil phase in the carrier is lanolin, stearic acid and liquid paraffin in a mass ratio of 1.6:2.5:1.8
  • the aqueous phase in the carrier is glycerol, hydroxyethyl ester, carbomer, marijuana 2 in a mass ratio of 7.3:1:1.
  • the mass ratio of phenol to carrier was 1:40.
  • Example 12 Preparation of a topical cream for preventing and/or treating female dysmenorrhea
  • a topical medicine for preventing and/or treating dysmenorrhea in a female wherein the topical medicine is a cream, wherein the mass ratio of the cannabidiol to the penetration enhancer is 1:0.5, and the penetration enhancer is peppermint volatile oil.
  • the oil phase in the carrier is petrolatum, triethanolamine, stearic acid and liquid paraffin in a mass ratio of 2:1.2:2.8:1.9, and the aqueous phase in the carrier is glycerol, hydroxyphenylethyl ester, and kapoor in a mass ratio of 8:1.5:1.7.
  • the mass ratio of cannabidiol to the carrier is 1:50.
  • Vaseline, triethanolamine, stearic acid, liquid paraffin are uniformly mixed, heated to 65 ° C ⁇ 90 ° C, completely dissolved to obtain an oil phase; glycerin, hydroxyethyl ester, carbomer and part of water are mixed and heated to 65 ° C
  • the aqueous phase is obtained at ⁇ 90 ° C; the oil phase is added to the aqueous phase, the cream carrier is stirred, the cannabidiol is added to the cream carrier, and the mixture is uniformly stirred.
  • the volatile oil of the mint is added to the cream, and the external cream is obtained by stirring uniformly.
  • Example 13 Preparation of a topical liquid paint for preventing and/or treating dysmenorrhea in women
  • a topical medicine for preventing and/or treating dysmenorrhea in a female the external medicine being a liquid external preparation, wherein the mass ratio of the cannabidiol to the penetration enhancer in the liquid external preparation is 1:0.8, and the penetration enhancer is nitrogen
  • the ketone is a glycerol and ethanol having a mass ratio of 1:1, and the mass ratio of the cannabidiol to the carrier is 1:50.
  • the cannabidiol is dissolved in a mixture of glycerin and ethanol, stirred uniformly, and then added with azone, and stirred until a colorless transparent liquid is formed to obtain a liquid coating agent for external surface use.
  • Example 14 Effect of different cannabinol or subcannabinol content compositions on dysmenorrhea model in rats
  • Test sample a patch containing a mass ratio of cannabidiol to azone and a carrier of 1:0.8:4, 1:0.8:25, 1:0.8:50; mass ratio of subcannabinol to azone and carrier It is a patch of 1:0.8:4, 1:0.8:25, 1:0.8:50.
  • Test animals 200-220 g female rats.
  • Test method a patch containing a mass ratio of cannabidiol or secondary cannabinol to azone and a carrier of 1:0.8:4, 1:0.8:25, 1:0.8:50 is cut into small pieces of 3 ⁇ 3 cm 2 Spare, wherein the total dose of the combination of cannabidiol or secondary cannabinol, azone and carrier in each set of patches is the same.
  • the first group was a negative control group, and the rats were placed with an equal amount of physiological saline instead of a composition containing cannabidiol or secondary cannabinol, azone and a carrier;
  • the mass ratio of cannabidiol to azone and carrier in the abdomen of rats was 1:0.8:25;
  • the mass ratio of cannabidiol to azone and carrier in the abdomen of rats was 1:0.8:50;
  • the mass ratio of the cannabisdiol to the azone and the carrier in the abdomen of the rat is 1:0.8:4;
  • the mass ratio of the cannabisdiol to the azone and the carrier in the abdomen of the rat is 1:0.8:25;
  • the mass ratio of the cannabisdiol to the azone and the carrier in the abdomen of the rat was 1:0.8:50. Change daily for 4 consecutive days.
  • Rats in each group were injected subcutaneously (sc) with diethylstilbestrol for 4 consecutive days at a daily dose of 8 mg ⁇ kg -1 to improve uterine sensitivity. After 2 hours of administration on the 4th day, the rats were intraperitoneally injected with 2 IU of oxytocin, and the uterus of the rats was contracted to induce the writhing reaction. The number of writhings of each rat in the next 40 minutes was observed and recorded, and the writhing was calculated. Incidence. The results of the recording are shown in Table 1.
  • the second to seventh groups of patches have a significant alleviation effect on dysmenorrhea-induced rat dysmenorrhea-like reaction, and the higher the content of cannabidiol or subcannabinol, the more significantly slow the rats The writhing reaction can prolong the latency of the reaction.
  • Test sample A patch containing a mass ratio of cannabidiol to azone of 1:1, 1:0.8, 1:0.4, 1:0.1, 1:0.05.
  • Test animals 200-220 g female rats.
  • the mass ratio of cannabidiol to azone is 1:1, the mass ratio of cannabidiol to azone is 1:0.8, the mass ratio of cannabidiol to azone is 1:0.4, cannabisdiol
  • the mass ratio of azone to azone is 1:0.1, the mass ratio of cannabidiol to azone is 1:0.05, and the patch is cut into 3 ⁇ 3 cm 2 for use, wherein the dosage of cannabidiol in each group of patches is the same, and The mass ratio of cannabidiol to the carrier was 1:10.
  • the first group was a negative control group, and a patch of 3 ⁇ 3 cm 2 was replaced with an equal amount of physiological saline in place of a mixture of cannabidiol and azone.
  • the second group is provided with a patch having a mass ratio of cannabisdiol and azone to 1:1 in the abdomen;
  • the third group is provided with a patch having a mass ratio of cannabisdiol and azone to 1:0.8 in the abdomen;
  • the fourth group is provided with a patch having a mass ratio of cannabisdiol and azone to 1:0.4 in the abdomen;
  • the fifth group has a patch containing a mass ratio of cannabidiol to azone at a ratio of 1:0.1 in the abdomen;
  • a patch containing a mass ratio of cannabidiol to azone at a ratio of 1:0.05 was attached to the abdomen.
  • Rats in each group were injected subcutaneously (sc) with diethylstilbestrol for 4 consecutive days at a daily dose of 8 mg ⁇ kg -1 to improve uterine sensitivity. After 2 hours of administration on the 4th day, the rats were intraperitoneally injected with 2 IU of oxytocin, and the uterus of the rats was contracted to induce the writhing reaction. The number of writhings of each rat in the next 40 minutes was observed and recorded, and the writhing was calculated. Incidence. The results of the recording are shown in Table 2.
  • the patch containing a mixture of cannabidiol and azone was able to slow the writhing response of rats compared with the negative control group, especially the third group, the fourth group, and the fifth group.
  • the agent can significantly slow down the writhing reaction in rats, indicating that the mass ratio of cannabidiol to azone is 1:0.8, 1:0.4, 1:0.1 can better alleviate dysmenorrhea in mice.
  • Test sample a patch with a mass ratio of cannabisdiol and azone to 1:0.8; a mass ratio of cannabisdiol to ginger with a mass ratio of 1:0.8; the mass ratio of cannabisdiol to peppermint volatile oil is 1:0.8 A patch; a mass ratio of cannabidiol to DMI of 1:0.8.
  • Test animals 200-220 g female rats.
  • the mass ratio of cannabidiol to azone is 1:0.8; the mass ratio of cannabisdiol to ginger volatile oil is 1:0.8; the mass ratio of cannabidiol to peppermint volatile oil is 1:0.8; cannabisdiol and DMI
  • the patch having a mass ratio of 1:0.8 was cut into small pieces of 3 ⁇ 3 cm 2 for use, wherein the dose of the cannabidiol was the same in each of the patches, and the mass ratio of the cannabidiol to the carrier was 1:10.
  • Fifty female rats weighing 200-220 g were randomly divided into 5 groups, 10 in each group, and the hair on the abdomen skin was shaved.
  • the first group was a negative control group, and a patch of 3 ⁇ 3 cm 2 was replaced with an equal amount of physiological saline in place of a mixture of cannabidiol and a penetration enhancer in the abdomen;
  • the second group has a patch containing a mass ratio of cannabidiol and azone to 1:0.8 in the abdomen;
  • the third group has a patch containing a mass ratio of cannabisdiol and ginger volatile oil of 1:0.8 in the abdomen;
  • the fourth group has a patch containing a mass ratio of cannabisdiol and peppermint volatile oil of 1:0.8 in the abdomen;
  • a patch containing a mass ratio of cannabidiol to DMI of 1:0.8 was attached to the abdomen.
  • the patch containing the mixture of cannabidiol and the penetration enhancer significantly slowed the writhing reaction in rats compared with the negative control group, especially the second group of patches was significantly slower.
  • the writhing reaction of the mouse indicates that the patch made of cannabidiol and azone can better alleviate dysmenorrhea in mice.
  • Test sample a patch containing cannabidiol, cannabinol, azone and a carrier, the mass ratio of cannabidiol and cannabisdiol to azone and carrier in the patch is 1:0.8:10, and each group The mass ratios of cannabinol and subcannabinol were 1:0.1, 1:0.2, 1:1, 1:10, respectively.
  • Test animals 200-220 g female rats.
  • Each group of patches having a mass ratio of cannabidiol and cannabisdiol in the composition of 1:0.1, 1:0.2, 1:1, 1:10 was cut into 3 ⁇ 3 cm 2 pieces for use, and each group was pasted.
  • the total dose of cannabidiol and cannabinol in the agent is the same.
  • the first group has a patch containing a mass ratio of cannabidiol and cannabisdiol to 1:0.1 in the abdomen;
  • the second group has a patch containing a mass ratio of cannabidiol and subcannabinol to 1:0.2 in the abdomen;
  • the third group has a patch containing a mass ratio of cannabidiol and subcannabinol to 1:1 in the abdomen;
  • the fourth group was applied with a patch containing 1:10 mass ratio of cannabidiol and cannabisdiol in the abdomen.
  • patches containing different ratios of cannabidiol and cannabisdiol have a significant alleviation effect on dysmenorrhea-induced rat oxytocin-like reactions, but the proportion of cannabidiol in the composition is higher. When it is high, it can slow down the writhing reaction of rats, especially when the mass ratio of cannabidiol and cannabisdiol is 1:0.2.

Abstract

一种预防和/或治疗女性痛经的组合物，所述组合物包括大麻二酚和/或次大麻二酚、促透剂和载体，所述的大麻二酚和/或次大麻二酚与促透剂的质量比为1：0.1-0.8。所述的组合物可缓解女性痛经，并可用于制备预防和/或治疗女性痛经的女性卫生用品。

Description

含有大麻二酚和/或次大麻二酚的组合物及其在治疗痛经中的应用 技术领域
本发明涉及一种含有大麻二酚和/或次大麻二酚的组合物，特别是涉及一种含有大麻二酚和/或次大麻二酚的组合物在制备预防和/或治疗女性痛经外用药物以及女性卫生用品中的应用。
背景技术
痛经是妇科常见病和多发病，病因多，病机复杂，反复性大，治疗棘手，尤其是未婚女性及月经初期少女更为普遍，表现为经期或行经前后，周期性发生下腹部胀痛、冷痛、灼痛、刺痛、隐痛、坠痛、绞痛、痉挛性疼痛、撕裂性疼痛，疼痛延至骶腰背部，甚至涉及大腿及足部，甚至伴有全身症状，严重影响了女性的工作和学习，降低了生活的质量。
在临床经验中，中医以“舒肝解郁，疏通经脉，活血化瘀，理气止痛”为治疗理论，患者服用汤药以进行治疗，然而汤药味苦且易产生副作用。西医在治疗痛经中常用止痛类药物或激素类药物，而止痛药会造成神经系统功能紊乱，记忆力降低、失眠等不良后果。激素类药物会使人体产生依赖性，且会造成人体激素代谢紊乱。
大麻二酚(Cannabidiol，CBD)提取于天然植物大麻，具有抗惊厥、镇静催眠、抗焦虑、抗精神病、抗炎症及保护神经的作用，无精神效应，CBD与CB1和CB2受体的结合能力低于四氢大麻酚(THC)。2015年，美国GW制药公司使用CBD开发制成一种静脉注射剂，该药剂已获得美国食品药品监督管理局(FDA)授予的罕见病药物资格，用于治疗新生儿缺氧缺血性脑病(NHIE)。
专利CN103025325A公开了植物大麻素次大麻二酚(CBDV)在治疗癫痫中的用途，该现有技术公开了用于治疗癫痫发作的大麻植物提取物中含植物大麻素的组分构成至少50％(w/w)，并且包含作为主要植物大麻素的CBDV和作为次要大麻素的CBD。
专利CN1976690A公开了治疗关节炎的疾病和/或症状的药物组合物，其中，CBD或CBDV与THC或THCV的比率小于或等于19:1。
专利CN103826621A公开了包含植物大麻素次大麻二酚(CBDV)和大麻二酚(CBD)的药物组合物，该组合物中CBDV与CBD的质量比为7:1至1:2，该组合物用于治疗中枢神经系统的过度兴奋、惊厥或癫痫发作为特征的神经病症。
专利CN106074496A公开了大麻酚类化合物在制备治疗痛风药物中的应用，该现有技 术公开了大麻酚类化合物在制备治疗痛风、降血尿酸、治疗高尿酸血症药物中的应用，其中大麻二酚的含量为0.3％～99.7％，其它成分为四氢大麻酚，大麻酚，大麻萜酚，大麻环酚，大麻酚酸，四氢大麻酚酸，大麻二酚酸，大麻萜酚酸，六氢次大麻呋酚酸，次大麻酚，次大麻二酚，四氢次大麻酚，大麻色烯和次大麻色烯中的一种或几种的混合物。
专利CN103533930A中公开了用于治疗神经性疼痛的大麻素类化合物，该现有技术公开了大麻环萜酚、大麻萜酚、次大麻二酚和/或四氢大麻酚在治疗神经性疼痛中的应用。
专利CN038137291中公开了给予大麻制剂的薄膜形粘膜粘性的给药剂型，其中提及了该制剂能够治疗和改善痛经。该制剂包括至少含有一种选自包括四氢大麻酚、大麻二酚、大麻酚、和大麻色素的组。
专利CN028059956中公开了一种含有四氢大麻酚(THC)和大麻二酚(CBD)的组合物中，其中大麻素总重量的至少80wt％，THC/CBD的重量比是75∶25-20∶80，优选3∶1-1∶2，尤其优选2∶1。该组合物的止痛作用还可用于治疗除了由晚期癌症或者神经疾病以外的如痛经等疾病所引起的慢性疼痛。
专利US20160256411A1公开了一种通过向人类患者颈部后部施用大麻素药物来治疗人类疾病状态或病症的方法，其中包括痛经的治疗。
专利CN105031563A中公开了一种化瘀酒，将240份大麻仁粉末加到5000份白酒中，制成药酒，以用于痛经的治疗。
尽管目前已经开发了一系列含有大麻二酚和/或次大麻二酚的药物组合物，但是现有组合物均不能满足针对女性痛经病症的治疗。例如，口服药物中CBD不能快速吸收并在需要的部位释放药物；喷雾剂或气雾剂中往往含有刺激性的辅料，同时不能达到持续给药的目的；传统的中药酒剂中酒精会刺激胃粘膜，伤害人的中枢神经系统，尤其是对于未成年女性及处于学生阶段的女性，酒精会影响身体发育以及学习状态。
为克服现有技术中的缺陷，本发明提供一种可预防和/或治疗女性痛经的组合物以及女性卫生用品。
发明内容
本发明解决了现有技术中缺少有效预防和/或治疗女性痛经的大麻二酚和/或次大麻二酚组合物的缺陷，通过对组合物中大麻二酚和/或次大麻二酚含量的调整以及对促透剂的选择，提供了一种含有大麻二酚和/或次大麻二酚的外用组合物和女性卫生用品。
本发明的第一方面提供了一种预防和/或治疗女性痛经的组合物，所述的组合物中包括 大麻二酚和/或次大麻二酚、促透剂以及载体。
本发明所述组合物中可以仅含有大麻二酚或仅含有次大麻二酚，也可以同时含有大麻二酚和次大麻二酚，本领域技术人员可以理解，当组合物中同时含有大麻二酚和次大麻二酚时，大麻二酚和次大麻二酚的质量比可以是任意的，优选的，所述的大麻二酚与次大麻二酚的质量比为0.1～10:1，更优选的，所述的大麻二酚与次大麻二酚的质量比为2～8:1，特别优选的，所述的大麻二酚与次大麻二酚的质量比为3～7:1，最优选的，所述的大麻二酚与次大麻二酚的质量比为4～6:1。
本发明所述促透剂选自氮酮、挥发油、1,3-二甲基-2-咪唑啉酮(DMI)、丙二醇、乙醇、油酸中的一种或两种以上的组合，优选为氮酮。
本发明所述挥发油是由植物、动物、微生物及其衍生物经蒸馏、压榨或溶剂提取而获得的芳香油，优选的，本发明所述的挥发油指由植物原料提取获得的芳香油，更优选的，本发明所述的挥发油是从唇形科，如薄荷、紫苏、藿香等；伞形科，如茴香、当归、芫荽、白芷、川芎等；菊科，如艾叶、茵陈篙、苍术、白术、木香等；芸香科，如橙、桔、花椒等；樟科，如樟、肉桂等；姜科，如生姜、姜黄、郁金等提取获得的。特别优选的，本发明所述的挥发油为生姜挥发油或薄荷挥发油。
优选的，本发明所述的大麻二酚和/或次大麻二酚与促透剂质量比为1:0.1-0.8，更优选的，所述的大麻二酚和/或次大麻二酚与促透剂质量比为1:0.1-0.5，最优选的，所述的大麻二酚和/或次大麻二酚与促透剂质量比为1:0.2-0.4。
本发明通过对比大麻二酚和/或次大麻二酚与促透剂不同比例的组合物，惊奇的发现，当在特定的比例范围时，大麻二酚和/或次大麻二酚对痛经的改善效果呈现更加优异的表现，其原因可能是由于促透剂对皮肤药物吸收的渗透效果的改善，同时促透剂会影响分布于吸收组织的大麻素受体。而进一步的实验表明，不同类型的促透剂也会对大麻二酚和/或次大麻二酚治疗效果的发挥产生影响，特别的，氮酮能够进一步增强大麻二酚和/或次大麻二酚的作用。
本发明所述大麻二酚和/或次大麻二酚可以是提取得到的或人工合成的。
优选的，本发明所述大麻二酚和/或次大麻二酚是从大麻植株中提取得到的，所述大麻植株提取部位可以为大麻籽、大麻叶、大麻花、大麻秆芯、大麻根中的一种或任意两种及以上以任意比例的组合，优选的，所述大麻二酚和/或次大麻二酚是从大麻花、叶中提取得到的。
进一步地，所述大麻二酚和/或次大麻二酚可以是将大麻植株不同部位分别提取后组合，如大麻花提取得到的大麻二酚和/或次大麻二酚与大麻叶提取得到的大麻二酚和/或次大麻二酚的组合；大麻秆芯提取得到的大麻二酚和/或次大麻二酚、大麻花提取得到的大麻二酚和/或次大麻二酚与大麻叶提取得到的大麻二酚和/或次大麻二酚的组合等。所述大麻二酚和/或次大麻二酚也可以是将大麻植株不同的植物部位组合后同时提取，如大麻花与叶的提取得到的大麻二酚和/或次大麻二酚；大麻秆芯与花、叶的提取得到的大麻二酚和/或次大麻二酚；大麻秆芯和花的提取得到的大麻二酚和/或次大麻二酚；大麻秆芯和叶的提取得到的大麻二酚和/或次大麻二酚；大麻花、叶提取得到的大麻二酚和/或次大麻二酚与大麻叶、秆芯提取得到的大麻二酚和/或次大麻二酚的组合等形式。
本发明所述的大麻二酚和/或次大麻二酚可采用现有技术中常规的植物提取方法来制备，如溶剂提取法、水蒸气蒸馏法、升华法、超临界流体萃取、膜提取分离技术等等；优选的，可采用溶剂提取法，提取溶剂可为：低分子醇(如甲醇、乙醇、丁醇或者丙醇)、乙酸酯(如乙酸甲酯或者乙酸乙酯)、酮(如丙酮)、醚(如甲醚或者乙醚)、低沸点的脂肪烃或者芳香烃或者氯化烃等；提取的工艺可为加热回流，还可结合其他提取分离方式如萃取、蒸馏、结晶、色谱分离等中的一种或多种的组合对提取物进行进一步的提纯分离。
本发明所述的组合物可以为液体状，凝胶状，膏状或贴剂状。因此，本领域技术人员可以理解，本发明所述的载体可以为任意的适合于组合物的载体。
例如，当组合物为膏状时，所述的载体选自十六醇，凡士林，液体石蜡，单硬脂酸甘油酯，甘油，羟苯乙酯，三乙醇胺，尼泊金乙酯，羊毛脂，硬脂酸中的一种或两种以上的组合。
当组合物为凝胶状时，所述的载体选自卡波姆，聚乙烯醇，羧甲基纤维素及其钠盐，聚丙烯酸及其钠盐中的一种或两种以上的组合。
当组合物为贴剂状时，所述的载体选自热熔压敏胶、橡胶、高分子水凝胶、医用胶带和丙烯酸酯压敏胶中的一种或两种以上的组合。
当组合物为医用或卫生制品时，所述的载体也可以是纱线、棉线、大麻纤维中的一种或两种以上的组合。
当组合物为液体状时，所述的载体选自醇溶液，如乙醇溶液、甘油等，醚类，如聚氧 乙烯烷基醚等，酯类，如二元酸二酯，植物油类，如蓖麻油，玉米油中的一种或两种以上的组合。
在本发明的一个实施方式中，所述的载体还可以含有胶粘剂、填充剂、保湿剂、交联剂、着色剂、pH调节剂、增粘剂、防腐剂等。例如，所述的胶粘剂可以选自明胶、海藻酸钠、阿拉伯胶、淀粉、甲基纤维素、羧甲基纤维素及其钠盐、聚乙烯醇、聚乙二醇、聚乙烯吡咯烷酮、卡波姆、聚丙烯酸及其钠盐中的一种或两种以上的任意组合；所述的填充剂可以选自氧化锌、微粉硅胶、碳酸钙、硅藻土、二氧化钛中的一种或两种以上的任意组合；所述的保湿剂可以选自甘油、丙二醇、山梨醇、聚乙二醇中任意一种或两种以上的组合；所述的交联剂可以选自氢氧化钙、三氯化铝、甘氨酸铝、乙二胺四乙酸二钠中的任意一种或两种以上的组合。
本发明所述的组合物中所述的大麻二酚和/或次大麻二酚与载体的比例可以根据具体的制剂形态进行选择。优选的，所述的大麻二酚和/或次大麻二酚与载体的质量比为1:4-50，优选的，所述的大麻二酚和/或次大麻二酚与载体的质量比为1:10-40，更优选的，所述的大麻二酚和/或次大麻二酚与载体的质量比为1:20-30。
本发明还提供了一种女性卫生用品，所述的女性卫生用品由本发明所述的组合物制成，所述的组合物中包括活性物质、载体与促透剂，所述的活性物质与载体的质量比为1：4～50，所述的活性物质与促透剂质量比为1:0.1-0.8，所述的活性物质为大麻二酚和/或次大麻二酚，所述大麻二酚与次大麻二酚的质量比为0.1～10:1，优选的，所述的大麻二酚与次大麻二酚的质量比为2～8:1，更优选的，所述的大麻二酚与次大麻二酚的质量比为3～7:1，特别优选的，所述的大麻二酚与次大麻二酚的质量比为4～6:1。所述载体为纱线、棉线或大麻纤维中的一种或两种以上的组合。优选的，所述的组合物中载体为大麻纤维，所述的大麻纤维喷涂或浸渍活性物质和促透剂。更优选的，所述的女性卫生用品为卫生巾、卫生棉或卫生护垫。
本发明还提供含有大麻二酚和/或次大麻二酚的组合物在制备预防和/或治疗痛经的药物中的应用，所述的组合物中包括大麻二酚和/或次大麻二酚、促透剂以及载体，优选的，所述的药物为凝胶状、膏状或贴剂状外用药，更优选的，所述的药物为膏状或贴剂状外用药，特别优选的，所述的药物为贴剂状外用药。
本发明所述的痛经选自原发性痛经和继发性痛经。
本发明所述的预防和/或治疗痛经包括预防和/或治疗由痛经引起的选自下腹部膨胀、恶 心、呕吐、头痛、下痢、嗜眠、食欲不振、焦躁、腰痛、下肢痛、贫血、月经过多和倦怠感中的至少一种或两种以上的症状。
本发明还提供了一种预防和/或治疗痛经的方法，所述的方法包括施用组合物，所述的组合物中包括大麻二酚和/或次大麻二酚、促透剂以及载体。
优选的，所述组合物中包括大麻二酚和次大麻二酚，所述的大麻二酚与次大麻二酚的质量比为0.1～10:1。
优选的，所述的大麻二酚和/或次大麻二酚与促透剂的质量比为1:0.1-0.8。
本发明所述的术语“治疗”包括抑制、延迟、缓和、减弱、限制、减轻或消退疾病、障碍、病症或状态，其发生和/或进程，和/或其症状。
本发明所述的术语“预防”包括减小以下风险：患有、感染或经历疾病、障碍、病症或状态，其发生和/或进程，和/或其症状。
本发明所述的术语“包含”表示"开放"或"包含性"用语，使得它们包括列举的要素，而且还允许包括额外的、未提及的要素。
具体实施方式
实施例1大麻二酚的提取
1)将原材料大麻花、叶洗净风干；
2)将上述风干后的原材料粉碎至40目；
3)将所得粉末加入8倍量95％的乙醇冷浸提取3次，每次1小时；
4)合并提取液，脱色；
5)减压浓缩至相对密度1.05；
即得大麻二酚提取物，其中大麻二酚含量按质量百分比为99.5％。
需要说明的是，本发明中的“8倍量”等描述，是指采用的提取溶剂的体积是提取部位质量的8倍，比如，大麻提取部位为1g，提取溶剂的用量为8ml。
实施例2次大麻二酚的提取
1)将原材料大麻花、叶洗净风干；
2)将上述风干后的原材料粉碎至40目；
3)将所得粉末按质量体积比加入10倍量无水乙醇冷浸提取3次，每次1小时；
4)合并提取液，脱色，浓缩；
5)取柱色谱，以硅胶为填料装柱，将提取液上样过柱，流动相为80:20的石油醚和乙醚， 流速为3.0ml/min；
6)收集含有次大麻二酚组分的流出液，旋蒸除去溶剂，得到大麻二酚提取物，其中次大麻二酚含量按质量百分比为97.5％。
实施例3预防和/或治疗女性痛经的外用贴剂的制备
一种预防和/或治疗女性痛经的外用药物，所述的外用药物为贴剂状外用药，背衬层为无纺布，保护层为防粘纸，药物贮库层中大麻二酚与促透剂的质量比为1：0.5，促透剂为生姜挥发油，所述的药物贮库层的载体为高分子水凝胶，大麻二酚与载体的质量比为1:4，所述的高分子水凝胶是以质量比为10：30：40：0.1的羧甲基纤维素钠、甘油、水、氧化铝混合均匀制成。
将大麻二酚与生姜挥发油混匀后，再与高分子水凝胶混匀，然后将混合物倾入到涂布机中，均匀涂布到背衬层的无纺布上，再覆上保护层防粘纸，即制得贴剂。
实施例4预防和/或治疗女性痛经的外用贴剂的制备
一种预防和/或治疗女性痛经的外用药物，所述的外用药物为贴剂状外用药，背衬层为无纺布，保护层为防粘纸，药物贮库层中次大麻二酚与促透剂的质量比为1：0.1，促透剂为薄荷挥发油，所述的药物贮库层的载体为高分子水凝胶，次大麻二酚与载体的质量比为1:9，所述的高分子水凝胶是以质量比为7：25：30：0.2的羧甲基纤维素钠、丙二醇、水、氢氧化钙混合均匀制成。
将次大麻二酚与薄荷挥发油混匀后，再与高分子水凝胶混匀，然后将混合物倾入到涂布机中，均匀涂布到背衬层的无纺布上，再覆上保护层防粘纸，即制得贴剂。
实施例5预防和/或治疗女性痛经的外用贴剂的制备
一种预防和/或治疗女性痛经的外用药物，所述的外用药物为贴剂状外用药，背衬层为无纺布，保护层为防粘纸，药物贮库层中大麻二酚与次大麻二酚的质量比为5:1，大麻二酚与次大麻二酚的混合物与促透剂的质量比为1：0.8，促透剂为丙二醇，所述的药物贮库层的载体为高分子水凝胶，大麻二酚与次大麻二酚的混合物与载体的质量比为1:15，所述的高分子水凝胶是以质量比为8：40：55：0.3的羧甲基纤维素钠、甘油、水、氢氧化钙混合均匀制成。
将大麻二酚与次大麻二酚混匀后，加入到丙二醇中，搅拌混匀后，再与高分子水凝胶混匀，然后将混合物倾入到涂布机中，均匀涂布到背衬层的无纺布上，再覆上保护层防粘纸，即制得贴剂。
实施例6预防和/或治疗女性痛经的外用贴剂的制备
一种预防和/或治疗女性痛经的外用药物，所述的外用药物为贴剂状外用药，背衬层为无纺布，保护层为防粘纸，药物贮库层中次大麻二酚与促透剂的质量比为1：0.5，促透剂为氮酮，所述的药物贮库层的载体为热熔压敏胶，次大麻二酚与载体的质量比为1:20，所述的热熔压敏胶按质量比为2.8：3.3：2.1称取苯乙烯-丁二烯橡胶、增粘剂(增粘剂为质量比为1：1的氢化松香甘油酯、松香的季戊四醇酯)和角鲨烷加热熔化，混合均匀制成。
将次大麻二酚与氮酮混匀后，再与热熔压敏胶混匀，然后将混合物倾入到涂布机中，均匀涂布到背衬层的无纺布上，再覆上保护层防粘纸，即制得贴剂。
实施例7预防和/或治疗女性痛经的外用贴剂的制备
一种预防和/或治疗女性痛经的外用药物，所述的外用药物为贴剂状外用药，背衬层为无纺布，保护层为防粘纸，药物贮库层中大麻二酚与促透剂的质量比为1：0.1，促透剂为氮酮，所述的药物贮库层的载体为热熔压敏胶，大麻二酚与载体的质量比为1:25，所述的热熔压敏胶按质量比为3.9：3.3：2.4称取苯乙烯-丁二烯橡胶、增粘剂(增粘剂为质量比为1：1的氢化松香甘油酯、松香的季戊四醇酯)和角鲨烷加热熔化，混合均匀制成。
将大麻二酚与氮酮混匀后，再与热熔压敏胶混匀，然后将混合物倾入到涂布机中，均匀涂布到背衬层的无纺布上，再覆上保护层防粘纸，即制得贴剂。
实施例8预防和/或治疗女性痛经的外用贴剂的制备
一种预防和/或治疗女性痛经的外用药物，所述的外用药物为贴剂状外用药，背衬层为无纺布，保护层为防粘纸，药物贮库层中的药物大麻二酚与促透剂的质量比为1：0.8，促透剂为氮酮，所述的药物贮库层的载体为热熔压敏胶，大麻二酚与载体的质量比为1:30，所述的热熔压敏胶按质量比为3.5：4.7：3.5称取苯乙烯-丁二烯橡胶、增粘剂(增粘剂为质量比为1：1的氢化松香甘油酯、松香的季戊四醇酯)和角鲨烷加热熔化，混合均匀制成。
将大麻二酚与氮酮混匀后，再与热熔压敏胶混匀，然后将混合物倾入到涂布机中，均匀涂布到背衬层的无纺布上，再覆上保护层防粘纸，即制得贴剂。
实施例9预防和/或治疗女性痛经的载体为大麻纤维的组合物的制备
一种预防和/或治疗女性痛经的组合物的制备，所述的组合物的载体为大麻纤维，所述组合物中大麻二酚与载体的质量比为1:50，所述组合物中促透剂为氮酮，大麻二酚与氮酮的质量比为1：0.8。
取适量乙醇，将大麻二酚溶于乙醇中，再将氮酮加入到乙醇中，搅拌均匀，将大麻纤 维浸入溶有大麻二酚与氮酮的乙醇中，静置1h，将大麻纤维从乙醇中取出，于16℃无菌环境中晾置3h，重复上述步骤直至乙醇全部浸入大麻纤维，即制得所述组合物。
实施例10预防和/或治疗女性痛经的卫生巾的制备
1)一种预防和/或治疗女性痛经的组合物的制备，所述的组合物的载体为大麻纤维，所述组合物中大麻二酚与载体的质量比为1:45，所述组合物中促透剂为氮酮，大麻二酚与氮酮的质量比为1：0.7。取适量乙醇，将大麻二酚溶于乙醇中，再将氮酮加入到乙醇中，搅拌均匀，将大麻纤维浸入溶有大麻二酚与氮酮的乙醇中，静置1h，将大麻纤维从乙醇中取出，于16℃无菌环境中晾置3h，重复上述步骤直至乙醇全部浸入大麻纤维，即制得所述组合物。
2)采用步骤1)制备得到的含大麻纤维的组合物制备卫生巾，所述卫生巾由外层，内层和下层构成，所述的的外层由步骤1)制备得到的含大麻纤维的组合物纺织制成，所述卫生巾的内层为棉质材料，下层为膜材料。
实施例11预防和/或治疗女性痛经的外用乳膏的制备
一种预防和/或治疗女性痛经的外用药物，所述的外用药物为乳膏，所述的乳膏中大麻二酚与促透剂的质量比为1：0.3，促透剂为生姜挥发油，载体中油相为质量比为1.6：2.5：1.8的羊毛脂、硬脂酸、液体石蜡，载体中水相为质量比为7.3：1：1的甘油、羟苯乙酯、卡泊姆，大麻二酚与载体的质量比为1:40。
将羊毛脂、硬脂酸、液体石蜡混合均匀，加热至65℃～90℃，完全溶解后得油相；将甘油、羟苯乙酯、卡泊姆与部分水混合并加热至65℃～90℃得水相；将油相加入水相，搅拌得乳膏载体，在乳膏载体中加入大麻二酚，搅拌均匀，将生姜挥发油加入到乳膏中，搅拌均匀即得外用乳膏。
实施例12预防和/或治疗女性痛经的外用乳膏的制备
一种预防和/或治疗女性痛经的外用药物，所述的外用药物为乳膏，所述的乳膏中大麻二酚与促透剂的质量比为1：0.5，促透剂为薄荷挥发油，载体中油相为质量比为2：1.2：2.8：1.9的凡士林、三乙醇胺、硬脂酸、液体石蜡，载体中水相为质量比为8：1.5：1.7的甘油、羟苯乙酯、卡泊姆，大麻二酚与载体的质量比为1:50。
将凡士林、三乙醇胺、硬脂酸、液体石蜡混合均匀，加热至65℃～90℃，完全溶解后得油相；将甘油、羟苯乙酯、卡泊姆与部分水混合并加热至65℃～90℃得水相；将油相加入水相，搅拌得乳膏载体，在乳膏载体中加入大麻二酚，搅拌均匀，将薄荷挥发油加入到 乳膏中，搅拌均匀即得外用乳膏。
实施例13预防和/或治疗女性痛经的外用液体涂剂的制备
一种预防和/或治疗女性痛经的外用药物，所述的外用药物为液体外用药，所述的液体外用药中大麻二酚与促透剂的质量比为1：0.8，促透剂为氮酮，载体为质量比为1：1的甘油与乙醇，大麻二酚与载体的质量比为1：50。
将大麻二酚溶于甘油与乙醇混合液中，搅拌均匀后加入氮酮，搅拌直至形成无色透明的液体，得到体表外用液体涂剂。
实施例14不同大麻二酚或次大麻二酚含量的组合物对大鼠痛经模型的影响
试验样品：含有大麻二酚与氮酮和载体的质量比为1:0.8:4，1:0.8:25，1:0.8:50的贴剂；含有次大麻二酚与氮酮和载体的质量比为1:0.8:4，1:0.8:25，1:0.8:50的贴剂。
试验动物：200-220g的雌性大鼠。
试验方法：将含有大麻二酚或次大麻二酚与氮酮和载体的质量比为1:0.8:4，1:0.8:25，1:0.8:50的贴剂裁成3×3cm 2的小片备用，其中各组贴剂中大麻二酚或次大麻二酚、氮酮和载体的组合物总剂量相同。
取健康成年雌性大鼠70只，体重210g±8g，随机分成7组，剃除腹部皮肤上的毛。
第一组为阴性对照组，大鼠腹部贴用等量生理盐水代替含有大麻二酚或次大麻二酚、氮酮和载体的组合物；
第二组中大鼠腹部贴中大麻二酚与氮酮和载体的质量比为1:0.8:4；
第三组中大鼠腹部贴中大麻二酚与氮酮和载体的质量比为1:0.8:25；
第四组中大鼠腹部贴中大麻二酚与氮酮和载体的质量比为1:0.8:50；
第五组中大鼠腹部贴中次大麻二酚与氮酮和载体的质量比为1:0.8:4；
第六组中大鼠腹部贴中次大麻二酚与氮酮和载体的质量比为1:0.8:25；
第七组中大鼠腹部贴中次大麻二酚与氮酮和载体的质量比为1:0.8:50。每日更换，连续4天。
各组大鼠分别皮下注射(sc)乙烯雌酚，连续4天，每天剂量为8mg·kg -1，以提高子宫敏感度。各组再于第4天给药2h后腹腔注射缩宫素2IU/只，使大鼠子宫收缩，诱发其扭体反应，观察并记录随后40min内每只大鼠的扭体次数，计算扭体发生率。记录结果如表1所示。
其中，扭体发生率(％)＝各组发生扭体动物数/各组试验动物数×100％。
试验结果：
如表1所示，第二至七组贴剂对缩宫素所致大鼠痛经样反应具有明显的缓解作用，且大麻二酚或次大麻二酚含量越高，越能显著的减缓大鼠的扭体反应，越能延长反应潜伏期。
表1不同大麻二酚或次大麻二酚含量的组合物大鼠扭体试验结果
Figure PCTCN2018100835-appb-000001
实施例15大麻二酚与促透剂的比例对大鼠痛经模型的影响
试验样品：含有大麻二酚与氮酮的质量比为1：1、1：0.8、1：0.4、1：0.1、1：0.05的贴剂。
试验动物：200-220g的雌性大鼠。
试验方法：将含有大麻二酚与氮酮的质量比为1：1，大麻二酚与氮酮的质量比为1：0.8，大麻二酚与氮酮的质量比为1：0.4，大麻二酚与氮酮的质量比为1：0.1，大麻二酚与氮酮的质量比为1：0.05贴剂裁成3×3cm 2的小片备用，其中各组贴剂中大麻二酚的剂量相同，且大麻二酚与载体的质量比均为1:10。
将60只体重为200-220g的雌性大鼠随机分为6组，每组10只，剃除腹部皮肤上的毛。
第一组为阴性对照组，在大鼠腹部贴3×3cm 2的用等量生理盐水替代大麻二酚与氮酮混合物制成的贴剂；
第二组在腹部贴含有大麻二酚与氮酮的质量比为1：1的贴剂；
第三组在腹部贴含有大麻二酚与氮酮的质量比为1：0.8的贴剂；
第四组在腹部贴含有大麻二酚与氮酮的质量比为1：0.4的贴剂；
第五组在腹部贴含有大麻二酚与氮酮的质量比为1：0.1的贴剂；
第六组在腹部贴含有大麻二酚与氮酮的质量比为1：0.05的贴剂。
每日更换，连续4天。
各组大鼠分别皮下注射(sc)乙烯雌酚，连续4天，每天剂量为8mg·kg -1，以提高子宫敏感度。各组再于第4天给药2h后腹腔注射缩宫素2IU/只，使大鼠子宫收缩，诱发其扭体反应，观察并记录随后40min内每只大鼠的扭体次数，计算扭体发生率。记录结果如表2所示。
其中，扭体发生率(％)＝各组发生扭体动物数/各组试验动物数×100％。
试验结果：
如表2所示结果，与阴性对照组相比，含有大麻二酚与氮酮混合物的贴剂均能减缓大鼠的扭体反应，尤其是第三组、第四组、第五组的贴剂更能显著的减缓大鼠的扭体反应，说明大麻二酚与氮酮的质量比为1：0.8，1：0.4，1：0.1时能更好的缓解小鼠痛经。
表2不同促透剂含量的组合物大鼠扭体试验的试验结果
Figure PCTCN2018100835-appb-000002
实施例16促透剂的类型对大鼠痛经模型的影响
试验样品：大麻二酚与氮酮的质量比为1：0.8的贴剂；大麻二酚与生姜挥发油的质量比为1：0.8的贴剂；大麻二酚与薄荷挥发油的质量比为1：0.8的贴剂；大麻二酚与DMI的质量比为1：0.8的贴剂。
试验动物：200-220g的雌性大鼠。
试验方法：
将含有大麻二酚与氮酮的质量比为1：0.8；大麻二酚与生姜挥发油的质量比为1：0.8；大麻二酚与薄荷挥发油的质量比为1：0.8；大麻二酚与DMI的质量比为1：0.8的贴剂裁成3×3cm 2的小片备用，其中各组贴剂中大麻二酚的剂量相同，且大麻二酚与载体的质量比均为1:10。
将50只体重为200-220g的雌性大鼠随机分为5组，每组10只，剃除腹部皮肤上的毛。
第一组为阴性对照组，在大鼠腹部贴3×3cm 2的用等量生理盐水替代大麻二酚与促透剂混合物制成的贴剂；
第二组在腹部贴含有大麻二酚与氮酮的质量比为1：0.8的贴剂；
第三组在腹部贴含有大麻二酚与生姜挥发油的质量比为1：0.8的贴剂；
第四组在腹部贴含有大麻二酚与薄荷挥发油的质量比为1：0.8的贴剂；
第五组在腹部贴含有大麻二酚与DMI的质量比为1：0.8的贴剂。
每日更换，连续4天。
各组大鼠分别皮下注射(sc)乙烯雌酚，连续4天，每天剂量为8mg·kg -1(以大麻二酚计)，以提高子宫敏感度。各组再于第4天给药2h后腹腔注射缩宫素2IU/只，使大鼠子宫收缩，诱发其扭体反应，观察并记录随后40min内每只大鼠的扭体次数，计算扭体发生率。结果如表3所示，其中扭体发生率(％)＝各组发生扭体动物数/各组试验动物数×100％。
试验结果：
如表3所示结果，与阴性对照组相比，含有大麻二酚与促透剂混合物的贴剂能显著减缓大鼠的扭体反应，尤其是第二组的贴剂更能显著的减缓大鼠的扭体反应，说明大麻二酚与氮酮制成的贴剂能更好的缓解小鼠痛经。
表3不同种类促透剂大鼠扭体试验的试验结果
Figure PCTCN2018100835-appb-000003
实施例17组合物中大麻二酚与次大麻二酚含量比例对大鼠痛经模型的影响
试验样品：含有大麻二酚、次大麻二酚、氮酮和载体的贴剂，贴剂中大麻二酚和次大麻二酚与氮酮和载体的质量比为1:0.8:10，且各组中大麻二酚和次大麻二酚质量比分别为1:0.1、1:0.2、1:1、1:10。
试验动物：200-220g的雌性大鼠。
试验方法：
将组合物中大麻二酚和次大麻二酚质量比分别为1:0.1、1:0.2、1:1、1:10的各组贴剂裁成3×3cm 2的小片备用，其中各组贴剂中大麻二酚和次大麻二酚的总剂量相同。
将40只体重为200-220g的雌性大鼠随机分为4组，每组10只，剃除腹部皮肤上的毛。
第一组在腹部贴含有大麻二酚和次大麻二酚质量比为1:0.1的贴剂；
第二组在腹部贴含有大麻二酚和次大麻二酚质量比为1:0.2的贴剂；
第三组在腹部贴含有大麻二酚和次大麻二酚质量比为1:1的贴剂；
第四组在腹部贴含有大麻二酚和次大麻二酚质量比为1:10的贴剂。
每日更换，连续4天。
各组大鼠分别皮下注射(sc)乙烯雌酚，连续4天，每天剂量为8mg·kg -1(以大麻二酚计)，以提高子宫敏感度。各组再于第4天给药2h后腹腔注射缩宫素2IU/只，使大鼠子宫收缩，诱发其扭体反应，观察并记录随后40min内每只大鼠的扭体次数，计算扭体发生率。结果如表4所示，其中扭体发生率(％)＝各组发生扭体动物数/各组试验动物数×100％。
试验结果：
如表4所示结果，含有不同比例的大麻二酚与次大麻二酚的贴剂对缩宫素所致大鼠痛经样反应均具有明显的缓解作用，但组合物中大麻二酚含量比例较高时更能减缓大鼠的扭体反应，特别是大麻二酚和次大麻二酚质量比为1:0.2时，具有最佳的效果。
表4含不同比例的大麻二酚与次大麻二酚的组合物大鼠扭体试验的试验结果
Figure PCTCN2018100835-appb-000004
上述实施例不以任何方式限制本发明，凡是采用等同替换或等效变换的方式获得的技术方案均落在本发明的保护范围内。

Claims (18)

  1. 一种预防和/或治疗女性痛经的组合物，其特征在于，所述的组合物中包括大麻二酚和/或次大麻二酚、促透剂以及载体。
  2. 权利要求1所述的一种预防和/或治疗女性痛经的组合物，其特征在于，所述组合物中包括大麻二酚和次大麻二酚，所述的大麻二酚与次大麻二酚的质量比为0.1～10:1。
  3. 权利要求1所述的一种预防和/或治疗女性痛经的组合物，其特征在于，所述促透剂选自氮酮、挥发油、1,3-二甲基-2-咪唑啉酮、丙二醇、乙醇、油酸中的一种或两种以上的组合，优选的，所述促透剂为氮酮。
  4. 权利要求1所述的一种预防和/或治疗女性痛经的组合物，其特征在于，所述的大麻二酚和/或次大麻二酚与促透剂的质量比为1:0.1-0.8。
  5. 权利要求1所述的一种预防和/或治疗女性痛经的组合物，其特征在于，所述的大麻二酚和/或次大麻二酚是从大麻植株中提取得到的，所述大麻植株提取部位为大麻籽、大麻叶、大麻花、大麻秆芯、大麻根中的一种或任意两种及以上以任意比例的组合。
  6. 权利要求1所述的一种预防和/或治疗女性痛经的组合物，其特征在于，所述的组合物为液体状、凝胶状、膏状或贴剂状。
  7. 权利要求1所述的一种预防和/或治疗女性痛经的组合物，其特征在于，所述的载体选自十六醇，凡士林，液体石蜡，单硬脂酸甘油酯，甘油，羟苯乙酯，三乙醇胺，尼泊金乙酯，羊毛脂，硬脂酸中的一种或两种以上的组合；
    或者，所述的载体选自卡波姆，聚乙烯醇，羧甲基纤维素及其钠盐，聚丙烯酸及其钠盐中的一种或两种以上的组合；
    或者，所述的载体选自热熔压敏胶、橡胶、高分子水凝胶、医用胶带和丙烯酸酯压敏胶中的一种或两种以上的组合；
    或者，所述的载体选自纱线、棉线或大麻纤维中的一种或两种以上的组合；
    或者，所述的载体选自醇溶液、醚类、酯类、植物油类中的一种或两种以上的组合。
  8. 权利要求1所述的一种预防和/或治疗女性痛经的组合物，其特征在于，所述的载体中还含有胶粘剂、填充剂、保湿剂、交联剂、着色剂、pH调节剂、防腐剂中的一种或两种以上的组合。
  9. 权利要求8所述的一种预防和/或治疗女性痛经的组合物，其特征在于，所述的胶粘剂选自明胶、海藻酸钠、阿拉伯胶、淀粉、甲基纤维素、羧甲基纤维素及其钠盐、聚乙烯醇、 聚乙二醇、聚乙烯吡咯烷酮、卡波姆、聚丙烯酸及其钠盐中的一种或两种以上的任意组合；所述的填充剂选自氧化锌、微粉硅胶、碳酸钙、硅藻土、二氧化钛中的一种或两种以上的任意组合；所述的保湿剂选自甘油、丙二醇、山梨醇、聚乙二醇中任意一种或两种以上的组合；所述的交联剂选自氢氧化钙、三氯化铝、甘氨酸铝、乙二胺四乙酸二钠中的任意一种或两种以上的组合。
  10. 权利要求1所述的一种预防和/或治疗女性痛经的组合物，其特征在于，所述的组合物中所述的大麻二酚和/或次大麻二酚与载体的质量比为1:4-50。
  11. 一种女性卫生用品，所述的女性卫生用品由权利要求1所述的预防和/或治疗痛经的组合物制成，其特征在于，所述载体为纱线、棉线或大麻纤维中的一种或两种以上的组合。
  12. 权利要求11所述的女性卫生用品，其特征在于，所述的女性卫生用品为卫生巾、卫生棉或卫生护垫。
  13. 含有大麻二酚和/或次大麻二酚的组合物在制备预防和/或治疗痛经的药物中的应用，其特征在于，所述的组合物中包括大麻二酚和/或次大麻二酚、促透剂以及载体。
  14. 权利要求13所述的含有大麻二酚和/或次大麻二酚的组合物在制备预防和/或治疗痛经的药物中的应用，其特征在于，所述的痛经选自原发性痛经和继发性痛经。
  15. 权利要求13所述的含有大麻二酚和/或次大麻二酚的组合物在制备预防和/或治疗痛经的药物中的应用，其特征在于，所述的预防和/或治疗痛经包括预防和/或治疗由痛经引起的选自下腹部膨胀、恶心、呕吐、头痛、下痢、嗜眠、食欲不振、焦躁、腰痛、下肢痛、贫血、月经过多和倦怠感中的至少一种或两种以上的症状。
  16. 一种预防和/或治疗痛经的方法，其特征在于，所述的方法包括施用组合物，所述的组合物中包括大麻二酚和/或次大麻二酚、促透剂以及载体。
  17. 权利要求16所述的一种预防和/或治疗痛经的方法，其特征在于，所述组合物中包括大麻二酚和次大麻二酚，所述的大麻二酚与次大麻二酚的质量比为0.1～10:1。
  18. 权利要求16所述的一种预防和/或治疗痛经的方法，其特征在于，所述的大麻二酚和/或次大麻二酚与促透剂的质量比为1:0.1-0.8。
PCT/CN2018/100835 2017-09-15 2018-08-16 含有大麻二酚和/或次大麻二酚的组合物及其在治疗痛经中的应用 WO2019052303A1 (zh)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102020107937A1 (de) 2020-03-23 2021-09-23 Lts Lohmann Therapie-Systeme Ag DMEH - Enhancer
EP4054540A4 (en) * 2019-11-07 2023-08-30 Amyris, Inc. COMPOSITIONS AND METHODS OF DELIVERING CANNABINOIDS TO THE SKIN
US11839602B2 (en) 2020-11-25 2023-12-12 Nicoventures Trading Limited Oral cannabinoid product with lipid component
US11896711B2 (en) 2019-12-09 2024-02-13 Nicoventures Trading Limited Process of making nanoemulsion

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10239808B1 (en) 2016-12-07 2019-03-26 Canopy Holdings, LLC Cannabis extracts
WO2019152736A1 (en) 2018-01-31 2019-08-08 Canopy Holdings, LLC Hemp powder
US11040932B2 (en) 2018-10-10 2021-06-22 Treehouse Biotech, Inc. Synthesis of cannabigerol
CN110152050A (zh) * 2019-05-30 2019-08-23 厦门梓素生物科技有限公司 一种含大麻二酚提取物的功能性卫生巾及其制作方法
US20210045943A1 (en) * 2019-08-15 2021-02-18 Better Made Hemp, LLC Adjustable Absorbent Article
EP4045024A4 (en) * 2019-10-14 2023-10-25 Pike Therapeutics, Inc. TRANSDERMAL ADMINISTRATION OF CANNABIDIOL
CN113116869B (zh) * 2019-12-31 2022-08-23 汉义生物科技（北京）有限公司 一种预防和/或治疗抑郁的组合物
CN113116867B (zh) * 2019-12-31 2022-08-23 汉义生物科技（北京）有限公司 一种预防和/或治疗流感的组合物
CN111228241B (zh) * 2020-01-16 2023-08-04 全越 一种成膜组合物及其应用
CN113384561B (zh) * 2021-08-11 2021-11-30 寿光市中医医院 一种防过敏的痛经贴及其制备方法
US11857590B2 (en) 2021-10-26 2024-01-02 Ecofibre Limited Systems and methods for producing hemp extracts and compositions
CA3235080A1 (en) * 2021-10-26 2023-04-05 Alexandra M CAPANO Methods of treating endometriosis and other non-cancer gynecological disorders with hemp extract
CA3235074A1 (en) 2021-10-26 2023-05-04 Alexandra M CAPANO Methods of treating ovarian cancer with hemp extract
CN116159045B (zh) * 2021-11-24 2024-03-19 四川大学华西医院 大麻二酚和/或次大麻二酚在制备局部麻醉药药效增强剂中的应用

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1658840A (zh) * 2002-06-14 2005-08-24 Lts罗曼治疗方法有限公司 用于给予大麻制剂的薄膜形粘膜粘性的给药剂型
CN1976690A (zh) 2004-06-08 2007-06-06 Gw药物有限公司 治疗关节炎的疾病和/或症状的药物组合物
CN101815697A (zh) * 2007-07-30 2010-08-25 奥特兰兹公司 大麻二酚前药、包括大麻二酚前药的组合物及其使用方法
CN103025325A (zh) 2010-03-30 2013-04-03 Gw药品有限公司 植物大麻素次大麻二酚(cbdv)在治疗癫痫中的用途
CN103533930A (zh) 2011-05-20 2014-01-22 Gw药品有限公司 用于治疗神经性疼痛的大麻素类化合物
CN103826621A (zh) 2011-09-29 2014-05-28 Gw药品有限公司 包含植物大麻素次大麻二酚(cbdv)和大麻二酚(cbd)的药物组合物
CN105031563A (zh) 2015-06-12 2015-11-11 刘振标 化淤酒
US20160256411A1 (en) 2015-03-02 2016-09-08 Afgin Pharma, Llc Topical regional neuro-affective therapy with cannabinoids
CN106074496A (zh) 2016-06-14 2016-11-09 云南瑞酚生物科技有限公司 大麻酚类化合物在制备治疗痛风药物中的应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2392093B (en) * 2002-08-14 2006-03-08 Gw Pharma Ltd Pharmaceutical formulations
CA2760460C (en) * 2009-04-28 2019-04-02 Alltranz Inc. Transdermal formulations of cannabidiol comprising a penetration enhancer and methods of using the same
WO2016126592A1 (en) * 2015-02-02 2016-08-11 Axim Biotechnologies, Inc. Cannabinoid and sugar alcohol complex, methods to make and use

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1658840A (zh) * 2002-06-14 2005-08-24 Lts罗曼治疗方法有限公司 用于给予大麻制剂的薄膜形粘膜粘性的给药剂型
CN1976690A (zh) 2004-06-08 2007-06-06 Gw药物有限公司 治疗关节炎的疾病和/或症状的药物组合物
CN101815697A (zh) * 2007-07-30 2010-08-25 奥特兰兹公司 大麻二酚前药、包括大麻二酚前药的组合物及其使用方法
CN103025325A (zh) 2010-03-30 2013-04-03 Gw药品有限公司 植物大麻素次大麻二酚(cbdv)在治疗癫痫中的用途
CN103533930A (zh) 2011-05-20 2014-01-22 Gw药品有限公司 用于治疗神经性疼痛的大麻素类化合物
CN103826621A (zh) 2011-09-29 2014-05-28 Gw药品有限公司 包含植物大麻素次大麻二酚(cbdv)和大麻二酚(cbd)的药物组合物
US20160256411A1 (en) 2015-03-02 2016-09-08 Afgin Pharma, Llc Topical regional neuro-affective therapy with cannabinoids
WO2016141056A1 (en) * 2015-03-02 2016-09-09 Afgin Pharma, Llc Topical regional neuro-affective therapy with cannabinoids
CN105031563A (zh) 2015-06-12 2015-11-11 刘振标 化淤酒
CN106074496A (zh) 2016-06-14 2016-11-09 云南瑞酚生物科技有限公司 大麻酚类化合物在制备治疗痛风药物中的应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3673905A4

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4054540A4 (en) * 2019-11-07 2023-08-30 Amyris, Inc. COMPOSITIONS AND METHODS OF DELIVERING CANNABINOIDS TO THE SKIN
US11896711B2 (en) 2019-12-09 2024-02-13 Nicoventures Trading Limited Process of making nanoemulsion
DE102020107937A1 (de) 2020-03-23 2021-09-23 Lts Lohmann Therapie-Systeme Ag DMEH - Enhancer
US11839602B2 (en) 2020-11-25 2023-12-12 Nicoventures Trading Limited Oral cannabinoid product with lipid component

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