WO2020097765A1 - 大麻素类化合物在治疗神经性皮炎中的应用 - Google Patents

大麻素类化合物在治疗神经性皮炎中的应用 Download PDF

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Publication number
WO2020097765A1
WO2020097765A1 PCT/CN2018/115075 CN2018115075W WO2020097765A1 WO 2020097765 A1 WO2020097765 A1 WO 2020097765A1 CN 2018115075 W CN2018115075 W CN 2018115075W WO 2020097765 A1 WO2020097765 A1 WO 2020097765A1
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Prior art keywords
tetrahydrocannabinol
combination
hypocannabidiol
cbdv
thcv
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PCT/CN2018/115075
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English (en)
French (fr)
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张可
谭昕
常坦然
金倩
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汉义生物科技（北京）有限公司
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Application filed by 汉义生物科技（北京）有限公司 filed Critical 汉义生物科技（北京）有限公司
Priority to US17/289,230 priority Critical patent/US20210393574A1/en
Priority to PCT/CN2018/115075 priority patent/WO2020097765A1/zh
Priority to AU2018449013A priority patent/AU2018449013A1/en
Priority to CA3118535A priority patent/CA3118535C/en
Priority to EP18940322.3A priority patent/EP3868373B1/en
Priority to MX2021005573A priority patent/MX2021005573A/es
Priority to JP2021522031A priority patent/JP2022509008A/ja
Publication of WO2020097765A1 publication Critical patent/WO2020097765A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • 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
    • 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
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to the field of medicine, in particular to the use of a composition containing one or more cannabinoid compounds in the treatment of neurodermatitis.
  • Neurodermatitis also known as chronic simple moss, is a localized skin and nerve dysfunction skin disease. It is a chronic skin disease characterized by paroxysmal skin itching and skin lichenification. The etiology is not yet clear. It is generally believed to be related to long-term scratching, friction, neuropsychiatric factors and certain external stimuli. Among them, mental factors are currently considered to be the main causes of the disease, mood swings, excessive nervousness, anxiety, Sudden changes in living environment can make the condition worse and repeated.
  • neurodermatitis has a clear correlation with neuropsychiatric factors.
  • long-term gastrointestinal dysfunction, endocrine abnormalities, and infection lesions may all be pathogenic factors.
  • antidepressants are occasionally used to treat refractory pruritus, neurodermatitis and other skin diseases, such as trimethoprim and chlorpromazine, which can help treat the itching and sleep disorders that are common in chronic skin diseases.
  • these antidepressants Medicines also have many side effects and may interact with skin medications, and not every antidepressant can be used to treat neurodermatitis and other skin diseases.
  • Marijuana (scientific name: Cannabis sativa L.) Cannabis, cannabis plant, also known as hemp, hemp, hemp, hemp seed, jute, has important agricultural and medicinal value. Cannabis contains THC (tetrahydrocannabinol), a toxic ingredient, which can cause psychedelic addiction and can be used as a drug. It has been banned for a long time.
  • THC tetrahydrocannabinol
  • the raw material cannabis for industrial use is simply referred to as "industrial cannabis", and its tetrahydrocannabinol (THC) content in the growing cannabis flower leaf is less than three thousandths and does not have extraction
  • THC tetrahydrocannabinol
  • Cannabinoids are active substances extracted and synthesized from natural plant cannabis. At present, more than 500 substances have been isolated from cannabis plants, of which there are at least 86 cannabinoid compounds. Cannabinoids are a class of substances unique to cannabis plants and the main active ingredient in cannabis plants. Research on it has been a hot spot in cannabis research. The main cannabinoid compounds in cannabis plants are tetrahydrocannabinol (THC), cannabidiol (CBN), cannabidiol (CBD), hypocannabidiol (CBDV), tetrahydrocannabinol (THCV), etc. The first three account for more than 90% of cannabinoid compounds.
  • Patent WO0206999A2 discloses a drug containing at least 80 wt% of the total weight of cannabinoids, wherein the weight ratio of THC / CBD is 75: 25-20: 80, and mentions that the above composition can be used to treat neurodermatitis.
  • the above-mentioned prior art simply lists the therapeutic uses of the composition.
  • the instructions do not specifically verify the role of THC or cannabidiol in neurodermatitis, and the composition in US2014302086 also contains other It is difficult to clarify the effect of THC or cannabidiol for the ingredients that relieve neurodermatitis, that is, it cannot be clearly concluded from the above-mentioned prior art that CBD or THC can treat neurodermatitis.
  • the inventor of the present application has spent a lot of research to verify the role of natural plant-derived cannabinoid compounds in the treatment of neurodermatitis, screened among various cannabinoid compounds, and conducted a large number of clinical trials , Finally successfully clarified that several cannabinoid compounds and their combinations have a significant effect on neurodermatitis.
  • the present invention aims to address the deficiencies in the treatment of existing neurodermatitis and find that cannabinoid compounds can treat neurodermatitis and can be used to prepare drugs for treating neurodermatitis.
  • the present invention provides a method for treating neurodermatitis using these compositions, and the use of the composition in preparing a drug for treating neurodermatitis.
  • the present invention aims to provide the use of one or more cannabinoid compounds or pharmaceutically acceptable salts thereof in the preparation of a pharmaceutical composition for the treatment of neurodermatitis.
  • the present invention provides a cannabinoid compound selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), hypocannabidiol (CBDV), and tetrahydrocannabinol (THCV) or
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • CBDV hypocannabidiol
  • THCV tetrahydrocannabinol
  • the present invention provides the use of a cannabinoid compound or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating neurodermatitis.
  • the cannabinoid compound is selected from:
  • THC tetrahydrocannabinol
  • THCV tetrahydrocannabinol
  • CBD cannabidiol
  • CBDV hypocannabidiol
  • THC tetrahydrocannabinol
  • CBDV hypocannabidiol
  • CBD cannabidiol
  • THCV tetrahydrocannabinol
  • CBD cannabidiol
  • CBDV hypocannabidiol
  • THCV tetrahydrocannabinol
  • THC tetrahydrocannabinol
  • CBDV hypocannabidiol
  • THCV tetrahydrocannabinol
  • the present invention also provides a composition for treating neurodermatitis, which includes 1) a cannabinoid compound or a pharmaceutically acceptable salt thereof, and 2) one or more pharmaceutically acceptable carriers or excipients.
  • the cannabinoid compound is selected from one of tetrahydrocannabinol (THC), cannabidiol (CBD), hypocannabidiol (CBDV), and tetrahydrocannabinol (THCV).
  • THC tetrahydrocannabinol
  • CBD cannabidiol
  • CBDV hypocannabidiol
  • THCV tetrahydrocannabinol
  • the cannabinoid compound is selected from:
  • THC tetrahydrocannabinol
  • THCV tetrahydrocannabinol
  • CBD cannabidiol
  • CBDV hypocannabidiol
  • THC tetrahydrocannabinol
  • CBDV hypocannabidiol
  • CBD cannabidiol
  • THCV tetrahydrocannabinol
  • CBD cannabidiol
  • CBDV hypocannabidiol
  • THCV tetrahydrocannabinol
  • THC tetrahydrocannabinol
  • CBDV hypocannabidiol
  • THCV tetrahydrocannabinol
  • the cannabinoid compound is selected from:
  • THC tetrahydrocannabinol
  • THCV tetrahydrocannabinol
  • CBD cannabidiol
  • CBDV hypocannabidiol
  • THC tetrahydrocannabinol
  • CBDV hypocannabidiol
  • CBD cannabidiol
  • THCV tetrahydrocannabinol
  • Combination of cannabidiol (CBD), hypocannabidiol (CBDV) and tetrahydrocannabinol (THCV) by weight ratio of cannabidiol (CBD), hypocannabidiol (CBDV) and tetrahydrocannabinol Phenol (THCV) is 100: 20-50: 2.5-10;
  • the pharmaceutically acceptable salts of the present invention include acid addition salts formed with inorganic acids or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc .; and organic acids such as acetic acid, propylene Acid, hexanoic acid, heptanoic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, o- (4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, tert-valeric acid, tert-butylacetic acid, dodecyl sulfuric acid, gluconic acid, glutamic acid, naphthoic acid, salicylic acid, stearic acid, etc. .
  • organic acids such as acetic acid
  • composition of the present invention can be made into a specific dosage form by any suitable route such as oral administration, rectum, nose, lungs, topical (including oral cavity and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and gastric Parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes of administration, preferably oral routes.
  • suitable route such as oral administration, rectum, nose, lungs, topical (including oral cavity and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and gastric Parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal) routes of administration, preferably oral routes.
  • suitable route such as oral administration, rectum, nose, lungs, topical (including oral cavity and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and gastric Parenteral (including subcutaneous, intramuscular, intrathecal, intravenous, and intradermal)
  • compositions for oral administration include solid dosage forms, such as capsules, tablets, sugar-coated tablets, pills, lozenges, powders, and granules.
  • compositions for oral administration also include liquid dosage forms, such as solutions, emulsions, suspensions, syrups, and elixirs.
  • compositions for parenteral administration include sterile aqueous and non-aqueous injections, dispersions, suspensions or emulsions, and sterile powders that are redissolved in sterile injectable solutions or dispersions before use.
  • Suitable dosage forms include suppositories, sprays, creams, gels, inhalants, patches, implants, and the like.
  • composition of the present invention or the composition produced according to the present invention can be administered by any suitable route, for example, oral administration in the form of tablets, capsules, powders, syrups, etc., or parenteral injection in the form of a solution.
  • suitable route for example, oral administration in the form of tablets, capsules, powders, syrups, etc., or parenteral injection in the form of a solution.
  • methods known in the art can be used, and any pharmaceutically acceptable carriers, diluents, excipients, or other additives commonly used in the art can be used.
  • a sterile aqueous solution of one or more active ingredients for parenteral administration, a sterile aqueous solution of one or more active ingredients, an aqueous propylene glycol solution, an aqueous vitamin E solution, or a sesame oil or peanut oil solution can be used. If necessary, this aqueous solution should be properly buffered, and the liquid diluent is first made isotonic with enough salt or glucose.
  • Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous medium used is easily prepared by standard techniques known to those skilled in the art.
  • It can be prepared by dissolving one or more active ingredients and possible additives in a part of the solvent for injection (preferably sterile water), adjusting the solution to the required volume, sterilizing the solution and pouring it into an appropriate ampoule or vial Solution for injection.
  • a part of the solvent for injection preferably sterile water
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers examples include lactose, clay, sucrose, cyclodextrin, talc, agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, corn starch, potato starch, talc, stearic acid Magnesium, gelatin, etc.
  • Any other auxiliary materials or additives usually used for coloring, flavoring, preservative, etc. can be used as long as they are compatible with the active ingredient or the used ingredient.
  • liquid carriers examples include syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may contain any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or mixed with wax.
  • composition formed by mixing one or more active ingredients of the present invention with a pharmaceutically acceptable carrier can then be conveniently administered in various dosage forms suitable for the disclosed route of administration.
  • the preparation can be conveniently presented in unit dosage form by methods known in the pharmaceutical art.
  • the active ingredients of the present invention can be formulated into similar or dissimilar pharmaceutical compositions and their unit dosage forms.
  • the pharmaceutical composition of the present invention contains a unit dose of 2.5-400 mg of cannabinoid compounds or pharmaceutically acceptable salts thereof, more preferably, the pharmaceutical composition contains a unit dose of 25-300 mg of cannabis Most preferably, the pharmaceutical composition contains a unit dose of 50-200 mg of cannabinoid compounds or pharmaceutically acceptable salts thereof.
  • the The pharmaceutical composition contains a unit dose of 25mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg or 200mg cannabinoids Compound or its pharmaceutically acceptable salt.
  • the present invention also provides a method for preventing and / or treating neurodermatitis.
  • the method includes daily administration of a drug with a dosage of 1-500 mg of cannabinoid compounds or pharmaceutically acceptable salts thereof, more preferably, daily Administration of a pharmaceutical dose of 25-300 mg of cannabinoid compounds or pharmaceutically acceptable salts thereof, most preferably, daily administration of a pharmaceutical dose of 50-200 mg of cannabinoid compounds or pharmaceutically acceptable salts thereof, in an embodiment of the present invention
  • the daily dose of the drug can also be 25mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg or 200mg cannabinoids.
  • Compound or its pharmaceutically acceptable salt is also be 25mg, 30mg, 40mg, 50mg, 60mg, 70mg
  • the cannabinoid compound or the pharmaceutically acceptable salt thereof according to the present invention may be a chemical synthesis product, a biosynthesis product, a plant extract, or prepared by other methods.
  • the cannabinoid compound of the present invention is a plant extract, and the plant may be the outer shell of the stalk core, flower, leaf, root and / or seed of cannabis Cannabis sativa.
  • the extraction solvent may be a low molecular alcohol (such as methanol, ethanol, butanol, or propanol); acetate (such as methyl acetate or ethyl acetate); ketone (Such as acetone); ether (such as methyl ether or ether); low-boiling aliphatic hydrocarbons or aromatic hydrocarbons or chlorinated hydrocarbons.
  • Extraction methods include:
  • the extract is mixed with a 5% sulfuric acid solution to bring the pH to about 2-4, and then use a low boiling point Solvents (such as low-boiling aliphatic hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons, methyl acetate, ethyl acetate, or mixtures thereof) are extracted at least twice, and the solvent is removed under low temperature vacuum, followed by chromatographic separation, preferably mobile phase for chromatography
  • the mixture consists of methanol / water and acetic acid or ethanol / water and acetic acid.
  • the patient of the present invention is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • the patient is a human.
  • the term "pharmaceutically acceptable carrier or excipient” means that the ingredient has no biological activity or other adversely active impurities.
  • the ingredient can be included in the disclosed pharmaceutical preparation and given to the patient, but it does not cause Significant adverse biological effects may interact with other ingredients contained in the preparation in a harmful manner.
  • treatment includes inhibiting, delaying, alleviating, attenuating, limiting, alleviating or resolving a disease, disorder, condition or condition, its occurrence and / or progression, and / or its symptoms.
  • the term "about” generally means +/- 5% of the stated value, more generally +/- 4% of the stated value, more usually +/- 3% of the stated value, more Usually refers to +/- 2% of the value, more usually +/- 1% of the value, more usually +/- 0.5% of the value.
  • the present invention has verified through a large number of studies that cannabinoid compounds or pharmaceutically acceptable salts thereof have a significant effect on the treatment of neurodermatitis.
  • the individual cannabinoid compounds and the above-mentioned combinations all have various symptoms to improve neurodermatitis and can be used For the preparation of drugs for the treatment of neurodermatitis.
  • Preparation method The active ingredient is sieved and mixed with auxiliary materials, and the mixture is filled into hard gelatin capsules.
  • Preparation method The active ingredient is sieved and mixed with dextrin, microcrystalline cellulose, polyvinylpyrrolidone, sodium carboxymethyl starch until a homogeneous mixture is formed, sieved to obtain the mixture, and mixed with magnesium stearate. The resulting powder-type mixture is then compressed into tablets of the desired shape and size.
  • Preparation method The active ingredient is sieved and mixed with pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch until a uniform mixture is formed, sieved to obtain a mixture, and mixed with magnesium stearate. The resulting powder-type mixture is then compressed into tablets of the desired shape and size.
  • Preparation method The active ingredient is sieved and mixed with dextrin and sodium carboxymethyl starch until a uniform mixture is formed, sieved to obtain a mixture, and mixed with magnesium stearate. The resulting powder-type mixture is then compressed into tablets of the desired shape and size.
  • Preparation method The active ingredient is sieved and mixed with pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch until a uniform mixture is formed, sieved to obtain a mixture, and mixed with magnesium stearate. The resulting powder-type mixture is then compressed into tablets of the desired shape and size.
  • Preparation method The active ingredients are sieved and mixed with pregelatinized starch, microcrystalline cellulose, polyvinylpyrrolidone, sodium carboxymethyl starch until a uniform mixture is formed, sieved to obtain a mixture, and magnesium stearate mixing. The resulting powder-type mixture is then compressed into tablets of the desired shape and size.
  • Preparation method The active ingredients are sieved and mixed with pregelatinized starch, microcrystalline cellulose, polyvinylpyrrolidone, sodium carboxymethyl starch until a uniform mixture is formed, sieved to obtain a mixture, and magnesium stearate mixing. The resulting powder-type mixture is then compressed into tablets of the desired shape and size.
  • Preparation method The active ingredient is sieved and mixed with dextrin and sodium carboxymethyl starch until a uniform mixture is formed, sieved to obtain a mixture, and mixed with magnesium stearate. The resulting powder-type mixture is then compressed into tablets of the desired shape and size.
  • Preparation method The active ingredient is sieved and mixed with dextrin and sodium carboxymethyl starch until a uniform mixture is formed, sieved to obtain a mixture, and mixed with magnesium stearate. The resulting powder-type mixture is then compressed into tablets of the desired shape and size.
  • Example 11 Injection unit dosage form (10mL water injection)
  • Preparation method Take about 800ml of water for injection, add an appropriate amount of hydroxypropyl- ⁇ -cyclodextrin, then add tetrahydrocannabinol to dissolve it, adjust the pH to 6.2-6.5 with 0.1mol / L HCl, add water for injection To the full amount, stir well, add sodium chloride to make isotonic, filter, encapsulate in an ampoule, steam at 121 ° C for 15min, and fill in 10ml.
  • Example 12 Injection unit dosage form (10mL powder injection)
  • Preparation method Take about 800ml of water for injection, add a prescribed amount of mannitol and an appropriate amount of hydroxypropyl- ⁇ -cyclodextrin, then add the active ingredients of each cannabinoid to dissolve it, add an appropriate amount of 0.1mol / L HCl to adjust the pH The value is 6.2-6.5, then add water for injection to the full amount, add sodium chloride to make isotonic, filter, freeze-dry in accordance with the freeze-dried powder injection process, and make a powder injection, 10ml filling.
  • Example 13 The effect of cannabinoids alone on the itch effect of histamine phosphate
  • Cannabinoid compounds can regulate the central nervous system through the cannabinoid CB1 and / or CB2 receptors, so as to improve itching.
  • Seventy guinea pigs were randomly divided into blank control group (distilled water 100mg / day), cannabidiol group (50mg / day, 100mg / day, 200mg / day), tetrahydrocannabinol group (40mg / day, 80mg / day) , 100mg / day), hypocannabidiol group (40mg / day, 80mg / day, 100mg / day), tetrahydrocannabinol group (5mg / day, 10mg / day, 20mg / day), control group (Pall Min 10 mg / day), 5 animals per group.
  • blank control group distilled water 100mg / day
  • cannabidiol group 50mg / day, 100mg / day, 200mg / day
  • tetrahydrocannabinol group 40mg / day, 80mg / day
  • hypocannabidiol group 40mg
  • the guinea pigs in each group were shaved 2 cm ⁇ 2 cm on the right hind foot, and were orally administered according to the above-mentioned dosages for 3 consecutive days.
  • On the 3rd day of administration scratch the shaved area with coarse sandpaper, to the extent that the epidermis is injured and there is mild bleeding, and after 10 minutes, drop 0.05ml of 0.01% histamine phosphate solution on each guinea pig wound, After that, the concentration of histamine phosphate (eg 0.02% / 0.03% / 0.04% / 0.05% / 0.06%, etc.) is increased in sequence every 3 minutes until the guinea pig appears to lick its feet. Record the amount of histamine administered to each guinea pig The total amount is the threshold for itching.
  • Example 14 Effect of administration of a cannabinoid compound composition on the itching effect of histamine phosphate
  • THC Tetrahydrocannabinol
  • THCV tetrahydrocannabinol
  • CBD Cannabidiol
  • CBDV hypocannabidiol
  • THC Tetrahydrocannabinol
  • CBDV hypocannabidiol
  • CBD Cannabidiol
  • THCV tetrahydrocannabinol
  • CBD Cannabidiol
  • CBDV hypocannabidiol
  • THCV tetrahydrocannabinol
  • THC Tetrahydrocannabinol
  • CBDV hypocannabidiol
  • THCV tetrahydrocannabinol
  • Diagnostic criteria all meet the diagnosis of neurodermatitis in Clinical Dermatology. Its clinical manifestations are mainly characterized by skin lichenification and severe itching. Usually occur in the back of the neck or both sides, elbow fossa, rouge, forearm, thigh, calf and lumbosacral area. Conscious symptoms are usually paroxysmal severe itching, especially at night. Most patients have dizziness, insomnia, irritability, anxiety, and other symptoms of neurasthenia.
  • Exclusion criteria 1 Those with skin lesions combined with bacterial or fungal infections; 2 Women who are pregnant or lactating; 3 Those who have used glucocorticoid drugs locally or have taken antihistamine drugs within 1 week before enrollment; 4 Systemic application within 1 month Those who have taken glucocorticoid drugs; 5People who are known to be allergic to the study drug and its matrix components; 6People with chronic liver and kidney disease or other serious diseases; 7People with diabetes or severely immunocompromised.
  • Example 1 90 clinical observations of patients with neurodermatitis diagnosed were selected, and the patients were randomly divided into nine groups, including eight groups in the cannabinoid treatment group, a total of 80 people, 56 males and 24 females, aged 30 to 61 years, using Example 1
  • the preparations prepared in / 3/5/6/7/8/9/10 were randomly selected by 10 men and women in each group.
  • the control group had 10 people in the doxepin hydrochloride group, including 5 males and 5 females, aged 30-61 years.
  • the cannabinoid compound treatment group took the preparation prepared in Example 1/3/5/6/7/8/9/10 orally, once per day, before bedtime, and took it for 2 weeks;
  • the control group used hydrochloric acid Sapin 25mg / time, orally, once / day, taken before bedtime, even for 2 weeks.
  • Observation indicators include the degree of itching, inflammation, scale hypertrophy, and target skin lesions. The most severe skin lesions are selected as target skin lesions. The area, clinical symptoms and signs of target skin lesions are recorded at each follow-up. No other drugs are needed. Observe and evaluate the local lesions one week before treatment, two weeks during treatment and one month after withdrawal.
  • the skin lesion scoring method is as follows:
  • Criteria for curative effect The scoring standard is that each index is scored according to a 4-level scoring method at each evaluation, that is, 0 is none, 1 is mild, 2 is moderate, and 3 is severe. At the time of enrollment, all patients were required to have an erosion score of less than 1 point, and the skin lesion area was always recorded as 3 points, and the total score of each index was recorded. Efficacy judgment: The percentage of the reduction in the integral value is used as the efficacy index to determine the efficacy. The calculation formula of the efficacy index is: (total points at the first diagnosis-total points at each follow-up) / total points at the first diagnosis ⁇ 100%. Curative effect index> 90%, for recovery, 61% ⁇ 89%, for marked effect, 20% ⁇ 60% for effective, ⁇ 20%, for invalid.

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明公开了大麻素类化合物或其可药用的盐在制备用于治疗神经性皮炎的药物组合物中的用途，其中所述的大麻素类化合物可以选自四氢大麻酚、大麻二酚、次大麻二酚、四氢次大麻酚中的一种，或者所述的大麻素类化合物可以选自：(1)四氢大麻酚和四氢次大麻酚的组合；(2)大麻二酚和次大麻二酚的组合；(3)四氢大麻酚和次大麻二酚的组合；(4)大麻二酚和四氢次大麻酚的组合；(5)大麻二酚、次大麻二酚和四氢次大麻酚的组合；(6)四氢大麻酚、次大麻二酚和四氢次大麻酚的组合。

Description

大麻素类化合物在治疗神经性皮炎中的应用 技术领域
本发明涉及医药领域，特别涉及包含一种或两种以上大麻素类化合物的组合物在治疗神经性皮炎中的应用。
背景技术
神经性皮炎又称慢性单纯性苔藓，是一种局限性皮肤神经功能障碍性皮肤病。是以阵发性皮肤瘙痒和皮肤苔藓化为特征的慢性皮肤病。病因尚不明确，一般认为与长期搔抓、摩擦和神经精神因素及某些外在刺激因素有关，其中，精神因素目前认为是发生本病的主要诱因，情绪波动、精神过度紧张、焦虑不安、生活环境突然变化等均可使病情加重和反复。目前，临床上治疗神经性皮炎多采用组胺类药物、钙剂等对症止痒，辅以维生素B族内服；瘙痒严重者可选用镇静剂；皮疹泛发者可予普鲁卡因静脉封闭或联合使用雷公藤类药物。虽然其见效快，但是仅对症治疗，存在治标不治本、且易复发的不足。
一些研究表明,神经性皮炎与神经精神因素有明显的相关性，此外长期胃肠道功能障碍、内分泌异常和感染病灶等均可能成为发病因素。临床上偶有使用抗抑郁药来治疗顽固性瘙痒、神经性皮炎等皮肤病，例如三甲丙咪嗪和氯丙嗪，有助于治疗慢性皮肤病常有的瘙痒和睡眠紊乱，然而这些抗抑郁药也有很多副作用，还可能与皮肤用药产生药物相互作用，且并不是每种抗抑郁药都能用于神经性皮炎等皮肤病的治疗。
大麻(学名：Cannabis sativa L.)大麻科、大麻属植物，又名麻、汉麻、火麻、山丝苗、黄麻，具有重要的农用及药用价值。大麻中含有一种毒性成分THC(四氢大麻酚)可使人致幻成瘾，可作毒品，曾在相当长时期内禁种。由于大麻的经济、药用价值极高，专供工业用途的原料大麻简称为“工业大麻”，其生长期大麻花叶中的四氢大麻酚(THC)含量小于千分之三，不具备提取毒性成分四氢大麻酚的价值或直接作为毒品吸食，可以合法进行规模化种植与工业化开发利用。
大麻素是由天然植物大麻中提取、合成的活性物质。目前，人们已从大麻植株中分离出了500余种物质，其中大麻素类化合物至少有86种。大麻素类化合物是大麻植株中特有的一类物质，是大麻植物中主要的活性成分，有关它的研究一直是大麻研究的热点。大 麻植株中主要的大麻素类化合物有四氢大麻酚(THC)、大麻酚(CBN)、大麻二酚(CBD)、次大麻二酚(CBDV)、四氢次大麻酚(THCV)等，其中前三者占大麻素类化合物的90％以上。
TV Zanelati等(Antidepressant-like effects of cannabidiol in mice:possible involvement of 5-HT 1Areceptors,British journal of pharmacology,2010)发现大麻二酚可通过激活5-HT 1A受体诱导抗抑郁样作用，认为大麻二酚具有在小鼠中抗抑郁活性。专利US2014302086中公开了THC或大麻二酚和至少一种选自柠檬酸，抗坏血酸，柑橘精油等的小分子组合物，提及上述组合物可以治疗神经性皮炎。专利WO0206999A2公开了含有大麻素总重量至少80wt％的药物，其中THC/CBD的重量比是75:25-20:80，并提及上述组合物可用于治疗神经性皮炎。然而上述现有技术仅将所述组合物的治疗用途进行了简单的罗列，说明书并未对THC或大麻二酚在神经性皮炎中作用进行具体的验证，且US2014302086中的组合物还含有其他能够缓解神经性皮炎的成分，很难明确THC或大麻二酚的效果，即并不能从上述现有技术中明确得出CBD或THC能够治疗神经性皮炎的结论。
本申请的发明人花费了大量的研究，对天然植物来源的大麻素类化合物在治疗神经性皮炎方面的作用进行了验证，在多种大麻素类化合物中进行筛选，并进行了大量的临床试验，终于成功明确了几种大麻素类化合物及其组合对神经性皮炎具有明显的疗效。
发明内容
在阅读了优选实施方案和所附权利要求的详细描述后，本发明的目的、优点和用途将对本领域技术人员显示出来。本发明旨在针对现有神经性皮炎治疗上存在的不足，发现大麻素类化合物能治疗神经性皮炎，可用于制备治疗神经性皮炎的药物。
并且本发明提供了使用这些组合物治疗神经性皮炎的方法，以及所述组合物制备治疗神经性皮炎的药物中的应用。
本发明旨在提供一种或多种大麻素类化合物或其可药用的盐在制备用于治疗神经性皮炎的药物组合物中的用途。
优选的，本发明提供了选自四氢大麻酚(THC)、大麻二酚(CBD)、次大麻二酚(CBDV)、四氢次大麻酚(THCV)中的一种大麻素类化合物或其可药用的盐在单独制备用于治疗神经性皮炎的药物组合物中的用途。
优选的，本发明提供了大麻素类化合物或其可药用的盐在制备用于治疗神经性皮炎的药物组合物中的用途，所述的大麻素类化合物选自：
(1)四氢大麻酚(THC)和四氢次大麻酚(THCV)的组合；
(2)大麻二酚(CBD)和次大麻二酚(CBDV)的组合；
(3)四氢大麻酚(THC)和次大麻二酚(CBDV)的组合；
(4)大麻二酚(CBD)和四氢次大麻酚(THCV)的组合；
(5)大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合；
(6)四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合。
本发明还提供了一种用于治疗神经性皮炎的组合物，包括1)大麻素类化合物或其可药用的盐，2)一种或多种药学上可接受的载体或赋形剂。
优选的，所述的大麻素类化合物选自四氢大麻酚(THC)、大麻二酚(CBD)、次大麻二酚(CBDV)、四氢次大麻酚(THCV)中的一种。
优选的，所述的大麻素类化合物选自：
(1)四氢大麻酚(THC)和四氢次大麻酚(THCV)的组合；
(2)大麻二酚(CBD)和次大麻二酚(CBDV)的组合；
(3)四氢大麻酚(THC)和次大麻二酚(CBDV)的组合；
(4)大麻二酚(CBD)和四氢次大麻酚(THCV)的组合；
(5)大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合；
(6)四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合。
更优选的，所述大麻素类化合物选自：
(1)四氢大麻酚(THC)和四氢次大麻酚(THCV)的组合按重量比四氢大麻酚(THC)和四氢次大麻酚(THCV)为100:5-20；
(2)大麻二酚(CBD)和次大麻二酚(CBDV)的组合按重量比大麻二酚(CBD)和次大麻二酚(CBDV)为100:20-50；
(3)四氢大麻酚(THC)和次大麻二酚(CBDV)的组合按重量比四氢大麻酚(THC) 和次大麻二酚(CBDV)为100:40-100；
(4)大麻二酚(CBD)和四氢次大麻酚(THCV)的组合按重量比大麻二酚(CBD)和四氢次大麻酚(THCV)为100:2.5-10；
(5)大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合按重量比大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)为100:20-50:2.5-10；
(6)四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合按重量比四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)为100:40-100:5-20。
本发明所述的可药用的盐包括以无机酸或有机酸形成的酸加成盐，所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等；所述有机酸例如乙酸、丙酸、己酸、庚酸、丙酮酸、乳酸、丙二酸、丁二酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、邻-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、叔戊酸、叔丁基乙酸、十二烷基硫酸、葡萄糖酸、谷氨酸、萘甲酸、水杨酸、硬脂酸等。
本发明所述的组合物可制成具体的剂型，通过任何适当的途径例如口服，直肠、鼻、肺部、局部(包括口腔和舌下)、透皮、脑池内、腹腔内、阴道和胃肠外(包括皮下、肌内、鞘内、静脉内和皮内)途径给药，优选为口服途径。应理解，优选途径取决于待治疗患者的一般情况和年龄、待治疗疾病的性质和具体活性成分或所选择的活性成分。
口服给药的组合物包括固体剂型，例如胶囊剂、片剂、糖衣片、丸剂、锭剂、粉末剂和颗粒剂。
口服给药的组合物还包括液体剂型，例如溶液剂、乳剂、混悬剂、糖浆剂和酏剂。
胃肠外给药的组合物包括无菌的水性和非水性注射液、分散液、混悬液或乳液，以及在使用前重新溶解于无菌可注射溶液或分散液的无菌粉末。
其它的适合给药剂型包括栓剂、喷雾剂、乳膏剂、凝胶剂、吸入剂、贴剂、埋植剂等。
本发明的组合物或根据本发明生产的组合物可通过任何适当的途径给予，例如以片剂、胶囊剂、粉末剂、糖浆剂等形式口服，或以溶液的形式胃肠外注射。为了制备这种组合物，可采用本领域已知的方法，而且可采用本领域内通常使用的任何药物可接受的载体、稀释剂、赋形剂或其它添加剂。
对于胃肠外给药，可以使用一种或多种活性成分的无菌水溶液、含水丙二醇溶液、含水维他命E溶液或芝麻油或花生油溶液。如果有必要，这种含水溶液应恰当缓冲，而且液体稀释剂首先用足够的盐或葡萄糖制成等渗的。含水溶液尤其适合于静脉内、肌内、皮下和腹腔内给药。通过本领域技术人员已知的标准技术容易制得所采用的无菌含水介质。
通过将一种或多种活性成分和可能的添加剂溶解于一部分注射用溶剂(优选无菌水)，调整溶液至所需体积，灭菌溶液并将其灌注到适当的安瓿或小瓶中，可制备注射用溶液。可加入本领域内常用的任何恰当添加剂，例如张力剂、防腐剂、抗氧化剂等。
恰当的药物载体包括惰性固体稀释剂或填充剂、无菌水溶液和各种有机溶剂。
固体载体的实例有乳糖、白土、蔗糖、环糊精、滑石粉、琼脂、果胶、阿拉伯胶、硬脂酸、纤维素的低级烷基醚、玉米淀粉、马铃薯淀粉、滑石粉、硬脂酸镁、明胶等。
可使用任何其它通常用于着色、矫味、防腐等目的的辅料或添加剂，只要它们和活性成分或已使用的成分相容。
液体载体的实例有糖浆、花生油、橄榄油、磷脂、脂肪酸、脂肪酸胺、聚氧乙烯和水。相似的，载体或稀释剂可以包含本领域内已知的任何缓释材料，例如单独的或与蜡混合的单硬脂酸甘油酯或二硬脂酸甘油酯。
通过将一种或多种本发明的活性成分与药物可接受的载体混合而形成的组合物，然后可以以适合公开给药途径的各种剂型方便地给予。通过药学领域内已知的方法可方便地使制剂以单位剂型存在。
本发明的活性成分可配制为相似或不相似的药物组合物和其单位剂型。
优选的，本发明所述的药物组合物中含有单位剂量为2.5-400mg大麻素类化合物或其可药用的盐，更优选的，所述的药物组合物中含有单位剂量为25-300mg大麻素类化合物或其可药用的盐，最优选的，所述的药物组合物中含有单位剂量为50-200mg大麻素类化合物或其可药用的盐，在本发明的实施方式中，所述的药物组合物中含有单位剂量为25mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg或200mg大麻素类化合物或其可药用的盐。
本发明还提供了一种预防和/或治疗神经性皮炎的方法，所述的方法包括每日施用药物剂量为1-500mg大麻素类化合物或其可药用的盐，更优选的，每日施用药物剂量为25-300mg大麻素类化合物或其可药用的盐，最优选的，每日施用药物剂量为50-200mg大 麻素类化合物或其可药用的盐，在本发明的实施方式中，每日施用药物剂量还可以为25mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、110mg、120mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg或200mg大麻素类化合物或其可药用的盐。
本发明所述的大麻素类化合物或其可药用的盐可以是化学合成产物、生物合成产物、植物提取物或采用其他方式制备得到。优选的，本发明所述的大麻素类化合物是植物提取物，所述的植物可以为大麻Cannabis sativa L.的秆芯、花、叶、根和/或籽的外壳。
本发明所述的大麻素类化合物是植物提取物时，提取溶剂可以为低分子醇(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。提取的方法包括：
(1)使用约3-10倍重量的上述提取溶剂或其混合物对大麻Cannabis sativa L.的秆芯、花、叶、根和/或籽的外壳加热回流，优选至少处理约1小时，然后过滤除去残余物，随后除去溶剂，优选在真空条件除去溶剂，将获得的浸膏在温度约110-135℃加热约40分钟，随后进行色谱分离，优选用于色谱法的流动相混合物由甲醇/水和乙酸或者乙醇/水和乙酸组成。
(2)使用约3-10倍重量的上述提取溶剂或其混合物对大麻的秆芯、花、叶、根和/或籽的外壳加热回流，优选至少处理约1小时，过滤，然后用1-10％的氢氧化钠水溶液至少萃取两次，所述氢氧化钠水溶液优选含有约20wt％的乙醇，将萃取液与5％的硫酸溶液混合以使pH值为约2-4，然后使用低沸点溶剂(如低沸点脂肪烃、芳香烃、氯代烃、乙酸甲酯、乙酸乙酯或者其混合物)提取至少两次，低温真空下除去溶剂，随后进行色谱分离，优选用于色谱法的流动相混合物由甲醇/水和乙酸或者乙醇/水和乙酸组成。
本发明所述的患者为哺乳动物，例如人、小鼠、大鼠、豚鼠、狗、猫、马、牛、猪，或非人灵长类动物，如猴、黑猩猩或狒狒。优选的，所述的患者为人。
除非另有说明，否则术语“药学上可接受的载体或赋形剂”含义是该成分没有生物活性或其他不良活性的杂质，例如该成分可以纳入公开的药物制剂并给与患者，但不引起显著的不良生物效果或以有害的方式和该制剂中包含的其他成分产生相互作用。
除非另有说明，否则术语“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。
除非另有说明，否则术语“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。
除非另有说明，否则术语“约”通常意指所述值的+/-5％，更通常指所述值的+/-4％，更通常指所述值的+/-3％，更通常指所述值的+/-2％，更通常指所述值的+/-1％，更通常指所述值的+/-0.5％。
本发明通过大量的研究验证了大麻素类化合物或其可药用的盐对治疗神经性皮炎具有明显效果，单独的大麻素类化合物以及上述组合均具有改善神经性皮炎的各种症状，能用于制备治疗神经性皮炎的药物。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
实施例1 胶囊单位剂型
Figure PCTCN2018115075-appb-000001
制备方法：将所述活性成分过筛，并与辅料混合，将混合物装入硬明胶胶囊中。
实施例2 胶囊单位剂型
Figure PCTCN2018115075-appb-000002
制备方法同实施例1。
实施例3 片剂单位剂型
Figure PCTCN2018115075-appb-000003
制备方法：将所述活性成分过筛，并与糊精、微晶纤维素、聚乙烯吡咯烷酮、羧甲基淀粉钠混合直至形成均匀的混合物，过筛得到混合物，并与硬脂酸镁混合。然后将所得的粉型混合物压制成需要形状和大小的药片。
实施例4 片剂单位剂型
Figure PCTCN2018115075-appb-000004
制备方法：将所述活性成分过筛，并与预胶凝淀粉、微晶纤维素、羧甲基淀粉钠混合直至形成均匀的混合物，过筛得到混合物，并与硬脂酸镁混合。然后将所得的粉型混合物压制成需要形状和大小的药片。
实施例5 片剂单位剂型
Figure PCTCN2018115075-appb-000005
Figure PCTCN2018115075-appb-000006
制备方法：将所述活性成分过筛，并与糊精、羧甲基淀粉钠混合直至形成均匀的混合物，过筛得到混合物，并与硬脂酸镁混合。然后将所得的粉型混合物压制成需要形状和大小的药片。
实施例6 片剂单位剂型
Figure PCTCN2018115075-appb-000007
制备方法：将所述活性成分过筛，并与预胶凝淀粉、微晶纤维素、羧甲基淀粉钠混合直至形成均匀的混合物，过筛得到混合物，并与硬脂酸镁混合。然后将所得的粉型混合物压制成需要形状和大小的药片。
实施例7 片剂单位剂型
Figure PCTCN2018115075-appb-000008
制备方法：将所述活性成分过筛，并与预胶凝淀粉、微晶纤维素、聚乙烯吡咯烷酮、羧甲基淀粉钠混合直至形成均匀的混合物，过筛得到混合物，并与硬脂酸镁混合。然后将所得的粉型混合物压制成需要形状和大小的药片。
实施例8 片剂单位剂型
Figure PCTCN2018115075-appb-000009
制备方法：将所述活性成分过筛，并与预胶凝淀粉、微晶纤维素、聚乙烯吡咯烷酮、羧甲基淀粉钠混合直至形成均匀的混合物，过筛得到混合物，并与硬脂酸镁混合。然后将所得的粉型混合物压制成需要形状和大小的药片。
实施例9 片剂单位剂型
Figure PCTCN2018115075-appb-000010
制备方法：将所述活性成分过筛，并与糊精和羧甲基淀粉钠混合直至形成均匀的混合物，过筛得到混合物，并与硬脂酸镁混合。然后将所得的粉型混合物压制成需要形状和大小的药片。
实施例10 片剂单位剂型
Figure PCTCN2018115075-appb-000011
Figure PCTCN2018115075-appb-000012
制备方法：将所述活性成分过筛，并与糊精和羧甲基淀粉钠混合直至形成均匀的混合物，过筛得到混合物，并与硬脂酸镁混合。然后将所得的粉型混合物压制成需要形状和大小的药片。
实施例11 注射剂单位剂型(10mL水针剂)
Figure PCTCN2018115075-appb-000013
制备方法：取注射用水约800ml，加入适量羟丙基-β-环糊精，再加入四氢次大麻酚成分使之溶解，用0.1mol/L HCl调节pH值为6.2-6.5，加注射用水至全量，搅匀，加入氯化钠调配至等渗，滤过，灌封于安瓿中，通入蒸汽121℃灭菌15min，10ml灌装。
实施例12 注射剂单位剂型(10mL粉针剂)
Figure PCTCN2018115075-appb-000014
制备方法：取注射用水约800ml，加入处方量的甘露醇和适量羟丙基-β-环糊精，再加入所述各大麻素活性成分使之溶解，搅拌下加适量0.1mol/L HCl调节pH值为6.2-6.5，然后加注射用水至全量，加入氯化钠调配至等渗，滤过，按照冻干粉针剂工艺进行冷冻干燥，制成粉针剂，10ml灌装。
实施例13 单独施用大麻素类化合物对磷酸组胺致痒作用的影响
实验原理：
痒觉受中枢调节，该调节通过位于脊髓中神经元的兴奋和抑制回路以及阿片样系统实现的，因此心理因素可引起神经免疫变化，使中枢神经兴奋和抑制功能失调，导致痒觉调节机制发生紊乱引起中枢痒觉。大麻素类化合物则能够通过大麻素CB1和/或CB2受体调节中枢神经，达到改善瘙痒。
实施方法：
取豚鼠70只，随机均分为空白对照组(蒸馏水100mg/天)、大麻二酚组(50mg/天、100mg/天、200mg/天)、四氢大麻酚组(40mg/天、80mg/天、100mg/天)、次大麻二酚组(40mg/天、80mg/天、100mg/天)、四氢次大麻酚组(5mg/天、10mg/天、20mg/天)、对照组(扑尔敏10mg/天)，每组5只。各组豚鼠右后足背部剃毛2cm×2cm，分别按照上述给药剂量口服给药，连续给药3天。给药第3天，用粗砂纸分别擦伤剃毛处，以伤及表皮、有轻度渗血为度，10分钟后，分别在每只豚鼠创面处滴0.05ml 0.01％磷酸组胺溶液，此后每隔3min依次递增磷酸组胺的浓度(例如0.02％/0.03％/0.04％/0.05％/0.06％等)磷酸组胺溶液直至豚鼠出现回头舔足时，记录每只豚鼠所给予组胺的总量，以此总量为致痒阈。
实验结果：
Figure PCTCN2018115075-appb-000015
Figure PCTCN2018115075-appb-000016
从本实验可以看出，单独施用大麻二酚以及四氢大麻酚能够明显缓解磷酸组胺致痒作用。
实施例14 施用大麻素类化合物组合物对磷酸组胺致痒作用的影响
尽管单独施用大麻二酚和四氢大麻酚表现出一定的对磷酸组胺致痒作用的缓解，但更希望能够发现具有更佳效果的活性成分。因此，本实验比较了不同组别大麻素类化合物组合物对磷酸组胺致痒作用的影响。
实施方法：
取豚鼠90只，随机均分为：
四氢大麻酚(THC)和四氢次大麻酚(THCV)联合用药组；
大麻二酚(CBD)和次大麻二酚(CBDV)联合用药组；
四氢大麻酚(THC)和次大麻二酚(CBDV)联合用药组；
大麻二酚(CBD)和四氢次大麻酚(THCV)联合用药组；
大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)联合用药组；
四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)联合用药组：
每组5只，实验步骤同实施例13。
实验结果：
Figure PCTCN2018115075-appb-000017
Figure PCTCN2018115075-appb-000018
从本实验可以看出，与单独施用大麻二酚以及四氢大麻酚相比，两种以上大麻素类化合物的组合具有更优的效果，这可能与不同大麻素类化合物作用的受体靶点不同相关。
实施例15 大麻素类化合物对神经性皮炎的临床研究
选择皮肤科门诊和住院部的泛发性神经性皮炎患者。
诊断标准：均符合《临床皮肤病学》中有关神经性皮炎的诊断。其临床表现主要以皮肤苔癣样变及剧烈瘙痒为特征。多发生在颈后部或其两侧、肘窝、胭窝、前臂、大腿、小腿及腰骶部等。自觉症状常为阵发性剧烈瘙痒，夜间为甚，多数患者有头晕、失眠、烦躁易怒、焦虑不安等神经衰弱的症状。
排除标准：①皮损合并细菌或真菌感染者；②妊娠或哺乳期妇女；③入选前1周内局部用过糖皮质激素药物，或服用过抗组胺类药物者；④1个月内系统应用过糖皮质激素类药物者；⑤已知对研究药及其基质成分过敏者；⑥有慢性肝、肾疾病或其他严重病患者；⑦有糖尿病或严重免疫功能低下者。
选择确诊的神经性皮炎患者90例临床观察，病人随机分成九组，其中大麻素类化合物治疗组八组，共80人，男性56例，女性24例，年龄30～61岁，使用实施例1/3/5/6/7/8/9/10制备的制剂，每组10例男女随机选择。对照组盐酸多塞平组10人，其中男性5例，女性5例，年龄30～61岁。
治疗方法：大麻素类化合物治疗组口服实施例1/3/5/6/7/8/9/10制备的制剂，1次/d，睡前服用，连服2周；对照组采用盐酸多塞平25mg/次，口服，1次/d，睡前服用，连服2周。
观察指标包括瘙痒程度、炎症程度、鳞屑肥厚程度及靶皮损面，选择最严重的皮损部位作为靶皮损部位，每次随访时记录靶皮损的面积、临床症状和体征改变，治疗期间不用其他任何药物。治疗前1周、治疗中2周及停药1个月内每周进行皮损局部的观察、评估。皮损评分方法如下：
Figure PCTCN2018115075-appb-000019
疗效判定标准：评分标准为各指标在每次评估时均按4级评分法进行评分，即0为无，1为轻度，2为中度，3为重度。入组时要求所有患者的糜烂评分＜1分，皮损面积则一律记为3分，并记录各指标评分的合计值。疗效判定：以积分值减少的百分数作为疗效指数来判断疗效，疗效指数的计算公式为：(初诊时积分合计-每次随访时的积分合计)/初诊时积分合计×100％。疗效指数＞90％，为痊愈，61％～89％，为显效，20％～60％为有效，＜20％，为无效。
临床试验结果如下：
Figure PCTCN2018115075-appb-000020
Figure PCTCN2018115075-appb-000021
从本实验可以看出，单独施用大麻二酚、四氢大麻酚以及组合施用两种以上大麻素类化合物的组合对神经性皮炎均具有临床疗效，同时施用两种以上大麻素类化合物的组合具有更优的效果。

Claims (8)

  1. 选自四氢大麻酚(THC)、大麻二酚(CBD)、次大麻二酚(CBDV)、四氢次大麻酚(THCV)中的一种大麻素类化合物或其可药用的盐在单独制备用于治疗神经性皮炎的药物组合物中的用途。
  2. 大麻素类化合物或其可药用的盐在制备用于治疗神经性皮炎的药物组合物中的用途，所述的大麻素类化合物选自：
    (1)四氢大麻酚(THC)和四氢次大麻酚(THCV)的组合；
    (2)大麻二酚(CBD)和次大麻二酚(CBDV)的组合；
    (3)四氢大麻酚(THC)和次大麻二酚(CBDV)的组合；
    (4)大麻二酚(CBD)和四氢次大麻酚(THCV)的组合；
    (5)大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合；
    (6)四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合。
  3. 权利要求2所述的大麻素类化合物或其可药用的盐在制备用于治疗神经性皮炎的药物组合物中的用途，其中：
    (1)四氢大麻酚(THC)和四氢次大麻酚(THCV)的组合中按重量比四氢大麻酚(THC)和四氢次大麻酚(THCV)为100:5-20；
    (2)大麻二酚(CBD)和次大麻二酚(CBDV)的组合按重量比大麻二酚(CBD)和次大麻二酚(CBDV)为100:20-50；
    (3)四氢大麻酚(THC)和次大麻二酚(CBDV)的组合按重量比四氢大麻酚(THC)和次大麻二酚(CBDV)为100:40-100；
    (4)大麻二酚(CBD)和四氢次大麻酚(THCV)的组合按重量比大麻二酚(CBD)和四氢次大麻酚(THCV)为100:2.5-10；
    (5)大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合按重量比大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)为100:20-50:2.5-10；
    (6)四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合按重量比四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)为100:40-100: 5-20。
  4. 一种治疗神经性皮炎的药物组合物，其特征在于，所述药物组合物由以下组分组成：
    1)大麻素类化合物或其可药用的盐；
    2)一种或多种药学上可接受的载体或赋形剂；
    所述的大麻素类化合物选自四氢大麻酚(THC)、大麻二酚(CBD)、次大麻二酚(CBDV)、四氢次大麻酚(THCV)中的一种。
  5. 一种治疗神经性皮炎的药物组合物，其特征在于，所述药物组合物由以下组分组成：
    1)大麻素类化合物或其可药用的盐；
    2)一种或多种药学上可接受的载体或赋形剂；
    所述的大麻素类化合物选自：
    (1)四氢大麻酚(THC)和四氢次大麻酚(THCV)的组合；
    (2)大麻二酚(CBD)和次大麻二酚(CBDV)的组合；
    (3)四氢大麻酚(THC)和次大麻二酚(CBDV)的组合；
    (4)大麻二酚(CBD)和四氢次大麻酚(THCV)的组合；
    (5)大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合；
    (6)四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合。
  6. 如权利要求5所述的药物组合物，其特征在于，所述大麻素类化合物选自：
    (1)四氢大麻酚(THC)和四氢次大麻酚(THCV)的组合按重量比四氢大麻酚(THC)和四氢次大麻酚(THCV)为100:5-20；
    (2)大麻二酚(CBD)和次大麻二酚(CBDV)的组合按重量比大麻二酚(CBD)和次大麻二酚(CBDV)为100:20-50；
    (3)四氢大麻酚(THC)和次大麻二酚(CBDV)的组合按重量比四氢大麻酚(THC)和次大麻二酚(CBDV)为100:40-100；
    (4)大麻二酚(CBD)和四氢次大麻酚(THCV)的组合按重量比大麻二酚(CBD)和四氢次大麻酚(THCV)为100:2.5-10；
    (5)大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合按重量比大麻二酚(CBD)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)为100:20-50:2.5-10；
    (6)四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)的组合按重量比四氢大麻酚(THC)、次大麻二酚(CBDV)和四氢次大麻酚(THCV)为100:40-100:5-20。
  7. 根据权利要求4-6任意一项所述的组合物，其特征在于，所述药物组合物选自胶囊剂、片剂、丸剂、锭剂、颗粒剂、溶液剂、乳剂、混悬剂、糖浆剂、无菌注射剂、无菌粉末、栓剂、喷雾剂、软膏剂、乳膏剂、凝胶剂、吸入剂、皮肤贴片或埋植剂。
  8. 制备权利要求4-6任一项组合物的方法，其特征在于，包括如下步骤：将一种或多种所述大麻素类化合物或其可药用的盐，按比例混合均匀，得到所述组合物。
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