WO2021135665A1 - 四氢次大麻酚在肺动脉高压的预防和/或治疗中的应用 - Google Patents

四氢次大麻酚在肺动脉高压的预防和/或治疗中的应用 Download PDF

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WO2021135665A1
WO2021135665A1 PCT/CN2020/128319 CN2020128319W WO2021135665A1 WO 2021135665 A1 WO2021135665 A1 WO 2021135665A1 CN 2020128319 W CN2020128319 W CN 2020128319W WO 2021135665 A1 WO2021135665 A1 WO 2021135665A1
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Prior art keywords
cannabidiol
tetrahydrocannabinol
composition
pulmonary hypertension
specifically
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PCT/CN2020/128319
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English (en)
French (fr)
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谭昕
王曙宾
张可
孙武兴
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汉义生物科技（北京）有限公司
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Publication of WO2021135665A1 publication Critical patent/WO2021135665A1/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
    • A61K31/045—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
    • 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 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the technical field of medicine, in particular to the application of tetrahydrocannabinol (THCV) in the prevention and/or treatment of pulmonary hypertension, in particular to a composition containing tetrahydrocannabinol in pulmonary hypertension and its complications Application in prevention and/or treatment.
  • THCV tetrahydrocannabinol
  • Pulmonary arterial hypertension refers to a hemodynamic and pathophysiological state in which the pulmonary artery pressure rises above a certain threshold.
  • the diagnostic criteria for hemodynamics are: at sea level at rest, right heart catheterization
  • the mean pulmonary artery pressure is ⁇ 25mmHg.
  • Pulmonary hypertension mainly affects the pulmonary artery and right heart, manifested by right ventricular hypertrophy and right atrium dilation.
  • the main pulmonary artery is dilated, and the surrounding pulmonary arteries are sparse.
  • Pulmonary arterioles endothelial cells and smooth muscle cells proliferate and hypertrophy, vascular intimal fibrosis and thickening, media hypertrophy, lumen stenosis, occlusion, distortion, and plexiform changes. Intimal fibrous hyperplasia and lumen obstruction can also occur in the pulmonary venules.
  • Other manifestations of patients with pulmonary hypertension include hypertrophy of the adventitia of the pulmonary artery and veins, increased expression of TGF- ⁇ , and increased expression of matrix proteins such as elastin, fibronectin, cytochrome C, and mucopolysaccharide.
  • right heart failure caused by increased pulmonary artery vascular tension is a serious threat to human life and health.
  • Pulmonary hypertension is a disease that can be treated, but there is currently no specific cure.
  • Traditional treatment methods include oxygen inhalation, cardiotonic, diuretic, calcium channel blockers and anticoagulant adjuvant therapy, which mainly play a role in relieving symptoms.
  • the present invention provides an application of tetrahydrocannabinol in the preparation of products for preventing and/or treating pulmonary hypertension and its complications.
  • the present invention also provides a composition for preventing and/or treating pulmonary hypertension and its complications, which comprises two or more cannabinoid compounds.
  • the above composition includes tetrahydrocannabinol and at least one other cannabinoid compound, and the other cannabinoid compound may be selected from, for example, cannabidiol, cannabidiol, cannabidiol, and the like.
  • the above-mentioned composition comprises tetrahydrocannabinol and cannabidiol; specifically, wherein the mass ratio of tetrahydrocannabinol and cannabidiol is 1:10-60 (specifically as 1 :10, 1:20, 1:25, 1:30, 1:40, 1:50, 1:60), especially 1:20-40.
  • the above composition comprises tetrahydrocannabinol and hypocannabidiol; specifically, wherein the mass ratio of tetrahydrocannabinol and hypocannabidiol is 1:2-10 (specifically Such as 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:0), especially 1:4-8.
  • the above-mentioned composition comprises tetrahydrocannabinol and cannabidiol; specifically, wherein the mass ratio of tetrahydrocannabinol and cannabidiol is 1:0.5-5 (specifically as 1 :0.5, 1:1, 1:2, 1:3, 1:4, 1:5), especially 1:2-4.
  • the above-mentioned composition comprises tetrahydrocannabinol, cannabidiol and cannabidiol; specifically, wherein the mass ratio of tetrahydrocannabinol, cannabidiol and cannabidiol is It is 1:10-60:2-10, especially 1:20-40:4-8.
  • the above composition comprises tetrahydrocannabinol, cannabidiol and cannabidiol; specifically, wherein the mass ratio of tetrahydrocannabinol, cannabidiol and cannabidiol is 1 :10-60:0.5-5, especially 1:20-40:2-4.
  • the above-mentioned composition comprises tetrahydrocannabinol, cannabidiol, and cannabidiol; specifically, wherein the mass ratio of tetrahydrocannabinol, cannabidiol and cannabidiol is It is 1:2-10: 0.5-5, especially 1:4-8:2-4.
  • the above-mentioned composition includes tetrahydrocannabinol, cannabidiol, cannabidiol, and cannabidiol; specifically, wherein, tetrahydrocannabinol, cannabidiol, cannabidiol, and cannabidiol
  • the mass ratio of phenol and cannabidiol is 1:10-60:2-10:0.5-5, especially 1:20-40:4-8:2-4.
  • the above-mentioned tetrahydrocannabinol and at least one other cannabinoid compound may be a chemically synthesized product, a biosynthetic product, a plant extract, or prepared by other methods.
  • the above-mentioned tetrahydrocannabinol and at least one other cannabinoid compound can be the pure products of the respective components, and the above-mentioned composition can be obtained by mixing them; the above-mentioned tetrahydrocannabinol and at least one other cannabinoid Cannabinoid compounds can also be present in the same product at the same time, for example, a plant extract containing both the above-mentioned tetrahydrocannabinol and at least one other cannabinoid compound, such as the full-spectrum oil of industrial hemp, for example, the applicant’s self-made The full spectrum of industrial hemp oil, which contains: CBD 60-90% (specifically 60%, 65%, 70%, 75%, 80%, 90%), CBDV 2-12% (specifically 2%, 5%, 8%, 10%, 12%), CBG 1-5% (specifically 1%, 2%, 3%, 4%, 5%), THCV 0.5-2% (specifically 0.5%
  • the plant extraction part of the above-mentioned plant extract may be one or more of the stalk core, flower, leaf, seed, and seed shell of industrial hemp, especially the flower and/or leaf.
  • the above-mentioned industrial hemp full-spectrum oil is prepared by the following method:
  • step (3) The concentrate obtained in step (2) is added to the solvent to dissolve, purified by column chromatography, the eluent is collected, and concentrated under reduced pressure to obtain the crude oil of the whole spectrum;
  • step (3) (4) adding the crude oil of the full spectrum obtained in step (3) to a solvent for dissolution, purifying by column chromatography, collecting the eluate, and concentrating under reduced pressure.
  • the industrial hemp medicinal material in step (1) may be one or more of the stalk core, flower, leaf, seed, and seed shell of industrial hemp; in an embodiment of the present invention, the above-mentioned industrial hemp medicinal material It is the flower and/or leaf of industrial hemp.
  • the extraction solvent in step (1) is 60-80% (specifically, 60%, 65%, 68%, 70%, 72%, 75%, 80%) ethanol; in an embodiment of the present invention ,
  • the extraction solvent is 70% ethanol.
  • the material-to-liquid ratio of the industrial hemp medicinal powder to the extraction solvent in step (1) is 1:5-10 (w/v, specifically such as 1:5, 1:6, 1:7, 1:8, 1: 9. 1:10); In an embodiment of the present invention, the material-to-liquid ratio is 1:8.
  • the extraction in step (1) is room temperature extraction.
  • the number of extractions in step (1) is 1-3 times, and each time is 0.5-2 hours; in an embodiment of the present invention, the number of extractions in step (1) is 2 times, and each time is 1 hour.
  • the pressure condition of the vacuum concentration in step (2) is -0.08 ⁇ -0.09Mpa.
  • the temperature for concentration under reduced pressure in step (2) is 60-70°C (specifically, 60, 62, 64, 65, 66, 68, 70°C); in an embodiment of the present invention, the temperature is 65°C. °C.
  • the density of the concentrate in step (2) is 1.050-1.100.
  • the solvent in step (3) is water.
  • the chromatography column used in step (3) is a macroporous resin column.
  • the diameter-to-height ratio of the chromatography column used in step (3) is 1:5.
  • the column chromatography in step (3) uses eluent 1, eluent 2 and eluent 3 in sequence, wherein eluent 1 is water, and eluent 2 is 40-60% (specifically Such as 40%, 45%, 50%, 55%, 60%) ethanol, the eluent 3 is 70-90% (specifically, 70%, 75%, 80%, 85%, 90%) ethanol; in the present invention
  • the eluent 2 is 50% ethanol
  • the eluent 3 is 80% ethanol.
  • the flow rate of the eluent in the column chromatography in step (3) is 5-10 BV/h (specifically, 5, 6, 7, 8, 9, 10 BV/h); in an embodiment of the present invention, the The eluent flow rate is 9 BV/h.
  • the eluent collected in the column chromatography in step (3) is obtained by eluent 3 elution.
  • the pressure condition of the vacuum concentration in step (3) is -0.08 ⁇ -0.09Mpa.
  • the temperature for concentration under reduced pressure in step (3) is 60-70°C (specifically, 60, 62, 64, 65, 66, 68, 70°C); in an embodiment of the present invention, the temperature is 65°C. °C.
  • the solvent in step (4) is 60-80% (specifically, 60%, 65%, 68%, 70%, 72%, 75%, 80%) ethanol; in an embodiment of the present invention, The solvent is 70% ethanol.
  • the chromatography column used in step (4) is a polymeric chromatography packing column.
  • the diameter-to-height ratio of the chromatography column used in step (4) is 1:6.
  • the eluent of column chromatography in step (4) is 60-80% (specifically, 60%, 65%, 68%, 70%, 72%, 75%, 80%) ethanol; In one embodiment, the eluent is 70% ethanol.
  • the eluent flow rate in the column chromatography in step (4) is 1-4 BV/h (specifically, 1, 2, 3, 4 BV/h); in an embodiment of the present invention, the eluent flow rate It is 2BV/h.
  • the pressure condition of the vacuum concentration in step (5) is -0.08 ⁇ -0.09Mpa.
  • the temperature for concentration under reduced pressure in step (4) is 60-70°C (specifically, 60, 62, 64, 65, 66, 68, 70°C); in an embodiment of the present invention, the temperature is 65°C. °C.
  • the above-mentioned pulmonary hypertension may be primary pulmonary hypertension or secondary pulmonary hypertension, such as arterial pulmonary hypertension (for example, idiopathic pulmonary hypertension, hereditary pulmonary hypertension, pulmonary hypertension caused by drugs or poisons, or neonatal Children with persistent pulmonary hypertension), left heart disease-related pulmonary hypertension (e.g., pulmonary hypertension due to systolic insufficiency, pulmonary hypertension due to diastolic insufficiency, pulmonary hypertension due to valvular disease), pulmonary hypertension due to pulmonary disease (e.g.
  • arterial pulmonary hypertension for example, idiopathic pulmonary hypertension, hereditary pulmonary hypertension, pulmonary hypertension caused by drugs or poisons, or neonatal Children with persistent pulmonary hypertension
  • left heart disease-related pulmonary hypertension e.g., pulmonary hypertension due to systolic insufficiency, pulmonary hypertension due to diastolic insufficiency
  • hypoxemia e.g., pulmonary hypertension caused by sleep apnea syndrome, chronic Pulmonary hypertension caused by altitude sickness (such as high altitude heart disease) or chronic thromboembolic pulmonary hypertension, especially pulmonary hypertension caused by hypoxemia.
  • the above-mentioned complication of pulmonary hypertension may be chronic obstructive pulmonary emphysema, chronic pulmonary heart disease, right heart failure, liver function damage, etc., especially liver function damage.
  • the above composition may also contain other active ingredients for the prevention and/or treatment of pulmonary hypertension and its complications, such as prostacyclin drugs (for example, beraprost (Benapnost), Treprostinil (Treprostinil)).
  • prostacyclin drugs for example, beraprost (Benapnost), Treprostinil (Treprostinil)
  • Iloprost and Epoprostenol Iloprost and Epoprostenol
  • endothelin receptor antagonists e.g., Bosentan, Ambrisentan and Macitentan
  • Type 5 phosphodiesterase inhibitors e.g., sildenafil (Sildenafil), vardenafil (Vardenafil) and tadalafil (Tadalafil)
  • soluble guanylate cyclase agonists e.g., Liosi One or more of Riociguat
  • serotonin transporter inhibitors for example, Sarpogrelate
  • growth factor inhibitors and Rho kinase inhibitors.
  • composition of the present invention can be made into a specific dosage form, such as oral, rectal, nasal, pulmonary, topical (including oral and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral via any appropriate route.
  • a specific dosage form such as oral, rectal, nasal, pulmonary, topical (including oral and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral via any appropriate route.
  • subcutaneous, intramuscular, intrathecal, intravenous and intradermal route of administration preferably oral route. It should be understood that the preferred route depends on the general condition and age of the patient to be treated, the nature of the disease to be treated and the specific active ingredient or active ingredient selected.
  • 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 injectable solutions, dispersions, suspensions or emulsions, and sterile powders that are re-dissolved in sterile injectable solutions or dispersions before use.
  • Suitable dosage forms for administration include suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants and the like.
  • composition of the present invention or the composition produced according to the present invention can be administered by any appropriate route, such as oral administration in the form of tablets, capsules, powders, syrups, etc., or parenteral injection in the form of solutions.
  • routes such as oral administration in the form of tablets, capsules, powders, syrups, etc., or parenteral injection in the form of solutions.
  • 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 should first be made isotonic with enough salt or glucose.
  • the aqueous solution is particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • the sterile aqueous medium used can be 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 injection solvent (preferably sterile water), adjusting the solution to the required volume, sterilizing the solution and filling it into an appropriate ampoule or vial. Solution for injection. Any appropriate additives commonly used in the art can be added, such as tonicity agents, preservatives, antioxidants, etc.
  • Appropriate 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, lactose, gum, etc.
  • Any other auxiliary materials or additives commonly used for coloring, flavoring, anti-corrosion, etc. can be used as long as they are compatible with the active ingredient or the used ingredients.
  • liquid carriers examples include syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may comprise 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 administration route.
  • the preparation can be conveniently presented in unit dosage form by methods known in the pharmaceutical field.
  • the active ingredients of the present invention can be formulated into similar or dissimilar pharmaceutical compositions and unit dosage forms.
  • the preparation may be in the form of tablets, powders or pellets placed in hard gelatin capsules, or may be in the form of troches or lozenges.
  • the preparation may be a syrup, emulsion, soft gelatin capsule or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution.
  • Pharmaceutical preparations can be conveniently made into unit dosage forms according to standard procedures for pharmaceutical formulations.
  • the amount of active compound per unit dose may vary depending on the nature of the active compound and the intended dosage regimen. Generally, this will be in the range of 0.1 mg to 5000 mg per unit dose.
  • the present invention also provides a method for preparing the above composition, which may include the step of mixing the corresponding components uniformly in proportions or the step of extracting from plant raw materials (for example, extracting the full spectrum of industrial hemp oil from industrial hemp).
  • the present invention also provides an application of a combination of tetrahydrocannabinol and at least one other cannabinoid compound in a product for preventing and/or treating pulmonary hypertension and its complications, and the other cannabinoid compound is selected from: cannabis Diphenols, cannabidiol, cannabidiol, etc.
  • cannabidiol other cannabinoid compounds are cannabidiol; specifically, the mass ratio of tetrahydrocannabinol and cannabidiol is 1:10-60 (specifically, 1:10, 1:20 , 1:25, 1:30, 1:40, 1:50, 1:60), especially 1:20-40.
  • cannabidiol other cannabinoid compounds are cannabidiol; specifically, the mass ratio of tetrahydrocannabinol to cannabidiol is 1:2-10 (specifically, 1:2, 1 :3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:0), especially 1:4-8.
  • cannabidiol other cannabinoid compounds are cannabidiol; specifically, the mass ratio of tetrahydrocannabinol and cannabidiol is 1:0.5-5 (specifically, 1:0.5, 1:1 , 1:2, 1:3, 1:4, 1:5), especially 1:2-4.
  • the other cannabidiol compounds are cannabidiol and cannabidiol; specifically, the mass ratio of tetrahydrocannabinol, cannabidiol, and cannabidiol is 1:10-60 :2-10, especially 1:20-40:4-8.
  • cannabidiol and cannabidiol are cannabidiol and cannabidiol; specifically, the mass ratio of tetrahydrocannabinol, cannabidiol, and cannabidiol is 1:10-60:0.5 -5, especially 1:20-40:2-4.
  • cannabidiol and cannabidiol are cannabidiol and cannabidiol; specifically, the mass ratio of tetrahydrocannabinol, cannabidiol, and cannabidiol is 1:2-10 :0.5-5, especially 1:4-8:2-4.
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • cannabidiol cannabidiol
  • the invention also provides an application of industrial hemp full-spectrum oil in the preparation of products for preventing and/or treating pulmonary hypertension and its complications.
  • the above-mentioned products may be medicines, foods, and health products.
  • the present invention also provides a method for preventing and/or treating pulmonary hypertension and its complications.
  • the method includes the step of administering a therapeutically effective amount of tetrahydrocannabinol or the above-mentioned composition of the present invention to an individual in need.
  • the above-mentioned individuals are mammals, such as humans, mice, rats, guinea pigs, dogs, cats, horses, cows, pigs, or non-human primates, such as monkeys, chimpanzees or baboons; in particular, the above-mentioned individuals Be human.
  • the above-mentioned therapeutically effective amount depends on many factors, including the individual's age, weight, gender, natural health status, nutritional status, taking time, metabolic rate, severity of the disease, and the subjective judgment of the treating physician, etc.
  • the present invention provides the application of tetrahydrocannabinol in the prevention and/or treatment of pulmonary hypertension, especially a composition containing tetrahydrocannabinol in the prevention and/or treatment of pulmonary hypertension and its complications Application, among them, THC, especially the composition containing THC and other cannabinoid compounds, can significantly reduce the right ventricular systolic blood pressure and right ventricular hypertrophy index of pulmonary hypertension model mice, and improve pulmonary edema And hepatic edema can improve pulmonary hypertension. In particular, the combined administration can enhance the ameliorating effect of liver edema, which is of great value to the development of drugs for pulmonary hypertension.
  • the term "effective amount" refers to a dose that can treat, prevent, alleviate and/or alleviate the disease or condition of the present invention in a subject.
  • disease and/or disorder refers to a physical state of the subject, which is related to the disease and/or disorder described in the present invention.
  • treatment includes inhibiting, delaying, alleviating, attenuating, limiting, alleviating or relieving a disease, disorder, condition or state, its occurrence and/or progress, and/or its symptoms.
  • prevention includes reducing the risk of suffering from, infecting or experiencing a disease, disorder, condition or condition, its occurrence and/or progress, and/or its symptoms.
  • mice aged 4-6 weeks, healthy and lively, shiny coat, weight (25.15 ⁇ 2.15) g, C57BL/6 (Experimental Animal Center, Medical College of Military Science, SPF level).
  • the experimental animals are grouped as follows:
  • Group 1 normal oxygen wild type, as a control group: under normal oxygen conditions, 10 female rats and 10 male rats;
  • Group 2 hypooxic wild type, as a control group: under hypoxic conditions, 10 female rats and 10 male rats;
  • Group 3 THCV administration group, 0.2mg/kg body weight: intragastric administration under hypoxia, 10 female rats and 10 male rats;
  • Group 4 THCV administration group, 0.4mg/kg body weight: intragastric administration under hypoxic conditions, 10 female rats and 10 male rats;
  • Group 5 THCV administration group, 0.8mg/kg body weight: intragastric administration under hypoxia, 10 female rats and 10 male rats;
  • Group 6 THCV administration group, 1.6 mg/kg body weight: intragastric administration under hypoxic conditions, 10 female rats and 10 male rats.
  • mice in groups 2-6 Place the mice in groups 2-6 in a normal-pressure hypoxic animal breeding cabin for 14 days, maintain the oxygen concentration in the cabin at 9%-11%, and maintain the cabin temperature at 22-26°C to construct a pulmonary hypertension model; in Beginning on the 15th day, the mice in groups 3-6 were given intragastric administration, and the mice in the second group were given the same dose of normal saline once a day for 7 days. The mice were treated every day on the 21st day. Day detection. The mice in the first group were inhaled normal pressure air, and on the 15th day, the same dose of normal saline was given by gavage, once a day for 7 days, and other conditions were the same as the mice in groups 2-6.
  • RVSP right ventricular systolic blood pressure
  • mice in each group were anesthetized by intraperitoneal injection of sodium pentobarbital (35 mg/kg) according to Song et al. (Song, Y., Jones, JE, Beppu, H., Keaney, JF, Jr., Loscalzo, J., and Zhang, YY (2005).Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice.Circulation 112,553-562.) reported right heart catheterization, using a physiological instrument supporting catheter to measure the right ventricular systolic pressure.
  • the end of the catheter is connected to the multi-channel physiological recorder signal acquisition and processing system, and the position of the catheter tip is judged according to the blood pressure value displayed on the monitor and the transition change of the pressure curve waveform. After the catheter enters the right ventricle, the RVSP is measured and recorded.
  • mice of each group were anesthetized, the thoracic cavity was opened, the heart, lungs and liver were removed, the organs were washed with normal saline, and the excess fluid on the organs was sucked dry with filter paper. The lungs and liver were weighed and the weight of the mice In contrast, calculate the organ index.
  • the heart is used to detect the right ventricular hypertrophy index.
  • RVH right ventricular hypertrophy index
  • the extracted heart was stripped of all blood vessels and ventricles, the right ventricle was cut, the weight of the right ventricle and the weight of the left ventricle plus the diaphragm were respectively weighed, and the weight of the right ventricle was divided by the combined weight of the left ventricle and the diaphragm (RV/(LV+S )).
  • the nucleus After staining, the nucleus is blue-purple and the cytoplasm is pink.
  • Dye preparation Victoria Blue B 1g.
  • Xylene I 10min; Xylene II: 10min; 100% ethanol: 5min; 90% ethanol: 5min; tap water: 5min; 0.5% potassium permanganate for 5min; tap water for 2-3min; 1% oxalic acid solution 2-3min ( Just bleach); rinse with tap water for 2-3min; 95% ethanol for 2-3min; dye with Elastic dye solution for 2h; rinse with 95% ethanol to remove the dye solution; rinse with tap water for 2-3min; dye with Van Gieson dye solution for 1min; rapid dehydration: 80% Ethanol 1 min, 90% ethanol 1 min, anhydrous ethanol I 5 min, anhydrous ethanol II 5 min, xylene I 5 min, xylene II 5 min.
  • Measurement data are expressed as mean ⁇ standard error, and SPSS 22.0 is used for statistical processing, and statistical tests are based on two-tailed T test.
  • mice The results of the average right ventricular systolic blood pressure of each group of mice are shown in Table 1.
  • mice The results of the average right ventricular hypertrophy index of each group of mice are shown in Table 2.
  • Group 1 Group 2
  • Group 3 Group 4
  • Group 5 Group 6 liver/% 6.72 ⁇ 0.69 8.32 ⁇ 0.56 7.92 ⁇ 0.69 7.81 ⁇ 0.42 7.82 ⁇ 0.52 7.80 ⁇ 1.43 lung/% 0.65 ⁇ 0.11 0.85 ⁇ 0.64 0.73 ⁇ 0.55 0.71 ⁇ 0.34 0.72 ⁇ 0.61 0.71 ⁇ 0.65
  • mice were significantly increased, and the mice developed pulmonary edema and liver edema.
  • mice in each experimental group The index of lung and liver of pulmonary edema has decreased, pulmonary edema and liver edema have been improved to a certain extent, and the improvement effect of THCV on pulmonary edema is more obvious.
  • mice were taken and grouped as follows:
  • Group 1 combined administration group THCV 0.4 mg/kg body weight + CBD 10 mg/kg body weight: intragastric administration under hypoxic conditions, 10 female rats and 10 male rats;
  • Group 2 combined administration group THCV 0.4 mg/kg body weight + CBDV 2 mg/kg body weight: intragastric administration under hypoxic conditions, 10 female rats and 10 male rats;
  • Group 3 (combined administration group THCV 0.4 mg/kg body weight + CBG 0.5 mg/kg body weight): intragastric administration under hypoxic conditions, 10 female rats and 10 male rats.
  • Group 4 (combined administration group THCV 0.4 mg/kg body weight + CBD 10 mg/kg body weight + CBDV 2 mg/kg body weight): intragastric administration under hypoxic conditions, 10 female rats and 10 male rats;
  • Group 5 combined administration group THCV 0.4 mg/kg body weight + CBD 10 mg/kg body weight + CBG 0.5 mg/kg body weight: intragastric administration under hypoxic conditions, 10 female rats and 10 male rats;
  • Group 6 combined administration group THCV 0.4 mg/kg body weight + CBDV 2 mg/kg body weight + CBG 0.5 mg/kg body weight: intragastric administration under hypoxic conditions, 10 female rats and 10 male rats.
  • Example 2 With reference to the method steps of Example 1, the mouse right ventricular systolic blood pressure, right ventricular hypertrophy index, liver and lung indexes were detected. The results are shown in Table 4-6.
  • the total cannabinoid content reached 78.41%, of which CBDV 10.52%, CBG 1.57%, CBD 64.80%, THCV 1.52%, THC was not detected.
  • the full spectrum of industrial hemp oil obtained in Example 3 contains THCV, CBD, CBDV and CBG at the same time, and it is administered to pulmonary hypertension model mice to evaluate the experimental effect.
  • mice were taken, modeled, and the whole spectrum of industrial hemp oil obtained in Example 3 was administered by gavage at a dose of 60 mg/kg body weight.
  • the mouse right ventricular systolic blood pressure, right ventricular hypertrophy index, lung and liver indexes were detected.
  • the average right ventricular systolic blood pressure and the average right ventricular hypertrophy index were 17.28 ⁇ 1.24mmHg and 27.26 ⁇ 1.31%, respectively, and the average lung and liver indexes were 0.73 ⁇ 0.59% and 7.54 ⁇ 0.36, respectively.

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Abstract

一种组合物，包含四氢次大麻酚以及至少一种其他大麻素类化合物。一种四氢次大麻酚在制备预防和/或治疗肺动脉高压及其并发症的产品中的应用。一种四氢次大麻酚以及至少一种其他大麻素类化合物的组合在制备预防和/或治疗肺动脉高压及其并发症的产品中的应用。

Description

四氢次大麻酚在肺动脉高压的预防和/或治疗中的应用 技术领域
本发明涉及医药技术领域，具体涉及四氢次大麻酚(THCV)在肺动脉高压的预防和/或治疗中的应用，特别是一种包含四氢次大麻酚的组合物在肺动脉高压及其并发症的预防和/或治疗中的应用。
背景技术
肺动脉高压(pulmonary arterial hypertension，PAH)指肺动脉压力升高超过一定界值的一种血流动力学和病理生理状态，其血流动力学诊断标准为：海平面静息状态下，右心导管检测肺动脉平均压≥25mmHg。肺动脉高压主要累及肺动脉和右心，表现为右心室肥厚，右心房扩张。肺动脉主干扩张，周围肺小动脉稀疏。肺小动脉内皮细胞、平滑肌细胞增生肥大，血管内膜纤维化增厚，中膜肥厚，管腔狭窄，闭塞，扭曲变形，呈丛状改变。肺小静脉也可以出现内膜纤维增生和管腔阻塞。肺动脉高压患者的其它表现还包括肺动脉外膜以及静脉的肥大和TGF-β的表达升高，以及弹性蛋白、纤连蛋白、细胞色素C和粘多糖等基质蛋白表达升高。特别是增强肺动脉血管张力导致的右心衰，是严重威胁人类生命健康的疾病。
肺动脉高压是一种能够治疗的疾病，但目前尚无特效的治愈方法。传统的治疗方法包括吸氧、强心、利尿、钙通道阻滞剂和抗凝剂辅助治疗剂等，主要起到症状的缓解作用。
近年来，靶向治疗药物的研发与推广使用(主要包括前列环素类药物、内皮素受体拮抗剂、磷酸二酯酶-5抑制剂以及新近探索的可溶性鸟苷酸环化酶激动剂、5-羟色胺转运子抑制剂、生长因子抑制剂、Rho激酶抑制剂等)以及活体肺移植等治疗方法大大改善了患者的预后。
尽管这些药物能在一定程度上缓解PAH的症状，肺动脉高压目前仍然是一种无法治愈且病死率较高的疾病，患者接受治疗情况下的中位生存时间仅为2.7年， 目前肺动脉高压仍缺乏特效的治愈方法，因此，寻找新的特异性治疗药物显得尤为迫切。
发明内容
为克服现有技术的不足，本发明提供一种四氢次大麻酚在制备预防和/或治疗肺动脉高压及其并发症的产品中的应用。
本发明还提供一种预防和/或治疗肺动脉高压及其并发症的组合物，其包含两种以上大麻素类化合物。
具体地，上述组合物包含四氢次大麻酚以及至少一种其他大麻素类化合物，该其他大麻素类化合物例如可选自：大麻二酚、次大麻二酚、大麻萜酚等。
在本发明的一个实施方式中，上述组合物包含四氢次大麻酚和大麻二酚；具体地，其中，四氢次大麻酚和大麻二酚的质量比为1:10-60(具体如1:10、1:20、1:25、1:30、1:40、1:50、1:60)，特别是1:20-40。
在本发明的一个实施方式中，上述组合物包含四氢次大麻酚和次大麻二酚；具体地，其中，四氢次大麻酚和次大麻二酚的质量比为1:2-10(具体如1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:0)，特别是1:4-8。
在本发明的一个实施方式中，上述组合物包含四氢次大麻酚和大麻萜酚；具体地，其中，四氢次大麻酚和大麻萜酚的质量比为1:0.5-5(具体如1:0.5、1:1、1:2、1:3、1:4、1:5)，特别是1:2-4。
在本发明的一个实施方式中，上述组合物包含四氢次大麻酚、大麻二酚和次大麻二酚；具体地，其中，四氢次大麻酚、大麻二酚和次大麻二酚的质量比为1:10-60:2-10，特别是1:20-40:4-8。
在本发明的一个实施方式中，上述组合物包含四氢次大麻酚、大麻二酚和大麻萜酚；具体地，其中，四氢次大麻酚、大麻二酚和大麻萜酚的质量比为1:10-60:0.5-5，特别是1:20-40:2-4。
在本发明的一个实施方式中，上述组合物包含四氢次大麻酚、次大麻二酚和大麻萜酚；具体地，其中，四氢次大麻酚、次大麻二酚和大麻萜酚的质量比为1:2-10: 0.5-5，特别是1:4-8:2-4。
在本发明的一个实施方式中，上述组合物包含四氢次大麻酚、大麻二酚、次大麻二酚和大麻萜酚；具体地，其中，四氢次大麻酚、大麻二酚、次大麻二酚和大麻萜酚的质量比为1:10-60:2-10:0.5-5，特别是1:20-40:4-8:2-4。
具体地，上述四氢次大麻酚以及至少一种其他大麻素类化合物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。
具体地，上述四氢次大麻酚以及至少一种其他大麻素类化合物可以分别为各组分的纯净物产品，将其混合即可得到上述组合物；上述四氢次大麻酚以及至少一种其他大麻素类化合物也可以同时存在于同一种产品中，例如同时包含上述四氢次大麻酚以及至少一种其他大麻素类化合物的植物提取物，具体如工业大麻全谱系油，例如申请人自制的工业大麻全谱系油，其包含：CBD 60-90％(具体如60％、65％、70％、75％、80％、90％)，CBDV 2-12％(具体如2％、5％、8％、10％、12％)，CBG 1-5％(具体如1％、2％、3％、4％、5％)，THCV 0.5-2％(具体如0.5％、1％、1.5％、2％)。上述工业大麻全谱系油不含THC或其中THC含量低至无法检出的水平。
具体地，上述植物提取物的植物提取部位可以为工业大麻的秆芯、花、叶、籽和籽的外壳中的一种或多种，特别是花和/或叶。
在本发明的一个实施方式中，上述工业大麻全谱系油通过以下方法制得：
(1)取工业大麻药材粉末，用提取溶剂提取，得提取液；
(2)将步骤(1)所得提取液过滤，减压浓缩；
(3)将步骤(2)所得浓缩物加入溶剂溶解，通过柱层析纯化，收集洗脱液，减压浓缩，得全谱系油粗品；
任选地，(4)将步骤(3)所得全谱系油粗品加入溶剂溶解，通过柱层析纯化，收集洗脱液，减压浓缩。
具体地，步骤(1)中的工业大麻药材可以为工业大麻的秆芯、花、叶、籽和籽的外壳中的一种或多种；在本发明的一个实施例中，上述工业大麻药材为工业大麻的花和/或叶。
具体地，步骤(1)中的提取溶剂为60-80％(具体如60％、65％、68％、70％、72％、 75％、80％)乙醇；在本发明的一个实施例中，该提取溶剂为70％乙醇。
具体地，步骤(1)中工业大麻药材粉末与提取溶剂的料液比为1:5-10(w/v，具体如1:5、1:6、1:7、1:8、1:9、1:10)；在本发明的一个实施例中，该料液比为1:8。
在本发明的一个实施例中，步骤(1)中的提取为室温浸提。
具体地，步骤(1)中提取次数为1-3次，每次0.5-2小时；在本发明的一个实施例中，步骤(1)中提取次数为2次，每次1小时。
具体地，步骤(2)中减压浓缩的压力条件为-0.08～-0.09Mpa。
具体地，步骤(2)中减压浓缩的温度为60-70℃(具体如60、62、64、65、66、68、70℃)；在本发明的一个实施例中，该温度为65℃。
具体地，步骤(2)中的浓缩物密度为1.050-1.100。
在本发明的一个实施例中，步骤(3)中所述溶剂为水。
在本发明的一个实施例中，步骤(3)所用层析柱为大孔树脂柱。
在本发明的一个实施例中，步骤(3)所用层析柱的径高比为1：5。
具体地，步骤(3)中柱层析依次采用洗脱剂1、洗脱剂2和洗脱剂3洗脱，其中，洗脱剂1为水，洗脱剂2为40-60％(具体如40％、45％、50％、55％、60％)乙醇，洗脱剂3为70-90％(具体如70％、75％、80％、85％、90％)乙醇；在本发明的一个实施例中，洗脱剂2为50％乙醇，洗脱剂3为80％乙醇。
具体地，步骤(3)中柱层析中洗脱剂流速为5-10BV/h(具体如5、6、7、8、9、10BV/h)；在本发明的一个实施例中，该洗脱剂流速为9BV/h。
具体地，步骤(3)中柱层析中收集的洗脱液为洗脱剂3洗脱所得。
具体地，步骤(3)中减压浓缩的压力条件为-0.08～-0.09Mpa。
具体地，步骤(3)中减压浓缩的温度为60-70℃(具体如60、62、64、65、66、68、70℃)；在本发明的一个实施例中，该温度为65℃。
具体地，步骤(4)中的溶剂为60-80％(具体如60％、65％、68％、70％、72％、75％、80％)乙醇；在本发明的一个实施例中，该溶剂为70％乙醇。
在本发明的一个实施例中，步骤(4)所用层析柱为聚合色谱填料柱。
在本发明的一个实施例中，步骤(4)所用层析柱的径高比为1:6。
具体地，步骤(4)中柱层析的洗脱剂为60-80％(具体如60％、65％、68％、70％、72％、75％、80％)乙醇；在本发明的一个实施例中，该洗脱剂为70％乙醇。
具体地，步骤(4)中柱层析中洗脱剂流速为1-4BV/h(具体如1、2、3、4BV/h)；在本发明的一个实施例中，该洗脱剂流速为2BV/h。
具体地，步骤(5)中减压浓缩的压力条件为-0.08～-0.09Mpa。
具体地，步骤(4)中减压浓缩的温度为60-70℃(具体如60、62、64、65、66、68、70℃)；在本发明的一个实施例中，该温度为65℃。
本发明中，上述肺动脉高压可以为原发性肺动脉高压或继发性肺动脉高压，如，动脉性肺动脉高压(例如特发性肺动脉高压、可遗传性肺动脉高压、药物或毒物所致肺动脉高压或新生儿持续性肺动脉高压)、左心疾病相关性肺动脉高压(例如心脏收缩功能不全所致肺动脉高压、舒张功能不全所致肺动脉高压、瓣膜病所致肺动脉高压)、肺部疾病所致肺动脉高压(例如慢性阻塞性肺疾病所致肺动脉高压、肺气肿所致肺动脉高压或肺间质性疾病所致肺动脉高压)、低氧血症所致肺动脉高压(例如睡眠呼吸暂停综合征所致肺动脉高压、慢性高原病所致肺动脉高压比如高原性心脏病)或者慢性血栓栓塞性肺动脉高压，特别是低氧血症所致肺动脉高压。
本发明中，上述肺动脉高压的并发症可以为慢性阻塞性肺气肿、慢性肺源性心脏病、右心衰竭、肝功能损伤等，特别是肝功能损伤。
具体地，上述组合物中还可以包含其他用于预防和/或治疗肺动脉高压及其并发症的活性成分，如，前列环素类药物(例如，贝前列素(Benapnost)、曲前列素(Treprostinil)、伊洛前列素(Iloprost)和依前列醇(Epoprostenol))、内皮素受体拮抗剂(例如，波生坦(Bosentan)、安立生坦(Ambrisentan)和马西替坦(Macitentan))、5型磷酸二酯酶抑制剂(例如，西地那非(Sildenafil)、伐地那非(Vardenafil)和他达那非(Tadalafil))、可溶性鸟苷酸环化酶激动剂(例如，利奥西呱(Riociguat))、5-羟色胺转运子抑制剂(例如，沙格雷酯(Sarpogrelate))、生长因子抑制剂以及Rho激酶抑制剂中的一种或多种。
本发明上述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可注射溶液、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、软膏剂、乳膏剂、凝胶剂、吸入剂、皮肤贴片、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、乳糖、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。
如果口服给药采用固体载体，制剂可以是片剂、置于硬明胶胶囊中的粉末或小丸形式，或可以是含片或锭剂形式。
如果采用液态载体，制剂可以是糖浆剂、乳剂、软明胶胶囊或无菌可注射液体，例如水性或非水性液体混悬剂或溶液。药物制剂可根据药物配方的标准程序方便地制成单位剂型。每单位剂量的活性化合物的量可能会根据活性化合物的性质和预期的剂量方案而改变。一般来说，这会在每单位剂量0.1mg～5000mg的范围内。
本发明还提供一种上述组合物的制备方法，其可包括将相应组分按比例混合均匀的步骤或从植物原料中提取(例如从工业大麻中提取得到工业大麻全谱系油)的步骤。
本发明还提供一种四氢次大麻酚以及至少一种其他大麻素类化合物的组合在预防和/或治疗肺动脉高压及其并发症的产品中的应用，该其他大麻素类化合物选自：大麻二酚、次大麻二酚、大麻萜酚等。
具体地，上述应用中，其他大麻素类化合物为大麻二酚；具体地，其中，四氢次大麻酚和大麻二酚的质量比为1:10-60(具体如1:10、1:20、1:25、1:30、1:40、1:50、1:60)，特别是1:20-40。
具体地，上述应用中，其他大麻素类化合物为次大麻二酚；具体地，其中，四氢次大麻酚和次大麻二酚的质量比为1:2-10(具体如1:2、1:3、1:4、1:5、1:6、1:7、 1:8、1:9、1:0)，特别是1:4-8。
具体地，上述应用中，其他大麻素类化合物为大麻萜酚；具体地，其中，四氢次大麻酚和大麻萜酚的质量比为1:0.5-5(具体如1:0.5、1:1、1:2、1:3、1:4、1:5)，特别是1:2-4。
具体地，上述应用中，其他大麻素类化合物为大麻二酚和次大麻二酚；具体地，其中，四氢次大麻酚、大麻二酚、次大麻二酚的质量比为1:10-60:2-10，特别是1:20-40:4-8。
具体地，上述应用中，其他大麻素类化合物为大麻二酚和大麻萜酚；具体地，其中，四氢次大麻酚、大麻二酚、大麻萜酚的质量比为1:10-60:0.5-5，特别是1:20-40:2-4。
具体地，上述应用中，其他大麻素类化合物为次大麻二酚和大麻萜酚；具体地，其中，四氢次大麻酚、次大麻二酚、大麻萜酚的质量比为1:2-10:0.5-5，特别是1:4-8:2-4。
具体地，上述应用中，其他大麻素类化合物为大麻二酚、次大麻二酚和大麻萜酚；具体地，其中，四氢次大麻酚、大麻二酚、次大麻二酚、大麻萜酚的质量比为1:10-60:2-10:0.5-5，特别是1:20-40:4-8:2-4。
本发明还提供一种工业大麻全谱油在制备预防和/或治疗肺动脉高压及其并发症的产品中的应用。
具体地，上述产品可以为药物、食品、保健品。
本发明还提供一种预防和/或治疗肺动脉高压及其并发症的方法，该方法包括对有需要的个体给与治疗有效量的四氢次大麻酚或本发明上述组合物的步骤。
具体地，上述个体为哺乳动物，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；特别是，上述个体为人。
具体地，上述治疗有效量取决于诸多因素，包括个体的年龄、体重、性别、自然健康状况、营养状况、服用时间、代谢速率、病症的严重程度以及诊治医师的主观判断，等。
本发明提供了四氢次大麻酚在肺动脉高压的预防和/或治疗中的应用，特别是一 种包含四氢次大麻酚的组合物在肺动脉高压及其并发症的预防和/或治疗中的应用，其中，四氢次大麻酚，特别是包含四氢次大麻酚和其他大麻素类化合物的组合物，可显著降低肺动脉高压模型小鼠的右心室收缩压和右心室肥大指数，改善肺水肿和肝水肿，可改善肺动脉高压病症，特别是，联合给药均可增强对肝脏水肿的改善作用，对肺动脉高压治疗药物的开发具有重要的价值。
具体实施方式
除非另有定义，本发明中所使用的所有科学和技术术语具有与本发明涉及技术领域的技术人员通常理解的相同的含义，如在本发明中出现的以下缩写及其对应的物质为：
Figure PCTCN2020128319-appb-000001
本发明中，术语“有效量”是指可在受试者中实现治疗、预防、减轻和/或缓解本发明所述疾病或病症的剂量。
本发明中，术语“疾病和/或病症”是指所述受试者的一种身体状态，该身体状态与本发明所述疾病和/或病症有关。
本发明中，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。
本发明中，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。
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
1.实验动物、试剂和仪器
(1)实验动物
4-6周龄小鼠，健康活泼、毛色光泽，体重(25.15±2.15)g，C57BL/6(军事科学医学院实验动物中心，SPF级)。将实验动物分组如下：
第1组(常氧野生型，作为对照组)：常氧条件下，雌鼠10只，雄鼠10只；
第2组(缺氧野生型，作为对照组)：缺氧条件下，雌鼠10只，雄鼠10只；
第3组(THCV给药组，0.2mg/kg体重)：缺氧条件下灌胃给药，雌鼠10只，雄鼠10只；
第4组(THCV给药组，0.4mg/kg体重)：缺氧条件下灌胃给药，雌鼠10只，雄鼠10只；
第5组(THCV给药组，0.8mg/kg体重)：缺氧条件下灌胃给药，雌鼠10只，雄鼠10只；
第6组(THCV给药组，1.6mg/kg体重)：缺氧条件下灌胃给药，雌鼠10只，雄鼠10只。
(2)处理方法
将第2-6组小鼠置于常压低氧动物饲养舱内14天，维持舱内氧浓度在9％-11％，保持舱内温度为22-26℃，构建肺动脉高压的模型；在第15天开始，对第3-6组小鼠进行灌胃给药，对第2组小鼠灌胃给与等剂量生理盐水，每天给药一次，持续7天每天处理小鼠，在第21天检测。第1组小鼠吸入常压空气，第15天灌胃给与等剂量生理盐水，每天给药一次，持续7天，其它条件同第2-6组小鼠。
2.实验方法
(1)右心室收缩压(RVSP)测定
在第21天，将各组小鼠用戊巴比妥钠(35mg/kg)腹腔注射麻醉，参照Song等(Song,Y.,Jones,J.E.,Beppu,H.,Keaney,J.F.,Jr.,Loscalzo,J.,and Zhang,Y.Y.(2005).Increased susceptibility to pulmonary hypertension in heterozygous BMPR2-mutant mice.Circulation 112,553-562.)报道的右心导管插入术，用生理仪配套导管测右心室收缩压。导管末端连接多道生理记录仪信号采集处理系统，根据监视器所显示的 血压值与压力曲线波型的移行变化判断导管尖端的位置。待导管进入右心室后，测定并记录RVSP。
(2)脏器指数测定
将各组小鼠麻醉后，开胸腔，摘取心脏、肺脏和肝脏，将各脏器用生理盐水洗净，用滤纸将脏器上多余液体吸干，称量肺脏和肝脏重量，与小鼠体重相比，计算脏器指数。心脏用于检测右心室肥大指数。
(3)右心室肥大指数(RVH)测定
将摘取的心脏剥离所有血管和心室，剪下右心室，分别称量右心室重量和左心室加膈的重量，用右心室重除以左心室和膈的合重(RV/(LV+S))。
(4)HE染色
样品：小鼠肺组织的石蜡切片。
目的：看肺组织病理，是否有血管壁增厚的现象。
将切好的石蜡切片放入55℃烘箱中10min。
①石蜡切片经脱蜡下行至70％乙醇；
二甲苯I：15min
二甲苯II：7min
1：1二甲苯乙醇溶液：5min
各级乙醇：各5min
②苏木精溶液染色10-15min；
③自来水冲洗2min；
④0.5％盐酸酒精溶液分化8s；
⑤自来水返蓝10min；
⑥70％酒精→80％酒精各2min；
⑦0.5％伊红酒精染液50-70s；
⑧90％乙醇，95％乙醇分色各3min；
⑨无水乙醇I、II脱水各3min；
⑩无水乙醇：二甲苯(1:1)3min；
Figure PCTCN2020128319-appb-000002
二甲苯I 3min；
Figure PCTCN2020128319-appb-000003
二甲苯II 3min；
中性树胶封片；
染色完成后，胞核呈蓝紫色，胞质呈粉红色。
(5)弹性纤维染色(Elastic染色)
样品：小鼠肺组织的石蜡切片。
染液配制：维多利亚蓝B 1g。
新品红1g，结晶紫1g。
200ml热水溶解，按顺序加入间二苯酚4g，糊精4g，30％氯化铁50ml(现用现配)，煮5min过滤，沉淀和滤纸用200ml 95％乙醇溶解，煮沸15min-20min过滤(水浴)，95％乙醇补至200ml，最后加2ml浓盐酸。密封，避光保存。
染色方法：
二甲苯I：10min；二甲苯II：10min；100％乙醇：5min；90％乙醇：5min；自来水：5min；0.5％高锰酸钾5min；自来水冲洗2-3min；1％草酸溶液2-3min(漂白即可)；自来水冲洗2-3min；95％乙醇2-3min；Elastic染液染2h；95％乙醇洗去染液；自来水冲洗2-3min；Van Gieson染液染1min；快速脱水：80％乙醇1min，90％乙醇1min，无水乙醇I 5min，无水乙醇II 5min，二甲苯I 5min，二甲苯II 5min。
(6)统计学处理
计量资料以均数±标准误表示，采用SPSS 22.0进行统计处理，统计检验均基于双尾T检验。
3.实验结果
(1)PAH小鼠右心室收缩压
各组小鼠的平均右心室收缩压结果如表1所示。
表1 各组小鼠右心室收缩压结果
Figure PCTCN2020128319-appb-000004
Figure PCTCN2020128319-appb-000005
由表1结果可知，与常氧对照组相比，持续缺氧21天后，缺氧模型对照组平均右心室收缩压显著升高，给药THCV后，各实验组小鼠右心室收缩压均有所降低。
(2)PAH小鼠右心室肥大指数
各组小鼠的平均右心室肥大指数结果如表2所示。
表2 各组小鼠右心室肥大指数结果
Figure PCTCN2020128319-appb-000006
由表2结果可知，与常氧对照组相比，缺氧模型对照组小鼠右心室肥大指数明显升高，给药THCV后，各实验组小鼠右心室肥大指数均有所降低，但未降至正常水平(如常氧对照组相似的水平)，且各给药组差别不显著。
(3)PAH小鼠脏器指数
各组小鼠的平均脏器指数结果如表3所示。
表3 各组小鼠脏器指数结果
  第1组 第2组 第3组 第4组 第5组 第6组
肝脏/％ 6.72±0.69 8.32±0.56 7.92±0.69 7.81±0.42 7.82±0.52 7.80±1.43
肺脏/％ 0.65±0.11 0.85±0.64 0.73±0.55 0.71±0.34 0.72±0.61 0.71±0.65
由表2结果可知，与常氧对照组相比，缺氧模型对照组小鼠的肺脏和肝脏指数均显著升高，小鼠出现肺水肿、肝水肿，给药THCV后，各实验组小鼠的肺脏和肝脏指数有所下降，肺水肿、肝水肿有一定的改善，且THCV对肺水肿的改善作用更加明显。
(4)肺小动脉病理学改变
通过小鼠肺组织的染色切片发现，缺氧模型组小鼠管壁显著增厚，重构明显，给药后病理重构有所改善，动脉中层壁厚比和管壁中层横截面积比有所降低。
实施例2
参照实施例1相关参数，取实验小鼠，分组如下：
第1组(联合给药组THCV 0.4mg/kg体重+CBD 10mg/kg体重)：缺氧条件下灌胃给药，雌鼠10只，雄鼠10只；
第2组(联合给药组THCV 0.4mg/kg体重+CBDV 2mg/kg体重)：缺氧条件下灌胃给药，雌鼠10只，雄鼠10只；
第3组(联合给药组THCV 0.4mg/kg体重+CBG 0.5mg/kg体重)：缺氧条件下灌胃给药，雌鼠10只，雄鼠10只。
第4组(联合给药组THCV 0.4mg/kg体重+CBD 10mg/kg体重+CBDV 2mg/kg体重)：缺氧条件下灌胃给药，雌鼠10只，雄鼠10只；
第5组(联合给药组THCV 0.4mg/kg体重+CBD 10mg/kg体重+CBG 0.5mg/kg体重)：缺氧条件下灌胃给药，雌鼠10只，雄鼠10只；
第6组(联合给药组THCV 0.4mg/kg体重+CBDV 2mg/kg体重+CBG 0.5mg/kg体重)：缺氧条件下灌胃给药，雌鼠10只，雄鼠10只。
参照实施例1的方法步骤，检测小鼠右心室收缩压、右心室肥大指数、肝脏和肺指数。结果分别如表4-6所示。
表4 各组小鼠右心室收缩压结果
Figure PCTCN2020128319-appb-000007
表5 各组小鼠右心室肥大指数结果
Figure PCTCN2020128319-appb-000008
表6 各组小鼠脏器指数结果
  第1组 第2组 第3组 第4组 第5组 第6组
肝脏/％ 7.32±0.75 7.68±0.46 7.52±0.37 7.29±0.52 6.95±0.46 7.16±0.37
肺脏/％ 0.68±0.36 0.70±0.45 0.71±0.36 0.67±0.25 0.68±0.45 0.70±0.36
由表4-6结果可知，上述联合给药方案中，对于小鼠右心室收缩压和右心室肥大指数，第4组具有较佳的改善效果，第1、2、5组次之，第3和6组与实施例1中单独给药THCV相比差别不大，而对于脏器指数，联合给药均可增强对肝脏水肿的改善作用。
实施例3
取工业大麻花叶进行粉碎，过1号筛，100℃烘烤200min，取一定量烘烤后的大麻花叶药材，按料液比1:8(w/v)加入70％乙醇，室温搅拌提取两次，每次1小时，过滤，合并提取液，离心过滤，离心过滤液减压浓缩(65℃，-0.08～-0.09Mpa)至无醇味且密度为1.070(60℃)，补加纯化水至溶液重量为药材重量的8倍，搅拌均匀，即得上样液。
量取上样液，以4BV/h的流速经已处理好的大孔树脂柱(径高比为1：5)纯化，上样毕静置60min，再以9BV/h的流速依次用纯化水、50％乙醇、80％乙醇洗脱，用molish反应确定水洗脱终点，50％乙醇洗脱3BV，80％乙醇洗脱5BV，收集80％乙醇洗脱液，减压浓缩(65℃，-0.08～-0.09Mpa)至水分至5％以下，即得全谱系油粗品。
取全谱系油粗品，加入70％乙醇搅拌溶解，过滤，所得滤液以2BV/h的流速经已处理好的聚合色谱填料柱(径高比为1：6)纯化，上样毕，再以2BV/h的流速用70％乙醇洗脱5BV，70％乙醇洗脱液减压浓缩(65℃，-0.08～-0.09Mpa)至水分至5％以下，即得全谱系油。
所得全谱系油中，总大麻素含量达78.41％，其中CBDV 10.52％、CBG 1.57％、CBD 64.80％、THCV 1.52％，THC未检出。
实施例4
实施例3所得工业大麻全谱系油中同时包含THCV、CBD、CBDV和CBG，将其施用于肺动脉高压模型小鼠，评估实验效果。
参照实施例1的方法步骤，取小鼠10只，进行造模，灌胃给与实施例3所得 工业大麻全谱系油，给药剂量为60mg/kg体重。参照实施例1的方法步骤，检测小鼠右心室收缩压、右心室肥大指数、肺脏和肝脏指数。其中，平均右心室收缩压和平均右心室肥大指数分别为17.28±1.24mmHg、27.26±1.31％，肺脏和肝脏指数平均值分别为0.73±0.59％、7.54±0.36。虽然施用工业大麻全谱系油，未能取得与实施例2第4组纯化合物联合给药组相同或更佳的效果，但仍可显著降低肺动脉高压模型小鼠的右心室收缩压和右心室肥大指数，改善肺水肿和肝水肿，对肺动脉高压治疗药物的开发具有重要的价值。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换等，均应包含在本发明的保护范围之内。
本文中按照一定顺序列出方法的步骤并不构成对方法步骤顺序的任何限制。

Claims (16)

  1. 一种组合物，包含四氢次大麻酚以及至少一种其他大麻素类化合物，优选地，所述其他大麻素类化合物选自：大麻二酚、次大麻二酚和大麻萜酚。
  2. 如权利要求1所述的组合物，其特征在于，所述组合物包含四氢次大麻酚和大麻二酚，其中，四氢次大麻酚和大麻二酚的质量比为1:10-60。
  3. 如权利要求1所述的组合物，其特征在于，所述组合物包含四氢次大麻酚和次大麻二酚，其中，四氢次大麻酚和次大麻二酚的质量比为1:2-10。
  4. 如权利要求1所述的组合物，其特征在于，所述组合物包含四氢次大麻酚和大麻萜酚，其中，四氢次大麻酚和大麻萜酚的质量比为1:0.5-5。
  5. 如权利要求1所述的组合物，其特征在于，所述组合物包含四氢次大麻酚、大麻二酚和次大麻二酚，其中，四氢次大麻酚、大麻二酚和次大麻二酚的质量比为1:10-60:2-10。
  6. 如权利要求1所述的组合物，其特征在于，所述组合物包含四氢次大麻酚、大麻二酚和大麻萜酚，其中，四氢次大麻酚、大麻二酚和大麻萜酚的质量比为1:10-60:0.5-5。
  7. 如权利要求1所述的组合物，其特征在于，所述组合物包含四氢次大麻酚、次大麻二酚和大麻萜酚，其中，四氢次大麻酚、次大麻二酚和大麻萜酚的质量比为1:2-10:0.5-5。
  8. 如权利要求1所述的组合物，其特征在于，所述组合物包含四氢次大麻酚、大麻二酚、次大麻二酚和大麻萜酚，其中，四氢次大麻酚、大麻二酚、次大麻二酚和大麻萜酚的质量比为1:10-60:2-10:0.5-5。
  9. 如权利要求1-8任一项所述的组合物，其特征在于，所述四氢次大麻酚和其他大麻素类化合物为化学合成产物、生物合成产物或植物提取物。
  10. 如权利要求9所述的组合物，其特征在于，所述植物提取物的植物提取部位选自：工业大麻的秆芯、花、叶、籽和籽的外壳的一种或多种。
  11. 如权利要求9所述的组合物，其特征在于，所述植物提取物为工业 大麻全谱系油。
  12. 一种四氢次大麻酚在预防和/或治疗肺动脉高压及其并发症的产品中的应用。
  13. 一种四氢次大麻酚以及至少一种其他大麻素类化合物的组合在预防和/或治疗肺动脉高压及其并发症的产品中的应用。
  14. 一种工业大麻全谱油在制备预防和/或治疗肺动脉高压及其并发症的产品中的应用。
  15. 如权利要求12-14任一项所述的应用，其特征在于，所述肺动脉高压为低氧血症所致肺动脉高压。
  16. 如权利要求12-14任一项所述的应用，其特征在于，所述肺动脉高压并发症为肝功能损伤。
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