WO2019232740A1 - 一种用于防治糖尿病的药物组合物及其用途 - Google Patents

一种用于防治糖尿病的药物组合物及其用途 Download PDF

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WO2019232740A1
WO2019232740A1 PCT/CN2018/090226 CN2018090226W WO2019232740A1 WO 2019232740 A1 WO2019232740 A1 WO 2019232740A1 CN 2018090226 W CN2018090226 W CN 2018090226W WO 2019232740 A1 WO2019232740 A1 WO 2019232740A1
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metformin
glibenclamide
diabetes
pharmaceutically acceptable
caused
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PCT/CN2018/090226
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English (en)
French (fr)
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张可
谭昕
于朝晖
李向东
连萌
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汉义生物科技（北京）有限公司
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Priority to CA3104916A priority Critical patent/CA3104916C/en
Priority to PCT/CN2018/090226 priority patent/WO2019232740A1/zh
Priority to JP2020571540A priority patent/JP7344422B2/ja
Priority to EP18922061.9A priority patent/EP3804705B1/en
Priority to AU2018426503A priority patent/AU2018426503A1/en
Publication of WO2019232740A1 publication Critical patent/WO2019232740A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the invention belongs to the field of medicine and relates to a pharmaceutical composition for preventing and treating diabetes and its use.
  • diabetes At present, the prevalence of diabetes is rapidly increasing, and it has become another important non-communicable disease that seriously harms the health of residents after cardiovascular diseases and tumors.
  • the disability and lethality caused by diabetes and its various acute and chronic complications have become the world's third largest disease that currently threatens human health, seriously affecting the quality of life of patients.
  • Metformin (Metformin for short) or metformin hydrochloride is the first choice for the clinical treatment of type 2 diabetes. Since 1957, metformin has officially entered the market as a blood sugar-lowering drug for the treatment of type 2 diabetes. After half a century of clinical use, more and more studies have confirmed the safety and effectiveness of metformin. Therefore, metformin has gradually become the first-line treatment for diabetes. Due to its low price, it has become one of the most widely used hypoglycemic drugs in clinical practice. The 2017 edition of the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China" made metformin as the drug of choice, highlighting the important status of metformin. The guidelines state that metformin can be used in combination with insulin secretagogues, alpha-glucosidase inhibitors, insulin sensitizers, etc., in a dual drug. The structural formula of metformin is shown in Formula A below.
  • Metformin has a variety of mechanisms of action, including delaying glucose uptake from the gastrointestinal tract, increasing peripheral glucose utilization by increasing insulin sensitivity, and inhibiting excessive glycogenogenesis of the liver and kidneys without reducing blood glucose levels in non-diabetic patients And clinical trials prove that it can be taken for a long time.
  • the most common adverse reactions of metformin are gastrointestinal reactions, which are manifested as upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, and indigestion.
  • 10% of diabetic patients develop lactic acidosis after taking metformin. As a result, some patients gave up because of intolerance to metformin.
  • Glibenclamide is another common medication for diabetes. Glibenclamide specifically binds to sulfonylurea receptors on ⁇ -cell membranes and stimulates ⁇ -cells to release insulin.
  • long-term administration of glibenclamide can cause pancreatic islet atrophy; especially those with liver and kidney dysfunction, insulin-dependent diabetes, non-insulin-dependent diabetes with ketoacidosis, coma, severe burns, infection, trauma, and leukopenia Disabled.
  • glibenclamide also causes the aforementioned gastrointestinal reactions similar to metformin.
  • metformin and glibenclamide are also the most common dual drugs for the treatment of type 2 diabetes.
  • the above-mentioned adverse reactions have caused some patients to abandon the treatment with metformin and / or glibenclamide due to intolerance.
  • cannabidiol can effectively inhibit type 1 and type 2 diabetes, and at the same time, can reduce adverse reactions caused by metformin and the like.
  • the following inventions are thus provided:
  • One aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • One or more hypoglycemic agents are one or more hypoglycemic agents.
  • the pharmaceutical composition further comprises one or several pharmaceutically acceptable excipients.
  • the pharmaceutical composition wherein the hypoglycemic agent is selected from:
  • Biguanide hypoglycemic agents sulfonylurea secretion enhancers, ⁇ -glucosidase inhibitors, thiazolidinediones derivative sensitizers, phenanthrene derivatives secretion enhancers, GLP-1 receptor agonists , DPP-4 enzyme inhibitors, insulin and insulin analogs;
  • the biguanide is a metformin or a pharmaceutically acceptable salt thereof, such as metformin hydrochloride;
  • the sulfonylurea-type secretion-promoting agent is selected from the group consisting of: glibenclamide, glibenclamide, glimepiride, glipizide, glipizide, and glipidone.
  • the pharmaceutical composition wherein the hypoglycemic agent is selected from:
  • Metformin, metformin hydrochloride, and glibenclamide Metformin, metformin hydrochloride, and glibenclamide.
  • the pharmaceutical composition wherein the pharmaceutical composition comprises cannabidiol and / or a pharmaceutically acceptable salt or ester thereof, and one or more hypoglycemic agents Medicine and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition wherein a weight ratio of the cannabidiol and / or a pharmaceutically acceptable salt or ester thereof to the hypoglycemic agent is:
  • the weight ratio refers to the ratio of the total weight of cannabidiol and / or a pharmaceutically acceptable salt or ester thereof to the total weight of all hypoglycemic agents.
  • the pharmaceutical composition wherein the mass of the cannabidiol and / or a pharmaceutically acceptable salt or ester thereof is 5 to 500 mg, 10 to 300 mg, 20 -200mg, 50-150mg, 50-100mg, 100-300mg, 100mg, 200mg, 300mg, 400mg or 500mg.
  • the pharmaceutical composition is used for treating and / or preventing a disease or symptom selected from the following:
  • Diabetes such as type 1 or type 2 diabetes
  • hyperlipidemia such as hyperlipidemia
  • adverse reactions caused by metformin such as glibenclamide
  • the diabetes is accompanied by at least one of the following conditions or symptoms: liver and kidney dysfunction, ketoacidosis, coma, severe burns, infection, trauma, leukopenia, hyperlipidemia, retinopathy or chronic renal failure ;
  • the adverse reaction caused by metformin is at least one of the following conditions or symptoms caused by taking metformin: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion or lactic acidosis;
  • the adverse reaction caused by glibenclamide is at least one of the following conditions or symptoms caused by taking glibenclamide: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion, lactic acid Acidosis or islet atrophy;
  • the administration dose of cannabidiol and / or a pharmaceutically acceptable salt or ester thereof is 0.1-50 mg, 0.5-30 mg, 0.5-20 mg, 0.5-10 mg, 0.5-5 mg, 1- 10mg, 2-8mg, 3-7mg, 4-6mg, 4mg, 4.5mg, 5mg, 5.5mg or 6mg.
  • the formulation of the pharmaceutical composition can be any pharmaceutically acceptable dosage form, and these dosage forms include: tablets, sugar-coated tablets, film-coated tablets, enteric-coated tablets, capsules, hard capsules, soft capsules, Oral liquid, oral preparation, granules, granules, granules, pills, powders, ointments, elixirs, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches Oral dosage forms are preferred, such as: capsules, tablets, oral liquids, granules, pills, powders, elixirs, ointments and the like.
  • the oral dosage form may contain commonly used excipients, such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent, and a wetting agent.
  • Suitable fillers include cellulose, mannitol, lactose and other similar fillers;
  • suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate;
  • suitable lubricants include, for example, hard Magnesium stearate.
  • Suitable pharmaceutically acceptable humectants include sodium lauryl sulfate.
  • the pharmaceutical composition is an oral formulation.
  • Another aspect of the invention relates to a pharmaceutical product comprising a separately packaged first pharmaceutical formulation and a separately packaged second pharmaceutical formulation, wherein:
  • the first pharmaceutical formulation comprises cannabidiol and / or a pharmaceutically acceptable salt or ester thereof,
  • the second pharmaceutical preparation comprises one or more hypoglycemic agents
  • the first pharmaceutical preparation and / or the second pharmaceutical preparation further comprises one or several pharmaceutically acceptable excipients.
  • the pharmaceutical product wherein the hypoglycemic agent is selected from:
  • Biguanide hypoglycemic agents sulfonylurea secretion enhancers, ⁇ -glucosidase inhibitors, thiazolidinediones derivative sensitizers, phenanthrene derivatives secretion enhancers, GLP-1 receptor agonists , DPP-4 enzyme inhibitors, insulin and insulin analogs;
  • the biguanide is a metformin or a pharmaceutically acceptable salt thereof, such as metformin hydrochloride;
  • the sulfonylurea-type secretion-promoting agent is selected from the group consisting of: glibenclamide, glibenclamide, glimepiride, glipizide, glipizide, and glipidone.
  • the pharmaceutical product wherein the hypoglycemic agent is selected from:
  • Metformin, metformin hydrochloride, and glibenclamide Metformin, metformin hydrochloride, and glibenclamide.
  • the pharmaceutical product in one or more embodiments of the present invention, the pharmaceutical product,
  • the pharmaceutical product is composed of a first pharmaceutical preparation and a second pharmaceutical preparation
  • the first pharmaceutical preparation is composed of cannabidiol and / or a pharmaceutically acceptable salt or ester thereof, and one or more pharmaceutically acceptable excipients;
  • the second pharmaceutical preparation is composed of one or more hypoglycemic agents and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical product wherein a weight ratio of the cannabidiol and / or a pharmaceutically acceptable salt or ester thereof to the hypoglycemic agent is:
  • the mass of the cannabidiol and / or its pharmaceutically acceptable salt or ester is 5 to 500 mg, 10 to 300 mg, 20 to 200 mg, 50 to 150 mg, 50 to 100 mg, 100 to 300 mg, 100 mg, 200 mg, 300 mg, 400mg or 500mg.
  • the pharmaceutical product is used for treating and / or preventing a disease or symptom selected from the following:
  • Diabetes such as type 1 or type 2 diabetes
  • hyperlipidemia such as hyperlipidemia
  • adverse reactions caused by metformin such as glibenclamide
  • the diabetes is accompanied by at least one of the following conditions or symptoms: liver and kidney dysfunction, ketoacidosis, coma, severe burns, infection, trauma, leukopenia, hyperlipidemia, retinopathy or chronic renal failure ;
  • the adverse reaction caused by metformin is at least one of the following conditions or symptoms caused by taking metformin: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion or lactic acidosis;
  • the adverse reaction caused by glibenclamide is at least one of the following conditions or symptoms caused by taking glibenclamide: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion, lactic acid Acidosis or islet atrophy;
  • the administration dose of cannabidiol and / or a pharmaceutically acceptable salt or ester thereof is 0.1-50 mg, 0.5-30 mg, 0.5-20 mg, 0.5-10 mg, 0.5-5 mg, 1- 10mg, 2-8mg, 3-7mg, 4-6mg, 4mg, 4.5mg, 5mg, 5.5mg or 6mg.
  • Yet another aspect of the present invention relates to the use of a pharmaceutical composition according to any one of the present invention or a pharmaceutical product according to any one of the present invention in the manufacture of a medicament for the treatment and / or prevention of a disease or symptom selected from the following:
  • Diabetes such as type 1 or type 2 diabetes
  • hyperlipidemia such as hyperlipidemia
  • adverse reactions caused by metformin such as glibenclamide
  • the diabetes is accompanied by at least one of the following conditions or symptoms: liver and kidney dysfunction, ketoacidosis, coma, severe burns, infection, trauma, leukopenia, hyperlipidemia, retinopathy or chronic renal failure ;
  • the adverse reaction caused by metformin is at least one of the following conditions or symptoms caused by taking metformin: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion or lactic acidosis;
  • the adverse reaction caused by glibenclamide is at least one of the following conditions or symptoms caused by taking glibenclamide: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion, lactic acid Acidosis or islet atrophy.
  • Yet another aspect of the invention relates to the use of cannabidiol and / or a pharmaceutically acceptable salt or ester thereof in the manufacture of a medicament for the treatment and / or prevention of a disease or symptom selected from the following:
  • Diabetes e.g. type 1 or type 2 diabetes
  • hyperlipidemia e.g., hyperlipidemia, diarrhea, elevated lactic acid, adverse reactions caused by metformin or adverse reactions caused by glibenclamide;
  • the diabetes is accompanied by at least one of the following conditions or symptoms: liver and kidney dysfunction, ketoacidosis, coma, severe burns, infection, trauma, leukopenia, hyperlipidemia, retinopathy or chronic renal failure ;
  • the adverse reaction caused by metformin is at least one of the following conditions or symptoms caused by taking metformin: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion or lactic acidosis;
  • the adverse reaction caused by glibenclamide is at least one of the following conditions or symptoms caused by taking glibenclamide: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion, lactic acid Acidosis or islet atrophy.
  • a further aspect of the invention relates to cannabidiol and / or a pharmaceutically acceptable salt or ester thereof for use in the treatment and / or prevention of a condition or symptom selected from the group consisting of:
  • Diabetes e.g. type 1 or type 2 diabetes
  • hyperlipidemia e.g., hyperlipidemia, diarrhea, elevated lactic acid, adverse reactions caused by metformin or adverse reactions caused by glibenclamide;
  • the diabetes is accompanied by at least one of the following conditions or symptoms: liver and kidney dysfunction, ketoacidosis, coma, severe burns, infection, trauma, leukopenia, hyperlipidemia, retinopathy or chronic renal failure ;
  • the adverse reaction caused by metformin is at least one of the following conditions or symptoms caused by taking metformin: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion or lactic acidosis;
  • the adverse reaction caused by glibenclamide is at least one of the following conditions or symptoms caused by taking glibenclamide: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion, lactic acid Acidosis or islet atrophy;
  • cannabidiol and / or a pharmaceutically acceptable salt or ester thereof is administered at a dose of 0.1-50 mg, 0.5-30 mg, 0.5-20 mg, 0.5-10 mg, 0.5-5 mg, 1-10 mg per kilogram of body weight per day. , 2-8mg, 3-7mg, 4-6mg, 4mg, 4.5mg, 5mg, 5.5mg or 6mg.
  • a further aspect of the present invention relates to a method for treating and / or preventing a condition or symptom selected from the group consisting of administering to a subject in need thereof an effective amount of a pharmaceutical composition according to any one of the present invention or the present invention Steps for a pharmaceutical product according to any one of the following:
  • Diabetes such as type 1 or type 2 diabetes
  • hyperlipidemia such as hyperlipidemia
  • adverse reactions caused by metformin such as glibenclamide
  • the diabetes is accompanied by at least one of the following conditions or symptoms: liver and kidney dysfunction, ketoacidosis, coma, severe burns, infection, trauma, leukopenia, hyperlipidemia, retinopathy or chronic renal failure ;
  • the adverse reaction caused by metformin is at least one of the following conditions or symptoms caused by taking metformin: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion or lactic acidosis;
  • the adverse reaction caused by glibenclamide is at least one of the following conditions or symptoms caused by taking glibenclamide: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion, lactic acid Acidosis or islet atrophy;
  • the administration dose of cannabidiol and / or a pharmaceutically acceptable salt or ester thereof is 0.1-50 mg, 0.5-30 mg, 0.5-20 mg, 0.5-10 mg, 0.5-5 mg, 1- 10mg, 2-8mg, 3-7mg, 4-6mg, 4mg, 4.5mg, 5mg, 5.5mg or 6mg.
  • a further aspect of the invention relates to a method for treating and / or preventing a condition or symptom selected from the group consisting of administering to a subject in need thereof an effective amount of cannabidiol and / or a pharmaceutically acceptable salt or ester thereof
  • Diabetes e.g. type 1 or type 2 diabetes
  • hyperlipidemia e.g., hyperlipidemia, diarrhea, elevated lactic acid, adverse reactions caused by metformin or adverse reactions caused by glibenclamide;
  • the diabetes is accompanied by at least one of the following conditions or symptoms: liver and kidney dysfunction, ketoacidosis, coma, severe burns, infection, trauma, leukopenia, hyperlipidemia, retinopathy or chronic renal failure ;
  • the adverse reaction caused by metformin is at least one of the following conditions or symptoms caused by taking metformin: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion or lactic acidosis;
  • the adverse reaction caused by glibenclamide is at least one of the following conditions or symptoms caused by taking glibenclamide: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion, lactic acid Acidosis or islet atrophy;
  • cannabidiol and / or a pharmaceutically acceptable salt or ester thereof is administered at a dose of 0.1-50 mg, 0.5-30 mg, 0.5-20 mg, 0.5-10 mg, 0.5-5 mg, 1-10 mg per kilogram of body weight per day. , 2-8mg, 3-7mg, 4-6mg, 4mg, 4.5mg, 5mg, 5.5mg or 6mg.
  • a further aspect of the invention relates to a method for treating and / or preventing a condition or symptom selected from the group consisting of administering to a subject in need thereof an effective amount of cannabidiol and / or a pharmaceutically acceptable salt or ester thereof , And steps for an effective amount of one or more hypoglycemic agents:
  • Diabetes such as type 1 or type 2 diabetes
  • hyperlipidemia such as hyperlipidemia
  • adverse reactions caused by metformin such as glibenclamide
  • the diabetes is accompanied by at least one of the following conditions or symptoms: liver and kidney dysfunction, ketoacidosis, coma, severe burns, infection, trauma, leukopenia, hyperlipidemia, retinopathy or chronic renal failure ;
  • the adverse reaction caused by metformin is at least one of the following conditions or symptoms caused by taking metformin: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion or lactic acidosis;
  • the adverse reaction caused by glibenclamide is at least one of the following conditions or symptoms caused by taking glibenclamide: upper abdominal discomfort, abdominal pain, diarrhea, nausea, vomiting, bloating, fatigue, indigestion, lactic acid Acidosis or islet atrophy;
  • the cannabidiol and / or a pharmaceutically acceptable salt or ester thereof is administered simultaneously with the hypoglycemic agent or not at the same time;
  • the dosage of cannabidiol and / or a pharmaceutically acceptable salt or ester thereof is 0.1-50 mg, 0.5-30 mg, 0.5-20 mg, 0.5-10 mg, 0.5-5 mg, 1- 10mg, 2-8mg, 3-7mg, 4-6mg, 4mg, 4.5mg, 5mg, 5.5mg or 6mg.
  • the dosage and method of use of the active ingredient cannabidiol depends on many factors, including the patient's age, weight, sex, natural health status, nutritional status, the strength of the compound's activity, the time taken, the metabolic rate, and the condition of the disease. Severity and subjective judgment of the treating physician.
  • CBD cannabinoids
  • the cannabidiol that is, the compound of formula I, can be purchased through commercial channels (for example, purchased from Sigma, etc.) or synthesized by using existing materials using existing technologies. After synthesis, it can be further purified by column chromatography, liquid-liquid extraction, molecular distillation or crystallization. Cannabidiol can also be extracted from industrial cannabis at any time.
  • the pharmaceutically acceptable salt of cannabidiol may be cannabidiol (CBD) and sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, hydroxide Lithium, zinc hydroxide, barium hydroxide, ammonia, methylamine, dimethylamine, diethylamine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine , Choline, N, N′-diphenylmethylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, N-methylglucamine piperazine, Tris (hydroxymethyl) -aminomethane and the like.
  • CBD cannabidiol
  • sodium hydroxide sodium hydroxide
  • potassium hydroxide calcium hydroxide
  • magnesium hydroxide aluminum hydroxide
  • the pharmaceutically acceptable ester of cannabidiol may be a monoester of cannabidiol and one C 0 -C 6 alkyl carboxylic acid, or may be cannabidiol and two identical or Diesters formed by different C 0- C 6 alkyl carboxylic acids, the C 0 -C 6 alkyl carboxylic acid may be a linear alkyl carboxylic acid, a branched alkyl carboxylic acid or a cycloalkyl carboxylic acid,
  • HCOOH CH 3 COOH, CH 3 CH 2 COOH, CH 3 (CH 2 ) 2 COOH, CH 3 (CH 2 ) 3 COOH, CH 3 (CH 2 ) 4 COOH, (CH 3 ) 2 CHCOOH, (CH 3 ) 3 CCOOH, (CH 3 ) 2 CHCH 2 COOH, (CH 3 ) 2 CH (CH 2 ) 2 COOH, (CH 3 ) 2 CH (CH 3 ) CHCOOH, (CH 3 ) 3 CCOOH,
  • type 1 diabetes has a meaning well known to those skilled in the art. Its original name is insulin-dependent diabetes, which mostly occurs in children and adolescents, and can also occur at various ages. It is mainly an autoimmune disease and accounts for approximately all of diabetes. 5%. Onset is relatively rapid, there is absolutely insufficient insulin in the body, and ketoacidosis is prone to occur. Insulin treatment must be used to obtain satisfactory results, otherwise it will be life-threatening.
  • type 2 diabetes has a meaning well known to those skilled in the art. Its original name was adult-onset diabetes, which usually develops after the age of 35-50 years, and accounts for more than 90% of patients with diabetes. The ability to produce insulin in patients with type 2 diabetes is not completely lost, and some patients even produce too much insulin, but the use of insulin is poor, so the insulin in patients is a relative deficiency, which can be improved by oral medication. effectiveness. But in the later stages, some patients still need insulin therapy.
  • the term "effective amount” refers to a dose that can achieve the treatment, prevention, reduction, and / or alleviation of a disease or condition described herein in a subject.
  • subject may refer to a patient or other animal, particularly a mammal, such as a human, dog, monkey, cow, or animal, receiving a composition of the invention to treat, prevent, reduce, and / or alleviate a disease or condition described in the invention. Horse etc.
  • 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.
  • the first pharmaceutical preparation and the second pharmaceutical preparation are merely for the sake of clarity, and do not have a sequential meaning.
  • CBD can significantly inhibit type 1 and type 2 diabetes in mammals (such as mice or humans), and significantly increase insulin sensitivity; the effect is better than metformin alone;
  • CBD and metformin can significantly reduce the hyperlipidemia and cholesterol induced by STZ and high-fat diet, and can increase insulin secretion;
  • CBD can significantly inhibit diarrhea and lactic acidemia caused by metformin
  • CBD can also significantly reduce total urine protein in adriamycin-induced renal failure mice.
  • FIG. 1A Fasting blood glucose results of mice in each group.
  • Fig. IB Results of mouse glucose tolerance test (GTT).
  • FIG. 1C Results of mouse insulin resistance test (ITT).
  • FIG. 1A Fasting blood glucose in mice.
  • FIG. 2B Mouse glucose tolerance test (GTT) results.
  • FIG. 2C Mouse insulin resistance test (ITT) results.
  • Figure 3 Relative blood glucose values after administration of DB / DB mice.
  • Figure 4A Results of diarrhea index in mice on day 1 of induction.
  • Figure 4B Results of diarrhea index in mice on day 2 of induction.
  • Figure 4D Results of diarrhea index in mice on day 4 of induction.
  • Figure 4E Results of diarrhea index in mice on day 5 of induction.
  • Figure 4F Results of diarrhea index in mice on day 6 of induction.
  • Figure 4G Results of diarrhea index in mice on day 7 of induction.
  • Figure 5 Measurement of lactic acid concentration in mouse blood.
  • Figure 6A Cholesterol and insulin levels in mouse serum.
  • FIG. 6B Triglyceride levels in mouse serum.
  • Figure 6C High-density cholesterol levels in mouse serum.
  • Figure 6D Low-density cholesterol levels in mouse serum.
  • FIG. 6E Insulin levels in mouse serum.
  • FIG. 7 CBD reduces total protein levels in urine.
  • Figure 8A Fasting blood glucose values of 3 diabetic volunteers after CBD treatment.
  • Fig. 8B Glycated hemoglobin levels in 3 diabetic volunteers after CBD treatment.
  • CBD provided by Hanyi Biotechnology (Beijing) Co., Ltd .;
  • Metformin purchased from Aladdin (structure is the same as the previous formula A);
  • Insulin purchased from China Agricultural University Hospital;
  • Streptozotocin (STZ) was purchased from Aladdin.
  • ICR female rats purchased from Viton Lee Wah;
  • ICR female rats purchased from Viton Lee Wah;
  • Example 1 Establishment of a mouse type 1 diabetes model and drug treatment
  • mice C57 male mice aged 4-6 weeks were used as experimental animals. After fasting the mice for 10-12 hours, 50 mg / kg streptozotocin (STZ) was intraperitoneally injected for 5 consecutive days, and the test was performed on days 6 and 10. Detection of fasting blood glucose in mice was successful; fasting blood glucose was greater than 11.1 mmol / L as induction; applied to the second to sixth groups in step 2) below.
  • STZ streptozotocin
  • mice were randomly divided into 6 groups of 10 mice each:
  • the first group a blank control group, fed with ordinary feed, intraperitoneally injected with a buffer solution, a dose of 100 ⁇ l / head, administered once a day for 5 consecutive days;
  • the buffer solution is 0.1 mol / L and the citric acid buffer solution with a pH of 4.2 is sterilized by suction filtration;
  • the second group diabetes model group, fed with common feed, intraperitoneal injection of streptozotocin;
  • the third group the CBD prevention group, fed with ordinary feed, intraperitoneal injection of streptozotocin, and started to administer CBD through gastric gavage on the first day of induction, 50 mg / kg, once a day;
  • the fourth group the CBD treatment group, fed with ordinary feed, intraperitoneal injection of streptozotocin, and after successful induction, CBD administration was started by intragastric administration, 50 mg / kg, once a day;
  • the fifth group a positive drug control group, fed with common feed, intraperitoneal injection of streptozotocin, insulin injection was started after successful induction, 0.2U / kg, administered once a day;
  • metformin group fed with common feed, intraperitoneal injection of streptozotocin, metformin was administered by gavage after successful induction, 50 mg / kg, once a day.
  • GTT Glucose tolerance test
  • ITT insulin tolerance test
  • ITT insulin tolerance test
  • STZ can induce a mouse diabetes model; whether in the CBD prevention group or the CBD treatment group, the blood glucose increase caused by STZ can be significantly reduced after 10 days.
  • the CBD prevention group performed better than the CBD treatment group.
  • CBD can significantly enhance glucose regulation in mice.
  • CBD prevention group performed better than the CBD treatment group.
  • CBD can significantly enhance the sensitivity of mice to insulin, regulate their own blood glucose, and reduce the symptoms of type 1 diabetes.
  • the CBD prevention group performed better than the CBD treatment group.
  • metformin has no effect on type 1 diabetes, nor is metformin used as a clinical drug for the treatment of type 1 diabetes.
  • Example 2 Establishment of a mouse type 2 diabetes model and drug treatment
  • the experimental animals used 4-6 weeks old C57 male mice.
  • the mice were fed with high-fat diet. After the mice were fasted for 10-12 hours, 50 mg / kg streptozotocin (STZ) was injected intraperitoneally for 5 days. Detect whether the fasting blood glucose value of the mice was successfully induced on the 6th and 10th days (the fasting blood glucose was greater than 11.1mmol / L as the induction success, and it was found that the induction was successful on the 32nd day); on the 6th day, the blood glucose was not up to the standard ( Unsuccessful induction) The intraperitoneal injection of streptozotocin at a dose of 80 mg / kg; applied to the second to eighth groups in step 2) below.
  • High-fat feed is formed by adding 60% fat on the basis of ordinary feed.
  • mice were randomly divided into 8 groups of 10 mice each:
  • the first group a blank control group, fed with high-fat diet, intraperitoneally injected with a buffer solution, a dose of 100 ⁇ l / head, administered once a day for 5 consecutive days;
  • the buffer solution is 0.1 mol / L and the citric acid buffer solution with a pH of 4.2 is sterilized by suction filtration;
  • the second group diabetes model group, fed with high-fat diet, intraperitoneal injection of streptozotocin;
  • the third group the CBD prevention group, fed with high-fat diet, intraperitoneal injection of streptozotocin, and started to administer CBD by intragastric administration on the first day, 50 mg / kg, once a day;
  • the fourth group the CBD treatment group, fed with high-fat diet, intraperitoneal injection of streptozotocin, and after successful induction (day 32), CBD administration (50 mg / kg) was administered by gastric lavage every day;
  • metformin group fed with high-fat diet, intraperitoneal injection of streptozotocin, metformin administration on day 32, 50 mg / kg, once a day;
  • the sixth group metformin plus CBD group, fed with high-fat diet, intraperitoneal injection of streptozotocin, daily oral administration starting on day 32 (metformin 50mg / kg + CBD 50mg / kg);
  • the seventh group the metformin and glibenclamide (Gli) group, fed with high-fat diet, intraperitoneal injection of streptozotocin, and started to be administered orally every day after successful induction (metformin 50mg / kg + Gli0. 758mg / kg);
  • the eighth group Glibenclamide plus CBD group, fed with high-fat diet, intraperitoneal injection of streptozotocin, and began to be administered orally every day after successful induction (Gli 0.758 mg / kg + CBD 50 mg / kg).
  • GTT Glucose tolerance test
  • ITT insulin tolerance test
  • mice are fasted for 10 hours, and 20% (w / w) glucose is intraperitoneally injected according to body weight (10 ⁇ l / g).
  • body weight 10 ⁇ l / g.
  • ITT insulin tolerance test
  • CBD can improve the self-regulated glucose regulation performance induced by STZ and high-fat diet, and better control blood glucose.
  • CBD can improve the sensitivity of mice to insulin and better regulate their own blood glucose. Reduce the symptoms of type 2 diabetes.
  • the blood glucose of the mice in the combination group of CBD and metformin was significantly lower than that of the other groups, and the glucose tolerance and insulin sensitivity of the mice in this group were significantly improved.
  • Figures 2A to 2C show that the CBD prevention group is better than the CBD treatment group.
  • Example 3 Effect of combined use of CBD and metformin on type 2 diabetes
  • mice (spontaneous type 2 diabetic mice, purchased from the Model Animal Center of Nanjing University), and were randomly divided into 5 groups, 6 in each group:
  • the first group is the control group without any treatment
  • the second group was the CBD single administration group (50mg / kg);
  • the fourth group is a combination of metformin low dose (100mg / kg) and CBD (50mg / kg);
  • the third group and the fifth group are the positive control group of the treatment group, the third group is the metformin low-dose group, and the fifth group is the metformin high-dose group.
  • the patients first received low-dose metformin treatment, and then based on blood glucose The change gradually increases the amount of metformin, but it cannot exceed the maximum amount.
  • the experiment in this example is to prove that the combined effect of CBD and metformin is better than the low dose of metformin and the high dose of metformin.
  • the above five groups are administered by gavage once a day.
  • the blood glucose of the mice in each group was measured 4 weeks after the administration of the above groups.
  • the relative blood glucose results of the mice in each group are shown in FIG. 3.
  • mice in the combined CBD and metformin group had the fastest and most obvious blood glucose drop.
  • the fasting blood glucose of the mice co-administered with CBD and metformin was significantly lower than those treated with metformin alone (groups 3 and 5) and lower than those treated with CBD alone (group 2) .
  • Example 4 Establishment of a mouse diarrhea model and drug treatment
  • mice ICR female rats aged 4-6 weeks were used. The mice were given normal diet and drinking water. The mice were administrated with 8% (w / w) senna solution. 0.2ml / head, statistics were collected every half an hour. The mouse diarrhea index was counted for 6 hours.
  • Senna (Folium Sennae) was purchased from Beijing Tongrentang Pharmacy. 8 parts by weight of senna and 92 parts by weight of water were added to a conical flask and boiled for 10 minutes to prepare an 8% (w / w) senna solution.
  • mice were randomly divided into 7 groups of 10 mice each:
  • the first group irrigates mice with an equal volume of water daily
  • mice were given 150 mg / kg metformin every day;
  • mice were given 50 mg / kg CBD every day;
  • mice were irrigated with 8% senna solution every day;
  • mice were irrigated with a mixture of 8% senna leaves and 150 mg / kg metformin every day;
  • mice were irrigated with a mixture of 8% senna leaves and 50 mg / kg CBD every day;
  • mice were irrigated with a mixed solution of 150% metformin and 50 mg / kg CBD in 8% senna every day.
  • Diarrhea index stool thinning rate * stool thinning grade
  • Diarrhea rate the number of loose animals in this group / the total number of animals in this group * 100%;
  • Stool thinning rate the number of stools / total stools discharged by each animal
  • Defecation grade Describes the hardness of defecation, and grades the size of stains formed on filter paper by defecation. This is shown in Table 1 below.
  • Figures 4A to 4G are the results of inducing the diarrhea index of mice on the first to seventh days. From the statistical results of the diarrhea index of the mice in each group of FIG. 4A to FIG. 4G, it can be seen that senna can cause diarrhea in mice, metformin can aggravate diarrhea induced by senna in mice, and CBD can significantly slow down Rat diarrhea and metformin-induced and exacerbated mouse diarrhea.
  • Example 5 Establishment of mouse lactic acidosis model and drug treatment
  • ICR male rats of 4-6 weeks of age were used in the experimental animals for three inductions, each time metformin was administered (260 mg / kg), and the interval between three administrations was 12 hours.
  • mice were randomly divided into seven groups, five in each group:
  • the first group the control group, without treatment
  • the second group daily gavage
  • the third group give CBD to stomach once a day, 50mg / kg;
  • the fourth group on the first day, 260 mg / kg metformin was administered by gavage in the morning and evening, and 260 mg / kg metformin was administered by gavage in the morning, and samples were collected at 4 pm the next day;
  • the sixth group tail vein injection of 260mg / kg metformin, once every hour for four injections, and sample collection one hour after the fourth injection;
  • Group 7 50 mg / kg CBD was administered by gavage half an hour before the tail vein injection, and 260 mg / kg metformin was injected via the tail vein half an hour later. The injections were given every other hour for a total of four injections and one after the fourth injection. Hours of sample collection.
  • metformin can induce lactic acidemia in mice, while CBD can significantly inhibit metformin-induced increase in blood lactic acid.
  • Example 6 Study on the Combination of CBD and Metformin to Reduce the Blood Lipid Level of Mice Induced by High Fat
  • mice used 4-6 week old Kunming male rats. After the mice were fasted for 10-12 hours, 50 mg / kg streptozotocin (STZ) was intraperitoneally injected for 5 consecutive days. The fasting blood glucose level of the mice was tested for successful induction; fasting blood glucose greater than 11.1 mmol / L was used for successful induction; it was applied to the second to fifth groups in step 3) below.
  • STZ streptozotocin
  • mice were fed with a high-fat diet containing 60% fat added to the normal diet, and mice in the second to fifth groups were fed with high-fat diet.
  • mice were randomly divided into 5 groups of 10 mice each:
  • the first group a blank control group, fed with ordinary feed, intraperitoneally injected with a buffer solution, a dose of 100 ⁇ l / head, administered once a day for 5 consecutive days;
  • the buffer solution is 0.1 mol / L and the citric acid buffer solution with a pH of 4.2 is sterilized by suction filtration;
  • the second group diabetes model group, fed with high-fat diet, intraperitoneal injection of streptozotocin;
  • metformin low-dose group fed with high-fat diet, intraperitoneal injection of streptozotocin, and induced low-dose metformin administration by intragastric administration on the first day, 100 mg / kg, once a day;
  • the fourth group metformin low-dose + CBD group, low-dose metformin was administered by gavage, 100 mg / kg, once a day; CBD was added by gavage, 50 mg / kg, once a day, fed with high-fat diet , Intraperitoneal injection of streptozotocin, low-dose metformin and CBD administration by gavage on the first day of induction;
  • metformin high-dose group 250 mg / kg, once a day, fed with high-fat diet, intraperitoneal injection of streptozotocin induces high-dose metformin administration by gavage on the first day.
  • the fifth group served as a positive control treatment group.
  • mice After two months of treatment with the drug, the mice were sacrificed, blood was collected from the heart, and serum was collected to detect serum cholesterol, triglyceride, high density cholesterol, low density cholesterol, and insulin levels.
  • FIGS. 6A to 6E show that the combination of CBD and metformin can significantly reduce the hyperlipidemia and cholesterol induced by STZ and high-fat diet, and can increase insulin secretion.
  • FIG. 6E shows that metformin alone cannot increase insulin secretion.
  • Example 7 CBD significantly reduces doxorubicin-induced chronic renal failure mice urine total protein levels
  • a mouse model of adriamycin-induced chronic renal failure was constructed according to the conventional method of inducing kidney injury. Fourteen days after CBD treatment, total urine protein levels were measured. The specific method is as follows:
  • mice used 4-6 week old Kunming male rats. After the mice were fasted for 10-12 hours, 50 mg / kg streptozotocin (STZ) was intraperitoneally injected for 5 consecutive days. The fasting blood glucose level of the mice was tested for successful induction (fasting blood glucose greater than 11.1 mmol / L was considered successful for inducing diabetes); on the seventh day after the induction of diabetes, 10 mg / kg of adriamycin was injected into the tail vein of the nephropathy group mice; Apply to the third to sixth groups in step 2) below.
  • STZ streptozotocin
  • the experimental animals were randomly divided into 6 groups of 10 animals each:
  • the first group the control group was given saline
  • the second group the diabetes group
  • the third group diabetes plus CBD group, CBD administered by gavage, 50mg / kg, gavage, once a day;
  • the fourth group diabetes plus adriamycin group
  • the fifth group diabetic plus doxorubicin plus CBD group, CBD administered by gavage, 50mg / kg, intragastric administration, once a day;
  • the sixth group the diabetic plus doxorubicin plus metformin group, metformin was administered orally, 50 mg / kg, once a day.
  • the second and third groups above are to measure the total protein content in urine when chronic kidney failure is not induced and only diabetes is induced.
  • doxorubicin was injected into the tail vein of the mouse to induce the nephropathy model.
  • the urine of the mouse was collected on the 14th day of the induced nephropathy model and total urine protein was measured.
  • CBD can significantly reduce the total urine protein levels in mice with adriamycin-induced chronic renal failure.
  • Nephropathy is one of the complications of diabetes. It can be seen that CBD can treat chronic kidney failure caused by diabetes.
  • Example 8 CBD significantly lowers fasting blood glucose and glycated hemoglobin levels in patients with type 2 diabetes
  • Fig. 8A shows that after 8 weeks of CBD treatment, the fasting blood glucose of all three people decreased significantly (though it did not fall to the normal range);
  • Figure 8B shows that, after 8 weeks of CBD treatment, the glycated hemoglobin of the three people improved significantly before treatment (although it did not fall to the normal range, that is, 4% to 6%).

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Abstract

一种用于防治糖尿病的药物组合物，包含大麻二酚和/或其药学上可接受的盐或酯；以及一种或多种降糖药；可选地，所述药物组合物还包含一种或几种药学上可接受的辅料。所述药物组合物能够有效地降低血糖，显著减少二甲双胍类药物或者磺酰脲类促泌剂的不良反应。

Description

一种用于防治糖尿病的药物组合物及其用途 技术领域
本发明属于医药领域，涉及一种用于防治糖尿病的药物组合物及其用途。
背景技术
目前，糖尿病的患病率正在呈快速上升趋势，已成为继心血管疾病和肿瘤之后的另一个严重危害居民健康的重要慢性非传染性疾病。糖尿病及其各种急慢性并发症所引起的致残性和致死性已成为当前威胁人类健康的世界第三大疾病，严重影响患者的生活质量。
据统计，2015年全球20-79岁的人中有约4.15亿人患糖尿病(患病率8.8％)，另外有3.18亿人糖耐量受损(前期患病率6.7％)。中国是全球糖尿病患者第一大国，2015年病患人数高达1.096亿人，130万人死于糖尿病及其并发症。同时据IDF预测，如果不加干预，2040年全球糖尿病患者将达6.42亿，糖尿病前期人群4.81亿，我国患者数量将上升至1.54亿。
二甲双胍(metformin，简称为Met)或盐酸二甲双胍是临床治疗二型糖尿病的首选药。自1957年，二甲双胍作为降低血糖的药物正式进入市场用于治疗二型糖尿病。经过半个世纪的临床使用，越来越多的研究证实了二甲双胍的安全性和有效性，因此，二甲双胍逐渐成为了糖尿病治疗的一线用药。由于价格低廉，其已成为目前在临床上应用最广泛的降糖药物之一。2017年版《中国二型糖尿病防治指南》，把二甲双胍当成首选药，更加突出了二甲双胍的重要地位。该指南指出，在二联药物中，二甲双胍可以分别和胰岛素促泌剂、α-葡萄糖苷酶抑制剂、胰岛素增敏剂等联合使用。二甲双胍的结构式如下面的式A所示。
Figure PCTCN2018090226-appb-000001
二甲双胍具有多种作用机制，包括延缓葡萄糖由胃肠道的摄取，通过提高胰岛素的敏感性而增加外周葡萄糖的利用，以及抑制肝、肾过度的糖原异生，不降低非糖尿 病患者的血糖水平，且临床试验证明可以长期服用。二甲双胍最常见的不良反应为胃肠道反应，表现为上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良等。另外，还有10％的糖尿病病人在服用二甲双胍后出现乳酸性酸中毒。使得一部分病人因对二甲双胍不耐受而放弃。
格列本脲是另一种常见的治疗糖尿病的药物。格列本脲与β细胞膜上的磺酰脲受体特异性结合，刺激β细胞释放胰岛素作用。然而，长期服用格列本脲会导致胰岛萎缩；特别是对肝肾功能不全者、胰岛素依赖型糖尿病、非胰岛素依赖型糖尿病伴酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少者禁用。另外，格列本脲也会导致与二甲双胍类似的上述胃肠道反应。
更重要的是，二甲双胍和格列本脲也是最常见的治疗二型糖尿病的二联药物。上述不良反应，导致一部分病人由于不耐受而放弃使用二甲双胍和/或格列本脲治疗。
因此，寻找新的特异性治疗药物，在降糖的同时，减少二甲双胍和/或格列本脲的副作用，显得尤为迫切。
发明内容
本发明人经过深入的研究发现，大麻二酚能够有效地抑制一型和二型糖尿病的同时，又能够降低二甲双胍等引起的不良反应。由此提供了下述发明：
本发明的一个方面涉及一种药物组合物，其包含：
大麻二酚和/或其药学上可接受的盐或酯；以及
一种或多种降糖药；
可选地，所述药物组合物还包含一种或几种药学上可接受的辅料。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，所述降糖药选自：
双胍类降糖药、磺酰脲类促泌剂、α-葡萄糖苷酶抑制剂、噻唑烷二酮类衍生物促敏剂、苯茴酸类衍生物促泌剂、GLP-1受体激动剂、DPP-4酶抑制剂、胰岛素以及胰岛素类似物；
优选地，所示双胍类降糖药为二甲双胍或其药学上可接受的盐，例如盐酸二甲双胍；
优选地，所述磺酰脲类促泌剂选自：格列本脲、格列波脲、格列美脲、格列齐特、格列吡嗪和格列喹酮。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，所述降糖药选自：
二甲双胍、盐酸二甲双胍和格列本脲。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，所述药物组合物由大麻二酚和/或其药学上可接受的盐或酯、一种或多种降糖药以及一种或几种药学上可接受的辅料组成。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，所述大麻二酚和/或其药学上可接受的盐或酯与所述降糖药的重量比为：
(10:1)至(1:50)、(10:1)至(1:30)、(10:1)至(1:20)、(10:1)至(1:10)、(5:1)至(1:10)、(3:1)至(1:5)、(2:1)至(1:5)、(1:1)至(1:5)、(1:1)至(1:3)、(1:1)至(1:2)、1:1、1:2或1:3。在此以及下文中，如果没有特别说明，所述重量比是指大麻二酚和/或其药学上可接受的盐或酯的总重量与全部降糖药的总重量的比率。
在本发明的一个或多个实施方案中，所述的药物组合物，其中，所述大麻二酚和/或其药学上可接受的盐或酯的质量为5－500mg、10－300mg、20－200mg、50－150mg、50－100mg、100－300mg、100mg、200mg、300mg、400mg或500mg。
在本发明的一个或多个实施方案中，所述的药物组合物，其用于治疗和/或预防选自如下病症或者症状：
糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、二甲双胍所致不良反应或格列本脲所致不良反应；
优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩；
优选地，其中大麻二酚和/或其药学上可接受的盐或酯的给药剂量为每天每千克体重0.1－50mg、0.5－30mg、0.5－20mg、0.5－10mg、0.5－5mg、1－10mg、2－8mg、3－7mg、4－6mg、4mg、4.5mg、5mg、5.5mg或6mg。
所述药物组合物的制剂形式可以是任何可药用的剂型，这些剂型包括：片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、冲剂、丸剂、散剂、膏剂、丹剂、混悬剂、粉剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、滴剂、贴剂；优选口服剂型，如：胶囊剂、片剂、口服液、颗粒剂、丸剂、散剂、丹剂、膏剂等。所述的口服剂型可含有常用的赋形剂，诸如粘合剂、填充剂、稀释剂、压片剂、润滑剂、崩解剂、着色剂、调味剂和湿润剂，必要时可对片剂进行包衣。适宜的填充剂包括纤维素、甘露糖醇、乳糖和其它类似的填充剂；适宜的崩解剂包括淀粉、聚乙烯吡咯烷酮和淀粉衍生物，例如羟基乙酸淀粉钠；适宜的润滑剂包括，例如硬脂酸镁。适宜的药物可接受的湿润剂包括十二烷基硫酸钠。
优选地，所述药物组合物为口服制剂。
本发明的另一方面涉及一种药物产品，其包含独立包装的第一药物制剂和独立包装的第二药物制剂，其中：
所述第一药物制剂包含大麻二酚和/或其药学上可接受的盐或酯，
所述第二药物制剂包含一种或多种降糖药；
可选地，所述第一药物制剂和/或第二药物制剂还包含一种或者几种药学上可接受的辅料。
在本发明的一个或多个实施方案中，所述的药物产品，其中，所述降糖药选自：
双胍类降糖药、磺酰脲类促泌剂、α-葡萄糖苷酶抑制剂、噻唑烷二酮类衍生物促敏剂、苯茴酸类衍生物促泌剂、GLP-1受体激动剂、DPP-4酶抑制剂、胰岛素以及胰岛素类似物；
优选地，所示双胍类降糖药为二甲双胍或其药学上可接受的盐，例如盐酸二甲双胍；
优选地，所述磺酰脲类促泌剂选自：格列本脲、格列波脲、格列美脲、格列齐特、格列吡嗪和格列喹酮。
在本发明的一个或多个实施方案中，所述的药物产品，其中，所述降糖药选自：
二甲双胍、盐酸二甲双胍和格列本脲。
在本发明的一个或多个实施方案中，所述的药物产品，
其中，所述药物产品由第一药物制剂以及第二药物制剂组成，
其中，所述第一药物制剂由大麻二酚和/或其药学上可接受的盐或酯，以及一种或几种药学上可接受的辅料组成；
其中，所述第二药物制剂由一种或多种降糖药，以及一种或几种药学上可接受的辅料组成。
在本发明的一个或多个实施方案中，所述的药物产品，其中，所述大麻二酚和/或其药学上可接受的盐或酯与所述降糖药的重量比为：
(10:1)至(1:50)、(10:1)至(1:30)、(10:1)至(1:20)、(10:1)至(1:10)、(5:1)至(1:10)、(3:1)至(1:5)、(2:1)至(1:5)、(1:1)至(1:5)、(1:1)至(1:3)、(1:1)至(1:2)、1:1、1:2或1:3。
在本发明的一个或多个实施方案中，所述的药物产品，其中，
所述大麻二酚和/或其药学上可接受的盐或酯的质量为5－500mg、10－300mg、20－200mg、50－150mg、50－100mg、100－300mg、100mg、200mg、300mg、400mg或500mg。
在本发明的一个或多个实施方案中，所述的药物产品，其用于治疗和/或预防选自如下病症或者症状：
糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、二甲双胍所致不良反应或格列本脲所致不良反应；
优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩；
优选地，其中大麻二酚和/或其药学上可接受的盐或酯的给药剂量为每天每千克体重0.1－50mg、0.5－30mg、0.5－20mg、0.5－10mg、0.5－5mg、1－10mg、2－8mg、3－7mg、4－6mg、4mg、4.5mg、5mg、5.5mg或6mg。
本发明的再一方面涉及本发明中任一项所述的药物组合物或者本发明中任一项 所述的药物产品在制备治疗和/或预防选自如下病症或者症状的药物中的用途：
糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、二甲双胍所致不良反应或格列本脲所致不良反应；
优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩。
本发明的再一方面涉及大麻二酚和/或其药学上可接受的盐或酯在制备治疗和/或预防选自如下病症或者症状的药物中的用途：
糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、腹泻、乳酸升高、二甲双胍所致不良反应或格列本脲所致不良反应；
优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩。
本发明的再一方面涉及大麻二酚和/或其药学上可接受的盐或酯，其用于治疗和/或预防选自如下病症或者症状：
糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、腹泻、乳酸升高、二甲双 胍所致不良反应或格列本脲所致不良反应；
优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩；
优选地，大麻二酚和/或其药学上可接受的盐或酯的给药剂量为每天每千克体重0.1－50mg、0.5－30mg、0.5－20mg、0.5－10mg、0.5－5mg、1－10mg、2－8mg、3－7mg、4－6mg、4mg、4.5mg、5mg、5.5mg或6mg。
本发明的再一方面涉及一种治疗和/或预防选自如下病症或者症状的方法，包括给予有需求的受试者以有效量的本发明中任一项所述的药物组合物或者本发明中任一项所述的药物产品的步骤：
糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、二甲双胍所致不良反应或格列本脲所致不良反应；
优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩；
优选地，其中大麻二酚和/或其药学上可接受的盐或酯的给药剂量为每天每千克体重0.1－50mg、0.5－30mg、0.5－20mg、0.5－10mg、0.5－5mg、1－10mg、2－8mg、 3－7mg、4－6mg、4mg、4.5mg、5mg、5.5mg或6mg。
本发明的再一方面涉及一种治疗和/或预防选自如下病症或者症状的方法，包括给予有需求的受试者以有效量的大麻二酚和/或其药学上可接受的盐或酯的步骤：
糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、腹泻、乳酸升高、二甲双胍所致不良反应或格列本脲所致不良反应；
优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩；
优选地，大麻二酚和/或其药学上可接受的盐或酯的给药剂量为每天每千克体重0.1－50mg、0.5－30mg、0.5－20mg、0.5－10mg、0.5－5mg、1－10mg、2－8mg、3－7mg、4－6mg、4mg、4.5mg、5mg、5.5mg或6mg。
本发明的再一方面涉及一种治疗和/或预防选自如下病症或者症状的方法，包括给予有需求的受试者以有效量的大麻二酚和/或其药学上可接受的盐或酯，以及有效量的一种或多种降糖药的步骤：
糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、二甲双胍所致不良反应或格列本脲所致不良反应；
优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中 毒或胰岛萎缩；
优选地，所述大麻二酚和/或其药学上可接受的盐或酯与所述降糖药同时给药或不同时给药；
优选地，其中大麻二酚和/或其药学上可接受的盐或酯的给药剂量为每天每千克体重0.1－50mg、0.5－30mg、0.5－20mg、0.5－10mg、0.5－5mg、1－10mg、2－8mg、3－7mg、4－6mg、4mg、4.5mg、5mg、5.5mg或6mg。
需要指出的是，活性成分大麻二酚的使用剂量和使用方法取决于诸多因素，包括患者的年龄、体重、性别、自然健康状况、营养状况、化合物的活性强度、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。
下面对本发明涉及的部分术语进行解释。
本发明中，术语“大麻二酚”(Cannabidiol,，缩写为CBD)是大麻素类物质中的一种，其结构式如下面的式I所示：
Figure PCTCN2018090226-appb-000002
所述大麻二酚即式I化合物可通过商业途径购买(例如购自Sigma公司等)或者利用市售原料，通过现有技术合成。合成后可以通过柱色谱法、液液萃取法、分子蒸馏方法或结晶等方式进一步纯化。随时大麻二酚还可以从工业大麻中提取得到。
在本发明的一些实施方式中，大麻二酚的药学上可接受的盐可以为大麻二酚(CBD)与氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、氢氧化铝、氢氧化锂、氢氧化锌、氢氧化钡、氨、甲胺、二甲胺、二乙胺、甲基吡啶、乙醇胺、二乙醇胺、三乙醇胺、乙二胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N，N′-二苯甲基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苯甲基苯乙胺、N-甲基葡糖胺哌嗪、三(羟基甲基)-氨基甲烷等形成的盐。
在本发明的一些实施方式中，大麻二酚药学上可接受的酯可以为大麻二酚与一个C 0-C 6烷基羧酸形成的单酯，也可以为大麻二酚与两个相同或不同的C 0-C 6烷基羧酸形成的二酯，所述的C 0-C 6烷基羧酸可以是直链烷基羧酸、支链烷基羧酸或环烷基羧酸，例如HCOOH、CH 3COOH、CH 3CH 2COOH、CH 3(CH 2) 2COOH、CH 3(CH 2) 3COOH、 CH 3(CH 2) 4COOH、(CH 3) 2CHCOOH、(CH 3) 3CCOOH、(CH 3) 2CHCH 2COOH、(CH 3) 2CH(CH 2) 2COOH、(CH 3) 2CH(CH 3)CHCOOH、(CH 3) 3CCH 2COOH、CH 3CH 2(CH 3) 2CCOOH、环丙烷羧酸、环丁烷羧酸、环戊烷羧酸。
术语“一型糖尿病”具有本领域技术人员公知的含义，其原名为胰岛素依赖型糖尿病，多发生在儿童和青少年，也可发生于各种年龄，主要为自身免疫疾病，大约占所有糖尿病的5％。起病比较急剧，体内胰岛素绝对不足，容易发生酮症酸中毒，必须用胰岛素治疗才能获得满意疗效，否则将危及生命。
术语“二型糖尿病”具有本领域技术人员公知的含义，其原名为成人发病型糖尿病，多在35～50岁之后发病，占糖尿病患者90％以上。二型糖尿病患者体内产生胰岛素的能力并非完全丧失，有的患者体内胰岛素甚至产生过多，但胰岛素的利用效果较差，因此患者体内的胰岛素是一种相对缺乏，可以通过口服药物提高胰岛素的利用效率。但到后期仍有一些病人需要使用胰岛素治疗。
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。
术语“受试者”可以指患者或者其它接受本发明组合物以治疗、预防、减轻和/或缓解本发明所述疾病或病症的动物，特别是哺乳动物，例如人、狗、猴、牛、马等。
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，如果没有特别说明，所述第一药物制剂、第二药物制剂仅仅是为了指代清楚，并不具有次序的含义。
发明的有益效果
本发明取得了下述技术效果中的一项或多项：
(1)CBD能够显著地抑制哺乳动物(例如小鼠或人)的一型糖尿病和二型糖尿病，显著地增加胰岛素的敏感性；给药效果比二甲双胍单独给药更好；
(2)CBD和二甲双胍联合用药能够显著降低STZ和高脂饮食所诱导的高血脂和高胆固醇，能够增加胰岛素的分泌；
(2)CBD能够显著地抑制二甲双胍引起的腹泻和乳酸血症；
(3)CBD还能够显著地降低阿霉素诱导的肾衰竭小鼠尿总蛋白。
附图说明
图1A：各组小鼠空腹血糖结果。
图1B：小鼠葡萄糖耐受试验(GTT)结果。
图1C：小鼠胰岛素耐受试验(ITT)结果。
图2A：小鼠空腹血糖。
图2B：小鼠葡萄糖耐受试验(GTT)结果。
图2C：小鼠胰岛素抵抗试验(ITT)结果。
图3：DB/DB小鼠给药处理后相对血糖值。
图4A：诱导第1天小鼠腹泻指数的结果。
图4B：诱导第2天小鼠腹泻指数的结果。
图4C：诱导第3天小鼠腹泻指数的结果。
图4D：诱导第4天小鼠腹泻指数的结果。
图4E：诱导第5天小鼠腹泻指数的结果。
图4F：诱导第6天小鼠腹泻指数的结果。
图4G：诱导第7天小鼠腹泻指数的结果。
图5：小鼠血液检测乳酸浓度。
图6A：小鼠血清中胆固醇胰岛素水平。
图6B：小鼠血清中甘油三酯水平。
图6C：小鼠血清中高密度胆固醇水平。
图6D：小鼠血清中低密度胆固醇水平。
图6E：小鼠血清中胰岛素水平。
图7：CBD降低尿的总蛋白水平。
图8A：CBD治疗后，3位糖尿病志愿者的空腹血糖值。
图8B：CBD治疗后，3位糖尿病志愿者糖化血红蛋白水平。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
CBD，由汉义生物科技(北京)有限公司提供；
二甲双胍，购自阿拉丁(结构同前面的式A)；
胰岛素，购自中国农业大学校医院；
链脲佐菌素(STZ)，购自阿拉丁。
C57雄鼠，购自维通利华；
ICR雌鼠，购自维通利华；
ICR雌鼠，购自维通利华；
昆明白雄鼠，购自自维通利华。
实施例1：小鼠一型糖尿病模型的建立及药物处理
1)常规一型糖尿病模型诱导方法(多次小剂量诱导法)
实验动物使用4-6周龄C57雄鼠，在小鼠禁食10-12h后，采用腹腔注射50mg/kg链脲佐菌素(STZ)，连续注射5天，检测第6天和第10天小鼠空腹血糖值检测是否诱导成功；以空腹血糖大于11.1mmol/L为诱导成功；应用于下面步骤2)中的第二组至第六组。
2)实验分组和给药
小鼠随机分为6组，每组10只：
第一组：空白对照组，饲喂普通饲料，腹腔注射缓冲溶液，剂量为100μl/只，每天给药1次，连续给药5天；
其中缓冲溶液为0.1mol/L并且pH为4.2的柠檬酸缓冲液，经抽滤灭菌；
第二组：糖尿病模型组，饲喂普通饲料，腹腔注射链脲佐菌素；
第三组：CBD预防组，饲喂普通饲料，腹腔注射链脲佐菌素，诱导第一天开始通过灌胃进行CBD给药，50mg/kg，每天给药1次；
第四组：CBD治疗组，饲喂普通饲料，腹腔注射链脲佐菌素，诱导成功后开始通过灌胃进行CBD给药，50mg/kg，每天给药1次；
第五组：阳性药物对照组，饲喂普通饲料，腹腔注射链脲佐菌素，诱导成功后开始注射胰岛素，0.2U/kg，每天给药1次；
第六组：二甲双胍组，饲喂普通饲料，腹腔注射链脲佐菌素，诱导成功后开始通过灌胃进行二甲双胍给药，50mg/kg，每天给药1次。
3)糖耐量试验(GTT)和胰岛素耐受试验(ITT)
每隔三到四周检测上述各组小鼠的空腹血糖；给药一个月后(模型稳定)，进行糖耐量试验(GTT)，小鼠禁食10h，根据体重(10μl/g)腹腔注射20％(w/w)葡萄糖，分别检测注射前(0min)小鼠血糖和注射后15min、30min、60min及120min时间点的血糖值。
GTT一周之后进行胰岛素耐受试验(ITT)，小鼠禁食10h，腹腔注射0.75U/kg胰岛素，分别检测注射前(0min)小鼠血糖和注射后15min、30min、60min及120min时间点的血糖值。
4)实验结果
分别如图1A、图1B和图1C所示。
由图1A可以看出，STZ能够诱导出小鼠糖尿病模型；无论CBD预防组还是CBD治疗组，都能够从10天后，显著降低STZ所引起的血糖升高。另外，CBD预防组比CBD治疗组效果好。
由图1B的GTT结果可以看出，CBD能够显著增强小鼠对葡萄糖的调节。另外，CBD预防组比CBD治疗组效果好。
由图1C的ITT结果可以看出，CBD能够显著增强小鼠自身对胰岛素的敏感性，调节自身血糖，减轻一型糖尿病的症状。另外，CBD预防组比CBD治疗组效果好。
另外，对于一型糖尿病二甲双胍应该没有作用，在临床上也不使用二甲双胍作为治疗一型糖尿病的临床药物。
实施例2：小鼠二型糖尿病模型的建立及药物处理
1)二型糖尿病模型诱导方法(多次小剂量诱导法和高脂饮食诱导法)
实验动物使用4-6周龄C57雄鼠，小鼠饲喂高脂饲料，在小鼠禁食10-12h后，采用腹腔注射50mg/kg链脲佐菌素(STZ)，连续注射5天，检测第6天和第10天小鼠空腹血糖值检测是否诱导成功(以空腹血糖大于11.1mmol/L为诱导成功，实验中发现在第32天诱导成功)；第6天血糖未达标小鼠(没有诱导成功)在第8天腹腔注射链脲佐菌素剂量为80mg/kg；应用于下面步骤2)中的第二组至第八组。
高脂饲料为在普通饲料的基础上加入60％的脂肪形成。
2)实验分组和给药
小鼠随机分为8组，每组10只：
第一组：空白对照组，饲喂高脂饲料，腹腔注射缓冲溶液，剂量为100μl/只，每 天给药1次，连续给药5天；
其中缓冲溶液为0.1mol/L并且pH为4.2的柠檬酸缓冲液，经抽滤灭菌；
第二组：糖尿病模型组，饲喂高脂饲料，腹腔注射链脲佐菌素；
第三组：CBD预防组，饲喂高脂饲料，腹腔注射链脲佐菌素，诱导第一天开始通过灌胃进行CBD给药，50mg/kg，每天1次；
第四组：CBD治疗组，饲喂高脂饲料，腹腔注射链脲佐菌素，诱导成功后开始(第32天)每天通过灌胃进行CBD给药(50mg/kg)；
第五组：二甲双胍组，饲喂高脂饲料，腹腔注射链脲佐菌素，第32天，进行二甲双胍给药，50mg/kg，每天给药1次；
第六组：二甲双胍加CBD组，饲喂高脂饲料，腹腔注射链脲佐菌素，第32天开始每天灌胃给药(二甲双胍50mg/kg+CBD 50mg/kg)；
第七组：二甲双胍加格列本脲(Glibenclamide，简称为Gli)组，饲喂高脂饲料，腹腔注射链脲佐菌素，诱导成功后开始每天灌胃给药(二甲双胍50mg/kg+Gli0.758mg/kg)；
第八组：格列本脲加CBD组，饲喂高脂饲料，腹腔注射链脲佐菌素，诱导成功后开始每天灌胃给药(Gli 0.758mg/kg+CBD 50mg/kg)。
3)糖耐量试验(GTT)和胰岛素耐受试验(ITT)
给药一个月(在二型糖尿病模型稳定后)后，进行糖耐量试验(GTT)，小鼠禁食10h，根据体重(10μl/g)腹腔注射20％(w/w)葡萄糖，分别检测注射前(0min)小鼠血糖和注射后15min、30min、60min及120min时间点的血糖值。
给药一个月后(模型稳定后)，进行胰岛素耐受试验(ITT)，小鼠禁食10h，腹腔注射0.75U/kg胰岛素，分别检测注射前(0min)小鼠血糖和注射后15min、30min、60min及120min时间点的血糖值。
4)实验结果分别如图2A、图2B和图2C所示。
由图2A的结果可以看出STZ和高脂饲料能够引起小鼠血糖升高，CBD能够显著地降低STZ和高脂饮食所诱导的血糖升高。
由图2B小鼠葡萄糖耐受试验结果可以看出，CBD能够改善STZ和高脂饲料所诱导的自身对葡萄糖调节性能，更好地控制血糖。
由图2C小鼠胰岛素抵抗试验结果可以看出CBD能够改善小鼠自身对胰岛素的敏感性，能更好的调节自身的血糖。减轻二型糖尿病的症状。
由图2A至图2C可见，CBD和二甲双胍联合用药组(第六组)小鼠的血糖明显低于其它组的血糖，该组小鼠的糖耐量和胰岛素敏感性都有了明显的改善。
另外，图2A至图2C均显示，CBD预防组比CBD治疗组效果好。
实施例3：CBD和二甲双胍联合使用对二型糖尿病的效果研究
为了研究CBD和二甲双胍联合使用的效果，本发明人购买成年DB/DB小鼠(自发二型糖尿病鼠，购自南京大学模式动物中心)，随机分为5组，每组6只：
第一组为对照组，不做任何处理；
第二组为CBD单独给药组(50mg/kg)；
第三组为二甲双胍低剂量组(100mg/kg，参照人的最低给药剂量换算得到，小鼠的给药剂量＝9.1X人的给药剂量)；
第四组为二甲双胍低剂量(100mg/kg)和CBD(50mg/kg)联合用药组；
第五组为二甲双胍高剂量组(250mg/kg，参照人最高给药剂量换算得到，小鼠的给药剂量＝9.1X人的给药剂量)。
第三组和第五组都是治疗组的阳性对照组，第三组为二甲双胍低剂量组，第五组为二甲双胍高剂量组，在临床上病人最开始接受低剂量的二甲双胍治疗，随后根据血糖变化逐渐增加二甲双胍用量，但是不能超过最高用量，本实施例的实验是为了证明CBD和二甲双胍联合用药的效果优于二甲双胍低剂量以及二甲双胍高剂量。
以上5组给药途径均为灌胃，每天一次。
以上各组给药4周后开始检测各组小鼠血糖，各组小鼠相对血糖结果如图3。
结果显示，在给药期间，CBD和二甲双胍联合给药组(第四组)小鼠血糖下降最快，最明显。在给药5周后CBD和二甲双胍联合给药组小鼠的空腹血糖要明显低于单独使用二甲双胍治疗组(第三组和第五组)，也低于单独使用CBD治疗组(第二组)。
结果表明，CBD以及CBD和二甲双胍联合用药都能够降低DB/DB小鼠血糖，并且CBD和二甲双胍联合用药效果更好。
实施例4：小鼠腹泻模型的建立及药物处理
1)小鼠腹泻模型诱导方法(番泻叶诱导小鼠腹泻法)
实验动物使用4-6周龄ICR雌鼠，小鼠正常饮食和饮水，采用8％(w/w)番泻 叶溶液，给小鼠进行灌胃，0.2ml/只，每隔一个半小时统计一次小鼠腹泻指数，共统计6小时。番泻叶(Folium Sennae)购买于北京同仁堂药店，将8重量份番泻叶和92重量份水加入锥形瓶中，煮沸10min，制得8％(w/w)番泻叶溶液。
2)实验分组和给药
小鼠随机分为7组，每组10只：
第一组每天给小鼠灌同等体积的水；
第二组每天给小鼠灌150mg/kg二甲双胍；
第三组每天给小鼠灌50mg/kg CBD；
第四组每天给小鼠灌8％番泻叶溶液；
第五组每天给小鼠灌8％番泻叶和150mg/kg二甲双胍混合液；
第六组每天给小鼠灌8％番泻叶和50mg/kg CBD的混合液；
第七组每天给小鼠灌8％番泻叶150mg/kg二甲双胍和50mg/kg CBD混合液。
3)检测和统计方法
每天在灌胃后开始计时，每隔一个半小时统计一下每只小鼠的腹泻指数，共统计4次(每6小时1次)。
腹泻指数＝便稀率*便稀级
其中，
腹泻率：该组便稀动物数/该组总动物数*100％；
便稀率：每只动物所排稀便数/总便数；
便稀级：表述稀便的硬度，以稀便在滤纸上形成污迹大小的定级。如下面的表1所示。
表1：便稀级
级数 0 1 2 3 4
污迹直径(cm) 没有污迹 ＜1 1-1.9 2-2.9 ＞3
4)实验结果
分别如图4A至图4G所示。
图4A至图4G是诱导第一天到第七天小鼠腹泻指数的结果。由图4A至图4G各组小鼠腹泻指数的统计结果可以看出番泻叶能够引起小鼠腹泻，二甲双胍能够加重番泻叶诱导的小鼠腹泻，而CBD能够显著地减缓番泻叶诱导的小鼠腹泻以及二甲双胍诱导及加重的小鼠腹泻。
实施例5：小鼠乳酸中毒模型的建立及药物处理
1)小鼠乳酸中毒模型诱导方法
实验动物使用4-6周龄ICR雄鼠，进行三次诱导，每次二甲双胍灌胃(260mg/kg)，3次灌胃时间间隔为12小时。
2)实验分组和给药
实验将小鼠随机分为七组，每组5只：
第一组：对照组，不做处理；
第二组：每天灌胃给水；
第三组：每天灌胃给CBD 1次，50mg/kg；
第四组：第一天，早晚各通过灌胃给260mg/kg的二甲双胍，第二天早上通过灌胃给260mg/kg的二甲双胍，第二天下午四点进行样品采集；
第五组：第一天，早晚各通过灌胃给260mg/kg的二甲双胍，第二天早上通过灌胃给260mg/kg的二甲双胍，其中在每次灌胃给予二甲双胍的同时给予50mg/kg CBD；第二天下午四点进行样品采集；
第六组：尾静脉注射260mg/kg二甲双胍，每隔一小时注射一次，共注射四次，第四次注射后一个小时进行样品采集；
第七组：在尾静脉注射前半个小时通过灌胃给予50mg/kg CBD，半个小时之后尾静脉注射260mg/kg二甲双胍，每隔一小时注射一次，共注射四次，第四次注射后一个小时进行样品采集。
3)实验设计：处理前采血检测乳酸浓度，处理后采各组小鼠血液检测乳酸浓度。
4)实验结果如图5所示。
结果表明，二甲双胍能够诱导小鼠的乳酸血症，而CBD能够显著地抑制二甲双胍诱导的血液中乳酸升高。
实施例6：CBD和二甲双胍联用对降低高脂料诱导的小鼠的血脂水平的研究
1)糖尿病模型诱导方法(多次小剂量诱导法)
实验动物使用4-6周龄昆明白雄鼠，在小鼠禁食10-12h后，采用腹腔注射50mg/kg链脲佐菌素(STZ)，连续注射5天，检测第6天和第10天小鼠空腹血糖值检测是否诱导成功；以空腹血糖大于11.1mmol/L为诱导成功；应用于下面步骤3)中的第二组 至第五组。
2)高脂料诱导方法
在试验期间给小鼠饲喂含有在普通饲料的基础上加入60％的脂肪形成高脂饲料，第二组至第五组小鼠均饲喂高脂饲料。
3)实验分组和给药
小鼠随机分为5组，每组10只：
第一组：空白对照组，饲喂普通饲料，腹腔注射缓冲溶液，剂量为100μl/只，每天给药1次，连续给药5天；
其中缓冲溶液为0.1mol/L并且pH为4.2的柠檬酸缓冲液，经抽滤灭菌；
第二组：糖尿病模型组，饲喂高脂饲料，腹腔注射链脲佐菌素；
第三组：二甲双胍低剂量组，饲喂高脂饲料，腹腔注射链脲佐菌素，诱导第一天开始通过灌胃进行低剂量二甲双胍给药，100mg/kg，每天给药1次；
第四组：二甲双胍低剂量+CBD组，灌胃进行低剂量二甲双胍给药，100mg/kg，每天给药1次；加灌胃给药CBD，50mg/kg，每天1次，饲喂高脂饲料，腹腔注射链脲佐菌素，诱导第一天开始通过灌胃进行低剂量二甲双胍和CBD给药；
第五组：二甲双胍高剂量组，250mg/kg，每天1次，饲喂高脂饲料，腹腔注射链脲佐菌素诱导第一天开始通过灌胃进行高剂量二甲双胍给药。第五组作为阳性对照治疗组。
4)检测方法
使用药物治疗两个月后，处死小鼠，心脏采血，取血清，分别检测血清中胆固醇、甘油三酯、高密度胆固醇、低密度胆固醇和胰岛素水平。
5)实验结果
分别如图6A至图6E所示。
由图6A至图6E可以看出，CBD和二甲双胍联合用药能够显著降低STZ和高脂饮食所诱导的高血脂和高胆固醇，并且能够增加胰岛素的分泌。另外，图6E显示，单独给药二甲双胍不能增加胰岛素的分泌。
实施例7：CBD显著地降低阿霉素诱导的慢性肾衰竭小鼠尿总蛋白水平
按照常规的诱导肾损伤模型的方法，构建了阿霉素诱导的慢性肾衰竭小鼠模型。CBD处理14天后，检测的尿内总蛋白水平。具体方法如下：
1)糖尿病肾病模型诱导方法(多次小剂量诱导法)
实验动物使用4-6周龄昆明白雄鼠，在小鼠禁食10-12h后，采用腹腔注射50mg/kg链脲佐菌素(STZ)，连续注射5天，检测第6天和第10天小鼠空腹血糖值检测是否诱导成功(以空腹血糖大于11.1mmol/L为诱导糖尿病成功)；在诱导糖尿病开始后的第7天，给肾病组小鼠尾静脉注射10mg/kg阿霉素；应用于下面的步骤2)中的第三组至第六组。
2)实验分组和给药
将实验动物随机分为6组，每组10只：
第一组：对照组给生理盐水；
第二组：糖尿病组；
第三组：糖尿病加CBD组，CBD灌胃给药，50mg/kg，灌胃，每天1次；
第四组：糖尿病加阿霉素组；
第五组：糖尿病加阿霉素加CBD组，CBD灌胃给药，50mg/kg，灌胃，每天1次；
第六组：糖尿病加阿霉素加二甲双胍组，二甲双胍灌胃给药，50mg/kg，每天一次。
上面的第二组和第三组是为了检测不诱导慢性肾衰竭，只诱导糖尿病时，尿中的总蛋白含量。
3)检测方法
在诱导成功的小鼠糖尿病模型后，给小鼠尾静脉注射阿霉素，诱导肾病模型，取诱导肾病模型的第14天采集小鼠尿液，检测尿总蛋白。
4)实验结果
如图7所示。
结果显示，CBD能够显著地降低阿霉素诱导的慢性肾衰竭小鼠尿总蛋白水平。肾病是糖尿病并发症之一，可见，CBD能够治疗糖尿病引起的慢性肾衰竭。
实施例8：CBD显著地降低二型糖尿病病人的空腹血糖和糖化血红蛋白水平
临床上有三例糖尿病患者志愿者：两名男性，体重分别为65和70kg左右，年龄分别为47和52岁；一名女性，体重55kg左右，年龄74岁。
每位患者均接受300mg/天的口服CBD治疗，治疗期8周，第0、4、8周检测空 腹血糖值；第0、8周检测糖化血红蛋白值。结果分别如图8A和图8B所示。
图8A显示，在接受CBD治疗8周后，三人的空腹血糖均有显著下降(虽然没有降到正常范围)；
图8B显示，在接受CBD治疗8周后，三人的糖化血红蛋白与治疗前均有明显改善(虽然没有降到正常范围即4％-6％)。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。

Claims (18)

  1. 一种药物组合物，其包含：
    大麻二酚和/或其药学上可接受的盐或酯；以及
    一种或多种降糖药；
    可选地，所述药物组合物还包含一种或几种药学上可接受的辅料。
  2. 根据权利要求1所述的药物组合物，其中，所述降糖药选自：
    双胍类降糖药、磺酰脲类促泌剂、α-葡萄糖苷酶抑制剂、噻唑烷二酮类衍生物促敏剂、苯茴酸类衍生物促泌剂、GLP-1受体激动剂、DPP-4酶抑制剂、胰岛素以及胰岛素类似物；
    优选地，所示双胍类降糖药为二甲双胍或其药学上可接受的盐，例如盐酸二甲双胍；
    优选地，所述磺酰脲类促泌剂选自：格列本脲、格列波脲、格列美脲、格列齐特、格列吡嗪和格列喹酮。
  3. 根据权利要求1至2中任一权利要求所述的药物组合物，其中，所述降糖药选自：
    二甲双胍、盐酸二甲双胍和格列本脲。
  4. 根据权利要求1至3中任一权利要求所述的药物组合物，其中，所述药物组合物由大麻二酚和/或其药学上可接受的盐或酯、一种或多种降糖药以及一种或几种药学上可接受的辅料组成。
  5. 根据权利要求1至4中任一权利要求所述的药物组合物，其中，所述大麻二酚和/或其药学上可接受的盐或酯与降糖药的重量比为：
    (10:1)至(1:50)、(10:1)至(1:30)、(10:1)至(1:20)、(10:1)至(1:10)、(5:1)至(1:10)、(3:1)至(1:5)、(2:1)至(1:5)、(1:1)至(1:5)、(1:1)至(1:3)、(1:1)至(1:2)、1:1、1:2或1:3。
  6. 根据权利要求1至5中任一权利要求所述的药物组合物，其中，所述大麻二酚 和/或其药学上可接受的盐或酯的质量为5－500mg、10－300mg、20－200mg、50－150mg、50－100mg、100－300mg、100mg、200mg、300mg、400mg或500mg。
  7. 一种药物产品，其包含独立包装的第一药物制剂和独立包装的第二药物制剂，其中：
    所述第一药物制剂包含大麻二酚和/或其药学上可接受的盐或酯，
    所述第二药物制剂包含一种或多种降糖药；
    可选地，所述第一药物制剂和/或第二药物制剂还包含一种或者几种药学上可接受的辅料。
  8. 根据权利要求7所述的药物产品，其中，所述降糖药选自：
    双胍类降糖药、磺酰脲类促泌剂、α-葡萄糖苷酶抑制剂、噻唑烷二酮类衍生物促敏剂、苯茴酸类衍生物促泌剂、GLP-1受体激动剂、DPP-4酶抑制剂、胰岛素以及胰岛素类似物；
    优选地，所示双胍类降糖药为二甲双胍或其药学上可接受的盐，例如盐酸二甲双胍；
    优选地，所述磺酰脲类促泌剂选自：格列本脲、格列波脲、格列美脲、格列齐特、格列吡嗪和格列喹酮。
  9. 根据权利要求7至8中任一权利要求所述的药物产品，其中，所述降糖药选自：
    二甲双胍、盐酸二甲双胍和格列本脲。
  10. 根据权利要求7至9中任一权利要求所述的药物产品，
    其中，所述药物产品由第一药物制剂以及第二药物制剂组成，
    其中，所述第一药物制剂由大麻二酚和/或其药学上可接受的盐或酯，以及一种或几种药学上可接受的辅料组成；
    其中，所述第二药物制剂由一种或多种降糖药，以及一种或几种药学上可接受的辅料组成。
  11. 根据权利要求7至10中任一权利要求所述的药物产品，其中，所述大麻二酚 和/或其药学上可接受的盐或酯与降糖药的重量比为：
    (10:1)至(1:50)、(10:1)至(1:30)、(10:1)至(1:20)、(10:1)至(1:10)、(5:1)至(1:10)、(3:1)至(1:5)、(2:1)至(1:5)、(1:1)至(1:5)、(1:1)至(1:3)、(1:1)至(1:2)、1:1、1:2或1:3。
  12. 根据权利要求7至11中任一权利要求所述的药物产品，其中，
    所述大麻二酚和/或其药学上可接受的盐或酯的质量为5－500mg、10－300mg、20－200mg、50－150mg、50－100mg、100－300mg、100mg、200mg、300mg、400mg或500mg。
  13. 权利要求1至6中任一权利要求所述的药物组合物或者权利要求7至12中任一权利要求所述的药物产品在制备治疗和/或预防选自如下病症或者症状的药物中的用途：
    糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、二甲双胍所致不良反应或格列本脲所致不良反应；
    优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
    优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
    优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩。
  14. 大麻二酚和/或其药学上可接受的盐或酯在制备治疗和/或预防选自如下病症或者症状的药物中的用途：
    糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、腹泻、乳酸升高、二甲双胍所致不良反应或格列本脲所致不良反应；
    优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢 性肾衰竭；
    优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
    优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩。
  15. 根据权利要求1至6中任一权利要求所述的药物组合物或者权利要求7至12中任一权利要求所述的药物产品，其用于治疗和/或预防选自如下病症或者症状：
    糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、二甲双胍所致不良反应或格列本脲所致不良反应；
    优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
    优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
    优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩；
    优选地，其中大麻二酚和/或其药学上可接受的盐或酯的给药剂量为每天每千克体重0.1－50mg、0.5－30mg、0.5－20mg、0.5－10mg、0.5－5mg、1－10mg、2－8mg、3－7mg、4－6mg、4mg、4.5mg、5mg、5.5mg或6mg。
  16. 大麻二酚和/或其药学上可接受的盐或酯，其用于治疗和/或预防选自如下病症或者症状：
    糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、腹泻、乳酸升高、二甲双胍所致不良反应或格列本脲所致不良反应；
    优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮 症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
    优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
    优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩；
    优选地，大麻二酚和/或其药学上可接受的盐或酯的给药剂量为每天每千克体重0.1－50mg、0.5－30mg、0.5－20mg、0.5－10mg、0.5－5mg、1－10mg、2－8mg、3－7mg、4－6mg、4mg、4.5mg、5mg、5.5mg或6mg。
  17. 一种治疗和/或预防选自如下病症或者症状的方法，包括给予有需求的受试者以有效量的权利要求1至6中任一权利要求所述的药物组合物或者权利要求7至12中任一权利要求所述的药物产品的步骤：
    糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、二甲双胍所致不良反应或格列本脲所致不良反应；
    优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
    优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
    优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩；
    优选地，其中大麻二酚和/或其药学上可接受的盐或酯的给药剂量为每天每千克体重0.1－50mg、0.5－30mg、0.5－20mg、0.5－10mg、0.5－5mg、1－10mg、2－8mg、3－7mg、4－6mg、4mg、4.5mg、5mg、5.5mg或6mg。
  18. 一种治疗和/或预防选自如下病症或者症状的方法，包括给予有需求的受试者以有效量的大麻二酚和/或其药学上可接受的盐或酯的步骤：
    糖尿病(例如一型糖尿病或二型糖尿病)、高血脂症、腹泻、乳酸升高、二甲双胍所致不良反应或格列本脲所致不良反应；
    优选地，所述糖尿病为同时伴随有至少一种如下病症或症状：肝肾功能不全、酮症酸中毒、昏迷、严重烧伤、感染、外伤、白细胞减少、高血脂症、视网膜病变或慢性肾衰竭；
    优选地，所述二甲双胍所致不良反应为服用二甲双胍导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良或乳酸性酸中毒；
    优选地，所述格列本脲所致不良反应为服用格列本脲导致的至少一种如下病症或症状：上腹部不适、腹痛、腹泻、恶心、呕吐、胃胀、乏力、消化不良、乳酸性酸中毒或胰岛萎缩；
    优选地，大麻二酚和/或其药学上可接受的盐或酯的给药剂量为每天每千克体重0.1－50mg、0.5－30mg、0.5－20mg、0.5－10mg、0.5－5mg、1－10mg、2－8mg、3－7mg、4－6mg、4mg、4.5mg、5mg、5.5mg或6mg。
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