WO2021036884A1 - 海兰地嗪或其药学上可接受的盐在糖尿病或糖尿病并发症药物中的应用 - Google Patents

海兰地嗪或其药学上可接受的盐在糖尿病或糖尿病并发症药物中的应用 Download PDF

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WO2021036884A1
WO2021036884A1 PCT/CN2020/110030 CN2020110030W WO2021036884A1 WO 2021036884 A1 WO2021036884 A1 WO 2021036884A1 CN 2020110030 W CN2020110030 W CN 2020110030W WO 2021036884 A1 WO2021036884 A1 WO 2021036884A1
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acid
salt
pharmaceutically acceptable
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diabetic
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李�浩
邙志国
柏静
张帅
刘永海
李美娟
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East China University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • 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
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to the technical field of medicine, in particular to the application of hylandizine or a pharmaceutically acceptable salt thereof in medicines for diabetes or diabetic complications.
  • Diabetes is a lifelong metabolic disease characterized by chronic hyperglycemia caused by multiple causes. Diabetes itself does not necessarily cause harm, but long-term increase in blood sugar will damage the large blood vessels and capillaries, and seriously endanger the heart, brain, kidneys, peripheral nerves, eyes, and feet. According to statistics from the World Health Organization, there are more than 100 complications of diabetes, which is currently the disease with the most known complications. Among them, diabetic cardiovascular disease, diabetic nephropathy and diabetic retinopathy are the most serious complications of diabetes currently known, and are the main causes of death and disability from diabetes.
  • ADA American Diabetes Association
  • the treatment of diabetes is mainly divided into the following categories of drugs.
  • the first category increase insulin secretion and sensitivity to insulin.
  • the ability of insulin in type 2 diabetic patients is not completely lost, but insufficient insulin secretion or insulin resistance.
  • secretagogues and sensitizers Such as sulfonylureas and glitazones or glitazones.
  • This secretagogue mainly stimulates the secretion of insulin by pancreatic islets or increases the sensitivity of tissues to insulin, increasing the level of insulin in the body to lower blood sugar.
  • the disadvantage of this type of medicine is that it will cause the patient's hypoglycemia, and the blood sugar fluctuates too much, which leads to damage to the organs.
  • DPP-4 inhibitors namely dipeptidyl peptidase 4 inhibitors, which can inhibit the inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) It can increase the level of endogenous GLP-1 and GIP, promote the release of insulin from islet ⁇ cells, and inhibit the secretion of glucagon from islet ⁇ cells, thereby increasing insulin levels and lowering blood sugar.
  • GLP-1 glucagon-like peptide-1
  • GIP glucose-dependent insulinotropic peptide
  • the secretion of human insulin will be increased only when the human blood sugar is higher than the normal level, and will not cause hypoglycemia.
  • DPP-4 inhibitors are only third-line drugs.
  • the GLP-1 receptor agonist is the glucagon-like peptide-1 agonist. GLP-1 is secreted from the intestines and is obviously secreted after eating. Its increase will promote the secretion of insulin, thereby reducing blood sugar. However, this type of drug has a short clinical application time, is expensive, and requires injection. It is not recommended as a first-line drug.
  • ⁇ -glucosidase inhibitors ⁇ -glucosidase is a kind of complex carbohydrates that can not be absorbed into the small intestine absorbable monosaccharides, and glucosidase inhibitors by inhibiting the action of the enzyme , While delaying or reducing the increase in blood glucose after meals.
  • this kind of drugs is narrow, and it is generally used for patients with elevated blood sugar after a meal, or combined with other hypoglycemic drugs.
  • the fourth category inhibit the activity of SGLT-2, reduce the reabsorption of glucose by the kidneys, increase the excretion of urine sugar, thereby reducing blood sugar.
  • the results of a phase 2-3 clinical study lasting 12 to 78 weeks showed that among 7.5%-9.2% of patients with baseline HbA1c, compared with placebo, these drugs can only reduce HbA1c by an average of 0.7%.
  • Metformin is used as the first-line medication for diabetes. In addition to lowering blood sugar, it also has the effect of lowering blood lipids, anti-tumor, and weight reduction. Although these effects are relatively weak, at present, metformin is still the drug with the most extra-hyperglycemic effects among all hypoglycemic drugs. Metformin has been proven to be an indirect AMPK agonist.
  • the purpose of the present invention is to provide an application of hylandizine or its pharmaceutically acceptable salt in the preparation of anti-diabetic drugs.
  • hylandizine or a pharmaceutically acceptable salt thereof for the preparation of a medicine for the prevention and/or treatment of diabetes or diabetic complications.
  • the drug is used for one or more applications selected from the following group:
  • the medicine comprises:
  • Component ii a pharmaceutically acceptable carrier.
  • the content of hylandizine or its pharmaceutically acceptable salt is 0.01-99wt%, preferably 0.1-90wt%, more preferably 1-80wt% %.
  • the pharmaceutically acceptable salt is a salt of hylandizine selected from the group consisting of acid salt, basic salt, or a combination thereof;
  • the acid salt is a salt formed by hylandizine and an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, Malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid Acid, gallic acid, proline, phenylalanine, aspartic acid, glutamic acid, or a combination thereof;
  • the basic salt is a salt formed by hylandiazine and a base selected from the following group: alkali metal salt, alkaline earth metal salt, ammonium salt, amine salt, or a combination thereof.
  • the pharmaceutically acceptable salt is hylandiazine selected from the group consisting of hydrochloride, gallate, or a combination thereof.
  • the pharmaceutically acceptable salt is a salt of hylandizine selected from the group consisting of hydrochloride, hydrobromide, carbonate, sulfate, phosphate, nitrate, Maleate, fumarate, succinate, oxalate, trifluoroacetate, tartrate, ascorbate, N-benzoylglycinate, L-pyroglutamate, L-pro Amino acid, 2-hydroxyethanesulfonate, acetate, benzoate, glycinate, lysine, arginine, aspartate, gallate, lactate, whey Acid salt, malate, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or a combination thereof.
  • hylandizine selected from the group consisting of hydrochloride, hydrobromide, carbonate, sulfate, phosphate, nitrate, Maleate, fumarate
  • the diabetic complications are selected from the group consisting of hyperglycemia, hyperlipidemia, hypertension, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, diabetic foot, diabetic cardiovascular disease, or a combination thereof.
  • the diabetes is selected from the group consisting of type I diabetes and type II diabetes.
  • the medicine further comprises:
  • Component iii the second active ingredient that is not hylandiazine or its pharmaceutically acceptable salt for preventing and/or treating diabetes or diabetic complications.
  • the drug further comprises an active ingredient selected from the group consisting of an insulin signal pathway modulator, a compound that affects abnormal regulation of hepatic glucose production, an insulin sensitivity enhancer, an insulin secretion enhancer, or a combination thereof.
  • the drug further comprises an active ingredient selected from the group consisting of: a protein tyrosine phosphatase inhibitor, a glutamine-fructose-6-phosphate transamidase inhibitor, and fructose-1,62 Phosphatase inhibitor, glycogen phosphorylase inhibitor, glucagon receptor antagonist, pyruvate dehydrogenase inhibitor, ⁇ -glucosidase inhibitor, gastric emptying inhibitor, glucokinase activator, GLP -1 receptor agonist, GLP-2 receptor agonist, UCP modulator, RXR modulator, GSK-3 inhibitor, PPAR modulator, insulin and ⁇ 2-adrenergic antagonist, or a combination thereof.
  • an active ingredient selected from the group consisting of: a protein tyrosine phosphatase inhibitor, a glutamine-fructose-6-phosphate transamidase inhibitor, and fructose-1,62 Phosphatase inhibitor, glycogen phosphorylase inhibitor, glucagon
  • the drug further comprises an active ingredient selected from the group consisting of DPP-IV inhibitors, anti-diabetic thiazolidinediones, non-glitazone PPAR ⁇ agonists, dual PPAR ⁇ /PPAR ⁇ agonists , Retinoid X receptor agonists, ⁇ -3AR agonists, anti-diabetic biguanides, or combinations thereof.
  • an active ingredient selected from the group consisting of DPP-IV inhibitors, anti-diabetic thiazolidinediones, non-glitazone PPAR ⁇ agonists, dual PPAR ⁇ /PPAR ⁇ agonists , Retinoid X receptor agonists, ⁇ -3AR agonists, anti-diabetic biguanides, or combinations thereof.
  • the drug further comprises an active ingredient selected from the following group or a pharmaceutically acceptable salt thereof: gliclapide, glibenclamide, acetohexamide, chlorpropamide, gliclaide Polyuron, tolbutamide, tolazamide, glipizide, sulfambutazone, gliquidone, glibenclamide, tolbutamide, tolbutamide, glimepiride, glipizide Lezit, or a combination thereof.
  • an active ingredient selected from the following group or a pharmaceutically acceptable salt thereof: gliclapide, glibenclamide, acetohexamide, chlorpropamide, gliclaide Polyuron, tolbutamide, tolazamide, glipizide, sulfambutazone, gliquidone, glibenclamide, tolbutamide, tolbutamide, glimepiride, glipizide Lezit, or a combination thereof.
  • the medicine further comprises an active ingredient selected from the following group or a pharmaceutically acceptable salt thereof: acarbose, voglibose, miglitol, or a combination thereof.
  • the medicament further comprises an active ingredient selected from the following group or a pharmaceutically acceptable salt thereof: sitagliptin, vildagliptin, saxagliptin, alogliptin, ligagliptin Liliptin, troxagliptin, compound gliptin, ticagliptin, anesagliptin, duxagliptin, geagliptin, itagliptin, augliptin, or a combination thereof.
  • an active ingredient selected from the following group or a pharmaceutically acceptable salt thereof: sitagliptin, vildagliptin, saxagliptin, alogliptin, ligagliptin Liliptin, troxagliptin, compound gliptin, ticagliptin, anesagliptin, duxagliptin, geagliptin, itagliptin, augliptin, or
  • the drug further comprises an active ingredient selected from the group consisting of repaglinide, mitiglinide, nateglinide, or a combination thereof, or a pharmaceutically acceptable salt thereof.
  • the drug further comprises an active ingredient selected from the following group or a pharmaceutically acceptable salt thereof: insulin, pramlintide, exenatide, liraglutide, lixisenatide, a Biglutide, duraglutide, lixisenatide, tasglutide, or a combination thereof.
  • the medicament further comprises an active ingredient selected from the following group or a pharmaceutically acceptable salt thereof: pioglitazone, rosiglitazone, or a combination thereof.
  • the drug further comprises an active ingredient selected from the group consisting of canagliflozin, dapagliflozin, enpagliflozin, enpagliflozin, ruggliflozin, or pharmaceutically acceptable salts thereof. Lizoligen, togliflozin, or a combination thereof.
  • the second aspect of the present invention provides a pharmaceutical composition for preventing and/or treating diabetes or diabetic complications, comprising:
  • Component i a preventive and/or therapeutically effective amount of hylandizine or a pharmaceutically acceptable salt thereof;
  • Component ii a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable salt is a salt of hylandizine selected from the group consisting of hydrochloride, hydrobromide, carbonate, sulfate, phosphate, nitrate, Maleate, fumarate, succinate, oxalate, trifluoroacetate, tartrate, ascorbate, N-benzoylglycinate, L-pyroglutamate, L-pro Amino acid, 2-hydroxyethanesulfonate, acetate, benzoate, glycinate, lysine, arginine, aspartate, gallate, lactate, whey Acid salt, malate, citrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, or a combination thereof.
  • hylandizine selected from the group consisting of hydrochloride, hydrobromide, carbonate, sulfate, phosphate, nitrate, Maleate, fumarate
  • the pharmaceutically acceptable salt is hylandiazine selected from the group consisting of hydrochloride, gallate, or a combination thereof.
  • the third aspect of the present invention provides a method for preventing and/or treating diabetes or diabetic complications, comprising the steps of: administering a preventive and/or therapeutically effective amount of hylandizine or its pharmaceutically acceptable amount to a patient in need Of salt.
  • the applied dosage is 5-30 mg/kg, preferably 10-25 mg/kg, more preferably 15-25 mg/kg.
  • Figure 1 is the experimental result of the ipGTT experiment in Example 1.
  • Figure 2 is the insulin release curve of the insulin release experiment in Example 1.
  • Figure 3 shows the retinopathy of different treatment conditions in Example 5.
  • Figure 4 shows the oil red stained pathological section results of different treatment conditions.
  • Figure 5 shows the results of HE stained pathological sections under different treatment conditions.
  • Figure 6 shows the PASM stained pathological section results of different treatment conditions.
  • Figure 7 shows the results of kidney weight to weight ratio (left picture) and heart weight to weight ratio (right picture) for different treatment conditions.
  • Hernandezine (D901) has a structural formula as shown in formula I, a molecular formula of C 39 H 44 N 2 O 7 and a molecular weight of 652.79. It is a bisbenzyl isoquinoline alkaloid. It mainly exists in the genus Thalictrum of Ranunculaceae. Pharmacological studies have shown that hylandizine has a variety of biological activities and is a highly active natural multi-target drug. The present invention applies hylandizine to the treatment of diabetes, and the curative effect is obviously better than that of the clinical first-line drug metformin.
  • the term "pharmaceutically acceptable salt” refers to a salt of hylandizine and acid or base that is suitable for use as a drug.
  • Pharmaceutically acceptable salts include inorganic salts and organic salts.
  • a preferred type of salt is the salt of hylandizine and acid.
  • Acids suitable for salt formation include, but are not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid and other inorganic acids; formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid and other organic acids; and Amino acids such as amino acid, phenylalanine, aspartic acid and glutamic acid.
  • Another preferred salt is the salt formed by hylandizine and a base, such as alkali metal salt (such as sodium or potassium salt), alkaline earth metal salt (such as magnesium salt or calcium salt), ammonium salt (such as lower alkanol Ammonium salt and other pharmaceutically acceptable amine salts), such as methylamine salt, ethylamine salt, propylamine salt, dimethylamine salt, trimethylamine salt, diethylamine salt, triethylamine salt, tertiary Butylamine salt, ethylenediamine salt, hydroxyethylamine salt, dihydroxyethylamine salt, trihydroxyethylamine salt, and amine salts formed from morpholine, piperazine, and lysine, respectively.
  • alkali metal salt such as sodium or potassium salt
  • alkaline earth metal salt such as magnesium salt or calcium salt
  • ammonium salt such as lower alkanol Ammonium salt and other pharmaceutically acceptable amine salts
  • methylamine salt such as sodium or
  • the present invention finds that hylandizine or its pharmaceutically acceptable salt has a good anti-diabetic effect through animal experiments, and it is confirmed through animal experiments that hylandizine has a therapeutic effect on diabetes and has a therapeutic effect on diabetic complications.
  • the compound of the present invention has excellent anti-diabetic activity, the compound of the present invention and its various crystal forms, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and drugs containing the compound of the present invention as the main active ingredient
  • the composition can be used for the treatment, prevention and alleviation of diabetes-related diseases.
  • solvate refers to a complex in which the compound of the present invention coordinates with solvent molecules to form a specific ratio.
  • “Hydrate” refers to a complex formed by coordination of the compound of the present invention with water.
  • the compounds of the present invention also include prodrugs of hylandizine.
  • prodrug includes biologically active or inactive itself, and when taken in an appropriate way, it undergoes metabolism or chemical reaction in the human body to convert it into a class of compounds of formula I, or formula I A salt or solution of a compound.
  • the prodrugs include (but are not limited to) carboxylic acid esters, carbonate esters, phosphate esters, nitrate esters, sulfate esters, sulfone esters, sulfoxide esters, amino compounds, carbamates, and azo compounds of the compound , Phosphoramide, glucoside, ether, acetal and other forms.
  • the pharmaceutical composition of the present invention contains the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier within a safe and effective amount.
  • the "safe and effective amount” refers to: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound of the present invention/agent, more preferably, 10-1000 mg of the compound of the present invention/agent.
  • the "one dose" is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components in the composition can be blended with the compound of the present invention and between them without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, and solid lubricants (such as stearic acid).
  • Magnesium stearate calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as emulsifiers
  • wetting agents such as sodium lauryl sulfate
  • the pharmaceutical composition is injection, capsule, tablet, pill, powder or granule.
  • the method of administration of the compound or pharmaceutical composition of the present invention is not particularly limited.
  • Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration .
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) fillers or compatibilizers, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glycty
  • Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the active compound or the release of the compound in such a composition may be released in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into a microcapsule form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage form may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the compound of the present invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the compound of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds (such as anti-diabetic drugs).
  • the treatment method of the present invention can be administered alone or in combination with other treatment means or therapeutic drugs.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment.
  • the administered dose is usually 1 to 2000 mg, preferably 50 to 1000 mg.
  • the specific dosage should also consider factors such as the route of administration and the patient's health status, which are all within the skill range of a skilled physician.
  • the present invention has the following main advantages:
  • the first-line clinical drug for diabetes, hylandizine or its pharmaceutically acceptable salt has a better therapeutic effect on diabetes and diabetic complications.
  • Example 1 The effect of D901 on blood glucose and insulin sensitivity in db/db mice
  • mice 18 6-week-old db/db mice were divided into 6 solvent control group (Veh group), 6 drug high-dose group (D901 20 group, ie 20 mg/kg group), and 6 drug low-dose group (D901 10 Group, namely 10mg/kg group), 6 dbm mice served as normal control group.
  • the administration group was given intragastrically with sodium carboxymethyl cellulose, while the control group was given solvent at the same time for 8 weeks.
  • Fasting for 6 hours before the experiment intraperitoneal injection of glucose 1g/Kg, censored blood collection and determination of fasting blood glucose.
  • the blood samples were censored to measure blood glucose at 0 minutes, 20 minutes, 40 minutes, 60 minutes, and 90 minutes. No diet was allowed during the experiment.
  • Figure 1 shows the experimental results of the ipGTT experiment in Example 1.
  • Figure 2 is the insulin release curve of the insulin release experiment in Example 1.
  • the drug group can significantly increase the release of insulin in diabetic mice and improve insulin sensitivity.
  • Enzyme analysis method detects serum total cholesterol (TC) and serum triglycerides (TG), and glycosylated hemoglobin is determined by TBA colorimetric method, all according to the kit instructions.
  • D901 (10mg/kg), D901 (20mg/kg), metformin, and valsartan group have decreased KW/BW, GHb, TC and TG (p ⁇ 0.05), and D901 (10mg/kg) Compared with metformin and valsartan, D901 (20mg/kg) significantly reduces kidney weight/body weight ratio, serum total cholesterol and triglycerides. D901 (20mg/kg) shows a better hypoglycemic effect than metformin.
  • CBB color method for determination of urine protein Urine Prorein, UP
  • the product of urine protein concentration and urine volume is 24h urine protein volume (24h UP)
  • Serum creatinine (SCr) and blood urea nitrogen (BUN) were determined by diacetyl method according to the kit instructions.
  • TBA chromogenic method for the determination of malondialdehyde WST-8 method for determination of superoxide dismutase, visible light method for determination of catalase, all operations were determined in accordance with the kit instructions.
  • D901 (10mg/kg), D901 (20mg/kg), metformin and valsartan can all down-regulate the content of MDA in the kidney of diabetic rats, especially D901 (10mg/kg) and D901 (20mg/kg) have more obvious effects (P ⁇ 0.05), indicating that both D901 (10mg/kg) and D901 (20mg/kg) have anti-oxidative stress effects, thereby reducing or delaying diabetes
  • the occurrence and development of kidney disease, and the effect of D901 (20mg/kg) is significantly stronger than that of D901 (10mg/kg).
  • Figure 4 shows the oil red stained pathological section results of different treatment conditions.
  • Figure 5 shows the results of HE stained pathological sections under different treatment conditions.
  • Figure 6 shows the PASM stained pathological section results of different treatment conditions.
  • Organ coefficient is a commonly used index in toxicology experiments.
  • Heart-to-weight ratio and kidney-to-weight ratio can reflect the effects of drugs on the heart and kidneys.
  • Figure 7 shows the results of kidney weight to weight ratio (left picture) and heart weight to weight ratio (right picture) for different treatment conditions.
  • kidney weight-to-weight ratio (KW/BW) of each group of rats in Figure 7 that D901 can reduce the kidney weight-to-weight ratio of diabetic rats and has a renal protective effect.
  • the heart-weight-to-weight ratio showed that the ratio of diabetic rats in the D901 group was lower than that of the model group and the metformin group.

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Abstract

海兰地嗪或其药学上可接受的盐在糖尿病或糖尿病并发症药物中的应用。相比于糖尿病的临床1线药物二甲双胍，海兰地嗪或其药学上可接受的盐对糖尿病或糖尿病并发症具有更优异的治疗效果。

Description

海兰地嗪或其药学上可接受的盐在糖尿病或糖尿病并发症药物中的应用 技术领域
本发明涉及医药技术领域，具体地涉及海兰地嗪或其药学上可接受的盐在糖尿病或糖尿病并发症药物中的应用。
背景技术
糖尿病是一种由多病因引起的以慢性高血糖为特征的终身性代谢疾病。糖尿病本身不一定造成危害，但长期血糖增高会使大血管、微血管受损，并严重危及到心、脑、肾、周围神经、眼睛、足等。据世界卫生组织统计，糖尿病并发症高达100多种，是目前已知并发症最多的一种疾病。其中，糖尿病心血管病变、糖尿病肾病和糖尿病视网膜病变等，是目前已知的糖尿病最为严重的并发症，是糖尿病致死致残的主要原因。美国糖尿病协会(American Diabetes Association，ADA)统计数据显示，3年以上的糖尿病患者出现并发症的几率在46％以上；5年以上的糖尿病患者出现并发症的几率在61％以上；10年以上的糖尿病患者出现并发症的几率高达98％。其中糖尿病心血管病变和糖尿病肾病是导致75％以上糖尿病患者死亡的主要原因，糖尿病视网膜病变是造成全球成人不可逆性眼盲的主要原因。因此，预防与治疗糖尿病并发症已成为至关重要的社会问题。
对糖尿病的治疗主要分为以下几类药物。
第一类：增加胰岛素的分泌和对胰岛素的敏感。2型糖尿病病人胰岛素的能力并非完全丧失，而是胰岛素分泌不足或产生了胰岛素抵抗。这样就需要使用促泌剂和增敏剂。如磺酰脲类和格列奈类或格列酮类。这种促泌剂主要是通过刺激胰岛分泌胰岛素或增加组织对于胰岛素的敏感性，增加体内胰岛素水平以降低血糖。但这类药物的缺点是会造成病人的低血糖，血糖波动过大从而导致对器官的伤害。
第二类：DPP-4抑制剂即二肽基肽酶4抑制剂，该类药物能够抑制胰高血糖素样肽-1(GLP-1)和葡萄糖依赖性促胰岛素分泌多肽(GIP)的灭活，提高内源性GLP-1和GIP的水平，促进胰岛β细胞释放胰岛素，同时抑制胰岛α细胞分泌胰高血糖素，从而提高胰岛素水平，降低血糖。仅在人体血糖高于正常水平的情况下才会增加人体胰岛素的分泌，不会引起低血糖。但由于安全性和价格的原因，根据2010年中国糖尿病防治指南，DPP-4抑制剂仅是三线治疗药物。
GLP-1受体激动剂即胰高血糖素样肽-1激动剂，GLP-1是由肠道分泌，进食后分泌明显，它的增高会促进胰岛素的分泌，进而降低血糖。但这类药物临床应用时间短，价格昂贵，需注射用药，不推荐该药作为一线用药。
第三类：α-葡萄糖苷酶抑制剂，α-葡萄糖苷酶是一种能使不被吸收的复合碳水化合物分解成小肠可吸收的单糖,而葡萄糖苷酶抑制剂则通过抑制该酶作用,而延迟或减少餐后血糖升高。而这类药物适用范围较窄，一般用于单纯餐后血糖升高的患者，或与其他降糖药合用。
第四类：抑制SGLT-2活性，减少肾脏对葡萄糖的重吸收，增加尿糖排出，从而降低血糖。在为期12～78周的2-3期临床研究结果显示，在基线HbA1c 7.5％–9.2％的患者中，与安慰剂比较，该类药物仅可使HbA1c平均降低0.7％。
第五类：二甲双胍，二甲双胍作为糖尿病一线用药，除了降糖以外，还具有降低血脂，抗肿瘤，减轻体重的降糖外效应。虽然这些作用相对较弱，但目前二甲双胍仍是所有降糖药物中降糖外效应最多的药物。二甲双胍已经被证实是一种间接的AMPK激动剂。
发明内容
本发明的目的在于提供一种海兰地嗪或其药学上可接受的盐在制备抗糖尿病药物中的应用。
本发明的第一方面，提供了一种海兰地嗪或其药学上可接受的盐的用途，用于制备药物，所述药物用于预防和/或治疗糖尿病或糖尿病并发症。
在另一优选例中，所述药物用于选自下组的一种或多种应用：
(a)用于改善胰岛素耐受；
(b)促进胰岛素分泌；
(c)用于保护肾脏；
(d)用于降低血清总胆固醇；
(e)用于降低甘油三酯；
(f)用于降低尿蛋白；
(g)用于降低尿白蛋白比血清肌酐；
(h)用于降低血尿素氮
(i)用于上调肾脏SOD活性；
(j)用于上调肾脏CAT活性；
(k)用于下调肾脏MDA含量；
(l)用于预防视网膜病变；
(m)用于调节脂代谢。
在另一优选例中，所述药物包含：
组分i：海兰地嗪或其药学上可接受的盐；和
组分ii：药学上可接受的载体。
在另一优选例中，按所述药物的总重量计，海兰地嗪或其药学上可接受的盐的含量为0.01-99wt％，较佳地0.1-90wt％，更佳地1-80wt％。
在另一优选例中，所述药学上可接受的盐为选自下组的海兰地嗪的盐：酸式盐、碱式盐、或其组合；
所述酸式盐为海兰地嗪与选自下组的酸形成的盐：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸、没食子酸、脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸、或其组合；
所述碱式盐为海兰地嗪与碱形成的选自下组的盐：碱金属盐、碱土金属盐、铵盐、胺盐、或其组合。
在另一优选例中，所述药学上可接受的盐为海兰地嗪的选自下组的盐：盐酸盐、没食子酸盐、或其组合。
在另一优选例中，所述药学上可接受的盐为海兰地嗪的选自下组的盐：盐酸盐、氢溴酸盐、碳酸盐、硫酸盐、磷酸盐、硝酸盐、马来酸盐、富马酸盐、丁二酸盐、草酸盐、三氟乙酸盐、酒石酸盐、抗坏血酸盐、N-苯甲酰基甘氨酸盐、L-焦谷氨酸盐、L-脯氨酸盐、2-羟基乙磺酸盐、乙酸盐、苯甲酸盐、甘氨酸盐、赖氨酸盐、精氨酸盐、天冬氨酸盐、没食子酸盐、乳酸盐、乳清酸盐、苹果酸盐、柠檬酸盐、甲基磺酸盐、苯磺酸盐、对甲基苯磺酸盐、或其组合。
在另一优选例中，所述糖尿病并发症选自下组：高血糖、高血脂、高血压、糖尿病肾病、糖尿病性心肌病、糖尿病视网膜病变、糖尿病足、糖尿病心血管病变、或其组合。
在另一优选例中，所述糖尿病选自下组：I型糖尿病、II型糖尿病。
在另一优选例中，所述药物还包含：
组分iii：非海兰地嗪或其药学上可接受的盐的第二种预防和/或治疗糖尿病或糖尿病并发症的活性成分。
在另一优选例中，所述药物还包含选自下组的活性成分：胰岛素信号途径调节剂、影响肝葡萄糖产生调节异常的化合物、胰岛素敏感性增强剂、胰岛素分泌增强剂、或其组合。
在另一优选例中，所述药物还包含选自下组的活性成分：蛋白酪氨酸磷酸酶抑制剂、谷氨酰胺-果糖-6-磷酸转酰胺酶抑制剂、果糖-1，6二磷酸酶抑制剂、糖元磷酸化酶抑制剂、胰高血糖素受体拮抗剂、丙酮酸脱氢酶抑制剂、α-葡萄糖苷酶抑制剂、胃排空抑制剂、葡萄糖激酶活化剂、GLP-1受体激动剂、GLP-2受体激动剂、UCP调节剂、RXR调节剂、GSK-3抑制剂、PPAR调节剂、胰岛素和α2-肾上腺素能拮抗剂、或其组合。
在另一优选例中，所述药物还包含选自下组的活性成分：DPP-IV抑制剂、抗糖尿病的噻唑烷二酮类、非格列酮类PPARγ激动剂、双重PPARγ/PPARα激动剂、类视黄醇X受体激动剂、β-3AR激动剂、抗糖尿的双胍类、或其组合。
在另一优选例中，所述药物还包含选自下组的活性成分或其药学上可接受的盐：格列派特、格列苯脲、醋磺己脲、氯磺丙脲、格列波脲、甲苯磺丁脲、妥拉磺脲、格列吡嗪、氨磺丁脲、格列喹酮、格列己脲、苯磺丁脲、甲磺环己脲、格列美脲、格列齐特、或其组合。
在另一优选例中，所述药物还包含选自下组的活性成分或其药学上可接受的盐：阿卡波糖、伏格列波糖、米格列醇、或其组合。
在另一优选例中，所述药物还包含选自下组的活性成分或其药学上可接受的盐：西格列汀、维格列汀、沙格列汀、阿格列汀、利格列汀、曲格列汀、复格列汀、替格列汀、安奈格列汀、度格列汀、吉格列汀、伊格列汀、奥格列汀、或其组合。
在另一优选例中，所述药物还包含选自下组的活性成分或其药学上可接受的盐：瑞格列奈、米格列奈、那格列奈、或其组合。
在另一优选例中，所述药物还包含选自下组的活性成分或其药学上可接受的盐：胰岛素、普兰林肽、艾塞那肽、利拉鲁肽、利西拉来、阿必鲁肽、度拉鲁肽、利 司那肽、他司鲁肽、或其组合。
在另一优选例中，所述药物还包含选自下组的活性成分或其药学上可接受的盐：吡格列酮、罗格列酮、或其组合。
在另一优选例中，所述药物还包含选自下组的活性成分或其药学上可接受的盐：坎格列净、达格列净、恩格列净、依格列净、鲁格列净、托格列净、或其组合。
本发明的第二方面，提供了一种用于预防和/或治疗糖尿病或糖尿病并发症的药物组合物，包含：
组分i：预防和/或治疗有效量的海兰地嗪或其药学上可接受的盐；和
组分ii：药学上可接受的载体。
在另一优选例中，所述药学上可接受的盐为海兰地嗪的选自下组的盐：盐酸盐、氢溴酸盐、碳酸盐、硫酸盐、磷酸盐、硝酸盐、马来酸盐、富马酸盐、丁二酸盐、草酸盐、三氟乙酸盐、酒石酸盐、抗坏血酸盐、N-苯甲酰基甘氨酸盐、L-焦谷氨酸盐、L-脯氨酸盐、2-羟基乙磺酸盐、乙酸盐、苯甲酸盐、甘氨酸盐、赖氨酸盐、精氨酸盐、天冬氨酸盐、没食子酸盐、乳酸盐、乳清酸盐、苹果酸盐、柠檬酸盐、甲基磺酸盐、苯磺酸盐、对甲基苯磺酸盐、或其组合。
在另一优选例中，所述药学上可接受的盐为海兰地嗪的选自下组的盐：盐酸盐、没食子酸盐、或其组合。
本发明的第三方面，提供了一种预防和/或治疗糖尿病或糖尿病并发症的方法，包括步骤：向所需患者施用预防和/或治疗有效量的海兰地嗪或其药学上可接受的盐。
在另一优选例中，所述施用的施用量为5-30mg/kg，较佳地10-25mg/kg，更佳地15-25mg/kg。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1是实施例1ipGTT实验的实验结果。
图2是实施例1胰岛素释放实验的胰岛素释放曲线。
图3是实施例5中不同治疗情况的视网膜病变情况。
图4为不同治疗情况的油红染色的病理切片结果。
图5为不同治疗情况的HE染色的病理切片结果。
图6为不同治疗情况的PASM染色的病理切片结果。
图7为不同治疗情况的肾重体重比(左图)和心重体重比(右图)结果。
具体实施方式
本发明人经过长期而深入的研究，意外地发现海兰地嗪或其药学上可接受的盐可高效地治疗糖尿病或糖尿病并发症。在此基础上，发明人完成了本发明。
活性成分及其药学上可接受的盐
Figure PCTCN2020110030-appb-000001
海兰地嗪(Hernandezine)(D901)，结构式如式I所示，分子式为C 39H 44N 2O 7，分子量为652.79，是一种双苄基异喹啉生物碱。主要存在于毛莨科唐松草属植物中。药理研究表明，海兰地嗪具有多种生物活性，是一种高活性的天然多靶点药物。本发明将海兰地嗪应用于糖尿病的治疗，疗效明显优于临床1线药物二甲双胍。
如本文所用，术语“药学上可接受的盐”指海兰地嗪与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是海兰地嗪与酸形成的盐。适合形成盐的酸包括但并不限于：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸；甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸；以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是海兰地嗪与碱形成的盐，例如碱金属盐(例如钠盐或钾盐)、 碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐)，例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐，以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
用途
本发明通过动物实验，发现海兰地嗪或其药学上可接受的盐具有良好的抗糖尿病作用，通过动物实验证实海兰地嗪对糖尿病具有治疗作用，对糖尿病并发症具有治疗作用。
药物组合物
由于本发明化合物具有优异的抗糖尿病活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解与糖尿病相关的疾病。
术语“溶剂合物”指本发明化合物与溶剂分子配位形成特定比例的配合物。“水合物”是指本发明化合物与水进行配位形成的配合物。
此外，本发明化合物还包括海兰地嗪的前药。术语“前药”包括其本身可以是具有生物学活性的或非活性的，当用适当的方法服用后，其在人体内进行代谢或化学反应而转变成式I的一类化合物，或式I的一个化合物所组成的盐或溶液。所述的前药包括(但不局限于)所述化合物的羧酸酯、碳酸酯、磷酸酯、硝酸酯、硫酸酯、砜酯、亚砜酯、氨基化合物、氨基甲酸盐、偶氮化合物、磷酰胺、葡萄糖苷、醚、乙缩醛等形式。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-1000mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降 低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2020110030-appb-000002
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药，或者与其他药学上可接受的其他化合物(如抗糖尿病药物)联合给药。
本发明治疗方法可以单独施用，或者与其它治疗手段或者治疗药物联用。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
与现有技术相比，本发明具有以下主要优点：
(1)相比于糖尿病的临床1线药物二甲双胍，海兰地嗪或其药学上可接受的盐对糖尿病及糖尿病并发症具有更优异的治疗效果。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1 D901对db/db小鼠血糖及胰岛素敏感性的影响
6周龄db/db小鼠18只，分为溶剂对照组6只(Veh组)，药物高剂量组6只(D901 20组，即20mg/kg组)，药物低剂量组6只(D901 10组，即10mg/kg组)，dbm小鼠6只作为正常对照组。给药组羧甲基纤维素钠灌胃给药，对照组同时给予溶剂，给药8周。实验前禁食6小时，给予腹腔注射葡萄糖1g/Kg,截尾取血测定空腹血糖。分别截尾取血测定0分钟、20分钟、40分钟、60分钟、90分钟的血糖，实验期间不再进饮食。
图1是实施例1 ipGTT实验的实验结果。
从图1可知：药物组能明显降低糖尿病小鼠血糖，提高葡萄糖耐受能力。
胰岛素释放实验
实验前禁食6小时，给予腹腔注射胰岛素1U/Kg,截尾取血测定空腹血糖。分别截尾取血测定0分钟、30分钟、60分钟、120分钟的血糖，实验期间不再进饮食。
图2是实施例1胰岛素释放实验的胰岛素释放曲线。
从图2可知：药物组能明显使糖尿病小鼠胰岛素释放增加，提高胰岛素敏感性。
实施例2
D901(海兰地嗪)对大鼠肾重/体重比)(KW/BW)、糖化血红蛋白(GHb)、血清总胆固醇(TC)、血清甘油三酯(TG)的影响的对比实验。
酶分析法检测血清总胆固醇(TC)和血清甘油三酯(TG)、糖化血红蛋白使用TBA显色法测定，均按试剂盒说明书操作。
表1 实验8周后肾重/体重比，糖化血红蛋白，总胆固醇，甘油三酯的变化(x±s)
Figure PCTCN2020110030-appb-000003
Figure PCTCN2020110030-appb-000004
与正常组相比，*P<0.05；与糖尿病肾病组相比，#P<0.05
由表1可见，D901(10mg/kg)，D901(20mg/kg)，二甲双胍，缬沙坦组的KW/BW、GHb、TC及TG均降低(p<0.05)，且D901(10mg/kg)和D901(20mg/kg)比二甲双胍和缬沙坦显著降低肾重/体重比、血清总胆固醇及甘油三酯，D901(20mg/kg)显示出比二甲双胍更好的降糖效果。
实施例3
D901对大鼠24尿蛋白(UP)、尿微量白蛋白与肌酐比值(ACR)、尿素氮(BUN)的影响。
CBB显色法测定尿蛋白(urine Prorein,UP)，尿蛋白浓度与尿量乘积为24h尿蛋白量(24h UP)，溴甲酚绿法测定尿白蛋白(ALB)肌氨酸氧化酶法测定血清肌酐(SCr)，二乙酰釫法测定血尿素氮(BUN)，均按试剂盒说明书操作。
表2 实验8周后24h尿蛋白，尿白蛋白比血清肌酐，血尿素氮的水平变化(x±s)
Figure PCTCN2020110030-appb-000005
与正常组相比，*P<0.05；与糖尿病肾病组相比，#P<0.05
由表2可见，糖尿病肾病组大鼠24h尿蛋白、尿白蛋白比血清肌酐及血尿素氮与正常组大鼠相比显著增高,D901(10mg/kg)、D901(20mg/kg)、二甲双胍和缬沙坦均能不同程度的下调24h尿蛋白、尿白蛋白比血清肌酐及血尿素氮，且D901(10mg/kg)和D901(20mg/kg)下调24h尿蛋白、尿白蛋白比血清肌酐及血尿素氮的作用比二甲双胍和缬沙坦更显著，提示D901(10mg/kg)及D901(20mg/kg)具有肾脏保护作用。
实施例4
D901对大鼠丙二醛(MDA)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT) 的影响。
TBA显色法测定丙二醛，WST-8法测定超氧化物歧化酶，可见光法测定过氧化氢酶，所有操作均按照试剂盒说明书测定。
表3 实验8周后各组大鼠氧化应激水平的比较(x±s)
组别 鼠数 MDA(nmol/mg prot) SOD(U/mg prot) CAT(U/mg prot)
正常组 6 0.67±0.16 9.62±1.66 57.90±6.95
糖尿病肾病组 6 1.62±0.32 * 4.88±0.74 * 40.36±3.78 *
D901(10mg/kg)组 6 0.92±0.11 # 8.72±1.08 # 54.06±11.77 #
D901(20mg/kg)组 6 0.68±0.18 # 7.76±1.39 # 56.75±4.79 #
二甲双胍(20mg/kg)组 6 1.00±0.48 # 8.34±2.09 45.85±7.88 #
缬沙坦(20mg/kg)组 6 1.56±0.50 6.79±1.46 48.38±10.41
与正常组相比，*P<0.05；与糖尿病肾病组相比，#P<0.05。
由表3可见，糖尿病肾病大鼠肾脏SOD、CAT活性与正常组相比降低(P<0.05)，D901(10mg/kg)、D901(20mg/kg)、二甲双胍和缬沙坦均能不同程度的上调大鼠肾脏SOD、CAT的活性，且D901(10mg/kg)、D901(20mg/kg)上调大鼠肾脏CAT的活性较二甲双胍和缬沙坦更显著(P<0.05)；而糖尿病肾病组大鼠肾脏MDA含量较正常组相比显著升高(P<0.05)，D901(10mg/kg)、D901(20mg/kg)、二甲双胍和缬沙坦均能下调糖尿病大鼠肾脏MDA含量，尤其以D901(10mg/kg)和D901(20mg/kg)的作用更明显(P<0.05)，说明D901(10mg/kg)和D901(20mg/kg)均具有抗氧化应激的作用，从而减轻或延缓糖尿病肾病的发生发展，而且D901(20mg/kg)的作用明显强于D901(10mg/kg)。
实施例5
预防视网膜病变：以STZ诱导的2型糖尿病Wistar大鼠为研究对象，设D901低剂量组(10mg/kg)、D901高剂量组(20mg/kg)、二甲双胍组(20mg/kg)、缬沙坦组(20mg/kg)、模型组和正常组，每组8-10只大鼠，口服给药8周。视网膜病变情况如图3所示。
从图3可以看出，药物高剂量组(D901 20mg/kg)未见视网膜病变，可见药物可以有效预防视网膜病变。
实施例6
图4为不同治疗情况的油红染色的病理切片结果。
从图4可知：D901对于糖尿病小鼠的肝脏油脂染色表明，D901能明显调节脂 代谢。
图5为不同治疗情况的HE染色的病理切片结果。
从图5可以看出，糖尿病肾病大鼠的肾组织肾小球系膜轻度增生，显示D901减轻了糖尿病大鼠肾小球基底膜增厚，且有显示出一定的剂量依赖。与缬沙坦大鼠相比，D901组对足细胞增多的改善作用明显优于缬沙坦组。
图6为不同治疗情况的PASM染色的病理切片结果。
与正常大鼠肾组织PASM染色相比，从图6可以观察到糖尿病肾病大鼠肾小球基底膜增厚，系膜区增宽，基质增多，Kimmelstiel-Wilson(K-W)结节形成以及肾小球的纤维化，双胍组肾小球系膜中度增生，肾小囊内出现滴状病变，证实二甲双胍对肾组织的病变无明显的改善作用，而D901与缬沙坦相比，缬沙坦组肾间质出现嗜酸性粒细胞浸润情况较D901组更为严重，证实了D901的肾保护作用，且有一定的剂量依赖性。
实施例7
脏器系数
脏器系数是毒理实验中常用的指标。心重体重比和肾重体重比可以反应药物对心脏和肾脏的作用情况。
图7为不同治疗情况的肾重体重比(左图)和心重体重比(右图)结果。
通过图7中各组大鼠的肾重体重比(KW/BW)可以看出，D901能够降低糖尿病大鼠的肾重体重比，具有肾保护作用。心重体重比表明，D901组的糖尿病大鼠比值低于模型组和二甲双胍组。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种海兰地嗪或其药学上可接受的盐的用途，其特征在于，用于制备药物，所述药物用于预防和/或治疗糖尿病或糖尿病并发症。
  2. 如权利要求1所述的用途，其特征在于，所述药物用于选自下组的一种或多种应用：
    (a)用于改善胰岛素耐受；
    (b)促进胰岛素分泌；
    (c)用于保护肾脏；
    (d)用于降低血清总胆固醇；
    (e)用于降低甘油三酯；
    (f)用于降低尿蛋白；
    (g)用于降低尿白蛋白比血清肌酐；
    (h)用于降低血尿素氮
    (i)用于上调肾脏SOD活性；
    (j)用于上调肾脏CAT活性；
    (k)用于下调肾脏MDA含量；
    (l)用于预防视网膜病变；
    (m)用于调节脂代谢。
  3. 如权利要求1所述的用途，其特征在于，所述药物包含：
    组分i：海兰地嗪或其药学上可接受的盐；和
    组分ii：药学上可接受的载体。
  4. 如权利要求3所述的用途，其特征在于，按所述药物的总重量计，海兰地嗪或其药学上可接受的盐的含量为0.01-99wt％，较佳地0.1-90wt％，更佳地1-80wt％。
  5. 如权利要求1所述的用途，其特征在于，所述药学上可接受的盐为选自下组的海兰地嗪的盐：酸式盐、碱式盐、或其组合；
    所述酸式盐为海兰地嗪与选自下组的酸形成的盐：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸、没食子酸、脯氨酸、苯丙氨酸、天冬氨酸、谷氨 酸、或其组合；
    所述碱式盐为海兰地嗪与碱形成的选自下组的盐：碱金属盐、碱土金属盐、铵盐、胺盐、或其组合。
  6. 如权利要求1所述的用途，其特征在于，所述糖尿病并发症选自下组：高血糖、高血脂、高血压、糖尿病肾病、糖尿病性心肌病、糖尿病视网膜病变、糖尿病足、糖尿病心血管病变、或其组合。
  7. 如权利要求3所述的用途，其特征在于，所述药物还包含：
    组分iii：非海兰地嗪或其药学上可接受的盐的第二种预防和/或治疗糖尿病或糖尿病并发症的活性成分。
  8. 一种用于预防和/或治疗糖尿病或糖尿病并发症的药物组合物，其特征在于，包含：
    组分i：预防和/或治疗有效量的海兰地嗪或其药学上可接受的盐；和
    组分ii：药学上可接受的载体。
  9. 如权利要求8所述的药物组合物，其特征在于，所述药学上可接受的盐为海兰地嗪的选自下组的盐：盐酸盐、氢溴酸盐、碳酸盐、硫酸盐、磷酸盐、硝酸盐、马来酸盐、富马酸盐、丁二酸盐、草酸盐、三氟乙酸盐、酒石酸盐、抗坏血酸盐、N-苯甲酰基甘氨酸盐、L-焦谷氨酸盐、L-脯氨酸盐、2-羟基乙磺酸盐、乙酸盐、苯甲酸盐、甘氨酸盐、赖氨酸盐、精氨酸盐、天冬氨酸盐、没食子酸盐、乳酸盐、乳清酸盐、苹果酸盐、柠檬酸盐、甲基磺酸盐、苯磺酸盐、对甲基苯磺酸盐、或其组合。
  10. 如权利要求8所述的药物组合物，其特征在于，所述药学上可接受的盐为海兰地嗪的选自下组的盐：盐酸盐、没食子酸盐、或其组合。
PCT/CN2020/110030 2019-08-23 2020-08-19 海兰地嗪或其药学上可接受的盐在糖尿病或糖尿病并发症药物中的应用 Ceased WO2021036884A1 (zh)

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