阅读说明：本技术 鼠尾草酸或其衍生物在制备治疗糖尿病并发症药物中的应用 (Application of carnosic acid or derivatives thereof in preparing medicine for treating diabetic complications ) 是由 周应军 曹伟 邓旭 李元建 曾光尧 于 2020-07-23 设计创作，主要内容包括：本发明公开了鼠尾草酸及其衍生物在制备治疗糖尿病并发症的药物中的应用,所述鼠尾草酸及其衍生物包括如通式I所示的化合物或其药学上可接受的盐中的至少一种：<Image he="544" wi="551" file="DDA0002598135090000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R<Sup>1</Sup>选自甲基,羟甲基、羧基,酯基或酰胺；R<Sup>2</Sup>、R<Sup>3</Sup>分别选自氢或烷基。鼠尾草酸及其衍生物在治疗糖尿病并发症有很好的疗效,尤其适用于糖尿病心肌病和糖尿病血管损伤的治疗；且鼠尾草酸及其衍生物在迷迭香等植物中大量存在,且易于通过半合成、合成方式得到,价格便宜,本发明扩大了鼠尾草酸的应用范围,也为糖尿病并发症提供了新的治疗途径。(The invention discloses application of carnosic acid and derivatives thereof in preparing a medicament for treating diabetic complications, wherein the carnosic acid and the derivatives thereof comprise at least one of compounds shown as a general formula I or pharmaceutically acceptable salts thereof: wherein R is 1 Selected from methyl, hydroxymethyl, carboxyl, ester group or amide; r 2 、R 3 Are independently selected from hydrogen or alkyl. Carnosic acid and its derivatives have good therapeutic effect in treating diabetic complications, and are especially suitable for treating diabetic cardiomyopathy and diabetic vascular injury; in addition, carnosic acid and its derivatives are abundant in rosemary, and can be easily semi-synthesized and synthesizedThe invention enlarges the application range of carnosic acid and provides a new treatment way for diabetic complications.)

1. Use of carnosic acid or a derivative thereof in the manufacture of a medicament for the treatment of diabetic complications, said carnosic acid or derivative thereof being selected from the group consisting of compounds represented by formula I:

wherein R is¹Selected from methyl, hydroxymethyl, carboxyl, ester group or amide;

R²、R³are independently selected from hydrogen or alkyl.

2. The use according to claim 1, wherein the diabetic complication is diabetic cardiomyopathy and/or diabetic vascular injury.

3. Use according to claim 1 or 2, wherein the pharmaceutically acceptable salt is a salt of an alkali metal, an alkaline earth metal or a basic amino acid.

4. The use according to claim 1 or 2, wherein the medicament further comprises a pharmaceutically acceptable carrier.

5. Use according to claim 1 or 2, wherein the carnosic acid and derivatives thereof are present in an amount of 0.1 to 99 wt%; preferably, the content is 0.5-95 wt%; more preferably, the content is 10 to 20 wt%.

6. The use according to claim 1 or 2, wherein the medicament is in a dosage form selected from the group consisting of tablets, capsules, soft capsules, granules, pills, oral liquids, dry suspensions, drop pills, dry extracts, injections and infusions.

7. A pharmaceutical composition for the treatment of diabetic complications comprising carnosic acid or derivatives thereof and one or more antidiabetic agents.

8. The pharmaceutical composition of claim 7, wherein the anti-diabetic drug is a biguanide hypoglycemic agent; preferably, the antidiabetic agent is metformin.

9. The pharmaceutical composition of claim 7, wherein the weight ratio of carnosic acid or derivative thereof to the antidiabetic agent is 1: 1-10; preferably, the weight ratio of the carnosic acid or the derivative thereof to the antidiabetic drug is 1: 3-8; more preferably, the weight ratio of carnosic acid or a derivative thereof to the antidiabetic agent is 1: 4 to 6.

10. A kit for treating diabetic complications, the kit comprising: a preparation containing carnosic acid or a derivative thereof; wherein, the content of the carnosic acid or the derivatives thereof in the medicine box is prepared according to the daily dosage standard of 0.1-1000 mg/day.

Technical Field

The invention relates to the field of biological medicines, in particular to application of carnosic acid or derivatives thereof in preparing a medicine for treating diabetic complications.

Background

Diabetes is a group of clinical syndromes caused by genetic and environmental factors, and is mainly characterized by chronic hyperglycemia, and mainly clinically manifested by polyphagia, polydipsia, polyuria, weight loss and the like. The current data show that the number of people suffering from diabetes is on a rapidly increasing trend. Diabetes is largely divided into two categories, type 1 diabetes and type 2 diabetes. Among them, type 2 diabetes accounts for about more than 95% of the total population with diabetes. Type 2 diabetes is a group of complex metabolic disorders, the pathogenesis of which is only partially known, and which are clinically characterized by chronic elevation of blood glucose levels, insulin antagonism, excessive hepatic glucose production, and glucose-induced attenuation of insulin secretion in beta cells, among others (Nathan, d.m., n.eng.j.med.2002, 347, 1342) (Ross, s.a., Gulve, e.a., Wang, m.h., chem.rev., 2004, 104, 1255). Abnormal blood sugar level has a large negative effect on the glutathione level of a reducing substance of related tissues, so that oxidative stress and reactive oxygen species are increased, and further a series of serious complications including diabetic nephropathy, diabetic eye diseases, diabetic feet and the like are caused, and the complications become the third killer threatening to human health after cardiovascular diseases and malignant tumors. The traditional insulin treatment and urea and thiazolinone antidiabetic drugs have the problems of serious side effects or poor effects and the like in the aspect of treating diabetes, especially complications thereof, so that the current forms of preventing and treating diabetes and complications thereof are very severe, and a new antidiabetic complication drug is urgently needed to be searched.

Diabetic complications include damage to vascular complications caused by hyperglycemia, Diabetic Cardiomyopathy (DCM), which is characterized by ventricular insufficiency, and the like, and as the condition progresses, the patient may develop heart failure, thereby threatening the patient's health.

Carnosic acid is a rosin alkyl diesterTerpenoid components, which were first isolated from sage (salviaofcinalis L.) by Linde et al in 1965, have a typical tricyclic structure including a highly electron-rich catechol unit, are highly lipid-soluble and easily oxidized. Carnosic acid has the following structural formula:

carnosic acid has been found to have a wide range of pharmacological activities, however, the use of carnosic acid and its derivatives in the preparation of dietary or pharmaceutical compositions for the treatment of diabetic complications such as diabetic cardiomyopathy or vascular injury has not been reported.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art. Therefore, the invention provides the application of the carnosic acid or the derivatives thereof in preparing the medicine for treating the diabetic complications, and the treatment of the diabetic complications is effectively realized.

The invention also provides a pharmaceutical composition for treating diabetic complications.

The invention also provides a medicine box for treating diabetic complications.

According to an embodiment of the first aspect of the invention, the carnosic acid or derivative thereof is selected from at least one compound represented by formula I or a pharmaceutically acceptable salt thereof:

wherein R is¹Selected from methyl, hydroxymethyl, carboxyl, ester group or amide;

R²、R³are independently selected from hydrogen or alkyl.

The application of the embodiment of the invention has at least the following beneficial effects: the carnosic acid and the derivatives thereof have good curative effect on the diabetic complications, and the carnosic acid and the derivatives thereof exist in a large amount in rosemary and other plants, are easy to obtain by semisynthesis and synthesis modes, and have low price.

According to some embodiments of the invention, the diabetic complication is diabetic cardiomyopathy and/or diabetic vascular injury. The diabetic rat experiment proves that the carnosic acid and the derivative of the carnosic acid have certain protective effect on the vascular injury and myocardial fibrosis of the diabetic rat. In the invention, the evaluation of the protective activity of carnosic acid on cardiac muscle and blood vessel on a diabetic rat model shows that the carnosic acid has protective effect on the vascular injury and vascular collagen deposition of diabetic rats under the conditions of low dose (25mg/Kg) and high dose (50mg/Kg), and has stronger protective effect on the myocardial fibrosis of diabetic rats, and the human clinical test proves that the carnosic acid has good effect on the treatment of cardiomyopathy of diabetic patients and no adverse reaction.

According to some embodiments of the invention, the pharmaceutically acceptable salt is a salt of an alkali metal, an alkaline earth metal or a basic amino acid.

Further, the alkali metal is one of lithium, sodium and potassium; the alkaline earth metal is calcium or magnesium; the basic amino acid is lysine and the like.

According to some embodiments of the invention, the medicament further comprises a pharmaceutically acceptable carrier.

Further, the pharmaceutically acceptable carrier refers to a conventional pharmaceutical carrier in the pharmaceutical field, and can be any suitable physiologically or pharmaceutically acceptable pharmaceutical adjuvant; preferably, the pharmaceutical excipient is selected from at least one of a disintegrant, a diluent, a lubricant, a binder, a wetting agent, a flavoring agent, a suspending agent, a surfactant, or a preservative; more preferably, the disintegrant is selected from at least one of corn starch, potato starch, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, carboxymethylcellulose calcium, or alginic acid; more preferably, the diluent is selected from at least one of lactose, sucrose, mannitol, corn starch, potato starch, calcium phosphate, calcium citrate or crystalline cellulose; more preferably, the lubricant is selected from at least one of aerosil, magnesium stearate, calcium stearate, stearic acid, talc or anhydrous silica gel; more preferably, the binder is selected from at least one of acacia, gelatin, dextrin, hydroxypropyl cellulose, methyl cellulose or polyvinylpyrrolidone; more preferably, the wetting agent is selected from sodium lauryl sulfate; more preferably, the flavoring agent may be at least one of aspartame, stevioside, sucrose, maltitol, or citric acid; more preferably, the suspending agent is selected from at least one of acacia, gelatin, methylcellulose, sodium carboxymethylcellulose, hydroxymethylcellulose, or aluminum stearate gel; more preferably, the surfactant is selected from at least one of lecithin, sorbitan monooleate, or glyceryl monostearate; more preferably, the preservative is selected from at least one of methyl paraben or propyl paraben.

According to some embodiments of the invention, the carnosic acid and derivatives thereof are present in the medicament in an amount of 0.1 to 99 wt%; preferably, the content is 0.5-95 wt%; more preferably, the content is 10 to 20 wt%.

According to some embodiments of the invention, the pharmaceutical formulation is selected from the group consisting of tablets, capsules, soft capsules, granules, pills, oral liquids, dry suspensions, drop pills, dry extracts, injections and infusions.

According to some embodiments of the present invention, there is provided a carnosic acid tablet for treating diabetic complications, comprising the following components: carnosic acid, sodium carboxymethylcellulose, starch, microcrystalline cellulose and lactose; wherein the mass ratio of carnosic acid is 10-20%; preferably, the mass ratio of carnosic acid is 10%. The carnosic acid tablet is used for treating diabetic cardiomyopathy in human body clinical tests, can improve the cardiac function of a patient with DCM, can reduce the level of serum inflammatory factors, and has a more positive effect on accelerating the recovery of the patient.

A pharmaceutical composition according to an embodiment of the second aspect of the invention comprises carnosic acid or a derivative thereof, and further comprises one or more antidiabetic agents.

In the present invention, the antidiabetic agents include insulin secretion promoters (classified into sulfonylurea insulin secretagogues including glipizide, gliclazide, glimepiride and gliquidone, and non-sulfonylurea insulin secretagogues including repaglinide and nateglinide, etc.), biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose, voglibose and miglitol), insulin sensitizers (e.g., rosiglitazone and pioglitazone), SGLT2 inhibitors and dipeptidyl peptidase-4 inhibitors.

According to some embodiments of the invention, the antidiabetic agent is a biguanide hypoglycemic agent; preferably, the antidiabetic agent is metformin.

According to some embodiments of the invention, the weight ratio of carnosic acid or derivative thereof to the antidiabetic agent is 1: 1-10; preferably, the weight ratio of the carnosic acid or the derivative thereof to the antidiabetic drug is 1: 3-8; more preferably, the weight ratio of carnosic acid or a derivative thereof to the antidiabetic agent is 1: 4 to 6.

According to a third aspect of the invention, an embodiment of the kit comprises: a preparation containing carnosic acid or a derivative thereof; wherein, the content of the carnosic acid or the derivatives thereof in the medicine box is prepared according to the daily dosage standard of 0.1-1000 mg/day.

According to some embodiments of the invention, the amount of carnosic acid or derivative thereof in the kit is formulated according to a daily dosage standard of 10 to 500 mg/day.

Furthermore, the content of the carnosic acid or the derivative thereof in the kit is prepared according to the daily dosage standard of 50-200 mg/day.

Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.

Drawings

FIG. 1 shows HE staining (400X) of blood vessels of diabetic rats in Experimental example 1 of the present invention;

FIG. 2 shows HE staining (200X) of diabetic rat myocardium in Experimental example 1 of the present invention;

FIG. 3 shows Masson staining (400X) of blood vessels of diabetic rats in test example 1 of the present invention;

FIG. 4 shows Masson staining (200X) of the myocardium of diabetic rats in test example 1 of the present invention.

Detailed Description

In order to explain technical contents, achieved objects, and effects of the present invention in detail, the following description is made with reference to the accompanying drawings in combination with the embodiments. The test methods used in the examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are commercially available reagents and materials unless otherwise specified.

The formula of carnosic acid in the embodiment of the invention is as follows:

purchased from pharmaceutical limited of today's Chinese in Hunan province.