阅读说明：本技术 一种含有多扎格列艾汀与西格列汀的药物组合物及其制备方法 (Pharmaceutical composition containing doxagliptin and sitagliptin and preparation method thereof ) 是由 章燕 杨贵方 肖文礼 于 2021-08-31 设计创作，主要内容包括：本发明公开了一种含有多扎格列艾汀与西格列汀的药物组合物及其制备方法。含有多扎格列艾汀与西格列汀的药物组合物是通过自主合成的多扎格列艾汀搭配西格列汀、崩解剂和分散剂经过混合,压片、灭菌等步骤制备的。本发明所提供的一种含有多扎格列艾汀和西格列汀的药品组合物具有显著的降低血糖的药物效果,同时稳定性高,无毒副作用,降低了患者在服用过程中发生低血糖的概率。本发明适用于含有多扎格列艾汀和西格列汀的药品组合物的制备,用于安全、有效地降低II型糖尿病人的血糖浓度。(The invention discloses a pharmaceutical composition containing doxagliptin and sitagliptin and a preparation method thereof. The pharmaceutical composition containing the doxagliptin and the sitagliptin is prepared by mixing the self-synthesized doxagliptin with the sitagliptin, a disintegrating agent and a dispersing agent, tabletting, sterilizing and the like. The pharmaceutical composition containing the doxagliptin and the sitagliptin provided by the invention has a remarkable medicine effect of reducing blood sugar, is high in stability and free of toxic and side effects, and reduces the probability of blood sugar reduction of a patient in the taking process. The invention is suitable for preparing the medicine composition containing the doxagliptin and the sitagliptin and is used for safely and effectively reducing the blood sugar concentration of the type II diabetes mellitus patients.)

1. A pharmaceutical composition characterized by: the raw materials for preparing the effective components of the medicine comprise: the composition comprises the components of doxagliptin, sitagliptin, a disintegrating agent and a dispersing agent.

2. The pharmaceutical composition of claim 1, wherein: the weight ratio of the doragagliptin to the sitagliptin to the disintegrant to the dispersant is 15-42: 35-50: 3-8: 1 to 3.

3. The pharmaceutical composition of claim 1, wherein: the disintegrant is at least one of carboxymethyl starch, crospovidone and croscarmellose sodium; the dispersant is talcum powder.

4. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 3, characterized in that: the preparation method comprises the following steps:

s1, synthesizing the polyazagliptin;

s2, adding sitagliptin and a dispersing agent into the organic solvent, uniformly mixing, concentrating and drying to obtain a mixed material A;

s3, weighing a disintegrating agent, adding the disintegrating agent into the mixed material A, mixing by a dry method, and sterilizing to obtain a mixed material B;

s4, putting the mixed material B into a tabletting machine, and tabletting to obtain the medicinal composition.

5. The production method according to claim 4, characterized in that: the organic solvent is one of ethanol, dichloromethane and ethyl acetate.

6. The production method according to claim 4, characterized in that: the synthetic method of the doragliptin comprises the following steps of:

t1, adding the compounds shown in the formula SM1 and the formula SM2 into dichloromethane, uniformly mixing, adding anhydrous magnesium sulfate, stirring for 5min, adding HATU and sodium carbonate, uniformly mixing, raising the temperature of a system for reaction, after the reaction is finished, filtering and concentrating the filtrate to be dry, and cooling to obtain the compound shown in the formula SM 3;

t2, adding compounds shown as a formula SM3 and a formula SM4 into ethanol, uniformly mixing, adding potassium carbonate and cuprous iodide, carrying out etherification reaction, and obtaining a compound shown as a formula SM5 after the reaction is finished, namely the polyazeliptin, wherein the reaction formula is as follows:

7. the method of claim 6, wherein: the molar ratio of the compound represented by formula SM1 to the compound represented by formula SM2 is 1: 0.8 to 1.4; the molar ratio of the compound shown as the formula SM3 to the compound shown as the formula SM4 is 1: 2-3.

8. The method of claim 6, wherein: the reaction temperature of the T1 is 40-60 ℃, and the reaction time is 2-4 h.

9. The method of claim 6, wherein: the reaction temperature of the etherification reaction is 15-30 ℃, and the reaction time is 6-15 h.

10. A use of a pharmaceutical composition according to any one of claims 1 to 3, wherein: the medicine composition is used for regulating the blood sugar concentration of a human body and improving the function of beta cells.

Technical Field

The invention belongs to the field of drug synthesis, and relates to a drug composition for improving type II diabetes, in particular to a drug composition containing doxagliptin and sitagliptin and a preparation method thereof.

Background

Type II diabetes (diabetes mellitus type 2, T2DM), known as noninsulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes (adult-dependent diabetes mellitus), is a chronic metabolic disease that develops after 35 to 40 years of age, accounting for more than 90% of diabetic patients. Patients are characterized by hyperglycemia, relative insulin deficiency, insulin resistance, and the like. Common symptoms are polydipsia, pollakiuria, weight loss of unknown origin, and may also include polyphagia, fatigue, or soreness. Long-term complications from hyperglycemia include heart disease, stroke, diabetic retinopathy, which can lead to blindness, kidney failure, and even poor blood flow in the extremities requiring amputation, with few complications of diabetic ketoacidosis.

The current oral diabetes drugs comprise biguanides, sulfonylureas, thiazolidinediones, DPP-4 receptor inhibitors, SGLT-2 receptor inhibitors, GLP-1 analogues and other synthetic drugs, wherein the DPP-4 receptor inhibitors are a drug variety which is effective in oral administration and has good market prospect, and the representative compound is sitagliptin.

Sitagliptin (Sitagliptin), the first dipeptidyl peptidase-IV (DPP-IV) inhibitor for treating type II diabetes, is usually administered in the form of phosphate. Although sitagliptin can prevent and treat type II diabetes, hyperglycemia, insulin resistance, obesity and hypertension and other diabetic complications. However, the sole use of sitagliptin phosphate causes slow disintegration rate and insufficient long-acting property of the drug due to the limitation of the existing preparation process, so that the action time of the drug in a human body is short, the drug administration interval is shortened, the aim of controlling blood sugar can be achieved only by repeatedly administering the drug in a short time, and the action effect of the drug is indirectly reduced.

Although the compound medicine improves the situation, the toxic and side effects of the medicine compounded with the compound medicine are introduced, for example, the effect of the medicine is improved when the sitagliptin and the metformin are mixed in the sitagliptin, but the toxic and side effects of the metformin are larger, and the safety of the medicine is reduced.

Disclosure of Invention

In order to solve the defects in the prior art, the invention aims to provide a medicinal composition containing the doxagliptin and the sitagliptin so as to achieve the purposes of improving the disintegration rate of the effective ingredients of the medicament, improving the safety of the medicament and improving the action effect of the medicament.

In order to achieve the purpose, the technical scheme adopted by the invention is as follows:

a pharmaceutical composition comprises the following raw materials as active ingredients: the composition comprises dorxagliptin, sitagliptin, a disintegrating agent and a dispersing agent;

the weight ratio of the doxagliptin, the sitagliptin, the disintegrant and the dispersant is 15-42: 35-50: 3-8: 1-3;

as another limitation of the present invention, the disintegrant is at least one of carboxymethyl starch, crospovidone, and croscarmellose sodium; the dispersing agent is talcum powder;

the invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps:

s1, synthesizing the polyazagliptin;

s2, uniformly mixing the polyagliptin, sitagliptin and the dispersing agent in an organic solvent, concentrating and drying to obtain a mixed material A;

s3, weighing a disintegrating agent, adding the disintegrating agent into the mixed material A, mixing by a dry method, and sterilizing to obtain a mixed material B;

s4, putting the mixed material B into a tablet press, and performing tabletting treatment to obtain the medicinal composition;

as a third limitation of the present invention, the method for synthesizing doxagliptin comprises the following steps:

t1, adding the compounds shown in the formula SM1 and the formula SM2 into dichloromethane, uniformly mixing, adding anhydrous magnesium sulfate, stirring for 5min, adding HATU and sodium carbonate, uniformly mixing, raising the temperature of a system for reaction, after the reaction is finished, filtering and concentrating the filtrate to be dry, and cooling to obtain the compound shown in the formula SM 3;

t2, adding compounds shown as a formula SM3 and a formula SM3 into ethanol, uniformly mixing, adding potassium carbonate and cuprous iodide, carrying out etherification reaction, and obtaining a compound shown as a formula SM5 after the reaction is finished, namely the polyazeliptin, wherein the reaction formula is as follows:

as a further limitation of the present invention, the weight ratio of the compound of formula SM1 to the compound of formula SM2 is 1: 0.8 to 1.4; the weight ratio of the compound shown in the formula SM3 to the compound shown in the formula SM4 is 1: 2-3;

as a fourth limitation of the present invention, the reaction temperature of T1 is 40-60 ℃, and the reaction time is 2-4 h;

as a fifth limitation of the invention, the reaction temperature of the etherification reaction is 15 to 30 ℃, and the reaction time is 6 to 15 hours;

as a sixth limitation of the present invention, the organic solvent is one of ethanol, dichloromethane and ethyl acetate;

the invention also provides an application of the medicine composition, and the medicine composition is used for regulating the blood sugar concentration of a human body and improving the function of beta cells.

Due to the adoption of the technical scheme, compared with the prior art, the invention has the following beneficial effects:

(1) the doxagliptin in the pharmaceutical composition provided by the invention is a novel compound for preventing and treating type II diabetes, can effectively control the blood sugar concentration, obviously improves the beta cell function, has good safety and tolerance, and cannot cause hypoglycemia.

(2) The invention provides a method for synthesizing the doragliptin, which belongs to a new compound and needs high cost if being directly purchased, and the current selling price of the doragliptin is 5mg and 1270 yuan (extracted from www.chemicalbook.com).

(3) The pharmaceutical composition provided by the invention contains the multi-zagliptin and the sitagliptin, so that the specificity of the medicine is improved, the toxic and side effects caused by the combination of the sitagliptin and other compounds are avoided, meanwhile, the multi-zagliptin also has the effect of reducing blood sugar, and the medicine effect of the pharmaceutical composition can be obviously improved.

In conclusion, the pharmaceutical composition containing the doxagliptin and the sitagliptin provided by the invention has the remarkable effect of reducing blood sugar, is high in stability and free of toxic and side effects, and reduces the probability of blood sugar reduction of a patient in the taking process.

The invention is suitable for preparing the medicine composition containing the doxagliptin and the sitagliptin and is used for safely and effectively reducing the blood sugar concentration of the type II diabetes mellitus patients.

Detailed Description

The following description is given in conjunction with preferred embodiments of the present invention. It should be understood that the description of the preferred embodiment is only for purposes of illustration and understanding, and is not intended to limit the invention.

Example 1A preparation method of a pharmaceutical composition X1 containing Duzagliptin and sitagliptin

This example provides a process for the preparation of a pharmaceutical composition X1 comprising both dorxagliptin and sitagliptin, which comprises the steps of:

s1, synthesizing the doxagliptin

T1, respectively weighing 157g of a compound shown as a formula SM1 and 249g of a compound shown as a formula SM2, adding the 157g of the compound shown as the formula SM1 and the 249g of the compound shown as the formula SM2 into 500ml of dichloromethane, uniformly mixing, adding 100g of anhydrous magnesium sulfate, stirring for 5min, adding 570g of HATU (1.5eq) and 318g of sodium carbonate (3eq), uniformly mixing, heating to 40 ℃, preserving heat for reaction for 4h, monitoring the reaction progress by adopting TLC in the reaction process until fluorescence points of the compounds shown as the formula SM1 and the formula SM2 on a silica gel plate disappear, namely finishing the reaction, filtering after finishing the reaction, leaching a filter cake by using 300ml of ethyl acetate, collecting all filtrates, concentrating to be dry, cooling and obtaining 276.76g of the compound shown as a formula SM3 (the yield is 74%);

t2, adding 276.76g of compounds shown in formula SM3 and 216g of compounds shown in formula SM4 into 500ml of ethanol, uniformly mixing, adding 414g of potassium carbonate (3eq) and 380g of cuprous iodide (2eq), placing a reaction container in an environment at 20 ℃ for etherification reaction for 15h, taking a small amount of reaction liquid, adding acetonitrile for dilution, injecting into a high performance liquid chromatography, detecting according to the volume ratio of methanol to acetonitrile of 56:44, detecting that absorption peaks of the compounds shown in formula SM3 and formula SM4 disappear, and a new peak with the molecular weight of 480(M +18) appears on the left side of the spectrum, namely the reaction is finished, filtering the reaction liquid after the reaction is finished, leaching a filter cake with 500ml of ethanol, collecting filtrate, concentrating to dryness, adding 200ml of toluene, heating until the residual substances are completely dissolved, cooling to room temperature, adding 400ml of petroleum ether, placing into a refrigerator for cooling and crystallizing for 5h, filtering and drying to obtain 276.92g of dorgetin (the compounds shown in formula SM5, yield 81%, overall yield 59.94%), according to the following reaction scheme:

s2, weighing 276g of polyazagliptin, 243.14g of sitagliptin and 19.71g of talcum powder respectively, uniformly mixing in 1000ml of ethanol, concentrating, and drying to obtain 530g of mixed material A1;

s3, weighing 32.85g of carboxymethyl starch, adding into 530g of the mixed material A, mixing by a dry method, and sterilizing to obtain 560g of mixed material B1;

s4, 560g of the mixed material B1 is put into a tablet machine for tabletting, and after the tabletting treatment, the medicine composition X1 is obtained after sorting, sterilization and packaging.

The obtained medicinal composition X1 containing doxagliptin and sitagliptin can also be prepared by directly sterilizing and bottling mixture A1

Examples 2 to 6 methods for producing pharmaceutical compositions X2 to X6 containing both Dutagliptin and sitagliptin

Examples 2 to 6 provide methods for preparing pharmaceutical compositions X2 to X6 containing both docetaxel and sitagliptin, which are substantially the same as in example 1 except that some process parameters are different, and the specific process parameters are shown in table 1.

Table 1: preparation process table of medicine composition X2-X6 containing dorxagliptin and sitagliptin

The other process parameters were the same as in example 1.

Experimental example 1 repeated administration test

Randomly selecting 18 mice with similar physical signs, good health conditions and half sex for repeated administration tests, randomly dividing the 18 mice with half sex into three groups, wherein the first group is fed with a hypoglycemic drug containing single sitagliptin, the second group is fed with a pharmaceutical composition containing sitagliptin and metformin, and the third group is fed with the pharmaceutical composition containing the multi-zagliptin and sitagliptin X3 prepared in example 3;

the three groups of experiments are all orally administrated, the administration is carried out according to the specification of 2mg/kg every day when the experiment is started, the administration dosage is increased after 3 weeks, the administration is changed into the administration according to the specification of 10mg/kg, after the experiment is fed for 3 weeks again, the dosage of the medicine is increased to 50mg/kg, the administration is continued for 3 weeks, the dosage without adverse reaction in the experiment is 10mg/kg, the dosage level is about 6 times of the exposure amount of a human body according to the recommended daily dosage of 100mg for adults. When the feeding amount was increased to 50mg/kg, the mice in all three groups exhibited transient drug-related signs including mouth-breathing, salivation, vomiting of white foam, ataxia, tremors, decreased activity and/or dorsiflexion. In 4-9 weeks of toxicity test, the histological examination results of the second group of mice indicate mild skeletal muscle degeneration, and the other two mice have no skeletal muscle degeneration. That is, pharmaceutical compositions containing both dorxagliptin and sitagliptin were demonstrated to have the same drug toxicity as sitagliptin.

Experimental example 2 drug effect comparative experiment

Randomly selecting 24 mice with similar signs, good health conditions and male and female halves for repeated administration experiments, destroying islet beta cells by utilizing alloxan to induce animal hyperglycemia, establishing a type II diabetes model, randomly dividing 18 mice in male and female halves into three groups, feeding the first group with jiranov (Meishaodong pharmaceutical Co., Ltd., Hangzhou, specification 100mg X7 s), feeding the second group with jiranoda (Pateon Puerto Rico Inc., specification 50mg X28 s), feeding the third group with the pharmaceutical composition X1 containing multi-zagliptin and sitagliptin prepared in example 1, and feeding the fourth group as a blank, wherein the fourth group is not normally fed with the pharmaceutical composition.

All groups were fed for one month and fasting blood glucose measurements were performed every other week on all mice and the average fasting blood glucose concentration was calculated and the results are shown in table 2.

Table 2: drug effect comparison test result table

The result shows that the medicine composition X1 prepared in the example 1 has obvious blood sugar reducing effect, the blood sugar concentration of normal mice is 16-176 mmol/L, the blood sugar of other groups is reduced but still has high blood sugar value after being fed with the medicine composition X1 prepared in the example 1 after one month, and therefore the medicine composition containing the polyagliptin and the sitagliptin provided by the invention has good medicine effect.

Although the present invention has been described in detail with reference to the above embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described above, or equivalents may be substituted for elements thereof. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.