CN113069438A

CN113069438A - Pharmaceutical composition containing metformin and bupropion and application thereof

Info

Publication number: CN113069438A
Application number: CN202110353041.9A
Authority: CN
Inventors: 刘冠; 闫晓娜; 金鑫
Original assignee: Shenyang Xinrui Pharmaceutical Co ltd
Current assignee: Shenyang Xinrui Pharmaceutical Co ltd
Priority date: 2021-04-01
Filing date: 2021-04-01
Publication date: 2021-07-06

Abstract

The invention relates to a pharmaceutical composition containing metformin and bupropion and application thereof. Compared with the single drug of metformin, the drug composition has stronger curative effect and higher safety. The composition can be used for lowering blood sugar, treating diabetes, preventing diabetic complications and reducing weight.

Description

Pharmaceutical composition containing metformin and bupropion and application thereof

Technical Field

The invention relates to the field of medicines, in particular to a pharmaceutical composition containing metformin and bupropion and application thereof.

Background

Metformin has been on the market for about 60 years, is an oral hypoglycemic medicament which is most widely applied clinically at present, and is in the first-line medication position in various type-2 diabetes mellitus prevention and treatment guidelines. Compared with other oral hypoglycemic drugs, the hypoglycemic drug has definite hypoglycemic effect, low risk of hypoglycemia occurrence and low price. Metformin can promote the utilization of glucose by peripheral tissues, inhibit the generation of glycogen, increase anaerobic glycolysis, improve insulin resistance and increase the sensitivity of organisms to insulin. In addition, studies have shown that metformin also contributes to weight management and is therefore particularly useful in obese diabetic patients, as well as in obese patients for weight loss.

Bupropion belongs to the family of aminoketone antidepressants, marketed in the united states in 1989, and is currently widely used in the treatment of depression and smoking cessation. Its chemical structure and mechanism of action are different from other antidepressants, and has high clinical remission rate for patients with SSRI resistance, and no adverse reactions such as weight gain, sexual dysfunction and excessive sedation which are common in other antidepressants. Has good tolerance and high safety, and can be used as the first choice for clinically treating monophasic depression and biphasic depression.

The most common adverse reaction of metformin is digestive tract reaction, which can cause abdominal pain, vomiting or diarrhea and the like; the most serious adverse reaction is lactic acidosis, which, although rare, can be fatal in severe cases; prolonged use of metformin may also affect the absorption of vitamin B12. The adverse reaction of the metformin is positively correlated with the dosage of the medicament, and the greater the dosage of the medicament is, the more the adverse reaction is correspondingly increased. Therefore, it is necessary to develop hypoglycemic drugs with better therapeutic effect and higher safety. At present, no compound preparation of metformin and bupropion is sold on the market, and no related report on the combined use of metformin and bupropion exists.

Disclosure of Invention

The object of the present invention is to provide a novel pharmaceutical composition comprising metformin and bupropion. It was found that metformin, when used in combination with bupropion, has enhanced efficacy. Therefore, under the condition of equivalent curative effect, when the bupropion is used together, the dosage of the metformin is less, and the safety is higher.

In order to realize the purpose, the invention adopts the technical scheme that:

a pharmaceutical composition comprising two active ingredients: 1) metformin or a pharmaceutically acceptable salt thereof and 2) bupropion or a pharmaceutically acceptable salt thereof.

The weight ratio of the metformin or the pharmaceutically acceptable salt thereof to the bupropion or the pharmaceutically acceptable salt thereof is 4-8:1, preferably 6: 1.

The pharmaceutically acceptable salt is selected from one of hydrochloride, hydrobromide and mesylate.

The pharmaceutical composition is prepared into oral preparations by adopting a conventional pharmaceutical method.

The oral preparation can be one of tablet, granule and capsule.

The invention also aims to provide multiple uses of the pharmaceutical composition:

the application of the pharmaceutical composition in preparing hypoglycemic drugs.

The application of the pharmaceutical composition in preparing a medicament for treating diabetes.

The application of the pharmaceutical composition in preparing the medicine for preventing diabetic complications.

The application of the pharmaceutical composition in preparing weight-reducing medicines.

The pharmaceutical composition provided by the invention has the following advantages:

1) the composition can effectively reduce blood sugar, avoid chronic damage and dysfunction of various tissues caused by long-term existence of hyperglycemia, and has the effect of effectively treating diabetes or preventing diabetic complications.

2) The composition combines metformin and bupropion, and compared with the single metformin, the dosage of the metformin is smaller when the same hypoglycemic effect is achieved, the metformin is safer than the single metformin, and the incidence rate and degree of adverse reactions can be reduced.

3) Weight gain is one of the important factors that induce diabetes. Under the same dietary conditions, obese people are at a 7-fold higher relative risk of developing diabetes than non-obese people. Proper weight loss is beneficial for the prevention and treatment of diabetes. Experiments prove that the combined use of the metformin and the bupropion has better weight reduction effect than that of the metformin single ingredient, and is more favorable for preventing and treating diabetes.

4) The composition only reduces pathological hyperglycemia, has no influence on physiological blood sugar, does not cause serious hypoglycemia, and is superior to other common hypoglycemic drugs such as sulfonylureas, glinides, insulin and the like. It is convenient to use, unrestricted, and the security is high.

5) The composition has low cost, and because diabetes needs to be taken for a long time, the low-cost medicine can benefit more poor patients, alleviate the influence of diseases on the patients and improve the life quality of the patients.

Detailed Description

The present invention will be further explained below by way of specific embodiments, but the present invention is not limited to these.

Example 1 Effect of metformin in combination with bupropion administration on blood glucose and body weight in db/db mice

Test animals: 10C 57BL/6J mice, age of 6-8 weeks, weight of 20-30g, used for blank control group; db/db mice are divided into 5 groups of 10 mice on average, and the groups are used for model control groups and administration groups, wherein the mice are aged for 6-8 weeks and have the weight of 40-60 g.

The test method comprises the following steps: animals were fed free diet and given by oral gavage according to the dosing schedule of table 1 for 1 time/day for 4 consecutive weeks, and animal body weight and food intake were weighed once a week. After 2 weeks, 4 weeks after administration, the animals were fasted for 4h for blood glucose determination.

Table 1 test groups and dosing regimens

And (3) test results:

1. effect of continuous administration on food intake in db/db mice over 4 weeks

Within 14-28 days of administration, the food intake of the mice in the metformin group is slightly lower than that of the control group of the model, but no statistical significant difference exists. The food intake of mice in each group after continuous administration for 7 days is obviously lower than that of the model control group and the metformin group. In addition, the food intake of the mice in each group after 28 days of continuous administration was significantly lower than that of the mice in the metformin group (table 2).

TABLE 2 Effect on food intake (g) in db/db mice within 28 days of dosing (n ═ 10)

2. Effect on body weight in db/db mice on continuous administration over 4 weeks

The weight of each group of mice gradually increases within 28 days of continuous administration, the weight of the model control group and the weight of the metformin group are basically kept consistent, and the weight of each group of mice with combined administration is slightly lower than that of the model control group and the metformin group within 7-28 days of administration (table 3).

Table 3 effect on body weight (g) of db/db mice within 28 days of dosing (n 10,

)

3. effect on blood glucose levels in db/db mice after 2 weeks of continuous dosing

After 2 weeks of continuous administration, the blood sugar of mice in the blank control group, the model control group and the metformin group did not fluctuate greatly, the blood sugar level of db/db mice in each group of the drug combination was reduced, and the blood sugar level of 2 groups of the drug combination was more significant (Table 4).

Table 4 effect on blood glucose (mmol/L) levels in db/db mice 2 weeks after dosing (n-10,

)

and (4) test conclusion:

in the experiment, after the combined drug is administrated for 28 days, the food intake, the body weight, the blood sugar and the glycosylated hemoglobin of db/db mice with type II diabetes are all obviously reduced, and each index shows that the drug effect of the combined drug is superior to that of the single drug of the metformin. The results show that the combined use of the metformin and the bupropion can better play the roles of reducing blood sugar and weight, and the effect is more obvious. When the same curative effect is achieved, the dosage of metformin can be reduced by combining bupropion, and the risk of adverse reaction is further reduced.

Example 2 Effect of metformin in combination with bupropion on blood glucose and body weight in db/db mice

Test animals: 10C 57BL/6J mice, age of 6-8 weeks, weight of 20-30g, used for blank control group; db/db mice 70, 6-8 weeks old, 40-60g in body weight, and divided into 7 groups of 10 mice each, were used for model control group and each administration group.

The test method comprises the following steps: animals were fed free diet and given by oral gavage according to the dosing schedule of table 5 for 1/day for 4 consecutive weeks, and animal body weight and food intake were weighed once a week. After 2 weeks, 4 weeks after administration, the animals were fasted for 4h for blood glucose determination.

Table 5 test groups and dosing regimens

OGTT test

At the end of the dosing period, the animals were fasted for 16h without water deprivation, and blood glucose was measured for 0 min. After 1 hour of administration according to the administration schedule of table 5, each group of animals was administered glucose solution (2g/kg, 10ml/kg) by oral gavage, blood glucose was measured 30min, 60min, 120min, 180min after the administration of sugar by tail tip blood sampling, and AUC of area under the blood glucose time curve was calculated. After the experiment, the free diet and drinking water are recovered.

ITT test

After completion of the OGTT test, the ITT test was performed every other day. The animals were fasted for 1 hour without water deprivation, and blood glucose was measured for 0 min. After 1 hour of administration according to the administration schedule of table 5, each group of animals was intraperitoneally injected with an insulin solution (1.0unit/kg, 5ml/kg), blood glucose values at 30min, 60min, 120min, and 180min after administration of insulin were measured, and the area under the blood glucose time curve AUC was calculated. After the experiment is finished, the animals are deeply anesthetized by excessive CO2 inhalation, blood is collected from the heart, the anticoagulation is carried out by EDTA-K2, and the glycosylated hemoglobin is detected.

And (3) test results:

The food intake of the mice in the blank control group and the model control group is basically kept unchanged within 28 days of continuous administration. After 7 days of administration, the food intake of the metformin in the medium and high dose groups is obviously lower than that of the model control group, but no statistical significant difference exists, and the food intake of the metformin in the low dose group is basically the same as that of the model control group. By 14d, the food intake of the mice decreased with the administration time and the administration dose gradually increased. Compared with a model control group, the food intake of mice in each group of the combined medicine is lower than that of corresponding metformin dosage group, and is obvious in high dosage. The consumption of the combination of metformin alone and metformin in combination with bupropion decreased the consumption of mice, but the reduction of the consumption of the combination was more pronounced (Table 6). The statistics of food intake are the average food intake per cage of animals (10 per group, 5 per cage) for 1 day, with statistics of time from 9:00 to 9:00 on the next day.

TABLE 6 Effect on food intake (g) in db/db mice by 28 days of continuous dosing (n 10)

The body weight of each group of mice showed a steady increase trend within 28 days of continuous administration. Compared with the model control group, the body weight of mice in each administration group is obviously reduced after 7 days of administration. Within 7-28 days, the weight growth trend of animals in each dose group of the combined drug is slightly lower than that of the model control group and the corresponding metformin dose group (Table 7).

Table 7 effect on body weight (g) of db/db mice over 28 consecutive days of administration (n 10,

)

3. effect on blood glucose levels in db/db mice after 2 and 4 weeks of continuous administration

After 2 weeks of continuous administration, the blood sugar of mice in the blank control group and the model control group did not fluctuate too much. The mean blood glucose level of mice in each dose group of the combined drug is obviously lower than that of a model control group and is lower than that of a corresponding metformin dose group. By 4 weeks after administration, the blood glucose levels of mice in each dose group of metformin began to decline and were dose-dependent, but were not significantly different from those in the model control group. Each dosage group of the combined drug shows good dose-effect relationship, the blood sugar level of mice in each dosage group is obviously lower than that of a model control group on average, and the blood sugar reducing effect of the low dosage group of the combined drug is better than that of the high dosage group of the metformin which is used alone (Table 8).

Table 8 effect on blood glucose levels (mmol/L) in db/db mice after 2 and 4 consecutive doses (n-10,

)

4. effect on OGTT blood glucose levels and AUC in db/db mice after 4 weeks of continuous dosing

1) Effects on blood glucose levels

After the continuous administration for 28 days, the mice of each group are administered for 1h and then are orally administered with the glucose solution by gavage, the animal blood sugar level of the model control group is obviously higher than that of the blank control group, the average blood sugar level of the mice reaches the peak value 30min after the administration of sugar, the animal blood sugar level is gradually reduced along with the time, and the blood sugar levels of the animals of the blank control group and the model control group are still higher than the blood sugar level of the 0 point after the administration of sugar for 180 min.

At each time point 30min after sugar administration, the blood glucose levels of the mice in each dose group of metformin were significantly lower on average than in the model control group. The dosage groups of the combined drug also obviously reduce the blood sugar level of mice, and also show a good dose-effect relationship at each time point, the trend of reducing the blood sugar level of the mice is basically consistent with that of singly taking the metformin, but the drug taking the metformin and the bupropion has obviously stronger force for reducing the blood sugar of the mice than that of singly taking the metformin.

2) Effect on AUC

AUC values of each dose group of metformin and combined drug are lower than those of the model control group. The AUC values for each dose group of the combination were lower than the corresponding metformin dose group, consistent with the results of blood glucose measurements, i.e., metformin combined with bupropion was more glucose tolerant than metformin alone in db/db mice (table 9).

Table 9 effect on OGTT blood glucose levels (mmol/L) in db/db mice after 28 consecutive days of administration (n 10,

)

5. effect on ITT blood glucose levels and AUC in db/db mice after 4 weeks of continuous dosing

1) Effects on blood glucose levels

After each mouse is administrated for 1h, the abdominal cavity is injected with insulin solution, the blood sugar of mice in the blank control group and the model control group reaches the trough 60min after the administration of insulin, the blood sugar level of animals gradually rises after 120min, and the blood sugar level of the mice returns to the normal level after 180 min.

The blood glucose levels of the mice in the high and medium metformin dose groups were significantly lower than those in the model control group 30min after insulin administration, the blood glucose levels were nearly lowest 180min later, the blood glucose levels of the animals in the low metformin dose group were also lower than those in the model control group at each time point, the blood glucose was lowest at 120min, and the blood glucose returned to nearly 0 point after 180 min. Each dosage group of metformin showed a good dose-response relationship at each time point 30min after insulin administration; the blood sugar level of the mice is obviously reduced after the insulin is administrated to each dose group, and the blood sugar level of the animals is reduced along with the increase of the dose; the blood sugar of the animals in the middle and low dose groups of the combined drug tends to be stable after 180min of insulin administration, and the blood sugar of the animals in the high dose group still tends to be reduced continuously. Compared with each dosage group of metformin, the blood sugar of mice in each corresponding dosage group of combined medication is slightly lower, and the high, medium and low dosage groups of combined medication have statistical significant difference (P <0.05) compared with the corresponding dosage groups of metformin taken alone at 180min, 60min and 180min respectively, which shows that the sensitivity of db/db mice to insulin can be improved by the combined medication of metformin and bupropion, and the drug effect of the combined medication is stronger than that of metformin taken alone.

2) Effect on AUC

The AUC for each dose group of metformin was lower than that of the model control group, and the AUC for each dose group of the combination was significantly lower than that of the model control group and lower than that of each corresponding dose group of metformin administered alone, which also demonstrates that metformin administered in combination with bupropion had a stronger effect on increasing the sensitivity to insulin in db/db mice than metformin administered alone (table 10).

Table 10 effect on OGTT blood glucose levels (mmol/L) in db/db mice after 28 consecutive days of administration (n 10,

)

6. effect on glycated hemoglobin in mice after 4 weeks of continuous administration

After the continuous administration for 28 days, the dosage group of the metformin single drug has obvious effect of reducing the content of the mouse glycosylated hemoglobin, and the content of the glycosylated hemoglobin is gradually reduced along with the increase of the dosage, but has no statistical significant difference compared with the model control group. The content of the glycosylated hemoglobin of mice in each dose group is obviously lower than that of a model control group, and the content of the glycosylated hemoglobin in a high dose group is obviously reduced (P <0.05v.s model control group), and the glycosylated hemoglobin also shows good dose-effect relationship. In addition, the content of glycated hemoglobin in mice in each dose group of the combination was lower than that in the corresponding dose group of metformin alone, indicating that the glycated hemoglobin reducing ability of mice is better than that of metformin alone (Table 11).

Table 11 effects on glycated hemoglobin in db/db mice 28 days after i.g. consecutive subjects (n 10,

)

and (4) conclusion:

1. after 7-28 days of continuous administration, compared with the application of the metformin alone, the application of the metformin combined with bupropion has larger influence on the food intake of the mice and stronger inhibition effect on the weight gain of the mice.

2. After 2 weeks and 4 weeks of continuous administration, the blood sugar level of mice can be obviously reduced by using the metformin and the bupropion, and the effect is superior to that of the metformin used alone;

3. in the OGTT experiment, the glucose tolerance of the metformin combined with the bupropion in db/db mice is stronger than that of the metformin taken alone;

4. in the ITT experiment, the effect of the metformin combined with bupropion on improving the insulin sensitivity of db/db mice is stronger than that of the metformin used alone;

5. after the continuous administration for 28 days, the metformin and bupropion combined administration can obviously reduce the content of glycosylated hemoglobin of mice, and the high-dose group is particularly obvious, and the effect is better than that of the metformin used alone.

In the research on the hypoglycemic effect of a db/db mouse with type II diabetes, the metformin bupropion combined drug for 28 days can obviously reduce the food intake, the body weight, the fasting blood sugar of 4 hours and the content of glycosylated hemoglobin of the db/db mouse, can obviously improve the tolerance capability of the db/db mouse to sugar, and improve the sensitivity of the db/db mouse to insulin. The indexes show that the drug effect is obviously superior to that of the single application of the metformin.

EXAMPLE 3 composition tablet

Prescription:

the preparation process comprises the following steps:

1. sieving all the raw materials with a 40-mesh sieve for later use.

2. And 3% hydroxypropyl methylcellulose solution is prepared to be used as the adhesive for standby.

3. The bupropion hydrochloride, the metformin hydrochloride, the microcrystalline cellulose, the pregelatinized starch and the croscarmellose sodium are placed in a high-speed mixing granulator according to the prescription amount, and are mixed for 5 minutes at a low speed.

4. Adding the adhesive into the uniformly mixed materials, and mixing at a low speed for 3 minutes to prepare a soft material.

5. And (3) mounting a 16-mesh sieve for granulation by using a swing granulator.

6. The wet granulate is dried at 70 ℃. + -. 5 ℃ for 2-3 hours.

7. And (4) arranging the dried granules with a 16-mesh sieve by using a swing type granulator.

8. After finishing the granules, adding the magnesium stearate and the aerosil in the prescribed amount, and totally mixing for 15 minutes by using a three-dimensional motion mixer.

9. And (5) intermediate checking.

10. And (6) tabletting.

11. And (6) inner packaging.

Example 4 composition granules

Prescription:

the preparation process comprises the following steps:

1. pulverizing sucrose and sucralose into 80 meshes for later use, and sieving the rest raw and auxiliary materials with a 40-mesh sieve for later use.

3. And (3) placing bupropion hydrochloride, metformin hydrochloride, cane sugar, dextrin, sucralose and essence in a high-speed mixing granulator according to the prescription amount, and mixing for 5 minutes at a low speed.

6. The wet granulate is dried at 70 ℃. + -. 5 ℃ for 2-3 hours.

7. And (4) screening the dry particles by using a rotary vibration screen provided with a 14-mesh screen, and finishing the large particles on the screen by using a swing type granulator provided with a 14-mesh screen.

8. After finishing all the granules were combined and mixed for a total of 15 minutes using a three-dimensional motion mixer.

9. And (5) intermediate checking.

10. And (6) inner packaging.

EXAMPLE 5 composition capsules

Prescription:

the preparation process comprises the following steps:

1. sieving all the raw materials with a 40-mesh sieve for later use.

6. The wet granulate is dried at 70 ℃. + -. 5 ℃ for 2-3 hours.

8. After finishing the granules, the prescribed amount of magnesium stearate was added and mixed for 15 minutes in total using a three-dimensional motion mixer.

9. And (5) intermediate checking.

10. And (5) filling into capsules.

11. And (6) inner packaging.

Claims

1. A pharmaceutical composition comprising two active ingredients: 1) metformin or a pharmaceutically acceptable salt thereof and 2) bupropion or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the weight ratio of metformin or a pharmaceutically acceptable salt thereof to bupropion or a pharmaceutically acceptable salt thereof is 4-8: 1.

3. The pharmaceutical composition according to claim 2, wherein the weight ratio of metformin or a pharmaceutically acceptable salt thereof to bupropion or a pharmaceutically acceptable salt thereof is 6: 1.

4. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide and mesylate.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutical composition is prepared into an oral preparation by a conventional pharmaceutical method.

6. The pharmaceutical composition of claim 5, wherein the oral formulation is one of a tablet, a granule, and a capsule.

7. Use of a pharmaceutical composition according to any one of claims 1 to 4 in the manufacture of a medicament for lowering blood glucose.

8. Use of a pharmaceutical composition according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of diabetes.

9. Use of a pharmaceutical composition according to any one of claims 1 to 4 in the manufacture of a medicament for the prevention of diabetic complications.

10. Use of a pharmaceutical composition according to any one of claims 1 to 4 in the manufacture of a weight loss medicament.