CN106580962B

CN106580962B - Metformin and vildagliptin compound tablet and preparation method thereof

Info

Publication number: CN106580962B
Application number: CN201611271866.1A
Authority: CN
Inventors: 操锋; 王罗
Original assignee: Jiangsu Jinglixin Pharmaceutical Technology Co ltd
Current assignee: Jiangsu Jinglixin Pharmaceutical Technology Co ltd
Priority date: 2016-12-30
Filing date: 2016-12-30
Publication date: 2020-11-10
Anticipated expiration: 2036-12-30
Also published as: CN106580962A

Abstract

The invention discloses a compound tablet containing metformin and vildagliptin and a preparation method thereof. The metformin and vildagliptin are used as active ingredients of the medicine, and a medicinal auxiliary material adhesive is combined into granules, and the granules are prepared into tablets after a lubricant is added, wherein the adhesive is one or more of polyvinylpyrrolidone K30, K45, K60, K70 and K80, and the dosage of the adhesive is 5-20% of the weight of the composition. The granules are prepared by adopting a one-step granulation mode or a mode of combining the one-step granulation with dry granulation. The invention improves the fluidity and compressibility of the granules, improves the dissolution property and stability of the preparation, and has good in vivo bioavailability and clinical curative effect.

Description

Metformin and vildagliptin compound tablet and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a compound tablet containing metformin and vildagliptin and a preparation method thereof.

Background

Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by a defect in insulin secretion or an impaired biological action, or both. The chronic hyperglycemic state of diabetes is significantly associated with long-term complications, namely damage, dysfunction and failure of numerous organs, particularly the kidneys, eyes, nerves, heart and blood vessels, etc. The complex treatment of diabetes should not only aim at lowering blood glucose to near normal levels, but also actively correct metabolic abnormalities and reduce cardiovascular risk factors.

Diabetes is currently defined according to the WHO/ADA standard, i.e., symptoms of diabetes plus random plasma glucose levels of 11.1mmol/L or more, or fasting plasma glucose levels of 7.0mmol/L or 11.1mmol/L or more 2-h after a 75g anhydrous glucose load in the oral glucose tolerance test. In the absence of typical symptoms of diabetes, diabetes cannot be diagnosed by only one blood glucose measurement, and must be diagnosed after confirmation every other day.

Diabetes can be classified into type I diabetes and type II diabetes according to pathological characteristics. Type II diabetes is a group of complex metabolic disorders whose pathogenesis is only partially known. It includes varying degrees of decreased islet beta cell function, insulin resistance in surrounding tissues, and abnormal liver glycogen metabolism. The glycemic control of type II diabetes tends to deteriorate progressively over time; when diet control and exercise therapy fail, a new glucose-lowering drug intervention treatment means needs to be used every 3-4 years on average to achieve or maintain good glucose control. Finally, even with current combination therapy and/or insulin therapy, a significant proportion of patients fail to achieve good glycemic control. Overweight, hypertension and hyperlipidemia often coexist with diabetes, and intervention treatment with multiple cardiovascular risk factors is an important factor to consider in the overall treatment of diabetes.

Diabetes has become the third largest disease that seriously harms human health following cardiovascular, malignant tumors. A 'national diabetes epidemiological survey (2007 + 2008)' shows that in the population over 20 years old in China, the prevalence rates of diabetes of men and women reach 10.6% and 8.8% respectively, and the prevalence rate of diabetes is 9.7% overall, so that the total population of people suffering from diabetes in China is estimated to be about 9200 ten thousands of people, which exceeds India, and becomes the country with the most diabetic patients in the world.

Currently, the annual treatment costs per diabetic patient in the united states are $ 11744, more than 2 times that of non-diabetic patients. Over the past 5 years, governments have paid 32% more for diabetics, costing as much as 1740 billion dollars. Of these, $ 1160 billion is used for the medical costs associated with diabetes, and $ 580 billion is due to indirect losses from patient treatment, malpractice, premature death, and the like. In only one area of hawaii in the united states, annual costs for diabetics can amount to billions of dollars. If it cannot be found early, the treatment is carried out until diabetic complications appear, the effect of diet and exercise is very limited, and medication is necessary. If the kidney failure needs dialysis, the treatment cost per year is not lower than 10 ten thousand yuan. The expenses for diabetes in 2002 in China account for about 4% of health expenses, and the total amount is 188.2 billion yuan. Generally, diabetes mellitus is consumed by 3726 yuan per year averagely, and once complications occur, the average cost is up to 13897 yuan

Metformin is a biguanide hypoglycemic drug, is an oral antihyperglycemic drug widely used in various countries in the world at present, can improve the tolerance of type II diabetes patients to sugar, and reduces the basal and postprandial plasma glucose concentration. Metformin hydrochloride does not promote insulin secretion, and the hypoglycemic effect of metformin hydrochloride mainly aims at promoting glucose uptake by adipose tissues, increasing anaerobic glycolysis of muscle tissues, increasing the utilization of glucose and reducing the absorption of glucose through the digestive tract.

Vildagliptin is a selective, competitive and reversible dipeptidyl peptidase IV (DPP-IV) inhibitor, also called an incretin enhancer, and can reduce the degradation speed of glucagon-like peptide I GLP-1 by inhibiting the activity of DPP-IV, further stimulate the secretion of insulin under high blood sugar concentration, and play a role in resisting type II diabetes by delaying gastric emptying, inhibiting the release of glucagon, promoting the proliferation and differentiation of islet beta cells, enhancing satiety and the like. And has no obvious influence on the body weight.

EMEA approved Novartis on 11 months 2007 for marketing metformin hydrochloride/vildagliptin compound tablets of Novartis, with trade names:

(Yiheui). The treatment of type II diabetes, in patients who are not yet able to effectively control blood glucose using the maximum tolerated dose of metformin or who have currently been treated with vildagliptin (Galvus) in combination with metformin. The specification of the compound tablet is 500mg/50mg, 850mg/50mg and 1000mg/50mg of metformin hydrochloride/vildagliptin.

The dosage of the metformin accounts for more than 80 percent, the dosage of the vildagliptin is less than 10 percent, and the metformin has poor fluidity and uneven mixing. Metformin is extremely poorly compressible and is highly dosed, and the roller compaction process is unacceptable for poorly compressible materials, and therefore is not conducive to dry granulation. Meanwhile, vildagliptin is a substance with poor compressibility and hygroscopicity, and is sensitive to water and can be easily degraded when meeting water. In order to overcome the problem, the vildagliptin is prepared into tablets by a direct compression method in a patent, and the vildagliptin tablet has good properties, but the direct compression method generally has the drug load not more than 20%, the effective component of the vildagliptin reaches more than 90%, and the effective component has poor liquidity, so the vildagliptin tablet cannot be prepared by a direct compression method. If the common wet granulation is adopted, the moisture and high temperature are difficult to avoid, and the stability of the vildagliptin is obviously influenced. The implementation process finds that: (1) dry granulation is adopted, the particle flowability is poor, and the difference between the appearance of the tablets and the weight of the tablets is unqualified; (2) the related substances of the tablets prepared by adopting the wet granulation process are increased too fast in stability research, and the quality of the medicines is unqualified.

CN103845326A discloses a compound composition containing metformin and vildagliptin and a preparation method thereof, comprising: (1) vildagliptin or a pharmaceutically acceptable salt thereof; (2) metformin or a pharmaceutically acceptable salt thereof; (3) a binder; the adhesive is hydroxypropyl cellulose or hydroxypropyl methylcellulose with apparent viscosity of 2-4 mpas in 1% aqueous solution, and the dosage of the adhesive is 20-30% of the weight of the composition. It discloses a compound tablet of metformin and vildagliptin and a preparation method thereof: (1) granulating metformin and 20-30% of adhesive (by dry weight) by using an organic solvent, mixing with vildagliptin and other auxiliary materials, and tabletting; (2) dissolving metformin and an adhesive in an organic solvent, performing rotary evaporation to obtain a solid, granulating, mixing with vildagliptin and other auxiliary materials, and tabletting; (3) the metformin, the adhesive and 50% of lubricant according to the prescription amount are granulated by a dry method, added with vildagliptin and other auxiliary materials, mixed and prepared into tablets. The application proposes three granulation methods, and the specific implementation process finds that: (1) the common wet granulation has influence on the stability of vildagliptin, and related substances in the influencing factor test process have high growth speed, thereby having adverse effect on the quality of the preparation; meanwhile, the dissolution speed is too high and is inconsistent with the dissolution behavior of a contrast medicament, so that good clinical curative effect is difficult to achieve; (2) the dry granulation method has poor compressibility of metformin, so that the flowability and compressibility of granules after the dry granulation method are obviously reduced, and the appearance and weight difference of tablets are unqualified due to poor flowability of granules in the process of preparing the tablets, thereby being not beneficial to the production of the tablets.

Disclosure of Invention

According to the problems in the technology, the invention overcomes the problems of poor dissolution, unstable quality and the like of the metformin and vildagliptin compound tablet, and aims to provide the metformin and vildagliptin compound tablet composition and the preparation method thereof, so that better stability and better quality are realized.

The invention also provides a preparation method of the metformin and vildagliptin compound tablet, which can effectively improve the flowability and compressibility of granules, and particularly solves the problem that vildagliptin is easy to degrade in a stability process after meeting water in a common wet granulation process, so that the bioavailability in vivo is ensured, and a good clinical effect is obtained.

The specific technical scheme of the invention is as follows:

a compound tablet of metformin and vildagliptin comprises metformin or its pharmaceutically acceptable salt, vildagliptin or its pharmaceutically acceptable salt and a binder, wherein the binder is one or more of polyvinylpyrrolidone K30, K45, K60, K70 and K80, and the dosage of the binder is 5-20% of the weight of the composition.

The mass ratio of the metformin to the vildagliptin is 5-30: 1, preferably 5-20: 1.

The pharmaceutical composition also comprises a lubricant, the dosage of the lubricant is 0.2-3% of the weight of the composition, the further preference is 0.3-1%, and the preference is one or more of magnesium stearate and talcum powder.

The invention provides a method for preparing a compound tablet of vildagliptin and metformin, which adopts a one-step granulation method for granulation.

The one-step granulation method is also called boiling granulation method, flow spray granulation method and fluidized bed granulation method: under the action of hot air passing from bottom to top, the powder is maintained in fluidized state and at the same time the solution containing adhesive is sprayed so as to make the powder agglomerate into granules. The three steps of mixing, granulating and drying of the conventional wet granulation are completed in a closed container at one time.

The preparation method comprises the following specific steps:

(1) respectively crushing and sieving the metformin, the vildagliptin and the adhesive according to the prescription amount, uniformly mixing, granulating by using a proper amount of organic solvent and a one-step granulator (fluidized bed granulator), and sieving;

or respectively crushing and sieving the metformin, the vildagliptin and part of the adhesive according to the prescription amount, uniformly mixing, dissolving the rest of the adhesive according to the prescription amount by using a proper amount of organic solvent, granulating by using a one-step granulator, and sieving;

(2) sieving the granules prepared in the step (1), grading, and uniformly mixing with a lubricant;

(3) tabletting with a tabletting machine.

Or,

(2) pressing the granules prepared in the step (1) into large tablets, and sieving and grading the large tablets;

(3) uniformly mixing the particles prepared in the step (2) with a lubricant;

(4) tabletting with a tabletting machine.

The one-step granulator of the invention is conventional in the art and can be selected from experimental multifunctional fluidized bed (Chuanzhi electromechanical technology development (Jiangsu) GmbH, model: FLZB-1.5, FLZB-3), multipurpose fluidized bed (Chongqing EngGelati granulation coating technology Co., model: WBF-3G, WBF-5G, WBF-15G), etc.

In the method, the organic solvent is an alcohol solvent or a mixed solvent of the alcohol solvent and water, preferably a 70-95% ethanol solution, and the amount of the organic solvent is 30-80% (V/W), more preferably 45-60% of the weight of the composition.

The adhesive of the partial prescription amount is 5% -95% of the adhesive amount, and is more preferably 40-70%.

The problem of uneven mixing is easily caused by large dosage difference of two active medicaments, namely vildagliptin and metformin, in the compound preparation. The method well improves the problem of uneven mixing.

Tablets prepared according to the invention are preferably anisotropically punched tablets, depending on the tablet weight, and tablets prepared are:

the surface of the tablet is smooth;

the hardness of the tablet in the long diameter is 100-300N;

the friability of the tablets is less than 1.0%;

the thickness of the tablet is 4-9 mm;

according to the invention, by selecting the type and adding mode of the adhesive in the formula and improving and optimizing the preparation method, the compressibility of the metformin and vildagliptin powder can be obviously further improved, the prepared compound tablet with small batch difference is qualified in friability and high in process feasibility, and the compressibility of granules and the dissolution property and stability of the preparation are well improved. The vildagliptin and metformin compound tablet provided by the invention has small batch difference and good process reproducibility, and is more suitable for industrial production.

Detailed Description

For a better understanding of the present invention, the present invention is illustrated below by specific embodiments, in which various processes and methods not described in detail are conventional knowledge in the art. It should be properly understood that: the present invention is illustrated by way of example and not by way of limitation, and therefore, it is within the scope of the present invention to provide a simple modification of the present invention in the context of the method of the present invention.

Example 1

The preparation process comprises the following steps: uniformly mixing metformin and vildagliptin with the formula amount shown in the table 1 and an adhesive, granulating by using a one-step granulator with 500ml of 75% ethanol, sieving by using a 30-mesh sieve, drying at 60 ℃, granulating by using a 30-mesh sieve, adding magnesium stearate, uniformly mixing, and tabletting.

TABLE 1

Name (R)	Prescription 1	Prescription 2	Prescription 3	Prescription 4
					Metformin hydrochloride	1000g	1000g	1000g	1000g
Vildagliptin	50g	50g	50g	50g
					HPC-SSL	315g	210g	/	/
PVP K45	/	/	/	120g
					PVP K60	/	/	100g	/
Magnesium stearate	12g	12g	5g	5g

Comparative study of influencing factors: samples prepared from the above different recipes were subjected to accelerated stability test for 6 months, and the results are shown in table 2:

TABLE 2 accelerated stability 6 month test results

	Total impurities (%)	Amide (%)	Cyclic amidine (%)	Diketone (%)
					Prescription 1	4.74	2.36	1.32	0.98
Prescription 2	4.21	2.22	1.09	0.77
					Prescription 3	2.41	1.11	0.69	0.37
Prescription 4	2.39	1.07	0.78	0.42
					Standard limit of	≤3.5	≤2.0	≤.0	≤1.0

The test result shows that: tablets prepared using HPC-SSL as the binder (prescription of patent CN 103845326A) were left under accelerated conditions for 6 months with amide impurities, cyclic amidine impurities and total impurities exceeding the drug standard limits, diketone impurities approaching the drug standard limits, and the drug quality was not acceptable. The tablets prepared by using the povidone as the binder are placed for 6 months under accelerated conditions, all impurities and total impurities do not exceed the standard limit of medicines, and the quality of the medicines is qualified.

Example 2

1000g of metformin hydrochloride, 50g of vildagliptin, PVP K45120 g and 5g of magnesium stearate are used as a prescription, and different preparation processes are adopted to prepare tablets.

The process 1 comprises the following steps: uniformly mixing metformin and PVP K45, adding 80ml of 75% ethanol, performing wet granulation, sieving with a 30-mesh sieve, drying at 60 ℃, granulating with a 30-mesh sieve, adding vildagliptin and magnesium stearate, uniformly mixing, and tabletting.

And (2) a process: uniformly mixing metformin, vildagliptin and 60g of PVP K45, dissolving 60g of PVP K45 in 500ml of 75% ethanol to serve as a binding agent, granulating in one step, adding magnesium stearate after granulating by a 30-mesh sieve, uniformly mixing, and tabletting.

And (3) a process: uniformly mixing metformin, vildagliptin and 60g of PVP K45, dissolving 60g of PVP K45 as a binding agent with 500ml of 75% ethanol, granulating by one step, granulating by a dry method after a 30-mesh sieve is used for granulation, pressing into large tablets, sieving by the 30-mesh sieve for granulation, adding magnesium stearate, uniformly mixing, and tabletting.

And (4) a process: uniformly mixing the metformin, the vildagliptin and the PVP K45, performing dry granulation, sieving with a 30-mesh sieve, adding the magnesium stearate, uniformly mixing, and tabletting.

TABLE 4

	Process 1	Process 2	Process 3	Process 4
					Plain sheet appearance	Smooth and flat without mottle	Smooth and flat without mottle	Smooth and flat without mottle	The surface of the tablet has mottle
Difference in tablet weight	Qualified	Qualified	Qualified	Fail to be qualified
					Degree of friability	Qualified	Qualified	Qualified	Fail to be qualified

Comparative study of influencing factors: the samples prepared by the different processes are subjected to a high temperature (60 ℃) influence factor 30-day test and an accelerated stability test for 6 months, and the results are shown in the following table:

TABLE 5 high temperature (60 ℃ C.) influencing factors 30 days test results

	Total impurities (%)	Amide (%)	Cyclic amidine (%)	Diketone (%)
					Process 1	14.87	10.59	0.38	3.90
Process 2	3.08	1.80	0.24	0.82
					Process 3	3.13	1.86	0.30	0.76
Process 4	13.78	7.47	2.86	3.45
					Standard limit of	≤3.5	≤2.0	≤1.0	≤1.0

TABLE 6 accelerated stability test 6 month results

	Total impurities (%)	Amide (%)	Cyclic amidine (%)	Diketone (%)
					Process 1	4.55	2.56	1.05	0.89
Process 2	2.62	1.16	0.82	0.35
					Process 3	2.51	1.12	0.78	0.38
Process 4	5.85	2.89	1.81	1.04
					Standard limit of	≤3.5	≤2.0	≤1.0	≤1.0

The test result shows that:

(1) dry granulation (process 4) is adopted, and in the process of preparing tablets, because the flowability of particles is poor, the appearance of plain tablets, the difference of tablet weight and the friability are not qualified (results are shown in table 4), the basic requirements of common tablets are not met, and the industrial production is not facilitated, so the dry granulation is not suitable for preparing the tablets of the invention.

(2) The tablets prepared by dry granulation (process 4) and wet granulation (process 1) are placed at the high temperature of 60 ℃ for 30 days, the growth rate of related substances of the tablets is obviously higher than that of the tablets prepared by the one-step granulation method (process 2 and process 3) of the invention, and the total impurity content of the tablets is about 3 times of that of the tablets prepared by the one-step granulation method (process 2 and process 3) (the result is shown in table 5).

(3) The tablets are placed for 6 months under the accelerated condition, the stability of the tablets prepared by adopting dry granulation (process 4) and wet granulation (process 1) is poor, the amide, the cyclic amidine and the total impurities exceed the standard limit of the medicine, and the quality of the medicine is unqualified. The related substances of the tablets prepared by the one-step granulation method (the process 2 and the process 3) meet the requirement of the drug standard limit, have good stability and qualified drug quality (the result is shown in the table 6).

In summary, the following steps:

(1) the quality of the compound tablet of the metformin and the vildagliptin is not only related to the auxiliary materials used in the prescription, but also is closely related to the selected preparation process, and the high-stability tablet can be prepared only by selecting the qualified prescription and process.

(2) The related substances are one of the key items in the medicine quality research, the content of the related substances is a direct index for reflecting the purity of the medicine, and the adverse reaction generated in the clinical use of the medicine is not only related to the pharmacological activity of the medicine, but also has a great relationship with the related substances existing in the medicine. The related substances of the tablets produced according to the prescription and the process of the invention are in accordance with the requirement of the drug standard limit after being placed for 6 months under the acceleration condition, the stability requirement of the drug quality is reached, and the drug quality is qualified.

Claims

1. A method for preparing a compound tablet of metformin and vildagliptin, the compound tablet comprises metformin or a pharmaceutically acceptable salt thereof, vildagliptin or a pharmaceutically acceptable salt thereof, a binding agent and a lubricant, wherein the mass ratio of the metformin to the vildagliptin is 5-30: 1, the binding agent is polyvinylpyrrolidone K45 and/or K60, the dosage of the binding agent is 5-20% of the weight of the composition, the compound tablet is prepared by granulating the metformin or the pharmaceutically acceptable salt thereof, the vildagliptin or the pharmaceutically acceptable salt thereof and the binding agent by a one-step granulation method or a mode of combining the one-step granulation method and a dry granulation method, and the method comprises the following specific steps:

(1) respectively crushing and sieving the metformin, the vildagliptin and the adhesive according to the prescription amount, uniformly mixing, granulating by using a proper amount of organic solvent and a one-step granulator, and sieving; or respectively crushing and sieving the metformin, the vildagliptin and a part of the adhesive according to the prescription amount, uniformly mixing, dissolving the rest adhesive according to the prescription amount by using a proper amount of organic solvent, granulating by using a one-step granulator, and sieving, wherein the organic solvent is 70-95% of ethanol solution, and the amount of the organic solvent is 30-80% of the weight of the composition; the part of the prescription amount of the adhesive is 40-70% of the dosage of the prescription adhesive;

(2) sieving the granules prepared in the step (1), grading, and uniformly mixing with a lubricant; or pressing the granules prepared in the step (1) into large tablets, sieving the large tablets, finishing the granules, and uniformly mixing the granules with the lubricant;

(3) tabletting with a tabletting machine.

2. A method according to claim 1, wherein the lubricant is present in an amount of from 0.2% to 3% by weight of the composition.

3. The method of claim 1, wherein the lubricant is selected from magnesium stearate and/or talc.

4. The method according to claim 1, wherein the organic solvent is a 70% to 95% ethanol solution and is used in an amount of 45% to 60% by weight of the composition.