WO2021258851A1

WO2021258851A1 - Pharmaceutical composition for treating diabetes and preparation method therefor

Info

Publication number: WO2021258851A1
Application number: PCT/CN2021/090963
Authority: WO
Inventors: 高悦译; 张倩; 卢江; 刘恩桂
Original assignee: 广州市力鑫药业有限公司
Priority date: 2020-06-22
Filing date: 2021-04-29
Publication date: 2021-12-30
Also published as: CN111588713B; CN111588713A

Abstract

A pharmaceutical composition for treating diabetes and a preparation method therefor, comprising tianagliflozin, metformin hydrochloride, and an additive. The mass ratio of the tianagliflozin, metformin hydrochloride and the additive is 1 to (100-250) to (15-30). The pharmaceutical composition has stable curative effects, good therapeutic effects on type II diabetes, and promotes patient compliance.

Description

Medicinal composition for treating diabetes and preparation method thereof

Technical field

This application relates to the technical field of hypoglycemic preparations, in particular to a pharmaceutical composition for treating diabetes and a preparation method thereof.

Background technique

At present, the incidence of diabetes is increasing year by year, and it has become one of the focuses of people's attention. Diabetes is divided into many types, but nearly 90% of the affected population are type 2 diabetes patients. According to relevant reports, about 6% of the world’s 20-79 age group of adults suffer from type 2 diabetes. According to relevant statistics, the number of people suffering from type 2 diabetes will continue to increase. By 2025, the number of people suffering from the disease is expected to reach 380 million, which will account for 7.1 of all adults in the 20-79 age range in the world. %.

As a chronic metabolic disease, type 2 diabetes is characterized by high blood sugar, which is mainly caused by relatively insufficient insulin secretion and insulin resistance. In addition, a significant feature of type 2 diabetes is that its condition is irreversible, which eventually causes many 2 Patients with type 1 diabetes develop into type 1 diabetes patients. At present, there is no clinically effective drug that can cure type 2 diabetes. In the early stage of the disease, long-term strict lifestyle control such as diet control and physical exercise is often required to reduce blood sugar and increase insulin. Resistance is improved to achieve the goal of controlling the development of type 2 diabetes.

At present, there are many drugs to treat diabetes, the most common of which is insulin and its analogues, in addition to sulfonylureas, PPAR-γ agonists, α-glycosidase inhibitors, dipeptidyl peptidase (DPP-IV) inhibitors and biguanide drugs, etc., in the specific treatment process, the doctor must first determine the time and severity of the onset of type 2 diabetes, and then give hypoglycemic drugs with different mechanisms of action, but in the actual application process However, it has been found that many existing drugs cannot achieve the ideal blood sugar lowering effect, and even the combination of several drugs with different mechanisms of action cannot achieve the ideal effect.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors include dapagliflozin, repaggliflozin, sepagliflozin, apagliflozin, etc., among which dapagliflozin is the first approved and marketed in Europe The effect of SGLT2 inhibitors in the treatment of diabetes has been initially confirmed by clinical studies.

Tianagliflozin (Tianagliflozin) is a new SGLT2 inhibitor with 5 chiral centers and its chemical name is: (IS)-1,5-dehydrate-6-deoxy-1-C-[4-chloro- 3-[(4-Ethoxyphenyl)methyl]phenyl]-D-glucitol, molecular formula: C ₂₁ H ₂₅ ClO ₅ , molecular weight: 392.87, structural formula:

At present, the SGLT2 inhibitor dapagliflozin (dapagliflozin) and extended-release metformin hydrochloride have been combined. For adult patients with type 2 diabetes who need dapagliflozin combined with metformin treatment, the drug is used as an adjuvant drug, combined with diet and exercise. Control blood sugar. EMEA approved Novartis's vildagliptin/metformin hydrochloride compound tablet on November 14, 2007, to treat type 2 diabetes, for the treatment of patients who cannot effectively control blood sugar with the maximum tolerated dose of metformin. The compound tablet The dosage specification of the drug is vildagliptin/guanidine diformate hydrochloride 50mg/850mg/1000mg. The surface efficacy of the compound preparation of the marketed product and guanidine diformate hydrochloride is better than that of single preparations. At present, tyagliptin and guanidine diformate hydrochloride are combined There are still few documents. Therefore, there is a need for a pharmaceutical composition for the treatment of diabetes with stable curative effect.

Summary of the invention

The application provides a pharmaceutical composition for treating diabetes and a preparation method thereof. The pharmaceutical composition has stable curative effect, good effect on treating type 2 diabetes, good patient compliance, and can prevent recurrence, which meets the needs of modern people.

On the one hand, the present application provides a pharmaceutical composition for the treatment of diabetes. The pharmaceutical composition comprises tyaggliflozin, guanidine diformate hydrochloride and additives, and the mass ratio of tyaggliflozin, guanidine diformate hydrochloride and additives is 1 :(100～250):(15～30).

Preferably, the mass ratio of typagliflozin, guanidine diformate hydrochloride and additives is 1: (150-250): (15-25).

Preferably, the mass ratio of tyaggliflozin, guanidine diformate hydrochloride and additives is 1:230:20.

More preferably, the additive includes sodium hyaluronate.

Preferably, the pharmaceutical composition further includes a binder, a filler and a disintegrant.

Preferably, the binder includes carboxymethyl cellulose, and the mass ratio of the carboxymethyl cellulose to sodium hyaluronate is 1: (1.5-4).

Preferably, the filler includes one of microcrystalline cellulose and dibasic calcium phosphate.

Preferably, the disintegrant includes one of calcium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.

On the other hand, this application provides a method for preparing a pharmaceutical composition for treating diabetes, including the following steps:

S1. Mix guanidine diformate hydrochloride and typagliflozin, add 4-6 times the total amount of guanidine diformate hydrochloride and typagliflozin in an ethanol solution with a mass concentration of 35%, and heat it in a water bath at 50-60°C. Stir until completely dissolved to obtain mixed solution A; and

S2. Add binders and additives to the mixed liquid A of step S1 to obtain mixed liquid B, then heat and concentrate to obtain a clear paste with a relative density of 1.20 to 1.30, then add filler and disintegrant to mix, dry, and weigh , Get a pharmaceutical composition.

Preferably, the net particle size of tyaglide is 10-18 μm.

This application uses an ethanol solution with a mass concentration of 35% to pre-treat guanidine diformate hydrochloride and typagliflozin to improve the dissolution of the active ingredients in the composition. In the obtained mixture A, carboxymethyl cellulose is added to make the hydrochloric acid dicarboxylic acid Guanidine and typagliflozin bind relatively tightly, but in the previous experiment, in the process of forming the clear ointment, it was found that the concentration time of the clear ointment became longer. It may be that the existence of carboxymethyl cellulose hindered the formation of the clear ointment. Function, in order to improve the above situation, the applicant has gone through a lot of creative experiments and found that adding sodium hyaluronate can significantly shorten the formation time of the clear ointment. It is speculated that the mechanism is that there may be a large number of fiber pores in carboxymethyl cellulose, causing guanidine diformate hydrochloride and tyaggliflozin to enter the fiber pores, which slows down the formation of clear cream, and the addition of sodium hyaluronate can expand The pore size of the fiber pores is convenient to disperse the guanidine diformate hydrochloride and tyaggliflozin that enter the fiber pores, thereby shortening the formation time of the cleanser. However, the amount of sodium hyaluronate added must be controlled within a certain range, otherwise the clearing cream will be too thin and the formation time of the clearing cream will be longer.

In summary, this application includes at least one of the following beneficial technical effects:

1. The pharmaceutical composition of this application is pre-treated with guanidine diformate hydrochloride and tyaggliflozin with a 35% ethanol solution, which improves the dissolution of the active ingredients in the composition and ensures that the subsequently prepared pharmaceutical composition can stably exert its efficacy effect;

2. The pharmaceutical composition of the application has stable curative effect, good effect in treating type 2 diabetes, good patient compliance, and can prevent recurrence, which meets the needs of modern people;

3. The preparation method of the pharmaceutical composition of the present application has controllable quality, simple operation, low cost, and can be industrially produced.

detailed description

The application is described in further detail below.

Embodiment 1. The pharmaceutical composition of the application and its preparation method

The formulation of the pharmaceutical composition of the application includes the following raw materials by weight:

Tyaggliflozin 1kg

Guanidine Diformate Hydrochloride 100kg

Carboxymethyl cellulose 2kg

Sodium Hyaluronate 15kg

Calcium hydrogen phosphate 1kg

Carboxymethyl cellulose calcium 1.5kg

The preparation method of the pharmaceutical composition of the present application includes the following steps:

S1. Take the formulated amount of guanidine diformate hydrochloride and pass it through an 80-mesh sieve, the particle size of tyaggliflozin is 10μm, and then put the sieved guanidine diformate hydrochloride and tyaggliflozin into the silo of the wet granulator to mix and mix The speed is 400rpm/min, dry mixing for 5min, then add 4 times the total amount of guanidine diformate hydrochloride and tyaggliflozin in an ethanol solution with a mass concentration of 35%, heat in a water bath at 50℃, stir until fully dissolved, stirring speed It is 450 rpm/min, and the stirring time is 20 minutes to obtain the mixed solution A;

S2. Take the formulated amount of carboxymethyl cellulose through an 80-mesh sieve, add carboxymethyl cellulose and sodium hyaluronate to the mixed solution A of step S1 to obtain mixed solution B, and then heat and concentrate to obtain a relative density of 1.20 Then add calcium hydrogen phosphate and carboxymethyl cellulose calcium to mix, dry for 15 minutes, control the moisture content ≤3.5%, and weigh to obtain the pharmaceutical composition.

Embodiment 2. The pharmaceutical composition of the application and its preparation method

Tyaggliflozin 1kg

Guanidine Diformate Hydrochloride 150kg

Carboxymethyl cellulose 1.5kg

Sodium Hyaluronate 20kg

Microcrystalline cellulose 1kg

Carboxymethyl cellulose calcium 1kg

S1. Take the formulated amount of guanidine diformate hydrochloride through a 75 mesh sieve, the particle size of tyaggliflozin is 12μm, then put the sieved guanidine diformate hydrochloride and tyaggliflozin into the wet granulator silo to mix and mix The speed is 450 rpm/min, dry mixing for 5 minutes, then add guanidine diformate hydrochloride and tyaggliflozin 5 times the total mass concentration of ethanol solution of 35%, heated in a water bath at 55 ℃, stir until fully dissolved, stirring The speed is 500rpm/min, the stirring time is 25min, and the mixture A is obtained;

S2. Take the formulated amount of carboxymethyl cellulose through an 80-mesh sieve, add carboxymethyl cellulose and sodium hyaluronate to the mixed solution A of step S1 to obtain mixed solution B, and then heat and concentrate to obtain a relative density of 1.20 Then add microcrystalline cellulose and carboxymethyl cellulose calcium to mix, dry for 20 minutes, control the moisture content ≤3.5%, and weigh to obtain the pharmaceutical composition.

Embodiment 3. The pharmaceutical composition of the present application and its preparation method

Tyaggliflozin 1.5kg

Guanidine Diformate Hydrochloride 300kg

Carboxymethyl cellulose 2kg

Sodium Hyaluronate 25kg

Microcrystalline cellulose 1.5kg

Carboxymethyl cellulose calcium 1.5kg

S1. Take the formulated amount of guanidine diformate hydrochloride and pass it through an 85 mesh sieve, the particle size of tyaggliflozin is 15μm, and then put the sieved guanidine diformate hydrochloride and tyaggliflozin into the silo of the wet granulator to mix and mix The speed is 550rpm/min, dry mixing for 10min, then add 6 times the total amount of guanidine diformate hydrochloride and tyaggliflozin in an ethanol solution with a mass concentration of 35%, heat in a water bath at 60℃, stir until fully dissolved, stirring speed It is 600rpm/min, the stirring time is 30min, and the mixed solution A is obtained;

S2. Take the formulated amount of carboxymethyl cellulose through an 80-mesh sieve, add carboxymethyl cellulose and sodium hyaluronate to the mixed liquid A of step S1 to obtain mixed liquid B, and then heat and concentrate to obtain a relative density of 1.25 Then add microcrystalline cellulose and carboxymethyl cellulose calcium to mix, dry for 20 minutes, control the moisture content ≤3.5%, and weigh to obtain the pharmaceutical composition.

Embodiment 4. The pharmaceutical composition of the present application and its preparation method

Tyaggliflozin 1.5kg

Guanidine Diformate Hydrochloride 375kg

Carboxymethyl cellulose 3kg

Sodium Hyaluronate 30kg

Microcrystalline cellulose 2kg

Carboxymethyl cellulose calcium 2kg

S1. Take the formulated amount of guanidine diformate hydrochloride and pass it through an 80-mesh sieve, the particle size of tyaggliflozin is 18μm, and then put the sieved guanidine diformate hydrochloride and tyaggliflozin into the silo of the wet granulator to mix and mix The speed is 550rpm/min, dry mixing for 10min, then add 6 times the total amount of guanidine diformate hydrochloride and tyaggliflozin in an ethanol solution with a mass concentration of 35%, heat in a water bath at 60℃, stir until fully dissolved, stirring speed It is 600rpm/min, the stirring time is 30min, and the mixed solution A is obtained;

S2. Take the formulated amount of carboxymethyl cellulose through an 80-mesh sieve, add carboxymethyl cellulose and sodium hyaluronate to the mixed liquid A of step S1 to obtain mixed liquid B, and then heat and concentrate to obtain a relative density of 1.30 Then add microcrystalline cellulose and carboxymethyl cellulose calcium to mix, dry for 30 minutes, control the moisture content to be ≤3.5%, and weigh to obtain the pharmaceutical composition.

Embodiment 5. The pharmaceutical composition of the application and its preparation method

Tyaggliflozin 1kg

Guanidine Diformate Hydrochloride 230kg

Carboxymethyl cellulose 2kg

Sodium Hyaluronate 20kg

Microcrystalline cellulose 1.5kg

Carboxymethyl cellulose calcium 1kg

S1. Take the formulated amount of guanidine diformate hydrochloride and pass it through an 80-mesh sieve, the particle size of tyaggliflozin is 15μm, then put the sieved guanidine diformate hydrochloride and tyaggliflozin into the silo of the wet granulator to mix and mix The speed is 500rpm/min, dry blending for 10min, then add guanidine diformate hydrochloride, tyaggliflozin 5 times the total mass concentration of ethanol solution of 35%, heated in a water bath at 55℃, stir until fully dissolved, stirring speed It is 600rpm/min, the stirring time is 30min, and the mixed solution A is obtained;

Comparative example 1

Similar to Example 5, the difference is that: Sodium hyaluronate is not added to the pharmaceutical composition, and other parameters are the same as Example 5.

Comparative example 2

Similar to Example 5, the difference is that the mass ratio of carboxymethyl cellulose to sodium hyaluronate in the pharmaceutical composition is 1:8, and other parameters are the same as in Example 5.

Comparative example 3

Similar to Example 5, the difference lies in that: an ethanol solution with a mass concentration of 70% is added to the pharmaceutical composition, and the remaining parameters are the same as in Example 5.

Test example 1: Concentration time test

Test method: Concentrate the mixed liquid B into a clear paste with a relative density of 1.30 under a vapor pressure of 0.15 MPa, and calculate the concentration time.

Table 1 Comparison of concentration time

According to the data in Table 1, compared with Example 5, the lack of sodium hyaluronate in Comparative Example 1 will lead to longer concentration time of the clear cream, and the excessive amount of sodium hyaluronate in Comparative Example 2 will also cause clear cream. The concentration time of the pyruvate becomes longer, so the range of the added amount of hyaluronic acid must be controlled. In Comparative Example 3, changing the mass concentration of the ethanol solution did not affect the concentration time of the clear ointment.

Test Example 2: Determination of the dissolution rate of the pharmaceutical composition

Determination of chromatographic conditions: According to high performance liquid chromatography, octadecyl-bonded silica gel is used as the packed column, methanol-water (80:20) is the mobile phase, and the detection wavelength is 222nm. Take the test solution and the reference solution respectively into Sample 20μL, the number of theoretical plates is not less than 3000 calculated by Tyaggliflozin.

Dissolution test method:

The pharmaceutical compositions prepared in Examples 1 to 5 and Comparative Examples 1 to 3 were prepared into capsules according to conventional methods. According to the dissolution test method (Chinese Pharmacopoeia 2015 Edition Sibu General Principle 0931 Method 1), 900 mL of 0.1 mol/L hydrochloric acid The solution is the dissolution medium, the rotating speed of the basket method is 50rpm, and the operation is carried out in accordance with the law. After 5, 15, 30, and 60 minutes, take the solution and filter, and take the subsequent filtrate as the test solution of Tyaggliflozin, and add the same temperature and equal volume Dissolution medium; take another 14mg of Tyagliptin reference substance, accurately weigh it, place it in a 100mL volumetric flask, add methanol to dissolve and dilute to the mark, shake well, accurately pipette 2mL into a 25mL volumetric flask, add 0.1mol/L Dilute the hydrochloric acid solution to the mark, shake it up, and use it as a reference solution. According to the high performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition Four General Rules 0512), take 20 μL of the test solution and the reference solution into the high performance liquid chromatograph, record the chromatogram, and calculate according to the external standard method.

Table 2

According to the data in Table 2, the drug dissolution rates of the pharmaceutical compositions prepared in Examples 1 to 5 are all different, and the drug tyaggliflozin dissolution rates of the drug compositions prepared in Comparative Examples 1 to 3 are all less than 90% after 60 minutes. 3 The dissolution rate of guanidine diformate hydrochloride of the prepared pharmaceutical composition was less than 100% after 60 minutes, and it could not dissolve completely. In the pharmaceutical composition prepared in Comparative Example 3, changing the mass concentration of ethanol had an impact on the dissolution of the drug.

Test Example Three: Determination of Glucose Tolerance in Rats

1. Test materials: 100 male rats with a body weight of 200-220g were selected. The pharmaceutical compositions prepared in Examples 1 to 5 and Comparative Examples 1 to 3 were each set as one set, tyaggliflozin was set as one set, and dicarboxylic acid hydrochloride Guanidine is a group.

2. Test method: The rats were fasted for 16 hours, the fasting blood glucose was measured, and the fasting blood glucose was randomly divided into 10 groups. The dosage of 5mg/kg (Taigliflozin group), 250mg/kg (guanidine diformate hydrochloride) Group), the dosage of the pharmaceutical compositions prepared in Examples 1 to 5 and Comparative Examples 1 to 3 were 300 mg/kg respectively, and 4.5 g/kg of glucose was orally administered 0.5 hours after the administration, and the dose of each group was determined 0.5 hours after the administration. Rat blood glucose value, calculate the inhibition rate of lowering blood glucose of rats in each administration group, calculate the ratio P1, P2 of the drug combination prepared in each example and comparative example to the blood glucose inhibition rate of tyaggliflozin and metformin hydrochloride, and judge the decrease after administration The effect of sugar.

table 3

According to the data in Table 3, it can be seen that the pharmaceutical composition prepared in Examples 1 to 5 has a greater effect on the glucose tolerance of normal rats, and the pharmaceutical composition prepared in Example 5 has the greatest effect on the glucose tolerance of normal rats, and the blood glucose inhibition rate High, indicating that the intensity of glucose tolerance in rats is affected by the mass ratio of tyaggliflozin and guanidine diformate hydrochloride.

Compared with Example 5, the pharmaceutical compositions prepared in Comparative Example 1 (lack of sodium hyaluronate) and Comparative Example 2 (the mass ratio of carboxymethyl cellulose to sodium hyaluronate is 1:8), the blood glucose inhibition rate is both The pharmaceutical composition prepared in Examples 1 to 5 is not as high, indicating that changes in the raw materials or content in the pharmaceutical composition will affect the blood glucose inhibition rate. Comparative Example 3 (the ethanol solution with a mass concentration of 70%) has a negative effect on the normal The rat glucose tolerance effect is relatively small and has an impact on the blood sugar inhibition rate. It shows that the ethanol solution with a mass concentration of 35% can increase the effective active ingredients in the pharmaceutical composition and make the blood sugar lowering effect better.

The above-mentioned embodiments only exemplarily illustrate the principles and effects of the present application, and are not used to limit the present application. Anyone familiar with this technology can modify or change the above-mentioned embodiments without departing from the spirit and scope of this application. Therefore, all equivalent modifications or changes completed by those with ordinary knowledge in the technical field without departing from the spirit and technical ideas disclosed in this application should still be covered by the claims of this application.

Claims

A pharmaceutical composition for the treatment of diabetes, comprising tyagliflozin, guanidine diformate hydrochloride and additives, wherein the mass ratio of tyaggliflozin, guanidine diformate hydrochloride and additives is 1:(100～250):(15 ~30).
The pharmaceutical composition for treating diabetes according to claim 1, wherein the mass ratio of the tyaggliflozin, guanidine diformate hydrochloride and additives is 1: (150-250): (15-25).
The pharmaceutical composition for treating diabetes according to claim 1, wherein the mass ratio of tyaggliflozin, guanidine diformate hydrochloride and additives is 1:230:20.
The pharmaceutical composition for treating diabetes according to any one of claims 1 to 3, wherein the additive comprises sodium hyaluronate.
The pharmaceutical composition for treating diabetes according to claim 1, wherein the pharmaceutical composition further comprises a binder, a filler and a disintegrant.
The pharmaceutical composition for treating diabetes according to claim 5, wherein the binder is carboxymethyl cellulose, and the mass ratio of the carboxymethyl cellulose to sodium hyaluronate is 1:(1.5-4 ).
The pharmaceutical composition for treating diabetes according to claim 5, wherein the filler includes one of microcrystalline cellulose and dibasic calcium phosphate.
The pharmaceutical composition for treating diabetes according to claim 5, wherein the disintegrant comprises one of calcium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose.
The preparation method of the pharmaceutical composition for treating diabetes according to claim 5, which comprises the following steps:

S1. Mix guanidine diformate hydrochloride and typagliflozin, add 4-6 times the total amount of guanidine diformate hydrochloride and typagliflozin in an ethanol solution with a mass concentration of 35%, and heat it in a water bath at 50-60°C. Stir until completely dissolved to obtain mixed solution A; and

S2. Add binders and additives to the mixed liquid A of step S1 to obtain mixed liquid B, then heat and concentrate to obtain a clear paste with a relative density of 1.20 to 1.30, then add filler and disintegrant to mix, dry, and weigh , Get a pharmaceutical composition.
The preparation method of the pharmaceutical composition for treating diabetes according to claim 9, wherein the tyaggliflozin particle size is 10-18 μm.