Metformin hydrochloride rapid-release capsule and preparation method thereof

Abstract

The invention discloses a metformin hydrochloride rapid-release capsule and a preparation method thereof, the preparation method comprising the following steps: ① putting the metformin hydrochloride raw material and the binder into a wet mixing granulator according to the prescription amount ratio, wet mixing and granulation; ② vacuum drying the wet granules obtained in step ①; ③ granulation; ④ adding the prescribed amount of lubricant and mixing; ⑤ capsule filling; the binder is selected from hydroxypropyl methylcellulose and / or polyvinyl pyrrolidone and the amount of the binder does not exceed 0.2% of the weight of the metformin hydrochloride raw material; the wet mixing granulation time in step ① is 1 to 5 minutes, and the vacuum drying time in step ② is 3 to 4 hours. The present invention can obtain a metformin hydrochloride rapid-release capsule with uniform particles, good fluidity, small loading difference and less impurity content by optimizing the formulation formula and process parameters, and the metformin hydrochloride rapid-release capsule has high bioavailability, fast disintegration in the gastrointestinal tract and good absorption.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a metformin hydrochloride rapid-release capsule and a preparation method thereof. Background Art

[0002] Metformin hydrochloride is a biguanide hypoglycemic drug for the treatment of diabetes. It is used for patients with type 2 diabetes who are not satisfied with diet control alone, especially those who are obese and have hyperinsulinemia. This drug not only has the effect of lowering blood sugar, but also has the effect of reducing weight and hyperinsulinemia. Its main pharmacological effect is not to promote insulin secretion, but to promote tissue anaerobic glycolysis, so that muscle and other tissues can use glucose more effectively, while inhibiting the production of glycogen in the liver, reducing the production of glycogen in the liver, and lowering blood sugar.

[0003] The chemical name of metformin hydrochloride is 1,1-dimethylbiguanide hydrochloride, and its structural formula is as follows:

[0004] .

[0005] Existing metformin hydrochloride capsules mainly include immediate-release capsules (also known as ordinary capsules), enteric-coated capsules (see CN102416007A, CN103284975A), sustained-release capsules (see CN103239424A, CN104922091A) and controlled-release capsules (see CN1742730A, CN103356661A).

[0006] Although enteric-coated capsules and sustained-release capsules can relieve and improve gastrointestinal irritation, their effects are relatively poor.

[0007] Controlled-release capsules can improve gastrointestinal irritation and have relatively better effects, but their production costs are high, resulting in a more expensive price.

[0008] The main problems with existing metformin hydrochloride immediate-release capsules are: poor particle uniformity and fluidity, which in turn lead to large differences in filling volume and high impurity content, especially the latest impurity F (ie, dimethylamine). Summary of the invention

[0009] The object of the present invention is to solve the above problems and provide a metformin hydrochloride rapid-release capsule with uniform particles, good fluidity, small filling volume difference and low impurity content and a preparation method thereof.

[0010] The technical solution to achieve the purpose of the present invention is: a method for preparing metformin hydrochloride rapid-release capsules, comprising the following steps:

[0011] ① Put the metformin hydrochloride API and the binder into a wet mixing granulator according to the prescription amount ratio, and wet mix and granulate;

[0012] ② vacuum drying the wet granules obtained in step ①;

[0013] ③Whole grain;

[0014] ④ Add the prescribed amount of lubricant and mix;

[0015] ⑤Capsule filling.

[0016] The metformin hydrochloride raw material drug described in the above step ① must be crushed through a 40-80 mesh sieve, preferably through a 60 mesh sieve.

[0017] The type and amount of the adhesive described in the above step ① is one of the key technical means to solve the above technical problems. The applicant has found through a large number of experiments that the adhesive is selected from hydroxypropyl methylcellulose and / or polyvinyl pyrrolidone and the amount of the adhesive does not exceed 0.2% by weight of the metformin hydrochloride raw material, which can effectively solve the above technical problems; preferably 0.05% to 0.18%.

[0018] The hypromellose is preferably a 10% to 15% aqueous solution or ethanol solution of hypromellose.

[0019] The nominal viscosity of the hypromellose is 1 to 100 mPa·s, preferably 1 to 20 mPa·s, and more preferably 3 to 15 mPa·s.

[0020] The described hydroxypropyl methylcellulose includes but is not limited to E3 PREMIUM LV1 and E5 PREMIUM LV1 of Dow Chemical Company, E3 PHARM, E5 PHARM and E6 PHARM of Ashland Company, 603, 606, SM-4, SM-15, 60SH-50 and other specifications of products of Shin-Etsu Company.

[0021] The polyvinyl pyrrolidone is preferably a polyvinyl pyrrolidone aqueous solution or ethanol solution with a concentration of 5% to 15%.

[0022] The K value of the polyvinyl pyrrolidone is 27-32, preferably 30.

[0023] The specific method in the above step ① is as follows: first add the metformin hydrochloride raw material, start stirring, shearing (15Hz), dry mixing for 5 to 15 minutes, then add the binder solution, continue stirring, shearing (30 to 40Hz), wet mixing and granulation for 1 to 5 minutes, and then stop discharging.

[0024] The vacuum degree of vacuum drying in the above step ② is ≤-0.06MPa, the water bath temperature is 60-70°C, the temperature in the box is 40-60°C, and the drying time is 3-4h.

[0025] The wet mixing granulation time in the above step ① and the drying time in the above step ② are another important technical means to solve the above technical problems. Long wet mixing granulation time and drying time will cause uneven particles, agglomeration and hardening to varying degrees, thereby affecting fluidity and loading differences, and also slightly increase the special impurity F (dimethylamine).

[0026] The sieve aperture used for granulation in step ③ is 0.8-3.0 mm, and the motor frequency is 20-30 Hz.

[0027] The lubricant in the above step ④ is one or two or more (including two) of sodium stearyl fumarate, magnesium stearate, talc, and silicon dioxide.

[0028] The amount of the lubricant used is 0.1% to 1.0% of the weight of metformin hydrochloride.

[0029] The mixing frequency of the total mixing in the above step ④ is 25 to 30 Hz, and the mixing time is 5 to 20 minutes.

[0030] The dosage and usage of the above-mentioned metformin hydrochloride rapid-release capsules are: oral. Take during or immediately after meals. Adults start with 0.25g (1 capsule) at a time, 2 to 3 times a day, and then adjust the dosage according to blood sugar and urine sugar. The maximum daily dose should not exceed 2.0g (8 capsules), or follow the doctor's advice.

[0031] The present invention has the following positive effects: (1) By optimizing the formulation formula and process parameters, the present invention can obtain metformin hydrochloride rapid-release capsules with uniform particles, good fluidity, small filling volume difference and low impurity content. The metformin hydrochloride rapid-release capsules have high bioavailability, fast disintegration in the gastrointestinal tract and good absorption. (2) The metformin hydrochloride rapid-release capsules of the present invention have fewer components, a relatively simple preparation process, and stable and controllable product quality. Compared with other existing capsule dosage forms, they not only have better hypoglycemic effects, but also have lower production costs, thereby greatly reducing the price of drugs and being more suitable for the general public. DETAILED DESCRIPTION

[0032] (Example 1)

[0033] The process recipe of the metformin hydrochloride rapid-release capsules of this embodiment is as follows: 75.0 kg of metformin hydrochloride raw material, 0.08 kg of hypromellose, and 0.5 kg of magnesium stearate.

[0034] The total packaging is 300,000 tablets, and each tablet theoretically contains 0.25g of metformin hydrochloride.

[0035] The preparation method of the metformin hydrochloride rapid-release capsule comprises the following steps:

[0036] ① 75.0 kg of metformin hydrochloride raw material crushed through a 60-mesh sieve was put into a wet mixing granulator, dry mixed for 5 minutes, and then 0.8 kg of a 10 wt% aqueous solution of hypromellose (E5PREMIUM LV1 was used in this embodiment) was added, and stirring was continued, and wet mixing and granulation was performed for 3 minutes.

[0037] ② Use a vacuum drying oven to vacuum dry the wet particles obtained in step ①, with a vacuum degree of ≤-0.06MPa, a water bath temperature of 70°C, and an oven temperature of 50°C. Dry for 3 hours, take samples, and measure the moisture content. If the requirements are met, stop the machine and discharge the material.

[0038] ③ The dried granules obtained in step ② were sized using a sieve with a pore size of 2.0 mm and a motor frequency of 20 Hz.

[0039] ④ Add 0.5 kg of magnesium stearate and mix them at a mixing frequency of 25 Hz and a mixing time of 10 min.

[0040] ⑤ Fill the granules mixed in step ④ into a No. 1 hard capsule shell according to the prescribed amount to obtain the product.

[0041] (Example 2 to Example 4)

[0042] The preparation methods of each embodiment are basically the same as that of embodiment 1, and the differences are shown in Table 1.

[0043] Table 1

[0044] Example 1 Example 2 Example 3 Example 4 Adhesives Hydroxypropyl methylcellulose E5 Hydroxypropyl methylcellulose E5 Polyvinylpyrrolidone K30 Polyvinylpyrrolidone K30 Adhesive dosage 0.8kg 0.9kg 0.6kg 0.7kg Binder concentration 10wt% 13wt% 10wt% 12wt% Wet mixing granulation time 3min 5min 2min 3min

[0045] (Comparative Example 1 to Comparative Example 4)

[0046] The preparation methods of the comparative examples are basically the same as those of Example 1, and the differences are shown in Table 2.

[0047] Table 2

[0048] Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Adhesives Hydroxypropyl methylcellulose E5 Hydroxypropyl methylcellulose E5 Polyvinylpyrrolidone K30 Hydroxypropyl methylcellulose E5 Polyvinylpyrrolidone K30 Adhesive dosage 0.8kg 1.2kg 2.0kg 0.8kg 0.8kg Binder concentration 10wt% 18wt% 10wt% 10wt% 10wt% Granulation time 3min 3min 3min 8min 8min Drying time 3h 3h 3h 5h 5h

[0049] (Comparative Example 5)

[0050] The preparation method of this comparative example is basically the same as that of Example 1, except that: in step ①, 2.0 kg of mannitol and 1.6 kg of corn starch are added together with the metformin hydrochloride raw material, and the dry mixing time is 20 min.

[0051] (Test example)

[0052] The same method and standard were used to test the properties of the particles after vacuum drying in step ②, the properties of the particles after total mixing in step ④, the difference in the filling amount in step ⑤, and the content of impurity F during the preparation of metformin hydrochloride rapid-release capsules in Examples 1 to 4 and Comparative Examples 1 to 5. The results are shown in Table 3.

[0053] Table 3

[0054] Step ② Particle properties after vacuum drying Step ④ Particle properties after total mixing Difference in filling volume Impurity F content Example 1 Slightly clumped, lightly pressed to loosen Uniform particles and good fluidity ±6.7% 0.005% Example 2 Slightly lumpy, press lightly to loosen Uniform particles and good fluidity ±5.9% 0.003% Example 3 Slightly clumped, lightly press to loosen Uniform particles and good fluidity ±5.6% 0.004% Example 4 Slightly lumpy, press lightly to loosen Uniform particles and good fluidity ±5.7% 0.004% Comparative Example 1 In large chunks, not broken even with slight pressure The particles are hard, uneven, and have average fluidity. ±8.3% 0.011% Comparative Example 2 In large chunks, not broken even with slight pressure The particles are hard, uneven, and have average fluidity. ±8.4% 0.009% Comparative Example 3 In large chunks, not broken even with slight pressure The particles are hard, uneven, and have average fluidity. ±8.2% 0.012% Comparative Example 4 In large chunks, not broken even with slight pressure The particles are hard, uneven, and have average fluidity. ±8.5% 0.010% Comparative Example 5 Slightly clumped, lightly pressed to loosen Uniform particles, general fluidity ±7.8% 0.016%

[0055] It can be seen from Table 3 that with the increase of the amount of binder used in wet granulation, the increase of wet granulation time and the increase of vacuum drying time, the particles will become uneven, agglomerated and hardened to varying degrees, thereby affecting the fluidity and filling volume difference, and at the same time, the special impurity F (dimethylamine) will increase slightly.

Claims

1. A method for preparing metformin hydrochloride rapid-release capsules, characterized in that The following steps are involved: ① Put the metformin hydrochloride API and the binder into a wet mixing granulator according to the prescription amount ratio, and wet mix and granulate for 1 to 5 minutes; the binder is hydroxypropyl methylcellulose and / or polyvinyl pyrrolidone; the amount of the binder is 0.05% to 0.18% of the weight of the metformin hydrochloride API; The hypromellose is a 10% to 15% aqueous solution of hypromellose E5; The polyvinyl pyrrolidone is a polyvinyl pyrrolidone K30 aqueous solution with a concentration of 5% to 15%; ② vacuum drying the wet granules obtained in step ① for 3 to 4 hours; ③Whole grain; ④ Add the prescribed amount of lubricant and mix them; the lubricant is magnesium stearate; the amount of the lubricant is 0.1% to 1.0% of the weight of the metformin hydrochloride API; ⑤Capsule filling.

2. The method for preparing a metformin hydrochloride rapid-release capsule according to claim 1, characterized in that: The metformin hydrochloride raw material drug described in the above step ① must be crushed through a 40-80 mesh sieve.

3. A metformin hydrochloride rapid-release capsule prepared by the preparation method according to claim 1 or 2.