Metformin empagliflozin tablet composition and preparation method thereof

Abstract

The invention discloses a metformin empagliflozin tablet composition and a preparation method thereof. The metformin empagliflozin tablet composition is prepared from the following raw materials: metformin hydrochloride, empagliflozin, corn starch, copovidone, colloidal silicon dioxide, magnesium stearate and a gastric-soluble film coating premix. According to the metformin empagliflozin composition and the preparation method thereof, empagliflozin is dispersed in part of auxiliary materials, then mixing granulation is carried out through a wet granulator, empagliflozin and part of the auxiliary materials are premixed, and the particle size range of a metformin hydrochloride raw material is controlled, so that the problems of poor empagliflozin content uniformity and large inter-batch dissolution difference of the metformin empagliflozin composition prepared by a traditional process are solved; by controlling the mesh number of the wet granulation screen, the problems that materials adhere to the screen, discharging is difficult, and production efficiency is low in the wet granulation process are solved; compared with a fluidized bed production process, the equipment cost is low, the operation is simpler, and the production efficiency is higher; the pharmaceutical composition prepared by the preparation method disclosed by the invention is uniform in component mixing, simple to prepare, controllable in quality and consistent in in-vitro dissolution with an original preparation.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and more particularly to a metformin empagliflozin tablet composition and a preparation method thereof. Background Art

[0002] The incidence of type 2 diabetes is increasing, and its complications (such as diabetic foot, blindness, renal failure, etc.) not only affect the quality of life of patients, but may even shorten their lifespan; empagliflozin is an oral inhibitor of sodium-glucose co-transporter-2 (SGLT-2-mainly responsible for reabsorbing glucose from the glomerular filtrate into the systemic circulation), which reduces the renal reabsorption of filtered glucose by inhibiting SGLT-2 and lowers the renal threshold for glucose, thereby promoting the excretion of glucose from the urine; metformin hydrochloride is used for patients who are not satisfied with diet alone For patients with type II diabetes, especially those who are obese and have hyperinsulinemia, this drug not only has the effect of lowering blood sugar, but also may have the effect of reducing weight and hyperinsulinemia; the compound single tablet composed of empagliflozin and metformin hydrochloride has two unique hypoglycemic mechanisms; the raw material of empagliflozin is a white to slightly yellowish powder, which is very slightly soluble in water, slightly soluble in acetonitrile, 50% methanol, and ethanol, soluble in 50% acetonitrile, slightly soluble in methanol, and almost insoluble in toluene; the raw material of metformin hydrochloride is a white crystalline powder, odorless; it is easily soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform or ether.

[0003] The original manufacturer of metformin empagliflozin tablets is Boehringer Ingelheim International GmbH in Germany. It was approved by EMA in May 2015 and marketed in the EU under the trade name "SYNJARDY". It was approved by FDA in August 2015 and marketed in the United States under the trade name "SYNJARDY". It was approved by NMPA in February 2019 and marketed in China with marketed specifications of 500mg / 5mg, 850mg / 5mg, 850mg / 12.5mg, 1000mg / 5mg and 1000mg / 12.5mg, under the trade name "JARDIANCE DUO®".

[0004] The Chinese patent with the patent publication number CN102573808A discloses a method for preparing a metformin empagliflozin composition; the preparation process of the preparation is a fluidized bed granulation process, in which empagliflozin and a binder solution are prepared into an empagliflozin suspension, and the empagliflozin suspension is sprayed into a mixed material of metformin hydrochloride and a filler by a fluidized bed process, spray granulation, and then granulation, and a flow aid and a lubricant are added to obtain a pharmaceutical composition of metformin empagliflozin; and then tableting and coating are performed to obtain metformin empagliflozin tablets; the Chinese patent with the publication number CN106924237B discloses a pharmaceutical composition containing empagliflozin and metformin hydrochloride, and the preparation process is a fluidized bed granulation process, in which the binder is prepared into a binder solution, and the mixture is subjected to a fluidized bed granulation process. Spray it into a mixture of empagliflozin, metformin hydrochloride and microcrystalline cellulose to granulate, then granulate it, add a flow aid and a lubricant to obtain a pharmaceutical composition of metformin empagliflozin; then compress it into tablets and coat it to make metformin empagliflozin tablets; Chinese patent publication number CN115154456B discloses a pharmaceutical composition containing empagliflozin and dimethoate hydrochloride, in which empagliflozin is prepared with a binder solution under heating conditions to form an empagliflozin suspension, which is sprayed into a mixture of metformin hydrochloride and a filler through a wet granulator, and the wet granulator is stirred and cut to make a soft material, then granulated, dried, granulated it, added a flow aid and a lubricant to obtain a pharmaceutical composition of metformin empagliflozin, and then compressed it into tablets and coated it to make metformin empagliflozin tablets.

[0005] The content of empagliflozin in the metformin empagliflozin composition is low, with a content of about 1.0% in the specification of 1000mg / 12.5mg and about 0.4% in the specification of 1000mg / 5mg, and the particle size is small, D90≤40μm, which is easy to agglomerate, resulting in empagliflozin being difficult to mix evenly; the fluidized bed granulation process and wet granulation process in the existing patents both use empagliflozin mixed into the binder solution to make a suspension, and spray granulation method to ensure the mixing uniformity of empagliflozin. However, the process for preparing a stable empagliflozin binder suspension is relatively complicated, and the stability of the suspension system is affected by many factors such as the binder concentration, the amount of binder solution, the preparation temperature, the stirring rate and the stirring time, and the preparation time is relatively long. The residual empagliflozin material in the preparation container and the spray line also needs to be cleaned with sufficient purified water, and other factors lead to low production efficiency. Summary of the invention

[0006] In view of this, the present invention provides a metformin empagliflozin tablet composition and a preparation method thereof. The pharmaceutical composition prepared by the preparation method has uniformly mixed components, simple preparation, controllable quality and consistent in vitro dissolution with the original formulation, effectively solving the problems existing in the above-mentioned background technology.

[0007] In order to achieve the above object, the present invention adopts the following technical solution: A metformin empagliflozin tablet composition, comprising the following raw materials in parts by weight: Metformin hydrochloride 900-1100 parts; Empagliflozin 5-13 parts; 80-85 parts of copolyvidone; 70-85 parts corn starch; 2-5 parts of colloidal silicon dioxide; 6-10 parts of magnesium stearate; 20-25 parts of film coating premix.

[0008] The present invention provides a method for preparing a metformin empagliflozin tablet composition, comprising the following steps: S1. Crush empagliflozin and metformin hydrochloride; S2, adding the crushed empagliflozin, corn starch and copovidone into a three-dimensional mixer, mixing for 5 minutes, and passing through a 30-mesh sieve to obtain an empagliflozin premix; S3, pouring metformin hydrochloride into a high-speed mixing granulator, adding empagliflozin premix, and mixing for 5 minutes to obtain a premixed material; S4, adding the binder solution to the premixed material, granulating for 2 minutes to obtain a soft material; S5, transferring the soft material to a swing granulator, sieving and granulating to obtain wet granules; S6, drying and granulating to obtain granulated particles; S7, pouring the whole granules and colloidal silicon dioxide into a three-dimensional mixer and mixing for 5 minutes; adding magnesium stearate and mixing for 5 minutes to obtain a total mixed material; S8, tabletting and coating to obtain metformin empagliflozin tablets.

[0009] Preferably, in step S1, the empagliflozin is pulverized to a size of D90≤40 μm.

[0010] Preferably, in step S1, the metformin hydrochloride is pulverized to a size of D90: 140 μm to 300 μm.

[0011] Preferably, in step S4, the adhesive solution is a 25% copovidone aqueous solution; Preferably, in step S5, the granulation screen has a mesh size of 6; Preferably, in step S6, the drying is to transfer the wet particles to a fluidized bed dryer, set the induced draft fan frequency to 45 Hz±5 Hz, the drying temperature to no higher than 35° C., and the moisture content of the dried particles to 1% to 3%.

[0012] Preferably, in step S6, the granulation is to transfer the dry granules to an oscillating granulator and granulate through a 14-mesh sieve to obtain granulated granules.

[0013] Preferably, in step S8, tableting is performed by adding the total mixed material into a high-speed tablet press and controlling the hardness to be 10kg to 25kg.

[0014] Preferably, in step S8, the coating is performed by setting the parameters of the coating machine, spraying the coating solution tablets onto the surface of the plain tablets, and controlling the coating weight gain to be 1.5% to 3.0%, to obtain metformin empagliflozin tablets.

[0015] It can be seen from the above technical solution that, compared with the prior art, the metformin empagliflozin tablet composition and preparation method thereof provided by the present invention have the following beneficial effects: The metformin empagliflozin tablet composition and preparation method thereof of the present invention first disperses empagliflozin in part of the auxiliary materials, and then performs wet granulation mixing and granulation. By premixing empagliflozin with part of the auxiliary materials and controlling the particle size range of the metformin hydrochloride raw material, the problems of poor empagliflozin content uniformity and large dissolution difference between batches of the metformin empagliflozin composition prepared by the traditional process are solved; by controlling the mesh number of the wet granulation screen, the problems of material sticking to the screen, difficulty in feeding, and low production efficiency during the wet granulation process are solved. Compared with the fluidized bed production process, the equipment cost is low, the operation is simpler, and the production efficiency is higher. The pharmaceutical composition prepared by the preparation method of the present invention has uniform component mixing, simple preparation, controllable quality, and consistent in vitro dissolution with the original preparation. DETAILED DESCRIPTION

[0016] The following will be combined with the data in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0017] Example 1 The embodiment of the present invention discloses a metformin empagliflozin tablet composition, wherein the raw material composition and weight proportion are: 1000 parts of metformin hydrochloride, 5 parts of empagliflozin, 82 parts of corn starch, 82 parts of copovidone, 4 parts of colloidal silicon dioxide, 7 parts of magnesium stearate, 20 parts of gastric soluble film coating premix, and the total tablet weight is 1200 mg.

[0018] The embodiment of the present invention discloses a method for preparing a metformin empagliflozin tablet composition, comprising the following steps: (1) Pulverization of empagliflozin: Pulverize empagliflozin to a value of D90 ≤ 40 μm.

[0019] (2) Grinding of metformin hydrochloride: Grinding of metformin hydrochloride to a particle size of 140 μm to 300 μm.

[0020] (3) Empagliflozin premix: Add empagliflozin, corn starch and copolyvidone into a three-dimensional mixer, mix for 5 minutes, and pass through a 30-mesh sieve to obtain an empagliflozin premix.

[0021] (4) Wet granulation machine granulation: a. Preparation of adhesive: Add part of copolyvidone to a certain amount of purified water and stir for 30 minutes to prepare an adhesive solution with a concentration of 25% (w / w).

[0022] b. Premixing: Pour metformin hydrochloride into a high-speed mixing granulator, then add the empagliflozin premix, start stirring at a low speed, cutting at a low speed, and mix for 5 minutes to obtain the premixed material.

[0023] c. Making soft material: Add the adhesive solution into the premixed material, start high-speed stirring and high-speed cutting, and granulate for 2 minutes to obtain the soft material.

[0024] (5) Granulation: Transfer the soft material to a swing granulator and granulate through a 6-mesh sieve to obtain wet granules.

[0025] (6) Drying: Transfer the wet granules to a fluidized bed dryer, set the induced draft fan frequency to 45 Hz ± 5 Hz, and the drying temperature to no higher than 35°C, and dry the granules until the moisture content is 1% to 3%, thereby obtaining dry granules.

[0026] (7) Granulation: The dry granules are transferred to an oscillating granulator and sieved through a 14-mesh sieve to obtain granulated granules.

[0027] (8) Total mixing: Pour the whole granules and colloidal silicon dioxide into a three-dimensional mixer and mix for 5 minutes; add magnesium stearate and mix for 5 minutes to obtain a total mixed material.

[0028] (9) Tabletting: Add the total mixed material into a high-speed tablet press and control the hardness to 10kg to 25kg.

[0029] (10) Coating: Set the parameters of the coating machine, spray the coating solution onto the surface of the plain tablets, and control the coating weight gain to 1.5% to 3.0% to obtain metformin empagliflozin tablets.

[0030] Example 2 The experimental preparation was a 1000 mg / 5 mg metformin empagliflozin tablet, and the raw material composition and weight proportions were the same as those in Example 1.

[0031] In the preparation method of the metformin empagliflozin tablet composition, the preparation method of Example 1 is used as a reference, step (3) "empagliflozin premixing" step is removed, and the material in step 3 is added to step (4) "b premixing" step; the remaining steps are the same as the preparation method of Example 1, and the mixing method of empagliflozin is studied.

[0032] The prescription dosage of empagliflozin is 0.42%, and the content is small; D90≤40μm, the particle size is small, it is easy to agglomerate, and it is not easy to mix evenly; the mixing process can affect the mixing uniformity of empagliflozin, so the mixing process is studied.

[0033] Table 1 Table of studies on the mixing method of empagliflozin

[0034] Among them, the preparation method of Example 1 carries out "premixing of empagliflozin"; the preparation method of Example 2 does not carry out "premixing of empagliflozin".

[0035] Conclusion: Empagliflozin was first mixed with corn starch and copolyvidone and then premixed to obtain a premixed powder with better mixing uniformity of empagliflozin.

[0036] Example 3 The metformin empagliflozin tablets 1000 mg / 5 mg were used as the experimental preparation, and the raw material composition and weight proportion were the same as those in Example 1.

[0037] In the preparation method of the metformin empagliflozin tablet composition, the preparation method of Example 1 was used as a reference, the "a. binder preparation" step in step (4) was removed, and the binder solution in the "c. soft material preparation" step was replaced with purified water; the rest of the preparation method was the same as in Example 1, and the amount of water added in wet granulation was studied. The metformin-empagliflozin composition is a compound preparation. In order to ensure the uniformity of empagliflozin material mixing, uniformity of the central controlled dosage unit and uniformity of the content, the particle size of the prescription material is small and the fluidity is poor, so wet granulation is required. The amount of water added is the key parameter of wet granulation. If too much water is added, the soft material will be too sticky and cannot be granulated by shaking. If too little water is added, the granulation effect is poor and the fluidity of the material cannot be effectively improved. Therefore, a study on the amount of water added is carried out.

[0038] Table 2 Water addition research table

[0039] Conclusion: When the amount of water added is 3%, the soft material has better humidity, "it can be lumped together when held, and it will fall apart when touched", and the fluidity of the whole particles is better, so the amount of water added is set to 3%.

[0040] Example 4 The experimental preparation was a 1000mg / 12.5mg metformin empagliflozin tablet, with the raw material composition and weight ratio being: 1000mg metformin hydrochloride, 12.5mg empagliflozin, 74.5mg corn starch, 82mg copovidone, 4mg colloidal silicon dioxide, 7mg magnesium stearate, 20mg film coating homogenizer, and a total tablet weight of 1200mg.

[0041] In the preparation method of the metformin empagliflozin tablet composition, the preparation method of Example 1 is used as a reference, and step (5) "granulation" is: transferring the soft material to a swing granulator, granulating through a 4-14 mesh screen to obtain wet granules. The rest of the preparation method is the same as in Example 1, and the effect of the mesh number of the granulation screen on the granulation condition is investigated.

[0042] During the wet granulation process of soft materials on the swing granulator, friction generates heat, the material temperature rises, and it is easy to become sticky, which will clog the screen and affect the production efficiency. Therefore, a study on the mesh size of the granulation screen was carried out.

[0043] Table 3 Study on the number of meshes for wet granulation

[0044] Conclusion: When the mesh number of the sieve is in the range of 4-8 meshes, the material basically does not stick to the sieve during the granulation process. The mesh number of the sieve for soft material granulation is determined to be 4-8 meshes.

[0045] Example 5 The experimental preparation was a 1000 mg / 12.5 mg metformin empagliflozin tablet, and the raw material composition and weight ratio were the same as those in Example 4.

[0046] In the preparation method of the metformin empagliflozin tablet composition, the preparation method of Example 1 is used as a reference, and step (4) "a. preparation of adhesive" is: adding part of copovidone to a certain amount of purified water, stirring for 30 minutes, and preparing an adhesive solution with a concentration of 20% to 35% (w / w); the rest of the preparation method is the same as Example 1, and the effect of the adhesive concentration on the dissolution rate of the active ingredient is investigated.

[0047] The concentration of the adhesive affects the dissolution rate of the active ingredient. When the adhesive concentration is low, the active ingredient dissolves quickly, while when the adhesive concentration is high, the active ingredient dissolves slowly, which further affects the in vivo bioequivalence. Therefore, a study on the adhesive concentration was carried out.

[0048] Table 4 Bulk density and tap density of particles obtained with different binder concentrations

[0049] Dissolution conditions: Determined according to the "General Chapter 0931 Method 1" of Part IV of the 2020 edition of the Chinese Pharmacopoeia, 900 ml of pH 1.0 medium, 50 revolutions per minute.

[0050] Table 5 Dissolution data of preparations made with different concentrations of binders in pH 1.0 medium

[0051] Conclusion: When the binder concentration was 20%-35%, the in vitro dissolution of metformin hydrochloride and empagliflozin in the homemade preparation and the original preparation was similar, and the similarity factor f2 was greater than 50; when the binder concentration was 25%-30%, the in vitro dissolution similarity of the active ingredients metformin hydrochloride and empagliflozin in the homemade preparation and the original preparation was high, and the similarity factor f2 was greater than 60; therefore, the binder concentration can be prepared to be 20%-35%, preferably 25%-30%.

[0052] Example 6 The experimental preparation was a 1000 mg / 5 mg metformin empagliflozin tablet, and the raw material composition and weight proportions were the same as those in Example 1.

[0053] The preparation method of the metformin empagliflozin tablet composition is the same as that of Example 1, but the particle size of metformin hydrochloride is different.

[0054] The prescription dosage of empagliflozin is 0.42%, the content is small, and D90≤40μm, the particle size is small, which makes the empagliflozin raw material easy to agglomerate and difficult to mix evenly. In addition, the particle size of metformin hydrochloride raw material, which accounts for about 85%, can affect the mixing uniformity of empagliflozin and the solubility of metformin hydrochloride and empagliflozin, so a metformin hydrochloride particle size study was conducted.

[0055] Table 6 Effect of metformin hydrochloride particle size on mixing uniformity of empagliflozin in the total blend

[0056] Dissolution conditions: Determined according to the "General Chapter 0931 Method 1" of Part IV of the 2020 edition of the Chinese Pharmacopoeia, 900 ml of pH 1.0 medium, 50 revolutions per minute.

[0057] Table 7 Effect of metformin hydrochloride particle size on the dissolution of active ingredients

[0058] Conclusion: When the D90 of metformin hydrochloride raw material is in the range of 140μm-300μm, the mixing uniformity of the prepared total blend of empagliflozin is good, RSD<3.0%, and the dissolution curve of the active ingredient in the prepared preparation is similar to that of the original preparation in pH 1.0 medium, and the similarity factor f2 is greater than 50; the preferred range of D90 of metformin hydrochloride raw material is 140μm-300μm.

[0059] Based on the above research, a process scale-up study of 100,000 tablets of 1000mg / 12.5mg metformin empagliflozin tablets was carried out, and the mixing uniformity of the premixed material empagliflozin, the mixing uniformity of the total mixed material empagliflozin, the uniformity of the controlled dose unit of empagliflozin in the plain tablets, the content uniformity of the finished product empagliflozin and the in vitro pH 6.8 medium dissolution curves of the finished product and the original preparation were obtained as follows.

[0060] Table 8 Data on mixing uniformity of empagliflozin in premixed materials

[0061] Table 9 Data on the uniformity of empagliflozin in the total blend

[0062] Table 10 Uniformity data of the central controlled dose unit of empagliflozin tablets

[0063] Table 11 Content uniformity data of homemade empagliflozin

[0064] Table 12 Similarity of dissolution in pH 6.8 medium between homemade and original preparations

[0065] The mixing uniformity of the premixed material empagliflozin, the mixing uniformity of the total mixed material empagliflozin, the uniformity of the controlled dosage unit of the plain empagliflozin tablets, and the content uniformity of the finished product empagliflozin obtained by the process of the present invention are all good and meet the requirements of relevant regulations; the in vitro dissolution curve of the prepared finished homemade preparation is similar to that of the original manufacturer's preparation in the pH 6.8 medium.

[0066] In this specification, each embodiment is described in a progressive manner, and each embodiment focuses on the differences from other embodiments. The same or similar parts between the embodiments can be referred to each other. For the device disclosed in the embodiment, since it corresponds to the method disclosed in the embodiment, the description is relatively simple, and the relevant parts can be referred to the method part.

[0067] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for preparing a metformin empagliflozin tablet composition, characterized in that: The steps include: S1. Crush empagliflozin and metformin hydrochloride; S2, adding the crushed empagliflozin, corn starch and copovidone into a three-dimensional mixer, mixing for 5 minutes, and passing through a 30-40 mesh sieve to obtain an empagliflozin premix; S3, pouring metformin hydrochloride into a high-speed mixing granulator, adding empagliflozin premix, and mixing for 5-10 minutes; adding a binder solution to prepare a soft material; S4. Pour the soft material into the swing granulator, swing and sieve to get wet granules. S5, drying, granulating, mixing, tableting and coating to obtain metformin empagliflozin tablets.

2. The method for preparing a metformin empagliflozin tablet composition according to claim 1, characterized in that: In the step S1, the empagliflozin is pulverized to a particle size of D90≤40 μm.

3. The method for preparing a metformin empagliflozin tablet composition according to claim 1, characterized in that: In the step S1, the metformin hydrochloride is pulverized to a particle size of 140 μm to 300 μm.

4. The method for preparing a metformin empagliflozin tablet composition according to claim 1, characterized in that: In the step S3, the adhesive solution is a 20%-30% copovidone aqueous solution.

5. The method for preparing a metformin empagliflozin tablet composition according to claim 1, characterized in that: In the step S4, the mesh size of the swing screening process is 4-8 meshes.

6. The method for preparing a metformin empagliflozin tablet composition according to claim 1, characterized in that: In step S5, the total mixing is as follows: pouring the whole granules and colloidal silicon dioxide into a three-dimensional mixer and mixing for 5 minutes; adding magnesium stearate and mixing for 5 minutes to obtain a total mixed material.

7. A metformin empagliflozin tablet composition, characterized in that: The preparation method is composed of the following raw materials in parts by mass: 900-1100 parts of metformin hydrochloride, 5-13 parts of empagliflozin, 80-85 parts of copovidone, 70-85 parts of corn starch, 2-5 parts of colloidal silicon dioxide, 6-10 parts of magnesium stearate and 20-25 parts of film coating premix.

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