Production process of saxagliptin metformin sustained release tablet coating

Abstract

The invention discloses a saxagliptin metformin sustained-release tablet coating production process, and relates to the technical field of pharmaceutical preparations, and the saxagliptin metformin sustained-release tablet coating production process comprises the following steps: firstly, weighing a certain amount of a film coating premix, hydrochloric acid and purified water; adding a required amount of purified water into a solution preparation container, then adding hydrochloric acid to prepare a 0.1 mol / L hydrochloric acid solution, and stirring to form a vortex; film coating premix powder is slowly and uniformly added into a solvent, and powder is prevented from floating on the liquid surface as much as possible; and after all the film coating premix powder is added, reducing the stirring speed to enable vortexes to almost disappear, continuously stirring for 50-60 minutes, and adjusting the pH value of the coating solution to 2.0 by using a 4mol / L sodium hydroxide solution to obtain the isolating layer film coating solution. According to the invention, the coating yield of the produced saxagliptin metformin sustained-release tablet is obviously improved, the production quality and stability of the coated tablet are improved, and the large-scale production requirements are met.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a coating production process for saxagliptin metformin sustained-release tablets. Background Art

[0002] Diabetes is a common chronic comprehensive disease that plagues the world. Diabetes is a common and frequently occurring disease characterized by high blood sugar. There are two types of diabetes: insulin-dependent and non-insulin-dependent. Type 2 diabetes accounts for about 90% to 95% of the total number of diabetic patients. It has become the third most serious chronic disease that endangers human health after tumors and cardiovascular diseases. Currently, the main drug for the treatment of diabetes is saxagliptin metformin sustained-release tablets. In the production process of saxagliptin metformin sustained-release tablets, an important process is to coat the tablet core.

[0003] After searching, the Chinese patent publication number is CN112546013B, which discloses a saxagliptin metformin double-layer tablet and its preparation process. The double-layer tablet consists of a sustained-release core and a rapid-release outer layer; the sustained-release core includes the following raw and auxiliary materials by weight: 150-300 parts of metformin hydrochloride, 30-80 parts of hypromellose, 10-40 parts of wetting agent, and 1-10 parts of lubricant; the rapid-release outer layer includes the following raw and auxiliary materials by weight: 2.5-10 parts of saxagliptin, 100-350 parts of hydrophilic diluent, and 1-10 parts of lubricant.

[0004] The prior art is similar to the above-mentioned preparation method, which only performs coating once in the coating process, resulting in the thickness of the tablet core coating layer being easily substandard, affecting the production quality and stability of the coated tablets, and therefore there is room for improvement. Summary of the invention

[0005] The purpose of the present invention is to solve the shortcomings of the prior art and propose a coating production process for saxagliptin metformin sustained-release tablets. The advantage is that the coating yield of the produced saxagliptin metformin sustained-release tablets is significantly improved, the production quality and stability of the coated tablets are improved, and the demand for large-scale production is met.

[0006] In order to achieve the above object, the present invention adopts the following technical solutions:

[0007] A coating production process for saxagliptin metformin sustained-release tablets comprises the following steps:

[0008] Step 1: Seal coating

[0009] First, a certain amount of film coating premix, hydrochloric acid and purified water are weighed; a required amount of purified water and then hydrochloric acid are added to a liquid preparation container to prepare a 0.1 mol / L hydrochloric acid solution, and stirred to form a vortex; the film coating premix powder is slowly and evenly added to the solvent, and the powder is prevented from floating on the liquid surface as much as possible; after all the film coating premix powder is added, the stirring speed is reduced to make the vortex almost disappear, and the stirring is continued for 50-60 minutes, and the pH of the coating solution is adjusted to 2.0 with a 4 mol / L sodium hydroxide solution to obtain an isolation layer film coating solution, and after preparation, the isolation layer film coating solution is poured into a coating machine for isolation layer coating;

[0010] Step 2: Drug coating

[0011] Next, a certain amount of saxagliptin, film coating premix, hydrochloric acid and purified water are weighed; a required amount of purified water is added to a liquid preparation container, followed by hydrochloric acid to prepare a 0.1 mol / L hydrochloric acid solution, and stirred to form a vortex; saxagliptin monohydrate is evenly added to the solvent, stirred for 5 minutes to dissolve it, and then the film coating premix powder is slowly and evenly added to the solvent, and the powder is prevented from floating on the liquid surface as much as possible; after all the film coating premix powder is added, the stirring speed is reduced to make the vortex almost disappear, and stirring is continued for 40-50 minutes; the pH of the coating solution is adjusted to 2.0 with a 4 mol / L sodium hydroxide solution to obtain a film coating solution for the upper drug layer, and after preparation, the film coating solution for the upper drug layer is poured into a coating machine for coating the upper drug layer;

[0012] Step 3: Protective layer coating

[0013] Finally, weigh a certain amount of film coating premix, hydrochloric acid and purified water; add the required amount of purified water and then hydrochloric acid into the liquid preparation container to prepare a 0.1 mol / L hydrochloric acid solution, and stir to form a vortex; slowly and evenly add the film coating premix powder to the solvent, and try to avoid powder floating on the liquid surface; after all the film coating premix powder is added, reduce the stirring speed to make the vortex almost disappear, and continue stirring for 40-50 minutes; adjust the pH of the coating solution to 2.0 with 4 mol / L sodium hydroxide solution to obtain a protective layer film coating solution, and after preparation, pour the protective layer film coating solution into a coating machine for protective layer coating.

[0014] The present invention is further configured that the isolation layer film coating liquid in every 150,000 tablets is composed of the following raw materials in mass: 14.6-15.2 kg of film coating premix, 0.85-0.92 kg of hydrochloric acid, 84.2-85.3 kg of purified water and 1.95-2.03 kg of sodium hydroxide solution.

[0015] The present invention is further configured that the upper drug layer film coating liquid in every 150,000 tablets is composed of the following raw materials in mass: 0.746-0.752 kg of saxagliptin, 2.96-3.02 kg of film coating premix, 0.756-0.762 kg of hydrochloric acid, 71.23-71.28 kg of purified water and 1.95-2.03 kg of sodium hydroxide solution.

[0016] The present invention is further configured that the protective layer film coating liquid in every 150,000 tablets is composed of the following raw materials in mass: 2.51-2.55 kg of film coating premix, 0.14-0.16 kg of hydrochloric acid, 14.32-14.36 kg of purified water and 0.98-1.03 kg of sodium hydroxide solution.

[0017] The present invention is further configured such that the concentration of the sodium hydroxide solution is 4 mol / L, 10 kg of purified water is added to a liquid preparation container, and then 1.6 kg of sodium hydroxide is added, and the mixture is stirred to completely dissolve to obtain the sodium hydroxide solution.

[0018] The present invention is further configured that, when coating the isolation layer, attention should be paid to material balance and product yield, and the material balance calculation formula is: (total weight of isolation layer coated tablets + tailings + waste + sampling amount) / (total weight of incoming tablets + coating liquid dosage × 15%) × 100%; the product yield calculation method is: (total weight of isolation layer coated tablets + sampling amount) / (total weight of incoming tablets + coating liquid weight × 15%) × 100%.

[0019] The present invention is further configured that when coating the drug layer, the coating liquid is prepared according to an 80% drug application efficiency, and all the coating liquid is sprayed, the content of the drug tablets is measured, and the actual drug amount and the drug application efficiency are calculated; then, the remaining required coating liquid is prepared according to the actual drug application efficiency, and the drug is applied to the target value.

[0020] The present invention is further configured as follows: the upper drug layer is divided into an upper drug layer 1 and an upper drug layer 2, and the material balance calculation formula of the upper drug layer 1 is: (total weight of coated tablets in the upper drug layer 1 + amount of tailings + amount of waste + sampling amount) / (total weight of coated tablets in the isolation layer + amount of coating liquid × 5%) × 100%; the product yield calculation formula of the upper drug layer 1 is: (total weight of coated tablets in the upper drug layer 1 + sampling amount) / (total weight of coated tablets in the isolation layer + amount of coating liquid × 5%) × 100%.

[0021] The present invention is further configured as follows: the material balance calculation method of the upper drug layer 2 is: (total weight of coated tablets in the upper drug layer 2 + amount of tailings + amount of waste + sampling amount) / (total weight of coated tablets in the upper drug layer 1 + amount of coating liquid × 5%) × 100%; the product yield calculation method of the upper drug layer 2 is: (total weight of coated tablets in the upper drug layer 2 + sampling amount) / (total weight of coated tablets in the upper drug layer 1 + amount of coating liquid × 5%) × 100%.

[0022] The present invention is further configured as follows: the material balance calculation formula of the protective layer is: (total weight of the protective layer coated tablets + tailings + waste + sampling amount) / (total weight of the upper drug layer 2 coated tablets + coating liquid dosage × 15%) × 100%; the calculation formula of the protective layer product yield is: (total weight of the protective layer coated tablets + sampling amount) / (total weight of the upper drug layer 2 coated tablets + coating liquid dosage × 15%) × 100%.

[0023] The beneficial effects of the present invention are as follows: the present invention discloses a coating production process for saxagliptin metformin sustained-release tablets, wherein the entire coating process is divided into isolation layer coating, drug layer coating and protective layer coating, which are performed in sequence, and at the same time, the isolation layer coating, drug layer coating and protective layer coating are respectively prepared with specific raw materials of different types and different qualities to form coating solutions, so that the coating yield of the produced saxagliptin metformin sustained-release tablets is significantly improved, the production quality and stability of the coated tablets are improved, and the needs of large-scale production are met. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 A schematic diagram of the production process of a coating production process for saxagliptin metformin sustained-release tablets proposed in the present invention;

[0025] Figure 2 A schematic diagram of the composition of the isolation layer coating raw materials of a coating production process for saxagliptin metformin sustained-release tablets proposed in the present invention;

[0026] Figure 3 A schematic diagram of the composition of the coating raw materials of the upper drug layer of a coating production process for saxagliptin metformin sustained-release tablets proposed in the present invention;

[0027] Figure 4 The present invention provides a schematic diagram of the composition of protective layer coating raw materials for the coating production process of saxagliptin metformin sustained-release tablets. DETAILED DESCRIPTION

[0028] The technical solution of this patent is further described in detail below in conjunction with specific implementation methods.

[0029] The embodiments of the present invention are described in detail below, and examples of the embodiments are shown in the accompanying drawings, wherein the same or similar reference numerals throughout represent the same or similar elements or elements having the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary and are only used to explain the present invention, and cannot be understood as limiting the present invention.

[0030] Reference Figure 1-4 A coating production process for saxagliptin metformin sustained-release tablets comprises the following steps:

[0031] Step 1: Seal coating

[0032] First, a certain amount of film coating premix, hydrochloric acid and purified water are weighed; a required amount of purified water and then hydrochloric acid are added to a liquid preparation container to prepare a 0.1 mol / L hydrochloric acid solution, and stirred to form a vortex; the film coating premix powder is slowly and evenly added to the solvent, and the powder is prevented from floating on the liquid surface as much as possible; after all the film coating premix powder is added, the stirring speed is reduced to make the vortex almost disappear, and the stirring is continued for 50-60 minutes, and the pH of the coating solution is adjusted to 2.0 with a 4 mol / L sodium hydroxide solution to obtain an isolation layer film coating solution, and after preparation, the isolation layer film coating solution is poured into a coating machine for isolation layer coating;

[0033] Step 2: Drug coating

[0034] Next, a certain amount of saxagliptin, film coating premix, hydrochloric acid and purified water are weighed; the required amount of purified water is added to the liquid preparation container, and then hydrochloric acid is added to prepare a 0.1 mol / L hydrochloric acid solution, and stirred to form a vortex; saxagliptin monohydrate is evenly added to the solvent, stirred for 5 minutes to dissolve it, and then the film coating premix powder is slowly and evenly added to the solvent, and the powder is prevented from floating on the liquid surface as much as possible; after all the film coating premix powder is added, the stirring speed is reduced to make the vortex almost disappear, and stirring is continued for 40-50 minutes; the pH of the coating solution is adjusted to 2.0 with a 4 mol / L sodium hydroxide solution to obtain a film coating solution for the upper drug layer, and after preparation, the film coating solution for the upper drug layer is poured into a coating machine for coating the upper drug layer.

[0035] Step 3: Protective layer coating

[0036] Finally, weigh a certain amount of film coating premix, hydrochloric acid and purified water; add the required amount of purified water and then hydrochloric acid into the liquid preparation container to prepare a 0.1 mol / L hydrochloric acid solution, and stir to form a vortex; slowly and evenly add the film coating premix powder to the solvent, and try to avoid powder floating on the liquid surface; after all the film coating premix powder is added, reduce the stirring speed to make the vortex almost disappear, and continue stirring for 40-50 minutes; adjust the pH of the coating solution to 2.0 with 4 mol / L sodium hydroxide solution to obtain a protective layer film coating solution, and after preparation, pour the protective layer film coating solution into a coating machine for protective layer coating.

[0037] Example 1

[0038] The isolation film coating solution for each 150,000 tablets is composed of the following raw materials in mass:

[0039] Table 1:

[0040]

[0041] The film coating liquid for the upper drug layer per 150,000 tablets is composed of the following raw materials in terms of mass:

[0042] Table 2:

[0043]

[0044] The protective film coating liquid for each 150,000 tablets is composed of the following raw materials in mass:

[0045] Table 3:

[0046]

[0047] Example 2

[0048] The isolation film coating solution for each 150,000 tablets is composed of the following raw materials in mass:

[0049] Table 4:

[0050]

[0051] The film coating liquid for the upper drug layer per 150,000 tablets is composed of the following raw materials in terms of mass:

[0052] Table 5:

[0053]

[0054] The protective film coating liquid for each 150,000 tablets is composed of the following raw materials in mass:

[0055] Table 6:

[0056]

[0057] Example 3

[0058] The isolation film coating solution for each 150,000 tablets is composed of the following raw materials in mass:

[0059] Table 7:

[0060]

[0061] The film coating liquid for the upper drug layer per 150,000 tablets is composed of the following raw materials in terms of mass:

[0062] Table 8:

[0063]

[0064] The protective film coating liquid for each 150,000 tablets is composed of the following raw materials in mass:

[0065] Table 9:

[0066]

[0067] The concentration of the sodium hydroxide solution is 4 mol / L. Add 10 kg of purified water into a liquid preparation container, then add 1.6 kg of sodium hydroxide, and stir until completely dissolved to obtain a sodium hydroxide solution.

[0068] It is worth mentioning that when coating the isolation layer, attention should be paid to material balance and product yield. The material balance calculation formula is: (total weight of isolation layer coated tablets + amount of tailings + amount of waste + sampling amount) / (total weight of input tablets + amount of coating liquid × 15%) × 100%; the product yield calculation method is: (total weight of isolation layer coated tablets + sampling amount) / (total weight of input tablets + weight of coating liquid × 15%) × 100%.

[0069] When coating the drug layer, prepare the coating liquid according to 80% drug application efficiency, spray all the coating liquid, measure the content of the drug tablets, calculate the actual drug amount and drug application efficiency; then prepare the remaining required coating liquid according to the actual drug application efficiency, and apply the drug to the target value; the drug layer is divided into drug layer 1 and drug layer 2, and the material balance calculation formula of drug layer 1 is: (total weight of drug layer 1 coated tablets + tailings + waste + sampling) / (total weight of isolation layer coated tablets + coating liquid dosage × 5%) × 100%; product yield calculation of drug layer 1 The formula is: (total weight of coated tablets in upper drug layer 1 + sampling amount) / (total weight of coated tablets in isolation layer + amount of coating liquid × 5%) × 100%; the material balance calculation method for upper drug layer 2 is: (total weight of coated tablets in upper drug layer 2 + amount of tailings + amount of waste + sampling amount) / (total weight of coated tablets in upper drug layer 1 + amount of coating liquid × 5%) × 100%; the product yield calculation method for upper drug layer 2 is: (total weight of coated tablets in upper drug layer 2 + sampling amount) / (total weight of coated tablets in upper drug layer 1 + amount of coating liquid × 5%) × 100%.

[0070] The material balance calculation formula for the protective layer is: (total weight of protective layer coated tablets + amount of tailings + amount of waste + sampling amount) / (total weight of upper drug layer 2 coated tablets + amount of coating liquid × 15%) × 100%; the calculation formula for the yield of the protective layer product is: (total weight of protective layer coated tablets + sampling amount) / (total weight of upper drug layer 2 coated tablets + amount of coating liquid × 15%) × 100%.

[0071] In order to verify the advantages of the above-mentioned embodiments 1, 2 and 3 over the prior art, the following experiments are conducted:

[0072] Orthogonal test method was adopted, and the yield of qualified coated tablets was selected as the inspection index, wherein the yield of coated tablets = [weight of qualified coated tablets / weight of qualified plain tablets + weight of coating liquid)] * ​​100%. Three groups of comparative tests were carried out in sequence, and the test results were recorded as shown in the following table:

[0073] Table 10:

[0074]

[0075] The results show that: the mean yields of Example 1, Example 2 and Example 3 are all greater than the prior art, and the variances are much smaller than the prior art. The coated tablets obtained by the coating processes disclosed in Example 1, Example 2 and Example 3 are of high quality and good stability, which meet the requirements of large-scale production. At the same time, the mean yield of Example 2 is greater than that of Example 1 and Example 3, and the variance is also smaller than that of Example 1 and Example 3. Therefore, Example 2 is the best embodiment.

[0076] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A coating production process for saxagliptin metformin sustained-release tablets, characterized in that: The following steps are involved: Step 1: Seal coating First, a certain amount of film coating premix, hydrochloric acid and purified water are weighed; a required amount of purified water and then hydrochloric acid are added to a liquid preparation container to prepare a 0.1 mol / L hydrochloric acid solution, and stirred to form a vortex; the film coating premix powder is slowly and evenly added to the solvent, and the powder is prevented from floating on the liquid surface as much as possible; after all the film coating premix powder is added, the stirring speed is reduced to make the vortex almost disappear, and the stirring is continued for 50-60 minutes, and the pH of the coating solution is adjusted to 2.0 with a 4 mol / L sodium hydroxide solution to obtain an isolation layer film coating solution, and after preparation, the isolation layer film coating solution is poured into a coating machine for isolation layer coating; Step 2: Drug coating Next, weigh a certain amount of saxagliptin, film coating premix, hydrochloric acid and purified water; add the required amount of purified water and then hydrochloric acid into the liquid preparation container to prepare a 0.1 mol / L hydrochloric acid solution, and stir to form a vortex; evenly add saxagliptin monohydrate to the solvent, stir for 5 minutes to dissolve it, and then slowly and evenly add the film coating premix powder to the solvent, and try to avoid the powder floating on the liquid surface; after all the film coating premix powder is added, reduce the stirring speed to make the vortex almost disappear, and continue stirring for 40-50 minutes; The pH of the coating solution is adjusted to 2.0 with a 4 mol / L sodium hydroxide solution to obtain a film coating solution for the upper drug layer. After preparation, the film coating solution for the upper drug layer is poured into a coating machine for coating the upper drug layer; Step 3: Protective layer coating Finally, weigh a certain amount of film coating premix, hydrochloric acid and purified water; add the required amount of purified water and then hydrochloric acid into the liquid preparation container to prepare a 0.1 mol / L hydrochloric acid solution, and stir to form a vortex; slowly and evenly add the film coating premix powder to the solvent, and try to avoid powder floating on the liquid surface; after all the film coating premix powder is added, reduce the stirring speed to make the vortex almost disappear, and continue stirring for 40-50 minutes; adjust the pH of the coating solution to 2.0 with 4 mol / L sodium hydroxide solution to obtain a protective layer film coating solution, and after preparation, pour the protective layer film coating solution into a coating machine for protective layer coating.

2. The coating production process of saxagliptin metformin sustained-release tablets according to claim 1, characterized in that: The isolation layer film coating solution for every 150,000 tablets is composed of the following raw materials in mass: 14.6-15.2 kg of film coating premix, 0.85-0.92 kg of hydrochloric acid, 84.2-85.3 kg of purified water and 1.95-2.03 kg of sodium hydroxide solution.

3. The coating production process of a saxagliptin metformin sustained-release tablet according to claim 1, characterized in that: The upper drug layer film coating solution for every 150,000 tablets is composed of the following raw materials in mass: 0.746-0.752 kg of saxagliptin, 2.96-3.02 kg of film coating premix, 0.756-0.762 kg of hydrochloric acid, 71.23-71.28 kg of purified water and 1.95-2.03 kg of sodium hydroxide solution.

4. The coating production process of saxagliptin metformin sustained-release tablets according to claim 1, characterized in that: The protective layer film coating solution for every 150,000 tablets is composed of the following raw materials in mass: 2.51-2.55 kg of film coating premix, 0.14-0.16 kg of hydrochloric acid, 14.32-14.36 kg of purified water and 0.98-1.03 kg of sodium hydroxide solution.

5. A coating production process for saxagliptin metformin sustained-release tablets according to any one of claims 2 to 4, characterized in that: The concentration of the sodium hydroxide solution is 4 mol / L. 10 kg of purified water is added to a liquid preparation container, and then 1.6 kg of sodium hydroxide is added, and the mixture is stirred to completely dissolve to obtain a sodium hydroxide solution.

6. The coating production process of saxagliptin metformin sustained-release tablets according to claim 1, characterized in that: When coating the isolation layer, attention should be paid to material balance and product yield. The material balance calculation formula is: (total weight of isolation layer coated tablets + amount of tailings + amount of waste + sampling amount) / (total weight of incoming tablets + amount of coating liquid × 15%) × 100%; the product yield calculation method is: (total weight of isolation layer coated tablets + sampling amount) / (total weight of incoming tablets + weight of coating liquid × 15%) × 100%.

7. The coating production process of saxagliptin metformin sustained-release tablets according to claim 1, characterized in that: When coating the drug layer, the coating liquid is prepared according to 80% drug application efficiency, and all the coating liquid is sprayed, the content of the drug tablets is measured, and the actual drug amount and drug application efficiency are calculated; then the remaining required coating liquid is prepared according to the actual drug application efficiency, and the drug is applied to the target value.

8. The coating production process for saxagliptin metformin sustained-release tablets according to claim 7, characterized in that: The upper drug layer is divided into upper drug layer 1 and upper drug layer 2. The material balance calculation formula of the upper drug layer 1 is: (total weight of coated tablets in upper drug layer 1 + amount of tailings + amount of waste + sampling amount) / (total weight of coated tablets in isolation layer + amount of coating liquid × 5%) × 100%; the product yield calculation formula of the upper drug layer 1 is: (total weight of coated tablets in upper drug layer 1 + sampling amount) / (total weight of coated tablets in isolation layer + amount of coating liquid × 5%) × 100%.

9. The coating production process of saxagliptin metformin sustained-release tablets according to claim 8, characterized in that: The material balance calculation method of the upper drug layer 2 is: (total weight of the coated tablets of the upper drug layer 2 + the amount of tailings + the amount of waste + the sampling amount) / (total weight of the coated tablets of the upper drug layer 1 + the amount of coating liquid × 5%) × 100%; the product yield calculation method of the upper drug layer 2 is: (total weight of the coated tablets of the upper drug layer 2 + the sampling amount) / (total weight of the coated tablets of the upper drug layer 1 + the amount of coating liquid × 5%) × 100%.

10. The coating production process of saxagliptin metformin sustained-release tablets according to claim 1, characterized in that: The material balance calculation formula for the protective layer is: (total weight of the protective layer coated tablets + tailings + waste + sampling amount) / (total weight of the upper drug layer 2 coated tablets + coating liquid dosage × 15%) × 100%; the calculation formula for the protective layer product yield is: (total weight of the protective layer coated tablets + sampling amount) / (total weight of the upper drug layer 2 coated tablets + coating liquid dosage × 15%) × 100%.

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