Acipimox capsule and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses an acipimox capsule and a preparation method thereof. The acipimox capsule provided by the invention comprises the following components: acipimox, modified starch, mannitol and a lubricant, the modified starch is obtained by sequentially performing microwave activation and alpha-amylase enzymolysis modification on starch. By adding the modified starch and the mannitol, the dependence of the acipimox capsule on traditional auxiliary materials in the preparation process is reduced, the formula is simplified, the production cost is reduced, the problem that the acipimox capsule is easy to adhere after being stored for a long time is effectively solved, the dissolution rate of the acipimox capsule is improved, and the bioavailability of the acipimox capsule is improved. The efficient release and better curative effect of the medicine are ensured.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an acipimox capsule and a preparation method thereof. Background Art

[0002] As an anti-lipid drug that plays an important role in the field of lipid-lowering, acipimox has a unique and significant mechanism of action. It effectively inhibits the release of free fatty acids from adipose tissue, which greatly reduces the amount of free fatty acids entering the liver. In this case, the synthesis of triglycerides (TG) is hindered, and the very low-density lipoprotein cholesterol (VLDL-C) formed with apolipoprotein B100 is correspondingly reduced, and the level of low-density lipoprotein cholesterol (LDL-C) is also reduced.

[0003] Acipimox is well, rapidly and completely absorbed orally, and the plasma concentration reaches a peak after 2 hours. At present, the storage conditions of Acipimox capsules are specified in the instructions as "light-shielded, sealed, and stored below 30°C". According to research, Acipimox raw materials are sensitive to temperature and humidity, and are prone to sticking together, resulting in a decrease in dissolution rate. Acipimox capsules prepared using existing public technologies are stored at room temperature for 24 months, or placed in a high temperature and high humidity environment for 10 days. The properties of the capsule contents change from loose to a cylinder with a certain hardness, the capsule disintegration time is extended by 3-5 times, and the dissolution rate (tested according to the quality standards for Acipimox capsules) decreases significantly. Due to changes in disintegration time and dissolution rate, the oral absorption and peak blood concentration time of this product are greatly affected, and there are risks to the safety and effectiveness of the drug. Summary of the invention

[0004] Aiming at the problem that the solubility of the existing acipimox capsule decreases after long-term storage, the present invention provides an acipimox capsule and a preparation method thereof.

[0005] In order to solve the above technical problems, the technical solution provided by the present invention is:

[0006] The first aspect of the present invention provides an acipimox capsule, comprising a core material and a hollow capsule;

[0007] The core material comprises the following components: acipimox, modified starch, mannitol and lubricant;

[0008] The modified starch is starch modified by sequentially microwave activation and α-amylase hydrolysis.

[0009] The inventors found during the research process that due to the large number of excipients added and the large amount of excipients added in the existing acipimox capsules, excessive excipients may change the dissolution rate of the drug to a certain extent; in addition, the increase in the types and amounts of excipients will also make the production process more complicated, and increase the cost to a certain extent; therefore, an acipimox capsule and a preparation method thereof are provided to solve the problems that the existing acipimox capsules have many excipients, are easy to stick together after long-term storage, and have low solubility.

[0010] Compared with the prior art, the acipimox capsule provided by the present invention first performs microwave activation on starch, so that the starch can be evenly heated in a short time, and the starch molecules are expanded by microwave radiation heating, thereby destroying the original structure of the starch and increasing the gaps between the starch molecules, thereby avoiding the adhesion of the acipimox raw material; alpha-amylase further destroys the long-chain structure of the starch, so that the small molecule substances obtained by starch enzymatic hydrolysis have good fluidity and dispersibility, and are not easy to agglomerate, and the starch is used as a dispersant to further improve the storage stability of the acipimox capsule; and the starch modified by microwave and alpha-amylase enzymatic hydrolysis has loose molecules and enhanced adsorption, and preferentially adsorbs water molecules than the acipimox raw material during long-term storage, thereby avoiding the adhesion of the acipimox raw material after long-term storage; more hydrophilic groups are exposed in the starch modified by alpha-amylase enzymatic hydrolysis after microwave activation, thereby further improving the solubility of the starch in water, and the starch is used as a cosolvent and a disintegrant to further improve the solubility of the acipimox capsule. However, after being placed for a long time, the modified starch will have the problem of starch agglomeration due to moisture absorption, which may reduce the solubility of the acipimox capsule to a certain extent. After a lot of research, the inventors further found that the problem of starch agglomeration can be further solved by adding mannitol to the acipimox capsule. Mannitol is interspersed and filled in the modified starch, and the two play a synergistic role, solving the problem of adhesion of the acipimox capsule after long-term placement. Only adding modified starch will also cause the acipimox capsule to have the problem of excessive fluidity and difficulty in operation during the preparation process. By adding mannitol, the hardness of the acipimox capsule core material can be increased to a certain extent, and the operability of the acipimox capsule core material during the preparation process is improved. In addition, since mannitol has a certain hydrophilicity, it synergizes with the modified starch to ensure the solubility of the acipimox raw material.

[0011] The modified starch and mannitol are added to the acipimox capsules provided by the present invention, thereby reducing the dependence of the acipimox capsules on traditional auxiliary materials during the preparation process, simplifying the formula, reducing the production cost, and effectively solving the problem of easy adhesion of the acipimox capsules during long-term storage, while improving the solubility of the acipimox capsules, ensuring efficient release of the drug and better therapeutic effect.

[0012] Preferably, the mass ratio of acipimox, modified starch, mannitol and lubricant is (78-80):(30-35):(15-18):(1-3).

[0013] Preferably, the lubricant is at least one of magnesium stearate or talc.

[0014] Preferably, the particle size D90 of the modified starch is 50 μm to 150 μm.

[0015] Preferably, the preparation method of the modified starch comprises the following steps:

[0016] Step 1, subjecting starch to microwave activation at a power of 400W to 500W to obtain microwave activated starch;

[0017] Step 2: adding the microwave activated starch and α-amylase into water, performing enzymolysis at 50° C. to 55° C., performing solid-liquid separation, washing, and drying to obtain modified starch.

[0018] In the preparation method of the modified starch provided by the present invention, microwave activated starch can heat the starch in a short time, greatly shortening the heating activation time, and through enzymatic hydrolysis of microwave activated starch, specific temperature and amylase can accurately destroy the long chain structure of starch to obtain modified starch with good performance; the preparation method of the modified starch provided by the present invention is simple to operate and easy to realize industrial production.

[0019] Preferably, in step 1, the microwave activation time is 2 min to 3 min.

[0020] Preferably, in step 2, the mass ratio of the microwave-activated starch to α-amylase is 100:(2-4).

[0021] By limiting the amount of α-amylase used, excessive enzymatic hydrolysis of microwave-activated starch can be avoided, thereby ensuring the performance of the modified starch.

[0022] Preferably, in step 2, the mass ratio of the microwave-activated starch to water is 100:(750-850).

[0023] Preferably, in step 2, the enzymatic hydrolysis time is 1.5 h to 2 h.

[0024] By limiting the heat preservation time, the solubility of the modified starch in water can be further improved, thereby improving the dissolution rate of the acipimox capsule.

[0025] Preferably, in step 2, during the enzymatic hydrolysis, stirring can be performed at a rate of 100 r / min to 300 r / min.

[0026] The second aspect of the present invention provides a method for preparing the above-mentioned acipimox capsule, comprising the following steps:

[0027] S1, mixing the weighed acipimox, modified starch and mannitol uniformly to obtain a first mixture;

[0028] S2. placing the first mixture in a dry granulator for granulation, uniformly mixing the prepared granules and lubricant, and filling the mixture into hollow capsules to obtain acipimox capsules.

[0029] Preferably, in S2, the particle size of the particles obtained by granulation is 20 to 60 meshes. DETAILED DESCRIPTION

[0030] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0031] In order to better illustrate the present invention, further examples are given below.

[0032] Example 1

[0033] This embodiment also provides an acipimox capsule, comprising the following components: acipimox, modified starch, mannitol and magnesium stearate, wherein the mass ratio of acipimox, modified starch, mannitol and magnesium stearate is 78:35:15:1;

[0034] The preparation method of modified starch comprises the following steps:

[0035] Step 1, activating starch by microwave at 400 W power for 2 min to obtain microwave activated starch;

[0036] Step 2, adding microwave activated starch and α-amylase into water, performing enzymolysis at 55° C. for 1.5 h, stirring at a speed of 100 r / min during enzymolysis, solid-liquid separation, washing, and drying to obtain modified starch with a particle size D90 of 50 μm; the mass ratio of microwave activated starch, α-amylase, and water is 100:2:750.

[0037] This embodiment also provides a method for preparing the above-mentioned acipimox capsule, comprising the following steps:

[0038] S1, mixing the weighed acipimox, modified starch and mannitol uniformly to obtain a first mixture;

[0039] S2. The first mixture is placed in a dry granulator for granulation. The particle size of the granules obtained by granulation is 20-60 meshes. The prepared granules and magnesium stearate are evenly mixed and filled into hollow capsules to obtain acipimox capsules.

[0040] Example 2

[0041] This embodiment also provides an acipimox capsule, comprising the following components: acipimox, modified starch, mannitol and talcum powder, wherein the mass ratio of acipimox, modified starch, mannitol and talcum powder is 80:30:18:3;

[0042] The preparation method of modified starch comprises the following steps:

[0043] Step 1, activating starch by microwave at 500 W power for 3 min to obtain microwave activated starch;

[0044] Step 2, adding microwave activated starch and α-amylase into water, performing enzymolysis at 50° C. for 2 h, stirring at a speed of 300 r / min during enzymolysis, solid-liquid separation, washing, and drying to obtain modified starch with a particle size D90 of 150 μm; the mass ratio of microwave activated starch, α-amylase, and water is 100:4:850.

[0045] This embodiment also provides a method for preparing the above-mentioned acipimox capsule, comprising the following steps:

[0046] S1, mixing the weighed acipimox, modified starch and mannitol uniformly to obtain a first mixture;

[0047] S2. The first mixture is placed in a dry granulator for granulation. The particle size of the granules obtained by granulation is 20-60 meshes. The prepared granules and talcum powder are evenly mixed and filled into hollow capsules to obtain acipimox capsules.

[0048] Example 3

[0049] This embodiment also provides an acipimox capsule comprising the following components: acipimox, modified starch, mannitol and talcum powder, wherein the mass ratio of acipimox, modified starch, mannitol and talcum powder is 79:33:16:2;

[0050] The preparation method of modified starch comprises the following steps:

[0051] Step 1, activating the starch by microwave at 450 W for 2.5 min to obtain microwave activated starch;

[0052] Step 2, adding microwave activated starch and α-amylase into water, performing enzymolysis at 52° C. for 1.8 h, stirring at a speed of 200 r / min during enzymolysis, solid-liquid separation, washing, and drying to obtain modified starch with a particle size D90 of 100 μm; the mass ratio of microwave activated starch, α-amylase, and water is 100:3:800.

[0053] This embodiment also provides a method for preparing the above-mentioned acipimox capsule, comprising the following steps:

[0054] S1, mixing the weighed acipimox, modified starch and mannitol uniformly to obtain a first mixture;

[0055] S2. The first mixture is placed in a dry granulator for granulation. The particle size of the granules obtained by granulation is 20-60 meshes. The prepared granules and talcum powder are evenly mixed and filled into hollow capsules to obtain acipimox capsules.

[0056] Comparative Example 1

[0057] This comparative example provides an acipimox capsule, and its preparation method is exactly the same as that of Example 1, except that mannitol in the formula is replaced by an equal amount of sorbitol, and other operations are the same as those of Example 1.

[0058] Comparative Example 2

[0059] This comparative example provides an acipimox capsule, and its preparation method is exactly the same as that of Example 1, except that the modified starch in the formula is starch modified by α-amylase enzymatic hydrolysis, and the microwave activation method is not used. The preparation method of the modified starch comprises the following steps:

[0060] Step 2: Add starch and α-amylase into water, perform enzymolysis at 55° C. for 1.5 h, stir at a speed of 100 r / min during enzymolysis, separate solid from liquid, wash, and dry to obtain modified starch with a particle size D90 of 50 μm; the mass ratio of starch, α-amylase, and water is 100:2:750.

[0061] The other operations are the same as those in Example 1.

[0062] Comparative Example 3

[0063] This comparative example provides an acipimox capsule, and its preparation method is exactly the same as that of Example 1, except that the modified starch in the formula is microwave-activated modified starch, and the method of α-amylase enzymolysis is not used. The preparation method of the modified starch comprises the following steps:

[0064] Step 1: Activate the starch by microwave at a power of 400 W for 2 min to obtain a modified starch with a particle size D90 of 50 μm.

[0065] The other operations are the same as those in Example 1.

[0066] Comparative Example 4

[0067] This comparative example provides an acipimox capsule, and its preparation method is exactly the same as that of Example 1, except that the α-amylase in the formula is replaced by an equal amount of β-amylase, and the other operations are the same as those of Example 1.

[0068] The stability test of the acipimox capsule products prepared in Examples 1-3 and Comparative Examples 1-4 was conducted, wherein the temperature treatment condition was: 40±2°C, and the humidity treatment condition was: 75±5%. The results are shown in Tables 1 to 5;

[0069] Table 1 Treatment 0 day test results

[0070]

[0071] Table 2 Accelerated treatment 30 days test results

[0072]

[0073]

[0074] Table 3 Accelerated treatment 60 days test results

[0075]

[0076] Table 4 Accelerated treatment 90 days test results

[0077]

[0078]

[0079] Table 5 Accelerated treatment 180 days test results

[0080]

[0081]

[0082] It can be seen from the above test data that, compared with comparative examples 1 to 4, the acipimox capsules prepared in Examples 1 to 3 of the present invention have higher stability. During the accelerated tests of 1 month, 2 months, 3 months and 6 months, the contents of the acipimox capsules appear as off-white particles without any sticking phenomenon. Moreover, by comparing the dissolution rate, the acipimox capsules provided in the embodiments of the present invention can still reach a dissolution rate of 95.3% after the 6-month accelerated test. This proves that the acipimox capsules prepared in the embodiments of the present invention will not stick during long-term storage and have a higher solubility, which is more conducive to improving the safety of clinical application.

[0083] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. An acipimox capsule, characterized in that: The invention comprises the following components: acipimox, modified starch, mannitol and lubricant; The modified starch is starch modified by sequentially microwave activation and α-amylase hydrolysis.

2. The acipimox capsule according to claim 1, characterized in that The mass ratio of acipimox, modified starch, mannitol and lubricant is (78-80):(30-35):(15-18):(1-3).

3. The acipimox capsule according to claim 1, characterized in that The lubricant is at least one of magnesium stearate or talc.

4. The acipimox capsule according to claim 1, characterized in that The particle size D90 of the modified starch is 50 μm to 150 μm.

5. The acipimox capsule according to claim 1, characterized in that: The preparation method of the modified starch comprises the following steps: Step 1, subjecting starch to microwave activation at a power of 400W to 500W to obtain microwave activated starch; Step 2: adding the microwave activated starch and α-amylase into water, performing enzymolysis at 50° C. to 55° C., performing solid-liquid separation, washing, and drying to obtain modified starch.

6. The acipimox capsule according to claim 5, characterized in that: In step 1, the microwave activation time is 2 min to 3 min.

7. The acipimox capsule according to claim 5, characterized in that In step 2, the mass ratio of the microwave activated starch to α-amylase is 100:(2-4).

8. The acipimox capsule according to claim 5, characterized in that In step 2, the mass ratio of the microwave-activated starch to water is 100:(750-850).

9. The acipimox capsule according to claim 5, characterized in that: In step 2, the enzymatic hydrolysis time is 1.5h to 2h.

10. A method for preparing the acipimox capsule according to any one of claims 1 to 9, characterized in that: The steps include: S1, mixing the weighed acipimox, modified starch and mannitol uniformly to obtain a first mixture; S2. placing the first mixture in a dry granulator for granulation, uniformly mixing the prepared granules and lubricant, and filling the mixture into hollow capsules to obtain acipimox capsules.

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