A Captopril and Hydrochlorothiazide Tablet and Its Preparation Method

Abstract

The present invention discloses a captopril and hydrochlorothiazide tablet and a preparation method thereof. The captopril and hydrochlorothiazide tablet is prepared from the following components in parts by weight: 1-3 parts of captopril; 0.6-1.8 parts of hydrochlorothiazide; 60-75 parts of lactose; 17-25 parts of microcrystalline cellulose; 1-3 parts of hydroxypropyl cellulose; 1-3 parts of sodium carboxymethyl starch; 0.3-0.8 part of sodium lauryl sulfate; 0.3-0.8 part of magnesium stearate; 0.3-0.9 part of silicon dioxide. By adding sodium lauryl sulfate to the formula, the dissolution rate and bioavailability of the product are improved. The preparation method adopts the direct powder compression method, avoiding direct contact with moisture and heat, reducing the impurity level, and at the same time correspondingly avoiding the influence of particle differences on the finished tablet pressing and dissolution, which is more conducive to the stability between batches of the product and the controllability of production.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a captopril and hydrochlorothiazide tablet and a preparation method thereof. Background Art

[0002] Captopril is widely used clinically for hypertension and heart failure, especially with excellent effect on renal hypertension. It is also suitable for treating hypertensive patients accompanied by diabetes, hyperlipidemia, bronchial asthma, left ventricular hypertrophy and heart failure. Captopril is one of the first-choice antihypertensive drugs for clinicians. Hydrochlorothiazide is a thiazide diuretic compound and is a commonly used diuretic and antihypertensive drug. It is mainly applicable to cardiac edema, hepatic edema and renal edema: such as nephrotic syndrome, acute glomerulonephritis, chronic renal failure, and edema caused by excessive adrenal cortical hormones and estrogen; hypertension; diabetes insipidus. When captopril and hydrochlorothiazide are used together, the antihypertensive effect is significantly improved, and at the same time, the adverse reactions are reduced. Clinically, it is used for the treatment of mild and moderate primary hypertension.

[0003] The existing captopril and hydrochlorothiazide tablets are prepared by a wet granulation process, and their dissolution rate is only about 80%, and the bioavailability is relatively low. At the same time, the applicant found that when using wet granulation, captopril is prone to hydrolysis under aqueous conditions to produce impurity B, and new impurity C will also be produced under heating conditions; and when using gradient elution for the detection of related substances, it is found that for the products of this process during the validity period, although they meet the limits specified in the quality standards, the content of degradation impurities shows an obvious increasing trend, and the content of individual batches approaches the limit during the validity period, making it difficult to meet the internal requirements of the enterprise to improve product quality and adapt to market demands.

[0004] In view of this, this patent application is proposed. Summary of the Invention

[0005] In order to solve the above problems, the purpose of this patent application is to provide a captopril and hydrochlorothiazide tablet and a preparation method thereof, which solve the problems of low bioavailability of the existing captopril and hydrochlorothiazide tablets and the impurity problems in the production process.

[0006] The present invention is achieved through the following technical solutions:

[0007] The first object of the present invention is to provide a captopril and hydrochlorothiazide tablet, which is made from the following components in parts by weight:

[0008] Captopril: 1 - 3 parts;

[0009] Hydrochlorothiazide: 0.6 - 1.8 parts;

[0010] Lactose: 60 - 75 parts;

[0011] Microcrystalline cellulose: 17 - 25 parts;

[0012] Hydroxypropyl cellulose: 1 - 3 parts;

[0013] Sodium carboxymethyl starch: 1 - 3 parts;

[0014] Sodium dodecyl sulfate: 0.3 - 0.8 parts;

[0015] Magnesium stearate: 0.3 - 0.8 parts;

[0016] Silica: 0.3 - 0.9 parts.

[0017] In the embodiment of the present invention, sodium dodecyl sulfate is added to the formulation, which is beneficial to improving the dissolution rate of the product and enhancing the bioavailability of the product.

[0018] In an alternative embodiment, it is made from the following components in parts by weight:

[0019] Captopril: 2 parts;

[0020] Hydrochlorothiazide: 1.2 parts;

[0021] Lactose: 67 parts;

[0022] Microcrystalline cellulose: 20 parts;

[0023] Hydroxypropyl cellulose: 2 parts;

[0024] Sodium carboxymethyl starch: 2 parts;

[0025] Sodium dodecyl sulfate: 0.5 part;

[0026] Magnesium stearate: 0.5 part;

[0027] Silica: 0.5 part.

[0028] In an alternative embodiment, it is made from the following components in parts by weight:

[0029] Captopril: 2 parts;

[0030] Hydrochlorothiazide: 1.2 parts;

[0031] Lactose: 67 parts;

[0032] Microcrystalline cellulose: 20 parts;

[0033] Sodium carboxymethyl starch: 3 parts;

[0034] Hydroxypropyl cellulose: 1 part;

[0035] Sodium dodecyl sulfate: 0.5 part;

[0036] Magnesium stearate: 0.5 part;

[0037] Silica: 0.5 parts.

[0038] In an alternative embodiment, the microcrystalline cellulose has a molecular weight of 36,000 and a particle size of 150 - 200 μm.

[0039] The second object of the present invention is to provide a method for preparing captopril and hydrochlorothiazide tablets, comprising the following steps:

[0040] (1) Take captopril, hydrochlorothiazide, mix with microcrystalline cellulose, sieve, mix evenly, and then mix with part of lactose to obtain a mixed powder;

[0041] (2) After mixing the above mixed powder with the remaining lactose, sodium carboxymethyl starch, hydroxypropyl cellulose, sodium lauryl sulfate, and silica evenly, add magnesium stearate and mix, take samples for testing, and press tablets;

[0042] (3) Use blister packaging, with a desiccant inside and a composite film bag outside.

[0043] In the embodiments of the present invention, on the basis of adding sodium lauryl sulfate to the formula, the method of direct powder compression is used for preparation, which can avoid direct contact with moisture and heat, reduce the impurity level, and improve the product quality. At the same time, direct powder compression also correspondingly avoids the influence of particle differences on the finished tablets and dissolution, and is more conducive to the stability between batches of products and production controllability. It has the advantages of simple process, short production cycle, and low cost.

[0044] In an alternative embodiment, the sieve mesh during sieving in step (1) is 80 - 100 meshes.

[0045] In an alternative embodiment, the mass ratio of lactose in step (1) to that in step (2) is 1:1.

[0046] In an alternative embodiment, in step (3), the blister is an aluminum-plastic blister.

[0047] In an alternative embodiment, in step (3), the aluminum-plastic blister packaging is PVC + aluminum foil.

[0048] In an alternative embodiment, the desiccant in step (3) is silica gel or molecular sieve.

[0049] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0050] (1) A captopril and hydrochlorothiazide tablet provided in the embodiments of the present invention adds sodium lauryl sulfate to the formula, which is beneficial to improving the dissolution rate of the product and the bioavailability of the product.

[0051] (2) A preparation method of captopril and hydrochlorothiazide tablets provided in the embodiments of the present invention is prepared by the method of direct powder compression, which can avoid direct contact with moisture and heat, reduce the impurity level, and improve the product quality. At the same time, direct powder compression also correspondingly avoids the influence of particle differences on the finished tablet pressing and dissolution, and is more conducive to the stability and production controllability among batches of products. It has the advantages of simple process, short production cycle, and low cost.

[0052] (3) In the embodiments of the present invention, through the dual action of sodium dodecyl sulfate and the direct powder compression method, the dissolution rate and bioavailability of the tablet products are greatly improved, and at the same time, the product impurities are also significantly reduced. Detailed implementation manners

[0053] To make the purpose, technical solutions and advantages of the present invention clearer and more understandable, the present invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of the present invention are only used to explain the present invention and do not limit the present invention.

[0054] In the following description, a large number of specific details are set forth in order to provide a thorough understanding of the present invention. However, it is obvious to those of ordinary skill in the art that the present invention does not have to adopt these specific details. In other embodiments, well-known methods are not specifically described in order to avoid confusing the present invention.

[0055] Throughout the specification, the reference to "an embodiment", "embodiment", "an example" or "example" means that the specific features, structures or characteristics described in connection with the embodiment or example are included in at least one embodiment of the present invention. Therefore, the phrases "an embodiment", "embodiment", "an example" or "example" that appear throughout the specification do not necessarily all refer to the same embodiment or example. In addition, the specific features, structures or characteristics can be combined in any appropriate combination and / or sub-combination in one or more embodiments or examples.

[0056] In the description of the present invention, the orientation or positional relationship indicated by the terms "front", "rear", "left", "right", "up", "down", "vertical", "horizontal", "high", "low", "inner", "outer", etc. is only for the convenience of describing the present invention and simplifying the description, rather than indicating or implying that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on the protection scope of the present invention.

[0057] Example 1:

[0058] A kind of captopril and hydrochlorothiazide tablets is made from the following components in parts by weight as raw materials:

[0059] Captopril: 1 part;

[0060] Hydrochlorothiazide: 0.6 parts;

[0061] Lactose: 60 parts;

[0062] Microcrystalline cellulose: 17 parts;

[0063] Sodium carboxymethyl starch: 1 part;

[0064] Hydroxypropyl cellulose: 1 part;

[0065] Sodium lauryl sulfate: 0.3 parts;

[0066] Magnesium stearate: 0.3 parts;

[0067] Silica: 0.3 parts.

[0068] Its preparation method is carried out according to the following steps:

[0069] (1) According to the above ratios, take captopril, hydrochlorothiazide, and mix with microcrystalline cellulose, sieve, and mix evenly; the sieve mesh for sieving is 80 mesh;

[0070] (2) Then mix with a part of lactose;

[0071] (3) Mix the above mixed powder with the remaining lactose, sodium carboxymethyl starch, hydroxypropyl cellulose, sodium lauryl sulfate, and silica evenly; the amount of lactose added in this step is equal to the amount of lactose in step (2);

[0072] (4) Finally, add magnesium stearate and mix, take samples for testing, and press tablets;

[0073] (5) Use aluminum-plastic blister packaging, with a desiccant inside and a composite film bag outside. The aluminum-plastic blister packaging is PVC + aluminum foil, and the desiccant is silica gel.

[0074] The molecular weight of the microcrystalline cellulose used in this example is 36000, the particle size is 150 - 200um, and it is purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd. The microcrystalline cellulose used in the following examples and comparative examples is the same as that in this example.

[0075] Example 2:

[0076] A captopril and hydrochlorothiazide tablet is composed of the following components in parts by weight:

[0077] Captopril: 3 parts;

[0078] Hydrochlorothiazide: 1.8 parts;

[0079] Lactose: 75 parts;

[0080] Microcrystalline cellulose: 25 parts;

[0081] Sodium carboxymethyl starch: 3 parts;

[0082] Hydroxypropyl cellulose: 3 parts;

[0083] Sodium lauryl sulfate: 0.8 part;

[0084] Magnesium stearate: 0.8 part;

[0085] Silica: 0.9 part.

[0086] Its preparation method is carried out according to the following steps:

[0087] (1) Take captopril, hydrochlorothiazide, mix with microcrystalline cellulose, sieve, and mix evenly; the sieve mesh for the sieving is 100 mesh

[0088] (2) Then mix with part of lactose;

[0089] (3) Mix the above mixed powder with the remaining lactose, sodium carboxymethyl starch, hydroxypropyl cellulose, sodium lauryl sulfate, and silica evenly; the amount of lactose added in this step is equal to the amount of lactose in step (2);

[0090] (4) Finally, add magnesium stearate and mix, take samples for detection, and press tablets;

[0091] (5) Adopt aluminum-plastic blister packaging, with a desiccant inside and a composite film bag outside; the aluminum-plastic blister packaging is specifically: PVC + aluminum foil, and the desiccant is molecular sieve.

[0092] Example 3:

[0093] A captopril hydrochlorothiazide tablet is made from the following components in parts by weight:

[0094] Captopril: 2 parts;

[0095] Hydrochlorothiazide: 1.2 parts;

[0096] Lactose: 67 parts;

[0097] Microcrystalline cellulose: 20 parts;

[0098] Sodium carboxymethyl starch: 2 parts;

[0099] Hydroxypropyl cellulose: 2 parts;

[0100] Sodium lauryl sulfate: 0.5 part;

[0101] Magnesium stearate: 0.5 part;

[0102] Silica: 0.5 part.

[0103] Its preparation method is carried out according to the following steps:

[0104] (1) Take captopril and hydrochlorothiazide, mix them with microcrystalline cellulose, sieve, and mix evenly; the sieve mesh for sieving is 80 mesh;

[0105] (2) Then mix with a part of lactose;

[0106] (3) Mix the above mixed powder with the remaining lactose, sodium carboxymethyl starch, hydroxypropyl cellulose, sodium lauryl sulfate, and silicon dioxide; the amount of lactose added in this step is equal in weight to the lactose in step (2);

[0107] (4) Finally, add magnesium stearate and mix, take samples for testing, and press tablets;

[0108] (5) Use aluminum-plastic blister packaging, with a desiccant inside and a composite film bag outside. The aluminum-plastic blister packaging is specifically: PVC + aluminum foil, and the desiccant is silica gel.

[0109] Example 4:

[0110] A captopril and hydrochlorothiazide tablet is made from the following components in parts by weight:

[0111] Captopril: 2 parts;

[0112] Hydrochlorothiazide: 1.2 parts;

[0113] Lactose: 67 parts;

[0114] Microcrystalline cellulose: 20 parts;

[0115] Sodium carboxymethyl starch: 3 parts;

[0116] Hydroxypropyl cellulose: 1 part;

[0117] Sodium lauryl sulfate: 0.5 part;

[0118] Magnesium stearate: 0.5 part;

[0119] Silicon dioxide: 0.5 part.

[0120] Its preparation method is carried out according to the following steps:

[0121] (1) Take captopril and hydrochlorothiazide, mix them with microcrystalline cellulose, sieve, and mix evenly; the sieve mesh for sieving is 80 mesh;

[0122] (2) Then mix with a part of lactose;

[0123] (3) Mix the above mixed powder with the remaining lactose, sodium carboxymethyl starch, hydroxypropyl cellulose, sodium lauryl sulfate, and silicon dioxide;

[0124] (4) Finally, add magnesium stearate and mix, take samples for testing, and press tablets;

[0125] (5) It is packaged with an aluminum-plastic blister, with a desiccant inside and covered with a composite film bag. The aluminum-plastic blister packaging is specifically: PVC + aluminum foil, and the desiccant is silica gel.

[0126] Example 5:

[0127] A captopril and hydrochlorothiazide tablet is made from the following components in parts by weight:

[0128] Captopril: 2 parts;

[0129] Hydrochlorothiazide: 1.2 parts;

[0130] Lactose: 67 parts;

[0131] Microcrystalline cellulose: 20 parts;

[0132] Sodium carboxymethyl starch: 1 part;

[0133] Hydroxypropyl cellulose: 3 parts;

[0134] Sodium lauryl sulfate: 0.5 part;

[0135] Magnesium stearate: 0.5 part;

[0136] Silica: 0.5 part.

[0137] The direct compression process for captopril and hydrochlorothiazide tablet powder includes the following steps:

[0138] (1) Take captopril and hydrochlorothiazide, mix them with microcrystalline cellulose, sieve them, and mix well; the sieve mesh for sieving is 80 mesh;

[0139] (2) Then mix with part of the lactose;

[0140] (3) Mix the above mixed powder with the remaining lactose, sodium carboxymethyl starch, hydroxypropyl cellulose, sodium lauryl sulfate, and silica; the amount of lactose added in this step is equal to the amount of lactose in step (2);

[0141] (4) Finally, add magnesium stearate and mix, take samples for testing, and compress tablets;

[0142] (5) It is packaged with an aluminum-plastic blister, with a desiccant inside and covered with a composite film bag. The aluminum-plastic blister packaging is specifically: PVC + aluminum foil, and the desiccant is silica gel.

[0143] Comparative Example 1:

[0144] Using the traditional wet granulation prescription process to produce captopril and hydrochlorothiazide tablets, the formula is as follows:

[0145]

[0146] The specific process steps are:

[0147] Take the main drugs captopril and hydrochlorothiazide, sieve them (80 - 100 mesh), and by the equal - increment method, successively mix them evenly with hydroxypropyl cellulose, sodium carboxymethyl starch (inner part), lactose, and microcrystalline cellulose. Then add an appropriate amount of 5% povidone (K30) solution to make suitable soft materials, granulate through a 20 - mesh sieve, and dry. Screen the dried granules through an 18 - mesh sieve, add sodium carboxymethyl starch (outer part) and magnesium stearate, mix evenly, and press tablets to obtain the product.

[0148] Comparative Example 2:

[0149] A captopril and hydrochlorothiazide tablet is prepared from the following components by weight:

[0150] Captopril: 1 part;

[0151] Hydrochlorothiazide: 0.6 part;

[0152] Lactose: 60 parts;

[0153] Microcrystalline cellulose: 17 parts;

[0154] Sodium carboxymethyl starch: 1 part;

[0155] Hydroxypropyl cellulose: 1 part;

[0156] Magnesium stearate: 0.3 part;

[0157] Silicon dioxide: 0.3 part;

[0158] The direct - compression process of captopril and hydrochlorothiazide tablet powder includes the following steps:

[0159] (1) Take captopril and hydrochlorothiazide, mix them with microcrystalline cellulose, sieve them, and mix evenly; the sieve mesh for sieving is 80 mesh;

[0160] (2) Then mix with part of lactose;

[0161] (3) Mix the above - mentioned mixed powder with the remaining lactose, sodium carboxymethyl starch, hydroxypropyl cellulose, and silicon dioxide evenly;

[0162] (4) Finally, add magnesium stearate and mix, take samples for testing, and press tablets;

[0163] (5) Use aluminum - plastic blister packaging, with a desiccant inside and a composite film bag outside. The aluminum - plastic blister packaging is specifically: PVC + aluminum foil, and the desiccant is silica gel.

[0164] Impurity detection was carried out on the captopril and hydrochlorothiazide tablets obtained in each example and Comparative Example 1, and the results are shown in Table 1 below. The names of impurities B, C, D, and E can be seen in the following table.

[0165]

[0166] Table 1: Product performance test of each example and comparative example 1

[0167]

[0168] Dissolution and bioavailability tests were carried out on the examples and comparative examples, and the results are shown in Table 2 below:

[0169] Table 2: Dissolution and bioavailability test results of each example and comparative example

[0170]

[0171] The hardness and friability of the tableted products obtained from each example and comparative example were tested, and the results are shown in Table 3.

[0172] Table 3

[0173]

[0174]

[0175] As can be seen from Tables 1 to 3, when captopril hydrochlorothiazide was prepared by the traditional process method in Comparative Document 1, the related substances were relatively high. However, after direct powder compression in each example of the present invention, the related substances were significantly reduced. Although the direct powder compression method was also used in Comparative Document 2, sodium lauryl sulfate was missing in the formula, resulting in significantly lower dissolution and bioavailability of captopril and hydrochlorothiazide than those of each example.

[0176] Remove the outer packaging (composite film and desiccant) of the product obtained in Example 1, retain the aluminum-plastic blister, place it in an open container, and place it under strong light, high temperature, and high humidity conditions. Detect the related substances, dissolution, and content on the 5th day and 10th day respectively to investigate the stability of the drug under high temperature, light, and high humidity conditions. The results are shown in Table 4.

[0177] Table 4

[0178]

[0179] According to the results of the stress test, it shows that for the product obtained in Example 1, under strong light, high temperature, and high humidity conditions, the appearance, dissolution, moisture, content, and related substances have no obvious changes, and the dissolution at 15 minutes is greater than 85%. It can be seen that the preparation by direct powder compression can effectively reduce the impurity level in the product. By adding sodium lauryl sulfate to the formula, the bioavailability of the product can be significantly improved, and the yield of the product can also be increased.

[0180] The above specific embodiments have further elaborated in detail the object, technical solution and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A Captopril Hydrochlorothiazide Tablet, characterized in that: The composition is made from the following components in parts by weight: Captopril: 1-3 servings; Hydrochlorothiazide: 0.6-1.8 parts; Lactose: 60-75 parts; Microcrystalline cellulose: 17-25 parts; Hydroxypropyl cellulose: 1-3 parts; Sodium starch glycolate: 1-3 parts; Sodium lauryl sulfate: 0.3-0.8 parts; Magnesium stearate: 0.3-0.8 parts; Silicon dioxide: 0.3-0.9 parts; The preparation method of the captopril hydrochlorothiazide tablets comprises the following steps: (1) Captopril and hydrochlorothiazide are mixed with microcrystalline cellulose, sieved, mixed, and then mixed with part of lactose to obtain a mixed powder; (2) mixing the above mixed powder with the remaining lactose, sodium carboxymethyl starch, hydroxypropyl cellulose, sodium lauryl sulfate, and silicon dioxide, adding magnesium stearate, mixing, sampling, testing, and tableting; (3) Blister packaging with built-in desiccant and covered with composite film bag.

2. A captopril hydrochlorothiazide tablet according to claim 1, characterized in that: The composition is made from the following components in parts by weight: Captopril: 2 parts; Hydrochlorothiazide: 1.2 parts; Lactose: 67 parts; Microcrystalline cellulose: 20 parts; Hydroxypropylcellulose: 2 parts; Sodium starch glycolate: 2 parts; Sodium lauryl sulfate: 0.5 parts; Magnesium stearate: 0.5 parts; Silicon dioxide: 0.5 parts.

3. A captopril hydrochlorothiazide tablet according to claim 1, characterized in that: The composition is made from the following components in parts by weight: Captopril: 2 parts; Hydrochlorothiazide: 1.2 parts; Lactose: 67 parts; Microcrystalline cellulose: 20 parts; Sodium starch glycolate: 3 parts; Hydroxypropylcellulose: 1 part; Sodium lauryl sulfate: 0.5 parts; Magnesium stearate: 0.5 parts; Silicon dioxide: 0.5 parts.

4. The captopril hydrochlorothiazide tablets according to claim 1, characterized in that: The molecular weight of the microcrystalline cellulose is 36,000 and the particle size is 150-200 μm.

5. The method for preparing a captopril hydrochlorothiazide tablet according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) Captopril and hydrochlorothiazide are mixed with microcrystalline cellulose, sieved, mixed, and then mixed with part of lactose to obtain a mixed powder; (2) mixing the above mixed powder with the remaining lactose, sodium carboxymethyl starch, hydroxypropyl cellulose, sodium lauryl sulfate, and silicon dioxide, adding magnesium stearate, mixing, sampling, testing, and tableting; (3) Blister packaging with built-in desiccant and covered with composite film bag.

6. The method for preparing captopril hydrochlorothiazide tablets according to claim 5, characterized in that: The mesh size during sieving in step (1) is 80-100 mesh.

7. The method for preparing captopril hydrochlorothiazide tablets according to claim 5, characterized in that: The mass ratio of lactose in step (1) to that in step (2) is 1:

1.

8. The method for preparing captopril hydrochlorothiazide tablets according to claim 5, characterized in that: In the step (3), the blister is an aluminum-plastic blister.

9. The method for preparing captopril hydrochlorothiazide tablets according to claim 8, characterized in that: In the step (3), the aluminum-plastic blister packaging is PVC+aluminum foil.

10. The method for preparing captopril hydrochlorothiazide tablets according to claim 5, characterized in that: The desiccant in step (3) is silica gel or molecular sieve.

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