Preparation process of pitavastatin calcium tablet

Abstract

The invention relates to a preparation process of a pitavastatin calcium tablet, and belongs to the technical field of drug synthesis, the pitavastatin calcium tablet comprises a tablet core and a coating, the tablet core comprises the following components in parts by weight: 1-2 parts of pitavastatin calcium, 40-75 parts of a filler, 4-30 parts of a disintegrating agent, 0.5-1.5 parts of an adhesive, 0.4-0.75 part of a lubricant, 2-5 parts of a stabilizer and 1-2 parts of a solubilizer; the preparation method comprises the following steps: weighing pitavastatin calcium, sieving, and uniformly mixing with the stabilizer to obtain a mixture A; sieving the filling agent and the disintegrating agent, and uniformly mixing to obtain a mixture B; uniformly mixing the mixture A and the mixture B according to an equal increment method to obtain a mixture C; adding an adhesive into the mixture C, and sieving twice to prepare wet particles; placing the wet particles in a drying oven for forced air drying to obtain dry particles; and adding a lubricant and the like into the dry granules, uniformly mixing, tabletting, and coating to obtain the pitavastatin calcium tablet. The whole tablet has the advantages of high tablet stability, good content uniformity and high disintegration and absorption efficiency.

Description

Technical Field

[0001] The invention relates to a preparation process of a pitavastatin calcium tablet, and belongs to the technical field of pharmaceutical preparations. Background Art

[0002] Pitavastatin calcium is a commonly used drug that belongs to a class of drugs called statins. It is used to lower cholesterol levels and prevent and treat cardiovascular disease. It works by inhibiting the activity of an enzyme called HMG-CoA reductase. HMG-CoA is involved in the synthesis of cholesterol in the body, and pitavastatin calcium blocks the activity of this enzyme, reducing the production of cholesterol, lowering the levels of total cholesterol and low-density lipoprotein, while increasing the level of high-density lipoprotein.

[0003] Pitavastatin calcium has high activity and a low content in the prescription, so it has problems of low stability and poor content uniformity, and its disintegration and absorption efficiency in the human body is difficult to reach a high peak. Summary of the invention

[0004] The present invention aims at the defects existing in the above prior art and provides a preparation process of pitavastatin calcium tablets, which solves the problem of improving tablet stability, improving content uniformity and improving disintegration and absorption efficiency.

[0005] The object of the present invention is achieved by the following technical scheme: a preparation process of a pitavastatin calcium tablet, comprising a tablet core and a coating, wherein the proportions of the tablet core components are as follows: 1-2 parts of pitavastatin calcium, 40-75 parts of filler, 4-30 parts of disintegrant, 0.5-1.5 parts of binder, 0.4-0.75 parts of lubricant, 2-5 parts of stabilizer, 1-2 parts of solubilizer; The solubilizing agent is one of docusate sodium, sucrose laurate, and poloxamer 188; The preparation steps of pitavastatin calcium tablets are as follows: S1: Weigh pitavastatin calcium, sieve it and mix it evenly with the stabilizer to obtain mixture A; S2: sieve the filler and disintegrant and mix them evenly to obtain a mixture B; S3: Mix the mixture A and the mixture B by adding equal amounts to obtain a mixture C; S4: Mixture C is sieved twice after adding a binder to obtain wet granules; S5: Place the wet granules in an oven and dry them at 45-60°C with forced air. After the weight loss on drying reaches 2-6%, sieve the granules with a 20-mesh sieve to obtain dry granules. S6: adding a lubricant, a solubilizer, a stabilizer and a disintegrant to the dry granules, mixing them evenly, sending them to a tablet pressing device for tableting, and then coating them to obtain pitavastatin calcium tablets.

[0006] In the preparation process of the above-mentioned pitavastatin calcium tablets, preferably, the mass of the stabilizer added in step S1 is 25-40% of the total mass of the stabilizer, and the mass of the stabilizer added in step S6 is 60-75% of the total mass of the stabilizer.

[0007] In the above-mentioned preparation process of pitavastatin calcium tablets, preferably, the mass of the disintegrant added in step S2 is 50-80% of the total mass of the disintegrant, and the mass of the disintegrant added in step S6 is 20-50% of the total mass of the disintegrant.

[0008] In the preparation process of the above-mentioned pitavastatin calcium tablets, preferably, the filler is one of pregelatinized starch, microcrystalline cellulose and lactose.

[0009] In the preparation process of the above pitavastatin calcium tablets, preferably, the disintegrant is one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

[0010] In the preparation process of the above-mentioned pitavastatin calcium tablets, preferably, the binder is one of an ethanol solution of hypromellose, an ethanol solution of povidone or a starch slurry.

[0011] In the preparation process of the above-mentioned pitavastatin calcium tablets, preferably, the lubricant is one of sodium stearate, potassium stearate and polyethylene glycol.

[0012] In the preparation process of the above-mentioned pitavastatin calcium tablets, preferably, the stabilizer is one of magnesium aluminum silicate and magnesium hydroxide.

[0013] In summary, compared with the prior art, the present invention has the following advantages: 1. In the scheme of the present invention, a hydrophilic lubricant is used to replace the common magnesium stearate lubricant to avoid the lubricant forming a hydrophobic barrier on the tablet surface after tableting, thereby affecting the disintegration performance of the tablet; 2. In the scheme of the present invention, the use of active agents as solubilizers can reduce the surface tension of water, thereby improving the wettability of the tablet surface. The role of the active agent is to increase the wettability of the particles, making it easier for water molecules to penetrate into the tablet, thereby accelerating the disintegration process and facilitating the absorption of the drug in the gastrointestinal tract; 3. In the scheme of the present invention, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, etc. are selected as disintegrants, which can significantly improve the disintegration efficiency of pitavastatin calcium tablets in the small intestine and enhance the absorption effect of pitavastatin calcium by the human body. Among them, cross-linked sodium carboxymethyl cellulose has good disintegration performance in the pH range of 1-12, and is suitable for tablets that disintegrate rapidly in the small intestine. Sodium carboxymethyl starch is suitable for use in an environment above pH 4, so it is very suitable for playing a role in the small intestine. Low-substituted hydroxypropyl cellulose is suitable for rapid disintegration under neutral conditions. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 This is the synthetic route of the present invention. DETAILED DESCRIPTION

[0015] The technical solution of the present invention is further specifically described below through specific embodiments, but the present invention is not limited to these embodiments.

[0016] Example 1 The components of the pitavastatin calcium tablets of this embodiment are as follows by mass: Pitavastatin calcium 1mg, pregelatinized starch 50mg, cross-linked carboxymethyl cellulose sodium 10mg, 5% hydroxypropyl methylcellulose (50% ethanol solution) 20mg, sodium stearate 1mg, magnesium aluminum silicate 2.5mg, docusate sodium 1mg, coating 1mg.

[0017] After crushing pitavastatin calcium through a 100-mesh sieve, weigh a certain amount of pitavastatin calcium and 25% of the total weight of magnesium aluminum silicate and mix them evenly to obtain a mixture A; A mixture B is obtained by uniformly mixing a predetermined amount of pregelatinized starch with 60% of the total mass of cross-linked sodium carboxymethyl cellulose; Mixture A and mixture B are mixed evenly by equal amounts, thereby obtaining mixture C; Add 5% hydroxypropyl methylcellulose (50% ethanol solution) into mixture C to prepare a soft material, and sieve the soft material twice with a 20-mesh sieve to obtain wet granules; The wet granules were placed in a 55°C oven and dried with forced air until the drying loss reached 4%. Then, the granules were taken out and sized with a 20-mesh filter to obtain dry granules. Docusate sodium, sodium stearate and the remaining cross-linked sodium carboxymethyl cellulose and magnesium aluminum silicate were added to the dry granules and mixed evenly; the granules were sent to a tableting device for tableting, and then coated to obtain pitavastatin calcium tablets, with a coating weight gain of 1.2%.

[0018] Example 2 This example is a comparative example of Example 1, except that the reaction conditions are modified as follows: pregelatinized starch is replaced by microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose is replaced by sodium carboxymethyl starch, hydroxypropyl methylcellulose is replaced by povidone, sodium stearate is replaced by potassium stearate, and docusate sodium is replaced by sucrose laurate. Other conditions are the same, and pitavastatin calcium tablets are prepared using the scheme of this example.

[0019] Example 3 This example is a comparative example of Example 1, except that the reaction conditions are modified as follows: pregelatinized starch is replaced with lactose, cross-linked carboxymethyl cellulose sodium is replaced with low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose is replaced with starch slurry, sodium stearate is replaced with polyethylene glycol, and docusate sodium is replaced with poloxamer 188. Other conditions are the same, and pitavastatin calcium tablets are prepared using the scheme of this example.

[0020] Example 4 This example is a comparative example of Example 1, and the reaction conditions are modified as follows: 40% of the total mass of magnesium aluminum silicate is used when preparing mixture A, and 60% of the total mass of magnesium aluminum silicate is used in the process of adding auxiliary materials to dry particles. Other conditions are the same, and pitavastatin calcium tablets are prepared using this example scheme.

[0021] Example 5 This example is a comparative example of Example 1, and the reaction conditions are modified as follows: 80% of the total mass of cross-linked sodium carboxymethyl cellulose is used when preparing mixture B, and 20% of the total mass of cross-linked sodium carboxymethyl cellulose is used in the process of adding excipients to dry granules. Other conditions are the same, and pitavastatin calcium tablets are prepared using this example scheme.

[0022] Example 6 Comparison of the physicochemical properties of Examples 1 to 5 with commercially available tablets: Accelerated testing Examples 1 to 5 and commercially available tablets were placed in a constant temperature and humidity chamber to examine the stability of each formulation at 40±2°C and 75±5% relative humidity for 6 months. Table 2 compares the main physical and chemical properties of each formulation in the accelerated test.

[0023] Table 1 is a comparison of the main physical and chemical properties of each embodiment on day 0: Table 2 is a comparison of the main physical and chemical properties of the accelerated tests of various embodiments: The implementation of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the present invention, ordinary technicians in this field can make various changes and improvements to the present invention in form and detail, and these are considered to fall within the protection scope of the present invention.

Claims

1. A process for preparing a pitavastatin calcium tablet, characterized in that: It includes a tablet core and a coating, and the proportion of the tablet core components is as follows: 1-2 parts of pitavastatin calcium, 40-75 parts of filler, 4-30 parts of disintegrant, 0.5-1.5 parts of binder, 0.4-0.75 parts of lubricant, 2-5 parts of stabilizer, 1-2 parts of solubilizer; The solubilizing agent is one of docusate sodium, sucrose laurate, and poloxamer 188; The preparation steps of pitavastatin calcium tablets are as follows: S1: Weigh pitavastatin calcium, sieve it and mix it evenly with the stabilizer to obtain mixture A; S2: sieve the filler and disintegrant and mix them evenly to obtain a mixture B; S3: Mix the mixture A and the mixture B by adding equal amounts to obtain a mixture C; S4: Mixture C is sieved twice after adding a binder to obtain wet granules; S5: Place the wet granules in an oven and dry them at 45-60°C with forced air. After the weight loss on drying reaches 2-6%, sieve the granules with a 20-mesh sieve to obtain dry granules. S6: adding a lubricant, a solubilizer, a stabilizer and a disintegrant to the dry granules, mixing them evenly, sending them to a tablet pressing device for tableting, and then coating them to obtain pitavastatin calcium tablets.

2. A process for preparing a pitavastatin calcium tablet according to claim 1, characterized in that: The mass of the stabilizer added in step S1 is 25-40% of the total mass of the stabilizer, and the mass of the stabilizer added in step S6 is 60-75% of the total mass of the stabilizer.

3. A process for preparing a pitavastatin calcium tablet according to claim 2, characterized in that: The mass of the disintegrant added in step S2 is 50-80% of the total mass of the disintegrant, and the mass of the disintegrant added in step S6 is 20-50% of the total mass of the disintegrant.

4. The preparation process of a pitavastatin calcium tablet according to claim 3, characterized in that: The filler is one of pregelatinized starch, microcrystalline cellulose and lactose.

5. The preparation process of a pitavastatin calcium tablet according to claim 4, characterized in that: The disintegrant is one of cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, and low-substituted hydroxypropyl cellulose.

6. The preparation process of a pitavastatin calcium tablet according to claim 5, characterized in that: The adhesive is one of an ethanol solution of hypromellose, an ethanol solution of povidone or a starch slurry.

7. The preparation process of a pitavastatin calcium tablet according to claim 6, characterized in that: The lubricant is one of sodium stearate, potassium stearate and polyethylene glycol.

8. The preparation process of a pitavastatin calcium tablet according to claim 7, characterized in that: The stabilizer is one of magnesium aluminum silicate and magnesium hydroxide.

Images