CN113797173B

CN113797173B - High-stability simvastatin tablet and preparation method thereof

Info

Publication number: CN113797173B
Application number: CN202111278638.8A
Authority: CN
Inventors: 陈兴禹; 李琴; 裴书捷
Original assignee: HAINAN HAILING CHEMICAL PHARMACEUTICAL CO Ltd
Current assignee: HAINAN HAILING CHEMICAL PHARMACEUTICAL CO Ltd
Priority date: 2021-10-31
Filing date: 2021-10-31
Publication date: 2023-03-17
Anticipated expiration: 2041-10-31
Also published as: CN113797173A

Abstract

The invention provides a high-stability simvastatin tablet and a preparation method thereof, the simvastatin tablet takes simvastatin as a raw material, and takes colloidal silicon dioxide, polyvinylpyrrolidone, pre-emulsified starch, sodium stearyl fumarate, lecithin and hydroxypropyl methylcellulose as auxiliary materials, all the components are crushed into powder which is sieved by a sieve of 120-140 meshes, and then the powder is respectively mixed and coated, the high-stability simvastatin tablet is prepared by controlling the fineness of the simvastatin and the auxiliary materials and combining the preparation method, the simvastatin tablet is more stable in storage, and the effectiveness and the safety of a medicament in taking are ensured.

Description

High-stability simvastatin tablet and preparation method thereof

Technical Field

The invention relates to the field of simvastatin tablets, and particularly relates to a high-stability simvastatin tablet and a preparation method thereof.

Background

Simvastatin is an HMG-COA (β -hydroxy and β -methyl-glutaryl-COA) reductase inhibitor that reduces cholesterol biosynthesis and regulates blood lipids by competitively inhibiting an early rate-limiting enzyme (HMG-COA reductase) in cholesterol anabolism. Simvastatin can reduce the content of Total Cholesterol (TC), low-density lipoprotein (LDL-C) and very low-density lipoprotein cholesterol (VLDC-C), slightly increase high-density lipoprotein cholesterol (HDL-C) and reduce plasma Triglyceride (TG), simvastatin has high selectivity to liver after being orally taken, the concentration of simvastatin in liver is obviously higher than that of other non-target tissues, most of simvastatin is absorbed by liver tissues and converted into an active metabolite, namely an e-hydroxy acid structure, can reduce the synthesis of liver cholesterol and regulate low-density lipoprotein receptor, promotes the clearance of low-density lipoprotein to reduce the level of intracellular cholesterol, reduces the level of moderate serum triglyceride and increases the level of blood high-density lipoprotein, and mainly plays a role in the liver and is then excreted from bile. Simvastatin has the advantages of strong pertinence, obvious curative effect, small toxic and side effects, good tolerance and the like, and is one of the best medicines for treating hypercholesterolemia.

Currently, a lot of reports exist about a preparation method of simvastatin tablets, for example, CN103356494 a adopts a method of coating simvastatin and then performing dry pressing with other auxiliary materials twice, so as to improve the stability of the simvastatin tablets, and solve the problem that the simvastatin tablets in the prior art have poor stability, but the method has high requirements on production equipment and is troublesome to produce. CN 103330692A provides a simvastatin component for improving stability and a preparation method thereof, and the formula, the dosage and the adding mode of auxiliary materials are reasonably selected by adopting a mode of not adding an antioxidant, so that the stability of simvastatin is kept, but the method is direct tabletting and has higher requirements on auxiliary materials and equipment. The invention provides a preparation method of simvastatin tablets, and the prepared simvastatin tablets are stable in quality, simple in process and small in loss.

Disclosure of Invention

In view of this, the invention provides a simvastatin tablet with high stability and a preparation method thereof, and the stability of the simvastatin tablet is improved.

The technical scheme of the invention is realized as follows:

the simvastatin tablet with high stability comprises the following raw materials in parts by weight: 10-15 parts of simvastatin, 2-2.5 parts of colloidal silicon dioxide, 0.1-0.3 part of polyvinylpyrrolidone, 7-8 parts of pre-emulsified starch, 0.1-0.3 part of sodium stearyl fumarate, 0.1-0.5 part of lecithin and 1-3 parts of hydroxypropyl methylcellulose.

Further, the preparation method of the simvastatin tablet with high stability comprises the following steps:

s1, crushing the raw materials, and sieving the crushed raw materials through a 120-140-mesh sieve.

And S2, mixing the pre-emulsified starch with distilled water to prepare a pre-emulsified starch solution.

And S3, mixing simvastatin, colloidal silicon dioxide, polyvinylpyrrolidone and sodium stearyl fumarate to prepare a simvastatin mixture.

And S4, adding the pre-emulsified starch solution into the simvastatin mixture, and mixing to obtain a total mixed material.

And S5, tabletting the soft material to obtain the plain tablets.

S6, adding lecithin and hydroxypropyl methylcellulose into an ethanol solution with the mass concentration of 50-60% to prepare a coating solution.

And S7, putting the plain tablets into a coating pan, and coating to obtain the simvastatin tablets.

Further, in step S2, the mass ratio of the pre-emulsified starch to the distilled water is 1:3-5.

Further, in the step S6, the ethanol solution accounts for 93-97% of the total mass of the coating solution.

Further, in step S7, the air inlet temperature of the coating pan is 40-45 ℃, the air exhaust temperature is 30-35 ℃, the temperature of the slice bed is 40-50 ℃, the initial rotation speed is 4-5r/min, the rotation speed is gradually increased to 7-9r/min in the rotation process, and the spray rotation speed of the coating liquid is 15-20r/min.

Further, in step S7, the weight of the plain tablet is increased by 0.3% to 0.7% after the coating solution is sprayed.

Further, in step S5, the tabletting strength is 7-10Pa.

Further, in step S3, the mixing is carried out by using a three-dimensional multi-directional motion mixer at a rotation speed of 5-15rpm for 40-50min.

Further, in step S4, the mixing is carried out by using a three-dimensional multi-directional motion mixer at a rotation speed of 30-40rpm for 20-30min.

Compared with the prior art, the invention has the beneficial effects that:

the invention takes simvastatin as a raw material and takes colloidal silicon dioxide, polyvinylpyrrolidone, pre-emulsified starch, sodium stearyl fumarate, lecithin and hydroxypropyl methylcellulose as auxiliary materials to prepare the high-stability simvastatin tablet. According to the invention, the raw materials and the auxiliary materials are scientifically matched and combined with the preparation process, the synergistic effect of the colloidal silicon dioxide, the polyvinylpyrrolidone, the pre-emulsified starch and the sodium stearyl fumarate not only increases the compactness of the simvastatin tablet and improves the stability of the simvastatin tablet, but also effectively controls the degradation of the simvastatin tablet in the storage process, the coating solution is prepared by using the lecithin and the hydroxypropyl methylcellulose, and the coating process is combined, so that the coating solution is uniformly attached to the surface of the simvastatin tablet, has proper thickness, is beneficial to dissolution and absorption in vivo, and improves the stability of the simvastatin tablet. The results of content uniformity and influence factor tests in the invention show that the prepared simvastatin tablet has stable quality and uniform content of main drugs in the tablet. The total impurities are not obviously increased after being placed for 10 days under the conditions of high temperature, high humidity and strong light. Shows that the compatibility between the raw materials and the auxiliary materials is good, and no new impurities are generated.

Detailed Description

In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.

The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.

The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description.

Example 1 high stability simvastatin tablet and method for preparing the same

(1) Weighing the following raw materials in parts by weight: 13 parts of simvastatin, 2.3 parts of colloidal silicon dioxide, 0.2 part of polyvinylpyrrolidone, 7.5 parts of pre-emulsified starch, 0.2 part of sodium stearyl fumarate, 0.3 part of lecithin and 2 parts of hydroxypropyl methylcellulose for later use.

(2) Pulverizing the raw materials, and sieving with 130 mesh sieve.

(3) Mixing pre-emulsified starch with distilled water, wherein the mass ratio of the pre-emulsified starch to the distilled water is 1:4, preparing the pre-emulsified starch solution.

(4) Simvastatin, colloidal silicon dioxide, polyvinylpyrrolidone and sodium stearyl fumarate were mixed using a three-dimensional multidirectional motion mixer at a rotation speed of 10rpm for 45min to prepare a simvastatin mixture.

(5) And adding the pre-emulsified starch solution into the simvastatin mixture, and mixing for 25min by using a three-dimensional multi-directional motion mixer at the rotating speed of 35rpm to prepare a total mixed material.

(6) And tabletting the soft material with the tabletting strength of 9Pa to obtain the plain tablets.

(7) Adding lecithin and hydroxypropyl methylcellulose into an ethanol solution with the mass concentration of 55%, wherein the ethanol solution accounts for 95% of the total mass of the coating solution, and thus obtaining the coating solution.

(8) And putting the plain tablets into a coating pan for coating, wherein the air inlet temperature of the coating pan is 43 ℃, the air exhaust temperature is 33 ℃, the temperature of a tablet bed is 45 ℃, the initial rotation speed is 4r/min, the rotation speed is gradually increased to 8r/min in the rotating process, and the spray rotation speed of the coating solution is 18r/min, so that the simvastatin tablets are prepared.

Example 2 high stability simvastatin tablets and methods of making the same

(1) Weighing the following raw materials in parts by weight: 10 parts of simvastatin, 2 parts of colloidal silicon dioxide, 0.1 part of polyvinylpyrrolidone, 7 parts of pre-emulsified starch, 0.1 part of sodium stearyl fumarate, 0.1 part of lecithin and 1 part of hydroxypropyl methylcellulose for later use.

(2) Pulverizing the raw materials, and sieving with 120 mesh sieve.

(3) Mixing pre-emulsified starch with distilled water, wherein the mass ratio of the pre-emulsified starch to the distilled water is 1: and 3, preparing a pre-emulsified starch solution.

(4) Simvastatin, colloidal silicon dioxide, polyvinylpyrrolidone and sodium stearyl fumarate were mixed using a three-dimensional multidirectional motion mixer at a rotation speed of 5rpm for 40min to prepare a simvastatin mixture.

(5) And adding the pre-emulsified starch solution into the simvastatin mixture, and mixing for 20min by using a three-dimensional multi-directional motion mixer at the rotating speed of 30rpm to prepare a total mixed material.

(6) And tabletting the soft material with the tabletting strength of 7Pa to obtain the plain tablets.

(7) Adding lecithin and hydroxypropyl methylcellulose into an ethanol solution with the mass concentration of 50%, wherein the ethanol solution accounts for 93% of the total mass of the coating solution, and thus obtaining the coating solution.

(8) And putting the plain tablets into a coating pan for coating, wherein the air inlet temperature of the coating pan is 40 ℃, the air exhaust temperature is 30 ℃, the temperature of a tablet bed is 40 ℃, the initial rotation speed is 4r/min, the rotation speed is gradually increased to 7r/min in the rotating process, and the spray rotation speed of the coating solution is 15r/min, so as to prepare the simvastatin tablets.

Example 3 high stability simvastatin tablets and methods of making the same

(2) Weighing the following raw materials in parts by weight: 15 parts of simvastatin, 2.5 parts of colloidal silicon dioxide, 0.3 part of polyvinylpyrrolidone, 8 parts of pre-emulsified starch, 0.3 part of sodium stearyl fumarate, 0.5 part of lecithin and 3 parts of hydroxypropyl methylcellulose for later use.

(2) Pulverizing the raw materials, and sieving with 140 mesh sieve.

(3) Mixing pre-emulsified starch with distilled water, wherein the mass ratio of the pre-emulsified starch to the distilled water is 1: and 5, preparing a pre-emulsified starch solution.

(4) Simvastatin, colloidal silicon dioxide, polyvinylpyrrolidone and sodium stearyl fumarate were mixed using a three-dimensional multi-directional motion mixer at a rotation speed of 15rpm for 50min to prepare a simvastatin mixture.

(5) And adding the pre-emulsified starch solution into the simvastatin mixture, and mixing for 30min by using a three-dimensional multi-directional motion mixer at the rotating speed of 40rpm to prepare a total mixed material.

(6) And tabletting the soft material with the tabletting strength of 10Pa to obtain the plain tablets.

(7) Adding lecithin and hydroxypropyl methylcellulose into an ethanol solution with the mass concentration of 60%, wherein the ethanol solution accounts for 97% of the total mass of the coating solution, and thus obtaining the coating solution.

(8) And putting the plain tablets into a coating pan for coating, wherein the air inlet temperature of the coating pan is 45 ℃, the air exhaust temperature is 35 ℃, the temperature of a tablet bed is 50 ℃, the initial rotation speed is 5r/min, the rotation speed is gradually increased to 9r/min in the rotating process, and the spray rotation speed of the coating solution is 20r/min, so as to prepare the simvastatin tablets.

Comparative example 1

On the basis of the example 1, parameters of the three-dimensional multi-directional motion mixer in the step (4) are adjusted, specifically, simvastatin, colloidal silicon dioxide, polyvinylpyrrolidone and sodium stearyl fumarate are mixed, and the mixing is performed by using the three-dimensional multi-directional motion mixer, and the mixing speed is 30rpm and is 50min.

Comparative example 2

On the basis of the example 1, parameters of the three-dimensional multi-directional motion mixer in the step (5) are adjusted, specifically, simvastatin, colloidal silicon dioxide, polyvinylpyrrolidone and sodium stearyl fumarate are mixed, and the mixture is mixed for 30min at a rotating speed of 70rpm by using the three-dimensional multi-directional motion mixer, so that a total mixed material is prepared.

Comparative example 3

On the basis of the example 1, the powder size in the step (2) is adjusted, specifically, simvastatin, colloidal silicon dioxide, polyvinylpyrrolidone, pre-emulsified starch, sodium stearyl fumarate, lecithin and hypromellose are respectively crushed and sieved by a 80-mesh sieve.

Comparative example 4

On the basis of the embodiment 1, the parameters of the coating pan in the step (8) are adjusted, specifically, plain tablets are put into the coating pan for coating, the air inlet temperature of the coating pan is 50 ℃, the air exhaust temperature is 40 ℃, the tablet bed temperature is 60 ℃, the initial rotation speed is 6r/min, the rotation speed is gradually increased to 10r/min in the rotation process, and the spray rotation speed of the coating liquid is 25r/min.

Comparative example 5

On the basis of the example 1, the raw materials in the step (1) are adjusted, and specifically, the method comprises the following steps: 13 parts of simvastatin, 2.3 parts of colloidal silicon dioxide, 0.2 part of copovidone, 7.5 parts of pre-emulsified starch, 0.2 part of magnesium stearate, 0.3 part of lecithin and 2 parts of hydroxypropyl methylcellulose.

Test example 1 content uniformity test

The content uniformity of the simvastatin tablets prepared in examples 1-3 and comparative examples 1-5 was determined by referring to the simvastatin tablet quality standard of the second department of the Chinese pharmacopoeia (2020 edition).

TABLE 1 content uniformity of simvastatin tablets

Name (R)	Content uniformity
		Example 1	2.84
Example 2	2.89
		Example 3	2.81
Comparative example 1	5.31
		Comparative example 2	6.22
Comparative example 3	5.88
		Comparative example 4	3.55
Comparative example 5	4.92

Experimental results show that the content uniformity of the simvastatin tablet prepared by the preparation method meets the requirement, the rotating speed in the preparation method is adjusted in the comparative example 1, so that the raw materials and the auxiliary materials cannot be uniformly mixed, and the content uniformity is poor due to layering in the tabletting process. In the comparative example 2, the rotating speed of the mixer is adjusted, so that the viscosity of the material is increased, and the wall adhesion phenomenon of the premix is caused, so that the content uniformity is reduced; comparative example 3 the size of the powder is adjusted, resulting in uneven mixing, too fine powder, easy loss in the preparation process, too coarse powder, easy uneven mixing, resulting in reduced content uniformity; comparative example 4 the coating process was adjusted to affect the coating effect, resulting in a decrease in content uniformity; and in the comparative example 5, the types of the auxiliary materials are adjusted, the mixing effect of the auxiliary materials and the main medicine is reduced, and the content uniformity is reduced.

Test example 2 influence factor test

The simvastatin tablets prepared in examples 1 to 3 and comparative examples 1 to 5 were subjected to the influencing factor test under the conditions of strong light (5000 lx), high humidity (25 ℃,92.5% RH), high temperature (60 ℃), dissolution test (pH 7.0), related substance detection (total impurity content), content measurement at 0 day and 10 days. The detection method refers to the quality standard detection of simvastatin tablets in the second part (2020 edition) of Chinese pharmacopoeia.

TABLE 2 determination of dissolution, related substances and contents at day 0

TABLE 3 determination of dissolution, related substances and contents in 10-day influencing factor test

Experimental results show that the invention is placed for ten days in the environment of high temperature, high humidity and strong light, and has stable quality. The simvastatin tablet prepared by the preparation method disclosed by the invention has high stability. In the comparative examples 1 to 5, the impurities are obviously increased, the content is reduced and the dissolution effect is poor in the influencing factor test.

The above description is only for the purpose of illustrating the preferred embodiments of the present invention and should not be taken as limiting the scope of the present invention, which is intended to cover any modifications, equivalents, improvements, etc. within the spirit and scope of the present invention.

Claims

1. The simvastatin tablet with high stability is characterized by comprising the following raw materials in parts by weight: 10-15 parts of simvastatin, 2-2.5 parts of colloidal silicon dioxide, 0.1-0.3 part of polyvinylpyrrolidone, 7-8 parts of pre-emulsified starch, 0.1-0.3 part of sodium stearyl fumarate, 0.1-0.5 part of lecithin and 1-3 parts of hydroxypropyl methylcellulose;

the preparation method comprises the following steps:

s1, crushing the raw materials, and sieving the crushed raw materials by a 120-140-mesh sieve;

s2, mixing the pre-emulsified starch with distilled water to prepare a pre-emulsified starch solution;

s3, mixing simvastatin, colloidal silicon dioxide, polyvinylpyrrolidone and sodium stearyl fumarate, wherein a three-dimensional multidirectional motion mixer is used for mixing for 40-50min at the rotating speed of 5-15rpm to prepare a simvastatin mixture;

s4, adding the pre-emulsified starch solution into the simvastatin mixture, and mixing, wherein a three-dimensional multidirectional motion mixer is used for mixing for 20-30min at the rotating speed of 30-40rpm to prepare a total mixed material;

s5, tabletting the soft material to obtain a plain tablet;

s6, adding lecithin and hydroxypropyl methylcellulose into an ethanol solution with the mass concentration of 50-60% to prepare a coating solution;

s7, putting the plain tablets into a coating pan, and coating to obtain the simvastatin tablets, wherein the air inlet temperature of the coating pan is 40-45 ℃, the air exhaust temperature is 30-35 ℃, the temperature of a tablet bed is 40-50 ℃, the initial rotating speed is 4-5r/min, the rotating speed is gradually increased to 7-9r/min in the rotating process, and the liquid spraying rotating speed of the coating liquid is 15-20r/min.

2. The highly stable simvastatin tablet according to claim 1, wherein in the step S2, the mass ratio of the pre-emulsified starch to the distilled water is 1:3-5.

3. The highly stable simvastatin tablet according to claim 1, wherein the ethanol solution accounts for 93-97% of the total mass of the coating solution in step S6.

4. The highly stable simvastatin tablet of claim 1, wherein the plain tablet gains 0.3% -0.7% weight after spraying the coating solution in step S7.

5. The highly stable simvastatin tablet according to claim 1, wherein the tabletting strength in step S5 is 7-10Pa.