A simvastatin chewable tablet and its preparation method

Abstract

This invention belongs to the pharmaceutical field, specifically relating to a simvastatin chewable tablet and its preparation method. The simvastatin chewable tablet comprises simvastatin, a filler, a stabilizer, a disintegrant, a sweetener, and a lubricant. This invention, by optimizing the type and proportion of stabilizers and the filler addition process, provides a simvastatin chewable tablet with high dissolution and good stability, solving the problems of high related substance content and low dissolution in simvastatin chewable tablets. The preparation process of this invention is simple, eliminating the coating process, shortening the production cycle, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations, specifically relating to a simvastatin chewable tablet and its preparation method. Background Technology

[0002] Simvastatin is a lipid-soluble substance belonging to the statin class of lipid-lowering drugs, used to control cholesterol levels in the blood and prevent cardiovascular disease. Its chemical name is 2,2-dimethylbutyric acid-8-{(4R,6R)-6-(2-[(1S,2S,6R,8S,8aR)-1,2,6,7,8,8-α-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl]ethyl)}tetrahydro-4-hydroxy2H-pyran-2-one ester, with the following structural formula:

[0003]

[0004] Simvastatin tablets present many inconveniences when taken, especially for children, the elderly, and patients with swallowing difficulties, which undoubtedly reduces the target patient population. If simvastatin could be made into chewable tablets, it would not only make it easier to take and expand the target patient population, but the increased surface area of ​​the chewed tablets would also promote the dissolution and absorption of the drug in the body, thus improving the drug's performance.

[0005] Patent application CN104490805A discloses a simvastatin chewable tablet and its preparation method. The chewable tablet is composed of simvastatin, starch, sucrose and water. However, the experimental results of the examples show that its long-term stability is poor, the content of related substances is high, which increases the risk of medication. Moreover, the preparation method is cumbersome and complicated, which is not conducive to large-scale industrial production. Summary of the Invention

[0006] To overcome the shortcomings of existing technologies, this invention provides a simvastatin chewable tablet with high dissolution and good stability, solving the problems of high related substance content and low dissolution in simvastatin chewable tablets. It eliminates the coating process, simplifies the preparation process, shortens the production cycle, and is suitable for large-scale industrial production.

[0007] Specifically, the technical solution of the present invention is as follows:

[0008] This invention provides a simvastatin chewable tablet, which is composed of simvastatin, a filler, a stabilizer, a disintegrant, a sweetener, and a lubricant. The stabilizer is a combination of meglumine and sodium alginate.

[0009] Furthermore, the simvastatin chewable tablets of the present invention, calculated by weight, have the following components:

[0010]

[0011] Preferably,

[0012]

[0013] Furthermore, the filler is one or more of mannitol, microcrystalline cellulose, pregelatinized starch, and lactose, preferably one or two of mannitol and microcrystalline cellulose.

[0014] Furthermore, the disintegrant is one or more of sodium carboxymethyl starch, crospovidone, and crospovidone carboxymethyl cellulose.

[0015] Furthermore, the sweetener is one or more of aspartame and steviol glycosides.

[0016] Furthermore, the lubricant is one or more of magnesium stearate and sodium stearate fumarate.

[0017] Furthermore, the weight ratio of meglumine and sodium alginate is 1:1-3.

[0018] The second objective of this invention is to provide a method for preparing cetirizine hydrochloride tablets, specifically comprising the following steps:

[0019] (1) Pass simvastatin and 1 / 2 part by weight of filler through an 80-120 mesh sieve and mix them;

[0020] (2) Pass the disintegrant, stabilizer and sweetener through an 80-120 mesh sieve and mix them with the powder obtained in step (1);

[0021] (3) Mix the remaining 1 / 2 part by weight of filler through an 80-120 mesh sieve with the powder obtained in step (2), and then add the lubricant that has passed through an 80-120 mesh sieve and mix.

[0022] (4) Tableting.

[0023] Preferably, it includes the following steps:

[0024] (1) Simvastatin, 1 / 2 part by weight of mannitol and / or microcrystalline cellulose are passed through a 100-mesh sieve and mixed.

[0025] (2) Sodium carboxymethyl starch, meglumine, sodium alginate, and aspartame are passed through a 100-mesh sieve and mixed with the powder obtained in step (1);

[0026] (3) Mix the remaining 1 / 2 parts by weight of mannitol and / or microcrystalline cellulose through a 100-mesh sieve with the powder obtained in step (2), and then add magnesium stearate that has been passed through a 100-mesh sieve and mix.

[0027] (4) Tableting.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0029] 1) By optimizing the type and proportion of stabilizers, especially by using a weight ratio of meglumine and sodium alginate of 1:1-3, the content of related substances in simvastatin chewable tablets can be effectively reduced, the stability of the drug can be enhanced, and the quality of the drug can be improved.

[0030] 2) Optimize the process of adding fillers and control the key points in the process. Add the fillers mannitol and / or microcrystalline cellulose in two batches to the preparation process. This significantly improves the drug dissolution rate and reduces the content of related substances. The technical effect is significantly better than the existing technology.

[0031] 3) Chewable tablets are convenient to take, have a good taste, and are widely applicable.

[0032] 4) The preparation process is simple, eliminating the coating process, shortening the production cycle, and making it easy to mass-produce industrially. Detailed Implementation

[0033] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0034] Examples 1-11: Simvastatin Chewable Tablets

[0035] Prescription (10,000 tablets):

[0036]

[0037] Preparation method:

[0038] (1) According to the prescription, simvastatin, 1 / 2 part by weight of mannitol and / or microcrystalline cellulose are passed through a 100-mesh sieve and mixed.

[0039] (2) Sodium carboxymethyl starch, meglumine, sodium alginate, and aspartame are passed through a 100-mesh sieve and mixed with the mixture obtained in step (1);

[0040] (3) Mix the remaining 1 / 2 parts by weight of mannitol and / or microcrystalline cellulose through a 100-mesh sieve with the mixture obtained in step (2), and finally add magnesium stearate that has passed through a 100-mesh sieve and mix.

[0041] (4) Tableting.

[0042] Comparative Examples 1-7: Simvastatin Chewable Tablets

[0043] Prescription (10,000 tablets)

[0044]

[0045] Preparation method:

[0046] Same as Examples 1-11.

[0047] Comparative Example 8: Simvastatin Chewable Tablets

[0048] Prescription (10,000 tablets)

[0049]

[0050] Preparation method:

[0051] (1) Simvastatin, 1 / 2 part by weight of mannitol and microcrystalline cellulose are passed through a 100-mesh sieve and then mixed.

[0052] (2) Sodium carboxymethyl starch, butylated hydroxytoluene and aspartame are passed through a 100-mesh sieve and mixed with the mixture obtained in step (1);

[0053] (3) Mix the remaining 1 / 2 parts by weight of mannitol and microcrystalline cellulose through a 100-mesh sieve with the mixture obtained in step (2), and finally add magnesium stearate that has passed through a 100-mesh sieve and mix.

[0054] (4) Tableting.

[0055] Comparative Example 9: Simvastatin Chewable Tablets

[0056] Prescription (10,000 tablets)

[0057]

[0058] Preparation method:

[0059] (1) Pass the mannitol and microcrystalline cellulose mixture filler, disintegrant, meglumine and sodium alginate mixture stabilizer and sweetener through a 100-mesh sieve, mix them, and then add the lubricant that has passed through a 100-mesh sieve and mix them.

[0060] (2) Tableting.

[0061] Verification of Examples

[0062] Determination of content, related substances, and dissolution of simvastatin chewable tablets in each embodiment and comparative embodiment.

[0063] Related substances determination: Take an appropriate amount of the fine powder of this product (approximately equivalent to 80 mg of simvastatin), place it in a 100 ml volumetric flask, add an appropriate amount of solvent (same as the solvent under the related substances section of simvastatin), shake thoroughly to dissolve simvastatin and dilute to the mark, shake well, filter, and take the filtrate as the test solution. Determine the solution within 3 hours. Accurately measure 1 ml, place it in a 100 ml volumetric flask, dilute to the mark with solvent II, shake well, and use as the control solution. Determine according to the method under the related substances section of simvastatin. If there are impurity peaks in the chromatogram of the test solution, after deducting the excipient peaks before 0.3 times the relative retention time, the area of ​​a single impurity peak should not be greater than the area of ​​the main peak of the control solution (1.0%), and the sum of the areas of all impurity peaks should not be greater than 3 times (3.0%) the area of ​​the main peak of the control solution. Chromatographic peaks in the chromatogram of the test solution that are less than 0.05 times the area of ​​the main peak of the control solution are negligible.

[0064] Dissolution test: Take this product and perform the dissolution and release test (General Rule 0931, Method II) according to the method. Use 900 ml of 0.01 mol / L sodium dihydrogen phosphate buffer (adjusted to pH 7.0 with 50% sodium hydroxide solution) containing 0.5% sodium dodecyl sulfate as the dissolution medium. The rotation speed is 50 rpm. After 20 minutes, take 10 ml of the solution, filter it, and use the filtrate as the test solution. Separately, accurately weigh simvastatin reference standard, dissolve it in the dissolution medium, and quantitatively dilute it to prepare a solution containing approximately 6 μg (5 mg), 12 μg (10 mg), 24 μg (20 mg), or 48 μg (40 mg) per ml as the reference solution. Under the chromatographic conditions under the assay section, inject 20 μl each of the test solution and the reference solution into the liquid chromatograph, record the chromatograms, and calculate the amount dissolved per tablet by peak area using the external standard method. The limit is 80% of the labeled amount, and it should comply with regulations.

[0065] Content determination: Determined according to high performance liquid chromatography (General Rule 0512). Chromatographic conditions and system suitability test: Octadecylsilane-bonded silica gel was used as the stationary phase; 0.025 mol / L sodium dihydrogen phosphate solution (adjusted to pH 4.5 with phosphoric acid or sodium hydroxide test solution)-acetonitrile (35:65) was used as the mobile phase; the detection wavelength was 238 nm. Appropriate amounts of simvastatin and lovastatin reference standards were dissolved and diluted with solvent I to prepare a solution containing approximately 20 mg of each per ml. 20 ml of this solution was injected into the liquid chromatograph. The resolution between the simvastatin peak and the lovastatin peak should be greater than 3, and the theoretical plate number calculated based on the simvastatin peak should not be less than 2000. Assay: Accurately weigh 20 tablets of this product, grind them into a fine powder, and accurately weigh an appropriate amount (approximately equivalent to 10 mg of simvastatin). Place the powder in a 100 ml volumetric flask, add an appropriate amount of solvent I, sonicate to dissolve the simvastatin, dilute to the mark with solvent I, shake well, filter, and use the filtrate as the test solution. Accurately inject 20 ml of the filtrate into the liquid chromatograph and record the chromatogram. Separately, accurately weigh simvastatin reference standard, dissolve it in solvent I, and quantitatively dilute it to prepare a solution containing approximately 0.1 mg per ml. Determine the sample using the same method. Calculate the result by peak area using the external standard method.

[0066] Table 1 Comparison of content, dissolution rate, and related substances between the examples and comparative examples.

[0067]

[0068]

[0069] As can be seen from Table 1:

[0070] The examples all showed high content and good dissolution, with a dissolution rate of over 97% at 20 minutes. The content of related substances was low and showed no significant changes after long-term testing. The technical effects were superior to those of the comparative examples.

[0071] Compared with the present invention, the overall technical effect of the modified formulation components in Examples 1-4 is inferior.

[0072] Compared with Example 5, which did not add stabilizers, the amount of single and total impurities in related substances was significantly higher.

[0073] Comparative Examples 6-8, which varied the amount, ratio, and type of stabilizer, showed significantly higher levels of related substances and poorer stability compared to the examples.

[0074] Compared with Example 9, which changed the preparation process, the dissolution rate only reached 83.5% after 20 minutes, which is worse than that of the present invention.

Claims

1. A simvastatin chewable tablet, characterized by, consisting of simvastatin, a filler, a stabilizer, a disintegrant, a sweetener and a lubricant, the stabilizer being a combination of meglumine and sodium alginate; The preparation method of the simvastatin chewable tablet comprises the following steps: (1) passing simvastatin and 1 / 2 weight portion of the filler through an 80-120 mesh sieve and mixing them; (2) passing the disintegrant, the stabilizer and the sweetener through an 80-120 mesh sieve and mixing them with the mixture obtained in step (1); (3) passing the remaining 1 / 2 weight portion of the filler through an 80-120 mesh sieve and mixing it with the mixture obtained in step (2) and then adding the lubricant passed through an 80-120 mesh sieve and mixing; (4) tabletting.

2. The simvastatin chewable tablet according to claim 1, characterized by, The components are as follows in terms of weight ratio: Simvastatin 10 parts Filler 30-100 parts Stabilizer 0.05-2 parts Disintegrant 0.5-10 parts Sweetener 0.05-1.5 parts Lubricant 0.1-1 part.

3. The simvastatin chewable tablet according to claim 2, wherein The components are as follows in terms of weight ratio: Simvastatin 10 parts Filler 80 parts Stabilizer 0.15 parts Disintegrant 7 parts Sweetener 0.1 parts Lubricant 0.8 parts.

4. The simvastatin chewable tablet according to claim 1, wherein The filler is one or more of mannitol, microcrystalline cellulose, pre-gelatinized starch and lactose.

5. The simvastatin chewable tablet according to claim 4, wherein The filler is one or both of mannitol and microcrystalline cellulose.

6. The simvastatin chewable tablet according to claim 1, wherein the simvastatin is present in an amount of 5 mg. The disintegrant is one or more of sodium starch glycolate, cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose.

7. The simvastatin chewable tablet according to claim 1, wherein The sweetener is one or more of aspartame and stevioside.

8. The simvastatin chewable tablet according to claim 1, wherein The lubricant is one or more of magnesium stearate and sodium stearyl fumarate.

9. The simvastatin chewable tablet according to claim 1, wherein The weight ratio of meglumine to sodium alginate is 1:1-3.

10. The simvastatin chewable tablet according to any one of claims 1 to 9, wherein The filler is one or both of mannitol and microcrystalline cellulose, the disintegrant is sodium starch glycolate, the sweetener is aspartame and the lubricant is magnesium stearate; The preparation method of the simvastatin chewable tablet comprises the following steps: (1) passing simvastatin and 1 / 2 weight portion of the filler through an 80-120 mesh sieve and mixing them; (2) passing the disintegrant, the stabilizer and the sweetener through an 80-120 mesh sieve and mixing them with the mixture obtained in step (1); (3) passing the remaining 1 / 2 weight portion of the filler through an 80-120 mesh sieve and mixing it with the mixture obtained in step (2) and then adding the lubricant passed through an 80-120 mesh sieve and mixing; (4) tabletting. The components are as follows in terms of weight ratio: Simvastatin 10 parts Filler 30-100 parts Stabilizer 0.05-2 parts Disintegrant 0.5-10 parts Sweetener 0.05-1.5 parts Lubricant 0.1-1 part.

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