Pravastatin sodium capsule and preparation method thereof

Abstract

The invention belongs to the technical field of medicine, and particularly relates to a pravastatin sodium capsule and a preparation method thereof, the pravastatin sodium capsule provided by the invention has similar in-vitro dissolution behavior with an original pravastatin sodium tablet, has higher stability, and is beneficial to medicine storage and transportation.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and in particular relates to a pravastatin sodium capsule and a preparation method thereof. Background Art

[0002] Pravastatin sodium, whose English name is Pravastatin sodium, has the chemical name {1S-[1α(βS*, δS*), 2α, 6α, 8β(R*), 8aα]}-1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-1-naphthylheptanoic acid monosodium salt.

[0003] Structural formula:

[0004] Pravastatin sodium is an HMG-CoA reductase inhibitor, clinically indicated for patients with primary hypercholesterolemia or hypertriglyceridemia (type IIa and IIb) who cannot be controlled by dietary restrictions. The original research drug (RLD) of pravastatin sodium tablets is Mevalotin tablets, with a specification of 10 mg. It was approved in Japan in 1991. The original research manufacturer is Daiichi Sankyo Co. Ltd. (Japan Daiichi Sankyo), and it is used to treat hyperlipidemia and familial hypercholesterolemia. The reference drug is an uncoated, slightly red, scored immediate-release (IR) tablet. The tablet is swallowed directly without any changes and taken before bedtime. The maximum daily dose in the instructions is 40 mg, and the starting dose for adults is 10 mg to 20 mg, once a day.

[0005] Compared with tablets, capsules are rapidly absorbed after oral administration and have high bioavailability. Capsules can also mask the unpleasant smell of the drug and increase the stability of the drug. Summary of the invention

[0006] The invention provides a pravastatin sodium capsule, characterized in that each pravastatin sodium capsule contains 5% to 10%, preferably 7% to 7.5% of pravastatin sodium.

[0007] In certain embodiments of the present invention, the capsule further comprises a filler.

[0008] Preferably, the filler is selected from one or more of lactose and microcrystalline cellulose.

[0009] Preferably, the filler is selected from a mixture of lactose and microcrystalline cellulose.

[0010] Preferably, the mass ratio of the filler to pravastatin sodium is 20:1-5:1, preferably 15:1-10:1, preferably 12:1-10:1, more specifically 12:1, 11:1, 10:1.

[0011] Preferably, the ratio of lactose to microcrystalline cellulose in the mixture of lactose and microcrystalline cellulose is 1:3 to 3:1, preferably 1:1 to 3:1, preferably 1.7:1 to 2.3:1, more specifically 1:1, 2:1, 3:1.

[0012] In certain embodiments of the present invention, the capsule further comprises an alkalizing agent.

[0013] Preferably, the alkalizer is selected from one or more alkaline compounds such as magnesium oxide, aluminum oxide, alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (such as magnesium hydroxide, calcium hydroxide, etc.), aluminum hydroxide and sodium carbonate; preferably, the alkalizer is selected from magnesium oxide; preferably, the mass ratio of the alkalizer to pravastatin sodium is 1:10 to 1:1, preferably 1:8 to 1:2, more specifically 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2.

[0014] In certain embodiments of the present invention, the capsule further comprises a binder.

[0015] Preferably, the adhesive is selected from one or more of starch derivatives (such as starch, pregelatinized starch, etc.), cellulose derivatives (hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, etc.), dextrin, gelatin, gum, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), sucrose, sodium alginate, and polyvinyl alcohol (PVA); preferably, the adhesive is selected from one or more of polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC) and sodium carboxymethyl cellulose (CMC-Na); preferably, the adhesive is selected from hydroxypropyl cellulose (HPC); preferably, the mass ratio of the adhesive to pravastatin sodium is 1:10 to 3:2, preferably 1:8 to 1:1, more preferably 1:5 to 1:1, and more specifically 1:5, 1:4, 1:3, 1:2, and 1:1.

[0016] In certain embodiments of the present invention, the capsule further comprises a lubricant.

[0017] Preferably, the lubricant is selected from one or more of magnesium stearate, micropowdered silica gel, talc, hydrogenated vegetable oil, polyethylene glycols (such as PEG4000, PEG6000, etc.), sodium lauryl sulfate, and wheat starch; preferably, the lubricant is selected from magnesium stearate; preferably, the mass ratio of the lubricant to pravastatin sodium is 1:20 to 1:1, preferably 1:15 to 1:2, more preferably 1:10 to 1:3, and more specifically 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3.

[0018] In certain embodiments of the present invention, the capsule further comprises a disintegrant.

[0019] Preferably, the disintegrant is selected from one or more of starch derivatives (such as starch, sodium carboxymethyl starch, etc.), cellulose derivatives (low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, etc.), cross-linked polyvinylpyrrolidone (PVPP), alginic acid, and sodium alginate; preferably, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose (L-HPC) and cross-linked polyvinylpyrrolidone (PVPP); preferably, the disintegrant is selected from low-substituted hydroxypropyl cellulose (L-HPC); preferably, the mass ratio of the disintegrant to pravastatin sodium is 1:10 to 1:1, preferably 1:8 to 1:2, more preferably 1:5 to 3:10, and more specifically 1:6, 1:4, or 1:3.

[0020] In certain embodiments of the present invention, each pravastatin sodium capsule contains 10 mg of pravastatin sodium.

[0021] The present invention also provides a method for preparing the pravastatin sodium capsules described in any one of the above items, characterized in that the method comprises the following steps:

[0022] (1) Pass pravastatin sodium, filler, alkalizer, lubricant and / or disintegrant through 80-mesh sieve respectively for later use;

[0023] (2) dissolving the binder in purified water to prepare an aqueous solution for later use;

[0024] (3) mixing pravastatin sodium, filler, alkalizer and / or disintegrant, and granulating with an aqueous binder solution, and then passing through a sieve to size the granules, and drying the wet granules in a fluidized bed;

[0025] (4) using a sieve to size the dried granules, adding a lubricant to the size-sized granules, and mixing them uniformly;

[0026] (5) Filling the capsule: the capsule contents are compressed into a column by the filling system and then filled into the capsule shell; the column thickness parameter is 7 mm ± 0.50 mm;

[0027] (6) Packaging to obtain the finished product.

[0028] The percentages in the examples are by mass unless otherwise specified.

[0029] Unless otherwise specified, all numbers used in this specification and claims to indicate content, concentration, ratio, weight, percentage, technical effect, etc. should be understood as modified by the term "about" or "approximately" in any case. "About" represents a range of ±10% of the value it modifies, preferably a range of ±5%.

[0030] The advantages of the present invention are that the pravastatin sodium capsules provided by the present invention have similar in vitro dissolution behavior to the original pravastatin sodium tablets, and have higher stability, which is beneficial to the storage and transportation of drugs.

[0031] Specific embodiment

[0032] The present invention will be further described below in conjunction with specific examples, and the advantages and features of the present invention will become clearer as the description proceeds. If no specific conditions are specified in the examples, the process is carried out under conventional conditions or conditions recommended by the manufacturer. If no manufacturer is specified for the reagents or instruments used, all are conventional products that can be purchased from the market.

[0033] Dissolution method

[0034] Dissolution medium: pH 4.0 acetate buffer solution;

[0035] Dissolution speed: 50rpm;

[0036] Sampling volume: 10ml;

[0037] Filter using a 0.45 μm polyethersulfone membrane filter;

[0038] Sampling time points: 5min, 10min, 15min, 20min, 30min;

[0039] Testing equipment: UV-visible spectrophotometer;

[0040] The reference preparation is pravastatin sodium tablets, with a specification of 10 mg, batch number: DYA2315, and produced by Daiichi Sankyo Co., Ltd. of Japan.

[0041] According to the "Technical Guidelines for Dissolution Testing of Ordinary Oral Solid Preparations" issued by the Drug Review Center of the State Food and Drug Administration, when comparing the f2 value of a self-developed preparation with that of a reference preparation, only the dissolution at the first three points, i.e. 5 min, 10 min and 15 min, is compared.

[0042] Embodiment 1:

[0043] Table 1:

[0044]

[0045] The weight of the capsule content was 140 mg, and No. 2 gelatin capsule shells were used to prepare prescriptions 1-3 according to the prescription in Table 1. pH 4.0 acetate buffer was used as the dissolution medium to measure the dissolution of the homemade sample and the reference preparation, and the results are shown in Table 2.

[0046] Table 1:

[0047]

[0048] By comparison, it was found that the dissolution curve similarity factor f2 of the self-made capsules 1-3 of the present invention and the reference preparation in the pH 4.0 acetate buffer solution medium was ≥50, and the dissolution behaviors were similar.

[0049] Embodiment 2:

[0050] Table 2:

[0051]

[0052]

[0053] The weight of the capsule content was 140 mg, and No. 2 gelatin capsule shells were used to prepare prescriptions 4-6 according to the prescription in Table 3. pH 4.0 acetate buffer was used as the dissolution medium to measure the dissolution of the homemade samples and the reference preparations, and the results are shown in Table 4.

[0054] Table 3:

[0055]

[0056] By comparison, it was found that the dissolution curve similarity factor f2 of the homemade capsules 4-5 of the present invention and the reference preparation in the pH 4.0 acetate buffer solution medium was ≥50, and the dissolution behavior was similar; the dissolution curve similarity factor f2 of capsule 6 and the reference preparation in the pH 4.0 acetate buffer solution medium was ≤50, and the dissolution behavior was poor.

[0057] Embodiment 3:

[0058] Table 4:

[0059]

[0060] The weight of the capsule content was 140 mg, and No. 2 gelatin capsule shells were used to prepare prescriptions 7-9 according to the prescription in Table 5. pH 4.0 acetate buffer was used as the dissolution medium to measure the dissolution of the homemade samples and the reference preparations, and the results are shown in Table 6.

[0061] Table 5:

[0062]

[0063]

[0064] By comparison, it was found that the dissolution curve similarity factor f2 of the self-made capsules 7-9 of the present invention and the reference preparation in the pH 4.0 acetate buffer solution medium was ≥50, and the dissolution behaviors were similar.

[0065] Embodiment 4:

[0066] Table 6:

[0067]

[0068] The weight of the capsule content was 140 mg, and No. 2 gelatin capsule shells were used to prepare prescriptions 10-12 according to the prescription in Table 7. pH 4.0 acetate buffer was used as the dissolution medium to measure the dissolution of the homemade sample and the reference preparation, and the results are shown in Table 8.

[0069] Table 7:

[0070]

[0071] By comparison, it was found that the dissolution curve similarity factor f2 of the self-made capsules 10-12 of the present invention and the reference preparation in the pH 4.0 acetate buffer solution medium was ≥50, and the dissolution behaviors were similar.

[0072] Embodiment 5:

[0073] Table 8:

[0074]

[0075]

[0076] The weight of the capsule content was 140 mg, and No. 2 gelatin capsule shells were used to fill prescriptions 13-14 according to the prescription in Table 9. The dissolution of the homemade sample and the reference preparation was determined using pH 4.0 acetate buffer as the dissolution medium, and the results are shown in Table 10.

[0077] Table 9:

[0078]

[0079] By comparison, it was found that the dissolution curve similarity factor f2 of the homemade capsule 14 of the present invention and the reference preparation in the pH 4.0 acetate buffer solution medium was ≥50, and the dissolution behavior was similar. The dissolution curve similarity factor f2 of the capsule 13 and the reference preparation in the pH 4.0 acetate buffer solution medium was ≤50, and the dissolution behavior was poor.

[0080] Embodiment 6:

[0081] Table 10:

[0082]

[0083] The weight of the capsule content was 140 mg. No. 2 gelatin capsule shells were used to fill prescriptions 15-17 according to the prescription in Table 11. pH 4.0 acetate buffer was used as the dissolution medium to measure the dissolution of the homemade samples and the reference preparations. The results are shown in Tables 12-14.

[0084] Table 11:

[0085]

[0086] When the compressed thickness of the contents of Formulation 15 prepared by the content filling and compression followed by filling process was below 7 mm, the dissolution curve similarity factor f2 with that of the reference preparation in pH 4.0 acetate buffer solution medium was ≤50, indicating poor dissolution behavior.

[0087] Table 12:

[0088]

[0089] Table 13:

[0090]

[0091] When the contents of prescriptions 16 and 17 prepared by the filling and compression process were compressed to a thickness of about 7 mm, the dissolution curve similarity factor f2 was ≥50 with that of the reference preparation in pH 4.0 acetate buffer solution, some f2>60, some>70, and the dissolution behavior was optimal.

[0092] Embodiment 7:

[0093] The pravastatin sodium capsules of the present invention and the reference preparation were placed at 60°C to investigate the changes of related substances. The results are shown in Table 15.

[0094] Table 15:

[0095]

[0096]

[0097] The results showed that the impurity growth of the homemade sample was significantly less than that of the reference preparation after being exposed to high temperature of 60°C for 30 days, indicating that the stability of the homemade preparation is significantly better than that of the reference preparation.

[0098] The technical scheme of the present invention is further described in detail above in conjunction with specific embodiments. It should be understood that the above embodiments are only exemplary descriptions and explanations of the present invention, and should not be construed as limiting the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc. made based on the above contents of the present invention should be included in the scope of protection of the present invention.

Claims

1. A pravastatin sodium capsule, characterized in that: Each pravastatin sodium capsule contains 5% to 10%, preferably 7% to 7.5% of pravastatin sodium.

2. The pravastatin sodium capsule according to claim 1, characterized in that: The capsule further comprises a filler; preferably, the filler is selected from one or more of lactose and microcrystalline cellulose; preferably, the filler is selected from a mixture of lactose and microcrystalline cellulose; preferably, the mass ratio of the filler to pravastatin sodium is 20:1-5:1, preferably 15:1-10:1, preferably 12:1-10:1; preferably, the amount ratio of lactose to microcrystalline cellulose in the mixture of lactose and microcrystalline cellulose is 1:3-3:1, preferably 1:1-3:1, preferably 1.7:1-2.3:

1.

3. The pravastatin sodium capsule according to claim 1, characterized in that: The capsule further comprises an alkalizer; preferably, the alkalizer is selected from one or more of magnesium oxide, aluminum oxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, aluminum hydroxide and sodium carbonate; preferably, the alkalizer is selected from magnesium oxide; preferably, the mass ratio of the alkalizer to pravastatin sodium is 1:10 to 1:1, preferably 1:8 to 1:

2.

4. The pravastatin sodium capsule according to claim 1, characterized in that: The capsule further comprises a binder; preferably, the binder is selected from one or more of starch, pregelatinized starch, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, ethyl cellulose, dextrin, gelatin, gum, povidone, polyethylene glycol, sucrose, sodium alginate, and polyvinyl alcohol; preferably, the binder is selected from one or more of povidone, hydroxypropyl cellulose, and sodium carboxymethyl cellulose; preferably, the binder is selected from hydroxypropyl cellulose; preferably, the mass ratio of the binder to pravastatin sodium is 1:10 to 3:2, preferably 1:8 to 1:1, and more preferably 1:5 to 1:

1.

5. The pravastatin sodium capsule according to claim 1, characterized in that: The capsule further comprises a lubricant; preferably, the lubricant is selected from one or more of magnesium stearate, micropowdered silica gel, talc, hydrogenated vegetable oil, polyethylene glycols, sodium lauryl sulfate, and wheat starch; preferably, the lubricant is selected from magnesium stearate; preferably, the mass ratio of the lubricant to pravastatin sodium is 1:20 to 1:1, preferably 1:15 to 1:2, and more preferably 1:10 to 1:

3.

6. The pravastatin sodium capsule according to claim 1, characterized in that: The capsule further comprises a disintegrant; preferably, the disintegrant is selected from one or more of starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, alginic acid, and sodium alginate; preferably, the disintegrant is selected from one or more of low-substituted hydroxypropyl cellulose and cross-linked polyvinylpyrrolidone; preferably, the disintegrant is selected from low-substituted hydroxypropyl cellulose; preferably, the mass ratio of the disintegrant to pravastatin sodium is 1:10 to 1:1, preferably 1:8 to 1:2, and more preferably 1:5 to 3:

10.

7. The pravastatin sodium capsule according to claim 1, characterized in that: Each pravastatin sodium capsule contains 10 mg of pravastatin sodium.

8. A method for preparing the pravastatin sodium capsules according to any one of claims 1 to 7, characterized in that: The method comprises the following steps: (1) Pass pravastatin sodium, filler, alkalizer, lubricant and / or disintegrant through 80-mesh sieve respectively for later use; (2) dissolving the binder in purified water to prepare an aqueous solution for later use; (3) mixing pravastatin sodium, filler, alkalizer and / or disintegrant, and granulating with an aqueous binder solution, and then passing through a sieve to size the granules, and drying the wet granules in a fluidized bed; (4) using a sieve to size the dried granules, adding a lubricant to the size-sized granules, and mixing them uniformly; (5) Filling the capsule: the capsule contents are compressed into a column by the filling system and then filled into the capsule shell. The column thickness parameter is 7 mm ± 0.50 mm; (6) Packaging to obtain the finished product.

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