Cobamamide capsule and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a cobamamide capsule and a preparation method thereof. The cobamamide capsule comprises a content and a hollow capsule, the content comprises the following components in parts by weight: 0.4-0.6 part of cobamamide, 66-72 parts of microcrystalline cellulose and 57-63 parts of pregelatinized starch, and the cobamamide, the microcrystalline cellulose and the pregelatinized starch are mixed, filled and packaged to obtain the cobamamide capsule. The cobamamide capsule prepared by the invention is similar to a reference preparation in dissolution curve, good in content uniformity and excellent in stability.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a stable adenosylcobalamin capsule and its preparation method. Background Technology

[0002] Adenosylcobalamin, also known as adenosine coenzyme vitamin B12, with the chemical name 5,6-dimethylbenzimidazolyl-5'-deoxyadenosine nucleoside cobalamin, is an important active vitamin B12 preparation. It has significant effects in the medical field for treating various diseases, such as megaloblastic anemia, nutritional anemia, and anemia during pregnancy. It is also used for neurological disorders such as polyneuritis, radiculitis, trigeminal neuralgia, sciatica, nerve paralysis, nutritional neurological disorders, and leukopenia caused by radiation and drugs.

[0003] However, adenosylcobalamin raw material suffers from poor chemical stability, being photosensitive and possessing a certain degree of hydrophilicity. Currently, most commercially available adenosylcobalamin powder injections require a physician or pharmacist to prepare a solution before injection, a method that is inconvenient and leads to low patient acceptance. (Chinese invention)

[0004] CN106344532A discloses a formulation method for adenosylcobalamin tablets, which protects the adenosylcobalamin raw material by coating the tablet with a sugar coating. However, given the lack of a specific comparison of the hydrophilicity of sucrose and adenosylcobalamin, the stability of the adenosylcobalamin tablets disclosed in this patent is questionable. US Patent US20050042289A1 discloses a method for preparing tablets from photosensitive, hydrophilic raw materials such as adenosylcobalamin. This method utilizes the fact that the coating material is less hydrophilic than the raw material to inhibit the diffusion of the raw material in the tablet. Chinese Patent CN118680893A discloses a method for preparing adenosylcobalamin capsules. This method involves sieving, mixing, and filling raw materials and excipients using a gyratory granulator to obtain adenosylcobalamin capsules. However, in this method, the feeding and granulation processes are in an open state during sieving, exposing the material to air for extended periods. Drugs like adenosylcobalamin, which are susceptible to environmental influences, are easily degraded by exposure to strong light, oxygen, and moisture, thus affecting drug quality. In addition, mechanical swaying causes uneven force on the material during sieving, which can easily lead to inconsistent particle size and a wide particle size distribution. This has an adverse effect on the accuracy of capsule filling and the consistency of drug efficacy.

[0005] In conclusion, developing a highly stable and high-quality adenosylcobalamin formulation has become a critical issue that urgently needs to be addressed in this field. Summary of the Invention

[0006] Purpose of the invention: The technical problem to be solved by the present invention is to address the shortcomings of the prior art by providing an adenosylcobalamin capsule and its preparation method.

[0007] To solve the above-mentioned technical problems, the present invention discloses the following technical solution:

[0008] In a first aspect, the present invention discloses an adenosylcobalamin capsule.

[0009] The adenosylcobalamin capsules include contents and empty capsules.

[0010] The contents comprise the following components in parts by weight:

[0011] Adenosylcobalamin 0.4-0.6 parts

[0012] 66-72 parts of microcrystalline cellulose

[0013] 57-63 parts of pregelatinized starch.

[0014] The contents comprise the following components in parts by weight:

[0015] Adenosylcobalamin 0.4-0.6 parts

[0016] 68-70 parts of microcrystalline cellulose

[0017] 59-61 parts of pregelatinized starch.

[0018] The contents comprise the following components in parts by weight:

[0019] 0.5 parts of adenosylcobalamin

[0020] 69 parts of microcrystalline cellulose

[0021] 60 parts of pregelatinized starch.

[0022] In some embodiments, the adenosylcobalamin capsules, in each unit dose of the formulation, include the following raw and excipient components: adenosylcobalamin 0.4-0.6 mg, microcrystalline cellulose 68-70 mg, pregelatinized starch 59-61 mg; adenosylcobalamin 0.5 mg, microcrystalline cellulose 69.0 mg, pregelatinized starch 60.0 mg.

[0023] Wherein, the particle size D of the adenosylcobalamin 90 The microcrystalline cellulose and pregelatinized starch are below 40 μm; the microcrystalline cellulose and pregelatinized starch are microcrystalline cellulose and pregelatinized starch that have passed through a 30-mesh sieve.

[0024] The adenosylcobalamin capsules are made by mixing adenosylcobalamin, microcrystalline cellulose and pregelatinized starch, filling and packaging them.

[0025] The mixing is carried out in a wet granulator; preferably, the stirring speed of the wet granulator is 400-600 rpm, the cutting speed of the wet granulator is 500-700 rpm, and the mixing time is 500-700 s.

[0026] The filling process involves filling with hollow capsules, which are gelatin hollow capsules, such as 4. # Red gelatin empty capsules.

[0027] The packaging is made of polyvinylidene chloride solid pharmaceutical composite rigid sheet and pharmaceutical aluminum foil, or polyvinyl chloride solid pharmaceutical composite rigid sheet and pharmaceutical aluminum foil.

[0028] Secondly, the present invention discloses a method for preparing the above-mentioned adenosylcobalamin capsules.

[0029] The method includes mixing adenosylcobalamin, microcrystalline cellulose and pregelatinized starch, filling and packaging.

[0030] The filling process involves filling with hollow capsules, which are gelatin hollow capsules, such as 4. # Red gelatin empty capsules.

[0031] The mixing is carried out in a wet granulator; preferably, the stirring speed of the wet granulator is 400-600 rpm, the cutting speed of the wet granulator is 500-700 rpm, and the mixing time is 500-700 s.

[0032] The packaging is made of polyvinylidene chloride solid pharmaceutical composite rigid sheet and pharmaceutical aluminum foil, or polyvinyl chloride solid pharmaceutical composite rigid sheet and pharmaceutical aluminum foil.

[0033] The adenosylcobalamin capsules of this invention have the following release characteristics: in water, the solubility is 83%-93% (e.g., 86%-90%) after 5 minutes; the cumulative solubility is 96%-100% (e.g., 98%-100%) after 10 minutes. In pH 6.8 phosphate buffer, the solubility is 73%-83% (e.g., 76%-80%) after 5 minutes; the cumulative solubility is 96%-100% (e.g., 98%-100%) after 10 minutes.

[0034] The adenosylcobalamin capsules of the present invention have excellent stability. After being placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 30 days, the total impurity content of the adenosylcobalamin capsules is 0.4%-0.6%, such as 0.45%-0.55%.

[0035] All preparation steps described in this invention are carried out under illumination conditions below 500 lx.

[0036] Beneficial effects:

[0037] The adenosylcobalamin capsules provided by this invention comprise the active ingredient adenosylcobalamin, microcrystalline cellulose, pregelatinized starch, and gelatin empty capsules. This invention mixes adenosylcobalamin and excipients using a wet granulation machine, reducing raw material exposure time and avoiding repeated sieving. The operation is simple, and the adenosylcobalamin capsules are prepared using a direct powder filling process. Packaging is achieved using polyvinyl chloride / polyvinylidene chloride solid pharmaceutical composite hard sheets and pharmaceutical aluminum foil, improving product stability. The use of microcrystalline cellulose and pregelatinized starch as fillers ensures smooth mixing and capsule filling processes, resulting in good mixing uniformity. Furthermore, the pregelatinized starch in the formulation further improves material flowability, making the mixing and capsule filling production process smoother. Compared with existing processes, this invention has the advantages of simple and rapid preparation, excellent product stability, and good quality. Attached Figure Description

[0038] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0039] Figure 1 The dissolution curves of the formulations obtained in Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3, and the reference formulation in aqueous medium are shown.

[0040] Figure 2 The dissolution curves of the formulations obtained in Example 1, Comparative Example 1, Comparative Example 2, and Comparative Example 3, and the reference formulation, are shown in a medium at pH 6.8. Detailed Implementation

[0041] To better explain the present invention and facilitate understanding of its technical solutions, further descriptions are now provided in conjunction with the accompanying drawings and embodiments. It should be understood that the specific embodiments of the present invention are for illustrative purposes only and are not intended to limit the present invention.

[0042] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0043] The pregelatinized starch mentioned in the following examples is manufactured by Carvacrol (model: 2001-NEC); the microcrystalline cellulose is manufactured by Jiangsu Xidian Pharmaceutical Excipients Co., Ltd. (model: PH-102); 4 # The manufacturer of the red gelatin empty capsules is Zhejiang Xinchang Kangping Capsule Co., Ltd.

[0044] The reference formulation described in this invention is manufactured by Eisai Co., Ltd., under the trade name Hycobal.

[0045] Unless otherwise specified, each unit dose of the formulation described in this invention is one capsule.

[0046] Example 1

[0047] This embodiment presents a highly stable adenosylcobalamin capsule, wherein each unit dose contains 0.5 mg of adenosylcobalamin, 69.0 mg of microcrystalline cellulose, and 60.0 mg of pregelatinized starch, and is prepared using 4... # Red gelatin empty capsules.

[0048] This embodiment describes a method for preparing highly stable adenosylcobalamin capsules, comprising the following steps:

[0049] (1) Weighing and sieving: Weigh each raw material and auxiliary material according to the weight ratio. The particle size D of the raw material adenosylcobalamin is measured. 90 To achieve a particle size of less than 40 μm, microcrystalline cellulose and pregelatinized starch were passed through a 30-mesh sieve, respectively.

[0050] (2) Total mixing: The microcrystalline cellulose, adenosine cobaltamine and pregelatinized starch sieved in step (1) are added to the wet granulator in sequence. The stirring speed is set to 500 rpm and the cutter speed is set to 600 rpm. The mixture is mixed for 600 s to obtain the total powder.

[0051] (3) Filling: Place the total powder mixture obtained in step (2) into a capsule filling machine and use it for 4 hours. # Red gelatin capsule shells are filled to obtain adenosylcobalamin capsules;

[0052] (4) Packaging: Polyvinylidene chloride solid pharmaceutical composite hard sheet and pharmaceutical aluminum foil are used for packaging.

[0053] Example 2

[0054] Same as Example 1, except that the amounts of each component are different, as detailed below:

[0055] Example 2-1

[0056] Each unit dose of the formulation contains 0.5 mg of adenosylcobalamin, 68.0 mg of microcrystalline cellulose, and 61.0 mg of pregelatinized starch.

[0057] Example 2-2

[0058] Each unit dose of the formulation contains 0.5 mg of adenosylcobalamin, 70 mg of microcrystalline cellulose, and 59.0 mg of pregelatinized starch.

[0059] Example 3

[0060] Same as Example 1, except that the polyvinylidene chloride solid pharmaceutical composite rigid sheet and pharmaceutical aluminum foil packaging used in step (4) are replaced with polyvinyl chloride solid pharmaceutical composite rigid sheet and pharmaceutical aluminum foil packaging.

[0061] Comparative Example 1

[0062] Same as in Example 1, except that the wet granulation machine used in step (2) is replaced with a swing granulator, as detailed below:

[0063] (2) Total blending: The microcrystalline cellulose, adenosine cobaltamine and pregelatinized starch after sieving in step (1) are added to the oscillating granulator in sequence. The oscillating granulator is turned on and sieved with a 0.8 mm sieve. The sieving is repeated 3 times to obtain the total blended powder.

[0064] Comparative Example 2

[0065] Same as Example 1, except that the pregelatinized starch is replaced with corn starch.

[0066] Comparative Example 3

[0067] Same as Example 1, except that the amounts of each component are different, as detailed below:

[0068] Each unit dose of the formulation contains 0.5 mg of adenosylcobalamin, 69.0 mg of microcrystalline cellulose, and 30.0 mg of pregelatinized starch.

[0069] Experiment 1

[0070] Dissolution was measured using a Chinese Pharmacopoeia dissolution apparatus (1) at 37℃ and 100 rpm in 500 ml of water and pH 6.8 phosphate buffer. High-performance liquid chromatography (HPLC) was also used. The chromatographic conditions were: octadecylsilane-bonded silica gel as the stationary phase; 0.05 mol / L potassium dihydrogen phosphate solution (adjusted to pH 3.2 with phosphoric acid) - acetonitrile (85:15, v / v) as the mobile phase; column temperature 35℃; detection wavelength 260 nm; injection volume 10 μl. The experimental results are shown in Table 1 and... Figure 1-2 As shown, the dissolution rates of all embodiments and comparative examples of the present invention are qualified (cumulative dissolution rate greater than 85% at 15 minutes), and the dissolution curve of Example 1 is more similar to that of the reference formulation.

[0071] Table 1. Dissolution rates (%) of the formulations obtained in Example 1, Reference Formulation, and Comparative Examples 1-3 in different media.

[0072]

[0073] Experiment 2

[0074] Accelerated tests were simultaneously conducted on the formulations obtained in Examples 1, 2-1, 2-2, and 3, the reference formulation, and the formulations obtained in Comparative Examples 1, 2, and 3 (temperature 40℃±2℃, relative humidity 75%±5%) to study their properties and related substances. The liquid chromatography method used was the method described in the 2020 edition of the Chinese Pharmacopoeia: octadecylsilane-bonded silica gel was used as the packing material; the mobile phase was 0.05 mol / L potassium dihydrogen phosphate solution (pH adjusted to 3.2 with phosphoric acid)-acetonitrile (85:15, v / v); the column temperature was 35℃; the detection wavelength was 260 nm; and the injection volume was 10 μl.

[0075] For the test solution, accurately weigh about 25 mg of this product, place it in a 25 ml volumetric flask, add an appropriate amount of water, sonicate to dissolve and dilute to the mark, and shake well.

[0076] The results showed that the products of Examples 1-3, the reference formulation, and Comparative Examples 1-3 had similar properties at each time point, and the contents were all pink powders. At day 0, accelerated for 1 month, and accelerated for 3 months, the related substances in Example 1 were significantly better than those in the reference formulation and the formulations obtained in Comparative Examples 1 and 2, as shown in Table 2 below.

[0077] Table 2. Accelerated test related substances for each example, comparative example, and reference formulation.

[0078] Note: Other single impurities refer to the single impurities with the highest content among those other than hydroxycobalamin and cyanocobalamin.

[0079] Experiment 3

[0080] The angles of repose of Examples 1, 2-1, 2-2, and Comparative Examples 1-3 were measured and found to be 35°, 36°, 36°, 38°, 45°, and 40°, respectively. The powder flowability of Example 1 was much better than that of Comparative Examples 2 and 3.

[0081] Experiment 4

[0082] The content uniformity of the products of Examples 1, 2-1, 2-2, Comparative Example 1, Comparative Example 2 and Comparative Example 3 was determined. The experimental results are shown in Table 3. The measured values ​​of A+2.2S are all less than 15, and the content uniformity meets the requirements. The content uniformity of Example 1 is significantly better than that of Comparative Example 1, Comparative Example 2 and Comparative Example 3.

[0083] Table 3. Content uniformity of each group

[0084]

[0085] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. An adenosylcobalamin capsule, characterized in that, Includes the contents and empty capsules; The contents comprise the following components in parts by weight: Adenosylcobalamin 0.4-0.6 parts 66-72 parts of microcrystalline cellulose 57-63 parts of pregelatinized starch.

2. The adenosylcobalamin capsule according to claim 1, characterized in that, The contents comprise the following components in parts by weight: Adenosylcobalamin 0.4-0.6 parts 68-70 parts of microcrystalline cellulose 59-61 parts of pregelatinized starch.

3. The adenosylcobalamin capsule according to claim 1, characterized in that, The contents comprise the following components in parts by weight: 0.5 parts of adenosylcobalamin 69 parts of microcrystalline cellulose 60 parts of pregelatinized starch.

4. The adenosylcobalamin capsule according to any one of claims 1-3, characterized in that, The particle size D of the adenosylcobalamin 90 It is below 40μm.

5. The adenosylcobalamin capsule according to any one of claims 1-3, characterized in that, The hollow capsule is a gelatin hollow capsule.

6. The adenosylcobalamin capsule according to any one of claims 1-3, characterized in that, The adenosylcobalamin capsules have the following release characteristics: in water, the dissolution rate is 83%-93% at 5 minutes and the cumulative dissolution rate is 96%-100% at 10 minutes.

7. The method for preparing adenosylcobalamin capsules according to any one of claims 1-6, characterized in that, include: Adenosylcobalamin, microcrystalline cellulose, and pregelatinized starch are mixed and then filled.

8. The preparation method according to claim 7, characterized in that, The mixing is performed in a wet granulation machine.

9. The preparation method according to claim 8, characterized in that, The stirring speed of the wet granulator is 400-600 rpm, the cutting speed of the wet granulator is 500-700 rpm, and the mixing time is 500-700 s.

10. The preparation method according to claim 7, characterized in that, The preparation method also includes packaging; the packaging is made of polyvinylidene chloride solid pharmaceutical composite rigid sheet and pharmaceutical aluminum foil, or polyvinyl chloride solid pharmaceutical composite rigid sheet and pharmaceutical aluminum foil.

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