A Methylcobalamin Tablet and Its Preparation Method

Abstract

The present application discloses a methylcobalamin tablet, which contains, by weight ratio: 0.8 - 1.2 parts of mecobalamin, 15 - 18 parts of starch, 55 - 65 parts of microcrystalline cellulose, 100 - 110 parts of lactose, 0.4 - 0.5 parts of calcium stearate, and 8 - 10 parts of coating agent. Among them, the particle size range of the mecobalamin after micronization is 0.60μm ≤ D10 ≤ 0.90μm, 5.2μm ≤ D50 ≤ 6.3μm, 20μm ≤ D90 ≤ 26.5μm, and the particle size range of the lactose after micronization is 1.0μm ≤ D10 ≤ 2.5μm, 6.5μm ≤ D50 ≤ 10.5μm, 23μm ≤ D90 ≤ 35μm.

Description

Technical Field

[0001] This application belongs to the field of drug preparation and relates to a method for preparing methylcobalamin tablets. Background Art

[0002] Methylcobalamin is mecobalamin, which exists in blood and spinal fluid. Compared with methylcobalamin, it has a good effect on improving neuronal conduction. It can promote nucleic acid - protein - lipid metabolism through methyl transfer reactions. As a coenzyme of methionine synthase, it can convert homocysteine into methionine, participate in the process of deoxynucleoside synthesizing thymine, promote nucleic acid and protein synthesis, promote axonal transport, axonal regeneration and myelin formation, prevent axonal degeneration, and repair damaged nerve tissues. Mecobalamin was first launched as an injection by Eisai Co., Ltd. in Japan in 1972 and then launched as an oral product in 1978.

[0003] The preparation process of methylcobalamin tablets is relatively complex, mainly involving two steps: the reduction and methylation of cyanocobalamin. Common synthesis methods include using cyanocobalamin as the raw material, reducing it with sodium borohydride, and then methylating it with methyl iodide, dimethyl sulfate or methyl p - toluenesulfonate, etc., to finally obtain mecobalamin. During the preparation process, reaction conditions such as temperature, time, solvent selection and feeding ratio need to be strictly controlled to ensure the quality and yield of the product.

[0004] Although methylcobalamin tablets have achieved remarkable results in clinical applications, there are still some deficiencies in the existing technologies. For example, some production processes have problems such as high energy consumption, large pollution and low yield; at the same time, the quality of methylcobalamin tablets produced by different manufacturers may vary, affecting the efficacy and safety of the drug. In addition, with the continuous in - depth of medical research, the understanding of the indications, dosage and usage, and adverse reactions of methylcobalamin tablets is also constantly updated and improved. There is still room for improvement in the dissolution and stability of existing methylcobalamin tablets.

[0005] Patent document 1 (CN 112716909 A) discloses a methylcobalamin tablet and its preparation method. In this method, mecobalamin is first mixed with a part of starch, then mixed with the remaining starch to obtain a mixture, and then an amount of microcrystalline cellulose equivalent to 1 / 3 of the formula amount is mixed with this mixture to obtain a mixed powder, which is used for the next pre - mixing step. And it discloses that the particle size range of the raw material mecobalamin is 10μm < D90 < 30μm, 4μm < D50 < 10μm. However, this method only examines the stability and content uniformity of methylcobalamin tablets. Although it examines that the dissolution of the obtained tablets is > 85%, the stability of the obtained tablets is hard to say good, and there are problems with dissolution.

[0006] Patent document 2 (CN 110251477 B) discloses a methylcobalamin tablet and a preparation method thereof, wherein the methylcobalamin raw material is micronized, the raw material particle size D50 is controlled to be ≤10 μm, methylcobalamin and granular lactose are sequentially added to a high-speed stirring and mixing granulator, and then microcrystalline cellulose and cross-linked sodium carboxymethyl cellulose are sequentially added to the high-speed stirring and mixing granulator for stirring, and finally calcium stearate is added to the high-speed stirring and mixing granulator, stirred, and tableted. This method only investigates the stability of the obtained methylcobalamin tablets, and discloses that large-particle lactose is more suitable as a carrier for methylcobalamin tablets, but the stability of the obtained tablets is poor, and because lactose is added once, dissolution also has certain problems. Summary of the invention

[0007] In view of the deficiencies in the prior art, the present application provides a methylcobalamin tablet and a preparation method thereof. The inventors unexpectedly discovered that by controlling the particle size distribution of raw materials and auxiliary materials, especially controlling the particle size of methylcobalamin and lactose, which is one of the important links to ensure the quality of methylcobalamin tablets, and focusing on the mixing method with individual raw materials and auxiliary materials throughout the process, the deficiencies in the prior art are solved.

[0008] The present invention provides a methylcobalamin tablet, which contains, by weight:

[0009] Methylcobalamin 0.8-1.2 parts

[0010] 15-18 portions of starch

[0011] Lactose 100-110 parts

[0012] 0.4-0.5 parts of calcium stearate, and

[0013] 8-10 parts of coating agent,

[0014] The particle size range of the methylcobalamin after micronization is 5.2 μm≤D50≤6.3 μm and 20 μm≤D90≤26.5 μm.

[0015] In a preferred embodiment, the particle size range of the methylcobalamin after micronization is 5.6 μm≤D50≤6.1 μm, 21 μm≤D90≤25 μm.

[0016] In a preferred embodiment, the particle size range of the methylcobalamin after micronization is 0.60 μm≤D10≤0.90 μm, and more preferably 0.70 μm≤D10≤0.86 μm.

[0017] In a preferred embodiment, the particle size range of the lactose after micronization is 6.5μm ≤ D50 ≤ 10.5μm, 23μm ≤ D90 ≤ 35μm, and more preferably 7.0μm ≤ D50 ≤ 10.0μm, 25μm ≤ D90 ≤ 32μm.

[0018] In a preferred embodiment, the particle size range of the lactose after micronization is 1.0μm ≤ D10 ≤ 2.5μm, and more preferably 1.2μm ≤ D10 ≤ 2.0μm.

[0019] In a preferred embodiment, the methylcobalamin tablets contain, by weight:

[0020] Methylcobalamin 0.5mg

[0021] Starch 8.5mg

[0022] Microcrystalline cellulose 29.0mg

[0023] Lactose 51.8mg

[0024] Calcium stearate 0.2mg, and

[0025] The coating agent increases the weight by 3%.

[0026] In a preferred embodiment, the starch is extra white corn starch, and the microcrystalline cellulose is microcrystalline cellulose SH-102.

[0027] The present invention also provides a method for preparing methylcobalamin tablets, which includes:

[0028] (1) Pretreatment of raw and auxiliary materials: micronize the raw material methylcobalamin to obtain micronized methylcobalamin, micronize the lactose to obtain micronized lactose, mix the obtained micronized methylcobalamin with a part of lactose to obtain a mixed powder, and sieve the remaining lactose through a sieve to obtain a mixed material 1;

[0029] (2) Premixing: add the mixed material 1, microcrystalline cellulose, and starch obtained in (1) above into a hopper mixer and mix;

[0030] (3) Total mixing: add the externally added auxiliary material calcium stearate into the hopper mixer and mix;

[0031] (4) Tabletting: perform tabletting, and the tablet weight control range is within ±5%, and the hardness is tableted according to 60 - 100N;

[0032] (5) Coating: prepare a coating solution, coat, and obtain methylcobalamin tablets.

[0033] In a preferred embodiment, the amount of the part of lactose is the same as that of the remaining lactose.

[0034] In a preferred embodiment, the components of the coating solution include titanium dioxide, red iron oxide, hydroxypropyl cellulose, polyethylene glycol, and yellow iron oxide.

[0035] Advantages of the Invention

[0036] Dissolution optimization: By controlling the particle size distribution of mecobalamin and lactose, the tablets can release drug components more quickly during dissolution, improving the dissolution rate. At the same time, an appropriate particle size distribution helps reduce pores and cracks inside the tablets, further enhancing dissolution consistency.

[0037] Stability improvement: Tablets formed by particles with a reasonable particle size distribution have a more compact structure during tabletting, reducing the penetration paths of moisture and oxygen, thereby improving the physical and chemical stability of the tablets. In addition, the film coating layer further enhances the moisture resistance, light resistance, and antioxidant capacity of the tablets.

[0038] Production efficiency and cost: The granulation and tabletting process parameters are optimized using particle size control technology, making the production process more stable and controllable, and improving production efficiency. At the same time, the production cost is reduced due to the reduction in the generation of defective products and the rework rate. Specific Embodiments

[0039] The technical solutions in the embodiments of the present application will be clearly described below in conjunction with the embodiments of the present application. Obviously, the described embodiments are part of the embodiments of the present application, rather than all of them. All other embodiments obtained by those of ordinary skill in the art based on the embodiments in the present application belong to the scope protected by the present application.

[0040] The terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, rather than to describe a specific order or sequence. It should be understood that such data can be interchanged under appropriate circumstances so that the embodiments of the present application can be implemented in an order other than those illustrated or described herein, and the objects distinguished by "first", "second", etc. are usually of the same type, and the number of objects is not limited. For example, the first object can be one or multiple. In addition, "and / or" in the specification and claims means at least one of the connected objects, and the character " / " generally indicates an "or" relationship between the associated objects before and after.

[0041] For those technical or conditions not specified in the embodiments, they shall be carried out according to the techniques or conditions described in the literature in this field or according to the product specifications. The raw materials not indicated as sources in the embodiments are all conventional raw materials that those skilled in the art can obtain through regular purchase channels or prepare through conventional preparation methods.

[0042] The methylcobalamin tablets of the present invention contain, by weight ratio: 0.8 - 1.2 parts of mecobalamin, 15 - 18 parts of starch, 55 - 65 parts of microcrystalline cellulose, 100 - 110 parts of lactose, 0.4 - 0.5 parts of calcium stearate, and 8 - 10 parts of coating agent.

[0043] As a specific embodiment of the present invention, the raw material mecobalamin is micronized.

[0044] As the particle size distribution range of the micronized mecobalamin, as an embodiment of the present invention, the particle size range of the micronized mecobalamin is 5.2μm ≤ D50 ≤ 6.3μm, 20μm ≤ D90 ≤ 26.5μm, but is not limited thereto. Further preferably, 5.6μm ≤ D50 ≤ 6.1μm, 21μm ≤ D90 ≤ 25μm.

[0045] In addition, furthermore, the particle size range of the micronized mecobalamin is 0.60μm ≤ D10 ≤ 0.90μm, and further preferably 0.70μm ≤ D10 ≤ 0.86μm.

[0046] As the method for micronizing mecobalamin, there may be mentioned air jet milling, spray drying, spray freeze drying, supercritical fluid method, ball milling, etc. As long as the particle size can be refined to a specific range to optimize dissolution and tablet stabilizers, it is not limited thereto.

[0047] As a specific embodiment of the present invention, for example, the particle size range of the micronized mecobalamin is 0.70μm ≤ D10 ≤ 0.86μm, 5.6μm ≤ D50 ≤ 6.1μm, 21μm ≤ D90 ≤ 25μm to ensure better dissolution performance, but is not limited thereto.

[0048] As the particle size distribution range of the micronized lactose, as an embodiment of the present invention, the particle size range of the micronized lactose is 6.5μm ≤ D50 ≤ 10.5μm, 23μm ≤ D90 ≤ 35μm, but is not limited thereto. Further preferably, 7.0μm ≤ D50 ≤ 10.0μm, 25μm ≤ D90 ≤ 32μm.

[0049] In addition, furthermore, the particle size range of the micronized lactose is 1.0μm ≤ D10 ≤ 2.5μm, and further preferably 1.2μm ≤ D10 ≤ 2.0μm.

[0050] As the method for micronizing lactose, there may be mentioned air jet milling, spray drying, spray freeze drying, supercritical fluid method, ball milling, etc. As long as the particle size can be refined to a specific range to optimize dissolution and tablet stabilizers, it is not limited thereto.

[0051] As a specific embodiment of the present invention, for example, the particle size range of lactose after micronization is 1.2 μm ≤ D10 ≤ 2.0 μm, 7.0 μm ≤ D50 ≤ 10.0 μm, 25 μm ≤ D90 ≤ 32 μm to ensure better dissolution performance, but it is not limited thereto.

[0052] Examples of starches used as excipients in methylcobalamin tablets include, for example, corn starch, potato starch, tapioca starch, wheat starch, pregelatinized starch, hydroxypropyl starch, etc. One of them can be used or two or more of them can be mixed and used. Corn starch is preferably used, and especially preferably extra white corn starch, because of its good compressibility and disintegration property.

[0053] Examples of microcrystalline cellulose used as excipients in methylcobalamin tablets include, for example, type 101 / 102 (JRS, Germany), PH101 / 102 / 301 / 302, KG801 / 802 / 1000, etc. (Asahi Kasei, Japan), SH-102 (Huzhou Zhanwang). One of them can be used or two or more of them can be mixed and used. Microcrystalline cellulose SH-102 is particularly preferably used to enhance the tablet hardness with its superior fluidity and binding force.

[0054] As the coating agent used in the present invention, it is used to improve the stability and aesthetics of the tablets. Among them, the coating solution components can include titanium dioxide, red iron oxide, hydroxypropyl cellulose, polyethylene glycol, yellow iron oxide, etc., but it is not limited thereto.

[0055] The present inventors have found that the particle size distribution is a very crucial factor because it can affect properties such as the solubility, bioavailability, and stability of methylcobalamin tablets. By synergistically controlling the particle sizes of the raw material methylcobalamin and the excipient lactose within a specific range, the performance of the tablets can be optimized to meet specific application requirements. This control of the particle size distribution is crucial for the performance and quality of the product.

[0056] The following examples and comparative examples are given to illustrate the present invention by way of example.

[0057] Example 1

[0058] Prescription: Table 1

[0059] Ingredient Manufacturer Content (mg) Mecobalamin Hebei Huarong 0.5 Lactose Jiangsu Daoning / Pharmatose DCL 21 51.8 Microcrystalline Cellulose Huzhou Zhanwang / SH-102 29.0 Extra-white Corn Starch Roquette 8.5 Calcium Stearate Hunan Jiudian 0.2 Film Coating Premix -- Weight gain 3%

[0060] Preparation of Methylcobalamin Tablets

[0061] (1) Pretreatment of raw and auxiliary materials: Micronize the raw material methylcobalamin (manufacturer: Hebei Huarong), and use a wet laser particle size analyzer (purchased from Dandong Baite) to measure the particle size of the raw material. The particle size distribution (μm) of methylcobalamin is measured as follows: D10 = 0.70, D50 = 5.73, D90 = 24.19, and micronized methylcobalamin is obtained. Micronize lactose (Jiangsu Daoning) to obtain micronized lactose, and use a wet laser particle size analyzer (purchased from Dandong Baite) to measure the particle size of the raw material. The particle size distribution (μm) of lactose is measured as follows: D10 = 1.31, D50 = 7.80, D90 = 26.91. Sieve 0.5 mg of the obtained micronized methylcobalamin and 25.9 mg of lactose through a comminuting and granulating machine with a pore size of 1.00 mm to obtain a mixed powder. Wash and sieve the remaining 25.9 mg of lactose through a sieve mesh and mix it with the aforementioned mixed powder to obtain mixed material 1.

[0062] (2) Premixing: Add the mixed material 1 obtained in (1) above, 29.0 mg of microcrystalline cellulose SH-102, and 8.5 mg of extra-white corn starch in the prescription amount to a hopper mixer, set the rotation speed at 10 rpm, and mix for 10 min; Take out the material and sieve it quickly twice, and continue to mix for 10 min.

[0063] (3) Total mixing: Add 0.2 mg of calcium stearate as an external additive to the hopper mixer, set the parameter at 10 rpm, and mix for 5 min.

[0064] (4) Tabletting: Use a 6 mm round shallow concave punch for tabletting, control the tablet weight within the range of ±5%, and press the tablet with a hardness of 60 - 100 N.

[0065] (5) Coating: Prepare a 13% coating solution (titanium dioxide, red iron oxide, hydroxypropyl cellulose, polyethylene glycol, yellow iron oxide), set the inlet air temperature for coating at 60 °C, and increase the coating weight by 3% to obtain methylcobalamin tablets.

[0066] Example 2

[0067] In step (1) of the pretreatment of raw and auxiliary materials, micronize the raw material methylcobalamin (manufacturer: Hebei Huarong), and use a wet laser particle size analyzer (purchased from Dandong Baite) to measure the particle size of the raw material. The particle size distribution (μm) of methylcobalamin is measured as follows: D10 = 0.82, D50 = 5.85, D90 = 21.92, and micronized methylcobalamin is obtained. Except for this, other steps are the same as in Example 1 to obtain methylcobalamin tablets.

[0068] Example 3

[0069] In step (1) of the pretreatment of raw and auxiliary materials, the raw material mecobalamin (manufacturer: Hebei Huarong) was micronized, and a wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw material. The particle size distribution (μm) of mecobalamin was measured as follows: D10 = 0.78, D50 = 5.86, D90 = 22.74, and micronized mecobalamin was obtained. Except for this, other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0070] Example 4

[0071] In step (1) of the pretreatment of raw and auxiliary materials, the raw material mecobalamin (manufacturer: Hebei Huarong) was micronized, and a wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw material. The particle size distribution (μm) of mecobalamin was measured as follows: D10 = 0.84, D50 = 6.08, D90 = 24.97, and micronized mecobalamin was obtained. Except for this, other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0072] Comparative Example 1

[0073] In step (1) of the pretreatment of raw and auxiliary materials, the raw material mecobalamin (manufacturer: Hebei Huarong) was micronized, and a wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw material. The particle size distribution (μm) of mecobalamin was measured as follows: D10 = 0.79, D50 = 5.11, D90 = 21.87, and micronized mecobalamin was obtained. Except for this, other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0074] Comparative Example 2

[0075] In step (1) of the pretreatment of raw and auxiliary materials, the raw material mecobalamin (manufacturer: Hebei Huarong) was micronized, and a wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw material. The particle size distribution (μm) of mecobalamin was measured as follows: D10 = 0.81, D50 = 5.90, D90 = 27.73, and micronized mecobalamin was obtained. Except for this, other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0076] Comparative Example 3

[0077] In step (1) of the pretreatment of raw and auxiliary materials, the raw material mecobalamin (manufacturer: Hebei Huarong) was micronized, and a wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw material. The particle size distribution (μm) of mecobalamin was measured as follows: D10 = 0.80, D50 = 8.20, D90 = 23.22, and micronized mecobalamin was obtained. Except for this, other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0078] Comparative Example 4

[0079] In step (1) of the pretreatment of raw and auxiliary materials, the raw material mecobalamin (manufacturer: Hebei Huarong) was micronized, and a wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw material. The particle size distribution (μm) of mecobalamin was measured as follows: D10 = 0.66, D50 = 5.81, D90 = 17.18, and micronized mecobalamin was obtained. Except for this, the other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0080] Comparative Example 5

[0081] In step (1) of the pretreatment of raw and auxiliary materials, the raw material mecobalamin (manufacturer: Hebei Huarong) was micronized, and a wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw material. The particle size distribution (μm) of mecobalamin was measured as follows: D10 = 0.72, D50 = 4.93, D90 = 13.71, and micronized mecobalamin was obtained. Except for this, the other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0082] The particle size distributions of the micronized mecobalamin raw materials in each example and comparative example are summarized in Table 2 below:

[0083] Table 2

[0084]

[0085]

[0086] Dissolution Determination

[0087] Paddle method; medium 500 ml; rotation speed 50 rpm / min; temperature 37°C ± 0.5°C; filter membrane 0.45 μm PES filter membrane; sampling time points 5, 10, 15, 20, 30 min; sampling volume: take 10 ml and supplement 10 ml; test solution: discard 8 ml and retain 2 ml. The dissolution degrees of the above-mentioned methylcobalamin tablets in the examples and comparative examples were measured (in the following tables, 15 min is used as the boundary), and the results are shown in Table 2 below:

[0088] Table 3

[0089] Medium: Water 5 min 10 min 15 min 20 min 30 min f2 Reference Preparation 43.8 78.7 87.7 89.7 91.8 / Example 1 41.4 76.5 88.4 90.1 92.4 83 Example 2 40.8 77.9 88.1 90.4 91.4 81 Example 3 44.2 79.0 87.5 89.9 92.0 97 Example 4 44.0 79.4 86.9 90.0 92.7 98 Comparative Example 1 59.4 72.3 84.9 91.8 95.7 50 Comparative Example 2 30.7 70.6 84.2 87.5 94.2 52 Comparative Example 3 55.2 80.1 85.7 92.0 93.4 58 Comparative Example 4 63.5 81.4 94.8 97.7 99.8 46 Comparative Example 5 72.3 80.5 94.4 96.6 100.9 39

[0090] Table 4

[0091]

[0092]

[0093] Table 5

[0094] Medium: pH 6.8 5 min 10 min 15 min 20 min 30 min f2 Reference Preparation 34.3 83.8 96.6 101.2 102.9 / Example 1 37.8 84.9 94.3 99.2 99.8 81 Example 2 39.2 85.9 94.7 98.3 98.7 74 Example 3 33.2 84.3 92.7 98.4 100.3 80 Example 4 36.9 84.3 96.7 98.9 100.3 87 Comparative Example 1 47.5 84.9 88.7 97.6 100.3 52 Comparative Example 2 27.3 70.7 89.4 90.5 98.4 51 Comparative Example 3 50.2 80.9 93.4 95.7 98.5 51 Comparative Example 4 54.3 80.2 88.7 90.4 97.7 45 Comparative Example 5 55.7 78.7 90.8 93.4 99.7 44

[0095] Stability Test

[0096] Refer to the General Principles of Stability Testing of Raw Materials and Preparations (II) in the Chinese Pharmacopoeia 2020 Edition, Appendix 9001, and conduct accelerated stability tests on the methylcobalamin tablets obtained in the above examples and comparative examples. The results are as follows:

[0097] Table 6

[0098]

[0099] Comparative Example 6

[0100] The prescription composition of Comparative Example 6 is the same as that of Example 1.

[0101] Preparation of Methylcobalamin Tablets

[0102] (2) Pretreatment of raw and auxiliary materials: Micronize the raw material methylcobalamin (manufacturer: Hebei Huarong), and use a wet laser particle size analyzer (purchased from Dandong Baite) to measure the particle size of the raw material. The particle size distribution (μm) of methylcobalamin is: D10 = 0.701, D50 = 5.730, D90 = 24.19, and micronized methylcobalamin is obtained. Micronize lactose (Jiangsu Daoning), and use a wet laser particle size analyzer (purchased from Dandong Baite) to measure the particle size of the raw material. The particle size distribution (μm) of lactose is: D10 = 1.31, D50 = 7.80, D90 = 26.91.

[0103] (2) Premixing: First, add 0.5 mg of micronized methylcobalamin and 51.8 mg of lactose obtained in (1) above to a hopper mixer, set the rotation speed at 10 rpm, and mix for 10 min. Then, add 29.0 mg of microcrystalline cellulose SH-102 and 8.5 mg of extra-white corn starch to the hopper mixer, set the rotation speed at 10 rpm, and mix for 10 min; take out the material and sieve it twice, and continue to mix for 10 min.

[0104] (3) Total mixing: Add 0.2 mg of calcium stearate as an external additive to the hopper mixer, set the parameter at 10 rpm, and mix for 5 min.

[0105] (4) Tabletting: Use a 6 mm round shallow concave punch for tabletting, control the tablet weight within the range of ±5%, and tablet at a hardness of 60 - 100 N.

[0106] (5) Coating: Prepare a 13% coating solution (titanium dioxide, red iron oxide, hydroxypropyl cellulose, polyethylene glycol, yellow iron oxide), set the inlet air temperature for coating at 60°C, and increase the coating weight by 3% to obtain methylcobalamin tablets.

[0107] Comparative Example 7

[0108] The prescription composition of Comparative Example 7 is the same as that of Example 1.

[0109] Preparation of Methylcobalamin Tablets

[0110] (3) Pretreatment of raw and auxiliary materials: Micronize the raw material methylcobalamin (manufacturer: Hebei Huarong), and use a wet laser particle size analyzer (purchased from Dandong Baite) to measure the particle size of the raw material. The particle size distribution (μm) of methylcobalamin is measured as: D10 = 0.701, D50 = 5.730, D90 = 24.19, and micronized methylcobalamin is obtained. Pass 0.5 mg of the obtained micronized methylcobalamin and 14.5 mg of microcrystalline cellulose SH-102 through a sieve with a pore size of 1.00 mm using a pulverizing and granulating machine to obtain a mixed powder. Wash and sieve the remaining 14.5 mg of microcrystalline cellulose SH-102 through a sieve to obtain mixed material 2.

[0111] (2) Premixing: Micronize lactose (Jiangsu Daoning), and use a wet laser particle size analyzer (purchased from Dandong Baite) to measure the particle size of the raw material. The particle size distribution (μm) of lactose is measured as: D10 = 1.31, D50 = 7.80, D90 = 26.91. Add the mixed material 2 obtained in (1) above, 51.8 mg of lactose in the prescription amount, and 8.5 mg of special white corn starch to a hopper mixer, set the rotation speed at 10 rpm, and mix for 10 min; Take out the material and pass it through the sieve twice quickly, and continue to mix for 10 min.

[0112] (3) Total mixing: Add 0.2 mg of calcium stearate as an external additive to the hopper mixer, set the parameters at 10 rpm, and mix for 5 min.

[0113] (4) Tabletting: Use a 6 mm round shallow concave punch for tabletting, control the tablet weight within the range of ±5%, and carry out tabletting with a hardness of 60 - 100 N.

[0114] (5) Coating: Prepare a 13% coating solution (titanium dioxide, red iron oxide, hydroxypropyl cellulose, polyethylene glycol, yellow iron oxide), set the inlet air temperature for coating at 60°C, and increase the coating weight by 3% to obtain methylcobalamin tablets.

[0115] Comparative Example 8

[0116] The prescription composition of Comparative Example 8 is the same as that of Example 1.

[0117] Preparation of Methylcobalamin Tablets

[0118] (1) Pretreatment of raw and auxiliary materials: The raw material methylcobalamin (manufacturer: Hebei Huarong) was micronized. The particle size of the raw material was measured using a wet laser particle size analyzer (purchased from Dandong Baite). The particle size distribution (μm) of methylcobalamin was: D10 = 0.701, D50 = 5.730, D90 = 24.19, and micronized methylcobalamin was obtained. 0.5 mg of the obtained micronized methylcobalamin was mixed with 0.5 mg of special white corn starch for 10 min, then 8 mg of special white corn starch was added thereto and mixed for 10 min, and dispersed through a 60-mesh sieve twice to obtain the mixed material 3.

[0119] (2) Premixing: Lactose (Jiangsu Daoning) was micronized. The particle size of the raw material was measured using a wet laser particle size analyzer (purchased from Dandong Baite). The particle size distribution (μm) of lactose was: D10 = 1.31, D50 = 7.80, D90 = 26.91. The mixed material 3 obtained in (1) above, 51.8 mg of lactose in the prescription amount, and 29.0 mg of microcrystalline cellulose SH-102 were added to a hopper mixer, the rotation speed was set at 10 rpm, and mixed for 10 min; the material was taken out and sieved twice quickly, and continued to be mixed for 10 min.

[0120] (3) Total mixing: 0.2 mg of calcium stearate as an external additive was added to a hopper mixer, the parameters were set at 10 rpm, and mixed for 5 min.

[0121] (4) Tabletting: Tabletting was carried out using a 6 mm round shallow concave punch, the tablet weight control range was within ±5%, and the hardness was tabletted according to 60 - 100 N.

[0122] (5) Coating: A 13% coating solution (titanium dioxide, red iron oxide, hydroxypropyl cellulose, polyethylene glycol, yellow iron oxide) was prepared, the inlet air temperature for coating was set at 60 °C, and the coating weight gain was 3% to obtain methylcobalamin tablets.

[0123] Table 7

[0124]

[0125] Table 8

[0126] Medium: pH 4.5 5 min 10 min 15 min 20 min 30 min f2 Reference Preparation 52.6 89.6 94.9 97.0 98.8 / Example 1 50.8 87.6 93.2 96.5 97.9 84 Comparative Example 6 40.3 82.3 88.5 90.5 96.4 52 Comparative Example 7 39.2 81.8 85.9 88.4 93.2 49 Comparative Example 8 45.7 83.4 89.0 94.3 97.7 60

[0127] Table 9

[0128] Medium: pH 6.8 5 min 10 min 15 min 20 min 30 min f2 Reference Preparation 34.3 83.8 96.6 101.2 102.9 / Example 1 35.7 84.9 95.6 100.4 100.5 91 Comparative Example 6 28.3 79.3 88.9 93.5 97.9 72 Comparative Example 7 25.8 78.5 86.4 90.2 98.9 54 Comparative Example 8 27.8 76.8 89.0 89.9 95.9 57

[0129] In addition, the methylcobalamin tablets obtained in Comparative Examples 6 - 8 were tested for stability accelerated experiment by the same method as in Example 1, and the results are as follows:

[0130] Table 10

[0131]

[0132] Example 5

[0133] In step (1) of the pretreatment of raw and auxiliary materials, lactose (Jiangsu Daoning) was micronized. A wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw materials. The particle size distribution (μm) of lactose was measured as follows: D10 = 1.88, D50 = 9.32, D90 = 31.02, and micronized lactose was obtained. Except for this, other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0134] Example 6

[0135] In step (1) of the pretreatment of raw and auxiliary materials, lactose (Jiangsu Daoning) was micronized. A wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw materials. The particle size distribution (μm) of lactose was measured as follows: D10 = 1.51, D50 = 8.40, D90 = 27.55, and micronized lactose was obtained. Except for this, other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0136] Comparative Example 9

[0137] In step (1) of the pretreatment of raw and auxiliary materials, lactose (Jiangsu Daoning) was micronized. A wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw materials. The particle size distribution (μm) of lactose was measured as follows: D10 = 1.44, D50 = 33.10, D90 = 58.38, and micronized lactose was obtained. Except for this, other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0138] Comparative Example 10

[0139] In step (1) of the pretreatment of raw and auxiliary materials, lactose (Jiangsu Daoning) was micronized. A wet laser particle size analyzer (purchased from Dandong Baite) was used to measure the particle size of the raw materials. The particle size distribution (μm) of lactose was measured as follows: D10 = 1.72, D50 = 5.66, D90 = 76.10, and micronized lactose was obtained. Except for this, other steps were the same as those in Example 1, and methylcobalamin tablets were obtained.

[0140] Table 11

[0141] Medium: Water 5 min 10 min 15 min 20 min 30 min f2 Reference Preparation 43.8 78.7 87.7 89.7 91.8 / Example 5 42.8 78.9 88.4 91.3 92.0 96 Example 6 40.3 77.4 89.5 90.4 91.4 79 Comparative Example 9 33.2 67.4 80.9 83.4 89.0 50 Comparative Example 10 30.4 63.5 79.5 84.3 90.6 50

[0142] Table 12

[0143]

[0144]

[0145] Table 13

[0146] Medium: 6.8 5 min 10 min 15 min 20 min 30 min f2 Reference Preparation 34.3 83.8 96.6 101.2 102.9 / Example 5 35.9 84.7 97.1 100.3 101.4 91 Example 6 33.1 81.9 94.0 99.4 100.4 83 Comparative Example 9 20.4 71.5 84.3 90.9 94.5 44 Comparative Example 10 21.7 72.9 80.5 93.4 92.7 44

[0147] In addition, the methylcobalamin tablets obtained in Examples 5 and 6 and Comparative Examples 9 and 10 were tested for accelerated stability experiments in the same manner as in Example 1, and the results are as follows:

[0148] Table 14

[0149]

[0150] Combining the above tables, the specific analysis is as follows:

[0151] From Examples 1 to 4 and Comparative Examples 1 to 5, it can be seen that the particle size range of the micronized mecobalamin raw materials used in Examples 1 to 4 satisfies 0.60 μm ≤ D10 ≤ 0.90 μm, 5.2 μm ≤ D50 ≤ 6.3 μm, and 20 μm ≤ D90 ≤ 26.5 μm. From Tables 3 to 5, it can be seen that the methylcobalamin tablets of Examples 1 to 4 of the present invention have f2 values all above 85 after dissolution determination by adjusting the particle sizes of the raw material mecobalamin and the excipient lactose within a specific range, achieving a high similarity with the original research. And from Table 6, it can be seen that the methylcobalamin tablets obtained in Examples 1 to 4 have less impurity content after the accelerated stability experiment test and excellent stability.

[0152] For the methylcobalamin tablet of Comparative Example 1 of the present invention, the D50 of mecobalamin is 5.11, which is lower than the range value of the present invention; for the methylcobalamin tablet of Comparative Example 2, the D90 of mecobalamin is 27.73, which is higher than the range value of the present invention; for the methylcobalamin tablet of Comparative Example 3, the D50 of mecobalamin is 8.20, which is higher than the range value of the present invention; for the methylcobalamin tablet of Comparative Example 4, the D10 of mecobalamin is 0.66 and the D90 is 17.18, both of which do not meet the range of the present invention; for the methylcobalamin tablet of Comparative Example 4, the D50 of mecobalamin is 4.93 and the D90 is 13.71, both of which do not meet the range of the present invention, especially the D90 value is much lower than the limit range of the present invention. From Tables 3 to 6, it can be seen that the methylcobalamin tablets of Comparative Examples 1 to 5 of the present invention, due to the particle size distribution of the raw material mecobalamin not partially meeting the range of the present invention, not only have low dissolution similarity, but also have a large impurity content after the accelerated stability experiment test, completely not meeting the expectations.

[0153] As can be seen from Comparative Examples 6 to 8, the particle size distributions of mecobalamin and lactose obtained by micronization in the methylcobalamin tablets of Comparative Examples 6 to 8 all meet the scope of the present invention. On this premise, different preparation processes were investigated as follows: In Example 1 of the present invention, micronized mecobalamin was first mixed with half of the micronized lactose, granulated and sieved, then the obtained mixed powder was mixed with the other half of the lactose, and finally the mixed material was premixed with other excipients microcrystalline cellulose and starch, and then total mixed with the excipient calcium stearate and compressed into tablets; in Comparative Example 6, micronized mecobalamin was first mixed with the total amount of micronized lactose, and then successively mixed with other excipients and compressed into tablets; in Comparative Example 7, micronized mecobalamin was first mixed with the excipient microcrystalline cellulose SH-102, and then other excipients such as lactose and extra-white corn starch were added successively and mixed and compressed into tablets; in Comparative Example 8, micronized mecobalamin was first mixed with the excipient extra-white corn starch, and then other excipients such as lactose and microcrystalline cellulose SH-102 were added successively and mixed and compressed into tablets.

[0154] As can be seen from Tables 7 to 9, in the preparation of the methylcobalamin tablets of Example 1 of the present invention, the inventors adopted the method of adding micronized lactose in batches, while the addition methods of the methylcobalamin tablets of Comparative Examples 6 to 8 are quite different from those of the present invention. The methylcobalamin tablets obtained in Comparative Examples 6 to 8 not only have low dissolution similarity, but also have a large impurity content after the stability accelerated test, which completely does not meet the expectations.

[0155] The preparation processes of Examples 5 to 6 and the particle size ranges of micronized mecobalamin are the same as those of Example 1. The inventors only appropriately adjusted the particle size distribution of lactose, but all meet the scope of the present invention; although the particle size ranges of micronized mecobalamin in Comparative Examples 9 to 10 meet the scope of the present invention, the D50 of micronized lactose in Comparative Example 9 is 33.10 and the D90 is 58.38, and the D50 of Comparative Example 10 is 5.66 and the D90 is 76.10, both of which do not meet the scope of the present invention.

[0156] As can be seen from Tables 11 to 13 and Table 14, for the methylcobalamin tablets of Comparative Examples 9 to 10 of the present invention, since the particle size distribution of the excipient lactose partially does not meet the scope of the present invention, not only the dissolution similarity is not high, but also the impurity content after the stability accelerated test is large, which completely does not meet the expectations.

[0157] The embodiments of the present application have been described above in conjunction with the examples. However, the present application is not limited to the above specific embodiments. The above specific embodiments are merely illustrative and not restrictive. Under the inspiration of the present application, those of ordinary skill in the art can also make many forms without departing from the purpose of the present application and the scope protected by the claims, and all belong to the protection scope of the present application.

Claims

1. A methylcobalamin tablet, characterized in that, The methylcobalamin tablets contain, by weight ratio: 0.8 - 1.2 parts of mecobalamin 15 - 18 parts of starch 55 - 65 parts of microcrystalline cellulose 100 - 110 parts of lactose 0.4 - 0.5 parts of calcium stearate, and 8 - 10 parts of coating agent The starch is extra-white corn starch, and the microcrystalline cellulose is microcrystalline cellulose SH - 102. Among them, the particle size range of the micro - pulverized mecobalamin is 5.6μm ≤ D50 ≤ 6.1μm, 21μm ≤ D90 ≤ 25μm, 0.60μm ≤ D10 ≤ 0.90μm, and the particle size range of the micro - pulverized lactose is 7.0μm ≤ D50 ≤ 10.0μm, 25μm ≤ D90 ≤ 32μm, 1.0μm ≤ D10 ≤ 2.5μm. The preparation method of the methylcobalamin tablets includes: (1) Pretreatment of raw and auxiliary materials: Micro - pulverize the raw material mecobalamin to obtain micro - pulverized mecobalamin, micro - pulverize lactose to obtain micro - pulverized lactose, mix the obtained micro - pulverized mecobalamin with a part of lactose to obtain a mixed powder, sieve the remaining lactose through a sieve and wash the sieve, and mix it with the aforementioned mixed powder to obtain mixed material 1. The amount of the part of lactose is the same as that of the remaining lactose. (2) Premixing: Add the mixed material 1, microcrystalline cellulose, and starch obtained in (1) above into a hopper mixer and mix. (3) Total mixing: Add the external additive calcium stearate into the hopper mixer and mix. (4) Tabletting: Perform tabletting, and the tablet weight control range is within ±5%, and the hardness is pressed according to 60 - 100N. (5) Coating: Prepare a coating solution, coat, and obtain methylcobalamin tablets.

2. The methylcobalamin tablet according to claim 1, wherein The particle size range of the micro - pulverized mecobalamin is 0.70μm ≤ D10 ≤ 0.86μm.

3. The methylcobalamin tablet according to claim 1, wherein, The particle size range of the micro - pulverized lactose is 1.2μm ≤ D10 ≤ 2.0μm.

4. The methylcobalamin tablet according to any one of claims 1 to 3, wherein, The methylcobalamin tablets contain, by weight: 0.5mg of mecobalamin 8.5mg of starch 29.0mg of microcrystalline cellulose 51.8mg of lactose 0.2mg of calcium stearate, and The coating agent increases the weight by 3%.

5. The preparation method of the methylcobalamin tablet according to any one of claims 1 to 4, characterized in that, This preparation method includes: (1) Pretreatment of raw and auxiliary materials: Micro - pulverize the raw material mecobalamin to obtain micro - pulverized mecobalamin, micro - pulverize lactose to obtain micro - pulverized lactose, mix the obtained micro - pulverized mecobalamin with a part of lactose to obtain a mixed powder, sieve the remaining lactose through a sieve and wash the sieve, and mix it with the aforementioned mixed powder to obtain mixed material 1. The amount of the part of lactose is the same as that of the remaining lactose. (2) Premixing: Add the mixed material 1, microcrystalline cellulose, and starch obtained in (1) above into a hopper mixer and mix. (3) Total mixing: Add the external additive calcium stearate into the hopper mixer and mix. (4) Tabletting: Perform tabletting, and the tablet weight control range is within ±5%, and the hardness is pressed according to 60 - 100N. (5) Coating: Prepare a coating solution, coat, and obtain methylcobalamin tablets.

6. The preparation method of the methylcobalamin tablet according to claim 5, wherein, The components of the coating solution include titanium dioxide, red iron oxide, hydroxypropyl cellulose, polyethylene glycol, and yellow iron oxide.

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