Sustained-release microtablets of mecobalamin and a method for preparing the same

Abstract

The application provides a sustained-release meglumine microtablet, which is composed of a sustained-release layer, a release layer and a coating layer, the sustained-release layer and the release layer form a double release system, and the release speed of the meglumine is effectively controlled by controlling the drug proportion of the sustained-release layer and the release layer, so that the problem of fast drug release caused by small volume and large specific surface area of the microtablet is solved, and the microtablet realizes long-time and sustained and stable drug release. The meglumine sustained-release microtablet provided by the application has a diameter of 1-3 mm and a tablet weight of 20-60 mg, compared with common tablets, the sustained-release microtablet can reduce the drug administration frequency of patients, realizes once-a-day drug administration, improves the compliance of patients, and can meet the drug administration needs of children, the elderly and patients with dysphagia and the like.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and particularly relates to a mecobalamin sustained-release microtablet and a preparation method thereof. BACKGROUND

[0002] Mecobalamin is an endogenous vitamin B 12 , which exists in blood and marrow fluid, and has a good improvement effect on neuron conduction compared with vitamin B 12 . It can promote nucleic acid-protein-fat metabolism through a methylation reaction, and can convert homocysteine into methionine as a coenzyme of methionine synthetase, participate in the synthesis of deoxyribonucleoside thymine, promote nucleic acid and protein synthesis, promote intra-axonal transport and axon regeneration, and prevent axon degeneration and repair damaged nerve tissue.

[0003] At present, the products on the market in China are in the form of ordinary tablets, capsules and injection solutions. The mecobalamin tablet preparation specification is generally 0.5 mg, and the tablet weight is more than 90 mg. The main drug has a small proportion in the prescription, and there is a risk of poor tablet content uniformity. In addition, mecobalamin tablets are mainly used for the treatment of peripheral neuropathy, and need to be administered three times a day, which is relatively frequent. For patients with peripheral neuritis, swallowing is difficult due to motor disorders, especially for the elderly and children, and the compliance is poor. SUMMARY

[0004] The problem solved by the present application is to provide a mecobalamin sustained-release microtablet, which has good effective component dispersion uniformity, can realize long-term stable release of the drug, and is beneficial to improving the compliance of patients.

[0005] The mecobalamin sustained-release microtablet provided by the present application is composed of a sustained-release layer, a release layer and a coating layer.

[0006] The sustained-release layer is composed of the following raw materials: 0.4 parts by weight of mecobalamin, 5-15 parts by weight of a filler, 10-30 parts by weight of a sustained-release material, 0-3 parts by weight of a glidant and 0.5-3 parts by weight of a lubricant.

[0007] The release layer is composed of the following raw materials: 0.1 parts by weight of mecobalamin, 5-15 parts by weight of a filler, 0-2 parts by weight of a glidant and 0-2 parts by weight of a lubricant.

[0008] The coating layer is composed of the following raw materials: 1-6 parts by weight of hydroxypropyl methyl cellulose, 0.5-3 parts by weight of polyethylene glycol, 0-0.5 parts by weight of talc, 0.5-3 parts by weight of titanium dioxide and 0-0.5 parts by weight of yellow iron oxide.

[0009] The filler is one or more of microcrystalline cellulose, mannitol, lactose and starch.

[0010] According to a preferred embodiment of the present application, the filler is microcrystalline cellulose or starch.

[0011] According to a preferred embodiment of the present application, the filler is microcrystalline cellulose.

[0012] The sustained-release material is one or more of hypromellose, povidone, carbomer.

[0013] According to a preferred embodiment of the present application, the sustained-release material is hypromellose or povidone.

[0014] The glidant is any one of talc, micronized silica, silicon dioxide.

[0015] According to a preferred embodiment of the present application, the glidant is silicon dioxide.

[0016] The lubricant is any one of stearic acid, magnesium stearate, talc, micronized silica, sodium stearyl fumarate, etc.

[0017] According to a preferred embodiment of the present application, the lubricant is magnesium stearate.

[0018] According to a preferred embodiment of the present application, the sustained-release layer is composed of 0.4 parts by weight of mecobalamin, 10 parts by weight of microcrystalline cellulose, 20 parts by weight of hypromellose, 0.8 parts by weight of silicon dioxide, and 0.8 parts by weight of magnesium stearate; the release layer is composed of 0.1 parts by weight of mecobalamin, 10 parts by weight of microcrystalline cellulose, 0.2 parts by weight of silicon dioxide, and 0.1 parts by weight of magnesium stearate. The coating layer is composed of 1 part by weight of hypromellose, 1 part by weight of polyethylene glycol, 1 part by weight of titanium dioxide, 0.001 part by weight of talc, and 0.0003 part by weight of yellow iron oxide.

[0019] The present application also provides a preparation method of mecobalamin sustained-release microtablets, comprising the following steps:

[0020] (1) Under light-proof conditions, 0.4 parts by weight of mecobalamin, 5-15 parts by weight of a filler, 10-30 parts by weight of a sustained-release material, 0-3 parts by weight of a glidant, and 0.5-3 parts by weight of a lubricant are prepared into sustained-release layer granules; 0.1 parts by weight of mecobalamin, 5-15 parts by weight of a filler, 0-2 parts by weight of a glidant, and 0-2 parts by weight of a lubricant are prepared into release layer granules.

[0021] (2) Under light-proof conditions, dry powder compression is adopted, the sustained-release layer granules are pre-compressed, the tablet weight and the pre-compression pressure are adjusted to 1-5 kg / cm 2 , then the release layer granules are added for compression, thereby obtaining mecobalamin sustained-release microtablets with a double-layer structure.

[0022] (3) The tablets obtained in step (2) are coated with a coating material to increase the weight to 3% to 4%.

[0023] Compared with the prior art, the present application has the following beneficial technical effects:

[0024] (1) The sustained-release microtablets provided by the present application have a diameter of 1 to 3 mm and a tablet weight of 20 to 60 mg, which can meet the medication needs of children, the elderly and patients with difficulty in swallowing.

[0025] (2) The double-layer release system composed of the sustained-release layer and the release layer effectively improves the problem of fast drug dissolution and release of the microtablets by using different materials and proportions, so that the microtablets can reach an effective drug concentration in a short time and achieve long-term and sustained release of the drug.

[0026] (3) Compared with ordinary tablets, the sustained-release microtablets can reduce the number of medication of patients, achieve once-a-day medication and improve the compliance of patients. DETAILED DESCRIPTION

[0027] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0028] Embodiment 1

[0029] Under the condition of avoiding light, 0.4 parts by weight of methylcobalamin, 5 parts by weight of starch, 20 parts by weight of povidone, 0.8 parts by weight of silicon dioxide and 0.8 parts by weight of magnesium stearate are prepared into sustained-release layer granules; 0.1 parts by weight of methylcobalamin, 10 parts by weight of microcrystalline cellulose, 0.2 parts by weight of silicon dioxide and 0.1 parts by weight of magnesium stearate are prepared into release layer granules.

[0030] Under the condition of avoiding light, the sustained-release layer granules are pre-pressed by using the dry powder compression method, the tablet weight is controlled and the pre-pressing pressure is adjusted to 1 to 5 kg / cm 2 Then, the release layer granules are added for compression to obtain methylcobalamin sustained-release microtablets with a double-layer structure.

[0031] The coating layer is composed of 1 part by weight of hydroxypropyl methylcellulose, 1 part by weight of polyethylene glycol, 1 part by weight of titanium dioxide, 0.001 part by weight of talc and 0.0003 part by weight of yellow titanium oxide. The coating material is prepared into a coating liquid, and then the obtained tablets are coated with the coating material to increase the weight to 3%.

[0032] Embodiment 2

[0033] Mecobalamin 0.4 parts by weight, microcrystalline cellulose 15 parts by weight, hydroxypropyl methylcellulose 15 parts by weight, silicon dioxide 0.8 parts by weight, magnesium stearate 0.8 parts by weight were prepared into sustained release layer granules under light-protected conditions; and Mecobalamin 0.1 parts by weight, microcrystalline cellulose 10 parts by weight, silicon dioxide 0.2 parts by weight, magnesium stearate 0.1 parts by weight were prepared into release layer granules.

[0034] The sustained release layer granules were pre-pressed by dry powder tabletting under light-protected conditions, the tablet weight was controlled and the pre-pressing pressure was adjusted to 1-5 kg / cm 2 The release granules were added and compressed to obtain the double-layered structure of Mecobalamin sustained release microtablets.

[0035] The coating layer was composed of hydroxypropyl methylcellulose 1 part by weight, polyethylene glycol 1 part by weight, titanium dioxide 1 part by weight, talc 0.001 part by weight, and yellow titanium oxide 0.0003 part by weight. The coating material was prepared into a coating liquid, and then the obtained tablets were coated with the coating material to increase the weight to 3%.

[0036] Example 3

[0037] Mecobalamin 0.4 parts by weight, microcrystalline cellulose 15 parts by weight, hydroxypropyl methylcellulose 30 parts by weight, silicon dioxide 1 part by weight, magnesium stearate 1 part by weight were prepared into sustained release layer granules under light-protected conditions; and Mecobalamin 0.1 parts by weight, microcrystalline cellulose 15 parts by weight, silicon dioxide 2 parts by weight, magnesium stearate 0.1 parts by weight were prepared into release layer granules.

[0038] The sustained release layer granules were pre-pressed by dry powder tabletting under light-protected conditions, the tablet weight was controlled and the pre-pressing pressure was adjusted to 1-5 kg / cm 2 The release granules were added and compressed to obtain the double-layered structure of Mecobalamin sustained release microtablets.

[0039] The coating layer was composed of hydroxypropyl methylcellulose 1 part by weight, polyethylene glycol 1 part by weight, titanium dioxide 1 part by weight, talc 0.001 part by weight, and yellow titanium oxide 0.0003 part by weight. The coating material was prepared into a coating liquid, and then the obtained tablets were coated with the coating material to increase the weight to 3%.

[0040] Example 4

[0041] Mecobalamin 0.4 parts by weight, microcrystalline cellulose 10 parts by weight, hydroxypropyl methylcellulose 20 parts by weight, silicon dioxide 0.8 parts by weight, magnesium stearate 0.8 parts by weight were prepared into sustained release layer granules under light-protected conditions; and the release layer was prepared from Mecobalamin 0.1 parts by weight, microcrystalline cellulose 10 parts by weight, silicon dioxide 0.2 parts by weight, magnesium stearate 0.1 parts by weight.

[0042] The sustained-release layer is pre-pressed in a dry powder tabletting manner under light-proof conditions, the tablet weight is controlled, and the pre-pressing pressure is adjusted to 1-5 kg / cm 2 The release granules are added and pressed to obtain the methycobal sustained-release micro-tablets with a double-layer structure.

[0043] The coating layer is composed of 1 part by weight of hydroxypropyl methyl cellulose, 1 part by weight of polyethylene glycol, 1 part by weight of titanium dioxide, 0.001 part by weight of talc, and 0.0003 part by weight of yellow titanium oxide. The coating material is prepared into a coating liquid, and then the obtained tablets are coated with the coating material to increase the weight to 3%.

[0044] Comparative Example 1

[0045] Methycobal 0.2 parts by weight, microcrystalline cellulose 10 parts by weight, hydroxypropyl methyl cellulose 20 parts by weight, silicon dioxide 0.8 parts by weight, and magnesium stearate 0.8 parts by weight are prepared into sustained-release layer granules under light-proof conditions; and methycobal 0.3 parts by weight, microcrystalline cellulose 10 parts by weight, silicon dioxide 0.2 parts by weight, and magnesium stearate 0.1 parts by weight are prepared into release layer granules.

[0046] The sustained-release layer is pre-pressed in a dry powder tabletting manner under light-proof conditions, the tablet weight is controlled, and the pre-pressing pressure is adjusted to 1-5 kg / cm 2 The release granules are added and pressed to obtain the methycobal sustained-release micro-tablets with a double-layer structure.

[0047] The coating layer is composed of 1 part by weight of hydroxypropyl methyl cellulose, 1 part by weight of polyethylene glycol, 1 part by weight of titanium dioxide, 0.001 part by weight of talc, and 0.0003 part by weight of yellow titanium oxide. The coating material is prepared into a coating liquid, and then the tablets obtained in the above step are coated with the coating material to increase the weight to 3%.

[0048] Comparative Example 2

[0049] Methycobal 0.5 parts by weight, microcrystalline cellulose 10 parts by weight, hydroxypropyl methyl cellulose 20 parts by weight, silicon dioxide 0.8 parts by weight, and magnesium stearate 0.8 parts by weight are prepared into sustained-release layer granules under light-proof conditions; and microcrystalline cellulose 10 parts by weight, silicon dioxide 0.2 parts by weight, and magnesium stearate 0.1 parts by weight are prepared into release layer granules.

[0050] The sustained-release layer is pre-pressed in a dry powder tabletting manner under light-proof conditions, the tablet weight is controlled, and the pre-pressing pressure is adjusted to 1-5 kg / cm 2 The release granules are added and pressed to obtain the methycobal sustained-release micro-tablets with a double-layer structure.

[0051] The coating layer is composed of 1 part by weight of hydroxypropyl methylcellulose, 1 part by weight of polyethylene glycol, 1 part by weight of titanium dioxide, 0.001 part by weight of talc, and 0.0003 part by weight of yellow titanium oxide. The coating material is prepared into a coating liquid, and then the tablets obtained in the above step are coated with the coating material to increase the weight to 3%.

[0052] Comparative Example 3

[0053] Mecobalamin tablets (0.5 mg / tablet) produced by Nippon Shokuhin K.K. were used as the comparative example.

[0054] Test Example

[0055] The drug release degree in a pH 6.8 phosphate buffer solution was determined according to the first method in the dissolution and release determination method in the 2025 edition of the Chinese Pharmacopoeia.

[0056] Table 1: Drug cumulative release degree of each example and comparative example

[0057] Sampling time Example 1 (%) Example 2 (%) Example 3 (%) Example 4 (%) Comparative Example 1 (%) Comparative Example 2 (%) Comparative Example 3 (%) 30 min 27 31 23 25 64 9 97 2h 50 54 46 48 73 33 99 4h 67 72 65 64 86 54 / 8h 84 90 80 82 92 72 / 12h 94 97 90 91 97 85 / 18h 99 98 96 98 99 90 / 24h 99 101 100 99 99 94 /

[0058] From Table 1, it can be analyzed that Examples 1-4 adopt a double-layer sustained-release structure, and by adjusting the drug ratio of the sustained-release layer and the release layer, the drug can be released steadily and continuously while reaching the effective blood drug concentration quickly. Although double-layer sustained-release structures are adopted in Comparative Examples 1 and 2, the drug amount of the release layer in Comparative Example 1 is higher than that of Examples 1-4, which leads to rapid drug release. The drug amount of the sustained-release layer in Comparative Example 2 is higher than that of Examples 1-4, which leads to slow drug release and cannot reach the effective blood drug concentration in a short time, delaying the therapeutic effect of the drug.

[0059] The above describes the embodiments of the present application in combination with the examples, but the present application is not limited to the specific embodiments described above, which are only illustrative and not restrictive. Those skilled in the art can make many forms under the inspiration of the present application without departing from the scope of the present application and the protection scope of the claims, which all belong to the protection scope of the present application.

Claims

1. A sustained release microtablet of mecobalamin, characterized in that, The sustained-release layer, the release layer and the coating layer are composed of the following raw materials: The sustained-release layer is composed of the following raw materials: methylcobalamin 0.4 parts by weight, filler 5-15 parts by weight, sustained-release material 10-30 parts by weight, glidant 0-3 parts by weight, lubricant 0.5-3 parts by weight; The release layer is composed of the following raw materials: methylcobalamin 0.1 parts by weight, filler 5-15 parts by weight, glidant 0-2 parts by weight, lubricant 0-2 parts by weight; The coating layer is composed of the following raw materials: hydroxypropyl methyl cellulose 1-6 parts by weight, polyethylene glycol 0.5-3 parts by weight, talc 0-0.5 parts by weight, titanium dioxide 0.5-3 parts by weight, yellow iron oxide 0-0.5 parts by weight; The filler is one or more of microcrystalline cellulose, mannitol, lactose and starch; The sustained-release material is one or more of hydroxypropyl methyl cellulose, povidone and carbomer; The glidant is any one of talc, micro-powder silica gel and silicon dioxide; The lubricant is any one of stearic acid, magnesium stearate, talc, micro-powder silica gel and sodium stearyl fumarate.

2. The sustained-release microtablets of claim 1, wherein, The filler is microcrystalline cellulose or starch, and the sustained-release material is hydroxypropyl methyl cellulose or povidone.

3. The sustained-release microtablets of claim 2, wherein the miconazole is present in an amount of about 0.5 mg to about 2 mg. The glidant is silicon dioxide, and the lubricant is magnesium stearate.

4. The sustained-release microtablets of claim 3, wherein the miconazole is present in an amount of about 0.5 mg to about 2 mg. The sustained-release layer is composed of methylcobalamin 0.4 parts by weight, microcrystalline cellulose 10 parts by weight, hydroxypropyl methyl cellulose 20 parts by weight, silicon dioxide 0.8 parts by weight and magnesium stearate 0.8 parts by weight; the release layer is composed of methylcobalamin 0.1 parts by weight, microcrystalline cellulose 10 parts by weight, silicon dioxide 0.2 parts by weight and magnesium stearate 0.1 parts by weight; and the coating layer is composed of hydroxypropyl methyl cellulose 1 parts by weight, polyethylene glycol 1 parts by weight, titanium dioxide 1 parts by weight, talc 0.001 parts by weight and yellow iron oxide 0.0003 parts by weight.

5. The process for the preparation of sustained release microtablets of mecobalamin as claimed in any one of claims 1 to 4 wherein, The steps include the following: (1) Under light-proof conditions, prepare sustained-release layer granules from methylcobalamin 0.4 parts by weight, filler 5-15 parts by weight, sustained-release material 10-30 parts by weight, glidant 0-3 parts by weight and lubricant 0.5-3 parts by weight; and prepare release layer granules from methylcobalamin 0.1 parts by weight, filler 5-15 parts by weight, glidant 0-2 parts by weight and lubricant 0-2 parts by weight; (2) Under the condition of avoiding light, the granules of the sustained-release layer are pre-pressed by dry powder compression, the tablet weight and the pre-pressing pressure are adjusted to 1-5 kg / cm 2 , then the granules of the release layer are added for compression, so as to obtain a tablet with a double-layer structure; (3) Coat the tablets obtained in step (2) with coating materials to increase the weight by 3%-4%.