CN110251477B - Mecobalamin tablet and preparation method thereof - Google Patents

Mecobalamin tablet and preparation method thereof Download PDF

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CN110251477B
CN110251477B CN201910725284.3A CN201910725284A CN110251477B CN 110251477 B CN110251477 B CN 110251477B CN 201910725284 A CN201910725284 A CN 201910725284A CN 110251477 B CN110251477 B CN 110251477B
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mecobalamin
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mass
coating
tablet
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蔡正军
白杰
张正全
罗丽莲
肖艳皎
韩雅慧
易斌
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Beijing Silian Pharmaceutical Industry Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
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    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a mecobalamin tablet and a preparation method thereof. The mecobalamin tablet provided by the invention comprises a plain tablet and a coating; the tablet consists of mecobalamin, lactose for direct compression, microcrystalline cellulose, croscarmellose sodium and calcium stearate, effective components of the tablet can have good uniformity under proper selection and proportion of auxiliary materials, and materials and preparation processes are reasonable, so that the tablet is stable, and related substances grow slowly.

Description

Mecobalamin tablet and preparation method thereof
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a mecobalamin tablet and a preparation method thereof.
Background
Mecobalamin is an endogenous coenzyme B12It is involved in the circulation of one carbon unit, plays an important role in the transmethylation reaction process of methionine synthesized by homocysteine, and can be used for the synthesis of methionine due to vitamin B12The lack of megaloblastic anemia has also been reported to reduce the incidence of neural tube defects.
Mecobalamin is photosensitive and is easily decomposed by light. Therefore, how to maintain the stability of mecobalamin is a technical difficulty in the pharmaceutical field and a research hotspot. For example, in the patent application with the application number of 200510105797.2, the method of operation under the condition of keeping out of the sun is adopted to prevent the mecobalamin from degrading in the preparation process, the problem of uniformity is solved by adopting an equivalent incremental mixing process, the preparation process is the traditional wet granulation, the preparation method is not only tedious and difficult to realize in mass production, but also increases the risk of mecobalamin degradation; the patent with application number 201210178833.8 adopts a method of coating first and then tabletting, and the first step of the preparation process is to coat the mecobalamin and avoid light, so that the influence of light source on the mecobalamin can be eliminated in the subsequent process, thereby reducing the possibility of degradation of the mecobalamin in the preparation process. However, because the content of mecobalamin in the mecobalamin tablets is usually small, the uniformity of the mecobalamin is difficult to ensure by coating in the first step, and meanwhile, the sufficiency of the coating is difficult to determine, so that the distribution of the mecobalamin is easy to be uneven, and if the coating is insufficient, the shelf life of the mecobalamin preparation is influenced. The patent application with the application number of 201811454166.5 is used for stabilizing the effect of mecobalamin that is easily decomposed by light by adding stabilizers such as carmine and the like, so that the mecobalamin granules are more beneficial to storage and application. However, carmine and the like belong to chemical synthetic pigments, and can cause great harm to human bodies if being eaten for a long time or exceeding the standard, influence on liver and kidney functions and possibly cause serious cancer. The mecobalamin tablets belong to medicines taken for a long time, such pigments are not suitable to be added, and carmine can interfere with detection of related substances of the mecobalamin and influence product quality control.
Therefore, the prior art is complex in process and various in problems, and a simple and reliable method capable of simultaneously solving the stability and the uniformity of effective components of the mecobalamin tablets does not exist at present.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a mecobalamin tablet and a preparation method thereof, wherein the mecobalamin tablet has uniform and stable components.
The mecobalamin tablet provided by the invention comprises a plain tablet and a coating;
the number of the coating layers is 1-2; the mass ratio of the plain tablets to the coating is 100: (3-10); the plain tablets comprise the following components in parts by mass:
Figure BDA0002158710030000021
the invention screens the large-particle carriers by the ordered mixing process and controls the using amount of the large-particle carriers, and the result proves that the effective components in the obtained tablets can have good uniformity only under the condition of proper auxiliary materials and proportion. In particular, the ratio of lactose in the form of granules to microcrystalline cellulose for direct compression has a significant effect on the uniformity of the active ingredient in the tablet. The scheme solves the problems of bulk drug aggregation and layering in the random mixing process of the traditional powder direct-pressing process, and improves the content uniformity of the drug.
In some embodiments, the plain tablets are composed of the following components in parts by mass:
Figure BDA0002158710030000022
the invention screens the orderly mixed large-particle carrier, and the commonly used direct-compression lactose in the field comprises granular lactose, spray-dried lactose, anhydrous lactose and the like, wherein the uniformity of the drug content in the tablet taking the spray-dried lactose as the carrier is lower than that in the embodiment taking the granular lactose as the carrier. In addition, in the comparative examples in which calcium hydrogen phosphate and microcrystalline cellulose were used as carriers for large particles mixed in order, or in which granular lactose was used as a carrier but the amounts of microcrystalline cellulose and granular lactose were not appropriate, the uniformity of the drug content in the obtained tablets was also not good.
The type of microcrystalline cellulose also affects the uniformity of the drug in the tablet, and the research of the invention shows that the microcrystalline cellulose with the type number of 102 is more beneficial to the uniform distribution of the drug.
Preferably, the particle size of the lactose particles for direct compression is 150-400 μm.
In the invention, the particle size of the mecobalamin is D50≤10μm。
The invention finds that the particle size of the lactose particles for direct compression is controlled to be 150-400 mu m, which is beneficial to improving the stability of the mixture prepared by the ordered mixing process and the uniformity of the active ingredients in the mecobalamin tablets.
In some embodiments, the number of the coating layers is 1, and the mass ratio of the plain tablets to the coating layers is 100: (6-10);
the coating material comprises 20-40 parts by mass of titanium dioxide, 40-70 parts by mass of hydroxypropyl methyl cellulose or polyvinyl alcohol, 5-15 parts by mass of polyethylene glycol and 0.5-2.1 parts by mass of pigment.
In some single-layer coating schemes, the coating material consists of 35 parts by mass of titanium dioxide, 55 parts by mass of hydroxypropyl methylcellulose, 9.5 parts by mass of polyethylene glycol and 0.5 part by mass of pigment.
In other single-layer coating schemes, the coating material consists of 40 parts by mass of titanium dioxide, 70 parts by mass of hydroxypropyl methylcellulose, 15 parts by mass of polyethylene glycol and 2.1 parts by mass of pigment.
In other single-layer coating schemes, the coating material consists of 20 parts by mass of titanium dioxide, 40 parts by mass of polyvinyl alcohol, 5 parts by mass of polyethylene glycol and 2.1 parts by mass of pigment.
In the single-layer coating material, the pigments are iron oxide yellow and iron oxide red.
According to verification, the invention proves that under the condition that the weight of the coating is increased by 6-10%, the content of related substances is lower, wherein the effect of increasing the weight of the coating by 8-10% is the best, and the effect cannot be achieved by increasing the weight of the coating by 2-4%. The scheme of the invention can effectively control the growth of related substances by controlling the weight gain of the coating without adding other ingredients for maintaining the stability of the medicine into auxiliary materials, and the method is simple and reliable. In the invention, the mass ratio of the plain tablets to the coating is 100 (6-10). In some embodiments, the mass ratio of the plain tablets to the coating is 100 (8-10).
In other preferred embodiments, the coating is a double-layer coating, and the mass ratio of the plain tablets to the coating is 100 (3-6). The coating material specifically comprises the following components:
wherein the inner coating is prepared from 15-25 parts by mass of titanium dioxide, 40-70 parts by mass of hydroxypropyl methylcellulose or polyvinyl alcohol, 10-25 parts by mass of polyethylene glycol and 0.1-5 parts by mass of pigment;
the outer coating material comprises 25-40 parts by mass of titanium dioxide, 40-70 parts by mass of hydroxypropyl methyl cellulose or polyvinyl alcohol and 10-25 parts by mass of polyethylene glycol.
In some examples of the double-layer coating, the material of the inner layer coating is composed of 20 parts by mass of titanium dioxide, 64 parts by mass of hydroxypropyl methylcellulose, 15.5 parts by mass of polyethylene glycol and 0.5 part by mass of pigment;
the outer coating material consists of 35 parts by mass of titanium dioxide, 55 parts by mass of polyvinyl alcohol and 10 parts by mass of polyethylene glycol.
In other double-layer coating embodiments, the inner layer coating material consists of 15 parts by mass of titanium dioxide, 40 parts by mass of hydroxypropyl methylcellulose, 10 parts by mass of polyethylene glycol and 0.1 part by mass of pigment;
the outer coating material consists of 25 parts by mass of titanium dioxide, 40 parts by mass of polyvinyl alcohol and 10 parts by mass of polyethylene glycol.
In other double-layer coating embodiments, the inner layer coating material consists of 25 parts by mass of titanium dioxide, 70 parts by mass of hydroxypropyl methylcellulose, 25 parts by mass of polyethylene glycol and 5 parts by mass of pigment;
the outer coating material consists of titanium dioxide 40 weight portions, polyvinyl alcohol 70 weight portions and polyethylene glycol 25 weight portions.
Experiments prove that by adopting the double-layer coating technology, the weight of the inner-layer coating is controlled to be increased by 1-2%, the weight of the outer-layer coating is controlled to be increased by 2-4%, and the total weight increase of the coating is controlled to be 3-6%, so that the stability of the product can be well improved, the effect is better than that of the conventional coating technology, and the time and the coating materials are saved. In the embodiment adopting the double-layer coating technology, the two layers of coating materials are reasonable in component selection, scientific in proportioning, uniform and compact in texture, the outer layer of coating material is good in reflection performance, and the inner layer of coating material has a good light absorption effect. The stability of the active ingredient can be more effectively maintained with respect to the comparative example in which the packing material component is not properly distributed.
The invention adopts the powder direct-pressing process to prepare the sample, solves the problem of uniformity of active ingredients through orderly mixing, controls the weight increment of the coating to solve the problem of stability of the sample, has simple and feasible prescription process and greatly saves the production cost. Ordered mixing prevents aggregation and stratification of the drug, and produces a more homogeneous mixture than random mixing. In the present invention, the ordered mixing is mainly divided into 3 steps, the first step is to disperse the fine powder of the aggregated drug substance, the second step is to adhere the drug substance to the coarse large particles, and the third step is to rearrange the drug substance on the large particles (as shown in fig. 1).
The preparation method of the mecobalamin tablet comprises the following steps:
screening the mecobalamin raw material medicine through a 100-mesh sieve, and removing lumps;
evenly mixing mecobalamin and lactose granules for direct compression;
then adding microcrystalline cellulose and croscarmellose sodium in sequence, and mixing uniformly.
Adding calcium stearate and mixing uniformly;
then tabletting and coating the tablet to increase the weight by 3 to 10 percent to prepare the mecobalamin tablet.
Wherein, the parameters of the mecobalamin and the lactose for the direct compression are as follows: stirring at 120rpm/min, cutter at 1000rpm/min, time 10 min.
After adding microcrystalline cellulose or croscarmellose sodium, the mixing parameters were stirring 180rpm/min, cutter 1000rpm/min, and time 3 min.
After the calcium stearate is added, the mixture is stirred at 120rpm/min, and the mixing parameters are that the cutter rotates at 1000rpm/min and the time is 1 min.
In the invention, the mixing is completed in a high-speed stirring mixing granulator.
In the present invention, the tablet hardness is 8kg to 16kg.
In the invention, all the steps are completed under the red light with the wavelength of more than 600 nm.
The mecobalamin tablet provided by the invention comprises a plain tablet and a coating; the tablet consists of mecobalamin, lactose for direct compression, microcrystalline cellulose, croscarmellose sodium and calcium stearate, effective components of the tablet can have good uniformity under proper raw material selection and proportion, and materials and a preparation process are reasonable, so that the tablet is stable, and related substances grow slowly.
Compared with the traditional equivalent incremental process, the preparation method greatly reduces the operation steps and time, and is more suitable for large-scale production. On the basis of saving time, the uniformity of the effective components of the mecobalamin tablets is improved. In addition, the invention adopts a powder direct-pressing process, avoids the influence of temperature and humidity on stability, reduces the time of contacting light of the bulk drugs and reduces the generation of related substances in the preparation process of mecobalamin. Compared with other preparation processes, the powder direct-pressing process only has one mixing procedure, has higher production efficiency and saves the production cost.
Drawings
FIG. 1 illustrates the process of the present invention;
FIG. 2 shows the methylcobalamin content of the carrier particles.
Detailed Description
The invention provides a mecobalamin tablet and a preparation method thereof, and a person skilled in the art can realize the preparation by properly improving process parameters by referring to the content. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of this invention without departing from the spirit and scope of the invention.
The instruments adopted by the invention are all common commercial products and can be purchased in the market.
The invention is further illustrated by the following examples:
example 1
The formula of the plain tablet comprises:
Figure BDA0002158710030000061
the preparation method (the following steps are carried out under a red light lamp with the wavelength of more than 600 nm):
(1) micronizing mecobalamin raw material medicine, and controlling the particle size D of the raw material medicine50Sieving mecobalamin with 100 mesh sieve (removing lumps) to obtain mecobalamin granules, sieving lactose with 120 mesh sieve, and weighing the above-mentioned materials according to the prescription;
(2) sequentially adding lactose and mecobalamin granules into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 10 min;
(3) sequentially adding microcrystalline cellulose and croscarmellose sodium into a high-speed stirring and mixing granulator, stirring at 180rpm/min, and cutting at 1000rpm/min for 3 min;
(4) and adding the calcium stearate into a high-speed stirring mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 1 min.
(5) Tabletting: by adopting a circular shape
Figure BDA0002158710030000063
The hardness of the punched sheet is controlled to be 8-16 kg.
Example 2
The formula of the plain tablet comprises:
Figure BDA0002158710030000062
the preparation method (the following steps are carried out under a red light lamp with the wavelength of more than 600 nm):
(1) micronizing mecobalamin raw material medicine, and controlling the particle size D of the raw material medicine50Sieving mecobalamin with 100 mesh sieve (removing lumps) to obtain mecobalamin granules, sieving lactose with 120 mesh sieve, and weighing the above-mentioned materials according to the prescription;
(2) sequentially adding lactose and mecobalamin granules into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 10 min;
(3) sequentially adding microcrystalline cellulose and croscarmellose sodium into a high-speed stirring and mixing granulator, stirring at 180rpm/min, and cutting at 1000rpm/min for 3 min;
(4) and adding the calcium stearate into a high-speed stirring mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 1 min.
(5) Tabletting: by adopting a circular shape
Figure BDA0002158710030000074
The hardness of the punched sheet is controlled to be 8-16 kg.
Example 3
The formula of the plain tablet comprises:
Figure BDA0002158710030000071
the preparation method (the following steps are carried out under a red light lamp with the wavelength of more than 600 nm):
(1) micronizing mecobalamin raw material medicine, and controlling the particle size D of the raw material medicine50Sieving mecobalamin with 100 mesh sieve (removing lumps) to obtain mecobalamin granules, sieving lactose with 120 mesh sieve, and weighing the above-mentioned materials according to the prescription;
(2) sequentially adding lactose and mecobalamin granules into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 10 min;
(3) sequentially adding microcrystalline cellulose and croscarmellose sodium into a high-speed stirring and mixing granulator, stirring at 180rpm/min, and cutting at 1000rpm/min for 3 min;
(4) adding calcium stearate into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 1 min;
(5) tabletting: by adopting a circular shape
Figure BDA0002158710030000073
The hardness of the punched sheet is controlled to be 8-16 kg.
Example 4
The formula of the plain tablet comprises:
Figure BDA0002158710030000072
Figure BDA0002158710030000081
the preparation method (the following steps are carried out under a red light lamp with the wavelength of more than 600 nm):
(1) micronizing mecobalamin raw material medicine, and controlling the particle size D of the raw material medicine50Sieving mecobalamin with 100 mesh sieve (removing lump) to obtain granules with particle size of less than or equal to 10 μmThe particle size of the lactose is 150-400 mu m, and all the raw and auxiliary materials are weighed according to the prescription amount;
(2) sequentially adding lactose and mecobalamin granules into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 10 min;
(3) sequentially adding microcrystalline cellulose and croscarmellose sodium into a high-speed stirring and mixing granulator, stirring at 180rpm/min, and cutting at 1000rpm/min for 3 min;
(4) and adding the calcium stearate into a high-speed stirring mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 1 min.
(5) Tabletting: by adopting a circular shape
Figure BDA0002158710030000083
The hardness of the punched sheet is controlled to be 8-16 kg.
Comparative example 1
The formula of the plain tablet comprises:
Figure BDA0002158710030000082
the preparation method (the following steps are carried out under a red light lamp with the wavelength of more than 600 nm):
(1) micronizing mecobalamin raw material medicine, and controlling the particle size D of the raw material medicine50Sieving mecobalamin with 100 mesh sieve (removing lumps) to obtain mecobalamin powder with particle size of less than or equal to 10 μm, sieving spray-dried lactose with 120 mesh sieve, collecting oversize part, and weighing raw materials and adjuvants according to prescription amount;
(2) sequentially adding lactose and mecobalamin granules into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 10 min;
(3) sequentially adding microcrystalline cellulose and croscarmellose sodium into a high-speed stirring and mixing granulator, stirring at 180rpm/min, and cutting at 1000rpm/min for 3 min;
(4) adding calcium stearate into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 1 min;
(5) tabletting: by adopting a circular shape
Figure BDA0002158710030000093
The hardness of the punched sheet is controlled to be 8-16 kg.
Comparative example 2
The formula of the plain tablet comprises:
Figure BDA0002158710030000091
the preparation method (the following steps are carried out under a red light lamp with the wavelength of more than 600 nm):
(1) micronizing mecobalamin raw material medicine, and controlling the particle size D of the raw material medicine50Sieving mecobalamin with 100 mesh sieve (removing lumps) to obtain mecobalamin powder with particle size of less than or equal to 10 μm, sieving calcium hydrogen phosphate with 120 mesh sieve, collecting the oversize part, and weighing the raw and auxiliary materials according to the prescription amount;
(2) sequentially adding lactose and mecobalamin granules into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 10 min;
(3) sequentially adding microcrystalline cellulose and croscarmellose sodium into a high-speed stirring and mixing granulator, stirring at 180rpm/min, and cutting at 1000rpm/min for 3 min;
(4) adding calcium stearate into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 1 min;
(5) tabletting: by adopting a circular shape
Figure BDA0002158710030000094
The hardness of the punched sheet is controlled to be 8-16 kg.
Comparative example 3
The formula of the plain tablet comprises:
Figure BDA0002158710030000092
Figure BDA0002158710030000101
the preparation method (the following steps are carried out under a red light lamp with the wavelength of more than 600 nm):
(1) micronizing mecobalamin raw material medicine, and controlling the particle size D of the raw material medicine50Sieving mecobalamin with a 100-mesh sieve (removing lumps) at a particle size of less than or equal to 10 μm, sieving microcrystalline cellulose with a 120-mesh sieve, taking the oversize part, and weighing the raw and auxiliary materials according to the prescription amount;
(2) sequentially adding lactose and mecobalamin granules into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 10 min;
(3) sequentially adding microcrystalline cellulose and croscarmellose sodium into a high-speed stirring and mixing granulator, stirring at 180rpm/min, and cutting at 1000rpm/min for 3 min;
(4) adding calcium stearate into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 1 min;
(5) tabletting: by adopting a circular shape
Figure BDA0002158710030000103
A punching sheet with a hardness of 8-16 kg
Comparative example 4
The formula of the plain tablet comprises:
Figure BDA0002158710030000102
the preparation method (the following steps are carried out under a red light lamp with the wavelength of more than 600 nm):
(1) micronizing mecobalamin raw material medicine, and controlling the particle size D of the raw material medicine50Sieving the mecobalamin raw material medicine with a 100-mesh sieve with granularity of 150-400 mu m, and weighing the raw and auxiliary materials according to the prescription amount;
(2) sequentially adding lactose and mecobalamin granules into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 10 min;
(3) sequentially adding microcrystalline cellulose and croscarmellose sodium into a high-speed stirring and mixing granulator, stirring at 180rpm/min, and cutting at 1000rpm/min for 3 min;
(4) adding calcium stearate into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 1 min;
(5) tabletting: by adopting a circular shape
Figure BDA0002158710030000113
The hardness of the punched sheet is controlled to be 8-16 kg.
Comparative example 5
The formula of the plain tablet comprises:
Figure BDA0002158710030000111
preparation method (the following method is carried out under red light lamp with wavelength more than 600 nm):
(1) micronizing mecobalamin raw material medicine, and controlling the particle size D of the raw material medicine50Sieving the mecobalamin raw material medicine with a 100-mesh sieve, and weighing the raw and auxiliary materials according to the prescription amount, wherein the particle size is less than or equal to 10 mu m;
(2) adding lactose, mecobalamin, microcrystalline cellulose and croscarmellose sodium into a high-speed stirring mixing granulator in sequence, stirring at 120rpm/min, cutting at 1000rpm/min for 10 min;
(3) adding calcium stearate into a high-speed stirring and mixing granulator, stirring at 120rpm/min, cutting at 1000rpm/min for 1 min;
(4) tabletting: by adopting a circular shape
Figure BDA0002158710030000112
The hardness of the punched sheet is controlled to be 8-16 kg.
Effect verification
1. Uniformity determination of effective components in mecobalamin tablets
The experimental method comprises the following steps:
test solution: and (3) operating in a dark place, taking 1 tablet of the product, placing the tablet in a 10ml measuring flask, adding a proper amount of mobile phase, carrying out ultrasonic treatment for 10min to dissolve mecobalamin, cooling, diluting to a scale with the mobile phase, shaking up, filtering, and taking filtrate as a test solution.
Control solution: weighing appropriate amount of mecobalamin reference substance, dissolving with mobile phase, and quantitatively diluting to obtain solution containing 50ug per 1 ml.
The determination method comprises the following steps: precisely measuring 20ul of each of the test solution and the reference solution, injecting into a liquid chromatograph, recording chromatogram, and calculating according to external standard method by peak area.
Calculating the formula:
Figure BDA0002158710030000121
wherein: a. theSample (A): peak area of test solution
ATo pair: peak area of control solution
CTo pair: concentration of control solution (mg/ml)
CSample (A): concentration of test solution (mg/ml)
P: purity of control
The experimental results are as follows:
table 1 content uniformity results
Serial number A+2.2S
Example 1 5.58
Example 2 7.28
Example 3 8.45
Example 4 4.02
Comparative example 1 12.98
Comparative example 2 11.76
Comparative example 3 14.05
Comparative example 4 13.12
Comparative example 5 17.77
And (4) experimental conclusion: from the above results, it can be known that the mecobalamin sheet with good uniformity can be obtained by adopting the technical scheme of the invention. Compared with comparative examples 1-3, examples 1-4 are more uniform, which shows that the granular lactose is more suitable to be used as a carrier of the mecobalamin tablets; compared with the comparative example 4, the examples 1 to 4 are more uniform, which shows that better uniformity can be obtained only under the condition that the proportion of the auxiliary materials and the raw material medicines is proper; compared with the comparative example 5, the examples 1 to 4 and the comparative examples 1 to 4 are more uniform, which shows that the mixing process provided by the invention can obtain better uniformity on the premise of shortening the mixing time, and simultaneously ensure the stability of the effective substances. The better homogeneity of example 4 compared to examples 1-3 indicates that a suitable particle size selection facilitates a uniform distribution of the active substance in the tablet.
2. Stability test of mixture prepared by ordered mixing Process
The test method comprises the following steps: 10g of the mixture of mecobalamin and large-particle carriers prepared in the step (2) of examples 1 to 4 and comparative examples 1 to 4, respectively, was placed on a 200-mesh sieve and shaken for 5min, and the content of mecobalamin on the carrier particles before and after shaking was measured and measured in parallel for 3 times. The measuring method is the same as that of 1, the uniformity of the effective components in the mecobalamin tablets is measured.
The results are shown in Table 2:
TABLE 2 Carrier particle mecobalamin content
Figure BDA0002158710030000131
And (4) experimental conclusion:
the stability of the mixture prepared by orderly mixing is related to the types and the particle size distribution of the carrier particles and the ratio of the raw material medicines to the carrier, and compared with the comparative examples 1-3, the content of mecobalamin on the carrier is higher in examples 1-4, so that the large-particle lactose particles are more suitable for being used as the carrier of the mecobalamin tablets; compared with the comparative example 4, the stability of the examples 1 to 4 is better, and the proper proportion of the auxiliary material and the mecobalamin is more beneficial to the adsorption of the bulk drug by the particle carrier; compared with the examples 1-3, the example 4 has better adsorbability to mecobalamin, and shows that proper particle size selection is favorable for adsorbing effective substances in the tablets.
Example 5
The weight of the coating of the plain tablet prepared in the example 1 is increased by 6 to 8 percent to prepare the mecobalamin tablet. The formula of the coating is as follows:
Figure BDA0002158710030000132
Figure BDA0002158710030000141
example 6
The weight of the coating of the plain tablet prepared in the example 2 is increased by 6 to 8 percent, and the mecobalamin tablet is prepared. Wherein the coating formula is as follows:
components The mass portions of each component
Titanium dioxide
40 portions of
Hydroxypropyl methylcellulose (HPMC) 70 portions of
Polyethylene glycol 15 portions of
Iron oxide yellow 0.1 part
Iron oxide red 2 portions of
Example 7
The weight of the coating of the plain tablets prepared in the example 3 is increased by 6 to 8 percent, and the mecobalamin tablets are prepared. Wherein the coating formula is as follows:
components The mass portions of each component
Titanium dioxide
20 portions of
Polyvinyl alcohol (PVA) 40 portions of
Polyethylene glycol 5 portions of
Iron oxide yellow 2 portions of
Iron oxide red 0.1 part
Example 8
The weight of the coating of the plain tablet prepared in the example 1 is increased by 8 to 10 percent to prepare the mecobalamin tablet. Wherein the coating formula is as follows:
components The mass portions of each component
Titanium dioxide 35 portions of
Hydroxypropyl methylcellulose (HPMC) 55 portions of
Polyethylene glycol 9.5 parts of
Iron oxide yellow 0.1 part
Iron oxide red 0.4 portion of
Example 9
The plain tablets prepared in example 1 were double coated. The weight of the inner coating is increased by 1-2%, then the weight of the outer coating is increased by 2-4%, and the total weight of the coating is increased by 3-6%, so as to prepare the mecobalamin tablets.
The formula of the inner coating is as follows:
components The mass portions of each component
Titanium dioxide
20 portions of
Hydroxypropyl methylcellulose (HPMC) 64 portions
Polyethylene glycol 15.5 parts of
Pigment (Black) 0.5 portion
The outer coating formula is as follows:
components The mass portions of each component
Titanium dioxide 35 portions of
Polyvinyl alcohol PVA 55 portions of
Polyethylene glycol 10 portions of
Example 10
The plain tablets prepared in example 1 were double coated. The weight of the inner coating is increased by 1-2%, then the weight of the outer coating is increased by 2-4%, and the total weight of the coating is increased by 3-6%, so as to prepare the mecobalamin tablets.
The formula of the inner coating is as follows:
components The mass portions of each component
Titanium dioxide 15 portions of
Hydroxypropyl methylcellulose (HPMC) 40 portions of
Polyethylene glycol 10 portions of
Pigment (Brown red) 0.1 part
The outer coating formula is as follows:
components The mass portions of each component
Titanium dioxide 25 portions of
Polyvinyl alcohol (PVA) 40 portions of
Polyethylene glycol 10 portions of
Example 11
The plain tablets prepared in example 1 were double coated. The weight of the inner coating is increased by 1-2%, then the weight of the outer coating is increased by 2-4%, and the total weight of the coating is increased by 3-6%, so as to prepare the mecobalamin tablets.
The formula of the inner coating is as follows:
components The mass portions of each component
Titanium dioxide 25 portions of
Polyvinyl alcohol (PVA) 70 portions of
Polyethylene glycol 25 portions of
Pigment (Red) 5 portions of
The outer coating formula is as follows:
components The mass portions of each component
Titanium dioxide
40 portions of
Hydroxypropyl methylcellulose (HPMC) 70 portions of
Polyethylene glycol 25 portions of
Comparative example 6
The weight of the coating of the plain tablet prepared in the example 1 is increased by 2 to 4 percent to prepare the mecobalamin tablet. Wherein the coating formula is as follows:
components The mass portions of each component
Titanium dioxide 35 portions of
Hydroxypropyl methylcellulose (HPMC) 55 portions of
Polyethylene glycol 9.5 parts of
Iron oxide yellow 0.1 part
Iron oxide red 0.4 portion of
Comparative example 7
The plain tablets prepared in example 1 were double coated. The weight of the inner coating is increased by 1-2%, then the weight of the outer coating is increased by 2-4%, and the total weight of the coating is increased by 3-6%, so as to prepare the mecobalamin tablets.
The formula of the inner coating is as follows:
Figure BDA0002158710030000161
Figure BDA0002158710030000171
the outer coating formula is as follows:
components Mass of each componentPortions are
Titanium dioxide 20 portions of
Hydroxypropyl methylcellulose (HPMC) 64 portions
Polyethylene glycol 16 portions of
Effect verification
3. Test by intense light irradiation
The test method comprises the following steps: the mecobalamin tablets prepared in example 5, example 8, example 9, comparative example 6 and comparative example 7 and the commercially available product "MikeBao" were placed in a sealed clean container under the illumination of 4500Lx + -500 Lx, and samples were taken on days 0 and 10 to determine the substances of the mecobalamin tablets, and the substances of the samples were compared.
The related substance determination method comprises the following steps: and (4) avoiding light. Grinding and precisely weighing fine powder equivalent to 2.5mg of mecobalamin, placing the fine powder into a 10ml measuring flask, adding a mobile phase for dilution, and filtering to obtain a subsequent filtrate as a test solution; an appropriate amount of the subsequent filtrate was weighed out closely to prepare a solution containing 7.5ug of the filtrate per 1ml as a control solution. By C18(250 mm. times.4.6 mm 5 μm) column, mobile phase: acetonitrile: 0.03mol/L sodium dihydrogen phosphate aqueous solution (pH3.5) is 19:81, the flow rate is 1.0mL/min, the detection wavelength is 342mm, and the calculation is carried out according to a peak area external standard method. The results are shown in Table 3:
TABLE 3 contents of related substances
Figure BDA0002158710030000172
And (4) experimental conclusion: according to the powder direct compression process adopted by the invention, the prepared mecobalamin tablets can obtain mecobalamin tablets with lower impurity content than the commercial products only by increasing the coating weight or by double-layer coating. Examples 5, 8, 9 are more stable than comparative example 6, indicating that a suitable coating amount is a necessary condition to ensure stability of mecobalamin; compared with the comparative example 7, the examples 5, 8 and 9 are more stable, which shows that the proportion of each component of the coating material is important for maintaining the stability of the mecobalamin; compared with examples 5 and 8, example 9 realizes the improvement of the stability of the mecobalamin while reducing the coating amount, and shows that the coating material of example 9 is more suitable for maintaining the stability of the mecobalamin.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that it is obvious to those skilled in the art that various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be considered as the protection scope of the present invention.

Claims (6)

1. A mecobalamin tablet is characterized by comprising a plain tablet and a coating;
the number of the coating layers is 1-2; the mass ratio of the plain tablets to the coating is 100: (3-10);
the plain tablets comprise the following components in parts by mass:
0.5 part of mecobalamin;
45-80 parts of granular lactose for direct compression;
15-30 parts of microcrystalline cellulose;
1.8-10 parts of croscarmellose sodium;
0.18-0.9 parts of calcium stearate;
the particle size of the lactose particles for direct compression is 150-400 μm;
the particle size of the mecobalamin is D50≤10μm；
The number of the coating layers is 1, and the mass ratio of the plain tablets to the coating is 100: (6-10);
the coating material comprises 20-40 parts by mass of titanium dioxide, 40-70 parts by mass of hydroxypropyl methyl cellulose or polyvinyl alcohol, 5-15 parts by mass of polyethylene glycol and 0.5-2.1 parts by mass of pigment;
or the number of the coating layers is 2, and the mass ratio of the plain tablets to the coating layers is 100 (3-6);
wherein the inner coating is prepared from 15-25 parts by mass of titanium dioxide, 40-70 parts by mass of hydroxypropyl methylcellulose or polyvinyl alcohol, 10-25 parts by mass of polyethylene glycol and 0.1-5 parts by mass of pigment;
the outer coating material comprises 25-40 parts by mass of titanium dioxide, 40-70 parts by mass of hydroxypropyl methyl cellulose or polyvinyl alcohol and 10-25 parts by mass of polyethylene glycol.
2. The mecobalamin tablet according to claim 1, wherein the plain tablet consists of the following components in parts by mass: 0.5 part of mecobalamin, 60 parts of granular lactose for direct compression, 25 parts of microcrystalline cellulose, 5 parts of croscarmellose sodium and 0.5 part of calcium stearate.
3. A method for preparing mecobalamin tablets according to claim 1 or 2, comprising:
screening the mecobalamin raw material medicine, and removing lumps;
evenly mixing mecobalamin and lactose granules for direct compression;
then adding microcrystalline cellulose and croscarmellose sodium in sequence, and mixing uniformly;
finally, adding calcium stearate and uniformly mixing;
and tabletting, and increasing the weight of the coating by 3-10% to obtain the mecobalamin tablets.
4. The production method according to claim 3,
wherein the parameters of the mecobalamin and the lactose granules for direct compression are as follows: stirring at 120rpm/min, cutting at 1000rpm/min for 10 min;
after microcrystalline cellulose or croscarmellose sodium was added, the mixing parameters were: stirring at 180rpm/min, cutting at 1000rpm/min for 3 min;
after adding calcium stearate, stirring at 120rpm/min, and mixing parameters are as follows: the cutter was operated at 1000rpm/min for 1 min.
5. The method according to claim 3, wherein the tablet hardness is 8kg to 16kg.
6. A method according to any one of claims 3 to 5, wherein each step is carried out under red light having a wavelength of greater than 600 nm.
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