CN113367347A

CN113367347A - Preparation method of vitamin C sustained-release composition

Info

Publication number: CN113367347A
Application number: CN202110676194.7A
Authority: CN
Inventors: 林锦淮; 李健永
Original assignee: Sirio Pharma Co Ltd
Current assignee: Sirio Pharma Co Ltd
Priority date: 2021-06-18
Filing date: 2021-06-18
Publication date: 2021-09-10

Abstract

The invention provides a preparation method of a vitamin C sustained-release composition, which comprises the following steps: (a) taking 1-2 wt% of adhesive according to the total amount of raw materials, dissolving the adhesive in water to prepare adhesive solution, wherein 15-20 wt% of the adhesive is prepared into adhesive solution A with the viscosity range of 10-50 cps; 80-85 wt% of the binder is prepared into a binder solution B with the viscosity range of 5-40 cps; (b) placing 75-80 wt% of vitamin C and 10-16 wt% of filler into a wet granulator, stirring and mixing uniformly, adding the binder solution A for granulation, transferring the granules to a fluidized bed, and spraying the binder solution B for granulation; (c) drying and sieving; (d) adding 5-7% hydroxypropyl methyl cellulose K100M, and mixing; (e) adding 0.5-2.0% magnesium stearate, and mixing; and (f) tableting. The method only uses purified water as a solvent, does not need any organic solvent, is environment-friendly and safe, can be produced in a conventional production workshop, and has low process cost. The vitamin C sustained release preparation prepared by the method has good compressibility and high vitamin C content.

Description

Preparation method of vitamin C sustained-release composition

Technical Field

The invention relates to the field of health-care food, in particular to a preparation method of a vitamin C slow-release composition and the vitamin C slow-release composition obtained by the preparation method.

Background

Vitamin C (VC), also called L-ascorbic acid, is a water-soluble vitamin. Vitamin C in food is distributed to all water-soluble structures in the body once it is absorbed by the upper small intestine of the human body. The vitamin C metabolic activity pool in normal adults is about 1500mg vitamin C, with a peak storage peak of 3000mg vitamin C. Since vitamin C is required for the synthesis of collagen, collagen cannot be normally synthesized in the absence of VC, which results in cell adhesion failure. The human body is composed of cells, which are connected by an intercellular substance, the key component of which is collagen. Collagen accounts for 1/3 body proteins, generates connective tissue, constitutes body skeleton such as bones, blood vessels, ligaments, etc., and determines skin elasticity, protects the brain, and helps the healing of human wounds. The strength of the vessel wall has a large relationship with VC. The microvessels are the smallest of all vessels, and the wall of the vessel may have a thickness of only one cell, and its strength and elasticity are determined by collagen with a cementatious action responsible for connecting cells. When there is insufficient VC in the body, the microvasculature is easily ruptured and blood flows to adjacent tissues. When this occurs on the skin surface, blood stasis and purple spots occur. Occurring in vivo causes pain and joint pain. In severe cases, bleeding and even death may occur in the stomach, intestinal tract, nose, kidneys and under the periosteum. The vitamin C can protect other antioxidants such as vitamin A, vitamin E, unsaturated fatty acid, and prevent free radicals from damaging human body. The vitamin C reduces ferric iron which is difficult to absorb and utilize into ferrous iron, promotes the absorption of iron by intestinal tracts, improves the utilization rate of iron by livers and is beneficial to treating iron-deficiency anemia. VC can enhance chemotaxis and deformability of neutrophils and improve bactericidal ability; promoting the generation of lymphoblast, and improving the recognition and killing of the body to external and malignant cells; involved in the synthesis of immunoglobulins; increasing CI complement esterase activity, increasing complement CI production; promote the production of interferon, interfere the transcription of virus mRNA, and inhibit the proliferation of virus.

The most common dosage form of the product for supplementing the vitamin C is tablets, and the tablets have the advantages of stability, convenience in carrying, easiness in quantitative taking, convenience in taking and the like, but the structural property of the vitamin C is poor in forming property in the tablets, and the tablets are difficult to form, so that a large amount of auxiliary materials are required to be added in the formula to assist in forming the tablets. Therefore, the proportion of the vitamin C in the formula is low, the proportion of common vitamin C is mostly 10% -20%, the content of the vitamin C in the formula is low, and each tablet contains less vitamin C.

In the prior art, the compressibility of the vitamin C raw material is poor, the addition amount of the vitamin C raw material applied to tablets is low, and the compressibility of the tablets can be smoothly tabletted only by adding a large proportion of auxiliary materials to improve the compressibility. Therefore, the vitamin C proportion in the vitamin C tablet is low (10% -20%), and consumers need to take the tablet for many times a day, and the tablet is easy to miss. The sustained-release tablet adopts a skeleton sustained-release tablet granulated by a wet method or a sustained-release coated tablet coated with a sustained-release coating, ethanol is required for granulation or coating in the production process, the requirement on explosion resistance of a workshop is high, and potential safety hazards exist.

Accordingly, there is a need in the art for methods of preparing sustained release compositions containing high vitamin C.

Summary of The Invention

The invention aims to provide a method for preparing a high-vitamin C content sustained-release preparation with good compressibility. By the method, compressibility can be realized even if the vitamin C accounts for up to 80% of the formula, and the method only uses purified water as a solvent and does not need any organic solvent, so that the method is environment-friendly and safe, can be used for production in a conventional production workshop, and is low in process cost.

In one aspect, the present invention provides a method for preparing a vitamin C sustained-release composition, which comprises:

(a) taking 1-2 wt% of adhesive according to the total amount of raw materials, dissolving the adhesive in water to prepare adhesive solution, wherein 15-20 wt% of the adhesive is prepared into adhesive solution A with the viscosity range of 10-50 cps; 80-85 wt% of the binder is prepared into a binder solution B with the viscosity range of 5-40 cps;

(b) placing 75-80 wt% of vitamin C and 10-16 wt% of filler into a wet granulator, stirring and mixing uniformly, adding the binder solution A for granulation, transferring the granules to a fluidized bed, and spraying the binder solution B for granulation;

(c) drying and sieving;

(d) adding 5-7% hydroxypropyl methyl cellulose K100M, and mixing;

(e) adding 0.5-2.0% magnesium stearate, and mixing; and is

(f) And (6) tabletting.

In one embodiment, the binder is one or a combination of hypromellose, hydroxypropyl cellulose, and povidone K30.

In one embodiment, the binder is 0.8 wt% to 1.7 wt% hypromellose and 0.15 wt% to 0.4 wt% hydroxypropyl cellulose. In one embodiment, the binder is 1 wt% hypromellose and 0.2 wt% hydroxypropyl cellulose.

In one embodiment, the filler is a combination of two or more of maltodextrin, microcrystalline cellulose, pregelatinized starch.

In one embodiment, the method further comprises the step of (g) coating the tablet with a coating premix.

In one embodiment, the coating premix is one or a combination of hydroxypropyl cellulose, talc, and glycerin. In one embodiment, the coating premix is present in an amount greater than 0% and equal to or less than 3% by weight.

In one embodiment, binder solution a is a 5 wt% binder solution and/or binder solution B is a 2 wt% binder solution.

In one embodiment, step (c) comprises sieving the whole granules through a 20 mesh sieve.

In one embodiment, the hypromellose is hypromellose E50.

In one embodiment, the content of maltodextrin or pregelatinized starch is from 5% by weight to 12% by weight, and/or the content of microcrystalline cellulose is from 3% by weight to 10% by weight.

In another aspect, the present invention provides a vitamin C sustained-release composition prepared by the above-described method. In one embodiment, the vitamin C sustained release composition is a tablet, such as a coated tablet.

In another aspect, the invention provides the use of a vitamin C sustained release composition in a medicament, food or health product. In another aspect, the invention provides the use of a sustained release composition of vitamin C in the manufacture of a medicament. In one embodiment, the medicament is for the treatment of a vitamin C deficiency related disease. In one embodiment, the food or nutraceutical is used to supplement normal subjects (e.g., humans) with vitamin C.

In the process of the invention, no organic solvent, such as ethanol, is added.

The advantages of the invention include:

1. the method only uses purified water as a solvent, does not need any organic solvent, is environment-friendly and safe, can be produced in a conventional production workshop, and has low process cost;

2. the vitamin C sustained release preparation prepared by the method has good compressibility and high vitamin C content;

3. in the preparation of the hydrophilic gel matrix sustained-release tablet, the most commonly used hydrophilic gel matrix materials are high-viscosity hydroxypropyl cellulose K100M, K15M, K4M and the like. If a wet granulation process is used and hydroxypropyl cellulose is added to the granulation, the binder or wetting agent used generally requires the use of an organic solvent such as ethanol to reduce the viscosity to ensure that wet granulation can be completed properly. The hydroxypropyl cellulose K100M is added externally, and does not participate in wet granulation and does not need to use an organic solvent for granulation.

Detailed Description

The following is provided to facilitate an understanding of the present invention.

The present invention is based on the following findings of the inventors: the process of wet granulation firstly and then one-step granulation is adopted, and the obtained tablet is obviously superior to the tablet obtained by single wet granulation or single-step granulation in compressibility and slow release effect. In addition, the hydroxypropyl cellulose K100M is added externally, and does not participate in wet granulation, and organic solvent is not needed for granulation.

The invention provides a preparation method of a vitamin C sustained-release composition. The raw material formula of the vitamin C slow-release composition is as follows:

the method comprises the following steps

1. Weighing 15-20% of the adhesive according to the formula amount, and dissolving the adhesive in purified water to prepare an adhesive solution A with the viscosity range of 10-50 cps;

2. weighing 80-85% of the adhesive according to the formula amount, and dissolving in purified water to prepare an adhesive solution B with the viscosity range of 5-40 cps;

3. mixing vitamin C, maltodextrin and microcrystalline cellulose in a wet granulator, adding the binder solution A for granulation, transferring the granules to a fluidized bed, and spraying the binder solution B for granulation;

4. drying, sieving, e.g., sieving with a 20 mesh sieve;

5. adding hydroxypropyl methyl cellulose K100M, and mixing;

6. adding magnesium stearate and mixing;

7. tabletting;

8. optionally coated.

The method of the invention improves the compressibility of the vitamin C by combining the vitamin C and the specific filling agent, namely carrying out wet granulation and then carrying out granulation, thereby improving the ratio of the vitamin C to 80%. The sustained-release tablet prepared by adding the sustained-release matrix material has the release rate of about 26 percent in 2 hours, the release rate of about 57 percent in 4 hours and the release rate of about 100 percent in 8 hours, namely, the sustained-release effect is achieved.

The invention also provides the vitamin C sustained release tablet prepared by the method.

Herein, the vitamin C sustained-release composition may be a vitamin C sustained-release tablet in which the vitamin C content is 75 to 80 wt%, such as 76 wt%, 77 wt%, 78 wt% or 79 wt%. The prepared vitamin C slow-release composition can be used for supplementing vitamin C in an oral mode. Since the vitamin C sustained-release composition of the present invention has a high vitamin C content and a sustained-release effect, the amount thereof may be 1 tablet per day.

Fillers are used in the methods herein. The content of the filler is 10 to 16 wt%, for example 11 wt%, 12 wt%, 13 wt%, 14 wt% or 15 wt%. The filler may be a combination of two or more of maltodextrin, microcrystalline cellulose, and pregelatinized starch. The amount of maltodextrin or pregelatinized starch can be 5 wt% to 12 wt%, e.g., 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, or 11 wt%. The microcrystalline cellulose may be present in an amount of 3 wt% to 10 wt%, such as 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt% or 9 wt%.

An adhesive is used in the methods herein. The binder may be present in an amount of 1-2 wt%, e.g., 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, or 1.9 wt%. In one embodiment, the binder may be one or a combination of hypromellose, hydroxypropyl cellulose, or povidone K30. In the process of the invention, the binder is added in two stages of the preparation process: (1) mixing vitamin C, maltodextrin and microcrystalline cellulose in wet granulator, adding adhesive solution A, and granulating; and (2) transferring the granules to a fluidized bed, and spraying the binder solution B for granulation. That is, the raw material of the present invention is subjected to wet granulator granulation and fluidized bed granulation, and a binder solution is added in both processes. The binder solution A may be a binder made of 15-20 wt% of the binder amount. The viscosity of the binder solution A may range from 10 to 50 cps. The binder solution B may be a binder made of 80-85 wt% of the binder amount. The viscosity of the binder solution B may range from 5 to 40 cps. In one embodiment, the binder is 0.8 wt% to 1.7 wt% hypromellose and 0.15 wt% to 0.4 wt% hydroxypropyl cellulose. In one embodiment, the binder is 1 wt% hypromellose and 0.2 wt% hydroxypropyl cellulose. In one embodiment, the binder solution a is 4-8 wt%, such as 5 wt%, 6 wt% or 7 wt% binder solution, and/or the binder solution B is 1-3 wt%, such as 2 wt% binder solution.

Hydroxypropyl methylcellulose K100M was used in the process herein. The content of hydroxypropylmethylcellulose K100M may be 5-7 wt%, for example 6 wt%.

Magnesium stearate is used in the methods herein. The magnesium stearate may be present in an amount of 0.5-2.0 wt%, for example 1 wt% or 1.5 wt%.

The tablets are coated with a coating premix in the methods herein. The coating premix is one or combination of hydroxypropyl cellulose, talcum powder and glycerol, and preferably the content of the coating premix is more than 0% and less than or equal to 3 wt%, such as 1 wt% or 2 wt%.

Examples

The invention is further described by the following examples, which should not be construed as limiting the scope of the invention.

Materials and methods

1. The raw materials used in this example were as follows:

2. test method

Hardness of

The test method comprises the following steps: hardness of the samples was measured using a tablet friability hardness tester

The adopted instrument is as follows: CJY-2C type tablet friability hardness tester

Disintegration time limit

The test method comprises the following steps: USP disintegration time limit test method

The adopted instrument is as follows: BJ-3 disintegration time limit tester

The testing steps are as follows: the samples of examples and comparative examples were tested for disintegration time using water at 37 + -0.5 deg.C as a medium, and the time to complete disintegration was recorded, as specified in the United states Pharmacopeia.

Degree of release

The test method comprises the following steps: USP release degree test method

The adopted instrument is as follows: RCZ-8 model medicine dissolution instrument

The testing steps are as follows: according to the relevant provisions of United states Pharmacopeia, samples of the examples are taken for 1h, 4h and 8h by using 0.01mol/L hydrochloric acid 0.05% EDTA-2Na 0.05% L-cysteine aqueous solution at 37 +/-0.5 ℃ as a medium, the content of the vitamin C is detected, and the release degree is calculated.

Evaluation criteria:

pressure/hardness ratio: the examples were evaluated for compressibility, and a criterion of < 0.1 according to the invention was acceptable for compressibility, with smaller ratios indicating better compressibility.

Mean disintegration time limit: the standard of the invention is 2-6 h.

③ degree of release: the standard of the invention is that 1h is less than or equal to 30%, 4h is more than or equal to 50%, and 8h is more than or equal to 90%.

Example 1: comparison of preparation methods

The formulations in example 1, comparative example 1 and comparative example 2 are provided below in table 1.

TABLE 1

The preparation methods of example 1, comparative example 1 and comparative example 2 are provided in table 2 below.

TABLE 2

The experimental results obtained according to table 1 and the formulations and corresponding preparation methods in table 2 are provided in table 3 below.

TABLE 3

As can be seen from table 3, the compressibility and sustained-release effect of the vitamin C tablet prepared by the wet granulation process followed by the one-step granulation process in example 1 are significantly better than the compressibility and sustained-release effect of the vitamin C tablet prepared by the single wet granulation process or the single-step granulation process.

Examples 2 to 7: investigating the influence of the content of the components of the sustained-release composition on the effect of the vitamin C tablets

Tablets of the following formulation were prepared according to the method in example 1 above, and the tablets were tested for average hardness, compression/hardness, average disintegration time, and release degree, as shown in tables 4 and 5.

TABLE 4

TABLE 5

As shown in tables 4 and 5 above, the vitamin C content can reach 80%, and the formulation compressibility is poor when the content is 85%. When the content of the hydroxypropyl methylcellulose K100M is 4%, the sample is too fast to disintegrate, and the sample does not meet the standard. When the content of the hypromellose K100M is 8%, the disintegration speed of the sample is too slow, which does not meet the standard. Examples 8 to 11: investigating the influence of different binders and fillers on the effect of vitamin C tablets

The formulations of table 6 were followed and vitamin C tablets were prepared using the method of example 1 (except that lactose was used instead of microcrystalline cellulose; or pregelatinized starch was used instead of maltodextrin, the process conditions were not changed) and the effect of the different fillers on the vitamin C tablet effect was examined. The results are also shown in table 6.

TABLE 6

Lactose replaces microcrystalline cellulose, and the sample is too fast to disintegrate; the pregelatinized starch replaces maltodextrin, the formula has good compressibility, and the disintegration time and the release degree meet the standard requirements.

Formulations as in table 7, and vitamin C tablets were prepared using the method of example 1 (except that hydroxypropyl cellulose E50, hydroxypropyl cellulose, povidone K30 was used instead of the combination of hypromellose and hydroxypropyl cellulose, the process conditions were not changed for the other steps) and the effect of different fillers on the vitamin C tablet effect was examined. The results are also shown in table 7.

TABLE 7

The technical effect similar to that of the embodiment 1 can be obtained by using the hypromellose E50, the hydroxypropyl cellulose or the povidone K30 as the adhesive.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims

1. A method of preparing a vitamin C sustained release composition comprising:

(c) drying and sieving;

(d) adding 5-7 wt% of hydroxypropyl methyl cellulose K100M, and mixing uniformly;

(e) adding 0.5-2.0 wt% magnesium stearate, and mixing; and is

(f) And (6) tabletting.

2. The method of claim 1, wherein the binder is one or a combination of hypromellose, hydroxypropyl cellulose, and povidone K30; preferably, the binder is 0.8 wt% -1.7 wt% hypromellose and 0.15 wt% -0.4 wt% hydroxypropyl cellulose.

3. The method of claim 1 or 2, wherein the filler is a combination of two or more of maltodextrin, microcrystalline cellulose, pregelatinized starch.

4. The process of any of the preceding claims, further comprising the step of (g) coating the tablet with a coating premix.

5. The process of claim 4, wherein the coating premix is one or a combination of hydroxypropyl cellulose, talc and glycerol, preferably the content of the coating premix is more than 0% and less than or equal to 3% by weight.

6. The method of any of the preceding claims, wherein the binder solution a is 4 wt% to 8 wt%, such as 5 wt% binder solution, and/or the binder solution B is 1 wt% to 3 wt%, such as 2 wt% binder solution.

7. The process defined in any one of the preceding claims wherein step (c) includes sieving the whole granules through a 20 mesh sieve.

8. The method of any preceding claim, wherein the hypromellose is hypromellose E50.

9. The method of claim 3, wherein the maltodextrin or pregelatinized starch is present in an amount of 5% to 12% by weight and/or the microcrystalline cellulose is present in an amount of 3% to 10% by weight.

10. A vitamin C sustained release composition prepared according to the process of any one of the preceding claims, wherein the vitamin C sustained release composition is preferably a tablet, such as a coated tablet.

11. Use of the vitamin C sustained release composition of claim 10 in a medicament, food or health product.