Preparation method of a vitamin D3 preparation

Abstract

A preparation method of a vitamin D3 preparation according to the present invention is characterized by comprising the following steps: dissolving VD3 in ethanol to form a VD3 solution; adding a first binder to the VD3 solution for preliminary dilution to form a primary dilution solution; adding a second binder to the primary dilution solution for further dilution to form a secondary dilution solution; preparing wet granules by a wet granulation method with an excipient in combination with the VD3 secondary dilution solution; subjecting the wet granules to wet sizing, drying, and dry sizing in sequence. In the present invention, while vitamin D3 is precipitated in the form of nanocrystals through preliminary dilution, it is wrapped and protected by the first binder; through further dilution, the fluidity of the solution is reduced by the second binder, and the second binder assists the first binder in wrapping and protecting the vitamin D3 crystals. Not only is the yield increased, but also the process is more convenient, better meets the stable production requirements of the pharmaceutical production workshop, and the mixing uniformity is also better.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a preparation method of vitamin D3 preparation. Background Art

[0002] As an important fat-soluble vitamin, vitamin D3 has a wide range of applications in the fields of medicine, food, etc. However, the traditional preparation methods of vitamin D3 have problems such as poor stability and low bioavailability, which limit its development in practical applications.

[0003] The protection of vitamin D3 is mostly based on spray drying after microencapsulation to form intermediate vitamin D3 powder, and then the intermediate is added to processes such as granulation and mixing for the preparation of related preparations. For example, in the invention patent with the patent number 《CN 117899034A》, vitamin D3 is spray dried to obtain an embedded powder. However, the related process flow is relatively complex, and the stability of the preparation needs to be improved.

[0004] The patent with the patent number 《CN117695234A》 discloses a preparation method of an organic calcium vitamin D tablet. In this scheme, vitamin D3 is directly dissolved in ethanol to obtain a granulating agent, and wet granules are prepared by wet granulation with this granulating agent in combination with organic calcium, sucrose, a binder, and citric acid. Although the process is simplified, the stability is not high.

[0005] Therefore, it is of great significance and value to develop a more simple and efficient preparation technology to improve the stability and bioavailability of vitamin D3. Summary of the Invention

[0006] To solve or improve the technical problems existing in the prior art, the present disclosure provides a preparation method of vitamin D3, and this preparation method of vitamin D3 can be at least used for preparing granules or tablets of calcium carbonate / vitamin D3. Specifically, it includes the following steps:

[0007] VD3 is dissolved in ethanol to form a VD3 solution;

[0008] A first binder is added to the VD3 solution for preliminary dilution to form a primary dilution solution;

[0009] A second binder is added to the primary dilution solution for further dilution to form a secondary dilution solution;

[0010] An excipient is combined with the VD3 secondary dilution solution to prepare wet granules by the method of wet granulation;

[0011] The wet granules are successively subjected to wet sizing, drying, and dry sizing.

[0012] In the above solution, vitamin D3 is dissolved in ethanol, and the mass percentage of vitamin D3 in ethanol is (0.01%-1%). Through preliminary dilution, vitamin D3 is precipitated in the form of nano-crystals and simultaneously wrapped and protected by the first binder; through further dilution, the second binder reduces the fluidity of the solution and assists the first binder to wrap and protect the vitamin D3 crystals.

[0013] As one of the alternative solutions, in the preliminary dilution process, the first binder can be selected from aqueous starch solution, aqueous maltodextrin solution, aqueous solution of a mixture of starch and maltodextrin, or other binders with a branched macromolecular structure.

[0014] As a further preferred solution, in the preliminary dilution process, the first binder is an aqueous solution of a mixture of starch and maltodextrin, and starch and maltodextrin are proportioned at a ratio of 1:1. The mass percentage content of the single component of starch and maltodextrin in water is 30%-90%. When the aqueous starch and maltodextrin solution is added to the vitamin D3 solution, due to the decrease in ethanol concentration and the insolubility of vitamin D3 in water, it will precipitate in the form of nano-crystals in the aqueous starch and maltodextrin solution. The particle size of the precipitated nano-crystals is very small. Combining with the structural characteristics of the branched macromolecules of starch and maltodextrin, the precipitated vitamin D3 nano-crystals can be wrapped. The specific implementation method of wrapping adopts a stirring process, including but not limited to paddle stirring, shear by a disperser, and high-pressure homogenization.

[0015] As one of the alternative solutions, in the further dilution process, the second binder is an aqueous povidone solution, and the mass percentage content of the aqueous povidone solution in water is 20%-30%. The viscosity of the aqueous povidone solution can reduce the fluidity of the solution, help maintain the structure of the vitamin D3 crystals wrapped by starch and maltodextrin, and at the same time povidone also has film-forming properties and can also play a protective role during the drying process.

[0016] As one of the alternative solutions, the excipient includes: active ingredient, filler, and optionally disintegrant, flavoring agent. The active ingredient is other supplements.

[0017] As a further preferred solution, the active ingredient is one or more of calcium carbonate, calcium citrate, calcium gluconate, calcium phosphate, calcium lactate; the filler is one or more of mannitol, sorbitol, microcrystalline cellulose, lactose, sucrose; the disintegrant is one or more of croscarmellose sodium, corn starch, sodium carboxymethyl starch, crospovidone; the flavoring agent is one or more of aspartame, sucrose, stevioside, sucralose, erythritol.

[0018] As one of the alternative solutions, after the wet granules are subjected to wet screening, drying, and dry screening, granule agents are prepared, and then further total mixing and tableting are carried out to prepare tablets or chewable tablets.

[0019] As one of the optional solutions, a lubricant is added during the mixing process.

[0020] As a further preferred solution, the lubricant is magnesium stearate, and the component ratios are as follows:

[0021] Vitamin D3 ethanol solution (0.01%-1%): 0.05-0.15 parts

[0022] Aqueous solution of starch and maltodextrin mixture (mono-component content 30%-90%): 0.5-1.5 parts

[0023] Aqueous solution of polyvinylpyrrolidone (20%-30%): 7.0-10.0 parts

[0024] Active ingredient: 60-70 parts

[0025] Filler: 0-30 parts

[0026] Disintegrant: 0-4.0 parts

[0027] Flavoring agent: 0.05-5.0 parts

[0028] Magnesium stearate: 0-0.5 parts.

[0029] As a further preferred solution, the calcium carbonate is light calcium carbonate.

[0030] In summary, among the technical solutions and their optional solutions in the foregoing aspects, the process for preparing vitamin D3 of the present invention is more efficient than the process for preparing a preparation containing vitamin D3 in the prior art (the process for preparing a preparation containing vitamin D3 in the prior art includes: preparation of a vitamin D3 water-in-oil emulsion → spray drying of the vitamin D3 water-in-oil emulsion to obtain vitamin D3 microcapsule powder, and then adding the vitamin D3 microcapsule powder to other non-active excipients for mixing or further tableting), omitting the process of preparing intermediate vitamin D3 powder and simplifying the production process.

[0031] The existing process also has the following problems: 1. The yield of preparing vitamin D3 microcapsule powder by the conventional spray drying method is relatively low (a yield of 50% is already relatively high); 2. Since the addition amount of vitamin D3 in the preparation is extremely low, there is still a problem of mixing uniformity in the process of adding the intermediate vitamin D3 microcapsule powder. The process of the present invention directly adds vitamin D3 to the granulation process without going through the steps of vitamin D3 water-in-oil emulsion and emulsion curing, and these two steps are often the key steps determining the process stability and reproducibility. Therefore, the process of the present invention perfectly overcomes the above two difficulties existing in the existing process, ensuring that the added vitamin D3 is not lost due to process limitations; therefore, the present invention not only improves the yield, but also simplifies the process, better meets the stable production requirements of the pharmaceutical production workshop, and has better mixing uniformity. Detailed Embodiments

[0032] Unless otherwise defined, all technical and scientific terms used in the present invention have the same meaning as commonly used in the field to which the present invention belongs. For the purpose of explaining this specification, the following definitions will be applied, and where appropriate, terms used in the singular form will also include the plural form, and vice versa.

[0033] Unless the context clearly indicates otherwise, the expressions "a" and "an" used herein include plural referents.

[0034] The term "comprises" or "comprising" used herein means "including but not limited to". This term is intended to be open-ended, specifying the presence of any stated feature, element, integer, step or component, but not precluding the presence or addition of one or more other features, elements, integers, steps, components or groups thereof. Thus, the term "comprising" includes the more restrictive terms "consisting of" and "consisting essentially of". In one embodiment, the term "comprising" used throughout the application, particularly in the claims, may be replaced by the term "consisting of".

[0035] The terms "optionally", "any one", "any", or "any item" used herein mean that the subsequently described event or circumstance may or may not occur, and this description includes the instances where the event or circumstance occurs or does not occur. As used in the present invention, "a" and "an" are used in the present invention to refer to one or more than one grammatical object.

[0036] The term "and / or" used herein should be understood to mean any one of the alternatives or any combination of any two or more of the alternatives.

[0037] Currently, limited by the relatively complex related process flow, the low yield of vitamin D3 powder, and the low mixing uniformity, the stability of the preparation needs to be improved.

[0038] In view of this, the embodiments of the present disclosure provide a preparation method of a vitamin D3 preparation, aiming to provide a preparation method of a vitamin D3 preparation with simpler procedures, convenient production operation, low cost, high yield, and good mixing uniformity. Taking calcium carbonate / vitamin D3 chewable tablets as an example, the following is the specific preparation method of the chewable tablets:

[0039] Example 1

[0040]

[0041]

[0042] Preparation process:

[0043] Prepare the first binder: Weigh the prescribed amount of starch and maltodextrin, add 1.8 kg of purified water, stir to dissolve, and set aside;

[0044] Prepare the second binder: Weigh the prescribed amount of PVP, dissolve it in 21.56 kg of purified water, stir to dissolve, and set aside;

[0045] Prepare the primary dilution solution: Take the prescribed amount of ethanol, add VD3, slowly stir to dissolve VD3, add the first binder to the VD3-ethanol solution, stir for 5 - 10 min to mix evenly, and stir at a speed of 8000 rpm in the blender for 15 min to obtain the primary dilution solution;

[0046] Prepare the secondary dilution solution: Add the above VD3 primary dilution solution to the second binder, stir at 1000 rpm for 5 min, mix evenly to obtain the secondary dilution solution, and set aside;

[0047] Granulation: First, premix calcium carbonate, mannitol, and aspartame in a wet granulator for 5 min, then add the secondary dilution solution containing VD3 to the material through the viewing window. After adding, granulate for 10 min and discharge the material;

[0048] Wet screening: Screen the wet material in a swing granulator;

[0049] Drying: Transfer the granulated particles to a fluidized bed for drying. Set the drying temperature to 60 °C, and end the drying after the material temperature reaches 40 °C;

[0050] Dry screening: Screen the dried particles through a rapid screening machine and collect them in a feed hopper;

[0051] Total mixing: Add magnesium stearate to the dried and screened particles and mix for 5 min;

[0052] Tabletting: Adjust the tablet weight to 1.8 g and the hardness to 100 - 120 N for tabletting.

[0053] Example 2

[0054] Compared with Example 1, in this example, heavy calcium carbonate is used to replace the light calcium carbonate in Example 1, and the rest is the same as in Example 1.

[0055] Taking calcium carbonate / vitamin D3 granules as an example, the following is the specific preparation method of the granules:

[0056] Example 3

[0057]

[0058]

[0059] Preparation process:

[0060] Prepare the first binder: Weigh the prescription amount of starch and maltodextrin, slowly add them to 0.5 kg of purified water, and continuously stir until dissolved for standby.

[0061] Prepare the second binder: Weigh the prescription amount of PVP and dissolve it in 11.2 kg of purified water, stir to dissolve for standby.

[0062] Prepare the primary dilution: Take the prescription amount of ethanol, add VD3, and slowly stir to dissolve VD3; add the first binder to the VD3-ethanol, stir and mix evenly, and then stir at 8000 rpm for 15 min in a blender as the primary dilution.

[0063] Prepare the secondary dilution: Add the primary dilution to the second binder and stir at 1000 rpm for 5 min to obtain the secondary dilution.

[0064] Granulation: First, premix calcium carbonate and mannitol in a wet granulator for 5 min, then spray and add the secondary dilution containing VD3 to the materials. After adding, granulate for 10 min and discharge the materials.

[0065] Wet screening: Screen the wet materials in a swing granulator.

[0066] Drying: Transfer the granulated materials after screening to a fluidized bed for drying. The drying temperature is 60 °C, and the drying ends when the material temperature reaches 40 °C.

[0067] Dry screening: Screen the dried granules through a 14-mesh screen in a rapid granule screening machine to obtain uniform granules.

[0068] Taking calcium carbonate / vitamin D3 tablets as an example, the following is the specific preparation method of the tablets:

[0069] Example 4

[0070]

[0071]

[0072] Preparation process:

[0073] Prepare the first adhesive: weigh the prescribed amount of starch and maltodextrin, add 1.8 kg of purified water, stir to dissolve, and set aside;

[0074] Prepare the second adhesive: weigh the prescribed amount of PVP and dissolve it in 21.56 kg of purified water, stir and dissolve it for later use;

[0075] Prepare the primary diluent: take the prescribed amount of ethanol, add VD3, slowly stir to dissolve VD3, add the first adhesive to the VD3-ethanol solution, stir for 5-10 minutes to mix, and stir at 8000 rpm for 15 minutes to prepare the primary diluent;

[0076] Prepare secondary diluent: add the above VD3 primary diluent to the second adhesive, stir at 1000 rpm for 5 min, mix well to obtain secondary diluent, set aside;

[0077] Granulation: Premix calcium carbonate, microcrystalline cellulose and croscarmellose sodium in a wet granulator for 5 minutes, then add the secondary diluent containing VD3 to the material through the viewing window. After adding, granulate for 5 minutes and discharge.

[0078] Wet granulation: The wet material is granulated in a swing granulator;

[0079] Drying: After granulation, the granules are transferred to the fluidized bed for drying. The drying temperature is set at 60°C. When the material temperature reaches 40°C, the drying is completed.

[0080] Dry granulation: The dried granules are granulated by a rapid granulator and then collected into a material bucket;

[0081] Total mixing: Add magnesium stearate to the dry whole granules and mix for 5 minutes;

[0082] Tableting: Adjust the tablet weight to 1.8g and the hardness to 200N for tableting.

[0083] Intermediate stability test

[0084] The stability of the total mixed granules containing vitamin D3 prepared in Example 4 was compared with that of the commercially available vitamin D3 microcapsule powder. The granules were placed at a high temperature of 60° C. and the content of vitamin D3 was measured on days 0, 10 and 30. The results are as follows:

[0085] 60℃ 0 days 10 days 30 days Degradation amount in 30 days This solution 108.20％ 104.8％ 102.2％ 6％ Kingdomway 107.40％ 92.70％ 88.40％ 18％ NHU 125.50％ 120.30％ 111.90％ 11％

[0086] It can be seen from the above table that the vitamin D3 intermediate prepared by the present invention has higher stability.

[0087] Tablet product stability testing

[0088] The tablets prepared in Example 4 were compared with the commercially available vitamin D3 microcapsule powder tablets in terms of stability. They were respectively placed at a high temperature of 60 °C, and the content of vitamin D3 was measured on the 0th, 10th, and 30th days. The results are as follows:

[0089]

[0090] As can be seen from the above table, the stability of vitamin D3 in Example 4 was significantly improved.

[0091] The uniformity of the content of vitamin D3 in the vitamin D3-containing preparation prepared in Example 4 was compared with that of the commercially available similar products. The results are as follows:

[0092]

[0093] As can be seen from the above table, the uniformity of the content of the vitamin D3 tablets prepared in Example 1 was significantly improved.

[0094] The stability of vitamin D3 in Examples 1, 3, and 4 was determined and compared with that of the commercially available similar products. They were respectively placed at high temperatures of 40 °C and 60 °C, and the content of vitamin D3 was measured on the 0th, 5th, 10th, and 30th days. The results are as follows:

[0095]

[0096]

[0097]

[0098] As can be seen from the above table, the stability of the vitamin D3-containing preparations prepared in Examples 1, 3, and 4 was significantly improved compared with that of the commercially available products and the vitamin D3 in the comparative document scheme.

[0099] The vitamin D3-containing preparations prepared in Example 1 and Example 2 were respectively subjected to stability tests. They were respectively placed at high temperatures of 40 °C and 60 °C, and the content of vitamin D3 was measured on the 0th, 5th, 10th, and 30th days. The results are shown in the following table:

[0100]

[0101]

[0102] As can be seen from the above table, compared with Example 2, the stability of Example 1 using light calcium carbonate as the active ingredient was significantly improved at 40 °C and 60 °C.

[0103] As described above, it is only the specific implementation manner of the embodiments of the present invention, but the protection scope of the embodiments of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the embodiments of the present invention can easily think of changes or substitutions, which should all be covered within the protection scope of the embodiments of the present invention. Therefore, the protection scope of the embodiments of the present invention shall be subject to the protection scope of the claims.

Claims

1. A preparation method of a vitamin D3 preparation, characterized in that, It includes the following steps: VD3 is dissolved in ethanol to form a VD3 solution; A first binder is added to the VD3 solution for preliminary dilution to form a primary dilution solution. During the preliminary dilution process, the first binder is an aqueous solution of a mixture of starch and maltodextrin; A second binder is added to the primary dilution solution for further dilution to form a secondary dilution solution. During the further dilution process, the second binder is an aqueous solution of povidone; An excipient is combined with the VD3 secondary dilution solution to prepare wet granules by the wet granulation method. The excipient includes: light calcium carbonate, a filler, and optionally a disintegrant and a flavoring agent; The wet granules are successively subjected to wet sizing, drying, and dry sizing; Vitamin D3 ethanol solution: 0.05 - 0.15 parts Aqueous solution of a mixture of starch and maltodextrin: 0.5 - 1.5 parts Aqueous solution of povidone: 7.0 - 10.0 parts Light calcium carbonate: 60 - 70 parts Filler: 0 - 30 parts Disintegrant: 0 - 4.0 parts Flavoring agent: 0.05 - 5.0 parts Magnesium stearate: 0 - 0.5 parts.

2. The preparation method of a vitamin D3 preparation according to claim 1, wherein The filler is one or more of mannitol, sorbitol, microcrystalline cellulose, and lactose; the disintegrant is one or more of croscarmellose sodium, corn starch, sodium carboxymethyl starch, and crospovidone; the flavoring agent is one or more of aspartame, sucrose, stevioside, sucralose, and erythritol.

3. The preparation method of any one of the vitamin D3 preparations according to claims 1-2, characterized in that After the wet granules are subjected to wet sizing, drying, and dry sizing, a granule agent is obtained, and further total mixing and tabletting are carried out to obtain a tablet or a chewable tablet.

4. The preparation method of a vitamin D3 preparation according to claim 3, characterized in that, During the total mixing process, magnesium stearate or / and silicon dioxide is added and mixed evenly.

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