Choline bitartrate solid dispersion, preparation method and application thereof

Abstract

The application relates to a choline bitartrate solid dispersion, a preparation method and application thereof in the technical field of pharmaceutical preparations. The choline bitartrate solid dispersion is prepared by a melting method; the preparation raw materials of the choline bitartrate solid dispersion include the following components in percentage by mass: 20-50 wt% of choline bitartrate, 20-50 wt% of a sugar alcohol, 10-30 wt% of glycerin monostearate and 0.1-5 wt% of modified starch. In the solid dispersion prepared by the melting method, the choline bitartrate can be finely and amorphously dispersed and distributed in inert solid carriers such as the sugar alcohol and glycerin monostearate, so that the moisture absorption prevention effect is improved, and the bad smell of the choline bitartrate is effectively covered. When the solid dispersion is applied to the preparation of choline bitartrate preparations and composite vitamin preparations containing choline bitartrate, the stability of the preparations can be obviously improved.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparation technology, and in particular to a choline bitartrate solid dispersion, its preparation method, and its application. Background Technology

[0002] Choline is an essential component of the human and animal body, a necessary nutrient commonly known as B vitamins or vitamin B4, and plays a crucial role in the synthesis of the neurotransmitter acetylcholine. While choline can be synthesized in animals, it is often added to animal feed and is one of the most widely used vitamins. Currently, choline is a common food additive. The U.S. Federal Code classifies choline as "generally considered safe"; the European Union's 1991 regulations permitted its addition to infant formula. Choline bitartrate, a type of choline nutrient, is commonly used in nutritional supplements and fat-reducing agents, promoting fat metabolism and preventing fat accumulation in the liver. As a vitamin product, it is widely used in pharmaceuticals, health products, and food additives.

[0003] Choline bitartrate is a white crystalline powder; it has a fishy odor, a sour taste, and is highly hygroscopic; it is readily soluble in water, slightly soluble in alcohol, and insoluble in chloroform, ether, and benzene. Due to its strong hygroscopicity, choline bitartrate formulations and compound preparations exhibit poor stability. This is particularly true in multivitamin tablets, where its hygroscopicity leads to tablet cracking and swelling, and can cause rapid degradation of some vitamins (such as vitamin A, vitamin D, and vitamin K).

[0004] In existing technologies, when preparing solid dosage forms containing choline bitartrate, ethanol is commonly used to granulate the choline bitartrate to reduce its hygroscopicity. However, the ethanol granulation process has high requirements for explosion-proof equipment and is complex, thus increasing operating costs. Furthermore, ethanol granulation results in a large amount of fine powder, which is easily hygroscopic and has poor flowability. Therefore, there is an urgent need to provide a new method that can effectively reduce the hygroscopicity of choline bitartrate and thereby improve the stability of the formulation. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this application provides a choline bitartrate solid dispersion. By preparing choline bitartrate into a choline bitartrate solid dispersion, its hygroscopicity can be significantly improved, thereby significantly enhancing the stability of choline bitartrate preparations made from the choline bitartrate solid dispersion. At the same time, it can also effectively mask the unpleasant odor of choline bitartrate.

[0006] To this end, the first aspect of this application provides a choline bitartrate solid dispersion, which is prepared by a melt method; the raw materials for preparing the choline bitartrate solid dispersion include the following components by mass percentage: 20-50 wt% choline bitartrate, 20-50 wt% sugar alcohol, 10-30 wt% glyceryl monostearate and 0.1-5 wt% modified starch.

[0007] This application involves heating and melting the active substance choline bitartrate, and then dispersing the molten choline bitartrate as a fine amorphous powder in an inert solid carrier such as sugar alcohol and glyceryl monostearate during the cooling process. This significantly improves the hygroscopicity of choline bitartrate, giving the choline bitartrate solid dispersion excellent moisture-proof effect, while also effectively masking the unpleasant odor of choline bitartrate.

[0008] In some embodiments, the sugar alcohol content is 35-45 wt%, and the glyceryl monostearate content is 15-20 wt%.

[0009] In some specific embodiments, the content of sugar alcohol in the raw materials for preparing the choline bitartrate solid dispersion can be 35wt%, 40wt%, or 45wt%, etc., and the content of glyceryl monostearate can be 15wt%, 16wt%, 17wt%, 18wt%, 19wt%, or 20wt%.

[0010] In some preferred embodiments, the sugar alcohol content is 40 wt% and the glyceryl monostearate content is 17 wt%.

[0011] The inventors of this application discovered through research that a crystalline eutectic material (solid dispersion) formed by eutecticizing choline bitartrate with sugar alcohol and glyceryl monostearate and then cooling and solidifying it has excellent moisture-proof properties. Furthermore, by further limiting the content of the two substances within the aforementioned range, the moisture-proof effect of the final prepared choline bitartrate solid dispersion can be improved.

[0012] In some embodiments, the mass ratio of the sugar alcohol to glyceryl monostearate is (2-3):1.

[0013] In some specific embodiments, the mass ratio of the sugar alcohol to glyceryl monostearate can be 2:1, 2.2:1, 2.4:1, 2.6:1, 2.8:1, or 3:1, etc.

[0014] In some preferred embodiments, the mass ratio of the sugar alcohol to glyceryl monostearate is 2.4:1.

[0015] This application optimizes the mass relationship between sugar alcohol and glyceryl monostearate, which helps to further improve the moisture-proof effect of the prepared choline bitartrate solid dispersion.

[0016] In some embodiments, the modified starch content is 2-3 wt%, and the modified starch is selected from at least one of oxidized starch, cross-linked starch, and etherified starch.

[0017] In this application, the modified starch can be oxidized starch, cross-linked starch, or etherified starch, preferably etherified starch, and more preferably sodium carboxymethyl starch. The modified starch in this application, especially sodium carboxymethyl starch, helps promote rapid crystallization and solidification of the eutectic, thereby forming a crystalline low-melting-point eutectic (solid dispersion) with excellent moisture-proof properties. By controlling the content of modified starch in the raw materials within the above-mentioned range, the solid crystallization rate can be accelerated, and the moisture-proof effect of the choline bitartrate solid dispersion can be improved.

[0018] In some embodiments, the ratio of the content of choline bitartrate to the total content of sugar alcohol and glyceryl monostearate is 1:(1-2).

[0019] In the choline bitartrate solid dispersion described in this application, sugar alcohol is used as the crystalline carrier and glyceryl monostearate is used as the surfactant carrier. By controlling the relationship between the content of choline bitartrate and the total content of sugar alcohol and glyceryl monostearate within the above-mentioned range, it is helpful to improve the moisture-proof effect of the choline bitartrate solid dispersion.

[0020] In some embodiments, the sugar alcohol is selected from at least one of erythritol, maltitol, sorbitol, mannitol, and xylitol.

[0021] In some preferred embodiments, the sugar alcohol is erythritol.

[0022] In this application, the above-mentioned sugar alcohols, especially erythritol, have melting points close to those of choline bitartrate. Therefore, the above-mentioned sugar alcohols can be mixed with choline bitartrate under molten conditions, thereby serving as a crystalline carrier for choline bitartrate and improving the moisture-proof effect of the prepared choline bitartrate solid dispersion.

[0023] A second aspect of this application provides a method for preparing a choline bitartrate solid dispersion as described in the first aspect of this application, the method comprising the following steps: S1, heat and melt choline bitartrate, then add sugar alcohol and glyceryl monostearate to the melted choline bitartrate under stirring, keep warm until the sugar alcohol and glyceryl monostearate melt, stir and mix to obtain mixture 1; S2, under heat preservation conditions, the modified starch is added to the mixture 1 and stirred to obtain the mixture 2; S3, the mixture 2 is cooled and solidified, and then sieved and pulverized to obtain the choline ditartrate solid dispersion.

[0024] This application describes a process where sugar alcohol and glyceryl monostearate are first added to molten choline bitartrate to form a eutectic mixture. Modified starch is then added to promote rapid crystallization of the eutectic mixture, dispersing choline bitartrate as a fine amorphous powder within an inert solid carrier of sugar alcohol and glyceryl monostearate, thus obtaining a choline bitartrate solid dispersion. This melt-processing method effectively prepares a solid dispersion of choline bitartrate with sugar alcohol, glyceryl monostearate, and modified starch, and the preparation method is simple and rapid.

[0025] In some embodiments, the method further includes step S0 before step S1, specifically: passing choline tartrate, sugar alcohol, and glyceryl monostearate through a 20-30 mesh sieve, and passing modified starch through a 100-120 mesh sieve.

[0026] This application performs a sieving process on the raw materials before heating and melting them. The sieving process limits the particle size of the raw materials to the above-mentioned range, which makes it easier to melt and mix the raw materials in the subsequent process. This results in a better melting and mixing effect, which not only makes it easier to prepare the choline bitartrate solid dispersion, but also makes the choline bitartrate solid dispersion more moisture-proof.

[0027] In some embodiments, the heating temperature in step S1 is 140–160°C. In some specific embodiments, the heating temperature can be 150°C. At the above heating temperatures, this application can ensure that all raw materials are melted into a liquid phase, thereby achieving uniform mixing and yielding a choline bitartrate solid dispersion with superior performance.

[0028] In some embodiments, in steps S1-S2, the stirring speed is 300-900 r / min, for example, 600 r / min.

[0029] In some specific embodiments, the preparation method of the choline bitartrate solid dispersion includes the following steps: (1) Pass choline tartrate, sugar alcohol, and glyceryl monostearate through a 20-30 mesh sieve, and pass modified starch through a 100-120 mesh sieve. (2) Weigh out the prescribed amount of choline bitartrate and heat it to 140-160℃ to melt it; (3) Add the prescribed amount of sugar alcohol and glyceryl monostearate slowly to the melted choline bitartrate while stirring, maintain the temperature at 140-160℃ until the sugar alcohol and glyceryl monostearate are completely melted, and then continue stirring for 10-20 minutes to fully disperse and obtain mixture 1; the stirring speed is 300-900 r / min; (4) Maintain a temperature of 140-160℃, add modified starch, stir for 5-20 minutes at a stirring speed of 300-900 r / min, and obtain mixture 2; (5) The mixture 2 is rapidly cooled to 10-20°C and cooled until completely solidified. It is then pulverized through a 40-80 mesh sieve to obtain the choline tartrate solid dispersion.

[0030] The third aspect of this application provides the use of the choline bitartrate solid dispersion as described in the first aspect of this application or the choline bitartrate solid dispersion prepared by the method described in the second aspect in the preparation of choline bitartrate preparations and mineral-vitamin complex preparations containing choline bitartrate.

[0031] The choline bitartrate solid dispersion provided in this application has good moisture-proof effect, thus enabling choline bitartrate preparations and mineral-mineral compound preparations containing the choline bitartrate solid dispersion to have good stability.

[0032] In some embodiments, the choline bitartrate preparation includes choline bitartrate capsules, choline bitartrate tablets, choline bitartrate granules, and choline bitartrate powder; the vitamin and mineral compound preparation containing choline bitartrate includes vitamin and mineral capsules, vitamin and mineral tablets, vitamin and mineral granules, and vitamin and mineral powder.

[0033] In some embodiments, the raw materials for preparing the choline bitartrate capsules, by weight percentage, include the following components: 1-100 wt% of the choline bitartrate solid dispersion, 0-1 wt% of a flow aid, and 0-1 wt% of a lubricant.

[0034] In this application, the preparation method of the choline bitartrate capsule can be as follows: after mixing the choline bitartrate solid dispersion, optional flow aid and lubricant, the mixture is filled into the capsule shell to obtain the choline bitartrate capsule.

[0035] In some embodiments, the raw materials for preparing the choline bitartrate tablets, by weight percentage, include the following components: 1-80 wt% of the choline bitartrate solid dispersion, 10-50 wt% of microcrystalline cellulose, 0-1 wt% of a flow aid and 0-1 wt% of a lubricant.

[0036] In this application, the preparation method of the choline bitartrate tablets can be as follows: mixing choline bitartrate solid dispersion, microcrystalline cellulose, optional glidant and lubricant, and then compressing the mixture into tablets to obtain the choline bitartrate tablets.

[0037] In some embodiments, the raw materials for preparing the choline bitartrate granules, by weight percentage, include the following components: 20-70 wt% of the choline bitartrate solid dispersion, 5-30 wt% of microcrystalline cellulose and 5-30 wt% of hydroxypropyl methylcellulose.

[0038] In this application, the preparation method of the choline bitartrate granules can be as follows: mix choline bitartrate solid dispersion and microcrystalline cellulose evenly, then perform wet granulation using hydroxypropyl methylcellulose as a binder, and dry the prepared wet granules in a fluidized bed and then sieve them to obtain the choline bitartrate granules.

[0039] In some embodiments, the raw materials for preparing the choline bitartrate powder, by weight percentage, include the following components: 1-100 wt% of the choline bitartrate solid dispersion, 0-1 wt% of a flow aid, and 0-1 wt% of a lubricant.

[0040] In this application, the preparation method of the bitartrate choline powder can be as follows: after mixing bitartrate choline solid dispersion, microcrystalline cellulose, optional flow aid and lubricant, the mixture is pulverized and sieved to obtain the bitartrate choline powder.

[0041] In some embodiments, the raw materials for preparing the compound vitamin and mineral capsule containing choline bitartrate, by weight percentage, include the following components: 2-10 wt% vitamins, 20-50 wt% mineral element particles, 10-50 wt% of the choline bitartrate solid dispersion, 0-1 wt% glidant, and 0-1 wt% lubricant.

[0042] In this application, the preparation method of the compound vitamin and mineral capsule containing choline bitartrate can be as follows: after mixing vitamins, mineral element particles, choline bitartrate solid dispersion, optional glidant and lubricant, the mixture is filled into the capsule shell to obtain the compound vitamin and mineral capsule containing choline bitartrate.

[0043] In some embodiments, the raw materials for preparing the compound vitamin and mineral tablets containing choline bitartrate, by weight percentage, include the following components: 2-10 wt% vitamins, 10-30 wt% mineral element particles, 10-50 wt% of the choline bitartrate solid dispersion, 10-30 wt% microcrystalline cellulose, 0-1 wt% glidant, and 0-1 wt% lubricant.

[0044] In this application, the preparation method of the compound vitamin and mineral tablet containing choline bitartrate can be as follows: after mixing vitamins, mineral element particles, choline bitartrate solid dispersion, microcrystalline cellulose, optional glidant and lubricant, the mixture is compressed into tablets to obtain the choline bitartrate tablets.

[0045] In some embodiments, the raw materials for preparing the compound vitamin and mineral granules containing choline bitartrate, by weight percentage, include the following components: 2-10 wt% vitamins, 5-30 wt% mineral element particles, 10-30 wt% of the choline bitartrate solid dispersion, 10-30 wt% microcrystalline cellulose and 5-20 wt% hydroxypropyl methylcellulose.

[0046] In this application, the preparation method of the choline bitartrate granules can be as follows: vitamin, mineral element granules, choline bitartrate solid dispersion and microcrystalline cellulose are mixed evenly, and then wet granulation is performed using hydroxypropyl methylcellulose as a binder. The wet granules are placed in a fluidized bed for drying and then sieved to obtain the composite vitamin and mineral granules containing choline bitartrate.

[0047] In some embodiments, the raw materials for preparing the composite vitamin and mineral powder containing choline bitartrate, by weight percentage, include the following components: 2-10 wt% vitamins, 20-50 wt% mineral element particles, 10-50 wt% of the choline bitartrate solid dispersion, 0-1 wt% glidant, and 0-1 wt% lubricant.

[0048] In this application, the preparation method of the composite vitamin and mineral powder containing choline bitartrate can be as follows: after mixing vitamins, mineral element particles, choline bitartrate solid dispersion, optional flow aid and lubricant, the mixture is pulverized and sieved to obtain the choline bitartrate powder.

[0049] In this application, the vitamins include at least one of vitamin C, vitamin E, vitamin A, vitamin D3, vitamin B1, vitamin B2, vitamin B6, vitamin B12, nicotinamide, and folic acid.

[0050] In this application, the mineral element particles contain minerals including calcium, magnesium, manganese, iron, zinc, selenium, and copper. The mineral element particles are produced by mixing the above-mentioned minerals and then granulating them using hydroxypropyl methylcellulose as a binder via a wet granulation process.

[0051] In this application, the flow aid may be silicon dioxide, and the lubricant may be magnesium stearate.

[0052] In this application, the term "optional flow aids and lubricants" means that the raw materials for preparing the corresponding formulation may or may not contain flow aids and / or lubricants.

[0053] The beneficial technical effects of this application are as follows: The choline bitartrate solid dispersion provided in this application is prepared by a melt method using choline bitartrate, sugar alcohol, glyceryl monostearate, and modified starch. In the prepared choline bitartrate solid dispersion, the active substance choline bitartrate is dispersed as a fine amorphous powder in inert solid carriers such as sugar alcohol and glyceryl monostearate, significantly improving the hygroscopicity of choline bitartrate. This results in excellent moisture-proof properties and effectively masks the unpleasant odor of choline bitartrate. Applying the choline bitartrate solid dispersion to the preparation of choline bitartrate formulations can significantly improve the stability of the formulations, showing promising application prospects. Detailed Implementation

[0054] To make this application easier to understand, the following detailed description will be provided with reference to embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of application of this application. Unless otherwise specified, the raw materials or components used in this application can be obtained commercially or by conventional methods.

[0055] Example 1: Preparation of choline bitartrate solid dispersion The raw materials for preparation consist of: 40g choline bitartrate, 40g erythritol, 17g glyceryl monostearate, and 3g sodium carboxymethyl starch. The content of choline bitartrate, erythritol, glyceryl monostearate, and sodium carboxymethyl starch in the raw materials is 40wt%, 40wt%, 17wt%, and 3wt%, respectively. The mass ratio of erythritol to glyceryl monostearate is 2.4:1, and the ratio of choline bitartrate content to the total content of erythritol and glyceryl monostearate is 1:1.4.

[0056] The preparation method is as follows: (1) Pass choline tartrate, erythritol and glyceryl monostearate through a 30-mesh sieve, and pass sodium carboxymethyl starch through a 120-mesh sieve. (2) Weigh out the prescribed amount of choline bitartrate and heat it to 150°C to melt it; (3) Add the prescribed amount of erythritol and glyceryl monostearate to the melted choline bitartrate while stirring. Maintain the temperature at 150°C and stir until the erythritol and glyceryl monostearate are completely melted. Then continue stirring for 20 minutes to fully disperse and obtain mixture 1. The stirring speed is 600 r / min. (4) Keep the temperature at 150℃, add sodium carboxymethyl starch, stir for 10 min at a stirring speed of 600 r / min, and obtain mixture 2; (5) The mixture 2 was rapidly cooled to 15°C and cooled until it was completely solidified. It was then pulverized through a 40-mesh sieve to obtain a choline ditartrate solid dispersion.

[0057] Example 2: Preparation of choline bitartrate solid dispersion The raw materials for preparation consist of: 40g choline bitartrate, 38g erythritol, 19g glyceryl monostearate, and 3g sodium carboxymethyl starch. The content of choline bitartrate in the raw materials is 40wt%, erythritol is 38wt%, glyceryl monostearate is 19wt%, and sodium carboxymethyl starch is 3wt%. The mass ratio of erythritol to glyceryl monostearate is 2:1, and the ratio of the content of choline bitartrate to the total content of erythritol and glyceryl monostearate is 1:1.4.

[0058] The preparation method is the same as in Example 1.

[0059] Example 3: Preparation of choline bitartrate solid dispersion The raw materials for preparation consist of: 40g choline bitartrate, 47g erythritol, 10g glyceryl monostearate, and 3g sodium carboxymethyl starch. The content of choline bitartrate in the raw materials is 40wt%, erythritol is 47wt%, glyceryl monostearate is 10wt%, and sodium carboxymethyl starch is 3wt%. The mass ratio of erythritol to glyceryl monostearate is 4.7:1, and the ratio of the content of choline bitartrate to the total content of erythritol and glyceryl monostearate is 1:1.4.

[0060] The preparation method is the same as in Example 1.

[0061] Example 4: Preparation of choline bitartrate solid dispersion The raw materials for preparation consist of: 40g choline bitartrate, 27g erythritol, 30g glyceryl monostearate, and 3g sodium carboxymethyl starch. The content of choline bitartrate in the raw materials is 40wt%, erythritol is 27wt%, glyceryl monostearate is 30wt%, and sodium carboxymethyl starch is 3wt%. The mass ratio of erythritol to glyceryl monostearate is 0.9:1, and the ratio of the content of choline bitartrate to the total content of erythritol and glyceryl monostearate is 1:1.4.

[0062] The preparation method is the same as in Example 1.

[0063] Example 5: Preparation of choline bitartrate solid dispersion The raw materials for preparation consist of: 48.5g choline bitartrate, 34.2g erythritol, 14.3g glyceryl monostearate, and 3g sodium carboxymethyl starch. The content of choline bitartrate in the raw materials is 48.5wt%, the content of erythritol is 34.2wt%, the content of glyceryl monostearate is 14.3wt%, and the content of sodium carboxymethyl starch is 3wt%. The mass ratio of erythritol to glyceryl monostearate is 2.4:1, and the ratio of the content of choline bitartrate to the total content of erythritol and glyceryl monostearate is 1:1.

[0064] The preparation method is the same as in Example 1.

[0065] Example 6: Preparation of choline bitartrate solid dispersion The raw materials for preparation consist of: 25.5g choline bitartrate, 50.5g erythritol, 21.0g glyceryl monostearate, and 3g sodium carboxymethyl starch. The content of choline bitartrate in the raw materials is 25.5wt%, the content of erythritol is 50.5wt%, the content of glyceryl monostearate is 21.0wt%, and the content of sodium carboxymethyl starch is 3wt%. The mass ratio of erythritol to glyceryl monostearate is 2.4:1, and the ratio of the content of choline bitartrate to the total content of erythritol and glyceryl monostearate is 1:2.8.

[0066] The preparation method is the same as in Example 1.

[0067] Example 7: Preparation of choline bitartrate solid dispersion. Raw material composition: basically the same as in Example 1, except that erythritol in Example 1 is replaced with maltitol.

[0068] The preparation method is the same as in Example 1.

[0069] Example 8: Preparation of choline bitartrate solid dispersion. Raw material composition: basically the same as in Example 1, except that erythritol in Example 1 is replaced with a mixture of sorbitol and xylitol, and the mass ratio of sorbitol to xylitol in the mixture is 1:1.

[0070] The preparation method is the same as in Example 1.

[0071] Example 9: Preparation of choline bitartrate solid dispersion. Raw material composition: basically the same as in Example 1, except that erythritol in Example 1 is replaced with a mixture of erythritol and maltitol, and the mass ratio of erythritol to xylitol in the mixture is 2:1.

[0072] The preparation method is the same as in Example 1.

[0073] Example 10: Preparation of choline bitartrate solid dispersion. Raw material composition: basically the same as in Example 1, except that sodium carboxymethyl starch in Example 1 is replaced with oxidized starch.

[0074] The preparation method is the same as in Example 1.

[0075] Example 11: Preparation of choline bitartrate solid dispersion. Raw material composition: basically the same as in Example 1, except that sodium carboxymethyl starch in Example 1 is replaced with cross-linked starch.

[0076] The preparation method is the same as in Example 1.

[0077] Example 12: Preparation of choline bitartrate solid dispersion. Raw material composition: basically the same as in Example 1, except that sodium carboxymethyl starch in Example 1 is replaced with a mixture of sodium carboxymethyl starch and oxidized starch, and the mass ratio of sodium carboxymethyl starch to oxidized starch in the mixture is 1.5:1.

[0078] The preparation method is the same as in Example 1.

[0079] Comparative Example 1: Preparation of Choline Bitartrate Solid Dispersion The raw materials for preparation consist of: 40g of choline bitartrate, 57g of erythritol, and 3g of sodium carboxymethyl starch; the content of choline bitartrate in the raw materials is 40wt%, the content of erythritol is 57wt%, and the content of sodium carboxymethyl starch is 3wt%.

[0080] The preparation method is as follows: (1) Pass choline tartrate and erythritol through a 30-mesh sieve, and pass sodium carboxymethyl starch through a 120-mesh sieve. (2) Weigh out the prescribed amount of choline bitartrate and heat it to 150°C to melt it; (3) Add the prescribed amount of erythritol slowly to the melted choline bitartrate while stirring, maintain the temperature at 150°C and stir until the erythritol is completely melted, then continue stirring for 20 minutes to fully disperse and obtain mixture 1; the stirring speed is 600 r / min; (4) Keep the temperature at 150℃, add sodium carboxymethyl starch, stir for 10 min at a stirring speed of 600 r / min, and obtain mixture 2; (5) The mixture 2 was rapidly cooled to 15°C and cooled until it was completely solidified. It was then pulverized through a 40-mesh sieve to obtain a choline ditartrate solid dispersion.

[0081] Comparative Example 2: Preparation of Choline Bitartrate Solid Dispersion The raw materials for preparation consist of: 40g of choline bitartrate, 57g of glyceryl monostearate, and 3g of sodium carboxymethyl starch. The content of choline bitartrate, glyceryl monostearate, and sodium carboxymethyl starch in the raw materials is 40wt%, 57wt%, and 3wt%, respectively.

[0082] The preparation method is as follows: (1) Pass choline tartrate and glyceryl monostearate through a 30-mesh sieve respectively, and pass sodium carboxymethyl starch through a 120-mesh sieve. (2) Weigh out the prescribed amount of choline bitartrate and heat it to 150°C to melt it; (3) Add the prescribed amount of glyceryl monostearate slowly to the melted choline bitartrate while stirring. Maintain the temperature at 150°C and stir until all the glyceryl monostearate is melted. Then continue stirring for 20 minutes to fully disperse and obtain mixture 1. The stirring speed is 600 r / min. (4) Keep the temperature at 150℃, add sodium carboxymethyl starch, stir for 10 min at a stirring speed of 600 r / min, and obtain mixture 2; (5) The mixture 2 was rapidly cooled to 15°C and cooled until it was completely solidified. It was then pulverized through a 40-mesh sieve to obtain a choline ditartrate solid dispersion.

[0083] Comparative Example 3: Preparation of Choline Bitartrate Solid Dispersion The raw materials for preparation consist of: 40g of choline bitartrate, 30g of erythritol, and 30g of glyceryl monostearate. The content of choline bitartrate, erythritol, and glyceryl monostearate in the raw materials is 40wt%, 30wt%, and 30wt%, respectively.

[0084] The preparation method is as follows: (1) Pass choline tartrate, erythritol and glyceryl monostearate through a 30-mesh sieve respectively; (2) Weigh out the prescribed amount of choline bitartrate and heat it to 150°C to melt it; (3) Add the prescribed amount of erythritol and glyceryl monostearate to the melted choline bitartrate while stirring. Maintain the temperature at 150°C and stir until the erythritol and glyceryl monostearate are completely melted. Then continue stirring for 20 minutes to fully disperse and obtain a mixture. The stirring speed is 600 r / min. (4) The mixture was rapidly cooled to 15°C and cooled until it was completely solidified. The solidification time was much longer than that in Example 1. The mixture was then pulverized through a 40-mesh sieve to obtain a choline ditartrate solid dispersion.

[0085] Comparative Example 4: Preparation of a mixture of choline bitartrate The raw material composition is the same as in Example 1.

[0086] The preparation method is as follows: (1) Pass choline tartrate, erythritol and glyceryl monostearate through a 30-mesh sieve, and pass sodium carboxymethyl starch through a 120-mesh sieve. (2) Weigh out the prescribed amounts of choline tartrate, erythritol, glyceryl monostearate and sodium carboxymethyl starch, mix for 15 min to obtain a mixture of choline tartrate.

[0087] Test Example 1 200 grams each of the choline bitartrate solid dispersions prepared in Examples 1-12 and Comparative Examples 1-3, and the choline bitartrate mixture prepared in Comparative Example 4, were spread evenly on weighing paper of the same size and thickness and placed in a constant temperature and humidity chamber at 25°C and 70% RH. The weight gain rate was measured at 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 12 hours, and 24 hours to evaluate the moisture-proof effect of the choline bitartrate solid dispersions and the choline bitartrate mixture. The specific results are shown in Table 1. The formula for calculating the weight gain rate is: Weight gain rate = (Mass after moisture absorption - Original mass) / Original mass x 100%. A higher weight gain rate indicates a poorer moisture-proof effect.

[0088] Table 1 As shown in Table 1, the moisture-proof effect of the choline bitartrate solid dispersions prepared in Examples 1-12 of this application is better than that of the choline bitartrate solid dispersions prepared in Comparative Examples 1-3, while the choline bitartrate mixture prepared in Comparative Example 4 has the worst moisture-proof effect. This indicates that, compared to the choline bitartrate solid dispersions prepared by the melt method, the choline bitartrate mixtures obtained by simply mixing materials have no moisture-proof effect.

[0089] The test results of Examples 1-4 and Comparative Examples 1-2 in Table 1 show that erythritol and glyceryl monostearate in the raw materials have a combined promoting effect on the moisture-proof effect of choline tartrate solid dispersion. When the content of erythritol in the raw materials is 35-45 wt%, the content of glyceryl monostearate is 15-20 wt%, and the mass ratio of erythritol to glyceryl monostearate is (2-3):1, the synergistic effect of erythritol and glyceryl monostearate can be better exerted, thus making the moisture-proof effect of the prepared choline tartrate solid dispersion better.

[0090] As can be seen from the test results of Examples 1 and 5-6 in Table 1, when the ratio of the content of choline bitartrate in the raw materials to the total content of erythritol and glyceryl monostearate is controlled within the range of 1:(1-2), it helps to further improve the moisture-proof effect of the prepared choline bitartrate solid dispersion.

[0091] As can be seen from the test results of Examples 1 and 7-12 in Table 1, when the sugar alcohol in the raw materials is erythritol and the modified starch is sodium carboxymethyl starch, it helps to further improve the moisture-proof effect of the prepared choline bitartrate solid dispersion.

[0092] The test results of Comparative Example 3 show that when the raw materials do not contain sodium carboxymethyl starch, the mixture is not easy to crystallize and solidify, which increases the difficulty of preparing the choline bitartrate solid dispersion. At the same time, the moisture-proof effect of the prepared choline bitartrate solid dispersion is also poor.

[0093] Application Example 1: Preparation of Choline Bitartrate Capsules Raw materials: 300 parts of choline bitartrate solid dispersion prepared in Example 1, 0.3 parts of silica (flow aid) and 0.5 parts of magnesium stearate (lubricant); wherein the content of choline bitartrate solid dispersion is 99.7 wt%, the content of silica is 0.1 wt%, and the content of magnesium stearate is 0.2 wt%.

[0094] Preparation method: After the above-mentioned choline bitartrate solid dispersion, silica and magnesium stearate are mixed evenly, the mixture is filled into the capsule shell to obtain choline bitartrate capsules.

[0095] The choline bitartrate solid dispersion in the choline bitartrate capsules prepared in this application example has good moisture-proof properties, resulting in excellent stability of the prepared choline bitartrate capsules. There is no softening, stickiness, or swelling of the capsules within the shelf life.

[0096] Application Example 2: Preparation of Choline Bitartrate Tablets Raw materials: 300 parts of choline bitartrate solid dispersion prepared in Example 1, 200 parts of microcrystalline cellulose (filler), 2.5 parts of silica (flow aid), and 2.5 parts of magnesium stearate (lubricant); wherein the content of choline bitartrate solid dispersion is 59 wt%, the content of microcrystalline cellulose is 40 wt%, the content of silica is 0.5 wt%, and the content of magnesium stearate is 0.5 wt%.

[0097] Preparation method: Choline bitartrate solid dispersion, microcrystalline cellulose, silicon dioxide and magnesium stearate are mixed evenly and then compressed into tablets to obtain choline bitartrate tablets.

[0098] The choline bitartrate tablets prepared in this application example have good moisture-proof properties in the choline bitartrate solid dispersion, resulting in excellent stability of the prepared choline bitartrate tablets, with no cracking or swelling within the shelf life.

[0099] Application Example 3: Preparation of a composite vitamin and mineral powder containing choline bitartrate. Raw materials: 20 parts vitamin C, 12 parts vitamin E, 0.5 parts vitamin A, 1 part vitamin B1, 1 part vitamin B2, 1 part vitamin B6, 4 parts nicotinamide, 0.5 parts folic acid, 200 parts mineral element granules, 200 parts choline bitartrate solid dispersion prepared in Example 1, 2.5 parts silica (flow aid), and 2.5 parts magnesium stearate (lubricant); wherein the total vitamin content is 9 wt%, the mineral element granule content is 45 wt%, the choline bitartrate solid dispersion content is 45 wt%, the silica content is 0.5 wt%, and the magnesium stearate content is 0.5 wt%.

[0100] Preparation method: The choline bitartrate powder is prepared by mixing vitamins, mineral element granules, choline bitartrate solid dispersion, glidant and lubricant, followed by pulverization and passing through a 100-mesh sieve.

[0101] The choline bitartrate solid dispersion of the composite mineral powder containing choline bitartrate prepared in this application example has good moisture-proof effect, so the prepared composite mineral powder has excellent stability and does not have clumping or other phenomena within the shelf life.

[0102] It should be noted that the embodiments described above are only for explaining this application and do not constitute any limitation on this application. This application has been described with reference to typical embodiments, but it should be understood that the terms used therein are descriptive and explanatory terms, not limiting terms. Modifications can be made to this application within the scope of the claims, and revisions can be made to the invention without departing from the scope and spirit of this application. Although the application described herein relates to specific methods, materials, and embodiments, it does not mean that this application is limited to the specific examples disclosed herein; on the contrary, this application can be extended to all other methods and applications with the same function.

Claims

1. A choline bitartrate solid dispersion, characterized in that, The choline bitartrate solid dispersion is prepared by a melt method; by mass percentage, the raw materials for preparing the choline bitartrate solid dispersion include the following components: 20-50 wt% choline bitartrate, 20-50 wt% sugar alcohol, 10-30 wt% glyceryl monostearate and 0.1-5 wt% modified starch. The sugar alcohol is selected from at least one of erythritol, maltitol, sorbitol, mannitol and xylitol, and the modified starch is selected from at least one of oxidized starch, cross-linked starch and sodium carboxymethyl starch.

2. The choline bitartrate solid dispersion according to claim 1, characterized in that, The sugar alcohol content is 35-45 wt%, and the glyceryl monostearate content is 15-20 wt%.

3. The choline bitartrate solid dispersion according to claim 2, characterized in that, The mass ratio of the sugar alcohol to glyceryl monostearate is (2~3):

1.

4. The choline bitartrate solid dispersion according to any one of claims 1-3, characterized in that, The modified starch content is 2-3 wt%.

5. The choline bitartrate solid dispersion according to any one of claims 1-3, characterized in that, The ratio of the content of choline bitartrate to the total content of sugar alcohol and glyceryl monostearate is 1:(1~2).

6. A method for preparing a choline bitartrate solid dispersion as described in any one of claims 1-5, characterized in that, The method includes the following steps: S1, heat and melt choline bitartrate, then add sugar alcohol and glyceryl monostearate to the melted choline bitartrate under stirring, keep warm until the sugar alcohol and glyceryl monostearate melt, stir and mix to obtain mixture 1; S2, under heat preservation conditions, the modified starch is added to the mixture 1 and stirred to obtain the mixture 2; S3, the mixture 2 is cooled and solidified, and then sieved and pulverized to obtain the choline ditartrate solid dispersion.

7. The method according to claim 6, characterized in that, In step S1, the heating temperature is 140~160℃; and / or in steps S1-S2, the stirring speed is 300~900r / min.

8. The use of a choline bitartrate solid dispersion as described in any one of claims 1-5 or a choline bitartrate solid dispersion prepared by the method described in claim 6 or 7 in the preparation of choline bitartrate preparations and mineral-vitamin complex preparations containing choline bitartrate.

9. The application according to claim 8, characterized in that, The choline bitartrate preparations include choline bitartrate capsules, choline bitartrate tablets, choline bitartrate granules, and choline bitartrate powder; the vitamin and mineral compound preparations containing choline bitartrate include vitamin and mineral capsules, vitamin and mineral tablets, vitamin and mineral granules, and vitamin and mineral powder.

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