Preparation method of solid dispersion and aqueous gastric-soluble efficient moistureproof coating composition containing solid dispersion

Abstract

The invention belongs to the field of food additives-compound coating agents and medicine solid preparation thin film coating premixing agents, and relates to a preparation method of a solid dispersion and a water-based gastric-soluble efficient moisture-proof coating composition containing the solid dispersion. According to the solid dispersion provided by the invention, stearic acid and magnesium stearate are selected as indissolvable components, polyglycerol fatty acid ester is used as a surfactant, hydroxypropyl methylcellulose / hydroxy propyl cellulose / sodium alginate is used as a carrier, and a grinding process is combined to treat the raw materials, so that a good synergistic effect is formed among the components; and the solid dispersion which can be stably amorphized is prepared. Tests find that the content of insoluble components in the prepared solid dispersion is obviously improved unexpectedly, and a coating composition of a carrier containing the solid dispersion has extremely excellent moisture resistance after film formation.

Description

Technical Field

[0001] The invention belongs to the field of food additive-compound coating agents and film coating premixes for solid pharmaceutical preparations, and relates to a method for preparing a solid dispersion and an aqueous gastric-soluble high-efficiency moisture-proof coating composition containing the solid dispersion. Background Art

[0002] Among the natural and synthetic film-forming agents used in coating compositions for coating or encapsulating foods, health supplements, and pharmaceutical preparations, the most commonly used include polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, acrylic resin, HP55, corn gluten, shellac, sodium alginate, and pectin. Hydroxypropyl methylcellulose and hydroxypropyl cellulose are gastric-soluble film-forming agents suitable for water-based solvents and possess a certain degree of moisture-proofing properties. Their moisture-proofing properties are superior to polyvinyl alcohol. However, compared to coating or waxing the surface of the coating object to form a moisture-proof layer, the former still cannot match the latter's moisture-proofing properties. In actual coating or coating applications, traditional Chinese medicine sugar-coated or film-coated preparations are typically moisture-proofed using waxing or a combination of the more expensive gastric-soluble alcohol-soluble No. 4 acrylic resin (its international counterpart is EPO or E100 resin) as a film-forming agent. On the one hand, insect wax is difficult to dissolve in water or gastric juice and has non-pH-dependent solubility. The film-coated moisture-proof layer formed by it dissolves and disintegrates in water and gastric juice. Acrylic resin No. 4 is a gastric-soluble film-forming agent with pH-dependent solubility (dissolved in a medium with a pH of no more than 5). It does not dissolve in water but only dissolves and disintegrates in gastric juice. The Chinese Pharmacopoeia 0921 General Chapter on the determination of the disintegration time limit of Chinese medicine sugar-coated preparations and film-coated preparations stipulates that the determination is carried out in purified water and gastric juice (pH 1.0) as the medium, respectively. When waxing is used as a moisture-proof layer for Chinese medicine sugar-coated preparations and film-coated preparations, and when the No. 4 acrylic resin composition film is used as a moisture-proof layer for Chinese medicine sugar-coated preparations, their disintegration time in water or gastric juice will be affected to varying degrees. On the other hand, the coating method of both methods affects the disintegration time. Waxing involves directly heating and softening wax powder (mostly insect white wax granules) to melt and adhere to the surface of the coating object to form a film. The film thickness is uneven and difficult to quantify. If the film is too thick, it will not dissolve and disintegrate easily in gastric juice and water, affecting the release rate in gastric juice, often resulting in a disintegration time failure. The alcohol-soluble gastric-soluble type IV acrylic resin coating composition is formed by liquid spraying on the surface of the coating object. It is more convenient to use, with a uniform film thickness and easy to quantify. The weight gain can be controlled to meet the disintegration time requirement. However, when used as a weight gain to replace the wax moisture-proof layer of traditional Chinese medicine sugar-coated preparations, the disintegration time (aqueous medium) is often difficult to meet. In addition, in terms of regulatory compliance, both are not allowed to be used in food additives-compound coating agents.At present, in terms of usage, the waxing method for moisture-proofing of traditional Chinese medicine also appears to be spraying with wax emulsion. The quality of the fully-component stable insect wax emulsion that complies with GB2760-2024 needs to be improved. In addition, the film thickness or weight gain that meets the moisture-proof effect and the weight gain that meet the disintegration limit of No. 4 acrylic resin as a moisture-proof layer of traditional Chinese medicine sugar-coated preparations (the Chinese Pharmacopoeia stipulates that the disintegration limit of traditional Chinese medicine sugar-coated tablets is determined in a purified water medium, and the No. 4 acrylic resin coating film is insoluble in water) is not easy to take into account and control. When it is used as a moisture-proof layer coating of traditional Chinese medicine film-coated preparations, it requires organic solvents such as ethanol and isopropanol as solvents (the Chinese Pharmacopoeia stipulates that the disintegration limit of traditional Chinese medicine film-coated tablets is determined in a gastric juice pH 1.0 medium), which has defects in cost, environmental protection and explosion-proof safety.

[0003] In summary, the current moisture-proof coatings mainly include: waxing or corn protein coatings, which are water-insoluble and gastric-insoluble; No. IV acrylic resin coatings, which are water-insoluble and gastric-soluble. However, there are few literature reports or commercial applications of moisture-proof coatings that are moisture-proof and have easy-to-control coating film thickness or weight gain, and can use water as a solvent, that is, moisture-proof coatings that are water-soluble and gastric-soluble, and are compliant with food additives-compound coating agents and solid drug film coating premixes, especially film coatings of traditional Chinese medicine (including sugar coatings and film coatings) or chemical drugs, with a moisture-proof layer that can dissolve and disintegrate in water or gastric juice.

[0004] However, the coating composition obtained by the existing gastro-soluble aqueous film-forming agents with excellent moisture resistance and the general coating composition preparation method, such as the above-mentioned hydroxypropyl methylcellulose and hydroxypropyl cellulose as film-forming agents and the publicly known method of grinding or shear mixing all the components used in the current coating composition, has a moisture-proof layer that is difficult to achieve the moisture-proof effect of the alcohol-soluble No. IV acrylic resin coating composition.

[0005] Therefore, in order to fill the gap in the existing technology, a water-based gastric-soluble high-efficiency moisture-proof coating composition is provided, which has a disintegration time in water or gastric fluid medium that is not limited by weight gain and has a qualified disintegration limit in both media, and can be generally used for film coating premixes including food additives-compound coating agents and solid pharmaceutical preparations (traditional Chinese medicine, chemical medicine) to achieve the purpose of high-efficiency moisture-proofing, which has become a technical problem faced in this field. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the above-mentioned defects and provide an aqueous gastric-soluble high-efficiency moisture-proof coating composition and a preparation method, and the coating composition is generally applicable to the moisture-proof purpose including food additives-compounded film agents and pharmaceutical solid preparations.

[0007] To achieve the above object, a technical problem to be solved by the present invention is to provide a method for preparing a solid dispersion.

[0008] Solid dispersion is a pharmaceutical formulation technology that generally refers to the dispersion of poorly soluble drugs in a solid carrier in the form of molecules, microcrystals, and amorphous forms to form a uniform solid dispersion system. It is composed of a solid mixture of drug (dispersed phase) and carrier (continuous phase). Its characteristics are to improve the solubility and bioavailability of drugs; to achieve rapid release and sustained release of drugs: water-soluble carriers can significantly accelerate or increase the dissolution rate of poorly soluble drugs, and enteric-soluble carriers can control the release of drugs to specific parts of the small intestine; improve drug stability: delay drug hydrolysis and oxidation, and mask drug irritation and unpleasant odor. Preparation methods include spray drying, melting, solvent method, grinding method, etc.

[0009] Among the aforementioned solid dispersion preparation methods, milling is relatively economical and easy to implement. Its principle is to use mechanical forces such as shearing and grinding to embed the poorly soluble drug into the interstices of polymer chains, resulting in a uniform distribution of molecules, microcrystals, and amorphous forms, thereby forming a homogeneous system with the carrier. Its solubility can be adjusted by the water solubility or enteric solubility of the carrier to achieve different dissolution rates and bioavailability. Although milling is a relatively cost-effective method for preparing solid dispersions, the content of poorly soluble drugs in the solid dispersions obtained using this method is generally low.

[0010] Nevertheless, after careful research and repeated experiments, the inventors used stearic acid and magnesium stearate as insoluble components, and hydroxypropyl methylcellulose and hydroxypropyl cellulose as carriers of solid dispersions. By adding the screened surfactant polyglycerol fatty acid ester, the solid dispersion was prepared by grinding and using it as the main component of the composite film-forming agent (film-forming agent). After investigating its water solubility and moisture-proof coating performance, it was surprisingly found that the content of insoluble components in the solid dispersion prepared by the grinding method was unexpectedly significantly improved, and the coating composition containing the carrier of the solid dispersion had extremely excellent moisture resistance after film formation. At the same time, in order to facilitate the comparison of carriers with different moisture absorption rates, different gastrointestinal release functions and properties, the present invention also purposefully selected hygroscopic sodium alginate to replace hydroxypropyl methylcellulose and hydroxypropyl cellulose for experiments to investigate the content and water solubility of the insoluble components in the solid dispersion, providing a wider reference for the product formulation design of different application scenarios of the coating composition. The specific technical solutions include:

[0011] The preparation method of the solid dispersion comprises the following steps: grinding a poorly soluble component, a surfactant and a carrier to obtain a solid dispersion; the poorly soluble component comprises at least one of stearic acid and magnesium stearate; the surfactant comprises polyglycerol fatty acid ester; the carrier comprises at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium alginate; and the mass ratio of the poorly soluble component, the surfactant and the carrier is 1: (0.01-0.05): (1-60).

[0012] The polyglycerol fatty acid ester is preferably an oleic acid type ester with CAS numbers of 9007-48-1, 79665-93-3 and 33940-99-7.

[0013] Preferably, the insoluble component is stearic acid, the carrier includes at least one of hydroxypropyl methylcellulose and hydroxypropyl cellulose, and the mass ratio of the insoluble component, surfactant and carrier is 1:0.03:(1-6).

[0014] Preferably, the insoluble component is magnesium stearate, the carrier includes at least one of hydroxypropyl methylcellulose and hydroxypropyl cellulose, and the mass ratio of the insoluble component, surfactant and carrier is 1:0.05:(2-6).

[0015] Preferably, the insoluble component is stearic acid, the carrier includes sodium alginate, and the mass ratio of the insoluble component, surfactant and carrier is 1:0.01:(1.5-60).

[0016] Preferably, the insoluble component is magnesium stearate, the carrier includes sodium alginate, and the mass ratio of the insoluble component, surfactant and carrier is 1:0.01:(1.2-60).

[0017] Preferably, the method for preparing the solid dispersion comprises the following steps:

[0018] (S1) Weighing samples: Weigh and label each material according to the formula and proportion;

[0019] (S2) Pre-grinding: Add the carrier and surfactant polyglycerol fatty acid ester in the material of step (S1) into a micro powder grinder and grind for 60 seconds;

[0020] (S3) Total grinding: adding stearic acid, a poorly soluble component, to the material of step (S2) and grinding for 120-240 seconds;

[0021] (S4) Total mixing: combining multiple batches of materials from step (S3) and mixing them in a multi-dimensional mixer for 18-20 minutes;

[0022] (S5) Screening, testing and packaging: The total mixed material from step (S4) is discharged and screened with a 60-80 mesh sieve and packaged. A water-based gastric-soluble high-efficiency moisture-proof coating composition comprises a solid dispersion prepared by the above preparation method.

[0023] Preferably, calculated by mass percentage, the coating composition formula comprises: 60-90% solid dispersion and 10-40% plasticizer.

[0024] Preferably, the plasticizer comprises at least one of mannitol, erythritol, trehalose, and lactose. Further preferably, the plasticizer is mannitol.

[0025] By selecting plasticizers with excellent moisture resistance such as mannitol, erythritol, trehalose, and lactose, as well as hydroxypropyl methylcellulose and hydroxypropyl cellulose with low water vapor permeability as water-soluble carriers, and a solid dispersion composed of high content of stearic acid and magnesium stearate as insoluble components, the aqueous gastro-soluble high-efficiency moisture-proof coating composition is formed together. At the same time, the above materials are all food grade, and can achieve products that meet the usage and scope of use of food additives-compound coating agents specified in GB2760-2024. Therefore, the above solid dispersion is prepared by grinding, and its carriers and insoluble components are all compliant materials for food additives-compound coating agents and pharmaceutical solid preparation film coating premixes with excellent moisture resistance, which has pioneered the technical solution for preparing an aqueous gastro-soluble high-efficiency moisture-proof coating composition, thereby achieving the purpose of solving the above technical problems.

[0026] Preferably, the solvent of the coating composition is purified water.

[0027] Preferably, the materials involved in the coating composition are in compliance with relevant national food standards and relevant provisions of the Chinese Pharmacopoeia.

[0028] Compared with the prior art, the present invention has the following beneficial effects:

[0029] (1) Simple process: Solid dispersions are prepared by grinding, which is simple and efficient.

[0030] (2) The method has significant advantages: the solid dispersion is mainly composed of the preferred moisture-proof components stearic acid, magnesium stearate, hydroxypropyl methylcellulose and hydroxypropyl cellulose. The addition of a small amount of polyglycerol fatty acid ester surfactant significantly increases the content of the insoluble component. However, when the solid dispersion is prepared by the grinding method in the prior art, the content of the insoluble component is generally low, resulting in the solid dispersion with a low content of insoluble components being difficult to play a moisture-proof role as a component of the coating composition. This is an innovative technical solution for preparing a coating composition using a solid dispersion.

[0031] (3) The material is suitable for general coating of food, candy and medicine: the preparation of a water-soluble and gastric-soluble moisture-proof coating composition with high efficiency has been realized, thereby solving the existing technical problems in the background technology. It can be used as a substitute for the waxing layer of traditional Chinese medicine and can also be used as an ordinary coating, filling the gap in this field.

[0032] (4) The preparation of solid dispersions provides a useful reference for the formulation design and preparation of coating compositions. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The following is a brief introduction to the accompanying drawings:

[0034] Figure 1The DSC spectrum of a solid dispersion containing stearic acid, polyglycerol fatty acid ester and hypromellose;

[0035] Figure 2 The DSC spectrum of a solid dispersion containing stearic acid, polyglycerol fatty acid ester and hydroxypropyl cellulose;

[0036] Figure 3 The DSC spectrum of a solid dispersion containing magnesium stearate, polyglycerol fatty acid ester and hypromellose;

[0037] Figure 4 The DSC spectrum of a solid dispersion containing magnesium stearate, polyglycerol fatty acid ester and hydroxypropyl cellulose.

[0038] Figure 5 The DSC spectrum of a solid dispersion containing stearic acid, polyglycerol fatty acid ester and sodium alginate;

[0039] Figure 6 The DSC spectrum of a solid dispersion containing magnesium stearate, polyglycerol fatty acid ester and sodium alginate;

[0040] Figure 7 The DSC spectra of the solid dispersions of Comparative Example 13 and Comparative Example 14 are shown; wherein Spectrum 7-1 is the spectra of Comparative Example 14, and Spectrum 7-2 is the spectra of Comparative Example 13;

[0041] Figures 8 to 13 The following are the DSC integrated spectra of polyglycerol fatty acid ester (SOL), stearic acid (SA), magnesium stearate (Mgst), hypromellose (HPMC), hydroxypropyl cellulose (H-HPC), and sodium alginate (NaAlg). In the figure, SA represents stearic acid, Mgst magnesium stearate, HPCM hypromellose, H-HPC represents hydroxypropyl cellulose, NaAlg represents sodium alginate, and SOL represents polyglycerol fatty acid ester. DETAILED DESCRIPTION

[0042] The present invention will be further described below using specific embodiments. Those skilled in the art will be able to implement the present invention based on these descriptions. Furthermore, the embodiments of the present invention described below generally represent only a portion of the present invention, rather than all of the embodiments. Therefore, all other embodiments derived by those skilled in the art based on the embodiments of the present invention without inventive effort should fall within the scope of protection of the present invention.

[0043] Example 1

[0044] The composition of SDⅠ stearic acid-polyglycerol fatty acid ester-hydroxypropyl methylcellulose solid dispersion (parts by mass): the mass ratio of stearic acid, polyglycerol fatty acid ester, and hypromellose is 1:0.03:6.

[0045] The specific steps of the preparation method include:

[0046] (S1) Weighing samples: Weigh and label each material according to the formula and proportion;

[0047] (S2) Pre-grinding: Add the carrier and surfactant polyglycerol fatty acid ester in the material of step (S1) into a micro powder grinder and grind for 60 seconds;

[0048] (S3) Total grinding: adding stearic acid, a poorly soluble component, to the material of step (S2) and grinding for 240 seconds;

[0049] (S4) Total mixing: combining multiple batches of materials from step (S3) and mixing in a multi-dimensional mixer for 18 minutes;

[0050] (S5) Screening, testing and packaging: The mixed material from step (S4) is discharged and screened through a 60-80 mesh sieve and packaged. Testing for loss on drying and for residue, heavy metals, microbial limits, etc., is performed to obtain a solid dispersion composite component.

[0051] Example 2

[0052] The difference between this embodiment and embodiment 1 is that:

[0053] The mass ratio of stearic acid, polyglycerol fatty acid ester, and hypromellose was changed to 3:0.09:6; the grinding time in step (S2) was changed to 180 seconds, and the mixing time in step (S3) was changed to 19 minutes. Other changes were the same as in Example 1.

[0054] Example 3

[0055] The difference between this embodiment and embodiment 1 is that:

[0056] The mass ratio of stearic acid, polyglycerol fatty acid ester, and hypromellose was changed to 6:0.18:6; the grinding time in step (S2) was changed to 120 seconds, and the mixing time in step (S3) was changed to 20 minutes. Other changes were the same as in Example 1.

[0057] Examples 4-6

[0058] The differences between Examples 4, 5, and 6 and Example 1 are:

[0059] Composition of the SDIII stearic acid-polyglycerol fatty acid ester-hydroxypropyl cellulose solid dispersion (parts by mass): the mass ratios of stearic acid, polyglycerol fatty acid ester, and hydroxypropyl cellulose are as follows: Example 4: 1:0.03:6; Example 5: 3:0.09:6; and Example 6: 6:0.18:6. Other components are the same as in Example 1.

[0060] Examples 7-9

[0061] The difference between this embodiment 7-9 and embodiment 1 is:

[0062] Composition of SD II magnesium stearate-polyglycerol fatty acid ester-hydroxypropyl methylcellulose (parts by mass): the mass ratios of magnesium stearate, polyglycerol fatty acid ester, and hypromellose are: 1:0.05:6 for Example 7; 2:0.1:6 for Example 8; and 3:0.15:6 for Example 9. Other aspects are the same as in Example 1.

[0063] Examples 10-12

[0064] The difference between the present embodiments 10-12 and embodiment 1 is that:

[0065] SD IV magnesium stearate-polyglycerol fatty acid ester-hydroxypropyl cellulose composition (parts by mass): The mass ratios of magnesium stearate, polyglycerol fatty acid ester, and hydroxypropyl cellulose are: 1:0.05:6 for Example 10, 2:0.1:6 for Example 11, and 3:0.15:6 for Example 12. Other components are the same as in Example 1.

[0066] Examples 13-15

[0067] The difference between Examples 13-15 and Example 1 is that:

[0068] Composition of the SD V stearic acid-polyglycerol fatty acid ester-sodium alginate solid dispersion (parts by mass): the mass ratios of stearic acid, polyglycerol fatty acid ester, and sodium alginate are: 0.5:0.005:30 for Example 13; 10:0.1:30 for Example 14; and 20:0.2:30 for Example 15. Other components are the same as in Example 1.

[0069] Examples 16-18

[0070] The difference between Examples 16-18 and Example 1 is that:

[0071] Composition of the SDVI magnesium stearate-polyglycerol fatty acid ester-sodium alginate solid dispersion (parts by mass): The mass ratios of magnesium stearate, polyglycerol fatty acid ester, and sodium alginate are: 0.5:0.005:30 for Example 16; 10:0.1:30 for Example 17; and 25:0.25:30 for Example 18. Other components are the same as in Example 1.

[0072] Comparative Example 1

[0073] This comparative example differs from Example 3 in that:

[0074] Stearic acid, polyglycerol fatty acid ester, and hypromellose were replaced with a mass ratio of stearic acid to hypromellose of 1:1. Other conditions were the same as those in Example 3.

[0075] Comparative Example 2

[0076] The difference between this comparative example 2 and embodiment 6 is that:

[0077] Stearic acid, polyglycerol fatty acid ester, and hydroxypropyl cellulose were replaced with a mass ratio of stearic acid to hydroxypropyl cellulose of 1:1. Other modifications were the same as in Example 6.

[0078] Comparative Example 3

[0079] The difference between this comparative example 3 and example 9 is that:

[0080] The magnesium stearate, polyglycerol fatty acid ester, and hypromellose were replaced with magnesium stearate and hypromellose in a mass ratio of 1:2. Other ingredients were the same as in Example 9.

[0081] Comparative Example 4

[0082] The difference between this comparative example 4 and embodiment 12 is that:

[0083] The magnesium stearate, polyglycerol fatty acid ester and hydroxypropyl cellulose were replaced by magnesium stearate and hydroxypropyl cellulose in a mass ratio of 1:2. Other modifications were the same as in Example 12.

[0084] Comparative Examples 5-6

[0085] Comparative Examples 5 and 6 are respectively the same as Examples 15 and 18 except that polyglycerol fatty acid ester is not added.

[0086] Comparative Examples 7-8

[0087] Comparative Examples 7 and 8 are the same as in Examples 2 and 8, respectively, except that the surfactant polyglycerol fatty acid ester is not added and the hypromellose is replaced by polyethylene glycol 4000 (PEG).

[0088] Comparative Examples 9-10

[0089] Comparative Examples 9 and 10 are the same as in Examples 2 and 8, respectively, except that polyglycerol fatty acid ester is not added and hypromellose is replaced by copovidone (PVPVA64).

[0090] Comparative Example 11

[0091] This comparative example differs from Example 2 in that the polyglycerol fatty acid ester in Example 2 is replaced by polysorbate 80, and the rest is the same as Example 2.

[0092] Comparative Example 12

[0093] This comparative example differs from Example 8 in that the polyglycerol fatty acid ester in Example 8 is replaced by polysorbate 80, and the rest is the same as Example 8.

[0094] Comparative Example 13

[0095] The difference between this comparative example and comparative example 2 is:

[0096] The mass ratio of stearic acid to hypromellose (0.1:3) is 0.2:6. Other conditions are the same as those in Comparative Example 2.

[0097] Comparative Example 14

[0098] The difference between this comparative example and comparative example 11 is:

[0099] The mass ratio of stearic acid, polysorbate 80 and hypromellose is 0.3:0.3:6, and the rest are the same as Comparative Example 11.

[0100] Example 19 (Material Amount and Conditions)

[0101] In preliminary tests of the present invention, moisture resistance tests using alcohol as a solvent verified that when the insoluble components, stearic acid or magnesium stearate, account for 10% or more by mass in the coating composition of hypromellose or hydroxypropyl cellulose, the coating composition exhibits better moisture resistance. Therefore, it was determined that a solid dispersion prepared using stearic acid and magnesium stearate as insoluble components and water-soluble, gastric-soluble hypromellose or hydroxypropyl cellulose as carriers, is expected to exhibit excellent moisture resistance after film formation in the aqueous solvent of the coating composition. However, this is subject to the prerequisite that the content of the insoluble components in the solid dispersion is significantly increased compared to a solid dispersion prepared by conventional grinding methods, such that the content of the insoluble components in the coating composition containing the solid dispersion should not be less than 10%.

[0102] 1. Investigation of surfactant selection in solid dispersions

[0103] Span 20, polyglycerol fatty acid ester, sodium polyacrylate are selected to be added respectively in the solid dispersion consisting of stearic acid, magnesium stearate and hypromellose / hydroxypropyl cellulose / sodium alginate, in order to reach the content of stearic acid, magnesium stearate in the solid dispersion improving.For this reason, with the insoluble component mass parts in solid dispersion accounting for: insoluble component is 5 parts, and carrier is 30 parts, respectively add the surfactant (three mass ratios 1: 0.25: 6) accounting for insoluble component 5%, after grinding 240s in micronized powder grinder with 10% solid content dispensing, investigate the water solubility after the solid dispersion added by different kinds of surfactants, result is as shown in Table 1.

[0104] Table 1 Water solubility of insoluble components under different surfactants

[0105]

[0106] As can be seen from Table 1, among the three surfactants, Span 20 has no effect on improving the water solubility of insoluble components. The addition of polyglycerol fatty acid ester and sodium polyacrylate can make the prepared solid dispersion solution a uniform colloidal solution. However, the solution prepared after the addition of sodium polyacrylate is thicker, while the solution of polyglycerol fatty acid ester is thinner. Therefore, polyglycerol fatty acid ester is selected as the appropriate surfactant.

[0107] 2. Selection of the amount of polyglycerol fatty acid ester surfactant added

[0108] In the selection of the above surfactant types, the mass ratio of the insoluble component to the carrier was adjusted to: 15 parts of the insoluble component and 30 parts of the carrier. The polyglycerol fatty acid ester was added in an amount of 0.25-5% by mass of the insoluble component. The solubility of the solid dispersion was investigated at different addition amounts. The results are shown in Table 2.

[0109] Table 2 Investigation of the amount of polyglycerol fatty acid ester surfactant added

[0110]

[0111] As shown in Table 2, due to the hydrophilic and lipophilic properties of polyglycerol fatty acid esters, excessive amounts can negatively impact moisture resistance. In solid dispersion combinations such as stearic acid-hydroxypropyl methylcellulose and stearic acid-hydroxypropyl cellulose, a surfactant mass ratio of 2% of the insoluble stearic acid component is sufficient to form a uniform colloidal solution. In magnesium stearate-hydroxypropyl methylcellulose and magnesium stearate-hydroxypropyl cellulose, a surfactant mass ratio of 4% of the insoluble magnesium stearate component is sufficient to form a uniform colloidal solution. To ensure both water solubility and moisture resistance, a polyglycerol fatty acid ester mass ratio of 3% of stearic acid and a magnesium stearate mass ratio of 5% is appropriate. For the same reason, a polyglycerol fatty acid ester mass ratio of 1% is appropriate in stearic acid-sodium alginate and magnesium stearate-sodium alginate solid dispersions.

[0112] 3. Selection of polyglycerol fatty acid ester types

[0113] In preliminary experiments, based on HLB values, saturated and unsaturated alkane chain structures, water solubility, and the principle of "like dissolves like," oleic and stearic acid polyglycerol fatty acid esters with HLB values ​​of 9.0-13.5 were selected. When the carrier was hydroxypropyl methylcellulose or hydroxypropyl cellulose, stearic acid accounted for 3% and magnesium stearate accounted for 5%. When the carrier was sodium alginate, stearic acid and magnesium stearate accounted for 1%. Solid dispersions were prepared by grinding in a micronizer for 240 seconds. Liquids were prepared at a 10% solids content. The water solubility of these solid dispersions after adding surfactants from different polyglycerol fatty acid ester types was investigated. The results are shown in Table 3.

[0114] Table 3 Investigation of the effect of polyglycerol fatty acid types on the water solubility of solid dispersions

[0115]

[0116] The results in Table 3 above show that due to the hydrophobicity of the alkane chain and the characteristics of the molecular structure, when the carrier is sodium alginate, the solid dispersions prepared using other types of polyglycerol fatty acid esters, except polyglycerol-10 distearate, have better water solubility; polyglycerol-10 stearate with an HLB value of 13.5 has poor water solubility in the solid dispersions of magnesium stearate-containing hydroxypropyl methylcellulose and hydroxypropyl cellulose carriers; and among the oleic acid-based polyglycerol fatty acid esters, polyglycerol-10 oleate or dioleate exhibits better water solubility and, therefore, is the preferred surfactant for the solid dispersion.

[0117] What the inventors did not expect was that the polyglyceryl fatty acid esters of stearic acid, which were expected according to the principle of "like dissolves like" (the insoluble components stearic acid, magnesium stearate, and the stearic acid alkane chain structure in polyglyceryl fatty acid esters are closer to this principle), did not have the better water solubility of the polyglyceryl fatty acid esters of oleic acid. It should be pointed out that the surfactant polyglyceryl fatty acid ester in the present invention specifically refers to polyglyceryl-10 oleate or polyglyceryl-10 dioleate in the polyglyceryl fatty acid esters of oleic acid, i.e., the models with CAS numbers 9007-48-1 / 79665-93-3 and 33940-99-7, respectively.

[0118] 4. Process selection of feeding sequence

[0119] In the above-mentioned process for preparing the solid dispersion, the order of adding the materials is to first grind the carrier and the surfactant polyglycerol fatty acid ester, and then add the insoluble component stearic acid or magnesium stearate. In preliminary experiments, the inventors tried various combinations of the order of adding the insoluble component, surfactant, and carrier in order to screen out the following suitable addition order processes:

[0120] (1) Process 1: The carrier and surfactant are first ground, and then the insoluble component stearic acid or magnesium stearate is added;

[0121] (2) Process 2: The insoluble component and the surfactant polyglycerol fatty acid ester are first ground, and then the carrier is added;

[0122] (3) Process 3: The insoluble component and the carrier are first ground, and then the surfactant polyglycerol fatty acid ester is added;

[0123] (4) Process 4: The carrier, surfactant, polyglycerol fatty acid ester, and insoluble component are added and ground simultaneously.

[0124] The water solubility test of the solid dispersions prepared by the above four addition order processes was carried out, and the results are shown in Table 4.

[0125] Table 4 Investigation of the effect of different process addition order on the water solubility of solid dispersion

[0126]

[0127] From the results in Table 4, it can be seen that the water solubility of all solid dispersions in process 1 is a uniform colloidal solution. Therefore, it is the process with the preferred addition order.

[0128] 5. Investigation of the maximum addition amount of insoluble components in solid dispersions

[0129] In this solution, to improve the moisture-proof effect, it is beneficial to increase the content of the insoluble component in the solid dispersion. The purpose of adding a surfactant is also to this end. Based on the amount of surfactant added to the solid dispersion, namely: stearic acid-hydroxypropyl methylcellulose, in stearic acid-hydroxypropyl cellulose, polyglycerol fatty acid ester accounts for 3% of the mass of stearic acid; magnesium stearate-hydroxypropyl methylcellulose, in magnesium stearate-hydroxypropyl cellulose, polyglycerol fatty acid ester accounts for 5% of the mass of magnesium stearate; stearic acid-sodium alginate, in magnesium stearate-sodium alginate, polyglycerol fatty acid ester accounts for 1% of the mass of stearic acid or magnesium stearate. A series of solid dispersions were prepared with different ratios of the insoluble component: 0.5-35 parts of the insoluble component and 30 parts of the carrier. Their maximum content was investigated based on water solubility. The results are shown in Table 5.

[0130] Table 5 Investigation on the maximum addition amount of insoluble components in solid dispersion

[0131]

[0132]

[0133] In the results of Table 5 above, on the one hand, for stearic acid-hydroxypropyl methylcellulose, the maximum amount of stearic acid added in the stearic acid-hydroxypropyl cellulose solid dispersion is: the ratio of stearic acid to the mass parts of the carrier hypromellose or hydroxypropyl cellulose is 30:30; for magnesium stearate-hydroxypropyl methylcellulose, the maximum amount of magnesium stearate added in the magnesium stearate-hydroxypropyl cellulose solid dispersion is: the ratio of the mass parts of magnesium stearate to the mass parts of the carrier hypromellose or hydroxypropyl cellulose is 15:30; and for stearic acid-sodium alginate, the maximum amount of insoluble components added in the magnesium stearate-sodium alginate solid dispersion is: the ratio of stearic acid to the mass parts of the carrier sodium alginate is 20:30, and the ratio of magnesium stearate to the mass parts of the carrier sodium alginate is 25:30. On the other hand, preliminary test results using alcohol as the solvent showed that when the stearic acid or magnesium stearate in the solid dispersion accounts for 10% or more by weight of the coating composition, it has excellent moisture resistance. The insoluble components in the solid dispersion are at least 5:30. The suitable ranges for the insoluble components are: when the carrier is hypromellose or hydroxypropyl cellulose, the stearic acid content is (5-30):30, or (1-6):6; the magnesium stearate content is (5-15):30, or (1-3):6. When sodium alginate is used as the carrier, the maximum stearic acid content is 20:30, and the maximum magnesium stearate content is 25:30.

[0134] 6. Investigation of grinding time and stability of solid dispersion prepared by grinding method

[0135] The water solubility of the solid dispersions prepared with different milling times was confirmed by milling time and then accelerated in an acceleration chamber at 40±2°C and 75±5% RH for 3 months before water solubility was investigated. The results are shown in Table 6.

[0136] Table 6 Investigation of grinding time and stability of solid dispersions

[0137]

[0138] Table 6 shows the accelerated results. After three months of acceleration, the water solubility of the solid dispersions in the groups with grinding times of 120-240 seconds remained the same as before acceleration, and the insoluble components remained stable after being amorphized. To avoid the risk of steel rod chips entering the product due to excessive grinding time and to improve efficiency, a grinding time of 120-240 seconds is preferably selected.

[0139] Example 20 (Study on water solubility of solid dispersion preparation)

[0140] The solid dispersions prepared in Examples 1-18 and Comparative Examples 1-12 were added to the coating composition at a solid content of 10% at a ratio of 90% of the formula amount, and the solubility in water was evaluated to examine the solubility of each example. The results are shown in Table 7.

[0141] Table 7 Dissolution state of solid dispersion in water

[0142]

[0143]

[0144] As can be seen from the above table: Comparative Examples 1-6 did not add a surfactant, and despite the use of a grinding method, the obtained solid dispersions were difficult to form a uniform colloidal solution; Comparative Examples 7-10 used a hydrophilic carrier material commonly used in existing solid dispersions, and its water solubility was the same as that of Comparative Examples 1-6; in the preparation of solid dispersions in Comparative Examples 11-12 under the same conditions, when the surfactant polyglycerol fatty acid was replaced with polysorbate 80 (not allowed for use in food standards), no colloidal solution was formed in water, indicating that the solubility level of the examples was not reached; and the solid dispersion of the present invention, by adding a surfactant polyglycerol fatty acid ester and combining it with a grinding process, significantly increased the content of the insoluble components in the solid dispersion, forming a uniform colloidal solution in water, providing a film-forming basis for the realization of an aqueous gastric-soluble high-efficiency moisture-proof coating composition.

[0145] It should be noted that the corresponding mass ratio of Comparative Example 13 and Comparative Example 14 is the maximum addition of the insoluble component obtained by the stepwise change from less to more in the early stage of the exploratory test, and the water-soluble maximum addition amount of the insoluble component is investigated. Relative to Comparative Example 13, Comparative Example 14 is the maximum addition amount of the insoluble component to which a surfactant is added during grinding. It is obvious that after adding a surfactant, the maximum addition amount of stearic acid in the stearic acid solid dispersion is also significantly improved, but relative to having a moisture-proof composite film-forming agent or a film-forming agent, it is still far from enough, and the amount of the surfactant also significantly increases the moisture resistance of the rear film and is also greatly affected. Therefore, the two are compared with Example 3, and under the same carrier, the maximum addition amount of stearic acid, the addition amount of Example 3 is 20-30 times of the two, for providing a prerequisite for the realization of the moisture-proof coating composition.

[0146] Example 21 (Differential Scanning Calorimetry Analysis of Solid Dispersion)

[0147] To clearly characterize the material properties of the solid dispersion obtained in the present invention, this example, based on the previous example, conducted differential scanning calorimetry analysis on the solid dispersion itself. The specific measurement method was: using a TAQ2000 differential scanning calorimeter, using an N2 atmosphere, a heating rate of 10°C / min, and a measurement range of 25-250°C. To further reveal the impact of the raw material ratio design on the material properties of the present invention, this example also designed different raw material ratios and conducted simultaneous calorimetric analysis.

[0148] See also Figure 1This group uses stearic acid, polyglycerol fatty acid ester, and hypromellose as raw materials, with the ratio of the three being 1:0.03:1 in profile 1-1, 1:0.03:0.85 in profile 1-2, and 1:0.03:0.75 in profile 1-3. According to the calorimetric analysis results, pure stearic acid exhibits a distinct melting point peak in the range of 55.69-58.58°C, indicating that it exists in a highly crystalline state and therefore has poor solubility in water. However, in the solid dispersion prepared in Example 3 (profile 1-1), no melting point peak of stearic acid was observed within this temperature range, indicating that its crystalline structure has been destroyed, forming an amorphous solid dispersion. Furthermore, the solid dispersion can remain amorphous after mixing in a multidimensional mixer. Since the degree of amorphization directly affects water solubility, it can be inferred that the sample corresponding to profile 1-1 has a higher solubility. The water dissolution experimental results of this conclusion embodiment 3 are consistent, and it is further illustrated that the present invention is ground by stearic acid, polyglycerol fatty acid ester and hypromellose at a specific ratio, and successfully obtains amorphous solid dispersion with good water solubility, and this kind of amorphous solid dispersion itself has preferably stability, can still maintain its own amorphous state in the total mixing process, and finally effectively improves the solubility of stearic acid in water.In 1-2 and 1-3 collections of illustrative plates, as stearic acid addition ratio continues to increase, the melting point peak of stearic acid gradually shifts to the right, indicating that the amorphous degree of solid dispersion is relatively low at this time, so its water solubility is weakened compared to Example 3. This further proves that stearic acid, polyglycerol fatty acid ester and hypromellose three can prepare highly water-soluble and stable amorphous solid dispersions at a specific ratio.

[0149] See also Figure 2 , this group uses stearic acid, polyglycerol fatty acid ester and hydroxypropyl cellulose as raw materials, wherein the ratio of the three in 2-1 spectrum is 1:0.03:1, the ratio of the three in 2-2 spectrum is 1:0.03:0.85, and the ratio of the three in 2-3 spectrum is 1:0.03:0.75. It can be seen from the calorimetric analysis spectrum that the melting point peak of stearic acid is also absent in the solid dispersion prepared in Example 6 of the present invention (2-1 spectrum), indicating that under this ratio, stearic acid, polyglycerol fatty acid ester and hydroxypropyl cellulose can be ground to obtain an amorphous solid dispersion with good water solubility, and the solid dispersion can still maintain an amorphous state after mixing in a multidimensional mixer. In the 2-2 and 2-3 spectra, as the addition ratio of stearic acid continues to increase, the melting point peak of stearic acid gradually shifts to the right, indicating that a highly water-soluble and stable amorphous solid dispersion can be prepared under a specific ratio.

[0150] See also Figure 3This group uses magnesium stearate, polyglycerol fatty acid ester, and hypromellose as raw materials, wherein the ratio of the three in Spectrum 3-1 is 1:0.05:6, the ratio in Spectrum 3-2 is 1:0.05:3, the ratio in Spectrum 3-3 is 1:0.05:2, the ratio in Spectrum 3-4 is 1:0.05:1.5, and the ratio in Spectrum 3-5 is 1:0.05:1.2. From the calorimetric analysis spectrum, it can be seen that pure magnesium stearate has a clear melting point peak in the range of 97.44-102.67°C; however, in the solid dispersions prepared in Examples 7, 8, and 9 of the present invention (Spectra 3-1, 3-2, and 3-3), no melting point peak of magnesium stearate is observed in this temperature range, indicating that under this ratio condition, the solid dispersion has achieved amorphization and can still maintain the amorphous state after mixing in the multidimensional mixer. In Figures 3-4 to 3-5, as the magnesium stearate addition ratio increases, the melting point peak of magnesium stearate gradually shifts to the right, indicating a low degree of amorphization and, therefore, a relatively reduced water solubility. However, the inventors have experimentally discovered that for magnesium stearate, a poorly soluble component, at this ratio, the solid dispersion can still be sprayed to prepare a coating after dissolving in water, and the coating has a certain moisture-proof effect.

[0151] See also Figure 4 This group uses magnesium stearate, polyglycerol fatty acid ester and hydroxypropyl cellulose as raw materials, wherein the ratio of the three in 4-1 spectrum is 1:0.05:6, and the ratio of the three in 4-2 spectrum is 1:0.05:2. From the calorimetric analysis spectrum, it can be seen that pure magnesium stearate has a clear melting point peak in the range of 97.44~102.67℃, while in the solid dispersion prepared in Example 10 of the present invention (4-1 spectrum), no magnesium stearate melting point peak is observed in this temperature range, indicating that under this ratio condition, the solid dispersion has successfully achieved amorphization, thereby significantly improving its water solubility. However, in the solid dispersion prepared in Example 12 of the present invention (4-2 spectrum), a smooth peak of magnesium stearate is observed in this temperature range. Experiments have found that under this ratio, the solid dispersion aqueous solution can still be sprayed to prepare a coating, and the coating has a certain moisture-proof effect.

[0152] See also Figure 5This group uses stearic acid, polyglycerol fatty acid ester, and sodium alginate as raw materials. The ratio of the three in chromatogram 5-1 is 1:0.01:60, the ratio in chromatogram 5-2 is 1:0.01:3, and the ratio in chromatogram 5-3 is 1:0.01:1.5. The calorimetric analysis shows that the solid dispersion exhibits essentially no melting point peak at 54-65°C, indicating that under these ratios, the solid dispersion has successfully achieved amorphization. Furthermore, the solid dispersion remains amorphous after mixing in a multidimensional mixer, significantly improving its water solubility. This confirms the water solubility results of Examples 13-15.

[0153] See also Figure 6 This group uses magnesium stearate, polyglycerol fatty acid ester, and sodium alginate as raw materials. The ratio of the three in chromatogram 6-1 is 1:0.01:60, the ratio in chromatogram 6-2 is 1:0.01:3, and the ratio in chromatogram 6-3 is 1:0.01:1.2. The calorimetric analysis shows that the solid dispersion exhibits essentially no melting point peak between 75.49 and 116.61°C, indicating that under these ratios, the solid dispersion has successfully achieved amorphization. Furthermore, the solid dispersion can remain amorphous after mixing in a multidimensional mixer, significantly improving its water solubility. This confirms the water solubility results of Examples 16 to 18.

[0154] In addition, in order to investigate the effect of grinding process on the solubility of insoluble components in solid dispersion in water-soluble system, a control group was added based on Example 3, Example 6 and Example 15. Figure 1 、 Figure 2 and Figure 5 . Figure 1 0-1 map, Figure 2 The 0-2 graph and Figure 5In the 0-5 patterns, the raw materials and proportions identical with those in Example 3, Example 6 and Example 15 are respectively adopted, but in the solid dispersion preparation process, the step of grinding the micro-powder grinder in the above-mentioned step S2 is not included, and the material to be mixed is directly mixed using a multidimensional mixer. From the calorimetric analysis pattern, it can be seen that the obvious insoluble component melting point peak is still formed using the method of simple physical mixing, indicating that stearic acid still exists in crystalline form in the sample not subjected to grinding treatment, and effective amorphization is not achieved, thereby having an adverse effect on its water solubility. This is jointly demonstrated with the above-mentioned experiment, and the present invention is not to improve the dispersibility of insoluble components in water using the lipophilic / hydrophilic properties of the surfactant itself, but before solid dispersion is added to a water-soluble system, three specific solid components of hydroxypropyl methylcellulose / hydroxypropyl cellulose / sodium alginate, polyglycerol fatty acid ester and stearic acid are ground together to form a stable amorphous solid dispersion, and then stearic acid is caused to be dissolved in water with an ultrahigh addition amount. It is worth noting that the formation of amorphous solid dispersion is highly dependent on the selection of raw material types and their coordination relationship, and not all combinations can achieve stable amorphous by grinding. The water-soluble experimental results of Comparative Examples 1 to 14 fully demonstrate this point: in the absence of a key component or the use of incompatible excipients, even after the same process treatment, the ideal stable amorphization effect cannot be obtained. Under the action of mechanical force during the grinding process, the original crystal structure of stearic acid is destroyed and evenly dispersed between the polymer chains of water-soluble carriers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium alginate. At this time, the long carbon chain structure of stearic acid is restricted by the steric hindrance of the surrounding polymer chains, making it difficult to stack regularly, which can inhibit the orderly arrangement and recrystallization trend of molecules to a certain extent. At the same time, the insoluble components, surfactants and carriers may further stabilize the system structure through intermolecular forces such as hydrogen bonds and van der Waals forces, preventing the insoluble components from recrystallizing under the action of force in the blending step, thereby preparing a stable amorphous solid dispersion.

[0155] Examples 22-33

[0156] Huanglian Shangqing tablets were coated with the solid dispersions prepared in Examples 1-12 as an active component of an aqueous, gastro-soluble, moisture-proof coating composition. The composition by weight was: 60-90% solid dispersion, 10-40% mannitol. The components were shear-mixed to uniformity, and then a moisture-proof coating formulation for Huanglian Shangqing tablets was prepared to a coating weight gain of 3%.

[0157] Comparative Example 15

[0158] The solid dispersion prepared in Example 1: stearic acid, polyglycerol fatty acid ester, and hypromellose (mass ratio 1:0.03:6) accounting for 50% and mannitol 50% were shear-mixed uniformly, and then a moisture-proof coating preparation for Huanglian Shangqing tablets was prepared at a coating weight gain of 3%.

[0159] Comparative Example 16

[0160] The solid dispersion prepared in Example 1: stearic acid, polyglycerol fatty acid ester, and hydroxypropyl methylcellulose (mass ratio 1:0.03:6) accounting for 95% and mannitol 5% were shear-mixed and uniformly mixed, and the moisture-proof coating preparation of Huanglian Shangqing tablets was prepared according to a coating weight increase of 3%.

[0161] Comparative Example 17

[0162] The solid dispersion of Comparative Example 13 accounted for 90%, 10% mannitol was added, and the solid content was 10% of the liquid. The moisture-proof coating preparation of Huanglian Shangqing tablets was prepared according to the coating weight increase of 3%.

[0163] Comparative Example 18

[0164] The solid dispersion of Comparative Example 14 accounted for 90%, 10% mannitol was added, and the solid content was 10% of the liquid. The moisture-proof coating preparation of Huanglian Shangqing tablets was prepared according to the coating weight increase of 3%.

[0165] Comparative Example 19

[0166] Stearic acid, 90% hydroxypropyl cellulose (mass ratio 1:6), and 10% mannitol were sheared and mixed evenly according to mass proportions, and then a moisture-proof coating preparation for Huanglian Shangqing tablets was prepared according to a coating weight gain of 3%.

[0167] Comparative Example 20

[0168] According to 60% magnesium stearate, hydroxypropyl cellulose (mass ratio 1:6) and 40% mannitol, magnesium stearate and hydroxypropyl cellulose were first ground for 240S to prepare a co-processed product, and then mannitol was added and sheared and mixed evenly. The solution was prepared at 10% solid content and the coating weight was increased by 3% to prepare a moisture-proof coating preparation for Huanglian Shangqing tablets.

[0169] Comparative Example 21

[0170] 80% of No. IV acrylic resin, 10% of magnesium stearate, and 10% of triethyl citrate were sheared and mixed evenly, and then prepared with 80% ethanol solvent and 8% solid content, and the coating weight was increased by 3% to prepare a moisture-proof coating preparation for Huanglian Shangqing tablets.

[0171] Comparative Example 22

[0172] The moisture-proof coating preparation for Huanglian Shangqing tablets was prepared by shearing and mixing 75% No. IV acrylic resin, 10% stearic acid, and 15% triethyl citrate, and then adding 80% ethanol solvent and 8% solid content to prepare a liquid. The coating weight was increased by 3%.

[0173] Example 34 (Performance Evaluation of Examples 22-33 and Comparative Examples 13-18)

[0174] The coated tablets with a weight gain of 3% prepared in Examples 22-33 and Comparative Examples 15-22 were dried to reach moisture absorption equilibrium and placed in an acceleration box at 40±2°C and 75±5% RH for an accelerated test for 7 days in accordance with the provisions of the Guiding Principle 9001 of Part IV of the Chinese Pharmacopoeia 2025. The tablets were taken out and weighed respectively. The difference between the weighings before and after and the percentage of the original weight was the moisture absorption rate. The appearance, moisture absorption rate, and disintegration limit in purified water and gastric juice pH 1.0 after acceleration were examined. The results are shown in Table 8.

[0175] Table 8. Results of moisture-proof investigation on coating composition and coating preparation

[0176]

[0177]

[0178] As can be seen from the above table, the existing commonly used alcohol-soluble No. IV acrylic resin coating composition has a better moisture-proof effect. When used as a moisture-proof coating layer on the same core Huanglian Shangqing tablets, the moisture absorption rate after 7 days under the above conditions is 0.17%, while the coating compositions of Examples 22-33 have a moisture absorption rate of no more than 0.1% under the same conditions. The preparation method of the solid dispersion of the present invention and the coating composition with the prepared solid dispersion as the main component of the coating composition have a better moisture-proof effect. In the formula composition of the embodiment, the proportion of the solid dispersion is preferably 60-90%. In Comparative Examples 15-16, when the proportion is less than 60%, the film is soft, or when it is higher than 90%, the film is hard and brittle, and cracks appear quickly. , all lost their moisture-proof function; Comparative Example 17 is a group using a solid dispersion grinding method but without adding a surfactant, and the coating film of the coating composition has poor moisture-proof function; Comparative Example 18 is a group using other surfactants, and the moisture-proof effect of the coating film of the coating composition is still inferior to that of the present invention; Comparative Example 19 did not go through the solid dispersion preparation process, so it was not amorphized, and its coating composition had difficulty in liquid preparation or film formation; the coating composition of Comparative Example 20 was prepared by a co-processing method plus shear mixing, and the coating operation and film formation were improved compared with Comparative Example 19, but the moisture-proof property was still not improved; Comparative Examples 21-22 are alcohol solvent moisture-proof formulations, and their coating layers do not dissolve or disintegrate in water, but can dissolve and disintegrate in gastric juice. Therefore, according to the disintegration time (aqueous medium) of Chinese Pharmacopoeia 0921 General Chapter on Traditional Chinese Medicine Sugar-Coated Preparations, the coating layers of Comparative Examples 21-22 do not dissolve or disintegrate in water and cannot be used as moisture-proof coatings for traditional Chinese medicine sugar-coated tablets. The coating layers of Examples 22-33 of the all-water solvent type can dissolve and disintegrate in water and gastric juice, and are not subject to this limitation. They comply with the usage amount and scope of use specified in GB2760-2024 food additives, and their moisture-proof effect is also better than that of Comparative Examples 21-22 of the alcohol solvent type.

[0179] In summary, the present invention has innovatively realized the technical solution of a universal and compliant aqueous gastric-soluble, high-efficiency moisture-proof coating composition for food additives-compounded film-coating agents and pharmaceutical solid preparation film coating premixes, thus solving the technical problems faced in this field.

Claims

1. A method for preparing a solid dispersion, characterized in that: The following steps are involved: The insoluble component, a surfactant and a carrier are ground to obtain a solid dispersion; the insoluble component includes at least one of stearic acid and magnesium stearate; the surfactant includes polyglycerol fatty acid ester; the carrier includes at least one of hydroxypropyl methylcellulose, hydroxypropyl cellulose and sodium alginate; the mass ratio of the insoluble component, the surfactant and the carrier is 1: (0.01~0.05): (1~60).

2. The method for preparing a solid dispersion according to claim 1, wherein The insoluble component is stearic acid, the carrier includes at least one of hydroxypropyl methylcellulose and hydroxypropyl cellulose, and the mass ratio of the insoluble component, the surfactant and the carrier is 1:0.03:(1~6).

3. The method for preparing a solid dispersion according to claim 1, wherein The insoluble component is magnesium stearate, the carrier includes at least one of hydroxypropyl methylcellulose and hydroxypropyl cellulose, and the mass ratio of the insoluble component, the surfactant and the carrier is 1:0.05:(2~6).

4. The method for preparing a solid dispersion according to claim 1, wherein: The insoluble component is stearic acid, the carrier includes sodium alginate, and the mass ratio of the insoluble component, the surfactant and the carrier is 1:0.01:(1.5~60).

5. The method for preparing a solid dispersion according to claim 1, wherein: The insoluble component is magnesium stearate, the carrier includes sodium alginate, and the mass ratio of the insoluble component, the surfactant and the carrier is 1:0.01:(1.2~60).

6. The method for preparing a solid dispersion according to claim 1, wherein: The following steps are involved: (S1) adding the formulated amount of surfactant and carrier into a micronized grinder for pre-grinding; (S2) adding the insoluble components to a micro-powder grinder and grinding for 120-240 seconds; (S3) Mixing the solid dispersion prepared in step (S2) in a multidimensional mixer for 18-20 minutes.

7. An aqueous gastric-soluble high-efficiency moisture-proof coating composition, characterized in that: The invention relates to a solid dispersion prepared by the preparation method according to any one of claims 1 to 6.

8. The aqueous gastric-soluble high-efficiency moisture-proof coating composition according to claim 7, characterized in that: Calculated by mass percentage, the coating composition formula includes: 60-90% solid dispersion and 10-40% plasticizer.

9. The aqueous gastric-soluble high-efficiency moisture-proof coating composition according to claim 8, characterized in that: The plasticizer includes at least one of mannitol, erythritol, trehalose and lactose.

10. The aqueous gastric-soluble high-efficiency moisture-proof coating composition according to claim 8, characterized in that: The solvent of the coating composition is purified water.

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