A method for preparing a solid dispersion and an aqueous, stomach-soluble, high-efficiency moisture-proof coating composition containing the solid dispersion.

Abstract

This invention belongs to the field of food additives—compound coating agents and pharmaceutical solid dosage form film coating agents, 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. The solid dispersion provided in this application selects stearic acid and magnesium stearate as poorly soluble components, polyglycerol fatty acid esters as surfactants, and hydroxypropyl methylcellulose / hydroxypropyl cellulose / sodium alginate as carriers. Combined with a grinding process to treat the raw materials, a good synergistic effect is achieved among the components, resulting in a stable, amorphous solid dispersion. Experiments have shown that the content of poorly soluble components in the prepared solid dispersion is unexpectedly significantly increased. The coating composition containing the solid dispersion as a carrier exhibits extremely superior moisture resistance after film formation, and the coated formulation prepared using this method meets the disintegration limit in purified water / artificial gastric fluid media.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of food additive-coating agent and pharmaceutical solid preparation film coating agent, and relates to a preparation method of a solid dispersion and a water-based stomach soluble high-efficiency moisture-proof coating composition containing the solid dispersion. BACKGROUND

[0002] Among the natural and synthetic film-forming agents used in coating compositions for food, health products, and pharmaceutical preparations, the most commonly used include polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, pullulan, acrylic resin, HP55, zein, shellac, sodium alginate, and pectin. Of these, hydroxypropyl methylcellulose and hydroxypropyl cellulose are suitable for water-soluble, stomach-soluble film-forming agents with a certain degree of moisture resistance, exhibiting better moisture-proof performance than polyvinyl alcohol. However, compared to using zein or beeswax to coat or wax the surface of the object to form a moisture-proof coating, the former still cannot achieve the same level of moisture resistance. In practical coating applications, sugar-coated or film-coated preparations of traditional Chinese medicine typically use waxing for moisture protection or a more expensive stomach-soluble, alcohol-soluble No. IV acrylic resin (its corresponding EPO or E100 type resin abroad) as a film-forming agent to form a film for moisture protection. On the one hand, insect wax is difficult to dissolve in water or gastric juice, and is a pH-independent solubility. The resulting film-coated moisture-proof layer disintegrates in water and gastric juice. On the other hand, No. IV acrylic resin is a pH-dependent solubility (dissolves in media with a pH not greater than 5) gastric-soluble film-forming agent. It does not dissolve in water but only dissolves and disintegrates in gastric juice. The Chinese Pharmacopoeia General Chapter 0921 stipulates that the disintegration time limit test of sugar-coated and film-coated preparations of traditional Chinese medicine is carried out in purified water and gastric juice (pH 1.0) as media, respectively. When waxing is used as a moisture-proof layer for sugar-coated and film-coated preparations of traditional Chinese medicine, and when No. IV acrylic resin composition film is used as a moisture-proof layer for sugar-coated preparations of traditional Chinese medicine, it will affect their disintegration time in water or gastric juice to varying degrees. On the other hand, the coating method affects the disintegration time limit compliance of both coating methods, including film thickness and weight gain. Waxing involves directly heating and softening wax powder (mostly insect wax granules) to adhere to the surface of the object being coated, resulting in uneven film thickness and difficulty in quantitative measurement. Excessively thick coatings are difficult to dissolve and disintegrate in gastric juice and water, affecting the release rate in gastric juice and often leading to failure to meet the disintegration time limit. Alcohol-soluble, gastric-soluble type IV acrylic resin coating compositions, on the other hand, form a film on the surface of the object being coated via liquid spraying. This method is more convenient, produces a uniform film thickness, is easy to quantitatively measure, and the weight gain can be controlled to meet the disintegration time limit. However, when used as a substitute for the moisture-proof layer in traditional Chinese medicine sugar coating preparations, the weight gain of waxed coatings often makes it difficult to meet the disintegration time limit (in aqueous media). Furthermore, in terms of compliance, neither is permitted for use in food additives—compound coating agents.Currently, in terms of usage, waxing methods for moisture protection of traditional Chinese medicine also include spraying with wax emulsions. The quality of compliant GB2760-2024 full-component stabilized insect wax emulsions needs improvement. In addition, it is difficult to simultaneously achieve and control the moisture-proof film thickness or weight gain that meets the requirements for the disintegration limit when using No. IV acrylic resin as a moisture-proof layer for sugar-coated preparations of traditional Chinese medicine (the Chinese Pharmacopoeia stipulates that the disintegration limit of sugar-coated tablets of traditional Chinese medicine is determined in purified water, and No. IV acrylic resin coatings are insoluble in water). When used as a moisture-proof coating for film-coated preparations of traditional Chinese medicine, it requires organic solvents such as ethanol and isopropanol as solvents (the Chinese Pharmacopoeia stipulates that the disintegration limit of film-coated tablets of traditional Chinese medicine is determined in gastric juice at pH 1.0), which has defects in terms of cost, environmental protection, and explosion-proof safety.

[0003] In summary, current moisture-proof coatings mainly include: waxing or corn gluten coatings, which produce water-insoluble and gastric-insoluble moisture-proof films; and No. IV acrylic resin coatings, which produce water-insoluble and gastric-soluble moisture-proof films. However, there are currently very few literature reports and commercially available moisture-proof coating compositions that are both water-soluble and gastric-soluble, with easily controllable coating thickness or weight gain, and that allow water to be used as a solvent. These compositions are compliant with regulations for food additives, compound coating agents, and pharmaceutical solid dosage form film coatings, especially for film-coated formulations of traditional Chinese medicine (including sugar coatings and film coatings) or chemical drugs. For example, there are few reports in the literature and commercial applications of water-based, gastric-soluble, high-moisture-proof coating compositions where the moisture-proof layer on the outer layer of the film-coated formulation can dissolve and disintegrate in water or gastric juice.

[0004] However, the moisture-proof coating layer obtained by using existing water-based gastric-soluble film-forming agents with excellent moisture resistance and common coating composition preparation methods, such as the above-mentioned hydroxypropyl methylcellulose and hydroxypropyl cellulose as film-forming agents, through grinding or shearing mixing of all components currently used in coating compositions, is difficult to achieve the same moisture-proof effect as alcohol-soluble No. IV acrylic resin coating compositions.

[0005] Therefore, to fill the gap in the prior art, a water-based, gastric-soluble, high-efficiency moisture-proof coating composition is needed that has no weight gain limitation in water or gastric juice media and has a qualified disintegration limit in both media. This composition can be used in various applications, including food additives-compound coating agents and pharmaceutical solid dosage forms (traditional Chinese medicine, chemical drugs) film coating agents, to achieve high-efficiency moisture protection. This has become a technical problem in the 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 its preparation method, wherein the coating composition is applicable to moisture-proof purposes including food additives-compound coating agents and pharmaceutical solid dosage forms.

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

[0008] Solid dispersions are a pharmaceutical formulation technology that typically refers to the uniform solid dispersion system formed by dispersing poorly soluble drugs in molecular, microcrystalline, or amorphous forms within a solid carrier. They consist of a solid mixture of drug (dispersed phase) and carrier (continuous phase). Their characteristics include improved drug dissolution and bioavailability; enabling rapid or controlled release of drugs: water-soluble carriers can significantly accelerate or increase the dissolution rate of poorly soluble drugs, while enteric carriers can control drug release to specific sites in the small intestine; and improving drug stability: delaying drug hydrolysis and oxidation, and masking drug irritation and unpleasant odors. Preparation methods include spray drying, melt processing, solvent extraction, and grinding.

[0009] Among the aforementioned methods for preparing solid dispersions, grinding is relatively economical and easy to implement. Its principle involves using mechanical force to embed poorly soluble drugs into the gaps between polymer chains through shearing and pressing, resulting in a uniform distribution of molecules, microcrystals, or amorphous forms. This forms a homogeneous system with the carrier, and the solubility can be adjusted by utilizing the water solubility or enteric solubility of the carrier to achieve different dissolution rates and bioavailability. Although grinding is a relatively economical and effective method for preparing solid dispersions, the content of poorly soluble drugs in the solid dispersions obtained using this method is generally low.

[0010] Despite this, through meticulous research and repeated experiments, the inventors used stearic acid and magnesium stearate as poorly soluble components, and hydroxypropyl methylcellulose and hydroxypropyl cellulose as carriers for the solid dispersion. By adding selected surfactants such as polyglycerol fatty acid esters and then grinding, a solid dispersion was prepared. This dispersion was then used as the main component of a compound coating agent (film-forming agent). Surprisingly, the water solubility and moisture-proof coating performance were examined. The invention revealed that the content of poorly soluble components in the solid dispersion prepared by grinding was unexpectedly significantly increased. The coating composition containing this solid dispersion as a carrier exhibited extremely superior moisture-proof properties after film formation. Furthermore, to facilitate comparison of carriers with different moisture absorption rates, release functions at different gastrointestinal sites, and properties, the invention intentionally selected easily hygroscopic sodium alginate to replace hydroxypropyl methylcellulose and hydroxypropyl cellulose in experiments to examine the content and water solubility of poorly soluble components in the solid dispersion, providing a broader reference for product formulation design for different application scenarios of coating compositions. Specific technical solutions include:

[0011] The method for preparing the solid dispersion includes the following steps: grinding a poorly soluble component, a surfactant, and a carrier to obtain a solid dispersion; the poorly soluble 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 poorly soluble component, surfactant, and carrier is 1:(0.01-0.05):(1-60).

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

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

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

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

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

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

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

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

[0020] (S3) General grinding: Add the sparingly soluble component stearic acid or magnesium stearate to the material from step (S2) and grind for 120-240 seconds;

[0021] (S4) Total mixing: Combine the multiple batches of materials from step (S3) into a multidimensional mixer and mix for 18-20 minutes;

[0022] (S5) Sieving, Inspection, and Packaging: The total mixture from step (S4) is discharged and sieved through a 60-80 mesh sieve, then packaged. A water-based, stomach-soluble, high-efficiency moisture-proof coating composition comprises the solid dispersion prepared by the above method.

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

[0024] Preferably, the plasticizer includes at least one selected from mannitol, erythritol, trehalose, and lactose. More preferably, the plasticizer is mannitol.

[0025] By selecting mannitol, erythritol, trehalose, and lactose—plasticizers with excellent moisture-proof properties—and hydroxypropyl methylcellulose and hydroxypropyl cellulose with low water vapor permeability as water-soluble carriers, and a solid dispersion composed of high-content stearic acid and magnesium stearate as insoluble components, the aforementioned water-based, stomach-soluble, high-efficiency moisture-proof coating composition is formed. Furthermore, all the above materials are food-grade, enabling the production of food additives—compound coating agents—that comply with the usage amounts and scope specified in GB2760-2024. Therefore, by preparing the above solid dispersion through a grinding method, the carrier and insoluble components are compliant materials for food additives—compound coating agents and pharmaceutical solid dosage film coating agents with excellent moisture-proof properties. This innovative technical solution for preparing a water-based, stomach-soluble, high-efficiency moisture-proof coating composition achieves the goal of solving the aforementioned technical problems.

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

[0027] Preferably, all materials involved in the coating composition comply with relevant national food standards and the 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) Significant advantages of the method: The solid dispersion is mainly composed of preferred moisture-proof components stearic acid, magnesium stearate, hydroxypropyl methylcellulose and hydroxypropyl cellulose. After adding a small amount of polyglycerol fatty acid ester surfactant, the content of insoluble components is significantly increased. In the prior art, when preparing solid dispersions by grinding, the content of insoluble components is generally low, which makes it difficult for solid dispersions with low content of insoluble components to play a moisture-proof role as a component of the coating composition. This is an innovative technical solution for preparing coating compositions using solid dispersions.

[0031] (3) Material compliance with general coatings for food, confectionery and pharmaceuticals: A water-based, gastric-soluble, highly effective moisture-proof coating composition was prepared, which achieves both water-soluble and gastric-soluble moisture-proof properties. The coating formulations meet the disintegration limits in purified water / artificial gastric juice media, thus solving the existing technical problems in the background art. It can be used as a substitute for waxing layers of traditional Chinese medicine or as a general 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. Attached Figure Description

[0033] The attached diagram will be briefly described below:

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

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

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

[0037] Figure 4 This is a DSC spectrum of a solid dispersion containing magnesium stearate, polyglycerol fatty acid esters, 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 following are the DSC spectra of the solid dispersions of Comparative Example 13 and Comparative Example 14; wherein spectrum 7-1 is the spectrum of Comparative Example 14 and spectrum 7-2 is the spectrum of Comparative Example 13.

[0041] Figures 8-13 The following are, in order: DSC integral spectra of polyglycerol fatty acid esters (SOL), stearic acid (SA), magnesium stearate (Mgst), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (H-HPC), and sodium alginate (NaAlg). In the figure, SA represents stearate, Mgst represents magnesium stearate, HPMC represents hydroxypropyl methylcellulose, H-HPC represents hydroxypropyl cellulose, NaAlg represents sodium alginate, and SOL represents polyglycerol fatty acid esters. Detailed Implementation

[0042] The present invention will now be further described by way of 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 are generally only some, not all, of the embodiments of the present invention. Therefore, all other embodiments obtained 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] Composition (parts by weight) of SDⅠ type stearic acid-polyglycerol fatty acid ester-hydroxypropyl methylcellulose solid dispersion: stearic acid, polyglycerol fatty acid ester, and hydroxypropyl methylcellulose in a mass ratio of 1:0.03:6.

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

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

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

[0048] (S3) Total grinding: Add the sparingly soluble component stearic acid to the material from step (S2) and grind for 240 seconds;

[0049] (S4) Total mixing: Combine the multiple batches of materials from step (S3) into a multidimensional mixer and mix for 18 minutes;

[0050] (S5) Sieving, Testing and Packaging: The total mixture from step (S4) is discharged and sieved through a 60-80 mesh sieve, then packaged. The solid dispersion composite component is obtained after passing tests for loss on drying, residue, heavy metals, and microbial limits.

[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 hydroxypropyl methylcellulose was changed to 3:0.09:6; the grinding in step (S2) was changed to 180s, and the mixing in step (S3) was changed to 19min. Everything else was 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 hydroxypropyl methylcellulose was changed to 6:0.18:6; the grinding in step (S2) was changed to 120s, and the mixing in step (S3) was changed to 20min. Everything else was the same as in Example 1.

[0057] Examples 4-6

[0058] The difference between Examples 4, 5, and 6 and Example 1 is as follows:

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

[0060] Examples 7-9

[0061] The difference between Embodiments 7-9 and Embodiment 1 is as follows:

[0062] Composition (parts by weight) of SDII type magnesium stearate-polyglycerol fatty acid ester-hydroxypropyl methylcellulose: The mass ratio of magnesium stearate, polyglycerol fatty acid ester, and hydroxypropyl methylcellulose is as follows: Example 7: 1:0.05:6; Example 8: 2:0.1:6; Example 9: 3:0.15:6. Other aspects are the same as in Example 1.

[0063] Examples 10-12

[0064] The difference between Embodiments 10-12 and Embodiment 1 is as follows:

[0065] Composition (parts by weight) of SDⅣ type magnesium stearate-polyglycerol fatty acid ester-hydroxypropyl cellulose: The mass ratio of magnesium stearate, polyglycerol fatty acid ester, and hydroxypropyl cellulose is as follows: Example 10: 1:0.05:6; Example 11: 2:0.1:6; Example 12: 3:0.15:6. Other aspects are the same as in Example 1.

[0066] Examples 13-15

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

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

[0069] Examples 16-18

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

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

[0072] Comparative Example 1

[0073] The difference between this comparative example and Example 3 is as follows:

[0074] Replace stearic acid, polyglycerol fatty acid ester, and hydroxypropyl methylcellulose with a stearic acid to hydroxypropyl methylcellulose mass ratio of 1:1. All other aspects are the same as in Example 3.

[0075] Comparative Example 2

[0076] The difference between Comparative Example 2 and Example 6 is as follows:

[0077] Replace stearic acid, polyglycerol fatty acid ester, and hydroxypropyl cellulose with a stearic acid to hydroxypropyl cellulose mass ratio of 1:1. Everything else is the same as in Example 6.

[0078] Comparative Example 3

[0079] The difference between Comparative Example 3 and Example 9 is as follows:

[0080] Replace magnesium stearate, polyglycerol fatty acid ester, and hydroxypropyl methylcellulose with a magnesium stearate to hydroxypropyl methylcellulose mass ratio of 1:2. All other aspects are the same as in Example 9.

[0081] Comparative Example 4

[0082] The difference between Comparative Example 4 and Example 12 is as follows:

[0083] Replace magnesium stearate, polyglycerol fatty acid ester, and hydroxypropyl cellulose with a magnesium stearate to hydroxypropyl cellulose mass ratio of 1:2. All other aspects are the same as in Example 12.

[0084] Comparative Examples 5-6

[0085] Comparative Examples 5 and 6 are examples of Examples 15 and 18 respectively, without the addition of polyglycerol fatty acid esters, and are otherwise identical.

[0086] Comparative Examples 7-8

[0087] Comparative Examples 7 and 8 are the same as Examples 2 and 8, but without the addition of the surfactant polyglycerol fatty acid ester, and with hydroxypropyl methylcellulose replaced by polyethylene glycol 4000 (PEG).

[0088] Comparative Examples 9-10

[0089] Comparative Examples 9 and 10 are the same as Examples 2 and 8, but without the addition of polyglycerol fatty acid esters and with hydroxypropyl methylcellulose replaced by copovidone (PVPVA64).

[0090] Comparative Example 11

[0091] The difference between this comparative example and Example 2 is that the polyglycerol fatty acid ester in Example 2 is replaced with polysorbate 80, while the rest is the same as in Example 2.

[0092] Comparative Example 12

[0093] The difference between this comparative example and Example 8 is that the polyglycerol fatty acid ester in Example 8 is replaced with polysorbate 80, while the rest is the same as in 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 hydroxypropyl methylcellulose was 0.1:3, or 0.2:6. Other parameters were the same as 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 hydroxypropyl methylcellulose was 0.3:0.3:6, and the other components were the same as in Comparative Example 11.

[0100] Example 19 (Investigation of Material Addition Amount and Conditions)

[0101] In the preliminary tests of this invention, a moisture-proof test using an alcohol solvent verified that when the mass percentage of the sparingly soluble components stearic acid or magnesium stearate in the coating composition of hydroxypropyl methylcellulose or hydroxypropyl cellulose reaches 10% or more, the moisture-proof properties of the film formed by the coating composition are better. Therefore, it is determined that a solid dispersion prepared using stearic acid and magnesium stearate as sparingly soluble components and water-soluble gastrointestinal hydroxypropyl methylcellulose and hydroxypropyl cellulose as carriers, after forming a film in the water-soluble coating composition, is expected to have excellent moisture-proof properties. However, the prerequisite is that the content of the sparingly soluble components in the solid dispersion is significantly increased compared to solid dispersions prepared by ordinary grinding methods, so that the content of the sparingly soluble components containing the solid dispersion in the coating composition should not be less than 10%.

[0102] 1. Investigation into the selection of surfactants in solid dispersions

[0103] Span 20, polyglycerol fatty acid esters, and sodium polyacrylate were added to solid dispersions composed of stearic acid, magnesium stearate, and hydroxypropyl methylcellulose / hydroxypropyl cellulose / sodium alginate, respectively, to increase the content of stearic acid and magnesium stearate in the solid dispersions. To this end, with the following mass percentages of insoluble components in the solid dispersions: 5 parts insoluble components and 30 parts carrier, 5% of surfactants (mass ratio of the three components 1:0.25:6) were added to each (the insoluble components were 5 parts by mass, and the mixture was ground in a micronizer for 240 seconds and then prepared with a 10% solids content. The water solubility of the solid dispersions after adding different types of surfactants was investigated, and the results are shown in Table 1.

[0104] Table 1. Water solubility of sparingly soluble components under different surfactants

[0105]

[0106] As shown in Table 1, among the three surfactants, Span 20 has no effect on improving the water solubility of poorly soluble components. The addition of polyglycerol fatty acid ester and sodium polyacrylate can make the prepared solid dispersion solution a homogeneous 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 a suitable surfactant.

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

[0108] In the selection of the above surfactants, the mass ratio of the sparingly soluble component to the carrier was adjusted to: 15 parts of sparingly soluble component and 30 parts of carrier. Polyglycerol fatty acid esters were added at a mass ratio of 0.25-5% of the sparingly soluble component. The solubility of the solid dispersion was investigated at different addition amounts, and the results are shown in Table 2.

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

[0110]

[0111] Table 2 shows that, due to the hydrophilic and lipophilic properties of polyglycerol fatty acid esters, excessive amounts can negatively impact moisture resistance. In solid dispersion combinations: stearic acid-hydroxypropyl methylcellulose and stearic acid-hydroxypropyl cellulose, a surfactant concentration of 2% (by mass) of the insoluble stearic acid is sufficient to form a homogeneous colloidal solution; similarly, magnesium stearate-hydroxypropyl methylcellulose and magnesium stearate-hydroxypropyl cellulose, with a surfactant concentration of 4% (by mass) of the insoluble magnesium stearate, also achieve a homogeneous colloidal solution. To ensure both water solubility and moisture resistance, a polyglycerol fatty acid ester concentration of 3% stearic acid and 5% magnesium stearate is recommended. For the same reason, in stearic acid-sodium alginate and magnesium stearate-sodium alginate solid dispersions, a polyglycerol fatty acid ester concentration of 1% is preferable.

[0112] 3. Selection of Polyglycerol Fatty Acid Esters

[0113] In the preliminary experiment, among the aforementioned polyglycerol fatty acid esters, based on HLB value, saturated and unsaturated alkyl chain structure, water solubility, and the "like dissolves like" principle, the proportions of oleic acid and stearic acid polyglycerol fatty acid esters with HLB values ​​of 9.0-13.5 were selected as follows: 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. Solutions with a solid content of 10% were prepared, and the water solubility of solid dispersions with different types of polyglycerol fatty acid ester surfactants was investigated. The results are shown in Table 3.

[0114] Table 3. Effect of Polyglycerol Fatty Acid Types on the Water Solubility of Solid Dispersions

[0115]

[0116] As shown in Table 3 above, due to the hydrophobicity of alkyl chains and their molecular structure, solid dispersions prepared from polyglycerol fatty acid esters other than polyglycerol-10 distearate have better water solubility when sodium alginate is used as the carrier. Polyglycerol-10 stearate with an HLB value of 13.5 has poor water solubility in solid dispersions of magnesium stearate-based hydroxypropyl methylcellulose and hydroxypropyl cellulose carriers. In contrast, polyglycerol-10 oleate or dioleate among oleic acid-based polyglycerol fatty acid esters exhibits better water solubility. Therefore, the surfactants used in solid dispersions are preferred.

[0117] To the inventors' surprise, stearic acid-based polyglycerol fatty acid esters, which were expected to exhibit better water solubility according to the "like dissolves like" principle (as the stearic acid and magnesium stearate components have a stearic acid alkyl chain structure closer to this principle), did not show the same level of water solubility as oleic acid-based polyglycerol fatty acid esters. It should be noted that the surfactant polyglycerol fatty acid esters mentioned in this invention specifically refer to polyglycerol-10 oleate or polyglycerol-10 dioleate, specifically those with CAS numbers 9007-48-1 / 79665-93-3 and 33940-99-7, respectively.

[0118] 4. Selection of feeding sequence and process

[0119] In the above-mentioned process for preparing solid dispersions, the feeding sequence is as follows: first, the carrier and the surfactant polyglycerol fatty acid ester are ground together, and then the poorly soluble component stearic acid or magnesium stearate is added. In preliminary experiments, the inventors experimented with various combinations of the feeding sequence of the poorly soluble component, surfactant, and carrier to screen for a suitable feeding sequence.

[0120] (1) Process 1: The carrier and surfactant are ground first, and then the insoluble components stearic acid or magnesium stearate are 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) In process 3, the insoluble components and the carrier are first ground together, and then the surfactant polyglycerol fatty acid ester is added.

[0123] (4) Process 4: The carrier, surfactant, polyglycerol fatty acid ester and poorly soluble component are added and ground at the same time.

[0124] The water solubility of the solid dispersions prepared by the above four feeding sequences was investigated, and the results are shown in Table 4.

[0125] Table 4. Investigation of the effect of feeding sequence of different processes on the water solubility of solid dispersions

[0126]

[0127] As can be seen from the results in Table 4, the water solubility of all solid dispersions in process 1 is exhibited as a uniform colloidal solution. Therefore, it is the preferred process for the feeding sequence.

[0128] 5. Investigation on the maximum amount of sparingly soluble components added in solid dispersions

[0129] In this scheme, to improve the moisture-proof effect, it is beneficial to increase the content of the poorly soluble component in the solid dispersion. The purpose of adding surfactant is also for this purpose. Based on the amount of surfactant added to the solid dispersion, namely: stearic acid-hydroxypropyl methylcellulose, in which polyglycerol fatty acid ester accounts for 3% of the mass of stearic acid; magnesium stearate-hydroxypropyl methylcellulose, in which polyglycerol fatty acid ester accounts for 5% of the mass of magnesium stearate; stearic acid-sodium alginate, in which 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 proportions of poorly soluble component: 0.5-35 parts of poorly soluble component and 30 parts of carrier. The maximum content was examined by water solubility, and the results are shown in Table 5.

[0130] Table 5. Investigation of the maximum addition amount of sparingly soluble components in solid dispersions.

[0131]

[0132]

[0133] In the results of Table 5 above, on the one hand, the maximum amount of stearic acid added in the stearic acid-hydroxypropyl methylcellulose and stearic acid-hydroxypropyl cellulose solid dispersions is: the mass ratio of stearic acid to the carrier hydroxypropyl methylcellulose or hydroxypropyl cellulose is 30:30; on the other hand, the maximum amount of magnesium stearate added in the magnesium stearate-hydroxypropyl methylcellulose and stearic acid-hydroxypropyl cellulose solid dispersions is: the mass ratio of magnesium stearate to the carrier hydroxypropyl methylcellulose or hydroxypropyl cellulose is 15:30; and on the other hand, the maximum amount of insoluble components added in the stearic acid-sodium alginate and magnesium stearate-sodium alginate solid dispersions is: the mass ratio of stearic acid to the carrier sodium alginate is 20:30, and the mass ratio of magnesium stearate to the carrier sodium alginate is 25:30. On the other hand, in the preliminary test results using alcohol as a solvent, when the mass percentage of stearic acid or magnesium stearate in the solid dispersion in the coating composition is more than 10%, it exhibits superior moisture resistance. The ratio of the insoluble components in the solid dispersion is not less than 5:30. Therefore, the suitable range for the content of the aforementioned insoluble components is: when the carrier is hydroxypropyl methylcellulose or hydroxypropyl cellulose, the content of stearic acid is (5-30):30, i.e., (1-6):6; and the content of magnesium stearate is (5-15):30, i.e., (1-3):6. When sodium alginate is used as the carrier, the maximum content of stearic acid is 20:30, and the maximum content of magnesium stearate is 25:30.

[0134] 6. Investigation of grinding time and stability in the preparation of solid dispersions by grinding method

[0135] The water solubility of solid dispersions prepared with different grinding times was confirmed by grinding time, and the water solubility was further investigated after 3 months of accelerated testing in an accelerator at 40±2℃ and 75±5%RH. 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 results after acceleration. After accelerating the grinding time of each group of solid dispersions with a grinding time of 120-240s for 3 months, the water solubility was the same as before acceleration. The insoluble components remained stable after being amorphized. In order to avoid the risk of steel rod chips entering the product due to excessive grinding time and to improve efficiency, it is advisable to select a grinding time of 120-240s.

[0139] Example 20 (Water solubility assessment 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 90% of the formulation amount and the solid content was 10% when the solution was prepared. 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 Dispersions in Water

[0142]

[0143]

[0144] As can be seen from the table above: Comparative Examples 1-6, without the addition of surfactant, failed to form a uniform colloidal solution despite the use of grinding; Comparative Examples 7-10 used commonly used hydrophilic carrier materials for existing solid dispersions, and their water solubility was the same as that of Comparative Examples 1-6; Comparative Examples 11-12, under the same conditions, when the surfactant polyglycerol fatty acid was replaced with polysorbate 80 (which is not allowed to be used in the coating of compressed candies in GB2760-2024 food standard), the solid dispersions did not form a colloidal solution in water, indicating that the solubility levels of the examples were not achieved; In contrast, the solid dispersions of the present invention, with the addition of the surfactant polyglycerol fatty acid ester and the grinding process, significantly increased the content of the poorly soluble components in the solid dispersions, resulting in a uniform colloidal solution in water, thus providing a film-forming basis for the realization of water-based gastric-soluble, high-efficiency moisture-proof coating compositions.

[0145] It should be noted that the corresponding mass ratios in Comparative Examples 13 and 14 were determined during preliminary exploratory experiments by gradually increasing the amount of the sparingly soluble component to examine its water solubility, resulting in the maximum addition amount. Compared to Comparative Example 13, Comparative Example 14 represents the maximum addition amount of the sparingly soluble component after adding a surfactant during grinding. Clearly, the addition of the surfactant significantly increases the maximum addition amount of stearic acid in the stearic acid solid dispersion. However, this is still far from sufficient for use as a moisture-proof coating agent or film-forming agent, and the increased amount of surfactant also significantly affects the moisture-proof properties of the film. Therefore, compared to Example 3, under the same carrier, the maximum addition amount of stearic acid in Example 3 is 20-30 times higher, providing a prerequisite for the realization of a moisture-proof coating composition.

[0146] Example 21 (Investigation of Differential Scanning Calorimetry of Solid Dispersions)

[0147] To clearly characterize the material properties of the solid dispersion obtained by this invention, differential scanning calorimetry (DSC) analysis was performed on the solid dispersion itself based on the above embodiments. Specifically, a TAQ2000 DSC was used in a N2 atmosphere with a heating rate of 10℃ / min and a measurement range of 25-250℃. To further reveal the influence of the raw material ratio design on the material properties, this embodiment also simultaneously designed different raw material ratios and conducted DSC analysis accordingly.

[0148] Please see Figure 1In this group, stearic acid, polyglycerol fatty acid esters, and hydroxypropyl methylcellulose were used as raw materials. The ratio of these three components in spectrum 1-1 was 1:0.03:1, in spectrum 1-2 it was 1:0.03:0.85, and in spectrum 1-3 it was 1:0.03:0.75. According to the calorimetric analysis results, pure stearic acid exhibited a significant melting point peak in the temperature 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 (spectrum 1-1), no melting point peak of stearic acid was observed in this temperature range, indicating that its crystalline structure had been destroyed, forming an amorphous solid dispersion. Furthermore, the solid dispersion maintained its amorphous state even after mixing in a multidimensional mixer. Since the degree of amorphization directly affects water solubility, it can be inferred that the sample corresponding to spectrum 1-1 has higher solubility. This conclusion is consistent with the water solubility experiment results of Example 3, further demonstrating that the present invention successfully obtained an amorphous solid dispersion with good water solubility by grinding stearic acid, polyglycerol fatty acid ester, and hydroxypropyl methylcellulose in a specific ratio. Furthermore, this amorphous solid dispersion itself exhibits good stability, maintaining its amorphous state during the mixing process, ultimately effectively improving the water solubility of stearic acid. In spectra 1-2 and 1-3, as the proportion of stearic acid added increases, the melting point peak of stearic acid gradually shifts to the right, indicating that the degree of amorphization of the solid dispersion is lower at this point, thus its water solubility is weaker compared to Example 3. This further proves that a highly water-soluble and stable amorphous solid dispersion can only be prepared by using stearic acid, polyglycerol fatty acid ester, and hydroxypropyl methylcellulose in a specific ratio.

[0149] Please see Figure 2 In this group, stearic acid, polyglycerol fatty acid ester, and hydroxypropyl cellulose were used as raw materials. The ratio of these three components was 1:0.03:1 in spectrum 2-1, 1:0.03:0.85 in spectrum 2-2, and 1:0.03:0.75 in spectrum 2-3. The calorimetric analysis showed that the solid dispersion prepared in Example 6 of this invention (spectrum 2-1) also lacked a stearic acid melting point peak. This indicates that under these ratios, the grinding of stearic acid, polyglycerol fatty acid ester, and hydroxypropyl cellulose could yield a water-soluble amorphous solid dispersion, which maintained its amorphous state even after mixing in a multidimensional mixer. In spectra 2-2 and 2-3, as the proportion of stearic acid increased, the melting point peak of stearic acid gradually shifted to the right, indicating that a highly water-soluble and stable amorphous solid dispersion could only be prepared under specific ratios.

[0150] Please see Figure 3In this group, magnesium stearate, polyglycerol fatty acid ester, and hydroxypropyl methylcellulose were used as raw materials. The ratio of these three components was 1:0.05:6 in spectrum 3-1, 1:0.05:3 in spectrum 3-2, 1:0.05:2 in spectrum 3-3, 1:0.05:1.5 in spectrum 3-4, and 1:0.05:1.2 in spectrum 3-5. The calorimetric analysis showed that pure magnesium stearate exhibited a significant 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 this invention (spectrums 3-1, 3-2, and 3-3), no melting point peak of magnesium stearate was observed in this temperature range. This indicates that under these formulation conditions, the solid dispersions were amorphous, and they maintained their amorphous state even after mixing in a multidimensional mixer. In the spectra 3-4 to 3-5, as the proportion of magnesium stearate added increases, the melting point peak of magnesium stearate gradually shifts to the right, indicating a lower degree of amorphization and thus a relatively weaker water solubility. However, the inventors discovered through experiments that, for magnesium stearate, a poorly soluble component, at this proportion, 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] Please see Figure 4 In this group, magnesium stearate, polyglycerol fatty acid ester, and hydroxypropyl cellulose were used as raw materials. The ratio of these three components in spectrum 4-1 was 1:0.05:6, and in spectrum 4-2 it was 1:0.05:2. The calorimetric analysis showed that pure magnesium stearate exhibited a distinct melting point peak in the temperature range of 97.44–102.67 °C. However, in the solid dispersion prepared in Example 10 of this invention (spectrum 4-1), no magnesium stearate melting point peak was observed in this temperature range, indicating that the solid dispersion had successfully achieved amorphization under these conditions, thus significantly improving its water solubility. However, in the solid dispersion prepared in Example 12 of this invention (spectrum 4-2), a smooth peak of magnesium stearate was observed in this temperature range. Experiments showed that even at this ratio, the aqueous solution of the solid dispersion could still be coated, and the coating had a certain moisture-proof effect.

[0152] Please see Figure 5In this group, stearic acid, polyglycerol fatty acid ester, and sodium alginate were used as raw materials. The ratio of these three components was 1:0.01:60 in spectrum 5-1, 1:0.01:3 in spectrum 5-2, and 1:0.01:1.5 in spectrum 5-3. The calorimetric analysis showed that the solid dispersion essentially did not exhibit a melting point peak between 54 and 65 °C, indicating that the solid dispersion successfully achieved amorphization under these conditions. Furthermore, the solid dispersion maintained its amorphous state after mixing in a multidimensional mixer, thus significantly improving its water solubility. This is consistent with the water solubility results of Examples 13-15.

[0153] Please see Figure 6 In this group, magnesium stearate, polyglycerol fatty acid ester, and sodium alginate were used as raw materials. The ratio of these three components was 1:0.01:60 in spectrum 6-1, 1:0.01:3 in spectrum 6-2, and 1:0.01:1.2 in spectrum 6-3. The calorimetric analysis showed that the solid dispersion exhibited virtually no melting point peak between 75.49 and 116.61 °C, indicating that the solid dispersion successfully achieved amorphization under these conditions. Furthermore, the solid dispersion maintained its amorphous state after mixing in a multidimensional mixer, significantly improving its water solubility. This is consistent with the water solubility results of Examples 16-18.

[0154] In addition, to investigate the effect of grinding process on the solubility of sparingly soluble components in solid dispersions in aqueous systems, a control group was added to this group based on Examples 3, 6, and 15. Please refer to the appendix. Figure 1 , Figure 2 and Figure 5 . Figure 1 0-1 diagram, Figure 2 0-2 diagram and Figure 5The 0-5 spectra used the exact same raw materials and proportions as in Examples 3, 6, and 15. However, the solid dispersion preparation process did not include the micronizer grinding step in step S2; instead, a multidimensional mixer was used to directly mix the materials to be mixed. The calorimetric analysis shows that even with simple physical mixing, a significant melting point peak for the insoluble component is still formed, indicating that stearic acid in the un-ground sample remains in crystalline form and has not achieved effective amorphization, thus negatively impacting its water solubility. This, along with the aforementioned experiments, demonstrates that this invention not only utilizes the lipophilic / hydrophilic properties of surfactants to improve the dispersion of insoluble components in water, but also, before adding the solid dispersion to the water-soluble system, uses three specific solid components—hydroxypropyl methylcellulose / hydroxypropyl cellulose / sodium alginate, polyglycerol fatty acid ester, and stearic acid / magnesium stearate—to co-grind, forming a stable amorphous solid dispersion. This, in turn, promotes the dissolution of stearic acid / magnesium stearate in water at an extremely high addition rate. It is worth noting that the formation of amorphous solid dispersions is highly dependent on the selection of raw materials and their combination; not all combinations can achieve stable amorphization through grinding. The water solubility experiments of Comparative Examples 1–14 fully demonstrate this: even with the same processing method, the desired stable amorphization effect cannot be obtained when a key component is missing or incompatible excipients are used. During the grinding process, the original crystal structure of stearic acid / magnesium stearate is destroyed by mechanical force and uniformly dispersed between the polymer chains of water-soluble carriers such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sodium alginate. At this point, the long carbon chain structure of stearic acid / magnesium stearate is constrained by the steric hindrance of the surrounding polymer chains, making regular stacking difficult and inhibiting the ordered arrangement and recrystallization tendency of molecules to a certain extent. Simultaneously, 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 force during the blending step, thereby preparing a stable amorphous solid dispersion.

[0155] Examples 22-33

[0156] Using Huanglian Shangqing tablets as the coating material, the solid dispersions prepared in Examples 1-12 were used as effective components of the aqueous gastric-soluble moisture-proof coating composition. The mass fractions of the formulation were: 60-90% solid dispersion and 10-40% mannitol. The components were sheared and mixed evenly, and then the moisture-proof coating formulation of Huanglian Shangqing tablets was prepared according to a coating weight gain of 3%.

[0157] Comparative Example 15

[0158] The solid dispersion prepared in Example 1, consisting of stearic acid, polyglycerol fatty acid ester, and hydroxypropyl methylcellulose (mass ratio 1:0.03:6) accounting for 50% of the components, and mannitol accounting for 50%, was sheared and mixed evenly. The resulting mixture was then used to prepare a moisture-proof coating formulation for Huanglian Shangqing tablets with a coating weight gain of 3%.

[0159] Comparative Example 16

[0160] The solid dispersion prepared in Example 1, consisting of stearic acid, polyglycerol fatty acid ester, and hydroxypropyl methylcellulose (mass ratio 1:0.03:6) accounting for 95% of the components, and mannitol 5%, was sheared and mixed evenly to prepare a moisture-proof coating formulation for Huanglian Shangqing tablets with a coating weight gain of 3%.

[0161] Comparative Example 17

[0162] The solid dispersion of Comparative Example 13, comprising 90%, was mixed with 10% mannitol, resulting in a solid content of 10%. The solution was prepared by adding 10% mannitol and preparing a moisture-proof coating formulation of Huanglian Shangqing tablets based on a coating weight gain of 3%.

[0163] Comparative Example 18

[0164] The solid dispersion of Comparative Example 14, comprising 90%, was mixed with 10% mannitol, resulting in a solid content of 10%. The solution was prepared by adding 10% mannitol and preparing a moisture-proof coating formulation of Huanglian Shangqing tablets based on a coating weight gain of 3%.

[0165] Comparative Example 19

[0166] The ingredients of Huanglian Shangqing tablets were prepared by shearing and mixing 90% stearic acid, hydroxypropyl cellulose (mass ratio 1:6), and 10% mannitol according to the mass ratio, and then by coating to increase the weight by 3%.

[0167] Comparative Example 20

[0168] The mixture consists of 60% magnesium stearate, 60% hydroxypropyl cellulose (mass ratio 1:6), and 40% mannitol. The magnesium stearate and hydroxypropyl cellulose are first ground for 240 seconds to prepare a co-treated material. Then, mannitol is added and sheared and mixed evenly. The solution is prepared with a 10% solid content and a coating weight gain of 3% to prepare the moisture-proof coating formulation of Huanglian Shangqing tablets.

[0169] Comparative Example 21

[0170] The Huanglian Shangqing tablets were prepared by shearing and mixing 80% acrylic resin, 10% magnesium stearate, and 10% triethyl citrate, and then preparing the solution with 80% ethanol solvent and 8% solids content, with a coating weight gain of 3%.

[0171] Comparative Example 22

[0172] The Huanglian Shangqing tablets were prepared by shearing and mixing 75% acrylic resin, 10% stearic acid, and 15% triethyl citrate, and then preparing the solution with 80% ethanol solvent and 8% solids content, with a coating weight gain of 3%.

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

[0174] The 3% weight-gain Huanglian Shangqing tablets prepared in Examples 22-33 and Comparative Examples 15-22 were dried to reach moisture absorption equilibrium and then placed in an accelerated test chamber at 40±2℃ and 75±5%RH for 7 days according to the guidelines in Part IV of the 2025 edition of the Chinese Pharmacopoeia, as specified in Guideline 9001. The tablets were weighed after each test, and the percentage difference between the weights before and after the test was taken as the moisture absorption rate. The appearance, moisture absorption rate, and disintegration limit in purified water and gastric juice at pH 1.0 after the accelerated test were examined. The results are shown in Table 8.

[0175] Table 8. Results of moisture resistance test of coating compositions and coating formulations

[0176]

[0177]

[0178] As shown in the table above, the commonly used alcohol-soluble No. IV acrylate resin coating composition has better moisture-proof effect. When used as a moisture-proof coating layer on the same core of Coptis chinensis 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 solid dispersion preparation method of the present invention and the coating film of the coating composition with the prepared solid dispersion as the main component have better moisture-proof effect. In the formulation composition of the examples, the proportion of solid dispersion is preferably 60-90%. In Comparative Examples 15-16, when the proportion is less than 60%, the film is softer, or when it is higher than 90%, the film is harder and more brittle, and cracks appear more quickly. All of them lost their moisture-proof function; Comparative Example 17 used a solid dispersion grinding method but did not add surfactants, and the moisture-proof function of the coating film of the coating composition was poor; Comparative Example 18 used other surfactants, and the moisture-proof effect of the coating film of the coating composition was still not as good as 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 was difficult to prepare or form a film; The coating composition of Comparative Example 20 was prepared by co-treatment plus shear mixing, and the coating operation and film-forming properties were improved compared with Comparative Example 19, but the moisture-proof performance was still not improved; Comparative Examples 21-22 were alcohol solvent moisture-proof formulations, and their coating film layers were insoluble and did not disintegrate in water, but could dissolve and disintegrate in gastric juice. Therefore, according to the Chinese Pharmacopoeia 0921 General Chapter on the disintegration time limit (water medium) test of sugar-coated preparations of traditional Chinese medicine, the coating film layers of Comparative Examples 21-22 were insoluble and did not disintegrate in water, and could not be used as moisture-proof coatings for sugar-coated tablets of traditional Chinese medicine. The coating layer of the all-water-soluble type Examples 22-33 can dissolve and disintegrate in water and gastric juice, thus it is not subject to this limitation, and it complies with the usage and scope of food additives specified in GB2760-2024. Moreover, its moisture-proof effect is better than that of the alcohol-soluble type Comparative Examples 21-22.

[0179] In summary, this invention innovatively realizes a universal and compliant water-based gastric-soluble, high-efficiency moisture-proof coating composition for food additives, compound coating agents, and pharmaceutical solid dosage form film coating agents. The coating formulation meets the disintegration limit in purified water / artificial gastric juice, thus solving the technical problems faced in this field.

Claims

1. A method for preparing a solid dispersion, characterized in that, Includes the following steps: First, the surfactant and carrier are pre-ground, and then the poorly soluble components are added and mixed and ground to obtain a solid dispersion; the surfactant includes polyglycerol fatty acid esters; The poorly soluble component is stearic acid, and the carrier includes at least one of hydroxypropyl methylcellulose and hydroxypropyl cellulose. The mass ratio of the poorly soluble component, surfactant and carrier is 1:0.03:(1~6). or, The poorly soluble component is magnesium stearate, and the carrier includes at least one of hydroxypropyl methylcellulose and hydroxypropyl cellulose. The mass ratio of the poorly soluble component, surfactant and carrier is 1:0.05:(2~6).

2. The method for preparing a solid dispersion according to claim 1, characterized in that, Includes the following steps: (S1) Add the formulated amount of surfactant and carrier to a micronizer for pre-grinding; (S2) Add the sparingly soluble components to a micronizer and grind for 120-240 seconds; (S3) Mix the solid dispersion prepared in step (S2) in a multidimensional mixer for 18-20 min.

3. A water-based, stomach-soluble, high-efficiency moisture-proof coating composition, characterized in that, Includes solid dispersions prepared by the preparation method according to any one of claims 1 or 2.

4. The aqueous, stomach-soluble, high-efficiency moisture-proof coating composition according to claim 3, characterized in that, The coating composition formulation comprises, by weight percentage: 60-90% solid dispersion and 10-40% plasticizer.

5. The aqueous, stomach-soluble, high-efficiency moisture-proof coating composition according to claim 4, characterized in that, The plasticizer includes at least one of mannitol, erythritol, trehalose, and lactose.

6. The aqueous, stomach-soluble, high-efficiency moisture-proof coating composition according to claim 4, characterized in that, The solvent for the coating composition is purified water.

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