Compound soft capsule and preparation method thereof

Abstract

The invention relates to the technical field of capsules, in particular to a compound soft capsule and a preparation method thereof. The compound soft capsule comprises a capsule content and a capsule shell prepared from capsule liquid, and the capsule content is prepared from the following raw materials in parts by weight: 5-12 parts of calcium carbonate and 10-20 parts of a compound extract. The compound soft capsule product prepared by the invention has excellent storage stability, antibacterial property, good disintegration performance and high bioavailability.

Description

Technical Field

[0001] The invention relates to the technical field of capsules, and in particular to a compound soft capsule and a preparation method thereof. Background Art

[0002] Soft capsules are a new dosage form developed after tablets and injections. They have the characteristics of faster onset of action than tablets and granules, higher bioavailability, easier carrying, and diversified appearance. In the research and development of pharmaceutical chemistry, compound soft capsules, as an innovative drug delivery system, have an increasingly rich research background. Compound soft capsules can encapsulate two or more drug ingredients in the same soft capsule, improve the therapeutic effect through the synergistic effect between drugs, and reduce the side effects of a single drug, thus showing unique advantages in the field of medicine.

[0003] Medicinal chemists are constantly exploring the preparation methods of compound soft capsules through in-depth research on the interactions of drug ingredients, bioavailability, drug release characteristics, etc., in order to achieve the best combination of drug ingredients. In this process, issues such as drug compatibility, prescription optimization, preparation process research, and quality control have become the focus of research. Although compound soft capsules have achieved certain results in the field of medicinal chemistry, there are still many challenges in drug combination optimization, preparation process, quality control, and industrialization.

[0004] Chinese invention patent CN113041230B discloses a capsule skin of a soft capsule and a soft capsule prepared therefrom. The capsule skin comprises the following raw materials: gelatin, glycerol, proteoglycan, composite collagen fiber, brown iron oxide, purified water. Specifically, the capsule skin comprises the following raw materials by weight: 50-60 parts of gelatin, 15-25 parts of glycerol, 10-15 parts of proteoglycan, 10-15 parts of composite collagen fiber, 0.1-0.5 parts of brown iron oxide, and 45-55 parts of purified water. The invention discloses a capsule skin of a soft capsule, which reduces the effect of gelatin aging on the disintegration rate, has good mechanical strength and toughness, good stability, can still disintegrate quickly after long-term placement, and has stable performance. To this end, this patent proposes a compound soft capsule and a preparation method thereof to overcome the problem of single function in soft capsules in the prior art. Summary of the invention

[0005] In view of the above-mentioned deficiencies in the prior art, the present invention provides a compound soft capsule and a preparation method thereof.

[0006] In order to solve the above technical problems, the technical solution adopted by the present invention is:

[0007] A compound soft capsule comprises capsule contents and a capsule shell made of capsule liquid. The capsule contents are composed of the following raw materials in parts by weight: 5-12 parts by weight of calcium carbonate and 10-20 parts by weight of a compound extract.

[0008] In the present invention, calcium carbonate is used as an inorganic salt filler. After the capsule enters the gastrointestinal tract, its alkaline property helps the capsule contents to disintegrate faster in the gastric juice, thereby promoting the release of the drug; it can also improve the fluidity and uniformity of the capsule contents, help to improve the bioavailability of the drug ingredients, and facilitate the molding and packaging of the capsule.

[0009] The preparation method of the compound extract is as follows: Rhizoma Drynariae, Herba Epimedii, Herba Glehniae, Flos Lonicerae, Herba Portulacae and Rhizoma Coptidis are washed, dried and crushed to obtain Chinese medicine powder; the Chinese medicine powder is mixed with an ethanol aqueous solution, heated for extraction, and centrifuged to obtain a filtrate and a precipitate; the precipitate is subjected to supercritical carbon dioxide extraction to obtain an extract; the filtrate and the extract are combined, reduced pressure concentration is performed, and drying is performed to obtain the compound extract.

[0010] The capsule contents used in the present invention are all Chinese medicines with antibacterial and anti-inflammatory effects. Drynaria, Epimedium, Panax notoginseng, Flos Lonicerae, Herba Portulacae, and Rhizoma Coptidis are used for Chinese medicine compatibility. Its mechanism of action is mainly based on the interaction between various medicinal materials in the Chinese medicine compound, so as to exert a synergistic and enhanced effect, thereby achieving a better therapeutic effect. The specific mechanism of action is as follows: Flos Lonicerae and Rhizoma Coptidis extracts have strong antibacterial activity, can inhibit a variety of bacteria, and the components such as chlorogenic acid, flavonoids in Flos Lonicerae and berberine in Rhizoma Coptidis can destroy bacterial cell walls and membrane structures, interfere with bacterial metabolism, and thus play a bactericidal effect. Drynaria, Epimedium, Panax notoginseng, and Herba Portulacae extracts also have certain antibacterial effects, and Drynaria and Epimedium both have certain anti-inflammatory effects. In the theory of traditional Chinese medicine, bone and joint diseases are often related to "wetness" and "stasis", and the anti-inflammatory effects of Epimedium and Drynaria help eliminate joint inflammation and relieve pain. When used in combination with honeysuckle and coptis extracts, they can cover a wider range of bacterial types, achieve multi-target antibacterial effects, and enhance the overall antibacterial effect. Drynaria and purslane extracts have anti-inflammatory effects and can reduce the inflammatory response caused by bacterial infection. At the same time, epimedium and ginseng extracts have immunomodulatory effects, which can enhance the body's immune function and improve antibacterial ability. This synergistic effect of anti-inflammatory and immunomodulatory effects helps to accelerate the disappearance of inflammation and enhance the body's self-defense capabilities.

[0011] The combined use of the above-mentioned Chinese herbal medicine extracts can improve the chemical stability of the compound capsules and reduce the degradation of the drug during storage. In addition, the interaction between the different components may improve the absorption and distribution of the drug in the body, increase the bioavailability, and thus enhance the antibacterial and anti-inflammatory effects.

[0012] Preferably, the preparation method of the compound extract is as follows: 20-40 parts by weight of Drynaria fortunei, 20-40 parts by weight of Epimedium, 10-30 parts by weight of Panax notoginseng, 5-15 parts by weight of Honeysuckle, 5-15 parts by weight of Portulaca oleracea, and 5-15 parts by weight of Coptis chinensis are washed, dried, crushed, and passed through a 10-30 mesh sieve to obtain a Chinese medicine powder; the Chinese medicine powder and a 40-60wt% ethanol aqueous solution are mixed at a mass ratio of 1:15-25, extracted at 70-80°C for 1-3h, and centrifuged to obtain a filtrate and a precipitate; the precipitate is placed Extraction is performed in supercritical carbon dioxide for 1-3 hours to obtain an extract; the extraction pressure is 30-40MPa, the extraction temperature is 45-60°C, the flow rate is 25-35kg / h, the extraction entrainer is 85-95%vol ethanol aqueous solution, the amount of the extraction entrainer is 15-25% of the mass of the traditional Chinese medicine powder, the separation pressure is 8-12MPa, the filtrate and the extract are combined and concentrated under reduced pressure to 7-12% of the original volume, dried, baked to a moisture content of less than 4%, crushed, and passed through a 30-60 mesh sieve to obtain a compound extract.

[0013] The capsule liquid is prepared from the following raw materials: heating purified water, adding glycerol, titanium dioxide and chitosan, stirring and mixing evenly, adding konjac gum and modified gelatin, stirring, heating and stirring again, adding disintegrant, continuing stirring, vacuuming, removing bubbles, and obtaining capsule liquid.

[0014] The disintegrant is at least one of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl alginate; preferably, the disintegrant is a mixture of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl alginate in a mass ratio of 1.2-2:1.

[0015] The disintegrant added in the present application is a compound of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl alginate, which can improve the disintegration effect of the soft capsule, mainly because cross-linked sodium carboxymethyl cellulose has good water absorption and swelling properties, and sodium carboxymethyl alginate may provide additional disintegration power due to its unique structural characteristics. The compound of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl alginate has a synergistic effect. Different disintegrants may show different stabilities at different pH values. The compound use can optimize the stability of the soft capsule in the gastrointestinal tract and ensure that good disintegration performance can be maintained throughout the digestion process.

[0016] The preparation method of the carboxymethylated sodium alginate is as follows: sodium alginate and a sodium hydroxide aqueous solution are uniformly mixed, and stirred at 35-45° C. and 300-500 rpm for 15-40 minutes; then 1-3 parts by weight of monochloroacetic acid are added, and stirred at 75-85° C. and 300-500 rpm for 2-4 hours, and centrifuged, washed, and dried to obtain the carboxymethylated sodium alginate.

[0017] Gelatin is often used in capsule shells for capsule drugs because of its soft texture, easy digestion, good stability and high safety. However, gelatin is very sensitive to humidity and easily absorbs moisture, causing the capsule shell to soften, which will affect the physical stability and shelf life of the capsule. Currently, soft capsule products on the market generally have stability problems such as disintegration and delayed dissolution during long-term storage. Delayed dissolution will lead to delayed drug release and absorption, thereby affecting the bioavailability and efficacy of the drug.

[0018] The residual aldehyde groups and imino groups on gelatin are prone to self-crosslinking and aging, which leads to the disintegration of soft capsules, prolonged dissolution time, and even the inability of soft capsules to disintegrate for a long time. Therefore, the present invention uses modified gelatin to replace traditional gelatin, which not only improves the disintegration performance of the compound soft capsule, but also enhances its stability and reliability under different environmental conditions, thereby providing patients with a more efficient and safe treatment option.

[0019] Specifically, the reaction mechanism of modified gelatin is as follows: in S1, salicylic acid and epoxysuccinic acid are used as reaction raw materials, and N-ethylmorpholine is used as a catalyst. The cyclic anhydride of epoxysuccinic acid opens the ring under the attack of the hydroxyl group of salicylic acid, reacts with the hydroxyl group (-OH) in salicylic acid to form an ester bond, and an esterification reaction occurs under heating and stirring to obtain intermediate 1; reaction of intermediate 1 with dithionyl chloride: dithionyl chloride, as a chlorinating agent, will undergo a chlorination reaction with the hydroxyl group in intermediate 1 to generate the corresponding acyl chloride, and a pure modifier is obtained through reduced pressure distillation; in S2, the modifier is added to the gelatin aqueous solution, and under heating and stirring conditions, the acyl chloride group in the modifier undergoes an acylation reaction with the amino group and hydroxyl group in the gelatin molecule to form a stable amide bond and ester bond, thereby grafting the modifier onto the gelatin molecule to obtain pure modified gelatin powder.

[0020] The modified gelatin of the present invention effectively improves the pore structure and swelling performance of gelatin by introducing modifiers such as salicylic acid and epoxysuccinic acid, which helps to improve the release efficiency of drugs from capsules, thereby improving bioavailability, and can dissolve faster in gastric juice, thereby accelerating the disintegration speed of compound soft capsules; after modification, the uniformity and stability of the gelatin are improved, and the raw material used for preparing the shell of the compound soft capsule shows better consistency during the disintegration process, ensuring that each capsule can release the drug within the expected time; in addition, the hygroscopicity of the modified gelatin is reduced, so that the compound soft capsule can still maintain good disintegration performance in a humid environment, avoiding the problem of capsule shell softening due to moisture absorption.

[0021] The preparation method of the modified gelatin is as follows: S1: salicylic acid and ethanol aqueous solution are mixed, heated and stirred, epoxysuccinic acid and N-ethylmorpholine are added, reflux reaction is carried out, and after the reaction is completed, the solvent is removed by reduced pressure distillation to obtain intermediate 1; intermediate 1 and acetone are mixed evenly, dichlorothionyl is added, heated and refluxed, the solvent is removed by reduced pressure distillation, purified and dried to obtain a modifier;

[0022] S2: Mix gelatin and water, heat and stir, filter to obtain filtrate, and adjust pH with sodium hydroxide solution; add the above-mentioned modifier, heat and stir, centrifuge, wash, and freeze-dry to obtain modified gelatin powder.

[0023] Preferably, the preparation method of the modified gelatin is as follows: S1, at 50-70°C, 18-25 parts by weight of salicylic acid and 80-150 parts by weight of a 45-60wt% ethanol aqueous solution are mixed, stirred at 400-800rpm for 20-50min, and then 12-20 parts by weight of epoxysuccinic acid and 0.5-2 parts by weight of N-ethylmorpholine are added, and the reflux reaction is continued for 3-6h. After the reaction is completed, the solvent is removed by distillation under reduced pressure to obtain an intermediate 1; 25-40 parts by weight of the intermediate 1 and 120-240 parts by weight of acetone are mixed evenly, and then 15-25 parts by weight of thionyl chloride are added, and the mixture is refluxed at 70-80°C and 200-600rpm for 2.5-5h, the solvent is removed by distillation under reduced pressure, purified and dried to obtain a modifier;

[0024] S2: Mix 20-40 parts by weight of gelatin and 150-300 parts by weight of water, stir at 50-70°C and 300-500rpm for 20-50min, filter to obtain a filtrate, and adjust the pH to 8-9 with 1-3mol / L sodium hydroxide solution; add 15-24 parts by weight of the above-mentioned modifier, stir at 40-60°C and 300-500rpm for 20-50min, adjust the pH to 3.5-4, centrifuge, wash, and freeze-dry to obtain modified gelatin powder.

[0025] The preparation method of the compound soft capsule comprises the following steps:

[0026] A1: Heat 10-30 parts by weight of purified water to 37-45° C., add 10-20 parts by weight of glycerol, 1-4 parts by weight of titanium dioxide, and 3-5 parts by weight of chitosan, stir and mix evenly, add 15-25 parts by weight of konjac gum and 30-50 parts by weight of modified gelatin, stir at 300-500 rpm for 1-3 h, then stir at 75-90° C. and 300-500 rpm for 1-3 h, add disintegrant, continue stirring for 0.5-2 h, evacuate, and keep for 20-50 min to remove bubbles to obtain capsule liquid;

[0027] A2: The capsule contents and capsule liquid are placed on a pill press and pressed into pills. The pressed pills are sent to a rolling cage for preliminary drying and shaping. The pellets are treated at 8-14 r / min and a relative humidity of 20-40% for 1-3 h to obtain crude capsules. The crude capsules are washed with 95% ethanol and dried. The mass of the capsule contents in each capsule shell is 0.6-1 g. The crude capsules are bottled to obtain compound soft capsules.

[0028] Beneficial effects of the present invention: The present invention provides a compound soft capsule and a preparation method thereof. The present invention constructs a compound soft capsule by adjusting the raw material ratio and optimizing the process conditions. The capsule product has excellent storage stability, antibacterial property, good disintegration performance, and high bioavailability. The reaction of succinic acid derivatives with amino groups in the molecular structure of gelatin can increase its amino blocking rate, reduce the free amino group content, and increase its antibacterial property, thereby significantly reducing the cross-linking phenomenon of gelatin, thereby improving the dissolution, storage stability and bioavailability of the capsule product.

[0029] Instruction Manual

[0030] Figure 1 Prepared by the present invention Product image of compound soft capsules;

[0031] Figure 2 This is the test report of the soft capsule shell prepared in Example 3. DETAILED DESCRIPTION

[0032] The above content of the present invention is further described in detail below in conjunction with specific implementation modes, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following embodiments.

[0033] Introduction of some raw materials in this application:

[0034] Drynaria fortunei (Kunze) J.Sm.: [Nature and flavor and meridians] Bitter, warm. Enters the liver and kidney meridians. [Function] It has the effects of nourishing joints, strengthening bones, promoting blood circulation and relieving pain, relieving inflammation and itching, improving blood circulation, anti-oxidation and anti-inflammatory.

[0035] Epimedium brevicomu Maxim.: [Nature and flavor and meridians] Spicy, sweet, warm. Enters the liver and kidney meridians. [Function] Has certain bactericidal and anti-inflammatory effects, especially for certain external inflammations.

[0036] Disporum cantoniense (Lour.) Merr.: [Nature and flavor and meridians] Pungent; slightly bitter; warm in nature, lung; liver meridians. [Function] Has obvious anti-inflammatory and antioxidant effects.

[0037] Honeysuckle (Lonicerajaponica Thunb.): [Nature and flavor and meridians] Sweet, cold. Enters the lung, heart and stomach meridians. [Function] It has the effects of clearing away heat and detoxifying, detoxifying and antibacterial, and mainly has the effects of inhibiting and killing Staphylococcus aureus, hemolytic streptococci, mutans streptococci, Escherichia coli, etc.

[0038] Purslane (Portulaca oleracea L.): [Nature and flavor and meridians] Sour, cold. Enters the liver and large intestine meridians. [Function] It has the effects of eliminating heat, dispersing blood and inhibiting bacteria, and mainly has the effects of inhibiting and killing various bacteria.

[0039] Coptis chinensis Franch.: [Nature and flavor and meridians] Bitter, cold. Enters the heart, spleen, stomach, liver, gallbladder, and large intestine meridians. [Function] It has the effects of clearing away heat and detoxification, antibacterial and anti-inflammatory, and has a broad-spectrum antibacterial effect.

[0040] Chitosan was purchased from Shandong Siyang Biotechnology Co., Ltd., product number: 03121417, food grade.

[0041] Konjac gum was purchased from Nanjing Dulai Biotechnology Co., Ltd. with a viscosity of ≥15000 mPa·s.

[0042] Gelatin was purchased from Hebei Runbu Biotechnology Co., Ltd., item number: 454676987.

[0043] Cross-linked sodium carboxymethyl cellulose was purchased from Leshengyuan Biotechnology (Nanjing) Co., Ltd., with an apparent viscosity of 5000 mPa·s.

[0044] Example 1

[0045] A compound soft capsule comprises capsule contents and a capsule shell made of capsule liquid, wherein the capsule contents are composed of the following raw materials in parts by weight: 10 parts by weight of calcium carbonate and 15 parts by weight of a compound extract.

[0046] The preparation method of the compound extract is as follows: 30 parts by weight of Drynaria fortunei, 30 parts by weight of Epimedium, 20 parts by weight of Glehnia littoralis, 10 parts by weight of Honeysuckle, 10 parts by weight of Portulaca oleracea and 10 parts by weight of Coptis chinensis are washed, dried, crushed and passed through a 20-mesh sieve to obtain Chinese medicine powder; the Chinese medicine powder and a 50wt% ethanol aqueous solution are mixed at a mass ratio of 1:20, extracted at 75°C for 2h, centrifuged to obtain a filtrate and a precipitate; the precipitate is placed in supercritical carbon dioxide for extraction for 2h to obtain an extract; the extraction pressure is 35MPa, the extraction temperature is 50°C, the flow rate is 30kg / h, the extraction entrainer is 90%vol ethanol aqueous solution, the amount of the extraction entrainer is 20% of the mass of the Chinese medicine powder, the separation pressure is 10MPa, the filtrate and the extract are combined, reduced pressure concentrated to 10% of the original volume, dried, baked to less than 4% of moisture, crushed, passed through a 40-mesh sieve to obtain the compound extract.

[0047] The preparation method of the compound soft capsule is as follows:

[0048] A1: 20 parts by weight of purified water were heated to 40° C., 15 parts by weight of glycerol, 3 parts by weight of titanium dioxide and 4 parts by weight of chitosan were added and stirred to mix well, 20 parts by weight of konjac gum and 40 parts by weight of modified gelatin were added, and the mixture was stirred at 400 rpm for 2 h, and then stirred at 80° C. and 400 rpm for 1.5 h, a disintegrant was added, and the mixture was stirred for 1 h, and vacuum was applied for 30 min to remove bubbles to obtain a capsule solution;

[0049] A2: The capsule contents and capsule liquid are placed on a pill press and pressed into pills. The pressed pills are sent to a rolling cage for preliminary drying and shaping. The pellets are treated at 10 r / min and a relative humidity of 30% for 2 h to obtain crude capsules. The crude capsules are washed with 95% ethanol and dried. The mass of the capsule contents in each capsule shell is 0.8 g. The crude capsules are bottled to obtain compound soft capsules.

[0050] The disintegrant is a mixture of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl alginate in a mass ratio of 3:2.

[0051] The preparation method of the carboxymethylated sodium alginate is as follows: 10 parts by weight of sodium alginate and 10 parts by weight of a 2 mol / L sodium hydroxide aqueous solution are uniformly mixed, and stirred at 40° C. and 400 rpm for 20 minutes; then 2 parts by weight of monochloroacetic acid are added, and stirred at 80° C. and 400 rpm for 2.5 hours, centrifuged, washed, and dried to obtain the carboxymethylated sodium alginate.

[0052] The preparation method of the modified gelatin is as follows:

[0053] S1: 20 parts by weight of salicylic acid and 100 parts by weight of a 50 wt% ethanol aqueous solution were mixed at 60°C, stirred at 600 rpm for 30 min, and then 15 parts by weight of epoxysuccinic acid and 1 part by weight of N-ethylmorpholine were added, and the reaction was continued under reflux for 4 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain an intermediate 1; 30 parts by weight of the intermediate 1 and 150 parts by weight of acetone were mixed uniformly, and then 20 parts by weight of thionyl chloride were added, and the reaction was refluxed at 75°C and 400 rpm for 3.5 h, and the solvent was removed by distillation under reduced pressure, purified and dried to obtain a modifier;

[0054] S2: 30 parts by weight of gelatin and 200 parts by weight of water are mixed, stirred at 60°C and 400 rpm for 30 min, filtered to obtain a filtrate, and the pH value is adjusted to 8.5 with a 2 mol / L sodium hydroxide solution; 18 parts by weight of the above-mentioned modifier is added, stirred at 50°C and 400 rpm for 30 min, the pH value is adjusted to 3.7, centrifuged, washed, and freeze-dried to obtain modified gelatin powder.

[0055] Example 2

[0056] A compound soft capsule comprises capsule contents and a capsule shell made of capsule liquid, wherein the capsule contents are composed of the following raw materials in parts by weight: 5 parts by weight of calcium carbonate and 10 parts by weight of a compound extract.

[0057] The preparation method of the compound extract is as follows: 20 parts by weight of Drynaria fortunei, 20 parts by weight of Epimedium, 10 parts by weight of Glehnia littoralis, 5 parts by weight of Honeysuckle, 5 parts by weight of Portulaca oleracea and 5 parts by weight of Coptis chinensis are washed, dried, crushed and passed through a 10-mesh sieve to obtain Chinese medicine powder; the Chinese medicine powder and a 40wt% ethanol aqueous solution are mixed at a mass ratio of 1:15, extracted at 70°C for 1h, centrifuged to obtain a filtrate and a precipitate; the precipitate is placed in supercritical carbon dioxide for extraction for 1h to obtain an extract; the extraction pressure is 30MPa, the extraction temperature is 45°C, the flow rate is 25kg / h, the extraction entrainer is 85%vol ethanol aqueous solution, the amount of the extraction entrainer is 15% of the mass of the Chinese medicine powder, the separation pressure is 8MPa, the filtrate and the extract are combined and concentrated under reduced pressure to 7% of the original volume, dried, baked to a moisture content of less than 4%, crushed, passed through a 30-mesh sieve to obtain the compound extract.

[0058] The preparation method of the compound soft capsule is as follows:

[0059] A1: 10 parts by weight of purified water were heated to 37° C., 10 parts by weight of glycerol, 1 part by weight of titanium dioxide and 3 parts by weight of chitosan were added and stirred to mix well, 15 parts by weight of konjac gum and 30 parts by weight of modified gelatin were added, and the mixture was stirred at 300 rpm for 1 h, and then stirred at 75° C. and 300 rpm for 1 h, a disintegrant was added, and the mixture was stirred for 0.5 h, and vacuum was applied for 20 min to remove bubbles to obtain a capsule solution;

[0060] A2: The capsule contents and capsule liquid are placed on a pill press and pressed into pills. The pressed pills are sent to a rolling cage for preliminary drying and shaping. The pellets are treated at 8 r / min and a relative humidity of 20% for 1 h to obtain crude capsules. The crude capsules are washed with 95% ethanol and dried. The mass of the capsule contents in each capsule shell is 0.6 g. The crude capsules are bottled to obtain compound soft capsules.

[0061] The disintegrant is a mixture of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl alginate in a mass ratio of 1.2:1.

[0062] The preparation method of the carboxymethylated sodium alginate is as follows: 8 parts by weight of sodium alginate and 7 parts by weight of a 1 mol / L sodium hydroxide aqueous solution are uniformly mixed, and stirred at 35° C. and 300 rpm for 15 minutes; then 1 part by weight of monochloroacetic acid is added, and stirred at 75° C. and 300 rpm for 2 hours, centrifuged, washed, and dried to obtain the carboxymethylated sodium alginate.

[0063] The preparation method of the modified gelatin is as follows:

[0064] S1: 18 parts by weight of salicylic acid and 80 parts by weight of a 45 wt% ethanol aqueous solution were mixed at 50°C, stirred at 400 rpm for 20 min, and then 12 parts by weight of epoxysuccinic acid and 0.5 parts of N-ethylmorpholine were added, and the reaction was continued under reflux for 3 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain an intermediate 1; 25 parts by weight of the intermediate 1 and 120 parts by weight of acetone were mixed uniformly, and then 15 parts by weight of thionyl chloride were added, and the reaction was refluxed at 70°C and 200 rpm for 2.5 h, and the solvent was removed by distillation under reduced pressure, purified and dried to obtain a modifier;

[0065] S2: Mix 20 parts by weight of gelatin and 150 parts by weight of water, stir at 50°C and 300 rpm for 20 min, filter to obtain the filtrate, and adjust the pH to 8 with 1 mol / L sodium hydroxide solution; add 15 parts by weight of the above-mentioned modifier, stir at 40°C and 300 rpm for 20 min, adjust the pH to 3.5, centrifuge, wash, and freeze-dry to obtain modified gelatin powder.

[0066] Example 3

[0067] A compound soft capsule comprises capsule contents and a capsule shell made of capsule liquid, wherein the capsule contents are composed of the following raw materials in parts by weight: 12 parts by weight of calcium carbonate and 20 parts by weight of a compound extract.

[0068] The preparation method of the compound extract is as follows: 40 parts by weight of Drynaria fortunei, 40 parts by weight of Epimedium, 30 parts by weight of Glehnia littoralis, 15 parts by weight of Honeysuckle, 15 parts by weight of Portulaca oleracea and 15 parts by weight of Coptis chinensis are washed, dried, crushed and passed through a 30-mesh sieve to obtain Chinese medicine powder; the Chinese medicine powder and a 60wt% ethanol aqueous solution are mixed at a mass ratio of 1:25, extracted at 80°C for 3h, centrifuged to obtain a filtrate and a precipitate; the precipitate is placed in supercritical carbon dioxide for extraction for 3h to obtain an extract; the extraction pressure is 40MPa, the extraction temperature is 60°C, the flow rate is 35kg / h, the extraction entrainer is 95%vol ethanol aqueous solution, the amount of the extraction entrainer is 25% of the mass of the Chinese medicine powder, the separation pressure is 12MPa, the filtrate and the extract are combined and concentrated under reduced pressure to 12% of the original volume, dried, baked to a moisture content of less than 4%, crushed and passed through a 60-mesh sieve to obtain the compound extract.

[0069] The preparation method of the compound soft capsule is as follows:

[0070] A1: 30 parts by weight of purified water were heated to 45° C., 20 parts by weight of glycerol, 4 parts by weight of titanium dioxide and 5 parts by weight of chitosan were added and stirred to mix well, 25 parts by weight of konjac gum and 50 parts by weight of modified gelatin were added, and the mixture was stirred at 500 rpm for 3 h, and then stirred at 90° C. and 500 rpm for 3 h, a disintegrant was added, and the mixture was stirred for 2 h, and vacuum was applied for 50 min to remove bubbles to obtain a capsule solution;

[0071] A2: The capsule contents and capsule liquid are placed on a pill press and pressed into pills. The pressed pills are sent to a rolling cage for preliminary drying and shaping. The pellets are treated at 14 r / min and a relative humidity of 40% for 3 h to obtain crude capsules. The crude capsules are washed with 95% ethanol and dried. The mass of the capsule contents in each capsule shell is 1 g. The crude capsules are bottled to obtain compound soft capsules.

[0072] The disintegrant is a mixture of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl alginate in a mass ratio of 2:1.

[0073] The preparation method of the carboxymethylated sodium alginate is as follows: 12 parts by weight of sodium alginate and 14 parts by weight of a 3 mol / L sodium hydroxide aqueous solution are uniformly mixed, and stirred at 45° C. and 500 rpm for 40 minutes; then 3 parts by weight of monochloroacetic acid are added, and stirred at 85° C. and 500 rpm for 4 hours, and centrifuged, washed, and dried to obtain the carboxymethylated sodium alginate.

[0074] The preparation method of the modified gelatin is as follows:

[0075] S1: 25 parts by weight of salicylic acid and 150 parts by weight of 60 wt% ethanol aqueous solution were mixed at 70°C, stirred at 800 rpm for 50 min, and then 20 parts by weight of epoxysuccinic acid and 2 parts by weight of N-ethylmorpholine were added, and the reaction was continued under reflux for 6 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain intermediate 1; 40 parts by weight of intermediate 1 and 240 parts by weight of acetone were mixed evenly, and then 25 parts by weight of dichlorothionyl were added, and the reaction was refluxed at 80°C and 600 rpm for 5 h, and the solvent was removed by distillation under reduced pressure, purified and dried to obtain a modifier;

[0076] S2: 40 parts by weight of gelatin and 300 parts by weight of water are mixed, stirred at 70°C and 500 rpm for 50 min, filtered to obtain a filtrate, and the pH value is adjusted to 9 with a 3 mol / L sodium hydroxide solution; 24 parts by weight of the above-mentioned modifier are added, stirred at 60°C and 500 rpm for 50 min, the pH value is adjusted to 4, centrifuged, washed, and freeze-dried to obtain modified gelatin powder.

[0077] Comparative Example 1

[0078] A compound soft capsule comprises capsule contents and a capsule shell made of capsule liquid, wherein the capsule contents are composed of the following raw materials in parts by weight: 10 parts by weight of calcium carbonate and 15 parts by weight of a compound extract.

[0079] The preparation method of the compound extract is as follows: 30 parts by weight of Drynaria fortunei, 30 parts by weight of Epimedium, 20 parts by weight of Glehnia littoralis, 10 parts by weight of Honeysuckle, 10 parts by weight of Portulaca oleracea and 10 parts by weight of Coptis chinensis are washed, dried, crushed and passed through a 20-mesh sieve to obtain Chinese medicine powder; the Chinese medicine powder and a 50wt% ethanol aqueous solution are mixed at a mass ratio of 1:20, extracted at 75°C for 2h, centrifuged to obtain a filtrate and a precipitate; the precipitate is placed in supercritical carbon dioxide for extraction for 2h to obtain an extract; the extraction pressure is 35MPa, the extraction temperature is 50°C, the flow rate is 30kg / h, the extraction entrainer is 90%vol ethanol aqueous solution, the amount of the extraction entrainer is 20% of the mass of the Chinese medicine powder, the separation pressure is 10MPa, the filtrate and the extract are combined, reduced pressure concentrated to 10% of the original volume, dried, baked to less than 4% of moisture, crushed, passed through a 40-mesh sieve to obtain the compound extract.

[0080] The preparation method of the compound soft capsule is as follows:

[0081] A1: 20 parts by weight of purified water were heated to 40° C., 15 parts by weight of glycerol, 3 parts by weight of titanium dioxide and 4 parts by weight of chitosan were added and stirred to mix well, 20 parts by weight of konjac gum and 40 parts by weight of gelatin were added, and the mixture was stirred at 400 rpm for 2 h, and then stirred at 80° C. and 400 rpm for 1.5 h, a disintegrant was added, and the mixture was stirred for 1 h, and vacuum was applied for 30 min to remove bubbles to obtain a capsule solution;

[0082] A2: The capsule contents and capsule liquid are placed on a pill press and pressed into pills. The pressed pills are sent to a rolling cage for preliminary drying and shaping. The pellets are treated at 10 r / min and a relative humidity of 30% for 2 h to obtain crude capsules. The crude capsules are washed with 95% ethanol and dried. The mass of the capsule contents in each capsule shell is 0.8 g. The crude capsules are bottled to obtain compound soft capsules.

[0083] The disintegrant is a mixture of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl alginate in a mass ratio of 3:2.

[0084] The preparation method of the carboxymethylated sodium alginate is as follows: 10 parts by weight of sodium alginate and 10 parts by weight of a 2 mol / L sodium hydroxide aqueous solution are uniformly mixed, and stirred at 40° C. and 400 rpm for 20 minutes; then 2 parts by weight of monochloroacetic acid are added, and stirred at 80° C. and 400 rpm for 2.5 hours, centrifuged, washed, and dried to obtain the carboxymethylated sodium alginate.

[0085] Comparative Example 2

[0086] A compound soft capsule comprises capsule contents and a capsule shell made of capsule liquid, wherein the capsule contents are composed of the following raw materials in parts by weight: 10 parts by weight of calcium carbonate and 15 parts by weight of a compound extract.

[0087] The preparation method of the compound extract is as follows: 30 parts by weight of Drynaria fortunei, 30 parts by weight of Epimedium, 20 parts by weight of Glehnia littoralis, 10 parts by weight of Honeysuckle, 10 parts by weight of Portulaca oleracea and 10 parts by weight of Coptis chinensis are washed, dried, crushed and passed through a 20-mesh sieve to obtain Chinese medicine powder; the Chinese medicine powder and a 50wt% ethanol aqueous solution are mixed at a mass ratio of 1:20, extracted at 75°C for 2h, centrifuged to obtain a filtrate and a precipitate; the precipitate is placed in supercritical carbon dioxide for extraction for 2h to obtain an extract; the extraction pressure is 35MPa, the extraction temperature is 50°C, the flow rate is 30kg / h, the extraction entrainer is 90%vol ethanol aqueous solution, the amount of the extraction entrainer is 20% of the mass of the Chinese medicine powder, the separation pressure is 10MPa, the filtrate and the extract are combined, reduced pressure concentrated to 10% of the original volume, dried, baked to less than 4% of moisture, crushed, passed through a 40-mesh sieve to obtain the compound extract.

[0088] The preparation method of the compound soft capsule is as follows:

[0089] A1: 20 parts by weight of purified water were heated to 40° C., 15 parts by weight of glycerol, 3 parts by weight of titanium dioxide and 4 parts by weight of chitosan were added and stirred to mix well, 20 parts by weight of konjac gum and 40 parts by weight of modified gelatin were added, and the mixture was stirred at 400 rpm for 2 h, and then stirred at 80° C. and 400 rpm for 1.5 h, a disintegrant was added, and the mixture was stirred for 1 h, and vacuum was applied for 30 min to remove bubbles to obtain a capsule solution;

[0090] A2: The capsule contents and capsule liquid are placed on a pill press and pressed into pills. The pressed pills are sent to a rolling cage for preliminary drying and shaping. The pellets are treated at 10 r / min and a relative humidity of 30% for 2 h to obtain crude capsules. The crude capsules are washed with 95% ethanol and dried. The mass of the capsule contents in each capsule shell is 0.8 g. The crude capsules are bottled to obtain compound soft capsules.

[0091] The disintegrant is cross-linked carboxymethyl cellulose sodium.

[0092] The preparation method of the modified gelatin is as follows:

[0093] S1: 20 parts by weight of salicylic acid and 100 parts by weight of a 50 wt% ethanol aqueous solution were mixed at 60°C, stirred at 600 rpm for 30 min, and then 15 parts by weight of epoxysuccinic acid and 1 part by weight of N-ethylmorpholine were added, and the reaction was continued under reflux for 4 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain an intermediate 1; 30 parts by weight of the intermediate 1 and 150 parts by weight of acetone were mixed uniformly, and then 20 parts by weight of thionyl chloride were added, and the reaction was refluxed at 75°C and 400 rpm for 3.5 h, and the solvent was removed by distillation under reduced pressure, purified and dried to obtain a modifier;

[0094] S2: 30 parts by weight of gelatin and 200 parts by weight of water are mixed, stirred at 60°C and 400 rpm for 30 min, filtered to obtain a filtrate, and the pH value is adjusted to 8.5 with a 2 mol / L sodium hydroxide solution; 18 parts by weight of the above-mentioned modifier is added, stirred at 50°C and 400 rpm for 30 min, the pH value is adjusted to 3.7, centrifuged, washed, and freeze-dried to obtain modified gelatin powder.

[0095] Comparative Example 3

[0096] A compound soft capsule comprises capsule contents and a capsule shell made of capsule liquid, wherein the capsule contents are composed of the following raw materials in parts by weight: 10 parts by weight of calcium carbonate and 15 parts by weight of a compound extract.

[0097] The preparation method of the compound extract is as follows: 30 parts by weight of Drynaria fortunei, 30 parts by weight of Epimedium, 20 parts by weight of Glehnia littoralis, 10 parts by weight of Honeysuckle, 10 parts by weight of Portulaca oleracea and 10 parts by weight of Coptis chinensis are washed, dried, crushed and passed through a 20-mesh sieve to obtain Chinese medicine powder; the Chinese medicine powder and a 50wt% ethanol aqueous solution are mixed at a mass ratio of 1:20, extracted at 75°C for 2h, centrifuged to obtain a filtrate and a precipitate; the precipitate is placed in supercritical carbon dioxide for extraction for 2h to obtain an extract; the extraction pressure is 35MPa, the extraction temperature is 50°C, the flow rate is 30kg / h, the extraction entrainer is 90%vol ethanol aqueous solution, the amount of the extraction entrainer is 20% of the mass of the Chinese medicine powder, the separation pressure is 10MPa, the filtrate and the extract are combined, reduced pressure concentrated to 10% of the original volume, dried, baked to less than 4% of moisture, crushed, passed through a 40-mesh sieve to obtain the compound extract.

[0098] The preparation method of the compound soft capsule is as follows:

[0099] A1: 20 parts by weight of purified water were heated to 40° C., 15 parts by weight of glycerol, 3 parts by weight of titanium dioxide and 4 parts by weight of chitosan were added and stirred to mix well, 20 parts by weight of konjac gum and 40 parts by weight of modified gelatin were added, and the mixture was stirred at 400 rpm for 2 h, and then stirred at 80° C. and 400 rpm for 1.5 h, a disintegrant was added, and the mixture was stirred for 1 h, and vacuum was applied for 30 min to remove bubbles to obtain a capsule solution;

[0100] A2: The capsule contents and capsule liquid are placed on a pill press and pressed into pills. The pressed pills are sent to a rolling cage for preliminary drying and shaping. The pellets are treated at 10 r / min and a relative humidity of 30% for 2 h to obtain crude capsules. The crude capsules are washed with 95% ethanol and dried. The mass of the capsule contents in each capsule shell is 0.8 g. The crude capsules are bottled to obtain compound soft capsules.

[0101] The disintegrant is carboxymethylated sodium alginate.

[0102] The preparation method of the carboxymethylated sodium alginate is as follows: 10 parts by weight of sodium alginate and 10 parts by weight of a 2 mol / L sodium hydroxide aqueous solution are uniformly mixed, and stirred at 40° C. and 400 rpm for 20 minutes; then 2 parts by weight of monochloroacetic acid are added, and stirred at 80° C. and 400 rpm for 2.5 hours, centrifuged, washed, and dried to obtain the carboxymethylated sodium alginate.

[0103] The preparation method of the modified gelatin is as follows:

[0104] S1: 20 parts by weight of salicylic acid and 100 parts by weight of a 50 wt% ethanol aqueous solution were mixed at 60°C, stirred at 600 rpm for 30 min, and then 15 parts by weight of epoxysuccinic acid and 1 part by weight of N-ethylmorpholine were added, and the reaction was continued under reflux for 4 h. After the reaction was completed, the solvent was removed by distillation under reduced pressure to obtain an intermediate 1; 30 parts by weight of the intermediate 1 and 150 parts by weight of acetone were mixed uniformly, and then 20 parts by weight of thionyl chloride were added, and the reaction was refluxed at 75°C and 400 rpm for 3.5 h, and the solvent was removed by distillation under reduced pressure, purified and dried to obtain a modifier;

[0105] S2: 30 parts by weight of gelatin and 200 parts by weight of water are mixed, stirred at 60°C and 400 rpm for 30 min, filtered to obtain a filtrate, and the pH value is adjusted to 8.5 with a 2 mol / L sodium hydroxide solution; 18 parts by weight of the above-mentioned modifier is added, stirred at 50°C and 400 rpm for 30 min, the pH value is adjusted to 3.7, centrifuged, washed, and freeze-dried to obtain modified gelatin powder.

[0106] Test Example 1

[0107] Disintegration performance test of capsule shell: The disintegration time was tested according to the method in the appendix of the 2020 version of the "Chinese Pharmacopoeia". The compound soft capsules prepared in Examples 1-3 and Comparative Examples 1-3 were subjected to initial disintegration time testing in an artificial gastric fluid environment. The compound soft capsule shells were then placed in an intelligent disintegrator for accelerated aging at a temperature of 40°C and a relative humidity of 75%. Some samples were taken out at 30d and 120d for disintegration time testing and stability testing, respectively. The results are shown in Tables 1 and 2.

[0108] Table 1 Determination results of capsule shell disintegration time

[0109]

[0110] Table 2 Test results of capsule shell stability

[0111]

[0112]

[0113] Test Example 2

[0114] Antibacterial effect of the compound soft capsule: The minimum inhibitory concentration (MIC) of the compound soft capsule obtained in Example 1 and Comparative Examples 1-3 was determined by referring to the in vitro antibacterial effect test method in "Antibacterial and Anti-inflammatory Experimental Study on Antibacterial and Anti-inflammatory Effects" published by Liang Zhimin et al. The bacterial species used were Staphylococcus aureus CMCC26057, Escherichia coli CMCC (B) 44102, and Salmonella CMCC (B) 50094. Water was used as the control group. The dosage used was 6.0 g / kg. The average test group was averaged in each group, and the results are shown in Table 3.

[0115] Table 3 Antibacterial effect of compound soft capsules

[0116]

[0117] Test Example 3

[0118] Safety test: SPF female SD rats, 8 weeks old, weighing 180-200g, provided and raised by the Animal Experiment Center of Wenzhou Medical College, the prepared compound soft capsules were used for safety test of taking by mice. The general situation and estrous cycle change before the experiment showed that the rats in each group developed normally, moved flexibly, had thick and shiny fur, were sensitive to reactions, were in an attack-defense state to external stimuli, and had normal fecal pellets. The compound soft capsules of the present invention did not show any toxic side effects after long-term use in mice, and there was no abnormal reaction after stopping the drug, so it was safe to use.

[0119] As can be seen from the above results, the compound soft capsule prepared by the present invention has good disintegration performance, stability and antibacterial and anti-inflammatory effects, and is safe to use. Comparison of Example 1 and Comparative Example 1 shows that the modified gelatin of the present invention effectively improves the pore structure and swelling performance of gelatin by introducing modifiers such as salicylic acid and epoxysuccinic acid, helps to improve the release efficiency of the drug from the capsule, thereby improving the bioavailability, and can be dissolved faster in gastric juice, thereby accelerating the disintegration rate of the compound soft capsule; the uniformity and stability of the gelatin after modification are improved, and the raw material used for preparing the compound soft capsule shell shows better consistency during the disintegration process, ensuring that each capsule can release the drug within the expected time; in addition, the hygroscopicity of the modified gelatin is reduced, so that the compound soft capsule can still maintain good disintegration performance in a humid environment, avoiding the problem of capsule shell softening caused by moisture absorption.

[0120] It can be seen from Example 1 and Comparative Examples 2-3 that the addition of a disintegrant that is a compound of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl alginate can improve the disintegration effect of the soft capsule, mainly because cross-linked sodium carboxymethyl cellulose has good water absorption and swelling properties, and sodium carboxymethyl alginate may provide additional disintegration power due to its unique structural characteristics. The compound of cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl alginate has a synergistic effect. Different disintegrants may show different stabilities at different pH values. The compound use can optimize the stability of the soft capsule in the gastrointestinal tract and ensure that good disintegration performance can be maintained throughout the digestion process.

Claims

1. A compound soft capsule, comprising a capsule shell made of capsule contents and capsule liquid, characterized in that: The capsule content is composed of the following raw materials in parts by weight: 5-12 parts by weight of calcium carbonate and 10-20 parts by weight of a compound extract; the preparation method of the compound extract is as follows: Rhizoma Drynariae, Herba Epimedii, Herba Glehniae, Flos Lonicerae, Herba Portulacae and Rhizoma Coptidis are washed, dried and crushed to obtain Chinese medicine powder; the Chinese medicine powder is mixed with an ethanol aqueous solution, heated for extraction, and centrifuged to obtain a filtrate and a precipitate; the precipitate is subjected to supercritical carbon dioxide extraction to obtain an extract; the filtrate and the extract are combined, reduced pressure concentration is performed, and drying is performed to obtain the compound extract.

2. The compound soft capsule according to claim 1, characterized in that The extraction pressure of the supercritical carbon dioxide is 30-40MPa, the extraction temperature is 45-60°C, the flow rate is 25-35kg / h, the extraction entrainer is 85-95%vol ethanol aqueous solution, the amount of the extraction entrainer is 15-25% of the mass of the traditional Chinese medicine powder, and the separation pressure is 8-12MPa.

3. The compound soft capsule according to claim 1, characterized in that The capsule liquid is prepared from the following raw materials: heating purified water, adding glycerol, titanium dioxide and chitosan, stirring and mixing evenly, adding konjac gum and modified gelatin, stirring, heating and stirring again, adding disintegrant, continuing stirring, vacuuming, removing bubbles, and obtaining capsule liquid.

4. The compound soft capsule according to claim 3, characterized in that The disintegrant is at least one of cross-linked sodium carboxymethyl cellulose and carboxymethylated sodium alginate.

5. The compound soft capsule according to claim 4, characterized in that: The preparation method of the carboxymethylated sodium alginate is as follows: sodium alginate and a sodium hydroxide aqueous solution are uniformly mixed, and stirred at 35-45° C. and 300-500 rpm for 15-40 minutes; then 1-3 parts by weight of monochloroacetic acid are added, and stirred at 75-85° C. and 300-500 rpm for 2-4 hours, and centrifuged, washed, and dried to obtain the carboxymethylated sodium alginate.

6. The compound soft capsule according to claim 3, characterized in that: The preparation method of the modified gelatin is as follows: S1: salicylic acid and ethanol aqueous solution are mixed, heated and stirred, epoxysuccinic acid and N-ethylmorpholine are added, reflux reaction is carried out, and after the reaction is completed, the solvent is removed by reduced pressure distillation to obtain intermediate 1; intermediate 1 and acetone are mixed evenly, dichlorothionyl is added, heated and refluxed, the solvent is removed by reduced pressure distillation, purified and dried to obtain a modifier; S2: Mix gelatin and water, heat and stir, filter to obtain a filtrate, and adjust the pH with a sodium hydroxide solution; add the above-mentioned modifier, heat and stir, centrifuge, wash, and freeze-dry to obtain modified gelatin powder.

7. The compound soft capsule according to claim 6, characterized in that: The preparation method of the modified gelatin is as follows: S1: at 50-70° C., 18-25 parts by weight of salicylic acid and 80-150 parts by weight of a 45-60wt% ethanol aqueous solution are mixed, stirred at 400-800 rpm for 20-50 min, and then 12-20 parts by weight of epoxysuccinic acid and 0.5-2 parts by weight of N-ethylmorpholine are added, and the reflux reaction is continued for 3-6 hours. After the reaction is completed, the solvent is removed by reduced pressure distillation to obtain an intermediate 1; 25-40 parts by weight of the intermediate 1 and 120-240 parts by weight of acetone are mixed evenly, and then 15-25 parts by weight of thionyl chloride are added, and the mixture is refluxed at 70-80° C. and 200-600 rpm for 2.5-5 hours, the solvent is removed by reduced pressure distillation, and the mixture is purified and dried to obtain a modifier; S2: Mix 20-40 parts by weight of gelatin and 150-300 parts by weight of water, stir at 50-70°C and 300-500rpm for 20-50min, filter to obtain a filtrate, and adjust the pH to 8-9 with 1-3mol / L sodium hydroxide solution; add 15-24 parts by weight of the above-mentioned modifier, stir at 40-60°C and 300-500rpm for 20-50min, adjust the pH to 3.5-4, centrifuge, wash, and freeze-dry to obtain modified gelatin powder.

8. The method for preparing the composite soft capsule according to any one of claims 1 to 7, characterized in that: The steps include: A1: Heat 10-30 parts by weight of purified water to 37-45° C., add 10-20 parts by weight of glycerol, 1-4 parts by weight of titanium dioxide, and 3-5 parts by weight of chitosan, stir and mix evenly, add 15-25 parts by weight of konjac gum and 30-50 parts by weight of modified gelatin, stir at 300-500 rpm for 1-3 h, then stir at 75-90° C. and 300-500 rpm for 1-3 h, add disintegrant, continue stirring for 0.5-2 h, evacuate, and keep for 20-50 min to remove bubbles to obtain capsule liquid; A2: The capsule contents and capsule liquid are placed on a pill press and pressed into pills. The pressed pills are sent to a rolling cage for preliminary drying and shaping. The pellets are treated at 8-14 r / min and a relative humidity of 20-40% for 1-3 h to obtain crude capsules. The crude capsules are washed with 95% ethanol and dried. The mass of the capsule contents in each capsule shell is 0.6-1 g. The crude capsules are bottled to obtain compound soft capsules.

Images