A preparation process of hypromellose hollow hard capsules

Abstract

The invention discloses a preparation process of a hollow hard capsule of hypromellose, and relates to the technical field of the hollow hard capsule of hypromellose. The preparation process comprises the following steps: adding mixed hydroxypropyl starch, potassium citrate and modified chitosan into ultrapure water, heating and stirring to dissolve, and obtaining a glue solution; sequentially adding hydroxypropyl methylcellulose, carrageenan, succinic acid and a plasticizer into the glue solution, stirring evenly, adding gallic acid, stirring at room temperature for 10-15 minutes, adding alkyl dialdehyde, stirring at room temperature in the dark for 2 hours, removing bubbles, keeping warm for 2-4 hours, dipping in the glue to prepare capsules, and obtaining the hollow hard capsule of hypromellose.

Description

Technical Field

[0001] The invention relates to the technical field of hollow hard capsules of hypromellose, in particular to a preparation process of hollow hard capsules of hypromellose. Background Art

[0002] With the rapid development of the pharmaceutical industry, hollow hard capsules are a common packaging form for pharmaceutical preparations. Their quality and performance play an important role in the stability and efficacy of drugs. In the prior art, hollow hard capsules are mostly made of gelatin or other traditional materials. Although they have good biocompatibility and solubility, they still have certain deficiencies in antibacterial properties and oxidative stability. Especially when exposed to air, the surface of hollow hard capsules is susceptible to oxidation, which in turn breeds microorganisms such as bacteria and mold, affecting the safety and effectiveness of drugs. In addition, due to the lack of effective antibacterial function of traditional hard capsule materials, the storage and transportation of capsules are often restricted by environmental conditions, which can easily cause the capsules to become damp, deteriorate or contaminate, increasing the risk of adverse reactions to drugs.

[0003] Therefore, how to improve the antibacterial and antioxidant properties of hollow hard capsules and enhance their stability during storage and transportation has become an urgent problem to be solved. Developing a hollow hard capsule material with excellent antibacterial and antioxidant properties is of great practical significance. Summary of the Invention

[0004] The object of the present invention is to provide a preparation process of hypromellose hollow hard capsules to solve the problems raised in the prior art.

[0005] To achieve the above object, the present invention provides the following technical solutions:

[0006] A preparation process for hollow hard capsules of hydroxypropyl methylcellulose comprises the following steps: adding mixed hydroxypropyl starch, potassium citrate and modified chitosan into ultrapure water, heating to 80-82°C and stirring to dissolve, to obtain a glue solution; sequentially adding hydroxypropyl methylcellulose, carrageenan, succinic acid and a plasticizer into the glue solution, stirring evenly at 46-50°C, adding gallic acid, stirring at room temperature for 10-15 minutes, adding alkyl dialdehyde, stirring with weak acid at room temperature in the dark for 2 hours, removing bubbles, keeping the temperature at 46-50°C for 2-4 hours, dipping into the glue to form capsules, and obtaining hollow hard capsules of hydroxypropyl methylcellulose.

[0007] Furthermore, the proportions of the raw material components in the hydroxypropyl methylcellulose hollow hard capsules, by mass fraction, include: 600-630 parts of hydroxypropyl methylcellulose, 270-300 parts of mixed hydroxypropyl starch, 54-75 parts of modified chitosan, 9-13.5 parts of carrageenan, 2-2.5 parts of potassium citrate, 22.5-25 parts of succinic acid, 9-45 parts of gallic acid, 13.5-22.5 parts of alkyl dialdehyde, 6-8 parts of plasticizer, and 30,000-45,000 parts of ultrapure water.

[0008] Furthermore, the plasticizer includes any one of polyethylene glycol, sorbitol, and glycerol.

[0009] Furthermore, the alkyl dialdehyde is glutaraldehyde.

[0010] Furthermore, the mixed hydroxypropyl starch consists of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is (5-7):(3-5).

[0011] Furthermore, the preparation method of the modified hydroxypropyl starch comprises the following steps:

[0012] Hydroxypropyl starch was added to a 50% w / w sodium hydroxide solution, cooled to -20°C and maintained for 24 hours, the reaction system was transferred to isopropanol for thawing, 2-chloroethylamine hydrochloride was added, and the reaction was heated to 70-72°C for 18-20 hours. The pH of the reaction solution was adjusted to neutral with a 1 mol / L hydrochloric acid solution, the product was dialyzed with ultrapure water for 72 hours, and freeze-dried to obtain amino-modified hydroxypropyl starch;

[0013] Amino-modified hydroxypropyl starch was added to ultrapure water and stirred evenly. A phosphate buffer solution of collagen peptide was added to adjust the pH of the solution to 6. A phosphate buffer solution of purified microbial transglutaminase was added and heated to 40-42°C for 1-1.5 hours. The reaction solution was treated in boiling water for 10-12 minutes, cooled to room temperature, filtered, and the pH of the solution was adjusted to neutral using 20% w / w sodium hydroxide solution. The product was dialyzed using ultrapure water for 72 hours, concentrated by rotary evaporation, and freeze-dried to obtain modified hydroxypropyl starch.

[0014] Furthermore, in the preparation process of the amino-modified hydroxypropyl starch, the mass ratio of hydroxypropyl starch: 2-chloroethylamine hydrochloride is 1:2; in the preparation process of the modified hydroxypropyl starch, the mass ratio of amino-modified hydroxypropyl starch: collagen peptide: microbial glutamine transaminase is 1:1:0.1.

[0015] Furthermore, the preparation method of the modified chitosan comprises the following steps:

[0016] The mixed chitosan was added to a 1% w / w acetic acid solution, diluted with methanol, and a formaldehyde solution of benzaldehyde was added, stirred evenly, heated to 60-62°C for reaction for 3-4 hours, and the pH of the reaction solution was adjusted to 13.0 with a 5% w / w sodium hydroxide solution. The product was centrifuged and collected, extracted with anhydrous ethanol, and vacuum dried at 45-50°C for 24 hours to obtain Schiff base chitosan;

[0017] Adding Schiff base chitosan to N,N-dimethylformamide and stirring evenly to obtain a mixed solution A; adding a bromine-containing compound to N,N-dimethylformamide and stirring evenly to obtain a mixed solution B; adding the mixed solution A to the mixed solution B, adding pyridine, reacting at room temperature for 6-7 hours, adding acetone, precipitating, filtering, collecting the product, extracting the product with petroleum ether, and vacuum drying at 45-50°C for 24 hours to obtain a modified Schiff base chitosan;

[0018] The modified Schiff base chitosan was added to a 0.25 mol / L hydrochloric acid ethanol solution and stirred at room temperature for 24 h. The pH of the reaction solution was adjusted to neutral using a 10% w / w sodium carbonate solution, precipitated, filtered, and the product was collected. The product was extracted with acetone, dialyzed with ultrapure water, and vacuum dried at 45-50°C for 12 h to obtain the modified chitosan.

[0019] Furthermore, in the preparation process of the modified Schiff base chitosan, the molar ratio of Schiff base chitosan to bromine-containing compound is 1:(2-3); the mixed chitosan is composed of chitosan and 2-hydroxypropyltrimethylammonium chloride chitosan, wherein the mass ratio of chitosan to 2-hydroxypropyltrimethylammonium chloride chitosan is (4-6):(4-6).

[0020] Furthermore, the preparation method of the bromine-containing compound comprises the following steps:

[0021] Add an alcohol-containing compound and phosphorus tribromide to anhydrous ethanol, cool to -5°C and react for 30-45 minutes, extract the organic phase with 5% w / w sodium bicarbonate solution and saturated brine in sequence, dry the organic phase with anhydrous magnesium sulfate, filter, and vacuum distill to obtain a bromine-containing compound.

[0022] Furthermore, in the preparation process of the bromine-containing compound, the molar ratio of the alcohol-containing compound to phosphorus tribromide is (2.5-3):1.

[0023] Furthermore, the purification process of the microbial glutamine transaminase includes the following steps: adding the microbial glutamine transaminase to a phosphate buffer solution, centrifuging, taking the supernatant and adjusting the pH to 4.3 with a hydrochloric acid solution, continuing centrifugation, taking the supernatant and dialyzing it with ultrapure water for 72 hours, concentrating by rotary evaporation, and freeze-drying.

[0024] Furthermore, the alcohol-containing compound includes any one of geraniol and cinnamyl alcohol.

[0025] Furthermore, the concentration of the phosphate buffer solution is 0.2 mol / L and the pH is 6.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] 1. The present invention uses hydroxypropyl starch and 2-chloroethylamine hydrochloride as intermediate reactants to prepare amino-modified hydroxypropyl starch. Using microbial transglutaminase as a biocatalyst, an enzymatic reaction is performed to react the amino groups in the amino-modified hydroxypropyl starch with the carboxamide groups in the collagen peptide to prepare the modified hydroxypropyl starch. This modified hydroxypropyl starch is introduced into the preparation of the capsule glue to impart free radical scavenging and antioxidant activities to the capsule.

[0028] 2. The present invention prepares modified chitosan through protection, substitution, and deprotection reactions. The molecular chains of the mixed hydroxypropyl starch and modified chitosan are entangled through intermolecular hydrogen bonds, which are then cross-linked with glutaraldehyde via a Schiff base reaction. The interaction between the starch and chitosan improves the mechanical properties of the capsule. Succinic acid, a cross-linking agent, and gallic acid, an antibacterial agent, act between hydroxypropyl methylcellulose and the mixed hydroxypropyl starch, further enhancing the mechanical properties through cross-linking. The introduction of the non-toxic cross-linking agent, succinic acid, effectively reduces the amount of carrageenan required while imparting excellent antibacterial properties to the capsule.

[0029] 3. The hollow hard capsules of hypromellose prepared by the present invention can effectively extend the shelf life of capsule drugs when they are removed from the protection of aluminum foil and fully exposed to the air environment, effectively solving the trouble of people carrying the original packaging boxes of drugs with them in their daily lives because they need to take one or more drugs on time. It can meet the demand of long-term storage of drugs in timed and quantitative medicine boxes to avoid bacterial growth and oxidation, greatly expanding the application scenarios of capsules and greatly improving the safety of capsule drugs. DETAILED DESCRIPTION

[0030] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0031] In the following examples, the specifications of hydroxypropyl methylcellulose are: methoxy content is 27.0%, hydroxypropoxy content is 7.4%; the specifications of hydroxypropyl starch are: Mw=2270000, molar substitution degree is 0.89; the specifications of chitosan are: deacetylation degree is 82%; the specifications of 2-hydroxypropyltrimethylammonium chloride chitosan are: quaternization degree is 95%; and the remaining raw materials are commercially available.

[0032] The preparation method of modified hydroxypropyl starch comprises the following steps:

[0033] 2 g of hydroxypropyl starch was added to a 50% w / w sodium hydroxide solution, cooled to -20°C and maintained for 24 h. The reaction system was transferred to isopropanol for thawing, 4 g of 2-chloroethylamine hydrochloride was added, and the mixture was heated to 70°C for reaction for 18 h. The pH of the reaction solution was adjusted to neutral using a 1 mol / L hydrochloric acid solution. The product was dialyzed with ultrapure water for 72 h and freeze-dried to obtain amino-modified hydroxypropyl starch.

[0034] Add 1 g of amino-modified hydroxypropyl starch to ultrapure water and stir evenly. Add 1 g of collagen peptide in phosphate buffer solution and adjust the pH of the solution to 6. Add phosphate buffer solution containing 0.1 g of purified microbial glutamine transaminase and heat to 40 ° C for 1 hour. Treat the reaction solution in boiling water for 10 minutes, cool to room temperature, filter, and adjust the pH of the solution to neutral with 20% w / w sodium hydroxide solution. Use ultrapure water to dialyze the product for 72 hours, concentrate by rotary evaporation, and freeze-dry to obtain modified hydroxypropyl starch.

[0035] The preparation method of the bromine-containing compound comprises the following steps:

[0036] 2.5 g of cinnamyl alcohol and 1 g of phosphorus tribromide were added to anhydrous ethanol, cooled to -5°C and reacted for 30 min. The organic phase was extracted with 5% w / w sodium bicarbonate solution and saturated brine in sequence, and the organic phase was dried with anhydrous magnesium sulfate, filtered, and vacuum distilled to obtain a bromine-containing compound.

[0037] The preparation method of modified chitosan comprises the following steps:

[0038] 0.025 mol of mixed chitosan was added to 70 mL of 1% w / w acetic acid solution, diluted with 100 mL of methanol, and 100 mL of formaldehyde solution containing 10 mL of benzaldehyde was added, stirred evenly, heated to 60°C for 3 h, and the pH of the reaction solution was adjusted to 13.0 with 5% w / w sodium hydroxide solution. The product was collected by centrifugation, extracted with anhydrous ethanol, and dried in vacuum at 45°C for 24 h to obtain Schiff base chitosan;

[0039] 0.1 mol of Schiff base chitosan was added to N,N-dimethylformamide and stirred to obtain a mixture A; 0.3 mol of a bromine-containing compound was added to N,N-dimethylformamide and stirred to obtain a mixture B; the mixture A was added to the mixture B, and 0.005 mol of pyridine was added, and the mixture was reacted at room temperature for 6 h. Acetone was added to precipitate, and the product was filtered and collected. The product was extracted with petroleum ether and dried in vacuum at 45°C for 24 h to obtain a modified Schiff base chitosan;

[0040] The modified Schiff base chitosan was added to a 0.25 mol / L hydrochloric acid ethanol solution and stirred at room temperature for 24 h. The pH of the reaction solution was adjusted to neutral using a 10% w / w sodium carbonate solution, precipitated, filtered, and the product was collected. The product was extracted with acetone, dialyzed with ultrapure water, and vacuum dried at 45 ° C for 12 h to obtain modified chitosan.

[0041] Example 1: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: 270 parts of mixed hydroxypropyl starch, 2 parts of potassium citrate, and 54 parts of modified chitosan are added to 30,000 parts of ultrapure water, heated to 80°C and stirred to dissolve to obtain a glue solution; 630 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 are added to the glue solution in sequence, stirred evenly at 48°C, 9 parts of gallic acid are added, stirred at room temperature for 10 minutes, 13.5 parts of glutaraldehyde are added, stirred in a weak acid-protected manner at room temperature for 2 hours, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsules are dipped in glue to obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0042] The mixed hydroxypropyl starch is composed of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is 7:3;

[0043] In the preparation process of the modified chitosan, the mixed chitosan is composed of chitosan and 2-hydroxypropyltrimethylammonium chloride chitosan, wherein the mass ratio of chitosan to 2-hydroxypropyltrimethylammonium chloride chitosan is 6:4.

[0044] Example 2: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: 300 parts of mixed hydroxypropyl starch, 2 parts of potassium citrate, and 54 parts of modified chitosan are added to 30,000 parts of ultrapure water, heated to 80°C and stirred to dissolve to obtain a glue solution; 600 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 are added to the glue solution in sequence, stirred evenly at 48°C, 9 parts of gallic acid are added, stirred at room temperature for 10 minutes, 13.5 parts of glutaraldehyde are added, stirred at room temperature in the dark for 2 hours with weak acid, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsules are dipped in glue to obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0045] The mixed hydroxypropyl starch is composed of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is 7:3;

[0046] In the preparation process of the modified chitosan, the mixed chitosan is composed of chitosan and 2-hydroxypropyltrimethylammonium chloride chitosan, wherein the mass ratio of chitosan to 2-hydroxypropyltrimethylammonium chloride chitosan is 6:4.

[0047] Example 3: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: 300 parts of mixed hydroxypropyl starch, 2 parts of potassium citrate, and 54 parts of modified chitosan are added to 30,000 parts of ultrapure water, heated to 80°C and stirred to dissolve to obtain a glue solution; 600 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 are added to the glue solution in sequence, stirred evenly at 48°C, 45 parts of gallic acid are added, stirred at room temperature for 10 minutes, 13.5 parts of glutaraldehyde are added, stirred at room temperature in the dark for 2 hours with weak acid, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsules are dipped in glue to obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0048] The mixed hydroxypropyl starch is composed of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is 7:3;

[0049] In the preparation process of the modified chitosan, the mixed chitosan is composed of chitosan and 2-hydroxypropyltrimethylammonium chloride chitosan, wherein the mass ratio of chitosan to 2-hydroxypropyltrimethylammonium chloride chitosan is 6:4.

[0050] Example 4: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: 300 parts of mixed hydroxypropyl starch, 2 parts of potassium citrate, and 54 parts of modified chitosan are added to 30,000 parts of ultrapure water, heated to 80°C and stirred to dissolve to obtain a glue solution; 600 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 are added to the glue solution in sequence, stirred evenly at 48°C, 45 parts of gallic acid are added, stirred at room temperature for 10 minutes, 13.5 parts of glutaraldehyde are added, stirred at room temperature in the dark for 2 hours with weak acid, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsules are dipped in glue to obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0051] The mixed hydroxypropyl starch is composed of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is 5:5;

[0052] In the preparation process of the modified chitosan, the mixed chitosan is composed of chitosan and 2-hydroxypropyltrimethylammonium chloride chitosan, wherein the mass ratio of chitosan to 2-hydroxypropyltrimethylammonium chloride chitosan is 6:4.

[0053] Example 5: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: 300 parts of mixed hydroxypropyl starch, 2 parts of potassium citrate, and 54 parts of modified chitosan are added to 30,000 parts of ultrapure water, heated to 80°C and stirred to dissolve to obtain a glue solution; 600 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 are added to the glue solution in sequence, stirred evenly at 48°C, 45 parts of gallic acid are added, stirred at room temperature for 10 minutes, 13.5 parts of glutaraldehyde are added, stirred at room temperature in the dark for 2 hours with weak acid, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsules are dipped in glue to obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0054] The mixed hydroxypropyl starch is composed of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is 7:3;

[0055] In the preparation process of the modified chitosan, the mixed chitosan is composed of chitosan and 2-hydroxypropyltrimethylammonium chloride chitosan, wherein the mass ratio of chitosan to 2-hydroxypropyltrimethylammonium chloride chitosan is 4:6.

[0056] Example 6: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: 300 parts of mixed hydroxypropyl starch, 2 parts of potassium citrate, and 54 parts of modified chitosan are added to 30,000 parts of ultrapure water, heated to 80°C and stirred to dissolve to obtain a glue solution; 600 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 are added to the glue solution in sequence, stirred evenly at 48°C, 45 parts of gallic acid are added, stirred at room temperature for 10 minutes, 13.5 parts of glutaraldehyde are added, stirred at room temperature in the dark for 2 hours with weak acid, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsules are dipped in glue to obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0057] The mixed hydroxypropyl starch is composed of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is 5:5;

[0058] In the preparation process of the modified chitosan, the mixed chitosan is composed of chitosan and 2-hydroxypropyltrimethylammonium chloride chitosan, wherein the mass ratio of chitosan to 2-hydroxypropyltrimethylammonium chloride chitosan is 4:6.

[0059] Comparative Example 1: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: 270 parts of hydroxypropyl starch, 2 parts of potassium citrate, and 54 parts of modified chitosan are added to 30,000 parts of ultrapure water, heated to 80°C and stirred to dissolve to obtain a glue solution; 630 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 are sequentially added to the glue solution, stirred evenly at 48°C, 9 parts of gallic acid are added, stirred at room temperature for 10 minutes, 13.5 parts of glutaraldehyde are added, stirred with weak acid at room temperature in the dark for 2 hours, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsules are dipped in glue to obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0060] In the preparation process of the modified chitosan, the mixed chitosan is composed of chitosan and 2-hydroxypropyltrimethylammonium chloride chitosan, wherein the mass ratio of chitosan to 2-hydroxypropyltrimethylammonium chloride chitosan is 6:4.

[0061] Comparative Example 2: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: 270 parts of mixed hydroxypropyl starch, 2 parts of potassium citrate, and 54 parts of chitosan are added to 30,000 parts of ultrapure water, heated to 80°C and stirred to dissolve to obtain a glue solution; 630 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 are sequentially added to the glue solution, stirred evenly at 48°C, 9 parts of gallic acid are added, stirred at room temperature for 10 minutes, 13.5 parts of glutaraldehyde are added, stirred with weak acid at room temperature in the dark for 2 hours, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsules are dipped in glue to obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0062] The mixed hydroxypropyl starch consists of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is 7:3.

[0063] Comparative Example 3: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: 270 parts of mixed hydroxypropyl starch and 2 parts of potassium citrate are added to 30,000 parts of ultrapure water, heated to 80°C and stirred to dissolve to obtain a glue solution; 630 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 are added to the glue solution in sequence, stirred evenly at 48°C, 9 parts of gallic acid are added, stirred at room temperature for 10 minutes, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsules are dipped in glue to obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0064] The mixed hydroxypropyl starch consists of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is 7:3.

[0065] Comparative Example 4: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: 270 parts of mixed hydroxypropyl starch, 2 parts of potassium citrate, and 54 parts of modified chitosan are added to 30,000 parts of ultrapure water, heated to 80°C and stirred to dissolve to obtain a glue solution; 630 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 are sequentially added to the glue solution, stirred evenly at 48°C, 9 parts of gallic acid are added, stirred at room temperature for 10 minutes, 13.5 parts of glutaraldehyde are added, stirred with weak acid at room temperature in the dark for 2 hours, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsules are dipped in glue to obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0066] The mixed hydroxypropyl starch is composed of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is 7:3;

[0067] In the preparation process of the modified chitosan, the mixed chitosan is composed of chitosan and 2-hydroxypropyltrimethylammonium chloride chitosan, wherein the mass ratio of chitosan to 2-hydroxypropyltrimethylammonium chloride chitosan is 2:8.

[0068] Experiment: Preparation of capsule membrane for experiment: 10 g of the raw material glue prepared in the above examples and comparative examples was evenly spread on a preheated glass plate, and the glass plate was placed in a drying oven and dried at 30° C. for 3 h to obtain the capsule membrane for experiment.

[0069] Antibacterial activity test: A specific amount of Escherichia coli (ATCC25922) or Staphylococcus aureus (ATCC29213) strain (taken from -80°C storage) was added to 1 mL of sterile LB broth and then cultured at 37°C in a bacterial culture chamber at 200 rpm for 24 hours. Next, 100 μL of E. coli or Staphylococcus aureus culture was dispersed in sterile phosphate buffered saline (PBS, pH 7.0) to form the corresponding bacterial suspension (approximately 10 5 CFU·mL -1 );

[0070] Cut the film into squares (10 mm x 10 mm). After sterilization, disperse the squares in 4 mL of the E. coli or S. aureus suspension prepared above. Continue shaking at 200 rpm for 24 hours at 37°C. Measure the optical density (OD) of the suspension at 600 nm using a UV-visible spectrophotometer after 24 hours. 600 All measurements were repeated three times and the average value was taken.

[0071] Mechanical Properties Testing: The tensile strength of the capsule membrane was measured using a universal tensile testing machine according to GB / T1040.1-2006. The dried membrane was cut into strips 10 mm wide and the tensile speed was set at 50 mm / min. Three replicates were performed for each group, and the average value was calculated.

[0072] The experimental results are shown in Table 1 below.

[0073] Table 1 Performance test data of hydroxypropyl cellulose hollow hard capsules

[0074]

[0075] Conclusion: The hydroxypropyl cellulose hollow hard capsules prepared by the present invention have excellent mechanical properties and excellent antibacterial properties, which greatly expands the application scenarios of the capsules, makes it convenient for people to separate capsule drugs from medicine boxes into medicine boxes in daily life, is convenient to carry, and can effectively reduce bacterial erosion of the capsules and the drugs inside the capsules during storage.

[0076] In comparative example 1, hydroxypropyl starch was completely used to replace the mixed hydroxypropyl starch, resulting in a decrease in antibacterial performance; in comparative example 2, chitosan was completely used to replace the mixed chitosan, resulting in a decrease in antibacterial performance; in comparative example 3, no chitosan or mixed chitosan was added, resulting in a decrease in the mechanical properties and antibacterial properties of the capsule; in comparative example 4, the proportion of 2-hydroxypropyltrimethylammonium chloride chitosan in the mixed chitosan was too high, the Schiff base cross-linking structure was reduced, the mechanical properties of the capsule were reduced, the degree of cross-linking was reduced, and the antibacterial performance was slightly reduced.

[0077] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims rather than the foregoing description, and it is intended that all variations that come within the meaning and range of equivalents of the claims be embraced therein.

Claims

1. A process for preparing hollow hard capsules of hypromellose, characterized in that: The following steps are involved: Add mixed hydroxypropyl starch, potassium citrate, and modified chitosan into ultrapure water, heat to 80-82°C, and stir to dissolve to obtain a glue solution; add hydroxypropyl methylcellulose, carrageenan, succinic acid, and a plasticizer into the glue solution in sequence, stir evenly at 46-50°C, add gallic acid, stir at room temperature for 10-15 minutes, add alkyl dialdehyde, stir at room temperature in the dark for 2 hours, remove bubbles, keep warm at 46-50°C for 2-4 hours, dip into the glue to prepare capsules, and obtain hollow hard capsules of hydroxypropyl methylcellulose; The mixed hydroxypropyl starch is composed of hydroxypropyl starch and modified hydroxypropyl starch; wherein the mass ratio of hydroxypropyl starch to modified hydroxypropyl starch is (5-7):(3-5); The preparation method of the modified hydroxypropyl starch comprises the following steps: adding the hydroxypropyl starch to a 50% w / w sodium hydroxide solution, cooling to -20°C and maintaining for 24 hours, thawing, adding 2-chloroethylamine hydrochloride, heating to 70-72°C and reacting for 18-20 hours, adjusting the pH of the reaction solution to neutral, dialyzing, and freeze-drying to obtain the amino-modified hydroxypropyl starch; Add amino-modified hydroxypropyl starch to ultrapure water, stir evenly, add collagen peptide phosphate buffer solution, adjust the solution pH to 6, add purified microbial transglutaminase phosphate buffer solution, heat to 40-42 ° C for 1-1.5 hours, treat the reaction solution in boiling water for 10-12 minutes, cool to room temperature, filter, adjust the solution pH to neutral, dialyze, concentrate by rotary evaporation, and freeze-dry to obtain modified hydroxypropyl starch; The preparation method of the modified chitosan comprises the following steps: The mixed chitosan was added to a 1% w / w acetic acid solution, diluted with methanol, and then a formaldehyde solution of benzaldehyde was added, stirred evenly, heated to 60-62°C for 3-4 hours, and the pH of the reaction solution was adjusted to 13. The product was collected by centrifugation, extracted, and vacuum dried to obtain Schiff base chitosan; Adding Schiff base chitosan to N,N-dimethylformamide and stirring evenly to obtain a mixed solution A; adding a bromine-containing compound to N,N-dimethylformamide and stirring evenly to obtain a mixed solution B; adding the mixed solution A to the mixed solution B, adding pyridine, reacting at room temperature for 6-7 hours, adding acetone, precipitating, filtering, collecting the product, extracting, and vacuum drying to obtain a modified Schiff base chitosan; The modified Schiff base chitosan was added to a 0.25 mol / L hydrochloric acid ethanol solution, stirred at room temperature, the pH of the reaction solution was adjusted to neutral, precipitated, filtered, the product was collected, extracted, dialyzed, and vacuum dried to obtain the modified chitosan; The preparation method of the bromine-containing compound comprises the following steps: adding an alcohol-containing compound and phosphorus tribromide into anhydrous ethanol, cooling to -5°C and reacting for 30-45 minutes, extracting the organic phase, drying the organic phase, filtering, and vacuum distilling to obtain the bromine-containing compound.

2. The process for preparing a hollow hard capsule of hypromellose according to claim 1, wherein the raw material components in the hollow hard capsule of hypromellose comprise, by mass fraction: 600-630 parts of hydroxypropyl methylcellulose, 270-300 parts of mixed hydroxypropyl starch, 54-75 parts of modified chitosan, 9-13.5 parts of carrageenan, 2-2.5 parts of potassium citrate, 22.5-25 parts of succinic acid, 9-45 parts of gallic acid, 13.5-22.5 parts of alkyl dialdehyde, 6-8 parts of plasticizer, and 30,000-45,000 parts of ultrapure water.

3. The preparation process of a hollow hard capsule of hypromellose according to claim 1, characterized in that: In the preparation process of amino-modified hydroxypropyl starch, the mass ratio of hydroxypropyl starch: 2-chloroethylamine hydrochloride is 1:2; in the preparation process of modified hydroxypropyl starch, the mass ratio of amino-modified hydroxypropyl starch: collagen peptide: microbial glutamine transaminase is 1:1:0.

1.

4. The process for preparing a hollow hard capsule of hypromellose according to claim 1, wherein: During the preparation of the modified Schiff base chitosan, the molar ratio of the Schiff base chitosan to the bromine-containing compound is 1:(2-3); the mixed chitosan is composed of chitosan and 2-hydroxypropyltrimethylammonium chloride chitosan, wherein the mass ratio of chitosan to 2-hydroxypropyltrimethylammonium chloride chitosan is (4-6):(4-6).

5. The preparation process of a hollow hard capsule of hypromellose according to claim 1, characterized in that: During the preparation of the bromine-containing compound, the molar ratio of the alcohol-containing compound to phosphorus tribromide is (2.5-3):

1.

6. The process for preparing a hollow hard capsule of hypromellose according to claim 1, wherein: The purification process of the microbial transglutaminase comprises the following steps: adding the microbial transglutaminase to a phosphate buffer solution, centrifuging, adjusting the pH of the supernatant to 4.3, continuing the centrifugation, dialyzing the supernatant, concentrating by rotary evaporation, and freeze-drying.

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