Preparation process of hydroxypropyl methylcellulose hollow hard capsule

Abstract

The invention discloses a preparation process of a hydroxypropyl methylcellulose hollow hard capsule, and relates to the technical field of hydroxypropyl methylcellulose hollow hard capsules, the preparation process comprises the following steps: adding mixed hydroxypropyl starch, potassium citrate and modified chitosan into ultrapure water, heating, stirring and dissolving to obtain a glue solution; the preparation method comprises the following steps: sequentially adding hydroxypropyl methyl cellulose, carrageenan, succinic acid and a plasticizer into a glue solution, uniformly stirring, adding gallic acid, stirring at room temperature for 10-15 minutes, adding alkyl dialdehyde, stirring at room temperature in a dark place for 2 hours, removing bubbles, preserving heat for 2-4 hours, dipping glue and preparing a capsule, thereby obtaining the hydroxypropyl methyl cellulose hollow hard glue.

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 in pharmaceutical preparations, and 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 molds, 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 easily causes the capsules to become damp, deteriorate or contaminated, 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 has important practical significance. Summary of the invention

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

[0005] To achieve the above object, the present invention provides the following technical solutions: A preparation process of 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 DEG C, stirring and dissolving to obtain glue solution; adding hydroxypropyl methylcellulose, carrageenan, succinic acid and plasticizer into the glue solution in sequence, stirring evenly at 46-50 DEG C, adding gallic acid, stirring at room temperature for 10-15 minutes, adding alkyl dialdehyde, stirring at room temperature in the dark for 2 hours with weak acid, removing bubbles, keeping warm at 46-50 DEG C for 2-4 hours, dipping in glue to make capsules, and obtaining hollow hard capsules of hydroxypropyl methylcellulose.

[0006] 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 dialdehydes, 6-8 parts of plasticizers, and 30,000-45,000 parts of ultrapure water.

[0007] Furthermore, the plasticizer includes any one of polyethylene glycol, sorbitol and glycerol.

[0008] Furthermore, the alkyl dialdehyde is glutaraldehyde.

[0009] 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).

[0010] Furthermore, the preparation method of the modified hydroxypropyl starch comprises the following steps: Add hydroxypropyl starch to 50% w / w sodium hydroxide solution, cool to -20°C and keep for 24 hours, transfer the reaction system to isopropanol for thawing, add 2-chloroethylamine hydrochloride, heat to 70-72°C and react for 18-20 hours, adjust the pH of the reaction solution to neutral with 1 mol / L hydrochloric acid solution, dialyze the product with ultrapure water for 72 hours, and freeze-dry to obtain amino-modified hydroxypropyl starch; Add amino-modified hydroxypropyl starch to ultrapure water, stir evenly, add phosphate buffer solution of collagen peptide, adjust the pH of the solution to 6, add phosphate buffer solution of purified microbial glutamine transaminase, heat to 40-42°C for reaction for 1-1.5h, treat the reaction solution in boiling water for 10-12min, cool to room temperature, filter, use 20% w / w sodium hydroxide solution to adjust the pH of the solution to neutral, use ultrapure water to dialyze the product for 72h, concentrate by rotary evaporation, and freeze-dry to obtain modified hydroxypropyl starch.

[0011] 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.

[0012] Furthermore, the preparation method of the modified chitosan comprises the following steps: The mixed chitosan was added to a 1% w / w acetic acid solution, and methanol was added to dilute it. A formaldehyde solution of benzaldehyde was added, and the mixture was stirred evenly. The mixture was heated to 60-62°C for reaction for 3-4 hours. The pH of the reaction solution was adjusted to 13.0 using a 5% w / w sodium hydroxide solution. The mixture was centrifuged, and the product was collected. The product was extracted using anhydrous ethanol and vacuum dried at 45-50°C for 24 hours 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 the product with petroleum ether, and vacuum drying at 45-50°C for 24 hours 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 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 modified chitosan.

[0013] Furthermore, in the preparation process of the modified Schiff base chitosan, the molar ratio of Schiff base chitosan: 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: 2-hydroxypropyltrimethylammonium chloride chitosan is (4-6):(4-6).

[0014] Furthermore, the preparation method of the bromine-containing compound comprises the following steps: 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.

[0015] 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.

[0016] 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 using a hydrochloric acid solution, continuing centrifugation, taking the supernatant and dialyzing it with ultrapure water for 72 hours, rotary evaporation concentration, and freeze-drying.

[0017] Furthermore, the alcohol-containing compound includes any one of geraniol and cinnamyl alcohol.

[0018] Furthermore, the concentration of the phosphate buffer solution is 0.2 mol / L and the pH is 6.

[0019] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention uses hydroxypropyl starch and 2-chloroethylamine hydrochloride as intermediate reactants to prepare amino-modified hydroxypropyl starch, uses microbial transglutaminase as a biocatalyst, and uses an enzyme-catalyzed reaction to react the amino groups in the amino-modified hydroxypropyl starch with the carboxamide groups in the collagen peptide to prepare modified hydroxypropyl starch. The hydroxypropyl starch is introduced into the preparation process of the capsule glue in order to give the capsule free radical scavenging activity and antioxidant activity.

[0020] 2. The present invention prepares modified chitosan through protection, substitution and deprotection reactions. The molecular chains of mixed hydroxypropyl starch and modified chitosan are entangled together through intermolecular hydrogen bonds, and cross-linked with glutaraldehyde through Schiff base reaction. The mechanical properties of the capsule are improved by the interaction between starch and chitosan. Succinic acid is used as a cross-linking agent and gallic acid is used as an antibacterial agent to act between hydroxypropyl methylcellulose and mixed hydroxypropyl starch. Through reaction cross-linking, the mechanical properties of the capsule are further improved. The introduction of non-toxic cross-linking agent succinic acid effectively reduces the amount of carrageenan added, and at the same time gives the capsule excellent antibacterial properties.

[0021] 3. The hollow hard capsules of hydroxypropyl methylcellulose prepared by the present invention can effectively extend the validity period of the capsule medicine after it is removed from the protection of the aluminum foil and fully exposed to the air environment, effectively solving the trouble of people carrying the original packaging boxes of the medicines with them in their daily lives because they need to take one or more medicines on time. It can meet the demand of packaging the medicines in the timing and quantitative medicine boxes for long-term storage to avoid the breeding of bacteria and oxidation, greatly expanding the application scenarios of the capsules and greatly improving the safety of the capsule medicines. DETAILED DESCRIPTION

[0022] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0023] 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.

[0024] The preparation method of modified hydroxypropyl starch comprises the following steps: 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, heated to 70°C for reaction for 18 h, 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 h, and freeze-dried to obtain amino-modified hydroxypropyl starch; Add 1 g of amino-modified hydroxypropyl starch to ultrapure water, stir evenly, add 1 g of collagen peptide in phosphate buffer solution, adjust the pH of the solution to 6, add phosphate buffer solution containing 0.1 g of purified microbial glutamine transaminase, heat to 40 ° C for 1 h, treat the reaction solution in boiling water for 10 min, cool to room temperature, filter, use 20% w / w sodium hydroxide solution to adjust the pH of the solution to neutral, use ultrapure water to dialyze the product for 72 h, concentrate by rotary evaporation, and freeze-dry to obtain modified hydroxypropyl starch.

[0025] The preparation method of the bromine-containing compound comprises the following steps: 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. The organic phase was dried with anhydrous magnesium sulfate, filtered, and vacuum distilled to obtain a bromine-containing compound.

[0026] The preparation method of modified chitosan comprises the following steps: 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 reaction for 3 h, and the pH of the reaction solution was adjusted to 13.0 with 5% w / w sodium hydroxide solution, centrifuged, and the product was collected, extracted with anhydrous ethanol, and vacuum dried at 45°C for 24 h to obtain Schiff base chitosan; 0.1 mol of Schiff base chitosan was added to N,N-dimethylformamide and stirred evenly to obtain a mixed solution A; 0.3 mol of a bromine-containing compound was added to N,N-dimethylformamide and stirred evenly to obtain a mixed solution B; the mixed solution A was added to the mixed solution B, and 0.005 mol of pyridine was added, and the mixture was reacted at room temperature for 6 hours, acetone was added, precipitated, filtered, and the product was collected, and the product was extracted with petroleum ether, and vacuum dried at 45°C for 24 hours 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 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.

[0027] Embodiment 1: A preparation process of 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 at room temperature in a weak acid state for 2 hours in the dark, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The hollow hard capsules of hydroxypropyl methylcellulose are obtained by dipping in the glue.

[0028] 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; 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.

[0029] 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 a weak acid state for 2 hours in the dark, 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.

[0030] 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; 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.

[0031] 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 a weak acid state for 2 hours in the dark, 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.

[0032] 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; 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.

[0033] 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 a weak acid state for 2 hours in the dark, 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.

[0034] 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; 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.

[0035] 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 a weak acid state for 2 hours in the dark, 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.

[0036] 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; 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.

[0037] 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 a weak acid state for 2 hours in the dark, 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.

[0038] 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; 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.

[0039] Comparative Example 1: A preparation process for a hollow hard capsule of hydroxypropyl methylcellulose: add 270 parts of hydroxypropyl starch, 2 parts of potassium citrate, and 54 parts of modified chitosan to 30,000 parts of ultrapure water, heat to 80°C and stir to dissolve to obtain a glue solution; add 630 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 to the glue solution in sequence, stir evenly at 48°C, add 9 parts of gallic acid, stir at room temperature for 10 minutes, add 13.5 parts of glutaraldehyde, stir at room temperature in a weak acid state for 2 hours in the dark, remove bubbles, keep warm at 46°C for 2 hours, dip in glue to make capsules, and obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0040] 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.

[0041] Comparative Example 2: A preparation process for a hollow hard capsule 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 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 a weak acid state for 2 hours in the dark, bubbles are removed, and the mixture is kept warm at 46°C for 2 hours. The capsule is dipped in glue to obtain a hollow hard capsule of hydroxypropyl methylcellulose.

[0042] 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.

[0043] Comparative Example 3: A preparation process for hollow hard capsules of hydroxypropyl methylcellulose: add 270 parts of mixed hydroxypropyl starch and 2 parts of potassium citrate to 30,000 parts of ultrapure water, heat to 80°C and stir to dissolve to obtain a glue solution; add 630 parts of hydroxypropyl methylcellulose, 9 parts of carrageenan, 22.5 parts of succinic acid, and 6 parts of polyethylene glycol-4000 to the glue solution in sequence, stir evenly at 48°C, add 9 parts of gallic acid, stir at room temperature for 10 minutes, remove bubbles, keep warm at 46°C for 2 hours, dip in glue to make capsules, and obtain hollow hard capsules of hydroxypropyl methylcellulose.

[0044] 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.

[0045] 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 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 a weak acid state for 2 hours in a dark environment, 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.

[0046] 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; 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.

[0047] Experiment: Preparation of capsule membrane for experiment: 10 g of the raw material glue prepared in the above embodiments 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.

[0048] Antibacterial performance test: A specific amount of Escherichia coli (ATCC25922) or Staphylococcus aureus (ATCC29213) strain (taken out from -80°C storage) was added to 1 mL of sterile LB broth medium, and then cultured at 37°C in a bacterial culture chamber at 200 rpm for 24 hours. Next, 100 μL of Escherichia coli or Staphylococcus aureus culture was dispersed in sterile phosphate buffered saline (PBS, pH 7.0) to form the corresponding bacterial suspension (about 10 5 CFU·mL -1 ); The film was cut into squares (10 mm × 10 mm). After sterilization, the squares were dispersed in 4 mL of the E. coli or S. aureus suspension prepared above. The suspension was shaken at 200 rpm for 24 hours at 37 °C. The optical density (OD) of the suspension at 600 nm was measured using a UV-visible spectrophotometer after 24 hours. 600 All the measurements were repeated three times and the average value was taken.

[0049] Mechanical property test: According to GB / T1040.1-2006, the tensile strength of the capsule film was measured using a universal tensile tester. The dried film was cut to a strip width of 10 mm and the tensile speed was set to 50 mm / min. Each group was tested three times and the average value was taken.

[0050] The experimental results are shown in Table 1 below.

[0051] Table 1 Performance test data of hydroxypropyl cellulose hollow hard capsules

[0052] 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 capsules, makes it convenient for people to pack capsule drugs from medicine boxes into medicine boxes in daily life, is convenient to carry, and can effectively reduce bacterial erosion of capsules and drugs inside capsules during storage.

[0053] In comparative example 1, hydroxypropyl starch was completely used to replace the mixed hydroxypropyl starch, resulting in reduced antibacterial performance; in comparative example 2, chitosan was completely used to replace the mixed chitosan, resulting in reduced antibacterial performance; in comparative example 3, no chitosan or mixed chitosan was added, resulting in reduced mechanical 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.

[0054] 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 present invention can be implemented in other specific forms without departing from the spirit or essential features of the present invention. Therefore, the embodiments should be considered exemplary and non-restrictive in all respects, and the scope of the present invention is defined by the appended claims rather than the above description, and it is intended that all changes falling within the meaning and scope of the equivalent elements of the claims be included in the present invention.

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 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 away from light for 2 hours, remove bubbles, keep warm at 46-50°C for 2-4 hours, dip in glue to make capsules, and obtain hydroxypropyl methylcellulose hollow hard capsules.

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 30000-45000 parts of ultrapure water.

3. The preparation process of a hollow hard capsule of hypromellose according to claim 1, characterized in that: 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).

4. The process for preparing a hollow hard capsule of hypromellose according to claim 3, characterized in that: The preparation method of the modified hydroxypropyl starch comprises the following steps: Add hydroxypropyl starch to 50% w / w sodium hydroxide solution, cool to -20°C for 24 hours, thaw, add 2-chloroethylamine hydrochloride, heat to 70-72°C for 18-20 hours, adjust the pH of the reaction solution to neutral, dialyze, and freeze-dry to obtain amino-modified hydroxypropyl starch; Add amino-modified hydroxypropyl starch to ultrapure water, stir evenly, add phosphate buffer solution of collagen peptide, adjust the pH of the solution to 6, add purified phosphate buffer solution of microbial glutamine transaminase, heat to 40-42°C for reaction for 1-1.5h, treat the reaction solution in boiling water for 10-12min, cool to room temperature, filter, adjust the pH of the solution to neutral, dialyze, concentrate by rotary evaporation, and freeze-dry to obtain modified hydroxypropyl starch.

5. The process for preparing a hollow hard capsule of hypromellose according to claim 4, 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.

6. The process for preparing a hollow hard capsule of hypromellose according to claim 1, characterized in that: 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 a formaldehyde solution of benzaldehyde was added, stirred evenly, heated to 60-62°C for reaction for 3-4 hours, the pH of the reaction solution was adjusted to 13, centrifuged, the product was collected, 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 into 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.

7. The process for preparing a hollow hard capsule of hypromellose according to claim 6, characterized in that: In the preparation process of 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).

8. The process for preparing a hollow hard capsule of hypromellose according to claim 6, characterized in that: The method for preparing the bromine-containing compound comprises the following steps: Add the alcohol-containing compound and phosphorus tribromide into anhydrous ethanol, cool to -5°C and react for 30-45 minutes, extract the organic phase, dry the organic phase, filter, and vacuum distill to obtain the bromine-containing compound.

9. The process for preparing a hollow hard capsule of hypromellose according to claim 8, characterized in that: 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.

10. The process for preparing a hollow hard capsule of hypromellose according to claim 1, characterized in that: The purification process of the microbial glutamine transaminase comprises the following steps: adding the microbial glutamine transaminase into a phosphate buffer solution, centrifuging, taking the supernatant to adjust the pH to 4.3, continuing centrifuging, taking the supernatant for dialysis, rotary evaporation concentration, and freeze drying.

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