Sustained and controlled release hydroxypropyl methylcellulose hollow capsule

Abstract

The invention discloses a sustained and controlled release hydroxypropyl methylcellulose hollow capsule, and relates to the technical field of capsules, in order to realize a long-term sustained and controlled release effect of a drug, a hard shell of the capsule is improved, and antibacterial modified polysaccharide is added into raw materials, so that the compactness and barrier property of the capsule shell after curing and drying are improved, and the sustained and controlled release effect of the drug is improved. The drug protection performance is improved; in addition, in consideration of the fact that part of medicine capsules can be stored in medicine bottles which are taken for multiple times, the guanidyl and chitosan structures added into the prepared hollow capsule shell can provide excellent antibacterial and anti-pollution capacity for the capsules, growth and pollution of infectious microbes are avoided, and the efficacy of the medicine is maintained for a long time.

Description

Technical Field

[0001] The present invention relates to the technical field of capsules, and specifically to a sustained-release and controlled-release hydroxypropyl methylcellulose hollow capsule. Background Art

[0002] As a drug encapsulation material widely used in the fields of modern medicine and functional foods, the capsule shell occupies an irreplaceable core position in the pharmaceutical and health product industries by virtue of its significant technical advantages and convenience. Compared with tablets, the development process of capsules is more straightforward. The drug filling process does not require complex extrusion molding processes and is more convenient and efficient to operate. At the same time, capsules can effectively mask the unpleasant odor or taste of drugs, significantly improving the patient's medication experience. Since Maths first applied gelatin to the invention of medicinal capsules in the early 19th century, capsules have undergone technological innovation and are still the preferred option for dosage form development in industrial production to this day.

[0003] However, traditional capsules are mostly made of gelatin, with miscellaneous sources and uneven quality. In addition, the gelatin capsule shell has poor protection function for drugs sensitive to moisture and oxygen, and there are significant differences in dissolution and disintegration properties in the human stomach and intestines, making it impossible to achieve controlled release of drugs. Therefore, it is necessary to develop a capsule that can achieve sustained release and controlled release. Summary of the Invention

[0004] The purpose of the present invention is to provide a sustained-release and controlled-release hydroxypropyl methylcellulose hollow capsule to solve the problems raised in the prior art.

[0005] To achieve the above purpose, the present invention provides the following technical solution: A preparation method of a sustained-release and controlled-release hydroxypropyl methylcellulose hollow capsule, comprising the following steps: S1. Prepare antibacterial modified polysaccharide; S11. Disperse dextran in PBS buffer solution, add sodium periodate thereto, stir and react in the dark at room temperature for 18 - 24 h, then add ethylene glycol thereto, continue to stir in the dark for 1 - 1.5 h, place the obtained mixed solution in a dialysis bag with a molecular weight cut-off of 5000 - 15000 Da, dialyze with deionized water for 36 - 60 h, and then lyophilize the obtained product to obtain oxidized dextran; S12. Disperse oxidized dextran in a mixed solvent system with a volume ratio of ultrapure water to dimethyl sulfoxide of 1:1, add acetic acid thereto, adjust the pH value of the system to 5 - 6.5, then add 1-(diaminomethylene)guanidine thereto, raise the temperature to 50 - 75 °C, stir and reflux in the dark for 4 - 12 h, cool to a constant temperature, place it in a dialysis bag with a molecular weight cut-off of 8000 - 20000 Da, dialyze with deionized water for 36 - 60 h, and then lyophilize the obtained product to obtain guanidinylated dextran; S13. Disperse guanidinated dextran into ultrapure water. After adjusting the pH value to 4.5 - 5.5 using acetic acid, add carboxymethyl chitosan and 1,3 - dicyclohexylcarbodiimide thereto again. Continue reflux stirring for 8 - 24 h, then stop heating. Place the obtained mixture into a dialysis bag with a molecular weight cut - off of 50000 - 200000 Da, and perform dialysis treatment with deionized water for 48 - 72 h. Then, lyophilize the obtained product to obtain the antibacterial - modified polysaccharide. S2. Prepare the stock solution of the sustained - release capsule. Heat the ultrapure water to 60 - 65 °C, add hypromellose, antibacterial - modified polysaccharide, pigment, opacifier, and polyethylene glycol thereto, and mix them by magnetic stirring for 15 - 30 min. Then, perform high - speed dispersion homogenization on it for 3 - 5 min again, and conduct vacuum defoaming treatment to obtain the stock solution of the sustained - release capsule. S3. Prepare the sustained - release and controlled - release hypromellose hollow capsule. Immerse the capsule mold into the stock solution of the sustained - release capsule. After complete immersion, take it out and turn it over evenly, and place it in an environment at 40 - 50 °C for drying to obtain the sustained - release and controlled - release hypromellose hollow capsule.

[0006] Further, in step S11, the Mw of the dextran is 50000 - 100000.

[0007] Further, in step S11, by weight, the mass ratio of the dextran, sodium periodate, and ethylene glycol is 1:(0.4 - 1):(0.3 - 0.5).

[0008] Further, in step S12, by weight, the mass ratio of the oxidized dextran and 1 - (diaminomethylene)guanidine is 1:(0.1 - 0.6).

[0009] Further, in step S13, by weight, the mass ratio of the guanidinated dextran, carboxymethyl chitosan, and 1,3 - dicyclohexylcarbodiimide is 1:(0.25 - 0.7):(0.05 - 0.08).

[0010] Further, in step S2, by weight, the stock solution of the sustained - release capsule is composed of 75 - 110 parts of hypromellose, 30 - 60 parts of antibacterial - modified polysaccharide, 0.05 - 0.8 part of pigment, 0.2 - 0.9 part of opacifier, 10 - 30 parts of polyethylene glycol, and 300 - 450 parts of ultrapure water.

[0011] Further, in step S2, the polyethylene glycol is any one of polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 800.

[0012] Further, in step S2, the pigment is any one of edible pigments; the opacifier is titanium dioxide.

[0013] Furthermore, a sustained-release and controlled-release hypromellose hollow capsule is prepared by the above method.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: In order to achieve a long-term sustained-release and controlled-release effect of the drug, the present invention improves the hard shell of the capsule. When preparing the hard shell of the capsule, in order to achieve the purpose of slow release in the gastrointestinal tract, hypromellose is used as the main raw material of the shell. Hypromellose will form a gel in gastric juice, wrapping the drug components, thereby realizing the delayed release of the drug. On this basis, in order to achieve the purpose of controlled release, the present application also adds and prepares an antibacterial modified polysaccharide component in the raw material components. Using dextran as the raw material, aldehyde groups are generated after ring-opening oxidation with sodium periodate. The present invention further uses an excessive amount of 1-(diaminomethylene)guanidine containing guanidine and amino groups to react with the aldehyde groups in oxidized dextran, thereby introducing an amino structure into the oxidized dextran structure. Furthermore, the present invention further uses carboxymethyl chitosan to react with guanidinylated dextran, and uses the residual amino groups in 1-(diaminomethylene)guanidine to further introduce a chitosan polysaccharide structure into the polysaccharide, increasing the polysaccharide molecular weight and improving its film-forming performance. And the cross-linking of amino groups and carboxyl groups further improves the compactness and barrier properties of the capsule shell after curing and drying, enhancing the protection performance of the drug; The hollow capsule prepared by the present invention is suitable for taking drugs before meals. The residence time of the empty capsule in the stomach when taken on an empty stomach is generally 0.5 - 2 hours. During this time, since the antibacterial modified polysaccharide added in the preparation of the capsule shell by the present invention contains a chitosan structure, compared with hypromellose, the chitosan structure can be initially disintegrated in the gastric acid environment, so that the drug can be initially released in the stomach, and thus has a certain drug release function after taking. The remaining drugs will still be wrapped by hypromellose and enter the intestine, thereby realizing slow release in the intestine, so that the drug can maintain a relatively stable level in the human body; And the present invention takes into account that some drug capsules will be stored in a medicine bottle that is taken multiple times. During the multiple storage processes, the capsules will inevitably come into contact with the external environment and be contaminated by external miscellaneous bacteria. Therefore, the guanidine and chitosan structures added in the hollow capsule shell prepared by the present invention can also provide excellent antibacterial and anti-pollution capabilities for the capsule, avoiding the growth and pollution of miscellaneous bacteria and maintaining the efficacy of the drug for a long time. Description of the Drawings

[0015] The drawings are used to provide a further understanding of the present invention, and constitute a part of the specification. Together with the embodiments of the present invention, they are used to explain the present invention, and do not constitute a limitation to the present invention. In the drawings: Figure 11H NMR spectrum of the antibacterial modified polysaccharide prepared in Example 3 of the present invention; Figure 2 Chemical reaction formula S11 in Example 3 of the present invention; Figure 3 Chemical reaction formula S12 in Example 3 of the present invention; Figure 4 Chemical reaction formula S13 in Example 3 of the present invention. Detailed implementation mode

[0016] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0017] In this application, the dextran used has Mw = 70000; the hypromellose used is K100M type hypromellose; Example 1. A preparation method of a sustained-release and controlled-release hypromellose hollow capsule, comprising the following steps: S1. Prepare antibacterial modified polysaccharide; S11. By weight, disperse 1 part of dextran into PBS buffer solution, add 0.4 part of sodium periodate thereto, stir and react for 18 h in a dark room temperature environment, then add 0.3 part of ethylene glycol thereto, continue to stir in the dark for 1 h, place the obtained mixed solution in a dialysis bag with a molecular weight cut-off of 8000 Da, dialyze with deionized water for 36 h, and then freeze-dry the obtained product to obtain oxidized dextran; S12. By weight, disperse 1 part of oxidized dextran into a mixed solvent system with a volume ratio of ultrapure water to dimethyl sulfoxide of 1:1, add acetic acid thereto, adjust the pH value of the system to 5.5, then add 0.1 part of 1-(diaminomethylene)guanidine thereto, raise the temperature to 60 °C, and under a dark environment, reflux and stir for 8 h, then cool to a constant temperature, place it in a dialysis bag with a molecular weight cut-off of 15000 Da, dialyze with deionized water for 48 h, and then freeze-dry the obtained product to obtain guanidinylated dextran; S13. By weight, disperse 1 part of guanidinylated dextran into ultrapure water, adjust the pH value to 4.8 with acetic acid, then add 0.25 part of carboxymethyl chitosan and 0.05 part of 1,3-dicyclohexylcarbodiimide thereto, continue to reflux and stir for 18 h, stop heating, place the obtained mixed solution in a dialysis bag with a molecular weight cut-off of 70000 Da, dialyze with deionized water for 72 h, and then freeze-dry the obtained product to obtain antibacterial modified polysaccharide; S2. Prepare the sustained-release capsule stock solution; Weigh 300 parts of ultrapure water by weight, heat it up to 60 °C, add 80 parts of hypromellose, 30 parts of antibacterial modified polysaccharide, 0.1 part of edible pigment, 0.5 part of titanium dioxide sunscreen, and 10 parts of polyethylene glycol 400 to it. After magnetic stirring for 30 min, perform high-speed dispersion and homogenization on it again for 4 min, and then perform vacuum defoaming treatment to obtain the slow-release capsule stock solution; S3. Prepare sustained-release and controlled-release hypromellose hollow capsules; Immerse the capsule mold in the slow-release capsule stock solution. After complete immersion, take it out and turn it over evenly, and place it in an environment at 40 °C for drying for 4 h to obtain the sustained-release and controlled-release hypromellose hollow capsules.

[0018] Example 2. A method for preparing sustained-release and controlled-release hypromellose hollow capsules, comprising the following steps: Compared with Example 1, the addition amount of sodium periodate in step S11 is increased in this example; S1. Prepare antibacterial modified polysaccharide; S11. Weigh 1 part of dextran and disperse it in PBS buffer solution. Add 1 part of sodium periodate to it. After stirring and reacting in the dark at room temperature for 18 h, add 0.3 part of ethylene glycol to it. After continuing to stir in the dark for 1 h, place the obtained mixed solution in a dialysis bag with a molecular weight cut-off of 8000 Da, and perform dialysis treatment with deionized water for 36 h. Then freeze-dry the obtained product to obtain oxidized dextran; S12. Weigh 1 part of oxidized dextran and disperse it in a mixed solvent system with a volume ratio of ultrapure water to dimethyl sulfoxide of 1:1. Add acetic acid to it to adjust the pH value of the system to 5.5. Then add 0.1 part of 1-(diaminomethylene)guanidine to it, heat it up to 60 °C, and under a dark environment, reflux and stir for 8 h. After cooling to a constant temperature, place it in a dialysis bag with a molecular weight cut-off of 15000 Da, and perform dialysis treatment with deionized water for 48 h. Then freeze-dry the obtained product to obtain guanidinylated dextran; S13. Weigh 1 part of guanidinylated dextran and disperse it in ultrapure water. Use acetic acid to adjust the pH value to 4.8, and then add 0.25 part of carboxymethyl chitosan and 0.05 part of 1,3-dicyclohexylcarbodiimide to it again. Continue to reflux and stir for 18 h, then stop heating. Place the obtained mixed solution in a dialysis bag with a molecular weight cut-off of 70000 Da, and perform dialysis treatment with deionized water for 72 h. Then freeze-dry the obtained product to obtain antibacterial modified polysaccharide; S2. Prepare slow-release capsule stock solution; By weight parts, heat 300 parts of ultrapure water to 60 °C, add 80 parts of hypromellose, 30 parts of antibacterial modified polysaccharide, 0.1 part of edible pigment, 0.5 part of titanium dioxide opacifier, and 10 parts of polyethylene glycol 400 thereto, stir magnetically for 30 min, then perform high-speed dispersion homogenization on it for 4 min again, and perform vacuum defoaming treatment to obtain the slow-release capsule stock solution; S3. Prepare the sustained-release and controlled-release hypromellose hollow capsule; Immerse the capsule mold in the slow-release capsule stock solution, take it out and turn it over evenly after complete immersion, and dry it in an environment at 40 °C for 4 h to obtain the sustained-release and controlled-release hypromellose hollow capsule.

[0019] Example 3. A method for preparing a sustained-release and controlled-release hypromellose hollow capsule, comprising the following steps: Compared with Example 2, the addition amount of carboxymethyl chitosan in step S13 is increased in this example; S1. Prepare the antibacterial modified polysaccharide; S11. By weight parts, disperse 1 part of dextran in PBS buffer solution, add 1 part of sodium periodate thereto, stir and react in the dark at room temperature for 18 h, then add 0.3 part of ethylene glycol thereto, continue to stir in the dark for 1 h, place the obtained mixed solution in a dialysis bag with a molecular weight cut-off of 8000 Da, dialyze with deionized water for 36 h, and then freeze-dry the obtained product to obtain oxidized dextran; S12. By weight parts, disperse 1 part of oxidized dextran in a mixed solvent system with a volume ratio of ultrapure water to dimethyl sulfoxide of 1:1, add acetic acid thereto, adjust the pH value of the system to 5.5, then add 0.1 part of 1-(diaminomethylene)guanidine thereto, heat to 60 °C, and under a dark environment, reflux and stir for 8 h, then cool to a constant temperature, place it in a dialysis bag with a molecular weight cut-off of 15000 Da, dialyze with deionized water for 48 h, and then freeze-dry the obtained product to obtain guanidinylated dextran; S13. By weight parts, disperse 1 part of guanidinylated dextran in ultrapure water, adjust the pH value to 4.8 with acetic acid, then add 0.6 part of carboxymethyl chitosan and 0.05 part of 1,3-dicyclohexylcarbodiimide thereto again, continue to reflux and stir for 18 h, stop heating, place the obtained mixed solution in a dialysis bag with a molecular weight cut-off of 70000 Da, dialyze with deionized water for 72 h, and then freeze-dry the obtained product to obtain the antibacterial modified polysaccharide; S2. Prepare the slow-release capsule stock solution; Weigh 300 parts of ultrapure water by weight, heat it to 60 °C, add 80 parts of hypromellose, 30 parts of antibacterial modified polysaccharide, 0.1 part of edible pigment, 0.5 part of titanium dioxide opacifier, and 10 parts of polyethylene glycol 400 thereto, mix them by magnetic stirring for 30 min, then perform high-speed dispersion homogenization on it again for 4 min, and perform vacuum defoaming treatment to obtain the slow-release capsule stock solution; S3. Prepare sustained-release and controlled-release hypromellose hollow capsules; Immerse the capsule mold in the slow-release capsule stock solution, take it out and turn it over evenly after complete immersion, and dry it in an environment at 40 °C for 4 h to obtain the sustained-release and controlled-release hypromellose hollow capsules.

[0020] Example 4. A method for preparing sustained-release and controlled-release hypromellose hollow capsules, comprising the following steps: Compared with Example 3, the addition amount of the antibacterial modified polysaccharide in step S2 is increased in this example; S1. Prepare antibacterial modified polysaccharide; S11. Weigh 1 part of dextran by weight, disperse it in PBS buffer solution, add 1 part of sodium periodate thereto, stir and react in the dark at room temperature for 18 h, then add 0.3 part of ethylene glycol thereto, continue to stir in the dark for 1 h, place the obtained mixture in a dialysis bag with a molecular weight cut-off of 8000 Da, perform dialysis treatment with deionized water for 36 h, and then lyophilize the obtained product to obtain oxidized dextran; S12. Weigh 1 part of oxidized dextran by weight, disperse it in a mixed solvent system with a volume ratio of ultrapure water to dimethyl sulfoxide of 1:1, add acetic acid thereto, adjust the pH value of the system to 5.5, then add 0.1 part of 1-(diaminomethylene)guanidine thereto, heat it to 60 °C, and under a dark environment, reflux and stir for 8 h, then cool it to a constant temperature, place it in a dialysis bag with a molecular weight cut-off of 15000 Da, perform dialysis treatment with deionized water for 48 h, and then lyophilize the obtained product to obtain guanidinylated dextran; S13. Weigh 1 part of guanidinylated dextran by weight, disperse it in ultrapure water, adjust the pH value to 4.8 with acetic acid, then add 0.6 part of carboxymethyl chitosan and 0.05 part of 1,3-dicyclohexylcarbodiimide thereto again, continue to reflux and stir for 18 h, stop heating, place the obtained mixture in a dialysis bag with a molecular weight cut-off of 70000 Da, perform dialysis treatment with deionized water for 72 h, and then lyophilize the obtained product to obtain antibacterial modified polysaccharide; S2. Prepare slow-release capsule stock solution; Weigh 300 parts of ultrapure water by weight, heat it to 60 °C, add 80 parts of hypromellose, 45 parts of antibacterial modified polysaccharide, 0.1 part of edible pigment, 0.5 part of titanium dioxide opacifier, and 10 parts of polyethylene glycol 400 thereto, mix them by magnetic stirring for 30 min, then perform high-speed dispersion and homogenization on it again for 4 min, and then perform vacuum defoaming treatment to obtain the slow-release capsule stock solution; S3. Prepare the sustained-release and controlled-release hypromellose hollow capsule; Immerse the capsule mold in the slow-release capsule stock solution, take it out and turn it over evenly after complete immersion, and place it in an environment at 40 °C for drying for 4 h to obtain the sustained-release and controlled-release hypromellose hollow capsule.

[0021] Example 5. A method for preparing a sustained-release and controlled-release hypromellose hollow capsule, comprising the following steps: Compared with Example 4, the addition amount of the antibacterial modified polysaccharide in step S2 is further increased in this example; S1. Prepare the antibacterial modified polysaccharide; S11. Weigh 1 part of dextran by weight, disperse it in PBS buffer solution, add 1 part of sodium periodate thereto, stir and react in the dark at room temperature for 18 h, then add 0.3 part of ethylene glycol thereto, continue to stir in the dark for 1 h, place the obtained mixed solution in a dialysis bag with a molecular weight cut-off of 8000 Da, perform dialysis treatment with deionized water for 36 h, and then freeze-dry the obtained product to obtain oxidized dextran; S12. Weigh 1 part of oxidized dextran by weight, disperse it in a mixed solvent system with a volume ratio of ultrapure water to dimethyl sulfoxide of 1:1, add acetic acid thereto, adjust the pH value of the system to 5.5, then add 0.1 part of 1-(diaminomethylene)guanidine thereto, heat it to 60 °C, and under a dark environment, reflux and stir for 8 h, then cool it to a constant temperature, place it in a dialysis bag with a molecular weight cut-off of 15000 Da, perform dialysis treatment with deionized water for 48 h, and then freeze-dry the obtained product to obtain guanidinylated dextran; S13. Weigh 1 part of guanidinylated dextran by weight, disperse it in ultrapure water, adjust the pH value to 4.8 with acetic acid, then add 0.6 part of carboxymethyl chitosan and 0.05 part of 1,3-dicyclohexylcarbodiimide thereto again, continue to reflux and stir for 18 h, stop heating, place the obtained mixed solution in a dialysis bag with a molecular weight cut-off of 70000 Da, perform dialysis treatment with deionized water for 72 h, and then freeze-dry the obtained product to obtain the antibacterial modified polysaccharide; S2. Prepare the slow-release capsule stock solution; By weight, heat 300 parts of ultrapure water to 60 °C, add 80 parts of hypromellose, 60 parts of antibacterial modified polysaccharide, 0.1 part of edible pigment, 0.5 part of titanium dioxide sunscreen, and 10 parts of polyethylene glycol 400 thereto, mix them by magnetic stirring for 30 min, then perform high-speed dispersion and homogenization on the mixture for another 4 min, and then perform vacuum defoaming treatment to obtain the slow-release capsule stock solution; S3. Prepare the sustained-release and controlled-release hypromellose hollow capsule; Immerse the capsule mold in the slow-release capsule stock solution, take it out and turn it over evenly after complete immersion, and dry it in an environment at 40 °C for 4 h to obtain the sustained-release and controlled-release hypromellose hollow capsule.

[0022] Comparative Example 1. A method for preparing a sustained-release and controlled-release hypromellose hollow capsule, comprising the following steps: Compared with Example 1, in this comparative example, no modified polysaccharide was prepared and added, but only an equal amount of carboxymethyl chitosan was used as a substitute; S1. Prepare the slow-release capsule stock solution; By weight, heat 300 parts of ultrapure water to 60 °C, add 80 parts of hypromellose, 30 parts of carboxymethyl chitosan, 0.1 part of edible pigment, 0.5 part of titanium dioxide sunscreen, and 10 parts of polyethylene glycol 400 thereto, mix them by magnetic stirring for 30 min, then perform high-speed dispersion and homogenization on the mixture for another 4 min, and then perform vacuum defoaming treatment to obtain the slow-release capsule stock solution; S2. Prepare the sustained-release and controlled-release hypromellose hollow capsule; Immerse the capsule mold in the slow-release capsule stock solution, take it out and turn it over evenly after complete immersion, and dry it in an environment at 40 °C for 4 h to obtain the sustained-release and controlled-release hypromellose hollow capsule.

[0023] Comparative Example 2. A method for preparing a sustained-release and controlled-release hypromellose hollow capsule, comprising the following steps: Compared with Example 1, no modified polysaccharide was prepared and added in this comparative example; S1. Prepare the slow-release capsule stock solution; By weight, heat 300 parts of ultrapure water to 60 °C, add 110 parts of hypromellose, 0.1 part of edible pigment, 0.5 part of titanium dioxide sunscreen, and 10 parts of polyethylene glycol 400 thereto, mix them by magnetic stirring for 30 min, then perform high-speed dispersion and homogenization on the mixture for another 4 min, and then perform vacuum defoaming treatment to obtain the slow-release capsule stock solution; S2. Prepare the sustained-release and controlled-release hypromellose hollow capsule; Immerse the capsule mold in the slow-release capsule stock solution, take it out and turn it over evenly after complete immersion, and dry it in an environment at 40 °C for 4 h to obtain the sustained-release and controlled-release hypromellose hollow capsule.

[0024] Detection: The friability of the sustained-release hypromellose hollow capsules prepared in Examples 1-6 and Comparative Examples 1-2 of the present invention was detected respectively. During the detection, 60 capsules of each type were taken and placed at the bottom of a glass tube with an inner diameter of 25 mm and a length of 2600 mm. A polytetrafluoroethylene weight with a diameter of 23 mm and a weight of 22 ± 0.2 g was freely dropped from the tube opening to check whether the capsule samples were broken. The sustained-release hypromellose hollow capsules prepared in Examples 1-5 and Comparative Examples 1-2 of the present invention were placed in high-density polyethylene airtight plastic bottles at room temperature under the environment with a relative humidity of 75 ± 2% and a temperature of 25 ± 2°C. They were opened twice a day, each time for 3 minutes, and after 30 days of circulation, the number of molds and yeasts on the surface of the capsule shells was detected. The sustained-release hypromellose hollow capsules prepared in Examples 1-5 and Comparative Examples 1-2 of the present invention were placed under the environment with a relative humidity of 75 ± 2% and a temperature of 25 ± 2°C. After being stored for 48 hours, they were weighed and their moisture absorption rates were measured, as shown in Table 1 below.

[0025] After filling the sustained-release hypromellose hollow capsules prepared in Example 1 and Comparative Example 2 of the present invention with diprophylline pellets and closing them, they were respectively immersed in artificial gastric juice with a pH value of 1 and artificial intestinal juice with a pH value of 6.8 to detect their release rates. The detection results are shown in Table 2 below.

[0026] After filling the sustained-release hypromellose hollow capsules prepared in Example 3 and Comparative Example 2 of the present invention with diprophylline pellets and closing them, they were immersed in artificial gastric juice with a pH value of 1 for 2 hours, and then immersed in artificial intestinal juice with a pH value of 6.8 for another 2 hours to detect their release rates. The detection results are shown in Table 3 below.

[0027] The antibacterial modified polysaccharide prepared in Example 3 of the present invention was detected by nuclear magnetic resonance hydrogen spectrum. The detection results are shown in Figure 1 ; Chitosan is a linear polysaccharide formed by connecting N-acetyl-D-glucosamine through β-1,4-glycosidic bonds. Multiple characteristic peaks will appear in the NMR spectrum of chitosan in the range of 3-5.5 ppm. As can be seen from the correspondence in the figure, the chitosan structure was successfully introduced into the antibacterial modified polysaccharide prepared in this application, thus further introducing antibacterial chitosan into the dextran structure, improving the antibacterial property of the hollow capsule.

[0028] Finally, it should be noted that the above are only preferred embodiments of the present invention and are not used to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or perform equivalent replacements for some of the technical features. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A preparation method of a sustained-release and controlled-release hypromellose hollow capsule, characterized in that, It includes the following steps: S1. Prepare antibacterial modified polysaccharide; S11. Disperse dextran into PBS buffer solution, add sodium periodate to it, stir and react for 18 - 24 h in the dark at room temperature, then add ethylene glycol, continue to stir in the dark for 1 - 1.5 h, place the obtained mixture in a dialysis bag with a molecular weight cut-off of 5000 - 15000 Da, dialyze with deionized water for 36 - 60 h, and then lyophilize the obtained product to obtain oxidized dextran; S12. Disperse oxidized dextran into a mixed solvent system with a volume ratio of ultrapure water to dimethyl sulfoxide of 1:1, add acetic acid to it, adjust the pH value of the system to 5 - 6.5, then add 1-(diaminomethylene)guanidine, heat up to 50 - 75 °C, reflux and stir for 4 - 12 h in the dark, cool to a constant temperature, place it in a dialysis bag with a molecular weight cut-off of 8000 - 20000 Da, dialyze with deionized water for 36 - 60 h, and then lyophilize the obtained product to obtain guanidinylated dextran; S13. Disperse guanidinylated dextran into ultrapure water, adjust the pH value to 4.5 - 5.5 with acetic acid, then add carboxymethyl chitosan and 1,3-dicyclohexylcarbodiimide again, continue to reflux and stir for 8 - 24 h, stop heating, place the obtained mixture in a dialysis bag with a molecular weight cut-off of 50000 - 200000 Da, dialyze with deionized water for 48 - 72 h, and then lyophilize the obtained product to obtain antibacterial modified polysaccharide; S2. Prepare the stock solution of sustained-release capsules; Heat ultrapure water to 60 - 65 °C, add hypromellose, antibacterial modified polysaccharide, pigment, light-shielding agent, and polyethylene glycol to it, stir magnetically for 15 - 30 min, then disperse and homogenize it at high speed for 3 - 5 min, and perform vacuum degassing treatment to obtain the stock solution of sustained-release capsules; S3. Prepare sustained-release and controlled-release hypromellose hollow capsules; Immerse the capsule mold into the stock solution of sustained-release capsules, take it out and turn it evenly after complete immersion, and dry it in an environment of 40 - 50 °C to obtain sustained-release and controlled-release hypromellose hollow capsules.

2. The preparation method of a sustained-release and controlled-release hypromellose hollow capsule according to claim 1, characterized in that: In step S11, the Mw of the dextran is 50000 - 100000.

3. The preparation method of a sustained-release and controlled-release hypromellose hollow capsule according to claim 1, characterized in that: In step S11, by weight, the mass ratio of the dextran, sodium periodate, and ethylene glycol is 1:(0.4 - 1):(0.3 - 0.5).

4. The preparation method of a sustained-release and controlled-release hypromellose hollow capsule according to claim 1, characterized in that: In step S12, by weight, the mass ratio of the oxidized dextran and 1-(diaminomethylene)guanidine is 1:(0.1 - 0.6).

5. The preparation method of a sustained-release and controlled-release hypromellose hollow capsule according to claim 1, characterized in that: In step S13, by weight, the mass ratio of the guanidinylated dextran, carboxymethyl chitosan, and 1,3-dicyclohexylcarbodiimide is 1:(0.25 - 0.7):(0.05 - 0.08).

6. The preparation method of a sustained-release and controlled-release hypromellose hollow capsule according to claim 1, characterized in that: In step S2, by weight, the stock solution of sustained-release capsules is composed of 75 - 110 parts of hypromellose, 30 - 60 parts of antibacterial modified polysaccharide, 0.05 - 0.8 parts of pigment, 0.2 - 0.9 parts of light-shielding agent, 10 - 30 parts of polyethylene glycol, and 300 - 450 parts of ultrapure water.

7. The preparation method of a sustained-release and controlled-release hypromellose hollow capsule according to claim 1, characterized in that: In step S2, the polyethylene glycol is any one of polyethylene glycol 400, polyethylene glycol 600, and polyethylene glycol 800.

8. The preparation method of a sustained-release and controlled-release hypromellose hollow capsule according to claim 1, characterized in that: In step S2, the pigment is any one of edible pigments; the opacifier is titanium dioxide.

9. A sustained-release and controlled-release hypromellose hollow capsule prepared by the preparation method according to any one of claims 1-8.

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