Capsule medicament for endoscopic treatment of ulcerative colitis and preparation method thereof

Abstract

The invention discloses a capsule medicament for endoscopic treatment of ulcerative colitis and a preparation method thereof, and belongs to the technical field of biological medicine, the capsule medicament is composed of a capsule matrix and a drug matrix; by adopting a dual control mechanism of an enteric layer coating and a pH response layer coating, accurate release of a medicine at a colon diseased region is ensured, medicine waste of the stomach and the small intestine is reduced, the medicine concentration at a focus is improved, mesalazine or budesonide is combined with the composite composition for treatment, inflammatory response is rapidly inhibited, acute symptoms are controlled, and the curative effect is good. A multi-mechanism synergistic treatment mode is adopted, the anti-inflammatory and repairing effects are enhanced, the clinical remission rate and the mucous membrane healing rate are remarkably improved, the pH response layer is dissolved in a colon alkaline environment, and the MMP-9 peptide cross-linking agent is subjected to enzymolysis at an inflammation part, so that the medicine is continuously released at a focus, the administration frequency is reduced, the compliance of a patient is improved, and the curative effect is good. In addition, the spherical gel particles in the medicament can prevent the medicament from being disintegrated too early in the intestinal tract, and the long-acting effect can be maintained.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and specifically relates to a capsule medicament for endoscopic treatment of ulcerative colitis and a preparation method thereof. Background Art

[0002] Ulcerative colitis is a chronic, nonspecific intestinal inflammatory disease that primarily affects the colon and rectal mucosa, with clinical manifestations including diarrhea, abdominal pain, and bloody stools containing mucus and pus. Traditional treatments rely on oral or topical aminosalicylic acids, glucocorticoids, and immunosuppressants, but these can pose systemic side effects such as hormone dependency, infection risk, and uneven local drug distribution. Currently, endoscopic drug delivery usually involves injecting drugs directly into the submucosal layer or spraying them onto the mucosal surface through a colonoscope to accurately locate the lesion area and increase local drug concentration. However, this method is highly invasive, and the sprayed or injected drugs are easily diluted and washed away by intestinal fluid, making it difficult to maintain long-term effects, resulting in a short drug retention time. Summary of the Invention

[0003] In order to overcome the above-mentioned defects, the present invention provides a capsule medicine for endoscopic treatment of ulcerative colitis and a preparation method thereof, which solves the problem that drugs can be directly injected into the submucosal layer or sprayed onto the mucosal surface through colonoscopy, accurately locate the lesion area, and increase local drug concentration. However, the problem is that the invasiveness is high, the sprayed or injected drugs are easily diluted and washed away by intestinal fluid, and it is difficult to maintain a long-term effect, resulting in a short drug retention time.

[0004] To achieve the above object, the present invention provides the following technical solution: a capsule medicament for endoscopic treatment of ulcerative colitis, the capsule medicament comprising a capsule matrix and a drug matrix, wherein the mass ratio of the capsule matrix to the drug matrix is ​​3-4:6-7; The capsule matrix comprises an enteric layer coating and a pH responsive layer coating, wherein the mass ratio of the enteric layer coating to the pH responsive layer coating is 6-7:3-4; The drug matrix consists of a prepolymer liquid and a composite composition, and the mass ratio of the prepolymer liquid to the composite composition is 3-4:6-7.

[0005] As a further solution of the present invention: the preparation steps of the capsule matrix are as follows: An enteric coating solution is prepared by mixing 3-5 parts of an acrylic resin pH regulating release agent, 1-2 parts of triethyl citrate, and 80-100 parts of anhydrous ethanol; The capsule shell is made of hypromellose material, and the capsule shell is fixed on a rotating bracket and spray-coated with an enteric layer coating liquid at a spray rate of 2 mL / min and an inlet air temperature of 40° C. to obtain an enteric layer coating; A pH-responsive coating solution is prepared using 3-5 parts of gelatin, 1-2 parts of MMP-9 peptide cross-linker, 2-3 parts of Eudragit E PO, 1-2 parts of acetic acid, and 80-100 parts of ethanol; The pH-responsive layer coating liquid was sprayed twice on the outside of the enteric layer coating at a spray rate of 1 mL / min and an air inlet temperature of 35°C to obtain a capsule matrix. The capsule matrix was then ventilated and dried at 38-40°C for 24 hours to make the humidity of the capsule matrix ≤30%. The cured capsule matrix was then irradiated with UV.

[0006] As a further solution of the present invention: the preparation steps of the prepolymer solution are as follows: Dissolve 6-8 parts of sodium alginate, 3-5 parts of thiolated chitosan and 1-2 parts of polyacrylic acid in 80-100 parts of deionized water, and stir at 50°C for 2 hours until completely transparent; Next, add 1-2 parts of MMP-9 substrate peptide cross-linker, 1-2 parts of lipoic acid, and 4-5 parts of mannitol and continue stirring for 30 minutes; Then, 10-15 parts of mesalazine or 3-5 parts of budesonide are added and ultrasonic dispersion is performed to form a homogeneous drug-loaded sol, thereby completing the preparation of the prepolymer solution.

[0007] As a further solution of the present invention: the composite composition is prepared by mixing Pulsatilla scabra extract, Sanguisorba officinalis tannin microspheres and Bletilla striata colloid-coated Dragon's Blood nanoparticles, and the mass ratio of the Pulsatilla scabra extract, Sanguisorba officinalis tannin microspheres and Bletilla striata colloid-coated Dragon's Blood nanoparticles is 6-8:9-10:4-5.

[0008] A method for preparing a capsule medicament for endoscopic treatment of ulcerative colitis, the method comprising the following steps: S1. Preparation of capsule matrix: an acrylic resin pH regulating release agent, triethyl citrate and anhydrous ethanol are mixed to prepare an enteric layer coating solution, a capsule shell is prepared using hydroxypropyl methylcellulose material, the capsule shell is fixed on a rotating stand and spray-coated with the enteric layer coating solution at a spray rate of 2 mL / min and an inlet air temperature of 40°C to obtain an enteric layer coating, a pH responsive layer coating solution is prepared using gelatin, an MMP-9 peptide cross-linker, Eudragit E PO, acetic acid and ethanol, the pH responsive layer coating solution is sprayed a second time on the outside of the enteric layer coating at a spray rate of 1 mL / min and an inlet air temperature of 35°C to obtain a capsule matrix, and the capsule matrix is ​​ventilated and dried at 38-40°C for 24 hours to make the humidity of the capsule matrix ≤30%, and the cured capsule matrix is ​​irradiated with UV light; S2. Preparation of prepolymer solution: Sodium alginate, thiolated chitosan, and polyacrylic acid were dissolved in deionized water and stirred at 50°C for 2 hours until completely transparent. Then, MMP-9 substrate peptide cross-linker, lipoic acid, and mannitol were added and stirred for 30 minutes. Then, mesalazine or budesonide was added and ultrasonically dispersed to form a homogeneous drug-loaded sol, thus completing the preparation of the prepolymer solution. S3. Preparation of gel particles: A composite composition comprising Pulsatilla scabra extract, Sanguisorba officinalis tannin microspheres, and Bletilla striata colloid-coated Dragon's Blood nanoparticles was added to the drug-loaded sol. After thorough mixing, a calcium chloride solution was added dropwise and allowed to react for 30 minutes to form spherical gel particles with a diameter of 1.5-2 mm. The spherical gel particles were then immersed in an aqueous hydrogen peroxide solution and shaken at 35-37°C for 1-1.2 hours to induce sulfhydryl oxidation to form disulfide bonds and enhance mechanical strength. S4. Preparation of capsule medicine: The gel particles are freeze-dried and quickly frozen at -80°C for 4 hours, then maintained at -40°C / 0.1mBar for 24 hours, and finally maintained at 25°C / 0.01mBar for 6 hours to reduce the moisture content of the particles to ≤3%. This completes the preparation of the drug matrix, which is then placed in a capsule matrix to complete the preparation of the capsule medicine.

[0009] Compared with the prior art, the beneficial effects of the present invention are: by adopting a dual control mechanism of enteric layer coating and pH responsive layer coating, the drug is ensured to be accurately released at the site of colon lesions, reducing drug waste in the stomach and small intestine, and increasing the drug concentration at the lesion site. The compound composition is combined with mesalazine or budesonide for treatment, which quickly inhibits the inflammatory response and controls acute symptoms. The multi-mechanism synergistic treatment approach is adopted to enhance the anti-inflammatory and repair effects, significantly improve the clinical remission rate and mucosal healing rate, and the pH responsive layer dissolves in the alkaline environment of the colon, and the MMP-9 peptide cross-linker is enzymatically hydrolyzed at the site of inflammation, so that the drug is continuously released at the lesion site, reducing the frequency of administration and improving patient compliance. In addition, the spherical gel particles in the drug prevent the drug from prematurely disintegrating in the intestine, and can maintain a long-lasting effect. DETAILED DESCRIPTION

[0010] The technical solution of the present application will be further described in detail below in conjunction with specific implementation methods.

[0011] The present invention provides a technical solution: a capsule medicament for endoscopic treatment of ulcerative colitis, the capsule medicament comprising a capsule matrix and a drug matrix, wherein the mass ratio of the capsule matrix to the drug matrix is ​​3-4:6-7; The capsule matrix includes an enteric layer coating and a pH-responsive layer coating, and the mass ratio of the enteric layer coating to the pH-responsive layer coating is 6-7:3-4; The drug matrix consists of a prepolymer liquid and a composite composition, and the mass ratio of the prepolymer liquid to the composite composition is 3-4:6-7.

[0012] The preparation steps of the capsule matrix are as follows: An enteric coating solution is prepared by mixing 3-5 parts of an acrylic resin pH regulating release agent, 1-2 parts of triethyl citrate, and 80-100 parts of anhydrous ethanol; The capsule shell is made of hypromellose material, and the capsule shell is fixed on a rotating bracket and spray-coated with an enteric layer coating liquid at a spray rate of 2 mL / min and an inlet air temperature of 40° C. to obtain an enteric layer coating; A pH-responsive coating solution is prepared using 3-5 parts of gelatin, 1-2 parts of MMP-9 peptide cross-linker, 2-3 parts of Eudragit E PO, 1-2 parts of acetic acid, and 80-100 parts of ethanol; The pH-responsive layer coating liquid was sprayed twice on the outside of the enteric layer coating at a spray rate of 1 mL / min and an air inlet temperature of 35°C to obtain a capsule matrix. The capsule matrix was then ventilated and dried at 38-40°C for 24 hours to make the humidity of the capsule matrix ≤30%. The cured capsule matrix was then irradiated with UV.

[0013] The preparation steps of the prepolymer solution are as follows: Dissolve 6-8 parts of sodium alginate, 3-5 parts of thiolated chitosan and 1-2 parts of polyacrylic acid in 80-100 parts of deionized water, and stir at 50°C for 2 hours until completely transparent; Next, add 1-2 parts of MMP-9 substrate peptide cross-linker, 1-2 parts of lipoic acid, and 4-5 parts of mannitol and continue stirring for 30 minutes; Then, 10-15 parts of mesalazine or 3-5 parts of budesonide are added and ultrasonic dispersion is performed to form a homogeneous drug-loaded sol, thereby completing the preparation of the prepolymer solution.

[0014] The composite composition is prepared by mixing pulsatilla extract, sanguisorba officinalis tannin microspheres and bletilla striata colloid-coated dragon's blood nanoparticles, and the mass ratio of pulsatilla extract, sanguisorba officinalis tannin microspheres and bletilla striata colloid-coated dragon's blood nanoparticles is 6-8:9-10:4-5.

[0015] A method for preparing a capsule medicament for endoscopic treatment of ulcerative colitis, the preparation method comprising the following steps: S1. Preparation of capsule matrix: an acrylic resin pH regulating release agent, triethyl citrate and anhydrous ethanol are mixed to prepare an enteric layer coating solution, a capsule shell is prepared using hydroxypropyl methylcellulose material, the capsule shell is fixed on a rotating stand and spray-coated with the enteric layer coating solution at a spray rate of 2 mL / min and an inlet air temperature of 40°C to obtain an enteric layer coating, a pH responsive layer coating solution is prepared using gelatin, an MMP-9 peptide cross-linker, Eudragit E PO, acetic acid and ethanol, the pH responsive layer coating solution is sprayed a second time on the outside of the enteric layer coating at a spray rate of 1 mL / min and an inlet air temperature of 35°C to obtain a capsule matrix, and the capsule matrix is ​​ventilated and dried at 38-40°C for 24 hours to make the humidity of the capsule matrix ≤30%, and the cured capsule matrix is ​​irradiated with UV light; S2. Preparation of prepolymer solution: Sodium alginate, thiolated chitosan, and polyacrylic acid were dissolved in deionized water and stirred at 50°C for 2 hours until completely transparent. Then, MMP-9 substrate peptide cross-linker, lipoic acid, and mannitol were added and stirred for 30 minutes. Then, mesalazine or budesonide was added and ultrasonically dispersed to form a homogeneous drug-loaded sol, thus completing the preparation of the prepolymer solution. S3. Preparation of gel particles: A composite composition comprising Pulsatilla scabra extract, Sanguisorba officinalis tannin microspheres, and Bletilla striata colloid-coated Dragon's Blood nanoparticles was added to the drug-loaded sol. After thorough mixing, a calcium chloride solution was added dropwise and allowed to react for 30 minutes to form spherical gel particles with a diameter of 1.5-2 mm. The spherical gel particles were then immersed in an aqueous hydrogen peroxide solution and shaken at 35-37°C for 1-1.2 hours to induce sulfhydryl oxidation to form disulfide bonds and enhance mechanical strength. S4. Preparation of capsule medicine: The gel particles are freeze-dried and quickly frozen at -80°C for 4 hours, then maintained at -40°C / 0.1mBar for 24 hours, and finally maintained at 25°C / 0.01mBar for 6 hours to reduce the moisture content of the particles to ≤3%. This completes the preparation of the drug matrix, which is then placed in a capsule matrix to complete the preparation of the capsule medicine.

[0016] Example 1: A method for preparing a capsule medicament for endoscopic treatment of ulcerative colitis, the preparation method comprising the following steps: S1. Preparation of capsule matrix: an acrylic resin pH regulating release agent, triethyl citrate and anhydrous ethanol are mixed to prepare an enteric layer coating solution, a capsule shell is prepared using hydroxypropyl methylcellulose material, the capsule shell is fixed on a rotating stand and spray-coated with the enteric layer coating solution at a spray rate of 2 mL / min and an inlet air temperature of 40°C to obtain an enteric layer coating, a pH responsive layer coating solution is prepared using gelatin, an MMP-9 peptide cross-linker, Eudragit E PO, acetic acid and ethanol, the pH responsive layer coating solution is sprayed a second time on the outside of the enteric layer coating at a spray rate of 1 mL / min and an inlet air temperature of 35°C to obtain a capsule matrix, and the capsule matrix is ​​ventilated and dried at 38-40°C for 24 hours to make the humidity of the capsule matrix ≤30%, and the cured capsule matrix is ​​irradiated with UV light; S2. Preparation of prepolymer solution: Sodium alginate, thiolated chitosan, and polyacrylic acid were dissolved in deionized water and stirred at 50°C for 2 hours until completely transparent. Then, MMP-9 substrate peptide cross-linker, lipoic acid, and mannitol were added and stirred for 30 minutes. Mesalazine was then added and ultrasonically dispersed to form a homogeneous drug-loaded sol, thus completing the preparation of the prepolymer solution. S3. Preparation of gel particles: A composite composition comprising Pulsatilla scabra extract, Sanguisorba officinalis tannin microspheres, and Bletilla striata colloid-coated Dragon's Blood nanoparticles was added to the drug-loaded sol. After thorough mixing, a calcium chloride solution was added dropwise and allowed to react for 30 minutes to form spherical gel particles with a diameter of 1.5-2 mm. The spherical gel particles were then immersed in an aqueous hydrogen peroxide solution and shaken at 35-37°C for 1-1.2 hours to induce sulfhydryl oxidation to form disulfide bonds and enhance mechanical strength. S4. Preparation of capsule medicine: The gel particles are freeze-dried and quickly frozen at -80°C for 4 hours, then maintained at -40°C / 0.1mBar for 24 hours, and finally maintained at 25°C / 0.01mBar for 6 hours to reduce the moisture content of the particles to ≤3%. This completes the preparation of the drug matrix, which is then placed in a capsule matrix to complete the preparation of the capsule medicine.

[0017] Example 2: A method for preparing a capsule medicament for endoscopic treatment of ulcerative colitis, the preparation method comprising the following steps: S1. Preparation of capsule matrix: an acrylic resin pH regulating release agent, triethyl citrate and anhydrous ethanol are mixed to prepare an enteric layer coating solution, a capsule shell is prepared using hydroxypropyl methylcellulose material, the capsule shell is fixed on a rotating stand and spray-coated with the enteric layer coating solution at a spray rate of 2 mL / min and an inlet air temperature of 40°C to obtain an enteric layer coating, a pH responsive layer coating solution is prepared using gelatin, an MMP-9 peptide cross-linker, Eudragit E PO, acetic acid and ethanol, the pH responsive layer coating solution is sprayed a second time on the outside of the enteric layer coating at a spray rate of 1 mL / min and an inlet air temperature of 35°C to obtain a capsule matrix, and the capsule matrix is ​​ventilated and dried at 38-40°C for 24 hours to make the humidity of the capsule matrix ≤30%, and the cured capsule matrix is ​​irradiated with UV light; S2. Preparation of prepolymer solution: Sodium alginate, thiolated chitosan, and polyacrylic acid were dissolved in deionized water and stirred at 50°C for 2 hours until completely transparent. Then, MMP-9 substrate peptide cross-linker, lipoic acid, and mannitol were added and stirred for 30 minutes. Then, budesonide was added and ultrasonically dispersed to form a homogeneous drug-loaded sol, thus completing the preparation of the prepolymer solution. S3. Preparation of gel particles: A composite composition comprising Pulsatilla scabra extract, Sanguisorba officinalis tannin microspheres, and Bletilla striata colloid-coated Dragon's Blood nanoparticles was added to the drug-loaded sol. After thorough mixing, a calcium chloride solution was added dropwise and allowed to react for 30 minutes to form spherical gel particles with a diameter of 1.5-2 mm. The spherical gel particles were then immersed in an aqueous hydrogen peroxide solution and shaken at 35-37°C for 1-1.2 hours to induce sulfhydryl oxidation to form disulfide bonds and enhance mechanical strength. S4. Preparation of capsule medicine: The gel particles are freeze-dried and quickly frozen at -80°C for 4 hours, then maintained at -40°C / 0.1mBar for 24 hours, and finally maintained at 25°C / 0.01mBar for 6 hours to reduce the moisture content of the particles to ≤3%. This completes the preparation of the drug matrix, which is then placed in a capsule matrix to complete the preparation of the capsule medicine.

[0018] Example 3: A method for preparing a capsule medicament for endoscopic treatment of ulcerative colitis, the preparation method comprising the following steps: S1. Preparation of capsule matrix: an acrylic resin pH regulating release agent, triethyl citrate and anhydrous ethanol are mixed to prepare an enteric layer coating solution, a capsule shell is prepared using hydroxypropyl methylcellulose material, the capsule shell is fixed on a rotating stand and spray-coated with the enteric layer coating solution at a spray rate of 2 mL / min and an inlet air temperature of 40°C to obtain an enteric layer coating, a pH responsive layer coating solution is prepared using gelatin, an MMP-9 peptide cross-linker, Eudragit E PO, acetic acid and ethanol, the pH responsive layer coating solution is sprayed a second time on the outside of the enteric layer coating at a spray rate of 1 mL / min and an inlet air temperature of 35°C to obtain a capsule matrix, and the capsule matrix is ​​ventilated and dried at 38-40°C for 24 hours to make the humidity of the capsule matrix ≤30%, and the cured capsule matrix is ​​irradiated with UV light; S2. Preparation of prepolymer solution: Sodium alginate, thiolated chitosan, and polyacrylic acid were dissolved in deionized water and stirred at 50°C for 2 hours until completely transparent. Then, MMP-9 substrate peptide cross-linker, lipoic acid, and mannitol were added and stirred for 30 minutes. Mesalazine was then added and ultrasonically dispersed to form a homogeneous drug-loaded sol, thus completing the preparation of the prepolymer solution. S3. Preparation of gel particles: Next, calcium chloride solution is added dropwise to the drug-loaded sol and allowed to react for 30 minutes to form spherical gel particles with a diameter of 1.5-2 mm. The spherical gel particles are then immersed in a hydrogen peroxide solution and shaken at 35-37°C for 1-1.2 hours to induce oxidation of the sulfhydryl groups to form disulfide bonds and enhance mechanical strength. S4. Preparation of capsule medicine: The gel particles are freeze-dried and quickly frozen at -80°C for 4 hours, then maintained at -40°C / 0.1mBar for 24 hours, and finally maintained at 25°C / 0.01mBar for 6 hours to reduce the moisture content of the particles to ≤3%. This completes the preparation of the drug matrix, which is then placed in a capsule matrix to complete the preparation of the capsule medicine.

[0019] Example 4: A method for preparing a capsule medicament for endoscopic treatment of ulcerative colitis, the preparation method comprising the following steps: S1. Preparation of capsule matrix: an acrylic resin pH regulating release agent, triethyl citrate and anhydrous ethanol are mixed to prepare an enteric layer coating solution, a capsule shell is prepared using hydroxypropyl methylcellulose material, the capsule shell is fixed on a rotating stand and spray-coated with the enteric layer coating solution at a spray rate of 2 mL / min and an inlet air temperature of 40°C to obtain an enteric layer coating, a pH responsive layer coating solution is prepared using gelatin, an MMP-9 peptide cross-linker, Eudragit E PO, acetic acid and ethanol, the pH responsive layer coating solution is sprayed a second time on the outside of the enteric layer coating at a spray rate of 1 mL / min and an inlet air temperature of 35°C to obtain a capsule matrix, and the capsule matrix is ​​ventilated and dried at 38-40°C for 24 hours to make the humidity of the capsule matrix ≤30%, and the cured capsule matrix is ​​irradiated with UV light; S2. Preparation of prepolymer solution: Sodium alginate, thiolated chitosan, and polyacrylic acid were dissolved in deionized water and stirred at 50°C for 2 hours until completely transparent. Then, MMP-9 substrate peptide cross-linker, lipoic acid, and mannitol were added and stirred for 30 minutes. Ultrasonic dispersion was performed to form a homogeneous drug-loaded sol, thus completing the preparation of the prepolymer solution. S3. Preparation of gel particles: A composite composition comprising Pulsatilla scabra extract, Sanguisorba officinalis tannin microspheres, and Bletilla striata colloid-coated Dragon's Blood nanoparticles was added to the drug-loaded sol. After thorough mixing, a calcium chloride solution was added dropwise and allowed to react for 30 minutes to form spherical gel particles with a diameter of 1.5-2 mm. The spherical gel particles were then immersed in an aqueous hydrogen peroxide solution and shaken at 35-37°C for 1-1.2 hours to induce sulfhydryl oxidation to form disulfide bonds and enhance mechanical strength. S4. Preparation of capsule medicine: The gel particles are freeze-dried and quickly frozen at -80°C for 4 hours, then maintained at -40°C / 0.1mBar for 24 hours, and finally maintained at 25°C / 0.01mBar for 6 hours to reduce the moisture content of the particles to ≤3%. This completes the preparation of the drug matrix, which is then placed in a capsule matrix to complete the preparation of the capsule medicine.

[0020] Based on the medication examples and comparative data tables designed for capsule medicaments, the following table is obtained according to Examples 1-4:

[0021] From the comparison in the above table we can see that: In Example 1, the capsule medicament is prepared by combining mesalazine + the composite composition, which has the highest clinical remission rate, mucosal healing rate and targeted release efficiency; and the lowest recurrence rate and adverse reaction rate, and the actual application effect is obvious. Due to Examples 2-4, Example 1 is selected as the best solution for preparing the capsule medicament; The difference between Example 1 and Example 2 is that: Example 1 uses mesalazine, and Example 2 uses budesonide. The difference in the application effects of the capsule medicaments is small, and both are applicable. Since Examples 3 and 4 respectively used mesalazine and the compound composition as the pharmaceutical component, the capsule prepared in Example 3 had the worst efficacy.

[0022] Therefore, the best treatment effect is to use Western medicine to control acute inflammation and combine it with Chinese medicine ingredients to regulate immunity and repair the mucosa.

[0023] From the above we know that: By adopting a dual control mechanism of enteric layer coating and pH-responsive layer coating, the drug is precisely released at the site of colon lesions, reducing drug waste in the stomach and small intestine and increasing drug concentration at the lesion site. Treatment with mesalazine or budesonide combined with a composite composition can quickly inhibit inflammatory responses, control acute symptoms, and adopt a multi-mechanism synergistic treatment approach to enhance anti-inflammatory and repair effects, significantly improving clinical remission rates and mucosal healing rates. Moreover, the pH-responsive layer dissolves in the alkaline environment of the colon, and the MMP-9 peptide cross-linker is enzymatically hydrolyzed at the site of inflammation, allowing for sustained release of the drug at the lesion, reducing dosing frequency and improving patient compliance. The spherical gel particles in the medicine prevent the drug from disintegrating prematurely in the intestine and can maintain a long-lasting effect.

[0024] Finally, a few points should be explained: Although the present invention has been described in detail above with general descriptions and specific embodiments, on the basis of the present invention, the above embodiments are only used to illustrate the technical solution of the present invention, rather than to limit it; although the present invention has been described in detail with reference to the aforementioned embodiments, ordinary technicians in this field should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some or all of the technical features therein; and these modifications or replacements do not cause the essence of the corresponding technical solution to deviate from the scope of the technical solution of the embodiments of the present invention.

Claims

1. A capsule medicament for endoscopic treatment of ulcerative colitis, characterized in that: The capsule medicine is composed of a capsule matrix and a drug matrix, and the mass ratio of the capsule matrix to the drug matrix is ​​3-4:6-7; The capsule matrix comprises an enteric layer coating and a pH responsive layer coating, wherein the mass ratio of the enteric layer coating to the pH responsive layer coating is 6-7:3-4; The drug matrix consists of a prepolymer liquid and a composite composition, and the mass ratio of the prepolymer liquid to the composite composition is 3-4:6-7.

2. The capsule preparation for endoscopic treatment of ulcerative colitis according to claim 1, characterized in that: The preparation steps of the capsule matrix are as follows: An enteric coating solution is prepared by mixing 3-5 parts of an acrylic resin pH regulating release agent, 1-2 parts of triethyl citrate, and 80-100 parts of anhydrous ethanol; The capsule shell is made of hypromellose material, and the capsule shell is fixed on a rotating bracket and spray-coated with an enteric layer coating liquid at a spray rate of 2 mL / min and an inlet air temperature of 40° C. to obtain an enteric layer coating; A pH-responsive coating solution is prepared using 3-5 parts of gelatin, 1-2 parts of MMP-9 peptide cross-linker, 2-3 parts of Eudragit E PO, 1-2 parts of acetic acid, and 80-100 parts of ethanol; The pH-responsive layer coating liquid was sprayed twice on the outside of the enteric layer coating at a spray rate of 1 mL / min and an air inlet temperature of 35°C to obtain a capsule matrix. The capsule matrix was then ventilated and dried at 38-40°C for 24 hours to make the humidity of the capsule matrix ≤30%. The cured capsule matrix was then irradiated with UV.

3. The capsule preparation for endoscopic treatment of ulcerative colitis according to claim 1, characterized in that: The preparation steps of the prepolymer solution are as follows: Dissolve 6-8 parts of sodium alginate, 3-5 parts of thiolated chitosan and 1-2 parts of polyacrylic acid in 80-100 parts of deionized water, and stir at 50°C for 2 hours until completely transparent; Next, add 1-2 parts of MMP-9 substrate peptide cross-linker, 1-2 parts of lipoic acid, and 4-5 parts of mannitol and continue stirring for 30 minutes; Then, 10-15 parts of mesalazine or 3-5 parts of budesonide are added and ultrasonic dispersion is performed to form a homogeneous drug-loaded sol, thereby completing the preparation of the prepolymer solution.

4. The capsule preparation for endoscopic treatment of ulcerative colitis according to claim 1, characterized in that: The composite composition is prepared by mixing pulsatilla extract, sanguisorba officinalis tannin microspheres and bletilla striata colloid-coated dragon's blood nanoparticles, and the mass ratio of the pulsatilla extract, sanguisorba officinalis tannin microspheres and bletilla striata colloid-coated dragon's blood nanoparticles is 6-8:9-10:4-5.

5. A method for preparing a capsule medicament for endoscopic treatment of ulcerative colitis, according to any one of claims 1 to 4, characterized in that: The preparation method comprises the following steps: S1. Preparation of capsule matrix: an acrylic resin pH regulating release agent, triethyl citrate and anhydrous ethanol are mixed to prepare an enteric layer coating solution, a capsule shell is prepared using hydroxypropyl methylcellulose material, the capsule shell is fixed on a rotating stand and spray-coated with the enteric layer coating solution at a spray rate of 2 mL / min and an inlet air temperature of 40°C to obtain an enteric layer coating, a pH responsive layer coating solution is prepared using gelatin, an MMP-9 peptide cross-linker, Eudragit E PO, acetic acid and ethanol, the pH responsive layer coating solution is sprayed a second time on the outside of the enteric layer coating at a spray rate of 1 mL / min and an inlet air temperature of 35°C to obtain a capsule matrix, and the capsule matrix is ​​ventilated and dried at 38-40°C for 24 hours to make the humidity of the capsule matrix ≤30%, and the cured capsule matrix is ​​irradiated with UV light; S2. Preparation of prepolymer solution: Sodium alginate, thiolated chitosan, and polyacrylic acid were dissolved in deionized water and stirred at 50°C for 2 hours until completely transparent. Then, MMP-9 substrate peptide cross-linker, lipoic acid, and mannitol were added and stirred for 30 minutes. Then, mesalazine or budesonide was added and ultrasonically dispersed to form a homogeneous drug-loaded sol, thus completing the preparation of the prepolymer solution. S3. Preparation of gel particles: A composite composition comprising Pulsatilla scabra extract, Sanguisorba officinalis tannin microspheres, and Bletilla striata colloid-coated Dragon's Blood nanoparticles was added to the drug-loaded sol. After thorough mixing, a calcium chloride solution was added dropwise and allowed to react for 30 minutes to form spherical gel particles with a diameter of 1.5-2 mm. The spherical gel particles were then immersed in an aqueous hydrogen peroxide solution and shaken at 35-37°C for 1-1.2 hours to induce sulfhydryl oxidation to form disulfide bonds and enhance mechanical strength. S4. Preparation of capsule medicine: The gel particles are freeze-dried and quickly frozen at -80°C for 4 hours, then maintained at -40°C / 0.1mBar for 24 hours, and finally maintained at 25°C / 0.01mBar for 6 hours to reduce the moisture content of the particles to ≤3%. This completes the preparation of the drug matrix, which is then placed in a capsule matrix to complete the preparation of the capsule medicine.

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