A thermosensitive gel composition for adjuvant treatment of radiation proctitis and its preparation method

Abstract

This invention relates to the field of thermosensitive gel technology, specifically to a thermosensitive gel composition for adjuvant treatment of radiation-induced proctitis and its preparation method. The raw materials for preparing the thermosensitive gel composition include the following components in parts by weight: curcumin@sodium alginate 1.6-3.2 parts, CS-PCA-Arg 2-4 parts, poloxamer 407 45-90 parts, carbomer 940 3-6 parts, and sodium hyaluronate 6-12 parts. The obtained thermosensitive gel composition exhibits good stability and can be used as an adjuvant treatment for radiation-induced proctitis.

Description

Technical Field

[0001] This invention relates to the field of thermosensitive gel technology, specifically to a thermosensitive gel composition for adjuvant treatment of radiation proctitis and its preparation method. Background Technology

[0002] Radiation proctitis (RP) refers to a rectal complication that occurs in patients with pelvic malignant tumors during or after radiotherapy. The rectal mucosa may become eroded, ulcerated, or bleed. Clinical manifestations include abdominal pain, diarrhea, rectal bleeding, and mucus-containing bloody stools, severely impacting the patient's quality of life. Based on the speed of onset, radiation proctitis is classified as acute or chronic. Acute radiation proctitis mostly occurs 1-2 weeks after radiotherapy, primarily manifesting as diarrhea, tenesmus, painful defecation, and mucus-containing or bloody stools. Approximately 80% of patients experience acute diarrhea during radiotherapy. Chronic cases mostly occur months to years after radiotherapy, presenting as rectal stenosis, difficulty defecating, and even intestinal obstruction. Currently, there are no ideal drugs or treatments for radiation proctitis, either domestically or internationally. In actual clinical practice, the management of radiation proctitis mainly involves hormone therapy and symptomatic supportive treatment to alleviate symptoms, but the efficacy is not ideal. Hormone therapy has problems such as strong dependence, long treatment courses, and numerous side effects. Symptomatic treatments such as antibiotics, hemostatic drugs, and film-forming agents cannot fundamentally repair damaged mucous membranes. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention proposes a thermosensitive gel composition for the adjunctive treatment of radiation proctitis and its preparation method.

[0004] This invention is achieved through the following technical solution:

[0005] A thermosensitive gel composition for adjuvant treatment of radiation proctitis, comprising the following components in parts by weight: curcumin@sodium alginate 1.6-3.2 parts, CS-PCA-Arg 2-4 parts, poloxamer 407 45-90 parts, carbomer 940 3-6 parts, and sodium hyaluronate 6-12 parts.

[0006] Furthermore, the raw materials for preparing curcumin@sodium alginate include the following components in parts by weight: 2-3 parts sialic acid, 1-1.5 parts chitosan, 6-9 parts sodium alginate, and 1-1.5 parts curcumin.

[0007] Furthermore, the preparation method of curcumin@sodium alginate includes the following steps:

[0008] L1. Chitosan was dissolved in 1% v / v acetic acid solution to obtain CS solution. Sialic acid was dissolved in MES buffer at pH 6. EDC·HCl and NHS were added and stirred for 30 min. The mixture was then added to the CS solution and stirred at pH 6 for 24 h. The mixture was dialyzed with deionized water for 3 days and then freeze-dried under vacuum to obtain SA-chitosan.

[0009] L2. Add the SA-chitosan and sodium alginate obtained in step L1 to distilled water and stir until homogeneous. Add Tween 80 and mix well. Add curcumin and stir thoroughly. Sonicate to mix well. Homogenize at 4℃ and 10000 r / min for 30 min. Add dropwise to 2wt% CaCl2 solution. Stir at 100 r / min for 2 h at room temperature. Centrifuge at 3000 r / min for 5 min. Wash the precipitate with deionized water and ethanol. Dry under vacuum to obtain curcumin@sodium alginate.

[0010] Further, in step L1, the chitosan has a mass concentration of 20 mg / mL in a 1% v / v acetic acid solution.

[0011] Further, in step L1, the mass concentration of sialic acid in the MES buffer is 20-30 mg / mL.

[0012] Furthermore, in step L1, the mass ratio of sialic acid, EDC·HCl and NHS is 4:3:1.8.

[0013] Furthermore, in step L2, the sodium alginate has a mass concentration of 15 mg / mL in distilled water.

[0014] Furthermore, in step L2, the concentration of Tween 80 in distilled water is 0.5% v / v.

[0015] Furthermore, in step L2, the volume ratio of the CaCl2 solution to distilled water is 3:1.

[0016] Furthermore, the raw materials for preparing CS-PCA-Arg include the following components in parts by weight: 1.2-1.8 parts chitosan, 0.4-0.6 parts protocatechuic acid, and 0.5-0.8 parts arginine.

[0017] Furthermore, the preparation method of the CS-PCA-Arg includes the following steps:

[0018] V1. Chitosan was dissolved in 1% v / v acetic acid solution to obtain chitosan solution. EDC·HCl and NHS were dissolved in MES buffer solution at pH=5.5 to obtain EDC / NHS solution. Protocatechuic acid was dissolved in ethanol under nitrogen atmosphere and added to EDC / NHS solution. The mixture was stirred in an ice-water bath in the dark for 1 h. Then, the mixture was added to chitosan solution and stirred at room temperature in the dark for 24 h. The mixture was dialyzed with deionized water for 2 days and then freeze-dried under vacuum to obtain CS-PCA.

[0019] V2. Under a nitrogen atmosphere, the CS-PCA obtained in step V1 was added to a 1% v / v acetic acid solution at a ratio of 20 mg / mL and stirred in the dark to obtain mixture A. Arginine was dissolved in MES buffer at pH=5, and EDC·HCl and NHS were added. The mixture was stirred for 2 h to obtain mixture B. Mixture B was added to mixture A and stirred in the dark for 24 h. The mixture was dialyzed with deionized water for 3 days and then freeze-dried to obtain CS-PCA-Arg.

[0020] Further, in step V1, the chitosan has a mass concentration of 20 mg / mL in a 1% v / v acetic acid solution.

[0021] Further, in step V1, the mass concentration of EDC·HCl in the MES buffer solution is 12.5 mg / mL.

[0022] Furthermore, in step V1, the mass concentration of protocatechuic acid in ethanol is 0.1 g / mL.

[0023] Further, in step V1, the mass ratio of protocatechuic acid, EDC·HCl and NHS is 0.4:0.5:0.3.

[0024] Further, in step V2, the mass concentration of arginine in the MES buffer is 20 mg / mL.

[0025] Further, in step V2, the mass ratio of arginine EDC·HCl to NHS is 0.4:0.67:0.4.

[0026] Furthermore, the present invention also provides a method for preparing the thermosensitive gel composition for adjuvant treatment of radiation proctitis, comprising the following steps:

[0027] S1. Add CS-PCA-Arg to deionized water, sonicate at 300 W for 10 min at room temperature, add curcumin@sodium alginate while stirring, stir at 200-300 rpm for 1 h, filter, wash with deionized water, and vacuum dry to obtain coated curcumin@sodium alginate, disperse it in deionized water at a ratio of 50 mg / mL to obtain a dispersion.

[0028] S2. Add poloxamer 407 to deionized water and swell overnight at 4°C to obtain component A; add carbomer 940 to deionized water and swell overnight at 4°C, then add 5% triethanolamine solution and stir until homogeneous to obtain component B; add sodium hyaluronate to deionized water and swell overnight at 4°C to obtain component C.

[0029] S3. Mix components A, B and C obtained in step S2, add the dispersion obtained in step S1, and stir evenly to obtain a thermosensitive gel composition for adjuvant treatment of radiation proctitis.

[0030] Further, in step S1, the mass concentration of CS-PCA-Arg in deionized water is 10 mg / mL.

[0031] Furthermore, in step S2, the mass concentration of poloxamer 407 in deionized water is 0.45 g / mL.

[0032] Furthermore, in step S2, the mass concentration of Carbomer 940 in deionized water is 60 mg / mL.

[0033] Further, in step S2, the mass concentration of sodium hyaluronate in deionized water is 40 mg / mL.

[0034] Further, in step S2, the volume ratio of the triethanolamine solution to deionized water is 2:1.

[0035] Compared with the prior art, the present invention has the following beneficial effects:

[0036] This invention provides a thermosensitive gel composition and its preparation method for adjuvant treatment of radiation-induced proctitis. Through the scientific ratio and synergistic effect of specific components, combined with the properties of thermosensitive gel, it achieves highly effective adjuvant treatment for radiation-induced proctitis while ensuring good biocompatibility and stability. In the raw materials used in the thermosensitive gel composition prepared by this invention, chitosan is a natural polysaccharide with good biocompatibility and biodegradability; curcumin, protocatechuic acid, arginine, etc., are all naturally sourced or biocompatible substances; poloxamer, carbomer, etc., are also widely used in pharmaceutical preparations and have high biocompatibility. This invention uses water-soluble and highly biocompatible sialic acid (SA) to modify chitosan (CS) with EDC·HCl / NHS to obtain SA-chitosan, improving the water solubility of chitosan. SA-chitosan and sodium alginate are used as wall materials to encapsulate curcumin, and sodium alginate and Ca... 2+During cross-linking, SA-chitosan and sodium alginate form a network structure. SA-chitosan can fill surface pores, reduce curcumin leakage, improve the encapsulation rate of curcumin, and enhance storage stability. Sodium alginate is a natural anionic polysaccharide, and the resulting curcumin@sodium alginate has a negatively charged surface, which is beneficial for subsequent CS-PCA-Arg encapsulation. As a natural active ingredient, curcumin has anti-inflammatory, antioxidant, and mucosal repair potential. This invention utilizes SA-chitosan and sodium alginate as wall materials and curcumin as core material to encapsulate curcumin to obtain curcumin@sodium alginate, which can enhance the adjuvant therapeutic effect. This invention prepares CS-PCA-Arg by grafting protocatechuic acid onto chitosan. Protocatechuic acid, as a natural phenolic compound, has a catechol structure in its molecule that can effectively scavenge free radicals. Further grafting arginine onto CS-PCA enhances the water solubility of chitosan and the positive charge of CS-PCA-Arg, increasing its affinity for the surface of curcumin@sodium alginate. This allows for effective coating of the curcumin@sodium alginate surface. Furthermore, the positive charge in CS-PCA-Arg and the catechol groups of protocatechuic acid enhance adhesion to the intestines, improving in vivo retention, prolonging the duration of action, and enhancing therapeutic efficacy. Simultaneously, it enhances the stability of the system and reduces curcumin leakage. After forming a gel in the rectum, the temperature-sensitive gel of this invention slowly releases curcumin and other effective components, reducing inflammatory responses in the rectal mucosa and promoting mucosal repair. Attached Figure Description

[0037] To more clearly illustrate the technical solutions in this invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only for this invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0038] Figure 1 This is a scanning electron microscope image of the curcumin@sodium alginate coated according to Example 1 of the present invention;

[0039] Figure 2 The curcumin encapsulation efficiency of curcumin@sodium alginate described in Examples 1-3 and Comparative Example 1 of this invention;

[0040] Figure 3 To assess the stability of the curcumin@sodium alginate coating described in Example 1 and Comparative Examples 2-3 of this invention;

[0041] Figure 4 The therapeutic effects of the thermosensitive gel described in Example 1 and Comparative Examples 1-3 of this invention are shown. Detailed Implementation

[0042] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. However, this invention is not limited to the following embodiments. It should be noted that, unless otherwise specified, all chemical reagents involved in this invention are purchased through commercial channels.

[0043] Example 1: A thermosensitive gel composition for adjuvant treatment of radiation proctitis, the raw materials for preparation include the following components in parts by weight: 3.2 parts curcumin@sodium alginate, 4 parts CS-PCA-Arg, 90 parts poloxamer 407, 6 parts carbomer 940, and 12 parts sodium hyaluronate.

[0044] The raw materials for preparing curcumin@sodium alginate include the following components in parts by weight: 3 parts sialic acid, 1.5 parts chitosan, 9 parts sodium alginate, and 1.5 parts curcumin.

[0045] The preparation method of curcumin@sodium alginate includes the following steps:

[0046] L1. Dissolve 1.5 g of chitosan in 75 mL of 1% v / v acetic acid solution to obtain CS solution. Dissolve 3 g of sialic acid in 100 mL of MES buffer at pH 6. Add 2.25 g of EDC·HCl and 1.35 g of NHS, stir for 30 min, add to CS solution, stir and react at pH 6 for 24 h, dialyze with deionized water for 3 days, and freeze dry under vacuum to obtain SA-chitosan.

[0047] L2. Add the SA-chitosan and 9 g of sodium alginate obtained in step L1 to 600 mL of distilled water and stir until homogeneous. Add 3 mL of Tween 80 and mix well. Add 1.5 g of curcumin and stir thoroughly. Sonicate to mix well and homogenize at 4℃ and 10000 r / min for 30 min. Add dropwise to 1800 mL of 2wt% CaCl2 solution and stir at 100 r / min for 2 h at room temperature. Centrifuge at 3000 r / min for 5 min. Wash the precipitate with deionized water and ethanol and dry under vacuum to obtain curcumin@sodium alginate.

[0048] The raw materials for preparing CS-PCA-Arg include the following components in parts by weight: 1.8 parts chitosan, 0.6 parts protocatechuic acid, and 0.8 parts arginine.

[0049] The preparation method of CS-PCA-Arg includes the following steps:

[0050] V1. 1.8 g of chitosan was dissolved in 90 mL of 1% v / v acetic acid solution to obtain a chitosan solution. 0.75 g of EDC·HCl and 0.45 g of NHS were dissolved in 60 mL of MES buffer solution at pH=5.5 to obtain an EDC / NHS solution. Under a nitrogen atmosphere, 0.6 g of protocatechuic acid was dissolved in 6 mL of ethanol and added to the EDC / NHS solution. The mixture was stirred in an ice-water bath in the dark for 1 h. The mixture was then added to the chitosan solution and stirred at room temperature in the dark for 24 h. The mixture was dialyzed against deionized water for 2 days and then freeze-dried under vacuum to obtain CS-PCA.

[0051] V2. Under a nitrogen atmosphere, the CS-PCA obtained in step V1 was added to a 1% v / v acetic acid solution at a ratio of 20 mg / mL and stirred in the dark to obtain mixture A. Arginine 0.8 g was dissolved in 40 mL of MES buffer at pH=5, and EDC·HCl 1.34 g and NHS 0.8 g were added. The mixture was stirred for 2 h to obtain mixture B. Mixture B was added to mixture A and stirred in the dark for 24 h. The mixture was dialyzed with deionized water for 3 days and then freeze-dried to obtain CS-PCA-Arg.

[0052] This embodiment also provides a method for preparing the thermosensitive gel composition for adjuvant treatment of radiation proctitis, including the following steps:

[0053] S1. Add 4 g of CS-PCA-Arg to 400 mL of deionized water, sonicate at 300 W for 10 min at room temperature, and add 3.2 g of curcumin@sodium alginate while stirring. Stir at 300 rpm for 1 h, filter, wash with deionized water, and vacuum dry to obtain curcumin@sodium alginate coated with CS-PCA-Arg. Scanning electron microscopy image as shown below. Figure 1 As shown, the solution was dispersed in deionized water at a ratio of 50 mg / mL to obtain a dispersion.

[0054] S2. Add 90 g of poloxamer 407 to 200 mL of deionized water and swell overnight at 4°C to obtain component A; add 6 g of carbomer 940 to 100 mL of deionized water and swell overnight at 4°C, then add 200 mL of 5% triethanolamine solution and stir well to obtain component B; add 12 g of sodium hyaluronate to 300 mL of deionized water and swell overnight at 4°C to obtain component C;

[0055] S3. Mix components A, B and C obtained in step S2, add the dispersion obtained in step S1, and stir evenly to obtain a thermosensitive gel composition for adjuvant treatment of radiation proctitis.

[0056] Example 2: A thermosensitive gel composition for adjuvant treatment of radiation proctitis, the raw materials of which include the following components in parts by weight: 1.6 parts curcumin@sodium alginate, 2 parts CS-PCA-Arg, 45 parts poloxamer 407, 3 parts carbomer 940, and 6 parts sodium hyaluronate.

[0057] The raw materials for preparing curcumin@sodium alginate include the following components in parts by weight: 2 parts sialic acid, 1 part chitosan, 6 parts sodium alginate, and 1 part curcumin.

[0058] The preparation method of curcumin@sodium alginate includes the following steps:

[0059] L1. Dissolve 1 g of chitosan in 50 mL of 1% v / v acetic acid solution to obtain CS solution. Dissolve 2 g of sialic acid in 100 mL of MES buffer at pH 6. Add 1.5 g of EDC·HCl and 0.9 g of NHS, stir for 30 min, add to CS solution, stir and react at pH 6 for 24 h, dialyze with deionized water for 3 days, and freeze dry under vacuum to obtain SA-chitosan.

[0060] L2. Add the SA-chitosan and 6 g of sodium alginate obtained in step L1 to 400 mL of distilled water and stir until homogeneous. Add 2 mL of Tween 80 and mix well. Add 1 g of curcumin and stir thoroughly. Sonicate to mix well and homogenize at 4℃ and 10000 r / min for 30 min. Add dropwise to 1200 mL of 2wt% CaCl2 solution and stir at 100 r / min for 2 h at room temperature. Centrifuge at 3000 r / min for 5 min. Wash the precipitate with deionized water and ethanol and dry under vacuum to obtain curcumin@sodium alginate.

[0061] The raw materials for preparing CS-PCA-Arg include the following components in parts by weight: 1.2 parts chitosan, 0.4 parts protocatechuic acid, and 0.5 parts arginine.

[0062] The preparation method of CS-PCA-Arg includes the following steps:

[0063] V1. Dissolve 1.2 g of chitosan in 60 mL of 1% v / v acetic acid solution to obtain a chitosan solution. Dissolve 0.5 g of EDC·HCl and 0.3 g of NHS in 40 mL of MES buffer solution at pH=5.5 to obtain an EDC / NHS solution. Under a nitrogen atmosphere, dissolve 0.4 g of protocatechuic acid in 4 mL of ethanol and add it to the EDC / NHS solution. Stir in an ice-water bath in the dark for 1 h. Add the solution to the chitosan solution and stir at room temperature in the dark for 24 h. Dialyze with deionized water for 2 days and freeze-dry under vacuum to obtain CS-PCA.

[0064] V2. Under a nitrogen atmosphere, the CS-PCA obtained in step V1 was added to a 1% v / v acetic acid solution at a ratio of 20 mg / mL and stirred in the dark to obtain mixture A. 0.5 g of arginine was dissolved in 25 mL of MES buffer at pH=5, and 0.8375 g of EDC·HCl and 0.5 g of NHS were added. The mixture was stirred for 2 h to obtain mixture B. Mixture B was added to mixture A and stirred in the dark for 24 h. After dialyzing with deionized water for 3 days, the mixture was freeze-dried to obtain CS-PCA-Arg.

[0065] This embodiment also provides a method for preparing the thermosensitive gel composition for adjuvant treatment of radiation proctitis, including the following steps:

[0066] S1. Add 2 g of CS-PCA-Arg to 200 mL of deionized water, sonicate at 300 W for 10 min at room temperature, add 1.6 g of curcumin@sodium alginate while stirring, stir at 200 rpm for 1 h, filter, wash with deionized water, and vacuum dry to obtain coated curcumin@sodium alginate, disperse it in deionized water at a ratio of 50 mg / mL to obtain a dispersion;

[0067] S2. Add 45 g of poloxamer 407 to 100 mL of deionized water and swell overnight at 4°C to obtain component A; add 3 g of carbomer 940 to 50 mL of deionized water and swell overnight at 4°C, then add 100 mL of 5% triethanolamine solution and stir well to obtain component B; add 6 g of sodium hyaluronate to 150 mL of deionized water and swell overnight at 4°C to obtain component C;

[0068] S3. Mix components A, B and C obtained in step S2, add the dispersion obtained in step S1, and stir evenly to obtain a thermosensitive gel composition for adjuvant treatment of radiation proctitis.

[0069] Example 3: A thermosensitive gel composition for adjuvant treatment of radiation proctitis, the raw materials of which include the following components in parts by weight: 2.4 parts curcumin@sodium alginate, 3 parts CS-PCA-Arg, 67.5 parts poloxamer 407, 4.5 parts carbomer 940, and 9 parts sodium hyaluronate.

[0070] The raw materials for preparing curcumin@sodium alginate include the following components in parts by weight: 2.5 parts sialic acid, 1.25 parts chitosan, 7.5 parts sodium alginate, and 1.25 parts curcumin.

[0071] The preparation method of curcumin@sodium alginate includes the following steps:

[0072] L1. Dissolve 1.25 g of chitosan in 62.5 mL of 1% v / v acetic acid solution to obtain CS solution. Dissolve 2.5 g of sialic acid in 100 mL of MES buffer at pH 6. Add 1.875 g of EDC·HCl and 1.125 g of NHS, stir for 30 min, add to CS solution, stir and react at pH 6 for 24 h, dialyze with deionized water for 3 days, and freeze dry under vacuum to obtain SA-chitosan.

[0073] L2. Add the SA-chitosan and sodium alginate obtained in step L1 to 500 mL of distilled water and stir until homogeneous. Add 2.5 mL of Tween 80 and mix well. Add 1.25 g of curcumin and stir thoroughly. Sonicate to mix well and homogenize at 4℃ and 10000 r / min for 30 min. Add dropwise to 1500 mL of 2wt% CaCl2 solution and stir at 100 r / min for 2 h at room temperature. Centrifuge at 3000 r / min for 5 min. Wash the precipitate with deionized water and ethanol and dry under vacuum to obtain curcumin@sodium alginate.

[0074] The raw materials for preparing CS-PCA-Arg include the following components in parts by weight: 1.5 parts chitosan, 0.5 parts protocatechuic acid, and 0.6 parts arginine.

[0075] The preparation method of CS-PCA-Arg includes the following steps:

[0076] V1. Dissolve 1.5 g of chitosan in 75 mL of 1% v / v acetic acid solution to obtain a chitosan solution. Dissolve 0.625 g of EDC·HCl and 0.375 g of NHS in 50 mL of MES buffer solution at pH=5.5 to obtain an EDC / NHS solution. Under a nitrogen atmosphere, dissolve 0.5 g of protocatechuic acid in 5 mL of ethanol and add it to the EDC / NHS solution. Stir in an ice-water bath in the dark for 1 h. Add the solution to the chitosan solution and stir at room temperature in the dark for 24 h. Dialyze with deionized water for 2 days and freeze-dry under vacuum to obtain CS-PCA.

[0077] V2. Under a nitrogen atmosphere, the CS-PCA obtained in step V1 was added to a 1% v / v acetic acid solution at a ratio of 20 mg / mL and stirred in the dark to obtain mixture A. Arginine 0.6 g was dissolved in 30 mL of MES buffer at pH=5, and EDC·HCl 1.005 g and NHS 0.6 g were added. The mixture was stirred for 2 h to obtain mixture B. Mixture B was added to mixture A and stirred in the dark for 24 h. The mixture was dialyzed with deionized water for 3 days and then freeze-dried to obtain CS-PCA-Arg.

[0078] This embodiment also provides a method for preparing the thermosensitive gel composition for adjuvant treatment of radiation proctitis, including the following steps:

[0079] S1. Add 3 g of CS-PCA-Arg to 300 mL of deionized water, sonicate at 300 W for 10 min at room temperature, add 2.4 g of curcumin@sodium alginate while stirring, stir at 250 rpm for 1 h, filter, wash with deionized water, and vacuum dry to obtain coated curcumin@sodium alginate, disperse it in deionized water at a ratio of 50 mg / mL to obtain a dispersion;

[0080] S2. Add 67.5 g of poloxamer 407 to 150 mL of deionized water and swell overnight at 4°C to obtain component A; add 4.5 g of carbomer 940 to 75 mL of deionized water and swell overnight at 4°C, then add 150 mL of 5% triethanolamine solution and stir until homogeneous to obtain component B; add 9 g of sodium hyaluronate to 225 mL of deionized water and swell overnight at 4°C to obtain component C;

[0081] S3. Mix components A, B and C obtained in step S2, add the dispersion obtained in step S1, and stir evenly to obtain a thermosensitive gel composition for adjuvant treatment of radiation proctitis.

[0082] The only difference between Comparative Example 1 and Example 1 is that SA-chitosan was not added.

[0083] The only difference between Comparative Example 2 and Example 1 is that arginine is not added.

[0084] The only difference between Comparative Example 3 and Example 1 is that catechin was not added.

[0085] Example 1: Following the methods of Examples 1-3 and Comparative Example 1, curcumin@sodium alginate was prepared. 0.01 g of the obtained product was added to 1.5 mL of anhydrous ethanol, placed in a cryogenic grinder, and ground at -20°C for 5 min, followed by sonication for 10 min. The supernatant was collected by centrifugation, and the precipitate was washed with an appropriate amount of anhydrous ethanol. The washing liquid was mixed with the supernatant, and the curcumin content (m1) was determined. The curcumin encapsulation efficiency was calculated as follows: Encapsulation efficiency (%) = (m1 / m) × 100%, where m is the amount of curcumin added. The results are as follows: Figure 2 As shown.

[0086] Figure 2 The results showed that the encapsulation efficiency of curcumin in Examples 1-3 was significantly better than that in Comparative Example 1. In Comparative Example 1, no SA-chitosan was added, and the encapsulation efficiency of curcumin decreased, indicating that the SA-chitosan prepared by the present invention can effectively improve the encapsulation efficiency of active ingredients.

[0087] Experimental Example 2: Following the methods of Example 1 and Comparative Examples 2-3, curcumin@sodium alginate was prepared, and the encapsulation efficiency was measured. After being placed at room temperature, the encapsulation efficiency was measured again on days 7, 14, 30, 60, and 90. The encapsulation retention rate was calculated as follows: Encapsulation retention rate (%) = (Encapsulation efficiency after placement / Encapsulation efficiency before placement) × 100%. Results are as follows... Figure 3 As shown.

[0088] Figure 3 The results showed that the encapsulation retention rate of Example 1 was significantly better than that of Comparative Examples 2-3. Comparative Example 2 did not graft arginine onto chitosan, resulting in a decrease in the encapsulation effect of curcumin@sodium alginate and a decrease in the stability of the encapsulated curcumin@sodium alginate. Comparative Example 3 grafted protocatechuic acid onto chitosan, resulting in a decrease in the stability of the encapsulated curcumin@sodium alginate and a decrease in the encapsulation retention rate.

[0089] Experiment 3: A radiation-induced proctitis model was established using 6MV X-ray irradiation. Female SD rats (6-8 weeks old, weighing 180g-220g) were anesthetized by intraperitoneal injection of sodium pentobarbital (40mg / kg). The rats were then fixed supine on a flat plate. The irradiation range was adjusted from the pubic symphysis to the anus, with an irradiation field area of ​​4cm × 3cm, a source-to-skin distance of 100cm, an irradiation dose of 25Gy, and a dose rate of 400 cGy / min. After modeling, the rats exhibited decreased food and water intake, and excreted mucus, loose stools, and bloody stools, indicating successful model establishment. Rats that successfully developed the model were randomly divided into 5 groups of 7 rats each: the model group, Example 1 group, and Comparative Examples 1-3 groups. A control group (7 rats) was also included. On the second day after modeling, the drug was administered via rectal applicator at a position 3 cm from the anus. Examples 1 and Comparative Examples 1-3 groups were each given 1.5 mL of the thermosensitive gel composition, while the model group and control group were given an equal volume of physiological saline. Before each enema, the anus of the SD rats was stimulated with a cotton swab to encourage them to empty their bowels and bladders. The drug was administered once daily for 14 consecutive days. Rats were sacrificed by cervical dislocation, and rectal tissue was collected for HE staining. Histopathological changes were observed under an optical microscope. The rectal pathological condition was graded according to the pathological condition of radiation proctitis in rats, and a rectal pathological damage score was calculated. Grade 0: Normal rectal mucosa, 0 points; Grade 1: Very minor injury, very minor rectal inflammation and / or very minor rectal gland damage, 1 point; Grade 2: Minor injury, rectal inflammation or glandular changes are more pronounced than Grade 1, 2 points; Grade 3: Moderate injury, significant rectal epithelial shedding, 3 points; Grade 4: Severe injury, ulceration or necrosis, 4 points. The blank control group received a score of 0. The scores for the model group, Example 1 group, and Comparative Examples 1-3 groups are as follows: Figure 4 As shown.

[0090] Figure 4The results showed that the scores of Example 1 and Comparative Examples 1-3 were significantly lower than those of the model group, indicating that the thermosensitive gel composition prepared in this invention can be effectively used as an adjunct treatment for radiation proctitis. The thermosensitive gel composition can remain in rats, prolonging the drug effect and improving the therapeutic effect.

[0091] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.

Claims

1. A thermosensitive gel composition for adjunctive treatment of radiation proctitis, characterized in that, The raw materials for preparation include the following components in parts by weight: curcumin@sodium alginate 1.6-3.2 parts, CS-PCA-Arg 2-4 parts, poloxamer 407 45-90 parts, carbomer 940 3-6 parts, and sodium hyaluronate 6-12 parts; The preparation method of curcumin@sodium alginate includes the following steps: L1. Dissolve 1-1.5 parts of chitosan CS in 1% v / v acetic acid solution to obtain CS solution. Dissolve 2-3 parts of sialic acid SA in MES buffer, add EDC·HCl and NHS, stir, add to CS solution, stir reaction at pH 6, dialyze, freeze dry to obtain SA-chitosan. L2. Add 6-9 parts of SA-chitosan and sodium alginate obtained in step L1 to distilled water and stir evenly. Add Tween 80 and mix well. Add 1-1.5 parts of curcumin and stir. Sonicate and homogenize. Add dropwise to CaCl2 solution, stir, centrifuge, wash and dry to obtain curcumin@sodium alginate. The preparation method of the CS-PCA-Arg includes the following steps: V1. Dissolve 1.2-1.8 parts of chitosan CS in 1% v / v acetic acid solution to obtain chitosan solution. Dissolve EDC·HCl and NHS in MES buffer solution to obtain EDC / NHS solution. Dissolve 0.4-0.6 parts of protocatechuic acid PCA in ethanol, add to EDC / NHS solution, stir, add to chitosan solution, stir, dialyze, freeze dry to obtain CS-PCA. V2. Add the CS-PCA obtained in step V1 to a 1% v / v acetic acid solution and stir to obtain mixture A. Dissolve 0.5-0.8 parts of arginine (Arg) in MES buffer, add EDC·HCl and NHS, stir for 2 h to obtain mixture B. Add mixture B to mixture A, react, dialyze, and freeze dry to obtain CS-PCA-Arg.

2. The thermosensitive gel composition for adjuvant treatment of radiation proctitis according to claim 1, characterized in that, In step L1, the mass ratio of sialic acid, EDC·HCl and NHS is 4:3:1.

8.

3. The thermosensitive gel composition for adjuvant treatment of radiation proctitis according to claim 2, characterized in that, In step L2, the sodium alginate has a mass concentration of 15 mg / mL in distilled water.

4. The thermosensitive gel composition for adjuvant treatment of radiation proctitis according to claim 3, characterized in that, In step V1, the mass ratio of protocatechuic acid, EDC·HCl and NHS is 0.4:0.5:0.

3.

5. The thermosensitive gel composition for adjuvant treatment of radiation proctitis according to claim 4, characterized in that, In step V2, the mass ratio of arginine, EDC·HCl and NHS is 0.4:0.67:0.

4.

6. A method for preparing a thermosensitive gel composition for adjuvant treatment of radiation proctitis as described in any one of claims 1-5, characterized in that, Includes the following steps: S1. Add CS-PCA-Arg to deionized water, sonicate, add curcumin@sodium alginate, stir, filter, wash, and dry to obtain coated curcumin@sodium alginate, disperse in deionized water to obtain a dispersion; S2. Poloxamer 407 was added to deionized water and swollen to obtain component A; Carbomer 940 was added to deionized water and swollen, then triethanolamine solution was added and stirred until homogeneous to obtain component B; sodium hyaluronate was added to deionized water and swollen to obtain component C; S3. Mix components A, B and C obtained in step S2, add the dispersion obtained in step S1, and stir evenly to obtain a thermosensitive gel composition for adjuvant treatment of radiation proctitis.

7. The method for preparing the thermosensitive gel composition for adjuvant treatment of radiation proctitis according to claim 6, characterized in that, In step S2, the mass concentrations of poloxamer 407, carbomer 940, and sodium hyaluronate in deionized water are 0.45 g / mL, 60 mg / mL, and 40 mg / mL, respectively.

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