A hemorrhoid thermo-sensitive gel and a preparation method and application thereof

Abstract

This application provides a hemorrhoid thermosensitive gel, its preparation method, and its application, relating to the field of pharmaceutical biotechnology. By weight / volume percentage, the hemorrhoid thermosensitive gel comprises the following components: recombinant collagen 0.05% w / v~5% w / v, sodium hyaluronate 0.05% w / v~10% w / v, snail mucus extract 0.01% w / v~0.4% w / v, borneol 0.01% w / v~1.0% w / v, thermosensitive material 0.1% w / v~20% w / v, antibacterial agent 0.10% w / v~2.0% w / v, traditional Chinese medicine composition 0.10% w / v~10.0% w / v, nanoparticle soothing agent 0.10% w / v~5.0% w / v, penetration enhancer 1.2% w / v~25% w / v, and the balance being water. This invention uses recombinant collagen, sodium hyaluronate, snail mucus extract, borneol, thermosensitive materials, antibacterial agents, traditional Chinese medicine composition, nanoparticle soothing agents, and penetration enhancers to form a hemorrhoid thermosensitive gel. It has a good therapeutic effect on a rat hemorrhoid model induced by croton oil. The above-mentioned combination of components has a good anti-inflammatory effect, reduces the content of inflammatory factors TNF-α, IL-6, and IL-1β, helps improve local microcirculation, reduces vascular permeability, has a certain repair function on the vascular barrier, and helps enhance hemostasis, so that local inflammatory symptoms can be rapidly improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical biotechnology, and in particular to a thermosensitive gel for hemorrhoids, its preparation method, and its application. Background Technology

[0002] Hemorrhoids are a chronic condition characterized by one or more soft venous masses formed by varicose veins in the venous plexus at the bottom of the rectum and anal mucosa. Hemorrhoids are a common anorectal disease, often related to bowel habits, prolonged sitting or standing, constipation, obesity, and dietary habits. There are three main methods for treating hemorrhoids: first, lifestyle modifications, such as improving dietary habits, increasing dietary fiber intake, drinking more water, and maintaining appropriate exercise; second, medication, including topical hemorrhoid gels and oral medications, to relieve symptoms and promote the shrinkage of hemorrhoids; and third, surgical treatment, which may be necessary for severe hemorrhoids or when non-surgical treatments are ineffective.

[0003] Currently, clinical observations have shown that hemorrhoid gel can improve the clinical symptoms and signs of hemorrhoid patients, reduce anal pain and a feeling of heaviness, promote the dissipation of inflammation, and improve local blood and lymphatic circulation. Furthermore, hemorrhoid gel is easy to use, convenient to carry, and safe to use, making it easily accepted by a wide range of patients. Summary of the Invention

[0004] Therefore, the purpose of this invention is to provide a hemorrhoid thermosensitive gel, its preparation method and application, which can relieve patients' anal pain and distending sensation, promote the dissipation of inflammation in the body, and improve local blood and lymphatic circulation.

[0005] The technical solution of this invention is implemented as follows: One objective of this invention is to provide a hemorrhoid thermosensitive gel, comprising the following components by weight and volume percentage: Recombinant collagen 0.05% w / v~5% w / v, sodium hyaluronate 0.05% w / v~10% w / v, snail mucus extract 0.01% w / v~0.4% w / v, borneol 0.01% w / v~1.0% w / v, thermosensitive material 0.1% w / v~20% w / v, antibacterial agent 0.10% w / v~2.0% w / v, traditional Chinese medicine composition 0.10% w / v~10.0% w / v, nanoparticle soothing agent 0.10% w / v~5.0% w / v, penetration enhancer 1.2% w / v~25% w / v, and balance water; The temperature-sensitive material includes at least one of poloxamer, poly-N-isopropylacrylamide, and poly-N,N-diethylacrylamide; The antibacterial agent includes at least one of chitosan, chitosan derivatives, chlorhexidine acetate, chlorhexidine gluconate, benzalkonium bromide, benzalkonium chloride, and polyhexamethylene biguanide hydrochloride. The traditional Chinese medicine composition comprises Panax notoginseng extract, honeysuckle extract, gallnut extract, sophora flavescens extract, phellodendron bark extract, and belladonna extract. The nanoparticle soothing agent is prepared from berberine and casein; The penetration enhancer includes at least one of glycerol, propylene glycol, butylene glycol, hexanediol, and polysorbate.

[0006] A further option is to include the following components by weight-volume percentage: Recombinant collagen 3% w / v~5% w / v, sodium hyaluronate 5% w / v~8% w / v, snail mucus extract 0.1% w / v~0.4% w / v, borneol 0.3% w / v~0.6% w / v, thermosensitive material 5% w / v~20% w / v, antibacterial agent 0.5% w / v~2.0% w / v, traditional Chinese medicine composition 1% w / v~8.0% w / v, nanoparticle soothing agent 0.5% w / v~3.0% w / v, penetration enhancer 1.2% w / v~25% w / v, and balance water; The poloxamer is poloxamer 407 and / or poloxamer 188; The chitosan derivatives include carboxymethyl chitosan, hydroxypropyl chitosan, succinyl chitosan, and chitosan quaternary ammonium salts; The traditional Chinese medicine composition consists of Panax notoginseng extract, Lonicera japonica extract, Gallnut extract, Sophora flavescens extract, Phellodendron amurense extract, and Belladonna extract in a mass ratio of 1~5:1~5:1~5:1~5:1~5:0.5~2.

[0007] A further proposed solution includes the following components, by weight-volume percentage: Recombinant collagen 3% w / v~5% w / v, sodium hyaluronate 6% w / v~8% w / v, snail mucus extract 0.25% w / v~0.3% w / v, borneol 0.3% w / v~0.6% w / v, thermosensitive material 10% w / v~15% w / v, antibacterial agent 1.0% w / v~2.0% w / v, traditional Chinese medicine composition 1% w / v~8.0% w / v, nanoparticle soothing agent 0.5% w / v~3.0% w / v, penetration enhancer 10% w / v~15% w / v, and balance water; The traditional Chinese medicine composition consists of Panax notoginseng extract, Lonicera japonica extract, Gallnut extract, Sophora flavescens extract, Phellodendron amurense extract, and Belladonna extract in a mass ratio of 1~2:1~2:1~2:1~2:1~2:0.5~1.

[0008] A further embodiment is that the preparation method of the belladonna extract includes the following steps: Belladonna is crushed and added to a 60% v / v to 80% v / v ethanol solution at a material-to-liquid mass ratio of 1:10 to 30. After extraction at 30 to 40°C for 20 to 40 hours, the percolation flow rate is set to 3 to 5 mL / (min·kg) for percolation. The percolation liquid is collected, concentrated, and the belladonna extract is obtained.

[0009] A further embodiment is that the temperature-sensitive material is poloxamer, poly-N-isopropylacrylamide, and poly-N,N-diethylacrylamide in a mass ratio of 1:1 to 5:1 to 5.

[0010] A further embodiment is that the preparation method of the nanoparticle soothing agent includes the following steps: The pH of the casein aqueous solution was adjusted to 8.2-8.5 using sodium hydroxide solution. Berberine ethanol solution was added dropwise while stirring. The mixture was then allowed to stand at 30-40°C for 2-3 hours. The pH was adjusted to 6.8-7.0 using dilute hydrochloric acid solution. After ultrasonic treatment, the mixture was freeze-dried to obtain the nanoparticle soothing agent.

[0011] A further embodiment is that the mass concentration of the casein aqueous solution is 0.5-2%; The mass concentration of the berberine ethanol solution is 3-10%; The mass ratio of the casein aqueous solution to the berberine ethanol solution is 1:0.05~0.3; The ultrasonic treatment has a power of 600~800W and a duration of 3~10 hours.

[0012] A second objective of this invention is to provide a method for preparing the aforementioned hemorrhoid thermosensitive gel, comprising the following steps: (1) Take 60%~70% of the prescription amount of water, add the temperature-sensitive material and stir at 10~20℃ to dissolve the temperature-sensitive material, and obtain solution A; (2) Take the remaining water in the prescription, add recombinant collagen, sodium hyaluronate, snail mucus extract, borneol, antibacterial agent, traditional Chinese medicine composition, nanoparticle soothing agent and penetration enhancer, stir to dissolve, and prepare solution B; (3) Pour solution B into solution A and mix well to obtain the hemorrhoid thermosensitive gel.

[0013] A third objective of this invention is to provide the application of the above-mentioned hemorrhoid thermosensitive gel in reducing the levels of inflammatory factors TNF-α, IL-6, or IL-1β.

[0014] The above-mentioned hemorrhoid thermosensitive gel is used in hemostasis.

[0015] Compared with the prior art, the beneficial effects of the present invention are as follows: Traditional hemorrhoid thermosensitive gels are administered in gel form, making it difficult to reach the folds of skin. The product of this invention is liquid at temperatures below 30°C. Administering the product in liquid form allows it to reach the folds that traditional hemorrhoid gels cannot reach, thus achieving complete coverage of the wound. Under body temperature, it transforms into a gel within 2 minutes, adhering to the wound and forming a protective gel film that physically isolates the wound from external bacteria. This effectively treats symptoms such as itching, increased secretions, and foul odor caused by mucosal friction or bacterial infection during hemorrhoid flare-ups. Simultaneously, recombinant collagen provides nutrition to skin cells, stimulates endogenous collagen synthesis, and attracts inflammatory cells and fibroblasts to the wound site, participating in granulation tissue formation, promoting angiogenesis, and repairing and regenerating injured or damaged tissues, thereby accelerating the wound healing process. Exogenous sodium hyaluronate provides lubrication and moisturization, and promotes epidermal cell proliferation and differentiation, which helps repair damaged mucous membranes. Snail mucus extract has strong adhesion, forming a protective film on the surface of hemorrhoid wounds and promoting cell adhesion and proliferation, thus promoting mucosal wound healing and repair. Borneol has effects such as clearing heat and relieving pain, preventing decay and promoting tissue regeneration, anti-inflammation, hemostasis, and promoting wound healing. The nanoparticle soothing agent made from berberine and casein has effects such as repairing mucous membranes, enhancing immunity, anti-inflammatory and antibacterial properties, hemostasis, and reducing swelling. It can enhance the retention and permeability of components in the anorectal mucosa, forming a local continuous release, greatly reducing swelling and pain.

[0016] This invention uses recombinant collagen, sodium hyaluronate, snail mucus extract, borneol, thermosensitive materials, antibacterial agents, traditional Chinese medicine composition, nanoparticle soothing agents, and penetration enhancers to form a hemorrhoid thermosensitive gel. Through the synergistic effect of multiple active ingredients, it has significant effects in clearing heat and relieving pain, promoting blood circulation and removing blood stasis, reducing swelling and promoting tissue regeneration. It is effective in treating hemorrhoids quickly and with long-lasting effects. It has significant efficacy in treating symptoms of perianal ulceration and swelling caused by hemorrhoids. It can relieve symptoms such as anal distension and pain, mucosal congestion, rectal bleeding, and constipation caused by internal hemorrhoids and mixed hemorrhoids. During the treatment process, it accelerates repair and promotes wound healing, and has a higher clinical therapeutic effect than traditional hemorrhoid gels. Detailed Implementation

[0017] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate this invention.

[0018] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.

[0019] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.

[0020] The Panax notoginseng extract, honeysuckle extract, gallnut extract, sophora flavescens extract, and phellodendron bark extract used in this invention are all commercially available.

[0021] Snail mucus extract, Hubei Xinghong Agricultural Technology Development Co., Ltd.

[0022] KM mice and SD rats were obtained from Chengdu Dashuo Experimental Animal Co., Ltd.

[0023] Preparation Example 1 Preparation of belladonna fluid extract: Belladonna was crushed and added to a glass percolator. At a material-to-liquid ratio of 1:20, 70% v / v ethanol solution was added to the glass percolator. The mixture was first extracted with ethanol at 40°C for 30 h. Then, the percolation flow rate was set to 4 mL / (min·kg) for slow percolation. The percolate was collected and concentrated under reduced pressure to obtain belladonna fluid extract.

[0024] Preparation Example 2 Preparation method of nanoparticle soothing agent: (1) Add casein powder to deionized water and stir ultrasonically to prepare a casein aqueous solution with a mass concentration of 2%; dissolve berberine in ethanol solution to prepare a berberine ethanol solution with a mass concentration of 5%. (2) The pH of the casein aqueous solution was adjusted to about 8.2~8.5 using 0.1M sodium hydroxide solution. The casein aqueous solution was continuously stirred, and berberine ethanol solution was slowly added dropwise while stirring. The mass ratio of casein aqueous solution to berberine ethanol solution was 1:0.1. Then, the solution was allowed to stand at 40℃ for 2 h to allow berberine to electrostatically adsorb onto casein. (3) The pH of the mixed solution was adjusted to about 6.8~7.0 using 0.1M dilute hydrochloric acid solution to induce aggregation and self-assembly of casein molecules. Then, the solution was ultrasonically treated for 5 h at 600W. The ultrasonically dispersed solution was freeze-dried to obtain nanoparticle soothing agent.

[0025] Example 1 The formula for hemorrhoid thermosensitive gel is as follows: 3% (w / v) recombinant collagen 6% (w / v) Sodium Hyaluronate 0.25% (w / v) Snail mucus extract 0.3% (w / v) Borneol 12% (w / v) thermosensitive material (poloxamer 407, poloxamer 188, poly-N-isopropylacrylamide and poly-N,N-diethylacrylamide in a mass ratio of 1:1:2:2) 1.0% (w / v) antibacterial agent (chitosan) 5% (w / v) Traditional Chinese medicine composition (Panax notoginseng extract, Lonicera japonica extract, Galla chinensis extract, Sophora flavescens extract, Phellodendron chinense extract and Belladonna extract prepared in a mass ratio of 1:1:1:1:1:0.5) Example 2: Preparation of Nanoparticle Soothing Agent with 3% (w / v) 12% (w / v) penetration enhancer (glycerol, propylene glycol, and hexanediol in a 1:1:1 mass ratio) 0.3% (w / v) Preservative (phenoxyethanol) Remaining water.

[0026] The preparation method of hemorrhoid thermosensitive gel is as follows: (1) Take 70% of the prescribed amount of water, add the thermosensitive material, and stir at 15~20℃ to dissolve the gel matrix, thus obtaining solution A; (2) Take the remaining water in the prescription, add recombinant collagen, sodium hyaluronate, snail mucus extract, borneol, antibacterial agent, traditional Chinese medicine composition, nanoparticle soothing agent and penetration enhancer, stir to dissolve, and prepare solution B; (3) Pour solution B into solution A and mix well to obtain hemorrhoid thermosensitive gel.

[0027] Comparative Example 1 The difference between this comparative example and Example 1 is that the nanoparticle soothing agent is replaced with berberine.

[0028] Specifically, the formula for the hemorrhoid thermosensitive gel is as follows: 3% (w / v) recombinant collagen 6% (w / v) Sodium Hyaluronate 0.25% (w / v) Snail mucus extract 0.3% (w / v) Borneol 12% (w / v) thermosensitive material (poloxamer 407, poloxamer 188, poly-N-isopropylacrylamide and poly-N,N-diethylacrylamide in a mass ratio of 1:1:2:2) 1.0% (w / v) antibacterial agent (chitosan) 5% (w / v) Traditional Chinese medicine composition (Panax notoginseng extract, Lonicera japonica extract, Galla chinensis extract, Sophora flavescens extract, Phellodendron chinense extract and Belladonna extract prepared in a mass ratio of 1:1:1:1:1:0.5) 3% (w / v) berberine 12% (w / v) penetration enhancer (glycerol, propylene glycol, and hexanediol in a 1:1:1 mass ratio) 0.3% (w / v) Preservative (phenoxyethanol) Remaining water.

[0029] The preparation method of hemorrhoid thermosensitive gel is as follows: (1) Take 70% of the prescribed amount of water, add the thermosensitive material, and stir at 15~20℃ to dissolve the gel matrix, thus obtaining solution A; (2) Take the remaining water from the prescription, add recombinant collagen, sodium hyaluronate, snail mucus extract, borneol, antibacterial agent, traditional Chinese medicine composition, berberine and penetration enhancer, stir to dissolve, and prepare solution B; (3) Pour solution B into solution A and mix well to obtain hemorrhoid thermosensitive gel.

[0030] Comparative Example 2 The difference between this comparative example and Example 1 is that the snail mucus extract is replaced with mussel adhesive protein.

[0031] Specifically, the formula for the hemorrhoid thermosensitive gel is as follows: 3% (w / v) recombinant collagen 6% (w / v) Sodium Hyaluronate 0.25% (w / v) mussel adhesive protein 0.3% (w / v) Borneol 12% (w / v) thermosensitive material (poloxamer 407, poloxamer 188, poly-N-isopropylacrylamide and poly-N,N-diethylacrylamide in a mass ratio of 1:1:2:2) 1.0% (w / v) antibacterial agent (chitosan) 5% (w / v) Traditional Chinese medicine composition (Panax notoginseng extract, Lonicera japonica extract, Galla chinensis extract, Sophora flavescens extract, Phellodendron chinense extract and Belladonna extract prepared in a mass ratio of 1:1:1:1:1:0.5) Example 2: Preparation of Nanoparticle Soothing Agent with 3% (w / v) 12% (w / v) penetration enhancer (glycerol, propylene glycol, and hexanediol in a 1:1:1 mass ratio) 0.3% (w / v) Preservative (phenoxyethanol) Remaining water.

[0032] The preparation method of hemorrhoid thermosensitive gel is as follows: (1) Take 70% of the prescribed amount of water, add the thermosensitive material, and stir at 15~20℃ to dissolve the gel matrix, thus obtaining solution A; (2) Take the remaining water in the prescription, add recombinant collagen, sodium hyaluronate, mussel adhesive protein, borneol, antibacterial agent, traditional Chinese medicine composition, nanoparticle soothing agent and penetration enhancer, stir to dissolve, and prepare solution B; (3) Pour solution B into solution A and mix well to obtain hemorrhoid thermosensitive gel.

[0033] Test case (1) Croton oil-induced rat anal swelling model Fifty SD rats, half male and half female, aged 10-11 weeks and weighing 180-220 g, were selected as the experimental subjects.

[0034] Rats that had been acclimatized for one week were randomly divided into three groups: a control group, a model group, and an experimental group, with 10 rats in each group (half male and half female). Rats were fasted for 12 hours before the experiment, but allowed free access to water.

[0035] Distilled water, pyridine, ether, and 6% croton oil solution were mixed thoroughly in a volume ratio of 1:4:5:10 to obtain a croton oil mixture. A sterile cotton swab (d≈4 mm) soaked in the croton oil mixture was inserted into the rat's anus to a depth of approximately 20 mm and held for 20 seconds. The swab was then slowly rotated several times to enhance stimulation. This stimulation was performed once daily for 3 consecutive days. Significant anal swelling after modeling indicated successful establishment of the hemorrhoid model.

[0036] Use sterile cotton swabs (d≈4 mm) to absorb deionized water instead of croton oil mixture, and perform the same operation on the blank group.

[0037] Twenty-four hours after the modeling was completed, the experimental group was given different samples (1.0 g / kg) rectally for 3 consecutive days, once a day, while the control group and the model group were given the same amount of deionized water.

[0038] Vascular permeability test: 30 min before sacrifice, 1% Evans Blue (EB) dye was injected into the tail vein. 20 mm of anal and rectal tissue was taken from the sacrificed rats. After rinsing with physiological saline, the tissue was weighed. Evans Blue was extracted from the tissue by soaking in formamide. The absorbance of the sample was measured at 620 nm. The plasma exudation amount was obtained by plotting a standard curve using Evans Blue dye.

[0039] Inflammatory factor detection: After administration, fasting for 12 hours was performed, and blood was collected to prepare serum. The levels of TNF-α, IL-6, and IL-1β were detected using an ELISA kit.

[0040] Anorectal coefficient determination: Anorectal tissue was collected from euthanized rats, rinsed with physiological saline, weighed, and fixed with 10% paraformaldehyde for histological examination. Anorectal coefficient = (wet weight of anorectal tissue mg) / (rats' body weight g), reflecting the degree of inflammation, congestion and edema in the local tissue.

[0041] result: Table 1. EB plasma exudate volume in the anal and rectal tissues of rats in each group ( n =10)

[0042] Table 1 shows that, compared with the control group, the plasma exudation in the model group increased; compared with the model group, the plasma exudation in the experimental groups decreased to varying degrees; among them, the plasma exudation in experimental group 1 was lower than that in experimental groups 2 and 3, indicating that experimental group 1 has a good anti-inflammatory effect, helps to improve local microcirculation, reduces vascular permeability, and has a certain repair function on the vascular barrier.

[0043] Table 2. Serum levels of TNF-α, IL-6, and IL-1β in each group of rats ( n =10)

[0044] Table 2 shows that, compared with the control group, the levels of TNF-α, IL-6, and IL-1β increased in the model group; compared with the model group, the levels of TNF-α, IL-6, and IL-1β decreased to varying degrees in the experimental groups; among them, the levels of TNF-α, IL-6, and IL-1β in experimental group 1 were lower than those in experimental groups 2 and 3, indicating that experimental group 1 rapidly reduced the levels of inflammatory factors in the croton oil-induced hemorrhoid model, and experimental group 1 had a better anti-inflammatory effect.

[0045] Table 3. Anorectal coefficients of rats in each group ( n =10)

[0046] Table 3 shows that, compared with the control group, the anorectal coefficient of rats in the model group increased; compared with the model group, the anorectal coefficient of rats in the experimental groups decreased to varying degrees; among them, the anorectal coefficient of rats in experimental group 1 was lower than that in experimental groups 2 and 3, indicating that experimental group 1 rapidly reduced the anorectal coefficient in the croton oil-induced hemorrhoid model, and experimental group 1 had a better effect on reducing inflammation and swelling.

[0047] (2) Effects on hemorrhage and clotting time in mice Twenty adult SPF-grade KM mice, aged 8-9 weeks and weighing 20-25 g, were selected as the experimental subjects.

[0048] Mice that had been acclimatized for one week were randomly divided into a model group and an experimental group, with 5 mice in each group. The croton oil-induced hemorrhoid model in mice was established according to (1).

[0049] The tails of mice were tied with rubber bands. After 5 hours, the rubber bands were loosened, and different samples were applied to the tails of the mice. This was done twice a day for 3 consecutive days. One hour after the last administration, 4 mm of the mouse tail was removed. The time when bleeding stopped was recorded by gently touching the tail with a sterile, clean filter paper.

[0050] Table 4 Bleeding time in mice of each group ( n =5)

[0051] Table 4 shows that, compared with the model group, the bleeding time in the experimental groups was shortened to varying degrees; among them, the bleeding time in experimental group 1 was shorter, indicating that experimental group 1 helped to enhance hemostasis and improve local inflammatory symptoms.

[0052] This invention uses recombinant collagen, sodium hyaluronate, snail mucus extract, borneol, thermosensitive materials, antibacterial agents, traditional Chinese medicine composition, nanoparticle soothing agents, and penetration enhancers to form a hemorrhoid thermosensitive gel. It has a good therapeutic effect on a rat hemorrhoid model induced by croton oil. The above-mentioned combination of components has a good anti-inflammatory effect, reduces the content of inflammatory factors TNF-α, IL-6, and IL-1β, helps improve local microcirculation, reduces vascular permeability, has a certain repair function on the vascular barrier, and helps enhance hemostasis, so that local inflammatory symptoms can be rapidly improved.

[0053] Recombinant collagen provides nutrition to skin cells, stimulates endogenous collagen synthesis, and attracts inflammatory cells and fibroblasts to the wound site, participating in granulation tissue formation, promoting angiogenesis, and repairing and regenerating injured or damaged tissues, thereby accelerating the wound healing process. Exogenous sodium hyaluronate provides lubrication and hydration, and promotes epidermal cell proliferation and differentiation, which helps repair damaged mucous membranes. Snail mucus extract has strong adhesion, forming a protective film on the surface of hemorrhoid wounds and promoting cell adhesion and proliferation, thus promoting mucosal wound healing and repair. Borneol has effects such as clearing heat and relieving pain, preventing decay and promoting tissue regeneration, anti-inflammation, hemostasis, and promoting wound healing. The nanoparticle soothing agent made from berberine and casein has effects such as repairing mucous membranes, enhancing immunity, anti-inflammatory and antibacterial properties, and hemostasis and swelling reduction. It can enhance the retention and permeability of components in the anorectal mucosa, forming a local continuous release, greatly reducing swelling and pain.

[0054] This invention utilizes the synergistic effect of multiple active ingredients to achieve significant effects in clearing heat and relieving pain, promoting blood circulation and removing blood stasis, reducing swelling and promoting tissue regeneration. It is effective in treating hemorrhoids with rapid and long-lasting results. It has a significant therapeutic effect on the symptoms of perianal ulceration and swelling caused by hemorrhoids, and can relieve symptoms such as anal distension and pain, mucosal congestion, rectal bleeding, and constipation caused by internal hemorrhoids and mixed hemorrhoids. During the treatment process, it accelerates repair and promotes wound healing, and has a higher clinical therapeutic effect than traditional hemorrhoid gels.

[0055] Example 2 The formula for hemorrhoid thermosensitive gel is as follows: 5% (w / v) recombinant collagen 8% (w / v) Sodium Hyaluronate 0.4% (w / v) snail mucus extract 0.3% (w / v) Borneol 12% (w / v) thermosensitive material (poloxamer 407, poloxamer 188, poly-N-isopropylacrylamide and poly-N,N-diethylacrylamide in a mass ratio of 1:1:2:2) 1.0% (w / v) antibacterial agent (chitosan) 1% (w / v) Traditional Chinese medicine composition (Panax notoginseng extract, Lonicera japonica extract, Galla chinensis extract, Sophora flavescens extract, Phellodendron chinense extract and Belladonna extract of Preparation Example 1 in a mass ratio of 1:1:1:1:1:0.5) Example 2: Preparation of Nanoparticle Soothing Agent with 0.5% (w / v) 12% (w / v) penetration enhancer (glycerol, propylene glycol, and hexanediol in a 1:1:1 mass ratio) 0.3% (w / v) Preservative (phenoxyethanol) Remaining water.

[0056] The preparation method of hemorrhoid thermosensitive gel is as follows: (1) Take 70% of the prescribed amount of water, add the thermosensitive material, and stir at 15~20℃ to dissolve the gel matrix, thus obtaining solution A; (2) Take the remaining water in the prescription, add recombinant collagen, sodium hyaluronate, snail mucus extract, borneol, antibacterial agent, traditional Chinese medicine composition, nanoparticle soothing agent and penetration enhancer, stir to dissolve, and prepare solution B; (3) Pour solution B into solution A and mix well to obtain hemorrhoid thermosensitive gel.

[0057] Example 3 The formula for hemorrhoid thermosensitive gel is as follows: 1% (w / v) recombinant collagen 6% (w / v) Sodium Hyaluronate 0.03% (w / v) Snail mucus extract 0.3% (w / v) Borneol 12% (w / v) thermosensitive material (poloxamer 407, poloxamer 188, poly-N-isopropylacrylamide and poly-N,N-diethylacrylamide in a mass ratio of 1:1:2:2) 2.0% (w / v) antibacterial agent (chitosan) 8% (w / v) Traditional Chinese medicine composition (Panax notoginseng extract, Lonicera japonica extract, Galla chinensis extract, Sophora flavescens extract, Phellodendron chinense extract and Belladonna extract prepared in a mass ratio of 1:1:1:1:1:0.5) Example 2: Preparation of Nanoparticle Soothing Agent with 3% (w / v) 12% (w / v) penetration enhancer (glycerol, propylene glycol, and hexanediol in a 1:1:1 mass ratio) 0.3% (w / v) Preservative (phenoxyethanol) Remaining water.

[0058] The preparation method of hemorrhoid thermosensitive gel is as follows: (1) Take 70% of the prescribed amount of water, add the thermosensitive material, and stir at 15~20℃ to dissolve the gel matrix, thus obtaining solution A; (2) Take the remaining water in the prescription, add recombinant collagen, sodium hyaluronate, snail mucus extract, borneol, antibacterial agent, traditional Chinese medicine composition, nanoparticle soothing agent and penetration enhancer, stir to dissolve, and prepare solution B; (3) Pour solution B into solution A and mix well to obtain hemorrhoid thermosensitive gel.

[0059] Table 5. Serum levels of TNF-α, IL-6, and IL-1β in each group of rats ( n =10)

[0060] Example 4 The formula for hemorrhoid thermosensitive gel is as follows: 3% (w / v) recombinant collagen 6% (w / v) Sodium Hyaluronate 0.3% (w / v) Snail mucus extract 0.3% (w / v) Borneol 12% (w / v) thermosensitive material (poloxamer 407, poloxamer 188, poly-N-isopropylacrylamide and poly-N,N-diethylacrylamide in a mass ratio of 1:1:2:2) 1.0% (w / v) antibacterial agent (chitosan) 5% (w / v) Traditional Chinese medicine composition (Panax notoginseng extract, Lonicera japonica extract, Galla chinensis extract, Sophora flavescens extract, Phellodendron chinense extract and Belladonna extract prepared in a mass ratio of 1:1:1:1:1:0.5) Example 2: Preparation of Nanoparticle Soothing Agent with 3% (w / v) 20% (w / v) penetration enhancer (glycerol, propylene glycol, hexanediol, polysorbate 20 and polysorbate 80 in a mass ratio of 1:1:1:1:1) 0.3% (w / v) Preservative (phenoxyethanol) Remaining water.

[0061] The preparation method of hemorrhoid thermosensitive gel is as follows: (1) Take 70% of the prescribed amount of water, add the thermosensitive material, and stir at 15~20℃ to dissolve the gel matrix, thus obtaining solution A; (2) Take the remaining water in the prescription, add recombinant collagen, sodium hyaluronate, snail mucus extract, borneol, antibacterial agent, traditional Chinese medicine composition, nanoparticle soothing agent and penetration enhancer, stir to dissolve, and prepare solution B; (3) Pour solution B into solution A and mix well to obtain hemorrhoid thermosensitive gel.

[0062] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications are also considered to be within the scope of protection of the present invention.

Claims

1. A thermosensitive gel for hemorrhoids, characterized in that, By weight-volume percentage, it includes the following components: Recombinant collagen 0.05% w / v~5% w / v, sodium hyaluronate 0.05% w / v~10% w / v, snail mucus extract 0.01% w / v~0.4% w / v, borneol 0.01% w / v~1.0% w / v, thermosensitive material 0.1% w / v~20% w / v, antibacterial agent 0.10% w / v~2.0% w / v, traditional Chinese medicine composition 0.10% w / v~10.0% w / v, nanoparticle soothing agent 0.10% w / v~5.0% w / v, penetration enhancer 1.2% w / v~25% w / v, and balance water; The temperature-sensitive material includes at least one of poloxamer, poly-N-isopropylacrylamide, and poly-N,N-diethylacrylamide; The antibacterial agent includes at least one of chitosan, chitosan derivatives, chlorhexidine acetate, chlorhexidine gluconate, benzalkonium bromide, benzalkonium chloride, and polyhexamethylene biguanide hydrochloride. The traditional Chinese medicine composition comprises Panax notoginseng extract, honeysuckle extract, gallnut extract, sophora flavescens extract, phellodendron bark extract, and belladonna extract. The nanoparticle soothing agent is prepared from berberine and casein; The penetration enhancer includes at least one of glycerol, propylene glycol, butylene glycol, hexanediol, and polysorbate.

2. The hemorrhoid thermosensitive gel according to claim 1, characterized in that, By weight-volume percentage, it includes the following components: Recombinant collagen 3% w / v~5% w / v, sodium hyaluronate 5% w / v~8% w / v, snail mucus extract 0.1% w / v~0.4% w / v, borneol 0.3% w / v~0.6% w / v, thermosensitive material 5% w / v~20% w / v, antibacterial agent 0.5% w / v~2.0% w / v, traditional Chinese medicine composition 1% w / v~8.0% w / v, nanoparticle soothing agent 0.5% w / v~3.0% w / v, penetration enhancer 1.2% w / v~25% w / v, and balance water; The poloxamer is poloxamer 407 and / or poloxamer 188; The chitosan derivatives include carboxymethyl chitosan, hydroxypropyl chitosan, succinyl chitosan, and chitosan quaternary ammonium salts; The traditional Chinese medicine composition consists of Panax notoginseng extract, Lonicera japonica extract, Gallnut extract, Sophora flavescens extract, Phellodendron amurense extract, and Belladonna extract in a mass ratio of 1~5:1~5:1~5:1~5:1~5:0.5~2.

3. A thermosensitive gel for hemorrhoids according to claim 2, characterized in that, By weight-volume percentage, it includes the following components: Recombinant collagen 3% w / v~5% w / v, sodium hyaluronate 6% w / v~8% w / v, snail mucus extract 0.25% w / v~0.3% w / v, borneol 0.3% w / v~0.6% w / v, thermosensitive material 10% w / v~15% w / v, antibacterial agent 1.0% w / v~2.0% w / v, traditional Chinese medicine composition 1% w / v~8.0% w / v, nanoparticle soothing agent 0.5% w / v~3.0% w / v, penetration enhancer 10% w / v~15% w / v, and balance water; The traditional Chinese medicine composition consists of Panax notoginseng extract, Lonicera japonica extract, Gallnut extract, Sophora flavescens extract, Phellodendron amurense extract, and Belladonna extract in a mass ratio of 1~2:1~2:1~2:1~2:1~2:0.5~1.

4. A thermosensitive gel for hemorrhoids according to claim 1, characterized in that, The method for preparing the belladonna fluid extract includes the following steps: Belladonna is crushed and added to a 60% v / v to 80% v / v ethanol solution at a material-to-liquid mass ratio of 1:10 to 30. After extraction at 30 to 40°C for 20 to 40 hours, the percolation flow rate is set to 3 to 5 mL / (min·kg) for percolation. The percolation liquid is collected, concentrated, and the belladonna extract is obtained.

5. A thermosensitive gel for hemorrhoids according to claim 1, characterized in that, The temperature-sensitive material is poloxamer, poly-N-isopropylacrylamide, and poly-N,N-diethylacrylamide in a mass ratio of 1:1~5:1~5.

6. A hemorrhoid thermosensitive gel according to claim 1, characterized in that, The preparation method of the nanoparticle soothing agent includes the following steps: The pH of the casein aqueous solution was adjusted to 8.2-8.5 using sodium hydroxide solution. Berberine ethanol solution was added dropwise while stirring. The mixture was then allowed to stand at 30-40°C for 2-3 hours. The pH was adjusted to 6.8-7.0 using dilute hydrochloric acid solution. After ultrasonic treatment, the mixture was freeze-dried to obtain the nanoparticle soothing agent.

7. A thermosensitive gel for hemorrhoids according to claim 6, characterized in that, The casein aqueous solution has a mass concentration of 0.5-2%; The mass concentration of the berberine ethanol solution is 3-10%; The mass ratio of the casein aqueous solution to the berberine ethanol solution is 1:0.05~0.3; The ultrasonic treatment has a power of 600~800W and a duration of 3~10 hours.

8. The method for preparing the hemorrhoid thermosensitive gel according to any one of claims 1 to 7, characterized in that, Includes the following steps: (1) Take 60%~70% of the prescription amount of water, add the temperature-sensitive material and stir at 10~20℃ to dissolve the temperature-sensitive material, and obtain solution A; (2) Take the remaining water in the prescription, add recombinant collagen, sodium hyaluronate, snail mucus extract, borneol, antibacterial agent, traditional Chinese medicine composition, nanoparticle soothing agent and penetration enhancer, stir to dissolve, and prepare solution B; (3) Pour solution B into solution A and mix well to obtain the hemorrhoid thermosensitive gel.

9. The use of the hemorrhoid thermosensitive gel according to any one of claims 1 to 7 in reducing the levels of inflammatory factors TNF-α, IL-6 or IL-1β.

10. The hemorrhoid thermosensitive gel according to any one of claims 1 to 7, in the action of hemostasis.

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