A scar-removing gel and its preparation method

Abstract

The present invention belongs to the field of pharmaceutical technology and relates to a scar-removing (scar) gel and a preparation method thereof. By mass percentage, hydroxypropyl methylcellulose stearate (Sangelose) is 0.25-1.5%, 1,3-butanediol is 1%-10%, glycerol is 1%-10%, and the balance is water. Crocin is added to the scar-removing gel in an amount of 0.05-0.5% of its weight. The crocin gel for removing scars prepared by the present invention can form a protective barrier locally at the wound surface, effectively protect the wound surface from infection, and can promote the healing of wounds, inhibit the abnormal overgrowth of scars, remove pigmentation, whiten, prevent ultraviolet damage, and resist radiation.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and relates to a scar (keloid) removing gel and a preparation method thereof. Background Art

[0002] A scar (also known as a keloid) is a repair response of the body to tissue damage. When the skin injury reaches the dermis deeply or there is a large area of epidermal defect or the fibroblasts self-produced by the body are damaged, resulting in serious damage to the skin soft tissue and unable to fully repair itself normally, it is replaced by fibrous tissue for repair, and thus a scar appears. A scar is the trace left by wound healing and is also the final result of tissue repair and healing. Excessive scar hyperplasia will form keloids, that is, raised, hard, protruding papules and plaques with unclear boundaries, accompanied by erythema or brown pigmentation, resulting in darker color. Keloids not only cause morphological changes in the damaged area, but also can lead to organ dysfunction or even loss of function, seriously endangering the physical and mental health of patients. The characteristics of hypertrophic scars are the proliferation of dermal tissue, the excessive deposition of fibroblast-derived extracellular matrix over a long time, and persistent inflammation and fibrosis. Hypertrophic scars, due to the excessive deposition of collagen and the presence of abundant collagen nodules, can cause contracture, low tensile strength, and raised scars.

[0003] The use of physical methods to treat scars was first recorded in medical textbooks in 1965. With the progress of clinical treatment techniques, the methods of physical treatment of scars have expanded from simple surgical resection to radiotherapy, laser treatment, cryotherapy, and silicone gel compression treatment. Hydrogel dressings can keep the skin adequately hydrated, and based on the "moist wound healing" theory, hydrogel dressings can create a suitable microenvironment for wound healing, so they are widely used in clinical wound care to inhibit scar hyperplasia. Among the existing drugs for treating scars, silicone gel is widely used, but because it contains substances such as silicone oil, it can cause skin itching and flushing during scar treatment and has certain skin irritation. (Mohan PLB, IP Int J Aesthet Health Rejuvenation 2021; 4(1): 19-20.) However, the extremely high recurrence rate after using physical therapy or drugs alone to treat keloids has always been the biggest problem in clinical practice. To effectively reduce the recurrence rate, physical therapy is often combined with drug therapy for combined treatment. Nor N M et al. used silicone dressings combined with 0.05% clobetasol propionate cream treatment and intralesional injection of triamcinolone acetonide in randomly grouped patients and found that the curative effect of patients treated with combined silicone compression was the same as that of patients treated with intralesional triamcinolone acetonide, but the pain and side effects were significantly less (Nor N M, Clinical Drug Investigation, 2017, 37(3): 295-301.). However, corticosteroid drugs may cause side effects such as allergies and skin necrosis. Side effect 1. Allergy: If there is an allergy to glucocorticoids, causing an excessive immune response in the skin, it usually manifests as skin itching, swelling, etc. It is necessary to take drugs such as loratadine tablets and cetirizine hydrochloride tablets as prescribed by the doctor for treatment. Side effect 2. Skin necrosis: Injecting hormones into scars can gradually atrophy the local skin to achieve the effect of removing scars. However, improper operation may damage the surrounding nerves and cause skin necrosis.

[0004] Saffron, also known as Crocus sativus L., is a traditional precious Chinese medicine. Its original plant is Crocus sativus L. of the Iridaceae family. The medicinal part is its dried stigma. It is native to the Mediterranean and Central Asian regions and is currently widely cultivated in Shanghai and other places in China. Saffron can promote blood circulation to remove blood stasis, cool blood and detoxify, relieve depression and calm the mind. It is used for dysmenorrhea, amenorrhea, mass in the abdomen, epidemic febrile disease with toxin-induced maculae, postpartum blood stasis obstruction, melancholy and stuffiness, palpitation and mania, hematemesis, traumatic swelling and pain, etc. The water-soluble pigment of saffron is mainly crocin, which is a carotenoid diterpenoid compound, mainly a glycoside composed of crocetin and β-D-glucose, gentiobiose, etc., also known as crocins, and is an important active ingredient in saffron. Because crocin has a glycosyl structure, its ability to penetrate the skin is poor. After hydrolysis, crocin can be prepared into crocetin (Wang Jiyu et al., Science and Technology of Food Industry, 2021, 42(23): 176-183). Crocetin, also known as safranal and crocetin, is a low-molecular-weight carotenoid compound with the chemical formula C20H24O4 and has all-trans and cis isomers. Crocetin plays an important role in antioxidant, anti-tumor, anti-depressant, treatment of Parkinson's disease, treatment of Alzheimer's disease, improvement of eyesight, etc.

[0005] Currently, there is no research report on the inhibition of scar hyperplasia by crocetin. Summary of the Invention

[0006] The purpose of the present invention is to provide an anti-scar gel and its preparation method.

[0007] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0008] An anti-scar gel, by mass percentage, contains 0.25-1.5% of hypromellose stearate (Sangelose), 1%-10% of 1,3-butanediol, 1%-10% of glycerol, and the balance is water.

[0009] 0.05-0.5% by weight of crocetin is added to the anti-scar gel.

[0010] Preferably, by mass percentage, it contains 0.05-0.1% of crocetin, 1-2% of 0.1 mol / L sodium hydroxide, 0.5-1% of hypromellose stearate (Sangelose), 5-10% of 1,3-butanediol, 5-10% of glycerol, 0.1-0.2% of antioxidant, and the balance is water.

[0011] The crocetin is all-trans crocetin (A) and / or cis crocetin (B),

[0012]

[0013] The crocetin is all-trans crocetin (A) and cis-crocetin (B); the mass ratio of A to B is 70-95:5-30, preferably 80-87:13-20.

[0014] The antioxidant is one or more of sodium bisulfite, sodium thiosulfate, vitamin E, vitamin C, sodium isoascorbate, butylated hydroxyanisole (BHA), dibutylhydroxytoluene (BHT), propyl gallate (PG), tert-butylhydroquinone (TBHQ), and derivatives of the above substances.

[0015] The hydroxypropyl methylcellulose stearate (Sangelose) is of model 60L and / or 90L; wherein, the mass ratio of Sangelose 60L to Sangelose 90L during mixing is 1-2:0-1.

[0016] A preparation method of a scar-removing gel

[0017] (1) According to the above ratio, hydroxypropyl methylcellulose stearate (Sangelose) is added to water under stirring conditions to make it disperse evenly to form a gel solution; 1,3-butanediol and glycerol are added and mixed evenly to obtain the scar-removing gel.

[0018] Or,

[0019] (1) According to the above ratio, hydroxypropyl methylcellulose stearate (Sangelose) is added to water under stirring conditions to make it disperse evenly to form a gel solution; 1,3-butanediol and glycerol are added and mixed evenly for use.

[0020] (2) The crocetin is dispersed in an equivalent or excessive amount of sodium hydroxide solution to make it completely dissolve.

[0021] (3) The solutions obtained in the above steps (1) and (2) and the antioxidant are mixed and stirred evenly, the pH is adjusted to 4-7.4, preferably the pH value is 5.0-6.0, and continuous stirring is carried out until it is mixed evenly to form a crocetin gel.

[0022] An application of a scar-removing gel, the application of the scar-removing gel in inhibiting scar hyperplasia, inhibiting and removing scars.

[0023] An application of a scar-removing gel, the application of the crocetin gel in repairing wound surfaces, inhibiting abnormal hyperplasia of scars, removing pigmentation, whitening, preventing ultraviolet damage, and anti-radiation.

[0024] The advantages of the present invention:

[0025] The gel of the present invention is a gel with a high water content, which can inhibit the excessive proliferation of wound scars, make the skin wound heal smoothly and flatly, form a protective barrier locally on the wound surface, effectively protect the wound surface from infection, inhibit the abnormal proliferation of scars, remove pigmentation, whiten, prevent ultraviolet damage, and resist radiation, and has no irritation to the skin. Among them, crocetin is combined with Sangelose to promote the release of crocetin and increase the curative effect; at the same time, after the gel forms a film, this closed environment can promote the hydration of the skin, thereby reducing the activity of capillaries and reducing the collagen deposition and scar proliferation induced by fibroblasts. Description of the Drawings

[0026] Figure 1 ... Crocetin gel and blank gel;

[0027] Figure 2 ... Micrograph of crocetin gel;

[0028] Figure 3 ... Appearance photos of the high-temperature stability experiment of crocetin gel on the 0th, 5th, and 10th days (60 °C)

[0029] Figure 4 ... Effect of crocetin concentration on the migration of HKF cells;

[0030] Figure 5 ... Effect of crocetin concentration on the scratch healing rate of HKF cells;

[0031] Figure 6 ... Photos of scar hyperplasia on rabbit ears (28th day after administration);

[0032] Figure 7 ... HE staining micrograph of the scar site on the 28th day after administration;

[0033] Figure 8 ... Scar hyperplasia coefficient diagram 28 days after administration;

[0034] Figure 9 ... Masson staining micrograph of the scar site on the 28th day after administration;

[0035] Figure 10 ... Collagen fiber density diagram of the scar site on the 28th day after administration. Detailed Embodiments

[0036] The following is only the preferred detailed embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and should be covered by the protection scope of the present invention.

[0037] Example 1

[0038] Crocetin gel, by mass fraction, trans-crocetin 0.1%, 0.1 mol / L sodium hydroxide 1.0%, Sangelose 60L 1.0%, 1,3-butanediol 5%, glycerol 5%, antioxidant BHT 0.2%, add sterile water to the full volume.

[0039] Preparation method of crocetin gel, according to the mass fractions of the above components,

[0040] (1) Add Sangelose 60L to water under stirring at 1000 rpm to disperse it evenly to form a gel solution; then add 1,3-butanediol and glycerol and mix evenly to obtain a blank gel;

[0041] (2) Disperse crocetin in an equivalent or excessive amount of sodium hydroxide solution to completely dissolve it;

[0042] (3) Mix and stir evenly the solutions obtained in the above steps (1) and (2) and the antioxidant, adjust the pH to 5, continuously stir and cool to room temperature to form crocetin gel, and store it in the refrigerator for refrigeration.

[0043] Example 2

[0044] Crocetin gel, by mass fraction, trans-crocetin 0.1%, 0.1 mol / L sodium hydroxide 1.0%, Sangelose 60L 0.25%, Sangelose 90L 0.25%, 1,3-butanediol 10%, glycerol 10%, antioxidant BHT 0.2%, add sterile water to the full volume of 100%.

[0045] The preparation steps are as follows: according to the mass fractions of the above components,

[0046] (1) Add Sangelose 60L and Sangelose 90L to water under stirring at 1000 rpm to disperse it evenly to form a gel solution; then add 1,3-butanediol and glycerol and mix evenly to obtain a blank gel;

[0047] (2) Disperse crocetin in an equivalent or excessive amount of sodium hydroxide solution to completely dissolve it;

[0048] (3) Mix and stir evenly the solutions obtained in the above steps (1) and (2) and the antioxidant, adjust the pH to 6, continuously stir and cool to room temperature to form crocetin gel, and store it in the refrigerator for refrigeration.

[0049] Example 3

[0050] Crocin gel. By mass fraction, it contains 0.05% of trans-crocin, 1.0% of 0.1 mol / L sodium hydroxide, 1.5% of Sangelose 60L, 5.0% of 1,3-butanediol, 5.0% of glycerol, 0.2% of antioxidant vitamin E, and sterile water is added to make up the total amount.

[0051] The preparation method is the same as that of Example 2.

[0052] Example 4

[0053] Crocin gel. By mass fraction, it contains 0.5% of trans-crocin, 0.1% of 0.1 mol / L sodium hydroxide, 1.0% of Sangelose 60L, 0.5% of Sangelose 90L, 5.0% of 1,3-butanediol, 5.0% of glycerol, 0.2% of antioxidant BHT, and sterile water is added to make up the total amount.

[0054] The preparation method is the same as that of Example 2.

[0055] Example 5

[0056] Crocin gel. By mass fraction, it contains 0.1% of trans-crocin, 1.0% of 0.1 mol / L sodium hydroxide, 0.5% of Sangelose 60L, 0.5% of Sangelose 90L, 5% of 1,3-butanediol, 5% of glycerol, 0.2% of antioxidant vitamin E, and sterile water is added to make up the total amount of 100%.

[0057] The preparation method is the same as that of Example 2.

[0058] Example 6

[0059] Crocin gel. By mass fraction, it contains 0.5% of trans-crocin, 1.0% of 0.1 mol / L sodium hydroxide, 0.5% of Sangelose 90L, 10% of 1,3-butanediol, 10% of glycerol, 0.2% of antioxidant BHT, and sterile water is added to make up the total amount.

[0060] The preparation method is the same as that of Example 2.

[0061] Example 7

[0062] Crocin gel. By mass fraction, it contains 0.05% of trans-crocin, 0.05% of 0.1 mol / L sodium hydroxide, 1.5% of Sangelose 90L, 5% of 1,3-butanediol, 5% of glycerol, 0.2% of antioxidant vitamin E, and sterile water is added to make up the total amount.

[0063] The preparation method is the same as that of Example 2.

[0064] Example 8

[0065] Crocin gel, calculated by mass fraction, contains 0.1% of cis-crocin, 1.0% of 0.1 mol / L sodium hydroxide, 1.0% of Sangelose 60L, 5.0% of 1,3-butanediol, 5.0% of glycerol, 0.2% of antioxidant vitamin E, and sterile water is added to make up the total volume.

[0066] The preparation method is the same as that in Example 2.

[0067] Example 9

[0068] Crocin gel, calculated by mass fraction, contains 0.085% of trans-crocin, 0.015% of cis-crocin, 1.0% of 0.1 mol / L sodium hydroxide, 1.0% of Sangelose 60L, 0.5% of Sangelose 90L, 5.0% of 1,3-butanediol, 5.0% of glycerol, 0.2% of antioxidant BHT, and sterile water is added to make up the total volume.

[0069] The preparation method is the same as that in Example 2.

[0070] Example 10

[0071] Crocin gel, calculated by mass fraction, contains 0.5% of cis-crocin, 1.0% of 0.1 mol / L sodium hydroxide, 0.5% of Sangelose 60L, 0.5% of Sangelose 90L, 5.0% of 1,3-butanediol, 5.0% of glycerol, 0.2% of antioxidant BHT, and sterile water is added to make up the total volume.

[0072] The preparation method is the same as that in Example 2.

[0073] Example 11

[0074] Crocin gel, calculated by mass fraction, contains 0.05% of trans-crocin, 0.05% of cis-crocin, 1.0% of 0.1 mol / L sodium hydroxide, 0.5% of Sangelose 90L, 10% of 1,3-butanediol, 10% of glycerol, 0.2% of antioxidant vitamin E, and sterile water is added to make up the total volume.

[0075] The preparation method is the same as that in Example 1.

[0076] Example 12

[0077] Crocin gel, calculated by mass fraction, contains 0.05% of cis-crocin, 1.5% of 0.1 mol / L sodium hydroxide, 1.5% of Sangelose 90L, 5.0% of 1,3-butanediol, 5.0% of glycerol, 0.2% of antioxidant BHT, and sterile water is added to make up the total volume.

[0078] Example 13

[0079] Sangelose gel, by mass fraction, Sangelose 60L 1.0%, 1,3 - butanediol 5.0%, glycerol 5.0%, add sterile water to the total amount. Preparation method of Sangelose gel, according to the mass fraction of each component above,

[0080] Add Sangelose 60L to water under stirring condition of 1000 rpm to disperse evenly to form a gel solution; then add 1,3 - butanediol and glycerol and mix evenly to obtain the scar - removing gel.

[0081] Example 14

[0082] Sangelose gel, by mass fraction, Sangelose 60L 0.5%, Sangelose 90L 0.5%, 1,3 - butanediol 5.0%, glycerol 5.0%, add sterile water to the total amount. Preparation method of Sangelose gel, according to the mass fraction of each component above,

[0083] Add Sangelose 60L and Sangelose 90L to water under stirring condition of 1000 rpm to disperse evenly to form a gel solution; then add 1,3 - butanediol and glycerol and mix evenly to obtain the scar - removing gel.

[0084] Example 15

[0085] Sangelose gel, by mass fraction, Sangelose 90L 1.5%, 1,3 - butanediol 5.0%, glycerol 5.0%, add sterile water to the total amount.

[0086] The preparation method is the same as that of Example 13

[0087] Example 16

[0088] Sangelose gel, by mass fraction, Sangelose 90L 0.5%, 1,3 - butanediol 10%, glycerol 10%, add sterile water to the total amount.

[0089] The preparation method is the same as that of Example 13

[0090] Example 17

[0091] Sangelose gel, by mass fraction, Sangelose 60L 0.5%, 1,3 - butanediol 10%, glycerol 10%, add sterile water to the total amount.

[0092] The preparation method is the same as that of Example 13

[0093] Example 17

[0094] Sangelose gel, by mass fraction, Sangelose 60L 0.25%, Sangelose90L 0.25%, 1,3 - butanediol 5.0%, glycerol 5.0%, add sterile water to make up the total volume.

[0095] The preparation method is the same as that in Example 14

[0096] Example 18

[0097] Sangelose gel, by mass fraction, Sangelose 60L 1.5%, 1,3 - butanediol 10%, glycerol 10%, add sterile water to make up the total volume.

[0098] The preparation method is the same as that in Example 13

[0099] Application Example 1: Evaluation of Gel Appearance

[0100] The "Chinese Pharmacopoeia" 2020 Edition (Part IV) stipulates that the appearance of the gel should be uniform and delicate, and it should remain gelatinous at room temperature without drying or liquefying. The determined inspection indexes are the formability, spreadability, glossiness, uniformity, pH value and stability of the gel, and the forming situation of the gel is inspected. The full score of the comprehensive score in this experiment is 15.0 points, among which the formability accounts for 2.0 points, the spreadability accounts for 2.0 points, the glossiness accounts for 3.0 points, the uniformity accounts for 3.0 points, the pH

[0101] value accounts for 2.0 points, and the stability accounts for 3.0 points (centrifugation 1.0 point, heat constant temperature 1.0 point, low temperature 1.0 point). The comprehensive scoring criteria are shown in Table 1.

[0102] Select the gels prepared in the above examples for comprehensive scoring. The evaluation rules and results are as follows:

[0103] Table 1 Comprehensive Scoring Table (15 points)

[0104]

[0105] Experimental Results:

[0106] Table 2 Comprehensive Scoring Results

[0107]

[0108] The results show that the gel prepared by the present invention has uniform texture, is easy to spread, mild and non - irritating.

[0109] Application Example 2: Quality Evaluation of Crocin Gel

[0110] Experimental Method:

[0111] According to the prescription and preparation method of crocetin gel in Example 1, prepare 3 samples of crocetin gel, observe macroscopically, take pictures, and observe the appearance, color, and homogeneity of crocetin gel. Use a dissecting needle to pick up a small amount of crocetin gel and place it on a glass slide. Cover it with a coverslip and then observe the morphology of crocetin in the gel under an optical microscope and take pictures.

[0112] Use a pH meter to measure the pH value of crocetin gel. Take 1.0 g of each of the 3 samples of crocetin gel, add 10 mL of freshly boiled and cooled distilled water respectively, ultrasonicate for 10 min to disperse evenly, and measure the pH value of each sample according to the pH value determination method in General Principles 0631 of the Chinese Pharmacopoeia (Part III, 2020 Edition).

[0113] Take 0.1 g of each of the 3 samples of crocetin gel and place them in 25 mL conical flasks. After adding 1.0 mL of water, weigh them, ultrasonicate for 20 min to dissolve and disperse the gel, and weigh to make up for the weight loss. Use a 10 mL pipette to add 9.0 mL of methanol to the conical flasks, weigh them, place them in a refrigerator at 4 °C and let stand for 1 h for the macromolecular material to precipitate, ultrasonicate for 2 min, and weigh to make up for the weight loss. Take the supernatant and filter it through a 0.45 μm microporous membrane for HPLC analysis to determine the content of crocetin in the gel.

[0114] Experimental results:

[0115] The appearance and microscopic morphology of crocetin gel are as shown in Figure 1 and Figure 2 The prepared crocetin gel is a red, brightly colored, and appropriately viscous gel with a uniform and delicate appearance. The pH values of the three batches of crocetin gel are 5.81 ± 0.03, and the crocetin content is 0.101 ± 0.002%. Referring to the regulations on the drug content in gels in Part II of the Chinese Pharmacopoeia (2020 Edition), the content of the active ingredient in the product should be 90.0% - 110.0% of the labeled amount. The content of crocetin in this gel is qualified.

[0116] Application Example 3: High-temperature stability experiment of crocetin gel

[0117] Experimental method:

[0118] According to the prescription and preparation method of crocetin gel in Example 1, while replacing and adding different antioxidants, the prescription is shown in Table 3:

[0119] Table 3. Prescription of crocetin gel containing different antioxidants

[0120]

[0121] Prepare 3 parallel samples of crocetin gel. Take 3.0 g of each sample and dispense it into 5 mL transparent sample bottles. Place the bottles in an incubator at 60 °C and sample and take pictures on the 0th, 5th, and 10th days to detect the crocetin content in the preparation.

[0122] Experimental results:

[0123] Table 4 Experimental results of the high-temperature stability of crocetin preparation on the 0th, 5th, and 10th days (n = 6)

[0124]

[0125] After being placed at 60 °C for 0, 5, and 10 days, the appearance of the gel was as Figure 3 shown, and the change results of the crocetin content in the preparation were as shown in Table 4.

[0126] In the crocetin gel, after 5 days, the appearance of all formulations was uniformly red, showing no difference from that on the 0th day. The crocetin content in the crocetin gel containing 0.2% BHT was slightly higher than that in the crocetin gel without BHT. After 10 days, the appearance of all formulations was uniformly red, showing no difference from that on the 0th day. The crocetin content in the crocetin gel containing 0.2% BHT was significantly higher than that in the crocetin gel without BHT, indicating that at high temperatures, BHT has good antioxidant effects in the gel and can improve the stability.

[0127] Application Example 4: Cell scratch assay

[0128] Experimental method:

[0129] Human keloid fibroblasts (HKF) were inoculated in 6-well plates and grown to approximately 90% confluence. The cell monolayer was scratched in a straight line with a sterile pipette tip to form a wound with a width of 1 mm. The cells were washed twice with PBS to remove the detached cells, and then incubated with the control solution (one ten-thousandth DMSO added to the medium) and different concentrations (0.1, 1.0, 10.0 μM) of all-trans crocetin at 37 °C for 48 hours. Pictures were taken immediately after scratching and at 0, 12, 24, and 48 hours of culture, and the pictures were imported into ImageJ to determine the scratch healing rate.

[0130] Experimental results:

[0131] The pictures of human keloid fibroblasts (HKF) taken were as Figure 4 shown. The scratch areas in the pictures were statistically analyzed, and the relative scratch area change curves of each component were obtained as Figure 5 shown. The results showed that after 36 - 48 h of the experiment, crocetin (0.1 - 10.0 μmol / L) inhibited the migration of keloid fibroblasts in a concentration-dependent manner. This indicates that crocetin is a potential scar inhibitor and can be developed into a topical preparation for treating scars.

[0132] Application Example 5: Appearance Observation and Scar Quantification Score

[0133] Experimental Method:

[0134] Twenty-five clean-grade Japanese long-eared rabbits were used to establish a rabbit ear hypertrophic scar model (MORRIS D E, WU L, ZHAOL L, et al. Acute and chronic animal models for excessive dermal scarring: Quantitative studies[J]. Plastic and Reconstructive Surgery, 1997, 100(3): 674-681.). After successful model establishment, the 25 experimental rabbits were randomly divided into 5 groups (5 rabbits in each group): positive drug (dexamethasone) group, untreated model group, silicone scar gel group, crocetin gel group prepared in Example 1, and Sangelose gel group prepared in Example 13. For the wounds administered with drugs, 0.1 g of the drug was evenly applied to the surface of the wound every day, once in the morning and once in the evening, and used continuously for 4 weeks. On the 28th day of drug administration, the rabbits were sacrificed by intravenous injection of 5 mL of air, the wound morphology was recorded by digital camera photography, and the wound tissue was collected for histological evaluation.

[0135] After the start of drug administration, the Vancouver Scar Scale (Table 5) was used for scoring every week to evaluate the color, thickness, softness, and vascular distribution of the scar tissue. The highest score was 15 points and the lowest was 0 points. The higher the score, the more severe the scar hyperplasia of the rabbit ear. The scoring results are shown in Table 6.

[0136] Table 5: Scar Quantification Score Table

[0137]

[0138] Experimental Results:

[0139] As Figure 6As shown, on the 28th day after drug administration. Model group: There was an obvious bulge in the center of the wound surface, which was contracted, red, palpable, and there was an obvious phenomenon of scar hyperplasia, indicating successful modeling. Compared with the model group, the wound surface in the dexamethasone group was flat, with less redness and no scar hyperplasia. Compared with the model group, there was a very small protrusion in the center of the wound surface in the blank gel group, which was red and not palpable, with a mild tendency of scar hyperplasia. Compared with the model group, the wound surface of the silicone scar gel had a bulge, less redness, and a mild scar hyperplasia phenomenon. Compared with the model group, the wound surface of the crocetin gel group was flat, without redness and without scar hyperplasia. The scar appearance diagram showed that the crocetin gel had a good therapeutic effect on the hyperplasia of the scar area, which was superior to the silicone scar gel group. The silicone scar gel contains substances such as silicone oil, which can cause skin itching and flushing during scar treatment, while the crocetin gel does not contain silicone oil and has a high water content, which can promote better skin hydration during treatment and enhance the therapeutic effect.

[0140] Table 6: Rabbit ear scar scale scores after 1 week, 2 weeks, 3 weeks, and 4 weeks of drug administration

[0141]

[0142] As shown in Table 6, compared with the model group, the Sangelose gel group could effectively inhibit the growth of scars. Compared with the Sangelose gel, the crocetin gel group could significantly inhibit the hyperplasia of scars. Compared with the silicone scar gel group, the crocetin gel could significantly inhibit the hyperplasia of scars, making the scar appearance closer to the normal rabbit ear skin color.

[0143] Application Example 6: HE staining of the scar area and results of the scar hyperplasia index

[0144] Experimental method:

[0145] After administering the drug for 28 days according to the experimental method of the above Application Example 5, collect the rabbit ear scar tissue, perform section H&E staining on it, conduct microscopic examination, and collect and analyze the images. Use Image J to measure the scar hyperplasia index (SEI) of the images.

[0146] Experimental results:

[0147] Table 7: Determination of rabbit ear scar hyperplasia index after drug administration (x±s)

[0148]

[0149] Histological analysis of the anti-scar effect of crocetin gel on rabbit ear wounds, and the results are as Figure 7As shown. After 28 days of drug administration, compared with the model group, the stratum corneum of the crocetin gel group was intact, the epidermis was thin, there were a large number of fibroblasts in the dermis layer, arranged relatively neatly, the density of collagen fibers was low, and it had a good therapeutic effect on scar hyperplasia. Compared with the dexamethasone group, the therapeutic effect of the crocetin gel group was similar to it, but the stratum corneum recovered more completely and the epidermis was thinner. Compared with the model group, the stratum corneum of the Sangelose gel group was thinner, the epidermis was thinner, fibroblast infiltration was visible in the dermis layer, the distribution was uneven, the density of collagen fibers was large, and Sangelose gel also had a significant inhibitory effect on scar hyperplasia. The mechanism by which Sangelose gel inhibits scar hyperplasia may be the same as that of silicone gel in inhibiting scar hyperplasia, that is, the so-called "wet healing" theory, which can form a smooth wound healing surface.

[0150] To quantify the differences in hyperplasia of different scar sites, measure the scar hyperplasia coefficients of the scar sites of the above four components as Figure 8 and Table 7 show. Compared with the model group, the scar thickness of the dexamethasone group was significantly reduced (P<0.05), the SEI value was less than 1.6, and no hyperplasia occurred at the scar site of this group. Compared with the model group, the scar thickness of the Sangelose gel group was significantly reduced. Compared with the Sangelose gel group, the scar area thickness of the crocetin gel group was further significantly reduced, with statistical difference (P<0.05), the SEI value was less than 1.6, and no hyperplasia occurred at the scar site.

[0151] Application Example 7: Results of Masson staining and collagen fiber density of scar site

[0152] Experimental method:

[0153] After 28 days of drug administration according to the experimental method described in the above Application Example 5, collect the scar tissue of the rabbit ear, perform section Masson staining on it, microscopic examination, and image acquisition and analysis. Use Image J to measure the collagen fiber density of the image.

[0154] Experimental results:

[0155] Table.8 Collagen fiber density of scar site on the 28th day of drug administration (n = 5, compared with the model group, *P<0.05, compared with the blank gel group, # P<0.05)

[0156]

[0157] After 28 days of drug administration, perform Masson staining on the scar tissue, and the results are as above Figure 9 shown, and the measurement results of collagen density are as Figure 10As shown in Table 8. Compared with normal skin, the collagen fiber density in the model group was higher (*P<0.05), and the arrangement was disordered, indicating successful modeling. Compared with the model group, the collagen fiber density in the dexamethasone group was lower (*P<0.05), and the arrangement was regular. Compared with the model group, the collagen fiber density in the blank gel group was lower (*P<0.05), and the arrangement was relatively regular. Compared with the Sangelose gel group, the collagen fiber density in the crocetin gel group was significantly decreased ( # P<0.05), and the arrangement was regular, showing a statistical difference. It indicates that crocetin gel can significantly reduce the collagen fiber density at the scar site and inhibit scar hyperplasia.

[0158] In summary, the crocetin gel provided by the present invention can effectively remove scars and inhibit scar hyperplasia.

Claims

1. A scar-removing gel, characterized in that: By mass percentage, 0.05 - 0.1% of crocetin, 1 - 2% of 0.1 mol / L sodium hydroxide, 0.5 - 1% of hypromellose stearate (Sangelose), 5 - 10% of 1,3 - butanediol, 5 - 10% of glycerol, 0.1 - 0.2% of antioxidant, and the balance being water.

2. The scar-removing gel according to claim 1, characterized in that: The crocetin is all - trans crocetin (A) and / or cis - crocetin (B), 。 3. The scar-removing gel according to claim 2, wherein: The crocetin is all - trans crocetin (A) and cis - crocetin (B); the mass ratio of all - trans crocetin (A) to cis - crocetin (B) is 70 - 95:5 - 30.

4. The scar-removing gel according to claim 1, characterized in that: The antioxidant is one or more of sodium bisulfite, sodium thiosulfate, vitamin E, vitamin C, sodium iso - ascorbate, butylated hydroxyanisole (BHA), dibutylhydroxytoluene (BHT), propyl gallate (PG), tert - butylhydroquinone (TBHQ).

5. A method for preparing the scar - removing gel agent according to claim 1, characterized in that: (1) According to the above - mentioned ratio, under stirring conditions, add hypromellose stearate (Sangelose) to water to make it disperse evenly to form a gel solution; then add 1,3 - butanediol and glycerol and mix them evenly for standby; (2) Disperse crocetin in an equivalent amount or an excessive amount of sodium hydroxide solution to completely dissolve it; (3) Mix and stir evenly the solutions obtained in the above steps (1) and (2) and the antioxidant, adjust the pH to 4 - 7.4, and continuously stir until evenly mixed to form a crocetin gel.

6. Use of the scar-removing gel agent according to claim 1, characterized in that: The application of the scar - removing gel agent in the preparation of drugs for inhibiting scar hyperplasia, inhibiting and removing scars.

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