Temperature-sensitive hydrogel, preparation method thereof and application of temperature-sensitive hydrogel in preparation of medicine for treating intrauterine adhesion

Abstract

The invention discloses a temperature-sensitive hydrogel, a preparation method thereof and an application of the temperature-sensitive hydrogel in preparation of a medicine for treating intrauterine adhesion, and belongs to the technical field of medicines. The temperature-sensitive hydrogel is a buffer solution containing chondroitin sulfate and poloxamer. The thermo-sensitive hydrogel provided by the invention can be used for effectively treating intrauterine adhesion, and has very important clinical application value.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, and in particular to a thermosensitive hydrogel, its preparation method, and its application in the preparation of drugs for treating intrauterine adhesions. Background Technology

[0002] Intrauterine adhesions (IUA), also known as Asherman's syndrome, are a gynecological condition caused by damage to the basal layer of the endometrium, leading to partial or complete adhesions within the uterine cavity. This condition primarily results from induced abortion, curettage after miscarriage, or postpartum uterine injury. Its pathological essence lies in the abnormal proliferation of fibrous tissue following damage to the basal layer of the endometrium, forming adhesions that ultimately lead to structural destruction and loss of function of the uterine cavity.

[0003] The severity of intrauterine adhesions is closely related to their pathological changes. Mild adhesions affect only <25% of the uterine cavity surface area, with the endometrial basal layer relatively well preserved; moderate adhesions cover approximately 25%-75% of the uterine cavity area; while severe adhesions exceed 75% of the uterine cavity area, even presenting as a state of complete uterine cavity closure. Traditional treatments for moderate to severe cases have extremely poor prognoses; even with surgical separation, the re-adhesion rate within 3 months post-surgery is as high as 50%-75%.

[0004] The current standard treatment for intrauterine adhesions follows a three-pronged approach: surgical separation, physical barrier therapy, and hormonal repair. Hysteroscopic adhesiolysis, as the core technique, aims to mechanically or energetically remove the adhesions and restore the anatomical structure of the uterine cavity. However, surgery alone has limited efficacy, and postoperative anti-adhesion measures are necessary. Summary of the Invention

[0005] To solve at least one of the above-mentioned technical problems, the technical solution adopted in this application is as follows.

[0006] The first aspect of this application provides a thermosensitive hydrogel, wherein the thermosensitive hydrogel is a buffer solution comprising chondroitin sulfate and poloxamer, wherein the mass fraction of chondroitin sulfate in the hydrogel is 0.5% to 4%, and the amount of poloxamer added is determined such that the gelation temperature of the hydrogel is 30 to 36°C.

[0007] In this application, the thermosensitive hydrogel can undergo a reversible sol-gel transition in response to temperature changes. It exists as a sol (liquid) when the temperature decreases and forms a gel when the temperature increases.

[0008] In this application, the gelation temperature refers to the temperature required for the hydrogel to change from a sol state to a gel state.

[0009] Chondroitin sulfate (CS) is a type of glycosaminoglycan covalently linked to proteins to form proteoglycans. The inventors unexpectedly discovered that hydrogels containing chondroitin sulfate have a very good therapeutic effect on intrauterine adhesions.

[0010] Poloxamer is a synthetic triblock copolymer of poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide). Aqueous solutions of poloxamer can form thermally reversible gels. In this application, because the thermosensitive hydrogel needs to be liquid at room temperature and form a gel peptide in vivo, a high gelation temperature is required.

[0011] Those skilled in the art will understand that different proportions of poloxamer and / or other compounds can affect the gelation temperature. In some embodiments of this application, the poloxamer includes poloxamer 407 and poloxamer 188. In some embodiments of this application, the hydrogel contains poloxamer 407 at a mass percentage of 16% to 20% and poloxamer 188 at a mass percentage of 1% to 4%.

[0012] In some specific embodiments of this application, the hydrogel contains 16.8% poloxamer 407 by mass and 1% poloxamer 188 by mass.

[0013] In some embodiments of this application, the buffer solution is selected from one of PBS buffer, Tris-HCl buffer, HEPES buffer, bicarbonate buffer, and acetate buffer.

[0014] In some specific embodiments of this application, the buffer solution is a PBS buffer solution.

[0015] The second aspect of this application provides a method for preparing the thermosensitive hydrogel described in any of the first aspects of this application, comprising the following steps: The chondroitin sulfate and poloxamer were added to the buffer solution and stirred in an ice bath.

[0016] The third aspect of this application provides the use of the thermosensitive hydrogel described in any of the first aspects of this application in the preparation of a medicament for intrauterine adhesions.

[0017] In some embodiments of this application, the drug is administered via injection or vaginal tampon.

[0018] The fourth aspect of this application provides the use of the thermosensitive hydrogel described in any of the first aspects of this application in the preparation of carriers for delivering protein drugs.

[0019] In some embodiments of this application, the protein drug is selected from BSA analogs and BSA conjugates.

[0020] Bovine serum albumin (BSA) has good biocompatibility and biodegradability. In the pharmaceutical field, it is often used as a drug carrier. It can not only improve the water solubility of hydrophobic drugs and play a role in sustained drug release, but also reduce the toxic side effects of drugs.

[0021] In some embodiments of this application, the BSA-conjugated drug is a BSA-targeting peptide, which is a complex formed by covalently conjugating BSA with a specific targeting peptide (such as RGD, cRGD, GE11, LyP-1) to form a complex with targeting and good biocompatibility.

[0022] Compared with the prior art, this application has the following advantages: The thermosensitive hydrogel of this application has a gelation temperature of 33~35℃, thus it is in a liquid state at room temperature (25~30℃) and in a gel state in the in vivo environment (around 37℃), which can be well used to prepare drugs that can be administered in vivo.

[0023] The thermosensitive hydrogel of this application degrades rapidly, making it safer for use in vivo.

[0024] The thermosensitive hydrogel of this application can slowly release proteins or drugs, resulting in a longer-lasting therapeutic effect.

[0025] The thermosensitive hydrogel described in this application can effectively treat intrauterine adhesions and has significant clinical application value.

[0026] It should be understood that the description in this section is not intended to identify key or essential features of the embodiments of this application, nor is it intended to limit the scope of this application. Other features of this application will become readily apparent from the following description. Attached Figure Description

[0027] The above and other objects, features, and advantages of exemplary embodiments of this application will become readily apparent from the following detailed description taken in conjunction with the accompanying drawings. Several embodiments of this application are illustrated in the drawings by way of example and not limitation, wherein: Figure 1 The rheological results of the chondroitin sulfate-poloxam hydrogel in Example 2 of this application are shown. Figure 2 The results of in vitro degradation assays of the chondroitin sulfate-poloxam hydrogel in Example 3 of this application are shown. Figure 3 The results of in vitro sustained-release BSA assay of chondroitin sulfate-poloxam hydrogel in Example 4 of this application are shown. Figure 4 The results of morphological observation of the uterus in mice in each treatment group in Example 5 of this application are shown; Figure 5The results of H&E staining of mouse uterine tissue in each treatment group in Example 5 of this application are shown. Figure 6 The results of Masson staining of mouse uterine tissue in each treatment group in Example 5 of this application are shown.

[0028] Figure 7 The SEM images of the chondroitin sulfate-poloxam hydrogel prepared by formulation number 19 in Example 6 of this application are shown (top image 95×, bottom image 280×). Detailed Implementation

[0029] Unless otherwise stated, implied from the context, or as is customary in the art, all parts and percentages in this application are based on weight, and all testing and characterization methods used are concurrent with the filing date of this application. Where applicable, any patent, patent application, or disclosure relating to this application is incorporated herein by reference in its entirety, and its equivalent patent families are also incorporated herein by reference, particularly the definitions of relevant terms in the art disclosed in such documents. If any definition of a specific term disclosed in the prior art is inconsistent with any definition provided in this application, the definition provided in this application shall prevail.

[0030] The numerical ranges used in this application are approximate values ​​and therefore may include values ​​outside the range unless otherwise stated. The numerical range includes all values ​​from the lower limit to the upper limit, increasing by one unit, provided that there is an interval of at least two units between any lower and any higher value. For ranges containing values ​​less than 1 or fractions greater than 1 (e.g., 1.1, 1.5, etc.), one unit is appropriately considered as 0.0001, 0.001, 0.01, or 0.1. For ranges containing single digits less than 10 (e.g., 1 to 5), one unit is generally considered as 0.1. These are merely specific examples of what is intended to be expressed, and all possible combinations of values ​​between the listed minimum and maximum values ​​are considered to be clearly described in this application.

[0031] The terms “comprising,” “including,” “having,” and their derivatives do not exclude the presence of any other components, steps, or processes, regardless of whether such other components, steps, or processes are disclosed in this application. To eliminate any doubt, unless expressly stated otherwise, all compositions using the terms “comprising,” “including,” or “having” in this application may contain any additional additives, excipients, or compounds. Conversely, except for those necessary for operational performance, the term “substantially constitutes…” excludes any other components, steps, or processes described below with respect to that term. The term “consisting of…” does not include any components, steps, or processes not specifically described or listed. Unless expressly stated otherwise, the term “or” refers to the individual members listed or any combination thereof.

[0032] To make the technical problems, technical solutions and beneficial effects solved by this application clearer, the following detailed description is provided in conjunction with embodiments.

[0033] The following examples are used to illustrate preferred embodiments of this application. Those skilled in the art will understand that the techniques disclosed in the examples represent technologies discovered by the inventors that can be used to implement this application, and therefore can be considered preferred embodiments of this application. However, those skilled in the art should understand from this specification that many modifications can be made to the specific embodiments disclosed herein, still yielding the same or similar results, without departing from the spirit or scope of this application.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains, and all materials cited herein and referenced by them are incorporated herein by reference.

[0035] Those skilled in the art will recognize, or can learn through routine experimentation, many equivalents of the specific embodiments of the invention described herein. These equivalents will be included in the claims.

[0036] Unless otherwise specified, the experimental methods used in the following examples are conventional methods. Unless otherwise specified, the instruments and equipment used in the following examples are all conventional laboratory instruments and equipment; poloxamer 407 (P407) and poloxamer 188 (P188) used in the following examples were purchased from BASF, chondroitin sulfate (CS) was purchased from Maclean's, and other experimental materials were purchased from conventional biochemical reagent stores unless otherwise specified.

[0037] Example 1: Preparation of chondroitin sulfate-poloxam hydrogel Cool the membrane-passed PBS in an ice bath. Add P407, P188 and CS to the PBS according to Table 1, stir in an ice bath for 4 h, and store overnight at 4°C.

[0038] Table 1: Chondroitin Sulfate-Poloxamer Hydrogel Formulation

[0039] The gelation temperature of each formulation was measured using the following method: Take 0.8 mL of the solution into a 1.5 mL EP tube, place it in a constant temperature water bath, start heating from 20 °C, increase the temperature by 1 °C, hold each temperature for 5 min, then invert the EP tube and observe the gel flow. If the gel does not flow after 30 s, the temperature is considered the gelation temperature.

[0040] The gelation temperatures of each formulation in Table 1 are shown in Table 2 after testing.

[0041] Table 2 Gelation Temperatures of Each Formula

[0042] Because injectable thermosensitive gels are required to be solutions at room temperature and transform into semi-solid gels at body temperature, the gelation temperature should be higher than room temperature and slightly lower than body temperature. Furthermore, for ease of use, storage, and transportation of the hydrogel solution, the gelation temperature should not be lower than 30°C.

[0043] Taking all the above into consideration, the target value for the gelation temperature is set at 30~36℃, and the higher the gelation temperature within this range, the more advantageous it is. Therefore, only formulations 1, 2, 8, and 10 meet the requirements.

[0044] Example 2 Rheological determination of chondroitin sulfate-poloxam hydrogel The inventors first made adjustments and optimizations based on formulas 1, 2, 8 and 10, as shown in Table 3.

[0045] Table 3: Improved Chondroitin Sulfate-Poloxamer Hydrogel Formulation

[0046] Formula 17 is an adjustment based on Formula 1, that is, the mass fraction of P407 is adjusted from 17% to 16.8%; Formula 18 is the same as Formula 2; Formula 19 is an adjustment based on Formula 8, that is, the mass fraction of P407 is adjusted from 18% to 17.8%, and the mass fraction of P188 is adjusted from 8% to 2%; Formula 20 is an adjustment based on Formula 10, that is, the mass fraction of P407 is adjusted from 19% to 19.2%.

[0047] The inventors first used a rheometer to precisely measure the temperature of gels with formulation numbers 17, 18, 19, and 20, as detailed below: Place the sample flat on the test platform of the rheometer, ensuring uniform distribution. In the continuous temperature variation test, set the linear temperature variation rate (e.g., 1~5℃ / min, used in this embodiment), the measurement temperature range is 20~50℃, and the scan amplitude is 1Hz. Start the rheometer's test program to measure parameters such as storage modulus G' and loss modulus G". Observe the data changes during the test and record key data points. The results are as follows: Figure 1 As shown in Table 4.

[0048] Table 4: Determination of gelation temperature of chondroitin sulfate-poloxam hydrogel

[0049] Depend on Figure 1As shown in Table 4, the gelation temperature of the hydrogels with formulation numbers 17, 18, 19 and 20 is between 33 and 35℃.

[0050] Example 3: In vitro degradation of chondroitin sulfate-poloxam hydrogel The inventors determined the in vitro degradation rate of hydrogels with formulation numbers 17, 18, 19, and 20. Specifically, the hydrogels were freeze-dried for 12 hours, and the initial dry weight of the gel was recorded as (W1). The gels were then placed in 10 volumes of PBS (pH 7.4) and placed in a 37°C oven. The dry weight of the freeze-dried sample was recorded at each time point every 24 hours (W2), and the residual rate was calculated to characterize the degradation level. The lower the residual rate, the greater the degradation. Residual rate = W2 / W1 × 100%.

[0051] The results are as follows Figure 2 As shown, all four hydrogel formulations degrade by approximately 50% or more within about two days. The hydrogel prepared from formulation number 17 degraded the fastest, while the hydrogel prepared from formulation number 20 degraded the slowest.

[0052] Example 4: In vitro release of BSA from chondroitin sulfate-poloxam hydrogel. BSA has long been used as a model protein in protein sustained-release studies due to its low cost, ease of acquisition, high stability, mature and sensitive detection methods, and suitable molecular weight and charge characteristics for use as a model of medium-sized therapeutic proteins. This embodiment measures the in vitro release performance of BSA from chondroitin sulfate-poloxam hydrogel to preliminarily evaluate the physical sustained-release performance and controlled-release mechanism of the hydrogel as a protein delivery carrier, thereby verifying its ability to deliver protein growth factors or drugs as carriers.

[0053] In preparing the chondroitin sulfate-poloxam aqueous solution, bovine serum albumin (BSA) was added to make the BSA concentration 1 mg / mL. After mixing well, 300 μL was aspirated into a 6 cm culture dish and incubated at 37 °C for 30 min to fully gel. Then, 10 mL of PBS solution was added.

[0054] The samples were placed at 37℃, and 0.1 mL of PBS solution was collected at 0h, 0.5h, 3h, 6h, 2h, 48h, 72h, and 96h. 0.1 mL of PBS solution was added to the culture dish. The samples were stored at -80℃.

[0055] The concentration of BSA in the PBS solution collected at each time point was detected using an ELISA reader and a BCA kit, and the in vitro BSA release rate of the hydrogel was calculated.

[0056] The results are as follows Figure 3As shown, approximately 20%–30% of BSA is released within the first 6 hours, and about 40%–70% is released after 24 hours. The release rate then slows significantly, with over 70% of BSA released after 96 hours. The hydrogel prepared from formulation number 17 released the most BSA, while the hydrogel prepared from formulation number 20 released the least.

[0057] Therefore, it can be seen that chondroitin sulfate-poloxam hydrogel can subsequently achieve the continuous release of proteins or drugs.

[0058] Example 5: Chondroitin sulfate-poloxam hydrogel treatment of mice with intrauterine adhesions 1. Establishment of a mouse IUA model ICR mice were anesthetized, and the skin and abdominal wall layers were sequentially incised to expose the bilateral uterine horns using sterile surgical instruments. A 1-3 mm incision was carefully made in the lower third of the uterus (near the bifurcation), and the uterine cavity was scraped with a miniature curette until the uterus became swollen and congested. The uterine wall and abdominal cavity were then sutured with sterile sutures. The sham surgery group (Sham group) only underwent the opening and closing of the abdomen.

[0059] 2. Treatment Groups We conducted the first IUA model and treatment in 10-week-old large ICR female mice. The experiment was divided into 8 groups: (1) Model Group: ICR mice were anesthetized, and the skin and abdominal wall layers were cut open sequentially. The bilateral uterine horns were exposed using sterile surgical instruments. A 1-3 mm incision was carefully made in the lower 1 / 3 of the uterus (near the bifurcation of the uterus), and the inside of the uterine cavity was scraped with a micro curette until the uterus was swollen and congested. The uterine wall and abdominal cavity were then sutured with sterile sutures. No treatment was performed after modeling.

[0060] (2) Sham surgery group: Only the opening and closing of the abdomen was performed.

[0061] (3) Hyaluronic acid hydrogel treatment group (HA): HA treatment was performed after modeling.

[0062] (4) Poloxamer hydrogel treatment group (HP): After modeling, P407 (17%) + P188 (2%) were used for treatment.

[0063] (5) HP / CS (0.5%) group: After modeling, the patient was treated with chondroitin sulfate-poloxam hydrogel prepared according to formula number 17.

[0064] (6) HP / CS (1%) group: After modeling, the patients were treated with chondroitin sulfate-poloxam hydrogel prepared by formula number 18.

[0065] (7) HP / CS (2%) group: After modeling, the patients were treated with chondroitin sulfate-poloxam hydrogel prepared by formula number 19.

[0066] (8) HP / CS (4%) group: After modeling, the patients were treated with chondroitin sulfate-poloxam hydrogel prepared according to formula number 20.

[0067] A mouse IUA model was constructed using a mechanical manipulation method: After anesthetizing the mice, the abdominal skin and muscle layer were cut open, and the uterus was repeatedly scraped with a micro-scraper, resulting in swelling and cyanosis of the uterus. The uterus was then sutured layer by layer, and the mice were in good condition post-surgery. In the treatment groups (3) to (8), 20 μL of the corresponding hydrogel solution was injected 10 minutes after modeling, followed by layer-by-layer suturing. Two weeks after modeling, the mice were sacrificed, and the uterus was removed for observation.

[0068] The results are as follows Figure 4 As shown, compared with the sham surgery group, the uterus of the mice in the model group was swollen and red. Compared with the model group, the uterus of the mice in the poloxamer hydrogel treatment group was red and swollen without significant improvement, while the uterus of the mice in the hyaluronic acid hydrogel treatment group was significantly restored. The recovery of the uterus of the mice in each chondroitin sulfate-poloxamer hydrogel treatment group was also very significant, with the HP / CS (2%) group showing the most significant recovery.

[0069] Uterine tissues from each group of mice were fixed, embedded in paraffin, and sectioned for H&E staining and endometrial morphology assessment. The results are as follows: Figure 5 As shown.

[0070] from Figure 5 It can be seen that the endometrium in the sham surgery group was intact, with a clear boundary with the myometrium, and the columnar epithelial cells of the endometrium were arranged in a regular and orderly manner.

[0071] Compared with the sham surgery group, the model group mice showed significant damage to the endometrium (endometrium as shown by the red arrow in the figure), with unclear boundaries with the myometrium, significantly thinner endometrial thickness, obvious destruction of endometrial columnar epithelial cells, and destruction of glandular structure and a significant reduction in the number of glands.

[0072] In the poloxamer hydrogel treatment group, the endometrium did not show significant recovery compared to the model group; the boundary between the endometrium and myometrium remained indistinct, and the endometrial thickness did not increase significantly. A small number of intact glandular structures were observed within the endometrial stroma, and the number of glands showed a slight increase.

[0073] The hyaluronic acid hydrogel treatment group showed significantly improved endometrial morphology compared to the model group, with a clearer boundary between the endometrium and myometrium. Endometrial thickness showed no significant difference from the sham-operated group. Numerous intact glandular structures were observed within the endometrial stroma, occasionally clustered. The glandular cavities and endometrial columnar epithelium provided near-continuous coverage.

[0074] In the chondroitin sulfate-poloxam hydrogel treatment groups (HP / CS 0.5%, 1%, and 4%), the endometrial structure showed some recovery compared to the model group, with a clearer boundary with the myometrium. Endometrial thickness recovered slightly but remained significantly different from the sham-operated group. Numerous intact glandular structures were visible within the endometrial stroma. Columnar epithelial coverage of the endometrial surface and glandular surfaces was incomplete. In contrast, the HP / CS (2%) group showed significant recovery compared to the model group, with a clear boundary with the myometrium. Endometrial thickness increased significantly, with no significant difference from the sham-operated group. Many intact glandular structures were observed in the endometrial stroma, occasionally clustered. The glandular cavities and endometrial columnar epithelium provided continuous coverage. Furthermore, the recovery of glandular structure and number was significantly better than in the hyaluronic acid hydrogel treatment group.

[0075] Masson staining was further performed on the paraffin sections to assess the degree of fibrosis, and the results were as follows: Figure 6 As shown.

[0076] from Figure 6 It was found that in the sham surgery group, the endometrial epithelium, glands, blood vessels, and myometrium were all red, and collagen fibers were light blue and evenly distributed in the endometrial stroma, arranged in a regular and orderly manner. In the model group, collagen fibers were dark blue, randomly arranged, and significantly deposited in the endometrial stroma. The collagen fiber distribution in the poloxamer hydrogel treatment group was similar to that in the model group. The collagen fiber deposition in the endometrial stroma of the hyaluronic acid hydrogel treatment group was light blue, significantly less than that in the model group. The collagen fiber deposition in the endometrial stroma of the chondroitin sulfate-poloxamer hydrogel treatment groups (HP / CS 0.5%), HP / CS 1%), and HP / CS 4%) showed some improvement compared to the model group. However, the collagen fiber deposition in the HP / CS 2%) group was light blue, arranged more regularly, and significantly recovered compared to the model group, with little difference from the sham surgery group.

[0077] Example 6: Microstructure of chondroitin sulfate-poloxam hydrogel Chondroitin sulfate-poloxam hydrogel solution (No. 19) was prepared, and after gel formation at 37°C, it was frozen at -20°C for 24 hours. Immediately afterwards, it was freeze-dried for 2 days. The freeze-dried sample was then sputter-coated with gold. The microstructure of the sample was observed using scanning electron microscopy (SEM).

[0078] The results are as follows Figure 7 As shown, from Figure 7As observed, the chondroitin sulfate-poloxam hydrogel exhibits a typical highly porous three-dimensional network structure under SEM. Its main characteristics are interconnected pores of varying sizes, ranging from approximately 20 μm to 50 μm in diameter. The pore morphology is predominantly irregular and sponge-like, with some areas showing honeycomb-like polygonal pores. The pore walls are relatively thin, and the surface is relatively smooth. This open, interconnected micron-scale porous structure clearly reflects the successful preservation of the physical network framework in the hydrogel state during the freeze-drying process, providing a favorable topological structure for potential drug or cell loading and release.

[0079] Furthermore, it should be understood that after reading the foregoing teachings of this application, those skilled in the art can make various alterations or modifications to this application, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A temperature-sensitive hydrogel, characterized in that, The thermosensitive hydrogel is a buffer solution comprising chondroitin sulfate and poloxamer, wherein the mass fraction of chondroitin sulfate in the hydrogel is 0.5% to 4%, and the amount of poloxamer added is determined such that the gelation temperature of the hydrogel is 30 to 36°C.

2. The thermosensitive hydrogel according to claim 1, characterized in that, The poloxamers include poloxamer 407 and poloxamer 188.

3. The thermosensitive hydrogel according to claim 2, characterized in that, In the hydrogel, the mass percentage of poloxamer 407 is 16%~20%, and the mass percentage of poloxamer 188 is 1%~4%.

4. The thermosensitive hydrogel according to claim 3, characterized in that, In the hydrogel, the mass percentage of poloxamer 407 is 16.8%, and the mass percentage of poloxamer 188 is 1%.

5. The thermosensitive hydrogel according to any one of claims 1 to 4, characterized in that, The buffer solution is selected from one of PBS buffer, Tris-HCl buffer, HEPES buffer, bicarbonate buffer, and acetate buffer.

6. The method for preparing the thermosensitive hydrogel according to any one of claims 1 to 5, characterized in that, Includes the following steps: The chondroitin sulfate and poloxamer were added to the buffer solution and stirred in an ice bath.

7. The use of the thermosensitive hydrogel according to any one of claims 1 to 5 in the preparation of a drug for intrauterine adhesions.

8. The application according to claim 7, characterized in that, The drug is administered via injection or vaginal tampon.

9. The use of the thermosensitive hydrogel according to any one of claims 1 to 5 in the preparation of a carrier for delivering protein drugs.

10. The application according to claim 9, characterized in that, The protein drug is selected from BSA analogs and BSA conjugates.

Images