Reverse temperature-sensitive gel and preparation method thereof
By optimizing the gel composition and process, the prepared reverse thermosensitive gel is liquid at room temperature, but its viscosity increases at 37°C, allowing it to adhere tightly to the skin. This solves the problem of short residence time of thermosensitive gel at the drug administration site, achieving continuous action and antibacterial effect. It is suitable for vaginal administration and promotes inflammation healing.
Patent Information
- Application Number
- CN202511557310.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-10-29
- Publication Date
- 2026-01-13
AI Technical Summary
Existing thermosensitive gels are thin and highly fluid, have a short residence time at the administration site, cannot exert a sustained effect, and lack good biological functions, thus failing to effectively prevent the colonization of pathogenic microorganisms.
By optimizing the raw materials and process of the gel, a reverse thermosensitive gel was prepared. Using ingredients such as collagen, surfactant, sodium hyaluronate, polyol and methylparaben, the pH value was adjusted to form a gel that is liquid at room temperature but rapidly increases in viscosity at 37°C, adhering tightly to the skin to form a gel layer. This increases the residence time at the drug delivery site and has antibacterial properties and promotes cell proliferation and differentiation.
It achieves long-term retention of the thermosensitive gel at the drug delivery site, prevents the colonization of pathogenic microorganisms, and accelerates the healing of inflamed wounds, exhibiting good biological activity and sustained drug release effect.
Smart Images
Figure CN121313541A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of gel preparation technology, and in particular to a reverse thermosensitive gel and its preparation method. Background Technology
[0002] Gel is a commonly used medication for treating gynecological inflammations and other conditions. It can be administered directly to the affected area via the vagina, allowing for rapid onset of action. Suitable for treating various gynecological inflammations, it possesses anti-inflammatory, antibacterial, and antipruritic properties. Gynecological gels form a protective gel film on the vaginal wall, physically isolating the vagina from external bacteria and effectively preventing the colonization of pathogenic microorganisms. It serves as an adjunct treatment for symptoms such as vaginal itching, pain, increased vaginal discharge, and odor caused by vaginitis and cervicitis.
[0003] Thermosensitive gels are temperature-sensitive materials that undergo a sol-gel transition with temperature changes, and are widely used in medical and drug delivery fields. However, current thermosensitive gels are relatively thin and fluid, resulting in short residence time at the drug delivery site and an inability to exert a sustained effect. Furthermore, they lack good biological functions, only physically blocking the colonization of pathogenic microorganisms. Therefore, there is an urgent need to develop new thermosensitive gels to address these issues. Summary of the Invention
[0004] To address the shortcomings of existing technologies, this invention provides a reverse thermosensitive gel and its preparation method. The gel prepared by this invention through optimization of gel raw materials and processes exhibits superior reversible thermosensitive properties, adheres tightly to the skin at the drug administration site, increases the residence time at the administration site, and allows the drug to exert its effects more effectively. Simultaneously, it possesses good biological activity, promoting cell proliferation, differentiation, adhesion, and migration, and effectively inhibiting the colonization of pathogenic microorganisms.
[0005] The technical solution of the present invention is as follows: The first aspect of this invention protects a method for preparing a reverse thermosensitive gel, comprising the following steps: S1: Add water to the collagen raw material and stir to obtain a collagen solution; S2: Add surfactant, sodium hyaluronate, polyol, methylparaben, and phenoxyethanol to the collagen solution, stir, and let stand to obtain a gel solution; S3: Adjust the pH value of the adhesive solution to obtain the reverse temperature-sensitive gel; The molecular weight of the sodium hyaluronate is 600-1000 kDa.
[0006] Preferably, in step S1, the stirring speed is 60~120 r / min, more preferably 80~100 r / min.
[0007] Preferably, in step S1, the concentration of the collagen solution is 1.5 mg / mL to 2.5 mg / mL, more preferably 1.8 mg / mL to 2.2 mg / mL.
[0008] Preferably, in step S2, the surfactant is a nonionic surfactant; Preferably, the surfactant is poloxamer; Preferably, the mass ratio of the collagen solution to the surfactant is 100:27 to 100:28, more preferably 100:27.5.
[0009] Preferably, in step S2, the mass ratio of the collagen solution to the sodium hyaluronate is 250:1 to 500:3, more preferably 200:1.
[0010] Preferably, in step S2, the polyol includes at least one of glycerol, propylene glycol, and butylene glycol; The mass ratio of the collagen solution to the polyol is 100:1 to 100:3, preferably 100:2; The mass ratio of the collagen solution to methylparaben is 10000:1 to 1000:1, preferably 5000:1; The mass ratio of the collagen solution to phenoxyethanol is 10000:1 to 1000:1, preferably 5000:1.
[0011] Preferably, in step S2, the stirring speed is 200~400 r / min, more preferably 250~350 r / min.
[0012] Preferably, step S3 specifically includes: adding acid to the adhesive solution to adjust the pH value to 3.8~4.5, thereby obtaining the reverse temperature-sensitive gel.
[0013] Preferably, the acid includes hydrochloric acid; Preferably, the concentration of the hydrochloric acid is 1 mol / L to 3 mol / L, more preferably 2 mol / L.
[0014] A second aspect of this invention protects a reverse thermosensitive gel prepared by the preparation method described in the first aspect above.
[0015] The beneficial technical effects of this invention are as follows: This invention optimizes the gel components and ratios to prepare a gel with excellent reverse thermosensitive properties. It is liquid at room temperature, but its viscosity rapidly increases at approximately 37°C (human body temperature), forming a tightly adhering gel layer at the administration site. This increases the product's residence time at the administration site, allowing it to exert a sustained effect. The thermosensitive gel prepared by this invention is ideal for vaginal administration, effectively preventing pathogenic microorganism colonization and accelerating the healing of inflammatory wounds. Attached Figure Description
[0016] Figure 1 This is a schematic diagram of the process flow of the present invention. Detailed Implementation
[0017] The present invention will now be described in detail with reference to the embodiments.
[0018] To address the problems of existing thermosensitive gels being thin, highly fluid, having a short residence time at the drug delivery site, and thus failing to exert a sustained effect, this invention provides a reverse thermosensitive gel and its preparation method.
[0019] The first aspect of this invention provides a method for preparing a reverse thermosensitive gel, comprising the following steps: S1: Add water to the collagen raw material and stir to obtain a collagen solution.
[0020] S2: Add surfactant, sodium hyaluronate, polyol, methylparaben, and phenoxyethanol to the collagen solution, stir, and let stand to obtain a gel solution.
[0021] S3: Adjust the pH value of the adhesive solution to obtain the reverse temperature-sensitive gel.
[0022] In step S2, the sodium hyaluronate has a molecular weight of 600-1000 kDa. This molecular weight of sodium hyaluronate can increase the viscosity and hydration of the gel, improving the uniformity and stability of the system.
[0023] Understandably, by optimizing the gel components and ratios, the prepared gel exhibits excellent reverse thermosensitive properties. It is liquid at room temperature, but its viscosity rapidly increases at approximately 37°C (human body temperature), forming a tightly adhering gel layer at the administration site. This increases the product's residence time at the administration site, allowing it to exert a sustained effect. After use, it reverts to a liquid state upon cooling to room temperature, demonstrating excellent reversibility. The thermosensitive gel prepared in this invention is ideal for vaginal administration, achieving prolonged residence at the administration site, effectively preventing pathogenic microorganism colonization, and accelerating the healing of inflammatory wounds.
[0024] In some embodiments, the present invention does not limit the collagen raw material used, and any collagen that can achieve the purpose of the present invention is within the scope of protection of the present invention. Exemplarily, the collagen raw material of the present invention may be recombinant collagen, which is a commonly used recombinant collagen in the art, such as type I collagen, type III collagen, recombinant humanized type I collagen, recombinant humanized type III collagen, etc. Unless otherwise specified, the recombinant humanized type I collagen and recombinant humanized type III collagen of the present invention can be commercially available or commonly used raw materials in the art. For example, the recombinant humanized type I collagen of the present invention can be the recombinant humanized type I collagen sold by Jiangshan Juyuan; the recombinant humanized type III collagen can be the recombinant type III humanized collagen sold by Jiangshan Juyuan.
[0025] In some embodiments, the collagen solution is obtained by adding water to a lyophilized collagen product and stirring. For example, an existing lyophilized type I recombinant collagen product is added to water and stirred.
[0026] In some embodiments, in step S1, the stirring speed is 60~120 r / min, preferably 80~100 r / min.
[0027] Understandably, stirring too fast can cause localized overheating, damaging collagen activity and reducing the viscosity of the material; stirring too slowly can cause the raw materials to clump together, resulting in uneven dissolution and affecting the uniformity of the prepared gel.
[0028] In some embodiments, in step S1, the concentration of the collagen solution is 1.5 mg / mL to 2.5 mg / mL, preferably 1.8 mg / mL to 2.2 mg / mL.
[0029] In some embodiments, in step S2, the surfactant is a nonionic surfactant.
[0030] In some embodiments, the surfactant is poloxamer.
[0031] It is understood that the poloxamer used in this invention is preferably poloxamer 407, which has temperature-sensitive properties and can better realize the changes in the rheological properties such as viscosity and consistency of the gel as the temperature changes.
[0032] In some embodiments, the mass ratio of the collagen solution to the surfactant is 100:27 to 100:28, preferably 100:27.5.
[0033] In some embodiments, in step S2, the mass ratio of the collagen solution to the sodium hyaluronate is 250:1 to 500:3, preferably 200:1.
[0034] In some embodiments, in step S2, the polyol includes at least one of glycerol, propylene glycol, and butylene glycol.
[0035] In some embodiments, the mass ratio of the collagen solution to the polyol is 100:1 to 100:3, preferably 100:2.
[0036] In some embodiments, the mass ratio of the collagen solution to methylparaben is 10000:1 to 1000:1, preferably 5000:1.
[0037] In some embodiments, the mass ratio of the collagen solution to phenoxyethanol is 10000:1 to 1000:1, preferably 5000:1.
[0038] It is understood that the methylparaben and phenoxyethanol described in this invention have antibacterial properties, can inhibit bacterial growth, control microbial limits, and have low irritation.
[0039] In some embodiments, in step S2, the stirring speed is 200~400 r / min, preferably 250~350 r / min.
[0040] In some embodiments, step S3 specifically includes: adding acid to the adhesive solution to adjust the pH value to 3.8~4.5, thereby obtaining the reverse temperature-sensitive gel.
[0041] In some embodiments, the acid includes hydrochloric acid.
[0042] In some embodiments, the concentration of the hydrochloric acid is 1 mol / L to 3 mol / L, preferably 2 mol / L.
[0043] A second aspect of this invention protects a reverse thermosensitive gel prepared by the preparation method described in the first aspect above.
[0044] It is understood that the reverse temperature-sensitive gel of the present invention is a liquid sol at room temperature. When the temperature rises to about 37°C or even 42°C, it can be transformed into a gel state and has good stability within this temperature range. When the temperature gradually decreases and falls below 36°C, a sol will begin to appear. At room temperature, it is a completely liquid sol state. The room temperature mentioned in the present invention refers to about 25°C.
[0045] The following are specific examples.
[0046] Example 1 A reverse thermosensitive gel, the preparation method of which includes the following steps: (1) Preparation of collagen solution: Weigh the lyophilized recombinant type I humanized collagen, add purified water, stir at 80 r / min to completely dissolve the protein, and prepare a 2 mg / mL collagen aqueous solution for later use.
[0047] (2) Collagen preparation: Add 27% of the total mass of poloxamer 407, 0.4% sodium hyaluronate, 1% glycerin, 0.01% methylparaben and 0.01% phenoxyethanol to the collagen aqueous solution prepared in step (1). Stir magnetically at 250 r / min until completely dissolved, and let stand overnight to wait for the bubbles to completely disappear to obtain the gel solution.
[0048] (3) Adjusting the pH of the gel solution with 2 mol / L hydrochloric acid while stirring. When the pH of the solution stabilizes at 3.8, a transparent and uniform recombinant type I humanized collagen reverse thermosensitive gel is obtained.
[0049] Example 2 A reverse thermosensitive gel, the preparation method of which includes the following steps: (1) Preparation of collagen solution: Weigh the lyophilized recombinant type I humanized collagen, add purified water, stir at 90 r / min to completely dissolve the protein, and prepare a 2 mg / mL collagen aqueous solution for later use.
[0050] (2) Collagen preparation: Add 27.5% poloxamer 407, 0.5% sodium hyaluronate, 2% glycerin, 0.05% methylparaben and 0.05% phenoxyethanol to the collagen aqueous solution prepared in step (1). Stir magnetically at 300 r / min until completely dissolved, and let stand overnight to wait for the bubbles to completely disappear to obtain the gel solution.
[0051] (3) Adjusting pH: Adjust the pH of the gel solution with 2 mol / L hydrochloric acid while stirring. When the pH of the solution stabilizes at 4.2, a transparent and uniform recombinant type I humanized collagen reverse thermosensitive gel is obtained.
[0052] Example 3 A reverse thermosensitive gel, the preparation method of which includes the following steps: (1) Preparation of collagen solution: Weigh the lyophilized recombinant type I humanized collagen, add purified water, stir at 100 r / min to completely dissolve the protein, and prepare a 2 mg / mL collagen aqueous solution for later use.
[0053] (2) Collagen preparation: Add 28% of the total mass of poloxamer 407, 0.6% sodium hyaluronate, 3% glycerin, 0.1% methylparaben and 0.1% phenoxyethanol to the collagen aqueous solution prepared in step (1). Stir magnetically at 350 r / min until completely dissolved, and let stand overnight to wait for the bubbles to completely disappear to obtain the gel solution.
[0054] (3) Adjusting pH: Adjust the pH of the gel solution with 2 mol / L hydrochloric acid while stirring. When the pH of the solution stabilizes at 4.5, a transparent and uniform recombinant type I humanized collagen reverse thermosensitive gel is obtained.
[0055] Test example: The physical, chemical, and microbiological properties of the gels prepared in the embodiments of the present invention were tested, and the results are shown in Table 1.
[0056] Physical properties include appearance and odor. Appearance is determined by visual observation, while odor is determined by direct sensory perception.
[0057] Chemical properties include viscosity at different temperatures, protein content, and heavy metal content. Viscosity was determined using a rotational viscometer. Protein content was determined using the Kjeldahl method; and heavy metals were tested using atomic absorption spectrometry.
[0058] Table 1: Performance Tests of Gels Prepared in Various Embodiments of the Present Invention
[0059] As shown in Table 1, the thermosensitive gel prepared in the embodiments of the present invention is uniform and free of foreign matter and odor at room temperature. Its viscosity is less than 190 mPa·s at 4℃, and reaches 3305 mPa·s at 37℃ as the temperature increases, indicating that the gel prepared in this invention transitions between sol and gel states with temperature changes, and maintains a relatively stable gel state at 37℃ due to its high viscosity. Microbiological testing results show that the gel prepared in the embodiments also has good antibacterial properties.
[0060] The above description is merely a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and variations that are directly derived or conceived by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included within the protection scope of the present invention.
Claims
1. A method for preparing a reverse thermosensitive gel, characterized in that, Includes the following steps: S1: Add water to the collagen raw material and stir to obtain a collagen solution; S2: Add surfactant, sodium hyaluronate, polyol, methylparaben, and phenoxyethanol to the collagen solution, stir, and let stand to obtain a gel solution; S3: Adjust the pH value of the adhesive solution to obtain the reverse temperature-sensitive gel; The molecular weight of the sodium hyaluronate is 600-1000 kDa.
2. The preparation method according to claim 1, characterized in that, In step S1, the stirring speed is 60~120 r / min, preferably 80~100 r / min.
3. The preparation method according to claim 1, characterized in that, In step S1, the concentration of the collagen solution is 1.5 mg / mL to 2.5 mg / mL, preferably 1.8 mg / mL to 2.2 mg / mL.
4. The preparation method according to claim 1, characterized in that, In step S2, the surfactant is a nonionic surfactant; Preferably, the surfactant is poloxamer; Preferably, the mass ratio of the collagen solution to the surfactant is 100:27 to 100:28, more preferably 100:27.
5.
5. The preparation method according to claim 1, characterized in that, In step S2, the mass ratio of the collagen solution to the sodium hyaluronate is 250:1 to 500:3, preferably 200:
1.
6. The preparation method according to claim 1, characterized in that, In step S2, the polyol includes at least one of glycerol, propylene glycol, and butylene glycol; The mass ratio of the collagen solution to the polyol is 100:1 to 100:3, preferably 100:2; The mass ratio of the collagen solution to the methylparaben is 10000:1 to 1000:1, preferably 5000:1; The mass ratio of the collagen solution to phenoxyethanol is 10000:1 to 1000:1, preferably 5000:
1.
7. The preparation method according to claim 1, characterized in that, In step S2, the stirring speed is 200~400 r / min, preferably 250~350 r / min.
8. The preparation method according to claim 1, characterized in that, Step S3 specifically includes: adding acid to the gel solution to adjust the pH value to 3.8~4.5, thereby obtaining the reverse temperature-sensitive gel.
9. The preparation method according to claim 8, characterized in that, The acid includes hydrochloric acid; Preferably, the concentration of the hydrochloric acid is 1 mol / L to 3 mol / L, more preferably 2 mol / L.
10. A reverse thermosensitive gel prepared by the preparation method according to any one of claims 1-9.