Vagina temperature-sensitive antibacterial gel and preparation method thereof

Abstract

The invention discloses a vaginal temperature-sensitive antibacterial gel and a preparation method thereof, the gel is composed of water-soluble chitosan, poloxamer 407, hydroxy propyl cellulose, nano silver, plant polyphenol, a transdermal absorption enhancer, propylene glycol and deionized water, the poloxamer 407 is used as an only thermally induced hydrogel forming agent, and the nano silver, the plant polyphenol, the transdermal absorption enhancer, the propylene glycol and the deionized water are added into the gel; a solvation temperature-sensitive adjusting system is constructed through propylene glycol, and the sol-gel transition temperature is accurately regulated and controlled to 28-32 DEG C. The gel is a low-viscosity fluid (500-1000 mPa.s) at the normal temperature of 15-25 DEG C, and is easy to push and inject; and after contacting with the body temperature of 36 DEG C, the gel is instantly subjected to phase change within 30 seconds to form high-strength gel, and the gel is stably anchored on the vagina wrinkling wall for more than 8 hours by utilizing the synergistic effect of physical chimerism and electrostatic adsorption. The problems that an existing temperature-sensitive preparation is difficult in normal-temperature administration, slow in-vivo solidification and prone to loss are solved, a split-phase sterilization method is adopted in the preparation process, and the preparation method is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of gynecological drug delivery technology, and in particular to a vaginal thermosensitive antibacterial gel and its preparation method. Background Technology

[0002] The vaginal mucosa is an important physiological barrier for the human body. However, because this area is in a moist and warm environment for a long time, and the vaginal wall has natural and complex physiological folds, it is very easy for pathogens such as bacteria and fungi to hide, which can lead to gynecological diseases such as vaginitis and cervicitis.

[0003] Currently, commonly used vaginal medications in clinical practice mainly include suppositories, creams, and ordinary gels. However, these traditional preparations have significant application drawbacks: suppositories dissolve unevenly, making it difficult to evenly cover the deep folds of the vagina; creams and ordinary gels have poor mucosal adhesion and are easily washed away by gravity and secretions, resulting in a short residence time of the drug at the lesion site and low bioavailability.

[0004] Thermosensitive in-situ gels are a class of smart materials that undergo a sol-gel phase transition with temperature changes, theoretically making them ideal for intracavitary drug delivery. Currently, mainstream technologies often employ a blend of poloxamer 407 (P407) and poloxamer 188 (P188) to regulate the gelation temperature. However, existing technologies suffer from the following significant problems: To ensure rapid solidification at body temperature (36-37℃), it is often necessary to increase the polymer concentration. However, this leads to excessively high viscosity (semi-solid state) of the formulation at room temperature (20-25℃), making it difficult to inject with a device and resulting in poor patient compliance. The traditional P407 / P188 compound system has a slow phase transition rate in vivo (usually requiring more than 60 seconds). Before the gel is fully formed, it is easily diluted or expelled by vaginal secretions, failing to effectively fill vaginal folds. Furthermore, the compound system is sensitive to proportions, making production control difficult. In addition, some formulations use ordinary chitosan that is insoluble in water, requiring the introduction of acidic solvents, which increases the risk of irritation and process complexity. Therefore, developing a temperature-sensitive gel material with a simplified formulation that can maintain a low-viscosity fluid state at room temperature, solidify instantly after entering the body, and adhere to the vaginal fold wall for a long time is a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0005] The purpose of this invention is to address the technical shortcomings of existing vaginal thermosensitive gel formulations, such as excessively high viscosity at room temperature making them difficult to administer, slow coagulation response at body temperature, and easy wash-off by secretions. This invention proposes a vaginal thermosensitive antibacterial gel and its preparation method.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A vaginal thermosensitive antibacterial gel, by weight, comprises the following raw materials: 3-8 parts water-soluble chitosan; 18-25 parts poloxamer 407; 1-4 parts hydroxypropyl cellulose; 0.0005-0.002 parts nano silver; 2-5 parts plant polyphenols; 4-8 parts laurocapram; 15-25 parts propylene glycol; and deionized water, to a total of 100 parts. The vaginal thermosensitive antibacterial gel uses poloxamer 407 as the only thermogenic hydrogel forming agent and propylene glycol to adjust the sol-gel transition temperature of the system, so that it maintains a fluid dynamic liquid with a viscosity of 500-1000 mPa·s in the temperature range of 15℃-25℃, and undergoes a phase transition within 30 seconds after contact with a temperature of 36℃ to form a semi-solid gel with a viscosity ≥10000 mPa·s.

[0007] Furthermore, the water-soluble chitosan is specifically carboxymethyl chitosan with a degree of deacetylation of 85%-95% and an average molecular weight of 50-150 kDa.

[0008] Furthermore, the plant polyphenols are specifically tea polyphenols or grape seed proanthocyanidins; the nano-silver is spherical particles with a particle size distribution D50 of 10-50 nm.

[0009] Furthermore, the hydroxypropyl cellulose is low-substituted hydroxypropyl cellulose (L-HPC); the laurocapram, as a transdermal absorption enhancer, together with the propylene glycol, constitutes a solubilizing and phase change regulating system.

[0010] Furthermore, by weight, it also includes 1-3 parts of plant volatile oil, which is selected from one of clove volatile oil, Cnidium monnieri oil, or cinnamon oil.

[0011] Furthermore, the sol-gel transition temperature of the gel system is specifically 28℃-32℃, and the gel strength in a simulated vaginal environment at 36℃ is sufficient to remain in the vaginal folds for more than 8 hours.

[0012] Another object of the present invention is to provide a method for preparing the above-mentioned vaginal thermosensitive antibacterial gel, comprising the following steps: (1) Preparation of chitosan aqueous phase: The water-soluble chitosan is added to the first part of deionized water and stirred at 20℃-25℃ until completely dissolved to obtain a clear chitosan aqueous solution, which is defined as phase A; (2) Preparation of active alcohol phase: The laurocapram and optional plant volatile oil are dispersed in the propylene glycol, stirred and mixed evenly, and then the plant polyphenols and nano silver are added and stirred until a uniform alcohol dispersion is formed, which is defined as phase B; (3) Preparation of the matrix aqueous phase: The poloxamer 407 and the hydroxypropyl cellulose are dispersed in the second part of deionized water and allowed to swell for 12-24 hours under low temperature conditions of 4℃-10℃ to obtain a temperature-sensitive matrix solution, which is defined as phase C; (4) Phase separation sterilization: Phase A, Phase B and Phase C are respectively filtered and sterilized using microporous filter membranes with a pore size of 0.22 μm; (5) Mixing and molding: In a constant temperature and clean environment of 25℃-30℃, the sterilized phase B is slowly added to the sterilized phase C and stirred evenly at a speed of 300-500r / min; then the sterilized phase A is added and the mixture is stirred at a low speed until a uniform semi-transparent mixed sol is formed. (6) Filling: Fill the mixed sol into a sterile administration device and seal it.

[0013] Furthermore, the weight ratio of the first portion of deionized water to the second portion of deionized water is 1.2:1 to 1.5:1 to ensure that the viscosity of each phase system before mixing is below 500 mPa·s, which is suitable for membrane filtration.

[0014] Furthermore, step (3) also includes a step of ultrasonic degassing of phase C, wherein the ultrasonic degassing power is 120-140W and the treatment time is 15-20 minutes, until there are no visible bubbles in the solution.

[0015] Furthermore, the temperature of the mixing process in step (5) is strictly controlled below 32°C, and the stirring paddle is an anchor-type stirring paddle to prevent the material from undergoing local gelation under shear heat or ambient heat.

[0016] Compared with the prior art, the present invention has the following significant advantages: By using poloxamer 407 as a single thermosensitive backbone and constructing a mixed solvent system with a high content of propylene glycol, propylene glycol interferes with the hydration layer of the poloxamer molecular chain by changing the solvent polarity, effectively raising the sol-gel transition temperature of the system to the range of 28℃-32℃. This ensures that the gel maintains a low viscosity (500-1000 mPa·s) fluid state within a wide room temperature range of 15℃-25℃, allowing for smooth drug delivery. Once it enters the 36℃ vaginal environment, the large temperature difference drives a phase transition within 30 seconds, forming a high-viscosity gel. like Figure 4As shown, this invention utilizes the instantaneous curing characteristic of a single matrix to allow the fluid to penetrate into the micro-folds of the vagina in a liquid state, and then solidify in situ to form a physical interlocking. At the same time, the selected water-soluble chitosan (such as carboxymethyl chitosan) is rich in cationic groups, which can generate a strong electrostatic adsorption effect with the negatively charged vaginal mucosal epithelial cells. Through a dual mechanism, the gel can resist the flushing of secretions and the effect of gravity, and the retention time in the vaginal fold wall is extended to more than 8 hours, which significantly improves the bioavailability of the drug. By employing the synergistic antibacterial properties of nano-silver, plant polyphenols, and chitosan, with the nano-silver particle size controlled at 10-50nm, combined with the antioxidant and membrane-destructive effects of polyphenols, an inhibition rate of over 99% against Escherichia coli and Candida albicans can be achieved at extremely low dosages, while avoiding the toxicity risks of high-concentration drugs. Furthermore, by using water-soluble chitosan instead of traditional acid-soluble chitosan, the introduction of acetic acid / lactic acid solvents is avoided, resulting in a milder pH value and no irritation to the vaginal mucosa (irritation level 0).

[0017] Furthermore, to address the issue of high viscosity in polymeric gel formulations, which makes them difficult to pass through a 0.22μm sterilization filter membrane, a phase-separated preparation and phase-separated sterilization process is employed. Before mixing each component, the low-viscosity chitosan aqueous phase, active alcohol phase, and matrix aqueous phase are separately sterilized by membrane filtration. Finally, they are mixed in a sterile environment. This not only ensures the sterility level of the finished product but also avoids the damage to the gel structure that may be caused by terminal sterilization, thereby improving production efficiency and product quality stability. Attached Figure Description

[0018] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used together with the embodiments of the invention to explain the invention and do not constitute a limitation thereof.

[0019] Figure 1 The following is a flowchart of the preparation process of the vaginal thermosensitive antibacterial gel provided in Embodiment 1 of the present invention; Figure 2 This is a comparison graph of the viscosity-temperature rheological curves of Example 1 of the present invention, Comparative Example 1, and a traditional compound preparation. Figure 3 This is a curve comparing the cumulative in vitro drug release of the gel prepared in Example 1 of the present invention with that of a conventional formulation; Figure 4 This is a schematic diagram illustrating the dual anchoring mechanism of the gel in the vaginal environment of this invention. Detailed Implementation

[0020] The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0021] To ensure that the technical solution of this invention can be accurately understood and reproduced by those skilled in the art, the key raw material specifications and terms involved in this invention are clearly defined below. Unless otherwise stated, all raw materials used in this invention are pharmaceutical grade or chemically pure grade.

[0022] Water-soluble chitosan: specifically carboxymethyl chitosan (CAS No.: 83512-85-0). Products manufactured by Shenzhen Lijing Biochemical Technology Co., Ltd. (or of equivalent quality) are preferred, with a degree of substitution ≥90%, good water solubility, and a viscosity range of 10-1000 mPa·s.

[0023] Poloxamer 407: Polyoxyethylene-polyoxypropylene-polyoxyethylene triblock copolymer, CAS No.: 9003-11-6. The preferred product is manufactured by Dalian Meilun Biotechnology Co., Ltd., with an average molecular weight (MW) of approximately 12,000.

[0024] Nano silver: CAS No.: 7440-22-4. The nano silver powder supplied by Wuhan Lanabai Pharmaceutical Chemical Co., Ltd. is preferred, with a purity of 98% and an average particle size of approximately 20nm.

[0025] Propylene glycol: 1,2-propanediol, CAS No.: 57-55-6, pharmaceutical grade, purity ≥99.5%. Purchased from Jiangsu Runfeng Synthetic Technology Co., Ltd. or equivalent supplier.

[0026] Tea polyphenols: CAS No.: 84650-60-2, extracted from green leaves, total polyphenol content ≥98%. Purchased from Shaanxi Xinyanghe Biotechnology Co., Ltd. or a supplier of equivalent plant extracts.

[0027] Lauryl azelazone: CAS No.: 59227-89-3, pharmaceutical transdermal penetration enhancer, purity ≥98%. Purchased from Hubei Yushenghe Biotechnology Co., Ltd. or an equivalent pharmaceutical excipient supplier.

[0028] Hydroxypropyl cellulose: CAS No.: 9004-64-2, low-substituted hydroxypropyl cellulose (L-HPC), pharmaceutical grade.

[0029] Clove volatile oil: extracted from the flower buds of clove, a plant of the Myrtaceae family, and meets the standards of the Chinese Pharmacopoeia.

[0030] Deionized water: prepared in the laboratory, conductivity ≤2 μS / cm.

[0031] This invention employs a process of phase-separated preparation, phase-separated sterilization, and low-temperature mixing. The specific process flow is as follows: Figure 1 As shown, the detailed steps are described below: Preparation of Phase A (chitosan phase): Weigh the amount of water-soluble chitosan in the formula and add it to about 20%-25% of the total amount of deionized water. Stir at room temperature until clear.

[0032] Phase B (alcohol phase) preparation: Lauryl acetonide, plant volatile oil (if available), plant polyphenols, and nano-silver are added sequentially to the prescribed amount of propylene glycol. Since propylene glycol has good solubility for both fat-soluble components (such as lauryl acetonide) and polyphenolic components, a homogeneous dispersion can be formed.

[0033] Phase C (matrix phase) preparation: Poloxamer 407 and hydroxypropyl cellulose were dispersed in the remaining deionized water (approximately 30%-40% of the total volume) and placed in a refrigerator at 4°C overnight (12-24 hours) until fully hydrated. After removal, the mixture was degassed by sonication at 130W for 15 minutes.

[0034] Mixing: Filter phases A, B, and C separately through a 0.22 μm microporous membrane. In a constant temperature water bath at 30℃, first add phase B to phase C, and finally add phase A, stirring at 300 rpm for 30 minutes to obtain the final product.

[0035] Example 1: The raw material composition (by weight, total weight 100 parts) is as follows: Phase A (chitosan phase): 5.0 parts carboxymethyl chitosan (degree of deacetylation 90%, Mw 100kDa, water-soluble), 25.0 parts deionized water; Phase B (active alcohol phase): 20.0 parts propylene glycol (pharmaceutical grade, purity >99.5%), 5.0 parts laurocapram, 2.0 parts tea polyphenols, 0.001 parts nano silver, 1.0 part clove volatile oil; Phase C (matrix phase): 22.0 parts of poloxamer 407 (BASF F127), 2.0 parts of hydroxypropyl cellulose (L-HPC), and 18.0 parts of deionized water.

[0036] The above gel was prepared according to the following steps: (1) Preparation of phase A: At room temperature of 25℃, 5.0 parts of carboxymethyl chitosan were added to 25.0 parts of deionized water and stirred for 30 minutes until completely dissolved to obtain a clear liquid; then the liquid was filtered and sterilized using a 0.45μm microporous membrane. (2) Preparation of phase B: Add 5.0 parts of laurocapram and 1.0 parts of clove volatile oil to 20.0 parts of propylene glycol and stir to dissolve; then add 2.0 parts of tea polyphenols and 0.001 parts of nano silver and stir to disperse evenly to form a uniform alcohol dispersion; use a microporous filter membrane resistant to organic solvents for filtration and sterilization. (3) Preparation of phase C: 22.0 parts of poloxamer 407 and 2.0 parts of hydroxypropyl cellulose were dispersed in 18.0 parts of deionized water and placed in a refrigerator at 4°C for 24 hours to swell until a clear solution was formed; after taking it out, it was ultrasonically degassed for 15 minutes at 130W power; and then filtered and sterilized using a 0.22μm microporous membrane. (4) Mixing and filling: In a Class 100,000 clean area, the ambient temperature is controlled at 25℃-28℃. Sterilized phase B is slowly added to sterilized phase C, and stirred evenly using an anchor-type agitator at a speed of 300 r / min; then sterilized phase A is added, and stirring is continued for 20 minutes until the system presents a homogeneous, semi-transparent fluid. Finally, the mixture is filled into a sterile administration device and sealed.

[0037] The finished product has the following characteristics: Appearance: Pale yellow, semi-transparent, viscous liquid; Viscosity at 25℃: 850 mPa·s (flow dynamics, smooth injection); Phase transition temperature (T_sol-gel): 30.5℃; Gelation time at 36℃: 22 seconds; Gel strength at 36℃: viscosity reaches 13500 mPa·s, does not flow when inverted.

[0038] Example 2: The raw material composition is basically the same as in Example 1, except that: it does not contain nano silver, the tea polyphenols are increased to 4.0 parts, the water-soluble chitosan is adjusted to 4.0 parts, and the deionized water is adjusted accordingly.

[0039] Performance: Viscosity at 25℃: 820 mPa·s; Phase change temperature: 30.0℃; Antibacterial rate: slightly lower than Example 1 but still ≥95%.

[0040] Example 3: Raw material composition: 20.0 parts of poloxamer 407, 25.0 parts of propylene glycol, and the remaining excipients are the same as in Example 1.

[0041] Due to the increased propylene glycol content, the phase transition temperature rose to 31.8℃. It exhibited excellent fluidity at 25℃ (viscosity 600 mPa·s), but the solidification time at 36℃ was slightly extended to 28 seconds, still meeting the requirement of ≤30 seconds. This demonstrates that the temperature-sensitive window of the gel can be precisely controlled by adjusting the propylene glycol ratio.

[0042] Example 4: The raw material composition is as follows (total weight 100 parts): Phase A: 3.0 parts carboxymethyl chitosan, 20.0 parts deionized water; Phase B: 15.0 parts propylene glycol, 5.0 parts laurocapram, 2.0 parts tea polyphenols, 2.0 parts cinnamon oil, 0.001 parts nano silver; Phase C: Poloxamer 407 18.0 parts, methylcellulose 4.0 parts, deionized water 31.0 parts.

[0043] The preparation process is the same as in Example 1.

[0044] Performance test results: Viscosity at 25℃: 650 mPa·s (excellent flowability); Phase transition temperature: 31.5℃; 36℃ gelation time: 28 seconds (although the poloxamer content is as low as 18 parts, it can still solidify within 30 seconds, which meets the requirements); Adhesion duration: The retention time on the simulated vaginal fold model was 8.2 hours; Antibacterial rate: 99.1% against Escherichia coli and 99.0% against Candida albicans.

[0045] To better understand the technical solution of this application, the following explanation is provided in conjunction with comparative examples and experimental cases.

[0046] Comparative Example 1: Formula: Replace 20 parts of propylene glycol in Example 1 with an equal amount of deionized water.

[0047] Results: The prepared sol exhibited a high-viscosity gel state (viscosity > 50000 mPa·s) at room temperature (25℃), making it impossible to inject via a delivery device. Figure 2 As shown in the viscosity-temperature rheology curves, Comparative Example 1 (dashed square line) reaches high viscosity at 20°C, while Example 1 (solid dot line) remains a low-viscosity fluid until 28°C. This clearly demonstrates that in a single high-concentration P407 system, without the adjustment of propylene glycol, the technical goal of achieving a "room-temperature liquid state" cannot be achieved.

[0048] To verify the properties of the gel prepared in this embodiment, the following methods were used for testing, and the test results are shown in Table 1.

[0049] Appearance and viscosity determination: Visually inspect the appearance under constant temperature of 25℃. Use a rotational rheometer (or NDJ-79 rotational viscometer) equipped with rotor No. 2 to measure the shear rate at 10 s⁻ at 25℃ and 36℃. 1 The apparent viscosity at that time.

[0050] Gelation temperature (T_sol-gel) and gelation time determination (see typical test curves) Figure 2 ): The gelation temperature was determined using the inverted test tube method. The temperature was increased at a rate of 1℃ / min, and the test tube was inverted for observation after each 1℃ increase. The temperature at which the gel ceased to flow was recorded as the phase transition temperature. The gelation time was determined by injecting 2g of sample into simulated body fluid (SBF) at 36°C and recording the time required from contact with the liquid surface to the formation of a non-flowing gel.

[0051] In vitro adhesion test: A texture analyzer was used, with fresh porcine vaginal mucosa as a model. The gel was applied to the mucosal surface, and after equilibration at 36°C, the maximum peel force (F) between the probe and the gel surface was measured. max ) and work of adhesion.

[0052] In vitro release assay: Referring to the "Release Rate Determination Method" in Part IV of the Chinese Pharmacopoeia, a modified slurry method was adopted. Acetate buffer solution at pH 4.5 was used as the medium (simulating the vaginal environment), the rotation speed was 50 rpm, and the temperature was 37℃. The cumulative release rate of the main active ingredient (such as tea polyphenols or a mimic drug) over 8 hours was determined by HPLC. The results are as follows. Figure 3 As shown, Example 1 of the present invention (solid line) exhibits obvious sustained-release characteristics with no burst release phenomenon, while the ordinary formulation (dashed line) has a release rate of over 80% within 1 hour.

[0053] Antibacterial efficacy test: Referencing Section 1121, "Test Method for Antibacterial Efficacy," of the Chinese Pharmacopoeia, Escherichia coli, Candida albicans, and Staphylococcus aureus were used as test strains to determine the reduction in colony count or inhibition rate after contact with the gel.

[0054] Table 1: Performance Test Results of Finished Products in Example 1 Test Project Test Results Notes / Comparison Results 25℃ Appearance pale yellow semi-transparent fluid Uniform, without stratification Viscosity at 25℃ 850 mPa·s Good liquidity, easy to push bets gelation time at 36℃ 22 seconds Significantly better than the traditional compound group's 60+ seconds Viscosity after gelation 13,500 mPa·s Form a stable gel Mucosal adhesion 0.65 N It adheres firmly and is not easy to fall off. 8-hour cumulative release rate 88.50% Superior to 75% of the disclosed specifications. Escherichia coli inhibition rate >99.9% Powerful sterilization Candida albicans inhibition rate >99.5% Effectively inhibits fungi Experimental Example 1: To verify the performance stability of this product during storage, long-term and accelerated stability tests were conducted on the finished product prepared in Example 1.

[0055] Long-term stability test: Conditions: Store the sealed finished product in an environment of 25℃±2℃ and relative humidity of 60%±10% for 24 months.

[0056] Sampling points: Samples were taken and tested at 0, 6, 12, 18 and 24 months respectively.

[0057] result: Appearance: Remains a pale yellow, semi-transparent fluid for 24 months, without layering or precipitation; Rheological properties: Viscosity remained within the range of 750-900 mPa·s at 25℃; gelation time remained between 18-25 seconds at 36℃, with no significant extension; Antibacterial efficacy: The decrease in antibacterial inhibition rate is ≤2%.

[0058] Conclusion: This product maintains stable performance after 2 years of storage at room temperature.

[0059] Accelerated stability testing: Conditions: Store at 40℃±2℃ and 75%±5% relative humidity for 6 months.

[0060] Results: The temperature-sensitive response performance showed no significant change (gelation time ≤ 30 seconds), the cumulative drug release rate was ≥ 85%, and no demulsification or discoloration was observed. This indicates that the product has good thermal stability.

[0061] Experimental Example 2: Clinical application efficacy verification: Subjects: 120 patients diagnosed with bacterial vaginosis and vulvovaginal candidiasis were selected and randomly divided into an experimental group (using the gel prepared in Example 1 of this invention) and a control group (using commercially available traditional poloxamer compound gel), with 60 patients in each group.

[0062] Dosage regimen: 1 vial (5g) once daily for 7 consecutive days.

[0063] Results statistics: Symptom relief: After 3 days of medication, the relief rate of itching and odor in the experimental group reached 83.3%, which was significantly higher than the 65.0% in the control group.

[0064] Cure rate: After 7 days of medication, the cure rate (symptoms disappeared and pathogen detection was negative) in the experimental group was 78.3%, while that in the control group was 56.7%.

[0065] Recurrence rate: After a 1-month follow-up, the recurrence rate in the experimental group was 5.0%, which was significantly lower than the 18.3% in the control group.

[0066] Safety: No cases of vaginal irritation, burning or redness occurred in the experimental group.

[0067] Conclusion: In actual clinical applications, the gel of this invention has a faster onset of action, a higher cure rate, and a low recurrence rate, demonstrating its excellent mucosal adsorption and sustained drug release effect.

[0068] Experimental Example 3: The performance of the thermosensitive antibacterial gel prepared in Example 1 of this invention was compared with that of a traditional compound gel (poloxam 407 / 188 compound) and a common vaginal suppository. The results are shown in Table 2. Table 2 Performance indicators Thermosensitive antibacterial gel of the present invention Traditional poloxamer compound gel Regular vaginal suppositories Form / Viscosity at room temperature (15-25℃) Dynamic liquid (500-1000 mPa·s) Viscous liquid (1200-1800 mPa·s) Solid suppositories (non-flowing) 36℃ setting time ≤30 seconds 65-80 seconds Dissolving time: 15-30 minutes Duration of vaginal fold attachment ≥8 hours 4-6 hours 2-4 hours 8-hour cumulative drug release rate ≥85% 65%-75% 50%-60% Inhibition rate of pathogenic bacteria ≥99% ≥98% ≥97% Stimulation level Level 0 Level 1 (Minor mild irritation) Grade 1 (Irritation due to partial uneven dissolution) Convenience of administration High (smooth push notifications) Medium (sticky texture, difficult to push) Low (must be manually set) Production process Simple (no need to add temperature-sensitive agents) Complex (requires precise control of proportions) generally This invention abandons the traditional P407 / P188 compounding approach and uses propylene glycol to regulate the phase transition behavior of a single P407 matrix, which not only achieves a faster temperature-sensitive response speed (curing time reduced by more than 50%), but also significantly improves the adhesion time to the vaginal folds and the drug release rate.

[0069] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A vaginal thermosensitive antibacterial gel, characterized in that, By weight, its raw material components consist of the following parts by weight: The formula comprises: 3-8 parts water-soluble chitosan; 18-25 parts poloxamer 407; 1-4 parts hydroxypropyl cellulose; 0.0005-0.002 parts nano silver; 2-5 parts plant polyphenols; 4-8 parts laurocapram; 15-25 parts propylene glycol; and deionized water, to a total of 100 parts. The vaginal thermosensitive antibacterial gel uses poloxamer 407 as the only thermogenic hydrogel forming agent and utilizes propylene glycol to adjust the sol-gel transition temperature of the system, so that it maintains a fluid dynamic liquid with a viscosity of 500-1000 mPa·s within a temperature range of 15℃-25℃, and undergoes a phase transition within 30 seconds after contact with a temperature of 36℃ to form a semi-solid gel with a viscosity ≥10000 mPa·s.

2. The vaginal thermosensitive antibacterial gel according to claim 1, characterized in that, The water-soluble chitosan is specifically carboxymethyl chitosan with a degree of deacetylation of 85%-95% and an average molecular weight of 50-150 kDa.

3. The vaginal thermosensitive antibacterial gel according to claim 1, characterized in that, The plant polyphenols are specifically tea polyphenols or grape seed proanthocyanidins; the nano-silver is spherical particles with a particle size distribution D50 of 10-50 nm.

4. The vaginal thermosensitive antibacterial gel according to claim 1, characterized in that, The hydroxypropyl cellulose is low-substituted hydroxypropyl cellulose (L-HPC); the laurocapram, as a transdermal absorption enhancer, together with the propylene glycol, constitutes a solubilizing and phase change regulating system.

5. The vaginal thermosensitive antibacterial gel according to claim 1, characterized in that, The product also includes 1-3 parts by weight of plant volatile oil, which is selected from clove volatile oil, Cnidium monnieri oil or cinnamon oil.

6. The vaginal thermosensitive antibacterial gel according to claim 4, characterized in that, The sol-gel transition temperature of the gel system is specifically 28℃-32℃, and the gel strength in a simulated vaginal environment at 36℃ is sufficient to remain in the vaginal folds for more than 8 hours.

7. A method for preparing a vaginal thermosensitive antibacterial gel as described in any one of claims 1-6, characterized in that, Includes the following steps: (1) Preparation of chitosan aqueous phase: The water-soluble chitosan is added to the first part of deionized water and stirred at 20℃-25℃ until completely dissolved to obtain a clear chitosan aqueous solution, which is defined as phase A; (2) Preparation of active alcohol phase: The laurocapram and optional plant volatile oil are dispersed in the propylene glycol, stirred and mixed evenly, and then the plant polyphenols and nano silver are added and stirred until a uniform alcohol dispersion is formed, which is defined as phase B; (3) Preparation of the matrix aqueous phase: The poloxamer 407 and the hydroxypropyl cellulose are dispersed in the second part of deionized water and allowed to swell for 12-24 hours under low temperature conditions of 4℃-10℃ to obtain a temperature-sensitive matrix solution, which is defined as phase C; (4) Phase separation sterilization: Phase A, Phase B and Phase C are respectively filtered and sterilized using microporous filter membranes with a pore size of 0.22 μm; (5) Mixing and molding: In a constant temperature and clean environment of 25℃-30℃, the sterilized phase B is slowly added to the sterilized phase C and stirred evenly at a speed of 300-500r / min; then the sterilized phase A is added and the mixture is stirred at a low speed until a uniform semi-transparent mixed sol is formed. (6) Filling: Fill the mixed sol into a sterile administration device and seal it.

8. The preparation method according to claim 7, characterized in that, The weight ratio of the first part of deionized water to the second part of deionized water is 1.2:1 to 1.5:1 to ensure that the viscosity of each phase system is below 500 mPa·s before mixing, which is suitable for membrane filtration.

9. The preparation method according to claim 7, characterized in that, Step (3) also includes a step of ultrasonic degassing of phase C, wherein the ultrasonic degassing power is 120-140W and the treatment time is 15-20 minutes, until there are no visible bubbles in the solution.

10. The preparation method according to claim 7, characterized in that, In step (5), the temperature of the mixing process is strictly controlled below 32°C, and the stirring paddle is an anchor-type stirring paddle to prevent the material from undergoing local gelation under shear heat or ambient heat.

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