Temperature-sensitive hydrogel for prostate local administration and preparation method of temperature-sensitive hydrogel
Thermosensitive hydrogels, formulated with PLGA-PEG-PLGA and modified chitosan, solve the problems of biocompatibility, targeting, and antibacterial properties in local prostate drug delivery. This achieves long-term drug retention and targeted release, reduces side effects, and is suitable for industrial production.
Patent Information
- Application Number
- CN202512026523.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-12-30
- Publication Date
- 2026-01-30
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
Existing thermosensitive hydrogels for local prostate administration suffer from problems such as poor biocompatibility and adhesion, insufficient drug targeting, lack of antibacterial components, and imprecise preparation processes. These issues result in short drug retention time, poor targeting, and significant systemic side effects, making it difficult to achieve long-term retention and alleviate inflammatory responses.
A thermosensitive hydrogel was prepared by using a combination of PLGA-PEG-PLGA and modified chitosan as a thermosensitive polymer carrier, combined with prostate-targeting active ingredients, osmotic pressure regulators, antibacterial agents and bioadhesion promoters, and by precisely controlling the preparation process parameters. This hydrogel can rapidly gel at body temperature and achieve long-term drug retention and antibacterial effects.
It achieves long-term retention and targeted release of drugs in the prostate, reduces systemic drug exposure, minimizes side effects, improves biocompatibility and antibacterial effects, ensures batch-to-batch performance consistency, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a thermosensitive hydrogel for local administration of drugs to the prostate and its preparation method. Background Technology
[0002] Prostate diseases are common urinary system diseases in men, with prostate cancer and chronic prostatitis having particularly high incidence rates. Currently, clinical treatments for prostate diseases mainly include systemic and local drug administration. Systemic administration requires the drug to reach the prostate via the bloodstream, resulting in low bioavailability and significant systemic side effects. Traditional local drug delivery methods suffer from short retention times, uneven drug release, and poor targeting, making it difficult to achieve long-term, precise drug accumulation in the prostate.
[0003] Thermosensitive hydrogels are a class of smart materials that undergo sol-gel phase transition with temperature changes. At room temperature, they are in a flowable sol state, which is convenient for injection. After entering the human body, they quickly transform into a gel state at the temperature of the lesion site, achieving local retention and long-term release of drugs. They have become a research hotspot for local drug delivery formulations. However, existing thermosensitive hydrogels for local prostate drug delivery still have the following shortcomings: (1) Thermosensitive carriers have poor biocompatibility and adhesion, are easily metabolized and cleared by the human body, and are difficult to achieve long-term retention; (2) The drug has insufficient targeting and is easy to diffuse into the surrounding normal tissues, causing local irritation; (3) They lack synergistic antibacterial and anti-inflammatory components, making it difficult to alleviate the inflammatory response associated with prostate diseases; (4) The preparation process parameters are not precise, resulting in poor batch stability of products. Summary of the Invention
[0004] In view of this, the present invention proposes a thermosensitive hydrogel for local administration of drugs to the prostate and its preparation method, thereby solving the above problems.
[0005] The technical solution of the present invention is implemented as follows: a thermosensitive hydrogel for local administration of prostate, comprising the following raw materials by weight percentage: 15-25% thermosensitive polymer carrier, 0.5-3% prostate-targeting active ingredient, 2-8% cosolvent, 0.8-2.5% osmotic pressure regulator, 0.1-0.5% antibacterial agent, and a pharmaceutically acceptable solvent or dispersion medium.
[0006] Preferably, the temperature-sensitive polymeric carrier is a compound of polylactic acid-glycolic acid-polyethylene glycol triblock copolymer (PLGA-PEG-PLGA) and modified chitosan.
[0007] The modification method of hyaluronic acid grafting onto chitosan is as follows:
[0008] Chitosan was dissolved in 1-2% acetic acid solution to prepare a 2-5% (w / w) chitosan solution. Hyaluronic acid was dissolved in morpholine ethanesulfonic acid buffer, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and N-hydroxysuccinimide (NHS) were added to activate the solution for 30-60 min. The molar ratio of hyaluronic acid, EDC·HCl and NHS was 1:1.2:1.5. The activated hyaluronic acid solution was slowly added dropwise to the chitosan solution, and the reaction was stirred at 35-45℃ for 6-10 h. After the reaction, the solution was dialyzed for 3-5 days using a dialysis bag, with a molecular weight cutoff of 8000-14000 Da. The dialysate was freeze-dried to obtain hyaluronic acid-grafted modified chitosan.
[0009] Preferably, the prostate-targeting active ingredient is abiraterone, enzalutamide, or docetaxel in a mass ratio of 1:(1-2):(0.8-1.2).
[0010] Preferably, the cosolvent is one of polyethylene glycol 400, propylene glycol, and N-methylpyrrolidone; the osmotic pressure regulator is one of sodium chloride, mannitol, and glucose; the antibacterial agent is dipotassium glycyrrhizate, olive leaf extract, and centella asiatica extract in a mass ratio of (1.2-2.0):(2.5-5.5):1; and the solvent is water for injection or physiological saline.
[0011] Preferably, the extraction method of the olive leaf extract is as follows: take dried olive leaves, crush them and pass them through a 60-80 mesh sieve, add 8-12 times the weight of 60-75% (v / v) ethanol solution, reflux extract at 50-60℃ 2-3 times, each time for 1.5-2.5h, combine the extracts, filter, concentrate the filtrate under reduced pressure until there is no alcohol odor, then purify by adsorption with macroporous resin, and dry the eluent under reduced pressure to obtain the olive leaf extract.
[0012] Preferably, the extraction method of the Centella asiatica extract is as follows:
[0013] (4) Take the stems and leaves of Centella asiatica, remove impurities and wash them, dry them in a forced-air dryer at 40-50℃ until the moisture content is ≤8%, pulverize them and pass them through a 60-80 mesh sieve to obtain Centella asiatica powder;
[0014] (5) Mix the Centella asiatica powder with a composite enzyme aqueous solution containing 0.1-0.5% (w / w) cellulase and 0.05-0.2% (w / w) pectinase at a material-to-liquid ratio of 1:15-1:25 (g / mL), adjust the pH to 4.5-5.5, and enzymatically hydrolyze at 45-55℃ for 60-90 minutes;
[0015] (6) After enzymatic hydrolysis, add 60-80% (v / v) methanol aqueous solution to make up the total material-liquid ratio (g / mL) 1:20-1:30. Extract with ultrasound at 40-50℃ for 30-50 minutes, with an ultrasound power of 250-350W and a frequency of 30-40kHz. Repeat the extraction 1-3 times, combine the extracts, purify, concentrate and dry to obtain Centella asiatica extract powder.
[0016] Preferably, it further includes 0.3-1% by weight of a bioadhesion promoter and 0.1-0.8% by weight of a transdermal promoter, wherein the bioadhesion promoter is selected from one or more of carboxymethyl hyaluronic acid, quaternized chitosan or polyacrylic acid, and the transdermal promoter is one or a mixture of two of azone, menthol, and oleic acid.
[0017] Preferably, it also includes a method for preparing a thermosensitive hydrogel for local prostate drug delivery, comprising the following steps:
[0018] S1. Raw material pretreatment: Place the temperature-sensitive polymer carrier in a vacuum drying oven and dry at 40-50℃ for 8-12 hours; pulverize the modified chitosan and pass it through an 80-100 mesh sieve for later use.
[0019] S2. Preparation of temperature-sensitive carrier solution: The pretreated temperature-sensitive polymer carrier and modified chitosan are placed in a constant temperature water bath at 20-25℃, stirred and dissolved, and then a co-solvent is added. Stirring is continued for 30-60 minutes to obtain the temperature-sensitive carrier solution.
[0020] S3. Preparation of active ingredient dispersion: Add the prostate-targeting active ingredient to the solvent, ultrasonically disperse for 15-25 min, add osmotic pressure regulator and antibacterial agent, stir until completely dissolved, and obtain the active ingredient dispersion.
[0021] S4. Mixing and Adjustment: Slowly add the active ingredient dispersion prepared in step S3 to the temperature-sensitive carrier solution prepared in step S2, stir and mix evenly, adjust the pH of the system to 6.5-7.5, add the bioadhesion promoter and transdermal promoter, and stir evenly.
[0022] S5. Sterilization and packaging: The mixture obtained in step S4 is filtered and sterilized, and then packaged in a sterile environment to obtain a thermosensitive hydrogel for local prostate drug delivery.
[0023] Preferably:
[0024] The stirring speed in step S2 is 300-500 rpm;
[0025] In step S3, the ultrasonic power is 150-250W and the ultrasonic frequency is 20-40kHz.
[0026] In step S4, the mixing speed is 200-300 rpm and the mixing time is 40-80 min; during pH adjustment, the mixing speed is 100-200 rpm.
[0027] In step S5, a 0.22μm microporous filter membrane is used for filtration sterilization. After packaging, it is stored in a refrigerated environment at 2-8℃.
[0028] The application of the thermosensitive hydrogel of this invention in the preparation of drugs for the treatment or prevention of prostate diseases.
[0029] Compared with the prior art, the beneficial effects of the present invention are:
[0030] The thermosensitive hydrogel of this invention is in a flowable sol state at 20-25°C, facilitating local injection via the urethra or prostate. Upon entering the body, it rapidly undergoes a sol-gel phase transition at 35-37°C, forming a stable three-dimensional network structure, achieving local drug retention and preventing rapid drug loss. The prostate-targeting active ingredients are formulated in a specific ratio to synergistically exert therapeutic effects. Combined with a transdermal penetration enhancer, it promotes deep penetration of the drug into the prostate tissue, increasing the drug concentration at the lesion site, reducing systemic drug exposure, and minimizing side effects. The antibacterial agent is a combination of dipotassium glycyrrhizate and olive leaf extract or centella asiatica extract, exhibiting good antibacterial effects and inhibiting the release of local prostate inflammatory factors, thus alleviating inflammatory responses. The bioadhesion enhancer improves the adhesion of the hydrogel to the prostate mucosa, prolonging the dosing interval and improving patient compliance.
[0031] The thermosensitive polymer carrier of this invention is a blend of PLGA-PEG-PLGA and modified chitosan, exhibiting excellent biocompatibility and producing non-toxic degradation products that do not trigger local tissue irritation or immune responses. By precisely controlling process parameters such as raw material pretreatment conditions, stirring speed, and ultrasonic parameters, batch-to-batch performance consistency is ensured, making it suitable for industrial production. Detailed Implementation
[0032] To better understand the technical content of this invention, specific embodiments are provided below to further illustrate the invention.
[0033] Unless otherwise specified, the experimental methods used in the embodiments of this invention are all conventional methods.
[0034] Unless otherwise specified, all materials and reagents used in the embodiments of this invention are commercially available.
[0035] Example 1
[0036] 1. Raw material formula (by weight percentage):
[0037] 20% thermosensitive polymeric carrier: PLGA-PEG-PLGA and modified chitosan compounded at a mass ratio of 4:1;
[0038] Prostate-targeting active ingredient 1.5%: Abiraterone: Enzalutamide: Docetaxel = 1:1.5:1;
[0039] 5% cosolvent: polyethylene glycol 400;
[0040] Osmotic pressure regulator 1.5%: Mannitol;
[0041] Antibacterial agent 0.3% : Dipotassium glycyrrhizate : Olive leaf extract : Centella asiatica extract = 1.6 : 4 : 1;
[0042] Bioadhesion promoter 0.6%: Carboxymethyl hyaluronic acid;
[0043] Transdermal penetration enhancer 0.4%: Azone;
[0044] Add water for injection to bring the total volume to 100%.
[0045] 2. Preparation of key components:
[0046] The extraction method of olive leaf extract is as follows: take dried olive leaves, crush them and pass them through a 70-mesh sieve, add 10 times the weight of 70% (v / v) ethanol solution, reflux extract at 55℃ 3 times, 2 hours each time, combine the extracts, filter, concentrate the filtrate under reduced pressure until there is no alcohol odor, and then purify by adsorption with macroporous resin. After drying the eluent under reduced pressure, the olive leaf extract is obtained.
[0047] The extraction method for Centella asiatica extract is as follows:
[0048] (1) Take the stems and leaves of Centella asiatica, remove impurities and wash them, dry them in a forced-air dryer at 45°C until the moisture content is ≤8%, and pulverize them through a 70-mesh sieve to obtain Centella asiatica powder;
[0049] (2) The Centella asiatica powder was mixed with a composite enzyme aqueous solution containing 0.2% (w / w) cellulase and 0.15% (w / w) pectinase at a material-to-liquid ratio of 1:20 (g / mL), the pH was adjusted to 5, and the mixture was enzymatically hydrolyzed at 50°C for 70 minutes.
[0050] (3) After the enzymatic hydrolysis, add 70% (v / v) methanol aqueous solution to make up the total material-liquid ratio (g / mL) 1:25. Extract at 45℃ for 40 minutes with ultrasonic power of 300W and frequency of 35kHz. Repeat the extraction twice, combine the extracts, purify, concentrate and dry to obtain Centella asiatica extract powder.
[0051] The modification method of hyaluronic acid grafting onto chitosan is as follows:
[0052] Chitosan was dissolved in 1.5% acetic acid solution to prepare a 3% (w / w) chitosan solution. Hyaluronic acid was dissolved in morpholine ethanesulfonic acid buffer, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl) and N-hydroxysuccinimide (NHS) were added to activate the solution for 50 min. The molar ratio of hyaluronic acid, EDC·HCl and NHS was 1:1.2:1.5. The activated hyaluronic acid solution was slowly added dropwise to the chitosan solution, and the reaction was stirred at 40℃ for 8 h. After the reaction, the solution was dialyzed for 4 days using a dialysis bag. The molecular weight cutoff was 12000 Da. The dialysate was freeze-dried to obtain hyaluronic acid-grafted modified chitosan.
[0053] 3. Hydrogel preparation steps:
[0054] S1. Raw material pretreatment: Place the temperature-sensitive polymer carrier in a vacuum drying oven and dry at 45℃ for 10 hours; pulverize the modified chitosan and pass it through a 90-mesh sieve for later use.
[0055] S2. Preparation of temperature-sensitive carrier solution: The pretreated temperature-sensitive polymer carrier and modified chitosan were placed in a constant temperature water bath at 22℃ and stirred at 400 rpm to dissolve. Then, a co-solvent was added and stirring was continued for 50 min to obtain the temperature-sensitive carrier solution.
[0056] S3. Preparation of active ingredient dispersion: Add the prostate-targeting active ingredient to the solvent and ultrasonically disperse it for 20 minutes at an ultrasonic power of 200W and an ultrasonic frequency of 30kHz. Add an osmotic pressure regulator and an antibacterial agent and stir until completely dissolved to obtain the active ingredient dispersion.
[0057] S4. Mixing and Adjustment: Slowly add the active ingredient dispersion prepared in step S3 to the temperature-sensitive carrier solution prepared in step S2, and stir at 250 rpm for 60 min until the mixture is uniform. Adjust the pH of the system to 7.0, and stir at a low speed of 150 rpm during the adjustment process. Add the bioadhesion promoter and transdermal promoter, and stir at 250 rpm for 25 min until uniform.
[0058] S5. Sterilization and packaging: The mixture obtained in step S4 is filtered and sterilized, and then packaged in a sterile environment to obtain a thermosensitive hydrogel for local prostate drug delivery.
[0059] Example 2
[0060] 1. Raw material formula (by weight percentage):
[0061] 15% thermosensitive polymeric carrier: PLGA-PEG-PLGA and modified chitosan compounded at a mass ratio of 3:1;
[0062] Prostate-targeting active ingredient 0.5%: Abiraterone: Enzalutamide: Docetaxel = 1:1:0.8;
[0063] 2% cosolvent: propylene glycol;
[0064] Osmotic pressure regulator 0.8%: Sodium chloride;
[0065] Antibacterial agent 0.1%: dipotassium glycyrrhizate: olive leaf extract: centella asiatica extract = 1.2:2.5:1;
[0066] Bioadhesion promoter 0.3%: Quaternized chitosan;
[0067] Transdermal penetration enhancer 0.1%: Menthol;
[0068] Replenish with normal saline to 100%.
[0069] The preparation of key components and hydrogels are the same as in Example 1.
[0070] Example 3
[0071] 1. Raw material formula (by weight percentage):
[0072] 25% thermosensitive polymeric carrier: PLGA-PEG-PLGA and modified chitosan compounded at a mass ratio of 5:1;
[0073] Prostate-targeting active ingredient 3%: Abiraterone: Enzalutamide: Docetaxel = 1:2:1.2;
[0074] 8% cosolvent: N-methylpyrrolidone;
[0075] Osmotic pressure regulator 2.5%: glucose;
[0076] Antibacterial agent 0.5%: dipotassium glycyrrhizate: olive leaf extract: centella asiatica extract = 2.0:5.5:1;
[0077] Bioadhesion promoter 1.0%: polyacrylic acid;
[0078] Transdermal penetration enhancer 0.8%: azone ± oleic acid, mass ratio 1:1.
[0079] Add water for injection to bring the total volume to 100%.
[0080] Comparative Example 1
[0081] The difference between this comparative example and Example 1 is that ordinary chitosan is used instead of modified chitosan, while the rest is the same as in Example 1.
[0082] Comparative Example 2
[0083] The difference between this comparative example and Example 1 is that the thermosensitive carrier uses only PLGA-PEG-PLGA (20%), without the addition of modified chitosan, while the rest is the same as in Example 1.
[0084] Comparative Example 3
[0085] The difference between this comparative example and Example 1 is that the raw materials do not contain abiraterone, enzalutamide, or docetaxel; otherwise, they are the same as in Example 1.
[0086] Comparative Example 4
[0087] The difference between this comparative example and Example 1 is that the raw materials do not contain bioadhesion promoters and transdermal promoters, while the rest are the same as in Example 1.
[0088] Performance testing
[0089] Temperature-sensitive phase change performance test
[0090] Test method: Take 2 mL of each of the hydrogel samples prepared in Examples 1-3 and Comparative Examples 1-4, place them in a stoppered test tube, put them in a programmed temperature constant temperature water bath, and heat them from 20℃ to 40℃ at a rate of 1℃ / min. Use the inverted test tube method to determine the phase transition endpoint (complete gelation means no flow after 1 minute of inversion). Record the phase transition temperature (gelation initiation temperature) and the complete phase transition time.
[0091] Test results:
[0092]
[0093] Results Analysis: The phase transition temperatures of Examples 1-3 were all precisely matched to the physiological temperature of the prostate (35-37℃), and the complete phase transition time was ≤15min, which enabled rapid gelation at the lesion site to achieve drug retention. The phase transition temperatures of Comparative Examples 1 and 2 were increased and the phase transition time was significantly prolonged, indicating that the hyaluronic acid grafted modified chitosan and PLGA-PEG-PLGA compound have a synergistic thermosensitive effect and can precisely control the phase transition performance. The phase transition performance of Comparative Examples 3 and 4 was similar to that of the Examples, indicating that the active ingredients and bioadhesion / transdermal promoters had no adverse effects on the thermosensitive phase transition.
[0094] 2. Bioadhesion performance test
[0095] Test method: Using an isolated rabbit prostate mucosa model, a fully gelled sample (10 mm in diameter and 2 mm in thickness) was attached to the mucosa surface and placed at room temperature for 30 min. Then, a peel test was performed using a universal tensile testing machine at a speed of 5 mm / min. The maximum peel strength was recorded. Each group of samples was tested in parallel 5 times, and the mean ± standard deviation was taken.
[0096] Test results:
[0097]
[0098] Results analysis: The maximum peel strength of Examples 1-3 was all >28 kPa, indicating excellent adhesion to the prostate mucosa, with Example 1 showing the best performance. The peel strength of Comparative Examples 1 and 2 decreased significantly, indicating that hyaluronic acid grafted chitosan has a good bioadhesion basis. Comparative Example 4 had the lowest peel strength, confirming that the bioadhesion promoter is the key to improving adhesion performance and can prolong the retention time of the hydrogel at the lesion site. The performance of Comparative Example 3 was similar to that of Example 3, indicating that the active ingredient does not affect the adhesion effect.
[0099] 3. Antibacterial performance test
[0100] Test method: The agar diffusion method was used. Common clinical pathogens causing prostate infections (Escherichia coli ATCC25922 and Staphylococcus aureus ATCC 29213) were used as test strains. Each sample (200 μL) was added to an Oxford cup (6 mm inner diameter), and incubated at 37°C for 24 h. The diameter of the inhibition zone (0.1 mm) was then measured. Each group was tested in triplicate. An inhibition zone diameter >15 mm was considered strong inhibition, 10-15 mm was considered moderate inhibition, and <10 mm was considered weak inhibition.
[0101] Test results:
[0102]
[0103] Results Analysis: Examples 1-3 and each comparative example showed strong antibacterial effects against both pathogenic bacteria (inhibition zone diameter > 18 mm), and the antibacterial effect of the examples was slightly better than that of comparative examples 1-2, indicating that the ternary compound antibacterial system of dipotassium glycyrrhizate, olive leaf extract, and centella asiatica extract has a synergistic effect; the antibacterial effect of comparative examples 3-4 was similar to that of the examples, confirming that the active ingredients and bioadhesion / transdermal promoters do not interfere with the antibacterial function. This compound antibacterial system can effectively alleviate local prostate infection and reduce the inflammatory response during treatment.
[0104] 4. Drug release performance test
[0105] Test Method: The dialysis bag method (molecular weight cutoff 8000 Da) was used. 0.5 g of the drug-containing sample was accurately weighed and placed in a dialysis bag. 5 mL of pH 7.4 phosphate buffer (simulating prostate tissue fluid) was added, and the bag was sealed and immersed in 50 mL of release medium. The bag was then incubated at 37°C with constant shaking (100 rpm). 5 mL samples were taken at 2 h, 6 h, 12 h, 24 h, 48 h, 72 h, and 96 h (with an equal volume of fresh medium added simultaneously). The total concentrations of abiraterone, enzalutamide, and docetaxel were determined using high-performance liquid chromatography (HPLC), and the cumulative drug release rate was calculated. Comparative Example 3 was not tested due to the absence of active ingredients.
[0106] Test results:
[0107]
[0108] Results Analysis: The drug release curves of Examples 1-3 were stable, with a cumulative release rate of <20% in 2 hours, indicating no risk of burst release, and a cumulative release rate of 86-92% in 96 hours, achieving long-term controllable release. Comparative Example 2, without modified chitosan, showed significant initial burst release, with a release rate of >25% in 2 hours, and excessively rapid release in the later stages, indicating that modified chitosan can regulate the gel network structure and delay drug release. Comparative Example 4, without transdermal permeability enhancer, had a significantly lower cumulative release rate in 96 hours than the Examples, confirming that transdermal permeability enhancer can promote drug permeation and release from the gel matrix and improve drug bioavailability. The release performance of ordinary chitosan in Comparative Example 1 was slightly worse than that of the Examples, further demonstrating the structural advantages of hyaluronic acid-grafted modified chitosan.
[0109] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A temperature-sensitive hydrogel for local administration of a prostate, characterized by, The raw materials include the following weight percentages: a temperature-sensitive polymer carrier 15-25%, a prostate-targeting active ingredient 0.5-3%, a cosolvent 2-8%, an osmotic pressure regulator 0.8-2.5%, a bacteriostatic agent 0.1-0.5%, and a pharmaceutically acceptable solvent or dispersion medium.
2. The thermosensitive hydrogel for local administration to the prostate according to claim 1, wherein The temperature-sensitive polymer carrier is a compound of polylactic acid-glycolic acid-polyethylene glycol triblock copolymer and modified chitosan.
3. The thermosensitive hydrogel for local administration to the prostate according to claim 1, wherein The prostate-targeting active ingredient is a mass ratio of 1:(1-2):(0.8-1.2) of abiraterone, enzalutamide, and docetaxel.
4. The thermosensitive hydrogel for local administration to the prostate according to claim 1, wherein The cosolvent is one of polyethylene glycol 400, propylene glycol, and N-methyl pyrrolidone; the osmotic pressure regulator is one of sodium chloride, mannitol, and glucose; the bacteriostatic agent is a mass ratio of (1.2-2.0):(2.5-5.5):1 of dipotassium glycyrrhizinate, olive leaf extract, and Gynostemma pentaphyllum extract; and the solvent is water for injection or normal saline.
5. The thermosensitive hydrogel for local administration to the prostate according to claim 4, wherein the hydrogel is prepared by mixing the aqueous solution of the polymer and the aqueous solution of the drug. The extraction method of the olive leaf extract is as follows: dry olive leaves are crushed and sieved through a 60-80 mesh sieve, 8-12 times the weight of 60-75% (v / v) ethanol solution is added, and the mixture is refluxed at 50-60°C for 2-3 times, each time for 1.5-2.5 hours. The extract is combined, filtered, and concentrated under reduced pressure until no alcohol smell is detected. The filtrate is then purified by macroporous resin adsorption, and the eluate is dried under reduced pressure to obtain the olive leaf extract.
6. The thermosensitive hydrogel for local prostate drug delivery as described in claim 4, characterized in that, The extraction method of the Gynostemma pentaphyllum extract is as follows: (1) The stems and leaves of Gynostemma pentaphyllum are cleaned and dried at 40-50°C to a moisture content of ≤8%, crushed and sieved through a 60-80 mesh sieve to obtain Gynostemma pentaphyllum powder; (2) The Gynostemma pentaphyllum powder is mixed with a complex enzyme aqueous solution containing 0.1-0.5% (w / w) cellulase and 0.05-0.2% (w / w) pectinase at a solid-liquid ratio of 1:15-1:25 (g / mL), the pH is adjusted to 4.5-5.5, and the mixture is enzymatically hydrolyzed at 45-55°C for 60-90 minutes; (3) After the enzymatic hydrolysis is completed, 60-80% (v / v) methanol aqueous solution is added to bring the total solid-liquid ratio (g / mL) to 1:20-1:30, and the mixture is ultrasonically extracted at 40-50°C for 30-50 minutes at an ultrasonic power of 250-350W and a frequency of 30-40kHz. The extraction is repeated 1-3 times, the extract is combined, and the Gynostemma pentaphyllum extract powder is obtained by purification, concentration, and drying.
7. The thermosensitive hydrogel for local prostate drug delivery as described in claim 1, characterized in that, It also includes a biological adhesion promoter at a weight percentage of 0.3-1% and a transdermal enhancer at a weight percentage of 0.1-0.8%. The biological adhesion promoter is selected from one or more of carboxymethyl hyaluronic acid, quaternized chitosan, or polyacrylic acid. The transdermal enhancer is one or a mixture of two of azone, menthol, and oleic acid.
8. A method for preparing a thermosensitive hydrogel for local administration to the prostate according to any one of claims 1 to 7, wherein The method includes the following steps: S1, raw material pretreatment: the temperature-sensitive polymer carrier is placed in a vacuum drying oven and dried at 40-50°C for 8-12 hours. The modified chitosan is crushed and sieved through an 80-100 mesh sieve for later use. S2, preparation of temperature-sensitive carrier solution: the pretreated temperature-sensitive polymer carrier and modified chitosan were placed in a constant temperature water bath at 20-25°C, stirred and dissolved, then a cosolvent was added, and stirring was continued for 30-60 min to obtain a temperature-sensitive carrier solution; S3, preparation of active ingredient dispersion: the prostate-targeting active ingredient was added to a solvent and ultrasonically dispersed for 15-25 min, then a tonicity-adjusting agent and a bacteriostatic agent were added and stirred until completely dissolved to obtain an active ingredient dispersion; S4, mixing and adjustment: the active ingredient dispersion prepared in step S3 was slowly added to the temperature-sensitive carrier solution prepared in step S2, stirred and mixed uniformly, the pH of the system was adjusted to 6.5-7.5, a bioadhesion promoter and a transdermal enhancer were added, and stirring was continued until uniform; S5, sterilization and packaging: the mixture obtained in step S4 was filtered and sterilized, then packaged in a sterile environment to obtain a temperature-sensitive hydrogel for prostate local administration.
9. The preparation method of the temperature-sensitive hydrogel for prostate local administration according to claim 8, wherein the stirring speed in step S2 is 300-500 rpm; the ultrasonic power in step S3 is 150-250 W, and the ultrasonic frequency is 20-40 kHz; the mixing and stirring speed in step S4 is 200-300 rpm, and the stirring time is 40-80 min; the stirring speed during pH adjustment is 100-200 rpm; 0.22 μm microporous filter membranes are used for filtration sterilization in step S5, and the packaged product is stored in a cold storage environment at 2-8°C.
10. Use of the temperature-sensitive hydrogel according to any one of claims 1-7 in the preparation of a medicament for treating or preventing prostate diseases.