A sustained-release thermosensitive gel, its preparation method and its application

Abstract

This invention relates to a sustained-release thermosensitive blank gel containing 5-60 wt% of an amphiphilic block polymer, wherein the amphiphilic block polymer is selected from any one or a combination of A-B-A, B-A-B, A-B, and multi-arm star types. The drug is uniformly mixed with the sustained-release thermosensitive blank gel, or the drug is freshly prepared and uniformly mixed with the sustained-release thermosensitive blank gel to obtain a drug gel. The drug concentration in the obtained drug gel is 1-500 mg / mL. The drug in the drug gel is dissolved in the blank gel, or the drug and the blank gel form a stable gel suspension. The drug is selected from any one or a combination of micronized drugs, PLGA-encapsulated drug nanoparticles, and PLGA microspheres of drugs. It has advantages such as good formulation stability, high bioavailability, effective reduction of recurrence rate after glioma surgery, safety and efficacy, good biocompatibility, excellent biodegradability, good tolerability, and ease of use.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, specifically to a sustained-release thermosensitive gel, its preparation method, and its applications. Background Technology

[0002] Postoperative recurrence of glioblastoma is a significant factor severely limiting patient prognosis, resulting in a 5-year average survival rate of less than 5%. Most patients die from recurrent gliomas that cause unresectable lesions in key brain regions. Patients with recurrent gliomas often face the predicament of having no effective or even no available treatments.

[0003] Alkylating agents are chemotherapeutic drugs with non-specific cell-killing properties, inducing apoptosis in tumor cells while also attacking normal cells. Temozolomide, as a second-generation alkylating agent, has superior solubility and blood-brain barrier crossing ability compared to traditional chemotherapeutic drugs, and is used as a first-line treatment in glioma treatment guidelines in Europe, South Korea, and China. The equilibrium solubility of temozolomide in water is approximately 2-4 mg / mL, and its logP value at pH 7.4 is approximately -1.1, classifying it as a highly soluble drug with poor membrane permeability.

[0004] The clinically recommended dosage of temozolomide capsules is 75 mg / m². 2 During concurrent chemoradiotherapy, the usual dosage is 100 mg / day, lasting 42 days, with patients receiving approximately 4.2 g of temozolomide in one cycle. While the relative bioavailability of temozolomide capsules is close to 100%, its instability after absorption into the bloodstream after gastrointestinal tract is the main factor limiting its antitumor efficacy. Temozolomide undergoes ring-opening degradation under neutral and alkaline conditions to the extremely unstable active metabolite MTIC, which rapidly degrades into the stable intermediate AICA and the alkylating agent diazomethane, acting on DNA to methylate the N7 and O6 positions of guanine, thus inducing apoptosis. However, because the effective drug content of temozolomide capsules targeting tumor cells is extremely low, patients require repeated administration of high doses, leading to severe systemic toxicity (such as bone marrow suppression, liver and kidney damage, and hematopoietic dysfunction). Many patients cannot tolerate these systemic toxicities and discontinue treatment.

[0005] Drug sustained-release and controlled-release delivery systems formulate drugs into sustained-release dosage forms, controlling the release rate and extent of drug both in vivo and in vitro. This allows the drug to be released at a relatively slow or constant rate over a specific time period, providing excellent local drug release. It controls the area of ​​action of the released drug, improves bioavailability, and reduces systemic toxicity to achieve therapeutic effects. The development of sustained-release and controlled-release formulations has significantly reduced patient discomfort and improved medication adherence.

[0006] Reference 1 (CN101273965A) discloses a thermosensitive sustained-release injection, which is formulated with 20 mg temozolomide, 260 mg amphiphilic block copolymer, and 740 μL phosphate buffer. The amphiphilic block copolymer is a polyethylene glycol-glycolic acid-lactide copolymer-polyethylene glycol, with a molecular weight of 1000-1400, accounting for 15% of the weight of the amphiphilic block copolymer; the molar ratio of glycolide to lactide in the glycolide-lactide copolymer is 6-9:1. This gel formulation is an aqueous solution at room temperature with good fluidity, allowing the sustained-release agent to effectively cover the irregular tumor cavity after tumor resection. In warm-blooded animals, it can transform into a semi-solid or solid gel, acting locally at a high concentration at the surgical resection site, effectively clearing residual tumor cells after surgery, effectively treating postoperative hemostasis and preventing tumor cell spread. However, its gel uniformity and quality controllability need improvement. Therefore, there is an urgent clinical need for more efficient and safer sustained-release thermosensitive formulations. Summary of the Invention

[0007] The purpose of this invention is to provide a sustained-release thermosensitive blank gel containing an amphiphilic block polymer at a concentration of 5-60 wt%, wherein the amphiphilic block polymer is selected from any one or a combination of ABA-type, BAB-type, AB-type, multi-arm star-type, etc.

[0008] In a preferred embodiment of the present invention, the amphiphilic block polymer is selected from any one or a combination of polyoxyethylene-polyoxypropylene-polyoxyethylene (PEO-PPO-PEO), polyethylene glycol-polylactide-polyethylene glycol (PEG-PLGA-PEG), polylactide-polyethylene glycol-polylactide (PLGA-PEG-PLGA), methylated polyethylene glycol-polylactide (mPEG-PLGA), and pentaerythritol-initiated methylated polyethylene glycol-polylactide (C-(PLGA-mPEG)4).

[0009] In a preferred embodiment of the present invention, the hydrophobic block of the poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA) is a polylactic-co-glycolic acid copolymer block composed of lactic acid and glycolic acid (i.e., PLGA, polyester block B), and the hydrophilic block is polyethylene glycol (i.e., PEG, polyethylene glycol block A) composed of polyethylene oxide blocks with appropriate degree of polymerization, preferably BAB.

[0010] In a preferred embodiment of the present invention, the polyester block B is selected from any one or a combination of polyglycolic acid (PGA), poly-L-lactic acid (PL-LA), poly-L-lactic acid-glycolic acid copolymer (PL-LGA), poly-D,L-lactic acid-glycolic acid copolymer (PD,L-LGA), polycaprolactone copolymer (PCA), polycaprolactone-L-lactide copolymer (PCL-LA), polycaprolactone-D-lactide copolymer (PCD-LA), polycaprolactone-D,L-lactide copolymer (PCD,L-LA), polycaprolactone-glycolic acid copolymer (PCGA), polycaprolactone-L-lactide-glycolic acid copolymer (PCL-LGA), polycaprolactone-D-lactide-glycolic acid copolymer (PCD-LGA), and polycaprolactone-D,L-lactide-glycolic acid copolymer (PCD,L-LGA).

[0011] In a preferred embodiment of the present invention, the terminal group of the polyester block B is selected from any one or a combination of hydroxyl (-OH), carboxyl (-COOH), methyl (-CH3), acetyl (-COCH3), propionyl (-COCH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH2(CH3)2), n-butyl (-CH2 CH2 CH2CH3), isobutyl (-CH2CH(CH3)2), tert-butyl (-C(CH3)3), amino (-NH2), cyano (-C≡N), ethynyl (-C≡CH), phenyl (-C6H5), benzyl (-C7H7), -F, -Cl, -Br, and -I.

[0012] In a preferred embodiment of the present invention, the ratio of lactic acid (LA) to glycolic acid (GA) repeating units in polyester block B is 0.1:1-50:1, preferably 0.5:1-15:1, and more preferably 2:1-5:1.

[0013] In a preferred embodiment of the present invention, the number average molecular weight of the amphiphilic copolymer is 200-40000, preferably 1000-10000, and more preferably 3000-6000.

[0014] In a preferred embodiment of the present invention, the number average molecular weight of the polyester block B is 100-50000, preferably 500-10000, and more preferably 900-2000.

[0015] In a preferred embodiment of the present invention, the number average molecular weight of polyethylene glycol block A is 100-50000, preferably 500-10000, and more preferably 900-2000.

[0016] In a preferred embodiment of the present invention, the ratio of the sum of the number average molecular weights of the two polyester blocks B to the number average molecular weight of the polyethylene glycol block A is 1:1-10:1, preferably 1.5:1-5:1, and more preferably 2:1-3:1.

[0017] In a preferred embodiment of the present invention, the amphiphilic copolymer is composed of a mixture of multiple amphiphilic copolymers with different gel temperatures.

[0018] In a preferred embodiment of the present invention, the concentration of the amphiphilic copolymer contained in the blank gel is 10wt%-40wt%, preferably 15wt%-30wt%, and more preferably 20wt%-25wt%.

[0019] The sustained-release thermosensitive blank gel of the present invention is a low-viscosity liquid at room temperature, and transforms into a non-flowing gel at 35-38°C.

[0020] In a preferred embodiment of the present invention, the drug is uniformly mixed with a sustained-release thermosensitive blank gel or the drug is freshly prepared and uniformly mixed with a sustained-release thermosensitive blank gel to obtain a drug gel. The drug concentration in the obtained drug gel is 1-500 mg / mL. The drug in the drug gel is dissolved in the blank gel or the drug and the blank gel form a stable gel suspension. The drug is selected from any one or a combination of micronized drugs, PLGA-encapsulated drug nanoparticles, and PLGA microspheres of drugs.

[0021] In a preferred embodiment of the present invention, the drug concentration in the drug gel is 5-400 mg / mL, preferably 50-300 mg / mL, and more preferably 100-250 mg / mL.

[0022] In a preferred embodiment of the present invention, the weight ratio of the drug to the blank gel in the drug gel is 50-400:1, preferably 100-300:1, and more preferably 150-250:1.

[0023] In a preferred embodiment of the present invention, the drug is selected from any one or a combination of vincristine, vinorelbine, vinblastine, vindesine, vinrocin, vinorelbine, cephalotaxine, bleomycin, donomycin, arubicin, epirubicin, edabricin, pirarubicin, pentorubicin, mitomycin C, actinomycin D, loxoanthraquinone, mitoxanthraquinone, mitoxazolamide, and temozolomide.

[0024] In a preferred embodiment of the present invention, the D of the micronized drug in the drug gel 50 ≤10μm, D preferred 50 ≤5μm, preferably D 50 ≤3μm.

[0025] In a preferred embodiment of the present invention, the drug is selected from any one or a combination of micronized temozolomide, temozolomide nanoparticles encapsulated in PLGA, and temozolomide PLGA microspheres.

[0026] In a preferred embodiment of the present invention, the D of micronized temozolomide in the drug gel 50 ≤10μm, D preferred 50 ≤5μm, preferably D 50 ≤3μm.

[0027] In a preferred embodiment of the present invention, the concentration of temozolomide in the drug gel is 5-400 mg / mL, preferably 50-300 mg / mL, and more preferably 100-250 mg / mL.

[0028] In a preferred embodiment of the present invention, the drug gel optionally contains any one or a combination of buffers, stabilizers, and preservatives.

[0029] In a preferred embodiment of the present invention, the buffer is selected from any one or a combination of lactate buffer, phosphate buffer, citrate buffer, acetate buffer, and oxalate buffer.

[0030] In a preferred embodiment of the present invention, the buffer concentration in the drug gel is 1-200 mM, preferably 50-150 mM, and more preferably 80-120 mM.

[0031] In a preferred embodiment of the present invention, the stabilizer is selected from any one or a combination of L-cysteine, L-alanine, L-threonine, L-leucine, L-methionine, glycine, sorbitol, and mannitol.

[0032] In a preferred embodiment of the present invention, the concentration of the stabilizer in the drug gel is 0.1-10 mg / mL, preferably 1-8 mg / mL, and more preferably 2-5 mg / mL.

[0033] In a preferred embodiment of the present invention, the preservative is selected from any one or a combination of potassium sorbate, sodium benzoate, ethylparaben, methylparaben, calcium propionate, and sodium lactate.

[0034] In a preferred embodiment of the present invention, the concentration of the preservative in the drug gel is 0.01 mg-0.1 mg / mL.

[0035] In a preferred embodiment of the present invention, the drug gel contains 3-300 mg / mL temozolomide and 10-40 wt% PLGA-PEG-PLGA gel solution.

[0036] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide and 20 wt% PLGA-PEG-PLGA gel solution.

[0037] In a preferred embodiment of the present invention, the drug gel contains temozolomide 3-300 mg / mL, 15-30 wt% PLGA-PEG-PLGA gel solution, L-alanine 1-5 mg / mL, and methylparaben 0.01-0.1 mg / mL.

[0038] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide, 15 wt% PLGA-PEG-PLGA gel solution, 10 mM phosphate buffer, and 1 mg / mL L-cysteine.

[0039] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide, 25 wt% PLGA-PEG-PLGA gel solution, 10 mM citrate buffer, and 1 mg / mL L-cysteine.

[0040] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide, 30 wt% PLGA-PEG-PLGA gel solution, 5 mM acetate buffer, and 1 mg / mL L-cysteine.

[0041] In a preferred embodiment of the present invention, the blank gel or drug gel is liquid at ≤32°C and transforms into a gel at 35°C or higher.

[0042] In a preferred embodiment of the present invention, the blank gel and the drug are placed in two different chambers or storage spaces, and are prepared and used immediately before use.

[0043] The purpose of this invention is to provide a temozolomide sustained-release thermosensitive gel. The temozolomide is uniformly mixed with the sustained-release thermosensitive blank gel of this invention, or the temozolomide is uniformly mixed with the sustained-release thermosensitive blank gel of this invention before use to prepare a drug gel. The concentration of temozolomide in the obtained drug gel is 1-500 mg / mL. The temozolomide in the drug gel is dissolved in the blank gel or uniformly dispersed in the blank gel to form a gel suspension. The temozolomide is selected from any one or a combination of micronized temozolomide, PLGA-encapsulated temozolomide nanoparticles, and PLGA microspheres of temozolomide. The sustained-release thermosensitive blank gel contains 5-60 wt% of an amphiphilic block polymer, which is selected from any one or a combination of ABA-type, BAB-type, AB-type, and multi-arm star-shaped polymers.

[0044] In a preferred embodiment of the present invention, the concentration of temozolomide in the drug gel is 5-400 mg / mL, preferably 50-300 mg / mL, and more preferably 100-250 mg / mL.

[0045] In a preferred embodiment of the present invention, the D of the micronized temozolomide microcrystals 50 ≤10μm, D preferred 50 ≤5μm, preferably D 50 ≤3μm.

[0046] In a preferred embodiment of the present invention, the drug gel optionally contains any one or a combination of buffers, stabilizers, and preservatives.

[0047] In a preferred embodiment of the present invention, the buffer is selected from any one or a combination of lactate buffer, phosphate buffer, citrate buffer, acetate buffer, and oxalate buffer.

[0048] In a preferred embodiment of the present invention, the buffer concentration in the drug gel is 1-200 mM, preferably 50-150 mM, and more preferably 80-120 mM.

[0049] In a preferred embodiment of the present invention, the stabilizer is selected from any one or a combination of L-cysteine, L-alanine, L-threonine, L-leucine, L-methionine, glycine, sorbitol, and mannitol.

[0050] In a preferred embodiment of the present invention, the concentration of the stabilizer in the drug gel is 0.1-10 mg / mL, preferably 1-8 mg / mL, and more preferably 2-5 mg / mL.

[0051] In a preferred embodiment of the present invention, the preservative is selected from any one or a combination of potassium sorbate, sodium benzoate, ethylparaben, methylparaben, calcium propionate, and sodium lactate.

[0052] In a preferred embodiment of the present invention, the concentration of the preservative in the drug gel is 0.01 mg-0.1 mg / mL.

[0053] In a preferred embodiment of the present invention, the drug gel contains 3-300 mg / mL temozolomide and 10-40 wt% PLGA-PEG-PLGA gel solution.

[0054] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide and 20 wt% PLGA-PEG-PLGA gel solution.

[0055] In a preferred embodiment of the present invention, the drug gel contains temozolomide 3-300 mg / mL, 15-30 wt% PLGA-PEG-PLGA gel solution, L-alanine 1-5 mg / mL, and methylparaben 0.01-0.1 mg / mL.

[0056] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide, 15 wt% PLGA-PEG-PLGA gel solution, 10 mM phosphate buffer, and 1 mg / mL L-cysteine.

[0057] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide, 25 wt% PLGA-PEG-PLGA gel solution, 10 mM citrate buffer, and 1 mg / mL L-cysteine.

[0058] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide, 30 wt% PLGA-PEG-PLGA gel solution, 5 mM acetate buffer, and 1 mg / mL L-cysteine.

[0059] In a preferred embodiment of the present invention, the sustained-release thermosensitive blank gel contains an amphiphilic block polymer at a concentration of 5-60 wt%, wherein the amphiphilic block polymer is selected from any one or a combination of ABA-type, BAB-type, AB-type, and multi-arm star-type.

[0060] In a preferred embodiment of the present invention, the blank gel or drug gel is liquid at ≤32°C and transforms into a gel at 35°C or higher.

[0061] In a preferred embodiment of the present invention, the amphiphilic copolymer is obtained by blending multiple amphiphilic copolymer segments.

[0062] In a preferred embodiment of the present invention, the amphiphilic copolymer is obtained by blending two amphiphilic copolymer segments, wherein the gelation temperature of the first segment is 37-40℃ and the gelation temperature of the second segment is 25-30℃.

[0063] In a preferred embodiment of the present invention, the method for preparing the sustained-release thermosensitive blank gel is to mix an amphiphilic copolymer solution with a gelation temperature of 25-30℃ and an amphiphilic copolymer solution with a gelation temperature of 35-40℃ at a volume ratio of 1:1-4.

[0064] In a preferred embodiment of the present invention, the sustained-release thermosensitive blank gel is filtered using a 0.22 μm filter membrane.

[0065] In a preferred embodiment of the present invention, the sustained-release thermosensitive blank gel and temozolomide are placed in different chambers or storage spaces and mixed uniformly before use to form a drug gel.

[0066] In a preferred embodiment of the present invention, the concentration of temozolomide in the drug gel is 5-400 mg / mL, preferably 50-300 mg / mL, and more preferably 100-250 mg / mL.

[0067] In a preferred embodiment of the present invention, the D of the micronized temozolomide microcrystals 50 ≤10μm, D preferred 50 ≤5μm, preferably D 50 ≤3μm.

[0068] In a preferred embodiment of the present invention, the drug gel optionally contains any one or a combination of buffers, stabilizers, and preservatives.

[0069] In a preferred embodiment of the present invention, the buffer is selected from any one or a combination of lactate buffer, phosphate buffer, citrate buffer, acetate buffer, and oxalate buffer.

[0070] In a preferred embodiment of the present invention, the buffer concentration in the drug gel is 1-200 mM, preferably 50-150 mM, and more preferably 80-120 mM.

[0071] In a preferred embodiment of the present invention, the stabilizer is selected from any one or a combination of L-cysteine, L-alanine, L-threonine, L-leucine, L-methionine, glycine, sorbitol, and mannitol.

[0072] In a preferred embodiment of the present invention, the concentration of the stabilizer in the drug gel is 0.1-10 mg / mL, preferably 1-8 mg / mL, and more preferably 2-5 mg / mL.

[0073] In a preferred embodiment of the present invention, the preservative is selected from any one or a combination of potassium sorbate, sodium benzoate, ethylparaben, methylparaben, calcium propionate, and sodium lactate.

[0074] In a preferred embodiment of the present invention, the concentration of the preservative in the drug gel is 0.01 mg-0.1 mg / mL.

[0075] In a preferred embodiment of the present invention, the drug gel contains 3-300 mg / mL temozolomide and 10-40 wt% PLGA-PEG-PLGA gel solution.

[0076] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide and 20 wt% PLGA-PEG-PLGA gel solution.

[0077] In a preferred embodiment of the present invention, the drug gel contains temozolomide 3-300 mg / mL, 15-30 wt% PLGA-PEG-PLGA gel solution, L-alanine 1-5 mg / mL, and methylparaben 0.01-0.1 mg / mL.

[0078] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide, 15 wt% PLGA-PEG-PLGA gel solution, 10 mM phosphate buffer, and 1 mg / mL L-cysteine.

[0079] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide, 25 wt% PLGA-PEG-PLGA gel solution, 10 mM citrate buffer, and 1 mg / mL L-cysteine.

[0080] In a preferred embodiment of the present invention, the drug gel contains 100 mg / mL temozolomide, 30 wt% PLGA-PEG-PLGA gel solution, 5 mM acetate buffer, and 1 mg / mL L-cysteine.

[0081] In a preferred embodiment of the present invention, the blank gel or drug gel is liquid at ≤32°C and transforms into a gel at 35°C or higher.

[0082] In a preferred embodiment of the present invention, the blank gel and the drug are placed in two different chambers or storage spaces, and are prepared and used immediately before use.

[0083] Another objective of this invention is to provide a method for preparing a temozolomide thermosensitive hydrogel, comprising the following steps: uniformly mixing temozolomide with a sustained-release thermosensitive blank gel or uniformly mixing temozolomide with a sustained-release thermosensitive blank gel before use to obtain a drug gel, wherein the concentration of temozolomide in the obtained drug gel is 1-500 mg / mL, and the sustained-release thermosensitive blank gel contains 5-60 wt% of an amphiphilic block polymer, wherein the amphiphilic block polymer is selected from any one or a combination of ABA-type, BAB-type, AB-type, and multi-arm star-type, wherein the temozolomide in the drug gel is dissolved in the blank gel or uniformly dispersed in the blank gel to form a gel suspension, wherein the temozolomide is selected from any one or a combination of micronized temozolomide, temozolomide nanoparticles coated with PLGA, and temozolomide PLGA microspheres.

[0084] In a preferred embodiment of the present invention, the blank gel or drug gel is liquid at ≤32°C and transforms into a gel at 35°C or higher.

[0085] In a preferred embodiment of the present invention, the blank gel and the drug are placed in two different chambers or storage spaces, and are prepared and used immediately before use.

[0086] Another object of the present invention is to provide the use of the sustained-release thermosensitive drug gel of the present invention in the preparation of a drug for reducing or inhibiting postoperative recurrence of glioblastoma.

[0087] In a preferred embodiment of the present invention, the sustained-release thermosensitive drug gel is a temozolomide sustained-release thermosensitive gel.

[0088] In a preferred embodiment of the present invention, the sustained-release thermosensitive blank gel or drug gel is liquid at ≤32°C and transforms into a gel at 35°C or higher.

[0089] In a preferred embodiment of the present invention, the blank gel and the drug are placed in two different chambers or storage spaces, and are prepared and used immediately before use.

[0090] In a preferred embodiment of the present invention, the temozolomide sustained-release thermosensitive gel is used on the surface of the resection cavity after local resection of glioblastoma to form a temozolomide gel layer, which slowly releases temozolomide to induce apoptosis of glioma cells that were not completely resected, thereby reducing or even inhibiting tumor recurrence.

[0091] In a preferred embodiment of the present invention, the sustained-release thermosensitive drug gel is prepared and used immediately. The sustained-release thermosensitive blank gel is mixed evenly with temozolomide before use and then applied to the resection cavity wound during or after glioma resection.

[0092] Unless otherwise stated, when this invention relates to percentages between liquids, the percentage is volume / volume percentage; when this invention relates to percentages between liquids and solids, the percentage is volume / weight percentage; when this invention relates to percentages between solids and liquids, the percentage is weight / volume percentage; the remainder is weight / weight percentage.

[0093] Unless otherwise stated, the present invention employs the following detection method:

[0094] 1. Thermosensitive gel's T gel .

[0095] The gelation temperature of the gel solution was determined using the inverted vial method. If the prepared gel solution remained non-flowing within 30 seconds, this transition temperature was defined as the gelation temperature, and a curve was plotted. The gelation temperature was determined using a dynamic rotational rheometer; the point at which G' and G” first intersect was defined as the Tg of the temperature-sensitive gel. gel .

[0096] Test instrument: TA Instruments HR10 Discovery; Test mode: Temperature Oscillation; Test fixture: 20mm aluminum plate with solvent well; Temperature range: 20℃-50℃; Heating rate: 0.5℃ / min; Gap: 500μm; Vibration frequency: 1Hz; Stress deformation: 1%; Test volume: 178μL.

[0097] Compared with the prior art, the present invention has the following beneficial effects:

[0098] 1. This invention scientifically screens the composition and ratio of temozolomide sustained-release thermosensitive gel. The resulting temozolomide thermosensitive sustained-release gel is a low-viscosity gel solution with excellent flowability at room temperature, facilitating filtration and sterilization. The drug can be prepared and used immediately with the sustained-release thermosensitive blank gel, significantly reducing drug degradation during drug formulation and improving drug stability. The drug forms a solution or uniformly dispersed suspension with the sustained-release thermosensitive gel, adapting to cavities of different shapes. This facilitates the drug gel entering the tumor surgical resection cavity and transforming into a gel within the cavity, occupying space at the surgical site and forming a local drug reservoir, which is beneficial for achieving high local drug concentration and drug delivery at the surgical site. This drug is specifically designed for local administration during or after surgery for glioblastoma. It slowly and continuously releases high drug-loaded concentrations locally, effectively inhibiting the formation of lesions in the brain parenchyma. It continuously induces apoptosis in glioblastoma cells that have not been completely surgically removed within the glioma resection cavity, significantly reducing postoperative recurrence rates, significantly reducing systemic adverse drug reactions, and significantly improving patient compliance. It avoids the use of organic solvents, thus significantly improving the safety of the formulation. Furthermore, it possesses advantages such as good formulation stability, high bioavailability, effective reduction of postoperative recurrence rates, safety and efficacy, good biocompatibility, excellent biodegradability, good tolerability, and ease of use.

[0099] 2. The PLGA-PEG-PLGA structure in the temozolomide thermosensitive sustained-release gel of the present invention exhibits good biocompatibility and biodegradability. PEG forms a hydrophilic crown, and PLGA forms a hydrophobic core in a spherical micelle structure. Upon temperature increase, the hydrophobicity of the PEG blocks rapidly increases, causing them to aggregate and transform from flat-headed micelles to semi-bald micelles, exposing the hydrophobic core of PLGA and forming hydrophobic channels and a hydrogel network structure between micelles. This achieves sustained release and long-lasting effect of the drug in the gel, while local release reduces systemic toxicity and improves the local therapeutic concentration and efficacy.

[0100] 3. The preparation method of the present invention has the advantages of simple operation, good process stability, no special equipment requirements, and suitability for industrial production. Attached Figure Description

[0101] Figure 1Drug release curve in sustained-release thermosensitive drug gel in Experiment Example 1;

[0102] Figure 2 Experimental Example 2: Biocompatibility of Temozolomide Thermosensitive Hydrogel in the Brain (A. Flowchart of Local Safety Experiment of Gel in the Brain; B. Anatomical Diagram and HE Staining Diagram of the Gel Group in the Blank Group, Saline Group, and Gel Group after Each Intervention);

[0103] Figure 3 Experiment 3: The effect of temozolomide thermosensitive hydrogel on the recurrence of U87-MG / Luc glioma cells in Balb / c nude mice (A. Flowchart of the experiment on the inhibition of local glioma recurrence in the brain by gel; B. Glioma resection group, glioma resection + blank hydrogel group, glioma resection + temozolomide intraperitoneal injection group, glioma resection + temozolomide thermosensitive gel group, and glioma resection + temozolomide thermosensitive gel group, with 3 representative mice in each group showing the prognosis of glioma size and degree under different interventions; C. Kaplan-Meier survival curves under each intervention, *: p<0.05). Detailed Implementation

[0104] The present invention will be further described below through specific embodiments and in conjunction with the figures. However, this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not depart from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0105] All raw and auxiliary materials used in the specific implementation method were commercially purchased.

[0106] Temozolomide (purity 99.9%) was purchased from Nanjing Hairun Pharmaceutical Co., Ltd.; the D-value of temozolomide raw material was determined using a dry laser particle size analyzer. 50 =30.08μm, temozolomide crystals were pulverized using an ultrafine airflow mill with an airflow pressure of 5 bar to obtain micronized temozolomide D. 50 =2.57μm.

[0107] PLGA-PEG-PLGA(M w =4900, PLGA block M w =1700, PEG block M w =1500, LA / GA=3 / 1), purchased from Shandong Academy of Biomedical Sciences Co., Ltd., denoted as Copolymer-1.

[0108] PLGA-PEG-PLGA(M w =5500, PLGA segment M w =2000, PEG block M w=1500, LA / GA=3 / 1), purchased from Shandong Academy of Biomedical Sciences, labeled as Copolymer-2;

[0109] U87-MG / Luc cells, ATCC, purchased from Hunan Fuheng Biotechnology Co., Ltd.

[0110] Balb / c mice and balb / c nude mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0111] Example 1 Preparation of PLGA-PEG-PLGA blank gel solution

[0112] The preparation of the PLGA-PEG-PLGA blank gel solution includes the following steps:

[0113] (1) Weigh 2g of Copolymer-1, place it in a 10ml screw-top bottle, add 8g of distilled water, and place it in a 4℃ water bath shaker until completely dissolved; under ice bath conditions, filter it with a 0.22μm microporous membrane to obtain a Copolymer-1 solution with a concentration of 20wt%.

[0114] (2) Weigh 2g of Copolymer-2, place it in a 10mL screw-top bottle, add 8g of double-distilled water, and place it in a 4℃ water bath shaker until completely dissolved; filter it with a 0.22μm microporous membrane under ice bath conditions to obtain a Copolymer-2 solution with a concentration of 20wt%.

[0115] (3) The prepared Copolymer-1 solution and Copolymer-2 solution are mixed uniformly at a volume ratio of 1:1 to obtain a PLGA-PEG-PLGA blank gel solution.

[0116] Example 2. Preparation of Temozolomide Sustained-Release Thermosensitive Gel

[0117] Weigh 50 mg of micronized temozolomide crystals and add them to 1 mL of the PLGA-PEG-PLGA blank gel solution prepared in Example 1. Shake the solution in a water bath at 4 °C to disperse it into a uniform suspension.

[0118] Example 3 Preparation of Temozolomide Sustained-Release Thermosensitive Gel

[0119] Weigh 100 mg of micronized temozolomide crystals and add them to 1 mL of the PLGA-PEG-PLGA gel solution prepared in Example 1. Shake the solution in a water bath at 4°C to disperse it into a uniform suspension.

[0120] Example 4Preparation of Temozolomide Sustained-Release Thermosensitive Gel

[0121] Weigh 150 mg of micronized temozolomide crystals and add them to 1 mL of the PLGA-PEG-PLGA gel solution prepared in Example 1. Disperse the solution into a uniform suspension under a water bath at 4 °C.

[0122] Example 5 Preparation of Temozolomide Sustained-Release Thermosensitive Gel

[0123] Weigh 250 mg of micronized temozolomide crystals and add them to 1 mL of the PLGA-PEG-PLGA gel solution prepared in Example 1. Shake the solution in a water bath at 4°C to disperse it into a uniform suspension.

[0124] Experimental Example 1 Dissolution test of the temozolomide sustained-release thermosensitive gel of the present invention

[0125] Take 1 ml of the temozolomide sustained-release thermosensitive gel prepared in Examples 2-5 and place it in a 10 ml test tube. Then, place the test tube vertically in a 37°C water bath shaker and shake for 10 min to allow complete gelation. Slowly add 5 mL of phosphate buffer (pH 7.4, 290 mOsm) as the dissolution medium on top of the gel. Take 4 mL of the dissolution medium at 1 h, 2 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, and 118 h (and thereafter, every 24 h). Filter the medium through a 0.22 μm microporous membrane and detect the content of temozolomide and its metabolite AICA in the dissolution medium using high-performance liquid chromatography (HPLC). After each 4 mL of dissolution medium is taken, another 4 mL is added. Calculate the recovery rate of temozolomide and the degradation amount of temozolomide using AICA. Then, sum the results to calculate the total release of temozolomide at the detection sampling points. The test continued until the temozolomide sustained-release thermosensitive gel reached 100% of its theoretical release capacity. Results are shown below. Figure 1

[0126] Experimental Example 2 Biosafety Study of Temozolomide Sustained-Release Thermosensitive Gel of the Present Invention

[0127] Eighteen female Balb / c mice, aged 4-8 weeks and weighing approximately 19-21 grams, were selected as experimental animals. They were randomly divided into three groups: a blank control group, a saline brain injection group (negative control group), and a temozolomide gel group (experimental group, temozolomide thermosensitive gel of Example 3). There were 6 mice in each group.

[0128] The experimental animals were placed in an environment of 25°C, 50% relative humidity, free access to food and water, and 12h / 12h day-night alternation for 2 days for acclimatization before the experiment began.

[0129] Nude mice were anesthetized with urethane solution at a dose of 1250 mg / kg body weight and fixed in a brain localization device. The scalp was disinfected with 75% ethanol, and an incision of approximately 5 mm was made along the sagittal suture using ophthalmic scissors. Soft tissue and fascia were dissected to expose the parietal bone. 0.2 mm diameter bone holes were made using a high-speed cranial drill at locations 3 mm posterior to the coronal suture and 2 mm lateral to the anterior fontanelle. Guided by the brain localization device, a needle was inserted vertically 3 mm through the bone holes, and physiological saline and the temozolomide thermosensitive gel from Example 3 were injected into the mouse brain at an injection rate of 0.5 μL / min. The surgical incision was disinfected and sutured with PGA surgical sutures. The mice were then placed on a 35°C constant-temperature plate for resuscitation. Daily changes in mouse body weight were recorded for 14 days. On day 14, all experimental mice were sacrificed, and their brains were harvested, preserved in 4% formalin solution, and subjected to HE staining to observe local inflammatory responses.

[0130] See results Figure 2 Brain anatomical images show that the temozolomide thermosensitive gel in the experimental group maintained its gel shape after 14 days. In the negative control group, the injection sites healed almost completely. HE staining comparisons among the three groups showed no significant differences in neuronal apoptosis and inflammatory responses. Therefore, the temozolomide thermosensitive gel of this invention exhibits excellent biocompatibility and is well-tolerated by the brain.

[0131] Experimental Example 3 Experimental study on the inhibition of glioma cell recurrence by temozolomide thermosensitive gel

[0132] U87-MG / Luc cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) at 37°C and 5% CO2 for 120 h. Cells were then digested with trypsin to detach them from the cell wall, resulting in a cell suspension. Cell concentration was determined using a cell counting chamber, and the cell suspension was diluted with DMEM to a concentration of 1 × 10⁻⁶ cells / mL. 6 Cells were prepared at a density of 1 cell / mL to obtain a cell suspension.

[0133] Glioma modeling was performed on day 0: Thirty-two 4-8 week old, female Balb / c nude mice weighing approximately 19-21 grams were used. The animals were acclimatized for two days in an environment of 25°C, 50% relative humidity, with free access to food and water, and a 12h / 12h day / night cycle. The mice were anesthetized with urethane solution at 1250 mg / kg body weight and fixed in a brain localizer. The scalp was disinfected with 75% ethanol, and an incision of approximately 5 mm was made along the sagittal suture using ophthalmic scissors. Soft tissue and fascia were dissected to expose the parietal bone. A 0.2 mm diameter bone hole was made 3 mm posterior to the coronal suture and 2 mm lateral to the anterior fontanelle using a high-speed cranial drill. 8 μL of the cell suspension was aspirated using a microsyringe, and under the guidance of the brain localizer, the needle was inserted vertically 3 mm through the bone hole, injecting the cells into the brain at an injection rate of 0.5 μL / min. The surgical incision was disinfected and sutured with PGA surgical sutures. The mice were then placed on a 35°C constant-temperature plate for resuscitation. One week after glioma cells were grown, D-fluorescein potassium was injected intraperitoneally at a dose of 150 mg / kg. Mice with similar fluorescence intensity and range were grouped together under the observation of a small animal in vivo imaging device IVIS (Perkin-Elmer) (instrument parameters: exposure time 1s, scale bar: 50-1000), and tumor-bearing mouse modeling was completed.

[0134] On day 6, IVIS observation was performed before glioma resection. Mice with similar fluorescence intensity and range were grouped together and treated with different interventions, resulting in four groups:

[0135] 1. Blank group: Surgery + no intervention group

[0136] 2. Control Group 1: Surgery + Temozolomide Intraperitoneal Injection Group. Administer 50 mg / kg of temozolomide per kg of body weight, daily for 6 consecutive days, using a solution containing 1 mg of temozolomide (prepared by adding 1 ml of distilled water to 1 mg of temozolomide raw material).

[0137] 3. Control group 2: surgery + blank gel group.

[0138] 4. Experimental group: Surgery + Temozolomide thermosensitive gel group, 8ul of temozolomide thermosensitive gel from Example 3 was injected at one time.

[0139] On day 7, glioma resection was performed on the experimental animals. Both the control and experimental groups received corresponding interventions during the glioma resection. Mice bearing gliomas that had successfully developed the model were anesthetized with urethane solution at a concentration of 1250 mg / kg body weight and fixed to a brain localization device. The scalp was disinfected with 75% ethanol, and the previous wound was reopened using ophthalmic scissors. Soft tissue and fascia were dissected to expose the bone hole. The bone hole diameter was enlarged to 2 mm using a high-speed cranial drill to expose the glioma. Using a Miltex™ 1.5 mm biopsy gun, the drill was inserted approximately 4 mm into the brain parenchyma through the bone hole, slowly rotated clockwise 3 times, and then removed to clear the glioma from the naked eye.

[0140] Both the control group and the experimental group were administered the drug at this time. 8 μL of thermosensitive gel was slowly injected into the resection cavity. After complete gelation, the surgical incision was disinfected and sutured with PGA sutures. The mice were then placed on a 35°C constant-temperature plate to resuscitate. One week after glioma cell growth, D-fluorescein potassium was injected intraperitoneally at a dose of 150 mg / kg, and the cells were observed using a small animal in vivo imaging device IVIS (Perkin-Elmer) (instrument parameters: exposure time 1 s, scale bar: 50-1000).

[0141] The control group received intraperitoneal injections of temozolomide solution from day 8 to day 13. D-fluorescein potassium was injected intraperitoneally at a dose of 150 mg / kg, and the fluorescence intensity and extent of mouse gliomas were observed on days 14, 21, 28, and 35 using an IVIS (Perkin-Elmer) small animal in vivo imaging system (instrument parameters: exposure time 1 s, scale bar: 50-1000).

[0142] See results Figure 3 The study examined the outcomes of three representative mice from each group after glioma surgery under different interventions. In both the control group and the experimental group, the fluorescence intensity emitted by the glioma decreased to an acceptable level after intervention. However, two mice in the control group died after six consecutive days of treatment, and their deaths occurred earlier than in the control group. The experimental group demonstrated good inhibition of glioma recurrence under IVIS observation, with a 40% survival rate without glioblastoma recurrence, which was statistically significant. The temozolomide sustained-release thermosensitive gel of this invention provides local brain administration via a drug reservoir, effectively preventing and inhibiting postoperative recurrence of glioma resection safely and effectively.

[0143] The above description of specific embodiments of the present invention does not limit the present invention. Those skilled in the art can make various changes or modifications based on the present invention, and as long as they do not depart from the spirit of the present invention, they should all fall within the scope of protection of the claims of the present invention.

Claims

1. A sustained-release thermosensitive blank gel, characterized in that, The gel contains 10wt%-40wt% of an amphiphilic block polymer, wherein the amphiphilic block polymer is a BAB-type polylactic acid-glycolic acid copolymer block-polyethylene glycol-polylactic acid-glycolic acid copolymer block PLGA-PEG-PLGA, where polylactic acid-glycolic acid copolymer block B is a hydrophobic block and polyethylene glycol block A is a hydrophilic block. The ratio of lactic acid to glycolic acid repeating units in polylactic acid-glycolic acid copolymer block B is 2:1-5:

1. The number average molecular weight of the amphiphilic block polymer is 3000-6000. The number average molecular weight of block B is 900-2000, and the number average molecular weight of polyethylene glycol block A is 900-2000. The ratio of the sum of the number average molecular weights of the two polylactic acid-glycolic acid copolymer blocks B to the number average molecular weight of polyethylene glycol block A is 2:1-3:

1. The method for preparing the sustained-release thermosensitive blank gel is to mix an amphiphilic block polymer solution with a gelation temperature of 25-30℃ and an amphiphilic block polymer solution with a gelation temperature of 35-40℃ at a volume ratio of 1:1-4. The sustained-release thermosensitive blank gel is a low-viscosity liquid at room temperature and transforms into a non-flowing gel at 35-38℃.

2. The gel as described in claim 1, characterized in that, The sustained-release thermosensitive blank gel contains an amphiphilic block polymer concentration of 15wt%-30wt%.

3. The gel as described in claim 2, characterized in that, The sustained-release thermosensitive blank gel contains an amphiphilic block polymer concentration of 20wt%-25wt%.

4. A pharmaceutical gel, characterized in that, The drug is uniformly mixed with the sustained-release thermosensitive blank gel as described in any one of claims 1-3, or the drug is freshly prepared and uniformly mixed with the sustained-release thermosensitive blank gel as described in any one of claims 1-3 to prepare a drug gel. The drug concentration in the obtained drug gel is 1-500 mg / mL. The drug in the drug gel is dissolved in the sustained-release thermosensitive blank gel or the drug and the sustained-release thermosensitive blank gel form a stable gel suspension. The drug is a micronized drug.

5. The gel as described in claim 4, characterized in that, The weight ratio of the drug to the sustained-release thermosensitive blank gel in the drug gel is 50-400:

1.

6. The gel as described in claim 5, characterized in that, The weight ratio of the drug to the sustained-release thermosensitive blank gel in the drug gel is 100-300:

1.

7. The gel as claimed in claim 6, characterized in that, The weight ratio of the drug to the sustained-release thermosensitive blank gel in the drug gel is 150-250:

1.

8. The gel as described in claim 4, characterized in that, The drug gel contains any one or a combination of buffers, stabilizers, and preservatives.

9. The gel as described in claim 8, characterized in that, The buffer is selected from any one or a combination of lactate buffer, phosphate buffer, citrate buffer, acetate buffer, and oxalate buffer.

10. The gel as claimed in claim 8, characterized in that, The buffer concentration in the drug gel is 1-200 mM.

11. The gel as claimed in claim 10, characterized in that, The buffer concentration in the drug gel is 50-150 mM.

12. The gel as claimed in claim 11, characterized in that, The buffer concentration in the drug gel is 80-120 mM.

13. The gel as claimed in claim 8, characterized in that, The stabilizer is selected from any one or a combination of L-cysteine, L-alanine, L-threonine, L-leucine, L-methionine, glycine, sorbitol, and mannitol.

14. The gel as claimed in claim 8, characterized in that, The concentration of stabilizer in the drug gel is 0.1-10 mg / mL.

15. The gel as claimed in claim 14, characterized in that, The stabilizer concentration in the drug gel is 1-8 mg / mL.

16. The gel as claimed in claim 15, characterized in that, The stabilizer concentration in the drug gel is 2-5 mg / mL.

17. The gel as claimed in claim 8, characterized in that, The preservative is selected from any one or a combination of potassium sorbate, sodium benzoate, ethylparaben, methylparaben, calcium propionate, and sodium lactate.

18. The gel as claimed in claim 8, characterized in that, The concentration of preservative in the drug gel is 0.01 mg-0.1 mg / mL.

19. The gel according to any one of claims 4-18, characterized in that, The drug gel is liquid at ≤32℃ and transforms into a gel at above 35℃.

20. The gel according to any one of claims 4-18, characterized in that, The sustained-release thermosensitive blank gel and the drug are placed in two different chambers or storage spaces and should be prepared and used immediately before use.

21. A temozolomide sustained-release thermosensitive gel, characterized in that, The temozolomide is uniformly mixed with the sustained-release thermosensitive blank gel as described in any one of claims 1-3, or the temozolomide is uniformly mixed with the sustained-release thermosensitive blank gel as described in any one of claims 1-3 before use to prepare a drug gel. The concentration of temozolomide in the obtained drug gel is 1-500 mg / mL. The temozolomide in the drug gel is dissolved in the sustained-release thermosensitive blank gel or uniformly dispersed in the sustained-release thermosensitive blank gel to form a gel suspension. The temozolomide is selected from micronized temozolomide, wherein the D of the micronized temozolomide microcrystals is... 50 ≤10μm.

22. The temozolomide sustained-release thermosensitive gel as described in claim 21, characterized in that, The concentration of temozolomide in the drug gel is 5-400 mg / mL.

23. The temozolomide sustained-release thermosensitive gel as described in claim 22, characterized in that, The concentration of temozolomide in the drug gel is 50-300 mg / mL.

24. The temozolomide sustained-release thermosensitive gel as described in claim 23, characterized in that, The concentration of temozolomide in the drug gel is 100-250 mg / mL.

25. The temozolomide sustained-release thermosensitive gel as described in claim 21, characterized in that, The D of the micronized temozolomide microcrystals 50 ≤5μm.

26. The temozolomide sustained-release thermosensitive gel as described in claim 25, characterized in that, The D of the micronized temozolomide microcrystals 50 ≤3μm.

27. The temozolomide sustained-release thermosensitive gel as described in claim 21, characterized in that, The drug gel contains any one or a combination of buffers, stabilizers, and preservatives.

28. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The buffer is selected from any one or a combination of lactate buffer, phosphate buffer, citrate buffer, acetate buffer, and oxalate buffer.

29. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The buffer concentration in the drug gel is 1-200 mM.

30. The temozolomide sustained-release thermosensitive gel as described in claim 29, characterized in that, The buffer concentration in the drug gel is 50-150 mM.

31. The temozolomide sustained-release thermosensitive gel as described in claim 30, characterized in that, The buffer concentration in the drug gel is 80-120 mM.

32. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The stabilizer is selected from any one or a combination of L-cysteine, L-alanine, L-threonine, L-leucine, L-methionine, glycine, sorbitol, and mannitol.

33. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The concentration of stabilizer in the drug gel is 0.1-10 mg / mL.

34. The temozolomide sustained-release thermosensitive gel as described in claim 33, characterized in that, The concentration of stabilizer in the drug gel is 1-8 mg / mL.

35. The temozolomide sustained-release thermosensitive gel as described in claim 34, characterized in that, The stabilizer concentration in the drug gel is 2-5 mg / mL.

36. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The preservative is selected from any one or a combination of potassium sorbate, sodium benzoate, ethylparaben, methylparaben, calcium propionate, and sodium lactate.

37. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The concentration of preservative in the drug gel is 0.01 mg-0.1 mg / mL.

38. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The drug gel contains temozolomide 3-300 mg / mL and PLGA-PEG-PLGA gel solution 10-40 wt.

39. The temozolomide sustained-release thermosensitive gel as described in claim 38, characterized in that, The drug gel contains 100 mg / mL temozolomide and 20 wt% PLGA-PEG-PLGA gel solution.

40. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The drug gel contains temozolomide 3-300 mg / mL, 15-30 wt% PLGA-PEG-PLGA gel solution, L-alanine 1-5 mg / mL and methylparaben 0.01-0.1 mg / mL.

41. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The drug gel contains 100 mg / mL temozolomide, 15 wt% PLGA-PEG-PLGA gel solution, 10 mM phosphate buffer, and 1 mg / mL L-cysteine.

42. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The drug gel contains 100 mg / mL temozolomide, 25 wt% PLGA-PEG-PLGA gel solution, 10 mM citrate buffer, and 1 mg / mL L-cysteine.

43. The temozolomide sustained-release thermosensitive gel as described in claim 27, characterized in that, The drug gel contains 100 mg / mL temozolomide, 30 wt% PLGA-PEG-PLGA gel solution, 5 mM acetate buffer, and 1 mg / mL L-cysteine.

44. The temozolomide sustained-release thermosensitive gel according to any one of claims 21-43, characterized in that, The drug gel is liquid at ≤32℃ and transforms into a gel at above 35℃.

45. The temozolomide sustained-release thermosensitive gel as described in claim 21, characterized in that, The sustained-release thermosensitive blank gel was filtered through a 0.22 μm filter membrane.

46. ​​The temozolomide sustained-release thermosensitive gel as described in claim 21, characterized in that, The sustained-release thermosensitive blank gel and temozolomide were placed in different chambers or storage spaces and mixed evenly before use to prepare a drug gel.

47. A method for preparing a temozolomide sustained-release thermosensitive gel, characterized in that, The preparation method includes the following steps: uniformly mixing temozolomide with the sustained-release thermosensitive blank gel according to any one of claims 1-3, or uniformly mixing temozolomide with the sustained-release thermosensitive blank gel according to any one of claims 1-3 before use, to obtain a drug gel, wherein the concentration of temozolomide in the obtained drug gel is 1-500 mg / mL, and the temozolomide in the drug gel is dissolved in the sustained-release thermosensitive blank gel or uniformly dispersed in the sustained-release thermosensitive blank gel to form a gel suspension, wherein the temozolomide is selected from micronized temozolomide, and the micronized temozolomide microcrystals are D 50 ≤10μm.

48. The preparation method according to claim 47, characterized in that, The drug gel is liquid at ≤32℃ and transforms into a gel at above 35℃.

49. The preparation method according to claim 47, characterized in that, The sustained-release thermosensitive blank gel and the drug are placed in two different chambers or storage spaces and should be prepared and used immediately before use.

50. The use of a temozolomide sustained-release thermosensitive drug gel as described in any one of claims 21-46 or a temozolomide sustained-release thermosensitive drug gel prepared by the preparation method as described in any one of claims 47-49 in the preparation of a drug for reducing or inhibiting postoperative recurrence of glioblastoma.

51. The application as described in claim 50, characterized in that, The drug gel is liquid at ≤32℃ and transforms into a gel at above 35℃.

52. The application as described in claim 50, characterized in that, The sustained-release thermosensitive blank gel and the drug are placed in two different chambers or storage spaces and should be prepared and used immediately before use.

53. The application as described in claim 50, characterized in that, The temozolomide sustained-release thermosensitive gel is used on the surface of the resection cavity after local resection of glioblastoma to form a temozolomide gel layer, which slowly releases temozolomide, inducing apoptosis of glioma cells that were not completely resected, thereby reducing or even inhibiting tumor recurrence.

54. The application as described in claim 50, characterized in that, The sustained-release thermosensitive drug gel is prepared and used immediately. The sustained-release thermosensitive blank gel is mixed evenly with temozolomide before use and then applied to the resection cavity wound during or after glioma resection.

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