Anti-cancer sustained-release implant containing paclitaxel as well as preparation and application of anti-cancer sustained-release implant

Abstract

The invention discloses a paclitaxel-containing anti-cancer sustained-release implant, the active ingredient of which is paclitaxel or a combination of paclitaxel and cis-platinum, and PLGA (poly (lactic-co-glycolic acid)) or a mixture of PLGA and polystyrene is taken as a carrier. The invention also discloses a preparation method and application of the compound. The anti-cancer sustained-release implant is prepared by adopting a hot-melt extrusion process, and the whole production process is free of any organic solvent, so that the anti-cancer sustained-release implant has lower toxic and side effects than a conventional solvent method.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an anticancer sustained-release implant containing paclitaxel, its preparation, and its application. Background Technology

[0002] Cancer has become a major threat to human health. Currently, cancer treatment mainly relies on conventional methods such as surgery, chemotherapy, and radiotherapy. Although new treatments and technologies offer hope for improving the prognosis of cancer patients, chemotherapy remains the most commonly used basic treatment for most cancer patients.

[0003] Among various drug treatments, antimitotic drugs, represented by paclitaxel, and cytotoxic drugs, represented by cisplatin, are the most commonly used, especially for the treatment of malignant tumors such as lung cancer, testicular cancer, ovarian cancer, cervical cancer, liver cancer, head and neck tumors, and malignant lymphoma.

[0004] Paclitaxel, a tetracyclic diterpenoid derived from the yew tree, is primarily used for ovarian and breast cancer. It also shows some efficacy against head and neck cancer, esophageal cancer, colorectal cancer, melanoma, lymphoma, and brain tumors. It is a highly effective, low-toxicity, broad-spectrum natural anticancer drug. Paclitaxel inhibits tumor cell proliferation by binding to microtubules, interfering with the mitotic process of tumor cells and inducing terminal arrest and apoptosis. Cisplatin, a heavy metal complex, is a cell cycle-nonspecific anticancer drug with a broad anticancer spectrum. Cisplatin's mechanism of action in killing tumor cells involves cross-linking with DNA to form a relatively stable complex that locks in DNA, causing DNA damage, disrupting DNA replication and transcription, and thus inhibiting DNA and RNA synthesis.

[0005] Paclitaxel and cisplatin have poor water solubility, low oral bioavailability, and significant toxic side effects on other organs, which limits their clinical application.

[0006] To reduce the toxic side effects of paclitaxel and cisplatin, several modified dosage forms have been developed, such as the cisplatin implant from Anhui Zhongren and the cisplatin liposome from Regulon Pharmaceuticals in the United States; however, these are all still in the clinical trial stage. To overcome the issue of paclitaxel not using polyoxyethylene castor oil and ethanol as solubilizers, Nanjing Luyesco developed the world's first marketed paclitaxel liposome, approved for marketing in China in 2003. However, it requires intravenous infusion over more than 3 hours and pre-treatment with dexamethasone, diphenhydramine, and cimetidine (see the dosage and administration section of the package insert for paclitaxel liposomes for injection for details). Samyang Pharmaceuticals in South Korea developed paclitaxel polymer micelles (Genexol-PM), which was approved for marketing in South Korea in 2007. Genexol-PM uses polymer micelle self-assembly technology, does not contain polyoxyethylene castor oil or ethanol, has no serious allergic reactions, and requires no pre-treatment for desensitization before administration. However, in clinical applications, it was found that the micelle formulation of this drug exhibits poor micelle stability after entering the human body, with 65% release within 24 hours and 95% release within 48 hours (Werner ME, Cummings ND, Sethi M, et al. Preclinical Evaluation of Genexol-PM, a Nanoparticle Formulation of Paclitaxel, as a Novel Radiosensitizer for the Treatment of Non-Small Cell Lung Cancer. International Journal of Radiation Oncology Biology Physics. 2013;86(3):463~468), and its price is relatively high. Celgene developed and marketed paclitaxel injection (albumin-bound, Abraxane), which was approved by the FDA in 2005 and is the world's first albumin-bound drug. This drug does not require polyoxyethylene castor oil and ethanol solubilization, significantly reduces adverse reactions, does not require desensitization pretreatment before administration, and shortens the administration time to about half an hour. However, the drug requires the use of chloroform and ethanol to dissolve paclitaxel during preparation, which poses a risk of residual organic solvents and potential toxicity to the formulation.

[0007] Cisplatin and paclitaxel combination chemotherapy is a commonly used regimen in clinical practice for treating various solid tumors, including non-small cell lung cancer, small cell lung cancer, breast cancer, gastric cancer, ovarian cancer, cervical cancer, and endometrial cancer. It can be used as adjuvant therapy after surgery for these cancers or as chemotherapy for these cancer types in advanced stages. The cisplatin-paclitaxel combination regimen has significant advantages in synergistic effects, reduced drug resistance, expanded indications, optimized dosage, and comprehensive treatment. However, the combination regimen may also bring additive toxic side effects (such as neurotoxicity and myelosuppression), as well as nephrotoxicity, allergic reactions, and gastrointestinal reactions. Some patients (especially elderly patients or those in poor physical condition) may not tolerate the combination regimen, leading to treatment interruption or dosage adjustment, affecting efficacy. During treatment, because cisplatin inhibits cytochrome P450 enzymes, it reduces the clearance rate of paclitaxel in the patient's body. To prevent toxic side effects caused by paclitaxel retention, paclitaxel must be used first, followed by a period of time before cisplatin can be administered. Furthermore, the infusion time must be strictly controlled during intravenous infusion to prevent it from being too rapid. In addition, dexamethasone and diphenhydramine should be used before paclitaxel administration to prevent allergic reactions. Before and after cisplatin infusion, the vein should be thoroughly flushed with saline or other flushing solutions to reduce damage to blood vessels caused by the drug.

[0008] To ensure the efficacy of cisplatin and paclitaxel, especially their combination with radiotherapy, while reducing the toxic side effects and usage limitations of this combination, several companies have made strategic investments and conducted research in the field of modified new drugs. Patent CN112656764A discloses a long-circulating liposome co-loaded with paclitaxel and cisplatin and its application. The liposomes prepared in this patent use a thin-film dispersion method, which is costly and difficult to scale up. The encapsulation efficiency of the cisplatin compounds in this patent is very low; for example, the encapsulation efficiency of cisplatin is only about 42.85%, oxaliplatin is only about 44.10%, and carboplatin is only about 54.33%. In general, the drawbacks of liposomes include poor stability, low encapsulation efficiency, high cost, unreliable targeting, immunogenicity, and difficulty in release control. CN104721131A discloses an in-situ gel drug formulation of cisplatin and paclitaxel. The gel formulation disclosed in this patent has a relatively complex preparation process, requiring the preparation of upstream polymers polyethylene glycol-polycaprolactone-polyethylene glycol (PEG-PCL-PEG) and polyethylene glycol-polycaprolactone (PECE-PCl), as well as the preparation of paclitaxel micelles. Some of these operations are quite complex, and the preparation process may require precise control of conditions such as temperature, which to some extent leads to high production costs and makes large-scale production difficult. In addition, the temperature-sensitive hydrogel prepared by this method has relatively low mechanical strength. In the in vivo environment, the hydrogel may also degrade rapidly due to enzymatic hydrolysis, hydrolysis, or mechanical wear, affecting its long-term efficacy. CN112089729A discloses an injectable hydrogel co-loaded with paclitaxel micelles and cisplatin, and its preparation method is also relatively complex, with similar drawbacks.

[0009] As a leader in the implant field, BlueGold disclosed a method for preparing a paclitaxel sustained-release formulation in patent CN101380291A. However, this method requires the use of dichloromethane, which introduces the risk of organic solvent residue and potential toxicity into the formulation. CN101336900A also uses dichloromethane in the preparation process of paclitaxel implants. These patents for paclitaxel preparation employ dichloromethane dissolution in their processes, limiting their application in production. These modified dosage forms present certain problems in terms of toxicity control, production processes, and quality control.

[0010] Plylide-glycolic acid copolymer (PLGA) is a biodegradable biomedical polymer material whose degradation time and mechanical properties can be controlled by adjusting the component ratios. The final degradation products are water and carbon dioxide, exhibiting non-toxicity and biocompatibility. Polystyrene is a biodegradable polymer material primarily used in biomedical materials and antibacterial fields, specifically in areas such as drug carriers, tissue engineering scaffolds, and antibacterial materials.

[0011] Gliadel is a typical example of an implantable drug, using poly(p-carboxyphenylpropane) [p-CPP: sebacic acid (SA) copolymer, 20:80] as its sustained-release carrier. However, this product has many defects in its drug release characteristics, such as: unstable sustained-release system, unstable release, significant burst release, poor efficacy, and relatively large toxic side effects. These defects limit the clinical application of this product. The carmustine (BCNU) loading in the Gliadel implant is low (3.85%), with a short release period (5-7 days) and a very significant burst release, with more than 50%-60% released within 1-2 days of in vivo placement. Dang (1996) reported that after placing Gliadel implants in the rat brain, the cumulative release of BCNU on days 1, 2, and 5 were 60%, 70%, and 100%, respectively (Dang W et al., Journal of Controlled Release 42(1996):83-92). Lawrence (1998) reported that approximately 40% and 70% of BCNU were released on days 1 and 4, respectively, in PBS (pH 7.4), while approximately 95% of BCNU was released on days 5–7 in monkey brains (Lawrence K. Fung et al., Cancer Research 58(1998):672–684). To address these shortcomings, researchers working on Gliadel implants attempted various methods to overcome them, such as increasing drug loading, co-loading other active pharmaceutical ingredients like temozolomide, and adjusting the ratio of p-CPP and SA in the carrier. However, the results were not entirely satisfactory. Subsequently, researchers tried using other excipients, such as polylactide (PLA) and PLGA.

[0012] Zoladex, a goserelin implant, is a representative product using PLGA as a carrier. It is a long-acting, sustained-release formulation with an effect lasting up to one month. Zoladex is manufactured using freeze-dried heated melt extrusion (HEM) technology (patent US5366734). However, its release has certain limitations. After a very small burst of drug release in the body, it enters a long release latency period, ceasing to release effective drugs until the PLGA is fully hydrated, undergoes initial degradation, and forms new drug pathways, at which point a rapid release phase resumes.

[0013] To address the release behavior of PLGA-based sustained-release formulations, including delayed and burst release, many researchers have conducted extensive studies. For example, patent CN109288821A uses low molecular weight PLGA to improve release; patent CN115804830A discloses the addition of optically active PLGA75 / 25 to improve the release of sustained-release implants; and patent CN1208616A uses inhibitors (stearic acid, magnesium stearate, calcium stearate, etc.) and pore-forming agents (sodium chloride, potassium chloride, carboxymethyl cellulose, polyethylene glycol, low molecular weight polyvinyl alcohol, etc.) to improve release. Patent CN106692031A uses polyethylene glycol to improve the release of implants; patents CN101336894A, CN1875931A, CN1923172A, CN1957920A, CN1875928A, CN1957913A, CN1973824A, and CN101336898A all mention that implants can be prepared using a mixture of PLGA and polystyrene excipients. CN101336894A even directly proposes that sustained-release implants can be prepared using a mixture of PLGA and polystyrene excipients. However, none of these patents have studied in detail the effect of the ratio of these two excipients on improving release behavior, nor have they conducted a detailed study on the effect of different ratios of PLGA and polystyrene on release. Summary of the Invention

[0014] This invention discloses an anticancer sustained-release implant containing paclitaxel, the active ingredient of which is paclitaxel, or a combination of paclitaxel and cisplatin, and the carrier is a copolymer of lactide and glycolide (PLGA), or a mixture of PLGA and polystyrene.

[0015] In some embodiments, the molar ratio of lactide (LA) to glycolide (GA) in PLGA is 10:90 to 90:10, preferably 50:50 to 75:25, 50:50, or 75:25, and the number average molecular weight is 10K to 40K Daltons, preferably 10K to 30K Daltons, 25K to 40K Daltons, 25K to 30K Daltons, 10K Daltons, 25K Daltons, or 30K Daltons; the molar ratio of p-carboxyphenylpropane to sebacic acid in polystyrene is 10:90 to 60:40, preferably 20:80 to 50:50, or 20:80, and the number average molecular weight is 10K to 40K Daltons, preferably 20K to 40K Daltons, 10K to 30K Daltons, 20K to 30K Daltons, or 30K Daltons.

[0016] In some embodiments, the carrier is PLGA and polystyrene-acrylic acid, and the mass ratio of the two is 40:60 to 90:10.

[0017] In some embodiments, the mass ratio of PLGA to polystyrene in the carrier is 60:40 to 80:20, preferably 80:20; PLGA has a number-average molecular weight greater than 10 K Daltons and less than 40 K Daltons, with a molar ratio of lactide to glycolide of 50:50; or PLGA has a number-average molecular weight of 10 K Daltons, with a molar ratio of lactide to glycolide of 75:25. The number average molecular weight of polystyrene is 30 kDa, and the molar ratio of p-carboxyphenylpropane to sebacic acid is 20:80.

[0018] In some embodiments, the active ingredient is paclitaxel; the drug loading is 1-60%, preferably 5-60%, 5-50%, 5-45%, 5-40%, 5-35%, 5-30%, 5-25%, 10-60%, 10-50%, 10-45%, 10-40%, 10-35%, 10-30%, 10-25%, 15-60%, 15-50%, 15-45%, 15-40%, 15-35%, 15-30%, 15-25%, 20-60%, 20-50%, 20-45%, 20-40%, 20-35%, 20-30%, 20-25%, 20%, 30%, 35%, 40%, 45%, 50%, or 55%.

[0019] In some embodiments, the active ingredients are paclitaxel and cisplatin, with drug loadings of 1%–60% and 0%–50% by weight, or 5%–60% and 1%–50%, or 5%–30% and 5%–30%, or 5%–25% and 5%–25%, or 10%–30% and 5%–30%, or 20%–30% and 5%–30%, or 25%–30% and 5%–30%, or 5%–30% and 10%–30%, or 5%–30% and 20%–30%. Or 5-30% and 25-30%, or 20-30% and 20-30%, or 5% and 5%, or 10% and 10%, or 10% and 20%, or 10% and 30%, or 15% and 15%, or 20% and 10%, or 20% and 20%, or 20% and 30%, or 25% and 25%, or 30%-10%, or 30% and 20%, or 30% and 30%, or 50% and 10%, or 45% and 15%, or 40% and 20%, or 35% and 25%.

[0020] In some embodiments, the material is prepared by a hot melt extrusion process, which includes: Step 1: Mix the active ingredient with a particle size D90 of 10 micrometers to 250 micrometers and the carrier evenly to obtain a mixed powder; Step 2: Add the mixed powder to a hot melt extruder and extrude it at a heating temperature of 90~120℃ or 90~115℃ and an extrusion temperature of 50~80℃ to obtain the extrudate. Step 3: Cut the extrudate, package it, and sterilize it by irradiation to obtain the anticancer sustained-release implant containing paclitaxel.

[0021] In some embodiments, the paclitaxel-containing anticancer sustained-release implant is prepared by the following steps: Step 1: Mix the active ingredient with a particle size D90 of 10 micrometers to 150 micrometers and the carrier evenly to obtain a mixed powder; Step 2: Add the mixed powder to a twin-screw hot melt extruder and extrude it at an extrusion temperature of 50~80℃, a torque of 4~8N·m, and a 1mm die to obtain a cylindrical extruder with a diameter of 1mm. Step 3: Cut the cylindrical extruder, bottle it, and sterilize it by irradiation to obtain the anticancer sustained-release implant containing paclitaxel.

[0022] In some embodiments, the particle size D90 of the active ingredient in step 1 is less than 80 μm, or less than or equal to 65 μm, or 60-65 μm, or less than 20 μm; the particle size D90 of the carrier is less than 250 μm, or less than or equal to 120 μm, or 100-105 μm. Further, the particle size D90 of paclitaxel is 65 μm, the particle size D90 of cisplatin is 60 μm, the particle size D90 of PLGA is 100 μm, and the particle size D90 of polystyrene is 105 μm.

[0023] The implants produced by the hot melt extrusion process of the present invention are available in various specifications and styles, not limited to rods, granules, flakes, columns, films and irregular shapes, but are preferably rods and flakes.

[0024] In some embodiments, the paclitaxel-containing anticancer sustained-release implant is rod-shaped, with a diameter of 0.5-5.0 mm, preferably 1-3.0 mm, and most preferably 1-2.0 mm; and a length of 0.2-20 mm, preferably 0.5-15 mm, and most preferably 5-10 mm.

[0025] In some embodiments, the paclitaxel-containing anticancer sustained-release implant is in the form of a tablet with a diameter of 0.2-30 mm, preferably 0.5-25 mm, and most preferably 5-20 mm; and a thickness of 0.2-8.0 mm, preferably 0.2-6 mm, and most preferably 0.5-5 mm.

[0026] In some embodiments, the paclitaxel-containing anticancer sustained-release implant is in the form of a tablet, which is round, rectangular, or irregularly elliptical.

[0027] On the other hand, the present invention provides a method for preparing the paclitaxel-containing anticancer sustained-release implant as described above, comprising the following steps: Step 1: Mix the active ingredient with a particle size D90 of 10 micrometers to 250 micrometers and the carrier evenly to obtain a mixed powder; Step 2: Add the mixed powder to a hot melt extruder and extrude it at a heating temperature of 90~120℃ or 90~115℃ and an extrusion temperature of 50~80℃ to obtain the extrudate. Step 3: Cut the extrudate, package it, and sterilize it by irradiation to obtain the anticancer sustained-release implant containing paclitaxel.

[0028] In some embodiments, the preparation method includes the following steps: Step 1: Mix the active ingredient with a particle size D90 of 10 micrometers to 150 micrometers and the carrier evenly to obtain a mixed powder; Step 2: Add the mixed powder to a twin-screw hot melt extruder and extrude it at an extrusion temperature of 50~80℃, a torque of 4~8N·m, and a 1mm die to obtain a cylindrical extruder with a diameter of 1mm. Step 3: Cut the cylindrical extruder, bottle it, and sterilize it by irradiation to obtain the anticancer sustained-release implant containing paclitaxel.

[0029] In some embodiments, the particle size D90 of the active ingredient in step 1 is less than 80 μm, or less than or equal to 65 μm, or 60-65 μm, or less than 20 μm; the particle size D90 of the carrier is less than 250 μm, or less than or equal to 120 μm, or 100-105 μm. Further, the particle size D90 of paclitaxel is 65 μm, the particle size D90 of cisplatin is 60 μm, the particle size D90 of PLGA is 100 μm, and the particle size D90 of polystyrene is 105 μm.

[0030] In some embodiments, step 1 achieves uniform mixing by mixing for more than 30 minutes at a speed of 20-50 rpm. Further, step 2 includes preheating in a hot melt extruder at a temperature of 50-90°C, followed by entering a heating zone at 90-120°C, then holding at 90-120°C in a heat preservation zone, and finally entering a cooling forming zone at 50-80°C or 60-80°C, with a screw speed of 5-40 rpm.

[0031] Preferred molding conditions: The preheating and mixing zone of the extruder is preferably 60~80℃, which can ensure that the active pharmaceutical ingredient and the carrier do not degrade and do not stick together when mixed, effectively ensuring uniform mixing. The preferred temperature range for the heating zone is 90~115℃, and the preferred temperature range for the heat preservation zone is 90~115℃. This temperature range can ensure that paclitaxel, cisplatin, and PLGA do not degrade, and that PLGA can remain in a molten state. The cooling and forming zone is preferably 60~80℃. The extrusion speed varies depending on the shape and specifications of the implant, and is preferably 10~25rpm. Under these conditions, the extrudate can be effectively formed, and the extrusion pressure can be kept from being overloaded to ensure smooth discharge.

[0032] This invention employs a hot-melt extrusion process to prepare an anticancer sustained-release implant. The entire production process is solvent-free, resulting in lower toxicity compared to conventional solvent-based methods. This invention also makes innovative contributions in improving release, enhancing efficacy, and optimizing the production process, aiming to solve pressing clinical problems and meet the basic requirements of drug safety, efficacy, and quality control. Through extensive and detailed research on the ratio of PLGA to polyphenylene oxide, this invention unexpectedly discovered that specific ratios of PLGA and polyphenylene oxide can effectively address issues related to the release and delayed release of the active pharmaceutical ingredient.

[0033] The beneficial effects of this invention are as follows: 1. The implant is used for local administration, acting directly on the tumor site. It has a high drug concentration, few toxic side effects, and can effectively kill tumor cells. It can be used for advanced unresectable tumors, as well as for postoperative patients. It is placed in the tumor cavity throughout the body to effectively remove residual tumor cells and reduce the risk of postoperative recurrence.

[0034] 2. Puncture and implantation into the tumor can form a high concentration locally for a long duration, greatly reducing the toxic side effects of systemic administration and reducing the risk of drug resistance.

[0035] 3. The mixing, hot-melt extrusion, and automated cutting processes enable continuous production, aligning with the development direction of modern pharmaceutical industry technology. The entire production process is highly automated, controllable, and of controllable quality, with low costs, enabling mass production with minimal batch-to-batch variations. The entire production process does not use any organic solvents, making it energy-efficient and environmentally friendly, and eliminating the risks and potential toxicity associated with organic solvent residues from conventional formulation processes.

[0036] 4. The sustained-release carrier uses a combination of PLGA and polystyrene, which not only solves the delayed release behavior in the early stage of implant release, allowing the effective active ingredients of the drug to be released effectively in the early stage, but also effectively alleviates the burst release problem, ultimately improving the overall release behavior and enhancing the efficacy.

[0037] 5. Unlike conventional chemotherapy, which requires specific attention to the order of use of paclitaxel and cisplatin, as well as desensitization treatment and infusion care, this invention combines paclitaxel and cisplatin for enhanced efficacy without adding toxicity.

[0038] The route of administration of the anticancer implant of the present invention depends on various factors. In order to obtain an effective concentration at the site of the primary or metastatic tumor, the drug can be administered via various routes, such as subcutaneous, intracavitary (e.g., abdominal cavity, thoracic cavity, and spinal canal), intratumoral, and peritumoral placement, with intracavitary, intratumoral, and peritumoral placement being preferred. It can be placed intratumorally or peritumorally during or before and after surgery; it can be used simultaneously with or separately from radiation and systemic chemotherapy, but sustained-release implants are preferably placed intratumorally or peritumorally, with direct placement within the tumor being optimal.

[0039] The administration method of this invention can be a single dose or multiple doses every week to every two to three months depending on the drug release cycle. It can be administered simultaneously with two implants containing a single component (such as a single cisplatin implant or a single paclitaxel implant), or multiple times according to the drug release cycle. It can also be administered sequentially (e.g., administering the paclitaxel implant one week or one month before administering the cisplatin implant), or with a two-component implant, or multiple times according to the drug release cycle. Furthermore, it can be administered single or two-component implants together or sequentially (e.g., administering the paclitaxel implant one week or one month before administering the paclitaxel + cisplatin two-component implant), or multiple times.

[0040] The sustained-release implant prepared by this invention may also contain other pharmaceutical ingredients, such as, but not limited to, antibiotics, analgesics, anticoagulants, hemostatic agents, etc.

[0041] The following will further explain the concept, specific structure, and technical effects of the present invention in conjunction with the accompanying drawings, so as to fully understand the purpose, features, and effects of the present invention. Attached Figure Description

[0042] To more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0043] Figure 1 This is a comparison of paclitaxel release in different carrier ratios of paclitaxel implants in Experiment 2.

[0044] Figure 2 This is a comparison of paclitaxel release in different carrier ratios of paclitaxel and cisplatin implants in Experiment 3.

[0045] Figure 3 This is a comparison of cisplatin release in different carrier ratios of paclitaxel and cisplatin implants in Experiment 3.

[0046] Figure 4 This is a comparison of paclitaxel release in different carrier ratios of paclitaxel and cisplatin implants in Experiment 4.

[0047] Figure 5 This is a comparison of cisplatin release in Experiment 4, which uses different carrier ratios for paclitaxel and cisplatin implants.

[0048] Figure 6 This is a comparison of paclitaxel release in different carrier ratios of paclitaxel and cisplatin implants in Experiment 5.

[0049] Figure 7 This is a comparison of cisplatin release in Experiment 5, which uses different carrier ratios for paclitaxel and cisplatin implants.

[0050] Figure 8 This is a comparison of paclitaxel release in Experiment 6 with different carrier ratios for paclitaxel and cisplatin implants.

[0051] Figure 9 This is a comparison of cisplatin release in Experiment 6, which uses different carrier ratios for paclitaxel and cisplatin implants.

[0052] Figure 10 This is a comparison of paclitaxel release in Experiment 7 with different carrier ratios for paclitaxel and cisplatin implants.

[0053] Figure 11 This is a comparison of cisplatin release in Experiment 7, which uses different carrier ratios for paclitaxel and cisplatin implants.

[0054] Figure 12 This is a comparison of paclitaxel release in Experiment 8 with different carrier ratios for paclitaxel and cisplatin implants.

[0055] Figure 13 This is a comparison of cisplatin release in Experiment 8, which uses different carrier ratios for paclitaxel and cisplatin implants.

[0056] Figure 14 This is a comparison of paclitaxel release in different carrier ratios of paclitaxel and cisplatin implants in Experiment 9.

[0057] Figure 15 This is a comparison of cisplatin release in Experiment 9, which uses different carrier ratios for paclitaxel and cisplatin implants. Detailed Implementation

[0058] To facilitate understanding by those skilled in the art, some terms appearing in this document are explained and clarified.

[0059] In this document, the singular forms “an,” “a,” and “the” include their plural forms, unless the context otherwise requires.

[0060] In this document, unless otherwise stated, the terms “comprising,” “including,” “having,” or “containing” mean that the listed technical features are included, but do not exclude the inclusion of other technical features.

[0061] In this article, ordinal numbers such as "first" and "second" added before a component are used to distinguish these components, not to sort them according to the order of the ordinal numbers.

[0062] Examples 1-15: Single-component paclitaxel implants (1) Prescription (see Table 1) Table 1. Paclitaxel Implant Prescription Examples 5, 6, 7, and 8 were used in animal experiments to detect the inhibitory effects of different concentrations of single-component paclitaxel implants on liver cancer and non-small cell lung cancer cells. Examples 1-4 were used to study the effects of different ratios of PLGA (50 / 50 25K) and polystyrene (20 / 80 30K) on the release behavior of paclitaxel implants. Example 6 was used in animal experiments to detect the inhibitory effects of sustained-release formulations with different combinations of active pharmaceutical ingredients and carriers on liver cancer and lung cancer cells.

[0063] (2) Preparation and detection 1. Select a suitable sieve and pulverize paclitaxel and the sustained-release carrier lactide-glycolic acid copolymer (PLGA) at low temperature to obtain paclitaxel (particle size D90 of 65μm), polystyrene (particle size D90 of 105μm), and PLGA (particle size D90 of 95μm) micro powders. 2. Mix the raw material and carrier powders from step 1 in a mixer according to the prescription ratio to obtain a mixed powder; 3. Add the mixed powder obtained in step 2 to the feeder of the hot melt extruder, start the twin-screw hot melt extruder, and extrude it at an extrusion temperature of 50~80℃, a torque of 4~8N·m, and a 1mm die to obtain a cylindrical extruded rod with a diameter of 1mm. 4. After cooling the extrusion rod obtained in step 3, automatically cut it to a length of 10 mm, bottle it, and then sterilize it by irradiation to obtain the paclitaxel sustained-release implant.

[0064] 5. Send the paclitaxel sustained-release implant obtained in step 4 for testing to detect relevant substances and their content. If it passes the test, it can be released for release, animal experiments, etc.

[0065] Examples 16-30: Single-component cisplatin implants Prescription (see Table 2) Table 2. Cisplatin Implant Prescription Examples 20, 22, and 23 were used to test the inhibitory effects of single-component cisplatin implants with different concentrations on liver cancer and non-small cell lung cancer cells in animals. Example 21 was used to test the inhibitory effects of sustained-release implants with different combinations of active pharmaceutical ingredients and carriers on liver cancer cells in animals.

[0066] (2) Preparation and detection 1. Select a suitable sieve and pulverize cisplatin and the slow-release carrier lactide-glycolic acid copolymer (PLGA50 / 50) at low temperature to obtain cisplatin (particle size D90 of 60μm), polystyrene (particle size D90 of 105μm), and PLGA (particle size D90 of 95μm) micro powders. 2. Mix the raw material and carrier powders from step 1 in a mixer according to the prescription ratio to obtain a mixed powder; 3. Add the mixed powder obtained in step 2 to the feeder of the hot melt extruder, start the twin-screw hot melt extruder, and extrude it at an extrusion temperature of 50~80℃, a torque of 4~8N·m, and a 1mm die to obtain a cylindrical extruded rod with a diameter of 1mm. 4. After cooling the extrusion rod obtained in step 3, automatically cut it to a length of 10 mm, bottle it, and then sterilize it by irradiation to obtain cisplatin sustained-release implant. 5. Send the cisplatin sustained-release implant obtained in step 4 for testing to detect relevant substances and their content. If it passes the test, it can be released for release, animal experiments, etc.

[0067] Examples 31-51: Paclitaxel + Cisplatin Implants (100% PLGA) 1) Prescription (see Table 3) Table 3. Prescriptions for Paclitaxel + Cisplatin Implants Among them, Example 48 was used to study the effect of different ratios of PLGA (50 / 50 10K) and polyphenylene (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants; Example 47 was used to study the effect of different ratios of PLGA (50 / 50 25K) and polyphenylene (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants; Example 49 was used to study the effect of different ratios of PLGA (50 / 50 40K) and polyphenylene (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants; Example 31 was used to study the effect of different ratios of PLGA (50 / 50 25K) and polyphenylene (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants under a drug loading of 5%+5%; Example 45 was used to study the effect of different ratios of PLGA (50 / 50 10K) and polyphenylene (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants under a drug loading of 30%+30%. The effects of different ratios of PLGA (75 / 25 10K) and polyphenylene oxide (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants were investigated. Example 50 was used to study the effects of different ratios of PLGA (75 / 25 10K) and polyphenylene oxide (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants (25%+25%). Example 51 was used to study the effects of different ratios of PLGA (75 / 25 25K) and polyphenylene oxide (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants (25%+25%). Example 39 was used in animal experiments to detect the inhibitory effects of sustained-release implants with different combinations of active pharmaceutical ingredients and carriers on liver cancer and non-small cell lung cancer cells. Example 39 was used to detect the effect of different PLGA / polyphenylene oxide ratios on the release of paclitaxel implants.

[0068] (2) Preparation and detection 1. Select a suitable sieve and pulverize paclitaxel, cisplatin, and the sustained-release carrier lactide-glycolic acid copolymer PLGA at low temperature to obtain paclitaxel (particle size D90 of 65μm), cisplatin (particle size D90 of 60μm), and PLGA (particle size D90 of 100μm) micro powders. 2. Mix the two raw materials and the carrier powder from step 1 in a mixer according to the prescription ratio to obtain a mixed powder; 3. Add the mixed powder obtained in step 2 to the feeder of the hot melt extruder, start the twin-screw hot melt extruder, and extrude it at an extrusion temperature of 50~80℃, a torque of 4~8N·m, and a 1mm die to obtain a cylindrical extruded rod with a diameter of 1mm. 4. After cooling the extrusion rod obtained in step 3, automatically cut it to a length of 10 mm, bottle it, and sterilize it by irradiation to obtain paclitaxel + cisplatin sustained-release implant.

[0069] 5. The paclitaxel + cisplatin sustained-release implant obtained in step 4 is sent for testing to detect relevant substances and their contents. If it passes the test, it is released for use in release, animal experiments, etc.

[0070] Examples 52-99: Paclitaxel + Cisplatin Implant (PLGA + Polyphenylene) The processing steps for the sustained-release implant are the same as in Examples 23-39, but the differences lie in the weight percentage of the anticancer active ingredients and the ratio of the sustained-release carrier. The formulation is shown in Table 4.

[0071] Table 4. Prescriptions for Paclitaxel + Cisplatin Implants Examples 58, 59, 60, and 61 were used to study the effect of different ratios of PLGA (50 / 50 10K) and polyphenylene (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants; Examples 52, 53, 55, and 57 were used to study the effect of different ratios of PLGA (50 / 50 25K) and polyphenylene (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants; Examples 62, 63, 64, and 65 were used to study the effect of different ratios of PLGA (50 / 50 40K) and polyphenylene (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants; Examples 79, 80, 81, and 82 were used to study the effect of different ratios of PLGA (50 / 50 25K) and polyphenylene (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants under a drug loading of 5% ± 5%. The effects of different ratios of PLGA (50 / 50 25K) and polyphenylene oxide (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants were investigated. Examples 72, 83, 84, and 85 were used to study the effects of different ratios of PLGA (50 / 50 25K) and polyphenylene oxide (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants under a drug loading of 30%+30%. Examples 86, 87, 88, and 89 were used to study the effects of different ratios of PLGA (75 / 25 10K) and polyphenylene oxide (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants (25%+25%). Examples 51, 90, 91, 92, and 93 were used to study the effects of different ratios of PLGA (75 / 25 25K) and polyphenylene oxide (20 / 80 30K) on the release behavior of paclitaxel + cisplatin implants (25%+25%). Effects of different ratios of 30K on the release behavior of paclitaxel + cisplatin implants (25%+25%); Examples 66-68 were used in animal experiments to detect the inhibitory effect of different contents of paclitaxel + cisplatin sustained-release implants on non-small cell carcinoma cells; Example 69 was used in animal experiments to detect the inhibitory effect of sustained-release formulations with different combinations of active pharmaceutical ingredients and carriers on liver cancer and non-small cell lung cancer cells.

[0072] Experiment 1: Comparison of different preparation processes Table 5. Comparison of different preparation processes CN101380291A uses a solvent method to dissolve PLGA, which presents a difficult problem to solve: residual organic solvents. Drying is time-consuming and risky. To eliminate the organic solvents, repeating the experiment requires over 48 hours of drying, material handling, and testing. This problem is even more difficult to solve in scale-up production. Furthermore, the extended time poses a risk of pollution, and production costs are high, requiring significant time, manpower, and electricity. The hot-melt extrusion continuous preparation process (the preparation method used in this invention is detailed in the "Preparation and Testing" section of the embodiments) effectively solves the solvent residue problem. The entire preparation process is continuous and solvent-free, resulting in lower production costs, greater environmental friendliness, and more controllable quality.

[0073] Experiment 2: Effects of different ratios of PLGA (50 / 50 25K) and polyphenylene on the release behavior of paclitaxel implants (see [link to experiment 2]). Figure 1 ) The sustained-release implants used were derived from Examples 1-4. Figure 1 It can be seen that when PLGA is selected as 50 / 50 (LA to GA molar ratio of 50:50 25K) and polyphenylene sulfide is selected as 20 / 80 (p-carboxyphenylpropane to sebacic acid molar ratio of 20:80 30K), paclitaxel only begins to be released after 15 days when the sustained-release carrier is PLGA alone. Release is minimal in the first 15 days, with significant lag. Adding polyphenylene sulfide to the sustained-release carrier significantly improves this lag. When the proportion of polyphenylene sulfide in the sustained-release carrier reaches 60%, the cumulative release of paclitaxel in the first 5 days exceeds 60%. When the proportion of polyphenylene sulfide in the sustained-release carrier decreases to 40%, the cumulative release of paclitaxel in the first 5 days reaches 43%, still relatively high. For single-component paclitaxel implants, when the ratio of PLGA to polyphenylene sulfide is 4:1, the release of paclitaxel in the first 5 days is approximately 24%, and the overall release is appropriate, with no obvious burst release or lag.

[0074] Experiment 3: Effects of different ratios of PLGA (50 / 50 10K) and polyphenylene on the release behavior of paclitaxel + cisplatin implants (see [link to experiment 3]). Figure 2 , Figure 3 ) The implants used were derived from Examples 48, 58, 59, 60, and 61. Figure 2 and Figure 3We can see that when PLGA is selected at a 50 / 50 ratio (LA to GA molar ratio of 50:50 10K) and polystyrene is selected at a 20 / 80 ratio (p-carboxyphenylpropane to sebacic acid molar ratio of 20:80 30K), adding different proportions of polystyrene can improve the lag time of paclitaxel and cisplatin to some extent, but it cannot effectively solve the problem, and there is still a certain lag time. This may be related to the properties of PLGA itself or other factors. For example, low molecular weight PLGA has a higher proportion of terminal carboxyl groups and slightly stronger hydrophilicity, which may adsorb more water to form a gel layer, thus hindering the diffusion of paclitaxel and cisplatin.

[0075] Experiment 4. Effects of different ratios of PLGA (50 / 50 25K) and polyphenylene on the release behavior of paclitaxel + cisplatin implants (see [link to experiment 4]). Figure 4 , Figure 5 ) The implants used were derived from Examples 47, 52, 53, 55, and 57. Figure 4 and Figure 5 We can see that when PLGA is used in a 50 / 50 ratio (LA to GA molar ratio of 50:50 25K) and polyphenylene oxide is used in a 20 / 80 ratio (p-carboxyphenylpropane to sebacic acid molar ratio of 20:80 30K), different ratios of PLGA and polyphenylene oxide, the two sustained-release carriers, have different effects on the release of cisplatin and paclitaxel in the paclitaxel + cisplatin sustained-release implant. The optimal ratio of PLGA to polyphenylene oxide (4:1) results in the best release of both paclitaxel and cisplatin in the paclitaxel + cisplatin sustained-release implant. While a PLGA to polyphenylene oxide (3:2) ratio effectively controls delayed release, the system shows a higher release rate in the first 5 days, reaching approximately 46%, with nearly half released in the early stages, which is not ideal. Furthermore, the cumulative release of paclitaxel in the single-component paclitaxel implant (100% PLGA) at 15 days is 2.51% (see...). Figure 1 The release curve of paclitaxel + cisplatin extended-release implant (100% PLGA) showed a cumulative release of 3.87% of paclitaxel at 15 days (see...). Figure 2 This indicates that cisplatin in the paclitaxel + cisplatin sustained-release implant (100% PLGA, without polystyrene) can promote and improve the release of paclitaxel to a certain extent.

[0076] Experiment 5. Effects of different ratios of PLGA (50 / 50 40K) and polyphenylene on the release behavior of paclitaxel + cisplatin implants (see [link to experiment]). Figure 6 , Figure 7 ) The implants used were derived from Examples 49, 62, 63, 64, and 65. Figure 6 and Figure 7 , combined Figure 4 and Figure 5It can be seen that different molecular weights have a certain regulatory effect on the release of paclitaxel and cisplatin. For 50:50 PLGA (molar ratio of LA to GA is 50:50), with the molecular weight of polystyrene 20 / 80 (molar ratio of p-carboxyphenylpropane and sebacic acid is 20:80) remaining constant, as the molecular weight of PLGA increases, the release period of both paclitaxel and cisplatin is prolonged to a certain extent, and the lag period also increases.

[0077] Experiment 6: Effects of different ratios of PLGA (50 / 50 25K) and polyphenylene on the release behavior of paclitaxel + cisplatin implants under a drug loading of 5% ± 5% (see Experiment 6). Figure 8 , Figure 9 ) The implants used were derived from Examples 31, 79, 80, 81, and 82. Figure 8 and Figure 9 It can be seen that when PLGA is selected as 50 / 50 (molar ratio of LA to GA is 50:50 25K) and polyphenylene is selected as 20 / 80 (molar ratio of p-carboxyphenylpropane to sebacic acid is 20:80 30K), the release pattern of paclitaxel + cisplatin implants with a drug loading of 5%+5% is roughly similar to that with a drug loading of 25%+25%. When the ratio of PLGA to polyphenylene is 4:1, the release of paclitaxel and cisplatin in the paclitaxel + cisplatin sustained-release implant is also optimal.

[0078] Experiment 7: Effects of different ratios of PLGA (50 / 50 25K) and polyphenylene on the release behavior of paclitaxel + cisplatin implants under a drug loading of 30%+30% (see Experiment 7). Figure 10 , Figure 11 ) The implants used were derived from Examples 45, 72, 83, 84, and 85. Figure 10 and Figure 11 It can be seen that when PLGA is selected as 50 / 50 (the molar ratio of LA to GA is 50:50 25K) and polyphenylene is selected as 20 / 80 (the molar ratio of p-carboxyphenylpropane to sebacic acid is 20:80 30K), the release pattern of paclitaxel + cisplatin implants with a drug loading of 30%+30% is roughly similar to that with a drug loading of 25%+25%. When the ratio of PLGA to polyphenylene is 4:1, the release of paclitaxel and cisplatin in the paclitaxel + cisplatin sustained-release implant is also optimal.

[0079] Experiment 8. Effects of different ratios of PLGA (75 / 25 10K) and polyphenylene on the release behavior of paclitaxel + cisplatin implants (25%+25%) (see [link to experiment 8]). Figure 12 , Figure 13 ) The implants used were derived from Examples 50, 86, 87, 88, and 89. Figure 12and Figure 13 It can be seen that when PLGA is selected as 75 / 25 (molar ratio of LA to GA is 75:25 10K) and polystyrene is selected as 20 / 80 (molar ratio of p-carboxyphenylpropane and sebacic acid is 20:80 30K), the release period of paclitaxel and cisplatin in the paclitaxel + cisplatin implant is compared with that in Experiment 4 ( Figure 4 and Figure 5 The results were similar to those in Experiment 4. When the ratio of PLGA to polystyrene was 4:1, the release of paclitaxel and cisplatin in the paclitaxel + cisplatin sustained-release implant was also optimal.

[0080] Experiment 9. Effects of different ratios of PLGA (75 / 25 25K) and polyphenylene on the release behavior of paclitaxel + cisplatin implants (25%+25%) (see [link to experiment 9]). Figure 14 , Figure 15 ) The implants used were derived from Examples 51, 90, 91, 92, and 93. Figure 14 and Figure 15 It can be seen that when PLGA is selected at a ratio of 75:25 (molar ratio of LA to GA is 75:25 25K), increasing the proportion of polystyrene 20 / 80 (molar ratio of p-carboxyphenylpropane to sebacic acid is 20:80 30K) can improve the lag time of paclitaxel and cisplatin to some extent. The effect is more obvious when the polystyrene content is increased to more than 40%.

[0081] Experiment 10: Inhibitory effect of single-component paclitaxel sustained-release implants with different concentrations on liver cancer. Mice were used as experimental subjects (animals obtained from Beijing Vital River Laboratory Animal Technology Co., Ltd.). Hep G2 cells (purchased from American Type Culture Collection) were cultured in EMEM medium containing 10% fetal bovine serum (FBS) (GIBCO, USA). Cells were placed in a 37°C, humidified incubator with 5% CO2. Logarithmic growth phase Hep G2 cells were collected, resuspended in EMEM basal medium, and added 1:1 to Matrigel to adjust the cell concentration to 4. 10 7 / mL. Under aseptic conditions, 0.15 mL of cell suspension was injected subcutaneously into rats at an inoculation concentration of 4. 10 6 / 0.1mL / mouse, until the tumor grows to 200±50mm 3 Students were divided into a control group and a treatment group. After grouping, one paclitaxel implantation device was injected intratumorally; the day of administration was defined as day 0. Tumor volume was measured starting on day 14 of treatment. The longest diameter (L) and shortest vertical diameter (W) of the tumor were measured every 3-4 days using calipers, and the volume was calculated using the formula: Tumor Volume (mm²)3 )=0.5×L×W 2 Record weight changes (g) and observe and record clinical symptoms of the animals once daily. Assess drug toxicity. At the end of the experiment, euthanize all mice, remove the tumors, and weigh the tumors using an electronic balance. The tumor volume inhibition rate (TGI) is calculated using the formula: (TVC - TVT) / TVC 100%, where TVC is the average tumor volume of the blank solvent control group and TVT is the average tumor volume of the treatment group.

[0082] Note: The drugs given are derived from Examples 6, 7, and 8.

[0083] Table 6. Treatment efficacy of Experiment 10 (tumor growth inhibition rate %) The above results indicate that single-component paclitaxel sustained-release implants have a significant dose-related inhibitory effect on tumor growth, with 60% paclitaxel implants showing the best effect, followed by 30%.

[0084] Experiment 11: Inhibitory effect of single-component cisplatin sustained-release implants with different concentrations on liver cancer. The method for the inhibition of liver cancer by single-component cisplatin was the same as in Experiment 10, except for the different drugs used. The drugs used were derived from Examples 20, 22, and 23, and the therapeutic effects are shown in Table 7.

[0085] Table 7. Treatment efficacy of Experiment 11 (tumor growth inhibition rate %) The above results indicate that single-component cisplatin implants have a significant dose-related inhibitory effect on tumor growth, and the inhibitory effect of 30% cisplatin implants is better than that of 10% cisplatin implants. 60% cisplatin has a significant inhibitory effect in the early stage but greater toxicity in the later stage.

[0086] Experiment 12: Inhibitory effect of single-component paclitaxel sustained-release implants with different concentrations on lung cancer. The inhibitory effect of single-component paclitaxel sustained-release implants with different contents on lung cancer was the same as in Experiment 10, except that the selected lung cancer cells were Lewis cells (purchased from the Shanghai Cell Bank of the Chinese Academy of Sciences), and the drugs used were derived from Examples 5, 7, and 8. The therapeutic effects are shown in Table 8.

[0087] Table 8. Treatment efficacy of Experiment 12 (tumor growth inhibition rate %) The above results indicate that single-component paclitaxel implants have a significant dose-related inhibitory effect on the growth of lung cancer cells, with 60% paclitaxel implants showing the best effect, followed by 30%.

[0088] Experiment 13: Inhibitory effect of single-component cisplatin sustained-release implants with different concentrations on lung cancer. The inhibitory effect of single-component cisplatin sustained-release implants with different contents on lung cancer was consistent with that in Experiment 12, except that the selected drugs were different. The drugs were derived from Examples 20, 22, and 23, and the therapeutic effects are shown in Table 9.

[0089] Table 9. Treatment efficacy of Experiment 13 (tumor growth inhibition rate %) Similar to the results in Table 7, 60% of cisplatin resulted in mouse mortality at day 25, indicating significant toxicity. Single-component cisplatin implants showed a significant dose-related inhibitory effect on tumor growth, with the 30% cisplatin implant demonstrating superior inhibitory efficacy compared to the 10% cisplatin implant.

[0090] Experiment 14: Inhibitory effect of different combinations of implants on liver cancer cells. The experimental procedure for the inhibitory effect of different combinations of implants on liver cancer cells was the same as that in Experiment 10, except that the drugs administered were derived from Examples 6, 21, 39, and 69. The therapeutic effects are shown in Table 10. The method for direct injection of paclitaxel + cisplatin was as follows: paclitaxel injection solution was first injected intraperitoneally at a dose of 20 mg / kg, followed by cisplatin injection solution at a dose of 3 mg / kg after a 1-hour interval.

[0091] The method for preparing paclitaxel injection is as follows: Take 5 mg of paclitaxel powder in a test tube, add 100 μL of DMSO solution, shake thoroughly to dissolve, then add 800 μL of PEG300, shake to dissolve, then add 100 μL of Tween 80, dissolve, add 1 mL of double-distilled water, shake to mix, and prepare immediately before use. The animal dosage of paclitaxel injection is 8 mL / kg. The method for preparing cisplatin injection is as follows: Take 5 mg of cisplatin powder in a test tube, add 10 mL of physiological saline, shake thoroughly at 60℃ to dissolve, and prepare immediately before use. The animal dosage of cisplatin injection is 6 mL / kg. As shown in Table 10, the paclitaxel + cisplatin sustained-release implant is significantly more effective than the single-component implant. The addition of polyphenylene oxide to the sustained-release carrier further enhances tumor growth inhibition. This is mainly because the addition of polyphenylene oxide effectively solves the problem of delayed release in the implant, allowing for sufficient and sustained drug release when the tumor is still small in its early stages. This effectively and continuously kills tumor cells in the early stages of treatment, improving the therapeutic effect. Direct injection of chemotherapy drugs (paclitaxel + cisplatin injection) showed the worst effect, and the mice died within about half a month due to toxic side effects. Therefore, the experimental data shows that the two-component implant of paclitaxel + cisplatin has significant advantages in both efficacy and safety compared to traditional chemotherapy combination therapy. Furthermore, the two-component implant of paclitaxel and cisplatin complements each other, synergistically enhancing efficacy without significantly increasing toxicity. In addition, the addition of polyphenylene oxide to the sustained-release carrier further improves release and enhances the efficacy of the paclitaxel + cisplatin implant.

[0092] Experiment 15: Inhibitory effect of different concentrations of paclitaxel + cisplatin sustained-release implants on non-small cell lung cancer. The inhibitory effect of different concentrations of paclitaxel + cisplatin sustained-release implants on non-small cell lung cancer was consistent with that in Experiment 12, except that the drugs used were derived from Examples 66-68. The therapeutic effects are shown in Table 11. As shown in Table 11, the paclitaxel + cisplatin extended-release implant has a significant dose-response relationship in the inhibition of non-small cell lung cancer. The higher the content, the more obvious the tumor growth inhibition effect. The 30% paclitaxel + 30% cisplatin extended-release implant (PLGA + polystyrene) has the best effect.

[0093] This document uses specific examples to illustrate the principles and implementation methods of the present invention. The descriptions of the above embodiments are only for the purpose of helping to understand the method and core ideas of the present invention. At the same time, for those skilled in the art, based on the ideas of the present invention, there will be changes in the specific implementation methods and application scope. Modifications and improvements to the present invention are possible without exceeding the concept and scope defined by the claims. Therefore, the content of the embodiments in this specification should not be construed as a limitation of the present invention.

Claims

1. An anticancer sustained-release implant containing paclitaxel, characterized by comprising: The active ingredient is paclitaxel or a combination of paclitaxel and cisplatin, and the carrier is PLGA or a mixture of PLGA and polyparaphenylene.

2. The paclitaxel-containing anticancer slow-release implant of claim 1, wherein the paclitaxel is present in an amount of about 0.1 to about 10 mg. The molar ratio of lactide and glycolide in PLGA is 50:50~75:25, and the number average molecular weight is 10K~40K Dalton; the molar ratio of p-carboxyphenyl propane and sebacic acid in polyparaphenylene is 20:80~50:50, and the number average molecular weight is 10K~40K Dalton.

3. The paclitaxel-containing sustained-release anticancer implant of claim 1, wherein the paclitaxel is present in an amount of about 0.1 to about 10 mg. The carrier is a mixture of PLGA and polyparaphenylene, and the mass ratio of the two is 40:60~90:

10.

4. The paclitaxel-containing anticancer slow-release implant of claim 3, wherein the paclitaxel is present in an amount of about 0.1 to about 1.0 mg. The mass ratio of PLGA and polyparaphenylene in the carrier is 60:40~80:

20. The number average molecular weight of PLGA is greater than 10K Dalton and less than 40K Dalton, and the molar ratio of lactide and glycolide is 50:50; or the number average molecular weight of PLGA is 10K Dalton, and the molar ratio of lactide and glycolide is 75:25; The number average molecular weight of polyparaphenylene is 30K Dalton, and the molar ratio of p-carboxyphenyl propane and sebacic acid is 20:

80.

5. The paclitaxel-containing, sustained-release, anticancer implant of claim 1 wherein the paclitaxel is present in an amount of about 0.1 to about 1.0 mg. The active ingredient is paclitaxel, and the drug loading amount is 1~60%.

6. The paclitaxel-containing, sustained-release, anticancer implant of claim 1 wherein the paclitaxel is present in an amount of about 0.1 to about 1.0 mg. The active ingredient is paclitaxel and cisplatin, and the drug loading amount of each is 5%~60% and 1%~50% by mass, respectively.

7. The paclitaxel-containing sustained-release anticancer implant of any one of claims 1 to 6, wherein the paclitaxel is present in an amount of about 0.1 to about 10 mg. Prepared by a hot melt extrusion process, the hot melt extrusion process comprising: Step 1, uniformly mix the active ingredient with a particle size D90 of 10 microns to 250 microns and the carrier to obtain a mixed powder; Step 2, add the mixed powder to a hot melt extruder, and extrude at a heating temperature of 90~120℃ and an extrusion temperature of 50~80℃ to obtain an extrudate; Step 3, cut and package the extrudate, and irradiation sterilization to obtain the paclitaxel-containing anticancer sustained-release implant.

8. The method for preparing the anticancer sustained-release implant containing paclitaxel as described in any one of claims 1 to 6, characterized in that, Comprising the following steps: Step 1, uniformly mix the active ingredient with a particle size D90 of 10 microns to 150 microns and the carrier to obtain a mixed powder; Step 2, add the mixed powder to a hot melt extruder, and extrude at a heating temperature of 90~120℃ and an extrusion temperature of 50~80℃ to obtain an extrudate; Step 3, cut and package the extrudate, and irradiation sterilization to obtain the paclitaxel-containing anticancer sustained-release implant.

9. Use of the paclitaxel-containing anticancer sustained-release implant according to any one of claims 1~6 in the preparation of a drug for treating solid tumors in humans and animals.

10. The use according to claim 9, wherein the compound is ###0002### The human and animal solid tumors are selected from intracranial tumors and extracranial solid tumors; the intracranial tumors are selected from glioma and / or metastatic tumors; the metastatic tumors are cancers originating from the lungs, breasts, kidneys or stomachs; the extracranial solid tumors are selected from one or more of liver cancer, non-small cell lung cancer, gallbladder cancer, esophageal cancer, breast cancer, gastric cancer, thyroid cancer, head and neck tumors, pancreatic cancer, colorectal cancer, cervical cancer, ovarian cancer, lymphoma, prostate cancer, kidney cancer, testicular cancer, and penile cancer.

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