Sustained-release implant containing pemetrexed and application

Abstract

The invention discloses a pemetrexed-containing sustained-release implant and application thereof. The sustained-release implant is prepared from the following substances in percentage by weight: 5 to 60 percent of pemetrexed or pemetrexed sodium salt and 40 to 95 percent of sustained-release auxiliary materials. The preparation method has the beneficial effects that the degradable polymer auxiliary material is used as a dispersion matrix, the stability of medicine quality is ensured, the release period is prolonged, the release behavior is improved, no obvious sudden release or delayed release exists in in-vitro release, continuous production can be realized by adopting a solid-solid mixed hot-melt extrusion method, the production efficiency of the implant is remarkably improved, the production cost is reduced, and the preparation method is suitable for industrial production. The industrialization is easy; no solvent participates in the preparation process, no solvent residue exists, and the safety is high; the medicine is dispersed uniformly and released controllably; the preparation is safe and reliable in quality and more beneficial to clinical application.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a pemetrexed sustained-release implant and its application. Background Technology

[0002] Lung cancer is one of the most common malignant tumors. According to cell type, it is divided into non-small cell lung cancer and small cell lung cancer (15%). Non-small cell lung cancer has three subtypes: adenocarcinoma (40%), squamous cell carcinoma (30%), and large cell carcinoma (15%). The treatment and prognosis are different depending on the type. In my country, non-small cell lung cancer accounts for about 85% of all lung cancers. About 75% of patients are diagnosed at the middle or late stage, and have lost the opportunity for surgical intervention. The age-adjusted 5-year survival rate is only 16.1%. With the continuous progress in drug research and treatment, the emergence of anti-angiogenic drugs, molecularly targeted drugs, and immunotherapy drugs has greatly improved the treatment options for patients with non-small cell lung cancer and liver cancer. However, over time, patients may develop resistance to targeted drugs and anti-angiogenic therapies. For these patients, especially those with advanced disease who are not eligible for surgery and do not have effective targets, chemotherapy remains the main treatment method, playing a role in prolonging patients' lives and improving their quality of life. Due to the inherent pharmacological properties of chemotherapy drugs, while killing tumor cells, they also produce corresponding toxic side effects on normal cells. Since the drugs are dose-dependent, reducing the dose of a single chemotherapy session can reduce toxic side effects, but it will also affect the efficacy of chemotherapy. Many antidotes are commonly used to treat the toxic side effects caused by chemotherapy in clinical practice, but these drugs not only affect the efficacy of chemotherapy, but also increase the economic burden of treatment for patients (see the patent "Construction Method of Risk Prediction Model for Adverse Reactions after Pemetrexed Chemotherapy" Patent No. CN202110229968.1). For patients with surgically resectable lung and liver cancer, simple surgical resection cannot eliminate residual scattered tumor cells. Therefore, postoperative recurrence or metastasis caused by surgical stimulation seriously affects the patient's prognosis. Conventional chemotherapy is difficult to form and maintain an effective drug concentration in the tumor for a long time, resulting in poor efficacy. Increasing the dosage will affect postoperative recovery. See Kong Qingzhong et al. "Intratumoral placement of cisplatin plus carmustine for the treatment of rat brain tumors", Journal of Surgical Oncology, Vol. 69, pp. 76-82, 1998 (Kong Qet al., J Surg Oncol. 1998 Oct; 69(2): 76-82). Based on the aforementioned drawbacks of chemotherapy, researchers have attempted to place antitumor drugs locally, achieving certain results. Local administration can not only significantly increase the drug concentration at the tumor site but also significantly reduce systemic toxicity. Numerous in vitro and in vivo experiments have demonstrated therapeutic effects on solid tumors. See Kong Qingzhong et al., "Intratumoral placement of cisplatin combined with systemic administration of carmustine for the treatment of rat brain tumors," *Journal of Surgical Oncology*, Vol. 69, pp. 76-82, 1998 (Kong Q et al., JSurg Oncol. 1998 Oct; 69(2): 76-82), and Kong Qingzhong et al., "Intratumoral placement of cisplatin cures primary brain tumors in rats," *Journal of Surgical Oncology*, Vol. 64, pp. 268-273, 1997 (Kong Q et al., J Surg Oncol. 1997). Oct;64:268-273), extensive work has demonstrated that local administration is significantly superior to systemic administration, see Chinese patents CN104523566A, CN101185625A, CN101176714A, CN101176707A; However, solid tumors are composed of tumor cells and tumor stroma. The blood vessels in the tumor stroma not only provide a scaffold and essential nutrients for tumor cell growth, but also affect the penetration and diffusion of chemotherapy drugs around the tumor and within the tumor tissue. See Netti et al., “The Influence of Extracellular Stroma Condition on Drug Transport in Solid Tumors”, Cancer Research, Vol. 60, pp. 2497-503, 2000. Blood vessels in the tumor stroma are not sensitive to conventional chemotherapy drugs, which often leads to increased resistance of tumor cells to anticancer drugs, thus resulting in treatment failure. In addition, low-dose anticancer drug treatment can not only increase the drug tolerance of cancer cells, but also promote their invasive growth. See Liang et al., “Pulse screening of anticancer drugs increases the drug tolerance and in vitro invasive ability of human lung cancer cells and is accompanied by changes in gene expression”, International Journal of Cancer, Vol. 111, pp. 484-93, 2004. To address the aforementioned issues, this invention formulates anticancer drugs into sustained-release implants for local application. These implants can selectively target patients with advanced, inoperable solid tumors such as lung cancer, and can also be used for postoperative local chemotherapy in surgically removed patients. The released drug not only acts on the primary tumor cells but also effectively targets the cellular environment in which the tumor thrives and metastatic tumors. The preparation method utilizes hot-melt extrusion, eliminating the hazards of organic solvents and facilitating industrial production, thus possessing unique innovative advantages.

[0003] In view of the above, it is necessary to improve existing anticancer drugs and their preparation methods to make them adaptable to the current needs of anticancer drug use. Summary of the Invention

[0004] To address the aforementioned technical problems, the present invention provides a pemetrexed sustained-release implant, wherein the sustained-release implant comprises the following substances in weight percentage: 5-60% pemetrexed or pemetrexed sodium salt, and 40-95% sustained-release excipients.

[0005] Further supplements to this technical solution include one or a combination of polylactic acid (PLA), lactide-glycolic acid copolymer (PLGA), ethylene-vinyl acetate copolymer (EVAc), polystyrene, succinic acid and FAD copolymer, xylitol, oligosaccharides, chondroitin, chitosan, hyaluronic acid, collagen, gelatin and albumin.

[0006] The peak molecular weight of polylactic acid (PLA) in the aforementioned sustained-release excipients can be, but is not limited to, 5K. 100K Da, with 20K 60K Da is preferred, with 30K Da being the best option. 50 kDa is the optimal value; the molecular weight of polyglycolic acid (PGA) can be, but is not limited to, 5 kDa. 100K Da, with 20K 60K Da is preferred, with 30K Da being the best option. 50 kDa is the optimal choice; the molecular weight of lactide-glycolic acid copolymer (PLGA) can be, but is not limited to, 50 kDa. 100K Da, but with 20K 60K Da is preferred, with 30K Da being the best option. 50 kDa is the most preferred; the blending weight ratio of glycolic acid and glycolic acid is 10 / 90-90 / 10; in polystyrene (poly(1,3-bis(p-carboxyphenoxy)propane-sepiacetic acid), the weight ratio of p-carboxyphenylpropane (p-CPP) to sebacic acid (SA) is 10 / 90-90 / 10, preferably 20 / 80-75 / 25; in the copolymer of sebacic acid and FAD, the weight ratio of sebacic acid (SA) to FAD is 20 / 80-80 / 20, preferably 30 / 70-70 / 30.

[0007] The pharmaceutical excipients used in sustained-release implants can be any one or more of the substances mentioned above, but biocompatible and biodegradable polymers are preferred. Among various polymers, polylactic acid (PLA), sebacic acid (SGA), and mixtures or copolymers of polymers containing PLA or SGA are preferred. These mixtures and copolymers can be selected from, but are not limited to, PLA, PLGA, mixtures of PLA and PLGA, and mixtures or copolymers of SGA with aromatic or aliphatic polymers. The blending ratio of PLA to polyglycolic acid is 10 / 90-90 / 10 (by weight), preferably 25 / 75-75 / 25 (by weight). The blending method is arbitrary. The content of glycolic acid and lactic acid in copolymerization is 10-90% and 90-10% by weight, respectively. A representative aromatic polyphenol is p-CPP (p-CPP). When p-CPP is copolymerized with sebacic acid, the contents are 10-60% and 20-90% by weight, respectively, and the blending weight ratio is 10-40:50-90, preferably 15-30:65-85 by weight.

[0008] As a further supplement to this technical solution, the preferred pemetrexed sodium salt is pemetrexed disodium.

[0009] As a further supplement to this technical solution, the molar ratio of lactide to glycolide in the lactide-glycol copolymer is 25:75 to 75:25.

[0010] As a further supplement to this technical solution, the molecular weight range of the lactide-glycolic acid copolymer in the slow-release excipient is 10K-30KDa, 30K-60KDa, 60K-100KDa, or 100K-150KDa.

[0011] As a further supplement to this technical solution, the ratio of carboxyphenoxypropane to sebacic acid in the polystyrene is any one of 10:90, 20:80, 30:70, 40:60, 50:50, 60:40, and 80:20.

[0012] As a further supplement to this technical solution, the sustained-release implant is manufactured using a hot-melt extrusion process.

[0013] The optimal dosage form of the anticancer sustained-release implant of this invention is a biocompatible, biodegradable, and absorbable sustained-release implant, which can be formulated into various shapes and dosage forms to meet different clinical needs. The packaging methods and steps for its main components are described in detail in US Patent 5651986, including several methods for preparing sustained-release formulations, such as, but not limited to: (i) The carrier support powder is mixed with the drug and then pressed into an implant, which is called the mixing method; (ii) The carrier support is melted, mixed with the drug to be packaged, and then the solid is cooled, which is called the melt method; (iii) Dissolve the carrier support in a solvent, dissolve or disperse the drug to be packaged in the polymer solution, then evaporate the solvent and dry it, which is the so-called dissolution method; (iv) Spray drying method; (v) Freeze-drying, etc.

[0014] Among the aforementioned preparation methods, the dissolution method is a commonly used and important preparation technique in the field of sustained-release implants. Although this method is frequently used, its complex preparation process and the risk of residual organic solvents that are difficult to remove pose significant challenges to production. The use of organic solvents (such as dichloromethane and ethyl acetate) may result in local toxicity or inflammation due to residues, requiring strict purification processes. These processes are complex, and the solvent evaporation or freeze-drying steps are time-consuming. The methods described in patents CN101040865A and CN1923173A for removing dichloromethane to achieve a dichloromethane content ≤0.05% require several days and may also affect drug crystallinity or stability (such as protein denaturation), making scale-up production difficult. The freeze-drying method used in patent CN115778909A still takes more than 24 hours to remove organic solvents from the implant. Furthermore, the burst release effect may cause toxic side effects. Insufficient mechanical properties mean that solvent-formed implants may be brittle and prone to breakage during implantation, requiring the addition of plasticizers (such as PEG), which may interfere with drug release.

[0015] In addition, cost and environmental issues have led to many limitations in practical applications. The recycling and treatment of organic solvents increases costs and does not conform to the trend of green chemistry.

[0016] To address the above issues, the innovation of this invention lies in its low-toxicity / solvent-free technology, which balances degradation rates, improves mechanical properties, and reduces burst-release effects. Furthermore, the technological innovation of this invention lies in its design of a sustained-release implant using hot-melt extrusion technology, which effectively avoids many problems associated with solvent-based sustained-release implant preparation. The principle of hot-melt extrusion for preparing sustained-release implants essentially involves using high-temperature melting and strong shearing to achieve homogeneous mixing of the drug and sustained-release polymer at the molecular level, and then rapidly cooling and solidifying this mixture within a solid matrix. Once implanted, the drug is slowly and continuously released from the solid dispersion through diffusion and / or degradation and dissolution of the polymer matrix, thus achieving long-term therapeutic effects. Its core lies in precisely constructing a microstructure that regulates drug release kinetics through material selection and process control. Hot-melt extrusion (HME) technology demonstrates significant advantages in the preparation of sustained-release implants, combining innovations in materials science and formulation processes, and is particularly suitable for scenarios with high demands for precise drug release control and industrial-scale production.

[0017] The core advantage of the hot-melt extrusion (HME) technology of this invention is as follows: 1. No solvent residue, high safety: HME technology does not use organic solvents. It completely melts and mixes drugs and carrier materials at high temperatures, avoiding the toxicity or inflammatory risks caused by solvent residues in traditional dissolution methods. This feature makes it particularly suitable for solvent-sensitive implants (such as ophthalmic or subcutaneous and in vivo implants), ensuring biocompatibility and long-term safety.

[0018] 2. Uniform drug dispersion and controllable release; molecular-level mixing: Under high temperature and shear force, HME uniformly disperses the drug in the carrier in molecular, amorphous, or metastable states, significantly improving the dissolution and bioavailability of poorly soluble drugs; adjustable release curve: By selecting different carrier materials (such as ethyl cellulose, PLGA, etc.) or adjusting process parameters (screw speed, temperature), the drug release rate can be precisely controlled; for example, after ethyl cellulose matrix tablets are prepared by HME, the porosity decreases and the drug release rate is significantly slowed down, which conforms to the Higuchi model.

[0019] 3. High efficiency and continuous process; integrated operation: HME integrates multiple steps such as material mixing, melting, shearing, and molding into a single device, shortening the production cycle. The fastest batch preparation of implants can be completed in less than 1 hour, reducing manual intervention and making it suitable for industrial-scale production; high drug loading and reproducibility: The extrudate content has high uniformity, achieving a drug loading of up to 60%, with small batch-to-batch differences and strong process reproducibility.

[0020] 4. Multifunctional carrier material compatibility; HME supports a variety of functional polymer carriers to meet different release requirements: 5. Application expansion of this technology: By adjusting the shape of the extruder die, tubular, annular, or porous implants can be directly prepared; for example, EC tubular implants protect drugs from mechanical damage in the gastrointestinal tract, achieving zero-level release; Recent research shows that the tetrasodium dihydrogen phosphate ophthalmic implant prepared by HME has significantly improved bioavailability in in vitro experiments and can be released continuously, reducing the frequency of administration; the intermolecular interaction between the drug and polymer materials (such as Eudragit) can mask odor and improve the stability of heat-sensitive drugs. 6. The technology has environmental and economic advantages. Solvent-free use is in line with environmental protection trends and reduces waste disposal costs; continuous production reduces energy consumption; the equipment is highly versatile and suitable for the development of multiple dosage forms (such as implants, microcapsules, tablets, etc.).

[0021] Hot melt extrusion technology has become one of the core technologies for the development of sustained-release implants due to its advantages such as solvent-free, high dispersibility, multifunctional adaptability and high-efficiency production. Specifically, a certain amount of active ingredients (such as pemetrexed, pemetrexed disodium and lactide-glycolic acid copolymer) are mixed in a mixer at a suitable speed and then fed into the hot melt extruder at a feeding speed.

[0022] The present invention has found that as the molecular weight of the polymer increases, the selected heating and mixing temperature should also increase.

[0023] To ensure the smooth feeding and premixing of the active pharmaceutical ingredient and excipients, the preheating parameters are controlled at 70-90℃, preferably 75-85℃.

[0024] To ensure that the mixture transitions from powder to molten liquid without altering its properties, the temperature of the heating zone is selected to be 100-120℃, preferably 105-120℃.

[0025] To ensure that the materials are thoroughly mixed again in the molten liquid state, the temperature of the heating mixing zone is selected to be 100-160℃, preferably 110-130℃.

[0026] To ensure smooth extrusion and effective molding of the extrudate, the temperature of the cooling molding zone at the outlet should be selected between 70-90℃, with 70-80℃ being the optimal range. The extrusion speed varies depending on the shape and specifications of the implant, and can be set to 10-30 rpm, preferably 15-25 rpm. After molding, the material is dispensed and packaged by an automatic cutter, and finally sterilized.

[0027] The above process can also be carried out under aseptic conditions, and the product is manufactured in accordance with the requirements of online control; the resulting product meets the specifications and content required for clinical use.

[0028] The active pharmaceutical ingredient in the anticancer active ingredient is preferably one or a combination of pemetrexed (Alimta) and pemetrexed disodium; the weight percentage of the active ingredient in the sustained-release implant is 1%-60%, preferably 20% to 60%, and most preferably 20% to 40%.

[0029] The effective ingredient weight percentage of the implant of this invention is selected as representative of the following components and ranges: 1. 5-50% pemetrexed and 50-95% lactide-glycolic acid copolymer, preferably 20-40% pemetrexed and 60-80% lactide-glycolic acid copolymer, most preferably 25-35% pemetrexed and 65-75% lactide-glycolic acid copolymer.

[0030] 2. 5-50% pemetrexed, 40-75% lactide-glycolic acid copolymer and 10-45% polystyrene, preferably 20-40% pemetrexed, 60-80% lactide-glycolic acid copolymer and 15-35% polystyrene, most preferably 20-40% pemetrexed, 65-75% lactide-glycolic acid copolymer and 15-30% polystyrene.

[0031] As a further supplement to this technical solution, the sustained-release implant is in the form of tablets or rods.

[0032] Further supplementing this technical solution, the main components of the present invention can be made into various shapes, preferably rods or tablets. The rods have a diameter of 0.5-5.0 mm, preferably 1.0-3.0 mm, and most preferably 1.0-2.0 mm; and a length of 0.2-25 mm, preferably 5.0-10.0 mm. The tablets have a diameter of 0.2-30.0 mm, preferably 5.0-20.0 mm; and a thickness of 0.1-5.0 mm.

[0033] The route of administration of the sustained-release agent for treating cancer (or tumors) in this invention depends on a variety of factors, primarily the dosage form. To achieve an effective concentration at the site of the primary or metastatic tumor, it can be administered via various routes, such as subcutaneous, intracavitary (e.g., abdominal cavity, thoracic cavity, and spinal canal), intratumoral (including intratumoral / tumoral in some patients with mid-to-late stage unresectable tumors), peritumoral, selective arterial injection, intratumoral administration after tumor resection, intralymphatic, and intramedullary routes. Anticancer sustained-release implants can be placed via puncture or surgery, but can also be embedded, coated, or infused during surgery. Selective arterial, intracavitary, intratumoral, and peritumoral injection or placement are preferred.

[0034] The dosing cycle of the sustained-release agent of this invention depends on a variety of factors, primarily the release characteristics of the sustained-release implant used, the tumor growth rate, and patient adaptability. It can be administered as a single dose or multiple times per week / week / month depending on the drug release cycle.

[0035] This invention can be used to prepare drugs for treating various tumors (or cancers) in humans and animals, mainly as sustained-release implants or implants. The tumors referred to include primary or metastatic carcinomas or sarcomas or carcinosarcomas originating from the brain, central nervous system, kidneys, liver, gallbladder, head and neck, oral cavity, ears, nose and throat, eyes, thyroid gland, skin, mucous membranes, glands, blood vessels, bone tissue, lymph nodes, lungs, esophagus, stomach, breast, pancreas, uterus, ovary, endometrium, cervix, prostate, bladder, colon, and rectum.

[0036] Furthermore, cancers include liver cancer, non-small cell lung cancer, malignant pleural mesothelioma, ovarian cancer, brain tumors, esophageal cancer, stomach cancer, pancreatic cancer, colorectal cancer, kidney cancer, and thyroid tumors.

[0037] Other pharmaceutical ingredients may also be added to this invention, such as, but not limited to, antibiotics, analgesics, anticoagulants, hemostatic agents, etc.

[0038] A method for preparing a pemetrexed sustained-release implant involves placing 5-60% pemetrexed or pemetrexed sodium salt and 40-95% sustained-release excipients into a mixer and mixing for 20-40 minutes at 20-30 rpm. The mixture is then automatically fed into a 12mm hot melt extruder at a feeding speed of 5%. The extruder parameters are set as follows: preheating zone temperature 70-90℃, heating zone temperature 100-120℃, heating and mixing zone temperature 100-160℃, cooling and forming zone temperature 70-90℃, and extrusion speed 10-30 rpm. The extruder is then shaped using an automatic cutter, and subsequently packaged and sterilized.

[0039] Its beneficial effects are as follows: using biodegradable polymer excipients as the dispersion matrix ensures the stability of drug quality, prolongs the release cycle, improves release behavior, and eliminates obvious burst release and delayed release in vitro. The solid-solid mixing and hot-melt extrusion method enables continuous production, significantly improving the production efficiency of implants, reducing production costs, and facilitating industrialization. The preparation process is solvent-free, with no solvent residue, ensuring high safety. The drug is uniformly dispersed and its release is controllable. The formulation quality is safe and reliable, making it more conducive to clinical application. Attached Figure Description

[0040] Figure 1 This invention demonstrates the inhibitory effect of 15% pemetrexed implant on lung cancer in mice. Figure 2 This invention demonstrates the inhibitory effect of 15% pemetrexed implant on pancreatic cancer in mice. Figure 3 This study observes the efficacy of the 15% pemetrexed implant in the treatment of ovarian cancer. Figure 4 This invention relates to the inhibitory effect of the pemetrexed sustained-release implant on liver cancer. Figure 5 This invention demonstrates the dose-dependent inhibitory effect of the implant on lung cancer in mice. Detailed Implementation

[0041] To facilitate a clearer understanding of this technical solution for those skilled in the art, the following will be described in conjunction with the appendix. Figure 1-5 The technical solution of the present invention is described in detail below: Example 1: Preparation process of pemetrexed disodium sustained-release implant Take 15.0g of pemetrexed disodium powder and 85g of lactide-glycolic acid copolymer (molecular weight 23 kDa, molar ratio 50:50), put them into a mixer and mix for 30 minutes at 25 rpm. Then, automatically feed the mixture into a 12mm hot melt extruder at a feed rate of 5%. Set the extruder parameters to: preheating zone 80℃, heating zone 110℃, heating and mixing zone 115℃, cooling and forming zone 80℃, and extrusion speed 20 rpm. The mixture is then shaped using an automatic cutter, packaged, and finally sterilized. This produces 15% pemetrexed sustained-release implant sticks with dimensions of 1.5mm × 5.0mm.

[0042] Example 2: Preparation of pemetrexed sustained-release implant rods with different drug loading capacities Following the process described in Example 1, 10% pemetrexed and 90% lactide-glycolic acid copolymer, 20% pemetrexed and 80% lactide-glycolic acid copolymer, 30% pemetrexed and 70% lactide-glycolic acid copolymer, 40% pemetrexed and 60% lactide-glycolic acid copolymer, 50% pemetrexed and 50% lactide-glycolic acid copolymer, and 60% pemetrexed and 40% lactide-glycolic acid copolymer were prepared. The lactide-glycolic acid copolymer had a molecular weight of 20 kDa and a molar ratio of 75:25. The resulting pemetrexed implants had drug loadings of 10%, 20%, 30%, 40%, 50%, and 60%, and were 1.5 mm × 10.0 mm rods.

[0043] Example 3: Preparation of implant rods containing different drug loading capacities and sustained-release excipients The following sustained-release implants were prepared according to the process described in Example 1: 10% pemetrexed and 60% lactide-glycolic acid copolymer and 30% polyphenylene oxide; 20% pemetrexed and 40% lactide-glycolic acid copolymer and 40% polyphenylene oxide; and 40% pemetrexed and 40% lactide-glycolic acid copolymer and 20% polyphenylene oxide. The lactide-glycolic acid copolymer had a molecular weight of 20 kDa and a molar ratio of 50:50, and the polyphenylene oxide had a molecular weight of 20 kDa and a molar ratio of 80:20. This yielded pemetrexed implants with drug loadings of 10%, 20%, and 40%, and the implants were 1.5 mm × 10.0 mm rods.

[0044] Example 4: Preparation of Pemetrexed Sustained-Release Implant Tablets The following sustained-release implants were prepared according to the process described in Example 1: 20% pemetrexed and 80% lactide-glycolic acid copolymer, and 40% pemetrexed and 60% lactide-glycolic acid copolymer. The lactide-glycolic acid copolymer had a molecular weight of 29 kDa and a molar ratio of 50:50. This yielded implants with a drug loading of 20% pemetrexed and 40% pemetrexed, both formulated as implants with a diameter of 15.0 mm and a thickness of 1.0 mm.

[0045] Example 5: Antitumor effect of pemetrexed sustained-release implant on Lewis lung cancer tumor cells in mice.

[0046] Under aseptic conditions, healthy Lewis lung cancer-bearing mice were harvested. Tumor fragments were ground in a sterile glass mortar at a ratio of 1g tumor to 4mL of sterile saline. Tumor fluid was collected, and the right axilla of each C57BL / 6J mouse was disinfected with alcohol and iodine. 0.2mL of tumor fluid was subcutaneously inoculated into each mouse to establish a Lewis lung cancer xenograft mouse model. The model was established when the tumors grew to an average volume of 150-250mm². 3 Then, a tumor size of 200mm was selected. 3 Mice of approximately 100 mm² (characterized by tumors of the test substance size suitable for intratumoral puncture needle implantation) were grouped according to tumor size. Each group consisted of 5 animals, receiving the following treatments: Group 1 received a blank adjuvant; Group 2 received pemetrexed disodium implant (derived from Example 1). When the tumor volume reached 150-250 mm², a sterile puncture needle was loaded with the appropriate implant and implanted into the tumor. Administration was initiated on day 0. Following administration, the tumor length and width were measured twice weekly using calipers. Tumor volume (mm²) was recorded. 3 = 0.52 * length (mm) * width (mm) * width (mm) Record the animal's weight on the day of grouping. After administration, record the animal's weight change once a week. Record the animal's general condition. Measure the tumor volume, weigh the mouse, and record the data. See Table 1 for specific dosage and administration regimen.

[0047] The experimental indicators were to examine the effect of the drug on tumor growth, specifically the T / C percentage or tumor inhibition rate (TGI%). The tumor diameter is measured using vernier calipers. The tumor volume (V) is calculated using the formula: V = 1 / 2 × a × b 2 ; Where a and b represent length and width, respectively. The formula for calculating the tumor inhibition rate (TGI) (%) is: T / C (%) = (T-T0) / (C-C0) × 100, (TGI) (%) = 100 - T / C (%).

[0048] Where T and C are the tumor volumes at the end of the experiment, and T0 and C0 are the tumor volumes at the beginning of the experiment.

[0049] When tumor regression occurs, the tumor inhibition rate (TGI) (%) is calculated as 100 - (T - T0) / T0 × 100. Partial regression (PR) is defined as the tumor shrinking compared to its initial volume, i.e., T < T0 or C < C0; complete regression (CR) is defined as the tumor disappearing completely. The experiment ends when the endpoint is reached, or when the tumor volume reaches 2 mmHg. 3 CO2 anesthesia euthanasia substance.

[0050] Experimental data were analyzed and plotted using GraphPad Prism 6.0. A two-tailed t-test was used to compare tumor volumes between the two groups. A p-value < 0.05 was defined as statistically significant.

[0051] Table 1. Dosing regimens of the experimental sustained-release implant in Lewis mice. Table 2. Growth inhibition effect of sustained-release implant on Lewis xenografts in mice (%) Table 3. Data on body weight changes in the test mice Experimental results: 28 days after administration, the highest tumor inhibition rate of the pemetrexed disodium sustained-release implant was 70.13%; a significant tumor-inhibiting effect was observed. Figure 1 The weight changes in the experimental mice showed that the implant resulted in a weight loss of 11.65% within 28 days after administration, but this was below the 20% threshold (Table 3).

[0052] Example 6: Antitumor effect of pemetrexed sustained-release implant on pancreatic cancer PANC-1 tumor cells.

[0053] A 15% pemetrexed sustained-release implant was prepared according to the steps and methods described in Example 1. Its tumor-suppressive effect is shown in [the table below]. Figure 4 .

[0054] Table 4: Growth-inhibiting effect of pemetrexed sustained-release implant on pancreatic cancer PANC-1 tumor cells The results showed that 15% pemetrexed disodium sustained-release implant had a good tumor-suppressive effect on PANC-1 pancreatic cancer tumors in mice. Figure 2 ).

[0055] Example 7: Inhibitory effect of implant on ovarian cancer Using the pemetrexed sustained-release implant prepared in Example 1, a pemetrexed sustained-release implant with a size of 1.8 mm × 5 mm and a drug loading of 7.5% was made, achieving a tumor SKOV-3 volume of 200-300 mm. 3 At approximately 32 days, animals were randomly grouped according to tumor volume, and one vial was administered via intratumoral puncture. The day of administration was recorded as Day 0. The experimental period was 32 days. During the experiment, animal body weight and tumor volume were measured twice weekly, and clinical symptoms were observed and recorded daily. The growth inhibition curve of pemetrexed implantation against ovarian cancer is shown in (…). Figure 3 The results showed that pemetrexed sustained-release implant had a significant tumor-suppressive effect on ovarian cancer, with an inhibition rate of 65.77% (P<0.05).

[0056] Example 8: Inhibitory effect of implant on mouse liver cancer Using the pemetrexed sustained-release implant prepared in Example 1, a pemetrexed sustained-release implant with a specification of 1.5mm × 5mm and a drug loading of 15% was made, achieving a tumor volume of 200-300 mm² in the HepG2 tumor. 3 At approximately 32 days, animals were randomly grouped according to tumor volume, and one vial was administered via intratumoral puncture. The day of administration was recorded as Day 0. The experimental period was 32 days. During the experiment, animal body weight and tumor volume were measured twice weekly, and clinical symptoms were observed and recorded daily. The growth inhibition curve of pemetrexed implantation against liver cancer is shown in (…). Figure 4 ); The results showed that the sustained-release implant had a good tumor-suppressive effect. Figure 4 Compared with the control group, the tumor inhibition rate of the pemetrexed extended-release implant was 75.48%. Example 9 (1) Pemetrexed sustained-release implant with a specification of 1.5mm×5mm and a drug loading of 30% was prepared according to the preparation method in Example 1. The molecular weight range of the lactide-glycolic acid (75:25) copolymer was 20 kDa; the content was 29.97% and the content uniformity was RSD=1.2%. Six parallel samples were tested for in vitro release using the shaker method with PBS+SDS as the release medium. The shaker speed was 50 RPM. The sampling times were 7, 14, 21 and 28 days. 5 ml of solution was taken and the same volume of blank release medium at the same temperature was added at the same time. The samples were filtered through 0.45 μm and measured by HPLC. The cumulative release amount was calculated and the results are shown in Table 5. (2) Pemetrexed sustained-release implant with a specification of 1.5mm×5mm and a drug loading of 30% was prepared according to the preparation method in Example 1. The molecular weight range of poly(80:20) copolymer was 20 kDa; the content was 29.93% and the content uniformity was RSD=1.5%. Six parallel samples were tested for in vitro release using a shaker method with PBS+SDS as the release medium at a shaker speed of 50 RPM. Sampling times were 7, 14, 21 and 28 days. 5 ml of solution was taken and the same volume of blank release medium at the same temperature was added. The samples were filtered through 0.45 μm and measured by HPLC. The cumulative release amount was calculated and the results are shown in Table 5. (3) Following the preparation method in Example 1, a pemetrexed sustained-release implant with a specification of 1.5mm × 5mm and a drug loading of 30% was prepared. The excipients included lactide and glycolide (75:25, molecular weight 20KDa) 52.5% and polystyrene (80:20, molecular weight 20KDa) 17.5%, with a content of 29.96% and a content uniformity of RSD = 2.6%. Six parallel samples were tested for in vitro release using a shaker method with PBS+SDS as the release medium at a shaker speed of 50RPM. Sampling times were 7, 14, 21, and 28 days. 5ml of solution was taken, and the same volume of blank release medium at the same temperature was added simultaneously. The samples were filtered through a 0.45um filter and then measured by HPLC. The cumulative drug release was calculated, and the results are shown in Table 5 below. Table 5. Cumulative Release Statistics of Pemetrexed Extended-Release Implants Results: The pemetrexed implant group with PLGA as excipient showed some delayed release in weeks 1 and 2, while the pemetrexed sustained-release implant group with PLGA as excipient showed burst release in weeks 1 and 2. After mixing PLGA and PLGA, the release was stable and controllable, and no burst release or delayed release was observed.

[0057] Example 10: Dose-dependent inhibitory effect of implant on mouse lung cancer Pemetrexed sustained-release implants were prepared according to the preparation method in Example 1. Pemetrexed sustained-release implant rods with dimensions of 1.5mm × 5mm and drug loadings of 7.5%, 15%, and 30% were used, and compared with the saline group, pemetrexed injection, local pemetrexed injection, and a blank polymer group. This was observed in lung cancer tumors with a volume of 200-300 mm². 3At approximately 32 days, animals were randomly grouped according to tumor volume (see Table 6): G1 saline group, G2 pemetrexed intraperitoneal injection group, G3 pemetrexed local injection group, G4 blank polymer group, G5 low-dose pemetrexed implant group, G6 medium-dose pemetrexed implant group, and G7 high-dose pemetrexed implant group. The day of administration was recorded as Day 0, and the experimental period was 32 days. During the experiment, animal body weight and tumor volume were measured twice a week, and clinical symptoms were observed and recorded once daily.

[0058] Table 6. Growth inhibitory effect of pemetrexed sustained-release implant on Lewis lung cancer in mice. The results showed that, compared with the saline group, pemetrexed extended-release implants exhibited significant dose-dependent growth inhibition in lung cancer. The tumor inhibition rate was 49.77% in the 7.5% pemetrexed extended-release implant group, 65.93% in the 15% pemetrexed extended-release implant group, and 83.56% in the 30% pemetrexed extended-release implant group. Figure 5 The tumor inhibition rates of the low, medium and high dose implant groups were all better than those of the local injection group. In addition, although the weight of the animals in the medium and high dose implant groups decreased, it was less than 20%, while the weight of the local injection group and the systemic injection group decreased significantly, by 21% and 28%, respectively.

[0059] Example 11 A 10% pemetrexed sustained-release implant was prepared according to the preparation method in Example 1, wherein the molecular weight of the lactide-glycolic acid (50:50) copolymer was 20 kDa, the content was 9.94%, and the content uniformity was RSD = 1.1%. Example 12 A 10% pemetrexed sustained-release implant was prepared according to the preparation method in Example 1, wherein the lactide-glycolic acid (50:50) copolymer had a molecular weight range of 40 kDa, a content of 9.91%, and a content uniformity of RSD = 1.7%. Example 13 A 10% pemetrexed sustained-release implant was prepared according to the preparation method in Example 1, wherein the lactide-glycolic acid (50:50) copolymer had a molecular weight range of 60 kDa, a content of 9.96%, and a content uniformity of RSD = 2.0%. Example 14 A 10% pemetrexed sustained-release implant was prepared according to the preparation method in Example 1, wherein the molecular weight of the lactide-glycolic acid (75:25) copolymer was 20 kDa, the content was 9.95%, and the content uniformity was RSD = 1.3%. Example 15 A 10% pemetrexed sustained-release implant was prepared according to the preparation method in Example 1, wherein the molecular weight of the lactide-glycolic acid (75:25) copolymer was 40 kDa, the content was 9.95%, and the content uniformity was RSD = 0.8%. Example 16 A 10% pemetrexed sustained-release implant was prepared according to the preparation method in Example 1, wherein the molecular weight of the lactide-glycolic acid (75:25) copolymer was 60 kDa, the content was 10.2%, and the content uniformity was RSD = 1.7%. Example 17 A 10% pemetrexed sustained-release implant was prepared according to the preparation method in Example 1, wherein the molecular weight of the lactide-glycolic acid (25:75) copolymer ranged from 20 kDa, the content was 9.97%, and the content uniformity was RSD = 3.5%. Example 18 A 10% pemetrexed sustained-release implant was prepared according to the preparation method in Example 1, wherein the lactide-glycolic acid (25:75) copolymer had a molecular weight range of 40 kDa, a content of 9.96%, and a content uniformity of RSD = 2.0%. Example 19 A 10% pemetrexed sustained-release implant was prepared according to the preparation method in Example 1, wherein the molecular weight of the lactide-glycolic acid (25:75) copolymer ranged from 60 kDa, the content was 9.94%, and the content uniformity was RSD=1.4%.

[0060] The above technical solutions only embody the preferred technical solutions of the present invention. Any modifications that may be made by those skilled in the art to certain parts thereof embody the principles of the present invention and fall within the protection scope of the present invention.

Claims

1. A pemetrexed sustained-release implant, characterized in that, The sustained-release implant consists of the following substances in weight percentage: 5-60% pemetrexed or pemetrexed sodium salt, and 40-95% sustained-release excipients.

2. The pemetrexed sustained-release implant according to claim 1, characterized in that, The sustained-release excipient is any one or a combination of both of lactide-glycolic acid copolymer and polystyrene.

3. The pemetrexed sustained-release implant according to claim 1, characterized in that, The pemetrexed sodium salt is pemetrexed disodium.

4. A pemetrexed sustained-release implant according to claim 2, characterized in that, The molar ratio of lactide to glycolide in the lactide-glycol copolymer is 25:75 to 75:

25.

5. The pemetrexed sustained-release implant according to claim 4, characterized in that, The molecular weight range of the lactide-glycolic acid copolymer in the sustained-release excipient is 10K-30KDa, 30K-60KDa, 60K-100KDa, or 100K-150KDa.

6. The pemetrexed sustained-release implant according to claim 2, characterized in that, The ratio of carboxyphenoxypropane to sebacic acid in the polystyrene is any one of 10:90, 20:80, 30:70, 40:60, 50:50, 60:40, or 80:

20.

7. A pemetrexed sustained-release implant according to any one of claims 1-6, characterized in that, The sustained-release implant is manufactured using a hot melt extrusion process.

8. The pemetrexed sustained-release implant according to claim 7, characterized in that, The temperatures for hot melt extrusion are: 70-90℃ in the preheating zone, 100-120℃ in the heating zone, 100-160℃ in the heating and mixing zone, and 70-90℃ in the cooling and forming zone.

9. The pemetrexed sustained-release implant according to claim 8, characterized in that, The sustained-release implant is in the form of tablets or sticks.

10. A pemetrexed sustained-release implant according to any one of claims 1-9 for the treatment of cancer in humans and animals.

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