Controlled release drug implant, its preparation method and its application in preparing adjuvant therapy drug for breast cancer post-operation

Abstract

The application belongs to the technical field of medical biomaterials, and relates to a controlled-release drug implant, a preparation method thereof and application of the controlled-release drug implant in preparation of a breast cancer postoperative adjuvant therapy drug. A PDLLA solution is collected on a receiver by electrostatic spraying to obtain a PDLLA barrier layer; a PTMC solution containing a first drug active ingredient is collected on the PDLLA barrier layer by electrostatic spinning to obtain a first PTMC drug-loaded layer; a PTMC solution is collected on the first PTMC drug-loaded layer by electrostatic spinning to obtain a PTMC spacer layer; a PTMC solution containing a second drug active ingredient solvent is collected on the PTMC spacer layer by electrostatic spinning to obtain a second PTMC drug-loaded layer, and the controlled-release drug implant is obtained. The application utilizes the drug barrier property of PDLLA and the surface degradation property of PTMC, accurately controls release of doxorubicin and paclitaxel at different time points, and realizes programmed sequential release of the two drugs.

Description

Technical Field

[0001] This invention belongs to the field of medical biomaterials technology, and relates to a controlled-release drug implant, its preparation method, and its application in the preparation of adjuvant therapy drugs after breast cancer surgery. Background Technology

[0002] Breast cancer remains one of the most common cancers worldwide. Globally, it accounts for approximately 30% of all cancers in women, with a mortality rate of 15% of the incidence rate. Currently, the global incidence rate of breast cancer ranges between 27 per 100,000 (Africa and East Asia) and 97 per 100,000 (North America), reflecting the correlation between breast cancer incidence and economic development, as well as social and lifestyle factors. In contrast, with advancements in diagnostic and treatment technologies, the global breast cancer mortality rate is generally declining. Improving access to high-quality prevention, early diagnosis, and treatment services worldwide can further enhance the overall survival rate of breast cancer patients.

[0003] Surgical resection is the standard clinical strategy for treating early-stage primary breast tumors. Although surgical resection offers a certain chance of cure, the long-term prognosis for breast cancer patients after surgery remains unsatisfactory due to the high rates of recurrence and metastasis associated with breast cancer. Long-term follow-up studies have shown that the risk of recurrence after breast cancer surgery ranges from 10% to 41%, and most recurrences are accompanied by distant metastasis. Theoretically, surgical resection of the tumor tissue can directly remove the tumor, achieving a radical cure. However, for advanced breast tumors, minimal residual disease (MRD) often remains after surgical resection, such as residual tumor cells or small tumor tissues, which is the direct source of tumor recurrence. The inherent invasiveness of breast tumor cells makes MRD highly susceptible to invading surrounding tissues, ultimately leading to tumor cell migration to specific organs or distant metastasis.

[0004] Postoperative adjuvant chemotherapy and radiotherapy are currently the standard treatment for preventing local recurrence and metastasis of breast tumors after surgical resection, and have played a positive role over the years. However, the standard clinical protocols currently implemented are often accompanied by serious complications and side effects. Therefore, how to reduce the adverse reactions of postoperative adjuvant chemotherapy for breast cancer and improve the poor prognosis of patients due to tumor recurrence and metastasis is an urgent problem to be solved.

[0005] To address this issue, developing a delivery system that can locally and massively release chemotherapy drugs at the tumor site after surgery is of great significance. This can not only effectively improve postoperative treatment outcomes, reduce cancer recurrence and metastasis rates, but also avoid physical and psychological harm to patients, improve patient compliance, and ultimately increase the success rate of postoperative treatment and prolong patient survival.

[0006] Postoperative adjuvant chemotherapy is primarily administered via intravenous injection or oral administration. However, the drugs used clinically often lack the ability to target tumor tissue directly. Intravenous injection aims to deliver the drug directly to the tumor tissue through blood circulation, but this method suffers from significant off-target effects and systemic toxicity that can severely damage the patient's physical and mental health. Oral administration, on the other hand, involves the drug being metabolized by organs and enters the systemic circulation; due to the "first-pass effect" of the gastrointestinal tract and liver, drug utilization is low. Many clinical chemotherapy methods not only fail to achieve the desired effects but also easily cause serious harm to patients, resulting in very few patients being able to complete the entire course of treatment, thus significantly reducing the overall efficacy.

[0007] Local drug delivery systems (LDDSs) are a novel class of drug delivery systems that have attracted much attention in recent years. LDDSs can not only release large amounts of drugs locally in lesion tissues but also effectively reduce drug concentrations in off-target organs, thus they have been widely used in contraception, antibacterial, anti-inflammatory, and antitumor fields. Due to the advantages mentioned above, antitumor LDDSs have been used in clinical practice, with successful examples including the carmustine extended-release implant Gliadel tablets, the goserelin acetate extended-release implant Zoladex, the in-situ molded injectable leuprorelin acetate extended-release implant Eligard, and the fluorouracil extended-release implant Zhongren Fluoran. However, currently used antitumor LDDSs typically only provide sustained release of a single drug, and some products also suffer from problems such as non-degradable materials, severe drug burst release, and short dosing times.

[0008] According to the cancer treatment guidelines issued by the Chinese Society of Clinical Oncology (CSCO) and the National Comprehensive Cancer Network (NCCN) of the United States, the development of adjuvant therapy after breast cancer surgery has led to the clinical use of multiple cycles and combination therapies with various drugs to improve overall efficacy. Currently, clinically available products and preclinically developed drug delivery systems (LDDSs) often only achieve slow release of a single drug, with few methods allowing for programmed control, personalization, and combination therapy with different drugs. Therefore, currently developed anti-tumor implants are clearly insufficient to meet clinical needs, especially in the field of adjuvant chemotherapy after breast cancer surgery, which often employs multi-drug combination therapy. Therefore, developing biocompatible, biodegradable, multi-drug programmed delivery, and combination therapy local drug delivery systems for standard clinical therapies can reduce toxic side effects, improve the quality of life for breast cancer patients, and enhance overall treatment outcomes, thus providing a safe and effective treatment option for breast cancer clinical practice. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to provide a controlled-release drug implant that addresses the shortcomings of the prior art.

[0010] Another technical problem to be solved by the present invention is to provide a method for preparing the above-mentioned controlled-release drug implant.

[0011] The final technical problem to be solved by this invention is to provide the application of the above-mentioned controlled-release drug implant in the preparation of adjuvant therapy drugs after breast cancer surgery.

[0012] Invention Concept: This invention uses biodegradable polylactide (PDLLA), polytrimethylene carbonate (PTMC), and antitumor drugs as matrix materials. It employs electrospinning technology to process the implant, followed by vacuum heat treatment for drying and curing, thereby obtaining a biodegradable, multilayered, programmable controlled-release drug implant. The programmable local delivery of multiple drugs controlled-release drug implant prepared using electrospinning / spraying technology has a multilayered structure, using PTMC as the drug-controlled release matrix material and PDLLA as the drug penetration barrier material. PDLLA has a high glass transition temperature, remaining in a glassy state at body temperature. It also has a long degradation period and low permeability to various doxorubicins and paclitaxel. PTMC exhibits unique surface degradation behavior, capable of surface degradation through enzymatic hydrolysis in the human body environment.

[0013] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0014] This invention discloses a method for preparing a controlled-release drug implant, comprising the following steps:

[0015] (1) Polylactide is dissolved in a first solvent to obtain a PDLLA solution; the PDLLA solution is collected onto a receiver by electrostatic spraying to obtain a PDLLA barrier layer;

[0016] (2) Dissolve polytrimethylene carbonate and the first active pharmaceutical ingredient in a second solvent to obtain a PTMC solution containing the first active pharmaceutical ingredient; collect the PTMC solution containing the first active pharmaceutical ingredient onto the PDLLA barrier layer in step (1) by electrospinning to obtain the first PTMC drug-loaded layer.

[0017] (3) Dissolve polytrimethylene carbonate in a third solvent to obtain a PTMC solution; collect the PTMC solution onto the first PTMC drug-loaded layer in step (2) by electrospinning to obtain a PTMC spacer layer;

[0018] (4) Dissolve polytrimethylene carbonate and the second active pharmaceutical ingredient in a fourth solvent to obtain a PTMC solution containing the solvent of the second active pharmaceutical ingredient; collect the PTMC solution containing the solvent of the second active pharmaceutical ingredient onto the PTMC spacer layer in step (3) by electrospinning to obtain the second PTMC drug-loaded layer, which is the controlled-release drug implant.

[0019] In some embodiments, in step (1), the first solvent is a mixture of N,N-dimethylformamide and dimethyl carbonate in any proportion, preferably a mixture of N,N-dimethylformamide and dimethyl carbonate in a volume ratio of 1:9; the mass-volume ratio of polylactide to the first solvent is 0.5g to 1g:10mL, preferably 0.8g to 1g:10mL, and more preferably 1g:10mL.

[0020] In some embodiments, in step (1), the electrostatic spray has a positive high voltage of +4kV, a negative high voltage of -4kV, and a translation distance of 10-15cm; the receiver has a diameter of 0.5-2.0mm, preferably 0.5mm; and the PDLLA barrier layer has a thickness of 50-100μm, preferably 50-80μm, and more preferably 50μm.

[0021] In some embodiments, in step (2), the first active pharmaceutical ingredient is paclitaxel, docetaxel, or methylene blue; the second solvent is hexafluoroisopropanol or trifluoroethanol; the total mass ratio of the polytrimethylene carbonate and the first active pharmaceutical ingredient to the second solvent is 0.05 g to 0.2 g: 10 mL; and the mass ratio of the polytrimethylene carbonate to the first active pharmaceutical ingredient is 1.5 to 19: 1.

[0022] In some embodiments, preferably, in step (2), in the in vitro drug release experiment, the first active pharmaceutical ingredient is methylene blue; the second solvent is hexafluoroisopropanol; the total mass ratio of the polytrimethylene carbonate and the first active pharmaceutical ingredient to the second solvent is 0.1 g: 10 mL; and the mass ratio of the polytrimethylene carbonate to the first active pharmaceutical ingredient is 9:1.

[0023] In some embodiments, preferably, in step (2), during the in vivo drug release experiment, the first active pharmaceutical ingredient is paclitaxel; the second solvent is trifluoroethanol; the total mass ratio of the polytrimethylene carbonate and the first active pharmaceutical ingredient to the second solvent is 0.2 g: 10 mL; and the mass ratio of the polytrimethylene carbonate to the first active pharmaceutical ingredient is 4:1.

[0024] In some embodiments, in step (2), the electrospinning is performed with a positive high voltage of +6kV, a negative high voltage of -2kV, and a translation distance of 5 to 10cm; the first PTMC drug-loaded layer has a thickness of 30 to 120μm.

[0025] In some embodiments, preferably, in step (2), during the in vitro drug release experiment, the first PTMC drug-loaded layer has a thickness of 100 μm.

[0026] In some embodiments, preferably, in step (2), during the in vivo drug release experiment, the first PTMC drug-carrying layer has a thickness of 30 μm.

[0027] In some embodiments, in step (3), the third solvent is any one or a combination of several of the following: trifluoroethanol, hexafluoroisopropanol, a mixture of dichloromethane and N,N-dimethylformamide in a volume ratio of 9:1, and a mixture of chloroform and N,N-dimethylformamide in a volume ratio of 9:1, preferably trifluoroethanol; the mass-volume ratio of polytrimethylene carbonate to the third solvent is 0.05g to 0.2g:10mL, preferably 0.2g:10mL; the electrospinning is performed with a positive high voltage of +6kV, a negative high voltage of -2kV, and a translation distance of 5 to 10cm; the PTMC spacer layer has a thickness of 10 to 150μm.

[0028] In some embodiments, preferably, in step (3), during the in vitro drug release experiment, the PTMC spacer layer has a thickness of 50 to 150 μm, more preferably 50 μm, 100 μm or 150 μm.

[0029] In some embodiments, preferably, in step (3), during the in vivo drug release experiment, the PTMC spacer layer has a thickness of 10-100 μm, more preferably 20-80 μm, and even more preferably 20 μm.

[0030] In some embodiments, in step (4), during the in vitro drug release experiment, the second active pharmaceutical ingredient is doxorubicin hydrochloride or epirubicin, preferably doxorubicin hydrochloride; and the fourth solvent is hexafluoroisopropanol.

[0031] In some embodiments, in step (4), during the in vitro drug release experiment, the total mass ratio of the polytrimethylene carbonate and the second active pharmaceutical ingredient to the fourth solvent is 0.05 g to 0.2 g: 10 mL; the mass ratio of the polytrimethylene carbonate to the second active pharmaceutical ingredient is 1.5 to 19: 1.

[0032] In some embodiments, preferably, in step (4), during the in vitro drug release experiment, the total mass ratio of the polytrimethylene carbonate and the second active pharmaceutical ingredient to the fourth solvent is 0.1 g: 10 mL; the mass ratio of the polytrimethylene carbonate to the second active pharmaceutical ingredient is 9:1.

[0033] In some embodiments, in step (4), during the in vivo drug release experiment, polyethylene glycol is added when preparing a PTMC solution containing a solvent of the second active pharmaceutical ingredient. Polytrimethylene carbonate, polyethylene glycol, and the second active pharmaceutical ingredient are dissolved in a fourth solvent to obtain a PTMC solution containing a solvent of the second active pharmaceutical ingredient.

[0034] In some embodiments, in step (4), during the in vivo drug release experiment, the second active pharmaceutical ingredient is doxorubicin hydrochloride or epirubicin, preferably doxorubicin hydrochloride; and the fourth solvent is hexafluoroisopropanol.

[0035] In some embodiments, in step (4), during the in vivo drug release experiment, the number average molecular weight of the polyethylene glycol is 600 to 20000 Da; the total mass of the polytrimethylene carbonate, polyethylene glycol, and the second active pharmaceutical ingredient is in a mass-to-volume ratio of 0.05 g to 0.2 g: 10 mL to the fourth solvent; and the mass ratio of the polytrimethylene carbonate, polyethylene glycol, and the second active pharmaceutical ingredient is 6 to 8: 1: 1 to 3.

[0036] In some embodiments, preferably, in step (4), during the in vivo drug release experiment, the number average molecular weight of the polyethylene glycol is 4000 Da; the total mass of the polytrimethylene carbonate, polyethylene glycol, and the second active pharmaceutical ingredient is in a mass-to-volume ratio of 0.1 g: 10 mL to the fourth solvent; and the mass ratio of the polytrimethylene carbonate, polyethylene glycol, and the second active pharmaceutical ingredient is 8:1:1.

[0037] In some embodiments, in step (4), the electrospinning is performed with a positive high voltage of +6kV, a negative high voltage of -2kV, and a translation distance of 5 to 10cm; the second PTMC drug-loaded layer has a thickness of 17.5 to 100μm.

[0038] In some embodiments, preferably, in step (4), during the in vitro drug release experiment, the second PTMC drug-loaded layer has a thickness of 100 μm.

[0039] In some embodiments, preferably, in step (4), during the in vivo drug release experiment, the second PTMC drug-carrying layer has a thickness of 17.5–70 μm, more preferably 17.5 μm.

[0040] The controlled-release drug implants prepared by the above-described method are also within the scope of protection of this invention.

[0041] The application of the aforementioned controlled-release drug implant in the preparation of adjuvant therapy drugs after breast cancer surgery is also within the scope of protection of this invention.

[0042] Unless otherwise stated, the following terms as used in this invention have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0043] The term "postoperative treatment" refers to placing an implant directly at the surgical site of the tumor after tumor resection and then suturing; the implant releases the drug locally at the tumor bed, thus achieving a local delivery effect.

[0044] The term "adjuvant therapy after breast cancer surgery" refers to adjuvant therapy following breast cancer surgery. It is usually given after surgery, such as chemotherapy, radiotherapy, targeted therapy, and endocrine therapy, to eliminate any remaining cancer cells in the body.

[0045] The term "programmed control" or "controlled release" refers to the process of artificially setting and regulating the start time of drug release by adjusting the thickness of the PTMC spacer layer in the implant, thus achieving "programmed" release control of the drug.

[0046] The term "programmed multiple drug release" refers to the process of artificially setting and controlling the release duration of the first and second active pharmaceutical ingredients in the implant by adjusting the thickness of the first and second active pharmaceutical ingredient loading layers in the implant, and by adjusting the thickness of the PTMC spacer layer in the implant to artificially set and control the release interval of the first and second active pharmaceutical ingredients, thus achieving the effect of "programmed multiple drug release".

[0047] In the in vitro drug release experiment of the aforementioned controlled-release drug implant, the relationship between the thickness of the PTMC spacer layer and the release time interval of the active drug component in the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is as follows: Figure 1 As shown in (C), when the thickness of the PTMC spacer layer is 0 μm, the release time interval between the active pharmaceutical ingredients in the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is 0.2 days; when the thickness of the PTMC spacer layer is 50 μm, the release time interval between the active pharmaceutical ingredients in the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is 1.3 days; when the thickness of the PTMC spacer layer is 100 μm, the release time interval between the active pharmaceutical ingredients in the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is 2.9 days; and when the thickness of the PTMC spacer layer is 150 μm, the release time interval between the active pharmaceutical ingredients in the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is 3.4 days.

[0048] In the in vivo drug release experiment of the aforementioned controlled-release drug implant, the relationship between the thickness of the PTMC spacer layer and the release time interval of the active drug component in the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is as follows: Figure 3 As shown in (A), when the thickness of the PTMC spacer layer is 20 μm, the release time of the active drug components between the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is 4 days.

[0049] The aforementioned polylactide (PDLLA) can be prepared using other methods in the prior art, or it can be prepared using the following method:

[0050] The polymerization tube was preheated and dried, then quickly transferred to a desiccator and cooled to room temperature. Lactide (DL-LA) was weighed and placed into the polymerization tube, and stannous octoate (SnOct2) was added. The tube was then vacuum-dried at room temperature. After three cycles of evacuation and nitrogen purging, the tube was sealed under vacuum using a high-temperature flame torch. The reaction system was then completely immersed in an oil bath for heating. After the reaction was complete, the polymerization tube was removed, cooled to room temperature, and then crushed using liquid nitrogen. The extracted product was dissolved in dichloromethane, precipitated and purified in ethanol, and dried under vacuum to obtain the PDLLA material.

[0051] The PDLLA material has a number-average molecular weight of 50–500 kDa and a molecular weight distribution of 1.0–2.5.

[0052] The aforementioned polytrimethylene carbonate (PTMC) can be prepared using other methods in the prior art, or it can be prepared using the following method:

[0053] The polymerization tube was preheated and dried, then quickly transferred to a desiccator and cooled to room temperature. Trimethylene carbonate (TMC) was weighed and placed into the polymerization tube, and stannous octoate (SnOct2) was added. The tube was then vacuum-dried at room temperature. After three cycles of evacuation and nitrogen purging, the tube was sealed under vacuum using a high-temperature flame torch. The reaction system was then completely immersed in an oil bath for heating. After the reaction was complete, the polymerization tube was removed, cooled to room temperature, and then the glass polymerization tube was crushed by liquid nitrogen freezing. The extracted product was dissolved in dichloromethane, precipitated and purified in ethanol, and dried under vacuum to obtain the PTMC material.

[0054] The PTMC material has a number-average molecular weight of 200–500 kDa and a molecular weight distribution of 1.0–2.5.

[0055] Beneficial effects:

[0056] (1) This invention prepares a controlled-release drug implant for the programmed local delivery of doxorubicin and paclitaxel for adjuvant therapy after breast cancer surgery using an electrospinning / spraying method. Compared with traditional local drug delivery systems prepared by extrusion molding, compression molding, etc., the implant prepared by this invention has a multilayer structure, and the composition and size of its multilayer structure can be controlled by the electrospinning / spraying condition parameters. Therefore, the method used in this invention has the advantages of customized preparation and precise control of complex multilayer tubular structures.

[0057] (2) This invention utilizes the drug-blocking properties of PDLLA and the surface degradation properties of PTMC to precisely control the release of doxorubicin and paclitaxel at different time points, achieving programmed sequential release of the two drugs. Compared with traditional local drug delivery systems that can only achieve sustained release of a single drug, the implant prepared by this method can achieve programmed controlled release of two drugs, providing a basis for combined drug use.

[0058] (3) The PDLLA and PTMC biodegradable polymer materials used in this invention have good biosafety and biodegradability, and both are FDA-approved materials with rich clinical experience.

[0059] (4) The implant developed using biodegradable polymer materials in this invention is a fully degradable device that can completely degrade in the body without the need for a second surgery to remove it, thus reducing further harm to the patient. Compared with some non-degradable local drug delivery systems, this implant effectively improves patient compliance.

[0060] (5) The implant preparation platform developed in this invention has customization characteristics. It can be customized to design and prepare personalized local drug delivery systems that meet different clinical drug delivery regimens according to clinical drug delivery needs.

[0061] (6) The implantable doxorubicin and paclitaxel delivered locally by the present invention can release large amounts of antitumor drugs at the surgical site of breast tumors, and experiments have shown that the drug concentration at off-target sites is low. Compared with standard clinical systemic dosing regimens, the implantable dosing regimen of the present invention has significant advantages in improving the efficacy against breast cancer recurrence and metastasis and reducing toxic side effects. Attached Figure Description

[0062] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0063] Figure 1 This is a schematic diagram of a programmable multidrug release implant and a diagram showing the drug release performance.

[0064] Figure 2A schematic diagram and scanning electron microscope image of a controlled-release implant for the programmed local delivery of doxorubicin and paclitaxel.

[0065] Figure 3 In vivo drug release and tissue drug distribution maps for controlled-release implants that deliver doxorubicin and paclitaxel locally.

[0066] Figure 4 This is a graph used to assess the efficacy of a programmed doxorubicin hydrochloride-paclitaxel release implant in preventing postoperative tumor recurrence in breast cancer patients, as well as the changes in body weight and survival rate in animals.

[0067] Figure 5 To investigate the efficacy of a programmed controlled doxorubicin hydrochloride-paclitaxel release implant in inhibiting postoperative tumor metastasis in breast cancer patients.

[0068] Figure 6 The image shows the 1H NMR spectrum of the PDLLA material prepared in Example 1.

[0069] Figure 7 The image shows the 1H NMR spectrum of the PTMC material prepared in Example 1. Detailed Implementation

[0070] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0071] Doxorubicin hydrochloride, 99% pure, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0072] Paclitaxel, 98% purity, was purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.

[0073] Polyethylene glycol, number average molecular weight 4000 Da, was purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.

[0074] Methylene blue, 98% purity, purchased from Shanghai Yuanye Biotechnology Co., Ltd.

[0075] The lipase used in the embodiments of the present invention is derived from Aspergillus oryzae. The enzyme activity unit 1U of this lipase is defined as the amount of enzyme that releases 1 μmol of titratable butyrate per minute under given standard conditions.

[0076] Example 1: Preparation of polylactide and polytrimethylene carbonate

[0077] Preparation of polylactide (PDLLA): The polymerization tube was pre-dried at 100℃ for 6 hours, then quickly transferred to a desiccator and cooled to room temperature. 50 g of lactide (DL-LA) was weighed and placed into the polymerization tube, along with 0.05 g of stannous octoate (SnOct2). The tube was then vacuum-dried at room temperature for 1 hour, followed by evacuation and nitrogen purging, repeated three times. The tube was then sealed under vacuum using a high-temperature flame torch, and the reaction system was completely immersed in an oil bath at 130℃ for 12 hours. After the reaction was complete, the polymerization tube was removed, cooled to room temperature, and the glass polymerization tube was broken by liquid nitrogen freezing. The extracted product was dissolved in dichloromethane, precipitated and purified in ethanol, and then dried in a vacuum environment at 40℃ for 48 hours to obtain purified PDLLA material.

[0078] The prepared PDLLA material has a number-average molecular weight of 120 kDa and a molecular weight distribution of 1.89; the 1H NMR spectrum of the PDLLA material is shown below. Figure 6 .

[0079] Preparation of polytrimethylene carbonate (PTMC): The polymerization tube was pre-dried at 100℃ for 6 hours, then quickly transferred to a desiccator and cooled to room temperature. 50 g of trimethylene carbonate (TMC) was weighed and placed into the polymerization tube. 0.025 g of stannous octoate (SnOct2) was added, and the tube was vacuum dried at room temperature for 1 hour. Subsequently, a vacuum was drawn and nitrogen was purged, and the process was repeated three times. The tube was then sealed under vacuum using a high-temperature flame torch. The reaction system was then completely immersed in an oil bath at 130℃ for 12 hours. After the reaction was complete, the polymerization tube was removed, cooled to room temperature, and the glass polymerization tube was broken by freezing with liquid nitrogen. The extracted product was dissolved in dichloromethane, precipitated and purified in ethanol, and then dried in a vacuum environment at 40℃ for 48 hours to obtain purified PTMC material.

[0080] The prepared PTMC material has a number-average molecular weight of 430 kDa and a molecular weight distribution of 1.56; the 1H NMR spectrum of the PTMC material is shown below. Figure 7 .

[0081] Example 2: Preparation and drug release detection of a controlled-release drug implant for programmed local delivery of multiple drugs.

[0082] Preparation of a programmed local delivery multidrug implant: A programmed multidrug release implant was prepared using electrospinning / spraying technology, with doxorubicin hydrochloride (DOX) and methylene blue (MB) as model drugs. Specific experimental conditions were as follows: ambient temperature 40℃, humidity 30%–50% RH; receiver was a stainless steel wire (0.5 mm diameter), receiver rotation speed 60 rpm, receiver distance 5 cm; injection syringe 5 mL, needle 26 G, working solution injection rate 2 mL / h, syringe translation speed 50 cm / min. The PDLLA and PTMC materials prepared in Example 1 were used in this example, and the programmed multidrug release implant was prepared in the following order:

[0083] (1) A PDLLA solution (10% g / mL) was prepared by dissolving 1.00 g of PDLLA in 10 mL of a mixed solvent of N,N-dimethylformamide (DMF) and dimethyl carbonate (DMC) (DMF:DMC = 1:9 v / v). The PDLLA solution was collected onto a receiver by electrostatic spraying under the conditions of a injection volume of 0.18 mL, a positive high voltage of +4 kV, a negative high voltage of -4 kV, and a translation distance of 15 cm, to obtain a PDLLA barrier layer with a thickness of 50 μm.

[0084] (2) Dissolve 0.09 g of PTMC and 0.01 g of methylene blue (MB) in 10 mL of hexafluoroisopropanol to prepare a PTMC(MB) solution (1% g / mL). The PTMC(MB) solution was collected onto the PDLLA barrier layer of step (1) by electrospinning under the conditions of injection volume of 3.10 mL, positive high voltage of +6 kV, negative high voltage of -2 kV, and translation distance of 10 cm to obtain a PTMC(MB) drug-loaded layer with a thickness of 100 μm.

[0085] (3) Dissolve 0.2 g of PTMC in 10 mL of trifluoroethanol to prepare a PTMC solution (2% g / mL). The PTMC solution is collected onto the PTMC (MB) drug-loaded layer in step (2) by electrospinning under the conditions of positive high voltage +6 kV, negative high voltage -2 kV and translation distance of 10 cm to obtain a PTMC spacer layer.

[0086] To obtain PTMC spacer layers of different thicknesses (0 μm, 50 μm, 100 μm, 150 μm), the injection volumes were set to 0 mL, 0.94 mL, 1.99 mL, and 3.16 mL, respectively.

[0087] (4) Dissolve 0.09 g of PTMC and 0.01 g of doxorubicin hydrochloride (DOX) in 10 mL of hexafluoroisopropanol to prepare a PTMC(DOX) solution (1% g / mL). The PTMC(DOX) solution was collected onto the PTMC spacer layer from step (3) by electrospinning under positive high voltage of +6 kV, negative high voltage of -2 kV, and a translation distance of 10 cm, to obtain a PTMC(DOX) drug-loaded layer. For samples with PTMC spacer layers of different thicknesses (0 μm, 50 μm, 100 μm, 150 μm), the injection volumes were set to 3.99 mL, 4.43 mL, 4.88 mL, and 5.32 mL, respectively, to obtain a PTMC(DOX) drug-loaded layer of the same thickness (100 μm).

[0088] The reason why polyethylene glycol (PEG) is not added in step (4) is that the drug implant prepared in this embodiment is mainly used to study the in vitro drug release experiment of the implant, and the in vitro release of doxorubicin hydrochloride can be rapid without the addition of PEG.

[0089] After the reaction was complete, the receiver containing the sample was removed and dried and cured in a vacuum environment at 100°C for 4 hours. After natural cooling, the sample was removed and cut into 1 cm long programmable multidrug release implants. The length of the implants was measured with calipers, and the thickness was measured with a micrometer.

[0090] In vitro drug release assay of the implant: The programmed multidrug release implant was immersed in 20 mL of lipase solution (1000 U / mL) and placed at 37℃ and 100 rpm to evaluate drug release performance. All solutions were removed every 12 hours, and an equal volume of fresh lipase solution was added. The absorbance of the removed solutions at 480 nm and 664 nm was measured using a multi-mode microplate reader. The cumulative release rates of DOX and MB for the programmed multidrug release implant were calculated using DOX and MB standard curves. The relationship between the release interval of the two drugs and the thickness of the PTMC spacer layer was obtained by fitting the cumulative drug release curve. The results are shown below. Figure 1 As shown, Figure 1 (A) is a schematic diagram of the structure of a programmable multidrug release implant.

[0091] like Figure 1As shown in (C), when the thickness of the PTMC spacer layer is 0 μm, the release time interval between the active pharmaceutical ingredients in the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is 0.2 days; when the thickness of the PTMC spacer layer is 50 μm, the release time interval between the active pharmaceutical ingredients in the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is 1.3 days; when the thickness of the PTMC spacer layer is 100 μm, the release time interval between the active pharmaceutical ingredients in the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is 2.9 days; and when the thickness of the PTMC spacer layer is 150 μm, the release time interval between the active pharmaceutical ingredients in the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is 3.4 days.

[0092] Depend on Figure 1 (B) Figure 1 (C) shows that after the first drug (DOX) is released, the design of the PTMC spacer layer effectively delays the initial release point of the second drug (MB), and the drug release interval of the implant shows a good linear relationship with the thickness of the PTMC spacer layer. Therefore, the release time of the two drugs is programmably controllable, indicating that the programmable multidrug release implant can regulate the release interval between different drugs by changing the thickness of the PTMC spacer layer.

[0093] Example 3: Preparation and drug delivery study of implants for programmed local delivery of doxorubicin and paclitaxel

[0094] Preparation of a programmed local delivery implant for doxorubicin and paclitaxel: Doxorubicin and paclitaxel are first-line drugs for adjuvant chemotherapy after breast cancer surgery. In clinical practice, they are mainly administered sequentially because simultaneous administration can affect their metabolic processes, resulting in serious hematologic and cardiotoxic side effects. Therefore, this invention uses electrospinning / spraying technology to prepare a programmed controlled sequential release implant of doxorubicin hydrochloride and paclitaxel. Doxorubicin hydrochloride (DOX) and paclitaxel (PTX) are the drugs, and PTMC is used as the spacer layer. Specific experimental conditions are as follows: ambient temperature 40℃, humidity 30%–50%RH; receiver is stainless steel wire (0.5mm diameter), receiver rotation speed 60rpm, receiver distance 5cm; injection syringe 5mL, needle 26G, working solution injection rate 2mL / h, syringe translation speed 50cm / min. The PDLLA material and PTMC material prepared in Example 1 were used in this example, and the implant was prepared in the following order:

[0095] (1) A PDLLA solution (10% g / mL) was prepared by dissolving 1.00 g of PDLLA in 10 mL of a mixed solvent of N,N-dimethylformamide (DMF) and dimethyl carbonate (DMC) (DMF:DMC = 1:9 v / v). The PDLLA solution was collected onto a receiver by electrostatic spraying under the conditions of a injection volume of 0.18 mL, a positive high voltage of +4 kV, a negative high voltage of -4 kV, and a translation distance of 15 cm, to obtain a PDLLA barrier layer with a thickness of 50 μm.

[0096] (2) Dissolve 0.16 g of PTMC and 0.04 g of paclitaxel (PTX) in 10 mL of trifluoroethanol to prepare a PTMC(PTX) solution (2% g / mL). The PTMC(PTX) solution was collected onto the PDLLA barrier layer of step (1) by electrospinning under the conditions of injection volume of 0.42 mL, positive high voltage of +6 kV, negative high voltage of -2 kV, and translation distance of 10 cm, to obtain a PTMC(PTX) drug-loaded layer with a thickness of 30 μm.

[0097] (3) Dissolve 0.2 g of PTMC in 10 mL of trifluoroethanol to prepare a PTMC solution (2% g / mL). The PTMC solution is collected onto the PTMC (PTX) drug-loaded layer in step (3) by electrospinning under the conditions of injection volume of 0.30 mL, positive high voltage of +6 kV, negative high voltage of -2 kV, and translation distance of 10 cm, to obtain a PTMC spacer layer with a thickness of 20 μm.

[0098] (4) Dissolve 0.08 g of PTMC, 0.01 g of polyethylene glycol (PEG, 4000 Da), and 0.01 g of doxorubicin hydrochloride (DOX) in 10 mL of hexafluoroisopropanol to prepare a PTMC / PEG(DOX) solution (1% g / mL). Collect the PTMC / PEG(DOX) solution onto the PTMC spacer layer from step (3) by electrospinning under the conditions of injection volume of 0.56 mL, positive high voltage of +6 kV, negative high voltage of -2 kV, and translation distance of 10 cm, to obtain a PTMC / PEG(DOX) drug-loaded layer with a thickness of 17.5 μm, which is the DOX-PTX sequential release implant.

[0099] After the reaction was complete, the receiver containing the sample was removed and dried and cured in a vacuum environment at 100°C for 4 hours. After natural cooling, the sample was removed and cut into 1 cm long delayed-release drug-eluting implants. The length of the implants was measured with calipers, and the thickness was measured with a micrometer.

[0100] Drug Delivery Study - In Vivo Drug Release Assay for Implants: Two programmed DOX-PTX release implants (samples × 2, dosages of DOX 5 mg / kg and PTX 15 mg / kg for both implants) were sterilized under UV light for 1 hour and then implanted into the tumor bed of female, 20g 4T1 orthotopic tumor-bearing BALB / c mice using a 16G tissue puncture needle. Samples were collected every 24 hours (in experiments involving multiple mice, one mouse was sacrificed and its sample was collected every 24 hours), dissolved in 0.5 mL of dimethyl sulfoxide, and centrifuged at 3000 rpm for 3 min. 100 μL of the supernatant was collected, and the absorbance at 480 nm was measured using a multi-mode microplate reader. The cumulative DOX release rate was calculated using a DOX standard curve. 200 μL of the supernatant was collected, and 800 μL of acetonitrile was added. The cumulative PTX release rate was detected by high-performance liquid chromatography (HPLC).

[0101] Drug Delivery Study - In Vivo Drug Distribution: 24 hours after drug administration, the heart, liver, spleen, lung, kidney, and tumor tissues of mice were collected. Each tissue sample was homogenized in 1 mL of 20 mM KH₂PO₄ solution (pH = 2.8). 200 μL of the homogenate was added to 2 mL of 1 M NaOH, extracted with 1 mL of chloroform, dried, and dissolved in 1 mL of DMSO. After centrifugation at 3000 rpm for 3 min, the supernatant was collected, and the tissue concentration of DOX (λ) was measured and calculated using a fluorescence spectrophotometer. EX =480nm, λ EM =586nm).

[0102] Take 200 μL of homogenate from different tissue samples, add 20 μL of docetaxel (2 μg / mL) as an internal standard, add 700 μL of methanol to precipitate, vortex for 5 min, centrifuge at 13000 rpm for 10 min, take 500 μL of supernatant, dry with nitrogen, add 200 μL of acetonitrile / water (9 / 1) mixed solvent to reconstitute, vortex for 5 min, centrifuge at 13000 rpm for 5 min, take 120 μL of supernatant, and use liquid chromatography-mass spectrometry (HPLC-MS) to detect the PTX content in the supernatant.

[0103] Intravenous injection of GOX and PTX in mice: Female 20g 4T1 orthotopic tumor-bearing BALB / c mice were injected via the tail vein with 100μL of DOX (5mg / kg) and 250μL of PTX (15mg / kg).

[0104] Depend on Figure 2 (A) Figure 2(B) It can be seen that the implant for programmed local delivery of doxorubicin and paclitaxel has a multi-layered structure, consisting of a PDLLA barrier layer, a PTMC (PTX) drug-loaded layer, a PTMC spacer layer, and a PTMC / PEG (DOX) drug-loaded layer.

[0105] like Figure 3 (A) Figure 3 As shown in (B), the implant allows for programmed controlled release of DOX and PTX in mice. After DOX release is complete (first cycle, days 0-6), a resting period occurs from days 6 to 10 due to the presence of the spacer layer, during which the release rates of DOX and PTX are extremely low. Starting from day 10, drug release enters the second cycle, at which point PTX begins to be released, and by day 16, PTX has been almost completely released (cumulative release rate of 84.5%).

[0106] Among them, such as Figure 3 As shown in (A), when the thickness of the PTMC spacer layer is 20 μm, the release time of the active drug components between the first PTMC drug-loaded layer and the second PTMC drug-loaded layer is 4 days.

[0107] like Figure 3 (C) Figure 3 As shown in (D), within 24 hours after the end of each cycle, the intratumoral DOX and PTX drug concentrations of the implant administration regimen were 5.9 and 12.3 times higher, respectively, than those of the intravenous administration regimen (DOX 5 mg / kg, PTX 15 mg / kg). Meanwhile, the drug concentrations in the major organs (heart, liver, spleen, lung, and kidney) of mice in the implant group were 4.8 to 46.6 times lower than those in the intravenous administration group. This indicates that the implant can achieve a large release of DOX and PTX within the tumor and can significantly reduce the systemic drug concentration distribution.

[0108] Example 4: Application of implants containing programmed local delivery of doxorubicin and paclitaxel in adjuvant therapy after breast cancer surgery

[0109] This invention further establishes a mouse 4T1 orthotopic breast cancer postoperative model to evaluate the anti-tumor recurrence and metastasis effects of the controlled-release implant.

[0110] Establishment of a mouse 4T1 orthotopic breast cancer model after surgery: 4T1 breast cancer cells were collected by centrifugation (1000 rpm, 3 min), washed with PBS (pH = 7.4, 0.01 M), and the resulting cell suspension (cell density 1 × 10⁻⁶) was then collected. 6 Each female BALB / c mouse (18g) was injected subcutaneously into the abdominal mammary fat pad. Tumor growth was observed and tumor size was measured. Tumor size was calculated using calipers, and the specific formula is as follows:

[0111] V = W2 ×L / 2

[0112] Where V represents the tumor volume, W is the width of the tumor, and L is the length of the tumor.

[0113] When a breast tumor grows to approximately 300mm 3 During the procedure, approximately 90% of the tumor volume was surgically removed, and a programmed controlled DOX-PTX release implant (sample × 2, prepared in Example 3, with two implants containing DOX 5 mg / kg and PTX 15 mg / kg) was directly implanted into the tumor bed, followed by suturing.

[0114] Preparation of blank implant:

[0115] (1) A PDLLA solution (10% g / mL) was prepared by dissolving 1.00 g of PDLLA in 10 mL of a mixed solvent of N,N-dimethylformamide (DMF) and dimethyl carbonate (DMC) (DMF:DMC = 1:9 v / v). The PDLLA solution was collected onto a receiver by electrostatic spraying under the conditions of a injection volume of 0.18 mL, a positive high voltage of +4 kV, a negative high voltage of -4 kV, and a translation distance of 15 cm, to obtain a PDLLA barrier layer with a thickness of 50 μm.

[0116] (2) Dissolve 0.2 g of PTMC in 10 mL of trifluoroethanol to prepare a PTMC solution (2% g / mL). The PTMC solution is collected onto the PDLLA barrier layer of step (1) by electrospinning under the conditions of injection volume of 1.56 mL, positive high voltage of +6 kV, negative high voltage of -2 kV, and translation distance of 10 cm to obtain a blank PTMC polymer layer with a thickness of 100 μm, which is the blank implant.

[0117] Preparation of DOX+PTX simultaneous release implant:

[0118] (i) A PDLLA solution (10% g / mL) was prepared by dissolving 1.00 g of PDLLA in 10 mL of a mixed solvent of N,N-dimethylformamide (DMF) and dimethyl carbonate (DMC) (DMF:DMC = 1:9 v / v). The PDLLA solution was collected onto a receiver by electrostatic spraying under the conditions of a injection volume of 0.18 mL, a positive high voltage of +4 kV, a negative high voltage of -4 kV, and a translation distance of 15 cm, to obtain a PDLLA barrier layer with a thickness of 50 μm.

[0119] (ii) A PTMC(PTX) solution (2% g / mL) was prepared by dissolving 0.16 g of PTMC and 0.04 g of paclitaxel (PTX) in 10 mL of trifluoroethanol. The PTMC(PTX) solution was collected onto the PDLLA barrier layer of step (i) by electrospinning under the conditions of injection volume of 0.42 mL, positive high voltage of +6 kV, negative high voltage of -2 kV, and translation distance of 10 cm, to obtain a PTMC(PTX) drug-loaded layer with a thickness of 30 μm, thus obtaining an implant that releases PTX alone.

[0120] (iii) A PTMC / PEG(DOX) solution (1% g / mL) was prepared by dissolving 0.08 g of PTMC, 0.01 g of polyethylene glycol (PEG, 4000 Da), and 0.01 g of doxorubicin hydrochloride (DOX) in 10 mL of hexafluoroisopropanol. The PTMC / PEG(DOX) solution was collected onto the PDLLA barrier layer from step (i) by electrospinning under conditions of a bolus volume of 0.56 mL, a positive high voltage of +6 kV, a negative high voltage of -2 kV, and a translational distance of 10 cm, to obtain a PTMC / PEG(DOX) drug-loaded layer with a thickness of 20 μm, thus obtaining a DOX-releasing implant. The PTX-releasing implant prepared in step (ii) and the DOX-releasing implant prepared in step (iii) were combined to obtain a DOX+PTX simultaneous release implant.

[0121] The mice in the blank implant group were treated in the same way as above, but were implanted with a blank implant (sample × 2) without the drug.

[0122] The mice in the DOX+PTX simultaneous release implant group were treated in the same way as above, but implanted with an implant that could simultaneously release DOX and PTX (DOX+PTX simultaneous release implant × 2).

[0123] In the saline intravenous injection group: the sutures were closed directly after surgery, and then 100 μL of saline was injected into the tail vein on the 1st, 4th and 7th days after surgery.

[0124] The DOX+PTX simultaneous intravenous injection group: After surgery, the sutures were closed directly, and then on the 1st, 4th and 7th day after surgery, 100μL of DOX and 250μL of PTX were injected via the tail vein, respectively, at doses of 5mg / kg for DOX and 15mg / kg for PTX.

[0125] The DOX-PTX sequential intravenous administration group: After surgery, the sutures were closed directly, and then 100 μL of DOX was injected via the tail vein on postoperative days 1, 4, and 7. On postoperative days 10, 13, and 16, 250 μL of PTX was injected via the tail vein, with doses of 5 mg / kg for DOX and 15 mg / kg for PTX, respectively.

[0126] Figure 4 In the study, G1 was the intravenous injection group of normal saline, G2 was the sequential intravenous administration group of DOX-PTX, G3 was the intravenous administration group of DOX+PTX, G4 was the blank implantation group, G5 was the implantation group of DOX+PTX simultaneous release implantation, and G6 was the implantation group of programmed controlled DOX-PTX release implantation.

[0127] like Figure 4 (A) and Figure 4 As shown in (D), when a 4T1 breast tumor grows to ~300mm 3 At that time, approximately 90% of the primary breast tumor was removed, and an implant was inserted. Experimental results showed that, during the 22-day post-operative observation period, programmed controlled release of the DOX-PTX implant significantly inhibited the recurrence of 4T1 breast tumors, with the tumor-bearing size in mice measuring only 23.6 mm at 22 days post-surgery. 3 Its anti-tumor recurrence effect is significantly better than that of other control groups.

[0128] like Figure 4 As shown in (B), intravenous administration of DOX and PTX resulted in a significant decrease in animal body weight of 15%–18%, indicating that the intravenous administration regimen had relatively severe systemic toxicity. The simultaneous release of DOX and PTX via implantation in the experiment also caused a certain degree of weight loss in mice, suggesting the presence of drug toxicity. However, the programmed controlled release of DOX-PTX via implantation did not cause significant changes in animal body weight, indicating that this treatment regimen had good safety.

[0129] like Figure 4 As shown in (C), in a 75-day survival assessment experiment, mice treated with the programmed controlled DOX-PTX release implantation regimen achieved a survival rate of 83.3%, which significantly improved the survival rate after breast cancer surgery.

[0130] Figure 5 In the study, G1 was the intravenous injection group of normal saline, G2 was the sequential intravenous administration group of DOX-PTX, G3 was the intravenous administration group of DOX+PTX, G4 was the blank implantation group, G5 was the implantation group of DOX+PTX simultaneous release implantation, and G6 was the implantation group of programmed controlled DOX-PTX release implantation.

[0131] like Figure 5 As shown, when the lung tissue of mice was stained with Bouin's fixative and hematoxylin and eosin (H&E), tumor metastases could be found in the lungs of mice in the saline, blank implant, and intravenous administration groups. The programmed controlled DOX-PTX release implant administration regimen significantly inhibited breast cancer tumor metastasis.

[0132] This invention provides a controlled-release drug implant, its preparation method, and its application in the preparation of adjuvant therapy drugs after breast cancer surgery. Many methods and approaches exist to achieve this technical solution; the above description is merely a preferred embodiment of the invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for preparing a controlled-release drug implant, characterized in that, Includes the following steps: (1) Dissolve polylactide in a first solvent to obtain a PDLLA solution; collect the PDLLA solution onto a receiver by electrostatic spraying to obtain a PDLLA barrier layer; (2) Dissolve polytrimethylene carbonate and the first active pharmaceutical ingredient in a second solvent to obtain a PTMC solution containing the first active pharmaceutical ingredient; collect the PTMC solution containing the first active pharmaceutical ingredient onto the PDLLA barrier layer in step (1) by electrospinning to obtain the first PTMC drug-loaded layer. (3) Dissolve polytrimethylene carbonate in a third solvent to obtain a PTMC solution; collect the PTMC solution onto the first PTMC drug-loaded layer in step (2) by electrospinning to obtain a PTMC spacer layer; (4) Dissolve polytrimethylene carbonate and the second active pharmaceutical ingredient in a fourth solvent to obtain a PTMC solution containing the solvent of the second active pharmaceutical ingredient; collect the PTMC solution containing the solvent of the second active pharmaceutical ingredient onto the PTMC spacer layer of step (3) by electrospinning to obtain the second PTMC drug-loaded layer, which is the controlled-release drug implant. The PTMC spacer layer has a thickness of 10~150 μm; The controlled-release drug implant is dried and cured in a vacuum environment.

2. The preparation method according to claim 1, characterized in that, In step (1), the first solvent is a mixture of N,N-dimethylformamide and dimethyl carbonate in any proportion; the mass-volume ratio of polylactide to the first solvent is 0.5 g to 1 g: 10 mL.

3. The preparation method according to claim 1, characterized in that, In step (1), the electrostatic spray has a positive high voltage of +4 kV, a negative high voltage of −4 kV, and a translation distance of 10~15 cm; the receiver has a diameter of 0.5~2.0 mm; and the PDLLA barrier layer has a thickness of 50~100 μm.

4. The preparation method according to claim 1, characterized in that, In step (2), the first active pharmaceutical ingredient is paclitaxel, docetaxel, or methylene blue; the second solvent is hexafluoroisopropanol or trifluoroethanol; the total mass of the polytrimethylene carbonate and the first active pharmaceutical ingredient to the mass-volume ratio of the second solvent is 0.05 g to 0.2 g: 10 mL; and the mass ratio of the polytrimethylene carbonate to the first active pharmaceutical ingredient is 1.5 to 19:

1.

5. The preparation method according to claim 1, characterized in that, In step (2), the electrospinning is performed with a positive high voltage of +6 kV, a negative high voltage of −2 kV, and a translation distance of 5~10 cm; the first PTMC drug-loaded layer has a thickness of 30~120 μm.

6. The preparation method according to claim 1, characterized in that, In step (3), the third solvent is any one or a combination of several of the following: trifluoroethanol, hexafluoroisopropanol, a mixture of dichloromethane and N,N-dimethylformamide in a volume ratio of 9:1, and a mixture of chloroform and N,N-dimethylformamide in a volume ratio of 9:1; the mass-volume ratio of polytrimethylene carbonate to the third solvent is 0.05 g to 0.2 g: 10 mL; the electrospinning is performed with a positive high voltage of +6 kV, a negative high voltage of −2 kV, and a translation distance of 5 to 10 cm.

7. The preparation method according to claim 1, characterized in that, In step (4), polyethylene glycol is added when preparing the PTMC solution containing the solvent of the second active pharmaceutical ingredient. Polytrimethylene carbonate, polyethylene glycol and the second active pharmaceutical ingredient are dissolved in a fourth solvent to obtain the PTMC solution containing the solvent of the second active pharmaceutical ingredient.

8. The preparation method according to claim 1 or claim 7, characterized in that, In step (4), the second active pharmaceutical ingredient is doxorubicin hydrochloride or epirubicin; the fourth solvent is hexafluoroisopropanol.

9. The preparation method according to claim 1, characterized in that, In step (4), the total mass ratio of the polytrimethylene carbonate and the second active pharmaceutical ingredient to the fourth solvent is 0.05 g to 0.2 g: 10 mL; the mass ratio of the polytrimethylene carbonate to the second active pharmaceutical ingredient is 1.5 to 19:

1.

10. The preparation method according to claim 7, characterized in that, In step (4), the number average molecular weight of the polyethylene glycol is 600~20000 Da; the total mass of the polytrimethylene carbonate, polyethylene glycol and the second active pharmaceutical ingredient to the mass-volume ratio of the fourth solvent is 0.05 g~0.2 g:10 mL; and the mass ratio of the polytrimethylene carbonate, polyethylene glycol and the second active pharmaceutical ingredient is 6~8:1:1~3.

11. The preparation method according to claim 1, characterized in that, In step (4), the electrospinning is performed with a positive high voltage of +6 kV, a negative high voltage of −2 kV, and a translation distance of 5~10 cm; the second PTMC drug-loaded layer has a thickness of 17.5~100 μm.

12. The controlled-release drug implant prepared by the preparation method according to any one of claims 1 to 11.

13. The use of the controlled-release drug implant of claim 12 in the preparation of adjuvant therapy drugs after breast cancer surgery.

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