Long-acting goserelin injection type in-situ forming implant capable of stably releasing medicine as well as preparation method and application thereof

Abstract

The invention discloses a stable drug release long-acting goserelin injection type in-situ forming implant, which belongs to the field of biological drug manufacturing, and comprises 20-70 parts by weight of a biodegradable high polymer material, 25-75 parts by weight of a biocompatible organic solvent and 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof, the L / G ratio of the biodegradable polymer material PLGA is 50 / 50-95 / 5, and the intrinsic viscosity of the biodegradable polymer material PLGA is 0.08-0.3 dl / g. According to the goserelin injection type in-situ forming implant disclosed by the invention, four key attributes including the intrinsic viscosity of the biodegradable polymer, the glycolic acid aggregation block length, the end capping and the usage amount can be adjusted to be within a proper range in a coordinated manner; the goserelin burst release effect can be remarkably reduced, the delayed drug release platform period can be eliminated, and the treatment requirements of patients can be better met.

Description

Technical Field

[0001] The present invention belongs to the field of biopharmaceutical manufacturing, and in particular relates to a formulation, preparation method and application of a goserelin long-acting injectable in-situ forming implant pharmaceutical composition without a burst release effect. Background Art

[0002] Goserelin is a synthetic decapeptide that acts as an analog of luteinizing hormone-releasing hormone. Long-term use can inhibit the secretion of pituitary luteinizing hormone, thereby causing a decrease in male serum testosterone and female serum estradiol, which is reversible after discontinuation of the drug. The main indications of goserelin are the treatment of breast cancer, prostate cancer, endometriosis and precocious puberty in children. There are currently two clinical dosage forms, one of which is a solid preformed implant. There are two specifications: 3.6mg (one injection per month) and 10.8mg (one injection per three months). They need to be injected with a large-size needle (14G or 16G), and patient compliance is poor. The second is goserelin sustained-release microspheres (Bai Tuowei), which are only available in one specification of 3.6mg (one injection per month). Although the needle size is greatly reduced (21G), the production process and quality control of the microspheres are complex, the development cost is relatively high, and due to the limitations of the drug release mechanism related to the size of the preparation, it is difficult to achieve a longer-term sustained-release effect. In addition, the sustained-release microspheres need to be injected intramuscularly, and the pain is still strong.

[0003] Therefore, there is an urgent need for a long-acting drug delivery system for goserelin that allows for subcutaneous injection via a small-sized needle, has a better sustained-release effect, and is simple to prepare. An injectable in situ forming implant is an ideal choice.

[0004] Injectable, in situ-forming implants, based on the solvent exchange principle, are a high-end, long-acting liquid injectable formulation with unique advantages. Their primary materials, similar to those of solid preformed implants and microspheres, are hydrophobic, biodegradable polymers such as polylactic-co-glycolic acid (PLGA), polylactic acid (PLA), polylactic acid-polyethylene glycol diblock copolymer (PLA-PEG), and polylactic acid-polyethylene glycol-polylactic acid triblock copolymer (PLA-PEG-PLA). However, in injectable, in situ-forming implants, materials like PLGA are dissolved in a biocompatible organic solvent, such as N-methylpyrrolidone (NMP) or dimethyl sulfoxide (DMSO), mixed with the drug, and then injected directly in liquid form. After injection, the formulation undergoes solvent exchange with water at the injection site, solidifying in situ to form a gel reservoir. This releases the drug continuously and stably through two mechanisms: drug diffusion and polymer degradation. Therefore, injectable in-situ forming implants avoid development and quality control challenges such as particle size and encapsulation efficiency. Furthermore, by forming larger aggregates in vivo, they achieve better sustained and controlled drug release. Furthermore, in injectable in-situ forming implants, the polymer solution and drug are typically stored in separate syringes and mixed prior to injection, effectively preventing interactions between the components during storage.

[0005] PLGA and PLA are the most widely used polymer materials in injectable, in situ molded implants. The key physicochemical properties of PLGA include molecular weight, intrinsic viscosity (IV), L-lactide / glycolide (mol / mol) ratio (L / G), endcapping (acid or ester), and glycolic acid aggregate block length. The key physicochemical properties of PLA include molecular weight, intrinsic viscosity, and endcapping (acid or ester). While it is generally recognized that the properties of both PLGA and PLA influence drug release, how these multiple properties interact to improve release profiles remains unclear.

[0006] Because injectable in-situ molded implants solidify in situ via solvent exchange, some drug can rapidly leak out as the solvent exchange occurs, leading to a burst release. Subsequently, the hydrophobic nature and swelling of PLGA often lead to a delayed release plateau (lag phase) in the drug formulation. Existing long-acting injectable in-situ molded implants for goserelin suffer from both burst and delayed release issues. Currently, no long-acting injectable in-situ molded implants for goserelin are commercially available domestically or internationally.

[0007] Patent application EP2585092A1 "PHARMACEUTICAL COMPOSITION CONTAINING GOSERELIN FOR IN-SITU IMPLANT" discloses an in situ implantable pharmaceutical composition containing goserelin, wherein the release time of the protected preparation is one to three months, as shown in the disclosure of the application (EP2585092A1). Figure 1 and Figure 2 As shown, the drug release curve exhibits distinct plateaus for both burst and delayed release, particularly for the three-month formulation, where no drug is released for almost half of the time. Both burst and delayed release can affect the safety and efficacy of the formulation. Furthermore, the disclosed formulation preparation process is complex, requiring freeze-drying or spray-drying before mixing the polymer material with the solvent to prepare the polymer solution.

[0008] Another example is patent application WO2024117740 “Sustained release pharmaceutical composition capable of forming in-situ implants and preparation method therefor” discloses a sustained-release pharmaceutical composition capable of forming in-situ implants and its preparation method. The disclosed goserelin injectable in-situ forming implant reduces the burst effect by using a mixed solvent, but this strategy increases the complexity of quality control and safety evaluation to a certain extent, and the developed preparation can only release the drug for one month. More importantly, although the purpose of this patent application is to reduce the burst effect, according to the disclosure of the application (WO2024117740), Figure 3 It can be seen that the burst release effect is still relatively obvious (drug release > 10% in 24 hours), and there is also the problem of a long delayed drug release plateau period. Some embodiments even have a delay of up to half a month, and fail to achieve the desired effect.

[0009] For example, patent application JP2020147595 “PHARMACEUTICAL COMPOSITIONS WITH IMPROVEDSTABILITY” mentions the delivery of goserelin, which mainly emphasizes the effect of the residual amount of acid monomers in PLGA (i.e., the purity of PLGA) on drug stability and drug release. However, the examples only provide the drug release data of leuprorelin, and do not substantially examine the sustained-release effect of goserelin. Although goserelin and leuprorelin are both luteinizing hormone-releasing hormone analogs, they have different amino acid sequences and molecular weights, resulting in different physical and chemical properties such as rigidity and hydrophilicity. The injectable in situ molding implant formulation system developed for leuprorelin cannot be used for all luteinizing hormone-releasing hormone analogs. Therefore, the encapsulation of goserelin requires in-depth and systematic research on goserelin. In addition, the patent specification states that the PLGA used is acid-terminated or ester-terminated, with a molecular weight of 5-50KDa, and the intrinsic viscosity is not mentioned. There is a certain correlation between the molecular weight and intrinsic viscosity of PLGA. However, the molecular weight is often affected by the detection method and is usually a relative value. The intrinsic viscosity detection value is an absolute value, which is relatively constant and can more accurately reflect information such as the molecular weight and molecular chain structure of PLGA, and has a more important reference value. More importantly, the patent claims of JP2020147595 point out that the acid value of PLGA used in the injectable in situ molding implant should be less than 3 mgKOH / g and the residual lactic acid monomer content should be less than 0.3% by weight. The acid value of PLGA refers to the number of milligrams of potassium hydroxide (KOH) consumed by the free carboxyl groups in each gram of PLGA sample. Although this indicator has a certain relationship with the purity, that is, the acid monomer content and the acidic fragments produced by degradation, it mainly reflects the content of free carboxylic acid groups in the end-capping of PLGA under the condition that no significant degradation occurs and the acid monomer content is low (such as <0.3%), which is closely related to the molecular weight / intrinsic viscosity, lactide / glycolide ratio, and end-capping type of PLGA. However, most conventional commercial PLGA, especially acid-end-capped PLGA, cannot meet the requirement of an acid value of less than 3 mgKOH / g and need to be specially customized. The goserelin injectable in situ forming implants of the present invention all use conventional commercially available PLGA, and the acid value is greater than 3 mgKOH / g, but still achieves an ideal drug release effect, proving that the key factors considered in the claims of JP2020147595 are not applicable to the present invention.

[0010] In summary, providing a long-acting goserelin injectable in-situ forming implant pharmaceutical composition that does not have the problem of drug burst release and can release the drug steadily has become an urgent problem to be solved in the industry. Summary of the Invention

[0011] In order to overcome the shortcomings of the existing technology, the purpose of the present invention is to provide a long-acting goserelin injectable in situ molding implant pharmaceutical composition that has no burst effect and can release the drug smoothly, as well as its preparation method and application. The composition can achieve 1-month and 3-month sustained release of goserelin by adjusting the properties and formulation of a single solvent and conventional commercial PLGA / PLA, and the drug burst effect is greatly reduced.

[0012] To achieve the above objectives, the present invention provides the following technical solutions:

[0013] In a first aspect, the present invention provides a long-acting goserelin injectable in situ forming implant with stable drug release, comprising: a biodegradable polymer material, a biocompatible organic solvent, and goserelin or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the stable drug-releasing long-acting goserelin injectable in situ forming implant comprises: 20-70 parts by weight of a biodegradable polymer material, 25-75 parts by weight of a biocompatible organic solvent, and 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof.

[0015] Through research, the applicant found that in this application, when the amount of biodegradable polymer material used is less than 20 parts by weight, the microstructure of the reservoir formed is loose, resulting in serious drug leakage, excessive burst release, and too rapid drug release; when the amount of biodegradable polymer material used is more than 70 parts by weight, the viscosity of the preparation is too high and pre-filling is too difficult; when the amount of biocompatible organic solvent used is less than 25 parts by weight, the injectability of the preparation is affected; when the amount of biocompatible organic solvent used is more than 75 parts by weight, too much drug is released with solvent exchange, resulting in excessive burst release; when the amount of goserelin or a pharmaceutically acceptable salt thereof is less than 0.2 parts by weight, the volume of the injected preparation is too large, causing discomfort to the patient; when the amount of goserelin or a pharmaceutically acceptable salt thereof is more than 22 parts by weight, the volume of the injected preparation is too small, resulting in inaccurate dosage.

[0016] In some embodiments, the stable drug-releasing long-acting goserelin injectable in situ forming implant comprises: 20-70 parts by weight of a biodegradable polymer material, 25-75 parts by weight of a biocompatible organic solvent, and 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the stable drug-releasing long-acting goserelin injectable in situ forming implant comprises: 33-60 parts by weight of a biodegradable polymer material, 30-66 parts by weight of a biocompatible organic solvent, and 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof.

[0018] Among them, when the usage amount of the biodegradable polymer material is 33 to 60 parts by weight, the usage amount of the biocompatible organic solvent is 30 to 66 parts by weight, and the usage amount of goserelin or a pharmaceutically acceptable salt thereof is 0.2 to 22 parts by weight, the viscosity and preparation volume of the implant are appropriate, and the drug release effect is stable and long-lasting.

[0019] In some embodiments, the biodegradable polymer material is one of polylactic acid-co-glycolic acid (PLGA), polylactic acid (PLA), polyorthoic acid, phospholipids, dioleylglycerol, polylactic acid-polyethylene glycol diblock copolymer (PLA-PEG), polylactic acid-polyethylene glycol-polylactic acid triblock copolymer (PLA-PEG-PLA), or any combination thereof.

[0020] In some embodiments, the biodegradable polymer material is one of acid-terminated lactide / glycolide (mol / mol) 50 / 50-95 / 5 poly(lactic acid-glycolic acid) copolymer or acid-terminated lactic acid, or any combination thereof.

[0021] The applicant has found through research that in the present application, when the biodegradable polymer material is ester-terminated, most of the goserelin drug is released via a burst release without a sustained release effect.

[0022] In some embodiments, the biodegradable polymer material has an average intrinsic viscosity of 0.08-0.3 dl / g.

[0023] Through research, the applicant discovered that the average intrinsic viscosity of the biodegradable polymer material significantly affects the burst release and plateau release period of the formulation. Conventional commercial PLGA typically has an average intrinsic viscosity exceeding 0.08. When the average intrinsic viscosity is too high, such as above 0.3, goserelin can experience increased hydrophobicity and final reservoir viscosity, leading to rapid phase transition and restricted diffusion release. This can result in excessive burst release of the peptide and a prolonged plateau release period.

[0024] In some embodiments, the poly(lactic acid-co-glycolic acid) has a glycolic acid aggregate block length of 1.5-4.0.

[0025] The applicant has found through research that in this application, when the length of the glycolic acid aggregation block of the biodegradable polymer material is greater than 4.0, the material degrades unevenly and rapidly, resulting in uneven drug release and a relatively short total drug release time.

[0026] In some embodiments, the biocompatible organic solvent is one of N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), triacetin, or other pharmaceutically acceptable solvents, or any combination thereof.

[0027] In some embodiments, the biocompatible organic solvent is N-methyl-2-pyrrolidone.

[0028] In some embodiments, the biocompatible organic solvent is dimethyl sulfoxide.

[0029] In some embodiments, the goserelin is goserelin or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the goserelin is goserelin acetate.

[0031] In some embodiments, the goserelin is goserelin mesylate.

[0032] The goserelin injectable in situ forming implant of the present invention can achieve sustained release of goserelin for 1-3 months by selecting conventional commercial PLGA / PLA (polylactic acid-co-glycolic acid / polylactic acid) of different specifications. The drug burst effect is greatly reduced and the delayed release period is greatly shortened by simultaneously regulating the amount of PLGA used and three key properties, namely, intrinsic viscosity, glycolic acid aggregation block length, and end capping, or the amount of PLA used and two key properties, namely, intrinsic viscosity and end capping.

[0033] During experiments, the applicants creatively discovered for the first time that the four key quality parameters of PLGA / PLA, intrinsic viscosity, glycolic acid block length, and endcapping are crucial for the burst release of goserelin. Simultaneously controlling these four parameters within appropriate ranges significantly reduces the burst release of goserelin.

[0034] In a second aspect, the present invention provides an injection of a long-acting goserelin injectable in situ formed implant with a steady drug release, the injection comprising a single pre-filled syringe injection in which 20-70 parts by weight of a biocompatible organic solvent, 25-75 parts by weight of a biodegradable polymer material, and 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof are pre-mixed, or an injection in which 20-70 parts by weight of a biocompatible organic solvent and 25-75 parts by weight of a biodegradable polymer material are prepared into a solution and stored in a pre-filled syringe A, 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof are stored in a pre-filled syringe B, and the mixture is reconstituted before use.

[0035] Preferably, in the second aspect, the injection comprises a single prefilled syringe injection in which 33-60 parts by weight of a biocompatible organic solvent, 30-66 parts by weight of a biodegradable polymer material and 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof are premixed, or a solution of 33-60 parts by weight of a biocompatible organic solvent and 30-66 parts by weight of a biodegradable polymer material is prepared and stored in a prefilled syringe A, 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof is stored in a prefilled syringe B, and the injection is reconstituted before use.

[0036] In a third aspect, the present invention provides a method for preparing a long-acting goserelin injectable in situ formed implant with stable drug release, comprising uniformly mixing 20-70 parts by weight of a biodegradable polymer material, 25-75 parts by weight of a biocompatible organic solvent, and 0.2-22 parts by weight of goserelin, followed by filtration and sterilization, and packaging the mixture into pre-filled syringes for sealed storage.

[0037] Preferably, in the third aspect, the preparation method of the stable drug-releasing long-acting goserelin injectable in situ forming implant comprises: uniformly mixing 33-60 parts by weight of a biodegradable polymer material, 30-66 parts by weight of a biocompatible organic solvent and 0.2-22 parts by weight of goserelin, followed by filtering and sterilizing, and packaging into pre-filled syringes for sealed storage.

[0038] In a fourth aspect, the present invention provides a method for preparing a long-acting injectable in-situ formed implant of goserelin with stable drug release, comprising the following steps:

[0039] (1) Mix 20-70 parts by weight of a biodegradable polymer material and 25-75 parts by weight of a biocompatible organic solvent, and divide the mixture into pre-filled syringes A and seal them for storage;

[0040] (2) Dissolve 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof in a solvent, filter and sterilize, and dispense into pre-filled syringes B and seal for storage.

[0041] The method of storing pre-filled syringes A and B separately is more conducive to maintaining the stability of the drug.

[0042] In some embodiments, step (1) comprises: dissolving 20-70 parts by weight of a biodegradable polymer material in 25-75 parts by weight of a biocompatible organic solvent, sterilizing by filtration or radiation, and packaging the solution into pre-filled syringes A and sealing the solution for storage.

[0043] In some embodiments, step (1) comprises: dissolving 20-70 parts by weight of a biodegradable polymer material in 25-75 parts by weight of a biocompatible organic solvent, filling the pre-filled syringe A into sealed pre-filled syringes A for storage, and sterilizing the syringes by radiation.

[0044] In some embodiments, step (2) comprises: dissolving 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof in water to prepare a 10-200 mg / mL solution, filtering and sterilizing, and filling the solution into pre-filled syringes B, freeze-drying, and sealing for storage.

[0045] In a fifth aspect, the present invention provides a method for preparing a long-acting injectable in-situ formed implant of goserelin with stable drug release, comprising the following steps:

[0046] (1) Mix 20-70 parts by weight of a biodegradable polymer material and 10-74.5 parts by weight of a biocompatible organic solvent, and divide the mixture into pre-filled syringes A and seal them for storage;

[0047] (2) Dissolve goserelin or a pharmaceutically acceptable salt thereof in 0.5-15 parts of a biocompatible organic solvent to prepare a 30-300 mg / mL solution, filter and sterilize, and dispense into pre-filled syringes B and seal for storage.

[0048] In a sixth aspect, the present invention provides a method for using a long-acting, injectable, in-situ molded implant with stable drug release, including two scenarios: 1) The active ingredient goserelin and the polymer solution are premixed and stored together in a prefilled syringe, which is then connected to a needle for direct injection. 2) The active ingredient goserelin and the polymer solution are prepared and stored separately in separate prefilled syringes (prefilled syringes A and B). These syringes require premixing upon use. Specifically, prefilled syringes A and B are connected via a Luer lock, injected back and forth for 60-100 cycles, and the contents of the two syringes are mixed. The mixture is then injected into syringe A, which is then connected to a needle for injection.

[0049] In a seventh aspect, the present invention provides a long-acting injectable in situ formed implant of goserelin with stable drug release for use in breast cancer, prostate cancer, endometriosis and precocious puberty in children.

[0050] By adopting the above technical solutions, the present invention has at least achieved the following technical effects: (1) the goserelin injectable in situ forming implant provided by the present invention can significantly reduce the burst release effect of goserelin and eliminate the delayed drug release plateau by simultaneously controlling the usage amount, intrinsic viscosity, glycolic acid aggregation block length and end capping of PLGA or simultaneously controlling the usage amount, intrinsic viscosity and end capping of PLA, thereby achieving a stable sustained release of goserelin for 1 month and at least 3 months; (2) the goserelin injectable in situ forming implant provided by the present invention can be injected into the patient through a small needle. (20G or finer needle) subcutaneous injection can improve patient compliance and therapeutic effect from two perspectives: more stable blood drug concentration and small needle size comparable to microspheres; (3) The goserelin injectable in situ forming implant provided by the present invention only needs to use conventional commercial polymer materials during the preparation process, and does not require additional freeze-drying or spray-drying pretreatment of PLGA or PLA materials, does not require further purification of PLGA or PLA materials to meet specific acid values ​​or acid monomer residues, and does not require the use of mixed solvents, thereby greatly reducing production costs and formulation evaluation costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 This is the drug release curve of the one-month preparation of Example 1 of the present invention;

[0052] Figure 2 This is the drug release curve of the one-month preparation of Example 2 of the present invention;

[0053] Figure 3 This is the drug release curve of the three-month preparation of Example 7 of the present invention;

[0054] Figure 4 This is the drug release curve of the one-month preparation of Comparative Example 1 of the present invention;

[0055] Figure 5 This is the drug release curve of the three-month preparation of Comparative Example 2 of the present invention;

[0056] Figure 6 This is the drug release curve of the three-month preparation of Comparative Example 3 of the present invention;

[0057] Figure 7 The results of the burst release study of the preparations of Example 2, Example 3, Example 4 and Comparative Example 4 are shown; Figure 8 Viscosity data for the formulations of Examples 2 and 7;

[0058] Figure 9 The results of the subcutaneous irritation test on ICR mice of the preparations of Examples 2 and 7 are as follows;

[0059] Figure 10The drug reservoir and skin HE staining results of ICR mice of the preparations of Example 2 and Example 7;

[0060] Figure 11 These are the results of the in vivo drug release performance study in ICR mice of the formulations of Examples 2 and 7. DETAILED DESCRIPTION

[0061] In order to make the purpose, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the embodiments described are part of the embodiments of the present invention, not all of the embodiments. The experimental methods used in the embodiments are all conventional methods unless otherwise specified; the materials, reagents, etc. used are all commercially available unless otherwise specified. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.

[0062] As a non-limiting embodiment, the present invention provides a long-acting goserelin injectable in situ forming implant with stable drug release, comprising: a biodegradable polymer material, a biocompatible organic solvent, and goserelin or a pharmaceutically acceptable salt thereof.

[0063] The present invention will be further described below with reference to the examples.

[0064] Examples 1 to 9

[0065] Weigh the prescribed amounts of polymer and solvent listed in Table 1 into a glass bottle and mix thoroughly by vortexing overnight. Sterilize by gamma irradiation or filtration. Aseptically dispense the prescribed amount of goserelin acetate into syringe A and the prescribed amount of polymer solution into syringe B. Seal and store until ready for use. Before use, connect syringes A and B using a Luer connector and mix the drug and polymer solution thoroughly.

[0066] Table 1

[0067]

[0068] Examples 10 and 11

[0069] Weigh the polymer material, solvent, and goserelin mesylate in the amounts specified in Table 2 into a glass bottle and vortex overnight to mix thoroughly. Filter sterilize. Aseptically dispense the prescribed amount of drug solution into syringes, seal, and store until ready for use.

[0070] Table 2

[0071]

[0072] Comparative Examples 1 to 4

[0073] Weigh the prescribed amounts of polymer and solvent listed in Table 3 into a glass bottle and mix thoroughly by vortexing overnight. Sterilize by gamma irradiation or filtration. Aseptically dispense the prescribed amount of goserelin acetate into syringe A and the prescribed amount of polymer solution into syringe B. Seal and store until ready for use. Before use, connect syringes A and B using a Luer connector and mix the drug and polymer solution thoroughly.

[0074] Table 3

[0075]

[0076] In vitro release study

[0077] (1) Investigation experiment

[0078] 100 mg of each of the formulations in Examples 1-11 was dripped dropwise into 25 mL of release medium (pH 7.4 phosphate buffer) and placed on an air shaker at 37°C and 100 rpm to investigate the in vitro drug release behavior of the formulations. At predetermined time points, 1 mL of release medium was sampled, filtered through a 0.22 μm filter, and the drug content was determined by HPLC. After each sample was sampled, 1 mL of the solution was added, and the release medium was completely replaced every other week. The values ​​were measured and statistically analyzed as a release curve.

[0079] Examples 1-11 all showed no significant burst release effect and delayed drug release plateau, and had a steady drug release effect. The release results of the representative one-month preparations of Examples 1 and 2 and the three-month preparation of Example 7 were as follows: Figure 1 、 Figure 2 and Figure 3 shown.

[0080] (2) Comparative investigation experiment

[0081] The preparations in Comparative Examples 1, 2, 3, and 4 were subjected to comparative investigations in the same manner as in the investigation experiment. The values ​​were measured and statistically calculated as drug release curves.

[0082] The results are as follows Figure 4-Figure 7 shown.

[0083] in, Figure 4 In Comparative Example 1, the excessively high glycolic acid aggregate block length (>4.0) resulted in significant burst and delayed drug release, with a rapid release phase after 15 days. The overall release curve was unsatisfactory, with release rates being either too fast or too slow at each stage, and the total release duration being relatively short (20 days).

[0084] Figure 5In Comparative Example 2, although the PLGA end-capping and glycolic acid aggregation blocks are suitable, the inherent viscosity is relatively high, resulting in a very significant burst release of the drug and an excessively long delayed release plateau period.

[0085] Figure 6 In Comparative Example 3, although the molecular weight and glycolic acid aggregation block of PLGA are suitable, the ester end-capping results in the release of all drugs in a burst release manner, and the preparation has no sustained release effect.

[0086] Figure 7 In Comparative Example 4, although the three properties of PLGA are within the appropriate range, the low amount of PLGA used results in a very significant burst release of the drug.

[0087] It can be seen from this that only by limiting the usage amount and three key properties of PLGA (i.e., intrinsic viscosity, glycolic acid aggregate block length and end-capping) or the usage amount and two key properties of PLA (i.e., intrinsic viscosity and end-capping) within appropriate ranges can a goserelin injectable in situ forming implant with a stable drug release, greatly reduced burst effect and greatly shortened drug release delay period be obtained.

[0088] Viscosity investigation

[0089] 0.3 mL of the formulations of Example 2 and Example 7 were loaded and the viscosity of the formulations was measured using a rheometer (Anton Paar MCR 302) at 25°C and a shear rate of 10-100 (1 / s). Figure 8 The viscosity of the preparations was less than 5 Pa.s. A gel preparation with a viscosity less than 10 Pa.s at a shear rate of 10-100 (1 / s) showed good injectability. This result suggests that the goserelin injectable in situ forming implant of the present invention has good injectability.

[0090] In vivo safety study

[0091] 50 mg of the formulations of Example 2 and Example 7 were injected subcutaneously into male ICR mice, and the mice's behavior was observed. The mice were sacrificed 1 day and 7 days after injection, and the skin tissue surrounding the solidified reservoir of the formulation was observed by autopsy. The study found that the mice did not scratch after injection, indicating that the formulations were not significantly irritating. Figure 9 ) and HE staining results ( Figure 10 ) showed that there was no obvious inflammatory lesion in the subcutaneous tissue of the two preparation groups 7 days after injection. These results indicate that the preparation has good in vivo safety.

[0092] Investigation of drug release behavior in vivo

[0093] 100 mg of the preparations of Example 2 and Example 7 were injected subcutaneously into male SD rats. Blood was collected at preset time points, and LC-MS was used to investigate the in vivo pharmacokinetics and testosterone inhibition of the preparations. Alternatively, 50 mg of the preparations of Example 2 and Example 7 were injected subcutaneously into male ICR mice. The mice were killed one day after the injection, and the solidified reservoirs were dissected to extract the remaining drug. The drug content was detected by HPLC, and the drug release at different time points of the two preparations was calculated based on the total amount injected. The results are shown in FIG. Figure 11 Consistent with the in vitro release results, Examples 2 and 7 demonstrated improved burst release in ICR mice. The average burst release in Example 2 was less than 5%, and the average burst release in Example 7 was approximately 10%, both exceeding the burst release reported in the literature.

[0094] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A long-acting goserelin injectable in situ forming implant with stable drug release, characterized in that: include: 20-70 parts by weight of a biodegradable polymer material, 25-75 parts by weight of a biocompatible organic solvent and 0.2-22 parts by weight of goserelin or a pharmaceutically acceptable salt thereof.

2. The stable drug-releasing long-acting goserelin injectable in situ forming implant according to claim 1, wherein the biodegradable polymer material is one of polylactic acid-co-glycolic acid, polylactic acid, polyorthoacid, phospholipid, diolein, polylactic acid-polyethylene glycol diblock copolymer, polylactic acid-polyethylene glycol-polylactic acid triblock copolymer, or any combination thereof.

3. The stable drug-releasing, long-acting goserelin injectable in situ forming implant according to claim 1, wherein the biodegradable polymer material is one of acid-terminated poly(lactic acid-glycolic acid) copolymers with a lactide / glycolide (mol / mol) ratio of 50 / 50-95 / 5 or acid-terminated lactic acid, or any combination thereof. 4 . The stable drug-releasing long-acting goserelin injectable in-situ forming implant according to claim 3 , wherein the average intrinsic viscosity of the biodegradable polymer material is 0.08-0.3 dl / g. 5 . The stable drug-releasing long-acting goserelin injectable in situ forming implant according to claim 4 , wherein the glycolic acid aggregation block length of the poly(lactic acid-glycolic acid) copolymer is 1.5-4.

0.

6. The stable drug release long-acting goserelin injectable in-situ forming implant according to claim 1, characterized in that: The biocompatible organic solvent is one of N-methyl-2-pyrrolidone, dimethyl sulfoxide, triacetin or other pharmaceutically acceptable solvents, or any combination thereof.

7. The stable drug-releasing long-acting goserelin injectable in-situ forming implant according to claim 1, wherein the goserelin is goserelin acetate. The stable drug-releasing long-acting goserelin injectable in-situ forming implant according to claim 1 , wherein the goserelin is goserelin mesylate.

9. The method for preparing the long-acting injectable in-situ formed implant of goserelin with stable drug release according to any one of claims 1 to 8, characterized in that: The following steps are involved: (1) Mixing the biodegradable polymer material with the biocompatible organic solvent, and filling the mixture into pre-filled syringes A and sealing them for storage; (2) Dissolve goserelin or a pharmaceutically acceptable salt thereof in a solvent, filter and sterilize, and dispense into pre-filled syringes B and seal for storage.

10. A stable drug-releasing, long-acting goserelin injectable in situ forming implant for use in breast cancer, prostate cancer, endometriosis and precocious puberty in children, characterized in that: The stable drug-releasing long-acting goserelin injectable in situ molded implant is the stable drug-releasing long-acting goserelin injectable in situ molded implant according to any one of claims 1 to 8 or the stable drug-releasing long-acting goserelin injectable in situ molded implant prepared by the preparation method according to claim 9.

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