Perampanel long-acting sustained-release microsphere as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medical biology, in particular to a perampanel long-acting sustained-release microsphere as well as a preparation method and application thereof. The invention firstly provides a composition for preparing the micromolecular drug long-acting sustained-release microspheres. The composition comprises two or three polylactic acid-glycolic acid copolymers. According to the perampanel long-acting sustained-release microspheres and the preparation method thereof, the perampanel long-acting sustained-release microspheres are prepared from a polylactic acid-glycolic acid copolymer mixed system obtained by mixing at least two polylactic acid-glycolic acid copolymers with different lactide-glycolide proportions and molecular weights, the in-vitro release of each microsphere is consistent, and the in-vitro release is more stable and controllable; therefore, a near-zero-order release curve which is free of hysteresis and burst release and has a long release period is obtained.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical biotechnology, specifically to a long-acting sustained-release microsphere of perampanel, its preparation method, and its application. Background Technology

[0002] Epilepsy is a chronic brain disorder characterized by recurrent seizures, primarily caused by excessive discharge of brain neurons. It is characterized by its paroxysmal, transient, repetitive, and stereotyped nature. It is a common chronic neurological disorder, second only to stroke, caused by multiple etiologies, and requires long-term medication. For newly diagnosed epilepsy patients, antiepileptic drugs (AEDs) remain the first-line treatment; however, approximately 30% of patients do not achieve satisfactory disease control, and many experience significant adverse reactions. Current research and development of antiepileptic drugs primarily targets patients requiring long-term medication, aiming to improve the convenience of long-term use and reduce the toxic side effects of traditional drugs.

[0003] Perampanel is a highly selective, non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor antagonist developed by Eisai, Japan. Perampanel reduces neuronal overexcitation by non-competitively binding to AMPA receptors, thus preventing and treating epilepsy. Original research data shows that perampanel has strong AMPA selectivity (IC50 = 93 nM), and even at concentrations as high as 30 μM, it has only a weak effect on NMPA, therefore the risk of side effects is low. Furthermore, perampanel is currently the first highly selective AMPA receptor antagonist approved for marketing, characterized by a unique mechanism of action, good tolerability, and broad-spectrum antiepileptic properties. The molecular formula of perampanel is: .

[0004] Currently available perampanel formulations include tablets, granules, and oral suspensions, all administered once daily. Common adverse reactions to perampanel include dizziness, irritability, fatigue, aggressive behavior, nausea, and weight gain. Studies show that perampanel's adverse reactions are dose-dependent. Furthermore, research has found that current common formulations suffer from drawbacks such as high dosing frequency and long treatment cycles, poor convenience, and large fluctuations in blood drug concentrations. Stable blood drug concentrations are expected to reduce the incidence of adverse reactions.

[0005] Sustained-release microspheres, using macromolecular materials to encapsulate drugs, improve drug stability and are widely used to encapsulate proteins and peptides. They can be administered via intramuscular injection every two weeks, with an initial three-week release stagnation requiring the use of oral tablets to maintain efficacy. The duration of treatment with the active ingredient is 4-6 weeks. This significantly improves upon the drawbacks of frequent dosing associated with traditional formulations, resulting in better patient compliance. Injectable perampanel microspheres are more effective than oral formulations in treating epilepsy. However, the need for initial oral medication and the difficulty in accurately calculating dosages when switching from long-acting injectable drugs to oral medications still present challenges, as peak and trough concentrations cannot be avoided.

[0006] Therefore, preparing perampanel into sustained-release microspheres can achieve the effect of two weeks to several months of medication with a single injection. Moreover, the precise and controlled release of the microspheres is stable, and theoretically, the blood concentration of perampanel in the body will be much lower than that of repeated and high-frequency oral administration, thus ensuring efficacy while reducing the risk of side effects.

[0007] Furthermore, since perampanel was listed as a Class II psychotropic drug by the NMPA on July 1, 2023, there is a need to control its abuse (the dosage of a single prescription for ordinary formulations should not exceed 7 days). If the perampanel microspheres produced have long-acting sustained-release properties, they can be effective for several weeks to several months with just a single injection, which can solve the need to prevent abuse.

[0008] Chinese patent document CN 117530933 A discloses a long-acting sustained-release microsphere of perampanel, its preparation method, and a sustained-release injection. This prior art, based on an emulsion system, prepared a long-acting sustained-release microsphere of perampanel. The microspheres have a spherical morphology, good drug loading, high encapsulation efficiency, suitable particle size, and uniform distribution, and can continuously release perampanel for 14-42 days. The prepared long-acting sustained-release microspheres of perampanel can be further developed into a long-acting sustained-release injection of perampanel. Compared to the once-daily dosing of commercially available perampanel formulations, this significantly extends the dosing interval, reduces the number of visits to the doctor for medication, increases convenience, improves patient compliance, and reduces the risk of seizures induced by missed doses. Especially for patients unsuitable for oral administration, such as those with choking, difficulty swallowing, nasogastric feeding, or stomas, the long-acting perampanel microspheres and formulations provide a more convenient and safer new option for administration. However, this prior art struggles to achieve a near-zero-order release curve with a long release period.

[0009] Chinese patent document CN118717720A discloses a microsphere mixture—perampanel long-acting controlled-release microspheres and its preparation method. These perampanel long-acting controlled-release microspheres are prepared using a microfluidic method from an inner phase solution and an outer phase solution. The inner phase solution contains perampanel and its derivatives, PLGA, and a good solvent for both; the outer phase solution contains a surfactant, a good solvent for the surfactant, and the inner phase solvent. In this prior art, the perampanel long-acting controlled-release microspheres are prepared using a single type of PLGA, and then the microspheres are mixed in a specific ratio. This type of mixed microsphere releases rapidly in the early stages but slowly in the later stages, resulting in insufficient stability in the release rate.

[0010] To address the shortcomings of microsphere technology and better meet clinical requirements, it is necessary to propose a new microsphere drug preparation strategy to alleviate the drug release lag period, achieve immediate release upon administration, reduce the frequency of administration, overcome the drawback of the release delay period in currently marketed sustained-release microsphere injections, and enhance drug efficacy and patient compliance. Summary of the Invention

[0011] The purpose of this invention is to provide a long-acting sustained-release microsphere of perampanel, its preparation method and application. The long-acting sustained-release microsphere of perampanel prepared by using a polylactic acid-glycolic acid copolymer (PLGA) mixed system with different ratios and molecular weights of lactide-glycolic acid has consistent in vitro release and more stable and controllable in vitro release; it can obtain a near-zero order release curve with a long release period without hysteresis or burst release.

[0012] To solve the aforementioned technical problems, the present invention specifically adopts the following technical solution: A first aspect of the present invention is to provide a composition for preparing long-acting sustained-release microspheres.

[0013] A composition for preparing long-acting sustained-release microspheres of small molecule drugs, the composition comprising two or three polylactic acid-glycolic acid copolymers (PLGA). When the composition comprises two polylactic acid-glycolic acid copolymers, it is a first polylactic acid-glycolic acid copolymer and a second polylactic acid-glycolic acid copolymer; The first polylactic acid-glycolic acid copolymer is a low molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.08-0.30 dL / g; the second polylactic acid-glycolic acid copolymer is a medium-to-high molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.15-0.45 dL / g; the ratio of lactide to glycolide in the polylactic acid-glycolic acid copolymer is 50:50-95:5; When the composition comprises three polylactic acid-glycolic acid copolymers, they are a first polylactic acid-glycolic acid copolymer, a second polylactic acid-glycolic acid copolymer, and a third polylactic acid-glycolic acid copolymer; the first polylactic acid-glycolic acid copolymer is a low molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.08-0.30 dL / g; the second polylactic acid-glycolic acid copolymer is a medium molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.15-0.45 dL / g; and the third polylactic acid-glycolic acid copolymer is a high molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.25-0.80 dL / g; the ratio of lactide to glycolide in the polylactic acid-glycolic acid copolymer is 50:50-95:5.

[0014] Optionally, when the composition comprises two polylactic acid-glycolic acid copolymers, the mass ratio of the first polylactic acid-glycolic acid copolymer to the second polylactic acid-glycolic acid copolymer is in the range of (1-5):1.

[0015] Optionally, when the composition comprises three polylactic acid-glycolic acid copolymers, the mass ratio of the first polylactic acid-glycolic acid copolymer, the second polylactic acid-glycolic acid copolymer and the third polylactic acid-glycolic acid copolymer is in the range of (1~9):(1~3):1.

[0016] Furthermore, the polylactic acid-glycolic acid copolymer comprises two monomer forms: lactide (LA) and glycolide (GA); the ratio of lactide to glycolide in the first polylactic acid-glycolic acid copolymer is 50:50-75:25; the ratio of lactide to glycolide in the second polylactic acid-glycolic acid copolymer is 50:50-85:15; and the ratio of lactide to glycolide in the third polylactic acid-glycolic acid copolymer is 75:25-95:5.

[0017] 1) The LA:GA ratio in PLGA significantly affects the slope of the release curve, which is influenced by the initial hysteresis time and the effective release time after the inflection point: the hysteresis time of PLGA with 50% LA content is less than that of PLGA with 65% LA content, which is less than that of PLGA with 75% LA content; the release rate of PLGA with 50% LA content is greater than that of PLGA with 65% LA content, which is greater than that of PLGA with 75% LA content. 2) The molecular weight of PLGA is also a crucial factor determining the lag time: the larger the molecular weight of PLGA, the longer the lag time. In summary, to address the initial lag issue, a PLGA ratio of 50:50 (LA:GA) is preferred; to ensure long-lasting sustained release, a PLGA ratio of 75:25 (LA:GA) is preferred. This selection of PLGA achieves the goal of controllable sustained release time.

[0018] Furthermore, the composition comprises a small molecule drug; the small molecule drug includes perampanel, donepezil, buripiperazole, cariprazine, progesterone, rotigotine, alanine, cabotevir, or meloxicam.

[0019] The aforementioned small molecule drugs are all used for the long-term management of chronic complex diseases, requiring patients to take medication for an extended period. Furthermore, these small molecule drugs share similar properties, with most being lipid-soluble and exhibiting similar characteristics in terms of administration routes (e.g., long-acting injections).

[0020] As a preferred embodiment, the polylactic acid-glycolic acid copolymer mixture system may contain two or three of the following: PLGA (LA:GA=50:50, viscosity 0.2 dL / g), PLGA (LA:GA=75:25, viscosity 0.15-0.25 dL / g), and PLGA (LA:GA=75:25, viscosity 0.35-0.45 dL / g).

[0021] A second aspect of the present invention is to provide a long-acting sustained-release microsphere of perampanel.

[0022] A perampanel long-acting sustained-release microsphere, wherein the perampanel long-acting sustained-release microsphere comprises perampanel and two or three polylactic acid-glycolic acid copolymers; When it contains two polylactic acid-glycolic acid copolymers, it is polylactic acid-glycolic acid copolymer 1 and polylactic acid-glycolic acid copolymer 2; The first polylactic acid-glycolic acid copolymer is a low molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.08-0.30 dL / g; the second polylactic acid-glycolic acid copolymer is a medium-to-high molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.15-0.45 dL / g; the mass ratio of the first polylactic acid-glycolic acid copolymer is greater than or equal to the mass ratio of the second polylactic acid-glycolic acid copolymer. When the product contains three polylactic acid-glycolic acid copolymers, they are a first polylactic acid-glycolic acid copolymer, a second polylactic acid-glycolic acid copolymer, and a third polylactic acid-glycolic acid copolymer; the first polylactic acid-glycolic acid copolymer is a low molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.08-0.30 dL / g; the second polylactic acid-glycolic acid copolymer is a medium molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.15-0.45 dL / g; the third polylactic acid-glycolic acid copolymer is a low molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.25-0.80 dL / g; the mass ratio of the first polylactic acid-glycolic acid copolymer is greater than or equal to the mass ratio of the second polylactic acid-glycolic acid copolymer, and greater than the mass ratio of the third polylactic acid-glycolic acid copolymer.

[0023] Furthermore, the effective drug loading capacity of the perampanel ranges from 5% to 50%.

[0024] Furthermore, the polylactic acid-glycolic acid copolymer comprises two monomer forms: lactide and glycolide; the ratio of lactide to glycolide in the first polylactic acid-glycolic acid copolymer is 50:50-75:25; the ratio of lactide to glycolide in the second polylactic acid-glycolic acid copolymer is 50:50-85:15; and the ratio of lactide to glycolide in the third polylactic acid-glycolic acid copolymer is 75:25-95:5.

[0025] Furthermore, the form of the perampanel includes perampanel or perampanel hydrochloride. The application of the above-mentioned long-acting sustained-release perampanel microspheres in the preparation of antiepileptic drugs.

[0026] The preparation method of the above-mentioned perampanel long-acting sustained-release microspheres includes the following steps: S01: Select two or three polylactic acid-glycolic acid copolymers to mix and obtain a mixed reaction solution; when two polylactic acid-glycolic acid copolymers are selected, it is polylactic acid-glycolic acid copolymer 1 and polylactic acid-glycolic acid copolymer 2; when three polylactic acid-glycolic acid copolymers are selected, it is polylactic acid-glycolic acid copolymer 1, polylactic acid-glycolic acid copolymer 2 and polylactic acid-glycolic acid copolymer 3. S02: Add perampanel to the mixed reaction solution, add a good oil-phase solvent, dissolve thoroughly, filter, and obtain an oil-phase solution for later use; S03: Mix and stir the surfactant solution and the aqueous solvent, and let it stand completely; take the supernatant and filter to obtain the aqueous solution for later use; S04: Add the oil phase solution and the aqueous phase solution to the device, adjust the flow rates of the oil phase and the aqueous phase to obtain oil-in-water emulsion droplets, and collect the oil-in-water emulsion droplets; S05: The collected oil-in-water emulsion droplets are dried and washed to obtain the perampanel long-acting sustained-release microspheres.

[0027] As a preferred embodiment, in the oil phase solution, both the good solvent in the oil phase and the good solvent in the aqueous phase are any one of dichloromethane, ethyl acetate, chloroform, and acetone.

[0028] As a preferred embodiment, in the aqueous solution, the surfactant comprises any one or more of PVA, poloxamer, or PVP.

[0029] As a preferred embodiment, the polylactic acid-glycolic acid copolymer mixture has a mass fraction of 2.0~40.0 wt% in the oil phase solution.

[0030] The theoretical drug loading of perampanel and its derivatives is calculated by dividing the mass of perampanel and its derivatives by the sum of the masses of perampanel and its derivatives and PLGA.

[0031] The surfactant solution has a mass fraction of 0.1~5.0 wt% in the aqueous phase solution.

[0032] Preferably, the surfactant solution is a 0.5% (w / v) polyvinyl alcohol (PVA) solution; both the oil-phase solvent and the aqueous-phase solvent are dichloromethane. The purpose of using the same solvent in both the oil-phase and aqueous-phase solvents is to saturate the aqueous solution with the reagent and prevent the solvent in the oil-phase solution from diffusing into the external phase during shearing.

[0033] Preferably, the PVA is any one or more of PVA1788, PVA1799, and PVA0588.

[0034] Preferably, the PVA is PVA1788.

[0035] Preferably, the polylactic acid-glycolic acid copolymer mixture has a mass fraction of 5.0~25.0 wt% in the oil phase solution.

[0036] Preferably, the polylactic acid-glycolic acid copolymer mixture has a mass fraction of 5.0~10.0 wt% in the oil phase solution; and the theoretical drug loading of perampanel and its derivatives is 10~40.0 wt%.

[0037] Preferably, the theoretical drug loading of perampanel and its derivatives is 10.0~30.0 wt%.

[0038] Preferably, the surfactant solution has a mass fraction of 0.5 to 2.0 wt% in the aqueous phase solution.

[0039] Preferably, in step S04, the oil phase solution and the aqueous phase solution are injected into the microfluidic device using a syringe pump. Preferably, step S05 specifically involves: starting heating and stirring; and maintaining drying conditions to continue drying after the droplet shearing is complete.

[0040] Preferably, the drying of S05 is carried out by liquid drying; the purpose is to remove dichloromethane from the pirampanel droplets and solidify them to obtain pirampanel microspheres.

[0041] Preferably, when preparing a 0.5% (W / V) polyvinyl alcohol (PVA) solution in SO3, the water is first heated to 90°C~98°C, and then PVA is added under stirring to obtain a 0.5% (W / V) polyvinyl alcohol solution.

[0042] Preferably, when preparing a 0.5% (w / v) polyvinyl alcohol (PVA) solution in SO3, the water is first heated to 95°C.

[0043] Preferably, the washing in S06 involves taking the dried microspheres, adding them to pure water for resuspension and washing, discarding the supernatant, and repeating this step 5 times.

[0044] The final aspect of this invention relates to the application of perampanel long-acting sustained-release microspheres in predicting in vitro release formulations, the specific steps of which are as follows: S-1: Perampanel long-acting sustained-release microspheres prepared by polylactic acid-glycolic acid copolymer mixtures with different ratios of lactide-glycolic acid and molecular weight and / or mixing ratios were tested in vitro. The release medium was phosphate buffer containing 1.0% (w / w) Tween 80, pH 7.2, and the release conditions were a constant temperature water bath at 37℃ and a shaking speed of 150 rpm. S-2: When sampling, wait for the microspheres to completely settle, take out 5 ml of the upper release medium, and add the corresponding volume of release medium. At the same time, monitor the pH of the release medium to keep it at around 7.2. S-3: Next, perform high performance liquid chromatography analysis on the sample, calculate the cumulative release percentage, and plot the release rate curve of cumulative release percentage versus time. S-4: Based on the in vitro release test results, predict the cumulative release percentage-time release curves of different perampanel long-acting sustained-release microspheres, and verify the accuracy of the prediction results by comparing them with the release curves of the actual samples obtained in step S-3.

[0045] Beneficial technical effects: (1) The long-acting sustained-release microspheres of perampanel are prepared by mixing polylactic acid-glycolic acid copolymers with at least two different ratios and molecular weights of lactide-glycolic acid copolymers. The in vitro release of each microsphere is consistent, and the in vitro release is more stable and controllable, thus obtaining a near-zero order release curve with a longer release period without lag or burst release.

[0046] (2) The present invention uses a mixture of different PLGA to prepare microspheres, which makes the preparation process simpler. At the same time, the long-acting controlled-release microspheres of perampanel prepared by microfluidic method are very uniform, have high encapsulation efficiency, and have highly stable repeatability and regularity.

[0047] (3) The actual percentage-time release curves were obtained by using different perampanel long-acting sustained-release microspheres. The actual release curves were compared with the predicted release curves. It was found that the in vitro release trend of different PLGA mixtures could be accurately predicted, the experimental cycle was shortened, and the experimental cost (a lot of manpower and material resources) was greatly saved. Attached Figure Description

[0048] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. In all the drawings, similar elements or parts are generally identified by similar reference numerals. The elements or parts in the drawings are not necessarily drawn to scale. Obviously, the drawings described below are some embodiments of the present invention, and those skilled in the art can obtain other drawings based on these drawings without any creative effort.

[0049] Figure 1 Scanning electron microscope image of specific embodiment 4 of the present invention. Figure 2 In vitro release curves of perampanel / PLGA microspheres in blank examples 1-5 of the present invention; Figure 3 This is a comparison of the in vitro release curves of perampanel / mixed PLGA microspheres in Specific Embodiment 4 of the present invention and perampanel mixed microspheres in Comparative Example 1; Figure 4 The in vitro release curve and the corresponding predicted value release curve are shown in Specific Embodiment 1 of the present invention; Figure 5 The in vitro release curve and the corresponding predicted value release curve are shown in Specific Embodiment 2 of the present invention. Figure 6 The in vitro release curve and the corresponding predicted value release curve are shown in Specific Embodiment 3 of the present invention. Figure 7 The in vitro release curve and the corresponding predicted value release curve are shown in Specific Embodiment 4 of the present invention. Figure 8 The in vitro release curve and the corresponding predicted value release curve are shown in Specific Embodiment 5 of the present invention. Figure 9 The in vitro release curves of specific embodiments 6 and 7 of the present invention are shown below; Figure 10 The blood concentration-time curve of perampanel microspheres in rats is shown in Example 4 of the present invention. Detailed Implementation

[0050] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0051] In this document, "and / or" includes any and all combinations of one or more of the listed related items.

[0052] In this article, "multiple" means two or more, that is, it includes two, three, four, five, etc.

[0053] In this article, "front end" can also refer to "left end" and "end end" can also refer to "right end", referring to one end of a pipe and the other end.

[0054] As used in this specification, the term "about" typically means + / -5% of the value, more typically + / -4% of the value, more typically + / -3% of the value, more typically + / -2% of the value, even more typically + / -1% of the value, and even more typically + / -0.5% of the value.

[0055] In this specification, certain embodiments may be disclosed in a range-bound format. It should be understood that this "range-bound" description is merely for convenience and brevity and should not be construed as a rigid limitation on the disclosed range. Therefore, the description of a range should be considered as having specifically disclosed all possible subranges and the individual numerical values ​​within those ranges. For example, a description of the range 1-6 should be considered as having specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., and the individual numbers within those ranges, such as 1, 2, 3, 4, 5, and 6. This rule applies regardless of the breadth of the range.

[0056] Definition of noun: 1. Polyvinyl alcohol (PVA) is an organic compound with the chemical formula [C₂H₄O]. n Polyvinyl alcohol (PVA) appears as a white, flaky, flocculent, or powdery solid, odorless. It is soluble in water (above 95℃), slightly soluble in dimethyl sulfoxide, and insoluble in gasoline, kerosene, vegetable oil, benzene, toluene, dichloroethane, carbon tetrachloride, acetone, ethyl acetate, methanol, ethylene glycol, etc. PVA is an important chemical raw material used in the manufacture of polyvinyl acetal, gasoline-resistant pipes and vinylon, fabric treatment agents, emulsifiers, paper coatings, adhesives, and glues. The physical properties of PVA are affected by its chemical structure, degree of alcoholysis, and degree of polymerization. The main structure in the PVA molecule is 1,3-propanediol, i.e., a "head-tail" structure. The degree of polymerization of PVA is classified as ultra-high degree of polymerization (molecular weight 250,000-300,000), high degree of polymerization (molecular weight 170,000-220,000), medium degree of polymerization (molecular weight 120,000-150,000), and low degree of polymerization (25,000-35,000).

[0057] The degree of alcoholysis is generally found in three types: 78%, 88%, and 98%. Partial alcoholysis typically has a degree of alcoholysis of 87%–89%, while complete alcoholysis has a degree of alcoholysis of 98%–100%. It is common practice to place the thousands and hundreds digits of the average degree of polymerization first, followed by the percentage of the degree of alcoholysis. For example, PVA(1788) indicates a degree of polymerization of 1700 and a degree of alcoholysis of 88%. PVA1799 indicates a degree of polymerization of 1700 and a degree of alcoholysis of 99%. PVA0588 indicates a degree of polymerization of 500 and a degree of alcoholysis of 88%.

[0058] 2. Poly(lactic-co-glycolic acid) copolymer (PLGA) is a biodegradable functional polymer organic compound formed by the random polymerization of two monomers: lactic acid and glycolic acid. It possesses good biocompatibility, is non-toxic, and exhibits excellent encapsulation and film-forming properties, making it widely used in pharmaceuticals, medical engineering materials, and modern industrial fields. PLGA is primarily prepared using ring-opening polymerization. A common ring-opening polymerization method involves dehydrating and cyclizing glycolic acid and lactic acid separately to synthesize glycolide (GA) and lactide (LA) monomers, followed by ring-opening polymerization of GA and LA to obtain the random copolymer of PLGA.

[0059] The ratio of glycolide (GA) to lactide (LA) is the most critical factor determining the performance of PLGA, directly affecting its degradation rate, crystallinity, and solubility. The molecular weight of PLGA is usually expressed as "weight-average molecular weight (Mw)" or "number-average molecular weight (Mn)". Molecular weight directly affects its mechanical strength, solubility, and degradation cycle (the higher the molecular weight, the slower the degradation).

[0060] Example: The perampanel long-acting sustained-release microspheres comprise an oil phase solution and an aqueous phase solution. The aqueous phase solution comprises a surfactant solution and a good aqueous solvent. The oil phase solution comprises a mixture of perampanel and its derivatives, polylactic acid-glycolic acid copolymer (PLGA), and a good oil solvent. The polylactic acid-glycolic acid copolymer (PLA-GA) mixture system is formed by mixing at least two PLA-GA copolymers with different ratios and molecular weights of lactide and glycolide, wherein the ratio of lactide (LA) to glycolide (GA) is (95:5) to (5:95); the viscosity of the PLA-GA copolymer is 0.08-0.8 dl / g. In some specific embodiments, the polylactic acid-glycolic acid copolymer mixing system is a mixture of two or three polylactic acid-glycolic acid copolymers with different ratios and molecular weights of lactide-glycolic acid. When two different polylactic acid-glycolic acid copolymers are selected for mixing, the mixing ratio of the two different polylactic acid-glycolic acid copolymers is 1~3:1; When three different polylactic acid-glycolic acid copolymers are selected for mixing, the mixing ratio of the three different polylactic acid-glycolic acid copolymers is (1~9):(1~3):1.

[0061] In some specific embodiments, the ratio of lactide to glycolide in at least two different polylactic acid-glycolic acid copolymers selected in the polylactic acid-glycolic acid copolymer mixture system is (75:25) to (25:75); In some specific embodiments, the ratio of at least two different lactide and glycolide selected in the polylactic acid-glycolic acid copolymer mixture is (75:25) to (50:50); In some specific embodiments, the polylactic acid-glycolic acid copolymer mixture system contains two or three of the following: PLGA (LA:GA=50:50, viscosity 0.08-0.3 dl / g), PLGA (LA:GA=75:25, viscosity 0.15-0.45 dl / g), and PLGA (LA:GA=75:25, viscosity 0.25-0.8 dl / g).

[0062] In some specific embodiments, in the oil phase solution, both the good solvent in the oil phase and the good solvent in the aqueous phase are any one of dichloromethane, ethyl acetate, chloroform, and acetone; In an aqueous solution, the surfactant includes any one or more of PVA, poloxamer, or PVP. In some specific embodiments, the polylactic acid-glycolic acid copolymer mixture has a mass fraction of 2.0~40.0 wt% in the oil phase solution. The theoretical drug loading of the perampanel and its derivatives is 10~60.0 wt%; The remainder is a good solvent in the oil phase; The theoretical drug loading capacity of perampanel and its derivatives is calculated as follows: the mass of perampanel and its derivatives divided by the sum of the masses of perampanel and its derivatives and PLGA. The surfactant solution has a mass fraction of 0.1~5.0 wt% in the aqueous phase solution.

[0063] In some specific embodiments, the surfactant solution is a 0.5% (W / V) polyvinyl alcohol (PVA) solution; both the oil-phase solvent and the aqueous-phase solvent are dichloromethane.

[0064] In some specific embodiments, the PVA is any one or more of PVA1788, PVA1799, and PVA0588.

[0065] In some specific embodiments, the PVA is PVA1788.

[0066] In some specific embodiments, the polylactic acid-glycolic acid copolymer mixture has a mass fraction of 5.0~25.0 wt% in the oil phase solution. In some specific embodiments, the polylactic acid-glycolic acid copolymer mixture has a mass fraction of 5.0~10.0 wt% in the oil phase solution; the theoretical drug loading of perampanel and its derivatives is 10~40.0 wt%.

[0067] In some specific embodiments, the theoretical drug loading of perampanel and its derivatives is 10.0~30.0 wt%.

[0068] In some specific embodiments, the surfactant solution has a mass fraction of 0.5 to 2.0 wt% in the aqueous phase solution.

[0069] The preparation method of the perampanel long-acting sustained-release microspheres is as follows: The perampanel long-acting sustained-release microspheres are prepared by microfluidic method, and the specific steps are as follows: S1: Select at least two polylactic acid-glycolic acid copolymers with different ratios and molecular weights of lactide-glycolic acid and mix them to obtain a polylactic acid-glycolic acid copolymer mixture system; S2: Weigh out the mixture of perampanel and polylactic acid-glycolic acid copolymer separately, add a good oil phase solvent, sonicate to fully dissolve, and then filter. Filter the above solution to obtain the oil phase solution for later use. S3: Stir and mix the surfactant solution and the aqueous solvent; filter the supernatant to obtain the aqueous solution for later use; Specifically: Prepare a 0.5% (w / v) polyvinyl alcohol (PVA) solution, add excess dichloromethane, turn on the stirrer, and mix thoroughly; take the supernatant and filter to obtain the aqueous solution for later use; S4: Connect the oil phase solution and the aqueous phase solution to the microfluidic device respectively, and inject them into the microfluidic device. Adjust the flow rate ratio of the oil phase and the aqueous phase. The dispersed phase is sheared by the continuous phase in the microfluidic device to obtain an oil-in-water emulsion. Then collect the droplets. S5: Then pass the droplets collected during the shearing process into the receiving liquid and dry them; Specifically: turn on heating and stirring to ensure temperature stability before receiving the sample; after the droplet shearing is complete, maintain drying conditions and continue drying; S6: Collect the dried droplets, wash them with pure water, filter them, and freeze-dry them to obtain long-acting sustained-release microspheres of perampanel.

[0070] In some specific embodiments, in step S1, two or three polylactic acid-glycolic acid copolymers with different ratios and molecular weights of lactide-glycolic acid are selected and mixed; wherein the ratio of lactide to glycolide LA:GA is (75:25)~(25:75); and the viscosity of the polylactic acid-glycolic acid copolymer is 0.08-0.8 dl / g; When two different polylactic acid-glycolic acid copolymers are selected for mixing, the mixing ratio of the two different polylactic acid-glycolic acid copolymers is 1~3:1; When three different polylactic acid-glycolic acid copolymers are selected for mixing, the mixing ratio of the three different polylactic acid-glycolic acid copolymers is (1~9):(1~3):1.

[0071] In some specific embodiments, in step S4, the oil phase solution and the aqueous phase solution are injected into the microfluidic device by an injection pump, and the flow rate of the aqueous phase solution is controlled to be greater than that of the oil phase solution.

[0072] In some specific embodiments, step S5 specifically involves: turning on heating and stirring to ensure temperature stability before receiving the sample; and maintaining drying conditions and continuing drying after the droplet shearing is complete.

[0073] In some specific embodiments, the drying in step S5 is performed by liquid drying; the purpose is to remove dichloromethane from the perampanel microemulsion and solidify it to obtain perampanel microspheres.

[0074] In some specific embodiments, when preparing a 0.5% (W / V) polyvinyl alcohol (PVA) solution in step S3, the water is first heated to 90°C~98°C, and then PVA is added under stirring conditions to obtain a 0.5% (W / V) polyvinyl alcohol solution.

[0075] In some specific embodiments, when preparing the 0.5% (w / v) polyvinyl alcohol (PVA) solution in step S3, the water is first heated to 95°C.

[0076] In some specific embodiments, the washing in step S6 involves taking the dried microspheres, adding an appropriate amount of pure water to resuspend and wash them, discarding the supernatant, and repeating this step 5 times.

[0077] The application of these perampanel long-acting sustained-release microspheres in predicting in vitro release formulations involves the following steps: S-1: Perampanel long-acting sustained-release microspheres prepared by polylactic acid-glycolic acid copolymer mixtures with different ratios of lactide-glycolic acid and molecular weight and / or mixing ratios were tested in vitro. The release medium was phosphate buffer containing 1.0% (w / w) Tween 80, pH 7.2, and the release conditions were a constant temperature water bath at 37℃ and a shaking speed of 150 rpm. S-2: When sampling, wait for the microspheres to completely settle, take out 5 ml of the upper release medium, and add the corresponding volume of release medium. At the same time, monitor the pH of the release medium to keep it at around 7.2. S-3: Next, perform high performance liquid chromatography analysis on the sample, calculate the cumulative release percentage, and plot the release rate curve of cumulative release percentage versus time. S-4: Based on the in vitro release test results, predict the cumulative release percentage-time release curves of different perampanel long-acting sustained-release microspheres, and verify the accuracy of the prediction results by comparing them with the release curves of the actual samples obtained in step S-3.

[0078] This invention relates to the application of perampanel long-acting sustained-release microspheres in the preparation of perampanel long-acting sustained-release injections.

[0079] The following are specific examples of the perampanel long-acting sustained-release microspheres prepared according to the present invention. The perampanel long-acting sustained-release microspheres of the present invention are referred to as mixed PLGA microspheres in the following specific examples. The formulations of the specific examples and comparative examples (hereinafter referred to as mixed microspheres) are shown in Table 1.

[0080] Table 1. Formulations for specific embodiments, blank examples, and comparative examples. Blank Example 1: The preparation process of this long-acting sustained-release microsphere involves an oil phase solution and an aqueous phase solution, wherein the aqueous phase solution includes a surfactant solution and a good aqueous solvent; The oil phase solution comprises perampanel and its derivatives, polylactic acid-glycolic acid copolymer (PLGA), and a good oil phase solvent (dichloromethane); the ratio of LA to GA in PLGA is 50:50; the viscosity is 0.2 dL / g, and the PLGA is carboxyl-terminated; 1.4 g of PLGA and 0.6 g of perampanel and its derivatives are weighed and dissolved in an appropriate amount of dichloromethane. The aqueous solution comprises a 0.5% (w / v) polyvinyl alcohol solution and a good aqueous solvent (dichloromethane).

[0081] Blank Example 2: The preparation process of this long-acting sustained-release microsphere involves an oil phase solution and an aqueous phase solution, wherein the aqueous phase solution includes a surfactant solution and a good aqueous solvent; The oil phase solution comprises perampanel and its derivatives, polylactic acid-glycolic acid copolymer (PLGA), and a good oil phase solvent (dichloromethane); the ratio of LA to GA in PLGA is 75:25; the viscosity is 0.15-0.25 dL / g, and it is carboxyl-terminated; 1.4g of PLGA and 0.6g of perampanel and its derivatives are weighed and dissolved in an appropriate amount of dichloromethane. The aqueous solution comprises a 0.5% (w / v) polyvinyl alcohol solution and a good aqueous solvent (dichloromethane).

[0082] Blank Example 3: The preparation process of this long-acting sustained-release microsphere involves an oil phase solution and an aqueous phase solution, wherein the aqueous phase solution includes a surfactant solution and a good aqueous solvent; The oil phase solution comprises perampanel and its derivatives, polylactic acid-glycolic acid copolymer (PLGA), and a good oil phase solvent (dichloromethane); the ratio of LA to GA in PLGA is 75:25; the viscosity is 0.35-0.45 dL / g, and it is carboxyl-terminated; 1.4g of PLGA and 0.6g of perampanel and its derivatives are weighed and dissolved in an appropriate amount of the good oil phase solvent dichloromethane. The aqueous solution comprises a 0.5% (w / v) polyvinyl alcohol solution and a good aqueous solvent (dichloromethane).

[0083] Blank Example 4: The preparation process of this long-acting sustained-release microsphere involves an oil phase solution and an aqueous phase solution, wherein the aqueous phase solution includes a surfactant solution and a good aqueous solvent; The oil phase solution comprises perampanel and its derivatives, polylactic acid-glycolic acid copolymer, and a good oil phase solvent (dichloromethane); PLGA (LA:GA=85:15, viscosity 0.55-0.65 dL / g); carboxyl-terminated; weigh 1.4g of PLGA and 0.6g of perampanel and its derivatives, add an appropriate amount of the good oil phase solvent dichloromethane, and dissolve thoroughly; The aqueous solution comprises a 0.5% (w / v) polyvinyl alcohol solution and a good aqueous solvent (dichloromethane).

[0084] Blank Example 5: The preparation process of this long-acting sustained-release microsphere involves an oil phase solution and an aqueous phase solution, wherein the aqueous phase solution includes a surfactant solution and a good aqueous solvent; The oil phase solution comprises perampanel and its derivatives, polylactic acid-glycolic acid copolymer, and a good oil phase solvent (dichloromethane); PLGA (LA:GA=95:5, viscosity 0.7-0.8 dL / g); carboxyl-terminated; weigh 1.4g of PLGA and 0.6g of perampanel and its derivatives, add an appropriate amount of the good oil phase solvent dichloromethane, and dissolve thoroughly; The aqueous solution comprises a 0.5% (w / v) polyvinyl alcohol solution and a good aqueous solvent (dichloromethane).

[0085] Specific Example 1: The preparation process of this long-acting sustained-release microsphere involves an oil phase solution and an aqueous phase solution, wherein the aqueous phase solution includes a surfactant solution and a good aqueous solvent; The oil phase solution includes perampanel and its derivatives, a polylactic acid-glycolic acid copolymer mixture, and a good oil phase solvent (dichloromethane). A polylactic acid-glycolic acid copolymer (PLGA) mixture system was prepared by mixing PLGA (LA:GA=50:50, viscosity 0.2 dL / g) and PLGA (LA:GA=75:25, viscosity 0.15-0.25 dL / g) in a 1:1 ratio. 0.7 g each of PLGA (LA:GA=50:50, viscosity 0.2 dL / g) and PLGA (LA:GA=75:25, viscosity 0.15-0.25 dL / g), and 0.6 g of perampanel and its derivatives were added and dissolved in a suitable amount of dichloromethane, a good oil-phase solvent. The aqueous solution comprises a 0.5% (w / v) polyvinyl alcohol solution and a good aqueous solvent (dichloromethane).

[0086] The specific steps of the preparation method are as follows: S1: Two selected polylactic acid-glycolic acid copolymers, PLGA (LA:GA=50:50, viscosity 0.2dL / g) and PLGA (LA:GA=75:25, viscosity 0.15-0.25dL / g), are mixed in a 1:1 ratio to obtain a polylactic acid-glycolic acid copolymer mixture system; S2: Weigh out the mixture of perampanel and polylactic acid-glycolic acid copolymer, add dichloromethane, sonicate to dissolve completely, then filter. Filter the above solution to obtain the oil phase solution for later use. S3: Prepare a 0.5% (w / v) polyvinyl alcohol (PVA) solution by adding excess dichloromethane, stirring, and mixing thoroughly; filter the supernatant to obtain the aqueous solution for later use. S4: Connect the oil phase solution and the aqueous phase solution to the microfluidic device respectively, and inject them into the microfluidic device. Adjust the flow rate of the oil and aqueous phase solutions. The continuous phase in the microfluidic device shears the dispersed phase to obtain an oil-in-water emulsion, and then collect the droplets. S5: The droplets collected during the shearing process are then received by the receiving liquid and dried. S6: Collect the dried droplets, wash them with pure water, filter them, and freeze-dry them to obtain long-acting sustained-release microspheres of perampanel.

[0087] Specific Example 2: The difference from Specific Example 1 is that the polylactic acid-glycolic acid copolymer mixing system selected is PLGA (LA:GA=50:50, viscosity 0.2dL / g), PLGA (LA:GA=75:25, viscosity 0.15-0.25dL / g) and PLGA (LA:GA=75:25, viscosity 0.35-0.45dL / g), and the three types of PLGA are mixed in a ratio of 1:1:1.

[0088] Specific Example 3: The difference from Specific Example 1 is that the polylactic acid-glycolic acid copolymer mixing system uses PLGA (LA:GA=50:50, viscosity 0.2dL / g) and PLGA (LA:GA=75:25, viscosity 0.35-0.45dL / g), and the PLGA (LA:GA=50:50, viscosity 0.2dL / g) and PLGA (LA:GA=75:25, viscosity 0.35-0.45dL / g) are mixed in a 1:1 ratio.

[0089] Specific Example 4: The difference from Specific Example 2 is that the PLGA (LA:GA=50:50, viscosity 0.2dL / g), PLGA (LA:GA=75:25, viscosity 0.15-0.25dL / g), and PLGA (LA:GA=75:25, viscosity 0.35-0.45dL / g) selected in the polylactic acid-glycolic acid copolymer mixture system are mixed in a ratio of 6:3:1.

[0090] Specific Example 5: The difference from Specific Example 2 is that the PLGA (LA:GA=50:50, viscosity 0.2dL / g), PLGA (LA:GA=75:25, viscosity 0.15-0.25dL / g), and PLGA (LA:GA=75:25, viscosity 0.35-0.45dL / g) selected in the polylactic acid-glycolic acid copolymer mixing system are mixed in a ratio of 8:1:1.

[0091] Specific Example 6: The difference from Specific Example 2 is that the PLGA (LA:GA=75:25, viscosity 0.15-0.25 dL / g), PLGA (LA:GA=75:25, viscosity 0.35-0.45 dL / g), and PLGA (LA:GA=85:15, viscosity 0.55-0.65 dL / g) selected in the polylactic acid-glycolic acid copolymer mixture are mixed in a ratio of 1:1:1.

[0092] Specific Example 7: The difference from Specific Example 2 is that the PLGA (LA:GA=75:25, viscosity 0.15-0.25 dL / g), PLGA (LA:GA=75:25, viscosity 0.35-0.45 dL / g), and PLGA (LA:GA=95:5, viscosity 0.7-0.8 dL / g) selected in the polylactic acid-glycolic acid copolymer mixing system are mixed in a ratio of 1:1:1.

[0093] Comparative Example 1: The difference from Specific Example 4 is that the selected PLGA was made into perampanel microspheres, and then the obtained microspheres were mixed in proportion. Specifically, the process involves preparing PLGA (LA:GA=50:50, viscosity 0.2 dL / g), PLGA (LA:GA=75:25, viscosity 0.15-0.25 dL / g), and PLGA (LA:GA=75:25, viscosity 0.35-0.45 dL / g) microspheres to obtain PLGA (LA:GA=50:50, viscosity 0.2 dL / g) microspheres, PLGA (LA:GA=75:25, viscosity 0.15-0.25 dL / g) microspheres, and PLGA (LA:GA=75:25, viscosity 0.35-0.45 dL / g) microspheres. Then, the three types of microspheres are mixed in a ratio of 6:3:1 to obtain mixed microspheres. The specific steps for preparing this hybrid microsphere are as follows: (1) PLGA (LA:GA=50:50, viscosity 0.2 dL / g) microspheres, PLGA (LA:GA=75:25, viscosity 0.15-0.25 dL / g) microspheres and PLGA (LA:GA=75:25, viscosity 0.35-0.45 dL / g) microspheres were prepared respectively according to the following steps: 1) Weigh out perampanel and polylactic acid-glycolic acid copolymer separately, add dichloromethane, sonicate to dissolve them completely, filter the above solution with a needle nylon filter head to obtain the oil phase solution, and set aside for later use; 2) Prepare a 0.5% (w / v) polyvinyl alcohol solution by adding excess dichloromethane, stirring, and mixing thoroughly. Filter the supernatant to obtain the aqueous solution, and set aside. 3) Connect the oil phase and water phase to the microfluidic device separately, inject them into the microfluidic device through a syringe pump, adjust the flow rate of the oil and water phase solutions, and the continuous phase in the microfluidic device shears the dispersed phase to obtain an oil-in-water emulsion, and collect the droplets; 4) During the shearing process, the collected droplets enter the receiving and drying stage, and heating and stirring are turned on. Once the droplet shearing is complete, maintain the drying conditions and continue drying; 5) Collect the dried droplets, wash with pure water, filter, and dry to obtain bripiprazole long-acting sustained-release microspheres; PLGA (LA:GA=50:50, viscosity 0.2 dL / g) microspheres, PLGA (LA:GA=75:25, viscosity 0.15-0.25 dL / g) microspheres and PLGA (LA:GA=75:25, viscosity 0.35-0.45 dL / g) microspheres were obtained respectively; (2) Then, PLGA (LA:GA=50:50, viscosity 0.2dL / g) microspheres, PLGA (LA:GA=75:25, viscosity 0.15-0.25dL / g) microspheres and PLGA (LA:GA=75:25, viscosity 0.35-0.45dL / g) microspheres are mixed in a ratio of 6:3:1 to obtain mixed microspheres.

[0094] Comparative Example 2: The difference from Comparative Example 1 is that PLGA (LA:GA=50:50, viscosity 0.2dL / g) microspheres, PLGA (LA:GA=75:25, viscosity 0.15-0.25dL / g) microspheres and PLGA (LA:GA=75:25, viscosity 0.35-0.45dL / g) microspheres were mixed in a ratio of 8:1:1 to obtain mixed microspheres, which were then compared with Specific Example 5.

[0095] The PLGA microspheres prepared in blank examples 1-3 and specific example 1 were compared with those in specific example 1. 5. The prepared mixed PLGA microspheres were characterized, and the main properties included drug loading, encapsulation efficiency, dichloromethane residue, PVA residue, and in vitro release. The relevant characterization methods and results are shown in Table 2 below.

[0096] (1) Drug loading (DL) and encapsulation efficiency (EE): Weigh approximately 5 mg of the microsphere sample and add 20 mL of N2O2. Methylpyrrolidone (NMP) was fully dissolved, and then the content of perampanel was detected by HPLC. The drug loading and encapsulation efficiency of the perampanel microspheres were calculated; see Table 2. (2) Dichloromethane (DCM) residue: The amount of dichloromethane residue in the microspheres was detected by gas chromatography; see Table 2; (3) PVA residue: The amount of PVA residue in the microspheres was detected using a UV-Vis spectrophotometer; see Table 2.

[0097] Table 2. Results of drug loading, encapsulation efficiency, and residual dichloromethane and polyvinyl alcohol in microspheres. As can be seen from Table 2, the perampanel microspheres prepared by the method of the present invention have high drug loading and encapsulation efficiency, with encapsulation efficiency of over 90%, while reducing the residual amount of dichloromethane and PVA, making them safer.

[0098] (4) In vitro release method, the specific steps are as follows: A certain amount of microspheres were taken for in vitro release detection. The release medium was phosphate buffer containing 1.0% (w / w) Tween 80, pH 7.2, and the release conditions were a constant temperature water bath at 37℃ and a shaking speed of 150 rpm. During sampling, wait until the microspheres have completely settled, take out 5 ml of the upper release medium, and add the corresponding volume of release medium. At the same time, monitor the pH of the release medium to keep it at around 7.2. The sample was analyzed by high performance liquid chromatography, the cumulative release percentage was calculated, and a release rate curve of cumulative release percentage versus time was plotted.

[0099] like Figure 2 The figure shows the in vitro release curves of perampanel / PLGA microspheres in blank examples 1-3; from Figure 1 As can be seen, single PLGA release in vitro has the problem of short release cycle or early lag, making it difficult to achieve stable sustained release over a long period; different PLGAs can achieve drug release at a relatively stable rate at different stages.

[0100] like Figure 3 The figure shown is a comparison of the in vitro release curves of perampanel / mixed PLGA microspheres in Specific Example 4 and perampanel mixed microspheres in Comparative Example 1; from Figure 3 As can be seen, there are differences in in vitro release between the two preparation processes: preparing microspheres by mixing PLGA (mixed PLGA microspheres) and preparing microspheres of different PLGAs followed by mixing (mixed microspheres). Mixed microspheres show faster initial release followed by slower release, while mixed PLGA microspheres exhibit a more stable release rate throughout the entire process. This suggests that the release of mixed microspheres is dominated by the PLGA specific to each microsphere, resulting in differences between microspheres. In contrast, the in vitro release of each microsphere in mixed PLGA microspheres is consistent, leading to a more stable and controllable in vitro release. Furthermore, the preparation process of mixed PLGA microspheres is simpler; therefore, this process is preferred. Moreover, mixing PLGA allows for a near-zero-order release curve with a longer release period and no hysteresis or burst release.

[0101] Figures 4-8 The in vitro release curves and corresponding predicted release curves for specific examples 1-5 are shown respectively. The results show that the predicted values ​​and measured values ​​are basically consistent, and the release curves basically overlap. Therefore, the in vitro release rate of mixed PLGA microspheres over time can be accurately predicted by observing the in vitro release of a single PLGA. Based on this, in vitro release formulations with different release cycles can be obtained according to the prediction, which greatly shortens the experimental cycle and saves a lot of manpower and resources.

[0102] (5) The specific steps of the animal experimental method are as follows: Animals: SD rats (SPF grade), 6-8 weeks old, weighing 180-200g, 4 rats per group, half male and half female. The drug was administered subcutaneously. Whole blood was collected at 0h before administration and at 1h, 2h, 4h, 6h, 10h, 24h, 48h, 72h, 96h, 120h (5d), 168h (7d), 240h (10d), 336h (14d), 408h (17d), 504h (21d), 576h (24d), 672h (28d), 744h (31d), and 840h (35d) after administration and placed in EDTA-K2 anticoagulant tubes. The plasma concentration of perampanel was determined using a validated LC-MS / MS method. The animal experiments of specific Example 4 were conducted, and the results are as follows... Figure 10 As shown.

[0103] Figure 10 The image shows the blood concentration-time curve of the perampanel microspheres in rats according to Example 4. The results show that the microspheres prepared in Example 4 can be stably and sustainedly released in rats for one month with minimal fluctuation in blood drug concentration, indicating that Example 4 is the optimal formulation.

[0104] The embodiments of the present invention have been described above with reference to the accompanying drawings. However, the present invention is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of the present invention without departing from the spirit and scope of the claims. All of these forms are within the protection scope of the present invention.

Claims

1. A composition for preparing long-acting sustained-release microspheres of small molecule drugs, characterized in that, The composition comprises two or three polylactic acid-glycolic acid copolymers; When the composition comprises two polylactic acid-glycolic acid copolymers, it is a first polylactic acid-glycolic acid copolymer and a second polylactic acid-glycolic acid copolymer; The first polylactic acid-glycolic acid copolymer is a low molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.08-0.30 dL / g; the second polylactic acid-glycolic acid copolymer is a medium-to-high molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.15-0.45 dL / g; the ratio of lactide to glycolide in the polylactic acid-glycolic acid copolymer is 50:50-95:5; When the composition comprises three polylactic acid-glycolic acid copolymers, they are a first polylactic acid-glycolic acid copolymer, a second polylactic acid-glycolic acid copolymer, and a third polylactic acid-glycolic acid copolymer; the first polylactic acid-glycolic acid copolymer is a low molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.08-0.30 dL / g; the second polylactic acid-glycolic acid copolymer is a medium molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.15-0.45 dL / g; and the third polylactic acid-glycolic acid copolymer is a high molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.25-0.80 dL / g; the ratio of lactide to glycolide in the polylactic acid-glycolic acid copolymer is 50:50-95:

5.

2. The composition according to claim 1, characterized in that, When the composition comprises two polylactic acid-glycolic acid copolymers, the mass ratio of the first polylactic acid-glycolic acid copolymer to the second polylactic acid-glycolic acid copolymer is in the range of (1-5):1; or, when the composition comprises three polylactic acid-glycolic acid copolymers, the mass ratio of the first polylactic acid-glycolic acid copolymer, the second polylactic acid-glycolic acid copolymer, and the third polylactic acid-glycolic acid copolymer is in the range of (1~9):(1~3):

1.

3. The composition according to claim 1, characterized in that, The polylactic acid-glycolic acid copolymer comprises two monomers: lactide and glycolide; the ratio of lactide to glycolide in the first polylactic acid-glycolic acid copolymer is 50:50-75:25; the ratio of lactide to glycolide in the second polylactic acid-glycolic acid copolymer is 50:50-85:15; and the ratio of lactide to glycolide in the third polylactic acid-glycolic acid copolymer is 75:25-95:

5.

4. The composition according to claim 1, characterized in that, The composition comprises a small molecule drug; the small molecule drug includes perampanel, donepezil, buripiperazole, cariprazine, progesterone, rotigotine, alanine, cabotevir, or meloxicam.

5. A long-acting sustained-release microsphere of perampanel, characterized in that, The perampanel long-acting sustained-release microspheres contain perampanel and two or three polylactic acid-glycolic acid copolymers; When it contains two polylactic acid-glycolic acid copolymers, it is polylactic acid-glycolic acid copolymer 1 and polylactic acid-glycolic acid copolymer 2; The first polylactic acid-glycolic acid copolymer is a low molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.08-0.30 dL / g; the second polylactic acid-glycolic acid copolymer is a medium-to-high molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.15-0.45 dL / g; the mass ratio of the first polylactic acid-glycolic acid copolymer is greater than or equal to the mass ratio of the second polylactic acid-glycolic acid copolymer. When the product contains three polylactic acid-glycolic acid copolymers, they are a first polylactic acid-glycolic acid copolymer, a second polylactic acid-glycolic acid copolymer, and a third polylactic acid-glycolic acid copolymer; the first polylactic acid-glycolic acid copolymer is a low molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.08-0.30 dL / g; the second polylactic acid-glycolic acid copolymer is a medium molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.15-0.45 dL / g; the third polylactic acid-glycolic acid copolymer is a low molecular weight polylactic acid-glycolic acid copolymer with an intrinsic viscosity range of 0.25-0.80 dL / g; the mass ratio of the first polylactic acid-glycolic acid copolymer is greater than or equal to the mass ratio of the second polylactic acid-glycolic acid copolymer, and greater than the mass ratio of the third polylactic acid-glycolic acid copolymer.

6. The perampanel long-acting sustained-release microspheres as described in claim 5, characterized in that, The effective drug loading range of the perampanel is 5%-50%.

7. The perampanel long-acting sustained-release microspheres as described in claim 5, characterized in that, The polylactic acid-glycolic acid copolymer comprises two monomers: lactide and glycolide; the ratio of lactide to glycolide in the first polylactic acid-glycolic acid copolymer is 50:50-75:25; the ratio of lactide to glycolide in the second polylactic acid-glycolic acid copolymer is 50:50-85:15; and the ratio of lactide to glycolide in the third polylactic acid-glycolic acid copolymer is 75:25-95:

5.

8. The perampanel long-acting sustained-release microspheres as described in claim 5, characterized in that, The forms of perampanel include perampanel or perampanel hydrochloride.

9. The method for preparing perampanel long-acting sustained-release microspheres according to any one of claims 5-8, characterized in that, Includes the following steps: S01: Select two or three polylactic acid-glycolic acid copolymers to mix and obtain a mixed reaction solution; when two polylactic acid-glycolic acid copolymers are selected, it is polylactic acid-glycolic acid copolymer 1 and polylactic acid-glycolic acid copolymer 2; when three polylactic acid-glycolic acid copolymers are selected, it is polylactic acid-glycolic acid copolymer 1, polylactic acid-glycolic acid copolymer 2 and polylactic acid-glycolic acid copolymer 3. S02: Add perampanel to the mixed reaction solution, add a good oil-phase solvent, dissolve thoroughly, filter, and obtain an oil-phase solution for later use; S03: Mix and stir the surfactant solution and the aqueous solvent, and let it stand completely; take the supernatant and filter to obtain the aqueous solution for later use; S04: Add the oil phase solution and the aqueous phase solution to the device, adjust the flow rates of the oil phase and the aqueous phase to obtain oil-in-water emulsion droplets, and collect the oil-in-water emulsion droplets; S05: The collected oil-in-water emulsion droplets are dried and washed to obtain the perampanel long-acting sustained-release microspheres.

10. The use of the perampanel long-acting sustained-release microspheres according to any one of claims 5-8 in the preparation of antiepileptic drugs.

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