Drug sustained-release microsphere for injection and preparation method therefor

Abstract

A drug sustained-release microsphere for injection and a preparation method therefor. A sustained-release microsphere preparation for injection prepared by means of the preparation method has a relatively narrow particle size distribution with regard to microspheres, and the release time of the active ingredients of a drug can last about four weeks to six weeks. The small molecule sustained-release microsphere has a stable blood concentration, can maintain the blood concentration within 4-6 weeks relatively well, and has no significant fluctuation in blood concentration, which better avoids the occurrence of toxic side effects.

Description

A kind of sustained-release microspheres for injection and preparation method thereof Technical Field

[0001] The present invention relates to the technical field of sustained-release injections, and more particularly to sustained-release microspheres for injection and a preparation method thereof. Background Art

[0002] Sustained-release preparations are those that continuously release drugs over an extended period of time after administration, achieving a long-lasting effect. These drugs are gaining increasing clinical attention due to their advantages, including fewer dosing times, minimal fluctuations in blood concentrations, diverse routes of administration, minimal irritation, and long-lasting efficacy and safety. Among the various sustained-release preparations currently on the market and in development, oral sustained-release systems, transdermal drug delivery systems, and targeted drug delivery systems are the primary research areas. Sustained-release drugs have also evolved from anti-inflammatory, antipyretic, analgesic, antibacterial, and anti-cancer agents to cell growth factors. Currently, sustained-release preparations primarily come in the form of microcapsules, microspheres, microparticles, nano-microspheres, and membranes.

[0003] Microspheres are tiny spherical entities formed by dispersing or adsorbing drugs within a polymer matrix, with particle sizes generally ranging from 1 to 250 μm. Due to their long-lasting sustained-release or targeted effects, microsphere preparations can significantly improve patient convenience and compliance, demonstrating their clinical advantages and representing a highly promising dosage form. Microsphere preparations offer targeted, sustained-release, long-lasting effects, embolic properties, masking of drug odor and taste, improved drug stability, reduced gastric irritation, and solidification of liquid drugs. Furthermore, microsphere preparations offer significant added value and broad market prospects, making them a hot topic in drug research and development in recent years.

[0004] Currently, there are 14 microsphere-related drugs in the world (two of which have been withdrawn from the market due to clinical inefficiency). Approved domestically include Luye's risperidone, Livzon and Berndt's leuprorelin acetate, and imported products include exenatide, octreotide acetate microspheres, and triptorelin. Triptorelin is a synthetic decapeptide analog of GnRH. Its microsphere formulation was first developed by the French company Ipsen and launched in France in 1986, becoming the world's first peptide microsphere product. The product entered the US market in 1989 and is currently available in over 80 countries. Approved indications include endometriosis, uterine fibroids, premenopausal breast cancer, prostate cancer, and precocious puberty. Ipsen launched the 3-month and 6-month extended-release injectable triptorelin pamoate in France in 2000 and 2010, respectively, with longer dosing cycles. The 3-month extended-release version is indicated for advanced prostate cancer, endometriosis, and precocious puberty, while the 6-month extended-release version is indicated for locally advanced or metastatic prostate cancer and precocious puberty. Decapeptyl's global sales in 2019 were US$480 million. The original product, Decapeptyl (1 month), entered the Chinese market in 2000 under the trade name Decapeptyl. Its indications include metastatic prostate cancer, precocious puberty, endometriosis (stages I to IV), female infertility, and preoperative treatment of uterine fibroids. The daily formulation (triptorelin acetate) was launched in 2004 for the adjuvant treatment of female infertility. The 3-month extended-release version of triptorelin pamoate was launched in 2010 and is approved only for the treatment of locally advanced or metastatic prostate cancer. In addition, Germany's Ferring's Decapeptyl Depot (1-month sustained release) was launched in China in 2001.

[0005] Schizophrenia is a chronic mental illness with a slow or subacute onset, often in young adults. Clinically, it presents as a syndrome of varying symptoms, involving disturbances in perception, thinking, emotion, and behavior, as well as incoordination of mental activity. While patients generally maintain clear consciousness and generally have normal intelligence, some experience cognitive impairment during the course of the disease.

[0006] Currently, the microsphere product used for schizophrenia is risperidone microspheres, a two-week sustained-release formulation developed and launched by Janssen Pharmaceuticals in 2003. Luye Pharma also launched this product in 2021. A 2007 survey on medication compliance among schizophrenia patients in China, conducted jointly by the Chinese Medical Association's Psychiatry Branch and Xi'an Janssen, found that at least 30% of schizophrenia patients have medication compliance issues.

[0007] Brepiprazole (epirazole, prepiprazole) is a well-known atypical antipsychotic drug that modulates the brain's monoaminergic neurotransmission system. It is a partial agonist at 5-hydroxytryptamine (5-HT1A) and dopamine D2 receptors, an antagonist at 5-hydroxytryptamine (5-HT2A) receptors and dopamine α1 / 2 receptors, and has broad binding affinity for other central monoaminergic receptor subtypes. Brepiprazole was jointly developed by Lundbeck Pharmaceuticals of Denmark and Otsuka Pharmaceuticals. In July 2015, brepiprazole was approved by the US FDA for the treatment of schizophrenia and major depressive disorder. In January and July 2018, brepiprazole was approved in Japan and the European Union, respectively. In December 2021, the FDA approved a supplemental new drug application for brepiprazole for the treatment of schizophrenia in children aged 13 to 17 years.

[0008] While the receptor binding characteristics and mechanism of action of irinotecan are not fully understood, irinotecan has been shown to have affinity for multiple receptors, including 5-HT1A, dopamine D2, and D3, and to exhibit antagonistic activity at 5-HT2A, 5-HT2B, 5-HT7, α1, and α2 receptors. Furthermore, it exhibits activity at histamine H1 and muscarinic M1 receptors. Compared with aripiprazole, irinotecan has lower intrinsic D2 receptor antagonism and stronger effects at 5-HT2A receptors, which may help explain irinotecan's lower risk of EPS. The lack of significant 5-HT2C antagonism with irinotecan theoretically reduces the risk of weight gain and metabolic syndrome. irinotecan's low affinity for the histamine system may explain its lower risk of sedation and somnolence.

[0009] Microsphere formulations have been developed for over 30 years and are a key branch of novel drug delivery systems. As a novel drug delivery vehicle, microspheres offer numerous advantages. ① Stable drug properties: Microsphere delivery vehicles allow drugs to maintain their activity in the stomach, resulting in more stable performance. ② Targeted delivery: Microsphere drug delivery vehicles can enhance bioavailability and concentrate drug concentrations in target organs and tissues. ③ Controlled release: Microsphere formulations can control the rate of drug release, prolonging the duration of stable blood drug concentrations. ④ Reduced irritation: Microsphere formulations can reduce drug irritation and mask unpleasant odors and tastes. my country's large population of chronic disease patients, coupled with rising mortality rates from malignant tumors, cerebrovascular disease, and heart disease, will stimulate demand for cardiovascular and oncology drugs, driving drug research and development. Furthermore, my country's rapid socioeconomic development, increasing urbanization, and changing lifestyles leading to increased mental stress are driving demand for medications related to mental illnesses. Microsphere technology is widely used in the development and application of long-acting sustained-release injections due to its potential to prolong drug efficacy, improve patient compliance, and optimize therapeutic outcomes. At present, the five types of microsphere preparations that have been marketed in China have applications in areas including malignant tumors, diabetes, cardiovascular diseases, and mental illnesses.

[0010] Summary of the Invention

[0011] The inventors discovered that using an emulsification method to prepare an injectable sustained-release microsphere formulation containing a pharmaceutical active ingredient and a biocompatible polymer material can overcome poor compliance, reduce unnecessary medication errors and missed doses, and maintain stable blood drug concentrations for a month or even longer. This method requires simultaneous control of the following steps:

[0012] 1. Dissolve the active pharmaceutical ingredient and biocompatible polymer material in an organic solvent to form an organic solution.

[0013] 2. Adjust the mass percentage of biocompatible polymer material and oil phase, adjust the surface morphology of microspheres, and avoid sudden drug release; at the same time, adjust the mass percentage of active pharmaceutical ingredient and organic solvent to achieve a satisfactory drug loading;

[0014] 3. Adjust the amount of surfactant in the external aqueous phase to control the size of the emulsion droplets during the preparation process to form a stable emulsion;

[0015] 4. Adjust the volume ratio of the oil phase and the external water phase, use different emulsification preparation methods (such as shear method, emulsification method, etc.) to optimize the morphology and release of microspheres.

[0016] Therefore, in response to the above technical problems, the purpose of the present invention is to provide a method for preparing sustained-release microspheres for injection. The purpose of the present invention is also to provide sustained-release microspheres for injection, which have a narrow particle size distribution, high encapsulation rate and small burst release.

[0017] In order to achieve the above objectives, the technical solutions of the present invention are as follows:

[0018] A method for preparing sustained-release microspheres for injection comprises the following steps:

[0019] A) dissolving the pharmaceutical active ingredient and the biocompatible polymer material in an organic solvent to prepare an oil phase;

[0020] B) dissolving a surfactant in water to prepare an external aqueous phase;

[0021] C) emulsifying and mixing the oil phase and the external aqueous phase to prepare a mixed emulsion;

[0022] D) solidifying and drying the mixed emulsion to obtain sustained-release microspheres containing the active pharmaceutical ingredient.

[0023] Preferably, the mass percentage of the active pharmaceutical ingredient to the organic solvent is 0.5-10 wt %, more preferably 5%-8 wt %.

[0024] Preferably, the mass percentage of the biocompatible polymer material to the oil phase is 9.5-30 wt %, more preferably, 10%-20 wt %.

[0025] Preferably, the mass percentage concentration of the surfactant in the external aqueous phase is 0.1-10.0 wt %, more preferably, 2%-4 wt %.

[0026] Preferably, the ratio of the mass of the organic solvent to the volume of the external aqueous phase is 1:10-1:300 (g / mL), and more preferably, 1:50-1:100 (g / mL).

[0027] Preferably, the organic solvent is dichloromethane.

[0028] Preferably, the active ingredient of the drug is a small molecule drug, which can be any one of the following: epiriprazole and / or a pharmaceutically acceptable salt thereof, lurasidone and / or a pharmaceutically acceptable salt thereof, cariprazine and / or a pharmaceutically acceptable salt thereof, brelaxaquin and / or a pharmaceutically acceptable salt thereof.

[0029] Preferably, the biocompatible polymer material is one or a mixture of poly(lactic-co-glycolic acid) (PLGA), poly(lactic acid) (PLA), poly(glycolide) (PGA) and poly(vinyl lactone) (PCL).

[0030] Preferably, the surfactant is one or a mixture of polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), β-cyclodextrin, poloxamer 188, Pluronic F88, Pluronic F127, gelatin, glycine, lysine, histidine, arginine, aspartic acid, glutamic acid, span and Tween.

[0031] Preferably, in step D, the mixed emulsion is solidified into wet microspheres, a protective agent is added, and the microspheres are dried.

[0032] Preferably, the preparation method further comprises the following steps: after obtaining the mixed emulsion, stirring, solidifying, filtering, and washing the mixed emulsion to form wet microspheres, and adding a protective agent to the wet microspheres and then drying them to obtain sustained-release microspheres containing the active pharmaceutical ingredient.

[0033] Preferably, the protective agent is one or a mixture of polyethylene glycol (PEG), gelatin, glycerol, mannitol, sucrose, trehalose, lactose, glucose, propylene glycol, sorbitol, zinc chloride, zinc sulfate, zinc acetate and human serum albumin.

[0034] Preferably, other auxiliary materials are added at the same time as the protective agent, and the other auxiliary materials are surfactants or excipients.

[0035] As another aspect of the present invention, there is also provided a sustained-release microsphere for injection prepared according to any one of the above methods.

[0036] According to the present invention, in step A) of the method for preparing the sustained-release injectable microspheres of the present invention, the oil phase contains a pharmaceutically active ingredient. The pharmaceutically active ingredient may be eripiprazole or a pharmaceutically acceptable salt thereof; lurasidone or a pharmaceutically acceptable salt thereof; cariprazine or a pharmaceutically acceptable salt thereof; or brelaxaquin or a pharmaceutically acceptable salt thereof.

[0037] In an embodiment of the present invention, the mass percentage of the active pharmaceutical ingredient to the organic solvent is 0.5-10 wt %, and the calculation formula is: mass percentage of the active pharmaceutical ingredient to the organic solvent = mass of the active pharmaceutical ingredient / mass of the organic solvent * 100%.

[0038] In a preferred embodiment according to the present invention, the biocompatible polymer material is poly(lactic acid-co-glycolic acid) (PLGA), and the molar ratio of glycolide (LA) to lactide (GA) in PLGA is 25:75 to 85:15, the molecular weight is 5 to 100 kilodaltons, and the viscosity characteristic is 0.1 to 0.6 dL / g; wherein, the type and molecular weight of PLGA include but are not limited to: PLGA (LA:GA is 50:50; Mw 10,000 to 25,000 daltons), PLGA (LA:GA is 55:45; Mw 15,000 to 55,000 daltons), PLGA (LA:GA is 65:35; Mw 15,000 to 55,000 daltons), PLGA (LA:GA is 75:25; Mw 10,000 to 25,000 daltons), PLGA (LA:GA is 50:50; Mw 20,000 to 80,000 Daltons), PLGA (LA:GA is 75:25; Mw 30,000 to 90,000 Daltons), or PLGA (LA:GA is 85:15; Mw 55,000 to 85,000 Daltons), etc.

[0039] In another preferred embodiment according to the present invention, the biocompatible polymer material is polylactic acid (PLA) with a molecular weight of 10 to 55 kilodaltons and a viscosity characteristic of 0.1 to 0.6 dL / g, such as PLA (Mw 10,000 to 25,000 Daltons) and PLA (Mw 15,000 to 55,000 Daltons).

[0040] In the present invention, the mass percentage of the biocompatible polymer material to the oil phase is calculated as follows: mass percentage of the biocompatible polymer material to the oil phase = mass of the biocompatible polymer material / (mass of the biocompatible polymer material + mass of the organic solvent + mass of the active pharmaceutical ingredient) * 100%.

[0041] In an embodiment according to the present invention, the mass percentage of PLGA to oil phase is preferably 9.5-30 wt %.

[0042] According to the present invention, in step B) of the method for preparing sustained-release microspheres for injection, the surfactant can be selected from one or a mixture of polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), β-cyclodextrin, poloxamer 188, Pluronic F88, gelatin, glycine, lysine, histidine, arginine, aspartic acid, glutamic acid, span and Tween; preferably, the surfactant is PVA, PVP or a combination thereof, and particularly preferably, the surfactant is PVA.

[0043] In the present invention, the mass percentage concentration of the surfactant in the external water phase is calculated as follows: mass percentage concentration of the surfactant in the external water phase = mass of the surfactant / (mass of the surfactant+mass of water)*100%.

[0044] In an embodiment according to the present invention, the mass percentage concentration of the surfactant in the external aqueous phase is preferably 0.1-10.0 wt %.

[0045] According to the present invention, in step C) of the method for preparing sustained-release injectable microspheres, the emulsification preparation method can be a high-shear emulsifier, a high-pressure homogenizer, or a combination thereof. The rotation speed of the high-shear emulsifier can be 8000 rpm to 10000 rpm, and the shearing time can be 1 min to 5 min.

[0046] In a preferred embodiment of the present invention, in step C) of the method for preparing sustained-release microspheres for injection, the ratio of the mass of the organic solvent to the volume of the external aqueous phase is preferably 1:10-1:300, expressed in g / mL.

[0047] According to the present invention, in step D) of the method for preparing sustained-release microspheres for injection, if stirring is performed, the stirring speed may be 1500-5000 rpm, and the stirring time may be 15-250 min.

[0048] According to the present invention, in step D) of the method for preparing sustained-release microspheres for injection, the curing temperature may be 5° C. to 45° C., and the curing time may be 2 h to 20 h.

[0049] According to the present invention, a protective agent is added to the wet microspheres obtained by solidifying the mixed emulsion in step D) of the method for preparing sustained-release microspheres for injection. The protective agent is an excipient added to the wet microspheres to increase the fluidity and dispersibility of the dry microsphere powder obtained according to step D), regulate the osmotic pressure of the microspheres, and protect the stability and activity of the small molecule drug. The protective agent can be selected from one or a mixture of polyethylene glycol (PEG), gelatin, glycerol, mannitol, sucrose, trehalose, lactose, glucose, propylene glycol, sorbitol, zinc chloride, zinc sulfate, zinc acetate, and human serum albumin; preferably, the protective agent is mannitol.

[0050] The present invention also provides a sustained-release microsphere for injection, comprising the sustained-release microsphere for injection prepared according to the above method, wherein the sustained-release microsphere for injection comprises active ingredients of epiriprazole, lurasidone, cariprazine, and brelatin, a biocompatible polymer carrier material, and other pharmaceutically acceptable excipients.

[0051] The sustained-release microsphere preparation for injection has a sustained-release period of about 30 to 45 days, i.e., about four to six weeks, for example, about four weeks, five weeks, six weeks, or about one month, or one and a half months. The difference between "about" and "approximately" is "(±1 to 6 days)."

[0052] According to the present invention, the sustained-release microspheres for injection prepared by the above method have a particle size (D50) of 5-200 μm, and not only the particle size distribution of the microspheres is narrow (SPAN value (SPAN = (D 90 -D 10 ) / D 50 ) is less than 3), and the encapsulation efficiency is significantly improved and the burst release rate is reduced. Furthermore, compared to existing daily oral tablets, the injectable sustained-release microsphere preparation containing the pharmaceutical active ingredient according to the present invention provides a completely new mode of administration, leveraging the advantages of long-acting sustained-release microspheres. Ideally, it can achieve a sustained release of the drug for 4-6 weeks, providing a more optimal route of administration for patients with poor gastrointestinal absorption while also reducing the occurrence of drug tolerance and toxic side effects.

[0053] The technical solution of the present invention has the following advantages:

[0054] The preparation method of the present invention is simple to operate. At the same time, the microspheres prepared according to the preparation method have a narrow particle size distribution, significantly improve the encapsulation rate, reduce the burst release rate, extend the release time, and can quickly reach the therapeutic concentration.

[0055] 1) By controlling the ratio of the active pharmaceutical ingredient and the biocompatible polymer material in the organic solvent, the mass percentage concentration of the surfactant in the external aqueous phase, and the ratio of the mass of the organic solvent to the volume of the external aqueous phase in the preparation method, a microsphere preparation containing the active pharmaceutical ingredient is obtained by emulsification, and has a 24-hour in vitro burst release rate of less than 10%, a high encapsulation efficiency, and a simple preparation method, which is suitable for the industrialization of the microsphere preparation production process.

[0056] 2) The present invention also provides a method for adding a protective agent to the wet microspheres, which increases the fluidity and dispersibility of the microsphere dry powder, regulates the osmotic pressure of the microspheres, and protects the stability and activity of the drug.

[0057] 3) The sustained-release microsphere preparation for injection prepared according to the preparation method of the present invention has a narrow particle size distribution and can release the active pharmaceutical ingredient for approximately four to six weeks. Blood concentrations are stable. The small molecule sustained-release microspheres can effectively maintain blood drug concentrations for 4-6 weeks without significant fluctuations in blood drug concentrations, thus effectively preventing the occurrence of toxic side effects. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] FIG1 is an in vitro release-time curve of sustained-release microspheres for injection prepared according to Examples 1, 2, 3, 10, and 14 of the present invention;

[0059] FIG2 is an electron microscope image of the microspheres prepared in Example 1;

[0060] FIG3 is an electron microscope image of the microspheres prepared in Example 3;

[0061] FIG4 is an electron microscope image of the microspheres prepared in Example 7. DETAILED DESCRIPTION

[0062] The present invention will be further described below with reference to the accompanying drawings and specific embodiments, but the present invention should not be limited to the specific embodiments disclosed below.

[0063] In the following examples, small molecule microsphere preparations for injection will be exemplarily prepared by the method for preparing small molecule microspheres for injection according to the present invention.

[0064] The active ingredient of the present invention, ipilimumab, may be a compound having a molecular formula of C 25 H 27 N3O2S, an epiriprazole compound with a molar mass of 433.57 g / mol (DOI:10.1111 / pcn.13438).

[0065] Unless otherwise specified, the methods used in the following examples are commonly used by those skilled in the art.

[0066] Example 1 (epiprazole)

[0067] 1.2 g of irinotecan and 2.8 g of PLGA (wherein the molar ratio of glycolide to lactide is 50:50 and the intrinsic viscosity is 0.24 dL / g) are added to 24 g of dichloromethane and dissolved, forming an oil phase. 1200 mL of a 2 wt% aqueous solution of polyvinyl alcohol (PVA) for injection is prepared as an external aqueous phase. The oil phase and the external aqueous phase are mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent is removed from the emulsion at a stirring speed of 350 rpm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours. After the solidification is completed, the emulsion is filtered and the microspheres are collected using a filter. A protective agent is added and the microspheres are freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0068] The average particle size (D50) of the microspheres of the preparation was 45 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.22.

[0069] Example 2 (epiprazole)

[0070] 1.2 g of irinotecan and 3.5 g of PLGA (wherein the molar ratio of glycolide to lactide is 50:50 and the intrinsic viscosity is 0.24 dL / g) are added to 17.2 g of dichloromethane and dissolved, forming an oil phase. 860 mL of a 2 wt% aqueous solution of polyvinyl alcohol (PVA) for injection is prepared as an external aqueous phase. The oil phase and the external aqueous phase are mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent is removed from the emulsion at a stirring speed of 350 rpm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours. After the solidification is completed, the emulsion is filtered and the microspheres are collected using a filter. After adding a protective agent, the microspheres are freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0071] The average particle size (D50) of the microspheres of this preparation was 40 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.12.

[0072] Example 3 (epiprazole)

[0073] 1.2 g of irinotecan and 4.6 g of PLGA (wherein the molar ratio of glycolide to lactide is 50:50 and the intrinsic viscosity is 0.24 dL / g) are added to 17.2 g of dichloromethane and dissolved, forming an oil phase. 860 mL of a 2 wt% aqueous solution of polyvinyl alcohol (PVA) for injection is prepared as an external aqueous phase. The oil phase and the external aqueous phase are mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent is removed from the emulsion at a stirring speed of 350 rpm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours. After the solidification is completed, the emulsion is filtered and the microspheres are collected using a filter. A protective agent is added and the microspheres are freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0074] The average particle size (D50) of the microspheres of this preparation was 38 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.10.

[0075] Example 4 (epiprazole)

[0076] 1.2 g of irinotecan and 4.7 g of PLGA (wherein the molar ratio of glycolide to lactide is 50:50 and the intrinsic viscosity is 0.24 dL / g) are added to 17.2 g of dichloromethane and dissolved together to form an oil phase; 860 mL of a 2 wt% aqueous solution of polyvinyl alcohol (PVA) for injection is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion; the organic solvent is removed from the emulsion at a stirring speed of 350 rpm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours; the emulsion after solidification is filtered and the microspheres are collected using a filter, and a protective agent is added and then freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0077] The average particle size (D50) of the microspheres of this preparation was 40 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.12.

[0078] Example 5 (epiprazole)

[0079] 1.2 g of irinotecan and 3.5 g of PLGA (wherein the molar ratio of glycolide to lactide is 50:50 and the intrinsic viscosity is 0.24 dL / g) are added to 17.2 g of dichloromethane and dissolved, forming an oil phase. 860 mL of a 4 wt% aqueous solution of polyvinyl alcohol (PVA) for injection is prepared as an external aqueous phase. The oil phase and the external aqueous phase are mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent is removed from the emulsion at a stirring speed of 350 rpm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours. After the solidification is completed, the emulsion is filtered and the microspheres are collected using a filter. A protective agent is added and the microspheres are freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0080] The average particle size (D50) of the microspheres of this preparation was 43 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.19.

[0081] Example 6 (epiprazole)

[0082] 1.2 g of irinotecan and 3.5 g of PLGA (wherein the molar ratio of glycolide to lactide is 50:50 and the intrinsic viscosity is 0.24 dL / g) are added to 17.2 g of dichloromethane and dissolved, forming an oil phase. 1380 mL of a 3 wt% aqueous solution of polyvinyl alcohol (PVA) for injection is prepared as an external aqueous phase. The oil phase and the external aqueous phase are mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent is removed from the emulsion at a stirring speed of 400 rpm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours. After the solidification is completed, the emulsion is filtered and the microspheres are collected using a filter. A protective agent is added and the microspheres are freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0083] The average particle size (D50) of the microspheres of the preparation was 45 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.22.

[0084] Example 7 (epiprazole)

[0085] 1.2 g of irinotecan and 3.5 g of PLGA (wherein the molar ratio of glycolide to lactide is 75:25 and the intrinsic viscosity is 0.19 dL / g) are added to 17.2 g of dichloromethane and dissolved, forming an oil phase. 1380 mL of a 3 wt% aqueous solution of polyvinyl alcohol (PVA) for injection is prepared as an external aqueous phase. The oil phase and the external aqueous phase are mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent is removed from the emulsion at a stirring speed of 400 rpm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours. After the solidification is completed, the emulsion is filtered and the microspheres are collected using a filter. A protective agent is added and the microspheres are freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0086] The average particle size (D50) of the microspheres of the preparation was 45 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.32.

[0087] Example 8 (epiprazole)

[0088] 1.2 g of irinotecan and 3.5 g of PLGA (wherein the molar ratio of glycolide to lactide is 75:25 and the intrinsic viscosity is 0.19 dL / g) are added to 17.2 g of dichloromethane and dissolved, forming an oil phase. 1720 mL of a 3 wt% aqueous solution of polyvinyl alcohol (PVA) for injection is prepared as an external aqueous phase. The oil phase and the external aqueous phase are mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent is removed from the emulsion at a stirring speed of 500 rpm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours. After the solidification is completed, the emulsion is filtered and the microspheres are collected using a filter. A protective agent is added and the microspheres are freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0089] The average particle size (D50) of the microspheres of the preparation was 40 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.18.

[0090] Example 9 (epiprazole)

[0091] 0.18 g of irinotecan and 6.21 g of PLGA (wherein the molar ratio of glycolide to lactide is 75:25 and the intrinsic viscosity is 0.19 dL / g) were added to 35 g of dichloromethane and dissolved, forming the oil phase. 2800 mL of a 4 wt% aqueous solution of polyvinyl alcohol (PVA) for injection was prepared as the external aqueous phase. The oil phase and the external aqueous phase were mixed using a high-shear emulsifier at a shear rate of 3000 rpm for 2 minutes to form an emulsion. The organic solvent was removed from the emulsion at a stirring speed of 500 rpm and a temperature of 25° C., and the microspheres were volatilized and solidified for 4 hours. The solidified emulsion was filtered and collected using a filter, and a protective agent was added before freeze-drying to obtain an irinotecan sustained-release microsphere preparation.

[0092] The average particle size (D50) of the microspheres of the preparation was 40 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.22.

[0093] Example 10 (epiprazole)

[0094] 1.2 g of irinotecan and 3.94 g of PLGA (wherein the molar ratio of glycolide to lactide is 75:25 and the intrinsic viscosity is 0.19 dL / g) were added to 17.2 g of dichloromethane and dissolved, forming an oil phase. 1380 mL of a 4 wt% aqueous solution of polyvinyl alcohol (PVA) for injection was prepared, forming an external aqueous phase. The oil phase and the external aqueous phase were mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent was removed from the emulsion at a stirring speed of 500 rpm and a temperature of 25° C., and the microspheres were volatilized and solidified for 4 hours. After the solidification, the emulsion was filtered and the microspheres were collected using a filter. After adding a protective agent, the microspheres were freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0095] The average particle size (D50) of the microspheres of the preparation was 35 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.25.

[0096] Example 11 (epiprazole)

[0097] 1.2 g of irinotecan and 3.5 g of PLGA (wherein the molar ratio of glycolide to lactide is 75:25 and the intrinsic viscosity is 0.19 dL / g) are added to 17.2 g of dichloromethane and dissolved together to form an oil phase; 1380 mL of a 0.1 wt% aqueous solution of polyvinyl alcohol (PVA) for injection is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion; the organic solvent is removed from the emulsion at a stirring speed of 500 rpm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours; the emulsion after solidification is filtered and the microspheres are collected using a filter, and a protective agent is added and then freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0098] The average particle size (D50) of the microspheres of the preparation was 50 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.35.

[0099] Example 12 (epiprazole)

[0100] 1.2 g of irinotecan and 3.5 g of PLGA (wherein the molar ratio of glycolide to lactide is 75:25 and the intrinsic viscosity is 0.19 dL / g) were added to 17.2 g of dichloromethane and dissolved, forming an oil phase. 1380 mL of a 10 wt% aqueous solution of polyvinyl alcohol (PVA) for injection was prepared, forming an external aqueous phase. The oil phase and the external aqueous phase were mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent was removed from the emulsion at a stirring speed of 500 rpm and a temperature of 25° C., and the microspheres were volatilized and solidified for 4 hours. After the solidification, the emulsion was filtered and collected using a filter, and a protective agent was added and then freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0101] The average particle size (D50) of the microspheres of this preparation was 48 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.19.

[0102] Example 13 (epiprazole)

[0103] 1.2 g of irinotecan and 3.5 g of PLGA (wherein the molar ratio of glycolide to lactide is 75:25 and the intrinsic viscosity is 0.19 dL / g) are added to 17.2 g of dichloromethane and dissolved, forming an oil phase. 172 mL of a 3 wt% aqueous solution of polyvinyl alcohol (PVA) for injection is prepared as an external aqueous phase. The oil phase and the external aqueous phase are mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent is removed from the emulsion at a stirring speed of 500 rpm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours. After the solidification is completed, the emulsion is filtered and the microspheres are collected using a filter. A protective agent is added and the microspheres are freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0104] The average particle size (D50) of the microspheres of this preparation was 38 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.18.

[0105] Example 14 (epiprazole)

[0106] 1.2 g of irinotecan and 3.5 g of PLGA (wherein the molar ratio of glycolide to lactide is 75:25 and the intrinsic viscosity is 0.19 dL / g) were added to 17.2 g of dichloromethane and dissolved, forming an oil phase. 5160 mL of a 3 wt% aqueous solution of polyvinyl alcohol (PVA) for injection was prepared, forming an external aqueous phase. The oil phase and the external aqueous phase were mixed using a high shear emulsifier at a shear rate of 3000 rpm and an emulsification time of 2 minutes to form an emulsion. The organic solvent was removed from the emulsion at a stirring speed of 500 rpm and a temperature of 25° C., and the microspheres were volatilized and solidified for 4 hours. After the solidification, the emulsion was filtered and collected using a filter, and a protective agent was added and then freeze-dried to obtain an irinotecan sustained-release microsphere preparation.

[0107] The average particle size (D50) of the microspheres of the preparation was 50 μm, and the SPAN value (SPAN=(D90-D10) / D50) was 1.38.

[0108] Test Example 1: In vitro release rate test

[0109] In this test example 1, the sustained-release microsphere preparation for injection of epiliprazole prepared in the above examples 1-14 was used as an example to conduct an in vitro release rate test. The specific method is as follows:

[0110] 20 mg of the sustained-release microsphere preparation for injection prepared in Examples 1-14 were accurately weighed and added to a 15 mL centrifuge tube. 15 mL of preheated release medium was added, and the release medium was 0.05 M pH 7.4 phosphate buffer. The tube was then placed in a 37°C incubator. 1 mL of sample was taken at the corresponding time point and 1 mL of the corresponding release medium was added. Figure 1 (for Examples 1, 2, 3, 10, and 14) exemplarily shows the cumulative release rate curve obtained from the test. For the 24-hour burst release rate, release duration, and total cumulative release rate of Examples 1-14 obtained from the test, see Table 1:

[0111] Table 1 24-hour burst release rate, in vitro release duration and total cumulative release rate of Examples 1-14 obtained by testing

[0112] Combining the results in Table 1 and Figure 1, it can be seen that the sustained-release microsphere preparation for injection prepared according to the method of the present invention has a stable release performance; based on the composition of the biocompatible polymer carrier contained therein, the preparation can continuously release the drug for more than about four weeks, and the drug is basically completely released (at least about 85%) without the phenomenon of sudden drug release, thus meeting the requirements of sustained release.

Claims

1. A method for preparing sustained-release microspheres for injection, comprising the following steps: A) dissolving the active pharmaceutical ingredient and the biocompatible polymer material in an organic solvent to prepare an oil phase; B) dissolving a surfactant in water to prepare an external aqueous phase; C) emulsifying and mixing the oil phase and the external aqueous phase to obtain a mixed emulsion; D) solidifying and drying the mixed emulsion to obtain sustained-release microspheres containing the active pharmaceutical ingredient.

2. The method according to claim 1, characterized in that: The mass percentage of the active pharmaceutical ingredient to the organic solvent is 0.5-10wt%, and the mass percentage of the biocompatible polymer material to the oil phase is 9.5-30wt%.

3. The method according to claim 1, characterized in that: The mass percentage concentration of the surfactant in the external water phase is 0.1-10.0wt%.

4. The method according to claim 1, characterized in that: The ratio of the mass of the organic solvent to the volume of the external aqueous phase is 1:10-1:300 g / mL.

5. The method according to claim 1, characterized in that: The organic solvent is dichloromethane.

6. The method according to claim 1, characterized in that: The active pharmaceutical ingredient is any one of the following: epiprazole and / or a pharmaceutically acceptable salt thereof, lurasidone and / or a pharmaceutically acceptable salt thereof, cariprazine and / or a pharmaceutically acceptable salt thereof, brelasarzine and / or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1, characterized in that: The biocompatible polymer material is one or a mixture of polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polyglycolide (PGA) and poly(vinyl acetate) (PCL).

8. The method according to claim 1, characterized in that: The surfactant is one or a mixture of polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), β-cyclodextrin, poloxamer 188, Pluronic F88, Pluronic F127, gelatin, glycine, lysine, histidine, arginine, aspartic acid, glutamic acid, tween.

9. The method according to claim 1, characterized in that: The method further comprises the following steps: after obtaining the mixed emulsion, stirring, solidifying, filtering and washing the mixed emulsion to form wet microspheres, and adding a protective agent to the wet microspheres and then drying them to obtain sustained-release microspheres containing active pharmaceutical ingredients, wherein the protective agent is one or a mixture of several selected from the group consisting of polyethylene glycol (PEG), gelatin, glycerol, mannitol, sucrose, trehalose, lactose, glucose, propylene glycol, sorbitol, zinc chloride, zinc sulfate, zinc acetate and human serum albumin.

10. A sustained-release microsphere for injection prepared according to the method of any one of the preceding claims.

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