Drug sustained release microsphere for injection and preparation method thereof

Abstract

The invention relates to a drug sustained release microsphere for injection and a preparation method thereof. According to the sustained-release microsphere preparation for injection prepared by the preparation method disclosed by the invention, the particle size distribution of the microspheres is relatively narrow, and the release time of active pharmaceutical ingredients can last for about four weeks to six weeks. The micromolecular sustained-release microsphere is stable in blood concentration, can well maintain the blood concentration within 4-6 weeks, does not have large fluctuation of the blood concentration, and better avoids the occurrence of toxic and side effects.

Description

Technical Field

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

[0002] Sustained-release preparations refer to preparations that can continuously release drugs for a long time after administration to achieve long-term effects. This type of drug has the advantages of less administration times, less fluctuation in blood drug concentration, diversified administration routes, less irritation, long-lasting efficacy, and safety, and is increasingly valued in clinical practice. Among the various sustained-release preparations on the market and in development, the main research directions are oral sustained-release systems, transdermal drug delivery systems, and targeted drug delivery systems. Sustained-release drugs have also evolved from anti-inflammatory, antipyretic, analgesic, antibacterial, and anti-cancer to cell growth factors. At present, the main forms of sustained-release preparations are microcapsules, microspheres, microparticles, nano-microspheres, and membranes.

[0003] Microspheres refer to tiny spherical entities formed by drugs being dispersed or adsorbed in a polymer matrix, and their particle size is generally between 1 and 250 μm. Since microsphere preparations have long-lasting sustained release or targeting effects, they can greatly improve the convenience and compliance of patients' medication. They have shown their advantages in clinical practice and are a dosage form with great potential. Microsphere preparations have the characteristics of targeting, sustained release and long-term effect, embolic properties, masking the bad smell and taste of drugs, improving the stability of drugs and reducing gastric irritation, and solidification of liquid drugs. In addition, microsphere preparations have high added value and broad market prospects. In recent years, they have become a hot spot in drug research and development.

[0004] There are currently 14 microsphere-related drugs in the world (two of which have been withdrawn from the market due to clinical effects). Among them, the domestically approved ones include Luye's risperidone, Livzon and Berndt's leuprorelin acetate, and the imported ones include exenatide, octreotide acetate microspheres, triptorelin, etc. Triptorelin is a synthetic decapeptide analog of GnRH. Its microsphere preparation was first developed by the French company Ipsen and launched in France in 1986. It is the world's first polypeptide microsphere product. The product entered the US market in 1989 and is currently on the market in more than 80 countries. The approved indications include endometriosis, uterine fibroids, premenopausal breast cancer, prostate cancer, and precocious puberty. Ipsen launched the 3-month and 6-month sustained-release injectable triptorelin pamoate in France in 2000 and 2010, respectively. The 3-month sustained-release is indicated for advanced prostate cancer, endometriosis, and precocious puberty, and the 6-month sustained-release 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 dosage form (triptorelin acetate) was launched in 2004 and is suitable for the adjuvant treatment of female infertility. The 3-month sustained-release triptorelin pamoate was launched in 2010 and is only approved for the treatment of locally advanced or metastatic prostate cancer. In addition, Decapeptyl Depot (1-month sustained release) from Germany's Ferring was launched in China in 2001.

[0005] Schizophrenia is a chronic mental illness that usually develops slowly or subacutely in young adults. Clinically, it often manifests as a syndrome with different symptoms, involving multiple disorders in perception, thinking, emotion, behavior, and incoordination of mental activities. Patients are generally conscious and have basically normal intelligence, but some patients will experience cognitive impairment during the course of the disease.

[0006] The microsphere products currently used for schizophrenia include risperidone microspheres, a 2-week sustained-release preparation developed and marketed by Janssen Pharmaceuticals in 2003. Luye Pharma also launched this product in 2021. In 2007, the Chinese Medical Association Psychiatry Branch and Xi'an Janssen conducted a survey on medication compliance among domestic schizophrenia patients and found that at least 30% of schizophrenia patients had medication compliance problems.

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

[0008] Although the mechanism of action of the receptor binding characteristics of epriprazole is not fully understood, it has been shown that epriprazole has affinity for multiple receptors such as 5-HT1A, dopamine D2 and D3, and also has antagonistic effects on 5-HT2A, 5-HT2B, 5-HT7, α1, and α2 receptors. In addition, it also exhibits activity on histamine H1 and muscarinic M1 receptors. Compared with its adverse reactions and aripiprazole, epriprazole has lower intrinsic D2 receptor antagonistic activity and a stronger effect on 5-HT2A receptors, which may help explain the lower EPS risk of epriprazole. The lack of significant 5-HT2C antagonism by epriprazole theoretically leads to a lower tendency to weight gain and metabolic syndrome. The low affinity of epriprazole for the histamine system can explain its lower risk of sedation and somnolence.

[0009] The development of microsphere preparations has gone through more than 30 years and is an important branch of new preparations. As one of the new drug carriers, microspheres have many advantages. ① Stable drug properties: Through microsphere carriers, drugs can remain active in the stomach and perform more stably. ② Targeting: Microsphere drug carriers can improve bioavailability and concentrate drug concentrations in target organs and target tissues. ③ Sustained and controlled release: Microsphere preparations can control the rate of drug release and prolong the time that blood drug concentrations remain stable. ④ Reduce irritation: Microsphere preparations can reduce drug irritation and have the effect of masking the bad smell and taste of drugs. Due to its characteristics of extending the effectiveness of drugs, improving patient compliance, and optimizing treatment effects, microsphere technology is widely used in the development and application of long-acting sustained-release injections. At present, the five types of microsphere preparations that have been launched in China have applications in areas such as malignant tumors, diabetes, cardiovascular diseases, and mental illnesses. Summary of the invention

[0010] The inventors found that by using an emulsification method to prepare an injectable sustained-release microsphere preparation containing active pharmaceutical ingredients and biocompatible polymer materials, poor compliance can be overcome, unnecessary situations such as wrong medication and missed medication can be reduced, and stable blood drug concentrations can be maintained for one month or even longer. This method requires simultaneous regulation of the following steps:

[0011] 1. Dissolve the active pharmaceutical ingredient and biocompatible polymer material in an organic solvent to form an organic solution.

[0012] 2. Adjust the mass percentage of biocompatible polymer materials and oil phase, adjust the surface morphology of microspheres, and avoid sudden release of drugs; at the same time, adjust the mass percentage of active drug ingredients and organic solvents to achieve a satisfactory drug loading;

[0013] 3. Adjust the amount of surfactant in the external water phase to control the size of the emulsion droplets during the preparation process to form a stable emulsion;

[0014] 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 the microspheres.

[0015] Therefore, in view of the above technical problems, the object of the present invention is to provide a method for preparing sustained-release microspheres for injection. The present invention also provides sustained-release microspheres for injection, which have a narrow particle size distribution, a high encapsulation rate and a small burst release.

[0016] In order to achieve the above purpose, the technical solution of the present invention is as follows:

[0017] A method for preparing sustained-release microspheres for injection comprises the following steps:

[0018] A) dissolving the active pharmaceutical ingredient and the biocompatible polymer material in an organic solvent to prepare an oil phase;

[0019] B) dissolving a surfactant in water to prepare an external aqueous phase;

[0020] C) emulsifying and mixing the oil phase and the external aqueous phase to obtain a mixed emulsion;

[0021] D) solidifying and drying the mixed emulsion to obtain sustained-release microspheres containing the active pharmaceutical ingredient.

[0022] Preferably, the mass percentage of the active pharmaceutical ingredient to the organic solvent is 0.5-10 wt %, and more preferably, 5%-8 wt %.

[0023] Preferably, the mass percentage of the biocompatible polymer material to the oil phase is 9.5-30 wt %, and more preferably, 10%-20 wt %.

[0024] Preferably, the mass percentage concentration of the surfactant in the external water phase is 0.1-10.0 wt %, and more preferably, 2%-4wt %.

[0025] 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).

[0026] Preferably, the organic solvent is dichloromethane.

[0027] 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.

[0028] Preferably, the biocompatible polymer material is one or a mixture of polylactic acid-co-glycolic acid (PLGA), polylactic acid (PLA), polyglycolide (PGA) and poly(vinyl acetate) (PCL).

[0029] 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.

[0030] Preferably, in step D, the mixed emulsion is solidified into wet microspheres, a protective agent is added, and drying is performed.

[0031] 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 active pharmaceutical ingredients.

[0032] 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.

[0033] Preferably, other auxiliary materials are added together with the protective agent, and the other auxiliary materials are surfactants or excipients.

[0034] 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.

[0035] According to the present invention, in step A) of the method for preparing the sustained-release microspheres for injection of the present invention, the oil phase contains a pharmaceutically active ingredient. The pharmaceutically active ingredient may be epiprazole or a pharmaceutically acceptable salt thereof; lurasidone or a pharmaceutically acceptable salt thereof; cariprazine or a pharmaceutically acceptable salt thereof; brelasaqin or a pharmaceutically acceptable salt thereof.

[0036] In an embodiment according to the present invention, the mass percentage of the active pharmaceutical ingredient to the organic solvent is 0.5-10wt%, 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%.

[0037] 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 25:75-85:15, the molecular weight is 5-100 kilodaltons, and the viscosity characteristic is 0.1-0.6 dL / g; wherein the model and molecular weight of PLGA include but are not limited to: PLGA (LA:GA is 50:50; Mw10000-25000 Daltons), PLGA (LA:GA is 55:45; Mw1 5000-55000 Daltons), PLGA (LA:GA is 65:35; Mw 15000-55000 Daltons), PLGA (LA:GA is 75:25; Mw 10000-25000 Daltons), PLGA (LA:GA is 50:50; Mw 20000-80000 Daltons), PLGA (LA:GA is 75:25; Mw 30000-90000 Daltons), or PLGA (LA:GA is 85:15; Mw 55000-85000 Daltons), etc.

[0038] 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 10000 to 25000 Daltons) and PLA (Mw 15000 to 55000 Daltons).

[0039] 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%.

[0040] In the embodiment according to the present invention, the mass percentage of PLGA to oil phase is preferably 9.5-30 wt %.

[0041] 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.

[0042] 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 water phase is preferably 0.1-10.0 wt %.

[0045] According to the present invention, in step C) of the method for preparing sustained-release microspheres for injection, 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, 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 microsphere dry powder obtained according to step D), and to adjust the osmotic pressure of the microspheres and protect the stability and activity of small molecule drugs. 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, including the sustained-release microsphere for injection prepared according to the above method, the sustained-release microsphere for injection includes active ingredients of epiriprazole, lurasidone, cariprazine, and brelasazone, biocompatible polymer carrier materials, and other pharmaceutically acceptable excipients.

[0051] The sustained release time of the injection sustained-release microsphere preparation is about 30 to 45 days, that is, about four to six weeks, for example, about four weeks, five weeks, six weeks, or about one month, 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 microsphere particle size (D50) of 5-200 μm, and not only a narrow microsphere particle size distribution (SPAN value (SPAN = (D 90 -D 10 ) / D 50 ) is less than 3), and the encapsulation rate is significantly improved and the burst release rate is reduced. In addition, compared with the existing daily oral tablets, the sustained-release microsphere preparation for injection containing the active pharmaceutical ingredient according to the present invention provides a new way of medication, giving full play to the advantages of long-acting sustained-release microspheres. Under ideal conditions, the sustained release time of the drug can be achieved for 4-6 weeks, providing a better route of administration for patients with poor gastrointestinal absorption, while 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 invention is easy to operate, and the microspheres prepared by the preparation method have a narrow particle size distribution, significantly improve the encapsulation rate, reduce the burst release rate, prolong 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 obtained by emulsification has a 24-hour in vitro burst release rate of less than 10%, a high encapsulation rate, 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 wet microspheres, which increases the fluidity and dispersibility of the microsphere dry powder, and adjusts 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 by the preparation method of the present invention has a narrow particle size distribution of the microspheres and a release time of the active drug ingredient of about four to six weeks. The blood concentration is stable. The small molecule sustained-release microspheres can maintain the blood drug concentration well within 4-6 weeks without large fluctuations in blood drug concentration, and better avoid the occurrence of toxic side effects. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0059] Figure 2 This is an electron microscope image of the microspheres prepared in Example 1;

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

[0061] Figure 4 This is an electron microscope image of the microspheres prepared in Example 7. DETAILED DESCRIPTION

[0062] The present invention will be further described below in conjunction with 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 drug of epiriprazole in the present invention may be a compound having a molecular formula of C 25 H 27 N 3 O 2 S, an epiprazole 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 (epirazole)

[0067] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 1200 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 2 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 minutes, and the mixture is uniformly mixed 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 collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole 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 (epiprazol)

[0070] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 860 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 2 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 min, and the mixture is uniformly mixed 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 collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole sustained-release microsphere preparation.

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

[0072] Example 3 (epiprazol)

[0073] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 860 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 2 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 minutes, and the mixture is uniformly mixed 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 collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole sustained-release microsphere preparation.

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

[0075] Example 4 (epiprazol)

[0076] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 860 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 2 wt % is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 min, and the mixture is uniformly mixed 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 collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole sustained-release microsphere preparation.

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

[0078] Example 5 (epirazole)

[0079] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 860 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 4 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 minutes, and the mixture is uniformly mixed 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 collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole sustained-release microsphere preparation.

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

[0081] Example 6 (epiprazol)

[0082] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 1380 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 3 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 minutes, and the mixture is uniformly mixed 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; the emulsion after solidification is filtered and collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole 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 (epiprazol)

[0085] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 1380 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 3 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 minutes, and the mixture is uniformly mixed 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; the emulsion after solidification is filtered and collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole 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 (epiprazol)

[0088] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 1720 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 3 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 min, and the mixture is uniformly mixed to form an emulsion; the organic solvent is removed from the emulsion at a stirring speed of 500 pm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours; the emulsion after solidification is filtered and collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole 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 (epiprazol)

[0091] 0.18g of epiriprazole and 6.21g of PLGA (wherein the molar ratio of glycolide to lactide is 75:25 and the intrinsic viscosity is 0.19dL / g) are added to 35g of dichloromethane and mixed and dissolved as an oil phase; 2800mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 4wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000rpm, the emulsification time is 2min, and the mixture is uniformly mixed to form an emulsion; the organic solvent is removed from the emulsion at a stirring speed of 500pm and a temperature of 25°C, and the microspheres are volatilized and solidified for 4 hours; the emulsion after solidification is filtered and collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole 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 (epirazole)

[0094] 1.2 g of epiriprazole 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) are added to 17.2 g of dichloromethane and mixed and dissolved as an oil phase; 1380 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 4 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 minutes, and the mixture is uniformly mixed to form an emulsion; the organic solvent is removed from the emulsion at a stirring speed of 500 pm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours; the emulsion after solidification is filtered and collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole 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 (epirazole)

[0097] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 1380 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 0.1 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 minutes, and the mixture is uniformly mixed to form an emulsion; the organic solvent is removed from the emulsion at a stirring speed of 500 pm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours; the emulsion after solidification is filtered and collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole 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 (epirazole)

[0100] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 1380 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 10 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 minutes, and the mixture is uniformly mixed to form an emulsion; the organic solvent is removed from the emulsion at a stirring speed of 500 pm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours; the emulsion after solidification is filtered and collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole sustained-release microsphere preparation.

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

[0102] Example 13 (epiprazol)

[0103] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 172 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 3 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 min, and the mixture is uniformly mixed to form an emulsion; the organic solvent is removed from the emulsion at a stirring speed of 500 pm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours; the emulsion after solidification is filtered and collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole sustained-release microsphere preparation.

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

[0105] Example 14 (epiprazole)

[0106] 1.2 g of epiriprazole 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 mixed and dissolved as an oil phase; 5160 mL of a polyvinyl alcohol (PVA) aqueous solution for injection with a concentration of 3 wt% is prepared as an external aqueous phase; the oil phase and the external aqueous phase are mixed by a high shear emulsifier, the shear speed of the emulsifier is 3000 rpm, the emulsification time is 2 min, and the mixture is uniformly mixed to form an emulsion; the organic solvent is removed from the emulsion at a stirring speed of 500 pm and a temperature of 25° C., and the microspheres are volatilized and solidified for 4 hours; the emulsion after solidification is filtered and collected by a filter, and a protective agent is added and freeze-dried to obtain an epiriprazole 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 irinotecan prepared in the above-mentioned examples 1-14 was used as an example to conduct an in vitro release rate test. The specific method is as follows:

[0110] Accurately weigh 20 mg of the sustained-release microsphere preparation for injection prepared in Examples 1-14, add it to a 15 mL centrifuge tube, add 15 mL of preheated release medium, the release medium is 0.05 M pH 7.4 phosphate buffer, and then place it in a 37°C incubator. At the corresponding time point, sample 1 mL and add 1 mL of the corresponding release medium. Figure 1 The cumulative release rate curve obtained by the test is shown as an example (for Examples 1, 2, 3, 10, and 14). For the 24-hour burst release rate, release duration, and total cumulative release rate of Examples 1-14 obtained by 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] Test samples 24-hour burst release rate (%) In vitro release duration (days) Total cumulative release rate (%) Example 1 3.8 35 94 Example 2 4.0 38 96 Example 3 4.2 37 95 Example 4 3.9 30 88 Example 5 3.8 32 90 Example 6 2.9 46 92 Example 7 3.3 34 87 Example 8 3.8 30 91 Example 9 3.3 30 93 Example 10 3.9 36 87 Embodiment 11 4.2 30 85 Example 12 3.4 42 95 Embodiment 13 4.2 30 89 Embodiment 14 4.4 36 94

[0113] Combining Table 1 and Figure 1 It can be seen from the results that the sustained-release microsphere preparation for injection prepared according to the method of the present invention has a stable release performance; according to the composition of the biocompatible polymer carrier contained therein, the preparation can be continuously released for more than about four weeks, and the drug is basically completely released (at least about 85%), and there will be no sudden release of the drug, 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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