Method for preparing sustained-release microspheres by using small-particle-size drug particles and prepared microspheres

Abstract

The invention relates to a method for preparing drug sustained-release microspheres by using small-particle-size drug active ingredient particles and the prepared microspheres. According to the preparation, the medicine can be continuously released for one to two months, and the preparation process of the preparation is relatively simple, so that the preparation is relatively simple and feasible in industrial production and has better universality. The preparation is a sustained-release microsphere injection, and the prepared microspheres are narrower in particle size distribution, high in encapsulation efficiency and low in burst release rate. According to the preparation method, the particle size of the active pharmaceutical ingredient is controlled, and the ratio of the active pharmaceutical ingredient in the oil phase to the biocompatible high polymer material, the ratio of the mass of the organic solvent to the volume of the external water phase and the dosage of the surfactant are adjusted, so that the preparation can be matched with the property of the active pharmaceutical ingredient to achieve a sustained release effect.

Description

Technical Field

[0001] This invention relates to the technical field of sustained-release injections, and more specifically to a method for preparing sustained-release microspheres using small-diameter active pharmaceutical ingredient microparticles, and the prepared microspheres. Background Technology

[0002] Sustained-release injections have become a hot research area in the pharmaceutical field in recent years, especially in improving existing drug formulations to make drugs more effective in clinical practice. Clinically mature sustained-release injection formulations include liposomes, nanocrystals, implants, sustained-release gels, and sustained-release microspheres.

[0003] Microspheres are spheres with a particle size in the micrometer range formed when a drug is dissolved or dispersed in a carrier excipient. They are a type of drug-loaded microsphere. Currently marketed sustained-release injectable products mostly encapsulate small molecule compounds or peptides. Microspheres are mainly prepared from polymer materials into spherical bodies with a particle size of 5 to 100 μm. This allows the drug to be embedded within the polymer material or enriched on the surface of the microsphere. The stable properties of the polymer material ensure the sustained-release effect of the drug, thus extending the drug release period to several weeks or even months. Sustained-release microsphere formulations effectively solve the problem of patient medication compliance. A single injection can maintain the efficacy for several months, while maintaining a stable drug concentration in the body, reducing fluctuations in blood drug concentration caused by dosage and dosing intervals, and lowering the occurrence of toxic side effects.

[0004] The first marketed microsphere formulation was triptorelin microspheres, a one-month sustained-release formulation, successfully developed by Ipsen in France in 1986 for the treatment of prostate cancer, uterine fibroids, breast cancer, and endometriosis. A similar product, leuprorelin microspheres, developed by Takeda in Japan, was subsequently launched in 1995. In 1998, Novartis developed octreotide microspheres, a one-month sustained-release formulation, for the treatment of acromegaly and neuroendocrine tumors. Due to the specific needs of microsphere formulations in terms of drug targeting, process matching with polymer materials, and the long-term treatment requirements of their indications, only a dozen or so drug-loaded sustained-release microsphere products were marketed globally until 2024.

[0005] Schizophrenia is a multifactorial chronic disease that requires long-term medication. Currently, risperidone microspheres are a microsphere product used for schizophrenia. These are a two-week extended-release formulation developed and launched by Janssen Pharmaceuticals in 2003, and Luye Pharma launched the same product in 2021. Because schizophrenia patients require long-term medication and often experience missed doses or medication resistance, long-acting injectables offer a unique advantage in improving patient compliance.

[0006] Currently, most drugs for treating schizophrenia are small molecule compounds, characterized by poor water solubility and the need for specific dosages to achieve therapeutic effects. Therefore, many drugs cannot meet the requirements of long-acting microspheres, which can encapsulate a dose for a month or even longer. Janssen Pharmaceuticals' 2-week sustained-release risperidone microspheres for injection (trade name: Hengde) resulted in insufficient drug release in the first three weeks after administration, necessitating the addition of oral medication to achieve the desired therapeutic effect, causing inconvenience for patients. Drug burst release refers to a sudden increase in blood drug concentration after administration, which can trigger toxic side effects. Overcoming burst release in microsphere formulations has always been a challenge in the industry, and suppressing burst release, leading to insufficient initial drug release, also causes inconvenience for subsequent patient use. How to balance the initial drug release of microsphere formulations with a stable release that can last for a month or even longer, providing patients with better therapeutic effects and a better medication experience, is a problem that the pharmaceutical industry needs to solve.

[0007] Bripiprazole, also known as prepiperazole, was jointly developed by Lundbeck Pharmaceuticals of Denmark and Otsuka Pharmaceutical of Japan. Marketed under the brand name Rexulti, it was approved by the FDA in the United States in 2015 for the treatment of schizophrenia and major depressive disorder. It entered the European market in 2018. The original product was an oral tablet. Bripiprazole is an atypical antipsychotic drug, a partial agonist of 5-HT1A and dopamine D2 and D3 receptors, and a partial antagonist of 5-HT2A, 5-HT2B receptors and dopamine α-1 and α-2 receptors. It has a regulatory effect on the monoaminergic neurotransmission system in the brain.

[0008] Lurasidone is an atypical antipsychotic drug, an antagonist of dopamine D2 and 5-HT2A and 5-HT7 receptors. It is manufactured by Sumitomo Pharmaceuticals in Japan and was approved by the FDA in 2010. In 2019, it was approved for marketing in China under the brand name Rosuda. The original product is an oral tablet used to treat schizophrenia and depressive episodes caused by type I bipolar disorder.

[0009] Cariprazine is an atypical antipsychotic drug, a partial agonist of dopamine D2 and D3 receptors, with higher selectivity for D3 receptors, and also possesses some 5-HT1A receptor agonist activity. It is used to treat schizophrenia and mixed, manic episodes of type I bipolar disorder. Cariprazine is manufactured by AbbVie in the United States, and was approved by the FDA in 2015, followed by approval in the European Union in 2017. It is available as an oral tablet. Summary of the Invention

[0010] The inventors discovered in their research that by using a modified emulsification method to prepare injectable sustained-release microsphere formulations containing pharmaceutical active ingredients and biocompatible polymeric materials, they can overcome the problems of insufficient drug loading, drug burst release, and the inability to rapidly reach therapeutic concentrations, while maintaining stable blood drug concentrations for one month or even longer. This method requires simultaneous control of the following steps:

[0011] 1. Control the particle size of the active pharmaceutical ingredient. Pulverize the active pharmaceutical ingredient into microparticles with a diameter of less than 7 μm. This allows the pulverized microparticles to disperse evenly in an organic solvent to form a suspension, increasing the encapsulation efficiency of the microspheres. Simultaneously, the active pharmaceutical ingredient is evenly distributed within the microspheres, which is beneficial for the sustained-release effect of the microspheres.

[0012] 2. By adjusting the mass ratio of the active pharmaceutical ingredient microparticles, biocompatible polymer materials, and organic solvents, and utilizing the solubility saturation of the active pharmaceutical ingredient microparticles in the organic solvent, a portion of the active pharmaceutical ingredient microparticles dissolves in the organic solvent, while the other portion remains as solid microparticles insoluble in the organic solvent. Through dispersion, the resulting oil phase is a suspension containing the solid pharmaceutical microparticles.

[0013] 3. Adjust the mass percentage of biocompatible polymer material to oil phase to prevent excessive porosity in microspheres, avoiding burst drug release caused by overly loose microspheres or aggregation due to excessive concentration; at the same time, adjust the mass percentage of active pharmaceutical ingredient to organic solvent to ensure that the dosage of active pharmaceutical ingredient meets the requirements for long-acting effect, and control the concentration of solid particles to avoid affecting microsphere formation during microsphere preparation due to excessive concentration, thereby avoiding the formation of broken or irregularly shaped microspheres;

[0014] 4. Adjust the amount of surfactant in the aqueous phase to control the stable and uniform dispersion of oil phase droplets and form a stable emulsion;

[0015] 5. Adjusting the volume ratio of the oil phase and the external aqueous phase allows for the application of different emulsification preparation methods (such as shearing method, homogenization method, etc.), thereby optimizing the appearance and release behavior of microsphere formulations.

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

[0017] To achieve the above objectives, the technical solution of the present invention is as follows:

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

[0019] A) D 90Drug active ingredient microparticles smaller than 7 μm and biocompatible polymer materials are added to an organic solvent to form an oil phase. Some of the drug active ingredient microparticles are dissolved in the organic solvent, while the remaining drug active ingredient microparticles are insoluble solid microparticles. The resulting oil phase is a suspension containing solid drug active ingredient microparticles.

[0020] B) Dissolve the surfactant in water to prepare an external aqueous phase;

[0021] C) The oil phase and the external aqueous phase are emulsified and mixed to obtain a mixed emulsion;

[0022] D) The mixed emulsion is cured and dried 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 5.0-63.0 wt%.

[0024] Preferably, the mass percentage of the biocompatible polymeric material to the oil phase is 10.0-40.0 wt%.

[0025] More preferably, the mass percentage of the active pharmaceutical ingredient microparticles to the organic solvent is 5.6-61.3 wt%, and the mass percentage of the biocompatible polymer material to the oil phase is 10-38 wt%.

[0026] Preferably, the mass percentage concentration of the surfactant in the external aqueous phase is 0.1-5.0 wt%.

[0027] 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).

[0028] Preferably, the organic solvent is dichloromethane.

[0029] Preferably, in step A), the active pharmaceutical ingredient is dispersed in the organic solution using equipment such as a high-shear emulsifier or an ultrasonic instrument, wherein the rotation speed of the high-shear emulsifier can be 10,000 rpm to 20,000 rpm.

[0030] Preferably, the active pharmaceutical ingredient is a small molecule drug, which can be any of the following: epipiperazole and / or its pharmaceutically acceptable salt, lurasidone and / or its pharmaceutically acceptable salt, cariprazine and / or its pharmaceutically acceptable salt, bromerazine and / or its pharmaceutically acceptable salt.

[0031] Preferably, the biocompatible polymer material is one or a mixture of several of polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), and polyacetin lactone (PCL).

[0032] Preferably, the surfactant is one or a mixture of several of the following: polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), β-cyclodextrin, poloxamer 188, Pranic F88, Pranic F127, gelatin, glycine, lysine, histidine, arginine, aspartic acid, glutamic acid, Span, and Tween.

[0033] Preferably, in step D, the mixed emulsion is solidified into wet microspheres, a protective agent is added, and then dried.

[0034] Preferably, the preparation method further includes the following steps: after obtaining the mixed emulsion, the mixed emulsion is stirred, solidified, filtered, and washed with water to form wet microspheres, and a protective agent is added to the wet microspheres before drying to obtain sustained-release microspheres containing the active pharmaceutical ingredient.

[0035] Preferably, the protective agent is one or a mixture of several of the following: polyethylene glycol (PEG), gelatin, glycerin, mannitol, sucrose, trehalose, lactose, glucose, propylene glycol, sorbitol, zinc chloride, zinc sulfate, zinc acetate, and human serum albumin.

[0036] Preferably, other excipients, such as surfactants and / or excipients, are added at the same time as the protective agent.

[0037] As another aspect of the present invention, an injectable sustained-release drug microsphere prepared according to any of the above methods is also provided.

[0038] According to the present invention, in step A) of the method for preparing sustained-release drug microspheres for injection, the active pharmaceutical ingredient is pulverized and the particle size is controlled by D. 90 The drug is a small molecule compound smaller than 7 μm or a pharmaceutically acceptable salt thereof. The pulverization process can be performed using equipment such as an air jet mill, fluid dynamics mill, ball mill, needle mill, colloid mill, or micronizer. The oil phase is a suspension containing solid drug particles. The active pharmaceutical ingredient can be epipiperazole or a pharmaceutically acceptable salt thereof; lurasidone or a pharmaceutically acceptable salt thereof; caliracil or a pharmaceutically acceptable salt thereof; or bromerazine or a pharmaceutically acceptable salt thereof.

[0039] In embodiments of the present invention, the mass percentage of the active pharmaceutical ingredient to the organic solvent is 5.0-63.0 wt%, calculated as follows: mass percentage of active pharmaceutical ingredient to organic solvent = mass of active pharmaceutical ingredient / mass of organic solvent * 100%.

[0040] In a preferred embodiment of the present invention, the biocompatible polymer material is polylactic-glycolic acid copolymer (PLGA), and the molar ratio of glycolide (LA) to lactide (GA) in the PLGA is 50:50-85:15, the molecular weight is 5-100 kilodaltons, and the viscosity is 0.1-0.6 dL / g; wherein, the type and molecular weight of PLGA include, but are not limited to: PLGA (LA:GA is 50:50; Mw 10000-90000 Daltons), PLGA (LA:GA is 55:45; Mw 15000-90000 Daltons), PLGA (LA:GA is 65:35; Mw 15000-90000 Daltons), PLGA (LA:GA is 75:25; Mw 10000-90000 Daltons), or PLGA (LA:GA is 85:15; Mw 55000-90000 Daltons).

[0041] In another preferred embodiment of the invention, the biocompatible polymer material is polylactic acid (PLA) with a molecular weight of 10-55 kilodaltons and a viscosity of 0.1-0.75 dL / g, for example, PLA (Mw 8000-55000 Daltons).

[0042] In this invention, the mass percentage of biocompatible polymeric material to oil phase is calculated as follows: mass percentage of biocompatible polymeric material to oil phase = mass of biocompatible polymeric material / (mass of biocompatible polymeric material + mass of organic solvent + mass of active pharmaceutical ingredient) * 100%.

[0043] In embodiments of the present invention, the mass percentage of PLGA to the oil phase is preferably 10.0-40.0 wt%.

[0044] According to the present invention, in step B) of the method for preparing sustained-release microspheres for injection, the surfactant may be selected from one or a mixture of several of polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), β-cyclodextrin, poloxamer 188, Pranic F88, Pranic F127, 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.

[0045] In this invention, the mass percentage concentration of the surfactant in the external aqueous phase is calculated as follows: mass percentage concentration of surfactant in the external aqueous phase = surfactant mass / (surfactant mass + water mass) * 100%.

[0046] In embodiments of the present invention, the mass percentage concentration of the surfactant in the external aqueous phase is preferably 0.1-5.0 wt%.

[0047] 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, a static mixer, or a combination thereof. Specifically, the high-shear emulsifier can have a rotational speed of 2000 rpm to 20000 rpm and a shearing time of 0.5 min to 10 min; the high-pressure homogenizer can have a pressure of 100 bar to 800 bar and can perform continuous homogenization 2 to 6 times; the static mixer has a diameter of ND6 to DN25 and a mixing flow rate of 1 L / min to 20 L / min.

[0048] In a preferred embodiment of the present invention, in step C) of the method for preparing sustained-release microspheres for injection, the mass ratio of the organic solvent to the volume of the external aqueous phase is preferably 1:10-1:300, in g / mL.

[0049] 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 can be 200-2000 rpm.

[0050] According to the present invention, in step D) of the method for preparing sustained-release microspheres for injection, the curing temperature can be 5°C to 45°C and the curing time can be 2h to 24h.

[0051] 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. This protective agent is an excipient added to the wet microspheres to increase the flowability and dispersibility of the dry powder of the microspheres obtained according to step D), and to adjust the osmotic pressure of the microspheres and protect the stability and activity of the small molecule drug. The protective agent may be selected from one or a mixture of several 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.

[0052] The present invention also provides injectable sustained-release microspheres, comprising injectable sustained-release microspheres prepared according to the above method, wherein the injectable sustained-release microspheres comprise the active pharmaceutical ingredients of epipiperazole, lurasidone, cariprazine, and bromerazine, a biocompatible polymeric carrier material, and other pharmaceutically acceptable excipients.

[0053] Other pharmaceutically acceptable excipients include surfactants and excipients. Additionally, other pharmaceutically acceptable excipients may include protective agents.

[0054] The sustained-release microsphere formulation for injection has a continuous release time of approximately 28 to 56 days, which is approximately four to eight 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)".

[0055] According to the present invention, the microspheres for injection prepared by the above method have a particle size (D50) of 5-200 μm, and not only is the microsphere particle size distribution narrow (SPAN value (SPAN = (D50))... 90 -D 10 ) / D 50 The encapsulation efficiency is less than 3%, and the burst release rate is significantly improved and reduced. Furthermore, compared to existing daily oral tablets, the injectable sustained-release microsphere formulation containing the active pharmaceutical ingredient according to the present invention provides a novel route of administration, achieving the characteristics of long-acting sustained-release microspheres. Ideally, it can achieve a sustained drug release time of 4-8 weeks, providing a better route of administration for patients with poor gastrointestinal absorption, while reducing drug tolerance and toxic side effects.

[0056] The technical solution of the present invention has the following beneficial effects:

[0057] The preparation method of the present invention is relatively simple and easy to implement and can be used for industrial operation, and has universality. At the same time, the preparation method produces an injectable sustained-release microsphere formulation with a narrow microsphere size distribution, and its encapsulation efficiency is significantly improved, burst release rate is reduced, release time is prolonged, and it can quickly reach the therapeutic concentration.

[0058] 1) By controlling the particle size of the active pharmaceutical ingredient, the ratio of the active pharmaceutical ingredient and biocompatible polymer 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, and by obtaining microsphere formulations containing the active pharmaceutical ingredient through S / O / W emulsification, the burst release rate of the active pharmaceutical ingredient in vitro is less than 5% and the encapsulation efficiency is higher than 85% or even higher than 90%. The preparation method is simple and can be applied to the industrialization of the production process of this microsphere formulation.

[0059] 2) This invention provides a novel method for preparing microspheres. A portion of the drug powder is dissolved in an organic solution, while another portion is dispersed in the organic solution as microparticles, forming an oil phase suspension containing solid drug microparticles. The drug dissolved in the oil phase is dispersed on the surface of the microspheres, allowing for rapid drug release and quick attainment of therapeutic concentrations. The suspended microparticle portion of the drug increases the microspheres' encapsulation capacity, improving drug loading and ensuring sufficient drug to maintain a long-lasting dose. Furthermore, the slightly slower release of this portion of the drug prolongs the release time in vivo.

[0060] 3) The present invention also provides a method for adding a protective agent to wet microspheres, which increases the flowability and dispersibility of the dry microsphere powder, and adjusts the osmotic pressure of the microspheres and protects the stability and activity of the drug.

[0061] 4) The injectable sustained-release microsphere formulation prepared according to the method of the present invention has a narrow particle size distribution and the release time of the active pharmaceutical ingredient can be sustained for approximately one to two months. Furthermore, the small molecule microsphere formulation prepared by the present invention can maintain the drug concentration in the blood more precisely in animals. These small molecule sustained-release microspheres can maintain a good blood drug concentration for 4-8 weeks without significant fluctuations in blood drug concentration, thus better avoiding the occurrence of toxic side effects. Attached Figure Description

[0062] Figure 1 The image shows a scanning electron microscope (SEM) image of the sustained-release microspheres for injection prepared according to Example 3 of the present invention.

[0063] Figure 2 The image shows a scanning electron microscope (SEM) image of the sustained-release microspheres for injection prepared according to Example 5 of the present invention.

[0064] Figure 3 This is a scanning electron microscope image of the sustained-release microspheres for injection prepared according to Example 12 of the present invention.

[0065] Figure 4 This is a scanning electron microscope image of the sustained-release microspheres for injection prepared according to Example 13 of the present invention.

[0066] Figure 5 In vitro release-time curves of sustained-release microspheres for injection prepared according to Examples 3, 8, 12, 14 and comparative formulations 1, 2 of the present invention.

[0067] Figure 6 In vivo pharmacokinetic curves of the sustained-release microspheres for injection prepared according to Examples 3, 8, 12, 14 and comparative formulations 1, 2 of the present invention. Detailed Implementation

[0068] 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.

[0069] In the following embodiments, a small molecule injectable microsphere formulation will be prepared by way of the preparation method of the small molecule injectable microsphere according to the present invention.

[0070] The active pharmaceutical ingredient of epipiperazole referred to in this invention may be of the molecular formula C 25 H 27 N3O2S, an epilapiazole compound with a molar mass of 433.57 g / mol (DOI:10.1111 / pcn.13438).

[0071] The active pharmaceutical ingredient of lurasidone referred to in this invention can be of the molecular formula C 28 H 36 N4O2S, a lurasidone compound with a molar mass of 492.68 g / mol, or with the molecular formula C 28 H 37 ClN4O2S, lurasidone hydrochloride with a molar mass of 529.14 g / mol (DOI:10.1124 / jpet.110.167346).

[0072] The active pharmaceutical ingredient of the present invention, cariprazine, can be of the molecular formula C 21 H 32 Cl2N4O2, a carrillazine compound with a molar mass of 427.41 g / mol, or with the molecular formula C 21 H 33 Cl3N4O2, cariprazine hydrochloride with a molar mass of 463.87 g / mol (DOI:10.1007 / s12325-021-01797-5).

[0073] The active pharmaceutical ingredient of this invention, bromelain, can be of the molecular formula C 22 H 25 Cl2N3O3, a brenrazazine compound with a molar mass of 450.36 g / mol, CAS No. 1239729-06-6 (DOI:10.2147 / JEP.S259317).

[0074] The active pharmaceutical ingredients are pulverized using equipment such as air jet mills, fluid energy mills, ball mills, needle mills, colloid mills, and micronizers to obtain D. 90 Micropowder smaller than 7 μm was used in the example experiments; undiluted D... 90 Powders larger than 10 μm were used for comparative experiments. Unless otherwise specified, the methods used in the following examples are methods commonly used by those skilled in the art.

[0075] Example 1: Experiment on particle size determination of active pharmaceutical ingredients

[0076] In this test example, the particle size of the active pharmaceutical ingredient was determined using the following method:

[0077] Accurately weigh 20 mg of the active pharmaceutical ingredient (API), add a suitable dispersion medium, gently shake until a uniform suspension is formed, and then sonicate for 1 minute to ensure uniform dispersion. Then, perform a wet method determination according to "Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0982: Determination of Particle Size and Particle Size Distribution". Adjust the stirring speed to 2200 rpm, control the detector's light-blocking rate between 5% and 10%, and then begin the measurement. Perform three consecutive measurements, take the average of the three measurements, and calculate the SPAN value (SPAN = (D...). 90 -D 10 ) / D 50 See Table 1 for details.

[0078] Table 1: Particle size and particle size distribution of the tested drug active ingredient (API):

[0079]

[0080]

[0081] Test sample 1 was used for the preparation of comparative formulation 1; test sample 2 was used for the preparation of Examples 1-4 and comparative formulations 2-4; test sample 3 was used for the preparation of comparative formulation 5; test sample 4 was used for the preparation of Examples 5-8 and comparative formulation 6; test sample 5 was used for the preparation of comparative formulation 7; test sample 6 was used for the preparation of Example 9; test sample 7 was used for the preparation of Examples 10-12 and comparative formulation 8; and test sample 8 was used for the preparation of Examples 13-14. The particle size of the microsphere formulations obtained from the examples and comparative formulations was determined according to the above method.

[0082] Example 1 (epipiprazole)

[0083] After pulverizing 0.56g (D) 90 Epicipeazole microparticles (3.12 μm in size) and 2.24 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 4.16 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 12000 rpm as the oil phase. 1000 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a high-shear emulsifier at a shear rate of 3000 rpm for 4 min until a homogeneous emulsion was formed. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were volatilized and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the epicipeazole sustained-release microsphere formulation.

[0084] The average particle size (D) of the microspheres in this formulation50 The value is 45 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.22. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 98%, with a yield of 90%.

[0085] Example 2 (epipiprazole)

[0086] After crushing 1.50g (D) 90 Epicipeazole microparticles (3.12 μm in size) and 1.50 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 13.50 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. 1000 mL of a 5.0 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the epicipeazole sustained-release microsphere formulation.

[0087] The average particle size (D) of the microspheres in this formulation 50 The value is 44 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.24. The prepared sustained-release microspheres were quantitatively determined by HPLC, with an encapsulation efficiency of 99% and a yield of 89%.

[0088] Example 3 (epipiprazole)

[0089] After crushing 3.00g (D) 90Epicipeazole microparticles (3.12 μm in size) and 4.48 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.19 dL / g) were added to 6.72 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. 1000 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed multiple times with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the epicipeazole sustained-release microsphere formulation.

[0090] The average particle size (D) of the microspheres in this formulation 50 The value is 45 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.32. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 99%, with a yield of 93%.

[0091] Example 4 (epipiprazole)

[0092] After crushing 1.25g (D) 90 Epicipeazole microparticles (3.12 μm in size) and 0.68 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.36 dL / g) were added to 2.04 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15,000 rpm as the oil phase. 500 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed multiple times with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the epicipeazole sustained-release microsphere formulation.

[0093] The average particle size (D) of the microspheres in this formulation 50 The value is 51 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.37. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 100%, with a yield of 91%.

[0094] Example 5 (Lurasidone)

[0095] After crushing 1.50g (D) 90 Lurasidone hydrochloride microparticles (5.98 μm in diameter) and 2.70 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 15.50 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. 800 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a high-shear emulsifier at a shear rate of 3000 rpm for 4 min until a homogeneous emulsion was formed. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were volatilized and solidified for 6 hours. After solidification, the emulsion was filtered through a filter to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the lurasidone sustained-release microsphere formulation.

[0096] The average particle size (D) of the microspheres in this formulation 50 The value is 41 μm, and the SPAN value is (SPAN = (D 90 -D 10 ) / D 50 The value was 1.23. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 92%, with a yield of 92%.

[0097] Example 6 (Lurasidone)

[0098] After crushing 1.80g (D) 90 Lurasidone hydrochloride microparticles (5.98 μm in diameter) and 10.40 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 31.20 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. 800 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed multiple times with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the lurasidone sustained-release microsphere formulation.

[0099] The average particle size (D) of the microspheres in this formulation 50 The value is 45 μm, and the SPAN value (SPAN = (D 90 -D10 ) / D 50 The value was 1.33. The prepared sustained-release microspheres were quantitatively determined by HPLC, with an encapsulation efficiency of 95% and a yield of 89%.

[0100] Example 7 (Lurasidone)

[0101] After crushing 0.60g (D) 90 Lurasidone hydrochloride microparticles (5.98 μm in diameter) and 2.80 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 4.50 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15,000 rpm as the oil phase. 800 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the lurasidone sustained-release microsphere formulation.

[0102] The average particle size (D) of the microspheres in this formulation 50 The value is 42 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.26. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 92%, with a yield of 90%.

[0103] Example 8 (Lurasidone)

[0104] After crushing 1.60g (D) 90 Lurasidone hydrochloride microparticles (5.98 μm in diameter) and 2.00 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.36 dL / g) were added to 6.00 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15,000 rpm as the oil phase. 800 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the lurasidone sustained-release microsphere formulation.

[0105] The average particle size (D) of the microspheres in this formulation 50 The value is 48 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.21. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 87%, with a yield of 92%.

[0106] Example 9 (Cariprazine)

[0107] After pulverizing 0.46g (D) 90 Cariprazine microparticles (6.29 μm in diameter) and 4.14 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 7.69 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. 500 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a high-shear emulsifier at a shear rate of 3000 rpm for 4 min until a homogeneous emulsion was formed. The emulsion was stirred at 300 rpm and at 25°C to remove the organic solvent, and the microspheres were volatilized and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the cariprazine sustained-release microsphere formulation.

[0108] The average particle size (D) of the microspheres in this formulation 50 The value is 46 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.28. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 87%, with a yield of 86%.

[0109] Example 10 (Cariprazine)

[0110] After crushing 1.00g (D) 90Cariprazine microparticles (2.85 μm in diameter) and 9.00 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.19 dL / g) were added to 13.50 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. 200 mL of a 4.0 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the cariprazine sustained-release microsphere formulation.

[0111] The average particle size (D) of the microspheres in this formulation 50 The value is 46 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.39. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 86%, with a yield of 89%.

[0112] Example 11 (Cariprazine)

[0113] After crushing 2.00g (D) 90 Cariprazine microparticles (2.85 μm in diameter) and 8.00 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.19 dL / g) were added to 36.00 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. 3000 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed multiple times with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the cariprazine sustained-release microsphere formulation.

[0114] The average particle size (D) of the microspheres in this formulation 50 The value is 47 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.25. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 91% and the yield was 93%.

[0115] Example 12 (Cariprazine)

[0116] After crushing 2.40g (D) 90 Cariprazine microparticles (2.85 μm in size) and 2.40 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.50 dL / g) were added to 4.80 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. A 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution (600 mL) was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the cariprazine sustained-release microsphere formulation.

[0117] The average particle size (D) of the microspheres in this formulation 50 The value is 45 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.22. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 86%, with a yield of 91%.

[0118] Example 13 (Breira Sacin)

[0119] After pulverizing 0.62g (D) 90 Brisaraxacin microparticles (4.59 μm in diameter) and 2.45 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 5.77 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. 1400 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a high-shear emulsifier at a shear rate of 3000 rpm for 4 min until a homogeneous emulsion was formed. The emulsion was stirred at 300 rpm and at 25°C to remove the organic solvent, and the microspheres were volatilized and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the Brisaraxacin sustained-release microsphere formulation.

[0120] The average particle size (D) of the microspheres in this formulation 50 The value is 46 μm, and the SPAN value (SPAN = (D 90 -D10 ) / D 50 The value was 1.34. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 91%, with a yield of 88%.

[0121] Example 14 (Breira Sacin)

[0122] After crushing 1.64g (D) 90 Brisaraxacin microparticles (4.59 μm in diameter) and 2.45 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.36 dL / g) were added to 7.00 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15,000 rpm as the oil phase. 500 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the Brisaraxacin sustained-release microsphere formulation.

[0123] The average particle size (D) of the microspheres in this formulation 50 The value is 44 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.28. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 93%, with a yield of 91%.

[0124] Comparative examples of ipiperazole

[0125] Comparative Example 1: Comparison of the properties of the active ingredient epipiperazole in the oil phase and the concentration of excipients

[0126] In Comparative Example 1, the properties of the ipiliprazole active pharmaceutical ingredient forming a suspension in an organic solvent were compared based on Examples 1-4 of the present invention. The active pharmaceutical ingredient needs to be uniformly dispersed in the solution to prepare a microsphere formulation with sustained and gradual drug release and small burst release. Comparative formulations 1-4 were all prepared according to the process parameters of Examples 1 and 4.

[0127] The comparative formulations 1-4 were prepared using the same S / O / W method as in Example 1, with all process parameters kept consistent. The main difference in preparing comparative formulation 1 was that the active ingredient of epipiperazole was not pulverized (D... 90The concentration of PLGA in the oil phase is greater than 10 μm, and no shear dispersion occurs during suspension. The main difference in formulation 2 is that the concentration of the active ingredient, epipiperazole, in the organic solvent is greater than 40%, while the main difference in formulations 3 and 4 is that the concentration of PLGA in the oil phase is less than 10% or greater than 40%. The specific methods for preparing the above-mentioned comparative formulations 1-4 are as follows:

[0128] Comparative formulation 1

[0129] 3.00g of uncrushed (D) 90 Epicipazole particles (14.28 μm in diameter) and 4.48 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 6.72 g of dichloromethane solvent as the oil phase. A 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution of 1000 mL was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed multiple times with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the epicipazole sustained-release microsphere formulation.

[0130] The average particle size (D) of the microspheres in this formulation 50 The value is 52 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.92. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 56%, with a yield of 86%.

[0131] Comparative formulation 2

[0132] After crushing 1.60g (D) 90 Epicipeazole microparticles (3.12 μm in size) and 0.68 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.36 dL / g) were added to 2.04 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15,000 rpm as the oil phase. 250 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were allowed to evaporate and solidify for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the epicipeazole sustained-release microsphere formulation.

[0133] The average particle size (D) of the microspheres in this formulation 50 The value is 56 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.41. The prepared sustained-release microspheres were quantitatively determined by HPLC, with an encapsulation efficiency of 60% and a yield of 83%.

[0134] Furthermore, according to the in vitro release test method described in Example 1 of the present invention, comparative formulations 1 and 2 were tested for in vitro release. Comparative formulation 1 achieved a total cumulative release rate of 96% over 20 days, which was insufficient to meet the requirement of continuous release for one month. Comparative formulation 2 not only had a low encapsulation rate but also exhibited a large number of broken spheres, with a 24-hour burst release rate of 12%.

[0135] Comparative formulation 3

[0136] After crushing 0.25g (D) 90 Epicipeazole microparticles (3.12 μm in size) and 1.00 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 19.00 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. 200 mL of a 5.0 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed multiple times with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the epicipeazole sustained-release microsphere formulation.

[0137] During the preparation of this formulation, all the epilapiazole microparticles dissolved in the organic solvent, and most of the prepared particles broke down, resulting in an average particle size (D). 50 The value is 42 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.52. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 54%, with a yield of 46%.

[0138] Comparative formulation 4

[0139] After crushing 1.12g (D) 90Epicipeazole microparticles (3.12 μm in size) and 4.48 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.19 dL / g) were added to 4.48 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15,000 rpm as the oil phase. 700 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the epicipeazole sustained-release microsphere formulation.

[0140] The formulation forms a flocculent mass during emulsification, resulting in significant losses during the process. The average particle size of the microspheres (D) is [missing information]. 50 The value is 56 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.91. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 83%, with a yield of 53%.

[0141] Lurasidone Comparative Example

[0142] Comparative Example 2: Comparison of the properties of the active ingredient lurasidone in the oil phase and the concentration of excipients

[0143] In Comparative Example 2, the properties of the lurasidone active pharmaceutical ingredient forming a suspension in an organic solvent were compared based on Examples 5-8 of the present invention. The active pharmaceutical ingredient needs to be uniformly dispersed in the solution to prepare a microsphere formulation with sustained and gradual drug release and small burst release. Comparative formulations 5 and 6 were prepared using conventional microsphere preparation processes according to the process parameters of Example 5.

[0144] The methods for preparing comparative formulations 5 and 6 are the same as in Example 5, using the s / o / w preparation method. The main difference in preparing comparative formulation 5 is that the lurasidone active ingredient was not pulverized (D... 90 The main difference in preparing comparative formulation 6 (greater than 20 μm) is that the concentration of PLGA in the oil phase is less than 10%. The specific methods for preparing comparative formulations 5 and 6 are as follows:

[0145] Comparative formulation 5

[0146] 2.70g of uncrushed (D) 90Lurasidone hydrochloride particles (20.85 μm) and 2.70 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 8.18 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15000 rpm as the oil phase. 800 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a high-shear emulsifier at a shear rate of 3000 rpm for 4 min until a homogeneous emulsion was formed. The emulsion was stirred at 300 rpm and at 25°C to remove the organic solvent, and the microspheres were volatilized and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed multiple times with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the lurasidone sustained-release microsphere formulation.

[0147] The average particle size (D) of the microspheres in this formulation 50 The value is 59 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 2.17. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 54%, with a yield of 78%.

[0148] Comparative formulation 6

[0149] After crushing 1.40g (D) 90 Lurasidone hydrochloride microparticles (5.98 μm in diameter) and 2.60 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.36 dL / g) were added to 23.41 g of dichloromethane solvent and dispersed using a high-shear emulsifier at a shear rate of 15,000 rpm as the oil phase. 800 mL of a 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed repeatedly with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the lurasidone sustained-release microsphere formulation.

[0150] The average particle size (D) of the microspheres in this formulation 50 The value is 64 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50The value was 1.15. The prepared sustained-release microspheres were quantitatively determined by HPLC, showing an encapsulation rate of 58%, with a large number of broken microspheres, resulting in a yield of only 54%.

[0151] According to the in vitro release test method described in Example 1 of the present invention, comparative formulations 5 and 6 were subjected to in vitro release tests. The 24-hour burst release rates of comparative formulation 5 and comparative formulation 6 reached 18% and 15%, respectively. Moreover, the total cumulative release rate of comparative formulation 5 in 21 days exceeded 95%, which could not meet the requirement of continuous release for one month.

[0152] Comparative examples of caliprazine

[0153] Comparative Example 3: Comparison of the properties and concentrations of the active ingredient caliracil in the oil phase

[0154] In Comparative Example 3, the properties of the cariprazine active pharmaceutical ingredient forming a suspension in an organic solvent were compared based on Examples 9-12 of the present invention. The active pharmaceutical ingredient needs to be uniformly dispersed in the solution to prepare a microsphere formulation with sustained and gradual drug release and small burst release. Comparative formulations 7 and 8 were prepared using conventional microsphere preparation processes according to the process parameters of Examples 9 and 12, respectively.

[0155] The methods for preparing comparative formulations 7 and 8 are the same as those in Examples 9 and 12, using the s / o / w preparation method. The main difference in preparing comparative formulation 7 is that the active ingredient of cariprazine was not pulverized (D... 90 The concentration of the active pharmaceutical ingredient (API) is greater than 7 μm, and no shear dispersion occurs during suspension. The main difference in preparing comparative formulation 8 is that the mass percentage of the active pharmaceutical ingredient to the organic solvent is greater than 63%, and the concentration of the active pharmaceutical ingredient in the oil phase is greater than 35%. The specific methods for preparing the above comparative formulations 7 and 8 are as follows:

[0156] Comparative formulation 7

[0157] 1.20g of uncrushed (D) 90 Cariprazine particles (9.40 μm) and 2.40 g of PLGA (with a molar ratio of glycolide to lactide of 50:50 and an intrinsic viscosity of 0.24 dL / g) were added to 4.00 g of dichloromethane solvent as the oil phase. A 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution (500 mL) was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a high-shear emulsifier at a shear rate of 3000 rpm for 4 min until a homogeneous emulsion was formed. The organic solvent was removed from the emulsion by stirring at 300 rpm and at 25°C, and the microspheres were volatilized and solidified for 6 hours. After solidification, the emulsion was filtered through a filter to collect the microspheres, washed multiple times with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the cariprazine sustained-release microsphere formulation.

[0158] The average particle size (D) of the microspheres in this formulation 50 The value is 56 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.57. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 48%, with a yield of 77%.

[0159] Comparative formulation 8

[0160] After crushing 3.20g (D) 90 Cariprazine microparticles (2.85 μm in size) and 2.40 g of PLGA (with a molar ratio of glycolide to lactide of 75:25 and an intrinsic viscosity of 0.50 dL / g) were added to 4.80 g of dichloromethane solvent as the oil phase. A 0.25 wt% polyvinyl alcohol (PVA) injection aqueous solution of 600 mL was prepared as the external aqueous phase. The oil phase and external aqueous phase were mixed using a static mixer at a flow rate of 6 L / min for 1 min. The emulsion was stirred at 300 rpm and at 25 °C to remove the organic solvent, and the microspheres were evaporated and solidified for 6 hours. After solidification, the emulsion was filtered to collect the microspheres, washed multiple times with distilled water, collected, and then freeze-dried after adding a protective agent to obtain the cariprazine sustained-release microsphere formulation.

[0161] The average particle size (D) of the microspheres in this formulation 50 The value is 66 μm, and the SPAN value (SPAN = (D 90 -D 10 ) / D 50 The value was 1.90. The prepared sustained-release microspheres were quantitatively determined by HPLC, and the encapsulation efficiency was 59%, with a yield of 49%.

[0162] Test Example 2: In Vitro Release Rate Test

[0163] In this test example 2, the sustained-release microsphere formulations of epipiperazole, lurasidone, caliprazine, and bromerazine prepared in Examples 1-14 and Comparative Formulations 1-8 were used as examples to conduct an in vitro release rate test. The specific method is as follows:

[0164] Accurately weigh 20 mg of the sustained-release microsphere formulations for injection prepared in Examples 1-14 and Comparative Formulations 1-8, respectively, and add them to a 15 mL centrifuge tube. Add 15 mL of preheated release medium, which is 0.05 M pH 7.4 phosphate buffer. Then place the tube in a 37 °C incubator. Take 1 mL of sample at the corresponding time point and add 1 mL of the corresponding release medium. Figure 5(For Examples 3, 8, 12, 14 and Comparative Formulations 1, 2) Exemplary cumulative release rate graphs obtained from the tests are shown. See Table 2 for the 24-hour burst release rate, release duration, and total cumulative release rate of Examples 1-14 and Comparative Formulations 1, 2 obtained from the tests:

[0165] Table 2: 24-hour burst release rate, in vitro release duration, and total cumulative release rate of Examples 1-14 and Comparative Formulations 1 and 2 obtained from testing:

[0166] Test sample 24-hour burst release rate (%) Duration of in vitro release (days) Total cumulative release rate (%) Example 1 3.8 40 97 Example 2 3.9 34 96 Example 3 3.2 45 96 Example 4 1.6 55 90 Example 5 3.3 32 97 Example 6 3.5 45 97 Example 7 3.3 45 93 Example 8 4.3 50 97 Example 9 1.8 44 96 Example 10 4.2 42 89 Example 11 4.4 40 95 Example 12 3.1 55 96 Example 13 3.2 40 90 Example 14 4.4 55 97 Comparative formulation 1 9.8 20 96 Comparative formulation 2 12.1 25 95

[0167] Combine Table 2 and Figure 5 The results show that the sustained-release microsphere formulation for injection prepared by the method of the present invention has stable release performance; depending on the composition of the biocompatible polymer carrier contained therein, the formulation can continuously release for one to two months, and the drug is basically completely released (at least about 85%), without any drug burst release, thus meeting the requirements for continuous release.

[0168] Example 3: Single-dose pharmacokinetic experiment in rats

[0169] In Example 3 of this study, pharmacokinetic experiments were conducted in rats using the sustained-release microsphere formulations for injection prepared in Examples 1-14 and Comparative Formulations 1-8, respectively. The specific methods are as follows:

[0170] Male adult SD rats, weighing 300–450 g, were selected as the research subjects and administered the drugs via intramuscular injection. The sustained-release microsphere formulations for injection of epipiperazole, lurasidone, caliracil, and bromerazine, prepared according to Examples 1–14 of this invention, were administered at doses of 15 mg / kg (Example 3, Comparative Formulation 1, Comparative Formulation 2), 35 mg / kg (Example 8), 20 mg / kg (Example 12), and 15 mg / kg (Example 14), respectively. At specific time points after administration, 0.3 mL of blood was collected from the jugular vein and transferred to centrifuge tubes containing EDTA-K2 anticoagulant. The tubes were inverted 5–10 times to thoroughly mix the anticoagulant with the blood, and temporarily stored at room temperature on moist ice. Plasma samples were then rapidly centrifuged at 4000 rpm for 15 min at 4°C and stored at -80°C. The drug concentration (ng / mL) in the plasma samples at each time point was determined using LC / MS. The in vivo plasma concentration-time curves are shown below. Figure 6 .

[0171] from Figure 6It can be seen that the sustained-release microsphere formulation for injection prepared by the method of the present invention exhibits stable release in rats, and the drug concentration can be maintained within a stable range for four to eight weeks without significant fluctuations. This demonstrates that in the sustained-release microsphere formulation for injection according to the present invention, the selection of the preparation method and the selection of biocompatible polymer materials ensure the stability of the drug during continuous release without significant drug degradation.

[0172] Example 4: Microsphere Formulation Particle Size Determination Experiment

[0173] In this test example 4, particle size determination experiments were conducted using Example 1 and Comparative Formulation 1 as examples. The specific methods were the same as in test example 1, and the results are shown in Table 3.

[0174] Table 3: Particle size and particle size distribution of the microsphere formulations in Test Example 1 and Comparative Formulation 1:

[0175] Test sample <![CDATA[D 10 / μm]]> <![CDATA[D 50 / μm]]> <![CDATA[D 90 / μm]]> SPAN value Example 1 (Microsphere Formulation) 6.63 44.75 55.12 1.22 Comparative Formulation 1 (Microsphere Formulation) 8.28 52.36 72.35 1.92

[0176] According to the in vitro release test method described in Example 1 of the present invention, comparative formulations 7 and 8 were subjected to in vitro release tests. The 24-hour burst release rates of both comparative formulations 7 and 8 exceeded 20%. Furthermore, the total cumulative release rate of comparative formulation 7 exceeded 95% in 21 days, which is insufficient to meet the requirement of continuous release for one month.

[0177] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for preparing injectable sustained-release drug microspheres, comprising the following steps: A) Particle size D 90 Pharmaceutical active ingredient microparticles smaller than 7 μm and biocompatible polymer materials are added to an organic solvent to form an oil phase, wherein a portion of the pharmaceutical active ingredient microparticles are dissolved in the organic solvent, and the remaining pharmaceutical active ingredient microparticles are insoluble solid microparticles. The oil phase is a suspension containing the pharmaceutical active ingredient solid microparticles. B) Dissolve the surfactant in water to prepare an external aqueous phase; C) The oil phase and the external aqueous phase are emulsified and mixed to obtain a mixed emulsion; D) The mixed emulsion is cured and dried to obtain sustained-release microspheres containing the active pharmaceutical ingredient.

2. The method of claim 1, wherein: The mass percentage of the active pharmaceutical ingredient microparticles to the organic solvent is 5.0-63.0 wt%, and the mass percentage of the biocompatible polymer material to the oil phase is 10-40 wt%.

3. The method of claim 2, wherein: The mass percentage of the active pharmaceutical ingredient microparticles to the organic solvent is 5.6-61.3 wt%, and the mass percentage of the biocompatible polymer material to the oil phase is 10-38 wt%.

4. The method of claim 3, wherein: The surfactant has a mass percentage concentration of 0.1-5.0 wt% in the external aqueous phase.

5. The method of claim 4, wherein: The ratio of the mass (g) of the organic solvent to the volume (mL) of the external aqueous phase is 1:10-1:

300.

6. The method of claim 1 or 2, wherein: The organic solvent is dichloromethane.

7. The method of claim 1 or 2, wherein: The active pharmaceutical ingredient microparticles are any one of the following: epipiperazole and / or its pharmaceutically acceptable salts, lurasidone and / or its pharmaceutically acceptable salts, caliracil and / or its pharmaceutically acceptable salts, bromerazine and / or its pharmaceutically acceptable salts.

8. The method of claim 1 or 2, wherein: The biocompatible polymer material is one or a mixture of several of polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polyglycolic acid (PGA), and polyacetin lactone (PCL).

9. The method of claim 1 or 2, wherein: The surfactant is one or a mixture of several of the following: polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), carboxymethyl cellulose (CMC), hydroxyethyl cellulose (HEC), β-cyclodextrin, poloxamer 188, Pranic F88, Pranic F127, gelatin, glycine, lysine, histidine, arginine, aspartic acid, glutamic acid, Span, and Tween.

10. The method of claim 1 or 2, wherein: In step D, the mixed emulsion is solidified into wet microspheres, a protective agent is added, and then dried.

11. The method of claim 7, wherein: The active pharmaceutical ingredient (API) microparticles are epipiperazole, and the mass percentage of the API microparticles to the organic solvent is 11.1-61.3 wt%; or the API microparticles are lurasidone hydrochloride, and the mass percentage of the API microparticles to the organic solvent is 5.8-26.7 wt%; or the API microparticles are cariprazine, and the mass percentage of the API microparticles to the organic solvent is 5.6-50 wt%; or the API microparticles are bromerazine, and the mass percentage of the API microparticles to the organic solvent is 10.7-23.4 wt%.

12. A sustained-release microsphere for injection prepared by the method according to any one of claims 1-11.

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