Paliperidone sustained release microsphere and preparation method thereof

Abstract

The invention relates to paliperidone sustained release microspheres and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The preparation method comprises the following steps: S1, dissolving paliperidone and a degradable polymer containing a hydrophobic chain segment in an organic solvent to obtain a drug-containing polymer solution; dissolving a stabilizer in water to obtain a stabilizer solution; s2, adding the drug-containing polymer solution into the stabilizer solution through continuous homogeneous emulsification to obtain O / W type emulsion; and S3, under a stirring condition, adding the O / W type emulsion into water, curing, washing, and freeze-drying to obtain the paliperidone sustained-release microsphere. The preparation method disclosed by the invention is simple and rapid, and the sustained-release microspheres are controllable in particle size, proper in size and round in shape; the drug loading capacity and the encapsulation efficiency are high, the reproducibility is high, the burst release phenomenon is avoided, slow and continuous release can be realized for more than two months, and the compliance of a patient is effectively improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to paliperidone sustained-release microspheres and a preparation method thereof. Background Art

[0002] Schizophrenia is a common severe mental illness with an incompletely elucidated etiology. It often has disorders in perception, thinking, emotion, and behavior. Among them, perception and thinking disorders are the core symptoms of this disease, such as common auditory hallucinations and delusions of persecution, so it is also called "schizophrenia syndrome" in some areas. But generally there is no disorder of consciousness and intelligence is normal. Since the 1950s, traditional or typical antipsychotic drugs have mainly blocked dopamine receptors to effectively control hallucinations, delusions, and confusion associated with schizophrenia. Typical antipsychotic drugs include chlorpromazine, fluphenazine, trifluoperazine, etc. Although they help control the symptoms of schizophrenia, these drugs themselves can cause different side effects, such as restlessness, muscle cramps or spasms, and unconscious muscle twitches.

[0003] Paliperidone is the active metabolite of risperidone, also known as 9-hydroxyrisperidone. Like other antipsychotic drugs, the mechanism of action of paliperidone is currently believed to be to relieve positive psychotic symptoms and improve cognitive and emotional symptoms through the combined antagonism of central dopamine 2 (D2) receptors and 5-hydroxytryptamine 2 (5-HT2A) receptors. The 5-HT7 antagonist property can bring antidepressant activity, improve circadian rhythm and sleep structure, block α2 receptors, increase 5-HT and NE release, and exert antidepressant effects. As an atypical antipsychotic, paliperidone is a promising drug that reduces the risk of drug interactions and provides a new option for schizophrenia patients with mild to moderate liver damage. Its pharmacological activity is lower than that of risperidone, but it has a shorter half-life and higher steady-state blood concentration.

[0004] At present, paliperidone is mainly in the form of tablets and injections at home and abroad, but the drug has a short half-life, low persistence, and rapid degradation in the body, so patients sometimes need to take it for a long time or increase the dosage. At the same time, oral administration has many disadvantages, such as high frequency of administration and low bioavailability due to the first-pass effect. Patient compliance is poor if the drug is administered on time every day. The long-acting microcrystalline preparation of paliperidone palmitate suspension injection relies on the formation of insoluble paliperidone palmitate salt to reduce the solubility of the drug. The solubility is extremely low and the drug particles are large, which has certain limitations. It is necessary to use high-energy mechanical force to control the particle size of the raw material to affect the release in the body to exert the drug effect. As a special complex preparation, it has high requirements for excipients, process technology and commercial production capacity in pharmaceutical research. Therefore, there are extremely high technical barriers in product quality control, large-scale production, and bioequivalence test execution. It has been disclosed that paliperidone microspheres or long-acting preparations are prepared by a series of esterification and acylation reactions of paliperidone, and finally esterification with polylactic acid through chemical bonding to obtain microspheres. This method has a complex preparation process and is time-consuming. The obtained microspheres have a low drug loading of about 10%, and are completely released in just one month. In order to improve patient compliance and improve the utilization of medical resources, it is considered to prepare paliperidone into a long-acting polylactic-co-glycolic acid (PLGA) microsphere sustained-release preparation.

[0005] The following shortcomings were found in the preparation of paliperidone microspheres using existing technologies: First, in the early implementation process, due to the increase in PLGA molecular weight, the viscosity of the oil phase increased and it could not be evenly mixed with the water phase, which was manifested as PLGA precipitation during the traditional stirring process and poor microsphere forming properties. Second, after collection, it was found that the microsphere particle size was too large and uneven, the encapsulation rate and drug loading were extremely low, and the process loss was serious. Therefore, the development of paliperidone microsphere dosage forms is extremely challenging. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a paliperidone sustained-release microsphere and a preparation method thereof, which solves the problems of high viscosity, poor microsphere formability, uneven particle size and low encapsulation rate caused by large molecular weight biodegradable polymers containing hydrophobic segments through continuous homogenization emulsification technology.

[0007] The first object of the present invention is to provide a method for preparing paliperidone sustained-release microspheres, comprising the following steps:

[0008] S1, dissolving paliperidone and a degradable polymer containing a hydrophobic segment in an organic solvent to obtain a drug-containing polymer solution;

[0009] dissolving a stabilizer in water to obtain a stabilizer solution;

[0010] S2, adding the drug-containing polymer solution described in S1 to the stabilizer solution by continuous homogenization emulsification to obtain an O / W type emulsion;

[0011] S3. Under stirring conditions, the O / W emulsion described in S2 is added into water for solidification, and the paliperidone sustained-release microspheres are obtained by washing and freeze-drying.

[0012] In one embodiment of the present invention, in S1, the degradable polymer containing a hydrophobic segment is selected from one or more of polylactic acid-co-glycolic acid, polylactic acid, polylactic acid-polyethylene glycol and polycaprolactone.

[0013] In one embodiment of the present invention, the relative molecular mass of the polylactic acid-co-glycolic acid is 60 kDa-210 kDa; the polylactic acid-co-glycolic acid is composed of lactide and glycolide in a molar ratio of (85:15)-(50:50).

[0014] Furthermore, the relative molecular mass of the polylactic acid-glycolic acid copolymer is 90kDa-160kDa; the polylactic acid-glycolic acid copolymer is composed of lactide and glycolide in a molar ratio of (75:25)-(50:50).

[0015] In one embodiment of the present invention, in S1, the organic solvent is selected from one or more of dichloromethane, ethyl acetate and benzyl alcohol.

[0016] In one embodiment of the present invention, in S1, the weight ratio of paliperidone to the degradable polymer containing a hydrophobic segment is (1:1)-(1:10); the mass proportion of the degradable polymer containing a hydrophobic segment in the drug-containing polymer solution is 0.5%-20%.

[0017] Furthermore, in S1, the weight ratio of paliperidone to the degradable polymer containing a hydrophobic segment is (1:2)-(1:5); the mass proportion of the degradable polymer containing a hydrophobic segment in the drug-containing polymer solution is 1%-15%; when the concentration of the degradable polymer containing a hydrophobic segment is too high, it is easy to precipitate during the preparation process, affecting the preparation of the microspheres.

[0018] In one embodiment of the present invention, in S1, the stabilizer is selected from one or more of polyvinyl alcohol, polysorbate 20, polysorbate 80, polyethylene glycol and sodium dodecyl sulfate; and the mass concentration of the stabilizer in the stabilizer solution is 0.1%-2% (w / v).

[0019] Furthermore, in S1, the stabilizer is polyvinyl alcohol.

[0020] In one embodiment of the present invention, in S2, the rate of the continuous homogenization emulsification is 2000rpm-5000rpm, and the volatilization degree of the organic solvent during the continuous homogenization emulsification process is 2%-10%.

[0021] In one embodiment of the present invention, in S2, the volume ratio of the drug-containing polymer solution to the stabilizer solution is (1:3)-(1:50).

[0022] Furthermore, in S2, the volume ratio of the drug-containing polymer solution to the stabilizer solution is (1:3)-(1:10).

[0023] In one embodiment of the present invention, in S3, the stirring rate is 100 rpm-300 rpm; the curing time is 0.25 h-3 h; and the volume ratio of the stabilizer solution to water is (1:3)-(1:50).

[0024] Furthermore, in S3, the stirring rate is 100 rpm-200 rpm; the curing time is 0.5 h-3 h; and the volume ratio of the stabilizer solution to water is (1:3)-(1:10).

[0025] The second object of the present invention is to provide paliperidone sustained-release microspheres prepared by the method, wherein the paliperidone sustained-release microspheres have an average particle size of 50 μm-80 μm, a drug loading of 27%-35%, and an encapsulation efficiency of 90%-98%.

[0026] The technical solution of the present invention has the following advantages over the prior art:

[0027] (1) Paliperidone of the present invention is a hydrophobic drug, which is co-dissolved in an organic solvent with a degradable polymer containing a hydrophobic segment, thereby reducing drug loss. Secondly, a continuous homogenization emulsification technology is used to control the microspheres to have an appropriate particle size, thereby increasing the drug loading and encapsulation efficiency. In addition, water is used for further solidification, thereby effectively increasing the encapsulation efficiency of the microspheres and making the microspheres harder, thereby avoiding deformation during the collection process of the microspheres, and the microspheres have a good morphology.

[0028] (2) The preparation method described in the present invention is simple and rapid, and the particle size of the sustained-release microspheres is controllable, the size is appropriate, and the shape is round; the drug loading and encapsulation rate are high, the reproducibility is high, there is no burst release phenomenon, and the drug can be slowly and continuously released for more than two months, effectively improving patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

[0030] Figure 1 The scanning electron micrographs of the paliperidone sustained-release microspheres of Example 3 of the present invention (left image 200×, right image 400×);

[0031] Figure 2This is a scanning electron micrograph of the paliperidone sustained-release microspheres of Example 4 of the present invention (left image 200×, right image 400×);

[0032] Figure 3 This is a scanning electron micrograph of the paliperidone sustained-release microspheres of Example 5 of the present invention (left image 200×, right image 400×);

[0033] Figure 4 37°C in vitro release curve of paliperidone sustained-release microspheres of Examples 5 and 6 of the present invention;

[0034] Figure 5 The in vitro release curves of the paliperidone sustained-release microspheres of Example 5 of the present invention at 37°C and 45°C. DETAILED DESCRIPTION

[0035] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0036] In the present invention, unless otherwise specified, the experimental methods used in the embodiments and comparative examples of the present invention are conventional methods unless otherwise specified, and the materials, reagents, etc. used are all commercially available unless otherwise specified.

[0037] In the present invention, unless otherwise specified, the O / W suspensions in the examples and comparative examples of the present invention are continuously added dropwise below the liquid surface. In a fume hood, the organic solvent is usually removed by stirring and volatilization, and the microspheres of inappropriate size are filtered out using stainless steel mesh (pore sizes are 0.0385 mm and 0.15 mm, respectively).

[0038] In the present invention, unless otherwise specified, the model of the freeze-drying instrument in the embodiments and comparative examples of the present invention is FDU-2110.

[0039] Example 1

[0040] The paliperidone sustained-release microspheres and the preparation method thereof of the present embodiment specifically comprise the following steps:

[0041] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 90 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0042] 20 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0043] S2, placing the oil phase and the water phase in a container, continuously homogenizing and emulsifying at a rate of 3000 rpm, volatilizing the organic solvent (ethyl acetate volatility 3.5%), and forming an O / W emulsion;

[0044] S3. Add the O / W emulsion into 100 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 hours and wash them four times with purified water. Suspend them and prefreeze them in a -80°C refrigerator for 8 hours, then freeze-dry them for 48 hours to obtain paliperidone sustained-release microsphere powder.

[0045] Example 2

[0046] The paliperidone sustained-release microspheres and the preparation method thereof of the present embodiment specifically comprise the following steps:

[0047] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 90 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0048] 28 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0049] S2, placing the oil phase and the water phase in a container, continuously homogenizing and emulsifying at a rate of 3000 rpm, volatilizing the organic solvent (ethyl acetate volatility 3.5%), and forming an O / W emulsion;

[0050] S3. Add the O / W emulsion into 196 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 h and wash them 4 times with purified water. Suspend them in a -80 °C refrigerator for pre-freezing for 8 h, and freeze-dry them for 48 h to obtain paliperidone sustained-release microsphere powder.

[0051] Example 3

[0052] The paliperidone sustained-release microspheres and the preparation method thereof of the present embodiment specifically comprise the following steps:

[0053] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 160 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0054] 40 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0055] S2, placing the oil phase and the water phase in a container, continuously homogenizing and emulsifying at a rate of 3000 rpm, volatilizing the organic solvent (ethyl acetate volatility 7.0%), and forming an O / W emulsion;

[0056] S3. Add the O / W emulsion into 400 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 hours and wash them four times with purified water. Suspend them and prefreeze them in a -80°C refrigerator for 8 hours, then freeze-dry them for 48 hours to obtain paliperidone sustained-release microsphere powder.

[0057] Example 4

[0058] The paliperidone sustained-release microspheres and the preparation method thereof of the present embodiment specifically comprise the following steps:

[0059] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 130 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0060] 28 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0061] S2, placing the oil phase and the water phase in a container, continuously homogenizing and emulsifying at a rate of 3000 rpm, volatilizing the organic solvent (ethyl acetate volatility 5.0%), and forming an O / W emulsion;

[0062] S3. Add the O / W emulsion into 196 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 h and wash them 4 times with purified water. Suspend them in a -80 °C refrigerator for pre-freezing for 8 h, and freeze-dry them for 48 h to obtain paliperidone sustained-release microsphere powder.

[0063] Example 5

[0064] The paliperidone sustained-release microspheres and the preparation method thereof of the present embodiment specifically comprise the following steps:

[0065] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 130 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0066] 20 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0067] S2, placing the oil phase and the water phase in a container, continuously homogenizing and emulsifying at a rate of 3000 rpm, volatilizing the organic solvent (ethyl acetate volatility 5.0%), and forming an O / W emulsion;

[0068] S3. Add the O / W emulsion into 100 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 hours and wash them four times with purified water. Suspend them and prefreeze them in a -80°C refrigerator for 8 hours, then freeze-dry them for 48 hours to obtain paliperidone sustained-release microsphere powder.

[0069] Example 6

[0070] The paliperidone sustained-release microspheres and the preparation method thereof of the present embodiment specifically comprise the following steps:

[0071] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 160 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0072] 20 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0073] S2, placing the oil phase and the water phase in a container, continuously homogenizing and emulsifying at a rate of 3000 rpm, volatilizing the organic solvent (ethyl acetate volatility 7.0%), and forming an O / W emulsion;

[0074] S3. Add the O / W emulsion into 100 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 hours and wash them four times with purified water. Suspend them and prefreeze them in a -80°C refrigerator for 8 hours, then freeze-dry them for 48 hours to obtain paliperidone sustained-release microsphere powder.

[0075] Comparative Example 1

[0076] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 90 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0077] 20 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0078] S2, using a conventional method, stirring the oil phase and the water phase at a rate of 300 rpm for 30 min to volatilize the organic solvent (ethyl acetate volatility 3.5%), to form an O / W emulsion;

[0079] S3. Add the O / W emulsion into 100 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 hours and wash them four times with purified water. Suspend them and prefreeze them in a -80°C refrigerator for 8 hours, then freeze-dry them for 48 hours to obtain paliperidone sustained-release microsphere powder.

[0080] Comparative Example 2

[0081] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 90 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0082] 40 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0083] S2, using a conventional method, stirring the oil phase and the water phase at a rate of 300 rpm for 30 min to volatilize the organic solvent (ethyl acetate volatility 3.5%), to form an O / W emulsion;

[0084] S3. Add the O / W emulsion into 400 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 hours and wash them four times with purified water. Suspend them and prefreeze them in a -80°C refrigerator for 8 hours, then freeze-dry them for 48 hours to obtain paliperidone sustained-release microsphere powder.

[0085] Comparative Example 3

[0086] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 130 kDa), dissolve in 4.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0087] 25 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0088] S2, using a conventional method, stirring the oil phase and the water phase at a rate of 300 rpm for 30 min to volatilize the organic solvent (ethyl acetate volatility 5.0%), to form an O / W emulsion;

[0089] S3. Add the O / W emulsion into 125 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 hours and wash them four times with purified water. Suspend them in a -80°C refrigerator for pre-freezing for 8 hours, and freeze-dry them for 48 hours to obtain paliperidone sustained-release microsphere powder.

[0090] Comparative Example 4

[0091] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 160 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0092] 40 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0093] S2, placing the oil phase and the water phase in a container, continuously homogenizing and emulsifying at a rate of 3000 rpm, volatilizing the organic solvent (ethyl acetate volatility 1%), and forming an O / W emulsion;

[0094] S3. Add the O / W emulsion into 400 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 hours and wash them four times with purified water. Suspend them and prefreeze them in a -80°C refrigerator for 8 hours, then freeze-dry them for 48 hours to obtain paliperidone sustained-release microsphere powder.

[0095] Comparative Example 5

[0096] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 130 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 100 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0097] 20 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0098] S2, placing the oil phase and the water phase in a container, continuously homogenizing and emulsifying at a rate of 3000 rpm, volatilizing the organic solvent (ethyl acetate volatility 12%), and forming an O / W emulsion;

[0099] S3. Add the O / W emulsion into 100 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 hours and wash them four times with purified water. Suspend them and prefreeze them in a -80°C refrigerator for 8 hours, then freeze-dry them for 48 hours to obtain paliperidone sustained-release microsphere powder.

[0100] Comparative Example 6

[0101] S1. Weigh 250 mg of PLGA (molar ratio of lactide to glycolide = 75:25, Mw = 160 kDa), dissolve in 3.5 mL of ethyl acetate to obtain a PLGA solution; weigh 125 mg of paliperidone, dissolve in 0.5 mL of benzyl alcohol to obtain a paliperidone solution; add the PLGA solution to the paliperidone solution, vortex to evenly disperse, and obtain a drug-containing polymer solution as the oil phase;

[0102] 40 mL of 1% (w / v) polyvinyl alcohol aqueous solution as the aqueous phase;

[0103] S2, placing the oil phase and the water phase in a micro reaction channel, delivering them to the microfluidic device by a horizontal flow pump at a flow rate of 22.5 mL / min for the water phase and 4.5 mL / min for the oil phase to form an O / W colostrum, and then stirring at 300 rpm for 10 min at room temperature to volatilize the organic solvent (ethyl acetate volatility 7.0%) to form an O / W emulsion;

[0104] S3. Add the O / W emulsion into 400 mL of water at a stirring rate of 150 rpm to solidify. Collect the microspheres after 1.5 hours and wash them four times with purified water. Suspend them and prefreeze them in a -80°C refrigerator for 8 hours, then freeze-dry them for 48 hours to obtain paliperidone sustained-release microsphere powder.

[0105] Test Example 1 Microsphere Particle Size

[0106] Take an appropriate amount of the paliperidone sustained-release microsphere powder prepared in Examples 1-6 and Comparative Examples 1-6, suspend it with an appropriate amount of aqueous solution, and measure the particle size of the microspheres using a BT-2001 laser particle size distribution analyzer. The results are shown in Table 1:

[0107] Table 1

[0108] Sample Mean median diameter ± SD (μm) Example 1 64.96±1.47 Example 2 72.38±0.94 Example 3 65.88±1.53 Example 4 52.41±1.05 Example 5 68.16±0.92 Example 6 50.25±1.65 Comparative Example 1 123.64±1.8 Comparative Example 2 120.89±2.89 Comparative Example 3 116.73±1.65 Comparative Example 4 72.84±2.31 Comparative Example 5 56.25±0.70 Comparative Example 6 73.85±0.93

[0109] As can be seen from Table 1, the particle size of the microspheres in the embodiment is between 50μm-80μm, which is suitable for injection. The results of comparing Examples 1-5 and Comparative Examples 1-3 show that the particle size of the microspheres prepared by the traditional method is relatively large, all greater than 100μm, and the continuous homogenization emulsification technology can keep the particle size of the microspheres at 50μm-80μm, which can significantly reduce the particle size. On the other hand, for microspheres prepared by high molecular weight PLGA (Mw>90kDa), the traditional stirring is too easy to precipitate due to the excessive viscosity of the oil phase, and it is impossible to effectively mix with the water phase into spheres. If a high-speed (3000rpm) continuous homogenization emulsification is used in the preparation process, the homogenization process uses a large shear force to evenly mix the oil and water phases, and it is very easy to form an O / W type emulsion, which is conducive to solidification into paliperidone microspheres with smaller particle sizes.

[0110] Test Example 2 Microsphere Morphology

[0111] Take an appropriate amount of the paliperidone sustained-release microsphere powder prepared in Example 3-5, and measure the microsphere morphology using a scanning electron microscope. The results are as follows: Figure 1-3 As shown. Figure 1-3 It can be seen that the paliperidone sustained-release microspheres are spherical or quasi-spherical, with appropriate particle size, round and smooth, and good morphology.

[0112] Test Example 3 Drug loading and encapsulation efficiency of microspheres

[0113] Octadecylsilane bonded silica gel was used as filler, 0.05 mol / L ammonium dihydrogen phosphate: acetonitrile (70:30) was used as mobile phase, the main peak was adjusted so that the elution time was about 7 min, and the detection wavelength was 238 nm; 10 mg of paliperidone standard was weighed and the mobile phase was fixed to 50 mL, which was the control solution. Weigh 10 mg of paliperidone sustained-release microspheres prepared in two batches of Examples 1-6 and Comparative Examples 1-6, respectively. The first batch was diluted to 50 mL with 0.05 mol / L ammonium dihydrogen phosphate solution, and 1 mL was filtered with a 0.22 μm aqueous filter membrane, collected, and analyzed by HPLC to obtain free paliperidone drugs on the surface of the microspheres; the second batch was added with 1 mL of CHCl3 or CH2Cl2, vortexed to dissolve, and diluted to 100 mL with anhydrous methanol, and 1 mL was filtered with a 0.22 μm organic filter membrane, collected, and analyzed by HPLC to obtain the total drug amount, which was further converted into the drug loading and encapsulation efficiency of the microspheres. The calculation formulas of drug loading and encapsulation efficiency are as follows:

[0114]

[0115] The results are shown in Table 2:

[0116] Table 2

[0117]

[0118]

[0119] As can be seen from Table 2, the encapsulation efficiency of microspheres prepared by the continuous homogenous emulsification method in the examples is higher than that of the traditional method, which can reach more than 90%, and the drug loading under this premise can reach 33.19%. The results of Example 6 and Comparative Example 6 show that even if a microfluidic device is used and a reasonable flow rate is set, the oil phase composed of high molecular weight PLGA cannot be effectively sheared and emulsified, while the continuous homogenous emulsification method can effectively deal with the problem that the oil phase viscosity is too high to form a ball, and the encapsulation efficiency and drug loading of the formed microspheres are high. In addition, the molecular weight of PLGA and the volatility of the organic solvent have an important influence on the encapsulation rate of the microspheres. Only with an appropriate volatility can microspheres with a high encapsulation rate be obtained, that is, a higher molecular weight PLGA (160kDa) requires a higher degree of volatility (volatility 7.0%), a medium molecular weight PLGA (130kDa) requires a medium degree of volatility (volatility 5.0%), and a lower molecular weight PLGA (90kDa) requires a lower degree of volatility (volatility 3.5%).

[0120] Test Example 4 In vitro release curve of microspheres

[0121] Weigh 2.0 g of sodium hydroxide and dissolve it in 500 mL of water, discard 105 mL, add 6.8 g of sodium dihydrogen phosphate and 605 mL of water, and after complete dissolution, add 0.5% (w / v) sodium dodecyl sulfate to obtain a release medium 0.5% SDS-PBS solution.

[0122] About 20 mg of the paliperidone sustained-release microspheres prepared in Examples 5-6 were weighed and placed in a 50 mL conical flask. 50 mL of 0.5% SDS PBS solution (pH 7.4) was added and placed in a water bath constant temperature shaker. At 37°C, oscillate at a rate of 100 rpm, and 1 mL of the sample was taken out at different time points of 4h, 1d, 3d, 5d, 7d... and centrifuged (10000 rpm, 10 min), and 20 μL of the supernatant was taken for sample injection and analysis; at 45°C, 1 mL of the sample was taken out at different time points of 4h, 1d, 3d, 5d, 7d... and centrifuged (10000 rpm, 10 min), and 20 μL of the supernatant was taken for sample injection and analysis. The cumulative release percentage was calculated, and a release curve of the cumulative release percentage-time was drawn. The remaining microspheres were resuspended in fresh medium and continued to release. The results were as follows. Figure 4-Figure 5 As shown. Figure 4It can be seen from Examples 5-6 that paliperidone is slowly released from the microspheres, without burst release, and the release curve is gentle, and the release can be sustained for two months or even longer. This has a good and lasting therapeutic effect on schizophrenia and related diseases. From Example 8, it can be seen that the increase in the oil-water ratio leads to a faster release of paliperidone, because the drug diffuses in the external water phase, is more dispersed, and is easily released. Figure 5 It can be seen that temperature changes have an impact on the release of microspheres. As the temperature rises, the release of microspheres accelerates. This may be because the high temperature causes the PLGA shell of the microspheres to swell, allowing the encapsulated drugs to be released to a greater extent.

[0123] In summary, the present invention uses continuous homogenization emulsification technology to prepare paliperidone long-acting microspheres with appropriate particle size, high encapsulation efficiency and drug loading and capable of sustained release for more than two months.

[0124] Obviously, the above embodiments are merely examples for clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for preparing paliperidone sustained-release microspheres, characterized in that: The following steps are involved: S1, dissolving paliperidone and a degradable polymer containing a hydrophobic segment in an organic solvent to obtain a drug-containing polymer solution; dissolving a stabilizer in water to obtain a stabilizer solution; S2, adding the drug-containing polymer solution described in S1 to the stabilizer solution by continuous homogenization emulsification to obtain an O / W emulsion; S3. Under stirring conditions, the O / W emulsion described in S2 is added into water for solidification, and the paliperidone sustained-release microspheres are obtained by washing and freeze-drying.

2. The method for preparing paliperidone sustained-release microspheres according to claim 1, characterized in that: In S1, the degradable polymer containing a hydrophobic segment is selected from one or more of polylactic acid-co-glycolic acid, polylactic acid, polylactic acid-polyethylene glycol and polycaprolactone.

3. The method for preparing paliperidone sustained-release microspheres according to claim 2, characterized in that: The relative molecular mass of the polylactic acid-glycolic acid copolymer is 60kDa-210kDa; the polylactic acid-glycolic acid copolymer is composed of lactide and glycolide in a molar ratio of (85:15)-(50:50).

4. The method for preparing paliperidone sustained-release microspheres according to claim 1, characterized in that: In S1, the organic solvent is selected from one or more of dichloromethane, ethyl acetate and benzyl alcohol.

5. The method for preparing paliperidone sustained-release microspheres according to claim 1, characterized in that: In S1, the weight ratio of paliperidone to the degradable polymer containing a hydrophobic segment is (1:1)-(1:10); the mass proportion of the degradable polymer containing a hydrophobic segment in the drug-containing polymer solution is 0.5%-20%.

6. The method for preparing paliperidone sustained-release microspheres according to claim 1, characterized in that: In S1, the stabilizer is selected from one or more of polyvinyl alcohol, polysorbate 20, polysorbate 80, polyethylene glycol and sodium dodecyl sulfate; and the mass concentration of the stabilizer in the stabilizer solution is 0.1%-2% (w / v).

7. The method for preparing paliperidone sustained-release microspheres according to claim 1, characterized in that: In S2, the rate of the continuous homogenization emulsification is 2000rpm-5000rpm, and the volatilization degree of the organic solvent during the continuous homogenization emulsification process is 2%-10%.

8. The method for preparing paliperidone sustained-release microspheres according to claim 1, characterized in that: In S2, the volume ratio of the drug-containing polymer solution to the stabilizer solution is (1:3)-(1:50).

9. The method for preparing paliperidone sustained-release microspheres according to claim 1, characterized in that: In S3, the stirring rate is 100 rpm-300 rpm; the curing time is 0.5 h-3 h; and the volume ratio of the stabilizer solution to water is (1:3)-(1:50).

10. A paliperidone sustained-release microsphere prepared by the method according to any one of claims 1 to 9, characterized in that: The paliperidone sustained-release microspheres have an average particle size of 50 μm-80 μm, a drug loading of 27%-35%, and an encapsulation rate of 90%-98%.

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