Risperidone sustained-release microsphere without delay phase and preparation method of risperidone sustained-release microsphere

Abstract

The invention discloses a risperidone sustained-release microsphere without a delay phase and a preparation method thereof, the risperidone sustained-release microsphere is composed of three risperidone sustained-release microspheres A1, A2 and A3 with different release behaviors, and the mass ratio of A1: A2: A3 is [2-4]: [4-6]: [2-4]. The risperidone sustained-release microspheres obtained by mixing the three microspheres with different release characteristics according to a specific proportion can release risperidone after administration, and the risperidone sustained-release microspheres have the advantages of stable drug release rate, long drug effect duration and no delay phase.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to a risperidone sustained-release microsphere without a lag period and a preparation method thereof. Background Art

[0002] Risperidone, chemically named 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-α]pyrimidin-4-one, is a common atypical antipsychotic lipophilic drug, which was developed by Janssen Pharmaceutica N.V. in Belgium in 1984. It is a white powder crystal, insoluble in water, but soluble in methanol and 0.1 mol / L dilute hydrochloric acid, and is a lipophilic drug. As an antagonist, risperidone blocks the body's 5-hydroxytryptamine receptor and dopamine D2 receptor, and has significant curative effects on the negative and positive symptoms of schizophrenia patients. The chemical formula of risperidone is as shown in A, and it will degrade in vivo to 9-hydroxyrisperidone that plays the main pharmacological role, and the chemical formula is as shown in B.

[0003]

[0004] Currently, the commonly known clinical dosage forms of risperidone drugs include tablets, oral solutions, capsules, orally disintegrating tablets, etc. Tablets and capsules on the domestic market need to be taken twice a day. Patients need to take medicine every day, and the bioavailability of oral administration is relatively low. The compliance of patients taking medicine for a long time is poor, and there are drawbacks in ordinary preparations. Therefore, it is necessary to study a long-acting sustained-release preparation, which can solve the problems of short half-life and low bioavailability of traditional preparations. Among them, microsphere preparations have the advantages of sustained-release or controlled-release of drugs and targeted drug delivery, etc., can avoid the appearance of peak and trough blood drug concentrations, reduce the number of drug administrations, and improve patient compliance.

[0005] A microsphere refers to a particle with a particle size of 1-300 μm formed by dissolving or uniformly dispersing a drug in a polymer matrix. A microsphere is a new drug delivery system, which can encapsulate one or more drugs. The slow degradation of the polymer in the microsphere preparation can slow down and stabilize the drug release rate, prolong the time for the drug to produce a pharmacological effect in the body, reduce the adverse effects of the drug and have a sustained-release effect. There are mainly two ways for microsphere drug release: diffusion and erosion. In the early stage, the drug mainly diffuses out of the carrier material, and in the later stage, the degradation and erosion of the carrier material release the drug, so as to achieve the effect of prolonging drug release, reducing the dosing frequency, and thus improving patient compliance. When a microsphere injection enters the body, the carrier wraps the drug, thus avoiding the loss of drug efficacy due to the first-pass effect, making the drug have targeting, and at the same time, the structure of the carrier material can be appropriately changed to regulate the drug release behavior.

[0006] The sustained-release microspheres use macromolecular materials to encapsulate drugs, which can improve the drug stability and are widely used to encapsulate drugs such as proteins and polypeptides. Currently, those developed abroad include leuprorelin acetate microspheres, somatotropin microspheres, exenatide microspheres, risperidone microspheres for injection, etc. Currently, the long-acting sustained-release risperidone microspheres for injection "Hengde" developed by Janssen Pharmaceutical has been approved by the US FDA for marketing in 2003. The injection method of this dosage form is intramuscular injection once every two weeks. There is a 3-week drug release stagnation in the early stage, and it is necessary to cooperate with oral risperidone tablets to maintain the drug effect. The effective ingredient treatment maintenance time is 4 to 6 weeks. It has significantly improved the disadvantages of frequent administration of traditional preparations, improved the patient compliance, and the therapeutic effect of risperidone microspheres for injection on psychiatric patients is better than that of oral preparations. However, due to the need to cooperate with oral drugs in the early stage, and in addition, it is difficult to accurately convert the dosage when switching from long-acting injection drugs to oral drugs, and it is impossible to avoid the peak and trough concentrations caused by taking drugs. To solve the above deficiencies of the microsphere technology and better meet the clinical requirements, it is necessary to develop a new technology for preparing long-acting sustained-release microsphere injections to eliminate the drug release stagnation period, achieve the effect of immediate release after administration, reduce the number of administrations, make up for the disadvantages of the currently marketed risperidone sustained-release microsphere injections with a release lag period, and enhance the drug effectiveness and patient compliance.

[0007] In addition, a method for preparing a risperidone sustained-release composition disclosed in Patent CN106822043A adjusts the release rate of risperidone in the sustained-release composition by adding a release regulator. The voids generated by the release regulator enable the acidic substances generated by the internal degradation of the microspheres to be transmitted to the outside in a timely manner, reducing the self-degradation rate of the polymer, so that there is no obvious release lag period after administration, and reducing the pain of patients taking oral drugs. The organic solvents such as dichloromethane used in this patent are toxic to the human body, and there are likely to be solvent residues in the prepared microspheres, which may have adverse effects on organisms. The technology disclosed in Patent CN102579365A selects different molecular weights of polyesters mixed as the carrier material to prepare microspheres. The microspheres have a smooth and round surface and good dispersibility. The microspheres prepared by this method have good sustained-release effects, low burst release rates, a sustained-release period of more than two weeks, and no release lag period. However, the drug loading of the microspheres prepared by this method is too high, the preparation is unstable, and the in vivo release behavior will change after long-term storage. CN103126997A discloses a method for preparing risperidone sustained-release microspheres. During the preparation process, a plasticizer is added, preferably dibutyl phthalate or n-butyl stearate, and an antioxidant tert-butyl-p-hydroxyanisole or α-tocopherol is also added, and a layer of blank polymer material is coated on the surface of the microspheres to further reduce the burst release of the microspheres. Although it overcomes the defect of the drug release lag period, its drug sustained-effect period is too short, less than one week, and multiple administrations are still required, and the long-acting sustained-release effect cannot be achieved. Summary of the Invention

[0008] The object of the present invention is to provide a risperidone sustained-release microsphere without a lag period and a preparation method thereof. This risperidone sustained-release microsphere releases the drug immediately upon administration, and the drug release rate is stable, the drug efficacy lasts for a long time, and there is no lag period.

[0009] Another object of the present invention is to provide a preparation method of a risperidone sustained-release microsphere without a lag period.

[0010] The object of the present invention can be achieved by the following technical solutions:

[0011] A risperidone sustained-release microsphere without a lag period is composed of three types of risperidone sustained-release microspheres A1 (release curve: divided into a lag period, a rapid release period, and a sustained release period), A2 (release curve: also divided into a lag period, a rapid release period, and a sustained release period, but the release rate in the rapid release period is reduced), and A3 (without a lag period, and the sustained release period is shortened). The A1 and A2 microspheres are O / W type PLGA microspheres, and the A3 microsphere is an S / O / W type PLGA microsphere; the mass ratio of A1:A2:A3 microspheres is [2-4]:[4-6]:[2-4]; the risperidone sustained-release microsphere contains risperidone or 9-hydroxyrisperidone or its salt and PLGA; the molecular weight of PLGA is 20KD-200KD, wherein the molecular weight of PLGA in the A1 microsphere is 100-200KD, the molecular weight of PLGA in the A2 microsphere is 20-99KD, and the molecular weight of PLGA in the A3 microsphere is 100-200KD.

[0012] As a preference of the present invention, the ratio range of A1:A2:A3 is 2:6:2.

[0013] The risperidone sustained-release microsphere provided by the present invention contains risperidone or 9-hydroxyrisperidone or its salt and PLGA.

[0014] As a preference of the present invention, the present invention selects PLGA with a molecular weight of 60KD-150KD. Among them, the A1 microsphere is preferably 100-150KD, the A2 microsphere is preferably 60-90KD, and the A3 microsphere is preferably 100-150KD. The molecular weight described in the present invention refers to the "weight average molecular weight", simply referred to as "molecular weight".

[0015] As a preference of the present invention, the drug loading amount of the microsphere described in the present invention is between 30%-50%. The drug loading amount described in the present invention is the actual drug loading amount, and is calculated in the following manner: drug loading amount = [amount of drug in microsphere / (amount of drug in microsphere + high molecular weight)] × 100%.

[0016] As a preference of the present invention, the particle size range of the raw material drug of the risperidone sustained-release microsphere provided by the present invention is between 50-150um.

[0017] As a preference of the present invention, risperidone or 9-hydroxyrisperidone in the sustained-release microspheres provided by the present invention may exist in the form of a salt, and the acids forming salts therewith include inorganic acids such as hydrohalic acids (hydrochloric acid, hydrobromic acid, etc.), nitric acid, sulfuric acid, phosphoric acid, etc.; or organic acids such as acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, pamoate, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, 2-butenedioic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.

[0018] As a preference of the present invention, the risperidone sustained-release microspheres provided by the present invention are prepared by an emulsion-solvent evaporation method. Risperidone or 9-hydroxyrisperidone or its salt and PLGA can be dissolved in a suitable organic solvent, and the organic solvent is injected into an aqueous solution prepared from a water-soluble polymer for dispersion and emulsification, and then the organic solvent is evaporated, washed and filtered to obtain microspheres.

[0019] As a further preference of the present invention, when preparing A1 microspheres, the solvent for dissolving risperidone or 9-hydroxyrisperidone or its salt is a good solvent for risperidone or 9-hydroxyrisperidone or its salt; when preparing A3 microspheres, the solvent for dissolving risperidone or 9-hydroxyrisperidone or its salt is a poor solvent for risperidone or 9-hydroxyrisperidone or its salt.

[0020] As a further preference of the present invention, when preparing A1 microspheres, the good solvent used is benzyl alcohol; when preparing A3 microspheres, the poor solvent used is ethyl acetate; the water-soluble polymer can be selected from polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMC-Na), polyvinylpyrrolidone (PVP), sodium polymethacrylate, sodium polyacrylate or a mixture of one, two or more of them. The dispersion and emulsification method can adopt mechanical stirring dispersion and emulsification or dispersion and emulsification through a static mixer.

[0021] The preparation method of the risperidone sustained-release microspheres of the present invention uses the emulsion-solvent evaporation method to separately prepare risperidone sustained-release microspheres A1, A2, and A3, and the three microspheres are mixed evenly according to the mass ratio of A1:A2:A3 microspheres of [2-4]:[4-6]:[2-4] to obtain the risperidone sustained-release microspheres without a lag period.

[0022] As a preference of the present invention, the risperidone sustained-release microspheres provided by the present invention are prepared by an emulsion-solvent evaporation method. Risperidone or 9-hydroxyrisperidone or its salt and PLGA can be dissolved in a suitable organic solvent, and the organic solvent is injected into an aqueous solution prepared from a water-soluble polymer for dispersion and emulsification, and then the organic solvent is evaporated, washed and filtered to obtain microspheres.

[0023] As a further preference of the present invention, when preparing A1 microspheres, the solvent used to dissolve risperidone or 9-hydroxyrisperidone or its salt is a good solvent for risperidone or 9-hydroxyrisperidone or its salt; when preparing A3 microspheres, the solvent used to dissolve risperidone or 9-hydroxyrisperidone or its salt is a poor solvent for risperidone or 9-hydroxyrisperidone or its salt.

[0024] As a further preference of the present invention, when preparing A1 microspheres, the good solvent used is benzyl alcohol; when preparing A3 microspheres, the poor solvent used is ethyl acetate; the water-soluble polymer may be selected from polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMC-Na), polyvinylpyrrolidone (PVP), sodium polymethacrylate, sodium polyacrylate or a mixture of one, two or more of them. The dispersion emulsification method may adopt mechanical stirring dispersion emulsification or dispersion emulsification through a static mixer.

[0025] As a further preference of the present invention, the preparation method comprises the following steps:

[0026] (1) Prepare risperidone sustained-release microspheres A1, A2, and A3 respectively:

[0027] A1 microspheres:

[0028] Preparation of the oil-phase solution: Weigh PLGA and dissolve it in ethyl acetate, stir thoroughly until completely dissolved as the oil-phase solution A; accurately weigh the risperidone raw material drug, add benzyl alcohol, stir until completely dissolved as the oil-phase solution B, mix the oil-phase solutions A and B, mix evenly and then let it stand;

[0029] Preparation of the water-phase solution: Accurately weigh the water-soluble polymer and dissolve it in pure water, stir mechanically and place it in a hot water bath to completely dissolve until the solution is clear, pass the solution through a 500-mesh sieve to remove impurities and foreign matters, and cool it to 18 - 22 °C;

[0030] Add the above-mentioned mixed oil-phase solutions A and B and the water-phase solution to an SK static mixer to form O / W droplets, then add an ethyl acetate aqueous solution, stir to volatilize the organic solvent, solidify the emulsion into O / W-type PLGA microspheres, filter the hardened microspheres with 100-mesh and 500-mesh stainless steel sieves, wash the microspheres with qualified particle size with low-temperature distilled water, wash off the residual solvent on the surface of the microspheres, discard the microspheres adhered during the quenching process, collect the qualified microspheres, then place them in a 250-mL three-necked flask, wash them with 25% ethanol aqueous solution at 0 - 4 °C for 30 - 45 min, filter the solidified microspheres with 100-mesh and 500-mesh stainless steel sieves, wash the microspheres with qualified particle size with low-temperature distilled water, wash off the benzyl alcohol with a higher boiling point, and at the same time wash off the residual solvent on the surface of the microspheres. After washing and sieving, collect the material and place it in a self-made vacuum drying device for low-temperature vacuum drying. After drying, collect the microspheres to obtain microspheres A1;

[0031] A2 microspheres:

[0032] Preparation of oil-phase solution: Accurately weigh PLGA and dissolve it in ethyl acetate. Stir thoroughly until it is completely dissolved to obtain oil-phase solution A; accurately weigh risperidone raw material drug, add benzyl alcohol, and stir until it is completely dissolved to obtain oil-phase solution B. Mix oil-phase solutions A and B, and after mixing evenly, let it stand still.

[0033] Preparation of water-phase solution: Accurately weigh water-soluble polymer in pure water, stir mechanically and place it in a water bath to completely dissolve it until the solution is clear. Filter the solution through a 500-mesh sieve to remove impurities and foreign matters, and cool it to 18 - 22 °C.

[0034] Add the mixed oil-phase solutions A and B and the water phase to an SK static mixer to form O / W droplets. Then add an ethyl acetate aqueous solution, stir to volatilize the organic solvent, and solidify the emulsion into O / W-type PLGA microspheres. Filter the hardened microspheres using 100-mesh and 500-mesh stainless steel sieves. Wash the microspheres with qualified particle size using low-temperature distilled water to wash away the residual solvent on the surface of the microspheres. Discard the microspheres adhered during the quenching process, collect the qualified microspheres, and then place them in a 250 mL three-necked flask. Wash them with 25% ethanol aqueous solution at 0 - 4 °C for 30 - 45 min. Filter the solidified microspheres using 100-mesh and 500-mesh stainless steel sieves. Wash the microspheres with qualified particle size using low-temperature distilled water to wash away the benzyl alcohol with a higher boiling point and at the same time wash away the residual solvent on the surface of the microspheres. After washing and sieving, collect the materials and place them in a self-made vacuum drying equipment for low-temperature vacuum drying. After drying, collect the microspheres to obtain microspheres A2.

[0035] Microspheres A3:

[0036] Preparation of oil-phase solution: Accurately weigh PLGA in ethyl acetate and stir magnetically until it is completely dissolved to obtain oil-phase solution A; accurately weigh risperidone raw material drug, add 50 mL of ethyl acetate, and stir magnetically to mix it into a suspension to obtain oil-phase solution B. Mix oil-phase solutions A and B evenly, and stir magnetically for 30 s until the oil phase is uniformly transparent and has no obvious granular solids, and let it stand at room temperature of 20 °C.

[0037] Preparation of water-phase solution: Accurately weigh water-soluble polymer in pure water, stir mechanically and place it in a water bath to completely dissolve it until the solution is clear. Filter the solution through a 500-mesh sieve to remove impurities and foreign matters, and cool it to 18 - 22 °C.

[0038] The mixed oil phases A and B and the aqueous phase are added to an SK static mixer, and then 500 mL of an ethyl acetate aqueous solution is added. The organic solvent is stirred and volatilized to solidify the emulsion to form S / O / W type PLGA microspheres. The hardened microspheres are filtered using 100-mesh and 500-mesh stainless steel sieves. The microspheres with qualified particle sizes are rinsed with low-temperature distilled water to wash away the residual solvent on the surface of the microspheres, and the microspheres adhered during the quenching process are discarded. The qualified microspheres are collected and then placed in a 250 mL three-necked flask. They are washed with 25% ethanol aqueous solution at 0 - 4°C for 30 - 45 min. The solidified microspheres are filtered using 100-mesh and 500-mesh stainless steel sieves. The microspheres with qualified particle sizes are rinsed with low-temperature distilled water to wash away the benzyl alcohol with a higher boiling point and at the same time wash away the residual solvent on the surface of the microspheres. After washing and sieving, the collected material is put into a self-made vacuum drying device for low-temperature vacuum drying. After drying, the microspheres are collected to obtain microspheres A3;

[0039] (2) Mixed microspheres

[0040] The microspheres A1, A2, and A3 are mixed evenly in proportion to obtain the risperidone sustained-release microspheres without a lag period as described.

[0041] The present invention further provides the application of risperidone microspheres in the preparation of antipsychotic drugs. The psychoses include acute and chronic schizophrenia, obvious positive symptoms (such as hallucinations, delusions, thought disorders, hostility, suspicion) and obvious negative symptoms (such as slow reaction, flat affect and social apathy, less speech) of various other psychotic states, as well as affective symptoms related to schizophrenia (such as: depression, guilt, anxiety), preferably schizophrenia, anxiety, depression, periodic headache, etc.

[0042] A long-acting antipsychotic drug contains the risperidone sustained-release microspheres as described in the present invention, and preferably also contains various pharmaceutically acceptable excipients required for preparing the risperidone sustained-release microspheres into a pharmaceutical preparation.

[0043] The microspheres provided by the present invention can be prepared in the form of a sterile powder. Before administration to a patient, the microspheres are suspended in an acceptable dispersion medium, which is composed of one or several of a suspending agent, a pH regulator, an isotonic regulator, a surfactant, and injection water. The suspending agent can be one or more of sodium carboxymethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, glycerol, etc. The isotonic regulator can be one or more of sodium chloride, glucose, mannitol, sorbitol, etc. The surfactant is a non-ionic surfactant, such as the polysorbate series (such as polysorbate 80, polysorbate 60, etc.), the poloxamer series (such as poloxamer 188, etc.).

[0044] Beneficial effects:

[0045] By mixing three kinds of microspheres with different release characteristics in a specific proportion, the risperidone sustained-release microspheres obtained are released upon administration, and the drug release rate is stable, the drug efficacy lasts for a long time, and there is no lag period. Description of the Drawings

[0046] Figure 1 Release curves of three batches of microspheres in Example 1 in pH 7.4 phosphate buffer solution

[0047] Figure 2 Release curves of three batches of microspheres in Example 2 in pH 7.4 phosphate buffer solution

[0048] Figure 3 Release curves of three batches of microspheres in Comparative Example 1 in pH 7.4 phosphate buffer solution Detailed Description of the Invention

[0049] The present invention will be further described below through specific examples. It should be understood that the examples of the present invention are only for understanding the present invention and not for limiting the present invention. Unless otherwise specified, the terms of the present invention have the conventional meanings in the art, and all reagents are directly used after being purchased commercially.

[0050] Example 1

[0051] A1 Microspheres:

[0052] Preparation of the oil phase solution: Weigh 8.0 g of PLGA (molecular weight 120 KD) precisely into 50 mL of ethyl acetate, stir thoroughly until completely dissolved to obtain oil phase solution A; weigh 10.0 g of risperidone raw material drug precisely into 50 mL of benzyl alcohol, stir until completely dissolved to obtain oil phase solution B. Mix oil phase solutions A and B, mix evenly and then let stand.

[0053] Preparation of the aqueous phase solution: Weigh 50 g of polyvinyl alcohol (PVA) precisely into 10 L of pure water, stir mechanically and place in a water bath to completely dissolve until the solution is clear. Pass the solution through a 500-mesh sieve to remove impurities and foreign matters, and cool to about 20 °C.

[0054] Add the above-mentioned mixed oil phases A and B and the aqueous phase to an SK static mixer to form O / W droplets. Then add 500 mL of an ethyl acetate aqueous solution, stir to volatilize the organic solvent, and solidify the emulsion to form O / W-type PLGA microspheres. Filter the hardened microspheres using 100-mesh and 500-mesh stainless steel sieves, rinse the microspheres with qualified particle size with low-temperature distilled water to wash away the residual solvent on the surface of the microspheres, discard the microspheres adhered during the quenching process, and collect the qualified microspheres. Then place them in a 250-mL three-necked flask, wash with 25% ethanol aqueous solution at low temperature (0 - 4°C) for a certain time (about 30 min), filter the solidified microspheres using 100-mesh and 500-mesh stainless steel sieves, rinse the microspheres with qualified particle size with low-temperature distilled water to wash away benzyl alcohol with a higher boiling point and at the same time wash away the residual solvent on the surface of the microspheres. After washing and sieving, collect the material and place it in a self-made vacuum drying device for low-temperature vacuum drying. After drying, collect the microspheres and store them sealed at low temperature of 2 - 8°C.

[0055] A2 microspheres:

[0056] Preparation of the oil phase solution: Weigh accurately 8.0 g of PLGA (molecular weight 80 KD) into 50 mL of ethyl acetate, stir thoroughly until completely dissolved to obtain the oil phase A solution; weigh accurately 10.0 g of risperidone raw material drug and add it to 50 mL of benzyl alcohol, stir until completely dissolved to obtain the oil phase B solution. Mix the oil phases A and B, and let it stand after mixing evenly.

[0057] Preparation of the aqueous phase solution: Weigh accurately 50 g of polyvinyl alcohol (PVA) into 10 L of pure water, place it in a hot water bath with mechanical stirring until completely dissolved until the solution is clear, pass the solution through a 500-mesh sieve to remove impurities and foreign objects, and cool it to about 20°C.

[0058] Add the above-mentioned mixed oil phases A and B and the aqueous phase to an SK static mixer to form O / W droplets. Then add 500 mL of an ethyl acetate aqueous solution, stir to volatilize the organic solvent, and solidify the emulsion to form O / W-type PLGA microspheres. Filter the hardened microspheres using 100-mesh and 500-mesh stainless steel sieves, rinse the microspheres with qualified particle size with low-temperature distilled water to wash away the residual solvent on the surface of the microspheres, discard the microspheres adhered during the quenching process, and collect the qualified microspheres. Then place them in a 250-mL three-necked flask, wash with 25% ethanol aqueous solution at low temperature (0 - 4°C) for a certain time (about 30 min), filter the solidified microspheres using 100-mesh and 500-mesh stainless steel sieves, rinse the microspheres with qualified particle size with low-temperature distilled water to wash away benzyl alcohol with a higher boiling point and at the same time wash away the residual solvent on the surface of the microspheres. After washing and sieving, collect the material and place it in a self-made vacuum drying device for low-temperature vacuum drying. After drying, collect the microspheres and store them sealed at low temperature of 2 - 8°C.

[0059] A3 microspheres:

[0060] Preparation of the oil phase solution: Weigh precisely 8.0 g of PLGA (molecular weight 120 KD) and dissolve it completely in 50 mL of ethyl acetate by magnetic stirring to obtain the oil phase solution A; weigh precisely 10.0 g of risperidone raw material drug, add 50 mL of ethyl acetate, and mix it into a suspension by magnetic stirring to obtain the oil phase solution B (suspension). Mix the oil phase solutions A and B evenly, and stir magnetically for 30 s until the oil phase is uniformly transparent without obvious granular solids, then let it stand at room temperature of 20 °C. The mixture of the oil phase solutions A and B needs to be prepared and used immediately.

[0061] Preparation of the aqueous phase solution: Weigh precisely 50 g of polyvinyl alcohol (PVA) and dissolve it completely in 10 L of pure water by mechanical stirring in a hot water bath until the solution is clear. Filter the solution through a 500-mesh sieve to remove impurities and foreign matters, and then cool it to about 20 °C.

[0062] Add the mixed oil phase solutions A and B and the aqueous phase to an SK static mixer to form O / W droplets, then add 500 mL of an ethyl acetate aqueous solution, and stir to volatilize the organic solvent to solidify the emulsion to form S / O / W-type PLGA microspheres. Filter the solidified microspheres through 100-mesh and 500-mesh stainless steel sieves, wash the microspheres with qualified particle size with low-temperature distilled water to remove the residual solvent on the surface of the microspheres, discard the microspheres adhered during the quenching process, and collect the qualified microspheres. Then place them in a 250-mL three-necked flask, wash them with a 25% ethanol aqueous solution at a low temperature (0 - 4 °C) for a certain time (about 30 min), filter the solidified microspheres through 100-mesh and 500-mesh stainless steel sieves, wash the microspheres with qualified particle size with low-temperature distilled water to remove benzyl alcohol with a higher boiling point and at the same time remove the residual solvent on the surface of the microspheres. After washing and sieving, collect the materials and put them into a self-made vacuum drying equipment for low-temperature vacuum drying. After drying, collect the microspheres and store them sealed at a low temperature of 2 - 8 °C.

[0063] Mix the microspheres A1, A2, and A3 evenly according to the ratio of 2:6:2, and then a kind of risperidone sustained-release microsphere without a lag period can be obtained.

[0064] Effect Example 1

[0065] Precisely measure about 20 mg of the self-made microspheres into a bottle, add 200 mL of a pH 7.4 phosphate buffer medium, and prepare three parallel batches of samples; place each bottle in a 37 °C water bath and let it stand. Sampling is carried out on the 1st day after placement for a total of 42 days. Before sampling, slowly rotate the bottle to make the solution uniformly suspended, then let it stand for 10 minutes to make the microspheres fully settle. Filter the sample solution through a 0.45-μm microporous filter membrane, and take the subsequent filtrate as the test solution; calculate the concentration of risperidone in the test solution by the external standard method based on the peak area.

[0066]

[0067] In the formula:

[0068] C1——Concentration of the test solution obtained from this sampling calculation (mg / mL);

[0069] C2——Concentration of the test solution obtained from the previous sampling calculation (mg / mL).

[0070] Table 1

[0071]

[0072]

[0073] From Figure 1 and Table 1, it can be seen that the risperidone sustained-release pellets provided by the present invention are released immediately upon administration, and the drug release rate is stable, the drug effect lasts for a long time, and there is no lag period.

[0074] Example 2

[0075] Microspheres A1, A2, and A3 are all selected from Example 1. Mix the A1, A2, and A3 microspheres evenly according to the ratio of 3:5:2.

[0076] Effect Example 2

[0077] The experimental method is the same as that in Effect Example 1.

[0078] Table 2

[0079]

[0080]

[0081] From Figure 2 and Table 2, it can be seen that the risperidone sustained-release pellets provided by the present invention are released immediately upon administration, and the drug release rate is stable, the drug effect lasts for a long time, and there is no lag period.

[0082] Comparative Example 1

[0083] Microspheres A1, A2, and A3 are all selected from Example 1. Mix the A1, A2, and A3 microspheres evenly according to the ratio of 1:8:1.

[0084] Effect Comparative Example 1

[0085] The experimental method is the same as that in Effect Example 1.

[0086] Table 3

[0087]

[0088]

[0089] From Figure 3As can be seen from Table 3, the mixing ratio of the three microspheres is very important. If the mixing ratio is not within the protection scope of the present invention, a lag period will be significantly exhibited.

Claims

1. A risperidone sustained-release microsphere without a lag period, characterized in that It is composed of three kinds of risperidone sustained-release microspheres A1, A2, and A3 with different release behaviors. Microspheres A1 and A2 are O / W type PLGA microspheres, and microsphere A3 is S / O / W type PLGA microsphere; the mass ratio of A1:A2:A3 microspheres is [2-4]:[4-6]:[2-4]; the said risperidone sustained-release microspheres contain risperidone raw material medicine and PLGA; the molecular weight of PLGA is 20KD-200KD. Among them, the molecular weight of PLGA in microsphere A1 is 100-200KD, the molecular weight of PLGA in microsphere A2 is 20-99KD, and the molecular weight of PLGA in microsphere A3 is 100-200KD.

2. The risperidone sustained-release microspheres according to claim 1, wherein The drug loading of the said microspheres is 30%-50%.

3. The risperidone sustained-release microspheres according to claim 1, characterized in that The particle size range of the risperidone raw material medicine is: 50-150um; the said risperidone raw material medicine is risperidone or 9-hydroxyrisperidone or its salt; risperidone or 9-hydroxyrisperidone can exist in the form of a salt, and the acids forming salts with it include inorganic acids and organic acids. The said inorganic acids are preferably hydrohalic acids, nitric acid, sulfuric acid, phosphoric acid, etc.; the said organic acids are preferably acetic acid, propionic acid, glycolic acid, 2-hydroxypropionic acid, pamoate, 2-oxopropionic acid, oxalic acid, malonic acid, succinic acid, 2-butenedioic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid.

4. The risperidone sustained-release microspheres according to claim 1, characterized in that Microspheres A1, A2, and A3 are all prepared by the emulsion-solvent evaporation method. Risperidone or 9-hydroxyrisperidone or its salt and PLGA are respectively dissolved in appropriate organic solvents to prepare an oil phase, and the organic solvent is injected into an aqueous solution prepared with a water-soluble polymer for dispersion emulsification, and then the organic solvent is evaporated to dryness, washed, and filtered to obtain microspheres.

5. The risperidone sustained-release microsphere according to claim 4, characterized in that When preparing microsphere A1, the solvent used to dissolve risperidone or 9-hydroxyrisperidone or its salt is a good solvent for risperidone or 9-hydroxyrisperidone or its salt; when preparing microsphere A3, the solvent used to dissolve risperidone or 9-hydroxyrisperidone or its salt is a poor solvent for risperidone or 9-hydroxyrisperidone or its salt.

6. The risperidone sustained-release microsphere according to claim 5, characterized in that When preparing microsphere A1, the good solvent used is benzyl alcohol; when preparing microsphere A3, the poor solvent used is ethyl acetate; the said water-soluble polymer is selected from polyvinyl alcohol, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium polymethacrylate, sodium polyacrylate or one, two or a mixture of two or more of them, and the said dispersion emulsification method can adopt mechanical stirring dispersion emulsification or dispersion emulsification through a static mixer.

7. The preparation method of the risperidone sustained-release microspheres according to any one of claims 1-6, characterized in that The risperidone sustained-release microspheres A1, A2, and A3 are respectively prepared by the emulsion-solvent evaporation method, and the three kinds of microspheres are mixed evenly according to the mass ratio of A1:A2:A3 microspheres of [2-4]:[4-6]:[2-4] to obtain the said risperidone sustained-release microspheres without a lag period.

8. The preparation method according to claim 7, characterized in that The A1, A2, and A3 microspheres are all prepared by the emulsion-solvent evaporation method. Risperidone or 9-hydroxyrisperidone or its salt and PLGA are respectively dissolved in a suitable organic solvent to prepare an oil phase, and the organic solvent is injected into an aqueous solution prepared with a water-soluble polymer for dispersion and emulsification, and then the organic solvent is evaporated. After washing and filtering, microspheres are obtained. Among them, when preparing the A1 microspheres, the good solvent used is benzyl alcohol; when preparing the A3 microspheres, the poor solvent used is ethyl acetate; the water-soluble polymer is selected from polyvinyl alcohol, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sodium polymethacrylate, sodium polyacrylate, or a mixture of one, two, or more of them. The dispersion and emulsification method can adopt mechanical stirring for dispersion and emulsification or dispersion and emulsification through a static mixer.

9. Use of the risperidone sustained-release microspheres according to any one of claims 1-6 in the preparation of a long-acting antipsychotic drug, wherein the psychosis is selected from acute or chronic schizophrenia, obvious positive symptoms or obvious negative symptoms of various other psychotic states, and affective symptoms related to schizophrenia, preferably schizophrenia, anxiety, depression, and periodic headache.

10. A long-acting antipsychotic drug, characterized in that Containing the risperidone sustained-release microspheres according to any one of claims 1-6, and preferably further containing various pharmaceutically acceptable excipients required for preparing the risperidone sustained-release microspheres into a pharmaceutical preparation.

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