Risperidone sustained-release composition and application thereof

Abstract

The invention discloses a risperidone sustained-release composition and application thereof, the risperidone sustained-release composition comprises the following raw materials: risperidone, a lactide-glycolide copolymer and a solvent, the mass ratio of the lactide-glycolide copolymer to the solvent is 1: (1-10), and the mass of the risperidone is 4% of the total mass of the raw materials. By reducing the concentration of the PLGA and the ratio of the lactide to the glycolide and adding the high-fat substance into the solvent, the in-situ gel which is high in drug loading capacity, convenient to administrate and low in burst release is obtained, and the in-situ gel has a good process amplification prospect.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to a risperidone sustained-release composition and its application. Background Art

[0002] Risperidone is a first-line drug for the treatment of acute and chronic schizophrenia, and is also the only drug approved by the FDA for the treatment of adolescent schizophrenia. At present, common oral preparations of risperidone in clinical practice include tablets, capsules, solutions, etc. However, due to the short half-life of risperidone, only about 3 hours, it is necessary to administer the drug once or multiple times a day, which not only reduces the compliance of patients, but may also lead to fluctuations in blood drug concentration, thereby aggravating the symptoms of the disease and increasing the risk of recurrence. Studies have shown that more than 80% of patients receiving oral antipsychotic drugs will experience recurrence. Therefore, for this special group of schizophrenia patients, improving medication compliance is crucial.

[0003] In-situ gel is a type of preparation that can undergo a phase transition at the administration site after being administered in a solution state, transforming from a liquid state into a non-chemically crosslinked semi-solid gel; among them, the solvent-exchange type in-situ gel has good formability and biodegradability, and mainly uses polylactic acid (PLA), poly (lactic-co-glycolic acid) (PLGA), and polycaprolactone (PCL) as matrix materials. Currently, the risperidone in-situ gel of Indivior company has been launched To utilize An extended-release suspension developed by a delivery system; There are only two specifications of 90mg:0.6mL and 120mg:0.8mL, and the validity period of both is one month, and the flexibility of the administration time is limited. Among them, 90mg is equivalent to 3mg of oral risperidone per day, while 120mg corresponds to 4mg of oral risperidone per day. This product is not suitable for patients who need to take less than 3mg or more than 4mg of risperidone per day. Its applicable population is mainly adult and more severe schizophrenia or bipolar disorder patients, while children, adolescents and mild patients are not within the applicable range, which limits the wide clinical application.

[0004] At the same time, The clinical application of also has the following obvious limitations: (1) High system viscosity: The solubility of risperidone in N-methylpyrrolidone is limited. Due to the limitations of clinical application and the maximum volume, it is injected in the form of a suspension, and the system viscosity is high; (2) Low injectability; The suspension has a high viscosity, and a larger-sized needle (18G) needs to be used to ensure injectability, and the pain caused by injection is more intense; (3) A complex reconstruction process is required before clinical use: Adopt Technologies, including a solid drug syringe and another delivery system syringe, require rapid back-and-forth pushing of the double syringes before use to uniformly mix the drug, resulting in a complicated preparation process before administration and reducing the accessibility of drug use; (4) Severe burst release: The core problem of solvent-exchangeable ISFI is the burst release effect of the drug, which may be due to the time lag between the injection of the liquid and the formation of the solid reservoir, leading to a more complex drug release mechanism. The burst release effect was studied in US Patent US2015147398(A1) and US2018154001(A1). By increasing the ratio of lactide / glycolide segments and the PLGA concentration, the initial burst release rate of the in-situ gel was inhibited. However, this would increase the viscosity of the in-situ gel and reduce its injectability.

[0005] Therefore, for drug-loaded in-situ gels, it is necessary to find an application combination to increase the drug loading and injectability and slow down the drug burst release, so as to avoid the complicated and difficult-to-replicate reconstruction process before use, improve the patient compliance, and thus promote its clinical application. Summary of the Invention

[0006] One object of the present invention is to provide a risperidone sustained-release composition, the raw materials including risperidone, a lactide-glycolide copolymer, and a solvent, the mass ratio of the lactide-glycolide copolymer to the solvent being 1:1 - 10, and the mass of risperidone being 4% of the total mass of the raw materials.

[0007] Further, the mass ratio of the lactide-glycolide copolymer to the solvent is 1:2 - 8, preferably 1:3 - 5.

[0008] Further, the solvent is any one of the following:

[0009] (1) The solvent is one or a mixture of several of N-methylpyrrolidone, PEG 400, PEG 600, benzyl alcohol, dimethyl sulfoxide, propylene glycol, acetone, ethanol, 2-pyrrolidone, or propylene carbonate;

[0010] (2) The solvent consists of solvent A and a highly lipophilic substance, the mass ratio of solvent A to the highly lipophilic substance being 1:0.05 - 0.3, solvent A being selected from one or several of N-methylpyrrolidone, PEG 400, PEG 600, benzyl alcohol, dimethyl sulfoxide, propylene glycol, acetone, ethanol, 2-pyrrolidone, or propylene carbonate, and the highly lipophilic substance being selected from one or several of stearic acid, palmitic acid, benzyl benzoate, ethyl acetate, ethyl lactate, glyceryl triacetate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, or medium-chain triglyceride.

[0011] Further, when the solvent is (1), the solvent is one or a mixture of N-methylpyrrolidone, ethyl lactate, dimethyl sulfoxide, and benzyl benzoate.

[0012] Further, when the solvent is (2), the solvent A is selected from one or more of N-methylpyrrolidone, ethyl lactate, dimethyl sulfoxide, and benzyl benzoate, and the highly lipophilic substance is selected from one or more of benzyl benzoate, ethyl acetate, glyceryl monooleate, glyceryl dioleate, and glyceryl trioleate.

[0013] Further, the lactide-glycolide copolymer is ester-capped or acid-capped, and the molar ratio of lactide to glycolide is (50-85):(15-50).

[0014] Further, the intrinsic viscosity of the lactide-glycolide copolymer is 0.1-3 dl / g.

[0015] The second object of the present invention is to provide the use of the above-mentioned risperidone sustained-release composition in the preparation of a therapeutic drug for schizophrenia.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] (1) In the present invention, a high molecular polymer is selected as the matrix in combination with (organic solvent + highly lipophilic substance). In the present invention, an organic solvent + highly lipophilic substance is selected for combination. It is found in the research that when a highly lipophilic substance is used, the interaction force between the solvent molecules and the drug molecules will be increased (i.e., the principle of like dissolves like), and the drug loading capacity of risperidone will be improved. For example, a preferred example is to select a mixture of N-methylpyrrolidone and glyceryl monooleate, wherein the content of glyceryl monooleate is 5-30%, and the content of N-methylpyrrolidone is 40-80%. This combination form can strengthen the solvation of risperidone, significantly increase the drug solubility compared with the use of organic solvents, and multiple long-chain highly lipophilic substances contribute to improving the drug bioavailability.

[0018] (2) Compared with the solvent-exchange in-situ gel of the PLGA system widely used on the market, the present invention is a single pre-filled device and can directly complete the administration process by injection. Compared with the technology adopted by the commercially available products, rapid mixing before use is not required, and its complex and difficult-to-replicate reconstruction process can be avoided. Compared with the prior art that requires connecting the solid and liquid syringes and pushing them back and forth 60-100 times before use, the complicated preparation before administration is reduced, the requirements for medical staff and the place are lowered, and the drug accessibility is improved. Compared with Compared with using PLGA alone and NMP as a blank matrix, by adopting the method of adding a mixture of highly lipophilic substances, the drug loading of risperidone in the present invention is increased by nearly 40%; by increasing the drug loading, the dosage limit for children, adolescents, and patients with mild schizophrenia and bipolar disorder can be achieved in the form of a solution-type in-situ gel, expanding the scope of the applicable population; the solution-type in-situ gel can effectively avoid unnecessary drug loss during the mixing process, the dosage is more accurate, and the repeatability is high; and the solution-type in-situ gel is more convenient for administration, increasing the possibility of self-administering drugs at home and meeting the clinical medication needs.

[0019] (3) In terms of improving patient compliance, by adopting the method of mixing organic solvents + highly lipophilic substances, the drug loading of risperidone is increased in the present invention, solving the problem that the commercially available products use the drug suspension administration form due to solubility limitations. The present invention can be administered in the form of a solution-type in-situ gel, avoiding administration in the form of a suspension and reducing the viscosity of the in-situ gel. The present invention is a subcutaneous injection-type in-situ gel, which is a low-viscosity liquid when not injected, ensuring that the product can smoothly pass through the syringe and needle during administration, improving the convenience of injection and the comfort of the patient. After applying the above technology, compared with existing products such as commercially available risperidone products compared, a syringe with a needle 8G smaller can be used for injection, reducing the pain caused by injection, being more suitable for low-age schizophrenia patients such as those with mild symptoms and adolescents, and being more easily accepted by patients.

[0020] (4) When the in-situ gel contacts an aqueous medium or body fluid, it will trigger the phase transition of the polymer solution. The most core problem of the solvent-exchange type in-situ gel lies in the serious burst release effect; the burst release of the drug is closely related to the phase transition in the matrix solidification stage, and the key parameters of the phase transition kinetics are the inflow of the non-solvent and the outflow of the polymer solvent, which depend on the mutual solubility of the solvent and non-solvent used. The commercially available products currently use highly miscible solvents such as N-methylpyrrolidone, which will cause the solvent to rapidly diffuse into the water medium and are more likely to form a loose interconnected porous structure, resulting in serious drug burst release (as Figure 7 shown). The research of the inventor found that by adding highly lipophilic substances, the lipophilicity of the mixed solvent can be increased, thereby reducing the miscibility with water, slowing down the phase transition speed, restricting the formation of the polymer dilution phase, forming a dense drug reservoir, with a low internal porosity, reducing the drug diffusion rate, increasing the diffusion path length, and slowing down the drug burst release degree. The present invention can flexibly adjust the drug release rate by adjusting the type and / or ratio of the highly lipophilic substances, realizing a drug release cycle of 3 to 15 days.

[0021] (5) PLGA is obtained by copolymerizing glycolide and lactide. Its composition ratio, end-capping, and dosage all affect the drug release behavior. Among them, PLGA with ester end-capping and a high lactide / glycolide segment ratio can inhibit burst release and prolong the drug sustained release time. In addition, the PLGA concentration also has a great influence on the drug release rate of ISFI. Using a lactide-glycolide ratio of 80:20 and a PLGA concentration of 38% can inhibit the initial burst release of the in-situ gel, but there are problems such as poor injectability and long biodegradation time. The present invention reduces the PLGA concentration and the lactide-glycolide ratio, and instead uses highly lipophilic PLGA to inhibit the initial burst release. For example, the initial burst release rate of the in-situ gel prepared with 24% PLGA of model 7502 is less than 5%. Using ester-capped PLGA for preparation can achieve the effect of inhibiting the initial burst release, improve injectability, shorten the biodegradation time, and also save the PLGA dosage, bringing greater economic benefits.

[0022] Compared with other non-in-situ gel sustained release systems, such as the particle system, the present invention has the advantages of simple administration, uniform drug dispersion, and good needle penetration. Compared with preformed implants, the present invention has the advantages of no need for invasive techniques, low pain, and high compliance. In addition, if an allergy or adverse reaction occurs, the present invention can also simply surgically remove the drug depot formed in-situ, having the advantage of being able to interrupt drug administration at any time, and the drug is not prone to hydrolysis, oxidation and other reactions in the system, so it has good drug storage stability. At the same time, because its preparation process is simple, it has good prospects for process scale-up and is easy to industrialize. Description of the Drawings

[0023] Figure 1 It is the in-vitro forming appearance of Example 11 (left) and Control Example 1 (right).

[0024] Figure 2 It is the 6h in-vitro release burst results of the in-situ gels in Example 5, Example 8, Example 9, Example 11, and Control Example 1.

[0025] Figure 3 It is the in-vitro release comparison curve of the in-situ gels in Example 11 and Control Example 1.

[0026] Figure 4 It is the in-vivo drug release situation of the in-situ gel of Example 11.

[0027] Figure 5 It is the in-vivo forming appearance of the in-situ gel of Experimental Example 11.

[0028] Figure 6 It is the DSC results of risperidone, PLGA 752H, blank in-situ gel, and the risperidone in-situ gel of Example 11.

[0029] Figure 7 SEM results of the in-situ gels of Example 11 (upper) and Control Example 1 (lower). Detailed implementation manners

[0030] The preferred implementation manners of the present invention will be described in detail below in conjunction with embodiments. It should be understood that the following embodiments are given only for the purpose of illustration and are not used to limit the scope of the present invention. Those skilled in the art can make various modifications and substitutions to the present invention without departing from the purpose and spirit of the present invention.

[0031] Unless otherwise specified, the experimental methods used in the following embodiments are all conventional methods.

[0032] Unless otherwise specified, the materials, reagents, etc. used in the following embodiments can all be obtained from commercial channels.

[0033] Control Example 1

[0034] Weigh 30 mg of risperidone, dissolve it in 540 mg of N-methylpyrrolidone (NMP), add 180 mg of PLGA (Evonik Corporation, RG752H), stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution, and after sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0035] Control Example 2

[0036] Weigh 30 mg of risperidone, dissolve it in 540 mg of dimethyl sulfoxide (DMSO), add 180 mg of PLGA (Evonik Corporation, RG752H), stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution, and after sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0037] Example 1

[0038] Investigation of the dosage of PLGA

[0039] This example is for the screening of different PLGA / NMP ratio formulations and the investigation of the 6-hour burst release rate.

[0040] Prepare blank gels by mixing PLGA 752H and N-methylpyrrolidone according to the mass ratios of PLGA / NMP of 1 / 3, 1 / 4, and 1 / 5 respectively, add 4% (w / w) risperidone, stir magnetically for 1 hour under water bath heating to obtain a clear and transparent in-situ gel solution, and after sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0041] (1) Take 0.1 mL of the in-situ gel in a vial. Under the condition of heating in a water bath at 37 °C, add an appropriate amount of PBS with a pH of 7.4 at 37 °C to it slowly at regular intervals, observe the state of the preparation in the vial until a gel is formed, and investigate the water consumption for gelation of the in-situ gel.

[0042] (2) Use a syringe with a 26G needle. Draw 0.1 mL of the in-situ gel solution with a 1 mL syringe and then push it slowly, feel the resistance during the pushing process, and judge its injectability.

[0043] (3) Take 0.1 mL of the in-situ gel solution with different ratios of PLGA / NMP, inject it directly into 8 mL of 0.3% SDS PBS solution. After it solidifies and forms a shape, put it into a water bath shaker at 37 °C and 50 rpm. Take 3 mL of the supernatant at 6 h and quickly supplement an equal volume of the release medium, and measure the initial burst release rate of risperidone at 6 h. The results are shown in Table 1.

[0044] Table 1 Prescription screening of different polymers and investigation of related properties

[0045] Prescription PLGA / NMP Ratio PLGA Content Amount of Water for Gelation Needle Penetration 6h Burst Release Rate Prescription 1 1 / 3 24％ 74 μL +++ 49.03％ Prescription 2 1 / 4 19.2％ 79 μL +++ 53.66％ Prescription 3 1 / 5 16％ 85 μL +++ 58.77％

[0046] As can be seen from Table 1, the in-situ gels prepared with the above three dosage ratios of PLGA / NMP all have good needle penetration. With the increase in the content of PLGA, they have lower water consumption for gelation and initial burst release rate.

[0047] Example 2

[0048] Investigation of PLGA types

[0049] Prepare with a mass ratio of PLGA / NMP of 1 / 3, respectively according to 4% (w / w) of risperidone, 24% (w / w) of different polymer matrices, and 72% (w / w) of N-methylpyrrolidone. Stir magnetically for 1 hour under water bath heating to obtain a clear and transparent in-situ gel solution. After sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0050] 1. Prescription screening of different polymer matrices and investigation of gelation characteristics

[0051] Take 0.1 mL of the risperidone in-situ gel containing 4% (w / w) of risperidone and 24% (w / w) of different types of polymer matrices in a vial. Under the condition of heating in a water bath at 37 °C, add an appropriate amount of PBS with a pH of 7.4 at 37 °C to it slowly at regular intervals, observe the state of the preparation in the vial until a gel is formed, and investigate the water consumption for gelation of the in-situ gel.

[0052] Table 2 Prescription screening of different polymers and investigation of gelation characteristics

[0053] Prescription Polymer Matrix Polymer Content Amount of Water for Gelation Formability Prescription 1 PLGA 502H 24％ 80 μL Gel Skeleton Intact Prescription 2 PLGA 752H 24％ 74 μL Gel Skeleton Intact Prescription 3 PLGA 755S 24％ 70 μL Gel Skeleton Intact Prescription 4 PLGA 858S 24％ 67 μL Gel Skeleton Intact Prescription 5 PLGA 7525DLG 24％ 72 μL Gel Skeleton Intact Prescription 6 PLGA 7502S 24％ 71 μL Gel Skeleton Intact Prescription 7 PLGA 7502A 24％ 75 μL Gel Skeleton Intact Prescription 8 PLA 207S 24％ 60 μL Gel Skeleton Intact

[0054] As can be seen from Table 2, the in-situ gels prepared with the selected polymer matrices all have a low gelation water consumption and good formability, and can form solids with clear interfaces at the junction, complete gel skeletons, and good regular shapes.

[0055] 2. Injectability of different polymer matrices

[0056] Using a syringe with a 26G needle, a 1 mL syringe was used to aspirate 0.1 mL of risperidone in-situ gel containing 4% (w / w) risperidone and 24% (w / w) of different types of polymer matrices, and then slowly pushed to feel the resistance during the pushing process to judge its injectability.

[0057] Note: In the needle passing property, "-" means it cannot pass, "+" means there is a large resistance when passing, "++" means there is a slight resistance when passing, and "+++" means it passes smoothly without any resistance felt.

[0058] Fix the glass slide at an inclined angle, use a syringe to aspirate 0.1 mL of in-situ gel, and use the direct injection method to drop the in-situ gel onto the head end of the glass slide, and start timing to record the time required for the in-situ gel to flow to the bottom of the glass slide.

[0059] Table 3 Prescription screening and injectability investigation of different polymers

[0060] Prescription Polymer Matrix Polymer Content Flow Time (s) Needle Penetration Prescription 1 PLGA 502H 24％ 11.44 +++ Prescription 2 PLGA 752H 24％ 15.94 +++ Prescription 3 PLGA 755S 24％ 173.39 + Prescription 4 PLGA 858S 24％ 847.95 —— Prescription 5 PLGA 7525DLG 24％ 17.09 +++ Prescription 6 PLGA 7502 24％ 38.39 +++ Prescription 7 PLGA 7502A 24％ 14.51 ++ Prescription 8 PLA 207S 24％ 1918.74 ——

[0061] As can be seen from Table 3, except for using PLGA 858S and PLA 207S, the in-situ gels prepared with the other polymer models all have good needle passing properties.

[0062] 3. Investigation of the in-vitro burst release effect of in-situ gels with different polymer matrices

[0063] Take 0.1 mL of risperidone in-situ gel containing 4% (w / w) risperidone and 24% (w / w) of different types of polymer matrices, and directly inject it into 8 mL of 0.3% SDS PBS solution. After it solidifies and forms, place it in a water bath shaker at 37 °C and 50 rpm. Take 3 mL of the supernatant at 6 h and quickly supplement an equal volume of release medium to measure the 6 h burst release rate of risperidone. The results are shown in Table 4.

[0064] Table 4 Prescription screening and 6 h burst release rate investigation of different polymers

[0065] Prescription Polymer Matrix Polymer Content 6h Burst Release Rate (%) Prescription 1 PLGA 502H 24％ 58.58 Prescription 2 PLGA 752H 24％ 53.16 Prescription 3 PLGA 755S 24％ 45.08 Prescription 4 PLGA 7525DLG 24％ 44.52 Prescription 5 PLGA7502A 24％ 49.74 Prescription 6 PLGA7502 24％ 4.74 Control Example 2 PLGA752H 24％ 67.61

[0066] Polymer matrices of different models can affect the burst release of in-situ gels. The lactide / glycolide composition ratio, end-capping, and intrinsic viscosity can all affect the drug release behavior. As can be seen from Table 4, the in-situ gel prepared with PLGA that is end-capped with an ester group, has a high lactide / glycolide segment ratio, and high intrinsic viscosity has a slow solvent exchange rate and a low initial burst release rate. Moreover, compared with using dimethyl sulfoxide as a solvent, N-methylpyrrolidone has stronger lipophilicity, and the initial burst release rate of the prepared risperidone in-situ gel is also lower.

[0067] Example 3

[0068] Screening of highly lipophilic substances

[0069] 1. Solubility after adding different highly lipophilic substances

[0070] Prepare a single solvent and a mixed solvent with a highly lipophilic substance added according to Table 5. Add an excess of risperidone to it. After magnetic stirring at 25°C for 24 h, centrifuge and take the supernatant, and measure its solubility. The results are shown in Table 5.

[0071] Table 5 Solubility after mixing different highly lipophilic substances

[0072]

[0073]

[0074] As can be seen from Table 5, both highly lipophilic substances and biocompatible solvents have a certain solubility of risperidone. After mixing a highly lipophilic substance with a solvent, the solubility is higher than the theoretical solubility of simple addition, showing a trend of increased solubility. This indicates that the mixed solvent composed of a highly lipophilic substance and a solvent is not a simple physical mixture, but there is an interaction force, which enhances the interaction between risperidone and the highly lipophilic substance and the solvent, thereby increasing the solubility.

[0075] 2. Preparation and gelling properties of lipid sustained-release compositions

[0076] Prepare according to 4% (w / w) of risperidone, 24% (w / w) of PLGA752H, 10% (w / w) of different highly lipophilic substances, and 62% (w / w) of biocompatible solvent. Under water bath heating, magnetic stir for 1 hour to obtain a clear and transparent in-situ gel solution. After sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0077] Weigh 0.1 mL of the in-situ gel into a vial. Under the condition of water bath heating at 37°C, at regular intervals, slowly add an appropriate amount of PBS with a pH of 7.4 at 37°C to it, observe the state of the preparation in the vial until a gel is formed, and investigate the water consumption for gelling of the in-situ gel.

[0078] Weigh 0.1 mL of the in-situ gel and inject it into 8 mL of PBS with a pH of 7.4 at 37 °C by direct injection method to investigate the in-vitro formability of the in-situ gel. The results are shown in Table 6.

[0079] Table 6 Investigation on the preparation and gelation characteristics of different lipid sustained-release compositions

[0080]

[0081]

[0082] As can be seen from Table 6, the in-situ gel with N-methylpyrrolidone as the biocompatible solvent and the addition of high-lipid substances has good formability and can form a solid with clear interface junction, complete gel skeleton and good regular shape.

[0083] 3. Investigation on the in-vitro burst release effect of the in-situ gel prepared by adding different types of high-lipid substances

[0084] Take 4% (w / w) of risperidone, 24% (w / w) of PLGA752H and N-methylpyrrolidone (the sum with high-lipid substances is 72% w / w), prepare according to the different types and proportions of high-lipid substances in the following table, stir magnetically for 1 hour under water bath heating to obtain a clear and transparent in-situ gel solution, and after sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0085] Inject 0.1 mL directly into 8 mL of 0.3% SDS PBS solution. After it solidifies and forms, put it into a water bath shaker at 37 °C and 50 rpm. Take 3 mL of the supernatant at 6 h and quickly supplement the same volume of release medium, and measure the 6 h burst release rate of the in-situ gel. The results are shown in Table 7.

[0086] Table 7 6 h burst release rate of the in-situ gel after adding different types and proportions of high-lipid substances

[0087] Prescription Lipophilic Substance Ratio 6h Burst Release Rate (%) Prescription 1 Glycerol 10％ 47.81 Prescription 2 Palmitic Acid 10％ 30.25 Prescription 3 Stearic Acid 10％ 41.17 Prescription 4 Ethyl Acetate 10％ 18.61 Prescription 5 Ethyl Lactate 10％ 47.10 Prescription 6 Benzyl Benzoate 10％ 30.56 Prescription 7 Diolein 10％ 26.49 Prescription 8 Triacetin 10％ 45.80 Prescription 9 Triolein 10％ 26.25 Prescription 10 Medium Chain Triglycerides 10％ 31.51 Prescription 11 Monoolein 10％ 5.54 Prescription 12 Monoolein 8％ 14.72 Prescription 13 Monoolein 6％ 18.17 Control Example 1 None 0％ 49.27

[0088] According to Table 7, the sustained-release composition with the addition of high-lipid substances has the characteristic of inhibiting burst release compared with the sustained-release composition of the single solvent.

[0089] 4. Investigation on the in-vivo burst release effect of the in-situ gel prepared by different proportions of high-lipid substances

[0090] Prepare the in-situ gel containing 4% (w / w) of risperidone, the in-situ gel prepared by adding high-lipid substances and the in-situ gel without high-lipid substances. Inject 0.2 mL of the risperidone in-situ gel into the rat body by subcutaneous injection. At the set time points, dissect out the gel, wash it, and measure the 6 h release percentage in the rat body. The results are shown in Table 8.

[0091] Investigation on the initial burst effect in vivo of in-situ gels prepared by adding hyperlipidemic substances

[0092]

[0093] As can be seen from Table 8, the preparation added with hyperlipidemic substances has a good inhibitory effect on the initial burst.

[0094] Example 4

[0095] Weigh 30 mg of risperidone, dissolve it in 465 mg of N-methylpyrrolidone and 75 mg of palmitic acid, add 180 mg of PLGA752H, and stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution. After sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0096] Example 5

[0097] Weigh 30 mg of risperidone, dissolve it in 465 mg of N-methylpyrrolidone and 75 mg of ethyl acetate, add 180 mg of PLGA752H, and stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution. After sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0098] Example 6

[0099] Weigh 30 mg of risperidone, dissolve it in 465 mg of N-methylpyrrolidone and 75 mg of ethyl lactate, add 180 mg of PLGA752H, and stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution. After sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0100] Example 7

[0101] Weigh 30 mg of risperidone, dissolve it in 465 mg of N-methylpyrrolidone and 75 mg of benzyl benzoate, add 180 mg of PLGA752H, and stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution. After sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0102] Example 8

[0103] Weigh 30 mg of risperidone, dissolve it in 465 mg of N-methylpyrrolidone and 75 mg of glyceryl dioleate, add 180 mg of PLGA752H, and stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution. After sterile filtration through a 0.22 μm filter membrane, it is obtained.

[0104] Example 9

[0105] Weigh 30 mg of risperidone and dissolve it in 465 mg of N-methylpyrrolidone and 75 mg of glyceryl trioleate. Add 180 mg of PLGA752H and stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution. After sterile filtration through a 0.22-μm filter membrane, it is ready.

[0106] Example 10

[0107] Weigh 30 mg of risperidone and dissolve it in 465 mg of N-methylpyrrolidone and 75 mg of glyceryl triacetate. Add 180 mg of PLGA752H and stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution. After sterile filtration through a 0.22-μm filter membrane, it is ready.

[0108] Example 11

[0109] Weigh 30 mg of risperidone and dissolve it in 465 mg of N-methylpyrrolidone and 75 mg of glyceryl monolaurate. Add 180 mg of PLGA 752H and stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution. After sterile filtration through a 0.22-μm filter membrane, it is ready.

[0110] Example 12

[0111] Weigh 30 mg of risperidone and dissolve it in 480 mg of N-methylpyrrolidone and 60 mg of glyceryl monolaurate. Add 180 mg of PLGA 752H and stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution. After sterile filtration through a 0.22-μm filter membrane, it is ready.

[0112] Example 13

[0113] Weigh 30 mg of risperidone and dissolve it in 495 mg of N-methylpyrrolidone and 45 mg of glyceryl monolaurate. Add 180 mg of PLGA 752H and stir magnetically for about 1 hour until completely dissolved to obtain a clear and transparent solution. After sterile filtration through a 0.22-μm filter membrane, it is ready.

[0114] Next, the risperidone in-situ gel prepared in the above examples was tested.

[0115] 1. In vitro release experiment

[0116] Take the samples from Example 5, Example 8, Example 9, Example 11, and Control Example 1 and directly inject them into 8 mL of 0.3% SDS PBS solution. Wait for them to solidify and form. Their pictures are as Figure 1 shown; place them in a water bath shaker at 37°C and 50 rpm. Take 3 mL of the supernatant at 6 h and quickly supplement an equal volume of the release medium to measure the 6-h burst release rate of risperidone. The results are shown in Figure 2, Examples 5, 8, 9, and 11 have the characteristics of suppressing burst release and prolonging the release period compared with Control Example 1, and the release behavior can be flexibly regulated by adjusting the type or proportion of lipophilic substances. The results of the entire drug release process are shown in Figure 3 .

[0117] 2. In vivo release experiment

[0118] Take Example 11 and Control Example 1, and inject 0.2 mL subcutaneously in the scapular region of the rat's back. At the 6-hour time point, dissect out the gel, wash it, and measure the 6-hour burst release rate in the rat body.

[0119] The results are shown in Table 9. Example 11 has the characteristic of suppressing burst release compared with Control Example 1.

[0120] Take Example 11 and inject 0.3 mL subcutaneously in the scapular region of the rat's back. At the time points of 6 hours, 1 day, 2 days, 3 days, 5 days, and 7 days, dissect out the gel, wash it, and measure the drug release in vivo. The results are shown in Figure 4 .

[0121] Table 9 Investigation of in vivo burst release effect of in-situ gels prepared by adding lipophilic substances

[0122]

[0123]

[0124] 3. In vivo formability experiment

[0125] Take 0.2 mL of Example 11 and inject it subcutaneously in the scapular region of the rat's back to investigate the in vivo formability. The results are shown in Figure 5 , and the risperidone in-situ gel can form a gel morphology with a complete skeleton in vivo.

[0126] 4. In vivo biodegradability experiment

[0127] Take 0.2 mL of Example 11 and inject it subcutaneously in the scapular region of the rat's back. Take out the gel at the set time points and measure its length and width.

[0128] The results are shown in Table 10. The length of the gel implant formed by Example 11 was 1.68 cm and the width was 1.13 cm at 6 hours, while it had degraded to a length of 1.07 cm and a width of 0.72 cm on the seventh day, indicating that the risperidone lipid sustained-release composition has good biodegradability.

[0129] Table 10 Dimensions of the implant dissected at different time points

[0130] Time Length (cm) Width (cm) 6h 1.68 1.13 1d 1.46 1.05 2d 1.40 1.00 3d 1.40 0.95 5d 1.12 0.90 7d 1.07 0.72

[0131] 5. DSC Experiment

[0132] DSC analysis was performed on risperidone, PLGA752H, blank in-situ gel (the composition of the blank in-situ gel was 465 mg of N-methylpyrrolidone, 75 mg of glyceryl monooleate, and 180 mg of PLGA752H), and the risperidone in-situ gel formed in Example 11, respectively.

[0133] The results are as Figure 6 shown. Risperidone showed an obvious endothermic peak at 173.5 °C, indicating that it existed in a crystalline form; PLGA752H showed a weak endothermic peak at 43.1 °C, corresponding to its glass transition temperature. In the blank in-situ gel, the endothermic peak of PLGA completely disappeared because the dissolution of PLGA in NMP destroyed its crystalline structure; while in the risperidone in-situ gel, the characteristic endothermic peak of risperidone disappeared, indicating that there was an interaction between risperidone and the matrix, and it existed in the risperidone in-situ gel in a non-crystalline state.

[0134] 6. SEM Experiment

[0135] SEM analysis was performed on the gels formed in Example 11 and Control Example 1, respectively, and the results are as Figure 7 shown.

[0136] As Figure 7 shown in the upper figure above, for the in-situ gel of Example 11, due to the slower diffusion rate, nucleation started later, and many nuclei were generated at the same time. The growth of each nucleus was restricted by adjacent nuclei, and a "spongy" implant morphology was observed; while for the in-situ gel of Control Example 1, due to the fast water penetration rate, a typical "finger-like" pore structure was formed (as Figure 7 shown in the lower figure below).

Claims

1. A risperidone sustained-release composition, characterized in that, The raw materials include risperidone, poly(lactide-co-glycolide), and a solvent. The mass ratio of poly(lactide-co-glycolide) to the solvent is 1:1 - 10, and the mass of risperidone is 4% of the total mass of the raw materials.

2. The risperidone sustained-release composition according to claim 1, wherein The mass ratio of poly(lactide-co-glycolide) to the solvent is 1:2 - 8.

3. The risperidone sustained-release composition according to claim 1 or 2, characterized in that, The solvent is any one of the following: (1) The solvent is one or a mixture of several of N-methylpyrrolidone, PEG 400, PEG 600, benzyl alcohol, dimethyl sulfoxide, propylene glycol, acetone, ethanol, 2-pyrrolidone, or propylene carbonate; (2) The solvent consists of solvent A and a highly lipophilic substance. The mass ratio of solvent A to the highly lipophilic substance is 1:0.05 - 0.

3. Solvent A is selected from one or several of N-methylpyrrolidone, PEG 400, PEG 600, benzyl alcohol, dimethyl sulfoxide, propylene glycol, acetone, ethanol, 2-pyrrolidone, or propylene carbonate, and the highly lipophilic substance is selected from one or several of stearic acid, palmitic acid, benzyl benzoate, ethyl acetate, ethyl lactate, glyceryl triacetate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, or medium-chain triglycerides.

4. The risperidone sustained-release composition according to claim 3, characterized in that, The solvent is a mixture of one or several of N-methylpyrrolidone, ethyl lactate, dimethyl sulfoxide, or benzyl benzoate.

5. The risperidone sustained-release composition according to claim 3, wherein When the solvent is (2), solvent A is selected from one or several of N-methylpyrrolidone, ethyl lactate, dimethyl sulfoxide, or benzyl benzoate, and the highly lipophilic substance is selected from one or several of benzyl benzoate, ethyl acetate, glyceryl monooleate, glyceryl dioleate, or glyceryl trioleate.

6. The risperidone sustained-release composition according to claim 1 or 2, characterized in that, The poly(lactide-co-glycolide) is end-capped with an ester or an acid, and the molar ratio of lactide to glycolide is (50 - 85):(15 - 50).

7. The risperidone sustained release composition according to claim 6, wherein The intrinsic viscosity of the poly(lactide-co-glycolide) is 0.1 - 3 dl / g.

8. Use of the risperidone sustained-release composition according to claim 1 in the preparation of a therapeutic drug for schizophrenia.

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