CN101584652A - Risperidone sustained-release gel injection and preparation method thereof - Google Patents
Risperidone sustained-release gel injection and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a risperidone sustained-release gel injection and preparation method thereof. The risperidone sustained-release gel injection is composed of risperidone or analogue thereof, biological degradable polymer and biocompatible dissolvent, wherein the mass ratio between risperidone or analogue thereof and sum of biological degradable polymer and biocompatible dissolvant is 1:3-67. Continuous and constant-speed release of risperidone is up to several weeks immediately after the injection is injected into appropriate part in vivo, thereby improving compliance therapy in psychotic with risperidone analogue.
Description
Technical field
The present invention relates to pharmaceutical preparation and preparing technical field thereof, be specifically related to risperidone biodegradable long-acting slow-release gel injection and preparation method thereof.
Background technology
Risperidone is an atypical Psychotolytic thing of new generation, belong to benzo-isoxazole derivant, it is a kind of optionally monoaminergic antagonist, it and 5-hydroxy tryptamine can the 5-HT2 receptor and the D2 receptor of dopamine very high affinity is arranged, risperidone also can combine with alpha 1 adrenergic receptor, and combines with H1-histaminergic receptor and α 2-adrenoceptor with lower affinity.Risperidone does not combine with cholinoceptor, is strong D2 antagonist, can improve the schizoid positive symptom, but the motor function that it causes inhibition, and catalepsy all lacks than the psychosis of classics.It can reduce the possibility that EPS takes place to the 5-hydroxy tryptamine of cental system and the balance of dopamine antagonism, and its therapeutical effect is expanded to schizoid negative symptoms and emotion symptom.Because its good effect, side effect is light, this medicine at present on the market of antipsychotic drug the status leading.But because its oral usage is one day twice, the compliance of psychotic's long-term prescription is relatively poor, so therapy discontinued often causes the chronic migration and the recurrence of the course of disease.Therefore be administered once, several weeks, effective risperidone durative action preparation highlighted great advantage.An external now existing shot can continue the risperidone continuous release microsphere injection listing of two all curative effects.
At present, micro-balloon injection is the mainstream technology of risperidone durative action preparation, this dosage form is a carrier with the Biodegradable polymeric material, risperidone and polymer are passed through special technique, make the microsphere of tens microns of particle diameters, microsphere faces with before being distributed in the stabilizing agent or disperse medium of special formulation, can inject the subcutaneous or muscular tissue of implant into body by ordinary syringe, medicine slowly continues to discharge under the combined effect of diffusion and two kinds of mechanism of depolymerization, the performance curative effect, and the framework material of microsphere can be degraded in vivo automatically, absorbs for body at last.U.S. food Drug Administration (FDA) has ratified Jassen﹠amp; The listing of the risperidone microsphere of Jassen company, commodity be called Risperdal Consta, this microsphere discharges medicine injection in first three week hardly, after injection the around rise and continue release 2 weeks of medicine.
Prepare the risperidone durative action preparation with the microsphere technology, the technology very complicated, the production cycle is long, and is very high to the requirement of production equipment.In order to obtain stay-in-grade product, need carry out strict control to multinomial technological parameter.Toxicity such as some organic solvents of Yin Ruing such as dichloromethane are big during this time, and residual volume difficulty up to standard is big.The process that microsphere is collected and screened causes a large amount of losses of medicine and adjuvant again, and therefore qualified microsphere yield is not high.The quality control of finished microballoon products is also quite complicated, removes microspherulite diameter and must be controlled at inside and outside a certain size scope, also needs the higher drug envelop rate, and free risperidone must not surpass 10% usually.If microsphere can't fully disperse during drug administration by injection, the microsphere that flocks together so can't pass through pinprick, cause syringe to stop up the administration difficulty.Because the various unfavorable factors in preparation technology, quality control and the administration process, the technology barriers of risperidone microsphere and production cost are very high.The external in addition risperidone microsphere that goes on the market, first three not onset of week after the administration still needs oral risperidone to treat, and has caused very big inconvenience clinically.
Summary of the invention
The object of the invention is to overcome the deficiency of existing risperidone continuous release microsphere preparation technique, and risperidone sustained-release gel injection that a kind of technology is simple, Quality Control convenient, medication is convenient and safe and preparation method thereof is provided.The present invention can form the risperidone slow-release preparation of different pharmaceutical rate of release and release duration, to satisfy the different demands of clinical treatment by adjusting the mass ratio of each component in the risperidone sustained-release gel injection.
Risperidone sustained-release gel injection disclosed by the invention is made up of risperidone or its analog, biodegradable polymer and biocompatible solvent, wherein the mass ratio of risperidone or its analog and biodegradable polymer and biocompatible solvent sum is 1: 3-67 is preferably 1: 11-18.
Wherein said risperidone or its analog are meant other effective derivants of risperidone, 9-hydroxyl risperidone or risperidone.
Wherein said biodegradable polymer is meant the polyester biodegradable polymer, be selected from polylactic acid (poly lactic acid, PLA), poly lactic coglycolic acid (polylactic-co-glycolic acid, PLGA), polylactide-co-glycolide (poly lactide coglycolide, PLCG) and polyglycolic acid (poly glycolic acid, PLG) in one or more.The monomeric mass ratio of the lactic acid of PLGA and hydroxyacetic acid is 10: 90～90: 10, preferred 20: 80～80: 20; The lactide of PLCG and the mass ratio of glycolide monomer are 10: 90～90: 10, preferred 20: 80～80: 20; PLA, PLGA, PLCG and PLG polymer molecular weight are 5000～150000 dalton, are preferably 5000～100000 dalton.
Wherein said biocompatible solvent is selected from N-N-methyl-2-2-pyrrolidone N-(N-Methyl-2-Pyrrolidone, NMP), Tetrahydrofurfuryl polyethylene glycol ether (Glycofurol), triethyl citrate (Triethyl citrate, TEC) and acetyl triethyl citrate (Acetyltriethyl citrate, ATEC) in one or more.
The mass ratio of biodegradable polymer and biocompatible solvent is 1-7: 3-9 in the risperidone sustained-release gel injection of the present invention, is preferably 4-5.5: 4.5-6.
The preparation method of risperidone sustained-release gel injection disclosed by the invention is:
Earlier biodegradable polymer is dissolved in and forms polymer solution in the biocompatible solvent,, press the ejection preparation common process and prepare promptly again with the risperidone dissolving or be suspended in wherein; Or,
Elder generation dissolves risperidone or is suspended in the biocompatible solvent, adds biodegradable polymer again and dissolves, and presses the preparation of ejection preparation common process promptly.
Risperidone sustained-release gel injection compositions of the present invention is the material of control drug release with the biodegradable polymer, descends to form injectable gel the assisting of two solvophilics of safety.Be characterized in before injection, being polymer solution, be transformed into gel after the injection, can continue slowly to discharge several weeks to the several months with constant speed in suitable injection site, thereby improve the compliance of Mental Subnormality patient medication.
The biodegradable polymer PLA that the present invention selects for use, PLGA, PLCG and PLG all can be degraded to nontoxic small-molecule substances such as lactic acid, hydroxyacetic acid in vivo, these materials have been widely used in surgical sewing thread, orthopaedics gains public acceptance with fields such as nail, its safety and excellent drug controlled-release effect.Biocompatibility amphiphilic solvent NMP, Glycofurol, TEC and ATEC that the present invention selects for use all have excellent biological compatibility, toxicity is extremely low, and biodegradable polymer such as PLGA are dissolved in can form stable gel solution that is used for medicine carrying or suspension in these solvents.
The present invention discovers that the rate of release that influences risperidone sustained-release gel injection and the key factor of persistent period are: the molecular weight size of monomeric mass ratio and biodegradable polymer in the mass ratio of biodegradable polymer and biocompatible solvent, the biodegradable polymer.Telomerized polymer and solvent quality are than the rate of release that can control risperidone, polymer and solvent quality are mixed than in the scope of 1-7: 3-9 in the sustained-release gel injection of the present invention, can form the gel of different viscosities, especially at 4-5.5: during 4.5-6, risperidone sustained-release gel injection of the present invention more can satisfy the requirement of risperidone clinical treatment.Each monomeric quality is than the degradation speed of appreciable impact polymer in the polyesters biological degradation polyalcohol, thereby control principal agent risperidone continues time of discharging, and usually, the higher depolymerization speed of hydroxyacetic acid or glycolide monomer content is very fast.Simultaneously, the molecular weight of polymer also is the key factor of control risperidone rate of release.Preferred polyester class biological degradation polyalcohol molecular weight ranges of the present invention is 5000～100000 dalton, and the polymer in this scope can guarantee that the principal agent risperidone discharges fully in reasonable time.
Determine finally that through the screening of a large amount of inside and outside release tests the mass ratio of preferred risperidone of the present invention and biodegradable polymer and biocompatible solvent sum is 1: 11-18; Each preferred proportion of biodegradable polymer and biocompatible solvent is: the mass ratio of biodegradable polymer and biocompatible solvent is 4-5.5: 4.5-6, lactic acid and hydroxyacetic acid monomer mass ratio are that lactide and glycolide monomer mass ratio are 20: 80～80: 20 in 20: 80～80: 20, PLCG among the PLGA, and the biodegradable polymer molecular weight is 5000-100000 dalton.The risperidone sustained-release gel injection that makes on this basis can obtain the preparation of different release times and release concentration according to the needs of actual clinical, and rate of release is stable.
Though the present invention and prior art risperidone injectable microsphere all are the effects that obtains medicament slow release by biodegradable polymer,, the technical scheme of the present invention and microsphere is very different.Prior art must be by complexity technology the microsphere polymer of bag medicine carrying thing is prepared into particle diameter number micron to tens of microns spheroid, need be scattered in during injection in the specific diluent, single small microsphere enters in the body by the pin hole injection; The present invention then be medicine and polymer dissolution in the solvent of safety non-toxic, whole pharmaceutical composition is to be injected in the body by pin hole with polymer solution or suspension, so, can not cause pin hole to block.
Risperidone sustained-release gel injection preparation of compositions of the present invention is earlier polymer dissolution to be formed polymer solution in solvent, again the risperidone dissolving or be suspended in wherein; Also can earlier risperidone be dissolved or be suspended in the solvent, again dissolve polymer; Under aseptic condition, carry out fill.Above-mentioned drug-carrying polymer solution injects in the body, and two solvophilics and body fluid exchange, and polymer precipitation is got off, and become gel.Because preparation process of the present invention only relates to mixing and two steps of fill under the sterile production condition, omitted the step of polymer formation microsphere and two technical sophistications of microsphere bag medicine carrying thing, therefore, preparation technology of the present invention is simply many with respect to the preparation technology of prior art or commercially available risperidone long-acting injection microsphere, the Quality Control factor that involves still less, the final products yield is higher, and production cost is low, easy realization of industrialization.
Simultaneously, because the present invention begins to continue after injecting at once, the constant release medicine reaches several weeks, overcome the major defect of no drug releases in three weeks after the prior art micro-balloon injection is injected, improved the compliance of patient's medication greatly, had excellent drug economics and be worth.
To sum up, the present invention has following advantage:
1) discharges medicine immediately after the injection, can not discharge medicine, the essential alternate defective of first oral drugs immediately after having overcome prior art injection;
2) evade the preparation technology of prior art risperidone long-acting injection microsphere preparation complexity, be convenient to the quality control of medicine production process, helped Industry Promotion;
3) the obstruction defective of injecting pin hole, easy, the safety of administration process have been overcome;
4) production cost is low, and product market competitiveness improves.
5) by the adjustment of each constituent mass constituent ratio in the compositions, can produce different drug release rates and release duration, satisfy different clinical treatment demands.
Description of drawings
Fig. 1 is the vitro drug release curve of embodiment 1,2, and wherein vertical coordinate is a drug release cumulative percentage rate.
Fig. 2 is the vitro drug release curve of embodiment 3,4, and wherein vertical coordinate is a drug release cumulative percentage rate.
Fig. 3 is the vitro drug release curve of embodiment 5,6,7, and wherein vertical coordinate is a drug release cumulative percentage rate.
Fig. 4 is embodiment 5,6,7 rat drug disposition release profiles, and wherein vertical coordinate is a blood drug level.
Fig. 5 is the vitro drug release curve of embodiment 8,9, and wherein vertical coordinate is a drug release cumulative percentage rate.
Fig. 6 is the vitro drug release curve of embodiment 10,11, and wherein vertical coordinate is a drug release cumulative percentage rate.
The specific embodiment
Embodiment 1
Take by weighing PLA (molecular weight 20,000 dalton) 0.05g and be dissolved among the 0.2gNMP and form blank polymer solution, take by weighing risperidone 25.0mg again and its suspendible is dispersed in the above-mentioned solution, make medicine carrying solution.The medicine carrying solution that makes is placed the 10ml cillin bottle,, make it change gel into, more whole cillin bottle is soaked in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharges to the phosphate buffer number that wherein drips pH=7.4 droplet.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 6 hours after beginning, got release medium 2ml respectively in 1,2,4,7,9,11,14,17,21,25,30,35,40,45,49 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 1.
Embodiment 2
Take by weighing PLA (molecular weight 20,000 dalton) 0.035g and be dissolved among the 0.2gGlycofurol and form blank polymer solution, take by weighing risperidone 25.0mg again and its suspendible is dispersed in the above-mentioned solution, make medicine carrying solution.The medicine carrying solution that makes is placed the 10ml cillin bottle,, make it change gel into, more whole cillin bottle is soaked in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharges to the phosphate buffer number that wherein drips pH=7.4 droplet.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 6 hours after beginning, 1,2,4,7,9,11,14,17,21,25,30,40, got release medium 2ml respectively in 45,49 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 1.
Embodiment 3
Take by weighing PLGA (molecular weight 50,000 dalton, the polymer monomer quality is than lactic acid: hydroxyacetic acid=75: 25) 0.05g is dissolved in and forms blank polymer solution among the 0.2gTEC, takes by weighing risperidone 37.5mg again and its suspendible is dispersed in the above-mentioned solution, makes medicine carrying solution.The medicine carrying solution that makes is placed the 10ml cillin bottle,, make it change gel into, more whole cillin bottle is soaked in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharges to the phosphate buffer number that wherein drips pH=7.4 droplet.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 6 hours after beginning, 1,2,4,7,9,11,14,17, got release medium 2ml respectively in 21,25,30 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 2.
Embodiment 4
Take by weighing PLCG (molecular weight 75,000 dalton, the polymer monomer quality is than lactide: Acetic acid, hydroxy-, bimol. cyclic ester=75: 25) 0.05g is dissolved in the mixed solvent of 0.15gNMP and 0.05gTEC, form blank polymer solution, take by weighing risperidone 37.5mg again and its suspendible is dispersed in the above-mentioned solution, make medicine carrying solution.The medicine carrying solution that makes is placed the 10ml cillin bottle,, make it change gel into, more whole cillin bottle is soaked in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharges to the phosphate buffer number that wherein drips pH=7.4 droplet.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 6 hours after beginning, 1,2,4,7,9,11,14,17, got release medium 2ml respectively in 21,25,30 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 2.
Take by weighing PLGA (molecular weight 20,000 dalton, the polymer monomer quality is than lactic acid: 0.086g hydroxyacetic acid=75: 25) is dissolved in and forms blank polymer solution among the 0.2gNMP, take by weighing risperidone 25.0mg again and its suspendible is dispersed in the above-mentioned solution, make medicine carrying solution.The medicine carrying solution that makes is splashed into syringe in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharge.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 3,6 hours after beginning, 1,2,4,7,9,11,14,17, got release medium 2ml respectively in 21,25,30 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 3.Be equipped with medicine carrying solution with legal system, it is subcutaneous to be expelled to rat abdomen according to the dosage of 10mg risperidone/only, after the injection 6 hours, 1,2,4,7,10,14, got blood 0.3ml from the tail vein respectively in 17,20,23 days, separated plasma, measure the content of risperidone wherein and active metabolite 9-hydroxyl risperidone thereof, 3 parts of operation repetitives the results are shown in Figure 4.In-vitro release rate is constant, and 30 day time can discharge medicine fully, and the result shows that prominent releasing of the first day finish back release in sustainable 21 days medicine in the body.
Embodiment 6
(molecular weight 20,000 dalton, the polymer monomer quality is than lactic acid: 0.244g hydroxyacetic acid=50: 50) is dissolved in and forms blank polymer solution among the 0.2gNMP to take by weighing PLGA.Take by weighing risperidone 25.0mg again and its suspendible is dispersed in the above-mentioned solution, make medicine carrying solution.The medicine carrying solution that makes is splashed into syringe in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharge.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 3,6 hours after beginning, 1,2,4,7,9,11,14,17, got release medium 2ml respectively in 21,25,30 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 3.Be equipped with medicine carrying solution with legal system, it is subcutaneous to be expelled to rat abdomen according to the dosage of 10mg risperidone/only, after the injection 6 hours, 1,2,4,7,10,14, got blood 0.3ml from the tail vein respectively in 17,20,23 days, separated plasma, measure the content of risperidone wherein and active metabolite 9-hydroxyl risperidone thereof, 3 parts of operation repetitives the results are shown in Figure 4.Release in vitro shows 21 days and discharges fully, and the result shows that prominent releasing of the first day finish back release in sustainable 14 days medicine in the body.
Embodiment 7
(molecular weight 20,000 dalton, the polymer monomer quality is than lactide: 0.133g Acetic acid, hydroxy-, bimol. cyclic ester=50: 50) is dissolved in and forms blank polymer solution among the 0.2gNMP to take by weighing PLCG.Take by weighing risperidone 25.0mg again and its suspendible is dispersed in the above-mentioned solution, make medicine carrying solution.The medicine carrying solution that makes is splashed into syringe in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharge.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 3,6 hours after beginning, 1,2,4,7,9,11,14,17, got release medium 2ml respectively in 21,25,30 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 3.Be equipped with medicine carrying solution with legal system, it is subcutaneous to be expelled to rat abdomen according to the dosage of 10mg risperidone/only, after the injection 6 hours, 1,2,4,7,10,14, got blood 0.3ml from the tail vein respectively in 17,20,23 days, separated plasma, measure the content of risperidone wherein and active metabolite 9-hydroxyl risperidone thereof, 3 parts of operation repetitives the results are shown in Figure 4.Release in vitro shows 21 days and discharges fully, and the result shows that prominent releasing of the first day finish back release in sustainable 14 days medicine in the body, meets clinical use needs.
Embodiment 8
Taking by weighing risperidone 25.0mg is dissolved in and forms solution among the 0.4gNMP, take by weighing PLGA (molecular weight 5 again, 000 dalton, the polymer monomer quality is than lactic acid: hydroxyacetic acid=50: 50) 0.934g is dissolved in above-mentioned risperidone-nmp solution, makes drug-carrying polymer solution.The drug-carrying polymer solution that makes is splashed into syringe in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharge.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 6 hours after beginning, got release medium 2ml respectively in 1,2,4,7,9,11,14 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 5.
Embodiment 9
Taking by weighing risperidone 25.0mg is dissolved in and forms solution among the 0.4gNMP, take by weighing PLCG (molecular weight 150 again, 000 dalton, the polymer monomer quality is than lactide: Acetic acid, hydroxy-, bimol. cyclic ester=80: 20) 0.044g is dissolved in above-mentioned risperidone-nmp solution, makes drug-carrying polymer solution.The drug-carrying polymer solution that makes is splashed into syringe in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharge.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 6 hours after beginning, 1,2,4,7,9,11,14,17, got release medium 2ml respectively in 21,25,30 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 5.
Take by weighing PLCG (molecular weight 100,000 dalton, the polymer monomer quality is than lactide: Acetic acid, hydroxy-, bimol. cyclic ester=90: 10) 0.0857g is dissolved in and forms blank polymer solution among the 0.2gNMP, takes by weighing risperidone 12.5mg and its suspendible is dispersed in the above-mentioned solution, makes medicine carrying solution.The medicine carrying solution that makes is splashed into syringe in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharge.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 6 hours after beginning, 1,2,4,7,9,11,14,17, got release medium 2ml respectively in 21,25,30 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 6.
Embodiment 11
Take by weighing PLGA (molecular weight 20,000 dalton, the polymer monomer quality is than lactic acid: hydroxyacetic acid=10: 90) 0.1g is dissolved in and forms blank polymer solution among the 0.2gNMP, takes by weighing risperidone 100.0mg and its suspendible is dispersed in the above-mentioned solution, makes medicine carrying solution.The medicine carrying solution that makes is splashed into syringe in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharge.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Discharge 6 hours after beginning, got release medium 2ml respectively in 1,2,4,7,9,11,14 days, measure the wherein content of risperidone, calculate the cumulative release percentage rate, 3 parts of operation repetitives the results are shown in Figure 6.
Embodiment 12
(molecular weight 20,000 dalton, the polymer monomer quality is than lactic acid: 0.266g hydroxyacetic acid=50: 50) is dissolved in and forms blank polymer solution among the 0.4gNMP to take by weighing PLGA.Take by weighing the derivant 9-hydroxyl risperidone 10.0mg of risperidone again and its suspendible is dispersed in the above-mentioned solution, make medicine carrying solution.The medicine carrying solution that makes is splashed into syringe in the reagent bottle of the phosphate buffer 2000ml that fills pH=7.4 and discharge.Release conditions is 37 ℃ of waters bath with thermostatic control, 100rpm jolting speed.Measure release, discharged 9-hydroxyl risperidone in first day as a result and discharged 37.8%, the two ten one day in 10.2%, the 7 day and discharge 87.3%.
Claims (10)
1, risperidone sustained-release gel injection, it is characterized in that this injection is made up of risperidone or its analog, biodegradable polymer and biocompatible solvent, wherein the mass ratio of risperidone or its analog and biodegradable polymer and biocompatible solvent sum is 1: 3-67.
2, risperidone sustained-release gel injection according to claim 1, the mass ratio that it is characterized in that wherein said biodegradable polymer and biocompatible solvent is 1-7: 3-9.
3, risperidone sustained-release gel injection according to claim 1, the mass ratio that it is characterized in that wherein said risperidone or its analog and biodegradable polymer and biocompatible solvent sum is 1: 11-18, the mass ratio of biodegradable polymer and biocompatible solvent are 4-5.5: 4.5-6.
4, risperidone sustained-release gel injection according to claim 1, it is characterized in that wherein said biodegradable polymer molecular weight is 5000～150000 dalton, be selected from polylactic acid, poly lactic coglycolic acid, polylactide-co-glycolide and the polyglycolic acid one or more.
5, risperidone sustained-release gel injection according to claim 4, it is characterized in that lactic acid and the monomeric mass ratio of hydroxyacetic acid in the wherein said poly lactic coglycolic acid are 10: 90～90: 10, the lactide in the polylactide-co-glycolide and the mass ratio of glycolide monomer are 10: 90～90: 10.
6,, it is characterized in that wherein said biodegradable polymer molecular weight is 5000～100000 dalton according to claim 1 or 4 described risperidone sustained-release gel injections.
7, according to claim 4 or 5 described risperidone sustained-release gel injections, it is characterized in that lactic acid and the monomeric mass ratio of hydroxyacetic acid in the wherein said poly lactic coglycolic acid are 20: 80～80: 20, the lactide in the polylactide-co-glycolide and the mass ratio of glycolide monomer are 20: 80～80: 20.
8, risperidone sustained-release gel injection according to claim 1 is characterized in that wherein said biocompatible solvent is selected from one or more in N-N-methyl-2-2-pyrrolidone N-, Tetrahydrofurfuryl polyethylene glycol ether, triethyl citrate and the acetyl triethyl citrate.
9, the preparation method of the described risperidone sustained-release gel injection of claim 1, it is characterized in that this method is: biodegradable polymer is dissolved in forms polymer solution in the biocompatible solvent earlier, with risperidone dissolving or be suspended in wherein, press the ejection preparation common process and prepare promptly again.
10, the preparation method of the described risperidone sustained-release gel injection of claim 1, it is characterized in that this method is: elder generation dissolves risperidone or is suspended in the biocompatible solvent, add biodegradable polymer again and dissolve, press the preparation of ejection preparation common process promptly.
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| CN101829047A (en) * | 2010-05-24 | 2010-09-15 | 中国人民解放军军事医学科学院放射与辐射医学研究所 | Long-acting injectable risperidone in-situ gel |
| CN102274164A (en) * | 2011-08-22 | 2011-12-14 | 长春健欣生物医药科技开发有限公司 | Sustained release gel for injection for paliperidone and paliperidone derivative |
| WO2012146052A1 (en) * | 2011-04-25 | 2012-11-01 | Shandong Luye Pharmaceutical Co., Ltd | Risperidone sustained release microsphere composition |
| CN101653422B (en) * | 2008-08-20 | 2013-03-20 | 山东绿叶制药有限公司 | Risperidone slow-release microsphere, preparation method and application thereof |
| DE102013011399A1 (en) | 2012-07-31 | 2014-02-06 | Amw Gmbh | Rod-shaped biodegradable implant useful for maintenance therapy in schizophrenia in patients comprises risperidone |
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| WO2018137630A1 (en) * | 2017-01-24 | 2018-08-02 | 广州帝奇医药技术有限公司 | Risperidone sustained release composition and preparation method therefor |
| CN107213136B (en) * | 2017-06-07 | 2021-06-01 | 广州帝奇医药技术有限公司 | Long-acting sustained-release medicinal preparation and preparation method thereof |
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| CA2687979C (en) * | 2007-05-25 | 2017-07-04 | Tolmar Therapeutics, Inc. | Sustained delivery formulations of risperidone compounds |
| CN101345623B (en) * | 2007-07-09 | 2010-11-10 | 中茂电子(深圳)有限公司 | Control system and method with authentication function |
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