CN101653422A - Risperidone slow-release microsphere, preparation method and application thereof - Google Patents
Risperidone slow-release microsphere, preparation method and application thereof Download PDFInfo
- Publication number
- CN101653422A CN101653422A CN200910167125A CN200910167125A CN101653422A CN 101653422 A CN101653422 A CN 101653422A CN 200910167125 A CN200910167125 A CN 200910167125A CN 200910167125 A CN200910167125 A CN 200910167125A CN 101653422 A CN101653422 A CN 101653422A
- Authority
- CN
- China
- Prior art keywords
- risperidone
- microsphere
- plga
- salt
- organic solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Abstract
The invention provides a risperidone slow-release microsphere, a preparation method and an application thereof. The microsphere comprises risperidone or 9-hydroxy risperidone or the salt thereof and anon-end-capped lactide-glycollide copolymer. The risperidone slow-release microsphere provided by the invention has higher medicine-carrying quantity, no in-vivo sudden-release phenomenon, stable blood concentration and no medicine release lag period, reduces the administration frequency of a patient greatly, reduces the administration volume of each time, enhances the conformance of the patientand reduces the generation of adverse reactions.
Description
Technical field
The present invention relates to a kind of microsphere and its production and application, be specifically related to risperidone long-acting slow-release microsphere and its production and application.
Background technology
Since the 1950's develop chlorpromazine as psychosis since, the target in this field just concentrates on the curative effect that improves psychosis and increases toleration.Traditional psychosis manifests obvious defects gradually through the practice of decades, is in particular in: 1. be not can both play effective therapeutical effect to all psychotics; 2. can not treat all symptoms of morbid state comprehensively; 3. untoward reaction is also bigger comparatively speaking.
Risperidone (risperidone) is the atypical antipsychotic agents of a new generation, aspect above-mentioned 3, more satisfactory effect is arranged all, this product was developed by Belgian Janssen Pharmaceutica in 1984, chemistry 3-[2-[4-(6-fluoro-1 by name, 2-benzoisoxazole-3-yl)-and piperidino] ethyl]-6,7,8,9-tetrahydrochysene-2-methyl-4H-pyrido [1,2-α] pyrimidin-4-one, for having the selectivity cholamine blocker of peculiar property, it and 5-HT2 receptor and dopaminergic D2 receptor have very high affinity, also can combine, and combine with H1-histamine receptor and α 2-adrenoceptor, and not combine with cholinoceptor with less affinity with α 1-adrenoceptor.Risperidone all has good curative effect to the schizophrenia positive symptom and negative symptoms, and extrapyramidal system untoward reaction (EPS) incidence rate is lower than traditional psychosis, and the patient is all better to the toleration and the compliance of this medicine.
The conventional tablet of risperidone in 1993 as atypical antipsychotic agents listing, studying for a long period of time shows: its good effect, after the medication untoward reaction less, relapse rate is lower, patient's compliance is better.At present the risperidone general formulation of listing also has capsule, oral administration solution, oral drop etc. [appoint white, Chen Guoguang etc., the research of psychosis risperidone novel formulation, Chinese Journal of New Drugs, 2005,14 (11): 1272-1275].
But the risperidone general formulation must take medicine on time common every day, once-a-day or administration repeatedly on the one be the comparison difficulty for general 75% psychotic, in therapeutic process, can reduce patient's compliance, make that sb.'s illness took a turn for the worse, thereby cause symptom to can not get effectively treating or the patient being admitted to hospital again.
For solving this type of problem, research worker is actively carried out the exploitation of risperidone long-acting slow-release preparation.For example, CN1137756 discloses the risperidone slow-release microsphere that a kind of use molecular weight 100,000 to 300,000 matrix material are made.Depot antipsychotics Risperidal Consta (Chinese name: permanent moral) based on this patented technology exploitation, go on the market in August, 2002, this product adopts molecular weight 150, lactide-glycolide copolymer of 000 (PLGA) is to the risperidone encapsulation, be suspended in the solution, intramuscular injection, per 2 weeks injection has once effectively been avoided the peak valley concentration of taking medicine every day.But said preparation only has a spot of drug release in the first day, there is the lag phase of a drug release in about subsequently 3 weeks, degraded along with the microsphere skeleton, most of drug release occurs in [Chen Qinghua, Chen Gang etc. between 4～6 weeks, the characteristics of pharmacokinetics of risperidone long-acting injection and clinical practice, China Dispensary, 2006,15 (15): 1235-1238].When therefore 3 weeks of patient's pro-are injected this medicine, also need to rely on oral risperidone tablet just can reach therapeutic effect, clinical use inconvenience, patient's compliance is poor.Old state extensively waits and has reported utilization PLGA (50: 50, molecular weight 30,000) the risperidone microsphere for preparing, drug loading is 18%, can keep stable blood drug level [Chen Guoguang, Tang Jun etc., the research of risperidone biodegradable microsphere, China Medicine University's journal in 5-20 days in the body, 2006,37 (6): 512-515].But this microsphere drug loading is lower and still have the prominent problem of releasing phenomenon when hanging down drug loading.
Summary of the invention
In order to overcome the above-mentioned defective that prior art exists, the inventor furthers investigate, and finds in vitro tests, and the risperidone slow-release microsphere of utilization end-blocking or not end capped lactide-glycolide copolymer (PLGA) preparation does not all have the prominent phenomenon of releasing; And in testing in vivo, the significantly prominent phenomenon of releasing has appearred in the risperidone microsphere of end capped PLGA preparation, but release problem when the risperidone microsphere that adopts identical characteristics viscosity (inherent viscosity), not end capped PLGA preparation then can obviously improve to dash forward, especially select for use the preparation-obtained risperidone microsphere of not end capped PLGA in the particular characteristics range of viscosities not have the prominent problem of releasing.
Based on above research, the inventor has creatively found to utilize not end capped PLGA to prepare a kind of risperidone slow-release microsphere, this sustained-release micro-spheres has following advantage: when having more high drug load, do not have in the body obviously prominently releases phenomenon, blood drug level is steady, and does not have the drug release lag phase.
Risperidone slow-release microsphere provided by the present invention contains risperidone or 9-hydroxyl risperidone or its salt and not end capped PLGA.Described not end-blocking PLGA is meant that end group is the PLGA of free carboxy, describes for convenient, hereinafter uses " PLGA-S " expression; End capped PLGA is meant that end group is the PLGA of ester group, with " PLGA-Z " expression.The mol ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester and its intrinsic viscosity are represented in bracket thereafter among the PLGA, represent that as " PLGA-S (75/25,0.50) " mol ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 75: 25, and intrinsic viscosity is the not end-blocking PLGA of 0.50dL/g.
It is the PLGA-S of 0.25～0.80dL/g that the present invention selects intrinsic viscosity (inherent viscosity) for use, preferred 0.40～0.70dL/g, more preferably 0.45～0.55dL/g.In the present invention, the intrinsic viscosity of PLGA is measured by following condition: with the solution of chloroform preparation into about 0.5% (w/v), adopt the Cannon-Fenske glass capillary tube viscometer to measure its intrinsic viscosity in 30 ℃ PLGA.
Find that after deliberation the size of PLGA-S intrinsic viscosity can influence deenergized period and release stationarity in the risperidone microsphere.When the PLGA-S intrinsic viscosity is low, does not reach the requirement that discharges the long period in vivo, and when the PLGA-S intrinsic viscosity is higher, can occur certain prominent phenomenon (seeing test example 6) of releasing again.Therefore, the invention provides the risperidone microsphere that can continue in vivo to discharge more than 3 weeks, selecting intrinsic viscosity for use is the PLGA-S of 0.25～0.80dL/g.The present invention further provides and can continue to discharge 4 weeks in vivo and not have the prominent risperidone microsphere of releasing, selecting intrinsic viscosity for use is the PLGA-S of 0.40～0.70dL/g, preferred 0.45～0.55dL/g.
Molecular weight of the present invention refers to " weight average molecular weight ", abbreviates " molecular weight " as.It is 20 that the present invention selects molecular weight for use, 000-140, and 000 PLGA-S, preferred 50,000-120,000, more preferably 60,000-80,000.
It is 85～50: 15～50 PLGA-S that the present invention selects the mol ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester for use, preferred 75: 25.
We find in the research, although drug loading does not have influence to vitro drug release, release has obvious influence to drug disposition.Animal experiment shows when drug loading is low, initial drug discharges seldom, cause medicine blood drug level the release lag phase of certain hour to occur, raising along with drug loading, the drug release lag phase progressively reduces, when drug loading reaches certain limit, drug release is promptly arranged after the administration, do not discharge lag phase.Test example 7 shows, when risperidone microsphere drug loading is 45% when above, medicine enters in the body and discharges at once, does not have the release lag phase.
Drug loading of the present invention is actual drug loading, calculates in such a way: drug loading=[microsphere Chinese medicine amount/(microsphere Chinese medicine amount+high molecular)] * 100%.
Improve the drug loading of microsphere, can reduce patient's microsphere injection volume and volume injected, improve patient's compliance.But high drug load then is easy to generate the prominent phenomenon of releasing, this be because the drug loading height then medicine easily in the microsphere surface enrichment, form the water solublity passage and can quicken the release of medicine when discharging, the inside and outside higher Concentraton gradient of microsphere impels the medicine of microsphere inside to external diffusion simultaneously.And prominent release may cause on the one hand in the body blood drug level near or surpass the poisoning level and produce tangible untoward reaction, also may influence later stage release level on the other hand and reduce therapeutic effect.Therefore, how to accomplish in high drug load that solving effectively dashes forward releases phenomenon, is the technical barrier of a key of microball preparation.
Risperidone slow-release microsphere provided by the invention has higher drug loading, injection back medicine can discharge immediately, and in high drug load, do not have obviously to dash forward and release phenomenon, blood drug level is kept the long time, reduced each administration volume, improve patient's compliance, lowered the generation of untoward reaction.Contain the risperidone of 45-65% or not end capped lactide-glycolide copolymer of 9-hydroxyl risperidone or its salt and 35-55% in the risperidone microsphere provided by the invention, preferably contain the risperidone of 45-60% or not end capped lactide-glycolide copolymer of 9-hydroxyl risperidone or its salt and 40-55%, more preferably contain the risperidone of 45-55% or not end capped lactide-glycolide copolymer of 9-hydroxyl risperidone or its salt and 45-55%; The drug loading that is microball preparation of the present invention can reach 45-65%, preferred 45-60%, more preferably 45-55%.
Risperidone or 9-hydroxyl risperidone can exist with the form of salt in the sustained-release micro-spheres provided by the present invention, wherein comprise mineral acid with the salifiable acid of its shape, for example halogen acids (hydrochloric acid, hydrobromic acid etc.), nitric acid, sulphuric acid, phosphoric acid etc.; Or organic acid, for example acetic acid, propanoic acid, hydroxyacetic acid, 2 hydroxy propanoic acid, embonate, 2-oxo propanoic acid, ethanedioic acid, malonic acid, succinic acid, 2-butylene diacid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, toluenesulfonic acid etc.
Risperidone slow-release microsphere provided by the invention can adopt conventional method to prepare, for example emulsifying-solvent evaporation method, spray drying method or spraying extraction method etc.
Emulsifying-solvent evaporation method: risperidone or 9-hydroxyl risperidone or its salt and PLGA can be dissolved in the suitable organic solvent, organic solvent is injected into carries out dispersion and emulsion in the aqueous phase solution of water soluble polymer preparation, volatilize organic solvent then, washing, filter and obtain microsphere.Described organic solvent can be selected from halogenated hydrocarbons (as dichloromethane, chloroform, ethyl chloride, dichloroethanes, trichloroethane etc.), ethyl acetate, Ethyl formate, ether, cyclohexane extraction, benzyl alcohol or their mixed solvent.Described water soluble polymer is optional from polyvinyl alcohol (PVA), sodium carboxymethyl cellulose (CMC-Na), polyvinylpyrrolidone (PVP), sodium polymethacrylate, sodium polyacrylate or a kind of, two or more mixing in them.Described dispersion and emulsion method can adopt the mechanical agitation dispersion and emulsion or pass through the static mixer dispersion and emulsion.
Spray drying method: risperidone or 9-hydroxyl risperidone or its salt and PLGA can be dissolved in the suitable organic solvent, filter, adopt conventional spray drying method for preparation microsphere.Described organic solvent can be selected from dichloromethane, chloroform, ethyl acetate, ether, acetone, benzyl alcohol, glacial acetic acid or their mixed solvent.
Spraying extraction method: risperidone or 9-hydroxyl risperidone or its salt and PLGA can be dissolved in the suitable organic solvent, it is sprayed in the organic non-solvent in (the undissolved therein organic solvent of risperidone or 9-hydroxyl risperidone or its salt and PLGA) or the water, after organic solvent extraction gone out, promptly make microsphere.Described organic solvent can be selected from dichloromethane, chloroform, ethyl acetate, ether, acetone, benzyl alcohol, glacial acetic acid or their mixed solvent.Described organic non-solvent can be selected from methanol, ethanol, propanol, isopropyl alcohol, petroleum ether, alkane, paraffin wet goods or their mixed solvent.
The present invention further provides the application of risperidone microsphere in the preparation antipsychotic drug, described psychosis comprises acute and chronic schizophrenia, the tangible positive symptom of other various psychotic disease states (as hallucination, vain hope, disturbance in thinking, be hostile to, suspect) and significantly negative symptoms (as bradykinesia, emotion is light and social indifferent, hypologia), and the emotion symptom relevant with schizophrenia (as: depression, sense of guilt, anxiety), be preferably schizophrenia, anxiety, depression, periodicity headache etc.Microsphere provided by the present invention can be prepared into the sterilized powder form, before patient's administration, microsphere is suspended in a kind of acceptable dispersion solvent, described dispersion solvent is by suspending agent, the pH regulator agent, isoosmotic adjusting agent, a kind of in the surfactant, or several and water for injection composition, described suspending agent can be a sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium alginate, in the glycerol one or more, described isoosmotic adjusting agent can be a sodium chloride, glucose, mannitol, in the sorbitol one or more etc., described surfactant is a nonionic surfactant, as Polysorbate series (as polyoxyethylene sorbitan monoleate, polysorbate 60 etc.), poloxamer series (as poloxamer 188 etc.).
Usually take parenteral, as injecting in intramuscular injection, subcutaneous injection, intradermal injection, the abdomen etc., dosage, patient for body weight 60kg, in risperidone, the per injection amount is 12.5～150mg, and the treatment effective dose that also is risperidone slow-release microsphere is 0.2～2.5mg risperidone/kg body weight, preferred 0.4～1.7mg risperidone/kg body weight.
Description of drawings
Blood drug level-the time graph of Fig. 1 for discharging in the body of testing example 1 show that the microsphere that adopts end-blocking PLGA has occurred significantly dashing forward releasing phenomenon, and the microsphere (the not microsphere of end-blocking PLGA) of the present invention's preparation do not have the obviously prominent phenomenon of releasing.
Blood drug level-the time graph of Fig. 2 for discharging in the body of testing example 2 show that the microsphere that adopts end-blocking PLGA has occurred significantly dashing forward releasing phenomenon, and the microsphere (the not microsphere of end-blocking PLGA) of the present invention's preparation do not have the obviously prominent phenomenon of releasing.
Blood drug level-the time graph of Fig. 3 for discharging in the body of testing example 3 show that the microsphere that adopts end-blocking PLGA has occurred significantly dashing forward releasing phenomenon, and the microsphere (the not microsphere of end-blocking PLGA) of the present invention's preparation do not have the obviously prominent phenomenon of releasing.
Blood drug level-the time graph of Fig. 4 for discharging in the body of testing example 4 show that the microsphere that adopts end-blocking PLGA has occurred significantly dashing forward releasing phenomenon, and the microsphere (the not microsphere of end-blocking PLGA) of the present invention's preparation do not have the obviously prominent phenomenon of releasing.
Blood drug level-the time graph of Fig. 5 for discharging in the body of testing example 5 show that the microsphere that adopts end-blocking PLGA has occurred significantly dashing forward releasing phenomenon, and the microsphere (the not microsphere of end-blocking PLGA) of the present invention's preparation do not have the obviously prominent phenomenon of releasing.
Blood drug level-the time graph that discharges in the body of Fig. 6 for test example 6 shows that intrinsic viscosity is that the microsphere of the PLGA-S preparation of 0.42dL/g, 0.52dL/g and 0.66dL/g is suitable for as the slow releasing preparation that continued to discharge 4 weeks most, and does not have the obviously prominent phenomenon of releasing.
Blood drug level-the time graph that discharges in the body of Fig. 7 for test example 7, show when drug loading be 45% when above, medicine enters in the body and discharges at once, nothing release lag phase.
The specific embodiment
The present invention will do further and elaborate in conjunction with following embodiment or test example, but should be appreciated that following embodiment only is used for setting forth and explaining the present invention, and not limit the scope of the invention.
Be to be understood that, for mentioning among the present invention but the method that does not have to describe in detail, step, device, instrument, material etc., those of ordinary skill can adopt correlation method well known in the art, step, device, instrument, material etc., and perhaps the conventional knowledge and technology according to this area obtains.
Take by weighing 4.0g PLGA-S (75/25,0.31) molecular weight 33,000, the 6.0g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane, this solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, dispersion and emulsion 1min transfers to 300rpm with rotating speed under 1000rpm, and rotating speed of agitator is 150rpm, organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 49.4%, and envelop rate is 82.3%.
Embodiment 2
Take by weighing 4.0g PLGA-S (75/25,0.42) molecular weight 53,000, the 6.0g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane, this solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, dispersion and emulsion 1min transfers to 300rpm with rotating speed under 1000rpm, and rotating speed of agitator is 150rpm, organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 49.0%, and envelop rate is 81.7%.
Embodiment 3
Take by weighing 4.0g PLGA-S (75/25,0.52) molecular weight 74,000, the 6.0g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and dispersion and emulsion 1min transfers to 300rpm with rotating speed under 1000rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 50.7%, and envelop rate is 84.5%.
Embodiment 4
Take by weighing 4.0g PLGA-S (75/25,0.66) molecular weight 105,000, the 6.0g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 1min transfers to 300rpm with rotating speed under 1000rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 50.1%, and envelop rate is 83.5%.
Embodiment 5
Take by weighing 4.0g PLGA-S (75/25,0.80) molecular weight 141,000, the 6.0g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 1min transfers to 300rpm with rotating speed under 800rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 50.5%, and envelop rate is 84.2%.
Embodiment 6
Take by weighing 4.0g PLGA-S (75/25,0.55) molecular weight 80,000, the 6.0g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 1min transfers to 300rpm with rotating speed under 800rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 50.3%, and envelop rate is 83.8%.
Embodiment 7
Take by weighing 4.5g PLGA-S (75/25,0.55) molecular weight 80,000, the 5.5g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 1min transfers to 300rpm with rotating speed under 800rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 45.5%, and envelop rate is 82.7%.
Embodiment 8
Take by weighing 5.0g PLGA-S (75/25,0.55) molecular weight 80,000, the 5.0g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 1min transfers to 300rpm with rotating speed under 800rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 40.3%, and envelop rate is 80.6%.
Embodiment 9
Take by weighing 5.5g PLGA-S (75/25,0.55) molecular weight 80,000, the 4.5g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 1min transfers to 300rpm with rotating speed under 800rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 35.6%, and envelop rate is 79.1%.
Take by weighing 3.5g PLGA-S (75/25,0.40) molecular weight 49,000, the 6.5g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 1min transfers to 300rpm with rotating speed under 800rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 55.8%, and envelop rate is 85.8%.
Embodiment 11
Take by weighing 3.0g PLGA-S (75/25,0.45) molecular weight 59,000, the 7.0g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 1min transfers to 300rpm with rotating speed under 800rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 60.3%, and envelop rate is 86.1%.
Embodiment 12
Take by weighing 600mg PLGA-S (50/50,0.25) molecular weight 24,000, the 900mg risperidone joins that stirring and dissolving gets settled solution in the 7.5ml dichloromethane; This solution is joined being chilled in 6 ℃ the 750ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 2min transfers to 400rpm with rotating speed under 1600rpm, stirs 1hr in psychrolusia, stirs 4hr under room temperature; Screen filtration, deionization washing 5 times, it is 47.8% that lyophilizing gets Powdered microsphere drug loading, envelop rate is 79.7%.
Embodiment 13
Take by weighing 4.0g PLGA-S (75/25,0.70) molecular weight 116,000, risperidone 6.0g joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 1min transfers to 300rpm with rotating speed under 800rpm, and rotating speed of agitator is 150rpm, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 49.1%, and envelop rate is 81.8%.
Embodiment 14
Take by weighing 4.0g PLGA-S (85/15,0.51) molecular weight 72,000, risperidone 6.0g joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, and emulsifying 1min transfers to 300rpm with rotating speed under 800rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 49.5%, and envelop rate is 82.5%.
Embodiment 15
Take by weighing 4.0g PLGA-S (85/15,0.51) molecular weight 72,000,6.0g pamoic acid risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is sprayed onto in the freezing alcoholic solution with vaporific through a shower nozzle, with ethanol with the continuous extracting of dichloromethane in the microsphere, screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, drug loading is 48.2%, envelop rate is 80.3%.
Embodiment 16
Take by weighing 4.2g PLGA-S (85/15,0.51) molecular weight 72,000,4.2g pamoic acid risperidone joins that stirring and dissolving gets settled solution in the 100ml acetone, obtains microsphere after spray-dried.Drug loading is 46.3%, and envelop rate is 92.6%.
Embodiment 17
Take by weighing 3.5g PLGA-S (75/25,0.52) molecular weight 74,000, the 6.5g risperidone joins that stirring and dissolving gets settled solution in the 50ml dichloromethane; This solution is joined being chilled in 6 ℃ the 5000mlPVA solution (0.5%) of high-speed stirred by peristaltic pump, and dispersion and emulsion 1min transfers to 300rpm with rotating speed under 1000rpm, and rotating speed of agitator is 150rpm, and organic solvent is removed in volatilization, and 6hr altogether volatilizees; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and drug loading is 55.6%, and envelop rate is 85.5%.
Embodiment 18
Take by weighing 450mg PLGA-S (75/25,0.52) molecular weight 74,000, the 1050mg risperidone joins that stirring and dissolving gets settled solution in the 7.5ml dichloromethane, and this solution is joined being chilled in 6 ℃ the 750ml PVA solution (0.5%) of high-speed stirred by peristaltic pump, dispersion and emulsion 2min under 1400rpm, rotating speed is transferred to 400rpm, in psychrolusia, stir 1hr, under room temperature, stir the 4hr volatilization and remove organic solvent; Screen filtration, deionization washing 5 times, lyophilizing gets Powdered microsphere, and measuring drug loading is 64.3%, and envelop rate is 91.9%.
Test example 1
Discharge contrast test in the risperidone microsphere dog body of PLGA-S (75/25,0.31) and PLGA-Z (75/25,0.31) preparation
1) test material
Trial drug: PLGA-S (75/25,0.31) risperidone microsphere prepares by embodiment 1;
PLGA-Z (75/25,0.31) risperidone microsphere adopts PLGA-Z (75/25,0.31) to prepare by embodiment 1.
Experimental animal: 8 of healthy Beagle dogs, male and female half and half, body weight 9.5～10.5kg.
Test apparatus: API 4000 type triple quadrupole bar tandem mass spectrometers are furnished with ionspray ionization source and Analyst 1.4. data processing software, U.S. Applied Biosystem company; The Agilent1100 highly effective liquid phase chromatographic system.
2) method and result
Animal is divided into 2 groups (PLGA-S group and PLGA-Z groups) at random, every group 4, difference intramuscular injection 1.72mg/kg (in risperidone), and before administration 1h, 3h, 6h, 1d, 2d, 4d, 6d, 8d, 10d, 12d, 14d, 16d, 18d, 20d, 22d, 24d, 26d after (0 hour) and the administration, get blood 3ml by dog forelimb vein, and move in the centrifuge tube that heparin is handled centrifugal 10min (3600rpm) immediately, separated plasma is preserved to be measured in-37 ℃ of refrigerators.Detect the blood drug level of risperidone in the blood plasma and metabolite 9-hydroxyl risperidone thereof respectively, the results are shown in Table 1 and Fig. 1.
The result shows: the risperidone microsphere that end-blocking PLGA prepares has occurred significantly prominently releasing phenomenon, and the risperidone microsphere for preparing of end-blocking PLGA does not discharge steadily the not prominent phenomenon of releasing.
The blood drug level (ng/mL) of different time behind the table 1 dog intramuscular injection microsphere
Annotate: blood drug level is risperidone and 9-hydroxyl risperidone sum
Test example 2
Discharge contrast test in the risperidone microsphere dog body of PLGA-S (75/25,0.42) and PLGA-Z (75/25,0.42) preparation
1) test material
Trial drug: PLGA-S (75/25,0.42) risperidone microsphere prepares by embodiment 2;
PLGA-Z (75/25,0.42) risperidone microsphere adopts PLGA-Z (75/25,0.42) to prepare by embodiment 2;
Experimental animal: 8 of healthy Beagle dogs, male and female half and half, body weight 9.5～10.5kg.
Test apparatus: with test example 1.
2) method and result
Test method is with test example 1, and getting the blood time is 0h, 1h, 3h, 6h, 1d, 2d, 4d, 6d, 8d, 10d, 12d, 14d, 16d, 18d, 20d, 22d, 24d, 26d, 28d, 30d, 32d, 34d, 36d.
Result of the test sees Table 2 and Fig. 2.
The result shows: the risperidone microsphere that end-blocking PLGA prepares has occurred significantly prominently releasing phenomenon, and the risperidone microsphere for preparing of end-blocking PLGA does not discharge steadily the obviously not prominent phenomenon of releasing.
The blood drug level (ng/mL) of different time behind the table 2 dog intramuscular injection microsphere
Annotate: blood drug level is risperidone and 9-hydroxyl risperidone sum
Test example 3
Discharge contrast test in the risperidone microsphere dog body of PLGA-S (75/25,0.52) and PLGA-Z (75/25,0.52) preparation
1) test material
Trial drug: PLGA-S (75/25,0.52) risperidone microsphere prepares by embodiment 3;
PLGA-Z (75/25,0.52) risperidone microsphere adopts PLGA-Z (75/25,0.52) to prepare by embodiment 3.
Experimental animal: 8 of healthy Beagle dogs, male and female half and half, body weight 9.5～10.5kg.
Test apparatus: with test example 1.
2) method and result
Test method is with test example 2.
Result of the test sees Table 3 and Fig. 3.
The result shows: the risperidone microsphere that end-blocking PLGA prepares has occurred significantly prominently releasing phenomenon, and the risperidone microsphere for preparing of end-blocking PLGA does not discharge steadily the obviously not prominent phenomenon of releasing.
The blood drug level (ng/mL) of different time behind the table 3 dog intramuscular injection microsphere
Annotate: blood drug level is risperidone and 9-hydroxyl risperidone sum
Test example 4
Discharge contrast test in the risperidone microsphere dog body of PLGA-S (75/25,0.66) and PLGA-Z (75/25,0.66) preparation
1) test material
Trial drug: PLGA-S (75/25,0.66) risperidone microsphere prepares by embodiment 4;
PLGA-Z (75/25,0.66) risperidone microsphere adopts PLGA-Z (75/25,0.66) to prepare by embodiment 4.
Experimental animal: 8 of healthy Beagle dogs, male and female half and half, body weight 9.5～10.5kg.
Test apparatus: with test example 1.
2) method and result
Test method is with test example 2.
Result of the test sees Table 4 and Fig. 4.
The result shows: the risperidone microsphere that end-blocking PLGA prepares has occurred significantly prominently releasing phenomenon, and the risperidone microsphere for preparing of end-blocking PLGA does not discharge steadily, prominently releases the microsphere that phenomenon is starkly lower than end-blocking PLGA preparation.
The blood drug level (ng/mL) of different time behind the table 4 dog intramuscular injection microsphere
Annotate: blood drug level is risperidone and 9-hydroxyl risperidone sum
Test example 5
Discharge contrast test in the risperidone microsphere dog body of PLGA-S (75/25,0.80) and PLGA-Z (75/25,0.80) preparation
1) test material
Trial drug: PLGA-S (75/25,0.80) risperidone microsphere prepares by embodiment 5;
PLGA-Z (75/25,0.80) risperidone microsphere adopts PLGA-Z (75/25,0.80) to prepare by embodiment 5.
Experimental animal: 8 of healthy Beagle dogs, male and female half and half, body weight 9.5～10.5kg.
Test apparatus: with test example 1.
2) method and result
Test method is with test example 2.
Result of the test sees Table 5 and Fig. 5
The result shows: the risperidone microsphere that end-blocking PLGA prepares has occurred significantly prominently releasing phenomenon, and the risperidone microsphere for preparing of end-blocking PLGA does not discharge steadily, prominently releases the microsphere that phenomenon is starkly lower than end-blocking PLGA preparation.
The blood drug level (ng/mL) of different time behind the table 5 dog intramuscular injection microsphere
Annotate: blood drug level is risperidone and 9-hydroxyl risperidone sum
Test example 6
Discharge the result in PLGA-S (75/25,0.31), PLGA-S (75/25,0.42), PLGA-S (75/25,0.52), PLGA-S (75/25,0.66), PLGA-S (75/25,0.80) the dog body relatively
1) Data Source: PLGA-S measurement result in the test example 1,2,3,4,5.
2) result of the test: see Table 6 and Fig. 6
The result shows: consider that from deenergized period and the prominent characteristic of releasing intrinsic viscosity is that the risperidone microsphere of the PLGA-S preparation of 0.42dL/g, 0.52dL/g, 0.66dL/g does not have obviously prominent releasing, for continuing to discharge the desirable preparation in 4 weeks.
The blood drug level (ng/mL) of different time behind the table 6 dog intramuscular injection microsphere
Annotate: blood drug level is risperidone and 9-hydroxyl risperidone sum
Test example 7
Discharge the result in the risperidone microsphere dog body of different drug loading relatively
1) test material
Trial drug: drug loading is respectively 50.3%, 45.5%, 40.3%, 35.6% risperidone microsphere, prepares respectively by embodiment 6-9;
Experimental animal: 12 of healthy Beagle dogs, 3 every group, male and female half and half, body weight 9.5～10.5kg.
Test apparatus: with test example 1.
2) method and result
Test method is with test example 2.
Result of the test sees Table 7 and Fig. 7.
The result shows: when drug loading is 45% when above, medicine enters in the body and discharges at once, does not have the lag phase of release.
The blood drug level (ng/mL) of different time behind the table 7 dog intramuscular injection microsphere
Annotate: blood drug level is risperidone and 9-hydroxyl risperidone sum.
Claims (12)
1. a risperidone slow-release microsphere is characterized in that, it contains risperidone or 9-hydroxyl risperidone or its salt and not end capped lactide-glycolide copolymer.
2. risperidone slow-release microsphere according to claim 1 is characterized in that the intrinsic viscosity of described not end capped lactide-glycolide copolymer is 0.25～0.80dL/g, is preferably 0.40～0.70dL/g, more preferably 0.45～0.55dL/g.
3. risperidone slow-release microsphere according to claim 1 is characterized in that, the weight average molecular weight Mw of described not end capped lactide-glycolide copolymer is 20,000-140, and 000, be preferably 50,000-120,000, more preferably 60,000-80,000.
4. according to each described risperidone slow-release microsphere in the claim 1 to 3, it is characterized in that risperidone that it contains or 9-hydroxyl risperidone or its salt are 45～65% weight, are preferably 45～60% weight, more preferably 45～55% weight; Not end capped lactide-glycolide copolymer is 35～55% weight, is preferably 40～55% weight, more preferably 45～55% weight.
5. according to each described risperidone slow-release microsphere in the claim 1 to 4, it is characterized in that the mol ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 85～50: 15～50 in described not end capped lactide-glycolide copolymer, is preferably 75: 25.
6. according to each described risperidone slow-release microsphere in the claim 1 to 5, it is characterized in that the salt of described risperidone or 9-hydroxyl risperidone is selected from inorganic acid salt and acylate; Preferably, described inorganic acid salt is selected from hydrochlorate, hydrobromate, nitrate, sulfate and phosphate etc., and described acylate is selected from acetate, propionate, hydroxyl acetate, 2 hydroxy propanoic acid salt, embonate salt, 2-oxo propionate, oxalate, malonate, succinate, 2-butylene diacid salt, mesylate, esilate, benzene sulfonate and toluenesulfonic acid etc.
7. prepare the method for each described risperidone slow-release microsphere in the claim 1 to 6, it is characterized in that, described method is selected from emulsifying-solvent evaporation method, spray drying method and spraying extraction method.
8. method according to claim 7, it is characterized in that, described emulsifying-solvent evaporation method may further comprise the steps: risperidone or 9-hydroxyl risperidone or its salt and not end capped lactide-glycolide copolymer are dissolved in form oil phase in the organic solvent, again this oil phase is injected in the aqueous phase solution by the water soluble polymer preparation, after carrying out dispersion and emulsion by mechanical agitation or static mixer, volatilize organic solvent, washing, filtration make microsphere; Preferably, described organic solvent is selected from halogenated hydrocarbons (as dichloromethane, chloroform, ethyl chloride, dichloroethanes, trichloroethane etc.), ethyl acetate, Ethyl formate, ether, cyclohexane extraction, benzyl alcohol or their mixed solvent; Described water soluble polymer is selected from polyvinyl alcohol, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sodium polymethacrylate, sodium polyacrylate or their mixture.
9. method according to claim 7, it is characterized in that described spray drying method may further comprise the steps: risperidone or 9-hydroxyl risperidone or its salt and not end capped lactide-glycolide copolymer are dissolved in form oil phase in the organic solvent, filter, adopt spray drying method, make microsphere; Preferably, described organic solvent is selected from dichloromethane, chloroform, ethyl acetate, ether, acetone, benzyl alcohol, glacial acetic acid or their mixture.
10. method according to claim 7, it is characterized in that, described spraying extraction method may further comprise the steps: risperidone or 9-hydroxyl risperidone or its salt and not end capped lactide-glycolide copolymer are dissolved in form oil phase in the organic solvent, be sprayed to this oil phase in organic non-solvent again or in the water, after extracting organic solvent, make microsphere; Preferably, described organic solvent is selected from dichloromethane, chloroform, ethyl acetate, ether, acetone, benzyl alcohol, glacial acetic acid or their mixture; Described organic non-solvent can be selected from methanol, ethanol, propanol, isopropyl alcohol, petroleum ether, alkane, paraffin wet goods or their mixture.
11. the purposes of each described risperidone slow-release microsphere in the psychotolytic medicine of preparation in the claim 1 to 6; Preferably, described psychosis comprises acute and chronic schizophrenia, the tangible positive symptom of other various psychotic disease states and tangible negative symptoms, and the emotion symptom relevant with schizophrenia.
12. one kind is used for the treatment of and/or prevents psychotic pharmaceutical composition, it is characterized in that described pharmaceutical composition comprises each described risperidone microsphere in the claim 1 to 6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101671252A CN101653422B (en) | 2008-08-20 | 2009-08-20 | Risperidone slow-release microsphere, preparation method and application thereof |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200810139243.8 | 2008-08-20 | ||
| CN200810139243 | 2008-08-20 | ||
| CN2009101671252A CN101653422B (en) | 2008-08-20 | 2009-08-20 | Risperidone slow-release microsphere, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101653422A true CN101653422A (en) | 2010-02-24 |
| CN101653422B CN101653422B (en) | 2013-03-20 |
Family
ID=41708026
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2009101671252A Active CN101653422B (en) | 2008-08-20 | 2009-08-20 | Risperidone slow-release microsphere, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101653422B (en) |
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102579365A (en) * | 2012-03-22 | 2012-07-18 | 中山大学 | Risperidone microsphere preparation and preparation method thereof |
| WO2012146052A1 (en) | 2011-04-25 | 2012-11-01 | Shandong Luye Pharmaceutical Co., Ltd | Risperidone sustained release microsphere composition |
| CN103893129A (en) * | 2012-12-28 | 2014-07-02 | 北大方正集团有限公司 | Paliperidone sustained release microsphere and injection thereof, and preparation method of sustained release microsphere |
| CN105106174A (en) * | 2015-09-06 | 2015-12-02 | 烟台大学 | Core-shell bilayer microsphere and preparation method thereof |
| CN105560192A (en) * | 2016-01-07 | 2016-05-11 | 万全万特制药江苏有限公司 | Preparation method of paliperidone palmitate long-acting microsphere injection |
| CN106474070A (en) * | 2015-08-26 | 2017-03-08 | 四川科伦药物研究院有限公司 | A kind of overcome lag phase, the microsphere of constant release hydrophobic drug and preparation method |
| CN106727358A (en) * | 2017-01-24 | 2017-05-31 | 广州帝奇医药技术有限公司 | The slow releasing composition of Aripiprazole and its derivative and the preparation method of the slow releasing composition |
| CN106822043A (en) * | 2017-01-24 | 2017-06-13 | 广州帝奇医药技术有限公司 | risperidone slow-release composition and preparation method thereof |
| CN106963746A (en) * | 2017-03-17 | 2017-07-21 | 广州帝奇医药技术有限公司 | A kind of shipwreck is molten/microsolubility pharmaceutical sustained release compositions |
| CN107137375A (en) * | 2017-04-28 | 2017-09-08 | 深圳市泛谷药业股份有限公司 | Asenapine microball preparation and preparation method thereof |
| CN108815138A (en) * | 2018-06-27 | 2018-11-16 | 丽珠医药集团股份有限公司 | Risperidone or derivatives thereof sustained-release micro-spheres, preparation method and the usage |
| EP3348268A4 (en) * | 2015-09-07 | 2019-04-10 | Nipro Corporation | Risperidone-containing microcapsule, method for manufacturing same and release control method |
| CN109718212A (en) * | 2017-10-30 | 2019-05-07 | 浙江圣兆药物科技股份有限公司 | A method of reducing low solvent flashing benzyl alcohol in Risperidone microballoon |
| 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 |
| CN116173098A (en) * | 2022-12-31 | 2023-05-30 | 河南农业大学 | Heatstroke-preventing mosquito-repellent woody cooling oil and preparation method and use method thereof |
| CN108815138B (en) * | 2018-06-27 | 2024-05-03 | 珠海市丽珠微球科技有限公司 | Risperidone or derivative sustained-release microsphere, preparation method and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6565874B1 (en) * | 1998-10-28 | 2003-05-20 | Atrix Laboratories | Polymeric delivery formulations of leuprolide with improved efficacy |
| CN101511347B (en) * | 2006-08-31 | 2012-11-28 | Sk化学株式会社 | Method for producing microspheres loaded with drugs and microspheres loaded with drugs produced thereby |
| NZ581862A (en) * | 2007-05-25 | 2012-06-29 | Tolmar Therapeutics Inc | Injectable subcutaneous formulation comprising risperidone capable of forming a solid, microporous implant in a patient |
| CN101584652B (en) * | 2009-06-19 | 2012-06-20 | 上海医药集团股份有限公司 | Risperidone sustained-release gel injection and preparation method thereof |
-
2009
- 2009-08-20 CN CN2009101671252A patent/CN101653422B/en active Active
Cited By (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9446135B2 (en) | 2011-04-25 | 2016-09-20 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| CN103338752A (en) * | 2011-04-25 | 2013-10-02 | 山东绿叶制药有限公司 | Risperidone sustained release microsphere composition |
| EP2701687B1 (en) | 2011-04-25 | 2016-09-21 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| EP3199146B1 (en) | 2011-04-25 | 2019-07-17 | Shan Dong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| US10406161B2 (en) | 2011-04-25 | 2019-09-10 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| CN103338752B (en) * | 2011-04-25 | 2014-10-29 | 山东绿叶制药有限公司 | Risperidone sustained release microsphere composition |
| CN104127385A (en) * | 2011-04-25 | 2014-11-05 | 山东绿叶制药有限公司 | Risperidone sustained release microsphere composition |
| KR101539313B1 (en) * | 2011-04-25 | 2015-07-24 | 산동 루예 파마슈티칼 컴파니 리미티드 | Risperidone sustained release microsphere composition |
| AU2012248038B2 (en) * | 2011-04-25 | 2015-11-12 | Geneora Pharma (Shijiazhuang) Co., Ltd. | Risperidone sustained release microsphere composition |
| CN104127385B (en) * | 2011-04-25 | 2017-08-04 | 山东绿叶制药有限公司 | Risperidone slow-release microsphere composition |
| US11110094B2 (en) | 2011-04-25 | 2021-09-07 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| RU2586306C2 (en) * | 2011-04-25 | 2016-06-10 | Шандонг Люие Фармацеутикал Ко., Лтд | Risperidone sustained release microsphere composition |
| US10098882B2 (en) | 2011-04-25 | 2018-10-16 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| WO2012146052A1 (en) | 2011-04-25 | 2012-11-01 | Shandong Luye Pharmaceutical Co., Ltd | Risperidone sustained release microsphere composition |
| EP3199146A1 (en) | 2011-04-25 | 2017-08-02 | Shan Dong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| US9532991B2 (en) | 2011-04-25 | 2017-01-03 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| EP3566696A1 (en) | 2011-04-25 | 2019-11-13 | Shan Dong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| EP3772354A1 (en) | 2011-04-25 | 2021-02-10 | Shandong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| EP3566696B1 (en) | 2011-04-25 | 2020-10-07 | Shan Dong Luye Pharmaceutical Co., Ltd. | Risperidone sustained release microsphere composition |
| CN102579365B (en) * | 2012-03-22 | 2014-06-11 | 中山大学 | Risperidone microsphere preparation and preparation method thereof |
| CN102579365A (en) * | 2012-03-22 | 2012-07-18 | 中山大学 | Risperidone microsphere preparation and preparation method thereof |
| CN103893129A (en) * | 2012-12-28 | 2014-07-02 | 北大方正集团有限公司 | Paliperidone sustained release microsphere and injection thereof, and preparation method of sustained release microsphere |
| CN103893129B (en) * | 2012-12-28 | 2016-10-05 | 北大方正集团有限公司 | Paliperidone sustained-release micro-spheres and injection thereof and the preparation method of this sustained-release micro-spheres |
| CN106474070A (en) * | 2015-08-26 | 2017-03-08 | 四川科伦药物研究院有限公司 | A kind of overcome lag phase, the microsphere of constant release hydrophobic drug and preparation method |
| CN105106174A (en) * | 2015-09-06 | 2015-12-02 | 烟台大学 | Core-shell bilayer microsphere and preparation method thereof |
| CN105106174B (en) * | 2015-09-06 | 2018-04-27 | 烟台大学 | A kind of core-shell structure copolymer bilayer microballoon and preparation method thereof |
| EP3348268A4 (en) * | 2015-09-07 | 2019-04-10 | Nipro Corporation | Risperidone-containing microcapsule, method for manufacturing same and release control method |
| CN105560192A (en) * | 2016-01-07 | 2016-05-11 | 万全万特制药江苏有限公司 | Preparation method of paliperidone palmitate long-acting microsphere injection |
| WO2018137627A1 (en) * | 2017-01-24 | 2018-08-02 | 广州帝奇医药技术有限公司 | Sustained release composition of aripiprazole and derivative thereof and preparation method for same |
| CN106822043A (en) * | 2017-01-24 | 2017-06-13 | 广州帝奇医药技术有限公司 | risperidone slow-release composition and preparation method thereof |
| CN106727358A (en) * | 2017-01-24 | 2017-05-31 | 广州帝奇医药技术有限公司 | The slow releasing composition of Aripiprazole and its derivative and the preparation method of the slow releasing composition |
| CN106963746A (en) * | 2017-03-17 | 2017-07-21 | 广州帝奇医药技术有限公司 | A kind of shipwreck is molten/microsolubility pharmaceutical sustained release compositions |
| CN107137375A (en) * | 2017-04-28 | 2017-09-08 | 深圳市泛谷药业股份有限公司 | Asenapine microball preparation and preparation method thereof |
| 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 |
| CN109718212A (en) * | 2017-10-30 | 2019-05-07 | 浙江圣兆药物科技股份有限公司 | A method of reducing low solvent flashing benzyl alcohol in Risperidone microballoon |
| CN108815138A (en) * | 2018-06-27 | 2018-11-16 | 丽珠医药集团股份有限公司 | Risperidone or derivatives thereof sustained-release micro-spheres, preparation method and the usage |
| CN108815138B (en) * | 2018-06-27 | 2024-05-03 | 珠海市丽珠微球科技有限公司 | Risperidone or derivative sustained-release microsphere, preparation method and application thereof |
| CN116173098A (en) * | 2022-12-31 | 2023-05-30 | 河南农业大学 | Heatstroke-preventing mosquito-repellent woody cooling oil and preparation method and use method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101653422B (en) | 2013-03-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101653422B (en) | Risperidone slow-release microsphere, preparation method and application thereof | |
| CN103338752B (en) | Risperidone sustained release microsphere composition | |
| CN100453067C (en) | Preparation of injectable suspensions having improved injectabity | |
| Wang et al. | Design of a long-term antipsychotic in situ forming implant and its release control method and mechanism | |
| CN101584652B (en) | Risperidone sustained-release gel injection and preparation method thereof | |
| CN107213136A (en) | A kind of long-acting slow-releasing medicine preparation and preparation method thereof | |
| CN102579362B (en) | Felodipine slow-release microspheres and preparation method thereof | |
| CN102784111A (en) | Sustained-release preparation of dopamine receptor agonist drugs | |
| CN103126997B (en) | Sustained-release micro-spheres containing risperidone and the like and preparation method thereof | |
| WO2023116517A1 (en) | Continuous delivery preparation capable of being stably released and preparation method therefor | |
| CN103893129A (en) | Paliperidone sustained release microsphere and injection thereof, and preparation method of sustained release microsphere | |
| CN104013578A (en) | Paliperidone derivative slow release microsphere preparation and preparation method thereof | |
| CN104352443A (en) | Iloperidone slow releasing microsphere and preparation method thereof | |
| KR20220170782A (en) | Sustained-release formulation composition comprising semaglutide or pharmaceutically acceptable salt thereof | |
| CN105796508A (en) | Sustained-release microspheres of glycine-arginine insulin, injection of glycine-arginine insulin microspheres, and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20161122 Address after: 264003 Laishan, Shandong Province Bao Road, No. 9 District, No. Patentee after: Shandong Luye Pharma Co., Ltd. Patentee after: NANJING LVYE PHARMA CO., LTD. Address before: 264003 Laishan, Shandong Province Bao Road, No. 9 District, No. Patentee before: Shandong Luye Pharma Co., Ltd. |