CN104922085B - A kind of risperidone implant and preparation method thereof - Google Patents
A kind of risperidone implant and preparation method thereof Download PDFInfo
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- CN104922085B CN104922085B CN201510291005.9A CN201510291005A CN104922085B CN 104922085 B CN104922085 B CN 104922085B CN 201510291005 A CN201510291005 A CN 201510291005A CN 104922085 B CN104922085 B CN 104922085B
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Abstract
The present invention provides a kind of risperidone implant and preparation method thereof, it is characterised in that it comprises risperidone 50 70 parts, biodegradable macromolecular material 20 40 parts.Risperidone implant can be injected implantation into the human body, as schizophrenic patients long-term prescription maintaining treatment, and can control the mental symptom that novel drug causes, and preventing and treating novel drug relapses.There is the feature of release steady in a long-term, thus improve the compliance of patient.
Description
Technical field
Risperidone implant that the present invention relates to and preparation method thereof, well solves medicine lag phase and prominent releasing is asked
Topic, release risperidone pharmaceutical compositions that can be the most stable in human body, its slow-release time was up to more than 100 days.
Background technology
Risperidone belongs to benzisoxazole analog derivative, is spirit a new generation antipsychotic drug, and chemical name is 3-[2-
[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-
2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one. molecular formula is C23H27FN4O2, and molecular weight is
410.49。
Treat mental symptom that schizoid main target is lasting remission patient, reduce recurrence, improve patient society
Can function and quality of life；Primary treatment medicine includes traditional antipsychotics (classical antipsychotic) and the anti-spirit of the second filial generation
Sick medicine (atypical antipsychotic agents).Within 1997, American Psychiatric Association's treatment of schizophrenia guide proposes, and needs one
Possesses long-acting and atypical antipsychotic agents advantage medicine.Then, first long-acting atypical antipsychotic pin
Agent injection risperidone microsphere occurs in that.
Risperidone microsphere uses Medisorb medicine controlled releasing technology, peptides and small-molecule drug is wrapped up by polymer
Form microgranule, add water and make suspension.After intramuscular injection, risperidone microsphere can rupture through hydration, drug diffusion, polymer
3 stages gradually discharge medicine.In hydration stage, the blood plasma level of risperidone isoreactivity composition is low, injects pharmaceutically active after 3 weeks
Composition reaches to treat concentration, about reaches peak concentration at 4 ~ 5 weeks.Within 7 weeks, post polymerization body is etched completely, and drug level is rapidly decreased to control
Treat below horizontal.Compared with oral risperidone, intramuscular injection avoided and absorbs and the impact of liver first-pass effect, every two weeks notes
Penetrate and once can maintain stable blood drug level.
Risperidone microsphere has atypical antipsychotic agents and long-acting advantage concurrently.Clinical trial confirms its effectiveness and peace
Quan Xing；Only can produce mild pain during injection, the compliance of patient significantly improves.Thus reduce recurrence.Although injection in 7 weeks is once
The misery of patient has reduced, but is also insufficient to its release time long due to still, just gets to effectively owing to injecting first three week
Concentration, i.e. patient need injection in 4 weeks once as maintained medicine effective concentration, and the misery of patient fails favorably to be alleviated.Need
The exploitation medicine initial stage comparatively fast reaches valid density, and the new product of the most lasting releasing effect.
Summary of the invention
It is an object of the invention to provide one and can prepare long-acting risperidone implant, and use a kind of injectable mode to incite somebody to action
Pharmaceutical preparation is implanted to human body subcutaneous layer of fat, such that it is able to be effectively improved therapeutic effect and the compliance of medicine.
The present invention provides a kind of risperidone implant, and it comprises risperidone 50-70 part, biodegradable macromolecular material
20-40 part.
Further, it comprises risperidone 65 parts, biodegradable macromolecular material 35 parts.
Further, described biodegradable macromolecular material viscosity coefficient is at chloroform for solvent 25 DEG C
0.3~1dl/g。
Further, described biodegradable macromolecular material viscosity coefficient is at chloroform for solvent 25 DEG C
0.5~0.6 dl/g。
Further, described biodegradable macromolecular material relative molecular weight should be 30,000 ~ 100,000.
Further, described biodegradable macromolecular material relative molecular weight is 50,000 ~ 60,000.
Further, described biodegradable macromolecular material is polylactic acid, Poly(D,L-lactide-co-glycolide,
One or more combination in polycaprolactone, PBGS, polyaniline, Merlon and poly-aspartate.
Further, described biodegradable macromolecular material is that PDLLA, Poly-L-lactic acid or dextrorotation are poly-
Lactic acid
The preparation method of the risperidone implant of the present invention, comprises the steps,
1) preparation 0.5% ~ 3%PVA aqueous solution is dissolved in dichloromethane as dispersion as continuous items, polylactic acid and risperidone
Phase,
2) stirring continuous phase, mixing speed is 800 ~ 2000 revs/min；
3) in continuous phase, dispersion phase it is slowly added to while stirring；
4) continuously stirred volatile organic solvent prepares microsphere；
5) it is pressed into element sheet, is coated process.
Solvent used by Cotton seeds is polylactic acid dichloromethane solution 3%～20%, the preferably solvent used by Cotton seeds
For polylactic acid dichloromethane solution 3%～8%, the polylactic acid dichloromethane solution of more preferably 3%, 4%, 5%, 6%, 7%, 8%..
Recommending quantity according to risperidone, every day, oral dose 2 ~ 6mg calculated, the drug release ratio of risperidone implant
Example size should between 0.5% ~ 2%, the size of release amount of medicine every day should be between 0.5 ~ 5mg, drug release scale exists
Time between 0.9 ~ 1.2% optimal, every day release amount of medicine size between 1.5 ~ 2.5mg time optimal.
The biodegradable macromolecular material that risperidone implant uses requires that its viscosity coefficient should be at 0.3 ~ 1dl/g
Between (chloroform, 25 DEG C), viscosity coefficient at 0.5 ~ 0.6dl/g(chloroform, 25 DEG C) between optimal；Require that its relative molecular weight should be
Between 30000 ~ 100,000, optimal between 50,000 ~ 60,000.
The input ratio of the preparation technology of risperidone implant, risperidone and PDLLA is at 70/30 ~ 50/50(W/W)
Between, use emulsion-solvent evaporation method prepare microsphere, the size of microsphere is 20 ~ 80 microns, is pressed into tablet, sheet with suitable pressure
Agent diameter is 3 ~ 8mm, hardness test size is 3 ~ 10kg, can carry out one or many Cotton seeds, the thickness of coating
Between 0.01 ~ 1mm.
Through many experiments and test, the preparation process of risperidone implant, the input ratio of risperidone and PDLLA
Example is at 65/35 ~ 55/45(W/W) between time optimal, use emulsion-solvent evaporation method to prepare microsphere, the size of microsphere is 30 ~ 50 micro-
During rice optimal, be pressed into tablet with suitable pressure, tablet diameters size is 4.8 ~ 5.5mm, hardness test size is 6 ~ 7kg, can
To carry out 1 ~ 2 Cotton seeds, the thickness of coating is optimal when 0.1 ~ 0.3mm.
Risperidone implant can be injected implantation into the human body, can maintain as schizophrenic patients long-term prescription and control
Treating, and control the mental symptom that novel drug causes, preventing and treating novel drug relapses.After administration can long term maintenance therapy concentration, keep away
Having exempted from first pass effect, bioavailability improves, and the compliance of patient improves, it is possible to meet the clinical demand of patient.During its slow release
Between up to more than 100 days.
Accompanying drawing explanation
The release curve of Fig. 1 embodiment 1 risperidone implant
The release curve of Fig. 2 embodiment 2 risperidone implant
The release curve of Fig. 3 embodiment 3 risperidone implant
The release curve of Fig. 4 embodiment 4 risperidone implant
Detailed description of the invention
Embodiment 1
Degradable macromolecular material selection PDLLA in risperidone implant, viscosity coefficient 0.5dl/g(chloroform,
25 DEG C), mean molecule quantity about 60,000.Risperidone is 65/35(W/W with the input ratio of PDLLA),
Preparation method comprises the steps
1) preparation 0.5% ~ 3%PVA aqueous solution is dissolved in dichloromethane as dispersion as continuous items, polylactic acid and risperidone
Phase,
2) stirring continuous phase, mixing speed is 800 ~ 2000 revs/min；
3) in continuous phase, dispersion phase it is slowly added to while stirring；
4) continuously stirred volatile organic solvent prepares microsphere, and the size of thus obtained microsphere is at 20 microns；
5) being pressed into element sheet, the pressure of 5kN is pressed into tablet, and tablet diameters size is 5.5mm, hardness test size is 7kg, enters
Row is by 3% polylactic acid dichloromethane solution Cotton seeds, and the thickness of coating is between 0.15mm.
Utilizing vitro release method of testing, the buffer salt solution of preparation PH=7.4 is containing 0.5% ~ 3% sodium lauryl sulphate
80ml, 37 DEG C of water-baths, shaking table 25 revs/min, first 7 day every day, ultraviolet 278nm measured burst size, within the most every 3 days, measured once, often
Changing new soln after secondary measurement, measure 93 days continuously, the burst size of every day is highly stable, releases the 89.6% of total dose altogether.
Embodiment 2
Degradable macromolecular material selection PDLLA in risperidone implant, viscosity coefficient 0.3dl/g(chloroform,
25 DEG C), mean molecule quantity about 30,000.Risperidone is 50/20(W/W with the input ratio of PDLLA),
Preparation method comprises the steps
1) preparation 0.5% ~ 3%PVA aqueous solution is dissolved in dichloromethane as dispersion as continuous items, polylactic acid and risperidone
Phase,
2) stirring continuous phase, mixing speed is 800 ~ 2000 revs/min；
3) in continuous phase, dispersion phase it is slowly added to while stirring；
4) continuously stirred volatile organic solvent prepares microsphere, and the size of thus obtained microsphere is at 20 microns；
5) being pressed into element sheet, the pressure of 5kN ~ 10kN is pressed into tablet, and tablet diameters size is 5.5mm, hardness test size is
7kg, carries out use 4% polylactic acid dichloromethane solution Cotton seeds, and the thickness of coating is between 0.1mm.
Utilizing vitro release method of testing, the buffer salt solution of preparation PH=7.4 is containing 0.5% ~ 3% sodium lauryl sulphate
80ml, 37 DEG C of water-baths, shaking table 25 revs/min, first 7 day every day, ultraviolet 278nm measured burst size, within the most every 3 days, measured once, often
Changing new soln after secondary measurement, measure 93 days continuously, the burst size of every day is highly stable, releases the 88.1% of total dose altogether.
Embodiment 3
Degradable macromolecular material selection PDLLA in risperidone implant, viscosity coefficient 0.6dl/g(chloroform,
25 DEG C), mean molecule quantity about 60,000.Risperidone is 70/40(W/W with the input ratio of PDLLA),
Preparation method comprises the steps
1) preparation 0.5% ~ 3%PVA aqueous solution is dissolved in dichloromethane as dispersion as continuous items, polylactic acid and risperidone
Phase,
2) stirring continuous phase, mixing speed is 800 ~ 2000 revs/min；
3) in continuous phase, dispersion phase it is slowly added to while stirring；
4) continuously stirred volatile organic solvent prepares microsphere, and the size of thus obtained microsphere is at 50 microns；
5) being pressed into element sheet, the pressure of 10kN is pressed into tablet, and tablet diameters size is 5.5mm, hardness test size is 7kg,
Carrying out use 6% polylactic acid dichloromethane solution Cotton seeds, the thickness of coating is between 0.15mm.
Utilizing vitro release method of testing, the buffer salt solution of preparation PH=7.4 is containing 0.5% ~ 3% sodium lauryl sulphate
80ml, 37 DEG C of water-baths, shaking table 25 revs/min, first 7 day every day, ultraviolet 278nm measured burst size, within the most every 3 days, measured once, often
Changing new soln after secondary measurement, measure 93 days continuously, the burst size of every day is highly stable, releases the 85.7% of total dose altogether.
Embodiment 4
Degradable macromolecular material selection PDLLA in risperidone implant, viscosity coefficient 0.6dl/g(chloroform,
25 DEG C), mean molecule quantity about 60,000.Risperidone is 65/35(W/W with the input ratio of PDLLA),
Preparation method comprises the steps
1) preparation 0.5% ~ 3%PVA aqueous solution is dissolved in dichloromethane as dispersion as continuous items, polylactic acid and risperidone
Phase,
2) stirring continuous phase, mixing speed is 800 ~ 2000 revs/min；
3) in continuous phase, dispersion phase it is slowly added to while stirring；
4) continuously stirred volatile organic solvent prepares microsphere, and the size of thus obtained microsphere is at 20 microns；
5) being pressed into element sheet, the pressure of 5kN is pressed into tablet, and tablet diameters size is 5.5mm, hardness test size is 7kg, enters
Row is with by 8% polylactic acid dichloromethane solution Cotton seeds, and the thickness of coating is between 0.1mm.
Utilizing vitro release method of testing, the buffer salt solution of preparation PH=7.4 is containing 0.5% ~ 3% sodium lauryl sulphate
80ml, 37 DEG C of water-baths, shaking table 25 revs/min, first 7 day every day, ultraviolet 278nm measured burst size, within the most every 3 days, measured once, often
Changing new soln after secondary measurement, measure 93 days continuously, the burst size of every day is highly stable, releases the 81.9% of total dose altogether.
Product to be tested: risperidone implant sample prepared by embodiment 1-4；
The mensuration of vitro release: take product to be tested 1 and put into conical flask, containing 80mL release medium (0.5% ~ 3% 12 in bottle
Alkyl sodium sulfate, pH is 7.4 buffer salts) in, it being placed in 37 DEG C of constant-temperature tables, shaking table speed is set to 25 revs/min, and first 7 days are every
It sampling, ultraviolet spectrophotometer 278nm wavelength measurement trap also calculates burst size, the most every 3 days sampling and measurings once, often
New soln is changed after secondary measurement.Take sample feeding analysis, calculate cumulative release rate, with release time (d) and cumulative release rate
(%) draw release profiles, refer to Fig. 1-4.
Above-mentioned detailed description is illustrating for one of them possible embodiments of the present invention, and this embodiment is also not used to
Limiting the scope of the claims of the present invention, all equivalences done without departing from the present invention are implemented or change, are intended to be limited solely by the technology of the present invention
In the range of scheme.
Claims (1)
1. a risperidone implant, it is characterised in that in risperidone implant, degradable macromolecular material selects racemization to gather
Lactic acid, viscosity coefficient at chloroform for solvent 25 DEG C as 0.5dl/g, mean molecule quantity 60,000, risperidone and PDLLA
Input ratio is 65:35,
Preparation method comprises the steps,
1) preparation 0.5% ~ 3%PVA aqueous solution is dissolved in as dispersion phase in dichloromethane as continuous items, polylactic acid and risperidone,
2) stirring continuous phase, mixing speed is 800 ~ 2000 revs/min；
3) in continuous phase, dispersion phase it is slowly added to while stirring；
4) continuously stirred volatile organic solvent prepares microsphere, and the size of thus obtained microsphere is at 20 microns；
5) being pressed into element sheet, the pressure of 5kN is pressed into tablet, and tablet diameters size is 5.5mm, hardness test size is 7kg, with 3%
Polylactic acid dichloromethane solution is coated process, and the thickness of coating is at 0.15mm；
Described biodegradable macromolecular material viscosity coefficient at chloroform for solvent 25 DEG C as 0.5dl/g.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510291005.9A CN104922085B (en) | 2015-06-01 | 2015-06-01 | A kind of risperidone implant and preparation method thereof |
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| CN201510291005.9A CN104922085B (en) | 2015-06-01 | 2015-06-01 | A kind of risperidone implant and preparation method thereof |
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| CN104922085B true CN104922085B (en) | 2016-10-26 |
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| CN110742866B (en) * | 2018-11-08 | 2020-07-10 | 深圳善康医疗健康产业有限公司 | Paliperidone implant and preparation method thereof |
| CN113209050A (en) * | 2021-05-14 | 2021-08-06 | 浙江恒冀制药有限责任公司 | Long-acting in vivo skin-embedded or implanted sustained-release preparation based on biocompatible polymer |
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| CN1284537C (en) * | 2005-04-07 | 2006-11-15 | 中国人民解放军第二军医大学 | Nimustine brain slow release implantation agent and its preparation method |
| CN1686118A (en) * | 2005-04-07 | 2005-10-26 | 中国人民解放军第二军医大学 | Tiemozolenium brain slow release implantation agent and its preparation method |
| MX2008000573A (en) * | 2005-07-18 | 2008-03-14 | Univ Pennsylvania | Drug-containing implants and methods of use thereof. |
| PL2529756T3 (en) * | 2011-05-31 | 2021-11-15 | Laboratorios Farmaceuticos Rovi, S.A. | Risperidone and/or Paliperidone implant formulation |
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Effective date of registration: 20180125 Address after: 518048 Guangdong city of Shenzhen province Futian District Fuhua Road No. 88 business center building six floor 6G Patentee after: SHENZHEN SCIENCARE MEDICAL INDUSTRIES Co.,Ltd. Address before: 410205, Changsha, Hunan hi tech Development Zone, Tongzi slope West Road, No. 229, microelectronics research building, room 602 Patentee before: HUNAN SAIWO PHARMACEUTICAL Co.,Ltd. |
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Address after: 6G, 6th floor, central business building, 88 Fuhua 1st Road, Futian District, Shenzhen, Guangdong 518048 Patentee after: Shenzhen shankang Pharmaceutical Technology Co.,Ltd. Address before: 6G, 6th floor, central business building, 88 Fuhua 1st Road, Futian District, Shenzhen, Guangdong 518048 Patentee before: SHENZHEN SCIENCARE MEDICAL INDUSTRIES Co.,Ltd. |