CN102274164B - Sustained release gel for injection for paliperidone and paliperidone derivative - Google Patents
Sustained release gel for injection for paliperidone and paliperidone derivative Download PDFInfo
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- CN102274164B CN102274164B CN201110241546.2A CN201110241546A CN102274164B CN 102274164 B CN102274164 B CN 102274164B CN 201110241546 A CN201110241546 A CN 201110241546A CN 102274164 B CN102274164 B CN 102274164B
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Abstract
The invention discloses a sustained release gel for injection for paliperidone and paliperidone derivative. The sustained release gel consists of paliperidone or paliperidone derivative, lactide-glycolide and dimethyl sulfoxide. The sustained release gel disclosed by the invention has small initial burst and high drug-loading rate and the dosages of a polymer and an organic solvent in the drug delivery system is reduced greatly; not only the production cost is reduced, but more significantly, the discomfort at the injection site is improved effectively; the sustained release formulation is more beneficial to improving compliance of a patient and provides a valuable option to the clinical care for metal diseases.
Description
Technical field
The invention provides the Injectable sustained release gel of a kind of Paliperidone and Paliperidone derivant, there is long-acting slow-release, compared with high drug load and lower burst drug release feature, its preparation method is also provided simultaneously.Belong to medical science pharmaceutical technology field.
Background technology
Paliperidone is that FDA's approval in 2006 is used for the treatment of schizoid new drug, and the slow releasing tablet that this medicine has gone on the market is administered once every day, is administered systemically by drug osmotic pump.But its absolute bioavailability is only 28%, its every consumption per day is increased greatly, cause the increase of the front side effect of system.In addition, complicated dosage form also cause product cost and price high, improved treatment cost.To greatly improve bioavailability to the exploitation of the long-term slow releasing preparation of Paliperidone, the treatment failure that avoidance breakout administration causes, but not yet have at present long-term slow releasing preparation listing.
The prodrug (disclosed patent No. CN 200710098304.6) of Paliperidone by the Paliperidone derivant shown in logical formula II, in vivo can be rapid, change Paliperidone completely into, through Pharmacodynamics preliminary study, medicine for the researchs such as characteristic and safety EARLY STAGE EVALUATION and patent medicine feature optimized more than ten have good become the compound of the property of medicine, bioavailability is all higher than the Paliperidone oral sustained release sheet having gone on the market.Paliperidone prodrug is made to long-term slow releasing preparation, be conducive to strengthen patient's compliance in treatment, its slow-releasing gel used exploitation can be used as the alternative dosage form of conventional microball preparation, will greatly reduce patient's treatment cost.
Injectable sustained-release gel is compared with traditional Atrigel, and technique is simple, and cost is low, not only can be used as the carrier of hydrophobic drug, is applicable to again hydrophilic medicament simultaneously.Wherein, removal of solvents type in-situ gelling system is that medicine and insoluble polymer are dissolved in to the biocompatibility organic solvent dissolving each other with water, makes injectable colloidal sol, in the time that this colloidal sol is injected in body, organic solvent and body fluid exchange, and polymer in situ precipitation forms drug depot.It is little that this dosage form can solve many dissolubility, and labile drug is made the problem of slow releasing preparation.At present, a difficult problem that restricts this drug sustained release system is: on the one hand, the application of organic solvent can bring potential injection site side reaction, need guarantee, under the prerequisite of preparation injectable mobility, to reduce the consumption of solvent as far as possible; On the other hand, this drug-supplying system is prominent to be released greatlyr, in order to suppress burst drug release, conventionally will reduce drug loading, or increase the ratio of polymer/organic solvent, thereby reduce injection flow, has increased the burden that polymer is eliminated in patient body simultaneously.Thus, how prominent release to control with improving between drug loading average out, reduce the consumption of organic solvent simultaneously, will greatly improve the clinical practice of this drug-supplying system.Although existing bibliographical information a kind of risperidone sustained-release gel injection and preparation method thereof (publication CN200910053425.8), when its drug loading is 50%, the release of 15d reaches 80%, and when its drug loading is 9.3%-22.5%, in body, experimental result shows one week interior Cmax/Cmin ≈ 14.Thereby, how to solve the balance between drug loading and prominent releasing, effectively reduce the consumption of organic solvent and polymer, be still this area and wait the crucial difficult problem solving.
Summary of the invention
The invention provides the Injectable sustained release gel of a kind of Paliperidone and Paliperidone derivant, can be by drug use frequency from being reduced to once a day or repeatedly one week, within two weeks, even one month once, thereby greatly alleviate the misery of extensive patients, improve its quality of life.
The present invention further provides Paliperidone and the slow-releasing gel used preparation method of Paliperidone derivant, be applicable to suitability for industrialized production.
the Injectable sustained release gel of Paliperidone of the present invention and Paliperidone derivant, is characterized in that:
This is slow-releasing gel used by Paliperidone (I) or the Paliperidone derivant shown in logical formula II as follows, and polylactide-co-glycolide, dimethyl sulfoxide composition,
（Ⅰ）
（Ⅱ）
Wherein, chiral centre (*) can be R or S or RS (racemic mixture), and R contains the fatty alkoxyl of 1 to 20 C atom or aromatic radical or fragrant alkoxyl containing 6 to 20 C atoms; R is preferred: isobutoxy, n-pentyloxy, phenoxy group, phenyl.
The Injectable sustained release gel of described Paliperidone and Paliperidone derivant, it is characterized in that being made up by ratio of quality and the number of copies of following raw material:
Paliperidone or Paliperidone derivant 1～20, polylactide-co-glycolide 3～5, dimethyl sulfoxide 9～20.
The Injectable sustained release gel of described Paliperidone and Paliperidone derivant, is characterized in that: the molecular weight of polylactide-co-glycolide is at 20,000-150, between 000 dalton.
The Injectable sustained release gel of described Paliperidone and Paliperidone derivant, is characterized in that: in polylactide-co-glycolide, lactide and Acetic acid, hydroxy-, bimol. cyclic ester polymerization ratio are in (95 ~ 5): (5 ~ 95), preferably (40 ~ 75): (60 ~ 25).
The production method of the Injectable sustained release gel of described Paliperidone and Paliperidone derivant, is characterized in that:
Dimethyl sulfoxide is added in polylactide-co-glycolide and dissolved, then Paliperidone or Paliperidone derivant are dissolved or dispersed in this continuous phase, make.
The production method of the Injectable sustained release gel of described Paliperidone and Paliperidone derivant, is characterized in that:
Paliperidone or Paliperidone derivant are dissolved or dispersed in dimethyl sulfoxide, then add polylactide-co-glycolide, vortex to make fully to mix, make.
The production method of the Injectable sustained release gel of described Paliperidone and Paliperidone derivant, is characterized in that:
Be, after Paliperidone or Paliperidone derivant and polylactide-co-glycolide are mixed, to join dimethyl sulfoxide vortex and make fully to mix, make.
other guide of the present invention and advantage can further to define by describing in detail below.
Paliperidone of the present invention and Paliperidone derivant sustained-release gel, from keeping the prominent ability of executing of slow release effect, biological degradability and inhibition, the mass fraction of polylactide-co-glycolide is worked as 3～5.Consumption is very few, can affect slow release effect, causes prominent releasing; Consumption is too much, by the elimination cycle in extension body, increases patient burden.
In sustained-release gel of the present invention, as long as can realize the object of slow release, the content of active medicine is not particularly limited, but the enough slow release effect of long effective blood drug concentration and balance angles of assurance slow release effect of collateral security, and preferably active medicine mass fraction is 1～20.If medicament contg is too low, keep suitable blood density of medicine, must increase the injection volume of gel, bring misery to patient; Otherwise medicament contg is too high, likely cause prominent releasing, bring side effect.
In sustained-release gel of the present invention, the consumption that can accelerate the biocompatibility organic solvent of above-mentioned medicinal high polymer adjuvant in-situ precipitate needs only and guarantees that degradable pharmaceutic adjuvant can dissolve completely, and the injection flow of gel preparation, just do not limit, safety between organic solvent for human body, and improve the discomfort of injection site, and should reduce consumption of organic solvent as far as possible, preferred proportion is 9～20.
The organic solvent that can accelerate above-mentioned medicinal high polymer adjuvant in-situ precipitate should possess biocompatibility, and miscible with water, polylactide-co-glycolide is had to good dissolubility, specifically such as dimethyl sulfoxide, N-Methyl pyrrolidone etc. and mixed solvent of being formed by them etc.Preferential, the biocompatibility organic solvent that can accelerate above-mentioned medicinal high polymer adjuvant in-situ precipitate is selected from dimethyl sulfoxide.
The method for the treatment of mental sickness of the present invention is to adopt Paliperidone and the Paliperidone derivant sustained-release gel injection of the invention described above to need the patient of above-mentioned treatment to carry out.Administering mode, as long as using injection, can be regardless of use.Such as intramuscular injection, subcutaneous injection, intradermal injection etc.From convenient drug administration angle, preferably administered intramuscular and subcutaneous injection administration.
The mechanism of action of sustained-release gel of the present invention is after it is injected in body, water-miscible organic solvent in gel and injection site body fluid exchange, in gel, water-insoluble high polymer adjuvant precipitates immediately, form drug depot, because biodegradable resin can be progressively degraded to water and carbon dioxide by body as polylactide-co-glycolide, the medicine comprising in gel is progressively discharged, and progressively spreads with blood circulation, realizes thus slow release and long-acting.
Sustained-release gel of the present invention is investigated through beasle dog pharmacokinetics, after subcutaneous injection, sustainable release 4 weeks, and maintain effective treatment concentration of 1 week, in 1 week, Cmax/Cmin is less than 3, investigates through inside and outside correlation models, and sustained-release gel of the present invention can reach 50% drug loading, 1 Tiantu is released below 10%, and drug loading can be increased to 50%.The demonstration of pharmacodynamic study result, sustained-release gel of the present invention, after the subcutaneous single-dose of mice, can produce an above effective inhibition in month to the mice schizophrenia model of MK801 induction, and inhibitory action has statistical significance.
Adopt the sustained-release gel of Paliperidone of the present invention and Paliperidone derivant, can realize at lower cost and compared with low dosage and reach therapeutic purposes, reduce toxic and side effects, therefore be expected to greatly improve the quality of life of psychiatric patient, reduce the manpower and materials of the every day of the required cost of dosed administration on time simultaneously.
good effect of the present invention is:employing can be worked in coordination with and suppressed the biodegradable medicinal high polymer adjuvant of burst drug release and can accelerate the biocompatibility organic solvent of above-mentioned medicinal high polymer adjuvant in-situ precipitate as the medicine-carried system of Paliperidone and Paliperidone derivant, make Injectable sustained release gel preparation, burst drug release in 1 day can be controlled to 5%-15%, reduce consumption of organic solvent, improve injection site discomfort and waited side reaction, reduce polymer volume, reduce human body and eliminated burden, reduced commercial production cost simultaneously, injection once can maintain January or longer time, Cmax/Cmin is in steady-state level, pharmacodynamic study shows, sustainable one month above significantly inhibitory action.Technique is simple, and cost is low, for psychotic's fabulous Gospel beyond doubt.
Accompanying drawing explanation
Curve when Fig. 1 is average medicine in beasle dog body of the sustained-release gel of embodiment 1 gained;
Curve when Fig. 2 is average medicine in beasle dog body of the sustained-release gel of embodiment 2 gained;
Curve when Fig. 3 is average medicine in beasle dog body of the sustained-release gel of embodiment 3 gained;
Fig. 4 is that the sustained-release gel of embodiment 4 gained discharges the broken line graph of the preparation in liquid in the simulation of PH7.4;
Fig. 5 is that the sustained-release gel of embodiment 5 gained discharges the broken line graph of the preparation in liquid in the simulation of PH7.4;
Fig. 6 is that the sustained-release gel of embodiment 6 gained discharges the broken line graph of the preparation in liquid in the simulation of PH7.4;
Fig. 7 is that the sustained-release gel of embodiment 7 gained discharges the broken line graph of the preparation in liquid in the simulation of PH7.4;
Fig. 8 is that the sustained-release gel of embodiment 4 and 8 gained discharges the first day cumulative release broken line graph in liquid in the simulation of PH7.4;
Fig. 9 is that the sustained-release gel of embodiment 9 gained discharges the broken line graph of the preparation in liquid in the simulation of PH7.4;
Figure 10 is that the sustained-release gel of embodiment 10 gained discharges the broken line graph of the preparation in liquid in the simulation of PH7.4;
Figure 11 is that the sustained-release gel of embodiment 11 gained discharges the broken line graph of the preparation in liquid in the simulation of PH7.4;
Figure 12 is that the sustained-release gel of embodiment 12 gained discharges the broken line graph of the preparation in liquid in the simulation of PH7.4.
The specific embodiment
Preparation method and the slow release effect of Paliperidone of the present invention and Paliperidone derivant sustained-release gel will be further illustrated by embodiment below, but following examples do not form any restriction to the present invention.
In following examples the release in vitro of sustained-release gel adopt high performance liquid chromatography (HPLC) to measure containing concentration, method is according to literature method, for example can be according to as modern Application pharmaceutical journal, 1993,10(1), 51-52; Chinese Journal of Pharmaceuticals, 1999,30(8), the disclosed person such as 363-365.Determination of plasma concentration adopts LC-MS method, for example can be according to pharmaceutical analysis magazine, and 2005,25 (7), 795-798 is disclosed.
embodiment 1
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=75:25, molecular weight 105,000) is dissolved in 2.0ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add Paliperidone 0.1g, make dispersedly, be prepared into the sustained-release gel of drug loading 20%.
This sustained-release gel is carried out to vivo releasing test to beasle dog.Press Paliperidone 0.37 mg/kg administration, in subcutaneous injection, in 1 to 30 day, get blood with 1ml disposable syringe, HPLC-MS-MS detects, and when medicine, curve is shown in accompanying drawing 1, and result proves that sustained-release gel of the present invention is in vivo more than at least 1 week of sustained release.
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=50:50, molecular weight 44,000) is dissolved in 1.6ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add Paliperidone 0.17g, make dispersedly, be prepared into drug loading and be about 30% sustained-release gel.
This sustained-release gel is carried out to vivo releasing test to beasle dog.Press Paliperidone 0.37 mg/kg administration, in subcutaneous injection, in 1 to 30 day, get blood with 1ml disposable syringe, HPLC-MS-MS detects, and when medicine, curve is shown in accompanying drawing 2, and result proves that sustained-release gel of the present invention is in vivo more than at least 2 weeks of sustained release.
embodiment 3
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=50:50, molecular weight 113,000) is dissolved in 1.6ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add Paliperidone 0.4g, make dispersedly, be prepared into drug loading and be about 30% sustained-release gel.
This sustained-release gel is carried out to vivo releasing test to beasle dog.Press Paliperidone 0.37 mg/kg administration, in subcutaneous injection, in 1 to 30 day, get blood with 1ml disposable syringe, HPLC-MS-MS detects, and when medicine, curve is shown in accompanying drawing 3, and result proves sustained-release gel of the present invention sustained release more than at least 1 month in vivo.
Take Paliperidone 0.10g, make to be dispersed in 1.6ml dimethyl sulfoxide, by the polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=50:50, molecular weight 113,000) be dissolved in this suspension, vortex vibration is dissolved macromolecule completely, is prepared into drug loading and is about 20% sustained-release gel.
By Paliperidone 0.17g, with polylactide-co-glycolide (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=50:50, the molecular weight 113 of 0.4g, 000) mix homogeneously, add 1.6ml dimethyl sulfoxide, vortex vibration is dissolved macromolecule completely, is prepared into drug loading and is about 30% sustained-release gel.
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=50:50, molecular weight 113,000) is dissolved in 1.6ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add Paliperidone 0.27g, make dispersedly, be prepared into drug loading and be about 40% sustained-release gel.
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=50:50, molecular weight 113,000) is dissolved in 1.6ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add Paliperidone 0.40g, make dispersedly, be prepared into drug loading and be about 50% sustained-release gel.
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=50:50, molecular weight 113,000) is dissolved in 1.6ml N-Methyl pyrrolidone, under vortex oscillating condition, dissolves.Add Paliperidone 0.1g, make dispersedly, be prepared into drug loading and be about 20% sustained-release gel.
embodiment 9
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=50:50, molecular weight 39,000) is dissolved in 1.6ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add 3-{2-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] ethyl }-2-methyl-4-oxo-6,7,8,9-tetrahydrochysene-pyrido [1,2-α] pyrimidine-9-base isobutoxy formic acid esters 0.1g, make dispersedly, be prepared into drug loading and be about 20% sustained-release gel.
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=50:50, molecular weight 113,000) is dissolved in 1.6ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add 3-{2-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] ethyl }-2-methyl-4-oxo-6,7,8,9-tetrahydrochysene-pyrido [1,2-α] pyrimidine-9-base isobutoxy formic acid esters 0.1g, make dispersedly, be prepared into drug loading and be about 20% sustained-release gel.
embodiment 11
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=75:25, molecular weight 105,000) is dissolved in 1.6ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add 3-{2-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] ethyl }-2-methyl-4-oxo-6,7,8,9-tetrahydrochysene-pyrido [1,2-α] pyrimidine-9-base n-pentyloxy formic acid esters 0.1g, make dispersedly, be prepared into drug loading and be about 20% sustained-release gel.
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=75:25, molecular weight 105,000) is dissolved in 2.0ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add 3-{2-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] ethyl }-2-methyl-4-oxo-6,7,8,9-tetrahydrochysene-pyrido [1,2-α] pyrimidine-9-base n-pentyloxy formic acid esters 0.27g, make dispersedly, be prepared into drug loading and be about 40% sustained-release gel.
embodiment 13
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=75:25, molecular weight 105,000) is dissolved in 2.0ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add 3-{2-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] ethyl }-2-methyl-4-oxo-6,7,8,9-tetrahydrochysene-pyrido [1,2-α] pyrimidine-9-phenoxyl formic acid esters 0.1g, make dispersedly, be prepared into drug loading and be about 20% sustained-release gel.
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=75:25, molecular weight 105,000) is dissolved in 2.0ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add 3-{2-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] ethyl }-2-methyl-4-oxo-6,7,8,9-tetrahydrochysene-pyrido [1,2-α] pyrimidine-9-phenoxyl formic acid esters 0.4g, make dispersedly, be prepared into drug loading and be about 50% sustained-release gel.
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=75:25, molecular weight 105,000) is dissolved in 2.0ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add 3-{2-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] ethyl }-2-methyl-4-oxo-6,7,8,9-tetrahydrochysene-pyrido [1,2-α] pyrimidine-9-yl benzoic acid ester 0.1g, make dispersedly, be prepared into drug loading and be about 20% sustained-release gel.
The polylactide-co-glycolide of 0.4g (lactide: Acetic acid, hydroxy-, bimol. cyclic ester=75:25, molecular weight 105,000) is dissolved in 2.0ml dimethyl sulfoxide, under vortex oscillating condition, dissolves.Add 3-{2-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] ethyl }-2-methyl-4-oxo-6,7,8,9-tetrahydrochysene-pyrido [1,2-α] pyrimidine-9-yl benzoic acid ester 0.4g, make dispersedly, be prepared into drug loading and be about 50% sustained-release gel.
test example
In the body of Paliperidone sustained-release gel, medicine, for experiment, adopts the gel of embodiment 1-3, and laboratory animal is beasle dog.
The extracorporeal releasing test of the sustained-release gel of Paliperidone and Paliperidone derivant, the gel of employing embodiment 4-12, sets up inside and outside dependency in-vitro evaluation standard according to the experimental result of embodiment 1-3, and in analogue body, condition is carried out release test.
Adopt the buffer solution (buffer solution of sodium phosphate) of certain pH value (pH7.4) according to the present invention, similar in drug release behavior and body, although therefore its environment and human internal environment incomplete same, roughly think and can show the release mode in body.
Experimental apparatus: constant temperature oscillator, centrifuge.
Experiment condition: temperature: 37 ± 0.5 ℃, rotating speed: 100rpm.
Experimental technique: precision takes the sustained-release gel of pastille approximately 1 ㎎, being placed in volume is the tool lid plastic centrifuge tube bottom of 50 ml, add 35 ml release medium (pH=7.4 buffer solution of sodium phosphate) and be placed in constant temperature oscillator, keep certain temperature and rotating speed, on time sampling.
Sampling method: centrifuge tube is centrifugal 5min under 3000 rpm conditions, accurately draws 20 ml solution, simultaneously, to the release medium of adding again 20ml in centrifuge tube, takes out liquid and detects with HPLC.
Sampling time point in 1 day (hour): 0,1,3,6,8,12, wherein within the 0th hour, refer to the drug level before the administration administration on the same day.
Sampling time point after 1 day (my god): 1,2,3,4,5,6,7,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,44,48,52,56.
In the sustained-release gel beasle dog body of embodiment 1-3, curve is shown in accompanying drawing 1-3 when average medicine.
The sustained-release gel of embodiment 4-7 external releasing effect figure under the condition of pH7.4 is shown in respectively accompanying drawing 4-7.
The sustained-release gel of embodiment 4 and 8 first day releasing effect figure under the condition of pH7.4 is shown in accompanying drawing 8.
The sustained-release gel of embodiment 9-12 external releasing effect figure under the condition of pH7.4 is shown in respectively accompanying drawing 9-12.
Claims (4)
1. an Injectable sustained release gel for Paliperidone or Paliperidone derivant, it is characterized in that being made up by ratio of quality and the number of copies of following raw material:
Paliperidone or Paliperidone derivant 1～20, polylactide-co-glycolide 3～5, dimethyl sulfoxide 9～20;
Wherein, Paliperidone derivant is 3-{2-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] ethyl }-2-methyl-4-oxo-6,7,8,9-tetrahydrochysene-pyrido [1,2-α] pyrimidine-9-base isobutoxy formic acid esters or 3-{2-[4-(6-fluoro-1,2-benzisoxa oxazole-3-yl)-piperidino] ethyl }-2-methyl-4-oxo-6,7,8,9-tetrahydrochysene-pyrido [1,2-α] pyrimidine-9-base n-pentyloxy formic acid esters;
The molecular weight of polylactide-co-glycolide is at 20,000-150, between 000 dalton;
In polylactide-co-glycolide, lactide and Acetic acid, hydroxy-, bimol. cyclic ester polymerization ratio are between 95:5-5:95.
2. the production method of the Injectable sustained release gel of Paliperidone or Paliperidone derivant according to claim 1, is characterized in that:
Polylactide-co-glycolide is added in dimethyl sulfoxide and dissolved, then Paliperidone or Paliperidone derivant are dissolved or dispersed in this continuous phase, make.
3. the production method of the Injectable sustained release gel of Paliperidone or Paliperidone derivant according to claim 1, is characterized in that:
Paliperidone or Paliperidone derivant are dissolved or dispersed in dimethyl sulfoxide, then add polylactide-co-glycolide, vortex to make fully to mix, make.
4. the production method of the Injectable sustained release gel of Paliperidone or Paliperidone derivant according to claim 1, is characterized in that:
Be, after Paliperidone or Paliperidone derivant and polylactide-co-glycolide are mixed, to join dimethyl sulfoxide vortex and make fully to mix, make.
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| CN101584652A (en) * | 2009-06-19 | 2009-11-25 | 上海医药(集团)有限公司 | Risperidone sustained-release gel injection and preparation method thereof |
| WO2011042453A1 (en) * | 2009-10-06 | 2011-04-14 | Ascendis Pharma As | Subcutaneous paliperidone composition |
| WO2011067220A1 (en) * | 2009-12-01 | 2011-06-09 | Chemo Ibérica, S.A. | A process for the purification of paliperidone |
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| CN102274164A (en) | 2011-12-14 |
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