CN103417492A - Olanzapine-containing biodegradable microsphere preparation and preparation method thereof - Google Patents
Olanzapine-containing biodegradable microsphere preparation and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an olanzapine-containing biodegradable microsphere preparation and a preparation method thereof. The olanzapine-containing biodegradable microsphere preparation comprises 10-50wt% of olanzapine or its salt, 0.5-20wt% of release adjusting agents and 30-89.5% of PLGA. In the invention, the PLGA having a proper monomer LA:GA ratio is selected as a matrix material, and above one release adjusting agents are added, so the olanzapine loading is improved to above 30%, and the particle size distribution and the in-vitro drug release of microspheres are improved. The utilization of a biodegradable material to encapsulate olanzapine to prepare the microspheres realizes a good slow release effect and the maintenance of an in-vivo relatively-stable drug concentration for above 15-45d or more.
Description
Technical field
The present invention relates to antipsychotic drug olanzapine (olanzapine) sustained release microsphere agents and preparation method thereof.
Background technology
Olanzapine (Olanzapine) is on the clozapine basis, the novel atypical antipsychotics formed through the chemical constitution transformation, successfully overcome the untoward reaction of clozapine granulocytopenia, and obviously strengthened the therapeutical effect to negative symptoms of schizophrenia.Olanzapine was got permission the listing in the U.S. in 1996, be that first gets permission the psychosis for schizophrenia long-term treatment and acute manic episodes of bipolar disorder disease.
Olanzapine is 5 ~ hydroxytryptamine/dopamine (5 ~ HT/DA) dual antagonist, to ambitus cerebri and the selective effect of midbrain cortex.But its rapid recovery spirit acute symptom, all have the significance curative effect to its feminine gender and the positive symptom, and can improve patient's social function and cognitive function, can effectively treat organic mental disorders, Mental Disorder Caused by Alcohol and schizophrenia.In addition, olanzapine is by blocking-up D
2,
1, H
1And plan ~ aminobutyric acid receptor alleviates manic; By blocking 5 ~ HT
2AWith
2The receptor antidepressant, can effectively treat the relevant mental disorder of affective disorders, neurosis and children and youth.With traditional psychosis, compare, olanzapine is evident in efficacy to feminine gender and the positive symptom of spiritual acute symptom, and the extrapyramidal system side reaction obviously reduces.
The olanzapine in treatment predose is 10mg every day, by the state of an illness, in every day, in 5 ~ 20mg scope, adjusts afterwards.In the clinical use of olanzapine, oral absorption is good, within 5 to 8 hours, reaches plasma peak concentration, and by combination and oxidation reaction, at liver metabolism, mean half-life is 33 hours.The olanzapine formulations of external listing is the tablet that gift comes (Lilly) company at present
Disintegrating tablet (Zyprexa Zydis
TM) and long-acting suspensoid injectio (Zyprexa
).Wherein, the durative action preparation Zyprexa of olanzapine
For olanzapine palmoxiric acid salt (olanzapine pamote) suspensoid, be used for the treatment of the excitement that schizophrenia or bipolar I type disease cause January for 1 time.Domestic listing product be every day the oral coated tablet of 1 time (as Ou Lan
).Because the olanzapine conventional formulation all needs take every day, can not solve the poor difficult problem of mental patient's long-term prescription and drug compliance.Therefore, research olanzapine durative action preparation has important clinical significance.In recent years the sustained-release preparation of olanzapine research has more bibliographical information.Nahata has prepared olanzapine PLGA microsphere, drug loading 20% left and right, effectively release period is 12 days, large (the Optimization of formulation variables for the development of long acting microsphere based depot injection of olanzapine of burst size fluctuation every day, Journal of Microencapsulation, 2008,25 (6): 426-433).The people such as Vivek adopt multiple fatty glyceride to prepare the olanzapine solid lipid nanoparticle, slow release 2 days but poor (the Investigations of the Effect of the Lipid Matrix on Drug Entrapment of storage-stable, In Vitro Release, and Physical Stability of Olanzapine-Loaded Solid Lipid Nanoparticles, AAPS PharmSciTech, 2007,8 (4): 16-24).Document (Mucoadhesive nanoemulsion-based intranasal drug delivery system of olanzapine for brain targeting, Journal of Drug Targeting, 2008,16 (10): 806 – 814) in, the people such as Kumar have developed olanzapine per nasal brain targeted nano emulsion formulation, the 1st day cumulative release approximately 41%.The people such as Seju are at document (Development and evaluation of olanzapine-loaded PLGA nanoparticles for nose-to-brain delivery:In vitro and invivo studies, Acta Biomaterialia, 2011,7 (12): 4169 – 4176) reported and prepared olanzapine per nasal brain Targeted PLGA nanoparticle, drug loading 8.61%, discharge 25.69% in 7h, certain slow release effect is arranged, but final cumulative release amount is only 43.3%, and in preparation, olanzapine degree of crystallinity is high.Document (Bimodal Release of Olanzapine from Lipid Microspheres, Journal of Pharmaceutical Sciences, 2010,99 (10): 4251 – 4260) in, the persons such as Fini have prepared the olanzapine lipid microsphere with curing Oleum Ricini and stearic acid, drug loading 10%, be 3 hours deenergized period.In addition, the patent application of existing some olanzapine sustained-release preparations abroad.Gift comes company to select oleic acid and cholesterol to develop the olanzapine lipid microsphere, but slow release 7 days (2-methyl-thieno-benzodiazepine formulation, US6617321).Liversidge etc. have prepared the olanzapine nano crystallization preparation, and the pharmacokinetics experiment shows to maintain 7 days effective blood drug concentrations (injectable nanoparticulate olanzapine formulations, US20060154918).Illum etc. have prepared olanzapine PLGA microsphere, have added fatty acid in substrate, drug loading 30%, but slow release 14 days (Controlled release microsphere delivery system, WO9912549A2).
As mentioned above, existing technology fails to develop the long-acting carrier controlled release preparation of the olanzapine of 1 time in January, therefore, can not meet the needs of clinical practice.
Summary of the invention
The purpose of this invention is to provide a kind of biodegradable microspheres preparation that contains olanzapine and preparation method thereof, the above-mentioned defect existed to overcome prior art.
The described biodegradable microspheres preparation that contains olanzapine comprises the component of following percentage by weight:
Olanzapine or its salt 10 ~ 50%
Release regulator 0.5 ~ 20%
Particle diameter is 30 ~ 150 μ m;
Preferably, the described biodegradable microspheres preparation that contains olanzapine comprises the component of following percentage by weight:
Olanzapine or its salt 30～38%
Particle diameter is 30 ~ 120 μ m;
Described olanzapine salt comprises olanzapine palmoxiric acid salt, olanzapine maleate, olanzapine malonate, olanzapine benzene olanzapine formates, olanzapine tartrate, olanzapine tosilate, olanzapine naphthalene sulfonate, mandelate, olanzapine diphenyl sulfonate or olanzapine dimethanesulfonate;
Described release regulator is selected from fat-soluble good amphipathic small molecules compound and high molecular polymer, preferably one or more of tricaprylin, oleic acid polyethyleneglycol glyceride, Gelucire 44/14, Labraso, polyoxyethylene ~ polyoxypropylene block copolymers, dimyristoyl phosphatidyl choline (DMPC), dipalmitoyl phosphatidyl choline (DPPC), DSPC (DSPC);
Described PLGA[poly (d, l ~ lactic ~ co ~ glycolic acid)] be polylactic acid ~ co-glycolic acid or derivatives thereof, can adopt ring-opening polymerisation method or melt phase polycondensation preparation, perhaps adopt commercially produced product, as the companies such as Alkerme, Boehringer Ingelheim, Birmingham Polymers, PURAC America have obtained the extensively product of approval of industry.
The weight average molecular weight of PLGA is 10,000 ~ 150,000 dalton;
Preferably, the weight average molecular weight of PLGA is 50,000 ~ 90,000 dalton;
Monomer lactic acid: hydroxyacetic acid (LA: GA)=10: 90 ~ 90: 10, mol ratio;
Preferably, LA: GA=75: 25 ~ 85: 15, mol ratio;
The preparation method of the described biodegradable microspheres preparation that contains olanzapine, comprise the steps:
(1) PLGA and olanzapine or its salt are dissolved in to organic solvent, add release regulator, be uniformly mixed, obtain oil phase;
Described organic solvent is selected from more than one of dichloromethane, ethyl acetate, butyl acetate, butyl formate, N-Methyl pyrrolidone, acetone, oxolane, benzyl alcohol, isopropyl alcohol, propylene glycol, dioxane or dimethyl sulfoxide;
A kind of mixture in dichloromethane and ethyl acetate, butyl acetate, butyl formate, N-Methyl pyrrolidone, acetone, oxolane, benzyl alcohol, isopropyl alcohol, propylene glycol, dioxane or dimethyl sulfoxide preferably, volume ratio is 1: 1～1: 30;
The mixture of dichloromethane and N-Methyl pyrrolidone preferably, volume ratio is 1: 2～1: 20;
In described oil phase, the weight content of olanzapine or its salt is 10～50%, preferably 30～38%, and the weight content of PLGA is 40～70%, preferably 45～59%, the weight content of release regulator is 1～30%, preferably 5～17%;
(2) osmotic pressure regulator and PH regulator are added to the nonionic emulsifier aqueous solution, obtain water;
Described osmotic pressure regulator is selected from sodium chloride, sucrose or mannitol;
Described pH adjusting agent is selected from sodium hydroxide, phosphate or borate;
Described nonionic emulsifier is selected from more than one in polyvinyl alcohol, PVP, tween ~ 80, tween ~ 20, gelatin or tragcanth;
Wherein, preferentially select polyvinyl alcohol, alcoholysis degree is 87 ~ 90%, and the polymeric chain joint number is 1700 ~ 1750, and weight average molecular weight is 10,000 ~ 20,000;
In water, the weight concentration of described osmotic pressure regulator is 0.1 ~ 10%, and preferred concentration is 0.2～1%, and preferred sodium chloride;
In water, the weight content of described nonionic emulsifier is 0.5% ~ 3%, preferably 1～2%;
In water, the consumption of described pH adjusting agent is that to make the pH of water be 7.4～10.0, preferably 7.5～9.0, thus at utmost reduce the loss that drug diffusion to water causes;
(3) under 10～20 ℃, oil phase is injected to water, stirring and emulsifying 0.5～1h, change supernatant, add short chain alcohol, stir 0.5～1h, change supernatant, continue to stir 3～5h, then collect microsphere from system, lyophilization, obtain the described biodegradable microspheres preparation that contains olanzapine;
The weight ratio of organic solvent and water is 1: 80～120, preferably 1: 100;
Described short chain alcohol is selected from unit or the polyhydric alcohol of C1 ~ C3, and in water, the weight concentration of short chain alcohol is 1 ~ 30wt%, preferred 10 ~ 20wt%, preferred alcohol and isopropyl alcohol;
Add ethanol or isopropyl alcohol to contribute to remove organic solvent, and can effectively remove the release regulator of microsphere surface, improve roundness and the mobility of microsphere.In addition, because olanzapine is slightly soluble in ethanol, so the wash phase of microsphere can not cause the decline of drug loading.
In the present invention, the release regulator added is fat-soluble good amphipathic small molecules compound or high molecular polymer, good with the organic facies compatibility, easy to operate, increases the dissolubility of medicine in PLGA early stage, improves envelop rate and effectively reduces prominent releasing; Later stage, along with the dissolving diffusion of release regulator to water, has increased the formation of PLGA inner duct, thereby has improved the preparation of medicine.
The present invention, by the temperature of kind, consumption and the emulsion process of control emulsifying agent, can control distribution and the microsphere porosity of olanzapine in macromolecular material, thereby regulate better the drug release mode of this microball preparation.
The present invention uses mixed solvent, increase the compatibility of medicine and macromolecular material, reduce the required surface tension of balling-up, improved the balling-up of microsphere, the crystallization that simultaneously suppresses insoluble medicine, increase preparation stability, improved the dispersity of medicine in microsphere, reduce prominent releasing, obtain stable drug release characteristics.
Preparation of the present invention, can be used for muscle or subcutaneous injection administration, can reduce frequency injection, improves patient's compliance, facilitates clinical use.
The invention has the beneficial effects as follows: selecting the PLGA of suitable monomer LA:GA ratio is host material, by adding one or more release regulator, not only the drug loading of olanzapine is brought up to more than 30%, and improved particle size distribution and the tablets in vitro situation of microsphere.Utilize Biodegradable material to seal olanzapine and make microsphere, play good slow release effect, can maintain in body that metastable drug level reaches 14 ~ 45 days and more than.
The accompanying drawing explanation
Fig. 1 is the release in vitro curve of embodiment 1;
Fig. 2 is the release in vitro curve of embodiment 2;
Fig. 3 is the release in vitro curve of embodiment 3;
Fig. 4 is the release in vitro curve of embodiment 4;
Fig. 5 is the release in vitro curve of embodiment 5;
Fig. 6 be embodiment 6 and the release in vitro curve.
The specific embodiment
Embodiment 1
The preparation of olanzapine microsphere:
(1) take PLGA(weight average molecular weight 6,5124, LA:GA is 75:25, mol ratio) 0.3g and olanzapine 0.2g are dissolved in 6.5g dichloromethane and N ~ methyl ~ ketopyrrolidine mixed solvent (volume ratio 1:9), add 0.05g oleic acid polyethyleneglycol glyceride, mix, obtain oil phase;
(2) take 5g PVA in the 500g distilled water, heating for dissolving, be chilled to room temperature, adds after the 1gNaCl stirring and dissolving and regulate water pH to 7.5 with NaOH, adds stirrer, under water bath condition, makes it keep 15 ℃;
Wherein the alcoholysis degree of PVA is 90%, and the average polymerization chain number is 1700, and weight average molecular weight is 20,000;
Oil phase is slowly injected under liquid level to water, change supernatant after stirring and emulsifying 1h, add ethanol, in water, the weight content of ethanol is 20wt%, after the room temperature lower magnetic force stirs 1h, changes supernatant, continues to stir 5h;
Sucking filtration, after collecting microsphere, be placed in lyophilization and obtain microsphere dry powder, obtains the described biodegradable microspheres preparation that contains olanzapine, the smooth rounding of thus obtained microsphere, and particle diameter is 30 ~ 150 μ m; The percentage by weight of each component is as follows:
Olanzapine 32.2%
Release regulator 9.1%
PLGA 58.7%
Drug loading is 32.2%;
Detect:
(1) content assaying method of olanzapine microsphere:
Precision takes the 25mg olanzapine, puts in the 50ml volumetric flask, is diluted to scale after adding dissolve with methanol, shakes up;
Precision measures the above-mentioned solution of 1ml and puts in the 10ml volumetric flask, adds mobile phase: methanol ~ 0.5% triethylamine aqueous solution (60:40, volume ratio) is diluted to scale, shakes up stock solution in contrast;
Precision takes the above-mentioned biodegradable microspheres preparation that contains olanzapine of 10mg, puts in the 10ml volumetric flask, adds oxolane 1ml to make to dissolve, and adds methanol to be diluted to scale, shakes up;
Precision measures above-mentioned solution 1ml and puts in the 10ml volumetric flask, add mobile phase: methanol ~ 0.5% triethylamine aqueous solution (60:40, volume ratio) is diluted to scale, gets 20 μ l solution injection liquid chromatographies, record chromatogram, the drug loading by external standard method with calculated by peak area olanzapine microsphere.
(2) the release in vitro detection method of olanzapine microsphere:
Get dry olanzapine microsphere appropriate (approximately containing olanzapine 10mg), accurately weighed, put in bag filter, and add physiology isotonic phosphate buffer liquid (pH7.4) (to get sodium dihydrogen phosphate 1.84g, sodium hydrogen phosphate 19.1g, Hydrazoic acid,sodium salt 0.2g, tween ~ 80 5g, sodium chloride 4.32g, 0.25g EDTA, be dissolved in water into 1000ml, regulate pH value to 7.4, shake up, ) 0.5ml is with dispersion microsphere, arrange into air as far as possible and tighten bag mouth, then bag filter is placed in to the tool plug bottle that fills 50ml physiology isotonic phosphate buffer liquid (pH7.4), 37 ℃ of water bath with thermostatic control vibrations, timing sampling 0.5ml, and regularly replace whole release medium, get 20 μ l solution injection liquid chromatographies, record chromatogram, burst size by external standard method with calculated by peak area olanzapine microsphere.Result shows:
The first Tiantu is interpreted as cumulative release 85.6% in 2.6%, 30 day.Referring to Fig. 1.
Embodiment 2
The preparation of olanzapine microsphere
Take PLGA(molecular weight 9,5726, LA:GA is 75:25) 0.3g and olanzapine 0.2g be dissolved in 5g dichloromethane and N-methyl-ketopyrrolidine mixed solvent (volume ratio 1:2), adds the 0.1g tricaprylin, mixes, and obtains oil phase;
Take 4g PVA in the 400g distilled water, dissolve, be chilled to room temperature, regulate water PH to 7.5 with NaOH after adding the 1.5gNaCl stirring and dissolving, add stirrer, under water bath condition, make it keep 20 ℃;
The average alcoholysis degree of PVA is 87%, and the average polymerization chain number is 1750, and weight average molecular weight is 10,000;
Oil phase is injected to water under liquid level, change supernatant after stirring and emulsifying 1h, add ethanol, in water, the content of ethanol is 20wt%, and the room temperature lower magnetic force is changed supernatant after stirring 1h, continues to stir 24h;
Sucking filtration, carry out lyophilization after the collection microsphere, obtains the described biodegradable microspheres preparation that contains olanzapine, the smooth rounding of thus obtained microsphere; Particle diameter is 30 ~ 120 μ m; The percentage by weight of each component is as follows:
Olanzapine 32.1%
Release regulator 16.7%
PLGA 51.2%
Drug loading is 32.1%;
Detection method is with embodiment 1..
The first Tiantu is interpreted as cumulative release 87.3% in 1.2%, 35 day.Referring to Fig. 2.
The preparation of olanzapine microsphere
Take PLGA(molecular weight 10,5328, LA:GA is 75:25) 0.275g and olanzapine 0.225g be dissolved in 5g dichloromethane and N ~ methyl ~ ketopyrrolidine mixed solvent (volume ratio 1:9), adds 0.1g dimyristoyl phosphatidyl choline (DMPC), obtains oil phase;
Take 6g PVA in the 600g distilled water, dissolve, be chilled to room temperature, add 1.5gNaCl, after stirring and dissolving, with NaOH, regulate water PH to 7.5, add stirrer, under water bath condition, make it keep 15 ℃;
The average alcoholysis degree of PVA is 88%, and the average polymerization chain number is 1720, and weight average molecular weight is 10,500;
Oil phase is injected to water under liquid level, after stirring and emulsifying 1h, change supernatant, add ethanol, in water, the content of ethanol is 30wt% ethanol, and the room temperature lower magnetic force is changed supernatant after stirring 1h, continues to stir 10h;
Sucking filtration, collect microsphere final vacuum drying, the biodegradable microspheres preparation that contains olanzapine, and the smooth rounding of thus obtained microsphere, particle diameter is 30 ~ 120 μ m; The percentage by weight of each component is as follows:
Olanzapine 37.4%
Release regulator 16.7%
PLGA 45.9%
Drug loading is 37.4%;
Detection method is with embodiment 1.
The first Tiantu is interpreted as cumulative release 84.7% in 2.4%, 45 day.Referring to Fig. 1.
Embodiment 4
The preparation of olanzapine microsphere
Take 0.3g PLGA(molecular weight 4,3625, LA:GA is 85:15) and the 0.2g olanzapine, be dissolved in the mixed solvent (volume ratio 1:20) of 7g dichloromethane and N-methyl-ketopyrrolidine, add 0.08g polyox-yethylene-polyoxypropylene block copolymer (trade name Pluronic F127), mix homogeneously, obtain oil phase;
Take 6g PVA in the 600g distilled water, dissolve, be chilled to room temperature, after adding the 1.5gNaCl stirring and dissolving, with NaOH, regulate water PH to 7.5, add stirrer, under water bath condition, make it keep 15 ℃;
The average alcoholysis degree of PVA is 90%, and the average polymerization chain number is 1750, and weight average molecular weight is 20,000;
Described oil phase is injected to water under liquid level, after stirring and emulsifying 1h, change supernatant, add ethanol, in water, the content of ethanol is 15wt%, after the room temperature lower magnetic force stirs 1h, changes supernatant, continues to stir 4h;
Sucking filtration, collect microsphere and be placed on drying in exsiccator, and desiccant is phosphorus pentoxide, obtains the described biodegradable microspheres preparation that contains olanzapine; The smooth rounding of thus obtained microsphere, particle diameter is 30 ~ 120 μ m;
The percentage by weight of each component is as follows:
Olanzapine 31.5%
Release regulator 13.8%
PLGA 54.7%
Drug loading is 31.5%;
Detection method is with embodiment 1.
The first Tiantu is interpreted as cumulative release 88.7% in 1.5%, 28 day.Referring to Fig. 3.
The preparation of olanzapine microsphere
Take 0.3g PLGA(molecular weight 2,0682, LA:GA is 75:15) be dissolved in 6.5g chloromethanes and N-methyl-ketopyrrolidine mixed solvent (volume ratio 1:20) with the 0.2g olanzapine, add the 0.1g Labraso, mix, obtain oil phase;
Take 5g PVA in the 500g distilled water, dissolve, be chilled to room temperature, after adding the 1.5gNaCl stirring and dissolving, with NaOH, regulate water PH to 7.5, add stirrer, under water bath condition, make it keep 15 ℃;
The average alcoholysis degree of PVA is 87%, and the average polymerization chain number is 1700, and weight average molecular weight is 10,000;
Oil phase is injected to water under liquid level, after stirring and emulsifying 1h, change supernatant, add ethanol, in water, the content of ethanol is 15wt%, after the room temperature lower magnetic force stirs 1h, changes supernatant, continues to stir 8h;
Sucking filtration, collect microsphere and be placed on drying in exsiccator, and desiccant is phosphorus pentoxide, obtains the described biodegradable microspheres preparation that contains olanzapine; The smooth rounding of thus obtained microsphere, particle diameter is 30 ~ 120 μ m; The percentage by weight of each component is as follows:
Olanzapine 31.5%
Release regulator 16.7%
PLGA 51.8%
Drug loading is 31.5%;
Detection method is with embodiment 1.
The first Tiantu is interpreted as cumulative release 92.7% in 2.3%, 14 day.Referring to Fig. 1.
The comparative example 1
The preparation of olanzapine microsphere
Take PLGA(molecular weight 68,457, LA:GA is 75:25) 0.3g and olanzapine 0.2g be dissolved in 6.5g dichloromethane and N-methyl-ketopyrrolidine mixed solvent (volume ratio 1:5), mixes, and obtains oil phase;
Take 5g PVA in the 500g distilled water, dissolve, be chilled to room temperature, regulate water PH to 7.5 with NaOH after adding the 1.5gNaCl stirring and dissolving, add stirrer, under water bath condition, make it keep 5 ℃;
The average alcoholysis degree of PVA is 87%, and the average polymerization chain number is 1750, and weight average molecular weight is 10,000;
Oil phase is injected to water under liquid level, change supernatant after stirring and emulsifying 1h, add ethanol, in water, the content of ethanol is 20wt%, and the room temperature lower magnetic force is changed supernatant after stirring 1h, continues to stir 24h;
Sucking filtration, carry out lyophilization after the collection microsphere, obtains the described biodegradable microspheres preparation that contains olanzapine, the smooth rounding of thus obtained microsphere; Particle diameter is 30 ~ 120 μ m; The percentage by weight of each component is as follows:
Olanzapine 29.7%
PLGA 70.3%
Drug loading is 32.1%;
Detection method is with embodiment 1..
The first Tiantu is interpreted as cumulative release 87.6% in 10.6%, 35 day.Referring to Fig. 6.
The comparative example 2
The preparation of olanzapine microsphere
Take PLGA(molecular weight 68,457, LA:GA is 75:25) 0.3g and olanzapine 0.2g be dissolved in 6.5g dichloromethane and N-methyl-ketopyrrolidine mixed solvent (volume ratio 1:5), mixes, and obtains oil phase;
Take 5g PVA in the 500g distilled water, dissolve, be chilled to room temperature, regulate water PH to 7.5 with NaOH after adding the 1.5gNaCl stirring and dissolving, add stirrer, under water bath condition, make it keep 15 ℃;
The average alcoholysis degree of PVA is 87%, and the average polymerization chain number is 1750, and weight average molecular weight is 10,000;
Oil phase is injected to water under liquid level, change supernatant after stirring and emulsifying 1h, add ethanol, in water, the content of ethanol is 20wt%, and the room temperature lower magnetic force is changed supernatant after stirring 1h, continues to stir 24h;
Sucking filtration, carry out lyophilization after the collection microsphere, obtains the described biodegradable microspheres preparation that contains olanzapine, the smooth rounding of thus obtained microsphere; Particle diameter is 30 ~ 120 μ m; The percentage by weight of each component is as follows:
Olanzapine 30.7%
PLGA 69.3%
Drug loading is 30.7%;
Detection method is with embodiment 1.
The first Tiantu is interpreted as cumulative release 74.4% in 2.3%, 35 day.Referring to Fig. 6.
From Fig. 1～6, olanzapine microsphere (Fig. 6) release characteristics that does not add release regulator is undesirable, and rate of release is too fast or sluggishness is arranged, and can not realize the constant release of 1 month of medicine.By adding amphipathic micromolecular compound or high molecular polymer as release regulator, regulate use amount, select suitable PLGA material, can prepare to discharge and stablize, effectively discharge the desirable olanzapine microball preparation (Fig. 1 ~ 5) of 14 ~ 45 days.
Claims (14)
1. contain the biodegradable microspheres preparation of olanzapine, it is characterized in that, comprise the component of following percentage by weight:
Olanzapine or its salt 10 ~ 50%
Release regulator 0.5 ~ 20%
PLGA 30～89.5%。
2. the biodegradable microspheres preparation that contains olanzapine according to claim 1, is characterized in that, particle diameter is 30 ~ 150 μ m.
3. contain the biodegradable microspheres preparation of olanzapine, it is characterized in that, comprise the component of following percentage by weight:
Olanzapine or its salt 30～38%
Release regulator 5～17%
PLGA 45～59%。
4. the biodegradable microspheres preparation that contains olanzapine according to claim 2, is characterized in that, particle diameter is 30 ~ 120 μ m.
5. according to the described biodegradable microspheres preparation that contains olanzapine of claim 1～4 any one, it is characterized in that, described release regulator is selected from more than one of tricaprylin, oleic acid polyethyleneglycol glyceride, Gelucire 44/14, Labraso, polyoxyethylene ~ polyoxypropylene block copolymers, dimyristoyl phosphatidyl choline (DMPC), dipalmitoyl phosphatidyl choline (DPPC), DSPC (DSPC).
6. the biodegradable microspheres preparation that contains olanzapine according to claim 5, is characterized in that, the weight average molecular weight of PLGA is 10,000 ~ 150,000 dalton; Preferably, the weight average molecular weight of PLGA is 50,000 ~ 90,000 dalton;
Monomer lactic acid: hydroxyacetic acid (LA: GA)=10: 90 ~ 90: 10, mol ratio; Preferably, LA: GA=75: 25 ~ 85: 15, mol ratio.
7. according to the described biodegradable microspheres preparation that contains olanzapine of claim 1～4 any one, it is characterized in that, described olanzapine salt comprises olanzapine palmoxiric acid salt, olanzapine maleate, olanzapine malonate, olanzapine benzene olanzapine formates, olanzapine tartrate, olanzapine tosilate, olanzapine naphthalene sulfonate, mandelate, olanzapine diphenyl sulfonate or olanzapine dimethanesulfonate.
8. the biodegradable microspheres preparation that contains olanzapine according to claim 6, it is characterized in that, described olanzapine salt comprises olanzapine palmoxiric acid salt, olanzapine maleate, olanzapine malonate, olanzapine benzene olanzapine formates, olanzapine tartrate, olanzapine tosilate, olanzapine naphthalene sulfonate, mandelate, olanzapine diphenyl sulfonate or olanzapine dimethanesulfonate.
9. the method for the described biodegradable microspheres preparation that contains olanzapine of preparation claim 1～8 any one, is characterized in that, comprises the steps:
(1) PLGA and olanzapine or its salt are dissolved in to organic solvent, add release regulator, be uniformly mixed, obtain oil phase;
Described organic solvent is a kind of mixture in dichloromethane and ethyl acetate, butyl acetate, butyl formate, N-Methyl pyrrolidone, acetone, oxolane, benzyl alcohol, isopropyl alcohol, propylene glycol, dioxane or dimethyl sulfoxide, and volume ratio is 1: 1～1: 30;
(2) osmotic pressure regulator and PH regulator are added to the nonionic emulsifier aqueous solution, obtain water;
Described osmotic pressure regulator is selected from sodium chloride, sucrose or mannitol;
Described pH adjusting agent is selected from sodium hydroxide, phosphate or borate;
Described nonionic emulsifier is selected from more than one in polyvinyl alcohol, PVP, tween 80, tween 20, gelatin or tragcanth;
(3) under 10～20 ℃, oil phase is injected to water, stirring and emulsifying 0.5～1h, change supernatant, add short chain alcohol, stir 0.5～1h, change supernatant, continue to stir 3～5h, then collect microsphere from system, lyophilization, obtain the described biodegradable microspheres preparation that contains olanzapine;
Described short chain alcohol is selected from unit or the polyhydric alcohol of C1 ~ C3.
10. method according to claim 9, is characterized in that, the mixture that described organic solvent is dichloromethane and N-Methyl pyrrolidone, and volume ratio is 1: 2～1: 20.
11. method according to claim 10, is characterized in that, in described oil phase, the weight content of olanzapine or its salt is 10～50%, preferably 30～38%, and the weight content of PLGA is 40～70%, preferably 45～59%, the weight content of release regulator is 1～30%, preferably 5～17%.
12. method according to claim 9, is characterized in that, described nonionic emulsifier is polyvinyl alcohol, and alcoholysis degree is 87 ~ 90%, and the polymeric chain joint number is 1700 ~ 1750, and weight average molecular weight is 10,000 ~ 20,000; In water, the weight concentration of described osmotic pressure regulator is 0.1 ~ 10%, and is sodium chloride;
In water, the weight content of described nonionic emulsifier is 0.5% ~ 3%;
In water, the consumption of described pH adjusting agent is that to make the pH of water be 7.4～10.0.
13. method according to claim 9, is characterized in that, described short chain alcohol is ethanol and isopropyl alcohol, and in water, the weight concentration of short chain alcohol is 1 ~ 30wt%.
14. according to the described method of claim 9～13 any one, it is characterized in that, the weight ratio of organic solvent and water is 1: 80～120, preferably 1: 100.
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