CN100400032C - Method for preparing oil soluble medicine slow releade micro ball - Google Patents
Method for preparing oil soluble medicine slow releade micro ball Download PDFInfo
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- CN100400032C CN100400032C CNB2004100664579A CN200410066457A CN100400032C CN 100400032 C CN100400032 C CN 100400032C CN B2004100664579 A CNB2004100664579 A CN B2004100664579A CN 200410066457 A CN200410066457 A CN 200410066457A CN 100400032 C CN100400032 C CN 100400032C
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Abstract
The present invention discloses a method for preparing a sustained release microsphere of an oil soluble medicine. In the method, water solution of polyvinyl alcohol (PVA), water solution of polyethylene glycol (PEG) or distilled water is used as a water phase; polylactic acid-polyethylene glycol copolymer (PLA-PEG) and medicine acetone solution are used as oil phases. The oil phases are added in the water phase under the stirring action to naturally volatilize so as to remove acetone; then, the mixture is put in a dialysis bag to be dialyzed in order to remove medicines which are not packed or sealed. When the particle diameter of the microsphere of the present invention is less than 150 nanometers, the microsphere of the present invention can be controlled; the microsphere has certain performance of sustained release.
Description
Technical field
The present invention relates to a kind of preparation method of oil soluble medicine slow releade micro ball, especially dissolve in the preparation method of the water-fast oil soluble medicine slow releade micro ball of acetone.
Background technology
Macromolecular material is used for biomedicine and pharmaceutical field more and more, wherein is most widely used with biodegradable polymer especially.They have and can be had following three big advantages by animal and the metabolic function of absorption of human body: 1. mainly by the degradation rate control of carrier, less to the dependence of pharmaceutical properties, the isoparametric range of choice of medicine parcel amount and geometry is wider for sustained release rate.2. rate of release is more stable.In the DIFFUSION CONTROLLED delivery systme, rate of release generally all can be successively decreased in time.If use degradation material to make carrier, along with the degraded of material, the permeability of medicine is accelerated, the reduction that can offset diffusion rate.In ideal conditions, rate of release can be kept constant, reaches zero level release dynamics pattern.2. be more suitable for the release request of labile drug.In the delivery systme of not degrading, the release of medicine at first diffuses to carrier inside by water, dissolved substance, and formation solution spreads and discharges.And in the degradable system, because the degradability of carrier, drug release need not be by this long process, and the time that drug microparticles is detained in solution is shorter.The phenomenon that some decompose, precipitate or gather such as polypeptide, the unlikely appearance of protein-based unsettled medicine.
In recent years, very fast about the research and development of biodegradable polymers, researcheres have been grasped the Biodegradable material that has different degradation rates in a large number.As polyesters such as polylactic acid, polycaprolactone, polyglycolic acid and copolymers thereof, polyamide, poly-anhydride, poly phosphate, poe etc.The applied research that with the biodegradable polymer is the medicament slow release system of matrix appears in the newspapers in recent years repeatly.Medicine can also can be present in the matrix by valence bond and main polymer chain or the strong form of closing of side chain with the dispersive state of physics.Drug release process is subjected to influencing jointly of factors such as chemistry, diffusion, environment.Preparation and sustained release performance to sustained-release micro-spheres such as cancer therapy drugs have more report.
Fenofibrate (fenofibrate) is a kind of clofibrate lipid lowerers; its chemical name is: 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) isopropyl propionate; its chemical name is: 2-methyl-2-(4-(4-chlorobenzene formacyl) phenoxy group) isopropyl propionate, about 4～7 hours blood drug level peakings in oral back.Long-term prescription can cause to be accumulated.Therefore, be necessary to improve its bioavailability, eliminate its release peak value, reach slowly stable and discharge.
Preparation for the fenofibrate microsphere does not at present appear in the newspapers, and common formulations is fenofibrate tablet and lipanthyl capsule.But the two all has the release peak, has the violent release phenomenon, so the inventor wishes to obtain discharging stable slow releasing preparation.
Summary of the invention
The preparation method that the purpose of this invention is to provide a kind of oil soluble medicine slow releade micro ball makes oil-soluble medicine obtain stable release.
The present invention takes following measures to achieve the above object: a kind of preparation method of oil soluble medicine slow releade micro ball, water adopts polyvinyl alcohol water solution or Polyethylene Glycol aqueous solution or distilled water itself, oil phase adopts polylactic acid-polyglycol copolymer and medicine acetone soln, oil phase is added aqueous phase, naturally acetone is removed in volatilization, puts it into to dialyse in the bag filter to remove not entrapped drug acquisition oil soluble medicine slow releade micro ball again.
When the aqueous phase described in the present invention adopted polyvinyl alcohol, polyvinyl alcohol water solution concentration was 1～20%, and the polyvinyl alcohol alcoholysis degree is higher than 88%; When water adopted Polyethylene Glycol, the Polyethylene Glycol concentration of aqueous solution was 1～20%, and Polyethylene Glycol PEG molecular weight is 2000～10000.
Better, copolymer concentration is 1～50g/l in the described oil phase.
Better, the drug level of described medicine acetone soln is 0.1～10g/l.
Better, medium oil water volume ratio of the present invention is 0.1～2.5.
Better, the copolymer described in the present invention in the oil phase can be polylactic acid, polycaprolactone, polyglycolic acid or its copolymer that forms mutually.
Better, the medicine of medicine acetone soln of the present invention is meant fenofibrate or toyomycin.
Modes such as employing stirring those skilled in the art will appreciate that oil phase adds in the process of water, if can be impelled the mixed more complete of oil phase and water; Oil phase adds in the process of water, and oil phase injects water fast also more makes both fully mixed than the slow water that splashes into of oil phase.
Parameters such as the kind of the kind that the present invention can be by telomerized polymer (or claim copolymer), the molecular weight of polymer formation component, copolymerization ratio, polymer concentration, oil-soluble medicine and drug level, water component, oil-water ratio control oil soluble medicine slow releade micro ball footpath grain thickness, entrapment efficiency size, stablize the length of release time, to satisfy more needs.For example can obtain the less sustained-release micro-spheres of particle diameter by reducing the profit volume; Water adopts Polyethylene Glycol, polyvinyl alcohol etc. can increase the stability of its microsphere emulsion, makes slow-release time longer; Increase the medicine concentration that feeds intake and to improve medicine parcel amount, but envelop rate descends.To the regulation and control of entrapment efficiency, slow-releasing, can satisfy in the application the different requirements of release amount of medicine with slow-release time etc.; To the regulation and control of medicine microspheres particle diameter, can satisfy the various requirement of different parts administration.
The invention has the beneficial effects as follows: preparation manipulation is simple, with the acetone is oil/water two-phase system, can obtain the stabilization medicines sustained-release micro-spheres, microsphere does not have adhesion, microsphere is a smooth, spherical, and discharge stability and be better than former medicine of fenofibrate and lipanthyl capsule, and sustained release performance is adjustable, can satisfy more instructions for use.Microspherulite diameter of the present invention is controlled below 150 nanometers, and has certain slow-releasing.
The specific embodiment
Be described in further detail below in conjunction with example, the example of being lifted below being to be understood that does not comprise all the elements of the present invention just in order to explain the present invention:
Embodiment 1
The polymer that oil phase adopts is the polylactic acid-polyglycol copolymer, and it is 4000 that polymer adopts molecular weight polyethylene glycol, and the copolymerization ratio is 4/1, intrinsic viscosity is the polylactic acid-polyglycol copolymer of 0.2175dl/g, concentration is 10g/l, and the fenofibrate drug level is 0.6694g/l, and water is a distilled water, the profit volume ratio is 1, under the 1000rpm stirring, when oil phase splashed into water, the thus obtained microsphere particle diameter was 83.1 ± 31nm, entrapment efficiency is 33.5%, sustainable stable release in 12 hours.
Embodiment 2
Copolymer concentration is 1g/l, and the fenofibrate drug level is 0.1014g/l, and other condition is with embodiment 1, and the thus obtained microsphere particle diameter is 68 ± 33nm.
Embodiment 3
Do not stir, other condition is with embodiment 2, and the thus obtained microsphere particle diameter is 4.005 ± 1.847 μ m, and medicine can not finely wrap up.
Embodiment 4
Adopt oil phase to inject the method for water, other condition is with embodiment 3, and the thus obtained microsphere particle diameter is 123 ± 19nm.
Embodiment 5
It is 4000 that polymer adopts molecular weight polyethylene glycol, and the copolymerization ratio is 5/1, and intrinsic viscosity is the polylactic acid-polyglycol copolymer of 0.3080dl/g, and copolymer concentration is 50g/l, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 138 ± 52nm, and the fenofibrate envelop rate is 50.9%, sustainable stable release in 12 hours.
Embodiment 6
It is 4000 that polymer adopts molecular weight polyethylene glycol, and the copolymerization ratio is 8/1, and intrinsic viscosity is the polylactic acid-polyglycol copolymer of 0.3415dl/g, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 88.8 ± 40nm, and the fenofibrate envelop rate is 38.2%, sustainable stable release in 12 hours.
Embodiment 7
It is 4000 that polymer adopts molecular weight polyethylene glycol, and the copolymerization ratio is 12/1, and intrinsic viscosity is the polylactic acid-polyglycol copolymer of 0.3408dl/g, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 95.9 ± 60nm, and the fenofibrate envelop rate is 17.5%, sustainable stable release in 12 hours.
Embodiment 8
It is 4000 that polymer adopts molecular weight polyethylene glycol, and the copolymerization ratio is 15/1, and intrinsic viscosity is the polylactic acid-polyglycol copolymer of 0.5001dl/g, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 96.7 ± 52nm, and the fenofibrate envelop rate is 55.3%, sustainable stable release in 12 hours.
Embodiment 9
It is 8000 that polymer adopts molecular weight polyethylene glycol, and the copolymerization ratio is 5/1, and intrinsic viscosity is the polylactic acid-polyglycol copolymer of 0.5901dl/g, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 83.9 ± 32nm, and the fenofibrate envelop rate is 19.7%, sustainable stable release in 25 hours.
Embodiment 10
Water is 1% Polyethylene Glycol-2000 aqueous solution, and polymer is a polycaprolactone, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 100.3 ± 30nm, and the fenofibrate envelop rate is 25.6%, sustainable stable release in 30 hours.
Embodiment 11
Water is 15% Polyethylene Glycol-4000 aqueous solution, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 104.6 ± 26nm, and the fenofibrate envelop rate is 32.8%, sustainable stable release in 31 hours.
Embodiment 12
Water is 20% Polyethylene Glycol-10000 aqueous solution, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 100.3 ± 30nm, and the fenofibrate envelop rate is 35.6%, sustainable stable release in 30 hours.
Embodiment 13
Water is 1% polyvinyl alcohol-1788 aqueous solution, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 99.4 ± 29nm, and the fenofibrate envelop rate is 26.8%, sustainable stable release in 30 hours.
Embodiment 14
Water is 15% polyvinyl alcohol-1788 aqueous solution, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 105.3 ± 29nm, and the fenofibrate envelop rate is 36.9%, sustainable stable release in 30 hours.
Embodiment 15
Water is 20% polyvinyl alcohol-1788 aqueous solution, and drug level is 5.5964g/l, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 115.6 ± 29nm, and the fenofibrate envelop rate is 16.9%, sustainable stable release in 30 hours.
Embodiment 16
Water is a distilled water, and the profit volume ratio is 0.1, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 75.8 ± 19nm, and the fenofibrate envelop rate is 18.6%, sustainable stable release in 12 hours.
Embodiment 17
Water is 20% polyvinyl alcohol-1788 aqueous solution, and drug level is 9.9825g/l, and the profit volume ratio is 2, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 133.8 ± 35nm, and the fenofibrate envelop rate is 10.5%, sustainable stable release in 30 hours.
Embodiment 18
Water is a distilled water, and the profit volume ratio is 2.5, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 148.9 ± 28nm, and the fenofibrate envelop rate is 20.7%, sustainable stable release in 12 hours.
Embodiment 19
Water is a distilled water, and polymer is polyglycolic acid-copolymer of poly lactic acid, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 86.6 ± 28nm, and the fenofibrate envelop rate is 39.6%, sustainable stable release in 12 hours.
Embodiment 20
Water is a distilled water, and medicine is a toyomycin, and drug level is 1g/l, and other conditions are with embodiment 1.The thus obtained microsphere particle diameter is 90.3 ± 21nm, and the toyomycin envelop rate is 28.7%, sustainable stable release in 15 hours.
Embodiment 21: the contrast experiment
Compare polylactic acid-polyglycol copolymer (molecular weight polyethylene glycol is 4000, and polylactic acid/Polyethylene Glycol copolymerization ratio is 5/1) fenofibrate and the former medicine of fenofibrate, the capsular sustained release performance of lipanthyl.Get 4ml microsphere emulsion and place bag filter, put into the phosphate buffered solution of PH=7.4, measure its sustained release performance under 37 ℃ of conditions.Experiment finds that the former medicine of fenofibrate, lipanthyl capsule all the drug release peak occurred in the time of 7～9 hours, and the attached fenofibrate microsphere of polymer bag has better release performance, can reach 30 hours stable releases.
Claims (7)
1. the preparation method of an oil soluble medicine slow releade micro ball, it is characterized in that: water adopts polyvinyl alcohol water solution or Polyethylene Glycol aqueous solution or distilled water itself, oil phase adopts polylactic acid-polyglycol copolymer and medicine acetone soln, oil phase is added aqueous phase, naturally acetone is removed in volatilization, puts it into to dialyse in the bag filter to remove not entrapped drug acquisition oil soluble medicine slow releade micro ball again.
2. the preparation method of a kind of oil soluble medicine slow releade micro ball according to claim 1 is characterized in that: when described water adopted polyvinyl alcohol water solution, polyvinyl alcohol water solution concentration was 1～20%, and the polyvinyl alcohol alcoholysis degree is higher than 88%.
3. the preparation method of a kind of oil soluble medicine slow releade micro ball according to claim 1 is characterized in that: when described water adopted the Polyethylene Glycol aqueous solution, the Polyethylene Glycol concentration of aqueous solution was 1～20%, and Polyethylene Glycol PEG molecular weight is 2000～10000.
4. according to the preparation method of claim 1 or 2 or 3 described a kind of oil soluble medicine slow releade micro balls, it is characterized in that: copolymer concentration is 1～50g/l in the described oil phase.
5. the preparation method of a kind of oil soluble medicine slow releade micro ball according to claim 4, it is characterized in that: the drug level of described medicine acetone soln is 0.1～10g/l.
6. the preparation method of a kind of oil soluble medicine slow releade micro ball according to claim 5, it is characterized in that: the profit volume ratio is 0.1～2.5.
7. the preparation method of a kind of oil soluble medicine slow releade micro ball according to claim 1, it is characterized in that: the medicine of described medicine acetone soln is meant fenofibrate or toyomycin.
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| CNB2004100664579A CN100400032C (en) | 2004-09-16 | 2004-09-16 | Method for preparing oil soluble medicine slow releade micro ball |
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| CN100400032C true CN100400032C (en) | 2008-07-09 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4223282A1 (en) * | 2022-02-08 | 2023-08-09 | Servizo Galego de Saude | Microspheres for extended release of fenofibrate |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100418537C (en) * | 2005-07-15 | 2008-09-17 | 同济大学 | Amphotericin B slow-releasing microsphere, and its prepn. method |
| CN1947721B (en) * | 2006-09-18 | 2011-01-26 | 厦门大学 | Method for preparing epirubicin slow-release prepn |
| NZ596610A (en) * | 2009-05-27 | 2014-04-30 | Samyang Biopharmaceuticals | A poorly soluble drug containing microsphere with improved bioavailability and method of preparing the same |
| CN101890016B (en) * | 2010-08-02 | 2011-10-26 | 郝志艳 | Piperacillin sodium-tazobactam sodium medicinal composition microsphere injection |
| CN106109441B (en) * | 2016-07-06 | 2018-08-07 | 广东岭南职业技术学院 | A kind of asparaginase microballoon and preparation method thereof |
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| CN1132758A (en) * | 1995-04-06 | 1996-10-09 | 中国科学院成都有机化学研究所 | High-molecular microglobe and its prepn and use |
| CN1140058A (en) * | 1996-03-29 | 1997-01-15 | 中国科学院成都有机化学研究所 | Slow-release microsphere powder injection of androgenic hormone, its preparing method and use |
| CN1398585A (en) * | 2002-07-15 | 2003-02-26 | 裴福兴 | Slow-releasing bFGF-PLA-PEG microball and its prepn and use |
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- 2004-09-16 CN CNB2004100664579A patent/CN100400032C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1132758A (en) * | 1995-04-06 | 1996-10-09 | 中国科学院成都有机化学研究所 | High-molecular microglobe and its prepn and use |
| CN1140058A (en) * | 1996-03-29 | 1997-01-15 | 中国科学院成都有机化学研究所 | Slow-release microsphere powder injection of androgenic hormone, its preparing method and use |
| CN1398585A (en) * | 2002-07-15 | 2003-02-26 | 裴福兴 | Slow-releasing bFGF-PLA-PEG microball and its prepn and use |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP4223282A1 (en) * | 2022-02-08 | 2023-08-09 | Servizo Galego de Saude | Microspheres for extended release of fenofibrate |
| WO2023152138A1 (en) | 2022-02-08 | 2023-08-17 | Servizo Galego De Saúde | Microspheres for extended release of fenofibrate |
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