CN100528224C - Slow release microphere for injection containing interferon alpha-1b and its preparation method - Google Patents
Slow release microphere for injection containing interferon alpha-1b and its preparation method Download PDFInfo
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- CN100528224C CN100528224C CNB2004100826944A CN200410082694A CN100528224C CN 100528224 C CN100528224 C CN 100528224C CN B2004100826944 A CNB2004100826944 A CN B2004100826944A CN 200410082694 A CN200410082694 A CN 200410082694A CN 100528224 C CN100528224 C CN 100528224C
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- alfacon
- microsphere
- slow release
- injection
- release microphere
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Abstract
The invention relates to slow release microballoons for injection of alpha-1b and the process for preparation, wherein the slow release microballoons comprise (by weight ratio), 0.1-10% (w/w) of interferon alpha-1b or its derivatives, 50-99.9% (w/w) of biodegradable and biologically compatible medicinal macromolecular material with a molecular weight between 5000-70000 Daltons. The microballoons can be prepared through W/O/W method, S/O/O method and spray-drying method.
Description
Technical field
The present invention relates to slow release microphere for injection of Alfacon-1 b and preparation method thereof.
Background technology
Find by retrieval, the preparation of Alfacon-1 b or derivatives thereof or salt has buccal tablet, solution, injection, patch, ointment etc., these dosage forms or since half-life of Alfacon-1 b shorter, cause eliminating very fast, or owing to non local use makes medicine on the low side and the whole body toxic and side effects is big at partial dose, clinical practice is restricted.
Summary of the invention
The technical problem to be solved in the present invention, purpose promptly of the present invention provides a kind of slow release microphere for injection of Alfacon-1 b or derivatives thereof.
Through research for a long time, the present inventor finds, to account for Alfacon-1 b or derivatives thereof and 50～99.9% (w/w) molecular weight of 0.1～10% (w/w) of microsphere weight 5,000～70, the pharmaceutical polymers of the biodegradable and bio-compatible between 000 dalton is made slow release microphere for injection by appropriate methodology, can realize above-mentioned purpose of the present invention.
Therefore, the invention provides a kind of slow release microphere for injection, it is characterized in that it comprises in microsphere weight, 0.1 Alfacon-1 b or derivatives thereof and 50～99.9% (w/w) molecular weight of～10% (w/w) is 5,000～70, biodegradable between 000 dalton and have the pharmaceutical polymers of biocompatibility, the mean diameter of described microsphere is between 10～100 μ m.
Slow release microphere for injection of the present invention can prepare by the either party's method in the following method.
Multi-emulsion method, it is characterized in that after an amount of Alfacon-1 b or derivatives thereof and stabilizing agent dissolving or being suspended in the aqueous solution that contains nonionic emulsifier, join in the organic solution that contains described pharmaceutical polymers, after treatment, join the outer aqueous phase that contains nonionic emulsifier again and form microsphere.
No water law, it is characterized in that the micropowder of an amount of Alfacon-1 b or derivatives thereof and stabilizing agent thereof is joined in the organic solvent of pbz polymer material, behind the ultrasonic suspendible of water-bath, join again in a certain amount of Oleum Gossypii semen, make it be solidified into microsphere with the decentralized photo extraction, add light petroleum ether then, make the microsphere completion of cure.
The cold nebulization extraction method, it is characterized in that an amount of Alfacon-1 b or derivatives thereof powder suspension in being dissolved with the organic solvent of macromolecular material, form droplet by spraying, freezing in liquid nitrogen, make with low temperature organic cosolvent extracting dissolve polymer.
The phase coacervation after it is characterized in that an amount of Alfacon-1 b or derivatives thereof is scattered in suitable macromolecule material solution, adds flocculating agent in this solution, the macromolecular material dissolubility is reduced and separate out, and forms good microsphere.
Sustained-release micro-spheres of the present invention also can be by after being prepared into liposome with Alfacon-1 b or derivatives thereof earlier, and the described pharmaceutical polymers that reuse is fit to is rolled into the method preparation of microsphere.
Sustained-release micro-spheres of the present invention also can be by after being prepared into nanoparticle with Alfacon-1 b or derivatives thereof earlier, and the described pharmaceutical polymers that reuse is fit to is rolled into the method preparation of microsphere.
Sustained-release micro-spheres of the present invention also can be by joining Alfacon-1 b or derivatives thereof solution in the micropowder silica gel, and after fully being adsorbed by micropowder silica gel, the described pharmaceutical polymers that reuse is fit to is rolled into the method preparation of microsphere.
Alfacon-1 b derivant of the present invention comprise various Alfacon-1 b salt, PEGization, methylate and the derivant of the various Alfacon-1 b that modify with other group.
Pharmaceutical polymers of the present invention is a gelatin, albumin, polylactide-co-glycolide, polylactic acid, polyglycolic acid, poly--the 3-butyric ester, poly-adjacent ester, polyanhydride, poly butyric ester-hydroxyl pentanoate copolymer, the polypropylene glucosan, polylactone, polyvinyl alcohol (PVA), Polyethylene Glycol (PEG), hydroxyacetic acid, polylactic acid-polyglycol, polylactic acid-glycolic guanidine-acetic acid copolymer (PLGA), a kind of in polyglycolic acid-Polyethylene Glycol or two or more mixture wherein.
Be preferably polylactic acid, polylactide-co-glycolide, polylactic acid-glycolic guanidine-acetic acid copolymer or poly butyric ester-hydroxyl pentanoate copolymer.
More preferably molecular weight is 5,000～70, polylactic acid-glycolic guanidine-acetic acid copolymer between 000 dalton, wherein the ratio of lactic acid and hydroxyacetic acid is 20: 80～80: 20, perhaps molecular weight is 5, polylactide-co-glycolide between 000～70,000 dalton, wherein the polymerization ratio of lactide and Acetic acid, hydroxy-, bimol. cyclic ester is 20: 80～80: 20.
Injectable microsphere of the present invention also can comprise pharmaceutically acceptable protein stabiliser, surfactant and other additives etc.
Described protein stabiliser is selected from HSA, mannitol, trehalose, EDTA, Zn salt, Mg (OH)
2, CaCO
3, ZnCO
3Deng.
Described surfactant is selected from poloxamer, lecithin, Macrogol 2000 or Polyethylene Glycol 5000 etc.
Described other additives are selected from micropowder silica gel, carry positive ionic material such as aminoacid etc.
Microball preparation envelop rate of the present invention is greater than 75%, and sustainable release reduced the medication number of times about 15 days, 30 days or 60 days, improved bioavailability, reduced systemic toxic side effect, increased patient compliance.
The specific embodiment
Further specify the preparation method of the slow release microphere for injection of Alfacon-1 b or derivatives thereof of the present invention by the following examples.
Embodiment 1: multi-emulsion method prepares recombinantinterferon-1b sustained-release micro-spheres
(about 5mg is with Zn with a certain amount of Alfacon-1 b
2+In conjunction with the back) be dissolved in the 0.5ml20mg/ml gelatin solution and (contain EDTA, 10% mannitol or trehalose, Mg (OH)
2, CaCO
3Or ZnCO
3Micropowder etc.) in, after 5000rpm stirs 30s, join among the dichloromethane solution 1.25ml that contains 150mgPLGA (molecular weight is 5000～70,000), under the rotating speed of 5000rpm, stirred 2 minutes, joining 20ml then contains in the aqueous solution of 6%PVA/PEG, with 200rpm speed magnetic agitation 5 minutes, and then join in the 500ml aqueous solution that contains 2% PVA/PEG, stir and carry out solvent evaporates, washing, centrifugal, lyophilization then collected promptly.
Embodiment 2: anhydrous legal system is equipped with recombinantinterferon-1b sustained-release micro-spheres
The about 150mg of PLGA is dissolved among acetonitrile or the ethyl acetate 1ml, then to the micropowder that wherein adds Alfacon-1 b or derivatives thereof and stabilizing agent thereof, behind the ultrasonic suspendible of water-bath, join in the Oleum Gossypii semen (containing lecithin or poloxamer etc.) of 20-30ml as emulsifying agent, stirring and emulsifying, the acetonitrile solution that constantly extracts in the emulsion droplet with decentralized photo makes it be solidified into microsphere, add light petroleum ether (boiling point 60-90 ℃) then, continue to stir and to make the microsphere completion of cure, centrifugal, petroleum ether, lyophilization are promptly.
Embodiment 3: the cold nebulization extraction method prepares recombinantinterferon-1b sustained-release micro-spheres
Alfacon-1 b or derivatives thereof powder suspension is in being dissolved with the organic solvent of macromolecular material, freezing in liquid nitrogen by spraying to such an extent that method forms droplet, get solvent promptly with a low temperature organic cosolvent (for example ethanol) extracting dissolve polymer.
Embodiment 4: be rolled into microsphere again after making liposome earlier
Adopt film dispersion method or freeze-drying etc. to prepare Alfacon-1 b liposome, then the liposome powder after an amount of lyophilization is joined among the dichloromethane solution 1ml of 100mg/ml PLGA, behind ultrasonic/stirring suspendible, join among the aqueous solution 15ml of PVA, join in the dilution PVA solution of 200ml after stirring 5min with the rotating speed of about 2000rpm, after continue stirring 4h with the slow-speed of revolution, washing, centrifugal, lyophilization are promptly.
Embodiment 5: be rolled into microsphere again after making nanoparticle earlier
After adopting natural polymer method and emulsion polymerization method to be prepared into nano-granule freeze-dried powder, join among the dichloromethane solution 1ml of 100mg/ml PLGA, behind ultrasonic/stirring suspendible, join among the aqueous solution 15ml of PVA, join in the dilution PVA solution of 200ml after stirring 5min with the rotating speed of about 2000rpm, after continue stirring 4h with the slow-speed of revolution, washing, centrifugal, lyophilization are promptly.
Embodiment 6: be rolled into microsphere again after micropowder silica gel absorption
Earlier Alfacon-1 b buffer is joined in the micropowder silica gel; after fully being adsorbed by micropowder silica gel; add freeze drying protectants such as mannitol; after lyophilization is prepared into lyophilized powder, join in the dichloromethane solution of 100mg/ml PLGA, join among the PVA aqueous solution 15ml behind ultrasonic/stirring suspendible; join after the rotating speed stirring and emulsifying with about 2000rpm in the PVA solution of dilution; continue to stir 4h with the slow-speed of revolution, solvent flashing, after washing, centrifugal, the lyophilization promptly.
Embodiment 7: the phase coacervation prepares microsphere
Alfacon-1 b lyophilized powder or Alfacon-1 b solution are joined in the PLGA dichloromethane solution of 150mg/ml in right amount, and behind the rotating speed stirring 1min with about 2000rpm, the reduction rotating speed is 200rpm, and injects silicone oil.After being separated, suspension is changed in the hexane of 500ml, after 20 ℃ of rotating speeds with about 300rpm of constant temperature stir 30min, collect microsphere, the 500ml hexane wash, lyophilization is promptly.
The mensuration of microspherulite diameter
Test specimen: according to the microsphere of the embodiment of the invention 1,2,3,4,5,6,7 methods preparation.
Experimental apparatus: the optical microscope or the laser granulometry of band graduated eyepiece.
Experimental technique:
Light microscope determining: will observe down with last embodiment microsphere at microscope (laser counter) behind the microsphere powder homodisperse, and write down microspherulite diameter, the microsphere sum is no less than 200, and data are carried out statistical disposition, investigates the mean diameter and the particle size distribution situation of microsphere.
Laser granulometry is measured: take by weighing suitable laboratory sample, use laser granulometry to measure.
The mensuration of microsphere drug loading and envelop rate
Test specimen: according to the microsphere of the embodiment of the invention 1,2,3,4,5 methods preparation.
Experiment reagent: BCA determining the protein quantity test kit, NaOH, SDS
Experimental apparatus: ultraviolet spectrophotometer, vortex instrument, centrifuge
Experimental technique: precision takes by weighing the about 10mg of laboratory sample, adds in the mixed solution of 5.0ml 0.1MNaOH/0.5SDS (w/v), and 37 ℃ of water-baths vibration 24h dissolve microsphere fully, adds the about 280 μ l of 2MHCL and transfers pH about 7.0, carries out BCA method determining the protein quantity.
Microsphere prominent released the mensuration with release profiles
Laboratory sample: according to the microsphere of the embodiment of the invention 1,2,3 described method preparations.
Experiment reagent: pH is 7.4 phosphate buffer (contain 0.02% Hydrazoic acid,sodium salt as antibacterial, the 0.02%F-68 wetting agent is as release medium)
Experimental apparatus: constant temperature shaker, centrifuge, HPLC instrument.
Experiment condition: temperature: 37 ℃, rotating speed: rpm.
Experimental technique: precision takes by weighing pastille microsphere 10-30mg and puts in the 10ml centrifuge tube, adds 1.5ml10mM pH 7.4 buffer, places the water bath with thermostatic control shaking table, carries out the release in vitro degree of microsphere and measure under 100rpm hunting speed, 37 ℃ ± 0.5 ℃ temperature conditions.
Sampling method: take out centrifuge tube at 2h, 1d, 2d respectively, in the centrifugal 10min of 2000rpm,, took a sample once with above operational approach every 3-4 days later on, and measure the content of IFN with the BCA method with the release medium that whole release medium are taken out and more renewed.
Microsphere is measured at the intravital sustained release property of mice
Laboratory sample: according to the microsphere of the embodiment of the invention 1,2,3 described method preparations.
Laboratory animal: Kunming mouse
Experimental technique: get healthy Kunming mouse, after the random packet, vein gives the microspheres solution of rIFN α, and dosage is 1.5 * 10
4KU rIFN α/kg, 0,1,2,5,8,10,12,15 day eye socket is got blood after administration, and blood sample is got supernatant and is measured wherein IFN-α biological activity behind the centrifugal 15min of 3000rpm.
The bioactive assay method of Alfacon-1 b
Laboratory sample: plasma sample.
Experimental apparatus: freezer dryer, centrifuge.
Experimental technique: the bioactive mensuration of Alfacon-1 b: WISH cell through 0.25% trypsinization, is made into 2.5 * 10 with complete culture solution
5-3.5 * 10
5Individual cell/ml is inoculated in 96 porocyte culture plates, every hole 100 μ l.37 ℃, 5%CO
2Cultivated 4-6 hour under the condition, supernatant discarded, to disturb plain α-1b sample solution and standard solution and carry out adding 1-12 hole (sample solution that concentration is high dilutes in advance) from high to low by concentration behind the doubling dilution, set up the contrast of cell contrast and virus control and sample blank simultaneously.Similarity condition was cultivated 18-24 hour, and supernatant discarded adds VSV counteracting toxic substances culture fluid (dosage 100TCID50) 100 μ l, counteracting toxic substances 24 hours, and microscopy cell 50% pathological changes point under the inverted microscope, calculating is disturbed plain α-1b and is tired.
Claims (7)
1. slow release microphere for injection, it is characterized in that it comprises in microsphere weight, 0.1 the Alfacon-1 b of～10% (w/w) or its derivant and 50～99.9% (w/w) molecular weight of being selected from salt, the PEGization Alfacon-1 b of Alfacon-1 b or the Alfacon-1 b that methylates are 5,000～70, biodegradable between 000 dalton and have the pharmaceutical polymers of biocompatibility, the mean diameter of described microsphere is between 10～100 μ m.
2. according to the slow release microphere for injection of claim 1, wherein said pharmaceutical polymers is selected from a kind of in gelatin, albumin, polylactic acid, polyglycolic acid, poly--the 3-butyric ester, poly-adjacent ester, polyanhydride, poly butyric ester-hydroxyl pentanoate copolymer, polypropylene glucosan, polylactone, polyvinyl alcohol, Polyethylene Glycol, polylactic acid-glycolic guanidine-acetic acid copolymer and the polyglycolic acid-Polyethylene Glycol or two or more mixture wherein.
3. according to the slow release microphere for injection of claim 2, wherein said pharmaceutical polymers is a polylactic acid-glycolic guanidine-acetic acid copolymer, and wherein molecular weight is 5,000～70, and between 000 dalton, the ratio of lactic acid and hydroxyacetic acid is 20: 80～80: 20.
4. one kind prepares any one the method for slow release microphere for injection of claim 1 to 3, it is characterized in that the micropowder of an amount of Alfacon-1 b or described its derivant and stabilizing agent thereof is joined in the organic solvent of pbz polymer material, behind the ultrasonic suspendible of water-bath, join again in a certain amount of Oleum Gossypii semen, make it be solidified into microsphere with the decentralized photo extraction, add light petroleum ether then, make the microsphere completion of cure.
5. one kind prepares any one the method for slow release microphere for injection of claim 1 to 3, and it is characterized in that earlier will an amount of Alfacon-1 b or after described its derivant was prepared into liposome, the suitable described pharmaceutical polymers of reuse was rolled into microsphere.
6. one kind prepares any one the method for slow release microphere for injection of claim 1 to 3, and it is characterized in that earlier will an amount of Alfacon-1 b or after described its derivant was prepared into nanoparticle, the suitable described pharmaceutical polymers of reuse was rolled into microsphere.
7. one kind prepares any one the method for slow release microphere for injection of claim 1 to 3, it is characterized in that an amount of Alfacon-1 b or described its derivative solution are joined in the micropowder silica gel, after fully being adsorbed by micropowder silica gel, the described pharmaceutical polymers that reuse is fit to is rolled into microsphere.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNB2004100826944A CN100528224C (en) | 2004-09-27 | 2004-09-27 | Slow release microphere for injection containing interferon alpha-1b and its preparation method |
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|---|---|---|---|
| CNB2004100826944A CN100528224C (en) | 2004-09-27 | 2004-09-27 | Slow release microphere for injection containing interferon alpha-1b and its preparation method |
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| CN1754572A CN1754572A (en) | 2006-04-05 |
| CN100528224C true CN100528224C (en) | 2009-08-19 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UY33517A (en) * | 2010-07-19 | 2012-02-29 | Astrazeneca Ab | Pharmaceutical depot for 5-fluoro-2 - [[(1S) -1- (5-fluoro-2-pyridyl) ethyl] amino] -6 - [(5-isopropoxy-1H-pyrazol-3-yl) amino] pyridin -3-carbonitrile ?. |
| CN105878191B (en) * | 2016-04-26 | 2021-01-22 | 广州帝奇医药技术有限公司 | Preparation method of sustained-release microparticles, prepared sustained-release microparticles and application thereof |
| CN105878190B (en) * | 2016-04-26 | 2021-01-22 | 广州帝奇医药技术有限公司 | Preparation method of sustained-release microparticles, prepared sustained-release microparticles and application thereof |
| KR20220104797A (en) | 2019-11-25 | 2022-07-26 | 리제너론 파마슈티칼스 인코포레이티드 | Sustained release formulation using non-aqueous emulsion |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1154653A (en) * | 1994-07-25 | 1997-07-16 | 阿尔克姆斯控制治疗公司 | Controlled release of metal cation-stabilized interferon |
| WO1999020301A1 (en) * | 1997-10-18 | 1999-04-29 | Boehringer Ingelheim International Gmbh | Tumour vaccine |
-
2004
- 2004-09-27 CN CNB2004100826944A patent/CN100528224C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1154653A (en) * | 1994-07-25 | 1997-07-16 | 阿尔克姆斯控制治疗公司 | Controlled release of metal cation-stabilized interferon |
| US6379701B1 (en) * | 1994-07-25 | 2002-04-30 | Alkermes Controlled Therapeutics, Inc. | Controlled release of metal cation-stabilized interferon |
| WO1999020301A1 (en) * | 1997-10-18 | 1999-04-29 | Boehringer Ingelheim International Gmbh | Tumour vaccine |
Non-Patent Citations (6)
| Title |
|---|
| Biodegradable micro- and nanoparticles as long-term deliveryvehicles for interferon-alpha. Alejandro Sanchez, Maria Tobio, Libia Gonzalez, et al.European Journal of Pharmaceutical Sciences,Vol.18 . 2003 |
| Biodegradable micro-and nanoparticles as long-term deliveryvehicles for interferon-alpha. Alejandro Sanchez, Maria Tobio, Libia Gonzalez, et al.European Journal of Pharmaceutical Sciences,Vol.18. 2003 * |
| Stabilization of recombinant interferon-α by pegylation forencapsulation in PLGA microspheres. Manish Diwan, Tae Gwan Park.International Journal of Pharmaceutics,Vol.252 . 2003 |
| Stabilization of recombinant interferon-αby pegylation for encapsulation in PLGA microspheres. Manish Diwan1&Tae Gwan Park.International Journal of Pharmaceutics,Vol.252 . 2003 |
| 重组人干扰素α长效注射微球的研究. 吴诚，7,18-20,33,63. 2004 |
| 重组人干扰素α长效注射微球的研究. 吴诚，7,18-20,33,63. 2004 * |
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| CN1754572A (en) | 2006-04-05 |
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