CN102552166A - Preparation method for lysozyme/poly (alpha-cyano acrylic butyl ester) medicine loading microsphere - Google Patents
Preparation method for lysozyme/poly (alpha-cyano acrylic butyl ester) medicine loading microsphere Download PDFInfo
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- CN102552166A CN102552166A CN2012100041892A CN201210004189A CN102552166A CN 102552166 A CN102552166 A CN 102552166A CN 2012100041892 A CN2012100041892 A CN 2012100041892A CN 201210004189 A CN201210004189 A CN 201210004189A CN 102552166 A CN102552166 A CN 102552166A
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- lysozyme
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Abstract
The invention relates to a lysozyme/poly (alpha-cyano acrylic butyl ester) medicine loading microsphere and a preparation method for the lysozyme/poly (alpha-cyano acrylic butyl ester) medicine loading microsphere. The medicine loading microsphere is characterized by comprising components of deioned water, a surface activate agent, alpha-cyano acrylic butyl ester, lysozyme and a potential of hydrogen (pH) adjusting agent. The preparation steps comprise weighing quantitative surface active agent, adding the surface active agent into the deioned water, after the surface active agent is sufficiently dissolved, utilizing the pH adjusting agent to adjust a systematical pH value to be 2.5 or so, utilizing a syringe to slowly drop alpha-cyano acrylic butyl ester under magnetic stirring of 800r/min, continuously stirring the liquid for a while, then utilizing the pH adjusting agent to adjust the systematical pH value to be 6.5 or so, then adding the lysozyme with certain amount, continuously stirring the liquid for 3-4 hours, and then filtering the liquid with a microporous filter membrane of 0.45mum pore diameter, after performing centrifugation, cleaning and vacuum refrigeration drying on obtained suspension, finally obtaining the lysozyme/poly (alpha-cyano acrylic butyl ester) medicine loading microsphere. The microsphere is smooth in surface, even in particle size, high in encapsulation rate, long in release time, simple in preparation method, short in periodicity and suitable for industrialized production and application.
Description
Technical field
The present invention relates to a kind of method for preparing of medicine carrying microballoons, is carrier material to gather (isobutyl alpha-cyanoacrylate) specifically, seals medicine carrying microballoons of lysozyme and preparation method thereof.
Technical background
Lysozyme (lysozyme) is a kind of hydrolytic enzyme that acts on microorganism wall specially; Can cut off the β-1 between the-acetylmuramic acid and N-acetylglucosamine in the Peptidoglycan; Connection between 4 glycosidic bonds; Destroy the Peptidoglycan support, cell spalling under the effect that internal penetration is pressed causes the antibacterial cracking.Lysozyme medically has effects such as anti-inflammation, antiviral, enhancing immunity, but its half-life is short, needs frequent drug administration by injection, and patient's compliance is low; And its molecular weight is big, diffusion is poor, partition coefficient is little, and it is difficult to through biological barrier and lipid film, and bioavailability is low.Gather (a-cyanoacrylate) microsphere because it has advantages such as high absorption capacity, release persistence, hypotoxicity, excellent biodegradability and biocompatibility, make its very suitable each histoorgan that medicine is sent to health as drug delivery carrier.Utilization gathers (isobutyl alpha-cyanoacrylate) and is drug carrier material, and the preparation particle diameter both can have been transported medicine through blood brain barrier less than the microsphere of 200nm, can reach the effect of slow release again.Chinese patent CN1840184A has prepared lysozyme liposome by lysozyme, phospholipid and lipotropy stabilizing agent, and envelop rate is high, and sustained release performance is good, and bactericidal effect is remarkable, but in the preparation process, needs to use organic solvent, and environment is had certain harm.Though Chinese patent CN1425464A, CN1732962A, CN1416812A are that disperse medium, Polyalkylcyanoacrylanano are carrier material with water; The medicine carrying microballoons that has prepared load insulin, amycin or mitomycin, but do not see the Polyalkylcyanoacrylanano medicine carrying microballoons of load lysozyme medicine.
The present invention is a carrier material to gather (isobutyl alpha-cyanoacrylate); Poloxamer 188 (poloxamer-188), macrodex (Dextran70) or both share and are surfactant, adopt emulsion polymerization method to prepare lysozyme/gather (isobutyl alpha-cyanoacrylate) microsphere.Envelop rate can reach more than 60%, and carrying drug ratio can reach more than 6.0%, about mean diameter 170nm, and microsphere features smooth surface, sustained release performance is better, and production technology is simple, is convenient to suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of size evenly, can be through blood brain barrier, lysozyme is steadily discharged, lysozyme that bioavailability is high/the gather preparation technology of (isobutyl alpha-cyanoacrylate) medicine carrying microballoons.
To achieve these goals, the present invention reacts by following component (mass fraction):
The surfactant that the present invention uses share as poloxamer 188 (poloxamer-188), macrodex (Dextran70) or both.
The pH value regulator that the present invention uses is the hydrochloric acid of 0.1mol/L and the sodium hydroxide of 0.1mol/L.
The present invention also provides a kind of method for preparing of above-mentioned microsphere, and the concrete processing step of this method is following:
Take by weighing a certain amount of poloxamer 188 (poloxamer-188); Macrodex (Dextran70) or both add in the deionized water by a certain percentage; After treating that it fully dissolves, about 2.5, slowly drip the isobutyl alpha-cyanoacrylate monomer with syringe under the 800r/min magnetic agitation with the hydrochloric acid solution regulation system pH value of 0.1mol/L; Continue to stir 2～3h; 6.5, add a certain amount of lysozyme with the sodium hydroxide solution regulation system pH value of 0.1mol/L, room temperature continues to stir behind 3～4h the filtering with microporous membrane with 0.45 μ m aperture; The gained milk-white coloured suspension is centrifugal, after the washing, vacuum lyophilization, finally obtain lysozyme/gather (isobutyl alpha-cyanoacrylate) medicine carrying microballoons.
The present invention has the following advantages: 1) decomposition of active constituents of medicine is slow, and active component discharges lasting; 2) it is stronger to gather (isobutyl alpha-cyanoacrylate) absorbability, and medicine is adsorbed on factor affecting such as not being vulnerable to chemistry, light and microorganism on the microsphere and medicine is decomposed; 3) use deionized water to make solvent, reduce the harm of organic solvent; 4) medicine can pass through blood brain barrier, improves bioavailability of medicament.
Description of drawings
Fig. 1 is lysozyme/the gather transmission electron microscope photo of (isobutyl alpha-cyanoacrylate) microsphere.
Fig. 2 is lysozyme/the gather electron scanning micrograph of (isobutyl alpha-cyanoacrylate) microsphere.
Fig. 3 is lysozyme/the gather particle size distribution figure of (isobutyl alpha-cyanoacrylate) microsphere.
The specific embodiment
Below the present invention will be described in more detail through specific embodiment.Embodiment only is to a kind of explanation of the present invention, and is not construed as limiting the invention.
Embodiment 1
Taking by weighing poloxamer 188 (poloxamer-188) 0.6g adds in the 50ml deionized water; After treating that it fully dissolves, the hydrochloric acid solution regulation system pH value 2.0 with 0.1mol/L slowly drips isobutyl alpha-cyanoacrylate monomer 0.6g with syringe under the 800r/min magnetic agitation; Continue to stir 3h; Transfer system pH 6.5 with the sodium hydroxide solution of 0.1mo l/L, add the 40mg lysozyme, room temperature continues to stir behind 3～4h the filtering with microporous membrane with 0.45 μ m aperture; The gained milk-white coloured suspension is centrifugal, after the washing, vacuum lyophilization, finally obtain lysozyme/gather (isobutyl alpha-cyanoacrylate) medicine carrying microballoons.
The envelop rate 55.23% of this product, carrying drug ratio 6.30%, mean diameter 170nm, particle size dispersion coefficient 0.053, lysozyme activity remains unchanged basically, can reach (table 1) more than the 30h at normal saline Chinese medicine slow release.
The slow release of table 1 lysozyme/gather (isobutyl alpha-cyanoacrylate) microsphere
| Slow-release time/h | 0.5 | 1 | 2 | 3 | 4 | 8 | 12 | 24 | 30 | 48 |
| Lysozyme cumulative release rate/% | 31 | 45 | 53 | 65 | 74 | 77 | 80 | 87 | 89 | 90 |
Embodiment 2
Taking by weighing macrodex (Dextran70) 0.5g adds in the 50ml deionized water; After treating that it fully dissolves, the hydrochloric acid solution regulation system pH value 2.5 with 0.1mol/L slowly drips isobutyl alpha-cyanoacrylate monomer 0.6g with syringe under the 800r/min magnetic agitation; Continue to stir 3h; Transfer system pH 6.5 with the sodium hydroxide solution of 0.1mol/L, add the 40mg lysozyme, room temperature continues to stir behind 3～4h the filtering with microporous membrane with 0.45 μ m aperture; The gained milk-white coloured suspension is centrifugal, after the washing, vacuum lyophilization, finally obtain lysozyme/gather (isobutyl alpha-cyanoacrylate) medicine carrying microballoons.
The envelop rate of this product is 51.48%, and carrying drug ratio is 4.52%, mean diameter 175nm, and particle size dispersion coefficient 0.086, lysozyme activity remains unchanged basically, can reach more than the 24h at normal saline Chinese medicine slow release.
Embodiment 3
Take by weighing in poloxamer 188 (poloxamer-188) 0.25g, macrodex (Dextran70) the 0.25g adding 50ml deionized water; After treating that it fully dissolves, the hydrochloric acid solution regulation system pH value 2.5 with 0.1mol/L slowly drips isobutyl alpha-cyanoacrylate monomer 0.6g with syringe under the 800r/min magnetic agitation; Continue to stir 3h; Transfer system pH 6.5 with the sodium hydroxide solution of 0.1mol/L, add the 40mg lysozyme, room temperature continues to stir behind 3～4h the filtering with microporous membrane with 0.45 μ m aperture; The gained milk-white coloured suspension is centrifugal, after the washing, vacuum lyophilization, finally obtain lysozyme/gather (isobutyl alpha-cyanoacrylate) medicine carrying microballoons.
The envelop rate 64.2% of this product, carrying drug ratio 6.80%, mean diameter 183nm, particle size dispersion coefficient 0.099, lysozyme activity remains unchanged basically, can reach more than the 20h at normal saline Chinese medicine slow release.
Claims (5)
1. a lysozyme/gather (isobutyl alpha-cyanoacrylate) microsphere, it is characterized in that: component (mass fraction) is:
2. lysozyme according to claim 1/gather (isobutyl alpha-cyanoacrylate) microsphere is characterized in that:
Described surfactant is poloxamer 188 (poloxamer-188), and macrodex (Dextran70) or both share.
3. lysozyme according to claim 1/gather (isobutyl alpha-cyanoacrylate) microsphere is characterized in that:
Described pH value acid regulator is the hydrochloric acid solution of 0.1mol/L.
4. lysozyme according to claim 1/gather (isobutyl alpha-cyanoacrylate) microsphere is characterized in that:
Described pH value alkaline conditioner is the sodium hydroxide solution of 0.1mol/L.
5. one kind prepares above-mentioned lysozyme/gather the method for (isobutyl alpha-cyanoacrylate) microsphere, it is characterized in that: may further comprise the steps:
Take by weighing a certain amount of poloxamer 188 (poloxamer-188); Macrodex (Dextran70) or both add in the deionized water by a certain percentage; After treating that it fully dissolves, about 2.5, slowly drip isobutyl alpha-cyanoacrylate with syringe under the 800r/min magnetic agitation with the hydrochloric acid solution regulation system pH value of 0.1mol/L; Continue to stir 2～3h; About 6.5, add a certain amount of lysozyme with the sodium hydroxide solution regulation system pH value of 0.1mol/L, room temperature continues to stir behind 3～4h the filtering with microporous membrane with 0.45 μ m aperture; The gained milk-white coloured suspension is centrifugal, after the washing, vacuum lyophilization, finally obtain lysozyme/gather (isobutyl alpha-cyanoacrylate) medicine carrying microballoons.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109967043A (en) * | 2019-04-01 | 2019-07-05 | 北京化工大学 | A kind of organic-inorganic hybrid material LYZ-PTA of novel adjustable particle size |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1256628A (en) * | 1997-04-18 | 2000-06-14 | 药物生物技术公司 | Sustained-release compositions and method for preparing same |
| WO2006017852A2 (en) * | 2004-08-12 | 2006-02-16 | Quest Pharmaceutical Services | Pharmaceutical compositions for controlled release delivery of biologically active compounds |
| US20070190163A1 (en) * | 2006-01-24 | 2007-08-16 | Malaknov Michael P | Technology for preparation of macromolecular microspheres |
| CN101618210A (en) * | 2008-06-30 | 2010-01-06 | 上海高科联合生物技术研发有限公司 | Staphylococcus lysozyme local sustained release preparation, preparation method and application thereof |
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- 2012-01-09 CN CN2012100041892A patent/CN102552166A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1256628A (en) * | 1997-04-18 | 2000-06-14 | 药物生物技术公司 | Sustained-release compositions and method for preparing same |
| WO2006017852A2 (en) * | 2004-08-12 | 2006-02-16 | Quest Pharmaceutical Services | Pharmaceutical compositions for controlled release delivery of biologically active compounds |
| US20070190163A1 (en) * | 2006-01-24 | 2007-08-16 | Malaknov Michael P | Technology for preparation of macromolecular microspheres |
| CN101618210A (en) * | 2008-06-30 | 2010-01-06 | 上海高科联合生物技术研发有限公司 | Staphylococcus lysozyme local sustained release preparation, preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 张强等: "硫酸庆大霉素聚氰基丙烯酸正丁酯毫微球制备工艺研究", 《中国药学杂志》, vol. 31, no. 1, 31 January 1996 (1996-01-31), pages 24 - 27 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109967043A (en) * | 2019-04-01 | 2019-07-05 | 北京化工大学 | A kind of organic-inorganic hybrid material LYZ-PTA of novel adjustable particle size |
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Application publication date: 20120711 |