CN1481902A - Preparation method for granula made of alpha-alcoholic acid resin ,and its use - Google Patents
Preparation method for granula made of alpha-alcoholic acid resin ,and its use Download PDFInfo
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- CN1481902A CN1481902A CNA031304478A CN03130447A CN1481902A CN 1481902 A CN1481902 A CN 1481902A CN A031304478 A CNA031304478 A CN A031304478A CN 03130447 A CN03130447 A CN 03130447A CN 1481902 A CN1481902 A CN 1481902A
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Abstract
The present invention belongs to the field of resin particle preparation. The resin particle is prepared with polylactic acid, polyglycolic adid, low molecular weight lactic acid-glycolic acid copolymer or their mixture as base material. The resin particle may be used in coating or carrying hydrophilic or hydrophobic medicine, bioactive macro molecule, cell, vaccine, and other chemical matter, such as cosmetics, pesticide, paint and dye. The present invention makes it possible to realize the control release of coated medicine in the period of one week to one month or even to one year with the low molecular weight poly-alpha-hydroxy acid resin to prepare medicine carrying particle.
Description
Technical field
The present invention relates to a kind of preparation method and application thereof of poly-'alpha '-hydroxy acids resin micron particle, belong to the resin particle technology of preparing.
Background technology
The medicine carrying microgranule that with the resin is substrate preparation is the novel pharmaceutical formulation that a class has wide application prospect.Medicine carrying microgranule produces synergism by the elimination of imbibition, resin degraded and the catabolite of microgranule, the control medicine is from the diffusion of microgranule to release medium, medicine is slowly discharged in the regular hour scope, realize the long-acting slow-release and the sustained release of medicine.
Up to now, existing multiple degradable macromolecule resin obtains in the drug delivery system field paying close attention to.But what research the most also had the related preparations launch mainly is poly-'alpha '-hydroxy acids resin, for example, and polylactic acid (PLA), polyglycolic acid (PGA), lactic acid-ethanol copolymer (PLGA).At present, owing to be the restriction of the microgranule technology of preparing of matrix with poly-'alpha '-hydroxy acids resin, the poly-'alpha '-hydroxy acids resin that is applied to prepare medicine carrying microgranule mainly is high molecular weight polymers (M
w＞10,000).When microgranule prepares, form (for example lactic acid (LA) and the segmental mol ratio of glycolic (GA) among the PLGA), the medicine carrying microgranule that can obtain having multiple drug release characteristics by selecting suitable polymers molecular weight or copolymer.However, the medicine-releasing performance of high-molecular weight poly-'alpha '-hydroxy acids resin medicine carrying microgranule also has big gap from requirements for clinical application, and many medicine-releasing performances that significant application value is arranged in clinical dispensing can't be provided, and shows:
(1) the release cycle of high-molecular weight poly-'alpha '-hydroxy acids resin medicine carrying microgranule is at least more than one month, can't realize the medicine controlled releasing in deenergized period short (several days to several weeks): in clinical application, the sustained release of medicine within several days to several weeks has very high using value in many occasions: for example after operation the patient is injected analgesic drug product, as the case may be, general medicine in several days to several weeks, discharge finish the most reasonable.The deenergized period of the medicine carrying microgranule that high-molecular weight poly-'alpha '-hydroxy acids resin is a base material is at least more than one month, this is because the medicine carrying microgranule of poly-'alpha '-hydroxy acids resins, have only when resin is degraded to certain molecular weight and cause the microgranule disintegrate, the medicine that bag carries in the microgranule is discharged fully, and high-molecular weight resin is degraded to enough low molecular weight and microgranule is disintegrated need at least time about one month, therefore, the sustained release of shorter deenergized period can't be provided for medicine.
(2) bag is stated from the medicine in the high-molecular-weight poly 'alpha '-hydroxy acids resin particle, in deenergized period, can not keep stable rate of release, particularly prominent to release phenomenon serious for the initial stage medicine, Release Performance can't satisfy the requirement of clinical application: when clinical dispensing, can normally bring into play drug effect for making medicine, the concentration of medicine in blood must remain in the effective blood drug concentration scope and (be higher than minimal effective concentration, be lower than the poisoning limting concentration), the rate of releasing drug that this requires medicine carrying microgranule to keep relative stability.The drug release of high-molecular weight poly-'alpha '-hydroxy acids resin medicine carrying microgranule generally comprises three phases: prominent releasing stage, diffusion controlled release stage and degraded controlled release stage of initial stage, the rate of release difference and the rate of releasing drug in each stage in each stage can not keep stable, particularly prominent the releasing of initial stage medicine often makes blood drug level substantially exceed the poisoning limting concentration in a short time, causes the human body medicine poisoning.So this type of drug-loading system can't be realized the stable release of medicine in deenergized period, be difficult in clinical dispensing, obtain promotion and application widely.
Summary of the invention
The object of the present invention is to provide with poly-'alpha '-hydroxy acids resin is the preparation method of the microgranule of base material, can realize the medicine controlled releasing that deenergized period is short, the initial stage burst effect is more weak as drug delivery system and deenergized period is long, rate of releasing drug keeps stable medicine controlled releasing with this method preparation with the poly-'alpha '-hydroxy acids resin microgranule that is base material.
For achieving the above object, the present invention is realized by following technical proposals: with the poly-'alpha '-hydroxy acids resin that comprises polylactic acid, polyglycolic acid, lactic acid-ethanol copolymer is base material, prepare micron-sized granule by resin fusion medicine carrying method, salting out method, solvent extraction, solvent evaporation method or self emulsifying-solvent evaporation method, it is characterized in that with weight average molecular weight M a certain in polylactic acid, polyglycolic acid, the lactic acid-ethanol copolymer
wBe 900-10,000 resin, or be that base material is prepared with the mixture of above-mentioned certain resin different molecular weight.
Above-mentioned resin particle can be used for bag and carries hydrophilic or hydrophobic drug (chemical medicine or Chinese medicine extract) and bioactive macromolecule (as protein and peptide class), also can be used for bag and carry cell and vaccine, can also be used to wrap the chemical substance (as cosmetics, pesticide, coating, dyestuff) of carrying other.
Resin particle provided by the invention applies to the medicine controlled releasing field and has outstanding advantage: with weight average molecular weight M
wBe 900-10, the medicine carrying microgranule of the poly-'alpha '-hydroxy acids resins of 000 low-molecular-weight can make all kinds of bag medicine carrying things discharge (deenergized period be 1 thoughtful 1 month) gradually in the microgranule in short deenergized period, the initial stage burst effect of drug release is little, can realize many medicine sustained release that arranged the short deenergized period of significant application value in clinical; The medicine carrying microgranule that the poly-'alpha '-hydroxy acids resin compound that adopts different molecular weight is a substrate preparation can realize that the drug release cycle is 1 month to 1 year a slow release, bag medicine carrying thing is in the release cycle, the initial stage burst effect is little, early stage and later stage discharge the stage drug release rate and keep stable, quicken dispose procedure no latter stage, can realize that medicine rate of releasing drug in whole deenergized period remains stable sustained release, satisfies requirements for clinical application.Some specific resin compound also can be realized the medicine zero level that general drug delivery system is difficult to provide for the medicine carrying microgranule of base material and discharge, both realize that rate of releasing drug remained constant sustained release in whole deenergized period.Because drug release rate remains constant in deenergized period, for realizing dispensing safely and effectively to greatest extent, have great significance, therefore, realize that this type of medicine carrying microgranule that the medicine zero level discharges is that a class has very high technical level, and the newtype drug transmission system that in clinical dispensing, is with a wide range of applications.
Description of drawings
What accompanying drawing 1 embodiment 1 prepared is the electromicroscopic photograph of the aspirin medicine carrying microgranule of base material with low-molecular-weight PLA;
What accompanying drawing 2 embodiments 1 prepared is the feature drug release curve of the aspirin medicine carrying microgranule of the aspirin medicine carrying microgranule of base material and the high-molecular weight PLA that the same terms prepares down with low-molecular-weight PLA; Wherein curve 1 is the drug release curve of low-molecular-weight PLA medicine carrying microgranule, and curve 2 is the drug release curve of high-molecular weight PLA medicine carrying microgranule;
What accompanying drawing 3 embodiments 2 prepared is the feature drug release curve of the aspirin medicine carrying microgranule of base material with low-molecular-weight PLGA resin;
The PLGA resin compound with different molecular weight of accompanying drawing 4 embodiments 3 preparations is that the bovine serum albumin medicine carrying microgranule of base material and the high-molecular weight PLGA of the following preparation of the same terms are the feature drug release curve of the bovine serum albumin medicine carrying microgranule of base material; Wherein curve 1 is the drug release curve of the medicine carrying microgranule of base material for the PLGA mixture of different molecular weight, and curve 2 is the drug release curve of high-molecular weight PLGA medicine carrying microgranule;
The PGA resin with different molecular weight of accompanying drawing 5 embodiments 4 preparations is the feature drug release curve of the bovine serum albumin medicine carrying microgranule of base material.
The specific embodiment
Embodiment 1: prepare the aspirin sustained release microgranule with low-molecular-weight PLA
Prepare low-molecular-weight PLA medicine carrying microgranule with solvent evaporation method: take by weighing low-molecular-weight PLA (weight average molecular weight M
w7,755) 30g is dissolved in and makes oil-phase resin solution in the 50mL dichloromethane; 908.1mg Type B gelatin being dissolved in the 10mL high purity water forming aqueous gelatin solution, is that the magnetic agitation low suspension of 200rpm is in gelatin solution with the 1.5g aspirin at rotating speed; The solution of gained mixes with oil-phase resin solution, employing ultrasonic generator ultrasonic 5 times to mixture, each ultrasonic time is 60s, ultrasonic output is 20W, to form water-in-oil emulsion, the gained emulsion in refrigerator and cooled but to 4 ℃, add then in the polyvinyl alcohol water solution of 500mL 0.5%, the mixture of gained is spared the matter device 10 with pin type, homogenate 2min forms the W/O/W complex emulsions under the rotating speed of 000rpm, is under the mechanical agitation of 230rpm at rotating speed with the gained emulsion, adds in the 12.5L distilled water, volatile oil phase solvent (volatilization time 3h) at room temperature obtains containing the suspension system of medicine carrying microgranule; With the sub-filtering suspension liquid of 90 mesh sieves, filtrate is changed in the centrifuge tube, centrifugal 5min (centrifugal force 400 * g power), collect the medicine carrying microgranule of centrifuge tube bottom, be suspended in the aqueous solution of 75mL D-mannitol (containing mannitol 1050 mg), the suspension system of lyophilization gained obtains aspirin medicine carrying microgranule lyophilized powder.
Under the same conditions, by identical raw material rate of charge, preparation high molecular PLA (M
w18,798) medicine carrying microgranule lyophilized powder.
Observe the size and the pattern of low-molecular-weight PLA medicine carrying microgranule with scanning electron microscope (SEM): medicine carrying microgranule was stacked on the aluminum sample platform metal spraying 90 seconds, under SEM, observes then, and photomicrograph.By accompanying drawing 1 as seen, the medicine carrying granule is the microsphere of 30-50 μ m, and adhesion is less between microgranule.
What take by weighing 20mg respectively is that the medicine carrying granule of base material is dissolved in the 1mL ethyl acetate with low-molecular-weight PLA and high molecular PLA, and (pH 7.4 for PBS, 20mM to add the 1mL phosphate buffer solution, contain 0.02% diazonium sodium as antibacterial) and the 1mL dehydrated alcohol, homogeneous mixed solution formed; Take out 0.5mL, adopt aspirin and salicylic content in efficient capillary electrophoresis apparatus (HPCE) test solution, calculate drug loading and envelop rate (the open-type fusion silicon capillary of employing 44cm * 50 μ m by following formula, with phosphate buffer solution (40mM, pH 10.5) be mobile phase, test under the wavelength of 236nm, operative temperature is 25 ℃).
The content of aspirin/particulate gross weight * 100 in the actual carrying drug ratio of microgranule (%)=granule
(in the formula in the granule content of aspirin by recording aspirin and salicylic total)
Microgranule envelop rate (%)=actual carrying drug ratio/theoretical carrying drug ratio * 100
(theoretical carrying drug ratio is calculated by the ratio of aspirin in the raw material and resin in the formula)
The carrying drug ratio and the envelop rate that calculate low-molecular-weight PLA and be the medicine carrying microgranule of base material are respectively 1.18% and 25.4%, the carrying drug ratio of high molecular PLA and envelop rate respectively 1.25% and 26.9%.
The resin medicine carrying granule 50mg that takes by weighing gained places testing tube, the phosphate buffer solution that adds 2mL pH 7.4, testing tube placed 37 ℃ water bath with thermostatic control oscillator, every the regular hour, with the centrifugal specimen mixture of the centrifugal force of 700 * g power (centrifugation time is 5 minutes), take out the 1.8mL centrifuged supernatant as test sample book, and in testing tube, add the phosphate buffer solution replacement supernatant of same amount; From sample, take out 0.5mL, adopt aspirin and salicylic content in the efficient capillary electrophoresis apparatus mensuration medicine.Test condition is identical with the mensuration of drug loading.The accumulation drug release rate is calculated as follows:
Accumulation drug release rate (%)=(M
a+ M
s)
t/ M
d* 100
(M wherein
aAnd M
sBe respectively the aspirin and the salicylic amount that discharge constantly at t, M
dBe PLGA
The grain drug loading)
Can realize wrapping that to carry aspirin deenergized period be 19 days, the more weak sustained release of initial stage burst effect by accompanying drawing 2 curves 1 visible low molecular weight medicine carrying microgranule, with curve 2 high molecular PLA is that the medicine carrying microgranule of base material is compared, the release cycle obviously shortens, and burst effect is not obvious.
Embodiment 2: prepare the aspirin sustained release microgranule with low-molecular-weight PLGA.
Adopt fusion medicine carrying legal system to be equipped with medicine carrying microgranule: (PLGA72/28, PLGA46/54, lactic acid and glycolic segmental mol ratio LA: GA was respectively 72: 28,46: 54, weight average molecular weight M to take by weighing 2 kinds of low-molecular-weight copolymers of different lactic acid-ethanols
wBe respectively 1368,990).Every kind of sample claims 5g, progressively softening for liquid in 120 ℃ of silicone oil baths, take by weighing the 0.5g aspirin, in mortar, grind, add in the liquid-state oligomers, the temperature that keeps mixture, make medicine and liquid-state oligomers mix homogeneously with the glass stirring rod, the mixture system of gained is transferred to a cylindrical die, and is cooled to-5 ℃, make the oligomer of medicine carrying molded, form bar-shaped; The PLGA oligomer of bar-shaped year aspirin of gained grinds in mortar with glass pestle, forms the oligomer particles of medicine carrying; Screen granule with screen, obtain the medicine carrying granule of particle diameter less than 200 μ m.
Measure carrying drug ratio, envelop rate and the medicine-releasing performance of medicine carrying microgranule by the method for embodiment 1.
The carrying drug ratio and the envelop rate that calculate PLGA72/28, PLGA46/54 are respectively 8.54%, 8.49% and 93.93%, 93.34%.
Can realize wrapping medicine carrying thing deenergized period by the curve 1 visible medicine carrying microgranule of accompanying drawing 3 is 9-12 days, the more weak slow release of initial stage burst effect, and with the raising of hydrophilic GA segment proportion in the resin, rate of releasing drug is accelerated.
Embodiment 3: the mixture with different molecular weight PLGA resin prepares the bovine serum albumin controlled release microparticle.
Prepare medicine carrying microgranule with solvent evaporation method: with two kinds of lactic acid-ethanol copolymers (PLGA:LA/GA75/25, Mw10,091,23.69g and PLGA:LA/GA75/25, Mw 1,715,7.14g) is dissolved in and makes oil-phase resin solution in the 50mL dichloromethane; 908.1mg Type B gelatin is dissolved in the 10mL high purity water forms aqueous gelatin solution, the 1g bovine serum albumin is dissolved in the gelatin solution; The solution of gained mixes with oil-phase resin solution, employing ultrasonic generator ultrasonic 5 times to mixture, and each ultrasonic time is 60s, ultrasonic output is 20W, to form water-in-oil emulsion; The gained emulsion is about refrigerator and cooled is but to 0 ℃, add then in the polyvinyl alcohol water solution of 500mL 0.5%, the mixture of gained is spared the matter device 10 with pin type, homogenate 2min forms the W/O/W complex emulsions under the rotating speed of 000rpm, with the gained emulsion is under the mechanical agitation of 230rpm at rotating speed, add in the 12.5L distilled water, volatile oil phase solvent (volatilization time 3h) at room temperature obtains containing the suspension system of medicine carrying microgranule; With the sub-filtering suspension liquid of 90 mesh sieves, filtrate is changed in the centrifuge tube, centrifugal 5min (centrifugal force 400 * g power), collect the medicine carrying microgranule of centrifuge tube bottom, be suspended in the aqueous solution of 75mL D-mannitol and (contain mannitol 1,050mg), lyophilization gained suspension system obtains bovine serum albumin medicine carrying microgranule lyophilized powder.
Under the same conditions, by identical raw material rate of charge, preparation high molecular PLGA (M
w10,091) medicine carrying microgranule lyophilized powder.
The freeze-drying particle of 20mg is added in the NaOH aqueous solution of 0.1N of sodium lauryl sulphate of 5mL 5%, at room temperature leave standstill 15h and change settled solution into until mixed system.(Prerce, IL USA) measure the content of BSA in the solution under the wavelength of 494nm, calculate the drug loading and the envelop rate (calculating of carrying drug ratio and envelop rate is referring to embodiment 1) of microgranule to adopt microBCA protein to survey method.The drug loading and the envelop rate that calculate the medicine carrying microgranule for preparing with different molecular weight PLGA resin compound are respectively 1.04% and 35.2%, are that the carrying drug ratio and the envelop rate of the medicine carrying microgranule of base material is respectively 0.99% and 33.5% with high molecular PLGA resin.
The 20mg freeze-drying particle is placed testing tube, add in the phosphate buffer solution of 4mL pH 7.4, isothermal vibration in 37 ℃ water-bath (rotating speed of water-bath oscillator is 60rpm), from centrifuge tube, take out the 2mL supernatant at regular intervals, and in centrifuge tube, add the release medium of same amount, measure bovine serum albumin content with the microBCA protein determination by preceding method, calculate drug release rate (computational methods are referring to embodiment 1).By accompanying drawing 4 as seen, this particle drug-loaded system can realize that the drug release cycle is 35 days, and rate of releasing drug meets the sustained release of zero level release rule substantially; And the medicine carrying microgranule of high molecular PLGA preparation in deenergized period, rate of releasing drug change in time is very obvious.
Embodiment 4: prepare the bovine serum albumin controlled release microparticle with different molecular weight PLA resin compound.
Prepare medicine carrying microgranule with solvent evaporation method: take by weighing weight average molecular weight respectively and be respectively two kinds of polylactic acid 22.19g of 22,313 and 2,127 and 7.14g and be dissolved in and make oil-phase resin solution in the 50mL dichloromethane; 1.04mg Type B gelatin is dissolved in the 10mL high purity water forms aqueous gelatin solution, the 1g bovine serum albumin is dissolved in the gelatin solution; The solution of gained mixes with oil-phase resin solution, employing ultrasonic generator ultrasonic 5 times to mixture, and each ultrasonic time is 60s, and ultrasonic output is 20W, and to form water-in-oil emulsion, the gained emulsion is about refrigerator and cooled is but to 0 ℃; Add then in the polyvinyl alcohol water solution of 500mL 0.5%, the mixture of gained is spared the matter device 10 with pin type, homogenate 2min forms the W/O/W complex emulsions under the rotating speed of 000rpm, with the gained emulsion is under the mechanical agitation of 230rpm at rotating speed, add in the 12.5L distilled water, volatile oil phase solvent (volatilization time 3h) at room temperature obtains containing the suspension system of medicine carrying microgranule; With the sub-filtering suspension liquid of 90 mesh sieves, filtrate is changed in the centrifuge tube, centrifugal 5min (centrifugal force 400 * g power), collect the medicine carrying microgranule of centrifuge tube bottom, be suspended in the aqueous solution of 75mL D-mannitol and (contain mannitol 1,050mg), lyophilization gained suspension system obtains bovine serum albumin medicine carrying microgranule lyophilized powder.
Calculate particle drug-loaded amount and envelop rate and medicine-releasing performance by the method for embodiment 3.The carrying drug ratio and the envelop rate that calculate microgranule are respectively 1.10% and 37.9%.By accompanying drawing 5 as seen, this particle drug-loaded system can realize that the drug release cycle is 37 days, and rate of releasing drug meets the sustained release of zero level release rule substantially.
Claims (3)
1, a kind of is the preparation method of the medicine carrying microgranule of base material with poly-'alpha '-hydroxy acids resin medicine carrying microgranule, it is characterized in that: with a certain weight average molecular weight M in the poly-'alpha '-hydroxy acids resin that comprises polylactic acid (PLA), polyglycolic acid (PGA), lactic acid-ethanol copolymer (PLGA)
wBe 900-10,000 resin, or be base material with the mixture of two or more different molecular weight of above-mentioned a certain resin, be prepared by resin fusion medicine carrying method, salting out method, solvent extraction, solvent evaporation method or self emulsifying-solvent evaporation method.
2, a class is described according to claim 1 is the application of the medicine carrying microgranule of base material with poly-'alpha '-hydroxy acids resin, it is characterized in that being used for bag and carry hydrophilic or hydrophobic drug and bioactive macromolecule, or be used for bag year cell and vaccine, or be used for bag year cosmetics, pesticide, coating, dyestuff, fine chemicals.
3, described according to claim 2 is the application of the medicine carrying microgranule of base material with poly-'alpha '-hydroxy acids resin, it is characterized in that hydrophilic or hydrophobic drug comprise chemical medicine or Chinese medicine extract; Bioactive macromolecule comprises protein and peptide class.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031304478A CN1481902A (en) | 2003-07-24 | 2003-07-24 | Preparation method for granula made of alpha-alcoholic acid resin ,and its use |
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|---|---|---|---|
| CNA031304478A CN1481902A (en) | 2003-07-24 | 2003-07-24 | Preparation method for granula made of alpha-alcoholic acid resin ,and its use |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101953776A (en) * | 2010-09-26 | 2011-01-26 | 中国医学科学院生物医学工程研究所 | Non-spherical drug-loaded particles and controlled release preparation of lactyl polymer and preparation methods thereof |
| CN103548823A (en) * | 2013-11-09 | 2014-02-05 | 福建农林大学 | Method for preparing thiophanate-methyl nano-pesticide |
| CN104013582A (en) * | 2014-06-27 | 2014-09-03 | 陶玲 | Aspirin polyethylene glycol-polylactic acid-glycolic acid copolymer (PEG-PLGA) microsphere and preparation method thereof |
| CN104857567A (en) * | 2015-05-11 | 2015-08-26 | 华南理工大学 | Calcium alginate/hydroxyapatite nano compound double drug loading porous scaffold containing biodegradable polyester microspheres and preparation method thereof |
| CN109898236A (en) * | 2019-03-15 | 2019-06-18 | 深圳市光远生物材料有限责任公司 | A kind of medicament-carrying nano-fiber membrane and its preparation method and application |
-
2003
- 2003-07-24 CN CNA031304478A patent/CN1481902A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101953776A (en) * | 2010-09-26 | 2011-01-26 | 中国医学科学院生物医学工程研究所 | Non-spherical drug-loaded particles and controlled release preparation of lactyl polymer and preparation methods thereof |
| CN101953776B (en) * | 2010-09-26 | 2012-07-04 | 中国医学科学院生物医学工程研究所 | Non-spherical drug-loaded particles and controlled release preparation of lactyl polymer and preparation methods thereof |
| CN103548823A (en) * | 2013-11-09 | 2014-02-05 | 福建农林大学 | Method for preparing thiophanate-methyl nano-pesticide |
| CN104013582A (en) * | 2014-06-27 | 2014-09-03 | 陶玲 | Aspirin polyethylene glycol-polylactic acid-glycolic acid copolymer (PEG-PLGA) microsphere and preparation method thereof |
| CN104857567A (en) * | 2015-05-11 | 2015-08-26 | 华南理工大学 | Calcium alginate/hydroxyapatite nano compound double drug loading porous scaffold containing biodegradable polyester microspheres and preparation method thereof |
| CN109898236A (en) * | 2019-03-15 | 2019-06-18 | 深圳市光远生物材料有限责任公司 | A kind of medicament-carrying nano-fiber membrane and its preparation method and application |
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