聚乳酸的降解性能及其微球剂的研究

目的 :研究聚乳酸的降解性能和制备聚乳酸红霉素微球。方法 :将聚乳酸薄膜置于模拟体液中水解 ,用正交设计优选微球制备工艺。结果 :分子量高的降解比分子量低的慢 ,消旋聚乳酸的降解比左旋聚乳酸的快。微球形态圆整 ,性质稳定 ,平均粒径为(10 98±0 15) μm ,体外释药符合Higuchi方程 (Q=28 067 +3 8515T1/2,r=0 9834)。结论 :聚乳酸的降解与分子量和构型有关 ,微球具有明显的缓释作用和满足肺靶向药物的要求     

聚乳酸微球生物降解机制和生物相容性研究进展

介绍了人工合成高分子材料聚乳酸（PLA）的性质，综述了PLA和乳酸／羟基乙酸共聚物（PLGA）微球的生物降解性和生物相容性。其生物降解为均匀降解，材料相对分子质量及其分布对降解行为有很大影响。注射微球的组织反应分为3个阶段，做组织相容性考察时应注意药物或生物活性物质的细胞毒性、抗原性和愈合作用对组织反应的影响。     

阿霉素聚乳酸微球的制备及体外释药特性研究

目的:对阿霉素聚乳酸微球的制备工艺、含量测定及体外释药特性进行初步研究.方法:以人工合成可生物降解聚合物聚乳酸为载体,采用乳化-溶剂挥发法制备阿霉素聚乳酸微球,用UV-260紫外分光光度计测定其药物含量和体外释药量.结果:所制备的阿霉素聚乳酸微球外形圆整,算术平均球径为55.2 μm,载药量为30.21 μg*mg-1,12 h体外累积释药量36%.结论:聚乳酸微球具有很好的控释能力,使用前景广阔.     

生物可降解性高分子载药微球研究进展

药物载体是用于包埋或负载药物的微球或微囊。制备微球所采用的基质材料一般可分为两大类：不可降解高分子材料（如己基纤维素、玻璃等）；可降解高分子材料，包括天然可降解性高分子材料（如淀粉、自蛋白、明胶、环糊精、甲壳素和壳聚糖等）和合成可降解性聚合物材料（如聚乳酸、聚烷基氰基丙烯酸脂等）。生物可降解性高分子载药微球为具有良好的生物相     

聚乳酸-乙醇酸微球的生物降解性和生物相容性研究

目的 考察基因重组人干扰素α-聚乳酸乙醇酸微球的生物降解性和生物相容性.方法 以缓冲液为介质,通过光学显微镜观察聚乳酸乙醇酸微球的体外降解;以Wistar大鼠为研究对象,观察给药部位的病理切片,评价微球的体内生物降解和生物相容性.结果 聚乳酸乙醇酸微球在体外,6周降解百分率超过80%,在体内6周可降解完全;给药部位病理切片观察,仅见轻微炎症反应,未见病理变化.结论 聚乳酸乙醇酸微球具有良好的生物降解性和生物相容性.     

替莫唑胺聚乳酸-羟基醋酸微球的制备及体外释药

目的:对替莫唑胺聚乳酸-羟基醋酸微球的制备工艺、含量测定及体外释药特性进行初步研究。方法:以人工合成可生物降解聚合物聚乳酸-羟基醋酸为载体,采用乳化-溶剂挥发法制备替莫唑胺聚乳酸-羟基醋酸微球,用紫外分光光度计测定其药物含量和体外释药量。结果:所制备的替莫唑胺聚乳酸-羟基醋酸微球外形圆整,算术平均球径为62.2μm,载药量为7.47%,包封率为83.53%,体外释放可达1个月。结论:替莫唑胺聚乳酸-羟基醋酸微球具有很好的控释能力,使用前景广阔。     

碱性成纤维细胞生长因子缓释微球的制备及其性质研究

目的 通过碱性成纤维细胞生长因子(bFGF)缓释微球的制备研究,为bFGF的缓释制剂提供科学依据。方法 以聚乳酸-聚乙二醇共聚物为包裹材料,采用复乳包囊法制备bFGF-聚乳酸-聚乙二醇共聚物缓释微球,并对微球的形态学、粒径分布、载药量、包封率和体外释药等进行研究。结果 所制备的微球表面光滑圆整,球体均匀度好;微球平均粒径为1.543±0.070 μm,平均径距为1.273±0.08;载药量和包封率分别为0.0267％和65.32％;微球的体外释药过程较为稳定,两周释药率为59.98％。结论 bFGF缓释微球比bFGF有明显的缓释作用。     

聚乳酸-羟基乙酸共聚物载药微球性质及缓释行为的影响因素

聚乳酸-羟基乙酸共聚物（PLGA）包裹药物制成缓释微球是药物缓释方向的研究热点,PLGA微球作为载体,具有良好的生物相容性和降解性,但载药微球的性质和释药性能易受很多因素影响,如PLGA相对分子质量,LA/GA比例,微球制备工艺等,这些因素对载药体系在生物医学领域的应用造成一定限制。结合国内外相关文献,本文综述了PLGA微球在制备及释药过程中,影响其理化性质和重要性能的因素,包括载药量,包封率,突释问题等方面,为PLGA微球进一步研究和优化提供思路。     

聚乳酸分子量对利福平聚乳酸微球性质的影响

目的 :考察聚乳酸分子量对利福平聚乳酸微球性质的影响。方法 :采用分散一溶媒扩散法制备利福平聚乳酸微球 ,测定微球的粒径分布和包封率 ,进行体外释药和稳定性试验。结果 :在本制备方法中 ,聚乳酸分子量对微球粒径分布的影响作用不明显 ;药物包封率随聚乳酸分子量增大而增加 ;聚乳酸分子量减小 ,微球体外释药速度加快。稳定性试验表明 ,微球在 4℃和室温 (2 0～ 2 5℃ )条件下性质稳定 :3 7℃条件下因聚乳酸软化 ,微球发生粘连聚集。结论 :应根据实验目的选择适宜分子量的聚乳酸 ,以获得所需性质的微球。     

甲睾酮聚乳酸微球的制备及其释药性能研究

目的制备甲睾酮聚乳酸微球,研究其体外释药过程。方法采用乳化-溶剂挥发法制备甲睾酮聚乳酸微球;以0.25%SDS-5%乙醇(pH3.4)为释放介质,采用高效液相色谱法测定甲睾酮聚乳酸微球的体外释药量。结果甲睾酮聚乳酸微球开始释药较快,存在一定突释效应,随后以缓慢的方式释药,可用双相动力学方程100-R=35.77e0.1321t+63.91e7.372E-4t描述。结论制成的甲睾酮聚乳酸微球具有明显的缓释作用。     

Degradation behaviour of microspheres prepared by spray-drying poly(D,L-lactide) and poly(D,L-lactide-co-glycolide) polymers

Polymeric microsphere degradation must be taken into account in the design of drug delivery systems to be injected in in vivo systems, thus a prior analysis of in vitro degradation behaviour of microspheres appears to be necessary. In this study degradation characteristics of poly(lactide-co-glycolide) (PLGA) and poly(D,L-lactide) (PLA) microspheres prepared by the spray-drying technique have been examined. It was found that a slow decrease in molecular weight took place during the first stage of degradation, and the value of the rate constant decreased with the increase of the percentage of lactic acid of the polymer in a linear way. Thus, the period of time of this first stage decreased with the increase of content of glycolidyl units of the polymer, and it was the unique stage observed in PLA microspheres after 5 months of study. During this period of time, significant mass loss was not observed in the microspheres. The second stage of degradation of PLGA microspheres showed a larger rate constant, whose value increased with the content of glycolidyl units of the polymer. Mass loss was observed from number-average molecular weight about 6000. A sharp decrease of glass transition temperature (T(g)) was observed coinciding with the start of mass loss. This fact was accompanied by a physical change of the samples, fusion of microspheres to form large particles, which also fusion to form a unique mass of polymer; moment from that the degradation process was quicker.     

Microencapsulation and dissolution properties of a neuroleptic in a biodegradable polymer, poly(d,l-lactide)

Polylactide was polymerized from dilactide under various conditions to yield polymers in the molecular weight range from 11,000 to 21,000 as determined by osmometry. Chlorpromazine was encapsulated by the polylactide polymers by using an emulsification-solvent evaporation method. Microscopic observation revealed that when drug loading was less than or equal to 18%, the drug was in the form of a solid solution in microspheres of polylactide. At higher drug loadings, crystalline drug was present. In vitro dissolution of the encapsulated drug was followed in hydroalcoholic and aqueous buffer media. Studies with the hydroalcoholic media revealed that the drug release rate decreased as microcapsule size increased. However, dissolution in the hydroalcoholic media did not reflect the effect of molecular weight or percentage loading observed in the aqueous system. Dissolution in aqueous buffer showed that t50% increased with molecular weight and that release rates-surface area increased with increasing drug loading.     

Morphological changes in degrading PLGA and P(DL)LA microspheres: implications for the design of controlled release systems

The in vitro degradation of microspheres of polymers of lactic and glycolic acids were investigated by monitoring the mass loss from the device, the molecular weight of the polymer and the morphological changes of the particles with time. Two different sequences of morphological changes were found to be operative, depending upon the polymer from which they were made-one, (I) for the high molecular weight P(DL)LA, and the other, (II) for all PLGAs and the low molecular weight P(DL)LA. Microspheres of category I showed clear evidence of heterogeneous degradation, where the initially dense microsphere developed a hollow interior. Microspheres of category II plasticized on hydration due to reduction in the T g of the polymer below the incubation temperature of 37#176;C. There was suppression of release of entrapped globular proteins from microspheres that underwent plasticization (category II), while slow and sustained release was seen from those that did not (category I). It is proposed that plasticization renders the matrix of category II microspheres non-porous, which prevents release by pore-diffusion. The mass loss profiles of PLGA were found to be different from those reported in the literature, in that the rates of mass loss after an initial lag time were not as rapid as has been reported. The experimental conditions used, namely the use, or otherwise, of agitation, is suggested as the reason for these differences and the need to draw a correlation between in vitro experimental conditions and in vivo behaviour is emphasized.     

Morphological changes in degrading PLGA and P(DL)LA microspheres: implications for the design of controlled release systems.

The in vitro degradation of microspheres of polymers of lactic and glycolic acids were investigated by monitoring the mass loss from the device, the molecular weight of the polymer and the morphological changes of the particles with time. Two different sequences of morphological changes were found to be operative, depending upon the polymer from which they were made--one, (I) for the high molecular weight P(DL)LA, and the other, (II) for all PLGAs and the low molecular weight P(DL)LA. Microspheres of category I showed clear evidence of heterogeneous degradation, where the initially dense microsphere developed a hollow interior. Microspheres of category II plasticized on hydration due to reduction in the Tg of the polymer below the incubation temperature of 37 degrees C. There was suppression of release of entrapped globular proteins from microspheres that underwent plasticization (category II), while slow and sustained release was seen from those that did not (category I). It is proposed that plasticization renders the matrix of category II microspheres non-porous, which prevents release by pore-diffusion. The mass loss profiles of PLGA were found to be different from those reported in the literature, in that the rates of mass loss after an initial lag time were not as rapid as has been reported. The experimental conditions used, namely the use, or otherwise, of agitation, is suggested as the reason for these differences and the need to draw a correlation between in vitro experimental conditions and in visa behaviour is emphasized.     

In Vitro Protein Release and Degradation of Poly-dl-lactide-poly(ethylene glycol) Microspheres with Entrapped Human Serum Albumin: Quantitative Evaluation of the Factors Involved in Protein Release Phases

Purpose. To quantitatively evaluate the correlations between the amount of initial burst release and the surface-associated protein, and between the onset time for the second burst release and the matrix polymer degradation.Methods. Human serum albumin (HSA) was microencapsulated in polylactide (PLA) and poly-dl-lactide-poly(ethylene glycol) (PELA) with PEG contents of 5, 10, 20, and 30%, respectively, using the solvent extraction procedure based on formation of double emulsion w/o/w. Microspheres with similar particle size (1.7-2.0m), similar protein entrapment (2.1-2.8%) but different surface-associated proteins (9.3-53.6%) were used to evaluate the in vitro matrix degradation and protein release profiles. Degradation was characterized by studying the intrinsic viscosity decrease, medium pH change, and weight loss of the microspheres.Results. The matrix degradation and protein release profiles were highly dependent on the polymer composition of the microspheres. Faster decreases in the intrinsic viscosity of recovered matrix polymer, the microspheres weight, and the pH of degradation medium, and earlier onsets for the break in intrinsic viscosity reduction and the mass loss were detected for PELA microspheres with higher PEG content. The hydration and swelling of microspheres matrix contributed greatly to the degradation of matrix polymer. The HSA release showed triphasic profile and involved two mechanisms for all the microsphere samples. Smaller amount of initial burst release, larger gradual release rate, and earlier onset for the second burst release were observed for HSA from matrix polymer with higher PEG content. The extent of the initial burst release was quantitatively related with the surface-associated protein. The second burst release of HSA was observed to occur within 1 week after the onset for mass loss, which was also the break in the intrinsic viscosity reduction rate.Conclusion. Protein release profiles could be rationalized by optimizing the matrix polymer degradation and microsphere characteristics.     

Morphological characterization of microspheres, films and implants prepared from poly(lactide-co-glycolide) and ABA triblock copolymers: is the erosion controlled by degradation, swelling or diffusion?

Erosion of biodegradable parenteral delivery systems (PDS) based on ABA copolymers consisting of poly(L-lactide-co-glycolide) (PLGA) A-blocks attached to polyethylene oxide (PEO) B-blocks, or PLGA is important for the release of macromolecular drugs. The degradation behavior of four types of PDS, namely extruded rods, tablets, films and microspheres, was studied with respect to molecular weight, mass, polymer composition and shape and microstructure of the PDS. For each device the onset time of bulk erosion (t(on)) and the apparent rate of mass loss (k(app)) were calculated. In the case of PLGA, the t(on) was 16.2 days for microspheres, 19.2 days for films and 30.1 days for cylindrical implants and tablets. The k(app) was 0.04 days(-1) for microspheres, 0.09 days(-1) for films, 0.11 days(-1) for implants and 0.10 days(-1) for tablets. The degradation rates were in the same range irrespective of the geometry and the micrographs of eroding PDS demonstrated pore formation; therefore, a complex pore diffusion mechanism seems to control the erosion of PLGA devices. In contrast, PDS based on ABA copolymers showed swelling, followed by a parallel process of molecular weight degradation and polymer erosion, independent of the geometry. The contact angles of ABA films increased either with decreasing PEO content or with increasing chain length of the PEO B-blocks. In summary, the insertion of a hydrophilic B-block leads to an erosion controlled by degradation of ABA copolymers, whereas for PLGA a complex pore diffusion of degradation products controls the rate of bulk erosion.     

Versatility of biodegradable poly(D,L-lactic-co-glycolic acid) microspheres for plasmid DNA delivery.

In this study, we have optimized different formulations of DNA encapsulated into PLGA microspheres by correlating the protocol of preparation and the molecular weight and composition of the polymer, with the main characteristics of these systems in order to design an efficient non-viral gene delivery vector. For that, we prepared poly(D,L-lactic-co-glycolic acid) (PLGA) microparticles with an optimized water-oil-water double emulsion process, by using several types of polymers (RG502, RG503, RG504, RG502H and RG752), and characterized in terms of size, zeta potential, encapsulation efficiency (EE%), morphology, DNA conformation, release kinetics, plasmid integrity and erosion. The size of the particles ranged between 0.7 and 5.7 microm depending on the protocol of formulation and the molecular mass of the polymer used. The microspheres prepared by using in their formulation polymers of high molecular weight (RG503 and RG504) were bigger in size than in the case of using a lower molecular weight polymer (RG502). The EE (%) of plasmid DNA increased with increasing the molecular mass of the polymer and by using the most hydrophilic polymer RG502H, which contains terminal acidic groups in its structure. The plasmid could be encapsulated without compromising its structural and functional integrity. Also a protective effect of PLGA on endonuclease digestion is observed. Plasmid DNA release from microspheres composed of low molecular weight or hydrophilic polymers, like RG502H, was faster than from particles containing high molecular weight or hydrophobic polymers. These PLGA microspheres could be an alternative to the viral vectors used in gene therapy, given that may be used to deliver genes and other bioactive molecules, either very rapidly or in a controlled manner.     

Paclitaxel loaded poly(L-lactic acid) microspheres: properties of microspheres made with low molecular weight polymers

Microspheres were prepared from poly(L-lactic acid) polymers having molecular weights between 500 and 50k g/mol. The polymers were synthesized using two initiator molecules, L-lactic acid oligomer (PLLA-LA) or stearyl alcohol (PLLA-SA). For both PLLA-LA and PLLA-SA polymers, glass (Tg) and melting (Tm) transition temperatures and enthalpy of melting all increased as the polymer molecular weight increased. PLLA-SA showed the greatest change in Tg (-13 to 54 degrees C) as molecular weight increased from 500 to 10k x g/mol, compared to 25 to 55 degrees C for PLLA-LA polymers. Changes in Tm and enthalpy of melting with increasing molecular weight were similar for both PLLA-LA and PLLA-SA. Paclitaxel release from 30% paclitaxel loaded microspheres in the size range of 50-90 microm was affected by these changes in polymer properties as molecular weight increased. As the molecular weight increased from 2k to 50k x g/mol the amount of drug released from microspheres over 14 days decreased from 76 to 11% of the initial drug load. The release profiles were consistent with a diffusion controlled mechanism provided a two-compartment model was employed. According to this model, the total amount of 'available' drug (compartment 1) was released by diffusion in 14 days while the remainder (compartment 2) was confined within the polymeric matrix and could not diffuse out at a measurable rate. Following the in vitro release study, microsphere made from 2k-10k g/mol polymers showed significant signs of disintegration whereas 50k x g/mol polymer microspheres remained intact.     

Hydrolytic Degradation and Drug Release of Ricinoleic Acid–Lactic Acid Copolyesters

A systematic study on the degradation and drug release from l-lactic acid and ricinoleic-acid-based copolyesters is reported. These copolyesters were synthesized by ring opening polymerization (ROP), melt condensation (COND) and transesterification (TRANS) of high molecular weight poly(lactic acid) (PLA) with ricinoleic acid (PLA-RA), and repolymerization by condensation to yield random and block copolymers of weight average molecular weights (Mw) between 3000 and 13,000. All polymers showed an almost zero-order weight loss, with a 20–40% loss after 60 days of incubation. Lactic acid release to the degradation solution is proportional to weight loss of the polymer samples. The main decrease in molecular weight was observed during the first 20 days, followed by a slow degradation phase, which kept the number average molecular weight (Mn) at 4000–2000 for another 40 days. Water-soluble 5FU was released from ricinoleic-acid-based polymers faster than slightly water-soluble triamcinolone. Drug release into phosphate-buffered saline (pH 7.4, 0.1 M) at 37°C from P(LA-RA) 60:40 prepared by condensation of the acids was faster than from pasty P(PLA-RA) 60:40 synthesized by transesterification for both drugs.     

Degradation of multi-phase microspheres fabricated via solvent removal

Multi-phase polymer microspheres for drug encapsulation have been fabricated via solvent removal using poly(-lactic) acid (PLLA) and poly(fumaric-co-sebacic) anhydride (20:80) (P(FA:SA) (20:80)). The process by which these spheres degrade was investigated. Characterization was conducted to determine the extent of degradation of the two polymer phases over 16 weeks using scanning-electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), gel-permeation chromatography (GPC), differential-scanning calorimetry (DSC) and nuclear magnetic resonance (NMR). These experiments showed that the P(FA:SA) (20:80) phase of the multi-phase microspheres degraded faster than the PLLA phase, leaving only some of the poly(sebacic) oligomers after 16 weeks in both the in vitro and in vivo studies. These portions could remain because they were entrapped in the PLLA phase, preventing more rapid degradation. The PLLA phase showed minimal changes over the 16 week period; there was no significant change in crystallinity and only a small decrease in molecular weight in both the in vitro and in vivo studies. The in vitro study showed a rapid mass loss initially (first 3 days), followed by a fairly constant mass through 16 weeks, while the in vivo study showed a mass gain due to tissue influx.