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.     

Paclitaxel loaded poly(L-lactic acid) (PLLA) microspheres. II. The effect of processing parameters on microsphere morphology and drug release kinetics

The kinetics of solvent removal in microsphere preparation and their effect on the morphology and release characteristics of paclitaxel-loaded PLLA microspheres were determined. Microspheres were analyzed by SEM and DSC and in vitro paclitaxel release was monitored by HPLC. During manufacture, dichloromethane evaporated at a constant rate, which increased with dispersion stirring speed and decreased with increasing paclitaxel content. Paclitaxel-loaded microspheres had a dimpled surface, due to surface deposition of the drug, while controls were smooth. In the formation of larger microspheres, the deposition of drug in the surface slowed the solidification process resulting in drug-loading dependent thermal properties. Paclitaxel release did not follow diffusion kinetics, rather it was characterized by a large burst followed by a linear phase. We speculate that non-uniform (surface-rich) drug distribution in the microspheres may contribute to the deviation from the theoretical pattern of kinetics for diffusion from a sphere.     

聚L-乳酸与聚乙二醇-b-聚L-乳酸电纺纤维中布洛芬的释放

目的制备并评价包载有布洛芬的聚L-乳酸和聚乙二醇嵌段聚L-乳酸电纺纤维毡。方法静电纺丝法制备包载布洛芬的纤维毡,扫描电子显微镜观察纤维形态,广角X射线衍射扫描观察纤维表面结晶状态,差示扫描量热评价药物在高分子材料中的结合状态。高效液相色谱测定体外酶降解药物释放结果。结果纤维直径在0.3～1.5μm之间,表面光滑无结晶态物质析出,X射线衍射没有发现布洛芬特征峰出现。差示扫描量热结果显示布洛芬的加入使纤维的玻璃化温度降低。药物释放结果显示相对于纯聚乳酸材料,当载体材料为聚乙二醇嵌段的聚乳酸时,纤维中的布洛芬呈现更快的释放速率,聚乙二醇有利于释放介质中酶对纤维的作用。20%载药量纤维中的药物释放速率大于10%载药量纤维中的药物释放速率,蛋白酶K加快药物的释放速率。结论成功制得布洛芬电纺纤维,药物被较好包裹在纤维内部,聚乳酸电纺纤维中聚乙二醇嵌段对布洛芬释放行为有明显的影响,需要在进一步研究中注意。     

Degradation kinetics of high molecular weight poly(L-lactide) microspheres and release mechanism of lipid:DNA complexes

Plasmid DNA encoding the green lantern protein was ion-paired with 1,2-dioleoyl, 3-trimethylammonium propane (DOTAP) at a (+/-) charge ratio of (1:1) to form a hydrophobic ion-pair (HIP) complex using the Bligh and Dyer method, and transferred into methylene chloride. Precipitation with a compressed antisolvent (PCA) was then employed to encapsulate plasmid DNA into poly(L-lactide) (PLLA) microspheres. The hydrophobicity of DOTAP:DNA complexes allowed consistently high encapsulation efficiencies (>70%) to be achieved. Release of the DOTAP:DNA complex from PLLA microspheres exhibited minimal burst and a short (ca. 1 week) lag phase, followed by sustained release over a 20 week period. Release kinetics were consistent with a simple Fickian diffusion model. No correlation was identified between release rate of soluble poly(L-lactide) species (< or =10 lactate units) from PLLA and the DNA release kinetics. Only approximately 12% of the polymer was degraded into soluble poly(L-lactide) over the time frame where approximately 90% of the plasmid load had been released.     

5-Fluorouracil-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(lactide-co-glycolide) polymers: Characterization and drug release

5-Fluorouracil (5-FU), a hydrosoluble anti-neoplastic drug, was encapsulated in microspheres of poly(D,L-lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) polymers using the spray-drying technique, in order to obtain small size microspheres with a significant drug entrapment efficiency. Drug-loaded microspheres included between 47?±?11 and 67?±?12?µg 5-FU?mg^?1 microspheres and the percentage of entrapment efficiency was between 52?±?12 and 74?±?13. Microspheres were of small size (average diameter: 0.9?±?0.4–1.4?±?0.8?µm microspheres without drug; 1.1?±?0.5–1.7?±?0.9?µm 5-FU-loaded microspheres) and their surface was smooth and slightly porous, some hollows or deformations were observed in microspheres prepared from polymers with larger T_g. A fractionation process of the raw polymer during the formation of microspheres was observed as an increase of the average molecular weight and also of T_g of the polymer of the microspheres. The presence of 5-FU did not modify the T_g values of the microspheres. Significant interactions between the drug and each one of the polymers did not take place and total release of the included drug was observed in all cases. The time needed for the total drug release (28–129?h) was in the order PLA?>?PLGA 75/25?>?PLGA 50/50. A burst effect (17–20%) was observed during the first hour and then a period of constant release rate (3.52?±?0.82–1.46?±?0.26?µg 5-FU?h^?1 per milligram of microspheres) up to 8 or 13?h, depending on the polymer, was obtained.     

5-Fluorouracil-loaded microspheres prepared by spray-drying poly(D,L-lactide) and poly(lactide-co-glycolide) polymers: characterization and drug release

5-Fluorouracil (5-FU), a hydrosoluble anti-neoplastic drug, was encapsulated in microspheres of poly(D,L-lactide) (PLA) and poly(lactide-co-glycolide) (PLGA) polymers using the spray-drying technique, in order to obtain small size microspheres with a significant drug entrapment efficiency. Drug-loaded microspheres included between 47 +/- 11 and 67 +/- 12 microg 5-FU mg(-1) microspheres and the percentage of entrapment efficiency was between 52 +/- 12 and 74 +/- 13. Microspheres were of small size (average diameter: 0.9 +/- 0.4-1.4 +/- 0.8 microm microspheres without drug; 1.1 +/- 0.5-1.7 +/- 0.9 microm 5-FU-loaded microspheres) and their surface was smooth and slightly porous, some hollows or deformations were observed in microspheres prepared from polymers with larger Tg. A fractionation process of the raw polymer during the formation of microspheres was observed as an increase of the average molecular weight and also of Tg of the polymer of the microspheres. The presence of 5-FU did not modify the Tg values of the microspheres. Significant interactions between the drug and each one of the polymers did not take place and total release of the included drug was observed in all cases. The time needed for the total drug release (28-129 h) was in the order PLA > PLGA 75/25 > PLGA 50/50. A burst effect (17-20%) was observed during the first hour and then a period of constant release rate (3.52 +/- 0.82-1.46 +/- 0.26 microg 5-FU h(-1) per milligram of microspheres) up to 8 or 13 h, depending on the polymer, was obtained.     

Microencapsulation using poly (L-lactic acid) III: Effect of polymer molecular weight on the microcapsule properties

Poly (L-lactic acid) microcapsules were prepared using an emulsification and organic solvent evaporation technique (w/o system) with phenobarbitone as a reference core. Three polymers of different molecular weight (61,300; 43,200, 2400), were used to prepare different core loaded microcapsules. Microcapsule size increased with increase in polymer molecular weight. Microcapsule size was also found to increase with increase in core loading with the two high molecular weight polymers, whilst the low molecular weight polymer tended to aggregate to form larger microcapsules than expected. The calculated microcapsule density was found to decrease with an increase in the polymer molecular weight and core loading. 'Encapsulation efficiency' was reduced with the decrease in initial theoretical core loading. However, the phenobarbitone content of the microcapsules was not affected by the difference in polymer molecular weight. Significant morphological differences were observed due to variations in the polymer molecular weight. The two high molecular weight polymers were found to produce non-uniform, porous microcapsules, whilst low molecular weight polymer formed a uniform non-porous surface when core loading was low. With increasing core loading, an increasing number of phenobarbitone crystals were observed on the surface and microcapsules became increasingly porous. This was more evident after release of the drug. Differential scanning calorimetry of the microcapsules showed thermal events for both the polymer and phenobarbitone.     

Assessment of biodegradability of polymeric microspheresin vivo: Poly (DL-lactic acid), poly (L-lactic acid) and poly (DL-lactide-co-glycolide) microspheres

To confirm a new evaluation technique for biodegradability of biopolymer microspheres in vivo condition, magnetic microsphere system was adopted for tracing the microspheres injected and lodged in mice. Microspheres of poly(DL-lactic acid), poly(L-lactic acid) and poly (DL-lactide-coglycolide)(PLGA) were prepared by solvent-extraction method and their organ distribution and biodegradation in mice was examined. Magnetic microspheres lodged in mice organs were recollected from the homogenates of mice organs with a constant flow magnetic separation apparatus. Recollected microspheres were observed by scanning electron microscopy and also were assayed for their magnetite content by atomic absorption spectrophotometry to evaluate the biodegradability of polymeric microspheres. This method seems to be practical and simple to estimate the biodegradability of biopolymers over the conventional methods.     

Solvent, emulsifier and drug concentration factors in poly(D,L-lactic acid) microspheres containing hexamethylmelamine.

Biodegradable poly(D,L-lactic acid) (PLA) microspheres containing hexamethylmelamine (HMM) were developed for potential use in chemoembolization and intraperitoneal implantation. The emulsion-solvent-evaporation/extraction method was used to prepare 15 formulations with different drug/polymer ratios, solvent compositions and emulsifer concentrations in the continuous aqueous phase. A central composite experimental design was used, with five levels of the three different factors. All formulations resulted in the formation of discrete matrix microspheres containing crystalline drug. The mean particle sizes of the microsphere formulations ranged from 62-348 microm and the effect of the independent variables on microsphere size was satisfactorily predicted using response surface methodology. For theoretical drug loads of 5-40%, efficiency of entrapment ranged from 75-107% and porosities of the microspheres were between 0-6.5%. The rate of drug release from the microspheres depended on drug loading and particle size. Microspheres with 22.5% or greater theoretical drug content released drug rapidly, with almost complete release occurring in 70 h or less. Formulations with drug loading of 5% and 9.57%, however, released drug very slowly, with less than 50% released in 40 days. Release kinetics of narrow sieve cuts of microspheres with high drug load (35.4%) followed square root of time profiles.     

The characterization of paclitaxel-loaded microspheres manufactured from blends of poly(lactic-co-glycolic acid) (PLGA) and low molecular weight diblock copolymers

Paclitaxel-loaded biodegradable drug delivery systems manufactured from poly(lactic-co-glycolic acid) (PLGA) are known to release the drug at extremely slow rates. The objective of this study was to characterize paclitaxel-loaded microspheres composed of blends of PLGA with low molecular weight ampipathic diblock copolymers. The encapsulation and release of a series of poly(epsilon-caprolactone) (PCL)- or poly(D,L-lactic acid) (PDLLA)-co-methoxypolyethylene glycol (MePEG) diblock copolymers was measured using quantitative gel permeation chromatography. Polymeric miscibility was determined by glass transition temperature measurements using differential scanning calorimetry and paclitaxel release was measured using HPLC methods. The PCL- and PDLLA-based diblock copolymers encapsulated at high efficiency and were miscible in PLGA microspheres (30-120m microm size range). The burst phase of paclitaxel release was increased up to 20-fold by the inclusion of diblock copolymers in PLGA microspheres. Approximately 10% of the more hydrophobic PCL-based copolymers released from the microspheres in a short burst over 3 days followed by very slow release over the following 10 weeks. Only the PDLLA-based copolymer released from the PLGA microspheres in a controlled manner over 10 weeks. All microspheres containing PEG were found to have more hydrophilic surfaces (as measured by contact angle) with improved biocompatibility (reduced neutrophil activation) compared to PLGA only microspheres. These results indicate that low molecular weight polyester-based diblock copolymers may be effectively encapsulated in PLGA microspheres to increase paclitaxel release (probably through a micellization process) and improve biocompatibility.     

Methotrexate loaded poly(L-lactic acid) microspheres for intra-articular delivery of methotrexate to the joint

A controlled release delivery system that localizes methotrexate (MTX) in the synovial joint is needed to treat inflammation in rheumatoid arthritis (RA). The purpose of this work was to develop and characterize MTX loaded poly(l-lactic acid) (PLLA) microspheres and evaluate in vivo tolerability and MTX plasma concentrations following intra-articular injection into healthy rabbits. MTX loaded PLLA (2 kg/mole) microspheres were prepared using the solvent evaporation method and characterized in terms of size, molecular weight, thermal properties, and release rates into phosphate buffered saline (PBS) (pH 7.4) at 37 degrees C. Biocompatibility was evaluated by observing the swelling of the joints of the rabbits and histological analysis following the injection of the microspheres. MTX concentrations in the plasma and urine samples of rabbits were evaluated by high-performance liquid chromatography (HPLC). MTX loaded microspheres showed a rapid burst phase followed by a slow release phase. MTX loaded and control microspheres were biocompatible and plasma concentrations of MTX were tenfold higher in rabbits injected intra-articularly with free MTX than MTX microspheres. MTX microspheres may retain the drug in the joint by reducing clearance from the joint into the blood.     

Effect of nanoprecipitation on the physicochemical properties of low molecular weight poly(L-lactic acid) nanoparticles loaded with salbutamol sulphate and beclomethasone dipropionate

A modified nanoprecipitation (interfacial polymer deposition following solvent displacement) method was used to produce nanoparticles from low molecular weight poly(L-lactic acid). Model drugs, either salbutamol sulphate or beclomethasone dipropionate, were encapsulated in the particles. The influence of the preparation method on the physicochemical state of the polymer and the drugs as well as on the drug-polymer interactions were studied by electron microscopy, X-ray diffractometry, thermal analysis and infrared spectroscopy. Nanoprecipitation lowered the crystallinity of the PLA polymer. The crystallinity of the polymer was higher in the particles containing salbutamol sulphate then those containing beclomethasone dipropionate. The crystal form of beclomethasone dipropionate was changed from an anhydrate to a monohydrate as a result of nanoprecipitation. Although changes in the crystallinity of the polymer and the model drugs were seen, no clear interactions between the polymer and the drug were detected.     

Production of GMP-grade radioactive holmium loaded poly(L-lactic acid) microspheres for clinical application

Radioactive holmium-166 loaded poly(L-lactic acid) microspheres are promising systems for the treatment of liver malignancies. The microspheres are loaded with holmium acetylacetonate (HoAcAc) and prepared by a solvent evaporation method. After preparation, the microspheres (Ho-PLLA-MS) are activated by neutron irradiation in a nuclear reactor. In this paper, the aspects of the production of a (relatively) large-scale GMP batch (4 g, suitable for treatment of 5-10 patients) of Ho-PLLA-MS are described. The critical steps of the Ho-PLLA-MS production process (sieving procedure, temperature control during evaporation and raw materials) were considered and the pharmaceutical quality of the microspheres was evaluated. The pharmaceutical characteristics (residual solvents, possible bacterial contaminations and endotoxins) of the produced Ho-PLLA-MS batches were in compliance with the requirements of the European Pharmacopoeia. Moreover, neutron irradiated Ho-PLLA-MS retained their morphological integrity and the holmium remained stably associated with the microspheres; it was observed that after 270h (10 times the half-life of Ho-166) only 0.3+/-0.1% of the loading was released from the microspheres in an aqueous solution. In conclusion, Ho-PLLA-MS which are produced as described in this paper, can be clinically applied, with respect to their pharmaceutical quality.     

Release of bovine serum albumin from preformed porous microspheres of poly(L-lactic acid)

Preformed porous microspheres of poly(L-lactic acid) (Accurel have been shown to sustain the release of highly water soluble solutes, like dextran and mannitol, for a time period of more than 4 months. The purpose of this investigation was to mechanistically characterize the release of a model protein, bovine serum albumin (BSA), from these highly porous microspheres. The microspheres were loaded with [14C]BSA in three different concentrations of 0.06, 0.26 and 0.59% w/w. The rate of release of [14C]BSA from microspheres was correlated to media ([3H]PBS) uptake. The release of BSA showed a biphasic pattern; an initial rapid release, followed by a sustained release. The initial burst of BSA was found to be inversely proportional to BSA loading and highly correlated to water penetration. The sustained release phase was independent of water penetration kinetics. Washing the microspheres did not remove either the surface bound BSA or the BSA incorporated in the microsphere matrix, indicating the tight binding of BSA to highly porous microspheres. Furthermore, addition of a surfactant induced a dramatic increase in the amount of BSA released, suggesting that the release is controlled by the surface binding of BSA to the polymer. Also, the release rate of BSA beyond the initial burst was found to be much slower than for the lower MW macromolecules like dextran at a similar level. The data from the present work suggests the BSA-polymer interaction to be a major contributing factor in explaining the overall BSA release kinetics.     

Release of bovine serum albumin from preformed porous microspheres of poly(L-lactic acid)

Preformed porous microspheres of poly(L-lactic acid) (Accurel) have been shown to sustain the release of highly water soluble solutes, like dextran and mannitol, for a time period of more than 4 months. The purpose of this investigation was to mechanistically characterize the release of a model protein, bovine serum albumin (BSA), from these highly porous microspheres. The microspheres were loaded with [14C]BSA in three different concentrations of 0.06, 0.26 and 0.59%w/w. The rate of release of [14C]BSA from microspheres was correlated to media ([3H]PBS) uptake. The release of BSA showed a biphasic pattern; an initial rapid release, followed by a sustained release. The initial burst of BSA was found to be inversely proportional to BSA loading and highly correlated to water penetration. The sustained release phase was independent of water penetration kinetics. Washing the microspheres did not remove either the surface bound BSA or the BSA incorporated in the microsphere matrix, indicating the tight binding of BSA to highly porous microspheres. Furthermore, addition of a surfactant induced a dramatic increase in the amount of BSA released, suggesting that the release is controlled by the surface binding of BSA to the polymer. Also, the release rate of BSA beyond the initial burst was found to be much slower than for the lower MW macromolecules like dextran at a similar level. The data from the present work suggests the BSA-polymer interaction to be a major contributing factor in explaining the overall BSA release kinetics.     

Biodegradable tablets having a matrix of low molecular weight poly-L-lactic acid and poly-D,L-lactic acid

Biodegradable Homo- and Copolymers of lactic and glycolic acids have been used for manufacture of microparticles and matrix implants^1,5). To ensure sufficient hydrolytic matrix stability lactic acids of high and medium degree of polymerization have been used. The manufacture of poly lactic acid tablets with an average molecular weight of 25000 and 6000 was reported recently, after finishing the following study²).     

Disodium norcantharidate-loaded poly(epsilon-caprolactone) microspheres II. Modification of morphology and release behavior

Disodium norcantharidate (DSNC)-loaded poly(epsilon-caprolactone) (PCL) microspheres were prepared by s/o/w solvent evaporation technique, and their morphology and drug release behavior were modified by adding NaCl (3, 6 and 9%) in the continuous phase during the preparation. The addition of NaCl decreased the water influx into the emulsion droplets and the porosity of the resultant microspheres. Higher NaCl concentration resulted in smaller particle size, lower density and higher drug loading of the microspheres. Despite higher drug loading and smaller particle size, the microspheres prepared with NaCl in the continuous phase exhibited slower drug release. The modification of the release profiles was correlated with the changes in the surface and internal morphology of the microspheres. Therefore, by adding NaCl in the continuous phase during the preparation, both morphology and release behavior of the microspheres can be modified to a certain extent.     

Sustained release of insulin by double-layered implant using poly(D,L-lactic acid)

This report describes the advantage of double-layered implants using low molecular weight poly(DL-lactic acid) in the sustained release of insulin. The double-layered implant consisted of a polymer matrix containing insulin and a polylactic acid layer which was coated partially on one of the surfaces of the insulin:polymer matrix. The double-layered implants were compared with single-matrix implants from the standpoint of the in vitro dissolution test and in vivo performance. In vitro release rates were controlled by changing the amount of poly(DL-lactic acid) used in the polymer layer. In an in vivo test using diabetic animals, the double-layered implants provided a sustained release of insulin for 19 d, as judged by the changes in blood glucose levels and serum insulin levels after the subcutaneous implantation.     

乳酸/羟基乙酸共聚物分子量对艾塞那肽微球性质的影响

目的:制备艾塞那肽一乳酸/羟基乙酸共聚物(PLGA)微球,并研究PLGA分子量对微球性质的影响.方法:选用不同分子量的PLGA,采用复乳法制备艾塞那肽PLGA微球;对微球的粒径、载药量、包封率和体外释放等指标进行测定.结果:PLGA分子量对艾塞那肽PLGA微球的性质有明显影响.结论:可通过调节PLGA分子量调控微球的性质.