Preparation of PLA or PLGA Microspheres with Estradiol the Effects of THF—adding on the Properties of MS

Aim Polylactic acid (PLA) or polylactide-co-glycolide (PLGA) was used asbiodegradable and biocom-patible carriers to achieve sustained release ofestradial-PLGA/PLA-Microspheres (E_2-PLGA/PLA-MS). THF was added in the organic phase to study itseffects on the properties of MS. Methods MS were formed by an emulsification-solvent extractionmethod with mixture of ethyl acetate (EtoAc) and tetrahydrofuran (THF) as the organic solvents, andthen the properties and in vitro drug release behavior were examined. Results The results indicatedthat the drug loading efficiency decreased when THF added, but when the ratio of EtoAc was more than50% , there was no obvious effect of THF ratio, but the particle size increased accordingly. Thecarriers' properties and the drug contents were the main factors influencing the in vitro drugrelease. Conclusions By controlling the technology and formulation, we can get sustained-release E_2biodegradable microsperes with proper particle size, drug content and low burst-release, althoughTHF with readily solubility in water was used in the organic phase.

Preparation and Characterization of Lung-targeting Cefquinome-loaded PLGA Microspheres

We developed poly lactic-co-glycolic acid（PLGA） microspheres loaded with cefquinome and tested their effectiveness in a mouse model. The microspheres were prepared by optimizing several key parameters such as PLGA molecular weight, drug/polymer ratio, internal water volume and ethyl acetate. Drug loading efficiency, stability, in vitro release and tissue distribution in mouse were evaluated. The average particle size of the microspheres was 27.84 μm. The drug loading efficiency was 64.57%. The in vitro release of cefquinome from microspheres after 4 h was about 40% compared with over 90% for the drug alone. The concentration of cefquinome in lung reached 25 μg/g 0.25 h after injection, and kept at 10 μg/g 4 h after injection. However, the concentration of cefquinome was very low in other organs even 0.25 h after injection. In conclusion, Cefquinome-loaded PLGA microspheres are compatible as an effective lung-targeting drug delivery system and have a good sustained release efficacy.

Preparation of PLA and PLGA nanoparticles by binary organic solvent diffusion method

The nanoparticles of polylactide (PLA) and poly(lactide-co-glycolide) (PLGA) were prepared by the bi-nary organic solvent diffusion method. The yield, particle size and size distribution of these nanoparticles wereevaluated. The yield of nanoparticles prepared by this method is over 90%, and the average size of the nanoparticlesis between 130-180 nm. In order to clarify the effect of the organic solvent used in the system on nanoparticle yieldand size, the cloud points of PLA and PLGA were examined by cloud point titration. The results indicate that theyields of nanoparticles increase with the increase of ethanol in the acetone solution and attain the maximum at thecloud point of ethanol, while the size of nanoparticles decreases with the increase of ethanol in the acetone solutionand attains the minimum at the cloud point of ethanol. The optimal composition ratio of binary organic solvents coin-cides to that near the cloud point and the optimal condition of binary organic solvents can be predicted.

A method of elevated temperatures coupled with magnetic stirring to predict real time release from long acting progesterone PLGA microspheres

The object of the study was to develop a quick and reproducible accelerated in vitro release method to predict and deduce the function of the real time(37 °C) release for long acting PLGA microspheres. The method could be described in several steps. First, the release of the microspheres were studied using the sample and separate method at 37 °C with normal orbital shaking and elevated temperatures with magnetic stirring to further accelerate the release. Second, the most similar profile at elevated temperatures with the real time release was chosen with the help of the n value in the fitted Korsmeyer-Peppas Function. Third,the Weibull function and conversion ratio were used to deduce the function of real time release according to the chosen profile at elevated temperatures. The key point in this study was to provide a quick and precise method to predict the real time release for long acting progesterone PLGA microspheres. So the elevated temperatures coupled with magnetic stirring were used to accelerate the release further, and when there have many similar release profiles with the real time release at elevated temperatures, releasing time at elevated temperatures and the R2 of the final deduced function will be used to help choosing the most similar release profile with the real time release. Four different types of progesterone PLGA microspheres were used to verify the method, and all the deduced function correlated well with the real time releases, for R2 = 0.9912, 0.9781, 0.9918 and 0.9972, respectively.

Development of composite PLGA microspheres containing exenatide-encapsulated lecithin nanoparticles for sustained drug release

This study aimed to prepare poly(D, L-lactic-co-glycolic acid) microspheres(PLGA-Ms)by a modified solid-in-oil-in-water(S/O/W) multi-emulsion technique in order to achieve sustained release with reduced initial burst and maintain efficient drug concentration for a prolonged period of time. Composite PLGA microspheres containing exenatideencapsulated lecithin nanoparticles(Ex-NPs-PLGA-Ms) were obtained by initial fabrication of exenatide-loaded lecithin nanoparticles(Ex-NPs) via the alcohol injection method,followed by encapsulation of Ex-NPs into PLGA microspheres. Compared to Ms prepared by the conventional water-in-oil-in-water(W/O/W) technique(Ex-PLGA-Ms), Ex-NPs-PLGAMs showed a more uniform particle size distribution, reduced initial burst release, and sustained release for over 60 d in vitro. Cytotoxicity studies showed that Ms prepared by both techniques had superior biocompatibility without causing any detectable cytotoxicity.In pharmacokinetic studies, the effective drug concentration was maintained for over 30 d following a single subcutaneous injection of two types of Ms formulation in rats, potentially prolonging the therapeutic action of Ex. In addition, administration of Ex-NPs-PLGA-Ms resulted in a more smooth plasma concentration-time profile with a higher area under the curve(AUC) compared to that of Ex-PLGA-Ms. Overall, Ex-NPs-PLGA-Ms prepared by the novel S/O/W method could be a promising sustained drug release system with reduced initial burst release and prolonged therapeutic efficacy.

Sustained release donepezil loaded PLGA microspheres for injection:Preparation,in vitro and in vivo study

The purpose of this study was to develop a PLGA microspheres-based donepezil(DP)formulation which was expected to sustain release of DP for one week with high encapsulation efficiency(EE).DP derived from donepezil hydrochloride was encapsulated in PLGA microspheres by the O/W emulsion-solvent evaporation method.The optimized formulation which avoided the crushing of microspheres during the preparation process was characterized in terms of particle size,morphology,drug loading and EE,physical state of DP in the matrix and in vitro and in vivo release behavior.DP microspheres were prepared successfully with average diameter of 30m,drug loading of 15.92±0.31%and EE up to 78.79±2.56%.Scanning electron microscope image showed it has integrated spherical shape with no drug crystal and porous on its surface.Differential scanning calorimetry and X-ray diffraction results suggested DP was in amorphous state or molecularly dispersed in microspheres.The Tg of PLGA was increased with the addition of DP.The release profile in vitro was characterized with slow but continuous release that lasted for about one week and fitted well with first-order model,which suggested the diffusion governing release mechanism.After single-dose administration of DP microspheres via subcutaneous injection in rats,the plasma concentration of DP reached peak concentration at 0.50 d,and then declined gradually,but was still detectable at 15 d.A good correlation between in vitro and in vivo data was obtained.The results suggest the potential use of DP microspheres for treatment of Alzheimer’s disease over long periods.

Effect of Excipients on Stability and Structure of rhCuZn-SOD Encapsulated in PLGA Microspheres

When a protein is encapsulated into poly( DL -lactide-co-glycolide)(PLGA) microspheres by means of the double-emulsion method,the harsh microspheres formation process including ultrasonification,exposure to an organic solvent and a polymer may cause the denaturation of the protein. In this study,we investigated the enzymatic activity change and the effect of the excipients on the stability of recombinant human Cu,Zn-superoxide dismutase(rhCu,Zn-SOD) during the emulsification. The specific activity recovery was found to be concentration dependent and the excipients involved such as PEG 600 and Tween 20,and trehalose were shown to increase the stability of rhCu,Zn-SOD. The protein structural integrity within the microspheres was analyzed by FTIR. The structure of rhCu,Zn-SOD within PLGA microspheres containing trehalose was found to be similar to that of the native solid state,whereas the protein encapsulated during the preparation in the absence of any excipient changed due to the possible hydrophobic interaction with the polymer. The results suggest that a rational stability strategy for protein to be encapsulated into microspheres should aim at different processes.

Immune Augmentation of Injectable PLGA – Dextran (PLDEX) a Double Polymeric Microspheres as an Adjuvant for Hepatitis B Vaccine

A new method has been developed to prepare microspheres by blending PLGA and dextran polymers (PLDEX) using solvent evaporation technique. Recombinant hepatitis B vaccine (HBsAg) was incorporated in to the double polymeric system. The objective of this study was to investigate the feasibility of PLDEX polymeric microspheres as an adjuvant for hepatitis B vaccine (HBsAg). The present study demonstrates the immunogenicity profile of HBsAg encapsulated in PLDEX and compared their efficacy with alum adsorbed HBsAg. The single intramuscular injection of HBsAg loaded PLDEX microspheres in Wistar rats resulted satisfactory antibody titers. Based on in vivo findings PLDEX microspheres were able induce satisfactory immune response.

Dexamethasone-Loaded PLGA Microspheres Incorporated PLLA/PLGA/PCL Composite Scaffold for Bone Tissue Engineering

The combination of micro-carriers and polymer scaffolds as promising bone grafts have attracted considerable interest in recent decades.The poly(L-lactic acid)/poly(lactic-co-glycolic acid)/polycaprolactone(PLLA/PLGA/PCL)composite scaffold with porous structure was fabricated by thermally induced phase separation(TIPS).Dexamethasone(DEX)was incorporated into PLGA microspheres and then loaded on the PLLA/PLGA/PCL scaffoldtopreparethedesiredcompositescaffold.The physicochemical properties of the prepared composite scaffold were characterized.The morphology of rat bone marrow mesenchymal stem cells(BMSCs)grown on scaffolds was observed using scanning electron microscope(SEM)and fluorescence microscope.The resultsshowedthatthePLLA/PLGA/PCLscaffoldhad interconnected macropores and biomimetic nanofibrous structure.In addition,DEX can be released from scaffold in a sustained manner.More importantly,DEX loaded composite scaffold can effectively support the proliferation of BMSCs as indicated by fluorescence observation and cell proliferation assay.The results suggested that the prepared PLLA/PLGA/PCL composite scaffold incorporating drug-loaded PLGA microspheres could hold great potential for bone tissue engineering applications.

Cellulose Nanocrystals-Coated Polylactide(PLA) Microspheres Obtained via a Pickering Emulsion Approach

In order to prepare cellulose nanocrystals( CNCs)-coated polylactide( PLA) microspheres for the use of drug delivery and tissue engineering,a Pickering emulsion route was applied. The stable Pickering emulsions were prepared using CNCs as efficient stabilizers without any additional surfactant. The microspheres were successfully fabricated after volatilization of the solvent. What's more,the size of microspheres could be controlled by fabrication parameters.

Recent research and development of PLGA/PLA microspheres/nanoparticles: A review in scientific and industrial aspects

Poly(D,L-lactic-co-glycolic acid)(PLGA)/poly (lactic acid)(PLA) microspheres/nanoparticles are one of the most successful drug delivery systems (DDS) in lab and clinic. Because of good biocompatibility and biodegradability, they can be used in various areas, such as longterm release system, vaccine adjuvant, tissue engineering, etc. There have been 15 products available on the US market, but the system still has many problems during development and manufacturing, such as wide size distribution, drug stability issues, and so on. Recently, many new and modified methods have been developed to overcome the above problems. Some of the methods are easy to scale up, and have been available on the market to achieve pilot scale or even industrial production scale. Furthermore, the relevant FDA guidance on the DDS is still incomplete, especially for abbreviated new drug application. In this review, we present some recent achievement of the PLGA/PLA microspheres/nanoparticles, and discuss some promising manufacturing methods. Finally, we focus on the current FDA guidance on the DDS. The review provides an overview on the development of the system in pharmaceutical industry.

PLGA/PLA共混纳米纤维膜的结构与性能

为制备组织工程支架材料,以具有优异生物相容性的PLGA和PLA为原料,通过静电纺丝法制备PLGA/PLA共混纳米纤维膜。通过扫描电镜、流变仪、TG-DSC热分析仪和电子强力仪测定共混纳米纤维膜的形貌结构、微细结构和力学性能。结果表明:通过静电纺丝法可成功制备PLGA/PLA共混微、纳米级纤维膜;随着PLA共混比例的增加,纺丝液的黏度逐渐增大,使得纳米纤维的直径增加、分布均匀、孔径增大、孔隙率减小;热分析结果表明,随着PLA共混比例的增加,支架的结晶度和结构稳定性提高,断裂强度增加,伸长减小;可通过调节PLGA和PLA的共混比例来调控支架材料的结构与性能,以满足不同组织工程支架的要求。

利用PLA、PGA、PLGA三种支架再生兔关节软骨

目的观察兔关节软骨细胞在聚乳酸(PLA),聚羟基乙酸(PGA),以及两者的共聚物PLGA三种三维支架上的贴附和生长情况,利用组织工程技术培养工程化关节软骨。方法多聚赖氨酸包埋PLA,PGA,PLGA三维细胞支架。分离培养兔关节软骨细胞,体外扩增后种植到三种支架中。在体外培养软骨细胞一支架复合物,4周终止培养,进行HE、Masson组织学染色、Ⅱ型胶原免疫组织化学染色。结果(1)体外培养发现,软骨细胞在PLGA支架材料内贴附生长良好,长期培养仍保持软骨细胞特性,其贴附生长能力,分泌Ⅱ型胶原能力较PGA,PLA支架组强。(2)支架经过多聚赖氨酸包埋后,软骨细胞的贴附生长及分泌Ⅱ型胶原能力均较对照组好。结论多聚赖氨酸处理的PLGA三维支架适合软骨细胞贴附生长和分泌Ⅱ型胶原,可作为软骨组织工程的细胞载体。

PLA/PLGA共聚物在组织工程中的应用

聚乳酸(Polylactic acid,PLA)及其聚羟基乙酸共聚物[Poly(D,L-lactic-co-glycolic)acid]是一种生物相容性良好的可降解生物材料,具有支架和缓释的双重作用,目前针对性的研究主要集中于组织工程学和药学领域。本文对PLA/PLGA共聚物的代谢特征、降解机制,以及在组织工程中的应用等方面进行综述。

Preparation and in Vitro Evaluation of Polylactic Acid (PLA) or Polylactic-co-Glycolic Acid (PLGA) Microcapsules Loaded with Estradiol

Aim PLA/PLGA was used as biodegradable and biocompatible carriers to achieve sustained release of estradiol (E 2). Methods Microcapsules (MC) were prepared by an emulsification solvent extraction method, and then the properties and in vitro drug release behavior of MC were examined. An analysis of variance (ANOVA) was used to test the statistical significance. Then, multiple comparisons were made with a T method between levels to examine the significance of difference further. For all the results a P value 】0 05 was considered statistically insignificant . Results Under the same conditions, the water adding speed and the particle size had significant effects ( P 【0 01) on the entrapment efficiency of MC; the water adding speed and the concentration of PLA in the oil phase had significant effects ( P 【0 01) on the diameter MC in medium. Release of E 2 from MC was influenced significantly ( P 【0 01) by the water adding speed and the type and molecule weight of the polymers. But the differences between levels of the variates were not all significant. Conclusion E 2 PLA/PLGA MC with various properties can be formed when the formulation and the technology were changed accordingly.

具生物降解型的聚合物PLA/PLGA—18甲基炔诺酮微球注射剂的体内、外研究

以PLA/PLGA等三种高分子聚合物为载体,以LNG为活性药物的微球长效避孕注射剂,进行了体内、外释药速率、载体的体内降解以及抑制大鼠动情周期的比较研究。实验结果认为三种微球注射剂均具有明显延缓药物释放的性能,其释药和聚合物降解速度随LA比例的减小而增快,但体外释放及抑制大鼠性周期的天数则无明显差别。

PLA/PLGA及其嵌段共聚物就地成形植入装置的研究进展

介绍了就地成形载药装置概念、形成机制和应用前景并以PLA/PLGA及PLA/PLGA与PEG的三嵌段共聚物为基质的就地成形植入物,在其形成机理、制备条件、降解特性方面的研究进展进行了综述。结论是由这两类聚合物制备的就地成形植入物在药物缓释方面有着许多优良特性,但同时也有各自不足之处,它们是处于进一步研究发展阶段的新型药物缓释装置。

超临界CO_2中合成PLA及PLGA研究进展

介绍了超临界二氧化碳(ScCO2)作为聚合反应介质的特点,从提高产物分子量、改善产物形貌和降低产物毒性3个方面阐述了在ScCO2中合成聚乳酸(PLA)和聚(乳酸-乙醇酸)(PLGA)的工艺方法,并指出了此类聚合反应的发展方向。

BCNU/PLGA microspheres:a promising strategy for the treatment of gliomas in mice

Objective：To investigate the effects of BCNU/PLGA microspheres on tumor growth,apoptosis and chemotherapy resistance in a C57BL/6 mice orthotopic brain glioma model using GL261 cell line.Methods：BCNU/PLGA sustained-release microspheres were prepared by the water-in-oil-in-water emulsion technique.GL261 cells were intracranially injected into C57BL/6 mouse by using the stereotactic technology.A total of 60 tumor-bearing mice were randomly and equally divided into three groups：untreated control,PLGA treated,BCNU/PLGA treated.Magnetic resonance imaging （MRI） was taken to evaluate tumor volume.BCNU/PLGA sustained-release wafers were implanted in the treatment group two weeks after inoculation.Survival time and quality were observed.Specimens were harvested,and immunohistochemical staining was used to check the expression of Bax,Bcl-2,and O6-methylguanine-DNA methyltransferase （MGMT）.Statistical methods was used for analysis of relevant data.Results：BCNU/PLGA sustained-release wafers were fabricated and implanted successfully.There is statistical difference of survival time between the BCNU/PLGA treated group and control groups （P＜0.05）.MRIscan showed inhibitory effect of BCNU/PLGA on tumor growth.Compared to the group A and B,BCNU/PLGA decreased the expression of apoptosis related gene Bcl-2 （P＜0.05）,but did not elevate the expression level of Bax （P＞0.05）,with the ratio of Bax/Bcl-2 increased.For MGMT protein expression,no statistically significant change was found in treated group （P＞0.05）.Conclusions：Local implantation of BCNU/PLGA microspheres improved the survival quality and time of GL261 glioma-bearing mice significandy,inhibited the tumor proliferation,induced more cell apoptosis,and did not increase the chemotherapy resistance.