Fabrication of hydrophilic paclitaxel-loaded PLA-PEG-PLA microparticles via SEDS process

In this work, chemically bonded poly(D, L-lactide)-polyethylene glycol-poly(D, L-lactide) (PLA-PEG-PLA) triblock copolymers with various PEG contents and PLA homopolymer were synthesized via melt polymerization, and were confirmed by FTIR and ¹H-NMR results. The molecular weight and polydispersity of the synthesized PLA and PLA-PEG-PLA copolymers were investigated by gel permeation chromatography. Hydrophilicity of the copolymers was identified by contact angle measurement. PLA-PEG-PLA and PLA microparticles loaded with and without PTX were then produced via solution enhanced dispersion by supercritical CO₂ (SEDS) process. The effect of the PEG content on the particle size distribution, morphology, drug load, and encapsulation efficiency of the fabricated microparticles was also studied. Results indicate that PLA and PLA-PEG-PLA microparticles all exhibit sphere-like shape with smooth surface, when PEG content is relatively low. The produced microparticles have narrow particle size distributions and small particle sizes. The drug load and encapsulation efficiency of the produced microparticles decreases with higher PEG content in the copolymer matrix. Moreover, high hydrophilicity is found when PEG is chemically attached to originally hydrophobic PLA, providing the produced drug-loaded microparticles with high hydrophilicity, biocompatibility, and prolonged circulation time, which are considered of vital importance for vessel-circulating drug delivery system.     

超临界CO2抗溶剂法制备紫杉醇缓释微球

采用超临界流体强制分散溶液技术,以D,L-聚乳酸和D,L-聚乳酸-聚乙二醇共聚物为载体材料,分别制备了紫杉醇缓释微球.通过扫描电镜、激光粒度仪检测微球外形及粒径分布;紫外吸光度法测量其载药量和包封率,恒温振荡透析法检测药物的体外释放性能;MTT法检测载药微球对Hela细胞的抑制作用.实验表明,两种载体的缓释微球球形度均较好,表面光滑,平均粒径较小,且粒径分布较窄.以聚乳酸和共聚物为载体的缓释微球载药量分别为5.4%±0.3%和5.3%±0.4%,包封率分别为51%±3%和45%±3%;药物释放呈缓释模式,共聚物载药微球药物释放速率较快.MTT法检测结果表明,载药微球对Hela细胞的增殖有明显抑制,共聚物载药微球对细胞增殖抑制更为明显.     

Enhanced water-solubility of Licorice extract microparticle prepared by antisolvent precipitation process

In this study, Licorice extract (LE) microparticles were successfully prepared using antisolvent precipitation process. Ethyl acetate and dimethyl sulfoxide, were used as the antisolvent and solvent, respectively. By means of orthogonal experimental design, the influences of several process parameters on the mean particle size (MPS) were investigated. The concentration range of the LE solution, the volume ratio of solvent to antisolvent, dripping speed, and temperature were 4.3–34.5 mg/mL, 1:1–1:12, 1–10 mL/min, and 20–35 °C, respectively. Based on the above orthogonal experiments, the optimum antisolvent precipitation process conditions were found to be: temperature 20 °C, concentration of the LE solution 17.2 mg/mL, volume ratio of solvent to antisolvent 1:4, dripping speed 10 mL/min. The LE microparticles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform-infrared (FT-IR) spectroscopy, thermal gravimetric analysis (TG), differential scanning calorimetry (DSC), HPLC analysis and dissolution test. And the morphology, crystalline state and chemical structure, drug purity, dissolution rate and bioavailability of LE microparticles were investigated. Under optimum antisolvent precipitation process conditions, the MPS of LE microparticles reached to 85.3 nm, and with uniform distribution. And the LE microparticles had the same chemical structure as the unprocessed drug, but the crystallinity was reduced, purity was increased. Furthermore, the water solubility increased from 4.82 mg/mL to 16.10 mg/mL, and bioavailability is increased by 64.36%.     

Influence of polymer blends on the characterization of gliclazide – encapsulated into poly (Æ-caprolactone) microparticles

Gliclazide (GLZ)-loaded microparticles made with a polymeric blend were prepared by a solvent evaporation technique. Organic solutions of two polymers, poly(?-caprolactone) (PCL) and Eudragit RS (E RS) or ethyl cellulose (EC), in different weight ratios, and 33.3% of GLZ were prepared and dropped into aqueous solution of poly vinyl alcohol, in different experimental conditions, achieving drug-loaded microparticles. The obtained microparticles were characterized in terms of yield of production, shape, size, surface properties, drug content, and in vitro drug release behavior. The physical state of the drugs and the polymer was determined by scanning electron microscopy (SEM), Fourier transform infra red and differential scanning calorimetry. Following the in vitro release studies microparticles made from blends of polymer, PCL/E RS or EC showed slower drug release than microparticles made from single PCL polymer. Surface morphology also revealed presence of porous and spherical structure of microparticles. Microparticles showing sustained release of GLZ were examined in rabbits and plasma GLZ concentrations were calculated using HPLC method of assay.     

超临界反溶剂过程制备乙基纤维素超细微粒

超临界反溶剂过程是近年来提出的一种制备纳微米粉体材料的新方法.文中利用超临界反溶剂过程制备乙基纤维素超细微粒.实验以乙醇为有机溶剂,超临界CO2为反溶剂,研究了操作压力、温度、溶液浓度、反溶剂流量等操作参数对制备的超细微粒的形态、粒径及其分布的影响.研究表明,采用乙醇作为有机溶剂可得到较理想的结果,能制备出平均直径在20 nm～40 nm范围内的乙基纤维素超细微粒.通过傅立叶红外光谱分析了乙基纤维素超细微粒结构,从特征基判断其结构未发生变化.     

Supercritical antisolvent synthesis of fine griseofulvin particles

Supercritical carbon dioxide (scCO₂) was used as antisolvent to precipitate griseofulvin (GF), an orally administered antifungal drug, from methylene chloride (DCM) using the supercritical antisolvent (SAS) process. The influence of different operating parameters such as antisolvent addition rate, temperature, concentration, and solution addition rate on product characteristics (particle size and size distribution, and morphology) has been analyzed. This investigation shows that with an adequate selection of process conditions it is possible to selectively produce crystalline needle-shaped particles with narrow size distribution.     

Study of poly(<Emphasis Type="SmallCaps">l</Emphasis>-lactide) microparticles based on supercritical CO<Subscript>2</Subscript>

Poly(l-lactide) (PLLA) microparticles were prepared in supercritical anti-solvent process. The effects of several key factors on surface morphology, and particle size and particle size distribution were investigated. These factors included initial drops size, saturation ratio of PLLA solution, pressure, temperature, concentration of the organic solution, the flow rate of the solution and molecular weight of PLLA. The results indicated that the saturation ratio of PLLA solution, concentration of the organic solution and flow rate of the solution played important roles on the properties of products. Various microparticles with the mean particle size ranging from 0.64 to 6.64 μm, could be prepared by adjusting the operational parameters. Fine microparticles were obtained in a process namely solution-enhanced dispersion by supercritical fluids (SEDS) process with dichloromethane/acetone mixture as solution.     

Production of pure indinavir free base nanoparticles by a supercritical anti-solvent (SAS) method

Context: This work investigated the production of pure indinavir free base nanoparticles by a supercritical anti-solvent method to improve the drug dissolution in intestine-like medium.

Objective: To increase the dissolution of the drug by means of a supercritical fluid processing method.

Materials and methods: Acetone was used as solvent and supercritical CO₂ as antisolvent. Products were characterized by dynamic light scattering (size, size distribution), scanning electron microscopy (morphology), differential scanning calorimetry (thermal behaviour) and X-rays diffraction (crystallinity).

Results and discussion: Processed indinavir resulted in particles of significantly smaller size than the original drug. Particles showed at least one dimension at the nanometer scale with needle or rod-like morphology. Results of X-rays powder diffraction suggested the formation of a mixture of polymorphs. Differential scanning calorimetry analysis showed a main melting endotherm at 152?°C. Less prominent transitions due to the presence of small amounts of bound water (in the raw drug) or an unstable polymorph (in processed IDV) were also visible. Finally, drug particle size reduction significantly increased the dissolution rate with respect to the raw drug. Conversely, the slight increase of the intrinsic solubility of the nanoparticles was not significant.

Conclusions: A supercritical anti-solvent method enabled the nanonization of indinavir free base in one single step with high yield. The processing led to faster dissolution that would improve the oral bioavailability of the drug.     

超临界二氧化碳中一种高分子弱凝胶的制备及性质

通过改变丙烯酸(AA)与可反应疏水单体甲基丙烯酸-3-三甲氧基硅丙酯(MPS)的投料比,在超临界二氧化碳介质中制备了一系列的AA与MPS共聚物(AA-co-MPS)。采用滴定法、扫描电镜和旋转黏度计对共聚物的组成及性质进行了表征。结果表明,MPS反应活性较丙烯酸高,共聚物形貌是直径约0.5μm左右的球形颗粒。共聚物的溶解试验结果表明,硅氧烷间化学反应形成弱凝胶体系,分子间交联使弱凝胶的黏度随着可反应疏水单体含量增加而增加。共聚物中可反应疏水单体质量百分比含量超过2.1%时,共聚物开始形成沉淀。由于共聚物具有pH敏感性,弱凝胶体系黏度随pH值变化先增加后减少,在pH=5.5出现峰值。     

Thermosensitive nanocontainers prepared from poly(N-isopropylacrylamide-co-N-(hydroxylmethyl) acrylamide)-g-poly(lactide)

Thermally-responsive graft copolymer of poly(N-isopropylacrylamide-co-N-(hydroxylmethyl)acrylamide)-g-poly(lactide) was synthesized by ring-opening polymerization of D,L-lactide (LA). The polymerization was initiated by the hydroxy group of poly(N-isopropyl acrylamide-co-N-(hydroxylmethyl) acrylamide), using stannous octoate as catalyst. The resulting polymer was temperature-sensitive and the lower critical solution temperature (LCST) was affected by their composition. The chemical structure and physical properties of the grafted copolymers were investigated by various methods. Nanocontainers formed from the self-assembly of poly(N-isopropylacrylamide-co-N-(hydroxylmethyl) acrylamide)-g-poly(lactide) were characterized by transmission electron microscopy (TEM), and a spherical structure was observed. Dynamic light scattering (DLS) results indicate that the particle size increased with the increase of polylactide content in the copolymer. The properties of this polymer are interesting for both industrial application and fundamental research. In particular it will combine a spatial specificity in a passive manner and a temperature-responsive active targeting mechanism for drug delivery system.     

Impact of surfactant selection on the formulation and characterization of microparticles for pulmonary drug delivery

The effect of suspension stabilizers, internal aqueous phase volume and polymer amount were investigated for the production of protein loaded poly(d,l?lactide-co-glycolide) (PLGA) microparticles suitable for pulmonary drug delivery. PLGA microparticles were produced adopting water-in-oil-in-water (W/O/W) solvent evaporation technique and were investigated for surface morphology, particle size, encapsulation efficiency (EE%) and in-vitro release profile. Porous surface morphologies with a narrow size distribution were observed when employing 0.5?ml internal aqueous phase; 23.04?µm (±0.98), 15.05?µm (±0.27) and 22.89?µm (±0.41) for PVA, Tween 80 and oleic acid. Porous microparticles exhibited increased size and reduction in EE% with increasing internal aqueous phase, with non-porous microparticles produced when adopting 2.0?ml internal aqueous phase. The selection of stabilizer influences the size of the pores formed thus offers potential for the aerodynamic properties of the microparticles to be manipulated to achieve suitable aerosolization characteristics for pulmonary delivery of proteins.     

Use of DSC to Study the Degradation Behavior of PLA and PLGA Microparticles

Abstract

Poly (D, L-lactide) (PLA) and poly (D, L-lactide-co-glycolide) (PLGA) microparticles were evaluated for their in vitro degradation behavior in 0.1 M phosphate buffer pH 7.4 at 37°C. The influence of polymer characteristics, particle size, and preparation technique was investigated. Differential scanning calorimetry (DSC) was used to follow the time-dependent physical and morphological changes within the hydrated and dried microparticles, to determine the physical state of the absorbed water, and to detect penetration of buffer ions into the particle bulk. Results were compared with degradation kinetics obtained by gel permeation chromatography (GPC) and gravimetry. The latter revealed triphasic degradation profiles for R 202 and RG 755 microparticles with a mean particle size of 55 μm and 60 μm, respectively. An induction period was followed by a period of accelerated ester cleavage pre-onset of erosion and a final period of slow ester cleavage post-onset of erosion. According to DSC data the induction period is characterized by a glassy hydrated polymer matrix with a T_gH > 37°C. The induction period (t_i) correlated well with the lag-time of T_gH to reach 37°C (t_{lag 37°C}), thus confirming the importance of chain mobility for the degradation kinetic. The final decrease in the rate of ester chain cleavage post-onset of erosion turned out to be the result of an increase in matrix permeability for buffer ions inducing sodium salt formation and phase separation of the water-soluble degradation products within the particle bulk. Particle size effects depended on the preparation technique. A decrease in the degradation rate with a decrease in mean particle size was only observed when the molecular weight distribution of the polymer was not affected by the prepa ration procedure used to reduce the particle size. According to DSC data, the effect is due to a faster and more continuous release of the water-soluble degradation products from the smaller particles, thus reducing their plasticizing and autocata-lytic effects within the particle bulk.     

超临界流体技术制备5-氟尿嘧啶-吲哚美辛-聚乳酸缓释微球

为了考察药物5-氟尿嘧啶(5-Fu)与吲哚美辛(IDMC)的协同作用, 采用超临界流体强制分散溶液技术(SEDS), 以二氯甲烷/二甲亚砜为共溶剂, 制备了复合5-Fu和IDMC的L-聚乳酸(PLLA)微球。利用单因素法探索了制备复合微球的最佳外部条件, 通过表面形貌、 载药量、 粒径分布、 释放性能的检测和体外细胞实验来表征微球的各项性能。结果表明: 当共溶剂二氯甲烷/二甲亚砜比例为30∶1时, 制备该微球的优化条件为39℃、 14MPa; 微球形貌呈类球形, 粒径分布在0.5~5μm; 复合IDMC后微球具有更优良的缓释效果; 载药微球对A549细胞系增殖有明显的抑制作用, 但与复合IDMC前后微球共培养的2组细胞的相对生长速率(RGR)无显著性差异。      

Preparation, characterization and in vitro release properties of morphine-loaded PLLA-PEG-PLLA microparticles via solution enhanced dispersion by supercritical fluids

Morphine-loaded poly(l-lactide)-poly(ethylene glycol)-poly(l-lactide) (PLLA-PEG-PLLA) microparticles were prepared using solution enhanced dispersion by supercritical CO₂ (SEDS). The effects of process variables on the morphology, particles size, drug loading (DL), encapsulation efficiency and release properties of the microparticles were investigated. All particles showed spherical or ellipsoidal shape with the mean diameter of 2.04–5.73 μm. The highest DL of 17.92 % was obtained when the dosage ratio of morphine to PLLA-PEG-PLLA reached 1:5, and the encapsulation efficiency can be as high as 87.31 % under appropriate conditions. Morphine-loaded PLLA-PEG-PLLA microparticles displayed short-term release with burst release followed by sustained release within days or long-term release lasted for weeks. The degradation test of the particles showed that the degradation rate of PLLA-PEG-PLLA microparticles was faster than that of PLLA microparticles. The results collectively suggest that PLLA-PEG-PLLA can be a promising candidate polymer for the controlled release system.     

沉淀聚合法制备聚酰胺酸微粒子及其酰亚胺化

利用沉淀聚合法,以均苯四酸二酐(PMDA)和4,4′-二氨基二苯醚(ODA)为单体,丁酮(MEK)和N-甲基吡咯烷酮(NMP)混合溶液为溶剂,在常温下,搅拌速度为500r/min,制备了聚酰亚胺的前驱体聚酰胺酸(PAA)。红外光谱表明,所得产物是聚酰胺酸。利用扫描电子显微镜(SEM)分析了混合溶剂的不同体积比对聚酰胺酸微粒子形貌的影响,结果表明,当MEK与NMP的体积比为8:1时,聚酰胺酸微粒子的平均粒径最大,为5.89μm。试制了聚酰亚胺(PI)微粒子,对其进行了SEM、红外光谱分析及热重(TG)分析。     

PLLA-PEG-PLLA/Fe_3O_4磁性微球的制备及性能

以聚乙二醇为引发剂,L-丙交酯为单体,开环聚合得到聚乳酸-聚乙二醇三嵌段共聚物(PLLA-PEG-PLLA),采用溶剂挥发法制备了PLLA-PEG-PLLA/Fe_3O_4磁性微球,并通过扫描电镜对其形态进行了表征。利用振动样品磁强计和Tg研究了微球的磁含量和磁性能,结果发现,相同粒径不同磁含量的磁性微球,磁含量越高,升温速率越快,当磁含量为70.57%时,升温速率最快,能达到磁热疗的有效温度42℃。对于磁含量相同,粒径不同的微粒,粒径越小,升温速率越快,粒径约为10μm时升温速率最快。     

Preliminary investigation on the design of biodegradable microparticles for ivermectin delivery: set up of formulation parameters

The aim was to design sterile biodegradable microparticulate drug delivery systems based on poly(dl-lactide) (PLA) and poly(?-caprolactone) (PCL) and containing ivermectin (IVM), an antiparasitic drug, for subcutaneous administration in dogs. The drug delivery system should: (i) ensure a full 12-month protection upon single dose administration; (ii) be safe with particular attention regarding IVM dosage and its release, in order to prevent over dosage side effects. This preliminary work involves: polymer selection, evaluation of the effects of γ-irradiation on the polymers and IVM, investigation and set up of suitable microparticle preparation process and parameters, IVM-loaded microparticles in vitro release evaluation.

Results of gel permeation chromatography analysis on the irradiated polymers and IVM mixtures showed that combination of IVM with the antioxidant α-tocopherol (TCP) reduces the damage extent induced by irradiation treatment, independently on the polymer type.

Solvent evaporation process was successfully used for the preparation of PLA microparticles and appropriately modified; it was recognized as suitable for the preparation of PCL microparticles. Good process yields were achieved ranging from 76.08% to 94.72%; encapsulation efficiency was between 85.76% and 91.25%, independently from the polymer used. The type of polymer and the consequent preparation process parameters affected microparticle size that was bigger for PCL microparticles (480–800?µm) and solvent residual that was >500?ppm for PLA microparticles. In vitro release test showed significantly faster IVM release rates from PCL microparticles, with respect to PLA microparticles, suggesting that a combination of the polymers could be used to obtain the suitable drug release rate.     

微波辐射细乳液聚合制备含氟丙烯酸酯乳液

在微波辐射下,采用细乳液聚合方法,合成了稳定的含氟丙烯酸酯(FA)、甲基丙烯酸甲酯(MMA)及丙烯酸丁酯(BA)三元共聚乳液。利用FT-IR表征了共聚物的结构组成;采用激光光散射粒度仪(PCS)研究了聚合过程中粒径变化;用称量法测定了转化率;用透射电子显微镜(TEM)观察了乳胶粒的形貌。结果表明,油溶性引发剂AIBN引发FA-MMA-BA三元细乳液共聚合的主要成核场所为单体液滴;所制得的乳胶粒呈球形,平均粒径为72 nm~98 nm;微波的引用能够加快反应速率,提高单体转化率,且制得的细乳液离心稳定性更好;耐水性随氟单体含量增加而提高。     

Engineering of poly(ε-caprolactone) microcarriers to modulate protein encapsulation capability and release kinetic

Drug delivery applications using biodegradable polymeric microspheres are becoming an important means of delivering therapeutic agents. The aim of this work was to modulate the microporosity of poly(ε-caprolactone) (PCL) microcarriers to control protein loading capability and release profile. PCL microparticles loaded with BSA (bovine serum albumin) have been de novo synthesized with double emulsion solvent evaporation technique transferred and adapted for different polymer concentrations (1.7 and 3% w/v) and stabilizer present in the inner aqueous phase (0.05, 0.5 and 1% w/v). SEM (scanning electron microscope) and CLSM (confocal laser scanning microscope) analysis map the drug distribution in homogeneously distributed cavities inside the microspheres with dimensions that can be modulated by varying double emulsion process parameters. The inner structure of BSA-loaded microspheres is greatly affected by the surfactant concentration in the internal aqueous phase, while a slight influence of polymer concentration in the oil phase was observed. The surfactant concentration mainly determines microspheres morphology, as well as drug release kinetics, as confirmed by our in-vitro BSA release study. Moreover, the entrapped protein remained unaltered during the protein encapsulation process, retaining its bio-activity and structure, as shown through a dedicated gel chromatographic analytical method.