用Doehlert设计优化辅酶Q_(10)纳米粒的处方和制备工艺

目的更好地指导处方设计。方法采用纳米沉淀法制备辅酶Q10纳米粒;以粒径、载药量、包封率及总评优化值为指标,评价纳米粒的质量;采用Doehlert设计安排试验,考察稳定剂维生素E琥珀酸聚乙二醇酯(vitamin E polyethylene glycol 1000 succinate,TPGS)质量分数、聚乳酸-羟基乙酸共聚物(poly lactic-co-glycolic acid,PLGA)质量浓度、PLGA与药物质量比、水相与有机相体积比对制备工艺的影响,并对结果分别进行多元线性回归和二项式方程拟合,预测最佳工艺条件。结果各指标的二项式拟合方程均优于多元线性回归方程,按优化条件制备的样品平均粒径为(130.7±5.8)nm,载药量为(8.80±0.15)%,包封率为(87.99±1.49)%,与预测值偏差均小于10%。结论Doehlert设计较好地完成了辅酶Q10纳米粒的多目标同步优化,所建立的数学模型预测性良好。     

星点设计-效应面法优化水飞蓟素固体脂质纳米粒的制备

以冷却-匀质法制备水飞蓟素固体脂质纳米粒,采用星点设计-效应面法优化制备工艺,以平均粒径、包封率、载药量为评价指标,考察了药物与Compritol 888 ATO的重量比、乳化剂用量、泊洛沙姆占乳化剂的比例、乳匀压力4因素对制备工艺的影响,对结果分别进行多元线性和二项式方程拟合,用效应面法预测最佳工艺条件.结果表明,各指标的二项式拟合方程均优于多元线性回归方程,以优化条件制备的样品平均粒径为190.9nm、包封率为95.9%、载药量为8.6%.     

盐酸表柔比星-聚乳酸-羟基乙酸共聚物纳米粒的制备

摘要目的制备盐酸表柔比星 聚乳酸 羟基乙酸（PLGA）共聚物纳米粒,对其进行质量评价。方法采用乳化 溶剂挥发法制备盐酸表柔比星纳米粒;对主要处方因素如PLGA用量、外水相中聚山梨酯 80用量、泊洛沙姆188和聚山梨酯 80比例进行正交设计,以药物的包封率、载药量和药物利用率等为考察指标。结果采用优化后处方制得的纳米粒药物包封率为（32.6±1.2）%,载药量为（7.2±0.5）%,药物利用率为（51.6±3.4）%,纳米粒平均粒径166.6 nm,药物可持续160 h释放。结论该方法制备盐酸表柔比星纳米粒工艺简单,无需使用聚乙烯醇,药物释放缓慢。     

星点设计-效应面法优化穿心莲内酯固体脂质纳米粒处方

以高压均质法制备穿心莲内酯固体脂质纳米粒。采用星点设计考察药物与脂质材料(即单硬脂酸甘油酯与山嵛酸甘油酯的1∶1混合物)比例、卵磷脂与脂质材料比值及表面活性剂(吐温-80)浓度对包封率和载药量的影响,并对结果进行多元线性和二项式方程拟合,用效应面法预测最佳处方。结果表明,载药量的多元线性回归拟合方程具有良好的相关性,而包封率的二项式拟合方程优于多元线性回归拟合方程。优化处方为药脂比9%、卵磷脂与脂质材料比值为1.6、吐温-80浓度为3%。优化后固体脂质纳米粒的包封率和载药量分别为(91.0±0.9)%和(3.49±0.03)%,粒径为(286.3±8.0)nm,电位为(-20.6±0.2)mV。     

星点设计-效应面法优化美斯地浓聚乳酸纳米粒处方

目的星点设计-效应面法优化美斯地浓聚乳酸纳米粒处方。方法以复乳液中干燥法制备美斯地浓聚乳酸纳米粒,以包封率和载药量为评价指标,在单因素试验的基础上,用星点设计对显著性因素进行优化,并进行二项式方程拟合,以效应面法选取较好的工艺条件进行预测。结果以效应面法优选出的最佳工艺为:美斯地浓投药量为49.20 mg,PLA浓度为3.31%,PVA浓度为3.41%。制备的美斯地浓聚乳酸纳米粒平均包封率和载药量分别为(51.98±1.28)%和(7.01±0.31)%(n=3),与二项式拟合方程预测值相差<2%。结论应用星点设计-效应面法优化美斯地浓聚乳酸纳米粒制备工艺,能够快速、准确的得到最佳制备工艺,预测性良好。     

星点设计-效应面法优化流化床制备盐酸普萘洛尔微囊工艺

目的优化盐酸普萘洛尔微囊的制备工艺。方法采用流化床制备普萘洛尔微囊,以平均粒径,包封率、载药量及总评归一值为评价指标,并运用星点设计考察囊材液流速、喷雾压力对制备工艺的影响,对结果进行多元线性和二项式拟合,效应面法选取最佳工艺条件进行预测分析。结果从复相关系数上看,各指标二项式拟合方程均优于多元线性回归方程,最佳工艺参数:囊材液流速1.00 mL·min-1,喷雾压力0.65 bar,在此工艺条件下得到微囊粒径为300μm,载药量为20.54%,包封率达89.63%。结论优选普萘洛尔微囊的流化床制备工艺稳定可行,包封率高,有利于工业化生产。     

星点设计-效应面法优化羟基喜树碱/mPEG-S-S-C18纳米粒的制备工艺

目的 制备载羟基喜树碱（hydroxycamptothecin,HCPT）还原响应mPEG-S-S-C18纳米粒,采用星点设计-效应面法筛选优化制备工艺。方法 采用乳化-溶剂挥发法制备HCPT/mPEG-S-S-C18纳米粒,应用单因素法考察投药量、水相/油相体积比、超声功率以及超声时间对载药纳米粒包封率和载药量的影响。在此基础上,以包封率和载药量作为评价指标,采用Design-Expert V8.0.6软件进行星点设计,优化载药纳米粒的制备工艺。结果 优化获得的HCPT/mPEG-S-S-C18纳米粒制备工艺投药量为1.0 mg,水相/油相体积比为4.56∶1,超声功率为562.5 W。该工艺制备的载药纳米粒包封率为（58.14±1.04）%,载药量为（3.46±0.22）%,平均粒径为（322.9±9.52） nm,多分散性指数为0.195±0.05,Zeta电位为（-17.5±2.11） mV。结论 乳化-溶剂挥发法适用于制备HCPT/mPEG-S-S-C18纳米粒,星点设计-效应面法可优化获得载药纳米粒的最佳制备工艺,所得的载药纳米粒包封率和载药量较高,所建立的数学模型预测性良好。     

口服胸腺五肽乳酸-羟基乙酸共聚物纳米粒的制备及物理性质考察

目的制备供口服给药的胸腺五肽乳酸-羟基乙酸共聚物(thymopentin-poly lactic-co-glycolicacid;TP5-PLGA)纳米粒,并对纳米粒的物理性质进行考察。方法用复乳-溶剂挥发法制备TP5-PLGA纳米粒,以包封率为评价指标,用L16(45)正交设计优选纳米粒制备的处方工艺条件,用HPLC法测定胸腺五肽的含量,用激光粒度仪测定纳米粒的粒径,用透射电镜观察纳米粒的形态,用动态透析法考察纳米粒的体外释药特征。结果正交设计确定纳米粒制备的最优处方工艺条件为胸腺五肽质量浓度50 g.L-1,载体材料PLGA质量浓度100 g.L-1,乳化剂PVA质量浓度20 g.L-1;优化处方与工艺制备的纳米粒为规整的圆球形,平均粒径为(150.3±9.6)nm,载药量与包封率分别为(2.403±0.066)%与(28.12±0.60)%;体外释药结果表明,前5 h药物释放(31.27±1.5)%,存在一定突释,4 d累积释药量为(43.60±2.3)%。结论以乳酸-羟基乙酸共聚物为载体材料制备胸腺五肽纳米粒工艺简便,制剂具有良好的物理性质和体外释药特征。     

因子设计-效应面法优化紫杉醇聚乳酸-羟基乙酸纳米粒处方和制备工艺

目的:优化紫杉醇聚乳酸-羟基乙酸(PLGA)纳米粒处方和制备工艺.方法:以PLGA为载体,采用溶剂扩散法制备紫杉醇PLGA纳米粒,用32满因子设计实验,考察因素PLGA在有机相中的浓度和理论载药量对纳米粒的粒径、载药量和包封率的影响,实验数据分别采用线性方程和二次多项式拟合,根据最佳数学模型绘制效应面并选出最优处方.结果:2个影响因素和3个评价指标之间存在定量关系,最优处方为:紫杉醇的理论载药量为9.09%、有机相中PLGA浓度为2%,制备得到的纳米粒粒径为281 nm,实际载药量为7.73%,包封率为57.43%.结论:采用因子设计-效应面法完成了紫杉醇纳米给药系统的多目标同步优化.     

星点设计-效应面法优化冬凌草甲素聚乳酸纳米粒的制备工艺

目的：优化改良自乳化溶剂扩散法制备冬凌草甲素聚乳酸纳米粒的制备工艺。方法：采用星点设计-效应面法,以冬凌草甲素在有机相中的浓度、载体在有机相中的浓度和水相与有机相的比例为考察因素,以包封率、载药量及药物利用率为考察指标,根据星点设计原理进行实验安排,并用多元线性回归及二项式拟合建立指标与因素之间的数学模型,经效应面法预测最佳工艺条件。结果：优化的最佳因素范围为药物浓度X1：0．5—0．8mg／mL;载体浓度X2：1．6～2．6mg／mL;水油比X3：1～1．5。以优化条件制备的样品平均粒径为98．5nm,包封率为（28．86±0．93）％,载药量为（8．23±0．35）％。结论：星点设计-效应面法适用于冬凌草甲素聚乳酸纳米粒的工艺优化,所建立的数学模型预测性良好。     

Optimized preparation of insulin-lauryl sulfate complex loaded poly (lactide-co-glycolide) nanoparticles using response surface methodology

Insulin-lauryl sulfate (INS-SDS) complex loaded poly (lactic acid-co-glycolic acid) (PLGA) nanoparticles were prepared by spontaneous emulsion solvent diffusion method. To improve the insulin entrapment efficiency (E.E), a five-level-two-factor central composite design and surface response methodology (RSM) was used to determine the optimum levels of PLGA/INS complex weight ratio and PVA/ acetone volume ratio, two important variables during nanoparticles fabrication. A quadratic model to express the E.E as a function of the two studied factors was developed. Only 10 experimental runs were necessary and the obtained model was adequate (P < 0.05). By partial derivative resolution of regression model, the optimum weight ratio of PLGA/INS complex and volume ratio of PVA/acetone was determined as 25/1 and 10/1, respectively. This preparing condition resulted E.E of insulin as high as 91% during nanoparticles production. Validation of the model was accomplished by experiments carried out on optimized formulation conditions. The experimental results were in good agreement with those predicted by the model. The results indicated that RSM represents an effective and potential technique for formulation optimization.     

Nano-encapsulation and characterization of baricitinib using poly-lactic-glycolic acid co-polymer

Baricitinib is a recently approved anti-rheumatic drug having very poor aqueous solubility and hence its performance suffers from low or inconsistent oral bioavailability. The purpose of the study was to develop and evaluate poly lactic-co-glycolic acid (PLGA) nanoparticles of baricitinib in order to enhance in vitro dissolution and performance. Nano-suspension of baricitinib with or without PLGA, a biodegradable, FDA approved semi-synthetic polymer, was developed by nanoprecipitation method. Research methodology employed a quantitative research utilizing experimental design wherein effect of independent variables such as amount of polymer, drug: polymer ratio, types of solvent, and solvent: anti-solvent ratio were evaluated over the size and size distribution of nanoparticles along with entrapment efficiencies. Among the several organic phases evaluated, acetone was found to be suitable solvent for drug and polymer. The aqueous phase (anti-solvent) was deionized water containing 1% w/v pluronic 127 as the stabilizer of nanoparticle suspension. The optimized nanoparticles had particle size less than 100 nm (91 nm ± 6.23) with a very narrow size distribution (0.169 ± 0.003), high zeta potential (−12.5 mV ± 5.46) and entrapment efficiency (88.0%). The optimized nanoparticles were characterized by scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, infrared spectroscopy and in vitro dissolution studies. In-vitro dissolution study of PLGA nanoparticles exhibited sustained release with approximately 93% release of baricitinib during 24-h period.     

Formulation and characterization of acetaminophen nanoparticles in orally disintegrating films

Abstract

The purpose of this study was to prepare orally disintegrating films containing nanoparticles loaded with acetaminophen. Nanoparticles were prepared by the emulsion-solvent evaporation method where acetone phase containing acetaminophen and poly(lactide-co-glycolide acid) (PLGA) was added to water phase containing hydroxypropyl methyl cellulose, poly ethylene glycol, polyvinyl alcohol (PVA) and aspartame in a rate of 1.5 drop?s^?1 and agitated at 1200?rpm. The size, polydispersity index (PI) and drug entrapment (DE) were measured. The emulsions were cast to form films, which were evaluated physico-mechanically. The effect of different degrees of hydrolization of PVA and polymerization of PLGA and the effect of different ratios of PVA to PLGA was studied. Films with acceptable physico-mechanical properties were further studied. The size and PI of the nanoparticles was dependent on PVA hydrolization, PLGA polymerization and the ratio of PVA to PLGA. All films disintegrated in less than one minute, but acetaminophen was not free in the dissolution media even after six days. These results may indicate that although the nanoparticles released from the films immediately when impressed in solution the drug is sustained in the nanoparticles for longer time, which is to be clarified in future work.     

Nimodipine loaded PLGA nanoparticles: formulation optimization using factorial design, characterization and in vitro evaluation

The present study was aimed at developing a sustained release formulation of Nimodipine (NIM) nanoparticles using the biodegradable polymers, poly (lactide-co-glycolide) (PLGA 50:50 and 85:15) as carrier. NIM is a widely used calcium channel blocker which has to be administered as an intravenous infusion for a prolonged period of 1-2 weeks in the treatment of cerebral vasospasm. A sustained release biodegradable formulation would serve to replace this conventional therapy of continuous intravenous administration. PLGA nanoparticles were prepared by a modified precipitation method using high pressure homogenizer at 10,000 to 14,000 psi. A 3(2) factorial design was applied for optimization of the formulation parameters and for studying the effect of two independent variables [drug: polymer ratio and concentration of surfactant (Pluronic F 127)] on entrapment efficiency and mean particle size (response variables). Contour plots were plotted which gave a visual representation of the two variables on the dependent variables and also indicated non-linear relationship between them. The nanoparticles had particle size of 131+/-1.9 nm for PLGA 50:50 and 196+/-2.2 nm for PLGA 85:15. Scanning Electron Microscopy studies indicated that nanoparticles had spherical shape with a regular surface. The nanoparticles had high entrapment efficiency (96.42+/-2.09% for PLGA 50:50 and 94.50+/-1.25% for PLGA 85:15). DSC thermograms indicated that NIM was dispersed as an amorphous state in the nanoparticles. In vitro drug release from the lyophilized nanoparticles showed 94.35 +/- 3.8% NIM release from PLGA (50:50) nanoparticles and 63.32 +/- 4.6% release from PLGA (85:15) nanoparticles in 25 days. The release was first ordered and fickian diffusion kinetics in both the cases. These preliminary results indicate that NIM loaded PLGA nanoparticles could be effective in sustaining its release for a prolonged period. However, further studies are needed to confirm its performance in vivo.     

Celecoxib-loaded poly(D,L-lactide-co-glycolide) nanoparticles prepared using a novel and controllable combination of diffusion and emulsification steps as part of the salting-out procedure

A novel procedure for the manufacture of celecoxib-loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles is described that is based upon combining salting out and emulsion-evaporation steps. An entrapment efficiency, a measure of the actual to theoretical drug content, of 97.3% was achieved, being superior to that achieved when these popular techniques were used separately (emulsion evaporation, 40.1%; salting out, 10.0%). The ratio of a water miscible solvent (acetone) to a non water-miscible solvent (dichloromethane) was shown to be the primary determinants of size and drug loading. Once optimized, using an organic phase of 3 : 1 acetone : dichloromethane vol : vol ratio, further control on particle parameters could be exerted using modification of acetone diffusion by alterations in MgCl2 x 6H2O concentration. This step was shown to have a small effect on both the mean nanoparticle size and entrapment efficiency, but found to reduce the polydispersity considerably. Diffusion control using a 45% w/v MgCl2 x 6H2O solution produced nanoparticles with a mean size of 151.4 nm, a polydispersity index of 0.023 and 98.1% entrapment efficiency. Electron microscopy showed the particles to be smooth and spherical. Sheer homogenization during the emulsification step was shown to be not as effective as sonication, with the latter technique able to produce nanoparticles after 1 min of application. Drug release studies across a semi-permeable membrane demonstrated a reduction in the burst effect as the ratio of acetone in the organic phase was increased. Calorimetry studies suggested that celecoxib existed in the nanoparticle as a molecular dispersion, with additional evidence for a strong interaction between the PLGA and the absorbed poly(vinyl alcohol) stabilizer. Formation of a strong interaction between celecoxib and PLGA, together with the formation of a radial drug gradient give a release profile that does not possess the prevalent burst effect seen with other nanoparticulate drug-loaded systems.     

PLGA nanoparticles simultaneously loaded with vincristine sulfate and verapamil hydrochloride: systematic study of particle size and drug entrapment efficiency

PLGA nanoparticles simultaneously loaded with vincristine sulfate (VCR) and verapamil hydrochloride (VRP) were prepared via combining O/W emulsion solvent evaporation and salting-out method. Ten independent processing parameters and two materials characteristics were assessed systematically to enhance the incorporation of the two hydrophilic low molecular weight drugs into PLGA nanoparticles and minimize nanoparticles size. Approaches investigated for the enhancement of drug entrapment efficiencies and the minimization of particle size included the influence of the molecular weight (MW) of PLGA and the lactide to glycolide (L:G) ratio of PLGA, PLGA concentration, the degrees of hydrolyzation and polymerization of PVA, PVA concentration, initial VCR and VRP content, acetone to dichloromethane volume ratio, aqueous phase pH, salt concentration of aqueous phase, aqueous to organic phase volume ratio, sonication time, sonication energy and removal rate of organic solvents. The nanoparticles produced by optimal formulation were submicron size (111.4 ± 2.35 nm, n = 3) and of low polydispersity (0.062 ± 0.023, n = 3). Nanoparticles observed by transmission electron microscopy (TEM) showed extremely spherical shape. The entrapment efficiencies determined with high performance liquid chromatogram (HPLC) by ultracentrifuge method were 55.35 ± 4.22% for VCR and 69.47 ± 5.34% for VRP, respectively (n = 3).     

Celecoxib-loaded poly(D,L-lactide-co-glycolide) nanoparticles prepared using a novel and controllable combination of diffusion and emulsification steps as part of the salting-out procedure

A novel procedure for the manufacture of celecoxib-loaded poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles is described that is based upon combining salting out and emulsion-evaporation steps. An entrapment efficiency, a measure of the actual to theoretical drug content, of 97.3% was achieved, being superior to that achieved when these popular techniques were used separately (emulsion evaporation, 40.1%; salting out, 10.0%). The ratio of a water miscible solvent (acetone) to a non water-miscible solvent (dichloromethane) was shown to be the primary determinants of size and drug loading. Once optimized, using an organic phase of 3?:?1 acetone?:?dichloromethane vol?:?vol ratio, further control on particle parameters could be exerted using modification of acetone diffusion by alterations in MgCl₂?·?6H₂O concentration. This step was shown to have a small effect on both the mean nanoparticle size and entrapment efficiency, but found to reduce the polydispersity considerably. Diffusion control using a 45% w/v MgCl₂?·?6H₂O solution produced nanoparticles with a mean size of 151.4?nm, a polydispersity index of 0.023 and 98.1% entrapment efficiency. Electron microscopy showed the particles to be smooth and spherical. Sheer homogenization during the emulsification step was shown to be not as effective as sonication, with the latter technique able to produce nanoparticles after 1?min of application. Drug release studies across a semi-permeable membrane demonstrated a reduction in the burst effect as the ratio of acetone in the organic phase was increased. Calorimetry studies suggested that celecoxib existed in the nanoparticle as a molecular dispersion, with additional evidence for a strong interaction between the PLGA and the absorbed poly(vinyl alcohol) stabilizer. Formation of a strong interaction between celecoxib and PLGA, together with the formation of a radial drug gradient give a release profile that does not possess the prevalent burst effect seen with other nanoparticulate drug-loaded systems.     

Doxorubicin release from core-shell type nanoparticles of poly(DL-lactide-co-glycolide)-grafted dextran

In this study, we prepared core-shell type nanoparticles of a poly(DL-lactide-co-glycolide) (PLGA) grafted-dextran (DexLG) copolymer with varying graft ratio of PLGA. The synthesis of the DexLG copolymer was confirmed by 1H nuclear magnetic resonance (NMR) spectroscopy. The DexLG copolymer was able to form nanoparticles in water by self-aggregating process, and their particle size was around 50 nm approximately 300 nm according to the graft ratio of PLGA. Morphological observations using a transmission electron microscope (TEM) showed that the nanoparticles of the DexLG copolymer have uniformly spherical shapes. From fluorescence probe study using pyrene as a hydrophobic probe, critical association concentration (CAC) values determined from the fluorescence excitation spectra were increased as increase of DS of PLGA. 1H-NMR spectroscopy using D2O and DMSO approved that DexLG nanoparticles have core-shell structure, i.e. hydrophobic block PLGA consisted inner-core as a drug-incorporating domain and dextran consisted as a hydrated outershell. Drug release rate from DexLG nano-particles became faster in the presence of dextranase in spite of the release rate not being significantly changed at high graft ratio of PLGA. Core-shell type nanoparticles of DexLG copolymer can be used as a colonic drug carrier. In conclusion, size, morphology, and molecular structure of DexLG nanoparticles are available to consider as an oral drug targeting nanoparticles.     

PLGA nanoparticles containing praziquantel: effect of formulation variables on size distribution

Praziquantel has been shown to be highly effective against all known species of Schistosoma infecting humans. Spherical nanoparticulate drug carriers made of poly(d,l-lactide-co-glycolide) acid with controlled size were designed. Praziquantel, a hydrophobic molecule, was entrapped into the nanoparticles with theoretical loading varying from 10 to 30% (w/w). This study investigates the effects of some process variables on the size distribution of nanoparticles prepared by emulsion–solvent evaporation method. The results show that sonication time, PLGA and drug amounts, PVA concentration, ratio between aqueous and organic phases, and the method of solvent evaporation have a significant influence on size distribution of the nanoparticles.