Preparation,characterization and in vitro intestinal absorption of a dry emulsion formulation containing atorvastatin calcium

A redispersible dry emulsion (DE) formulation of atorvastatin calcium (AC) was developed to enhance the in vitro dissolution of AC, thereby increasing its gastrointestinal absorption. The spray-drying technology was used where Plurol Oleique CC 497 was chosen as the oil phase. Effects of carriers, surfactants, and homogenizers on the characteristics of DE containing AC were systematically investigated. The final formulation consisted of dextrin and Poloxamer 188 as carrier and surfactant, respectively, and was homogenized by a high pressure homogenizer before spray drying. The in vitro release of AC from the optimized DE was significantly higher than that of pure AC powder (76% vs. 30% at 24 hr). The in vitro intestinal absorption of AC from the DE formulation was 0.77 μg/cm² at 2 hr, which was a 2.33-fold increase compared to the pure unformulated AC powder. These results suggest that the oral dry emulsion formulation could improve the intestinal absorption of AC.     

尼群地平固体分散片的制备及其体外溶出度的测定

目的 制备尼群地平(NT)固体分散体片，提高其溶出度：方法 以聚乙烯吡咯烷酮(PVPk30)为载体，用溶剂法制备NT固体分散体；显微镜观察和差示热分析(DTA)鉴别药物在载体中的状态；制备普通片和固体分散体片，测定溶出度，并与市售国产片相比。结果 DTA曲线表明药物在固体分散体中以非晶体状态存在，其体外溶出速率明显提高，20min的累计释放率为73．2％，而普通片及市售国产片分别为22．5％和21．7％。结论 NT制成固体分散体片能明显增加NT的体外溶出度。     

伊曲康唑固体分散体制备及体外溶出实验

目的:运用固体分散体技术提高难溶性药物伊曲康唑的溶解度及体外溶出速率.方法:选用聚乙烯吡咯烷酮(PVPK30)为载体,采用喷雾干燥法制备伊曲康唑固体分散体,通过差热分析及X射线衍射对固体分散体进行鉴定,比较考察伊曲康唑及其物理混合物和固体分散体的溶出特性.结果:差热分析、X射线衍射图谱表明药物以无定形状态分散于载体中;体外溶出结果表明固体分散体能显著增加药物在水及人工胃液中的溶出度(45 min时1:4固体分散体体外溶出度为伊曲康唑的11.5倍.1:4固体分散体在0.1 mo1·L-1盐酸中溶解度是伊曲康唑的67倍).结论:伊曲康唑固体分散体能明显提高伊曲康唑的溶解度及体外溶出速率.     

紫杉醇-PVP固体分散体的制备、物相鉴定及细胞药效

用溶剂法制备紫杉醇-PVP固体分散体，对其溶解度及体外溶出特性进行考察并对物相进行鉴定。采用溶剂法制备紫杉醇-PVP固体分散体，对固体分散体中紫杉醇的溶解度和溶出率进行测定，研究固体分散体的溶出性质。同时，利用差热分析（Differential scanning calorimetry，DSC）、粉末X衍射（X-ray powder diffractometry,PXRD）、扫描电镜（Scanning electron microscopy，SEM）等方法对其进行物相鉴定。采用SRB法对紫杉醇-PVP固体分散体对SKOV-3细胞药效进行测定。紫杉醇-PVP固体分散体中紫杉醇的溶解度和溶出速率相对其原料药和物理混合物均有了明显的提高；热差分析及粉末X衍射结果表明固体分散体中紫杉醇呈非结晶形式；扫描电镜下固体分散体中无紫杉醇晶体。细胞药效结果表明紫杉醇-PVP固体分散体的细胞药效强于紫杉醇纯药。采用溶剂法制备的紫杉醇-PVP固体分散体可显著提高紫杉醇的溶解度和溶出速度。     

槲皮素PVP固体分散体的制备及物相鉴定

目的用溶剂法制备槲皮素-PVP固体分散体并考察其溶出特性并对物相进行鉴定。方法采用溶剂法制备槲皮素-PVP固体分散体,通过溶出实验对槲皮素溶出率的测定研究固体分散体的溶出性质,利用差热分析（Differentialscanning calorimetry,DSC）、红外光谱分析（Infrared spectroscopy,IR）、粉末X衍射（X-ray powder diffractometry,PXRD）、扫描电镜（Scanning electron microscopy,SEM）等方法对其进行物相鉴定。结果槲皮素-PVP固体分散体的溶出速率相对其物理混合物有了明显的改善; 溶解实验显示固体分散体中槲皮素的溶解度有了显著的提高;热差分析及粉末X衍射结果表明固体分散体中槲皮素呈非结晶形式;扫描电镜下固体分散体中无槲皮素晶体。结论采用溶剂法制备槲皮素-PVP固体分散体可显著提高槲皮素的溶解度及溶出速度。     

Improving the dissolution rate of poorly water soluble drug by solid dispersion and solid solution: pros and cons

The solid dispersions with poloxamer 188 (P188) and solid solutions with polyvinylpyrrolidone K30 (PVPK30) were evaluated and compared in an effort to improve aqueous solubility and bioavailability of a model hydrophobic drug. All preparations were characterized by differential scanning calorimetry, powder X-ray diffraction, intrinsic dissolution rates, and contact angle measurements. Accelerated stability studies also were conducted to determine the effects of aging on the stability of various formulations. The selected solid dispersion and solid solution formulations were further evaluated in beagle dogs for in vivo testing. Solid dispersions were characterized to show that the drug retains its crystallinity and forms a two-phase system. Solid solutions were characterized to be an amorphous monophasic system with transition of crystalline drug to amorphous state. The evaluation of the intrinsic dissolution rates of various preparations indicated that the solid solutions have higher initial dissolution rates compared with solid dispersions. However, after storage at accelerated conditions, the dissolution rates of solid solutions were lower due to partial reversion to crystalline form. The drug in solid dispersion showed better bioavailability in comparison to solid solution. Therefore, considering physical stability and in vivo study results, the solid dispersion was the most suitable choice to improve dissolution rates and hence the bioavailability of the poorly water soluble drug.     

盐酸小檗碱泊洛沙姆188固体分散体的制备

目的:制备盐酸小檗碱泊洛沙姆188固体分散体。方法:采用熔融法制备固体分散体,考察药物和载体的比例、熔融温度、冷却温度对溶出率的影响,比较固体分散体和物理混合物的溶出率的区别。结果:药物和载体比例达到1∶1时,载体的量足够使药物分散均匀;熔融温度对溶出率影响不大;冷却温度对溶出率影响较大,0℃时溶出率最快。与物理混合物相比,固体分散体将盐酸小檗碱的溶出率提高了近1倍。结论:盐酸小檗碱泊洛沙姆188固体分散体提高了盐酸小檗碱的体外溶出率。     

Physicochemical characterization and in vivo evaluation of flurbiprofen-loaded solid dispersion without crystalline change

To develop a novel flurbiprofen-loaded solid dispersion without crystalline change, various flurbiprofen-loaded solid dispersions were prepared with water, sodium carboxylmethyl cellulose (Na-CMC), and Tween 80. The effect of Na-CMC and Tween 80 on aqueous solubility of flurbiprofen was investigated. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared to commercial product. Unlike conventional solid dispersion systems, the flurbiprofen-loaded solid dispersion gave a relatively rough surface and changed no crystalline form of drug. These solid dispersions were formed by attaching hydrophilic carriers to the surface of drug without crystal change, resulting in changing the hydrophobic drug to hydrophilic form. Furthermore, the flurbiprofen-loaded solid dispersion at the weight ratio of flurbiprofen/Na-CMC/Tween 80 of 6/2.5/0.5 improved ～ 60-fold drug solubility. It gave higher AUC, T_max, and C_max compared to commercial product. The solid dispersion improved almost 1.5-fold bioavailability of drug compared to commercial product in rats. Thus, the flurbiprofen-loaded solid dispersion would be useful to deliver poorly water-soluble flurbiprofen with enhanced bioavailability without crystalline change.     

盐酸胺碘酮固体分散体的制备及溶出度测定

目的制备盐酸胺碘酮固体分散体,测定其体外溶出度,同时与普通胶囊剂的体外溶出度比较。方法以聚乙二醇6000(PEG6000)为载体,溶剂熔融法制备盐酸胺碘酮固体分散体,用紫外分光光度法测定体外溶出度。结果盐酸胺碘酮固体分散体的体外溶出度比普通胶囊剂显著提高。结论成功制备了盐酸胺碘酮固体分散体。     

Novel Tanshinone II A ternary solid dispersion pellets prepared by a single-step technique: In vitro and in vivo evaluation

Novel Tanshinone II A (TA) ternary solid dispersion (tSD) pellets with the combination of polyvinylpyrrolidone and poloxamer 188 as dispersing carriers were prepared by a single-step technique. A formulation screening study showed that the addition of poloxamer 188 to binary TA-PVP system could remarkably promote the dissolution rate of TA from 60% to 100% after 60 min. Scanning electron microscopy study revealed a smooth surface and a tightly packed coating structure. Differential scanning calorimetry analysis confirmed the formation of solid dispersions. In vivo test showed that TA tSD pellets presented significantly larger AUC_0-t, which was 0.76 times more than that of binary solid dispersion (bSD) pellets, 2.87 times more than that of physical mixtures (PMs) and 5.40 times more than that of TA. C_max of TA tSD pellets also increased by 1.82-8.97-fold as that of bSD pellets, PMs and TA. TA tSD pellets generated obviously shortened T_max of (3.80 ± 0.398) h, compared to bSD pellets with (4.15 ± 0.456) h, PMs with (4.65 ± 0.226) h and TA with (5.52 ± 0.738) h. In conclusion, the addition of poloxamer 188 to pellets containing PVP-based solid dispersions could achieve complete dissolution, accelerated absorption rate and superior oral bioavailability. The fluid-bed technique becomes an alternative approach to obtain solid dispersion-coated pellets.     

依布硒固体分散体的制备及体外溶出度研究

目的提高依布硒的体外溶出速率。方法以固体分散技术制备依布硒固体分散体,并测定其体外溶出度,采用差示扫描量热法(DSC)进行物相分析。结果DSC分析表明,依布硒是以非晶体状态存在,用水溶性载体普朗尼克制备的分散体体外溶出60min大于60%。结论制备依布硒固体分散体可以提高其体外溶出度。     

Preparation, characterization and in vivo evaluation of amorphous atorvastatin calcium nanoparticles using supercritical antisolvent (SAS) process

In this work, amorphous atorvastatin calcium nanoparticles were successfully prepared using the supercritical antisolvent (SAS) process. The effect of process variables on particle size and distribution of atorvastatin calcium during particle formation was investigated. Solid state characterization, solubility, intrinsic dissolution, powder dissolution studies and pharmacokinetic study in rats were performed. Spherical particles with mean particle size ranging between 152 and 863 nm were obtained by varying process parameters such as precipitation vessel pressure and temperature, drug solution concentration and feed rate ratio of CO2/drug solution. XRD, TGA, FT-IR, FT-Raman, NMR and HPLC analysis indicated that atorvastatin calcium existed as anhydrous amorphous form and no degradation occurred after SAS process. When compared with crystalline form (unprocessed drug), amorphous atorvastatin calcium nanoparticles were of better performance in solubility and intrinsic dissolution rate, resulting in higher solubility and faster dissolution rate. In addition, intrinsic dissolution rate showed a good correlation with the solubility. The dissolution rates of amorphous atorvastatin calcium nanoparticles were highly increased in comparison with unprocessed drug by the enhancement of intrinsic dissolution rate and the reduction of particle size resulting in an increased specific surface area. The absorption of atorvastatin calcium after oral administration of amorphous atorvastatin calcium nanoparticles to rats was markedly increased.     

Preparation of esomeprazole zinc solid dispersion and study on its pharmacokinetics

Esomeprazole zinc (EZ) is a poorly water-soluble substance. In order to increase its dissolution rate and bioavailability, solid dispersions of esomeprazole zinc (SDEZ) in polyethylene glycol 4000 (PEG4000) with different EZ to PEG4000 ratios were prepared by solvent method. Our studies showed that dissolution rate of EZ were distinctively increased in the solid dispersion system compared to that in pure EZ or physical mixtures. The increase of dissolution rate was obviously related to the ratio of EZ to PEG4000. The solid dispersion system (EZ/PEG4000=1/8, w/w) gave the highest dissolution rate: about 14.7-fold higher than that of the pure EZ. EZ was proved to be in amorphous state in this solid dispersion by using differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) techniques. In vivo administration studies, SDEZ in enteric capsule (SDEZ-EC) has a lower Cmax and a longer Tmax than that of esomeprazole magnesium enteric-coated tablet (Nexium), and the differences of Cmax and Tmax between SDEZ-EC and Nexium are significant. This result suggests SDEZ-EC has a lower absorption rate than Nexium and corresponds with the in vitro dissolution.     

Preparation, dissolution and characterization of albendazole solid dispersions

In this study, solid dispersion systems of the sparingly water soluble drug, albendazole (ABZ), were mixed with varying concentrations of polyvinylpyrrolidone (PVP K 12) in an attempt to improve the solubility and dissolution rate of ABZ. Physical characteristics were investigated by Powder X-ray diffraction. As expected, the albendazole dissolution rate, expressed as the dissolution efficiency, and also the solubility coefficient were increased when albendazole was mixed with PVP. An increase in the concentration of the polymer in the solid dispersion produced an increase in both parameters. The powder X-ray diffraction patterns showed that the solid dispersion presented an amorphous form of albendazole in this coprecipitate system.     

Revaprazan-loaded surface-modified solid dispersion: physicochemical characterization and in vivo evaluation

The purpose of this research was to develop a novel revaprazan-loaded surface-modified solid dispersion (SMSD) with improved drug solubility and oral bioavailability. The impact of carriers on aqueous solubility of revaprazan was investigated. HPMC and Cremophor A25 were selected as an appropriate polymer and surfactant, respectively, due to their high drug solubility. Numerous SMSDs were prepared with various concentrations of carriers, using distilled water, and the drug solubility of each was assessed. Moreover, the physicochemical properties, dissolution and pharmacokinetics of selected SMSD in rats were assessed in comparison to revaprazan powder. Of the SMSDs assessed, the SMSD composed of revaprazan/HPMC/Cremophor A25 at the weight ratio of 1:0.28:1.12 had the most enhanced drug solubility (～6000-fold). It was characterized by particles with a relatively rough surface, suggesting that the carriers were attached onto the surface of the unchanged crystalline revaprazan powder. It had a significantly higher dissolution rate, AUC and C_max, and a faster T_max value in comparison to revaprazan powder, with a 5.3-fold improvement in oral bioavailability of revaprazan. Therefore, from an environmental perspective, this SMSD system prepared with water, and without organic solvents, should be recommended as a revaprazan-loaded oral pharmaceutical alternative.     

壬二酸固体分散体的制备及其表征

目的:制备壬二酸固体分散体,改善壬二酸的溶出度,从而提高其生物利用度。方法:分别以聚乙二醇6000(PEG)、泊洛沙姆188为载体并选取药物与其不同比例(1:3、1:6、1:9),采用熔融法、溶剂-熔融法制备壬二酸固体分散体,并对其进行体外溶出度的考察及比较;采用差示扫描量热法、X射线粉末衍射法鉴别壬二酸在固体分散体中的存在状态。结果:以PEG为载体的固体分散体的药物溶出优于以泊洛沙姆188为载体的固体分散体(90min内溶出分别为100%和80%);且当药物与PEG的比例为1:9时,药物的溶出效果最好,与原料药比较药物溶出50%所需的时间大大缩短(12.65、45.65min)。壬二酸-PEG固体分散体中药物部分呈分子状态分散,部分呈微晶状态分散。结论:壬二酸与PEG(1:9)的固体分散体能显著提高药物的溶出度。     

Development and optimisation of atorvastatin calcium loaded self-nanoemulsifying drug delivery system (SNEDDS) for enhancing oral bioavailability: in vitro and in vivo evaluation

The objective of this study was to develop and optimise self-nanoemulsifying drug delivery system (SNEDDS) of atorvastatin calcium (ATC) for improving dissolution rate and eventually oral bioavailability. Ternary phase diagrams were constructed on basis of solubility and emulsification studies. The composition of ATC–SNEDDS was optimised using the Box–Behnken optimisation design. Optimised ATC–SNEDDS was characterised for various physicochemical properties. Pharmacokinetic, pharmacodynamic and histological findings were performed in rats. Optimised ATC–SNEDDS resulted in droplets size of 5.66?nm, zeta potential of ?19.52?mV, t₉₀ of 5.43?min and completely released ATC within 30?min irrespective of pH of the medium. Area under the curve of optimised ATC–SNEDDS in rats was 2.34-folds higher than ATC suspension. Pharmacodynamic studies revealed significant reduction in serum lipids of rats with fatty liver. Photomicrographs showed improvement in hepatocytes structure. In this study, we confirmed that ATC–SNEDDS would be a promising approach for improving oral bioavailability of ATC.     

长春西汀固体分散体的制备及体外溶出特性

目的:制备长春西汀固体分散体,提高其溶出速度和程度。方法:以泊洛沙姆188(F68)为载体,用溶剂-熔融法制备固体分散体;差热分析、X-射线粉末衍射分析以鉴别药物在载体中的存在状态;并考察载体的用量、溶出介质和转速对药物体外溶出特性的影响。结果:长春西汀的固体分散体中药物部分以分子状态分散,部分以微晶分散。固体分散体VIN-F68(1∶6,w/w)的溶出参数t50t、d与相应物理混合物、原料药粉末和市售片剂间差异存在显著性(P<0.01),溶出介质和转速的选择对药物的溶出有一定影响。结论:长春西汀的固体分散体能显著提高药物的溶出速度和程度。     

尼群地平固体分散片的制备及体外评价

目的 制备尼群地平固体分散片.方法 采用溶剂法、熔融法制备尼群地平固体分散体,再与适当辅料混合压片制备分散片.结果 采用固体分散法制备的分散片较原料药直接制备的分散片溶出更快,且聚乙二醇(PEG)为载体制备的分散片较聚乙烯吡咯烷酮(PVP)溶出更快.结论 先制备固体分散体再制备分散片,有助于提高难溶性药物的溶出速度和程度.     

泊洛沙姆固体分散体对穿心莲内酯溶出特性的影响

目的:考察泊洛沙姆固体分散体对难溶性药物穿心莲内酯体外溶出特性的影响。方法:以泊洛沙姆为载体材料,采用熔融法制备不同比例的穿心莲内酯-泊洛沙姆固体分散体,并考察其体外溶出特性。通过红外光谱和X射线衍射图谱研究药物在固体分散体的存在状态。结果:与穿心莲内酯空白药物相比,穿心莲内酯固体分散体在蒸馏水、pH1.2盐酸溶液与pH6.8磷酸盐缓冲液中溶出速率明显提高,载药固体分散体15min时累积释药量是穿心莲内酯空白药物的3.6倍;穿心莲内酯以微晶态高度分散于载体材料中。结论:以泊洛沙姆188为载体制备穿心莲内酯固体分散体,能有效提高难溶性药物的溶出速率。