葛根黄豆甙元-PVP分散物的研究

本文采用聚乙烯吡咯烷酮(PVP)为载体,制备了葛根黄豆甙元固体分散物。经差热分析、X-射线衍射、偏光显微镜观察实验证明黄豆甙元-PVP 1∶9固体分散物为固体溶液或共沉淀物,其胶囊在人工胃液中最高累积释放百分量和人工肠液中平衡溶解度均是普通胶囊的8倍左右。     

葛根黄豆甙原与其固体分散物的药效学比较

本文比较了葛根黄豆甙原及葛根黄豆甙原固体分散物的作用强度。药效学研究结果表明,对氯化钡所致大白鼠实验性心律失常的预防作用、对小白鼠常压耐缺氧的存活时间及减慢麻醉家兔的心率等作用,葛根黄豆甙原固体分散物的作用均强于等剂量的葛根黄豆甙原。同时我们也观察到了葛根黄豆甙原固体分散物对麻醉家兔的血压有一个相对早而弱的降压作用。     

葛根黄豆甙元固体分散物对自发性高血压大鼠血压的影响

本文研究了葛根黄豆甙元及其固体分散物对清醒的自发性高血压大鼠血压的影响。口服葛根黄豆甙元固体分散物300mg/kg,2h血压下降达高峰,收缩压下降12.8%,而等量的葛根黄豆甙元及PVP均无明显改变,葛根黄豆甙元固体分散物使自发性高血压大鼠血浆中血管紧张素下降52.4%,使wistar大鼠的PRA下降24.7%.麻醉猫iv.25mg/kg,收缩压下降18.6±10.6%,舒张压下降43.0±19.2%.     

改善葛根黄豆甙元体外溶出

目的 :提高葛根黄豆甙元水溶性及溶出度 ,改善其生物利用度。方法 :采用研磨法减小药物粒径 ,制成固体分散物及 β 环糊精包合法。 结果 :溶解度试验结果为甙元 3 1 4 ,而上述不同改良后的结果为 5 4 2～ 50 0 8之间。 2h溶出度结果 ,甙元片为 8 87% ,而改良后结果在 1 3 67%。结论 :三种方法均不同程度提高该药溶解性及溶出度 ,其中以PVP不同比例固体分散物溶解性及溶出度提高幅度最大。     

黄豆苷元胶囊健康人体生物等效性研究

目的研究两种黄豆苷元胶囊在健康志愿受试者中的药动学和人体生物等效性.方法20名男性健康志愿者随机交叉单次口服黄豆苷元胶囊受试制剂和参比制剂各150 mg后,采用反相高效液相色谱法,测定血浆中黄豆苷元的浓度,采用Das 2.1程序计算其药动学参数,评价黄豆苷元胶囊的人体生物等效性.结果受试制剂和参比制剂的主要药动学参数分别为t1/2(3.35 ±1.20)和(3.39±1.46)h;C…(150.8 ±30.5)和(154.6±31.1)ng·mL-1;Tmax(1.04 4-0.55)和(1.30 ±0.76)h;AUC0-l(474 ±85)和(486 ±114)ng·h·mL-l.以AUCo-l计算,与参比制剂相比受试制剂中黄豆苷元的平均相对生物利用度为(99.4 ±13.1)%.结论两种黄豆苷元胶囊具有生物等效性.     

利福定固体分散物的制备及生物利用度测定

用溶媒法制备了利福定固体分散物。经X—射线衍射实验证明,利福定在固体分散物中呈无定形或以分子状态分散于载体中。固体分散物2小时的体外溶出量和人体生物利用度分别较原药提高了88％和21.8％。     

索拉非尼衍生物CEP固体分散体的制备及大鼠体内生物利用度研究

目的制备CEP-PVP K30固体分散体,考察其物相并提高其大鼠体内生物利用度。方法采用溶剂法制备CEP-PVP-K30固体分散体;利用溶出度法、差示扫描量热(DSC)、红外光谱(FTIR)等方法分析药物在载体中的存在状态;采用HPLC法测定大鼠血浆中药物浓度,与原料药比较,对CEP-PVP K30固体分散体进行大鼠体内生物利用度评价。结果物相分析结果表明,当药物与载体比例为1∶5时,固体分散体中CEP以非结晶态无定形存在。大鼠体内血药浓度-时间曲线表明,与原料药相比,CEP固体分散体达峰时间(t_(max))相对不变,达峰浓度(ρ_(max))提高794%,相对生物利用度为1 572%。结论采用溶剂法制备CEP-PVP K30固体分散体,CEP以无定形存在,其体外溶出速率和大鼠体内吸收均有显著性提高。     

固体分散无环鸟苷胶囊剂溶出度及人体内生物利用度

目的：用固体分散技术制得无环鸟苷胶囊剂以提高无环鸟苷体外溶出度和体内生物利用度。方法：8名HBsAg阳性受试者分别单次口服400 mg两种剂型后,用HPLC方法测定血清中无环鸟苷浓度,进行固体分散无环鸟苷胶囊剂与市售片剂的药代动力学和生物利用度研究。结果：两剂型血清药物浓度有显著差异,曲线下面积(AUC)固体分散无环鸟苷胶囊剂为6271.33 h.ng.mL^-1,市售片为4101.00 h.ng.mL^-1。固体分散无环鸟苷胶囊剂相对市售片剂的相对生物利用度为152.92%。30 min溶出度在不同的溶出介质中固体分散无环鸟苷胶囊剂也明显快于市售片剂。结论：经固体分散的无环鸟苷胶囊剂能显著地提高无环鸟苷的生物利用度。     

黄豆苷元磷脂复合物的制备及大鼠体内生物利用度的研究

目的制备黄豆苷元磷脂复合物并测定其在大鼠体内的生物利用度。方法以黄豆苷元与大豆磷脂的复合率为评价指标,采用单因素试验和正交设计优化制备工艺;分别测定黄豆苷元、黄豆苷元-磷脂的物理混合物及黄豆苷元磷脂复合物在水中和正辛醇中的表观溶解度;3组大鼠分别灌胃给予黄豆苷元原料药、黄豆苷元-磷脂的物理混合物及黄豆苷元磷脂复合物后,采用LC-MS/MS测定不同时间血浆中药物浓度,比较相对生物利用度。结果黄豆苷元磷脂复合物优化的制备条件为：反应溶剂为无水乙醇,投料比为1.5∶1（磷脂/药物的摩尔比）,1g·L^-1反应物浓度条件下60℃搅拌2h,结果显示：磷脂复合物在水和正辛醇中表观溶解度比原料药分别提高3.1倍和5.4倍;大鼠灌胃给予黄豆苷元和黄豆苷元磷脂复合物后,Cmax分别为（667±65）,（7509±688）ng·mL^-1,Tmax分别为（3.00±0.82）,（0.42±0.17）h,AUC0–∞分别为（8302±590）,（28870±2411）ng·h·mL^-1。黄豆苷元磷脂复合物口服生物利用度是黄豆苷元原料药的3.48倍。结论将黄豆苷元制成磷脂复合物后在水中的溶解度有所提高,在正辛醇中的溶解度有显著提高,增加了黄豆苷元在胃肠道中的吸收,明显提高黄豆苷元口服生物利用度。     

葛根素固体分散体的制备及大鼠体内生物利用度研究

本文采用新型的固体分散体技术,将葛根素,磷脂与PVP制成固体分散体,对其理化性质进行研究,考察固体分散体在大鼠体内的药一时曲线,计算其在大鼠体内的药动学参数,并与葛根素原料比较,研究固体分散体的相对生物利用度。结果表明以磷脂和PVP为载体制备的固体分散体（药物-磷脂-PVP,2：4：1）的表观油水分配系数最好,固体分散体相对生物利用度较纯葛根素提高了2．53倍。     

大豆苷元固体分散体胶囊的溶出度测定

目的:建立以高效液相色谱法测定大豆苷元固体分散体胶囊溶出度的方法。方法:色谱柱为HypersilC18,流动相为水-乙腈(70∶30),流速为1.0mL·min-1,检测波长为249nm,柱温为30℃;并按《中国药典》转篮法测定其溶出度。结果:大豆苷元检测浓度的线性范围为1.0～10.0μg.mL-1(r=0.9998);平均回收率为100.12%,RSD=1.65%;3批样品45min溶出度均在90.0%以上。结论:本方法灵敏、准确、专属性强,可用于该制剂的溶出度测定。     

Development of novel ibuprofen-loaded solid dispersion with improved bioavailability using aqueous solution

To develop a novel ibuprofen-loaded solid dispersion with enhanced bioavailability, various ibuprofen-loaded solid dispersions were prepared with water, HPMC and poloxamer. The effect of HPMC and poloxamer on aqueous solubility of ibuprofen was investigated. The dissolution and bioavailability of solid dispersion in rats were then evaluated compared to ibuprofen powder. When the amount of carrier increased with a decreased in HPMC/poloxamer ratio, the aqueous solubility of ibuprofen was elevated. The solid dispersion composed of ibuprofen/HPMC/poloxamer at the weight ratio of 10:3:2 improved the drug solubility approximately 4 fold. It gave significantly higher initial plasma concentration, AUC and Cmax of drug than did ibuprofen powder in rats. The solid dispersion improved the bioavailability of drug about 4-fold compared to ibuprofen powder. Thus, this ibuprofen-loaded solid dispersion with water, HPMC and poloxamer was a more effective oral dosage form for improving the bioavailability of poor water-soluble ibuprofen.     

Development of novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose

To develop a novel ibuprofen-loaded solid dispersion with enhanced bioavailability using cycloamylose, it was prepared using spray-drying techniques with cycloamylose at a weight ratio of 1:1. The effect of cycloamylose on aqueous solubility of ibuprofen was investigated. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with ibuprofen powder. This ibuprofen-loaded solid dispersion improved about 14-fold drug solubility. Ibuprofen was present in an unchanged crystalline state, and cycloamylose played the simple role of a solubilizing agent in this solid dispersion. Moreover, the dispersion gave 2-fold higher AUC (area under the drug concentration-time curve) value compared with a ibuprofen powder, indicating that it improved the oral bioavailability of ibuprofen in rats. Thus, the solid dispersion may be useful to deliver ibuprofen with enhanced bioavailability without crystalline change.     

A novel solid dispersion system for natural product-loaded medicine: silymarin-loaded solid dispersion with enhanced oral bioavailability and hepatoprotective activity

Abstract

A surface-attached silymarin-loaded solid dispersion with improved dissolution profile and enhanced oral bioavailability was formulated using silymarin, polyvinylpyrrolidone (PVP) and Tween 80 in water. In this solid dispersion, hydrophilic PVP was adhered onto the surface of crystalline drug rendering silymarin hydrophilic without changing its crystallinity. The drug solubility from the optimised solid dispersion prepared with silymarin/PVP/Tween 80 at the weight ratio of 5/2.5/2.5 increased by almost 650-fold compared to drug powder. The drug was physically and chemically stable in the solid dispersion for at least 6 months. Moreover, the solid dispersion enhanced the oral bioavailability of the drug in rats by almost 3-fold compared to the commercial product. The silymarin-loaded solid dispersion also exhibited advanced hepatoprotective bioactivity against CCl₄-induced liver damage compared to silymarin or the commercial product. Thus, this silymarin-loaded solid dispersion would be useful for the enhancement of oral bioavailability and hepatoprotective activity of poorly water-soluble silymarin.     

Development of raloxifene-solid dispersion with improved oral bioavailability via spray-drying technique

The purpose of this study was to develop a raloxifene-loaded solid dispersion with enhanced dissolution rate and bioavailability via spray-drying technique. Solid dispersions of raloxifene (RXF) were prepared with PVP K30 at weight ratios of 1:4, 1:6 and 1:8 using a spray-drying method, and characterized by differential scanning calorimetry, X-ray powder diffraction, scanning electron microscopy, and solubility and dissolution tests. The bioavailability of the solid dispersion in rats was also evaluated compared to those of RXF powder and commercial product. Results showed that the RXF-loaded solid dispersion was in amorphous form with increased solubility and dissolution rate. The absorption of RXF from solid dispersion resulted in approximately 2.6-fold enhanced bioavailability compared to pure drug. Moreover, RXF-loaded solid dispersion gave similar AUC, C_max and T_max values to the commercial product, suggesting that it was bioequivalent to the commercial product in rats. These findings suggest that an amorphous solid dispersion of RXF could be a viable option for enhancing the oral bioavailability of RXF.     

In vitro evaluation and pharmacokinetics in dogs of solid dispersion pellets containing Silybum marianum extract prepared by fluid-bed coating

The solid dispersion of a poorly water-soluble Silybum marianum extract (SME) was prepared by a one-step fluid-bed coating technique depositing onto non-pareil pellets. In vitro evaluation indicated that this technique was highly efficient and reproducible producing pellets with acceptable appearance, flowability, friability, uniformity of drug content and enhanced dissolution. Physical characterization by DSC, powder X-ray diffractometry and FT-IR suggested the formation of a solid dispersion and possible interaction between PVP and the flavonolignans. Stress testing showed that the drug content and dissolution profiles of the SME solid dispersion pellets were sensitive to heat and humidity, while they are not affected under accelerated and long-term testing conditions. The relative bioavailability of solid dispersion pellets in dogs based on quantification of silibinin was about five-fold that of the SME suspension confirming enhanced oral bioavailability. It was concluded that the solid dispersion pellets prepared by fluid-bed coating showed favorable in vitro characteristics and enhanced oral bioavailability.     

Formulation of solid dispersion of rebamipide evaluated in a rat model for improved bioavailability and efficacy

Objectives Rebamipide, a novel anti‐ulcer agent, is listed in biopharmaceutics classification class IV because of its low aqueous solubility and permeability. Consequently, the bioavailability of rebamipide is under 10% in humans. The aim of this study was to increase the solubility and determine the effect of solubility enhancement on the bioavailability and efficacy of rebamipide (RBM). Methods After taking into account the physiochemical properties of RBM (solubility, melting point, dosage etc.), solid dispersion was chosen as the solubility enhancement method. A rebamipide solid dispersion system containing the drug, l ‐lysine, PVP‐VA 64 and poloxamer 407 was obtained from a spray‐drying method. Solubility enhancement of RBM from the solid dispersion was determined by a dissolution test in 900 ml at pH 1.2. The bioavailability and efficacy of RBM solid dispersion were evaluated in a rat model. Key findings The aqueous solubility of RBM was improved 62.17 times by solid dispersion. The oral bioavailability of the drug was also increased 1.74‐fold from solid dispersion compared with the reference product in a rat model. With regard to the anti‐ulcer effect, the percentage inhibition of the solid dispersion was 2.71 times higher than that of the reference product in the ulcer‐induced rat model. Conclusions A solid dispersion of rebamipide was successfully formulated using the spray‐drying method. Bioavailability and efficacy of rebamipide were increased significantly by solubility enhancement of the drug.     

Enhanced solubility and bioavailability of flurbiprofen by cycloamylose

The effect of cycloamylose on the aqueous solubility of flurbiprofen was investigated. To improve the solubility and bioavailability of flurbiprofen (poor water solubility), a solid dispersion was spray dried with a solution of flurbiprofen and cycloamylose at a weight ratio of 1:1. The physicochemical properties of solid dispersions were investigated using SEM, DSC, and X-ray diffraction. The dissolution and bioavailability in rats were evaluated compared with a commercial product. Cycloamylose increased solubility of flurbiprofen approximately 12-fold and dissolution of it by 2-fold. Flurbiprofen was present in an unchanged crystalline state, and cycloamylose was a solubilizing agent for flurbiprofen in this solid dispersion. Furthermore, the dispersion gave higher AUC and C_max values compared with the commercial product, indicating that it improved the oral bioavailability of flurbiprofen in rats. Thus, the solid dispersion may be useful to deliver flurbiprofen with enhanced bioavailability without changes in crystalline structure.     

The use of three different solid dispersion formulations--melt extrusion, film-coated beads, and a glass thermoplastic system--to improve the bioavailability of a novel microsomal triglyceride transfer protein inhibitor

A bioavailable formulation for a water-insoluble microsomal triglyceride transfer protein inhibitor, R103757, was developed using solid dispersion technology. The need for an advanced formulation was tested in the dog by assessing the oral bioavailability of three generic concepts: a tablet (crystalline drug), a capsule (film-coated beads), and an oral solution. These screening studies steered further development in the direction of a solid dispersion. Three solid dispersion platforms were assessed: melt extrusion, film-coated beads, and a glass thermoplastic system. Thermal and spectrophotometric analysis revealed that no crystalline drug was present in any of the formulations. The dissolution profiles of the three dispersion systems showed that release was improved compared with the unmanipulated drug. In addition, stability studies confirmed the physical and chemical integrity of the formulation. A human clinical trial was performed to assess the pharmacokinetics of the three amorphous dispersions. Plasma levels were obtained after single oral administration in both the fasting and fed state. The study indicated that all three approaches improved the bioavailability of R103757 with the glass thermoplastic system providing the best performance. These studies point to the potential usefulness of solid dispersion approaches and expand the possible number of ways to implement these methodologies.     

Improving the oral bioavailability of albendazole in rabbits by the solid dispersion technique

We have investigated the oral bioavailability of granules of albendazole, a drug used for treating echinococcosis in man, prepared by the solid dispersion technique. Rapid dissolution and supersaturation were observed when hydroxypropylmethylcellulose and hydroxypropylmethylcellulose phthalate were used as carriers in the solid dispersion. They inhibited the crystallization of albendazole from the supersaturated solution and maintained an amorphous state for 8 h. Gastric acidity-controlled rabbits were used to evaluate the variation in absorption after oral administration of the albendazole solid dispersion. For rabbits with low gastric acidity the bioavailability of orally administered albendazole in the granular form prepared by solid dispersion was more than three times that of albendazole in physical mixtures. These results suggest that the bioavailability of albendazole in solid dispersions might be high even if there is a great variation in the gastric pH of patients.