Preparation, characterization and evaluation of kaempferol phospholipid complex: Improvement of its solubility and biological effect

Kaempferol(KA),as one of the flavonoids,has extensive pharmacological properties.However,the poor solubility of KA severely limits its clinical application.In our study,the kaempferol phospholipid complex(KA-PC)has been prepared by solvent evaporation for the enhancement of the bioavailability of KA.KA-PC was verified by scanning electron microscope characterization methods.Drug loading,solubility and long-term stability were measured.The characterization results showed that KA-PC was formed through the intermolecular interaction between KA and phospholipids.The solubility of KA-PC in water was 189 times higher than that of KA,and the solubility in n-octanol was also significantly improved.Besides,pharmacodynamic studies showed that KA-PC can significantly reduce the level of serum uric acid in mice without causing renal injury.This study expanded the clinical application of KA by preparing KA-PC.

Preparation and study of anti-hepatitis B virus activity in vitro of oxymatrine phospholipid complex

Aim The oxymatrine phospholipid complexs were prepared, and its activity against hepatitis B virus in vitro were studied. Methods Using tetrahydrofuran as a reaction medium, oxymatrine and phospholipids were resolved into the medium, Oxymatrine phospholipid eomplexs were prepared. The toxicity measurements and inhibitory effect on HBsAg, HBeAg, and HBVDNA of oxymatrine phospholipid complex in 2.2.15 cells were studied respectively. Results The content of oxymatrine in the phospholipids eomplexs prepared was 24,86% （W/W）. The TCO of the oxymatrine phospholipid eomplexs was 250 μmol·L^- 1 The inhibitory effect of HBsAg, HBeAg, HBV-DNA of 2.2.15 cells treated by oxymatrine phospholipid complex were higher than those of the oxymatrine. Conclusion Oxymatrine phospholipid complex can have stronger effective activity against hepatitis B virus compared with oxymatrine. So oxymatrine phospholipid eomplexs were showing its potential antiviral activity in hepatitis B treatment.

Phyto-phospholipid complexes(phytosomes): A novel strategy to improve the bioavailability of active constituents

Although active constituents extracted from plants show robust in vitro pharmacological effects, low in vivo absorption greatly limits the widespread application of these compounds. A strategy of using phyto-phospholipid complexes represents a promising approach to increase the oral bioavailability of active constituents, which is consist of ‘‘label-friendly'phospholipids and active constituents. Hydrogen bond interactions between active constituents and phospholipids enable phospholipid complexes as an integral part. This review provides an update on four important issues related to phyto-phospholipid complexes: active constituents, phospholipids, solvents, and stoichiometric ratios. We also discuss recent progress in research on the preparation, characterization, structural verification, and increased bioavailability of phyto-phospholipid complexes.

Anticancer effects of saponin and saponin–phospholipid complex of Panax notoginseng grown in Vietnam

Objective:To evaluate the antitumor activity both in vitro and in vivo of saponin–phospholipid complex of Panax notoginseng.Methods:The in vitro cytotoxic effect of saponins extract and saponin–phospholipid complex against human lung cancer NCI-H460 and breast cancer cell lines BT474 was examined using MTS assay.For in vivo evaluation of antitumor potential,saponin and saponin–phospholipid complex were administered orally in rats induced mammary carcinogenesis by 7,12-dimethylbenz(a)anthracene,for 30 days.Results:Our data showed that saponin–phospholipid complex had stronger anticancer effect compared to saponin extract.The IC50 values of saponin–phospholipid complex and saponin extract for NCI-H460 cell lines were 28.47 mg/m L and 47.97 mg/mL,respectively and these values for BT474 cells were 53.18 mg/mL and 86.24 mg/mL,respectively.In vivo experiments,administration of saponin,saponin–phospholipid complex and paclitaxel(positive control) effectively suppressed 7,12-dimethylbenz(a) anthracene-induced breast cancer evidenced by a decrease in tumor volume,the reduction of lipid peroxidation level and increase in the body weight,and elevated the enzymatic antioxidant activities of superoxide dismutase,catalase,glutathione peroxidase in rat breast tissue.Conclusions:Our study suggests that saponin extract from Panax notoginseng and saponin–phospholipid complex have potential to prevent cancer,especially breast cancer.

Preparation,physicochemical properties and antioxidant activity of genistein phospholipid complexes

Genistein phospholipid complex(GS-PC)was produced in order to increase the solubility and antioxidant activity of genistein(GS),an insoluble natural polyphenol compound.By using the solvent evaporation process,GS-PC was produced.Several characteristics techniques were used to confi rm the production of GS-PC,and its physicochemical characteristics and antioxidant activity were investigated.The outcome showed that GS-PC had a recombination rate of 96.84%±0.51%.The characterization results confi rmed that GS-PC was formed by the intermolecular interaction between GS and phospholipids.In vitro antioxidant studies showed that GS-PC had a certain scavenging ability on DPPH free radicals,ABTS free radicals and hydroxyl free radicals.In summary,the results of this study indicated that GS-PC could be used as a formula to improve its solubility and antioxidant activity.

Bioavailability of 10-hydroxycamptothecin-phospholipid complex loaded by solid dispersion and lipid-based formulations

Previous study has shown that 10-hydroxycamptothecin（HCPT） has well-established pharmacological effects in vitro.However,its in vivo bioavailability is very poor due to various problems,which severely restricts its clinical applications.In the present study,phospholipid complex（PC） technology was employed to improve the solubility and bioavailability of HCPT.XRD data confirmed the formation of HCPT-PC.However,our previously prepared HCPT-PC is too sticky,which may result in the slow dissolution rate and negative effects on its absorption.Therefore,we prepared HCPT-PC-solid dispersion（HCPT-PC-SD）and lipid-based formulations of HCPT-PC through simple preparation process.The results showed that the dissolution rate of HCPT-PC was effectively improved by solid dispersion technology,which reached 91.73%in 45 min.Pharmacokinetic study revealed that the AUC_（0-t） of HCPT-PC-SD and HCPT-PC lipid-based formulations was effectively further increased compared with HCPT-PC.Moreover,we found that the combination of SD technology and lipid-base formulations could be a promising drug-delivery system to improve the oral bioavailability of HCPT-PC.In addition,we showed that the bioavailability of HCPT-PC lipid-base formulations was even greater than that of HCPT-PC-SD.In particular,lipid-base formulations could be prepared just by a simple method,suggesting its feasibility of industrialization.

Combined use of phospholipid complexes and self-emulsifying microemulsions for improving the oral absorption of a BCS class IV compound, baicalin

The aim of this study was to develop a formulation to improve the oral absorption of baicalin(BA)by combining a phospholipid complex(PC)and self-emulsifying microemulsion drug delivery system(SMEDDS),termed BA–PC–SMEDDS.BA–PC was prepared by a solvent evaporation method and evaluated by complexation percentage(CP).The physicochemical properties of BA–PC were determined.The synergistic effect of PC and SMEDDS on permeation of BA was studied in vitro with Caco-2 cells and in situ with a single pass intestinal perfusion model.The improved bioavailability of BA in BA–PC–SMEDDS was confirmed in an in vivo rat model.The CP of BA–PC reached 100%when the molar ratio of drug to phospholipid(PP)was Z1:1.The solubility of BA–PC increased in both water and octanol,and the log P o/w of BA–PC was increased significantly.BA–PC–SMEDDS could be dispersed more evenly in water,compared to BA and BA–PC.Both the Caco-2 cell uptake and single-pass intestinal perfusion models illustrated that transport of BA in BA–PC was lower than that of free BA,while improved significantly in BA–PC–SMEDDS.The relative bioavailability of BA–PC(1:2)–SMEDDS was 220.37%.The combination system of PC and SMEDDS had a synergistic effect on improving the oral absorption of BA.

槲皮素-磷脂复合物的制备、表征及对核桃油氧化稳定性的影响

为扩大槲皮素的应用范围,采用溶剂法优化制备了槲皮素-磷脂复合物,对复合物进行了结构表征和体外抗氧化能力评价,并进一步研究了复合物对核桃油氧化稳定性的影响。结果表明,溶剂为无水乙醇,槲皮素与磷脂质量比为1:3,槲皮素浓度为0.5 mg/mL,50℃下复合反应4 h,槲皮素-磷脂复合物平均复合率可达99.49%。利用优化后的制备条件可以有效制备不同于槲皮素或磷脂的全新槲皮素-磷脂复合物,槲皮素的羟基可通过与磷脂的极性端产生氢键而形成复合物,其在水和正辛醇中的溶解性优于游离槲皮素及槲皮素与磷脂的物理混合物。在相同质量浓度下,槲皮素-磷脂复合物的体外抗氧化能力与游离槲皮素差异不显著。核桃油在60℃下贮藏18 d,结果表明槲皮素-磷脂复合物能更有效减缓核桃油的酸价、过氧化值、共轭二烯值(conjugated diene value,CD)和共轭三烯值(conjugated triene value,CT)的增加,抗氧化效果显著优于槲皮素(P<0.05),且核桃油的酸价与过氧化值、CD值和CT值显著正相关(P<0.05)。槲皮素-磷脂复合物能够在不影响感官品质的基础上,明显提高核桃油的抗氧化稳定性,延长保存期,具有良好的开发利用价值。

花旗松素磷脂复合物制备优化及其体外模拟消化释放研究

为了提高花旗松素的利用率,该研究制备花旗松素磷脂复合物,采用Box-Behnken响应面试验优化磷脂复合物制备工艺,并进行表征分析验证磷脂复合物的形成;通过平衡溶解度、油水分配系数及模拟消化实验对理化性质和释放度进行研究。结果表明,磷脂复合物最佳制备条件为花旗松素/磷脂质量比1∶3.71、反应溶剂体积12.82 mL、反应时间2.94 h,此条件下的复合率为95.55%。差示扫描量热分析、傅里叶红外光谱、X射线衍射实验表明花旗松素与磷脂间通过氢键作用形成磷脂复合物,且花旗松素由晶型转变为无定形态。磷脂复合物增加了花旗松素在水中的溶解度和水-正辛醇体系中的油水分配系数;体外模拟消化释放实验显示,6 h内磷脂复合物中花旗松素累积释放由48.26%提升至71.86%。磷脂复合物改善了花旗松素的理化性质和体外释放,为花旗松素的高效应用与食品制剂开发提供研究基础。

质量权重系数法整体表征雪菊黄酮提取物性质及其磷脂复合物的制备研究

目的 研究雪菊黄酮理化性质,优化雪菊黄酮磷脂复合物制备工艺。方法 以马里苷、木犀草素、槲皮万寿菊苷为指标成分,测定雪菊黄酮的平衡溶解度和油水分配系数,并通过质量权重系数整体表征药物性质;采用层次分析法(AHP)对雪菊黄酮磷脂复合物复合率赋权,设计Box-Behnken响应面试验,优化制备工艺。结果 雪菊黄酮在pH 1.0 ~ 8.0缓冲液和水中的平衡溶解度为0.056 6 ~ 1.861 5 mg/mL,为低溶解性药物,在pH 1.0 ~ 6.0溶液中LogP > 0,易透过胃和十二指肠等上消化道,为高渗透性药物;雪菊黄酮磷脂复合物最优工艺中无水乙醇为反应溶剂,脂药比为3∶1,药物浓度为0.5 mg/mL,反应温度为40 ℃,反应时间为2.0 h,复合率为(96.26±2.71)%,与预测值相比偏差< 3.00%。结论 雪菊黄酮为BCSⅡ类药物,制备为磷脂复合物,工艺稳定可行,可为BCSⅡ类药物设计提供参考。

原花青素B2磷脂复合物的制备工艺优化及表征

目的:优化原花青素B2磷脂复合物(PB2-PC)的制备工艺并对其进行表征。方法:采用单因素试验确定PB2-PC的最佳制备工艺;采用透射电镜、紫外光谱、差示扫描量热、X-射线衍射等方法对PB2-PC进行表征。结果:最佳工艺条件为以四氢呋喃作制备溶剂,磷脂与原花青素B2(PB2)的比值为2,其中PB2浓度为5 mg·mL^(-1),在40℃条件反应0.5 h,制得PB2-PC复合率为95.8%(RSD=0.38%,n=3)。PB2在磷脂复合物中油水分配系数(log P)增高3.17倍,转变为无定形态,且物相发生了改变。结论:PB2-PC制备工艺稳定可靠,为PB2下一步的研发奠定了实验基础。

柚皮素磷脂复合物纳米混悬剂制备及其体内药动学研究

目的制备柚皮素磷脂复合物纳米混悬剂,并考察其体内药动学。方法高压均质法制备磷脂复合物纳米混悬剂。以稳定剂种类、稳定剂与磷脂复合物用量比例、均质压力、均质次数为影响因素,粒径、PDI、Zeta电位为评价指标,单因素试验优化处方。在透射电镜下观察形态,进行X射线粉末衍射分析,测定溶解度、油水分配系数、磷脂复合物解离率、累积释放度。24只大鼠随机分为4组,分别灌胃给予柚皮素及其磷脂复合物、纳米混悬剂、磷脂复合物纳米混悬剂的0.5%CMC-Na混悬液(30 mg/kg),于0、0.25、0.5、1、1.5、2、3、4、5、6、8、10、12 h采血,HPLC法测定柚皮素血药浓度,计算主要药动学参数。结果最优处方为磷脂复合物用量50 mg,稳定剂PVP K30+TPGS(1∶1),稳定剂与磷脂复合物用量比例3∶1,均质压力100 MPa,均质次数10次。所得磷脂复合物纳米混悬剂呈类球形或椭圆形,平均粒径、PDI、Zeta电位分别为(260.53±25.86)nm、0.160±0.024、(-31.08±1.37)mV。柚皮素以无定型状态存在于磷脂复合物纳米混悬剂中,溶解度、油水分配系数、磷脂复合物解离率升高,4 h内累积释放度达90%以上。与原料药、纳米混悬剂比较,磷脂复合物纳米混悬剂t_(max)缩短(P<0.05),C_(max)、AUC_(0~t)、AUC_(0~∞)升高(P<0.05,P<0.01),相对生物利用度增加至4.38倍。结论磷脂复合物纳米混悬剂可提高柚皮素溶解度、溶出度,促进其体内吸收。

三叶苷-磷脂复合物处方工艺优化及理化性质的初步研究

为改善三叶苷溶解度、油水分配系数和溶出度,制备了三叶苷-磷脂复合物,并对理化性质进行考察。以复合率为指标,单因素考察结合Box-Behnken设计-效应面法优化三叶苷-磷脂复合物处方工艺。测试三叶苷-磷脂复合物的溶解度、溶出度和油水分配系数,采用X射线衍射法、红外光谱法、差式扫描量热法进行分析。结果表明,三叶苷-磷脂复合物最佳处方工艺为三叶苷用量为60 mg,磷脂用量为125 mg,制备温度为50℃,制备时间为3.9 h,三叶苷与磷脂的复合率达99.7%。与三叶苷相比,三叶苷-磷脂复合物溶解度及油水分配系数得到极显著性改善,12 h累积释放度增加至75.1%。三叶苷在三叶苷-磷脂复合物中转变为无定型状态。三叶苷和磷脂之间可能以氢键结合在一起形成三叶苷-磷脂复合物。本研究成功制备了三叶苷-磷脂复合物,改善了自身理化性质的缺陷,为进一步应用奠定了基础。

水飞蓟素磷脂复合物的制备及体外溶出行为评价

目的将水飞蓟素和磷脂复合以研制水飞蓟素磷脂复合物(silymarin phospholipids complex,SM-PC),并考察其基本理化性质。方法采用溶剂挥发法制备SM-PC。通过前期的单因素考察,选择脂药比、药物浓度以及反应温度作为星点设计-效应面法的考察因素,以SM-PC的复合率为衡量指标筛选最佳研制工艺,并测定SM-PC的体外溶出度。结果SM-PC的最优制备条件如下:以丙酮为反应溶剂,水飞蓟素与大豆卵磷脂的比例为1∶1.8,反应温度56℃,反应物的浓度8.0 mg/ml。在此条件下制备3批样品得到SM-PC的复合率为(95.15±1.55)%,偏差<3%。体外溶出试验表明,SM-PC各组分在60 min的溶出接近90%,主要成分水飞蓟宾的溶出行为与市售水飞蓟素胶囊相似,远高于原料药。结论采用星点设计-效应面法成功制备SM-PC,明显提高了溶出度,为后续制剂的研究奠定基础。

葛根素及其磷脂复合物在Beagle犬体内的药动学比较

目的研究葛根素及其磷脂复合物中葛根素在B eag le犬体内药动学。方法采用HPLC法测定犬血中葛根素,以同组犬(3只,雄性)交叉口服葛根素及其磷脂复合物,药-时曲线数据经3P 97药动学计算程序处理。结果分别以葛根素及其磷脂复合物给B eag le犬口服(剂量为葛根素52.5 m g/kg),葛根素的药-时过程符合开放型双室一级动力学模型,葛根素口服的AUC、Cm ax、tm ax分别为(10.91±4.83)m g.h/L、(3.00±1.13)m g/L、(1.62±0.30)h,而葛根素磷脂复合物的AUC、Cm ax、tm ax分别为(13.67±2.72)m g.h/L、(1.91±0.51)m g/L、(2.38±1.27)h,统计结果表明AUC之间差异有显著性。结论形成磷脂复合物可提高葛根素在B eag le犬体内的吸收。

葛根素及其磷脂复合物的体外透皮实验研究

目的 :考察葛根素及其磷脂复合物的体外透皮渗透情况 ,比较二者透皮速率与累积渗透量的差异。方法 :通过改进Franz扩散池进行小鼠体外皮肤渗透实验。结果 :葛根素磷脂复合物 1h内累积渗透量大于葛根素 ,以后其增加渐缓 ,而葛根素的渗透速率大于复合物。结论 :葛根素磷脂复合物经皮渗透能在短时间内较快地达到一定药量 ,随后缓慢持久地释放药物。

灯盏花素磷脂复合物的制备及溶解性能

采用溶剂挥发法制备灯盏花素(1)磷脂复合物,以1与磷脂的结合率为评估指标,采用正交设计优化处方,并考察了复合物的溶解性能。结果表明,1磷脂复合物的最佳制备条件为:1-大豆磷脂投料比为1∶4,以四氢呋喃为溶剂配制1浓度为30mg/ml的溶液,于40℃反应2.5h。所得磷脂复合物可明显改善1在水及正辛醇中的溶解性能。

水飞蓟宾磷脂复合物的制备与大鼠生物利用度的研究

目的制备水飞蓟宾磷脂复合物并对其理化性质进行考察,比较水飞蓟宾磷脂复合物与水飞蓟宾原料在大鼠体内的生物利用度.方法以丙酮为溶剂,加入水飞蓟宾和大豆磷脂,充分搅拌至澄清,真空干燥即得黄白色固体;用 DSC,UV,IR 等方法测定水飞蓟宾磷脂复合物的理化性质;两组大鼠分别灌胃给予水飞蓟宾磷脂复合物和水飞蓟宾原料后,用 RP-HPLC 法测定不同时间血浆中总的和游离的水飞蓟宾的浓度,通过3P97程序计算药代动力学参数。结果研究表明水飞蓟宾磷脂复合物是以非共价键结合,而不是新的化合物;水飞蓟宾磷脂复合物明显改善了水飞蓟宾在水中及正辛醇中的溶解性能;大鼠灌胃给予水飞蓟宾磷脂复合物,体内吸收符合一级吸收一室模型,血浆中游离药物和总的药物浓度的 T_(max)分别为10min 和2h;C_(max)分别为0.11和1.08μg·mL^(-1);T_(1/2)2分别为2.18和3.84h;AUC_(0-∞)。分别为1.71和12.94μg·mL^(-1)·h,而给予水飞蓟宾原料,大鼠体内吸收的浓度在检测限以下,不能测定。结论水飞蓟宾磷脂复合物与水飞蓟宾原料相比亲脂性显著增加,从而增强了水飞蓟宾在胃肠道中的吸收,提高了水飞蓟宾的口服生物利用度.

姜黄素磷脂复合物不同制剂对SD大鼠口服生物利用度的影响

目的比较姜黄素磷脂复合物以水分散体、固体分散体及油制剂形式给药时对SD大鼠口服吸收生物利用度的影响。方法 SD大鼠分别灌胃给予姜黄素磷脂复合物上述3种制剂,取血,以大黄素为内标,HPLC法测定姜黄素的血药浓度,并计算药动学参数。结果姜黄素磷脂复合物油制剂的曲线下面积(AUC0-∞)分别为原料药、水分散体及固体分散体的7.99、1.58和1.46倍,而且其tmax与t1/2也均有所延长。结论姜黄素磷脂复合物以油制剂给药时,可显著地提高其生物利用度,这可能与其在油中有更高的稳定性有关。

黄芩苷磷脂复合物制备工艺的研究

目的 :确定黄芩苷与磷脂形成复合物的最佳工艺。方法 :以黄芩苷与磷脂的结合百分率为评估标准 ,采用单因素考察和正交设计试验进行系统的研究。结果 :确定了黄芩苷磷脂复合物的最佳制备条件即在室温下以四氢呋喃为反应溶剂 ,反应时间为 1.5h ,不同磷脂酰胆碱 (PC)含量的磷脂与黄芩苷的最佳反应比例不同。结论 :黄芩苷磷脂复合物的形成受溶剂、反应物浓度和反应物投料比例的影响较大。