Preparation and physicochemical characterizations of tanshinone IIA solid dispersion

This investigation describes a novel approach to prepare solid dispersions of tanshinone IIA using a laboratory-scale planetary ball mill. Poloxamer 188 was employed as the surfactant carrier to improve the solubility and dissolution of the poorly soluble drug, tanshinone IIA. Solubility and dissolution were evaluated compared to the corresponding physical mixtures and pure drug. Furthermore, the physicochemical properties of the solid dispersions were investigated using scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry, Fourier transform infrared spectroscopy and ultraviolet spectrophotometry. The solid dispersion significantly enhanced drug solubility and dissolution compared with pure drug and the physical mixtures. Scanning electron microscopy, powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared spectroscopy analyses of tanshinone IIA/poloxamer 188 system confirmed that there were intermolecular interactions between tanshinone IIA and poloxamer 188 and no conversion to crystalline material. Tanshinone IIA existed in a microcrystalline form in the system. These results suggested that improvement of the dissolution rate could be correlated to the formation of a eutectic mixture between the drug and the carrier. After 60 days the solid dispersion samples were chemically and physically stable. The present studies indicated that the planetary ball mill technique could be considered as a novel and efficient method to prepare solid dispersion formulations.     

Pharmacokinetics, tissue distribution and anti-tumour efficacy of paclitaxel delivered by polyvinylpyrrolidone solid dispersion

Objectives Paclitaxel is a potent anti‐cancer drug that has exhibited clinical activity against several tumours. Unfortunately, serious side effects are associated with Taxol, the commercial formulation of paclitaxel, which contains Cremophor EL (CrEL). Currently, the main focus of developing paclitaxel formulations is on improving efficacy and reducing toxicity. A novel, Cremophor‐free, paclitaxel solid dispersion (PSD) was prepared in our laboratory previously. The primary aim of this study was to evaluate the pharmacokinetics, tissue distribution, acute toxicity and anti‐tumour efficacy of the PSD compared with Taxol. Methods SD rats were used to examine the pharmacokinetics and tissue distribution of PSD. The acute toxicity of PSD was evaluated in ICR mouse. The anti‐tumor activity of PSD was assessed in an in vivo anti‐tumor nude mice model inoculated with human SKOV‐3 cancer cells. Key findings The two formulations presented different pharmacokinetic behaviour. The plasma AUC of paclitaxel in the PSD was 5.84‐fold lower than that of Taxol, and the mean residence time, total body clearance and apparent volume of distribution of paclitaxel in the PSD were increased by 1.73, 4.67 and 8.57 fold, respectively. However, the two formulations showed similar tissue distribution properties. CrEL, the vehicle in Taxol, decreased the clearance of paclitaxel from plasma. The LD50 (median lethal dose) was 34.8 mg/kg for Taxol, whereas no death was observed at 160 mg/kg for the PSD. The anti‐tumour activity of PSD was similar to that of Taxol at a dose of 15 mg/kg. Most importantly, the improved tolerance of PSD enabled a higher administrable dose of paclitaxel, which resulted in improved efficacy compared with Taxol administered at its maximum tolerated dose. Conclusions These results suggest that the PSD, a CrEL‐free formulation, is a promising approach to increase the safety and efficacy of paclitaxel.     

Comparative pharmacokinetics and tissue distribution of cryptotanshinone,tanshinone IIA,dihydrotanshinone I,and tanshinone I after oral administration of pure tanshinones and liposoluble extract of Salvia miltiorrhiza to rats

Salvia miltiorrhiza is one of the most commonly used traditional Chinese medicines in the treatment of cardiovascular and cerebrovascular diseases. Cryptotanshinone (CTS), tanshinone IIA (Tan IIA), dihydrotanshinone I (diTan I), and tanshinone I (Tan I) are the main active compounds in the liposoluble extract of Salvia miltiorrhiza. The differences in the pharmacokinetic and tissue distribution behaviors of the four tanshinones after oral administration of the liposoluble extract of Salvia miltiorrhiza and pure compounds are not clear. This study aims to compare the pharmacokinetics and tissue distribution of the four tanshinones after oral administration of pure tanshinone monomers and the liposoluble extract of Salvia miltiorrhiza. An ultra-performance liquid chromatography–tandem mass spectrometry (UPLC–MS/MS) analysis method was developed for the determination of the four tanshinones. The results showed that the AUC and C_max of tanshinones in rats receiving the extract of Salvia miltiorrhiza were significantly increased compared with those receiving the pure tanshinones. In the tissue distribution experiments, the AUC of the four tanshinones in the extract was much greater than the AUC of the monomers in the lung, heart, kidney, liver, and brain, and the coexisting constituents particularly promoted the distribution of tanshinones into tissues that the drug cannot sufficiently penetrate. These findings suggested that the coexisting constituents in the liposoluble extract of Salvia miltiorrhiza play an important role in the alteration of plasma concentration and tissue distribution of the four tanshinones. Understanding these differences could be of significance for the development and application of Salvia miltiorrhiza extract and tanshinone components.     

姜黄素固体分散体在小鼠体内的药代动力学

目的以姜黄素混悬液为对照,研究姜黄素-聚维酮固体分散体灌胃给药后在小鼠体内的药代动力学。方法按300mg·kg-1的剂量小鼠灌胃姜黄素固体分散体溶液或姜黄素混悬液,采用高效液相色谱法测定血浆中姜黄素含量,用DAS软件拟合房室模型,计算药动学参数。并测定了给药3h时药物的吸收率。结果姜黄素-聚维酮固体分散体在小鼠体内的药代动力学符合二室开放模型,主要药动学参数如下:T12α和T12β分别为16.4和266min,AUC为89.6mg·mL-1.min-1,Vd为763.9L,V1为51.0L,CL为1.99L·min-1。姜黄素-聚维酮固体分散体在胃肠道的吸收率是姜黄素混悬液的6.75倍。结论姜黄素固体分散体灌胃可显著增加姜黄素的生物利用度,血药浓度较高。     

Pharmacokinetics, tissue distribution and relative bioavailability of puerarin solid lipid nanoparticles following oral administration

Puerarin has various pharmacological effects; however, poor water-solubility and low oral bioavailability limit its clinical utility. A delivery system of solid lipid nanoparticles could enhance its oral absorption. The objective of this study was to investigate the pharmacokinetics, tissue distribution and relative bioavailability of puerarin in rats after a single dose intragastric administration of puerarin solid lipid nanoparticles (Pue-SLNs). The puerarin concentrations in plasma and tissues were determined by rapid resolution liquid chromatography electrospray ionization-tandem mass spectrometry. The C(max) value of puerarin after the administration of Pue-SLNs was significantly higher than that obtained with puerarin suspension (0.33±0.05 μg/mL vs. 0.16±0.06 μg/mL, P<0.01). The T(max) value after the administration of the Pue-SLNs was significantly shorter than that after puerarin suspension administration (40±0 min vs. 110±15.49 min, P<0.01). The AUC(0→t) values of puerarin were 0.80±0.23 mg h/L, and 2.48±0.30 mg h/L after administration of the puerarin suspension and Pue-SLNs, respectively. Following administration of the Pue-SLNs, tissue concentrations of puerarin also increased, especially in the target organs such as the heart and brain. These data suggest that SLNs are a promising delivery system to enhance the oral bioavailability of puerarin.     

In situ intestinal absorption behaviors of tanshinone IIA from its inclusion complex with hydroxypropyl-beta-cyclodextrin

In this paper, the intestinal permeability of the inclusion complex of tanshinone IIA (TS IIA) with 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was investigated. The corresponding complexation of TS IIA-HP-beta-CD was obtained by coevaporation and characterized by differential scanning calorimetry and X-ray diffraction. The recirculation intestinal perfusion technique in rats was used to study the absorption behavior of free and complexed TS IIA. The change of concentration of TS IIA was separately calculated according to Michaelis-Menten and the Fick's equation to investigate its absorption rate-limiting step. Using the mathematical models above, it was concluded that the limit step to absorption of TS IIA was the dissolution process. Different concentrations of complexed TS IIA were administrated to three intestinal segments, with the intestinal permeability ranging from 3.16x10(-5) cm.s(-1) in the duodenum (50 microg.ml(-1)) to 4.11x10(-5) cm.s(-1) in the jejunum (100 microg.ml(-1)). With the increase of dosage of complex, TS IIA's absorption did not show saturated phenomenon, suggesting its transport mechanism in vivo might primary be passive transport. Besides, the permeability of TS IIA was not apparently influenced by the perfusion section studied, which indicated that there might not exist specific absorption site for TS IIA.     

Pharmacokinetics,tissue distribution and bioavailability of nitrendipine solid lipid nanoparticles after intravenous and intraduodenal administration

Purpose: The aim of this research was to study whether the bioavailability of nitrendipine (NDP) could be improved by administering nitrendipine solid lipid nanoparticles (SLN) duodenally to rats.

Methods: Nitrendipine was incorporated into SLN prepared by hot homogenization followed by ultrasonication method. SLN were produced using various triglycerides (trimyristin, tripalmitin and tristearin), soy phosphatidylcholine 95%, poloxamer 188 and charge modifiers (dicetyl phosphate, DCP and stearylamine, SA). Particle size and charge measurements were made with a Malvern Zetasizer. Pharmacokinetics of nitrendipine SLNs (NDP-SLNs) after intravenous (i.v.) and intraduodenal (i.d.) administration to conscious male Wistar rats were studied. Tissue distribution studies of NDP-SLNs were carried out in Swiss albino mice after i.v. administration and compared to nitrendipine suspension (NDP-Susp).

Results: Average size and zeta potential of SLNs of different lipids, with and without charge modifiers ranged from 101.9 ± 3.0 to 123.5 ± 3.0 nm and ? 35.1 ± 0.5 to +34.6 ± 2.3 mV, respectively. AUC_(0–∞) was increased (up to 4.51-folds) and clearance was decreased (up to 4.54-folds) after i.v. administration of NDP-SLNs with and without charge modifiers compared to NDP-Susp. Effective bioavailability of NDP-SLNs were 2.81–5.35-folds greater after i.d. administration in comparison with that of NDP-Susp. In tested organs, the AUC and MRT of NDP-SLNs were higher than those of NDP-Susp especially in brain, heart and reticuloendothelial cells containing organs.

Conclusions: SLN are suitable drug delivery systems for the improvement of bioavailability of nitrendipine. Negatively and positively charged SLN were better taken up by the liver and brain, respectively.     

Pharmacokinetics, tissue distribution and bioavailability of nitrendipine solid lipid nanoparticles after intravenous and intraduodenal administration

PURPOSE: The aim of this research was to study whether the bioavailability of nitrendipine (NDP) could be improved by administering nitrendipine solid lipid nanoparticles (SLN) duodenally to rats. METHODS: Nitrendipine was incorporated into SLN prepared by hot homogenization followed by ultrasonication method. SLN were produced using various triglycerides (trimyristin, tripalmitin and tristearin), soy phosphatidylcholine 95%, poloxamer 188 and charge modifiers (dicetyl phosphate, DCP and stearylamine, SA). Particle size and charge measurements were made with a Malvern Zetasizer. Pharmacokinetics of nitrendipine SLNs (NDP-SLNs) after intravenous (i.v.) and intraduodenal (i.d.) administration to conscious male Wistar rats were studied. Tissue distribution studies of NDP-SLNs were carried out in Swiss albino mice after i.v. administration and compared to nitrendipine suspension (NDP-Susp).RESULTS: Average size and zeta potential of SLNs of different lipids, with and without charge modifiers ranged from 101.9 +/- 3.0 to 123.5 +/- 3.0 nm and - 35.1 +/- 0.5 to +34.6 +/- 2.3 mV, respectively. AUC(0-infinity) was increased (up to 4.51-folds) and clearance was decreased (up to 4.54-folds) after i.v. administration of NDP-SLNs with and without charge modifiers compared to NDP-Susp. Effective bioavailability of NDP-SLNs were 2.81-5.35-folds greater after i.d. administration in comparison with that of NDP-Susp. In tested organs, the AUC and MRT of NDP-SLNs were higher than those of NDP-Susp especially in brain, heart and reticuloendothelial cells containing organs.CONCLUSIONS: SLN are suitable drug delivery systems for the improvement of bioavailability of nitrendipine. Negatively and positively charged SLN were better taken up by the liver and brain, respectively.     

冷冻干燥法制备丹参酮IIA纳米脂质体

目的:用大豆卵磷脂作为载体制备丹参酮IIA納米脂质体。方法:用超声-匀浆-冷冻干燥法制备丹参酮IIA納米脂质体。采用透射电镜测试丹参酮IIA脂质体的粒径,用激光粒度分布仪测试平均粒径及粒度分布。结果:冷冻干燥法制备丹参酮IIA納米脂质体的粒径25~117nm之间。随着大豆卵磷脂与丹参酮IIA配比的减小,粒径逐渐减小,包封率逐渐减小。体外释药表现为零级动力学释药特征。结论:用超声-匀浆-冷冻干燥法制备丹参酮IIA納米脂质体的方法可行。     

Enhancement of solubility and dissolution rate of cryptotanshinone, tanshinone I and tanshinone IIA extracted from Salvia miltiorrhiza

Cryptotanshinone, tanshinone I and tanshinone IIA are three major components in the extract of Salvia miltiorrhiza with pharmacological significance. However, their effective utilization is limited due to poor water solubility and bioavailability. Solid dispersion (SD) of the extract of Salvia miltiorrhiza was prepared to enhance solubility and dissolution of the three major components. Various carriers were screened for SD preparation by conventional solvent method. Dissolution of the components from selected SD systems was compared with commercial tablets of the extract from Salvia miltiorrhiza. The solubility of three components viz., cryptotanshinone, tanshinone I and tanshinone IIA, after forming SD with either of povidone K-30 (PVP K-30) or poloxamer 407, exhibited enhanced solubility in pH 6.8 buffer. Dissolution test revealed that the amount of three components released was higher from SD tablets as compared to the commercial tablets. Pharmacokinetic profile was evaluated using cryptotanshinone as a representative compound. AUC of cryptotanshinone was significantly increased when administered as a solid dispersion.     

依普黄酮固体分散体在大鼠的药物动力学评价(英文)

目的:评价依普黄酮固体分散体在大鼠体内的药物动力学行为。方法:测定它的药物动力学参数和相对生物利用度,采用高压液相色谱法测定大鼠血浆中依普黄酮的浓度。结果:大鼠灌胃依普黄酮固体分散体250mg·kg~(-1),其血药浓度-时间曲线符合一室模型,药物动力学参数为:K_e=0.21h~(-1),T_(1/2K_e)=5.19h,K_a=1.71h~(-1),T_(1/2K_a)=0.41h,T_(max)=0.67h,C_(max)=429μg·L~(-1),AUC=3916μg·h·L~(-1),相对生物利用度是323％。结论:依普黄酮固体分散体与依普黄酮的物理混合物比较,在大鼠体内有更多被吸收。     

Continuous synthesis and anti-myocardial injury of tanshinone IIA derivatives

A series of tanshinone IIA derivatives were synthesized through sulfonation, slat-forming, chlorination, and amidation reactions. Meanwhile, anti-myocardial injury activity was evaluated in vitro. D8 and D9 exhibited a slightly higher anti-myocardial injury (5.78, 7.46 μM) activity compared with esmolol (8.12 μM). In addition, they also displayed a concentration-dependent inhibition on the anti-myocardial injury.     

Pharmacokinetics, tissue distribution and excretion of vinflunine.

The plasma pharmacokinetics, tissue distribution, excretion and binding to plasma proteins of vinflunine, were investigated after intravenous (iv) administration. We obtained plasma profiles after iv administration of vinflunine at the doses of 3.5, 7 and 14 mg/kg in rats. The t1/2 values for vinflunine were estimated to be 18.38+/-1.20, 17.05+/-0.77, 18.35+/-1.57 h, and the mean AUC0-t values were 3.48+/-0.38, 6.54+/-0.68, 12.79+/-2.93 microg x h/ml, respectively. Of the various tissues tested, vinflunine was widely distributed into tissues, with the highest concentrations of vinflunine being found in well perfused organs. Maximal concentration of vinflunine was reached at 0.5 h postdose in the majority of tissues. In tumor-bearing mice, the similar pattern of tissue distribution was observable, except that vinflunine can be distributed into tumor. The binding of vinflunine in human and rat plasma proteins were 39.6% and 58.4% respectively. Within 96 h after administration, 9.58%, 15.36% and 0.71% of the given dose was excreted in urine, feces and bile, respectively. In conclusion, Vinflunine had a longer terminal half-life, a wide tissue distribution and less than 25% of the given dose was excreted as unchanged drug, suggesting metabolism as a major style of elimination.     

Pharmacokinetics and tissue distribution of crotonoside

1.?Crotonoside is a bioactive ingredient from Croton Herba with a strong antitumour activity. This study aimed to develop a highly sensitive and selective high-performance liquid chromatography (HPLC) method to quantify crotonoside in biological samples for pharmacokinetics and distribution studies.

2.?Protein precipitation by perchloric acid was used to separate crotonoside from the biological samples, and the recovery rates for crotonoside and the internal standard (luteoloside) were >80%. All calibration curves examining the crotonoside levels in plasma and tissues were linear (all correlation coefficients >?0.99).

3.?The response to crotonoside appeared to be dose disproportional to the maximum plasma concentration and the area under the time–concentration curve in plasma over the range of 12.5–50.0?mg/kg, and crotonoside was highly distributed in tissues after intravenous administration. The highest crotonoside level was detected in the liver (28.79?±?14.96?μg/g), whereas crotonoside was undetected in the brain.     

Pharmacokinetics and tissue distribution of idarubicin-loaded solid lipid nanoparticles after duodenal administration to rats

Idarubicin-loaded solid lipid nanoparticles (IDA-SLN) and idarubicin in solution were prepared and the two formulations were administered to rats, either by the duodenal route or intravenously (iv). The aim of this research was to study whether the bioavailability of idarubicin can be improved by administering IDA-SLN duodenally to rats. Idarubicin and its main metabolite idarubicinol were determined in plasma and tissues by reversed-phase high-performance liquid chromatography. The pharmacokinetic parameters of idarubicin found after duodenal administration of the two formulations were different: area under the curve of concentration versus time (AUC) and elimination half-life were approximately 21 times and 30 times, respectively, higher after IDA-SLN administration than after the solution administration. Tissue distribution also differed: idarubicin and idarubicinol concentrations were lower in heart, lung, spleen, and kidneys after IDA-SLN administration than after solution administration. The drug and its metabolite were detected in the brain only after IDA-SLN administration, indicating that SLN were able to pass the blood-brain barrier. After iv IDA-SLN administration, the AUC of idarubicin was lower than after duodenal administration of the same formulation. Duodenal administration of IDA-SLN modifies the pharmacokinetics and tissue distribution of idarubicin. The IDA-SLN act as a prolonged release system for the drug.     

拉西地平固体分散体在Beagle犬体内的药动学和生物等效性研究

目的研究不同拉西地平固体分散体在Beagle犬体内的药动学和生物等效性。方法采用Thermo C_(18)色谱柱(50 mm32.1 mm,2.6μm);流动相:0.2%甲酸水溶液–乙腈(17∶83);体积流量:0.2 mL/min;柱温:30℃;进样室温度:15℃;进样量:10μL。采用电喷雾离子源(ESI),多反应监测(MRM)方式扫描,以正离子方式进行检测;用于定量分析的离子对分别为拉西地平m/z 473.47(母离子)→354.28(子离子),内标尼莫地平m/z 419.25(母离子)→343.18(子离子)。6只健康Beagle犬分别给予4 mg参比制剂拉西地平片(R)、拉西地平-HPMC E5固体分散体(T_1)和拉西地平-Soluplus固体分散体(T_2),绘制血药浓度–时间曲线,采用DAS 2.1.1软件非隔室模型计算主要药动学参数,并进行生物等效性分析。结果拉西地平在0.25~100 ng/mL线性关系良好,定量下限为0.25 ng/mL。在0.5、5.0、80.0 ng/mL的提取回收率和基质效应分别为100.92%~102.89%和100.71%~102.89%,RSD值11%。T_1、T_2和R的主要动力学参数分别为峰浓度(C_(max))为(24.45±6.53)、(28.80±11.89)、(26.647±4.44)ng/mL;达峰时间(t_(max))为(1.13±0.70)、(1.29±0.64)、(1.79±1.36)h;t_(1/2)分别为(8.39±4.60)、(7.10±6.73)、(5.20±6.16)h。受试制剂相对生物利用度为(112.2±57.8)%、(110.6±51.6)%。生物等效性分析两组受试制剂与参比制剂均不具备生物等效性。结论该方法准确、灵敏度高、专属性强,可用于拉西地平制剂的药动学和生物等效性研究。自制拉西地平固体分散体与市售拉西地平片生物等效性不一致。     

Complexation of tanshinone IIA with 2-hydroxypropyl-beta-cyclodextrin: effect on aqueous solubility, dissolution rate, and intestinal absorption behavior in rats

In this paper, the effect of 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the aqueous solubility, dissolution rate, and intestinal permeability of the tanshinone IIA (TS IIA) was investigated. The corresponding inclusion complex of TS IIA/HP-beta-CD at the molar ratio of 1:1 was obtained by coevaporation and characterized by differential scanning calorimetry, and X-ray diffraction. The solubility of complexed TS IIA in water at 37+/-0.1 degrees C was 17 times greater than that for the uncomplexed drug. The dissolution rate of TS IIA was significantly increased by the complexation with HP-beta-CD, due to its solubilizing activity. The everted intestinal sac technique in rats was used to study the absorption behavior of TS IIA and this complexation through the intestinal tissues. The permeability rates of TS IIA across the intestinal epithelial membrane were enhanced by the formation of inclusion complex with HP-beta-CD about 5.2, 5.8 and 4.8 times of the uncomplexed TS IIA in duodenum, jejunum and ileum, respectively. It was revealed that the absorption rate-limiting step of TS IIA might be the dissolution process. The present results indicate the potential use of HP-beta-CD to improve the gastrointestinal tract absorption of TS IIA.     

依普黄酮固体分散体在大鼠的药物动力学评价

AIM: To evaluate pharmacokinetic behavior of ipriflavone solid dispersion in rats. METHODS: The plasma concentrations of ipriflavone in rats were determined by HPLC with UV detector. RESULTS: Plasma concentration-time curves after ig ipriflavone solid dispersion 250 mg.kg-1 in rats were fitted with one-compartment model. Pharmacokinetic parameters were as follows: Ke = 0.21 h-1, T1/2Ke = 5.19 h, Ka = 1.71 h-1, T1/2Ka = 0.41 h, Tmax = 0.67 h, Cmax = 429 micrograms.L-1, AUC = 3916 micrograms.h.L-1; The relative bioavailability of ipriflavone solid dispersion was 323%. CONCLUSION: Ipriflavone in solid dispersion was absorbed more effectively than that in physical mixture in rats.