Characterization and evaluation of self-microemulsifying sustained-release pellet formulation of puerarin for oral delivery

The present study aims to develop self-microemulsifying drug delivery systems (SMEDDS) in sustained-release pellets of puerarin to enhance the oral bioavailability of puerarin. The performances of puerarin-SMEDDS including oils, emulsifiers, and co-emulsifiers were evaluated. Pseudo-ternary phase diagrams shows that the optimized formulation consisted of castor oil as the oil phase, Cremophor EL as the emulsifier, and 1,2-propanediol as the co-emulsifier. SMEDDS sustained-release pellets were prepared via extrusion-spheronization. The particle size distributions of the formulations were determined using transmission electron microscopy and scanning electronic microscopy. The mean particle size was 50 ± 8 nm. The pharmacokinetics and bioavailability of the puerarin-SMEDDS sustained-release pellets and puerarin tablets were evaluated and compared in beagle dogs. The absolute bioavailability of the puerarin-SMEDDS sustained-release pellets was enhanced by approximately 2.6-fold compared with that of the puerarin tablet. The relative bioavailability (F(rel)) of the SMEDDS pellets was 259.7% compared with the tablet group. The results demonstrated that the puerarin-SMEDDS sustained-release pellets had a sustained-release effect, and could remarkably improve the oral bioavailability of puerarin.     

Synthesis, conformational and pharmacological studies of glycosylated chimeric peptides of Met-enkephalin and FMRFa

Our previous study showed that a chimeric peptide of Met-enkephalin and FMRFamide, YFa (YGGFMKKKFMRFa) not only caused antinociception and potentiated morphine analgesia but also blocked the development of tolerance and physical dependence. In the continuation of that study three chimeric analogues of YFa, [Ser5]YFa, [O-Glu-Ser5]YFa and [O-Gal-Ser5]YFa, were synthesized. To increase the bioavailability and penetration of blood brain barrier (BBB), glycosylated analogues, [O-Glu-Ser5]YFa and [O-Gal-Ser5]YFa, have been synthesized by solid phase peptide synthesis by building block method using anomeric acetate activation method. Circular dichroism studies showed that all the three chimeric peptides are stable and have a propensity for adopting helical conformation in the presence of membrane mimicking solvent. In comparison of parent chimeric peptide YFa, helicity of [Ser5]YFa, [O-Glu-Ser5]YFa and [O-Gal-Ser5]YFa has decreased. Pharmacological studies using tail-flick latency in mice showed that [O-Glu-Ser5]YFa have increased analgesia and bioavailability in comparison of [O-Gal-Ser5]YFa and non-glycosylated analogue [Ser5]YFa. Exhibition of enhanced analgesia by [O-Glu-Ser5]YFa as compared to [O-Gal-Ser5]YFa seems to be due to preference of GLUT-1 transporter system for glucose.     

Pharmacokinetics and bioavailability of cimicifugosides after oral administration of Cimicifuga foetida L. extract to rats

Ethnopharmacological relevance

Cimicifuga foetida L., a traditional Chinese medicine, has been used as an anti-inflammatory, antipyretic and analgesic remedy. The primary active constituents are believed to be present in the triterpene glycoside fraction.

Materials and methods

To develop an LC–MS/MS assay for four major cimicifugosides [cimicifugoside H-1 (Cim A), 23-epi-26-deoxyactein (Cim B), cimigenolxyloside (Cim C) and 25-O-acetylcimigenoside (Cim D)] obtained from C. foetida L. and apply it to investigate their pharmacokinetic (PK) properties and bioavailabilities through oral administration of C. foetida L. extract (12.5, 25 and 50 mg/kg) and single intravenous (i.v.) doses (5 mg/kg) of the individual cimicifugosides in rat. PK parameters were estimated by non-compartmental analysis.

Results

All calibration curves showed excellent linear regressions (all r>0.995) within the range of tested concentrations. The intra- and inter-day variations were <15% in terms of RSD. The molar ratio of Cims A, B, C, and D in the extract was 20.7:1.4:2.9:1. PK parameters for Cims A, B, C, and D following oral administration of the extract were respectively: C_max 4.05–17.69, 90.93–395.7, 407.1–1180 and 21.56–45.09 pmol/mL; T_max 0.46–1.28, 2.00–4.67, 14.67–19.67 and 8.08–14.27 h; absolute oral bioavailability (F) 1.86–6.97%, 26.8–48.5%, 238–319% and 32.9–48%. PK parameters after i.v. administration of individual cimicifugosides were respectively: elimination half-life 1.1, 2.5, 5.7 and 4.2 h; clearance 15.7, 0.48, 0.24 and 1.13 mL/h kg.

Conclusions

Systemic exposure to Cims B, C and D following oral administration of the extract was significantly greater than to Cim A despite the predominance of Cim A in the extract. Significantly different clearance and interconversion from Cim A to Cim C probably accounts for the different exposure to the four cimicifugosides.     

A mathematical model for fluoride uptake by the skeleton

Summary A mathematical model was developed that prediets fluoride accumulation and clearance from the skeleton based upon fluoride bioavailability, bone remodeling rate, and the fluoride binding characteristics of bone. It was assumed that fluoride binds to bone in a nonlinear fashion such that a smaller percentage of fluoride is bound to bone if fluoride intake is increased to high levels. Bone resorption rate was assumed to be proportional to the solubility of hydroxyfluorapatite which is inversely related to bone fluoride content. The predictions made by the model compared favorably with experimental results from fluoride uptake and clearance studies. Parametric studies done using the model showed the following: (1) fluoride can be cleared from the skeleton by bone remodeling, but fluoride clearance takes over four times longer than does fluoride uptake; and (2) fluoride uptake by the skeleton was positively associated with bone remodeling rate. However, the concentration of fluoride in newly formed bone does not decrease with reduced remodeling rates and surpasses 10,000 ppm for intakes of fluoride greater than 9 mg/day. For osteoporosis, daily dose and duration of fluoride treatment should be selected to avoid reaching a toxic cumulative bone fluoride content.     

国产尼莫地平片和尼莫通片的生物利用度比较

国产尼莫地平片和尼莫通片的生物利用度比较施孝金王宏图韦阳张静华张莉莉钟明康（上海医科大学华山医院临床药学研究室，上海２０００４０）钙离子通道拮抗剂尼莫地平（ｎｉｍｏｄｉｐｉｎｅ，ＮＭ），临床上主要用于治疗有明显症状的老年性脑功能损伤和由于蛛网膜下腔出...     

胰岛素直肠给药剂型研究 Ⅲ.用放射免疫分析法测定胰岛素栓家兔的生物利用度

本文报导了用可可豆油做基质含有1%表面活性剂(NO-10)的胰岛素栓(剂量按家兔体重3IU/kg 计)家兔直肠吸收的研究,并用胰岛素灌肠剂作对照。用放射免疫法测定各间隔时间的胰岛素血浓度并和用 Folin Malmoros 法测得的血糖浓度进行对比。从得到的 lg C-t 图中看出,胰岛素在体内的转运过程为单隔室模型,达峰时((?)max)为0.5hr,峰值为547 IU/kg,消除半衰期(t~1/2)为0.27hr,测得胰岛素栓的相对生物利用度为83%。实验结果看出,3 IU/kg 剂量的胰岛素栓直肠给药后,家免血糖在1.5小时时降至最低,胰岛素血浓度在0.5小时时出现峰值。     

辅料对四环素吸收影响的研究

本文应用紫外分光光度法研究了体外三硅酸镁吸附四环素的能力及其与介质 pH 的关系;并应用尿药法研究了三硅酸镁及其在表面活性剂和枸橼酸的存在下对四环素吸收的影响;测定了三种不同处方的四环素混悬剂的相对生物利用度并进行了有关参数的统计比较。实验结果表明:三硅酸镁的吸附能力随介质 pH 的高低而增减。月桂醇硫酸钠和枸橼酸在体外对三硅酸镁有明显的解吸作用,而 Brij-35的解吸作用不明显。四环素与三硅酸镁同服时,前者吸收明显减少(P<0.05)。015g月桂醇硫酸钠与0.3g 三硅酸镁同服使三硅酸镁对四环素的吸附作用有一定程度的抑制,且此抑制作用不随月桂醇硫酸钠剂量继续增大而加强。枸橼酸和 Brij-35在体内均无此作用。三种四环素混悬剂的生物利用度无显著差异(P<0.05)。     

Bioavailability of terfenadine in man

Fourteen normal male subjects were given either 60mg or 180mg of terfenadine suspension in a randomized two-way crossover study. Peak plasma concentrations of 1.544 +/- 0.726 (mean +/- S.D.) ng ml-1 were obtained in 0.786 h following the 60 mg dose and displayed an AUC or 11.864 +/- 3.369 ng h ml-1. Whereas peak plasma concentrations of 4.519 +/- 2.002 ng ml-1 in 1.071 +/- 0.514 h were obtained following the 180 mg dose. The AUC following the 180 mg dose was 44.341 +/- 22.041 ng h ml-1. When 60 mg of 14C terfenadine was given to six additional subjects, the peak plasma concentrations of 351 +/- 43 ng equivalents per ml were obtained in 1.67 +/- 0.41 h and the AUC was 2297.71 +/- 310.85 ng-equivalents h ml-1. This indicates that approximately 99.5 per cent of the terfenadine related material that is absorbed undergoes biotransformation. Urinary excretion of 14C accounted for 39.89 +/- 5.29 per cent of the dose while 60.58 +/- 2.44 per cent of the dose was recovered in the feces in twelve days. Thin-layer chromatographic (TLC) examination of fecal extracts showed only a trace of material chromatographing with terfenadine. This may indicate that the 14C present in the feces is not due to lack of absorption.     

Intramuscular Absorption of Carbamazepine in Rhesus Monkeys

The intramuscular absorption characteristics of carbamazepine were investigated in a group of six chair-adapted rhesus monkeys from three parenteral formulations [A:100 mg/ml of carbamazepine in PEG-400; B:50 mg/ml of carbamazepine in PEG-400; and C:50 mg/ml of carbamazepine in a PEG-400-Tween-80 mixture (9:1)]. The absolute bioavailability was determined by administering formulations A or B intravenously. The kinetic profiles obtained after intramuscular administration suggested biphasic absorption in the majority of animals: an initial rapid absorption phase yielding peak concentrations in less than 1 hr followed by a slower phase where absorption was probably rate limiting. The absolute bioavailability was 38% from formulation A, 81% from formulation B and 82% from formulation C. In two of four cases, Tween-80 eliminated the rate-limiting absorption phase. The data suggest that an intramuscular formulation of carbamazepine with acceptable bioavailability may be feasible.