Increased absorption of mangiferin in the gastrointestinal tract and its mechanism of action by absorption enhancers in rats

The therapeutic efficiency of mangiferin is restricted by its low intestinal permeability. In order to improve the oral absorption of mangiferin, potential of enhancers, including TPGS, sodium deoxycholate and Carbopol 974P, were investigated in a series of in vivo experiments. After administration of mangiferin at a dose of 30?mg/kg combining with sodium deoxycholate, the bioavailability of mangiferin increased four-fold, and this may be due to sodium deoxycholate weakening the compactness between lecithin molecules and increased the paracellular permeability. When Carbopol 974P (100?mg/kg) was combined with mangiferin, the oral bioavailability of it increased seven-fold compared with the control group, and this may be related to the mucoadhesive properties of Carbopol 974P and paracellular drug permeation. However, following coadministration of TPGS (50?mg/kg), the oral absorption of mangiferin increased slightly compared with that of the control group (p > 0.05). The increased oral absorption by the three coexcipients was in the order of Carbopol 974P > sodium deoxycholate > TPGS. The absolute bioavailability of mangiferin in the three different doses following oral administration were evaluated based on the AUC_(0–t) of the intravenous dose and there was no increase from low doses to high doses (25?mg/kg to 100?mg/kg). The above results show that the low absorption of mangiferin was due to presence of a narrow absorption window, which may also exist in these compounds, which have structures similar to mangiferin including three fused aromatic rings with polyphenolic hydroxyl groups. Bioadhesion polymers are effective enhancers of the absorption of mangiferin in the gastrointestinal tract.     

Spray-Dried Redispersible Emulsion to Improve Oral Bioavailability of Itraconazole

Dry emulsions are powdery, lipid-based formulations from which an o/w-emulsion can be easily reconstituted in vivo or when exposed to water. The objective of this work was to prepare and characterize dry emulsion of itraconazole (ITZ) to improve its solubility and bioavailability. Dry emulsions were prepared by spray-drying liquid o/w-emulsions containing carriers like maltodextrin, sucrose, and lactose. Propylene glycol monocaprylate was selected as oil phase, and surfactant blends of vitamin E tocopherol polyethylene glycol succinate and triblock PEO–PPO–PEO copolymer as emulsifying agents. Several oil:water and carrier:water ratios were tested. An optimum formulation was selected using 3² full factorial design. The droplet size, rheological behavior, and drug release from o/w-emulsion before and after reconstitution and the micromeritic properties of spray-dried product were investigated. Maltodextrin was used as a carrier for preparing dry emulsions. The optimized dry emulsion was characterized using DSC, SEM, PXRD, and in vivo study. The SEM analysis showed that dry emulsion consisted of well-separated particles with smooth surfaces. The DSC and XRD study showed that ITZ in the dry emulsion is in the molecular dispersion state. Globule size analysis showed that dry emulsion had good reconstitution properties. The emulsions were found to be thermodynamically stable when subjected to cyclical freeze–thaw cycles and centrifugation tests. The average globule size of emulsions ranged from 0.994 to 1.668 μm. A 71.35 % increase in C _max and 114.78 % increase in AUC was evident for ITZ dry emulsion as compared to plain ITZ.     

A novel mixed polymeric micelle for co-delivery of paclitaxel and retinoic acid and overcoming multidrug resistance: synthesis,characterization, cytotoxicity,and pharmacokinetic evaluation

In the current study, retinoic acid (RA) was conjugated to Pluronic F127 (PF127) through an esterification process. Mixed micelles were formed with tocopheryl polyethylene glycol 1000 (TPGS) for co-delivery of paclitaxel (PTX) and RA to the cancer cells. Mixed micelles of RA-PF127 and TPGS in different weight ratios (10:0, 7:3, 5:5, 3:7, 0:10 w/w) were prepared and physicochemical properties including, particle size, zeta potential, critical micelle concentration (CMC), drug loading content, entrapment efficiency, drug release, cellular uptake and in vitro cytotoxicity, were investigated in details. Furthermore, the pharmacokinetics of PTX-loaded optimized mixed micelles were evaluated in Sprague-Dawley rats and compared with Stragen^® (PTX in Cremophor EL^®). Particle sizes and zeta potentials of the drug-loaded micelles were in the range of 102.6–223.5?nm and ?5.3 to ?9.6?mV, respectively. The 7:3 and 5:5 micellar combinations had lower CMC values (0.034–0.042?mg/mL) than 0:10 (0.124?mg/mL). The entrapment efficiencies of 10:0, 7:3, and 5:5 were 53.4?±?9.3%, 61.3?±?0.5%, and 78.7?±?1.66%, respectively. The release rates of PTX from 7:3 and 5:5 mixed micelles were significantly slower than other formulations. Cytotoxicity assay demonstrated increased cytotoxic activity of PTX-loaded mixed micelles compared to free PTX. The V_d and t_1/2ß of PTX-loaded RA-PF127/TPGS (7:3) were increased by 2.61- and 1.27-fold, respectively, while the plasma area under the curve (AUC) of the micelles was 2.03-fold lower than those of Stragen^®. Therefore, these novel mixed micelles could be effectively used for delivery of PTX and RA to the cancer cells. Moreover, TPGS as part of micelle composition could enhance the therapeutic effect of PTX and reduce side effects.     

聚乙二醇1000维生素E琥珀酸酯在高分子药物释放体系的应用进展

许多由高分子药物释放体系给药的药物,由于载药量不够、或者由于癌细胞的多药耐药性导致药物外排等种种原因,不能以有效的药物浓度作用于目的器官,从而导致治疗效果不理想。人们已经尝试以不同方式添加聚乙二醇1000维生素E琥珀酸酯(D-α-tocopheryl polyethylene glycol 1000succinate,TPGS)来改良高分子药物释放体系中的各种不足。总结了近几年来各种添加TPGS的高分子药物释放体系的研究进展,对所有TPGS的添加情况进行了分类,从包埋率和载药量的测量,细胞检测以及动物实验等进行概述。以不同的方式添加TPGS均可大大提高高分子药物释放体系的载药量和包埋率,抑制多药耐药性,甚至使抗癌药物达到口服的效果,可从多方面改善高分子释放体系给药的性能。     

VE聚乙二醇琥珀酸酯的研究进展

VE聚乙二醇琥珀酸酯(TPGS)是由VE琥珀酸酯与聚乙二醇酯化反应而得,它既含有VE亲脂基团,又含有聚乙二醇长链的亲水基团,是一种非离子型表面活性剂.可用作增溶剂、乳化剂、吸收增强剂、水溶性VE的原料等,以提高药物的生物利用度、提高水溶性差的药物的溶解性和作为药物释放系统、抗癌药的载体等.还介绍了TPGS的国内外合成及检测方法,我们合成的粗产品采用薄层色谱定性检测.     

Preparation and characterization of mono‐ and di‐d‐α‐tocopheryl polyethylene glycol 1000 succinate

Mono‐d‐α‐tocopheryl polyethylene glycol 1000 (TPGS 1000) and di‐TPGS 1000 were prepared from the synthesized TPGS 1000 mixture. The key separation step was performed by a Simulating Moving Bed chromatographic process. The chemical structures and molecular weight distrubution were characterized by ¹H‐NMR and MALDI‐TOF mass spectroscopy. NMR and MALDI‐TOF MS data confirmed the occurrence of di‐TPGS. Both NMR and MALDI‐TOF MS results showed the degree of polymerization of the two esters and the molecular mass. The melting temperatures of the two polymers were investigated by DSC and the thermal decomposition temperatures have been determined by TGA. The melting temperatures of the two esters were 33 and 15°C, separately. And the two separated TPGS esters exhibited different thermal decomposition courses. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Design and evaluation of D-α tocopheryl polyethylene glycol 1000 succinate emulsified poly-ϵ-caprolactone nanoparticles for protein/peptide drug delivery

Background: Incorporation of proteins/peptide drugs into nanoparticulate drug delivery system is one of the effective approaches to increase the stability of protein/peptide drugs against enzymatic degradation, to release them in a controlled fashion and to achieve site-specific drug delivery.

Objective: Our goal was to design and evaluate poly-?-caprolactone (PCL) nanoparticles using bovine serum albumin (BSA) as a model protein. d-α-tocopheryl polyethylene glycol 1000 (vitamin E TPGS) was used as an emulsifier in the fabrication of these nanoparticles.

Methods: Double emulsion solvent evaporation method was employed to formulate BSA-loaded PCL nanoparticles and the nanoparticles thus prepared were further characterized.

Results: The size of BSA-loaded PCL nanoparticles were in the range of 400–500?nm with a polydispersity index (PDI) of 0.195 and zeta potential was about ?28.6 mV. Scanning electron microscopy (SEM) confirmed the presence of smooth and spherical surface of nanoparticles. Encapsulation efficiency was about 85% and a yield of 70–75% was attained. BSA was released in a biphasic pattern with an initial 20% release within 2?h followed by a slower release patter over 5 days. Flow cytometry and fluorescence microscopy was used to study the uptake of these nanoparticles. Circular dichroism (CD) results showed that there was no significant effect of formulation conditions on the secondary structure of BSA.

Conclusion: Based on the results obtained, these TPGS-emulsified PCL nanoparticles proved to be potential carriers for the delivery of protein/peptide drugs.     

Etodolac-Liquid-Filled Dispersion into Hard Gelatin Capsules: An Approach to Improve Dissolution and Stability of Etodolac Formulation

ABSTRACT

The formation of melt dispersion is an effective method of increasing the dissolution rate of poorly soluble drugs, and hence, of improving the bioavailability. The carrier fusion method was used to prepare different dispersion of etodolac using Gelucire 44/14 and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS). The physical characteristics of the binary systems were determined by differential scanning calorimetry (DSC), infrared spectroscopy (IR). The release rate from the resulting dispersion was determined from dissolution studies by use of USP dissolution apparatus II (paddle method). The dissolution rate of etodolac is increased in all the dispersion systems compared to that of pure drug. A liquid dispersion system of etodolac (20%) and Gelucire 44/14: TPGS blend (80%), in different ratios, was also prepared. The capsule formulation was subjected to stability studies at different temperature and humidity conditions as per ICH guidelines. Physical and chemical properties of the dispersion didn't change during a period of storage at room temperature and at 4°C, 0% RH. It was found that etodolac was chemically stable against the effects of temperature and humidity. However, the relative humidity and storage time exerted an effect on the dissolution behavior of etodolac. The changes in dissolution behavior after storage under conditions of high humidity and temperature might be related to the formation of etodolac microcrystal and to water absorption by the carrier during storage. It is predicted that acceptable shelf-lives should result when moisture-resistant packaging is used for pharmaceutical formulations of this type.     

Effect of Tocopheryl Polyethylene Glycol Succinate on the Percutaneous Penetration of Minoxidil from Water/Ethanol/Polyethylene Glycol 400 Solutions

ABSTRACT

We described to achieve the local retention of minoxidil which has penetrated the skin with minimization of its absorption into the general circulation and elimination of local irritation induced by propylene glycol. The effect of tocopheryl polyethylene glycol succinate (TPGS) on the penetration flux of minoxidil and its retention in the skin from topical minoxidil formulations consisting of water, alcohol, and polyethylene glycol 400 was characterized by an experimental design of ten solvent formulations in this study. Results show that the addition of TPGS was only able to improve the solubility of minoxidil in those solvent systems containing higher proportions of water and PEG 400, and the extent of improvement was also more profound with the addition of TPGS at concentrations higher than 5%. For those solvent systems containing a higher fraction of alcohol, an insignificant change in minoxidil solubility with increasing added amounts of TPGS was noted even with the tendency to decrease the solubility of minoxidil with higher amounts of TPGS. Increasing the amount of TPGS added gradually increased the flux and the corrected flux from solvent formulations with a lower solubility parameter, but decreased those from solvent systems with a higher solubility parameter. With the addition of TPGS, solvent formulation F6 (alcohol:PEG 400 of 50:50) was demonstrated to be the optimal choice by having an improved local effect and a reduced systemic effect compared to the reference of 2% Regaine®. Tocopheryl polyethylene glycol succinate (TPGS) was mainly retained locally in the stratum corneum, and the amount was proportional to the increase in the amount of TPGS added to these ten solvent formulations.