Haibing He

PEG–PLGA copolymers: Their structure and structure-influenced drug delivery applications

In the paper, we begin by describing polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA) which was chosen as a typical model copolymer for the construction of nano-sized drug delivery systems and also the types of PEG-PLGA copolymers that were eluted. Following this we examine the structure-influenced drug delivery applications including nanoparticles, micelles and hydrogels. After that, the preparation methods for nano-sized delivery systems are presented. In addition, the drug loading mode of PEG-PLGA micelles is divided into three aspects. Finally, the drug release profiles of PEG-PLGA micelles, both in terms of their in vitro and in vivo characteristics, are represented. PEG-PLGA copolymers are very suitable for the construction of micelles as carriers for insoluble drugs. This article reviews the structure and the different structure-influenced applications of PEG-PLGA copolymers, concentrating on the application of PEG-PLGA micelles.

Thiolated Eudragit nanoparticles for oral insulin delivery: Preparation, characterization and in vivo evaluation

In the present study thiolated Eudragit L100 (Eul) based polymeric nanoparticles (NPs) were employed to develop an oral insulin delivery system. Sulfydryl modification was achieved by grafting cysteine to the carboxylic acid group of Eudragit L100, which displayed maximum conjugate level of 390.3±13.4 μmol thiol groups per gram. Eudragit L100-cysteine (Eul-cys) and Eul nanoparticles were prepared by the precipitation method, in which reversible swelling of pH-sensitive material was used for insulin loading and release. Nanoparticles were characterized in terms of their particle size, morphology, loading efficiency (LE%) and in vitro insulin release behavior. The NPs had an average size of 324.2±39.0 nm and 308.8±35.7 nm, maximal LE% of 92.2±1.7% and 96.4±0.5% for Eul-cys and Eul, respectively. The release profile of NPs in vitro showed pH-dependent behavior. Circular dichroism (CD) spectroscopy analysis proved that the secondary structure of the insulin released from NPs was unchanged compared with native insulin. The mucoadhesion study in vitro showed that Eul-cys NPs produced a 3-fold and 2.8-fold increase in rat jejunum and ileum compared with unmodified polymer NPs, respectively, which was due to the immobilization of thiol groups on Eudragit L100. Oral administration of insulin-loaded Eul-cys NPs produced a higher and prolonged hypoglycemic action, and the corresponding relative bioavailability of insulin was found to be 7.33±0.33%, an increase of 2.8-fold compared with Eul NPs (2.65±0.63%). This delivery system is a promising novel tool to improve the absorption of protein and peptide drugs in the intestinal tract.

The influence of lipid characteristics on the formation, in vitro release, and in vivo absorption of protein-loaded SLN prepared by the double emulsion process

Purpose: To study the influence of lipid characteristics on the formation, in vitro release, and in vivo absorption of solid lipid nanoparticles (SLN) prepared by the double emulsion method. Methods: Stearic acid (SA), octadecyl alcohol (OA), cetyl palmitate (CP), glyceryl monostearate (GM), glyceryl palmitostearate (GP), glyceryl tripalmitate (GT), and glyceryl behenate (GB) were selected as the representatives of different kinds of lipids, insulin and thymopentin (TP5) were selected as the model protein drugs. Before preparation, the contact angles between water and lipids were determined to investigate their hydrophobicity. The influence of lipid hydrophobicity or lipid solution viscosity on the preparation of primary emulsion, double emulsion, and SLN were studied by evaluating the particle size, state, and stability of the systems. CP-SLN, GT-SLN, and GP-SLN were selected to be loaded with insulin and TP5 for the in vitro release and in vivo absorption examination. After oral administration to diabetic rats, the pharmacological availability (PA) of insulin-CP-SLN, insulin-GP-SLN, and insulin-GT-SLN were determined. Results: The hydrophobicity order of the lipids was GM<GP<GT<GB<SA<OA<CP. SLNs could be prepared successfully by CP, GT, and GP, and their particle size was 447.5 ± 50.8, 444.8 ± 72.5, and 213.7 38.4 nm, respectively. All of the three SLNs exhibited burst release, and the percentage insulin released in 4 hours from these three SLNs were 76.37%, 45.36%, and 33.28%, respectively, and the corresponding TP5 release percentages were 75.72%, 56.89%, and 47.43%. Particle sizes increased significantly for CP-SLN and GP-SLN after a 24 hours release study in simulated gastrointestinal fluid. The PA of insulin-CP-SLN, insulin-GT-SLN, and insulin-GP-SLN were 2.92%, 3.44%, and 4.53%, respectively. Conclusions: This study suggested that GP with a suitable hydrophobicity, relatively lower burst release, and higher PA was the most promising lipid material of SLN for oral delivery of proteins.

Evaluation of Docetaxel-Loaded Intravenous Lipid Emulsion: Pharmacokinetics, Tissue Distribution, Antitumor Activity, Safety and Toxicity

ABSTRACTPurposeThe purpose of this study was to carry out a detailed evaluation of an intravenous lipid emulsion for docetaxel (DLE) without Tween 80 before clinical administration.MethodsThe pharmacokinetics in rats and beagle dogs, tissue distribution, antitumor activity, safety test and toxicity of DLE have been investigated systematically to evaluate the formulation and compared with Taxotere® (DS).ResultsThe pharmacokinetic study in rats revealed that DLE exhibited higher plasma concentrations and AUC than DS, and a good correlation was observed between AUC and dose, while, in beagle dogs, the DLE was bioequivalent to DS. The tissue distribution study showed that the profiles of the two formulations were similar, indicating the DLE did not change the distribution of docetaxel in vivo. Furthermore, DLE was as safe as DS in the safety investigation and displayed significant antitumor activities against the A549, BEL7402 and BCAP-37 cell lines in nude mice, similar to DS. The corresponding results of the long-term toxic study demonstrated the DLE was less toxic than DS, and the toxic effects could be reversed.ConclusionsThe DLE investigated in this paper was found to be an attractive new formulation and an appropriate choice for the clinical administration of docetaxel.

The efficacy and safety of bufadienolides-loaded nanostructured lipid carriers

Bufadienolides-loaded nanostructured lipid carriers (BU-NLC) were prepared for parenteral application using glyceryl monostearate as solid core, medium-chain triglyceride and oleic acid as liquid lipid material, and Lipoid E-80, sodium deoxycholate and pluronic F68 as stabilizers. In this study, the in vitro cytotoxicity, pharmacokinetics, biodistribution, antitumor efficacy and safety of BU-NLC were evaluated. Against human astrocytoma cell line (U87-MG) and human gastric carcinoma cell line (HGC-27) BU-NLC exhibited cytotoxicity that was similar to that of the free drug, and superior to that of the commercially available fluorouracil injection. BU-NLC exhibited a linear pharmacokinetic behavior at doses ranging from 0.25 to 1.0 mg/kg. The improved pharmacokinetic profile of bufadienolides when formulated in BU-NLC resulted in a higher plasma concentration and lower clearance after intravenous administration compared with bufadienolides solution (BU-S). A biodistribution study indicated that bufadienolides were mainly distributed in the lung, spleen, brain and kidney, and the longest retention was observed in the brain. A sarcoma-180 tumor model further confirmed the advantages of BU-NLC versus BU-S. Hemolysis and acute toxicity investigations showed that BU-NLC was safe when given by intravenous injection with reduced toxicity. In conclusion, the NLC system is a promising approach for the intravenous delivery of bufadienolides.

A floating multiparticulate system for ofloxacin based on a multilayer structure: In vitro and in vivo evaluation.

The purpose of this research was to develop a novel gastroretentive multiparticulate system with floating ability. This system was designed to provide drug-loaded pellets coated with three successive coatings-the retarding film (ethyl cellulose), the effervescent layer (sodium bicarbonate) and the gas-entrapped polymeric membrane (Eudragit RL 30D). The floating pellets were evaluated for SEM, floating characteristic parameters, in vitro release and bioavailability in New Zealand rabbits. The zero-order release theory model is designed to interpret the release processes. Due to the swelling property, high flexibility and high water permeability, Eudragit RL 30D was used as a gas-entrapped polymeric membrane. The obtained pellets exhibit excellent floating ability and release characteristics. Analysis of the release mechanism showed a zero-order release for the first 8h because of the osmotic pressure of the saturated solution inside of the membrane, which was in accordance with that predicted. Abdominal X-ray images showed that the gastroretention period of the floating barium sulfate-labeled pellets was no less than 6h. The relative bioavailability of the floating pellets compared with reference tablets was 113.06 ± 23.83%. All these results showed that the floating pellets are a feasible approach for the gastroretentive drug delivery system.

Injectable nimodipine-loaded nanoliposomes: Preparation, lyophilization and characteristics

The main purpose of this study was to prepare nimodipine-loaded nanoliposomes for injection and evaluate their characteristics after lyophilization. Nimodipine-loaded nanoliposomes were prepared by the emulsion-ultrasonic method with sodium cholesterol sulfate (SCS) as the regulator and then lyophilized by adding different cryoprotectants. SCS was used as a blender of regulator and surfactant and helped to prepare smaller liposomes due to the steric hindrance of the sulfate group. The results showed that nimodipine-loaded nanoliposomes with a 20:1 of egg yolk lecithin PL-100M vs. SCS ratio had a particle size of 86.8±42.007 nm, a zeta potential of -13.94 mV and an entrapment efficiency (EE) of 94.34% and could be stored for 12 days at 25°C. Because of the good bulking effect of mannitol and the preservative effect of trehalose, they were used to obtain suitable lyophilized nanoliposomes. The lyophiles containing 10% mannitol and 20% trehalose had a good appearance and a slightly altered particle size after rehydration. In addition, the lyophilized products were characterized by differential scanning calorimetry, X-ray diffraction and scanning electron microscopy, which confirmed the morphous state of trehalose, mannitol and the mixture. Trehalose could inhibit mannitol crystallization to some extent. The drug release from nanoliposomes before and after lyophilization in pH 7.4 phosphate buffer containing 30% ethanol was also examined and both profiles were found to fit the Viswanathan equation. This means that the drug release was controlled by the pore diffusion resistance.

Clarithromycin-loaded liposomes offering high drug loading and less irritation

The aim of this study was to develop an efficient method of preparing less irritant clarithromycin-loaded liposomes (CLA-Lip) for injection with a high drug loading and to evaluate their physicochemical characteristics before and after lyophilization. CLA-Lip were prepared using the film-dispersion method with sodium cholesterol sulfate (SCS) and n-hexyl acid as the regulators and then lyophilized. The liposomes were characterized in terms of their size, size distribution, zeta potential, morphology, in vitro release, haemolysis, and lyophilization and irritation testing was carried out. The TEM images revealed that the structure of the CLA-Lip were multilamellar and of a regular size of around 100 nm. In addition, the lyophilized CLA-Lip were characterized by DSC and Infrared spectroscopy to confirm the structure. H-bonding and salt-forming reactions were used to ensure that clarithromycin (CLA) was stably encapsulated in the liposomes. This method provided a 30-fold increase in the concentration of clarithromycin relative to that in aqueous solution. Sucrose was found to be the best protective agent and was added in an amount of 12.5% (w/v). According to the mouse scratch test and the rat paw lick test, the pain of CLA-Lip was significantly reduce by approximately 80% compared with the solution of clarithromycin phosphate. In addition, rabbit ear vein experiments produced similar results. These findings suggested that CLA-Lip was a stable delivery system with less irritation, which should be extremely suitable for clinical application.

Enhancing effects of chitosan and chitosan hydrochloride on intestinal absorption of berberine in rats

Berberine chloride (BBR) is a plant alkaloid that has been used for centuries for treatment of inflammation, dysentery, and liver diseases. It is poorly absorbed from the gastrointestinal (GI) tract and its various clinical uses are limited because of its poor bioavailability. The object of the present study was to investigate the absorption enhancing effect of chitosan on BBR. Mixtures of BBR and chitosan were prepared and the absorption enhancement was investigated in rats. The results showed a dose-dependent absorption enhancement produced by chitosan. Formulations containing 0.5%, 1.5%, and 3.0% chitosan resulted in improvement of AUC0–36 h values by 1.9, 2.2, 2.5 times. The absorption enhancing ability of chitosan may be due to its ability to improve the BBR paracellular pathway in the intestinal tract. Chitosan hydrochloride, a salt of chitosan, was also investigated in this study. However, the addition of 2.0% and 3.3% chitosan hydrochloride to BBR solution did not produce any increase in either Cmax or AUC0–36 h of BBR. Subsequent solubility studies suggested that the reduced berberine chloride solubility in chitosan hydrochloride may limit the enhancement ability. This study showed that the optimum formulation producing the highest BBR absorption is the BBR solution containing 3.0% chitosan.

Preparation and in vitro-in vivo evaluation of double layer coated and matrix sustained release pellet formulations of diclofenac potassium.

The purpose of the present study was to prepare matrix extended release pellets of diclofenac potassium using low amount of release-modifying agents and, to compare its performance in vivo with coated pellets and matrix tablets. Coated pellets were prepared by extrusion-spheronization, followed by double layer coating using different polymers separately. Matrix pellets with different release rate in vitro were prepared by extrusion-spheronization with different kinds of retarding materials. Bioavailability study of different coated pellets revealed that the drug concentration in plasma of beagle dogs was too low to be detected and, implied that the drug was nearly not released from the preparations before reaching colon due to the appearance of lag time in the dissolution process. The phenomenon indicated that slow-release pellets of diclofenac potassium perhaps should not be developed as double membrane-controlled type. The AUC((0 → 24)) of the immediate release pellets, the two matrix pellets and the reference were 304.4, 87.7, 204.1 and 179.1 μg h/ml, respectively. The C(max) of the formulations mentioned above were 46.3, 13.0, 33.6 and 32.1 μg/ml, respectively. All the matrix formulations, including the reference, exhibited incomplete absorption due to the short small intestine transit time and termination of the drug release in the colon because of its limited solubility. The matrix pellets were bioequivalent with the commercially available tablet (Voltaren(®)) although the drug release in vitro of the former was much faster, while the bioavailability of the matrix pellets with similar in vitro drug release to the reference (Voltaren(®)) was much lower than the latter. The results perhaps was caused by lacking of physical robustness in the waxy tablet formulation, resulted in low wet strength and easily destroyed by the mechanical destructive forces and finally introduced faster drug release rate in vivo. It is apparent that preparations with similar performance in vitro may differ a lot in vivo because of the differences in drug release rate in vivo owing to various wet strengths of excipients contained, especially for sustained release products.