Kangjie Zhu

A novel approach to prepare tripolyphosphate/chitosan complex beads for controlled release drug delivery.

A novel approach was developed to improve the mechanical strength of tripolyphosphate (TPP)/chitosan beads prepared under coagulation condition at 4 degrees C in the presence of gelatin. Cross-sectional analysis indicated that the beads had a homogeneous crosslinked structure, as a result the beads were strengthened greatly (the mechanical strength increased more than ten times). Furthermore sodium alginate (a polyanion) can interact with cationic chitosan on the surface of these TPP/chitosan beads to form polyelectrolyte complex film for the improvement of the drug sustained release performances. The loading efficiency of model drugs (brilliant blue and FITC-dextran) in these beads was very high (more than 90%). Crosslinking time, TPP solution pH and other preparation factors had an effect on the drug release performance of beads. The release period of brilliant blue (a poor water soluble dye) was more than 2-months at a fairly constant rate in 0.9% NaCl, 10 mM PBS pH 7.4. However, for FITC-dextran (a water soluble polysaccharide) only 1-2 days in the same conditions. It seems that TPP/chitosan bead prepared by the novel method is a promising formulation for drug delivery.

Novel pH-sensitive citrate cross-linked chitosan film for drug controlled release

Turbidimetric titration revealed that there were electrostatic attractive interactions between citrate and chitosan in the pH region of 4.3-7.6, depending on their degree of ionization. Citrate cross-linked chitosan film was prepared simply by dipping chitosan film into sodium citrate solution. The swelling ratio of citrate/chitosan film was sensitive to pH, ionic strength etc. Under acidic conditions, citrate/chitosan film swelled and even dissociated in the pH less than 3.5, and the model drugs (brilliant blue and riboflavin) incorporated in the film were released quickly (usually within 2 h released completely in simulated gastric fluid at 37 degrees C) while under neutral conditions the swelling ratio of citrate/chitosan film was less significant and the release rate of brilliant blue and riboflavin was low (less than 40% released in simulated intestinal fluid in 24 h). Sodium chloride weakened the electrostatic interaction between citrate and chitosan, and therefore facilitated the film swelling and accelerated drug release. The parameters of film preparation such as citrate concentration, solution pH etc. influencing the film swelling and drug release profiles were examined. The lower concentration and the higher pH of citrate solution resulted in a larger swelling ratio and quicker riboflavin release. To improve the drug controlled release properties of citrate/chitosan film, heparin, pectin and alginate were further coated on the film surface. Among them only the coating of alginate prolonged riboflavin release noticeably (for 80% of drug released the time was extended from 1.5 to 3.5 h with 0.5% w/v alginate used). The results indicated that the citrate/chitosan film was useful in drug delivery such as for the site-specific drug controlled release in stomach.

Controlled drug release properties of ionically cross-linked chitosan beads: the influence of anion structure.

By adopting a novel chitosan cross-linked method, i.e. chitosan/gelatin droplet coagulated at low temperature and then cross-linked by anions (sulfate, citrate and tripolyphosphate (TPP)), the chitosan beads were prepared. Scanning electron microscopy (SEM) observation showed that sulfate/chitosan and citrate/chitosan beads usually had a spherical shape, smooth surface morphology and integral inside structure. Cross-sectional analysis indicated that the cross-linking process of sulfate and citrate to chitosan was much faster than that of TPP due to their smaller molecular size. But, once completely cross-linked, TPP/chitosan beads possessed much better mechanical strength and the force to break the beads was approximately ten times higher than that of sulfate/chitosan or citrate/chitosan beads. Release media pH and ionic strength seriously influenced the controlled drug release properties of the beads, which related to the strength of electrostatic interaction between anions and chitosan. Sulfate and citrate cross-linked chitosan beads swelled and even dissociated in simulated gastric fluid (SGF) and hence, model drug (riboflavin) released completely in 5 h; while in simulated intestinal fluid (SIF), beads remained in a shrinkage state and drug released slowly (release % usually <70% in 24 h). However, swelling and drug release of TPP/chitosan bead was usually insensitive to media pH. Chitosan beads, cross-linked by a combination of TPP and citrate (or sulfate) together, not only had a good shape, but also improved pH-responsive drug release properties. Salt weakened the interaction of citrate, especially sulfate with chitosan and accelerated beads swelling and hence drug release rate, but it was insensitive to that of TPP/chitosan. These results indicate that ionically cross-linked chitosan beads may be useful in stomach specific drug delivery.

Surface biodegradable copolymers—poly(d,l-lactide-co-1-methyl-1,3-trimethylene carbonate) and poly(d,l-lactide-co-2,2-dimethyl-1,3-trimethylene carbonate): preparation, characterization and biodegradation characteristics in vivo

Abstract Novel surface biodegradable copolymers, poly( d,l -lactide- co -1-methyl-1,3-trimethylene carbonate) (PLMCA) and poly( d,l -lactide- co -2,2-dimethyl-1,3-trimethylene carbonate) (PLDMCA), have been synthesized by ring-opening polymerization with Sn(Oct) 2 as catalyst. The copolymers were characterized by 1 H n.m.r., 13 C n.m.r. and d.s.c. Water content and static contact angle of distilled water on the polymer surface were used to evaluate the hydrophobicity of the copolymers. Samples were implanted in rats to observe degradation characteristics. It was found that, in both the PLMCA and the PLDMCA copolymer system, the surface biodegradation characteristics in vivo were related to polymer hydrophobicities, which mainly depended on the copolymer compositions. The degradation of PLMCA and PLDMCA having a smaller ester fraction became a typical surface reaction. These copolymers may be useful in protein delivery systems.

Pulsatile protein release from a laminated device comprising of polyanhydrides and pH-sensitive complexes

A laminated device comprising of polyanhydrides as isolating layers and pH-sensitive complexes as protein-loaded layers was designed to deliver proteins in a pulsatile manner. Poly(sebacic anhydride)-b-polyethylene glycol (PSA-b-PEG) and poly(trimellitylimidoglycine-co-sebacic anhydride)-b-polyethylene glycol (P(TMA-gly-co-SA)-b-PEG) were synthesized as isolating layers for their good processing properties at room temperature and suitable erosion duration. During the erosion period, pH of the dissolution fluid decreases to a low value (3.8-5.8). Poly(methacrylic acid)/polyethoxazoline (PMAA/PEOx) complex was used as protein-loaded layers, which could dissociate and release model proteins, Myoglobin (Mb) and Bovine Serum Albumin (BSA), at pH 7.4 while become stable and retained the drugs below pH 5.0. The protein release from the device showed a typical pulsatile fashion. The lag time prior to the pulsatile protein release correlated with the hydrolytic duration of the polyanhydrides, which varied from 30 to 165 h by selecting polyanhydride type and isolating layer thickness. In addition, the pulse duration could be adjusted from 18.5 to 40 h by varying the mass of the complex. The results can be attributed to the synergistic effects between the degrading polyanhydrides, pH-sensitive complexes and proteins.

Design of a core-shelled polymer cylinder for potential programmable drug delivery.

A cylindrical dosage form comprising a laminated composite polymer core and a hydrophobic polycarbonate coating was proposed for programmable drug delivery. In the core, poly[(ethyl glycinate) (benzyl amino acethydroxamate) phosphazene] was synthesized as drug-loaded layers for its strong pH-sensitive degradation (eroded after 1.5 days at pH 7.4 and more than 20 days at pH 5.0 and 6.0). Poly(sebacic anhydride)-b-polyethylene glycol or poly(sebacic anhydride-co-trimellitylimidoglycine)-b-poly(ethylene glycol) was selected as isolating layers for their good processing properties at room temperature and suitable erosion duration. The in vitro drug release studies of these devices were conducted under physiological conditions (pH 7.4). The results revealed that the model drugs (brilliant blue, FITC-dextran, myoglobin) could be released in typical pulsatile manner. Moreover, the duration time of drug release (24-40 h) and the lag time (18-118 h) could be separately regulated by the mass of polyphosphazene and the type or mass of polyanhydride. In this experiment, the cooperative effect of polyanhydrides and pH-sensitive degradable polyphosphazene was specially demonstrated, which offers a new idea to develop a programmable drug delivery system for single dose vaccine and other related applications.

Novel micelles from graft polyphosphazenes as potential anti-cancer drug delivery systems: drug encapsulation and in vitro evaluation.

In this study, a new class of amphiphilic methoxy-poly(ethylene glycol) grafted polyphosphazene with glycine ethyl ester side groups (PPP-g-PEG/GlyEt) was synthesized and characterized. An anti-cancer agent doxorubicin (DOX) was encapsulated into polymeric micelles derived from those copolymers, which exhibited considerably strong impact on micelle morphology: turned the rod-like and spherical drug free micelles into spheres and vesicles respectively. The in vitro release behavior of those drug-loaded micelles exhibits a sustained release manner and is affected by drug content. Cytotoxicity assay against adriamycin-resistant human breast cancer MCF-7 cell line showed that drug-loaded micelles based on PPP-g-PEG/GlyEt micelles can effectively suppress cell proliferation and the cytotoxicity was both time and concentration related, an enhanced cytotoxicity was observed either with increasing drug concentration or with prolonged incubation time. Moreover, flow cytometry results revealed a particle size dependency in cellular uptake of drug-loaded micelles. These findings suggest that the present copolymers can encapsulate water insoluble anti-cancer agents and contribute to improve drug sensitivity of adriamycin-resistant cell line.

Polymeric micelles as nanocarriers for drug delivery

Polymeric micelles are built from amphiphilic polymers through self-assembly effects. Due to their unique core shell structure, small size and modifiable surface, polymeric micelles have been widely investigated as nanoscale drug delivery carriers. Such systems may increase drug solubility and have possible applications in tumour targeting and gene therapy. These biomedical applications require that polymeric micelles are biocompatible, have prolonged blood circulation and possess high drug-loading efficiency. In addition, tumour targeting and smart drug release behaviour need special modification towards micelles with multiplicate functional substances. This review focuses on the present progress of polymeric micelles and highlights some critical issues for their application in drug delivery systems. Composition and micellisation procedures are also briefly discussed.

Reverse self-assemblies based on amphiphilic polyphosphazenes for encapsulation of water-soluble molecules

A novel series of amphiphilic polyphosphazenes (PNIPAm/AA-PPP) containing hydrophilic oligo-(N-isopropylacrylamide) (oligo-NIPAm) and various hydrophobic aliphatic amines as co-substitutes was synthesized via a two-step substitution reaction. The extraction and solubilization of water-soluble substances such as fluorescein sodium and trypan blue from an aqueous phase into the chloroform phase were supposed to result from the formation of polyphosphazene reverse self-assemblies in the organic phase. A field emission scanning electronic microscope was adopted to characterize the morphology of reverse assemblies in chloroform. Additionally, a significant improvement of encapsulation and release profiles of water-soluble substances was found for poly(lactic-co-glycolic acid) (PLGA) microparticles in the presence of amphiphilic copolymers, which was associated with the chemical structure of copolymers as well as the content of copolymer in the microparticles.

Thermosensitive self-assembly behaviors of novel amphiphilic polyphosphazenes

A series of amphiphilic thermosensitive polyphosphazenes (PNIPAm-g-PPP) bearing N-isopropylacrylamide oligomers (oligo-PNIPAm) and glycine ethyl groups (GlyEt) as co-substituents have been synthesized via polymer substitute reaction. UV-visible spectra indicated that the aqueous solution of PNIPAm-g-PPP exhibited the lower critical solution temperature (LCST). Furthermore, the LCST was seriously influenced by the substitution ratios of PNIPAm to GlyEt in the copolymer. The more GlyEt the copolymer contained, the lower LCST it had. The critical association concentration (cac) of copolymers was determined by fluorescence probe method. It was found that cac was decreased with increasing GlyEt content of polyphosphazene. Also the formation of self-assembled micelles or nano-particles was confirmed by TEM.