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In this paper, a novel method is presented for the preparation of dextran hydrogels and microspheres, based on crystallization. Although dextrans are known to be well soluble in water, precipitation was observed in concentrated aqueous solutions of low molecular weight dextran (dextran 6000), whereas for solutions of dextran with higher molecular weights (dextran 40,000 and 220,000) no precipitation was observed in the time-frame studied. The kinetics of the precipitation process were studied and showed that precipitation was faster when more concentrated dextran solutions were used. Furthermore, the precipitation process was accelerated by stirring and by the presence of salts. Depending on the precipitation time, microspheres or gels were obtained. The precipitates were insoluble in water at room temperature, but readily dissolved in boiling water or DMSO. IR spectroscopy and (modulated) differential scanning calorimetry ((M)DSC) demonstrated that the precipitates were crystalline. We hypothesize that crystallization is due to association of the chains through hydrogen bonding, induced by the large polymer/water ratio in concentrated dextran 6000 solutions.

A novel delivery concept based on the encapsulation of liposomes in biodegradable dextran microspheres was developed. The microspheres were prepared using a two-phase system, consisting of water/poly(ethylene glycol), and water/methacrylated dextran. Liposomes were encapsulated almost quantitatively and in their intact form, and were released with full preservation of their integrity. The effects of microsphere water content, degree of methacrylate substitution, and type of dextran derivative used on the release rate were investigated. The release of the liposomes from the dextran microspheres was fully controlled by the degradation rate of the spheres. This resulted, after a lag time, in a pulsed release of the liposomes from relatively rapidly degrading microspheres. On the other hand, slower degrading microspheres resulted in sustained release of liposomes over 100 days. The degradation rate of the dextran microspheres, in turn, depended on the water content, the degree of methacrylate substitution, and type of hydrolytically sensitive spacer present in the cross-links.

The average pore size of hydrated dextran microspheres is derived from rheological and protein release data. The microspheres were prepared by cross-linking an aqueous solution of methacrylated dextran emulsified in a continuous poly(ethylene glycol) phase. The rheological data were obtained using a novel micromanipulation technique, which enables the compression of a single microsphere. The so obtained pseudoelasticity moduli of the microspheres were derived from these compression data and corresponded well with the elasticity moduli of macroscopic hydrogels of the same composition, as determined with dynamic mechanical analysis. The modulus increased with decreasing water contents of the microspheres and with increasing degrees of methacrylate substitution of the dextran used. Furthermore, the average pore sizes calculated from the pseudoelasticity moduli were in good agreement with the pore sizes derived from protein release data. In conclusion, this study shows that micromanipulation provides insight into the average pore sizes of dextran microspheres, which is an important characteristic that will modulate the release of encapsulated proteins.

Purpose: To design liposome-loaded microspheres, which release the liposomes in a time-controlled manner and in intact form., Methods: Liposomes were encapsulated in biodegradable dextran-based microspheres, which were prepared using an aqueous two phase system consisting of poly(ethylene glycol) and methacrylated dextran. The effects of liposome size and membrane fluidity, microsphere water content, degree of methacrylate substitution, and type of dextran derivative used, on encapsulation efficiency, release, and integrity of the liposomes were investigated., Results: Liposomes were entrapped in dextran-based microspheres quantitatively and with full preservation of their integrity. Liposomes with a low, as well as with a high membrane fluidity, were released from the microspheres in their intact form and with preservation of their size. Release kinetics depended only on the degradation rate of the microspheres. For rapidly degrading systems, pulsed release was observed and the time after which the pulse occurred (from 5 until 25 days) could be tailored by the gel characteristics such as initial water content, degree of methacrylate substitution, and type of hydrolytically sensitive spacer present in the cross-links. This delay time was not dependent on the size of the liposomes in the range studied (0.1-0.2 microm). Microspheres which degraded more slowly showed, after a certain delay time, sustained release of the liposomes extended up to 100 days., Conclusions: A novel drug delivery concept based on the encapsulation of liposomes in biodegradable dextran-based microspheres was designed. The system released the liposomes in intact form in a controlled way after a prolonged period of time.

In this paper a method is presented to determine the equilibrium water content of microspheres with a hydrogel character based on cross-linked dextran. The water content was established by determination of the increase in blue dextran concentration after incubation of this solution with dried microspheres. An excellent correlation between the actual and predicted water contents was observed for microspheres with a moderate to high cross-link density. On the other hand, for particles with low cross-link density, the equilibrium water content was higher than predicted. This could be fully ascribed to swelling of the microspheres.

A novel procedure to prepare dextran microspheres, without the use of organic solvents was developed. The method is based on phase separation which occurs in aqueous solutions of PEG and methacrylated dextran (dexMA). After stirring this two phase system a water-in-water emulsion is formed. When dexMA forms the discontinuous phase, dextran microspheres can be obtained by polymerization of the methacryloyl groups attached to dextran. The aim of this study was to gain insight into the formulation parameters that affect the particle characteristics. Therefore, it was necessary to establish dexMA/PEG/water phase diagrams. Lower polymer molecular weights and higher degrees of MA substitution resulted in less pronounced phase separation (binodal shifts to higher concentrations). The volume weight mean microsphere diameter varied between 2.5 and 20 microm, depending on the viscosities of both phases and the PEG/dexMA volume ratio. A more viscous continuous phase and/or a less viscous discontinuous phase resulted in smaller microspheres. Furthermore, the particle size increased with decreasing PEG/dexMA volume ratios. The particle characteristics, like cross-link density, initial water content and size can be tailored by adjusting the formulation parameters.

Protein-loaded dextran microspheres were prepared by a water-in-water emulsion technique. With this technique, an aqueous solution of methacrylated dextran (dex-MA) is emulsified in an aqueous solution of poly(ethylene glycol) (PEG). Subsequently, the dispersed dex-MA phase is crosslinked by radical polymerization of the dextran-bound methacryloyl groups. This method renders microspheres with a hydrogel character of which the crosslink density can be controlled by the water content and the degree of substitution of the dex-MA (DS, the number of methacrylates per 100 glucopyranose residues). If an IgG solution was added to the dex-MA/PEG aqueous system prior to the polymerization reaction, the protein could be encapsulated in the dextran microspheres with a high yield (88-98%). The release of IgG was studied as a function of the water content, the DS and the degradation rate of the microspheres. The microspheres were rendered degradable by co-encapsulation of an endo-dextranase. Non-degrading microspheres mainly showed a burst release, which decreased with increasing crosslink density. By either a low water content (50%, w/w, or lower) or a high DS (DS 13), it was possible to reduce the burst release to about 10%, meaning that almost complete entrapment of the protein could be achieved. The release of IgG from degrading microspheres was predominantly dependent on the DS and the amount of encapsulated dextranase. No differences in release of IgG from microspheres with and without dextranase were observed at high DS (DS 13). This was ascribed to the inability of the enzyme to degrade these microspheres. On the other hand, the entrapped protein was completely released from enzymatically degrading microspheres with a DS 4. Moreover, the release rate of IgG was proportional to the degradation rate of these microspheres (depending on the amount of co-encapsulated dextranase). Interestingly, an almost zero-order release was observed from these microspheres for periods up to 30 days.

Purpose: The purpose of this study was to investigate the effect of the formulation parameters on the characteristics of dextran-based microspheres, prepared in an all-aqueous system., Methods: Dextran microspheres were formed by polymerization of methacryloyl groups attached to dextran (dexMA), emulsified in an aqueous poly(ethylene glycol) (PEG) solution. DexMA/PEG/water phase diagrams were established., Results: The binodals in the phase diagrams shifted to higher concentrations of dextran and PEG with decreasing molecular weight of both polymers, and with increasing degree of MA substitution. The volume-number mean diameter of the microspheres, varied between 2.5 and 20 microns. For a given formulation, the particle size was independent of the PEG/dexMA volume ratio > 40 and increased for volume ratios < 40. Furthermore, larger particles were obtained with decreasing viscosity of the continuous phase and increasing viscosity of the discontinuous phase., Conclusions: Particle characteristics of dextran microspheres prepared in an all-aqueous system, among which the size and initial water content, can be tailored by adjusting the formulation parameters.