Neil B. Graham

Hydrogels for controlled drug delivery

Physical properties such as number average molecular weight Mn, specific hydrates and changing diffusion coefficient of crystalline/rubbery hydrogels based on poly(ethylene glycol) Mn 3 000-8 000 which affect the diffusion of drugs through the water swollen matrix and across the polymer boundary are discussed. The advantage of starting with a dry, drug-impregnated polymer to obtain the desirable zero order release rate while the hydrogel absorbs water is illustrated. Drugs have been classified into five groups showing different release profiles. The effects of design and loading on the release profile, are described including the first clinical results of morphine loaded hydrogel suppositories.

Interaction of poly(ethylene oxide) with solvents: 2. Water-poly(ethylene glycol)

Abstract Differential scanning calorimetry (d.s.c.) and water vapour pressure measurement have been used to investigate the poly(ethylene glycol) (PEG) interaction with water. There is a clear evidence for the existence of stable crystalline complexes. One complex clearly contains three moles of water per ether group and exists even at a concentration of 1 part by weight of PEG in 17 parts of water. It melts below p°C. The vapour pressure results indicate a lower hydrate, which could be a monohydrate, but the evidence from the d.s.c. analysis for this hydrate is less definitive. The formation and stability of these hydrates as a function of molecular weight is further discussed relative to ΔH fus and ΔS fus values determined from d.s.c. curves.

Nanogels and microgels: The new polymeric materials playground

Microgels, or intramolecularly crosslinked macromolecules (ICMs), have been known for a number of years. They are formed during the polymerization of polyfunctional precursors en-route, but at incomplete reaction, to the macrogelation predicted by the theories of gelation initially propounded by Carothers and Flory. These gelation theories did not predict that such microgels made in solution could be prepared from such polyfunctional reactive solutions at complete reaction and high concentrations, without gelation. Microgels have been successfully and usefully prepared, however, at complete conversion of their contained reactive groups by the use of either aqueous or non-aqueous dispersion polymerization in which surface active agents are utilized to contain the polymerization to isolated submicron-size domains. The progression towards macrogelation is constrained to the maximum size of the dispersed domains. This paper demonstrates the contrasting general observation that macrogelation in solvents of such polyfunctional reactive precursors cannot occur below a Critical Gelation Concentration (CGC) if a carefully selected match of solvent solubility parameters for the polymerization solvent and the formed polymer is made. In some cases the addition of only ca. ten percent wlw of solvent is required to completely prevent macrogelation at complete conversion. In addition polymerization the molecular weight of the produced ICMs may be varied in a simple controllable manner from the low thousands (nanogels) to many millions (microgels) simply by the choice of concentration at which they are prepared. The products are a distinct form of polymer which is quite different to the linear analogue and almost certainly these solution-prepared products are different to the microgels formed by aqueous dispersion polymerization techniques. This new solution technique provides a simple and general new method for the ready synthesis and design of an enormous range of bespoke globular polymers having both fundamental academic interest and potential commercial utility.

Interaction of poly(ethylene oxide) with solvents: 1. Preparation and swelling of a crosslinked poly(ethylene oxide) hydrogel

Abstract Crosslinked polymer gels containing over 90 wt% poly(ethylene oxide) have been made and their swelling in a large number of solvents studied. The results confirm previous observations that the interaction of poly(ethylene oxide) with water is quite different from the interaction with most other solvents. Formamide also appears to be anomalous. The crosslinked polymer, swollen with water, shows dramatic syneresis between 0° and 100°C but at 100°C still retains approximately three molecules of water for each ether oxygen.

Porogens in the preparation of microporous hydrogels based on poly(ethylene oxides)

To enable the synthesis of hydrogels containing microporosity, a family of pore generating additives (porogens) were synthesized from poly(ethylene glycols) (PEGs) with different molecular weights using naphthyl acetic acid. The products formed were characterized by UV-vis, differential scanning calorimetry and solution nuclear magnetic resonance techniques. Subsequently, poly(ethylene oxide)-urethane hydrogels were synthesized incorporating the above mentioned PEG porogens to modify the structure of the hydrogel. These highly water soluble PEG porogens were inert and extracted out in water. The hydrogels obtained exhibited significant increase in the equilibrium water uptake. This was attributed to the formation of a microporous structure in the hydrogel. It was also evidenced by the observed increase in the diffusion coefficients of the drugs proxyphylline and vitamin B12 through this hydrogel. The proportional increase was greater for the higher molecular weight vitamin B12 than for the proxyphylline. These results may be useful in developing porous hydrogels for controlled release technology.

The Synthesis, Characterization and Molecular Recognition Properties of Imprinted Microgels

Molecular imprinting, an established technique for the synthesis of insoluble crosslinked polymers with specific cavities for selective molecular recognition and catalysis, has been applied to highly crosslinked polymer nanoparticles (microgels) able to build stable solutions in appropriate solvents. Imprinted microgels with a nominal crosslinking degree above 50 wt.-% could be prepared by solution polymerization in high dilution. They were characterized by GPC, viscometry and membrane osmometry, and were found to be highly crosslinked macromolecules with a molecular weight comparable to the one of proteins. Molecular recognition experiments clearly pointed out the presence of functionalized cavities within the microgels that were able to recognize and to selectively bind sugar molecules. The experiment can be carried out in homogeneous solution, after which the microgels are conveniently separated by ultracentrifugation. Although the obtained selectivities are still low compared to the results achieved with insoluble crosslinked polymers, the success of this approach represents an important step towards the development of what might be properly described as “artificial enzymes”.

Interaction of poly(ethylene oxide) with solvents: 4. Interaction of water with poly(ethylene oxide) crosslinked hydrogels

Abstract The nature of the association of water with poly(ethylene oxide) has been studied using crosslinked gels containing 78.4 to 92.5% by weight of poly(ethylene oxide). The interaction of the hydrogel with water is generally attributed to hydrogen bonding between the hydrogen of the water molecule and the ether oxygen of the network. The ether oxygen atom takes on one molecule of water to form a monohydrate and then complexes a further two molecules of water to form a stable trihydrate. Evidence for the formation of these hydrates has been obtained by measuring the heat of partial swelling, the specific heat of hydration and the crystalline melting endotherms. Differential scanning calorimetry showed that trihydrate formation depends quantitatively upon the weight fraction of poly(ethylene oxide) in the gel. A helix model for the stable trihydrate is tentatively proposed.

Distributed sensor for water and pH measurements using fiber optics and swellable polymeric systems

We report on the design, construction and test of a generic form of sensor for making distributed measurements of a range of chemical parameters. The technique combines optical time-domain reflectometry with chemically sensitive water-swellable polymers (hydrogels). Initial experiments have concentrated on demonstrating a distributed water detector; however, gels have been developed that enable this sensor to be readily adapted to distributed pH measurements.

Interaction of poly(ethylene oxide) with solvents: 3. Synthesis and swelling in water of crosslinked poly(ethylene glycol) urethane networks

Abstract Polymer networks were prepared from poly(ethylene glycol) (PEG), methylene bis(4-phenyl isocyanate) and 1,2,6 hexane triol. By varying the amount of crosslinking agent (1,2,6 hexane triol) and the molecular weight of the PEG, a wide range of networks of different crystallinity and swelling were tailored and the influence of temperature and crosslinking on their swelling is discussed.

Blood interactions with novel polyurethaneurea hydrogels

The influence on blood of polyurethaneurea hydrogels in vitro was investigated based on poly(ethylene oxide). A hydrogel was compared with the regenerated cellulose membrane Cuprophan in terms of complement activation, as determined by measurement of C3a concentration. The hydrogel induced less complement activation and the presence of poly(ethylene oxide) is likely to be beneficial to platelet reactivity. The ability to vary the polymer composition and the solubility of the polymers in organic solvents makes the polyurethaneurea hydrogels strong candidates for composite biomaterials.