Polymers that display a physicochemical response to stimuli are widely explored as potential drug-delivery systems. Stimuli studied to date include chemical substances and changes in temperature, pH and electric field. Homopolymers or copolymers of N-isopropylacrylamide and poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (known as poloxamers) are typical examples of thermosensitive polymers, but their use in drug delivery is problematic because they are toxic and non-biodegradable. Biodegradable polymers used for drug delivery to date have mostly been in the form of injectable microspheres or implant systems, which require complicated fabrication processes using organic solvents. Such systems have the disadvantage that the use of organic solvents can cause denaturation when protein drugs are to be encapsulated. Furthermore, the solid form requires surgical insertion, which often results in tissue irritation and damage. Here we report the synthesis of a thermosensitive, biodegradable hydrogel consisting of blocks of poly(ethylene oxide) and poly(L-lactic acid). Aqueous solutions of these copolymers exhibit temperature-dependent reversible gel-sol transitions. The hydrogel can be loaded with bioactive molecules in an aqueous phase at an elevated temperature (around 45 degrees C), where they form a sol. In this form, the polymer is injectable. On subcutaneous injection and subsequent rapid cooling to body temperature, the loaded copolymer forms a gel that can act as a sustained-release matrix for drugs.

Differential scanning calorimetry (DSC) was performed on aqueous solutions of polyCZVisopropylacrylamide-co-butyl methacrylate-co-X), with X being hydrophilic, hydrophobic, cationic, or anionic comonomers, to elucidate the mechanism of temperature-induced phase separation and the effect of comonomer content, hydrophilicity, and charge on the lower critical solution temperature (LCST). The endothermic heat of phase separation, which is related to the breaking of hydrogen bonds between water molecules surrounding hydrophobic moieties on the polymer, was a linear, decreasing function of the LCST. This suggests that the hydrophobic interactions between polymer side groups, which are the major driving force for phase separation, are enhanced at elevated temperatures due to a decrease in the structuring of water around hydrophobic side groups. It is concluded that the changes in LCST caused by the incorporation of comonomers are due to changes in overall hydrophilicity of the polymer and are not due to a direct influence of comonomer hydrophilicity or charge on the structuring of water around hydrophobic groups.

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