The poor retention and efficacy of instilled drops as a means of delivering drugs to the ophthalmic environment is well-recognised. The potential value of contact lenses as a means of ophthalmic drug delivery and consequent improvement of pre-corneal retention is one obvious route to the development of a more effective ocular delivery system. Furthermore, the increasing availability and clinical use of daily disposable contact lenses provides the platform for the development of viable single-day use drug delivery devices based on existing materials and lenses. In order to provide a basis for the effective design of such devices, a systematic understanding of the factors affecting the interaction of individual drugs with the lens matrix is required. Because a large number of potential structural variables are involved it is necessary to achieve some rationalisation of the parameters and physicochemical properties (such as molecular weight, charge, partition coefficients) that influence drug interactions. Ophthalmic dyes and structurally related compounds based on the same core structure were used to investigate these various factors and the way in which they can be used in concert to design effective release systems for structurally different drugs. Initial studies of passive diffusional release form a necessary precursor to the investigation of the features of the ocular environment that over-ride this simple behaviour. Commercially available contact lenses of differing structural classifications were used to study factors affecting the uptake of the surrogate actives and their release under "passive" conditions. The interaction between active and lens material shows considerable and complex structure dependence which is not simply related to equilibrium water content (EWC). The structure of the polymer matrix itself was found to have the dominant controlling influence on active uptake; hydrophobic interaction with the ophthalmic dye playing a major role.3

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Styrene-maleic acid (SMA) block copolymers with either acrylamide (AM) or N,N-dimethylacrylamide (DMA) have been synthesized via a 3-step process comprising: (1) photopolymerization of styrene and maleic anhydride in solution to yield an alternating styrene maleic anhydride (SMAnh) copolymer,(2) copolymerization of SMAnh with either AM or DMA to yield SMAnh-b-AM and SMAnh-b-DMA block copolymers and (3) hydrolysis of the anhydride groups to yield water-soluble SMA-b-AM and SMA-b-DMA block copolymers as the final products. With a view to their intended application in membrane protein solubilization, molecular weights are controlled to below 10,000 by the synthesis conditions employed in step (1), including using carbon tetrabromide (CBr 4 ) as a chain transfer agent. The CBr 4 also plays an important role in step (2). By terminating the SMAnh chain radicals from step (1) with C-Br bonds that are photolytically active, SMAnh chain radicals can be regenerated to act as macroinitiators for the polymerization of AM or DMA in step (2). Finally, following step (3) and due to the pH-dependency of the SMA chain conformation in solution, a pH of 7-8 is found to be optimal for enabling the final products to be precipitated in a solid form that is completely soluble in water.

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This study identifies and investigates the potential use of in-eye trigger mechanisms to supplement the widely available information on release of ophthalmic drugs from contact lenses under passive release conditions. Ophthalmic dyes and surrogates have been successfully employed to investigate how these factors can be drawn together to make a successful system. The storage of a drug-containing lens in a pH lower than that of the ocular environment can be used to establish an equilibrium that favours retention of the drug in the lens prior to ocular insertion. Although release under passive conditions does not result in complete dye elution, the use of mechanical agitation techniques which mimic the eyelid blink action in conjunction with ocular tear chemistry promotes further release. In this way differentiation between passive and triggered in vitro release characteristics can be established. Investigation of the role of individual tear proteins revealed significant differences in their ability to alter the equilibrium between matrix-held and eluate-held dye or drug. These individual experiments were then investigated in vivo using ophthalmic dyes. Complete elution was found to be achievable in-eye; this demonstrated the importance of that fraction of the drug retained under passive conditions and the triggering effect of in-eye conditions on the release process. Understanding both the structure-property relationship between drug and material and in-eye trigger mechanisms, using ophthalmic dyes as a surrogate, provides the basis of knowledge necessary to design ocular drug delivery vehicles for in-eye release in a controllable manner.