Self Regulated

Self-regulated devices are capable of altering drug output in response to an external change and can be classified into substrate-specific and environment-specific devices.

Substrate -Specific

Two different types of devices are under development. In one type, the substrate modulates drug release from the device, while in the other type the substrate triggers drug release from a passive device.

Modulated Devices The major driving force for developing such devices is a need to better control diabetes since it is now well tecogmzed that replacement of insulin by periodic injections does not adequately control this disease. Thus, many approaches are under way in attempts to develop devices that can release insulin in response to blood glucose concentrations.

In one such approach, a sugar is covalenrly attached to insulin and the sugar—insulin conjugate is complexed with the plant-derived, carbohydrate-binding protein Concanavalin A (Con A). Because the sugar-insulin conjugate is displaced from Con A in proportion to the external glucose concentration, such a device can deliver insulin in response to blood glucose levels (Makino et at., 1990).

Another approach utilizes pH changes resulting from the glucose oxidase conversion of glucose to gluconic acid and pH-sensitive polymers that can respond to that change. Such polymers can be membranes that reversibly alter their porosity by a protonation of tertiary amine functions in the polymer (Albin et at 1985; Ishlhara et ai., 1986) or by ionization of a grafted polv acrylic acid on a micro porous substrate (Ito et al., 1989; Iwata et al,, 1988), or they can be bioerodible polymers that alter their erosion rate in response to pH changes (Heller et ai, 1990)

Triggered Devices One important application is the development of a device capable of releasing the narcotic antagonist naltrexone in response to external morphine. Such a device would be useful in treating narcotic addiction by blocking the opiate-induced euphoria through a morphine-triggered release of the antagonist. Development of this device utilizes the reversible in activation of an enzyme by hapten-antibody interaction

(Schneider et al., 1973) as shown in Fig. 14, In the device under development, naltrexone is contained in a core surrounded by an enzymatically degradable coating that prevents its release. In the absence of external morphine, the device is stable, but upon exposure to morphine, the reversibly inactivated enzyme is activated and degrades the protective coating, which results in naltrexone release. The actual device utilizes the enzyme lipase and a triglyceride protective coating (Roskos et al., 1993).

tnvironment-SpecJflc Devices

In an environment-specific approach, devices are constructed that can alter drug release in response to changes in temperature or pH. One example of polymers that can reversibly respond to temperature changes are hydrogels based on N-isopropylacrylamide (Yangei al., 1990; Okano etaL, 1990). When this monomer is copolymerized with methylene bis-acrylamide, the resulting cross-linked materials have been shown to demix with water and to shrink abruptly when heated just above 31°C. Hie collapse of the hydrogel occurs as a result of a phase transition of poly(N-isopropylacrvlamide), which is soluble in water at its lower critical solution temperature (LCST) of 31=C hut becomes insoluble when the temperature is increased just past this temperature. Such materials are useful for the delivery or removal of biological molecules triggered by temperature changes.

pH-Sen skive systems can be constructed from lightly cross-linked copolymers of n-alkyl methacrylates (hydrophobic monomer) and N.N-dimethylaminoethy) methacrylates (ion-izable monomer) (Siegel, 1990). Such materials exhibit a strong dependence of swelling on external pH and can abruptly swell when the external pH is lowered. The pH at which the abrupt swelling occurs is a function of copolymer composition.

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