Proteins drug release

Brite-Euram Project BE-7052, Contract BRE2.CT94. 0530 Bioerodible-Biodegradable Polymeric Matrices for Targeted Protein Drug Release. 

A sustained drug release is favourable for drugs with short elimination half-life. It can be controlled by hydration and diffusion mechanisms or ionic interactions between the drug and the polymeric carrier. In the case of diffusion control the stability of the carrier system is essential, as its disintegration leads to a burst release. Therefore, the cohesiveness of the polymer network plays a crucial role in order to control the release over several hours. Due to the formation of disulphide bonds within the network thiomers offer adequate cohesive stability. Almost zero-order release kinetics could be shown for insulin embedded in thiolated polycarbophil matrices (Clausen and Bernkop-Schnurch 2001). In the case of peptide and protein drugs release can be controlled via ionic interactions. An anionic or cationic polymer has to be chosen depending... 

Scheme 1. Mechanism of protein drug release from pH/thermo-sensitive beads made of polymers with increasing molecular weight. Top - swelling and drug diffusion mechanism results in slow release suited for colon targeting. Bottom - bead dissolution results in fast release suited for duoden delivery. Center - combination of both mechanisms results in intermediate release suited for lower small intestine targeting.

Because of the extreme differences between conventional pharmaceuticals and the protein molecules in terms of formulation techniques and drug release kinetics, the two categories will be discussed separately here. 

Ethylene vinyl acetate has also found major applications in drug delivery. These copolymers used in drug release normally contain 30-50 wt% of vinyl acetate. They have been commercialized by the Alza Corporation for the delivery of pilocarpine over a one-week period (Ocusert) and the delivery of progesterone for over one year in the form of an intrauterine device (Progestasert). Ethylene vinyl acetate has also been evaluated for the release of macromolecules such as proteins. The release of proteins form these polymers is by a porous diffusion and the pore structure can be used to control the rate of release (3). Similar nonbiodegradable polymers such as the polyurethanes, polyethylenes, polytetrafluoroethylene and poly(methyl methacrylate) have also been used to deliver a variety of different pharmaceutical agents usually as implants or removal devices. 

As pharmaceutical scientists gain experience and tackle the primary challenges of developing stable parenteral formulations of proteins, the horizons continue to expand and novel delivery systems and alternative routes of administration are being sought. The interest in protein drug delivery is reflected by the wealth of literature that covers this topic [150-154]. Typically, protein therapeutics are prepared as sterile products for parenteral administration, but in the past several years, there has been increased interest in pulmonary, oral, transdermal, and controlled-release injectable formulations and many advances have been made. Some of the more promising recent developments are summarized in this section. 

Lee, V. H., et al. Biopharmaceutics of transmucosal peptide and protein drug administration role of transport mechanisms with a focus on the involvement of PepTl. J. Control. Release 1999, 62, 129-140. 

Akiyoshi K, Kobayashi S, Shichibe S et al (1998) Self-assembled hydrogel nanoparticle of cholesterol-bearing pullulan as a carrier of protein drugs Complexation and stabilization of insulin. J Control Release 54 313-320... 

Lin YH, Sonaje K, Lin KM et al (2008) Multi-ion-crosslinked nanoparticles with pH-responsive characteristics for oral delivery of protein drugs. J Control Release 132 141-149... 

Silicones are frequently used in transdermal drug delivery. Recently, the use of loosely cross-linked silicone elastomer blends for this application was surveyed.537 The mechanisms of controlled drug release in the silicone-based systems have been studied,538 as silicones are evaluated for relatively new protein drug-delivery systems.5... 

We have utilized thermoresponsive properties of PIPAAm and its gels as on-off switches for drug release [6,7], chromatography systems [9-11], and attachment/detachment of cells [12-14] (Scheme 1). Hydrophobic chains of collapsed PIPAAm above its LCST interact with cells and proteins. Although below the LCST, PIPAAms are highly hydrated flexible chains and... 

The design of new injectable dosage forms for the administration of peptide or protein drugs for the realization of the targeted release systems in the nanoscale range requires three fundamental ingredients ... 

---