Protein zero order release

The degradation rate can be controlled using acidic and basic excipients acidic excipients increase the degradation rates and facilitate a zero-order release rate over a 2-week period (Sparer et al. 1984). Basic additives increase the degradation time of the polymers and create a polymer that degrades specifically at the surface (Heller 1985). By careful choice of the excipient added, the degradation rate can be closely controlled. No experiments have shown the use of these polymers with proteins or peptides. This is not, however, indicative of the fact that these polymers are not compatible with proteins or peptides, but they are probably not the most appropriate polymeric carrier for oral delivery of biomacromolecules. 

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... 

The release mechanism was explained by assuming that chain scission decreased the amount of effective crosslinks or entanglements present in the swollen copolymer matrix. Therefore, the resistance to the diffusion of proteins through the copolymer hydrogels was reduced. In the case of the observed zero-order release, the increasing permeability of the matrix in time may have compensated for the decline in the release rate caused by the reduced protein concentration in the matrix, to yield a constant release rate (50). 

Figure 2.21. The designed elastic-contractile model proteins function by means of the apolar-polar repulsive free energy of hydration to achieve zero order release with simultaneous dispersal of delivery...

Thus, as shown in Figure E.7, a remarkable control of pharmaceutical release is possible. Furthermore, the pharmaceutical can vary all the way from a simple bare cation or anion to a protein or nucleic acid. Under favorable circumstances, as with carboxylate groups, the vehicle disappears as the pharmaceutical releases. With a cationic polymer such as a lysine-containing protein-based polymer, the chloride ion can displace the pharmaceutical to lessen the zero order release. Significantly, with elastic protein-based polymers, no fibrous capsule forms around the adequately purified polymer such that this does not affect the release process. 

McGee, J. P., Davis, S. S., and O Hagan, D. T., 1995, Zero order release of protein from poly(D,L-lactide-co-glycolide) microparticles prepared using a modified phase separation technique, J. Controlled Release 34 17-86. 

From this figure it appears that for gels with a high initial water content a first order release of the protein is observed (diffusion controlled release), whereas for gels with a lower initial water content an almost zero order release is observed for 35 days (degradation controlled release). 

As an example, myoglobin, which is the best studied protein in this respect, exists in two conformations, which are called the tensed and relaxed conformations, referring to the two states in which the ligand is bound or released. We associate a zero-order hierarchy level with these two conformations. The free enthalpy G as a function of a relevant configurational coordinate seems to have a well-defined minimum. 

Li et al., 2011). Solidified IFNa-2b was then encapsulated into microspheres made of PEGT/PBT-PLGA (poly(ethylene glycal/butylenes terephthalate)-poly(D,L-lactide-co-glycolide)). The protein was found to release from the microspheres following zero-order kinetics. These particles were administered to rats and a steady release of lFNa-2b was observed for 13 days. 

A biodegradable and biocompatible dextran hydrogel system has been developed of which the degradation time can be tailored between 2 days and 3 months. This chapter shows that hydrogels based on crosslinked dextrans have unique properties as protein releasing matrices. Both the release pattern (first-order, zero-order or biphasic) as well as the duration of the release can be controlled by an appropriate selection of the characteristics and the geometry of the hydrogel. 

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