Biphasic release

Recently, Brich and coworkers (40) reported the synthesis of lactide/glycolide polymers branched with different polyols. Polyvinyl-alcohol and dextran acetate were used to afford polymers exhibiting degradation profiles significantly different from that of linear poly-lactides. The biphasic release profile often observed with the linear polyesters was smoothened somewhat to a monophasic profile. Further, the overall degradation rate is accelerated. It was speculated that these polymers can potentially afford more uniform drug release kinetics. This potential has not yet been fully demonstrated. 

In a series of papers, Gupta et al. (109-112) studied the in vitro release properties of heat-stabilized BSA microspheres containing adriamycin. The biphasic release of drug was attributed to its location in the microsphere. The initial release results from surface desorption and diffusion through pores, while the later release arises from drug within the microsphere, which becomes available as the microsphere hydrates. 

The two sites also differ in their pH stability towards iron release. Experiments on serum transferrin showed that one site loses iron at a pH near 6.0, and the other at a pH nearer 5.0 (203, 204), giving a distinctly biphasic pH-induced release profile (Fig. 28). The acid-stable A site was later shown to be the C-terminal site (202). It is this differential response to pH, together with kinetic effects (below), that enables N-terminal and C-terminal monoferric transferrins to be prepared (200). Although the N-terminal site is more labile, both kinetically and to acid, the reasons are not necessarily the same the acid stability may depend on the protonation of specific residues (Section V.B) and is likely to differ somewhat from one transferrin to another in response to sequence changes. The biphasic acid-induced release of iron seen for transferrin is not shared by lactoferrin. Although biphasic release from lactoferrin, in the presence at EDTA, has been reported (205), under most conditions both sites release iron essentially together at a pH(2.5-4.0) several units lower than that for transferrin (Fig. 28). 

Norethisterone (Noristerat ) 95 Biphasic release 4-5 days 15-20 days... 

Ofori-Kwake K, Fell JT, Sharma HL, Smith AM. Gamma scintigraphic evaluation of film-coated tablets intended for colonic or biphasic release. Int J Pharm 2004 270(1—2) 307—313. 

Differences between the two sites become more pronounced for metal ions other than Fe " and anions other than COa . The differences are most pronounced for larger metal ions such as lanthanides. For transferrin some of the larger lanthanides appear to bind in only one of the two sites (Section IV.B.3), and for lactoferrin, although binding occurs in both sites, the second metal ion binds much more weakly, as shown by the curvature of the UV difference titration graph (Fig. 18) the biphasic release of Ce from lactoferrin contrasts with that of Fe (Fig. 28). Even metal ions of the first transition series, of similar size to Fe "", enhance the differences between the two sites. When Cr is bound to either transferrin 134) or lactoferrin (154), different EPR signals are seen for the two sites, and one Cr " ion is much more readily displaced by Fe than the other. Likewise, the EPR spectra of VO " -substituted transferrin indicate different metal configurations in the two sites (207), as do NMR studies of Co -substituted ovotransfer-rin (139). In these cases one metal ion is also released much more readily than the other as the pH is lowered. 

DL Theis, LJ Lucisano, GW Halstead. Use of stable isotopes for evaluation of drug delivery systems Comparison of ibuprofen release in vivo and in vitro from two biphasic release formulations utilizing different rate-controlling polymers. Pharm Res 11 1069—1076,1994. 

A mutation that substituted proline for a highly conserved ligand that does not bind iron, the leucine residue at position 134 which is not at the ferroxidase or nucleation sites, changed the rate of reductive iron release dramatically [49]. Initial rates of reductive iron release were increased four-fold in the pro/leu protein and were monophasic compared to wild-type proteins, which have a biphasic rate of iron release [52]. As a result, the time required to release all of the iron from the mineral (480 Fe/24-mer) was greatly decreased 5 minutes compared to 150 minutes for leu/pro compared to a biphasic release rate in wild-type protein (Table 12-1). 

Tiwari A, Bindal S, BohidarHB (2009) Kinetics of protein-protein complex coacervatirai and biphasic release of salbutamol sulfate fiorn coacervale matrix. Biomacrmnolecules... 

Biphasic release of PDGF was observed PU/PDGF scaffolds accelerated wound healing when implanted in rat skin excisional wounds Formation of new granulation tissue as early as day 3 Opened the opportunities for the development of novel injectable therapeutics [32]... 

Pectin, amylose, dextran and inulin provide coatings that degrade by enzymes of colonic flora. These polysaccharides are commonly combined with cellulose ethers or esters or synthetic polymers to obtain biphasic release profiles or colon-specific release [29-31]. Drugs conjugated to dextran (linear polymer backbone of a-D-glucopyranose units) show enhanced stability in the upper part of the gastrointestinal tract, but they can be absorbed in the colon [32]. 

Fig. 2 shows the kinetics of release of tightly bound nucleotides in media containing ADP and 2, 3 -0-(2,4,6-trinitrophenyl)-ADP (TNP-ADP) with or without Pj. The composition of the nucleotides released was analyzed by chromatography. With phosphate and ADP (or TNP-ADP) a biphasic release kinetics is obtained. Similar results were reported previously by Graber et al. (1977). The initial fast nucleotide release which exhibits a rate of about 40 ymol/mg chl/h. is followed by a slower one which resembles the... 

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