Drug release copolymers

Rate of hydration of the polymeric materials has been shown to be an important consideration in regard to drug release. Gilding and Reed (24) demonstrated that water uptake increases as the glycolide ratio in the copolymer increases. The extent of block or random structure in the copolymer can also affect the rate of hydration and the rate of degradation (25). Careful control of the polymerization conditions is required in order to afford reproducible drug release behavior in a finished product. Kissel (26) showed drastic differences in water uptake between various homopolymers and copolymers of caprolactone, lactide, and glycolide. 

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. 

Drug Release from PHEMA-l-PIB Networks. Amphiphilic networks due to their distinct microphase separated hydrophobic-hydrophilic domain structure posses potential for biomedical applications. Similar microphase separated materials such as poly(HEMA- -styrene-6-HEMA), poly(HEMA-6-dimethylsiloxane- -HEMA), and poly(HEMA-6-butadiene- -HEMA) triblock copolymers have demonstrated better antithromogenic properties to any of the respective homopolymers (5-S). Amphiphilic networks are speculated to demonstrate better biocompatibility than either PIB or PHEMA because of their hydrophilic-hydrophobic microdomain structure. These unique structures may also be useful as swellable drug delivery matrices for both hydrophilic and lipophilic drugs due to their amphiphilic nature. Preliminary experiments with theophylline as a model for a water soluble drug were conducted to determine the release characteristics of the system. Experiments with lipophilic drugs are the subject of ongoing research. 

T Niwa, H Takeuchi, T Hino, N Kunou, Y Kawa-shima. Preparations of biodegradable nanospheres of water-soluble and insoluble drugs with d,l-lacti-de/glycolide copolymer by a novel spontaneous emulsification solvent diffusion method, and the drug release behavior. J Control Rel 25 89-98, 1993. 

Lin J, Zhang S, Chen T et al (2007) Micelle formation and drug release behavior of polypeptide graft copolymer and its mixture with polypeptide block copolymer. Int J Pharm 336 49-57... 

Xu et al. (2001) synthesized the copolymers of a dimer fatty acid (dimer of oleic and linoleic acids) and sebacic acid (P(DA-SA)) by melt polycondensation of acetylated prepolymers. Degradation and drug release kinetics showed that increasing dimer acid content decreased the release rate (Xu et al., 2001). 

Poly(lactic acid) (PLA) has also been added to poly(SA) via melt polycondensation to produce the triblock copolymers poly(lactic acid-Wock-sebacic acid-Wock-lactic acid) (P(LA-block-SA-block-LA)) by Slivniak and Domb (2002). The PLA (d-, l-, and dl-) was incorporated by acetylation and addition to the PSA synthesis. They showed the formation of stable stereocomplexed particles with increased melting points and reduced solubility, and studied the degradation and drug release characteristics of the same (Slivniak and Domb, 2002). The stereocomplexes self-assemble as a consequence of the chirality in the PLA portions of the chains (Slivniak and Domb, 2002). 

The erosion of copolymers requires the hydrolytic cleavage of three bond types the A A bond, the A-B bond, and the B-B bond. If the degradation rates of these three bonds are unequal, as is likely the case, then the erosion will be inhomogeneous. And, if drugs are inhomogene-ously distributed in the polymer matrix, the drug release profile will not follow overall device erosion (Shen et al., 2002). Therefore, it is necessary to accurately describe the microstructure of microphase-separated systems. 

Whether in copolymers or blends, inhomogeneous erosion has a nontrivial effect on drug release kinetics as will be shown later. Leong et al. (1985) demonstrated that the pH of the degradation media also has a dramatic effect on the erosion rate, which increases with increasing pH. The acceleration of degradation of polyanhydrides with increase in pH is widely reported and has been used to speed up experiments (Shakesheff et al., 1994). 

Thermoresponsive polymeric micelles with PIPAAm block copolymers can be expected to combine passive spatial targeting specificity with a stimuli-responsive targeting mechanism. We have developed LCSTs of PIPAAm chains with preservation of the thermoresponsive properties such as a phase transition rate by copolymerization with hydrophobic or hydrophilic comonomers into PIPAAm main chains. Micellar outer shell chains with the LCSTs adjusted between body temperature and hyperthermic temperature can play a dual role in micelle stabilization at a body temperature due to their hydrophilicity and initiation of drug release by hyperthermia resulting from outer shell structural deformation. Simultaneously, micelle interactions with cells could be enhanced at heated sites due... 

Polyisobutylene-based block anionomers and cationomers, ( ), were prepared by Kennedy et al. (3) and used in drug release devices. Poly(2-dimethylami-no)ethyl methacrylate was quaternized after the block copolymer was synthesized to form a cationic block copolymer. 

Modulation of the drug release behavior from this polymer can be achieved by varying the drug/polymer ratio, by blending the basic block copolymer with other polymers, and by derivatizing the styrene end blocks. In this way, the hydrophilicity of the copolymer is varied (27). 

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