Steroidal polyphosphazenes

These discoveries generated a lot of effort over the successive 25 years in the preparation of especially designed drug delivery systems for the controlled release of radioactive progesterone [654], colchicine [656], naproxen [657,673, 674], mitomycin C [675-677], inulin [678], trimethoprin [657], succinylsul-fathiazole [657], ethacrynic acid [653], and steroids [633], regardless of whether these drugs are physically trapped in polyphosphazene matrices, or chemically bonded to the polymer skeleton. 

Although the hydrolytic stability of some phosphazene polymer makes them attractive as structural materials, it is possible to create hydrolytically sensitive phosphazenes that may be useful medically as slow-rdease drugs. Steroids, antibiotics. and catecholamines (e.g., dopamine and epinephrine) have been linked to a polyphosphazene skeleton (Fig. 16.27) with the intention that slow hydrolysis would provide these drugs in a therapeutic steady state. 

Polymer 3.87 has been evaluated as a matrix for the controlled release of progesterone.197 It was first shown that the rate of release of this steroid and of bovine serum albumen can be controlled by variations in the ratio of aryloxy to imidazolyl side groups atached to the polyphosphazene chain. In vitro and in vivo studies were conducted to examine the release rate of labelled steroid from devices implanted subcutaneously in rats. Typical data are shown in Figure 3.22. The biocompatibility of this system, at least in rats, was found to be good. 

Among new applications [192,193] attention has been focused on the biocompatible, bioactive, and biodegradable properties. Dopamine and several enzymes, e.g., trypsine, have been covalently bound to polyphos-phazene chain. AJso anestisics, steroids, and antibacterial agents may be linked to polyphosphazene with promising pharmaceutical applications. 

Biodegradable polyphosphazenes containing steroidal and amino acid ester groups have been prepared by Allcock et al. (1980) (Figure 20). 

A large variety of drugs and other bioactive molecules have been covalently linked to the polyphosphazene chain. Steroids were covalently linked by reaction of the sodium salt of steroidal alcohol functional groups with poly [ (dichloro) phosphazene ] (Allcock et al, 1980). Remaining chlorine side groups were replaced with methyl-amine, a side group which promotes the water solubility of the resulting polymer. 

Unlike most pol nmers (except poly(amino acids), poly (lactic acid), or poly(glycolic acid)), compounds such as XX hydrolyze slowly to yield ethanol, amino acid, phosphate, and ammonia. Thus, the polymer is biocompatible in the sense that it decomposes to materials that can be metabolized or excreted. Recent work in our laboratory has exploited the linkage of steroid molecules (XXI) to a polyphosphazene skeleton with a view to the utilization of these compounds as slow-release drugs. Furthermore, we have recently examined the use of poly[bis(methylamino)-phosphazene], [NP(NHCH3)2]n> a coordinative ligand for... 

Polyphosphazenes, substituted with steroids or transitional metal complexes, reagents, catalysts Poly(L-lysine)... 

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