ALBUTEROL PRODRUGS FOR OCULAR ADMINISTRATION - SYNTHESIS AND EVALUATION OF THE PHYSICOCHEMICAL AND IOP-DEPRESSANT PROPERTIES OF 3 ALBUTEROLTRIESTERS

Three albuterol (salbutamol) new triesters (acetyl, isobutyryl and piv alyl) were prepared and evaluated in vitro (rate of chemical hydrolysi s at different pH values, relative lipophilicity) and in vivo (depress ion of intraocular pressure, IOP, in a rabbit model of ocular hyperten sion). The three esters underwent quantitative hydrolysis in vitro to give the parent compound: first-order kinetics were observed, for seve ral half-lives, for the disappearance of the compounds from solution a t different pH values. The degradation mechanism, presumably involving a sequence of hydrolytic steps, was not investigated in detail. The r ate constants for disappearance of the triesters and for formation of albuterol were in the order acetyl > isobutyryl > pivalyl; the relativ e lipophilicities of the compounds, as estimated by the corresponding reversed phase HPLC 'capacity factors', were in the order albuterol < acetyl < isobutyryl < pivalyl. When tested for reduction of IOP, all t hree ester solutions proved significantly more active than albuterol a t several times after administration. The tripivalyl ester, in particu lar, after 5 h appeared more active than the other two esters, and, to gether with the triisobutyryl ester, was significantly more active tha n the triacetate after 8 h. These findings confirm the.important influ ence of (pro)drug lipophilicity on transcorneal penetration. The in vi vo tests also indicated that the ocular irritant properties of the par ent drug were still present, albeit to a smaller degree, in the triest er derivatives.