Albuterol prodrugs for ocular administration: Synthesis and evaluation of the physico-chemical and IOP-depressant properties of three albuterol triesters

Three albuterol (salbutamol) new triesters (acetyl, isobutyryl and pivalyl) were prepared and evaluated in vitro (rate of chemical hydrolysis at different pH values, relative lipophilicity) and in vivo (depression of intraocular pressure, IOP, in a rabbit model of ocular hypertension). The three esters underwent quantitative hydrolysis in vitro to give the parent compound: first-order kinetics were observed, for several half-lives, for the disappearance of the compounds from solution at different pH values. The degradation mechanism, presumably involving a sequence of hydrolytic steps, was not investigated in detail. The rate constants for disappearance of the triesters and for formation of albuterol were in the order acetyl > isobutyryl > pivalyl; the relative 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 three ester solutions proved significantly more active than albuterol at several times after administration. The tripivalyl ester, in particular, after 5 h appeared more active than the other two esters, and, together with the triisobutyryl ester, was significantly more active than the triacetate after 8 h. These findings confirm the.important influence of (pro)drug lipophilicity on transcorneal penetration. The in vivo tests also indicated that the ocular irritant properties of the parent drug were still present, albeit to a smaller degree, in the triester derivatives

ALKYLATION OF ADENOSINE DEAMINASE BY BENZYLBROMOACETATE AND 9-(PARA-BROMOACETAMIDOBENZYL)ADENINE

Adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4) from calf intestinal mucosa is not affected at pH 8 by haloacetate and haloacetamide, while benzylbromoacetate and 9-(p-bromoacetamidobenzyl)adenine inactivate the enzyme. Substrate analogs protect against inactivation by these reagents. 2. 2. One mole of reagent is bound per mole of inactivated enzyme. The alkylated amino acid has been identified as lysine. 3. 3. The reaction of alkylation consists of two stages: binding of the alkylating agent (fast reaction) and alkylation of the ε-amino group of lysine (slow reaction). 4. 4. Bromoacetate, which does not inactivate the enzyme, does not alkylate the reactive lysine. 5. 5. The difference in reactivity is explained on the basis of a selectivity of the alkylation site on the enzyme towards the alkylating reagents

Mucoadhesive ophthalmic vehicles: evaluation of polymeric low-viscosity formulations

A series of polyanionic natural or semi-synthetic polymers (polygalacturonic acid, hyaluronic acid, carboxymethylamylose, carboxymethylchitin, chondroitin sulfate, heparan sulfate and mesoglycan) were evaluated as potential mucoadhesive carriers for ophthalmic drugs. Solutions containing cyclopentolate (CY) or pilocarpine (PI) as salts (or polyanionic complexes) with the acidic polymers, all showing a low viscosity, were tested for miotic (resp. mydriatic) activity in albino rabbits. In the case of some polymeric complexes, small but significant increases of the areas under the activity vs. time curves (AUC) over reference cyclopentolate hydrochloride (CYHCl) or pilocarpine nitrate (PINO3) vehicles, and significant AUC decreases after removal bf precorneal mucin by treatment with N-acetylcysteine were observed. A correlation was found between these data, considered indicative of the occurrence of a mucoadhesive interaction ''in vivo'', and ''in vitro'' viscometric data expressing the polymers-mucin force of interaction. The advantages and limitations of the mucoadhesive non-viscous approach in the formulation of ophthalmic vehicles are presented and discussed