A polymer carrier system for taste masking of macrolide antibiotics.

A polymer carrier system was developed to reduce the bitterness of erythromycin and its 6-O-methyl derivative, clarithromycin, by absorption to Carbopol. The mechanism involves ionic bonding of the amine macrolide to the high molecular weight polyacrylic acid, thereby removing the drug from the solution phase in an ion-free suspension. After ingestion, endogenous cations displace the drug from the polymer in the gastrointestinal tract to achieve bioavailability. The macrolide-Carbopol complexes were prepared by dissolving or slurrying predetermined ratios of drug and polymer in water or hydroalcoholic mixtures. A series of in vitro equilibrium studies, taste screening, and bioavailability studies in dogs established the characteristics for the various drug-polymer ratios. Taste protection was further improved by encapsulating the adsorbate particles with polymer coatings. Hydroxypropyl methylcellulose phthalate (HP-55) provided the best combination of suspension stability, taste protection and bioavailability. Human bioavailability studies demonstrated that the microencapsulated Carbopol absorbates of erythromycin and clarithromycin gave blood levels comparable to those obtained from conventional solid formulations.

Thiol addition to quinones: model reactions for the inactivation of thymidylate synthase by 5-p-benzoquinonyl-2'-deoxyuridine 5'-phosphate.

The reaction of methyl mercaptoacetate (5) with phenyl-p-benzoquinone (6) or 5-p-benzoquinonyl-3',5'-di-O-acetyl-2'-deoxyuridine (10) resulted in the formation of the three possible adducts to the quinone rings of 6 and 10; an additional product in the reaction with 10 was the unsubstituted hydroquinone (14). Both reactions were found to be solvent dependent; in buffered aqueous acetonitrile the meta and para adducts of 10 were formed in the ratio of 2:1. In ethyl acetate the ortho adduct and the reduction product of 10 were isolated in a ratio of 2:3. The second-order rate constant for the reaction of 5 with 10 in acetonitrile was 0.53 M-1 s-1; the reaction was accelerated by the addition of water. Although the initially proposed mechanism-based enzyme inactivation cannot be excluded, the results of the model reactions support the alternative mechanism, active-site thiol addition to the quinone ring. If this is true the title compound would be classed as an affinity label, not a mechanism-based inhibitor.

Distribution of bile salts between 1-octanol and aqueous buffer.

The distribution of four bile salts: sodium cholate (I), sodium deoxycholate (II), sodium chenodeoxycholate (III), and sodium ursodeoxycholate (IV), between aqueous buffer and 1-octanol has been measured as a function of temperature between 25 and 55 degrees and as a function of bile salt concentration at concentrations less than 0.1 mole/liter in the aqueous phase. The distribution isotherms obtained have been explained on the basis of reversible association in the aqueous phase. The treatment assumes that the bile acid exists as a monomer in the organic phase, which is verified by vapor pressure osmometry. A graphical method has been employed to estimate the association constants in the aqueous phase for the various equilibria encountered. An aggregation number of four for IV and 12 for I, II, and III has been estimated. From the results, thermodynamic functions associated with the transfer of each of the bile salts from water to octanol and those associated with association processes in the aqueous phase were calculated. These results are consistent with previous findings that the premicellar association of bile salts occurs by hydrophobic interaction. The thermodynamics of transfer of bile salts revealed an unfavorable enthalpic and favorable entropic contribution for all four bile salts. However, for IV, which is an epimer of III, both enthalpic and entropic contributions are reduced, compared to III, suggesting a pronounced effect of stereochemical orientation on hydrophobic interaction.

Association of deoxycholic acid in organic solvents.

The distribution of deoxycholic acid (I) between aqueous buffer and an organic phase consisting of isooctane-1-octanol (70:30, v/v) (System A) or isooctane-chloroform (80:20, v/v) (System B) was studied. The distribution isotherms suggested that I associates strongly in the organic Systems A and B unlike in pure 1-octanol. Therefore, a previous model, describing distribution of bile salts between 1-octanol and aqueous buffer, was modified to include association of I in the organic phases to describe distribution behavior. The treatment suggested that I exists as monomer and dimer in System A with a dimerization constant of 820 M-1. A model consisting of monomer-tetramer-hexamer in the organic phase best describes the data for System B. The data support the view that association in the organic phase is due to hydrogen bonding between bile acid molecules.