Design and characterization of a surfactant-enriched tablet formulation for oral delivery of a poorly water-soluble immunosuppressive agent.

The feasibility of incorporating significant quantities of the anionic surfactant, sodium lauryl sulfate (SDS), into an immediate release tablet formulation of a poorly water-soluble immunosuppressive agent was investigated. Despite the extremely poor compressibility of SDS and poor chemical stability of the drug, a commercializable, direct-compression tablet formulation with satisfactory mechanical properties and acceptable chemical stability was achieved. Optimal in vitro release of the drug from the tablet formulation was achieved by establishing the minimum molar uptake ratio necessary to achieve complete micellar solubilization of the drug, after which formulation studies were conducted to determine the influence of formulation and process variables on the rate and extent of drug release. A model-independent analysis of dissolution results in a reduced volume (250 ml) of modified simulated gastric fluid demonstrated that the rate and extent of drug release was highly dependent on the mean particle size of the bulk drug, but independent of compression force above that required to achieve a compact of acceptable mechanical strength. Employing the Korsmeyer-Peppas model of Fickian and non-Fickian drug release, it was further shown that release of the drug from the dosage form was governed largely by surface erosion of the surfactant-enriched tablet matrix.

Identification of oxidative degradates of the thrombin inhibitor, 3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methyleneca rboxamidomethylpyridinyl)pyrazinone, using liquid chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry.

Liquid chromatography/mass spectrometry was used to identify reaction products from a solution of 3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methyleneca rboxamidomethylpyridinyl)pyrazinone (L-375,378) and hydrogen peroxide, a system that generates high levels of the oxidative degradates which form in the tablets and intravenous (i.v.) solutions of L-375,378. Two major hydrogen peroxide reaction products of L-375,378 (m/z 407) with m/z values of 369 and 370 were separated and identified. Both compounds were products of ring opening with elimination of three carbon atoms from the center pyrazinone ring. The structural assignments for these two products were alpha-amidinoamide and alpha-diamide compounds, respectively. In addition, five products (m/z 423) with a molecular weight 16 Da greater than that for L-375,378 were separated. Further liquid chromatography/tandem mass spectrometry experiments indicated that three of these M + 16 products were phenolic derivatives of L-375,378. Among them, the para-hydroxy compound has been verified using an authentic standard. The other two phenolic compounds were believed to be the meta- and ortho-hydroxy derivatives of L-375,378. The fourth M + 16 product was derived from hydroxylation of the methyl group on the center pyrazinone ring. The fifth M + 16 product was derived from oxidation on the aminopyridine moiety, most likely N-oxide of the pyridine ring. Other minor hydrogen peroxide reaction products were not studied in detail because they did not appear in tablets or i.v. formulations.

pH-dependent oral absorption of L-735,524, a potent HIV protease inhibitor, in rats and dogs.

L-735,524, a potent and specific inhibitor of human immunodeficiency virus protease, is currently under investigation for the treatment of acquired immunodeficiency syndrome. The aqueous solubility of L-735,524 was pH-dependent, > 100 mg/ml at pH below 3.5 and 0.03 mg/ml at pH 6. When L-735,524 was given orally as a suspension in 0.5% methocel (pH 6.5) at 10 mg/kg, the bioavailability was approximately 16% for both dogs and rats. When the same dose of the drug was administered in 0.05 M citric acid (pH 2.5), the bioavailability increased 4.5-fold in dogs (72%), but only slightly in rats (24%). The pH- and species-dependent differences in bioavailability observed in rats and dogs may be because of differences in the rate of gastric acid secretion and in the magnitude of hepatic first-pass effect. Gastric acid secretion is poor in dogs but substantial in rats. When L-735,524 was administered in 0.5% methocel, a large portion of the drug in dogs, but not in rats, remained undissolved, resulting in poor absorption in dogs. On the other hand, when L-735,524 was administered in citric acid, most of the drug would be in solution allowing for better absorption in dogs. The hypothesis of pH-dependent absorption was further supported by the findings that absorption was significantly increased in dogs after feeding, but substantially decreased in rats after pretreatment with famotidine, a potent H2-receptor antagonist. L-735,524 underwent an extensive first-pass metabolism in rats, but not in dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Regiospecific intestinal absorption of the HIV protease inhibitor L-735,524 in beagle dogs.

PURPOSE: To evaluate regional intestinal absorption and the feasibility of sustained release dosage form development for an HIV protease inhibitor, L-735,524, METHODS: L-735,524 free base or sulfate salt was administered orally as suspension, solution or in solid dosage forms to fasted or fed Beagle dogs. Delayed-release dosage forms with "slow" or "fast" in vitro dissolution rates were evaluated in vivo to assess plasma concentration profiles. In addition, drug was administered directly into the jejunum or colon of animals, and drug concentrations determined in portal circulation to characterize absorption from these sites. RESULTS: L-735,524 sulfate was well absorbed orally form a solution or capsule formulation if fasted animals' stomachs were preacidified with citric acid solution. A free base suspension, delivered in divided doses to fed animals, was also well absorbed. Prototype extended release dosage forms of L-735,524 produced a reduction in peak plasma levels but failed to prolong absorption and extend plasma concentrations compared to an immediate release capsule. Administration of L-735,524 sulfate solution (pH < 3) as bolus solution or by infusion into the jejunum resulted in rapid but incomplete absorption compared to oral gavage. The free base suspension (pH 6.5) delivered into jejunal or colonic regions did not produce measurable systemic plasma concentrations. CONCLUSIONS: Extended release formulations did not prolong absorption of L-735,524 in dogs. Optimal L-735,524 absorption was dependent on solubility in an acidic environment in the duodenum.

A rapid bioassay for the determination of non-nucleoside HIV-1 reverse transcriptase inhibitor plasma levels.

A rapid method for measuring pyridinone HIV-1 reverse transcriptase inhibitor plasma levels was necessary for identifying potential clinical candidates and for choosing a clinical formulation. Due to its sensitivity to the pyridinones, ability to tolerate extraneous material, and its capability for rapid, high through-put screening, the HIV-1 RT assay was developed into a bioassay for determining plasma levels of the pyridinones in Rhesus monkey plasma. With this assay, dose proportionality of L-697, 639 was established. Formulation studies using L-697, 639 indicated that the plasma levels achieved in Rhesus monkeys with the clinical formulation (peak levels = 3.9 microM at 30 min) fall between the levels achieved with polyethylene glycol 300 and hydroxypropyl methyl cellulose formulations (peak levels = 8.9 microM and 0.4 microM respectively, at 60 min). Two other pyridinones, L-696, 229 and L-697, 661, administered as the clinical formulation, had peak plasma levels of 1.6 microM (30 min) and 0.3 microM (60 min), respectively. In Rhesus monkeys, the bioavailabilities of these compounds (administered as the clinical formulation) ranged from 11 to 24% and their half-life values ranged from 24 to 120 min. The results of oral studies in Rhesus monkeys with these compounds were very similar to initial results of studies in humans.