An aminoboronic acid derivative inhibits thymopentin metabolism by mucosal membrane aminopeptidases.

Thymopentin is a pentapeptide with immunomodulatory activity. Transmucosal delivery may offer advantages over other routes, but published data have shown relatively poor efficacy when dosed nasally. Metabolism of thymopentin by the rat nasal mucosa and the effects of an aminoboronic acid aminopeptidase inhibitor, boroleucine, were evaluated. Thymopentin concentrations in a solution perfused through the isolated nasal cavity decayed with a first-order half-life of 12 minutes. Thymopentin was metabolized primarily by aminopeptidases, based on the amount of tetrapeptide metabolite formed. In the presence of boroleucine, at an inhibitor/substrate molar concentration ratio of 0.015/1, the degradation half-life was prolonged to 37 minutes. Appearance of the tetrapeptide metabolite of aminopeptidases was delayed. Boroleucine and other aminoboronic acid peptidase inhibitors may be useful for improving thymopentin delivery.

Improvement of the oral bioavailability of naltrexone in dogs: a prodrug approach.

In an effort to improve the oral bioavailability of naltrexone [17-(cyclopropylmethyl)-4,5 alpha-epoxy-3,14-dihydroxymorphinan-6-one;1], a number of prodrug esters on the 3-hydroxyl group were prepared: the anthranilate (2), acetylsalicylate (3), benzoate (4), and pivalate (5). The oral bioavailability of these prodrugs was determined in dogs. Compounds 2 and 3 exhibited the greatest enhancement of naltrexone bioavailability (45 and 28 times greater than 1, respectively). No correlation was found between the rates of plasma hydrolysis and bioavailability. Naltrexone-3-acetylsalicylate hydrolyzed in human and dog plasma with a fast deacetylation step to naltrexone salicylate followed by a slower hydrolysis step to naltrexone.

Solubilization of nicardipine hydrochloride via complexation and salt formation.

The solubility behavior of nicardipine (1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic+ ++ acid methyl 2-[methyl(phenyl-methyl)amino]ethyl diester), a calcium channel blocker, used in the treatment of chronic stable angina and mild essential hypertension was investigated. Two techniques that are known to improve solubility, complexation and salt formation, were examined. Concentrations were determined with a specific reversed-phase HPLC assay. The solubility of nicardipine hydrochloride was enhanced exponentially via complexation with aliphatic carboxylic acid buffer systems in a pH dependent fashion. The solubility increased from 5 to 68.6 and 270 mg/mL as the acetate or propionate buffer concentrations, respectively, increased from 0.001 to 5 M, showing a positive deviation from linearity. The conversion of nicardipine hydrochloride to the phosphate salt resulted in a approximately 10-fold solubility improvement. The surface tension of the nicardipine phosphate in water as a function of concentration indicated a critical micelle concentration of 5-6 mg/mL. The critical micelle concentration was greater than the equilibrium solubility of the hydrochloride salt in water, suggesting that a self-association phenomena is responsible for the enhanced solubility of the phosphate salt. Both routes provided potential alternatives for the solubilization of nicardipine.

Recovery of rat nasal mucosa from the effects of aminopeptidase inhibitors.

Aminopeptidase inhibitors may be useful for improving the systemic bioavailability of peptide drugs administered nasally or by other routes. Preferably, their effects would be rapidly reversible. The recovery of peptide hydrolytic activity after exposure of the rat nasal cavity to various aminopeptidase inhibitors was evaluated. Leucine enkephalin (0.1 mM) was used as a model peptide which is predominantly metabolized by aminopeptidases nasally. All experiments involved in situ perfusion of the rat nasal cavity with leucine enkephalin and the inhibitor for 90 min, followed by a washout with saline, and finally a second experimental phase of perfusion with leucine enkephalin but no inhibitor. Boroleucine (0.1 microM) was a potent inhibitor of leucine enkephalin metabolism, and, after its removal, the leucine enkephalin metabolism rate returned to control levels. Much higher concentrations of bestatin (0.1 mM) and puromycin (1 mM) did not inhibit leucine enkephalin metabolism as much as did boroleucine. Furthermore, when these inhibitors were washed out, the rates of leucine enkephalin disappearance rebounded to higher than control levels. With bestatin this could have been partially due to membrane disruption, as evidenced by significantly increased protein concentrations in the perfusates. However, protein release was much lower than that caused by sodium glycocholate, a nasal membrane permeation enhancer. In considering the use of peptidase inhibitors as pharmaceutical adjuvants for peptide drugs, the aminoboronic acid derivatives, including boroleucine, have the advantages of efficacy at very low concentrations and reversibility of effects.

Electrochemical determination of dissolution rates of lyophilized pharmaceutical formulations.

We present a method to measure dissolution times for rapidly dissolving lyophilized formulations. K4Fe(CN)6 was lyophilized in formulations containing sucrose, salts, and Tween 20. Dissolution of the lyophilized powders was measured by monitoring the time dependence of the oxidation of Fe(CN)6(4-) ion at the surface of a platinum rotating disk electrode. Reconstitution of lyophilized K4Fe(CN)6 formulations with aqueous solutions of 0.03% Tween 20 altered the time of dissolution for all cases. Salt and sucrose formulations without Tween 20 dissolved more slowly in a Tween 20 solution than in water alone. In contrast, formulations containing Tween 20 dissolved faster in the Tween 20 solution when compared to dissolution in water.

The effects of magnetic stabilization on the structure and performance of liquid fluidized beds.

Liquid fluidized beds containing porous magnetic ion-exchange particles with densities ca. 1.03-1.16 g mL-1 were examined. The effect of magnetic stabilization was studied, both in terms of bed physical characteristics and sorptive behavior. Maximum applied magnetic field strength was approximately 200 oersted. Breakthrough and pulse analyses were carried out with protein and acetone solutions, respectively, with liquid flow rates ranging from approximately 1 to 3 cm min-1. Acetone pulses in columns containing 7 mL of particles had plate numbers ranging from 2.5 to 18 for magnetically stabilized beds and from 7.8 to 20 for non-stabilized fluidized beds. Under any particular set of conditions, magnetic stabilization always resulted in poorer efficiency, both in pulse analyses and in protein breakthrough experiments.

Improved buccal delivery of opioid analgesics and antagonists with bitterless prodrugs.

Buccal delivery of opioid analgesics and antagonists is a useful way of improving bioavailability relative to the oral route. These compounds taste bitter, however. Various prodrugs of nalbuphine, naloxone, naltrexone, oxymorphone, butorphanol, and levallorphan, in which the 3-phenolic hydroxyl group was esterified, lacked a bitter taste. This taste difference was not due to differences in water solubility, suggesting that for these compounds the phenolic functional group is important for interaction with the taste receptor. In rats, nalbuphine, naloxone, and naltrexone administered buccally as prodrugs exhibited up to 90% bioavailability. In dogs, the bitter taste of buccally administered nalbuphine and naloxone caused salivation and swallowing, and bioavailability was low. Buccal dosing of the prodrugs of these compounds caused no adverse effects and the bioavailability ranged from 35 to 50%, a significant improvement relative to the oral bioavailability, which is 5% or less. The feasibility of buccal prodrug delivery using an adhesive patch formulation was demonstrated.