Ceftriaxone Absorption Enhancement for Noninvasive Administration as an Alternative to Injectable Solutions

Abstract

Neonatal sepsis is a major cause of infant mortality in developing countries because of delayed injectable treatment, making it urgent to develop noninjectable formulations that can reduce treatment delays in resource-limited settings. Ceftriaxone, available only for injection, needs absorption enhancers to achieve adequate bioavailability via nonparenteral administration. This article presents all available data on the nonparenteral absorption of ceftriaxone in humans and animals, including unpublished work carried out by F. Hoffmann-La Roche (Roche) in the 1980s and new data from preclinical studies with rabbits, and discusses the importance of these data for the development of noninjectable formulations for noninvasive treatment. The combined results indicate that the rectal absorption of ceftriaxone is feasible and likely to lead to a bioavailable formulation that can reduce treatment delays in neonatal sepsis. A bile salt, chenodeoxycholate sodium salt (Na-CDC), used as an absorption enhancer at a 125-mg dose, together with a 500-mg dose of ceftriaxone provided 24% rectal absorption of ceftriaxone and a maximal plasma concentration of 21 µg/ml with good tolerance in human subjects. The rabbit model developed can also be used to screen for the bioavailability of other formulations before assessment in humans.

Development of Rectodispersible Tablets and Granulate Capsules for the Treatment of Serious Neonatal Sepsis in Developing Countries

“…Suppositories were prepared with 20% w/w CTX, 5% NaCDC and 75% Suppocire AML, as formulated by Roche and tested in humans 22 . Powders were dispersed using a magnetic stirrer at 40°C in melted Suppocire.…”

“…Plasma was frozen immediately at -20°C and plasma concentration was determined by HPLC method. 22 Bioavailability was calculated from individual plasma profiles using trapezoidal rule.…”

“…However, CTX must be combined with an absorption enhancer to achieve adequate rectal absorption. A human bile salt, sodium chenodeoxycholate (NaCDC) in a ratio 1/4 with CTX, has previously been shown as the optimal absorption enhancer for CTX 22 . Pre-formulation studies of CTX have been performed 23 and these confirmed poor compatibility with most of liquid excipients but good compatibility with NaCDC, thus supporting the development of solid drug dosage formulations 23 .…”

“…Previous studies have suggested that rectal CTX therapy can achieve clinically relevant plasma concentrations in animals and man, and hence CTX was developed into rectal formulations that could be administered in the community to a neonate with a rapidly evolving serious sepsis infection, while awaiting transfer to hospital 22 . The formulations developed and tested by Hoffmann La Roche (Roche), the originator of CTX, was a wax suppository, which was not practical as a dosage form for tropical rural settings with high humidity and high day-time temperatures.…”

Design and Optimization of New Enteric Nanoparticles of Ceftriaxone for Oral Delivery: In vitro and in vivo Assessments

“…CTX has much slower eviction than penicillin and other third-generation cephalosporins, so single daily dose is possible. 1 Despite having these precious criteria, it is confined for injectable administration. This fact could be attributed to its gastric instability and lower permeability through GIT epithelia; both are the main bottlenecks that hinder its oral bioavailability.…”