Design, Synthesis, and Evaluation of a Liposaccharide Drug Delivery Agent:  Application to the Gastrointestinal Absorption of Gentamicin

Abstract

The design, synthesis, and evaluation of a liposaccharide (11) for use as an agent to enhance the gastrointestinal absorption of charged, hydrophilic drugs with poor membrane permeability is reported. 11 was designed to possess both surfactant and ion-pairing properties and was conveniently synthesized from d-glucuronic acid (2) and N-Boc-lipoamino acid (5) precursors in eight steps in good yield. Isothermal titration microcalorimetry was used to determine the critical micelle concentration of 11 (in PBS) to be 2.09 +/- 0.01 mM with an enthalpy of demicellization of 4.91 +/- 0.11 kJ/mol. The ability of 11 to enhance the gastrointestinal absorption of the aminoglycoside antibiotic gentamicin (1), a hydrophilic polycation with negligible oral bioavailability, was assessed in vivo using rats. Rats dosed orally with a mixture of 11 (100 mg/kg) and 1 (60 mg/kg) had a statistically significant (P < or = 0.034) increase in Cmax, AUC120, and percent absolute bioavailability (F) compared to control 1 (60 mg/kg) alone. The highest bioavailability (F = 9.1 +/- 2.0%) was achieved by dosing with the mixture 11 (100 mg/kg) and 1 (15 mg/kg). This represents a 6-fold increase in bioavailability compared to the control (F = 1.4 +/- 0.3%). These results suggest that the molar ratio of 1:11 may be critical in optimizing the delivery system, a finding ascribed in part to the ion-pairing properties of 11. The effect of 11 on the gastrointestinal mucosa was assessed using light microscopy to examine tissue samples from rats used in the pharmacokinetic study. No morphological changes were found in either the esophagi or duodena of the rats examined. One rat dosed with 11 (100 mg/kg) and 1 (60 mg/kg) exhibited slight gastric erosion, which could be attributed to 11.

Converting Peptides into Drug Leads by Lipidation

“…Glycosylation compensates the low aqueous solubility of lipidated pepitdes and increases their membrane transportation through glucose transporters. Liposaccharide, the combination of LAA lipidation and glycosylation, is applied in the development of small-molecule drugs, peptides, vaccines and antibiotics [59,72,73,80,[150][151][152][153][154]. Hemolytic potency of liposaccharides was correlated with the chain length of LAA [72].…”

Amphiphilic ion pairs of tobramycin with lipoamino acids

“…For instance, oral administration of an ampicillin-LAA conjugate significantly improved the antibacterial activity [22]. In a more recent study, a D-glucuronic acid-LAA conjugate has been ion paired with gentamicin resulting in a better oral absorption in rodents [14].…”

Microparticulate polyelectrolyte complexes for gentamicin transport across intestinal epithelia

“…The well known poor gastrointestinal membrane permeability and the consequent low bioavailability (class III of the biopharmaceutical classification system) are likely connected to the high polarity of this cationic compound. Various approaches have been investigated in order to increase GM oral bioavailability, including the co-administration of absorption-enhancing agents such as surfactants (Hu et al, 2001;Ito et al, 2005), bile salts and glucosteroids (Axelrod et al, 1998), and liposaccharides (Ross et al, 2004). Although good gastrointestinal absorptionenhancing effects were demonstrated, cytotoxicity and damage to the mucosa have been reported (Swenson et al, 1994;Aungst, 2000;Ross et al, 2004).…”