Tissue compatibility and pharmacokinetics of three potential subcutaneous injectables for low-pH drug solutions.
OBJECTIVE
The aim of the study was to investigate the tissue tolerance and bioavailability of four formulations containing 5% ricobendazole solubilised at low pH, following subcutaneous injection in sheep. Formulations were: a water-in-oil emulsion, a microemulsion, a hydroxypropyl-beta-cyclodextrin (HP-beta-CD, 20%) drug solution, and a low-pH drug solution (reference).


METHODS
In-vitro cytotoxicity of the formulations was investigated in L929 fibroblasts using MTS viability and lactate dehydrogenase leakage assays. Each formulation and respective vehicle was injected into either side of the back of a sheep to investigate the tissue tolerance and pharmacokinetics.


RESULTS
In-vitro studies suggested that both the emulsion and the microemulsion are unlikely to give a burst release of the low-pH drug solution in aqueous media. The microemulsion showed the greatest in-vitro cytotoxic effect but no significant difference was observed between the other formulations. In sheep, the three new formulations and vehicles caused little or no injection-site reactions compared with a marked response to the reference formulation. Bioavailabilities of HP-beta-CD formulation, emulsion and microemulsion formulations, relative to the reference formulation, were 194, 155 and 115%, respectively.


CONCLUSIONS
The three new subcutaneous injectables showed promise for reducing irritation of low-pH solubilised ricobendazole. HP-beta-CD significantly enhanced the drug absorption. Controlling the burst release of the low-pH drug solution may improve tissue tolerance and minimise post-injection precipitation, and hence increase drug bioavailability. The in-vitro cytotoxicity studies did not predict the in-vivo irritation effects.
Wu
Zimei
Z
School of Pharmacy, University of Auckland, New Zealand. z.wu@auckland.ac.nz
Tucker
Ian G
IG
Razzak
Majid
M
McSporran
Keith
K
Medlicott
Natalie J
NJ
D015766:Albendazole / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers / Q000009:adverse effects / Q000493:pharmacokinetics*; D004655:Emulsions; D005347:Fibroblasts / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D007267:Injections; D007279:Injections, Subcutaneous; D007770:L-Lactate Dehydrogenase; D019999:Pharmaceutical Solutions / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D012756:Sheep; D047392:beta-Cyclodextrins
D004337:Drug Carriers; D004655:Emulsions; D019999:Pharmaceutical Solutions; D047392:beta-Cyclodextrins; D007770:L-Lactate Dehydrogenase; D015766:Albendazole; C027186:albendazole sulfoxide