Tissue compatibility and pharmacokinetics of three potential subcutaneous injectables for low-pH drug solutions

Abstract

Objectives 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-b-cyclodextrin (HP-b-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. Key findings 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-b-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-b-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.

In-vitro prediction of bioavailability following extravascular injection of poorly soluble drugs: an insight into clinical failure and the role of delivery systems

“…The tissue damage induced by drug precipitation was circumvented by the use of HP‐β‐CD even though most of the RBZ in the formulation (94.6%) was not complexed . Previous in‐vitro studies suggested that while the low pH RBZ aqueous solutions readily precipitated on dilution with buffer, addition of HP‐β‐CD produced a concentration‐dependent inhibition to the drug precipitation by maintaining the mixture as a supernatant solution for long time …”

“…However, one of the concerns associated with these solubilization approaches is that these formulations often lead to products that cause injection site reactions. Moreover, even if the drugs are soluble in the formulation, post‐injection drug precipitation (PDP) may occur to both intravenous and extravascular injections . The occurrence of PDP is a major concern due to the potential local injection site reactions, haemolysis and thrombophlebitis associated with intravenous formulations, and has been reported to be responsible for poor and erratic drug absorption and tissue damage following intramuscular/subcutaneous injections …”

“…Moreover, even if the drugs are soluble in the formulation, post-injection drug precipitation (PDP) may occur to both intravenous [4] and extravascular injections. [5,6] The occurrence of PDP is a major concern due to the potential local injection site reactions, haemolysis and thrombophlebitis [7] associated with intravenous formulations, and has been reported to be responsible for poor and erratic drug absorption and tissue damage following intramuscular/ subcutaneous injections. [6] Until the late 1970s, drugs administered by injection were assumed to be absorbed rapidly and completely into the bloodstream, as the subcutaneous and intramuscular regions are well supplied by capillary and lymphatic (s.c. in particular) vessels.…”

Biocompatibility of differently proportioned HA/PLGA/BMP-2 composite biomaterials in rabbits

“…Rabbit femurs, a well-established model of bone tissue defects (Fu et al, 2008;Wu et al, 2010), were implanted with the composite biomaterials in this study.…”

Effect of external factors on the curcumin/2-hydroxypropyl-β-cyclodextrin: in vitro and in vivo study

“…It is well known that, external factors not only plays important role in in vitro evaluation of the complex [41][42][43][44][45], but also may have remarkable influence in in vivo study of the inclusion complex [46][47][48]. However, according to our knowledge, there is no report on the effect of HPbCD on pharmacokinetics controlled by pH of curcumin up to now.…”