Abstract:
Post-injection precipitation may cause poor and erratic drug absorption and tissue irritation at the injection site. Tissue tolerance and pharmacokinetics of a low pH ricobendazole (RBZ) injectable containing 20% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were simultaneously investigated after subcutaneous injection in sheep compared to a reference formulation without HP-beta-CD. Each animal received a RBZ containing formulation on one side of the back and the respective vehicle on the contralateral side. The HP-beta-CD vehicle showed good tissue tolerance and the acidic solution caused minimal injection site reactions. Both RBZ containing formulations caused pain on injection and tissue histological changes in some animals. Lack of elevation of plasma creatine kinase indicated that none of the formulations caused significant damage to the underlying muscle tissue. Compared to the reference formulation, AUC and C(max) of the HP-beta-CD formulation were 1.6 and 2.2 times higher, respectively, whereas t(max), MRT and t(1/2) were significantly shorter suggesting faster and greater absorption of RBZ in the presence of HP-beta-CD. This was attributed to the effect of inhibition of post-injection drug precipitation and drug absorption enhancement of HP-beta-CD. In conclusion, HP-beta-CD was shown to be a tissue-compatible excipient with potential to inhibit post-injection precipitation and increase absorption of poorly water soluble drugs. Additionally, the HP-beta-CD formulation showed promise as an injectable that potentially minimizes irritation by reducing the dose required.
