Bovine Mucosal Heparins Are Comparable to Porcine Mucosal Heparin at USP Potency Adjusted Levels. Journal Article


Authors: Jeske, W; Kouta, A; Farooqui, A; Siddiqui, F; Rangnekar, V; Niverthi, M; Laddu, R; Hoppensteadt, D; Iqbal, O; Walenga, J; Fareed, J
Article Title: Bovine Mucosal Heparins Are Comparable to Porcine Mucosal Heparin at USP Potency Adjusted Levels.
Abstract: Bovine mucosal heparins (BMH) are currently being developed for re-introduction for both medical and surgical indications. BMH active pharmaceutical ingredient (API) exhibits a somewhat weaker USP potency when compared to PMHs. We hypothesized that when dosages are normalized based on the USP reference heparin, BMH will exhibit comparable and effects to those produced by PMH. Therefore, studies were developed to compare the APIs of bovine and porcine heparin. API versions of PMH were obtained from Celsus Laboratories (Franklin, OH) and Medefil (Glen Ellen, IL). API versions of BMH were obtained from Kin Master (Passo Fundo, Brazil). Each of these heparins was assayed for their molecular weight profile, AT affinity, USP potency, and anticoagulant/antiprotease profiles using standard laboratory methods. protamine neutralization studies were carried out. Antithrombotic and hemorrhagic effects were measured in rats and pharmacodynamic profiles were assessed in primates. Size exclusion chromatography demonstrated that the mean molecular weight of BMH was ~15% higher than that of PMH (BMH: 20.1 ± 0.8 kDa and PMH: 17.5 ± 0.7 kDa). BMH exhibited an anti-Xa potency of 130 U/mg while PMH had an anti-Xa potency of 185 U/mg. In the anticoagulant and antiprotease assays, the BMH exhibited lower functionality which was proportional to USP potency. When the BMH was compared with PMH at potency adjusted concentrations, it showed identical concentration-response curves in the aPTT and anti-protease assays. However, in the protamine neutralization studies, BMH required slightly higher amounts of protamine in contrast to PMH. BMH and PMH administered to rats at equivalent anti-Xa unit dosages resulted in comparable antithrombotic activity and prolongation of bleeding time. Similar pharmacodynamic profiles were observed in primates when BMH and PMH were dosed on an anti-Xa U/kg basis. BMH, when used at comparable anti-Xa unit levels, is comparable to PMH, however, it requires proportionally higher amount of protamine due to the increased mass for adjusting to higher potency. Additional studies on the structural characterization, interactions with PF4 and neutralization studies are ongoing.
Journal Title: Frontiers in medicine
Publisher: Unknown  
Date Published: 2019