Effect of Excipients on the Particle Size of Precipitated Pioglitazone in the Gastrointestinal Tract: Impact on Bioequivalence

Abstract

This study sought to understand the reasons for the bioinequivalence of a newly developed generic product of pioglitazone hydrochloride and to improve its formulation so that it is equivalent to that of the reference listed drug (RLD). In this clinical study, despite a similar in vitro dissolution profile, the new oral product exhibited a lower plasma concentration of pioglitazone compared to the RLD. The strong pH-dependency of pioglitazone solubility as a weak base indicates that pioglitazone would precipitate in the small intestine after being dissolved in the stomach. Thus, in vitro experiments were performed to investigate the effect of excipients on the particle size distribution of precipitated pioglitazone. Then, the impact of particle size on in vivo absorption was discussed. The precipitated pioglitazone from the RLD showed a peak for small particles (less than 1 μm), which was not observed in the precipitate from the new product. As an excipient, hydroxypropyl cellulose (HPC) influenced the particle size of precipitated pioglitazone, and the amount of HPC in the formulation was increased to the same level as that in the RLD. The precipitate from this improved product showed approximately the same particle size distribution as that of the RLD and successfully demonstrated bioequivalence in the clinical study. In conclusion, for drugs with low solubility, this type of analysis of the particle size distribution of precipitated drugs, in addition to the dissolution test, may help to obtain a better in vitro-in vivo correlation for oral absorption and to develop a bioequivalent product.

Relative Bioavailability Risk Assessment: A Systematic Approach to Assessing In Vivo Risk Associated With CM&C-Related Changes

“…Some of these changes that could impact in vivo performance include solid form (e.g., polymorph), chemical entity (e.g., salt, co-crystal), and API particle size. [1][2][3] Changes in any of these properties contributes to the overall CM&C and Inherent Biopharmaceutics risk score in the RBA-RA. The changes are cumulative; therefore, the greater the number of changes, the higher the CM&C risk score.…”

“…Therefore, consideration must always be given to how the changes could impact the relative in vivo performance. [1][2][3][4][5] The "gold standard" to understanding the potential impact of these changes on the absorption of a drug is a human in vivo comparability study. Comparability studies can be classified in 2 groups: bioequivalence (BE) studies and relative bioavailability (RBA) studies.…”

Inhibition of Gastric H⁺,K⁺-ATPase Activity <i>in Vitro</i> by Dissolution Media of Original Brand-Name and Generic Tablets of Lansoprazole, a Proton Pump Inhibitor

“…This is in part because a multiunit system is less affected by the interdigestive migrating complex (IMC), which affects drug absorption. 7,10,11) Moreover, damage to the enteric coating of multiunit granules has less effect on the entire dose than it does on a single-unit system.…”

“…The bioequivalence study for oral dosage forms includes an in vitro dissolution test and a human clinical study. 12) After confirming the dissolution similarity of the generic tablet to the original brand-name tablet, the bioequivalence study moves to the subsequent human clinical study to evaluate its therapeutic effect. This means that the effects of generic PPIs on H + ,K + -ATPase activity in vitro have not been carefully evaluated during their development.…”

Characterization of pioglitazone cyclodextrin complexes: Molecular modeling to in vivo evaluation

“…PE, a Biopharmaceutical Classification System Class II drug is characterized with low aqueous solubility (0.015 mg/ml). [ 12 ] This water insolubility results in highly erratic and poor dissolution profile in gastrointestinal fluids. [ 13 ] Absorption is dissolution rate limited which may translate in poor absorption, distribution, metabolism, and excretion profile with a reduction in pharmacological activity.…”