Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: A mechanistic basis for utility

Abstract

The inclusion of certain polymers within solid dispersion or lipid-based formulations can maintain drug supersaturation after dispersion and/or digestion of the vehicle, leading to improvements in bioavailability and variability in exposure. This review presents an overview of the fundamental principles that underpin drug precipitation mechanisms, describes the mechanisms by which precipitation may be inhibited, discusses the methods that can be used to identify polymeric precipitation inhibitors (PPIs), and summarizes current literature evidence of the most effective PPIs. Preliminary data from our laboratory is also presented, which describes the precipitation inhibition behavior of 53 polymeric materials using supersaturated solutions of danazol as a model, poorly water-soluble drug. These studies identify a group of PPIs with superior precipitation inhibition qualities, the majority of which are cellulose-based. These new results in combination with previous published data indicate that PPIs represent an appealing new technology with the potential to improve drug absorption for poorly water-soluble drugs. The molecular determinants of polymer utility, however, remain relatively poorly understood, although the cellulose derivates appear, in general, to provide the most benefit. More detailed studies are therefore required to define the parameters that most effectively predict and quantify the drug–polymer relationships that control precipitation inhibition.

Keywords::

• Supersaturation
• lipid formulation
• crystallization
• polymer
• solid dispersion
• danazol
• inhibition
• metastable
• bioavailability

Acknowledgement

The authors wish to acknowledge the financial support of D.B. Warren by ARC Linkage Project Grant (LP0884059) and the support of Capsugel Research and Development, a division of Pfizer.

Declaration of interest

The authors declare no conflict of interest.