Title

Liposomal Drug Products: A Quality by Design Approach

Date of Completion

January 2012

Keywords

Health Sciences, Pharmacy|Nanotechnology|Biophysics, General

Degree

Ph.D.

Abstract

Quality by Design (QbD) principles has been applied to the development of two liposomal formulations, containing a hydrophilic small molecule therapeutic (Tenofovir) and a protein therapeutic (superoxide dismutase). The goal of the research is to provide critical information on 1) how to reduce the preparation variability in liposome formulations, and 2) how to increase drug encapsulation inside liposomes to reduce manufacturing cost. ^ Most notably, an improved liposome preparation method was developed which increased the encapsulation efficiency of hydrophilic molecules. In particular, this method allows for very high encapsulation efficiency. For example, encapsulation efficiencies of up to 50% have been achieved, whereas previously only 20% or less have been reported. ^ Another significant outcome from this research is a first principle mathematical model to predict the encapsulation efficiency of hydrophilic drugs in unilamellar liposomes. This mathematical model will be useful in: formulation development to rapidly achieve optimized formulations; comparison of drug encapsulation efficiencies of liposomes prepared using different methods; and assisting in the development of suitable process analytical technologies to achieve real-time monitoring and control of drug encapsulation during manufacturing. ^ A novel two-stage reverse dialysis in vitro release testing method has also been developed for passively targeted liposomes, which uses the first stage to mimic the circulation of liposomes in the body and the second stage to imitate the drug release process at the target. The developed in vitro release testing method can be used to distinguish formulations with varied compositions for quality control testing purposes. This developed method may pave the way to the development of more biorelevant quality control testing methods for liposomal drug products in the future. ^ The QbD case studies performed in this research are examples of how this approach can be used to obtain design space for liposome products to achieve the desired in vivo product performance criteria. From an industrial perspective, this study provides an in-depth understanding of the parameters (risks) involved in liposome formulation and processing. From a regulatory perspective, the development of QbD principles for liposomal drug products will facilitate their regulation assuring safety and efficacy of these complex delivery systems. ^