Drug Delivery Technology

P ARENTE RAL DELIVERY

Monodisperse Microspheres for Parenteral Drug Delivery

By: Gert Veldhuis, PhD, Míriam Gironès, PhD, MSc and Debra Bingham

INTRODUCTION

Drug Delivery Technology January 2009 Vol 9 No 1

Throughout the past few years, several products based on drug-loaded biodegradable microspheres have reached the pharmaceutical marketplace. Well-known examples are Lupron Depot^®(Abbott Laboratories), Trelstar^®Depot (Watson Pharmaceuticals), and Risperdal^®Consta ^TM( Ortho-McNeil-Janssen Pharmaceuticals). These types of injectable depot formulations (IM or SC) can provide sustained and controlled delivery of the active over a period of weeks or months and thus significantly increase patients’ comfort and compliance. From the perspective of the pharmaceutical companies, microsphere-based depot formulations of existing compounds offer an attractive tool in life cycle management, but most importantly, offer significant value to patients.

Although microsphere-based drug delivery is attractive from both the market and patient perspective, developers of microsphere formulations face many challenges in achieving the desired product performance and process efficiency. Many of these challenges are related to the lack of control over particle size and uniformity of conventional microsphere manufacturing methods. There are a number of techniques in development designed to overcome issues regarding size and uniformity. We believe that a novel manufacturing

process based on Microsieve ^TMemulsification offers the best and most straightforward opportunity to overcome these challenges.

KEY FACTORS IN
DESIGNING SUSTAINED-
RELEASE MICROSPHERE
FORMULATIONS

The most important goal in designing a microsphere formulation for sustained drug delivery is to achieve a gradual release of the active at a constant rate over the desired period of time. Given a certain microsphere size, such a zero-order release profile is typically achieved by careful selection of the biodegradable polymer matrix material. Usually, this is a poly (D,L-lactic-co-glycolic) acid, PLGA, which is biodegradable, biocompatible, and equally important, has been used in many FDA-approved products. The properties of PLGA can be tailored to the purpose by changing the block ratios and the molecular

weight, which have to be chosen such that the diffusion rate of the active and the degradation rate of the polymer match the desired release period. In addition, the polymer has to be selected such that the release rate reduction over time (typical for diffusion controlled release) is compensated by the degradation-related release rate, which increases over time.

An important parameter for robust drug formulation, and the focus of this paper, is the microsphere size. The chosen microsphere size is usually a compromise between two main considerations.

1. The smaller the microspheres, the better the syringability (Figure 1) and the smaller the needle gauge required, which translates into reduced patient discomfort. A 27-gauge needle has an inner diameter of 191 microns. Taking a fair safety margin of a factor 4, this suggests an upper limit for the