Review
Dense gas processing of polymeric controlled release formulations

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Abstract

Dense gas techniques, which utilize the properties of fluids in the vicinity of their critical points, are of increasing interest in the processing of pharmaceuticals. It is generally known that dense gases can be used for extractions, chromatographic separations and chemical synthesis due to their liquid-like solvation power and gas-like mass-transfer properties. The processes can be conducted at moderate operating conditions and are thus suitable for many heat-labile compounds such as proteins, biocompatible polymers and pharmaceuticals. Recent applications of dense gas techniques include micronization, crystallization of high-purity particles, sterilization and preparation of microencapsulated drug formulations. The following paper provides a brief overview of dense gases and various processing techniques to fabricate polymeric drug-loaded formulations for controlled release purposes.

Introduction

A pure substance generally exists as either a solid, liquid or gas phase, which are clearly defined by phase boundaries, as shown in Fig. 1. Based on this pressure–temperature diagram for a pure substance, various phases can exist up to the critical point for all molecules. As pressure and temperature increase above the critical point, the liquid and gas phases become indistinguishable. Beyond the critical point, the substance exists as a supercritical fluid (SCF), which is a homogeneous medium. Therefore, it is possible to construct a path from point A to point B to induce a phase change from liquid to gas without passing through a distinct phase transition. A substance close to, but not necessarily above, its critical point is referred to as a dense gas (DG). The properties of DGs can vary widely and are generally intermediate to those of gases and liquids. The density of a DG is generally closer to that of conventional liquids and several orders of magnitude higher than that of conventional gases and accounts for the solvating capabilities of the DGs.

The interest in DGs and their potential use for process improvements has significantly increased in the past decade. Due to the properties of these fluids, which can be tuned by small changes in pressure or temperature, DGs have potential as alternative media for classical separation processes and as reaction environments. Several conventional techniques, such as spray drying (Broadhead et al., 1992, Masters, 1979), emulsion–solvent extraction (Puisieux et al., 1994, Chasin and Langer, 1990, Bakan, 1994) and processes based on cavitation, attrition, high shear and impaction (i.e. high-pressure homogenization, microfluidization, media milling, air-jet milling and ball milling) (Byers and Peck, 1990, Rubinstein and Gould, 1987, Parrott, 1990, Aiache and Beyssac, 1994, Illig et al., 1996), have been utilized for particle processing. However, these processes may often incur undesired effects such as thermal and chemical degradation, inner-batch particle size variability and broad size distribution. Other disadvantages of some conventional particle processing techniques include the need for additional stages for the extraction of residual solvent and the extensive use of organic solvents, which may result in health and environmental concerns. Therefore, the limitation of conventional particle processing techniques has driven the focus of studies towards the potential replacement of traditional organic solvents with more environmentally friendly materials, such as DGs.

One of the applications of DG techniques in particle processing is the preparation of microencapsulated drug formulations. Microencapsulation can be defined as a process of coating or entrapping micron-sized material with another material without chemical interaction. Microencapsulation is often used to provide a protection for a drug from the reactive surroundings and to prevent drug degradation from light or exposure to oxygen. Furthermore, microencapsulation can be used to improve the formulation characteristics such as taste, stability and wettability. Microencapsulated formulations can also be used to extend the dosage time from a repeated to single administration and to provide controlled release of drugs in a desired part of the body. Therefore, microencapsulated drug formulations can be pharmaceutically beneficial since a drug is generally more effective for long-term treatment and exhibits fewer side effects when the drug concentration in the body is kept constant at some optimum level over the duration of therapy.

In this review, the concepts and parameters involved in the microencapsulation of pharmaceutical controlled release formulations and the utilization of different DG techniques for the preparation of microencapsulated drug formulations are discussed.

Section snippets

Microencapsulation in controlled release formulations

There have been significant developments in controlled release administration in the last three decades from primitive delayed-release dosage forms in the 1960s to highly sophisticated self-regulated delivery systems in the 1990s (Park, 1997). These advances have produced many clinically useful controlled release dosage forms and provided better shelf-life for many existing drugs. The market of pharmaceutical controlled release formulations is expected to rise exponentially from US$ 19 billion

Polymers in controlled release formulations

Particle encapsulation has been demonstrated to be of particular interest in the control of drug release and it offers some advantages such as protection of bioactive agents from enzymatic degradation. The concept of incorporating polymers for controlled release was developed in the early 1970s when it was discovered that the then available forms of delivery using silicone rubber and polyethylene left foreign material in the body even after surgical removal of the device (Dunn and Ottenbrite,

Preparation of controlled release formulations

In recent years, many studies have been conducted to develop controlled release systems with optimum characteristics and performance. Manufacturing processes for the preparation of polymeric controlled release systems, which include conventional and novel processing techniques, have been evaluated over the years. In fact, conventional processes for the preparation of controlled release systems are still widely used by several pharmaceutical companies nowadays. However, due to the limitations of

Summary

Controlled release formulations are invariably more expensive than conventional formulations thus they can only be justified when they offer one or more therapeutic advantages. Apart from the improvement of pharmacological responses, the other advantages of controlled release systems include the maintenance of therapeutic drug levels and minimization of drug level fluctuation, total amount of drug used, patient compliance and reduction of side effects. On the other hand, there are some

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