A recent paper addresses two major challenges in drug formulation: drug solubility and sustained release for greater therapeutic effectiveness, reduction of side effects, and improvement of patient’s comfort and compliance.

 

A review by  Dr. Carl D. Saquing, North Carolina State University

• G. Della Porta and E. Reverchon, “Nanostructured Microspheres Produced by Supercritical Fluid Extraction of Emulsions,” Biotechnology and Bioengineering, Vol. 100, No. 5, August 1, 2008. DOI: 10.1002/bit.21845

Almost half of new molecular entities (NMEs) identified by pharmaceutical industry screening programs have failed development because of poor water solubility (PWS). PWS makes drug formulation difficult or even impossible. One effective way to address PWS is to formulate the materials into nanoparticulate and/or nanostructured forms to increase their surface area and chemical potential. In drug release from biodegradable matrices, release kinetics are governed by microsphere particle size, surface morphology, and polymer/drug physico-chemical properties. Moreover, an ideal uniform release requires an optimum particle size and monodisperse microspheres.

This paper demonstrates the effective generation of nanostructured polymer/drug composite microspheres by supercritical fluid extraction of emulsion (SFEE)-- a technique based on the use of supercritical fluids. SFEE is akin to the conventional technique of particle formation in emulsions. However, the removal of the internal organic or oil phase containing the water-insoluble drug from the emulsion droplets is achieved neither by solvent extraction, evaporation, or diffusion, but by extraction using supercritical carbon dioxide.  A schematic of the process is shown in Figures 1 and 2.

Polymer/drug microspheres with particle size ranging from 1 to 3 µm and narrow size distribution were obtained due to short supercritical processing times thereby preventing particle agglomeration that usually takes place with the conventional emulsion techniques. Moreover, the particle sizes of the SFEE produced microspheres were found to be related to the emulsion droplet size (same polydispersity but interestingly, always 35% lower in all concentrations studied) and to increase with polymer/drug concentration. These findings underscore the importance of emulsion stability to attain precisely controlled particle size and morphology using this process. The researchers found that temperature and pressure have a crucial impact on the extraction efficiency due to vapor-liquid equilibrium thermodynamics of the CO2-water-ethyl acetate system as well as on particle morphology due to polymer swelling, polymer Tg lowering and surfactant/emulsion behavior modifying effects of supercritical CO2. A solvent residue an order of magnitude lower than the conventional technique was obtained (40 ppm) with an encapsulation efficiency of 90-95%. Drug release studies showed uniform concentration profiles without the problem of initial burst or delayed release common to composite microspheres with drugs nonuniformly distributed within the polymer matrix.

This work examined the successful leveraging of the flexibility of particle engineering using an emulsion system with the efficiency of supercritical processing to overcome the hurdles of high residual solvent content in the product, long processing times, and mass transfer limitations inherent with the emulsion/evaporation procedure. It has the potential for scale up with a continuous process for commercial production based on nanotechnology; however, the translation to other polymer/drug systems while maintaining stable emulsions as well as the economic implications of the use of high pressure equipment for long term commercial viability need further investigation.

Images from G. Della Porta and E. Reverchon, “Nanostructured Microspheres Produced by Supercritical Fluid Extraction of Emulsions,” Biotechnology and Bioengineering, Vol. 100, No. 5, August 1, 2008. Reprinted with permission (contract pending).