The effect of supercritical fluid processing parameters on product performance - controlled release biologics

To exert their effect biopharmaceuticals require the delivery of the native biologically active molecule to the site of action. However their labile nature and poor bioavailability often presents considerable challenges to their formulation into medicines and can obstruct development and commercialisation. Furthermore, their frequently unfavourable pharmacokinetics means that they are usually administered by frequent injections which is inconvenient for patients and can effect their compliance with the therapeutic regimen. One strategy to overcome some of these issues is to develop longer acting versions of the drug. Encapsulation of the protein within a matrix which slowly releases the drug is an attractive strategy to achieve this since this does not involve any chemical modification of the drug. However to date the manufacturing processes used to achieve this have suffered a number of draw backs when applied to biopharmaceuticals. The high temperatures used in various polymer melt processes are known to denature proteins causing them to lose their activity. Alternatively, emulsion processes can generate aqueous-organic interfaces with a very large surface area at which proteins can also denature. Furthermore, these emulsion processes are associated with the economic and environmental cost of solvent disposal. To date Nutropin Depot (a controlled release version of human growth hormone (hGH)) has been the only protein encapsulated within a polymeric matrix to successfully reach the market. This was manufactured using a proprietary emulsion process but was eventually withdrawn because it was reported that the manufacturing process was 'too resource intensive'. Critical Pharmaceuticals is a small specialty pharmaceutical company, with an innovative encapsulation technology using supercritical fluids (SCF). We have previously demonstrated the potential of SCF processing to encapsulate drugs within polymer microparticles in a single step process. This technology has the advantage that it operates at ambient temperatures and in the absence of solvents, permitting the formulation of biopharmaceuticals without adversely affecting their activity. We are currently developing the technology with the aim of gaining regulatory acceptance and are on track to initiate a phase 1 clinical trial in 2008 for our lead product, a controlled release protein formulation. The product properties need to be tailored to the specific application in order to successfully take these products to market, and aid downstream processing. For example, depending upon the application the particle size, shape and flow properties of the products needs to be tightly defined e.g. in order to aid injectability or vial filling. With this CASE award we hope to build on recent advances made both at the University of Nottingham and in Critical Pharmaceuticals' laboratories that have optimised the supercritical apparatus to allow the reproducible manufacture of polymer microparticles containing encapsulated biopharmaceuticals. These products have been shown to control the release of the drug both in vitro and in vivo. We have discovered that the nature of the products produced is influenced not only by the polymeric material itself and conditions that it is processed at, but also that the addition of excipients can impact upon particle size, morphology and performance. We have therefore identified a complex interplay between the SCF process and the formulation which impacts upon the products produced - their properties, performance and applicability. In this project we propose to apply experimental design to determine the key processing and formulation parameters which impact upon particle size, shape, surface area, flow, porosity and performance, with the aim of gaining a greater understanding how each of the variables interact. This will lead to the production of protein formulations with enhanced performance and ultimately help improve patient lives.