Development of a pH-sensitive solid dispersion platform for oral protein delivery

The mechanism of action of many protein-based drugs depends on tertiary structure, such as alpha-helices, beta-sheets and disulfide bonds, which can be lost rapidly through exposure to heat or extremes of pH. Pharmaceutically, this means that it is extremely difficult to deliver proteins via the oral route, because nearly all the activity of the drug will be lost through degradation in the acidic environment in the stomach. A further drawback of delivery via this route is that it can be difficult to get large biological structures absorbed through the membranes of the GI-tract. It is inescapable, however, that delivery via the oral route remains preferable, mainly because of patient convenience, and thus the target market for an oral drug delivery technology capable of delivering biologicals is lucrative. Delivery of biologicals orally requires technology that can protect the structure of the active during manufacture, storage and, most importantly, the low pH environment of the stomach. It must also ensure release of the active in the higher pH environments of the GI-tract. One very promising technology that could achieve these goals is the use of pH-sensitive polymer microparticles. Recent work has demonstrated that pH-sensitive microparticles can be used to encapsulate, protect and subsequently release model drugs and it is the development of this technology to protein drug delivery that is the main aim of this proposal. Microparticles will be prepared using a solvent evaporation technique. Polymer, protein and a stabilising surfactant are dissolved in a suitable medium (ethanol for instance) and dispersed in a non-aqueous solvent (such as liquid paraffin), forming an emulsion. The solvent is evaporated off leaving protein loaded microparticles. Selection of a suitable pH sensitive polymer allows the formulation both to protect the active under acidic conditions and also to release the active at any particular (higher) pH. In addition, ensuring a proportion of hydroxyl groups on the polymer chain should allow the polymer to stabilise protein structure (hydroxyl groups are thought to act as water replacements, stabilising tertiary protein structures in otherwise dry media). In this work, we propose to collaborate with a leading developer of novel pH-sensitive polymers, Revolymer Ltd, who will supply novel polymers from their extensive product portfolio. Recognising that a particular problem with oral protein delivery is absorption across membranes, we propose in the first instance to deliver a protein that acts locally in the GI-tract, beta-galactosidase. This protein, which hydrolyses lactose, has great potential in the food industry for dealing with lactose intolerance. It is entirely feasible that microparticles containing beta-galactosidase could be added to breakfast cereals, to digest the lactose present in milk. Once proof-of-concept is demonstrated then the technology could be applied to other therapeutic agents currently in development for treatment of GI-tract disorders, such as colon cancer or Crohn's disease. In addition, the microparticles are usually amorphous. This is advantageous because amorphous materials usually exhibit faster dissolution rates than crystalline materials, but is disadvantageous because stability can be an issue. It is also the case that while two materials may be amorphous, the degree of structural disorder in each may be different, which would manifest itself in a change in physical properties. A recently developed technology (CoFlux) allows the heat changes in processes occurring in batch reactors to be monitored directly. The solvent evaporation technique is uniquely suited to being undertaken in a batch reactor and CoFlux should allow the formation of the microparticles to be monitored in real-time from the change in the power signal over time. In principle, this would mean that the degree of structural disorder imparted to the microparticles could be controlled batch-to-batch.