Exploitation of Pressurised Gyration as an Innovative Manufacturing Route for Nanofibrous Structures

There has been considerable interest in developing nanofibrous systems, composed of meshes of ultra-thin fibres, for usage in several key industrial applications, for example in pharmacy. In brief, such systems allow very favourable physical characteristics such as a high surface area to volume ratio which in turn allows rapid drug release. However, a major obstacle to such approaches is the possibility of producing such systems at a realistic scale. For example, well established techniques such as electrospinning can only generally produce gram quantities of material in an hour. Our proposal is that by using a pressure gyration technique developed at UCL we will be able to rapidly produce drug or active-loaded nanofibres in kilogram quantities, thereby rendering the use of such materials commercially feasible. The method basically consists of a cylinder with a bank of holes around its middle axis. By applying gas under pressure and rotating the system rapidly, it is possible to extrude a solution of the polymer from the holes under ambient temperatures, with the solvent being driven off to produce nanofibres on a surrounding collecting plate. We will expand further the capabilities of the pressurised gyration process by building a more upmarket and powerful manufacturing device. We will also study the physics of the process in greater detail in order to be able to process control and predict the output characteristics of the products. We have already demonstrated that the technique can produce such quantities of unloaded material, hence it is entirely reasonable to suggest that the approach can be used for pharmaceutically relevant systems. We plan to demonstrate and explore the utility of the approach using three important and well-defined application areas. Firstly, we will study polymeric fibres loaded with fine particulates so that we can develop capability to use pressurised gyration to manufacture bioactive scaffolds, graphene precursors (via graphene oxide-loaded polymeric meshes), antibacterial fibrous bandages/masks etc. Secondly, we will look at the formulation of poorly water-soluble drugs for oral administration. This is a major problem for the pharmaceutical industry, as a drug must dissolve before it is absorbed through the gastrointestinal tract. It is known that dispersing such drugs in polymers may enhance that dissolution rate; we argue that the nanofibres will be even more effective due to the porous nature of the mesh and the very high surface area of such a system. Thirdly, we suggest that this method may be used as an alternative to freeze drying, whereby proteins are prepared in a solid form that may be easily reconstituted prior to injection on addition of aqueous solvent, a process that is expensive and physically and chemically traumatic for the protein. Hence if we are able to show that the pressure gyration technique also produces a stable, solid and easily reconstituted physical form then the implications for pharmaceutical production of injections would be considerable. By exploring these three application we will not only develop pre-competitive knowledge regarding the systems in question but we would also be introducing the pressure gyration technique into the industrial arena. In particular, we will be working with Astra Zeneca who have considerable expertise and interest in developing non-conventional pharmaceutical dosage forms to suit the requirements of their drug products; the company will work closely with the academic partners to advise on applicability and scale-up potential.

The project aims to develop a new method of nanofibre manufacture. The impact of this will be in two broad areas, relating to the development of the process for pharmaceutical use and to three specific areas of study that we propose here. In terms of the process itself, that of pressure gyration (PG), we will have explored and validated a method which allows nanofibre formation under much less invasive conditions than is currently the case and at a comparatively low cost, while also allowing large scale manufacture to be performed. These are crucial considerations as, at present, methods such as electrospinning are attracting considerable interest but uncertainties regarding, for example, the effect of the high voltage on the integrity of the incorporated active ingredients such as therapeutic species as well as the considerable worry regarding scale up are acting to limit the popularity of the technique. The PG method outlined here would overcome both such problems and would therefore introduce a commercially feasible method for bulk production of nanofibres and nanofibre assemblies. This in turn would open the door for the realistic commercial production of a wide range of nanofibrous systems, including the three examples outlined here as well as applications such as tissue engineering scaffolds, implants. The second area of impact lies in the three areas of study outlined here. Particle-loaded nanofibrous meshes are very much in demand by various industrial sectors and their manufacture and testing are sought by many academic researchers, e.g. bioactive scaffolds, graphene precursors, antibacterial bandages/masks. In particular, the network formed via PG lends itself extremely well to wound healing applications, where particulates such as Ag may be used to promote healing and reduce infection, while the porous nature of the mesh would allow fluid transport. Therefore this research could lead to the development of a new approach to wound healing and would therefore have a significant impact on the devices and dressings industry. Oral delivery of low molecular weight drugs is a major problem facing the industry, with some 40% of new drugs having problems of solubility and bioavailability. This method would build on existing solid dispersion technologies, which have been shown to be potentially highly effective, but would also have the advantage of presenting the drug as a very high surface area to volume ration form which would further enhance dissolution, while we hypothesise that the nanoscale dimension of the meshes would be more stable to morphological changes. Freeze drying is a major and highly costly process in the pharmaceutical industry which again invariably leads to some drug loss; here we would be looking at an alternative PG method for preparing proteinaceous drugs in an easily reconstituted form but using much milder conditions than conventional lyophilization. If successful, this approach could have a major impact in terms of reducing costs associated with production and loss of active. Overall, therefore, a successful outcome to the project would have a major beneficial effect on the pharmaceutical and related industries due to the introduction of a low cost, scalable approach to manufacture of a range of commercially relevant systems. In all three cases, however, the ultimate beneficiary of the new technology would be the public, in particular patients. In particular, the development of more effective delivery systems at lower manufacturing cost will have huge knock-on health benefits, as the drugs given orally would be absorbed more effectively and hence the pharmacokinetic profiles would be more uniform and predictable, while the lower cost and reduced degradation profile of the proteins prepared using PG would have lower extraneous material and be more affordable for the taxpayer.