Understanding polymer - drug interactions and their role in formulation of medicines

Formulation of drugs into medicines is necessary to enable them to be taken by patients and to maximise their effectiveness. Medicines are also known as drug delivery systems (DDS). Polymers are used in a variety of DDS, e.g. nanoparticles and matrix systems and in a variety of ways for example to improve drug solubility, provide delivery to a local area or to provide slow release of drug etc. For maximum efficacy of the medicine, a high incorporation of drug and control of drug release (especially slow release) are usually critical in producing clinically useful formulations. Producing such formulations depend on having biocompatible polymers with suitable physicochemical properties compatible with drugs having a diverse range of chemical structures and properties. In this project we aim to develop a better understanding of polymer drug interactions to develop improved DDS.
Solid molecular dispersions will be used in this project as a simple and easily measured DDS dependent on polymer-drug compatibility. A group of poor solubility drugs relevant to solid molecular dispersions have been identified and 25-30 drugs from this group will be selected for this project. To accommodate drugs of different properties, polymers with a range of characteristics will be required. In this project we will use a recently described biodegradable polymer, poly(glycerol adipate) (PGA), having a pendant hydroxyl group which can be chemically modified with acyl or amino acid moieties to generate a family of related polymers with different physicochemical properties.
The project will comprise two tracks of work each with an associated post-doctoral research assistant. The first track will be based on computational modelling, and the second track on the experimental determination of drug polymer interactions. Outputs from both tracks will then be correlated using the experimental determinations to validate the insight and understanding gained from the modelling studies.
The computer modelling will aim to provide an understanding of polymer drug interactions based on a description of the interactions derived from combined atomistic and coarse grained models.. From these models and existing software available at AstraZeneca NRTL-SAC and COSMO-SAC various solubility parameters for the drugs and polymers will be derived.
The second track will consist of synthesis of this family of polymers, the preparation of molecular dispersions of drugs with the polymers and the characterisation of those molecular dispersions for their stability and the experimental determination of their polymer-drug interactions. These characterisations will use a range of (mainly high throughput) spectroscopic, physico-chemical and formulation techniques at Nottingham and AstraZeneca. The solubility parameters and other metrics from the molecular modelling studies which describe the polymers will be correlated with the experimental determination of the properties of the molecular dispersions produced. Molecular modelling is an intensive means of determining compatibility so identification of alternative simpler factors, indicators and methods for predicting drug-polymer compatibility will be investigated. Once appropriate factors have been described these will be used to predict the most compatible polymers for a set of previously undetermined drug molecules chosen from our drug library and validated using the previously identified methodology. The project will thus develop new methodology, validate predictions, enhance understanding of polymer drug interactions and identify new polymer structures which may be useful in both solid dispersions and other polymer based drug delivery systems.

The pharmaceutical industry in the UK is an important industrial sector and formulated products are an important contributor with the UK market worth around £180bn a year and a potential in emerging overseas markets of around £1,000bn. Formulation of drugs into drug delivery systems (DDS) is becoming increasingly important for the pharmaceutical industry as the properties of new drugs render them more difficult to take to market. Polymers are used in a variety of DDS, e.g. micelles, nanoparticles, microparticles, polymer implants, stent coatings, and solid dispersions. These formulations are used in a variety of ways e.g. to improve drug solubility, for localised delivery or to provide slow release of drug. For maximum efficacy of the medicine, a high incorporation of drug and control of drug release are usually critical in producing useful formulations for the market. These factors are common to all the above DDS involving polymers, and these factors are dependent on polymer-drug compatibility. Formulating all of these delivery systems is at present largely carried out empirically or semi empirically and with little understanding of the principles by which appropriate drug polymer combinations can be achieved. The difficulties of producing appropriate drug polymer combinations are compounded by the paucity of biocompatible polymers with different and suitable properties.
The expertise and collaboration for this project has arisen from the EPSRC Astra Zeneca Doctoral Training Centre in Targeted Therapeutics. Astra-Zeneca, a major pharmaceutical company will play an active collaborative role in this project. This involvement will ensure that the drugs and methodology used in this project are relevant to the pharmaceutical industry, and that the findings from this project can be immediately employed in the development of new medicines.
The understanding of polymer-drug compatibility, together with the developments in methodology in computer modelling and the application of high throughput screening methods will contribute to the ability of the pharmaceutical industry to develop new polymer based formulations. Exploration of the solubility parameters for drugs and polymers will aid fundamental understanding of the science of formulation. It will in assist in understanding and prediction of the features of polymers which are important in interactions with drugs and also the understanding of what drug properties contribute to interactions with polymers. Together these factors will help us to determine what polymer drug combinations will work well together. These findings will be of particular significance to the pharmaceutical industry in both identifying suitable drug candidates for delivery systems and reducing the time and cost taken for formulation of these delivery systems.
The availability and study of a family of novel biodegradable polymers which can be chemically tailored to give a range of different physicochemical properties will also enable us to identify what polymer features are useful and enable the design of more appropriate polymers for future use in the pharmaceutical industry. These advances in scientific understanding and applied knowledge will rapidly lead to more and better DDS /medicines for a variety of different diseases. With better availability of DDS, this will impact on patient compliance in taking medicines and greater efficacy leading to an improvement in treatment and health. These advances will be initially most applicable in the formulation of solid molecular dispersions, but will later impact on development of other polymer based DDS.
We will disseminate the results at the most high profile conferences to ensure maximum exposure of EPSRC funded work and enhanced impact. PDRAs on the project will present at multiple research workshops to further their careers and to build lasting research networks to ensure the widest reach to other academic institutions and pharmaceutical companies.