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Advanced experimental and computational methods for optimising nasal drug delivery


   Institute of Pharmaceutical Science

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  Prof B Forbes, Dr C Dreiss  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

This studentship is an Industrial Cooperative Award in Science & Technology hosted at King’s College London in collaboration with NanoPharm Ltd.

Background

The deposition of particles in the nose is important in the transmission of infectious disease and the delivery of nasally administered therapies. The project will investigate the hypothesis that local and systemic exposure following nasal deposition of xenobiotics is determined by interactions with mucus at the site of deposition. We use formulations typical of nasally administered drug products to investigate this (Figure). The experimental and mechanistic computer models developed will be equally relevant to environmental (allergens/pollutants) and occupational (sprayed pesticide/healthcare/household products) exposures.

The fate of particles entering the nasal cavity depends on both the location of deposition (Calmet, et al. 2019) and the rate at which particles dissolve and are carried away by the mucocillary escalator (Rygg, Hindle and Longest 2016). For pharmaceutical aerosols, deposition can be controlled by particle size, flow characteristics, the configuration of the nozzle; dissolution depends on particle size and excipients, and the interaction with mucus depends on the interactions with particle surface chemistry.

Intranasal drug delivery is an attractive way to deliver many therapeutic agents both locally and systemically, from small drug molecules to large biomolecules. It presents a series of unique advantages. Moreover, targeted drug delivery, as sustained and nose-to-brain delivery, can be achieved through modulation of formulation composition, device performance and the interaction between formulation components and nasal mucosa. Interest in nasal delivery has increased particularly over the last two years due to the Covid-19 pandemic (Pyrć, et al. 2019), but this route has the potential to tackle and prevent a wide range of other infections, deliver vaccines, antibodies or chemical entities directly to the port of entry of their related pathogens (Chavda, et al. 2021).

The particle-mucus interaction can be optimised by surface modification with mucoadhesive polymers (Ugwoke, et al. 2005), such as chitosan, or through PEGylation; more recently a wide range of polymers have emerged as promising mucoadhesive candidates.

Project Plan

We aim to develop in vitro methods that can be used to screen the mucoadhesive properties of particles designed for delivery to the nose through three phases of investigation:

1.      Profile the physicochemical properties of mucus that are important for particle deposition, penetration and interactions,

2.      Develop a mucus simulant for in vitro testing to study post-deposition ‘partico-kinetics’ and apply these data in mechanistic computational models to predict drug bioavailability,

3.      Apply the in vitro tools to test marketed products and muco-interactive candidates for the development of novel formulations for small and large therapeutic molecules.

Skills/training

The aim is to characterise the biophysics of nasal mucus, from the nano- to macro-scale, and develop a biorelevant mucus simulant as an easy-to-handle, reproducible research tool to study physical and chemical interactions with pharmaceutical particles. The project will work across the boundaries of biology, formulation chemistry, materials science and machine learning/computational statistics to develop new tools to guide the design of novel nasally administered therapies (including mucus-modifying formulations).

As well as inter-sector and inter-disciplinary experience, the project will provide in-depth technical training in material characterisation techniques, including shear- and micro-rheology (particle-tracking), diffusion NMR, small-angle neutron scattering, light scattering and confocal microscopy. Other research skills include organotypic cell culture, nasal liquid formulation, nasal powder formulation, design of experiments methodology, statistical modelling, machine learning techniques.

Dissemination

The main routes of dissemination will be contributions to conferences and peer reviewed journal articles. The key targets will be Drug Delivery to the Lungs (UK) and Respiratory Drug Delivery which holds meeting in Europe and USA on alternate years. Other targets include the MVIC symposium (Sweden) and the Academy of Pharmaceutical Sciences PharmSci conference (UK). At least one peer reviewed publication per project stage is envisaged in a top quartile Pharmaceutical Science journal. In addition, regular updates on the project progress will be provided through Nanopharm and Aptar social media accounts.

 

Supervisory and Collaborative Arrangements

The scientific outcomes of each stage will be exchanged between the academic and the external (industry) partner through cooperation and joint project supervision in the following ways:

Phase 1

·    The Nanopharm and King’s College will collaborate on the manufacture of particles/droplets that will be used to investigate interactions with natural mucus

·    Nanopharm will provide training for the design of experiments approach and statistical modelling

Phase 2

·     A mucus surrogate developed by the academic project team will be incorporated into a number of in-vitro methods at King’s College and Nanopharm.

·     This will be facilitated by a placement at Nanopharm during this phase of the project.

Phase 3

·    Nanopharm and King’s will collaborate on selection and/or manufacture of novel formulations. It is likely that this will involve iterative steps as parameter space is explored.

·    The Nanopharm team will support the design of experiments approach and statistical modelling by providing training and guidance

There will be regular digital catch-up meetings of all supervisors, plus six-monthly face-to-face meetings.

Funding Notes:

This project is fully funded for four years, with the student receiving the following support:

-         Stipend: Students will receive a tax-free stipend for each year of study, starting on £20,562 in year 1 and increasing each year with inflation.

-         Tuition fees: Students tuition fees for each year of study are fully covered. The amount of £4,596 in 2022/23, rates for subsequent years will be announced by UKRI.

-         Bench fees: a generous allowance of £6,400 each year provided towards research consumable and project costs.

-         Travel and conference allowance: £300 each year provided to support students in attending UK and international conferences.

Funding source: this project is co-funded by King’s College London and the Industry Partner Nanopharm.

Eligibility:

To be classed as a home student, candidates must meet the following criteria:

•Be a UK National (meeting residency requirements), or

•Have settled status, or

•Have pre-settled status (meeting residency requirements), or

•Have indefinite leave to remain or enter

Enquiries email name and address:

Ben Forbes; [Email Address Removed]

Application Web Page:

Full details on how to apply here: https://kcl-mrcdtp.com/studentships/icase-studentships/icase-application-process/

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