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Development of novel and industrially-relevant liquid pharmaceutical formulations for combination drug therapy

Principal Supervisor: Dr Fotis Spyropoulos, School of Chemical Engineering

Co-supervisor: Dr Hannah Batchelor, School of Pharmacy

PhD project title: Development of novel and industrially-relevant liquid pharmaceutical formulations for combination drug therapy

University of Registration: University of Birmingham

Project outline:

The development of technological approaches enabling the encapsulation and delivery of functional species (e.g. active ingredients) is an area of major academic and industrial research activity with relevance to a wide range of applications (e.g. pharmaceutical, agrochemical, food). Although the majority of current research efforts focus on improving the (efficiency of) encapsulation and (controlled and/or triggered) release of a sole active component, there is increasing interest in designing structures that enable the co-encapsulation and co-delivery of two or more functional molecules within/from a sole formulation.1 To fully ‘harness’ the benefits associated with each of the two actives, the ideal carrier should enable their segregation (actives can be placed within different compartments of the carrier’s matrix), in order for potentially detrimental interactions between them to be discouraged, but in addition, and perhaps more importantly, so that their release can be independently modulated and/or triggered.

The pharmaceutical industry has been at the forefront of research activity in this area in order to develop pharmaceutical combination therapies, and in particular fixed-dose combination medicines, where the co-delivery of multiple active pharmaceutical ingredients (APIs) from a single formulation is required.2 Although there is growing evidence that this can be realised for solid dosage forms through the utilisation of various processing approaches (perhaps not always in line with industrial applicability) including 3D-printing3, co-delivery from liquid formulations, which amongst others offer dosage flexibility and address dosage form needs of specific patient populations (e.g. paediatrics, geriatrics), is limited.1,2

Emulsions are attractive microstructures for the encapsulation/controlled delivery of functional molecules (e.g. active ingredients) within/from a liquid formulation. This is due to their multiphase attributes, ease of formation, as well as their utilisation in a number of structured liquid/semi-liquid products currently on the market. Despite this, present encapsulation and delivery approaches within emulsions systems are usually only concerned with the encasing and release of a single active ingredient. More complex emulsion/colloidal architectures, such as double emulsions4,5, liposomes6 or niosomes7, have been put forward as potential candidates designed for the co-encapsulation/co-release of incompatible actives within/from a liquid disperse phase system. However, these types of structures have been associated with major stability issues and in some cases their large-scale manufacturing would require a significant level of interference to current technical/processing industrial infrastructure.4 In addition, the co-delivery performance of these microstructures is limited to sequential rather than independent release profiles; i.e. the release of one active is directly linked to that of the other (active) species and as such cannot be separately triggered/controlled. Finally current research has not focused on the nature of the constituents of these microstructures but rather on the release performance of the encapsulated actives and how this can be manipulated. Therefore, although there is scope for a range of species of biological origin (plant and/or animal) to be studied for their capacity to be utilised as the building blocks of microstructures with co-delivery functionalities, this is currently an area of research that remains unexplored. Overall, it is clear that in order for the impact of any co-delivery system to be effectively translated into an application, the designed microstructural approach has to be industrially relevant and thus easily manufactured via existing processing routes with no or minimal adjustments to current production pathways.

In addition to industrial relevance, the developed co-delivery strategy has to clearly address a currently unmet market need. Within the pharmaceutical sector there is a significant drive towards the development of formulations/medicines for exclusive use in the paediatric population. This is particularly relevant to the treatment of diseases requiring fixed-dose combination (FDC) drug therapies and where in many cases there is no currently acceptable age-appropriate medicine; e.g. despite the approval of a number of FDC (tuberculosis) products in 2011, none of these alone was deemed by the World Health Organization (WHO) as suitable for children, while in 2012 two FDC formulations (Malaria and HIV) were listed in WHO’s ‘priority life-saving medicines for children <5 years of age’. It is estimated that globally the lack of child-friendly formulations leaves 40% of the population at risk for avoidable adverse events, suboptimal dosing, non-compliance and lack of access to new medicines. In addition to addressing a clear patient need, companies exploiting technologies developed specifically for children will also benefit from the associated financial rewards offered by a paediatric-use marketing authorisation (PUMA) for off-patent drugs.

Therefore there is clear urgency within the industrial biotechnology arena to expand current portfolios of co-delivery systems in order to develop new child-friendly pharmaceutical formulations. The present project is responding to this industrial challenge by proposing a study that could ultimately lead to the development of paediatric (combination drug) liquid formulations. The overarching aim of this multi-disciplinary project is to design and implement a novel structuring strategy that enables the co-encapsulation and the subsequent independent (triggered) co-delivery of two (segregated) active ingredients within/from simple (oil-in-water, o/w) emulsions. The structuring approach taken in this project (see Fig.1) will be to fabricate novel sub-micrometre particles (e.g. biopolymer complexes8) that are carefully designed to function as encapsulants of an active species (“Active 1”) but at the same time are also able to stabilise simple o/w emulsions, containing a second active component (“Active 2”), through a Pickering mechanism (i.e. particle-stabilised emulsions). In addition to being dose-appropriate (liquid), the proposed co-delivery approach is to be realised within a simple emulsion microstructure in order to ensure it is easily adopted within an industrial biotechnology setting.


Figure 1. Structuring approach for the co-encapsulation/co-delivery of two actives in o/w emulsions

The project is envisaged to be realised through the delivery of the following objectives:

1. Design processing and formulation routes for the fabrication of particles from biological sources.

The fabrication of two different types of particles (lipid nano-crystals and polysaccharide/protein nano-complexes) will be investigated. We specifically aim to study a range of species of biological origin (plant and/or animal) for their capacity to be utilised as the building blocks of these colloidal particles. For example, we will assess selected plant and insect derived waxes (Sunflower wax, Rice bran wax, Soy wax, beeswax) as the lipid sources for the fabrication of stable crystalline particles. Both types of colloidal microstructures are to be fabricated using emulsification and mixing processing routes commonly encountered in industry.

2. Develop approaches to enable and enhance the encapsulation of active pharmaceutical ingredients (APIs) within the formed particles.

The approach employed here will be to encapsulate (initially) a model API within each of the two types of particles during their very fabrication. Model APIs (e.g. rhodamine B, fluorescein sodium salt, dimethyl phthalate) will be initially used to represent different generic classes of APIs; e.g. hydrophilic, hydrophobic, ionic, non-ionic, low molecular weight, higher molecular weight. Depending on our findings from the work involving model APIs and with the valuable contribution from Dr Batchelor, we will then progress into studying appropriate APIs of paediatric relevance.

3. Develop strategies to trigger API release from the formed particles.

The approach taken here will be to trigger the release of the encapsulated API by inducing the collapse of the particles’ structure. In the case of the lipid nano-crystals, this will be by increasing the temperature above their melting point (temperature trigger), while for the polysaccharide/protein nano-complexes it will be by increasing the pH to above the isoelectric point (pH trigger).

4. Devise approaches to promote the particle Pickering functionality.

Pickering functionality will be promoted by ensuring the size of the formed particles is maintained at a sub-micrometre level as well as by controlling the particles’ wettability.

5. Investigate the encapsulation of secondary active pharmaceutical ingredients (APIs) within emulsion droplets.

Similarly to 2, the project here focuses on encapsulation and release of a secondary API from within the droplets of a simple o/w emulsion. Emulsion studied here will be stabilised using the particles developed earlier.

 6. Study the co-encapsulation and co-delivery capacity of o/w emulsions.

The understanding developed in previous parts of the project regarding the encapsulation and release of a sole API either from particles or liquid droplets, will be combined to investigate co-encapsulation and co-delievry of two APIs. The stability of the emulsion microstructure itself and the APIs will be monitored as a function of time. Co-release studies will be carried out using dissolution testing and co-release performance will be assessed and compared to the simple release profiles obtained for the individual APIs.


  1. Čejková, J.; Štěpánek, F. Curr Pharm Des. 2013, 19(35), 6298-6314.
  2. Li, N.; Zhao, L.; Qi, L.; Li, Z.; Luan, Y. Prog Polym Sci. 2016, 58, 1-26.
  3. Khaled, S. A.; Burley, J. C.; Alexander, M. R.; Yang, J.; Roberts, C. Int J Pharm. 2015, 494, 643-650.
  4. Chong, D. T.; Liu, X. S.; Ma, H. J.; Huang, G. Y.; Han, Y. L.; Cui, X. Y.; Yan, J. J.; Xu, F. Microfluid Nanofluidics. 2015, 19(5), 1071-1090.
  5. Peres, L. B.; Peres, L. B.; de Araújo, P. H. H.; Sayer, C. Colloids Surf B. 2016, 140, 317-323.
  6. Cosco, D.; Paolino, D.; Maiuolo, J.; Di Marzio, L.; Carafa, M.; Ventura, C. A.; Fresta, M. Int J Pharm. 2015, 489(1-2), 1-10.
  7. Tavano, L.; de Cindio, B.; Picci, N.; Ioele, G.; Muzzalupo, R. Biomed Microdevices. 2014, 16(6), 851-8.
  8. Kurukji, D.; Norton, I. T.; Spyropoulos, F. Food Hydrocolloids. 2016, 53, 249-260.

BBSRC Strategic Research Priority: Industrial Biotechnology and Bioenergy

Techniques that will be undertaken during the project:

The project will involve the use of the following techniques (although not limited to these) for the purpose of:

  • particle/emulsion production: high pressure homogenisation (HPH), microfluidisation, high shear mixing, ultrasonic processing, membrane emulsification;
  • particle/emulsion characterisation: Laser diffraction, differential scanning calorimetry (DSC), rheological and interfacial measurement techniques, light and confocal microscopy; and
  • co-release performance: Dissolution testing for in vitro release measurements and high-performance liquid chromatography (HPLC) and ultraviolet-visible (UV-VIS) absorbance measurements for the determination of the concentration of released actives.
Contact: Dr Fotis Spyropoulos, University of Birmingham