Evaluation of lipid liquid crystalline phase particles as drug delivery vectors

Xerri, Rachael (2021) Evaluation of lipid liquid crystalline phase particles as drug delivery vectors. PhD thesis, University of Nottingham.

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Abstract

Lipids, of the glyceride sub-species, are amphiphilic molecules that will self-assemble in aqueous conditions. Based on the lipid’s critical packing parameter (CPP), i.e., the ratio between the lipid tail length, tail volume and the lipid head area, the lipids may self-assemble into different liquid crystalline phases, such as lamellar or cubic phases. Such phases may then be stabilised into discrete nanoparticles in an aqueous suspension through the utilisation of a polymer, namely here poloxamers. These stabilised liquid crystalline particles have many of the advantages of liposomes (one of the most used lipid nanoparticle formulations) such as biocompatibility and the ability to encapsulate both hydrophobic and hydrophilic moieties. Liquid crystalline phases additionally offer an improved stability of the formulation’s physicochemical properties and API stability during storage and in vivo compared to other lipid nanoparticle formulations; increasing the shelf-life of formulations and offering a wide variety of formulation administration strategies i.e. intravenous, intramuscular, oral. The primary types of liquid crystalline phases found within the literature, particularly for pharmaceutical applications, are cubosomes and hexasomes, formed from cubic phases and hexagonal phases respectively.

Explored here is the ability of liquid crystalline phase nanoparticles to encapsulate various active pharmaceutical ingredients (APIs) for drug delivery applications. Initial studies focused on the development of a robust formulation, examining both on the utilisation of the biocompatible lipid glycerol monooleate, and the commonly used poloxamer polymer. The development of a novel particle fabrication protocol, based on controlled mixing of the formulation’s constituent components, that could forego the use of high energy techniques, or the utilisation of a solvent was undertaken and achieved. Upon the establishment of this base formulation (utilising glycerol monooleate (CithrolTM) and poloxamer 407 (SynperonicTM F127) in a water suspension) the focus moved towards the encapsulation of a range of active pharmaceutical ingredients (including Amitriptyline, Imipramine, Progesterone, Hydrocortisone, Budesonide and Propofol).

15 different APIs were encapsulated into the base formulation. These new formulations were then evaluated by high performance liquid chromatography for their encapsulation efficiency (EE); this varied greatly, with the highest EE being observed for Amitriptyline where an EE of 96.4% was achieved. Pearson regressing analysis of API loading showed an increased loading could be achieved with a lower API molecular weight, polar surface area and a lower number of hydrogen bonding capabilities. API release was also evaluated, in these studies it was found that liquid crystalline phases exhibit a staggered release of APIs. No significant trend could be identified between APIs and their rate of release, however a potential link between API release and the API’s logD has been found during comparison of API release profiles.

Final investigations explored the impact of API loading upon the liquid crystalline phase as early studies revealed a confirmation shift in the liquid crystalline phase to phases existing with a lesser curvature upon the incorporation of an API, as displayed by a shift from an inverse hexagonal phase to an inverse cubic phase, as observed by small angle x-ray scattering and cryo-transmission electron microscopy. The degree of API loading altered the packing, it was found that with an increased concentration of API within the system a greater change in the critical packing parameter was observable. However, this degree of change was also dependent upon the physicochemical properties of the API. Analysis was performed comparing the different physicochemical properties of APIs and how this effected the packing of components within the formulation. Here it was found that an APIs LogS, polar surface area and API loading had significant influence upon the liquid crystalline phase structuring. The liquid crystalline structure and changes within it can be analysed with cryo-transmission electron microscopy, with allows the visualisation on the nano-scale of a particle’s morphology, structuring, and size; or, by small angle x-ray scattering which allows in-depth characterisation of the lipid phase behaviour.

Item Type: Thesis (University of Nottingham only) (PhD)
Supervisors: Stolnik, S
Zelzer, M
Mantovani, G
Smith, P. A.
Humphrey, J
Hubbard, A
Mellor, S
Keywords: lipids, drug delivery, liquid crystalline particles, nanoparticles
Subjects: R Medicine > RS Pharmacy and materia medica
Faculties/Schools: UK Campuses > Faculty of Science > School of Pharmacy
Item ID: 67177
Depositing User: Smith, Rachael
Date Deposited: 08 Dec 2021 04:41
Last Modified: 08 Dec 2021 04:41
URI: http://eprints.nottingham.ac.uk/id/eprint/67177

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