Physicochemical characterisation of inhalation grade lactose after the removal of intrinsic fines

Lactose is a common excipient in Dry Powder Inhaler (DPI) formulations, used as a carrier for the micronized drug particles. The presence of intrinsic lactose fines in the formulation influences its performance and their role and interactions between the lactose carrier and the micronized drug is still not fully understood. As a first step towards this investigation, “clean” lactose, with removed fines, was produced via wet decantation. Ethanol and isopropyl alcohol have been used in wet decantation, successfully removing lactose fines from the surface of the coarse particles. Differential Scanning Calorimetry (DSC) was employed to show that the powders maintained their crystalline character. Scanning Electron Microscopy (SEM) showed tomahawk-shaped particles in all the powders and some surface alteration occurring after decantation. An airflow titration method using laser diffraction (LDA) allowed the estimation of the removal of fines as well as the particle size distributions, while the non-polar and the polar components of the surface energy of the powders were calculated via Inverse Gas Chromatography-Surface Energy Analysis (iGC-SEA). As both solvents successfully removed fines, we propose the addition of isopropyl alcohol in the list of organic solvents suitable for this purpose.Peer reviewe

Computational and experimental studies on the formation of polymer-drug nanoparticles

Polymer based nanoparticle formulations attract attention as potentially highly tunable drug delivery systems. Interfacial deposition is a well-established technique, based on solvent displacement that is being used to form both polymer nanoparticles, as well as drug loaded polymer nanoparticles. However currently, there is limited understanding of the underlying polymer - nanoparticle assembly mechanisms and this limits our ability to rationally design and optimise them. At the same time, conventional methods for the preparation of polymer-drug nanoparticles suffer from low encapsulation efficiencies and drug loadings, making them undesirable to the pharmaceutical industry. In this thesis, a method used to polymer-coat the surface of iron oxide nanoparticles was translated to produce polymer-coated drug nanoparticles. In order to provide an holistic overview of the system and the underlying phenomena, both computational and experimental methods were used. More particularly, all atom molecular dynamics simulations were employed to study the behaviour of the drug nanoparticles and the polymers during the interfacial deposition method. The system was built as a biphasic model, containing an aqueous-drug loaded-phase and an organic-polymer rich-phase. The model was a miniature in the atomistic level of the expected experimental set-up, keeping the ratios and concentrations as close as possible to pre-existing iron oxide nanoparticle work. On a parallel path, experimental studies were performed. The polymers were synthesised and fully characterised. Then, the formation of drug-free polymer nanoparticles via the method was studied and the properties of these nanoparticles were analysed. Interestingly, when the drug was introduced into the method in the form of drug microparticles suspended in the aqueous region, polymer-coated drug nanoparticles were produced. These nanoparticles were stable, significantly different to the drug-free polymer nanoparticles and were characterised for their size and morphology. Further analysis of the polymer-coated drug nanoparticle suspensions revealed high encapsulation efficiencies and impressive drug loadings. We conclude with some proposed future work on modelling polymer-based drug delivery systems, moving towards a “structure based formulation design” to complement the process of “structure based drug design” which is already very well established in the pharmaceutical industry

Poly (glycerol adipate) (PGA), an enzymatically synthesized functionalizable polyester and versatile drug delivery carrier : A literature update

The enzymatically synthesized poly (glycerol adipate) (PGA) has demonstrated all the desirable key properties required from a performing biomaterial to be considered a versatile "polymeric-tool" in the broad field of drug delivery. The step-growth polymerization pathway catalyzed by lipase generates a highly functionalizable platform while avoiding tedious steps of protection and deprotection. Synthesis requires only minor purification steps and uses cheap and readily available reagents. The final polymeric material is biodegradable, biocompatible and intrinsically amphiphilic, with a good propensity to self-assemble into nanoparticles (NPs). The free hydroxyl group lends itself to a variety of chemical derivatizations via simple reaction pathways which alter its physico-chemical properties with a possibility to generate an endless number of possible active macromolecules. The present work aims to summarize the available literature about PGA synthesis, architecture alterations, chemical modifications and its application in drug and gene delivery as a versatile carrier. Following on from this, the evolution of the concept of enzymatically-degradable PGA-drug conjugation has been explored, reporting recent examples in the literature.Peer reviewedFinal Published versio

Optimising poly(lactic-co-glycolic acid) microparticle fabrication using a Taguchi orthogonal array design-of-experiment approach

© 2019 Mensah et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The objective of this study was to identify, understand and generate a Taguchi orthogonal array model for the formation of 10–50 μm microparticles with applications in topical/ocular controlled drug delivery. Poly(lactic-co-glycolic acid) (PLGA) microparticles were fabricated by the single emulsion oil-in-water method and the particle size was characterized using laser diffraction and scanning electronic microscopy (SEM). Sequential Taguchi L 12 and L 18 orthogonal array (OA) designs were employed to study the influence of ten and eight parameters, respectively, on microparticle size (response). The first optimization step using the L 12 design showed that all parameters significantly influenced the particle size of the prepared PLGA microparticles with exception of the concentration of poly(vinyl alcohol) (PVA) in the hardening bath. The smallest mean particle size obtained from the L 12 design was 54.39 μm. A subsequent L 18 design showed that the molecular weight of PLGA does not significantly affect the particle size. An experimental run comprising of defined parameters including molecular weight of PLGA (89 kDa), concentration of PLGA (20% w/v), concentration of PVA in the emulsion (0.8% w/v), solvent type (ethyl acetate), organic/aqeuous phase ratio (1:1 v/v), vortexing speed (9), vortexing duration (60 seconds), concentration of PVA in hardening bath (0.8% w/v), stirring speed of hardening bath (1200 rpm) and solvent evaporation duration (24 hours) resulted in the lowest mean particle size of 23.51 μm which was predicted and confirmed by the L 18 array. A comparable size was demonstrated during the fabrication of BSA-incorporated microparticles. Taguchi OA design proved to be a valuable tool in determining the combination of process parameters that can provide the optimal condition for microparticle formulation. Taguchi OA design can be used to correctly predict the size of microparticles fabricated by the single emulsion process and can therefore, ultimately, save time and costs during the manufacturing process of drug delivery formulations by minimising experimental runs.Peer reviewedFinal Published versio

Poly(triazolyl methacrylate) glycopolymers as potential targeted unimolecular nanocarriers

© The Royal Society of Chemistry 2019.Synthetic glycopolymers are increasingly investigated as multivalent ligands for a range of biological and biomedical applications. This study indicates that glycopolymers with a fine-tuned balance between hydrophilic sugar pendant units and relatively hydrophobic polymer backbones can act as single-chain targeted nanocarriers for low molecular weight hydrophobic molecules. Non-covalent complexes formed from poly(triazolyl methacrylate) glycopolymers and low molecular weight hydrophobic guest molecules were characterised through a range of analytical techniques-DLS, SLS, TDA, fluorescence spectroscopy, surface tension analysis-and molecular dynamics (MD) modelling simulations provided further information on the macromolecular characteristics of these single chain complexes. Finally, we show that these nanocarriers can be utilised to deliver a hydrophobic guest molecule, Nile red, to both soluble and surface-immobilised concanavalin A (Con A) and peanut agglutinin (PNA) model lectins with high specificity, showing the potential of non-covalent complexation with specific glycopolymers in targeted guest-molecule delivery.Peer reviewedFinal Published versio

High‐Throughput Miniaturized Screening of Nanoparticle Formation via Inkjet Printing

This is the peer reviewed version of the following article:Ioanna D. Styliari, et al, ‘High‐Throughput Miniaturized Screening of Nanoparticle Formation via Inkjet Printing’, Macromolecular Materials and Engineering, (2018), which has been published in final form at https://doi.org/10.1002/mame.201800146. Under embargo until 27 May 2019. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.The self‐assembly of specific polymers into well‐defined nanoparticles (NPs) is of great interest to the pharmaceutical industry as the resultant materials can act as drug delivery vehicles. In this work, a high‐throughput method to screen the ability of polymers to self‐assemble into NPs using a picoliter inkjet printer is presented. By dispensing polymer solutions in dimethyl sulfoxide (DMSO) from the printer into the wells of a 96‐well plate, containing water as an antisolvent, 50 suspensions are screened for nanoparticle formation rapidly using only nanoliters to microliters. A variety of polymer classes are used and in situ characterization of the submicroliter nanosuspensions shows that the particle size distributions match those of nanoparticles made from bulk suspensions. Dispensing organic polymer solutions into well plates via the printer is thus shown to be a reproducible and fast method for screening nanoparticle formation which uses two to three orders of magnitude less material than conventional techniques. Finally, a pilot study for a high‐throughput pipeline of nanoparticle production, physical property characterization, and cytocompatibility demonstrates the feasibility of the printing approach for screening of nanodrug delivery formulations. Nanoparticles are produced in the well plates, characterized for size and evaluated for effects on metabolic activity of lung cancer cells.Peer reviewe

Computational and experimental studies on the formation of polymer-drug nanoparticles

Polymer based nanoparticle formulations attract attention as potentially highly tunable drug delivery systems. Interfacial deposition is a well-established technique, based on solvent displacement that is being used to form both polymer nanoparticles, as well as drug loaded polymer nanoparticles. However currently, there is limited understanding of the underlying polymer - nanoparticle assembly mechanisms and this limits our ability to rationally design and optimise them. At the same time, conventional methods for the preparation of polymer-drug nanoparticles suffer from low encapsulation efficiencies and drug loadings, making them undesirable to the pharmaceutical industry. In this thesis, a method used to polymer-coat the surface of iron oxide nanoparticles was translated to produce polymer-coated drug nanoparticles. In order to provide an holistic overview of the system and the underlying phenomena, both computational and experimental methods were used. More particularly, all atom molecular dynamics simulations were employed to study the behaviour of the drug nanoparticles and the polymers during the interfacial deposition method. The system was built as a biphasic model, containing an aqueous-drug loaded-phase and an organic-polymer rich-phase. The model was a miniature in the atomistic level of the expected experimental set-up, keeping the ratios and concentrations as close as possible to pre-existing iron oxide nanoparticle work. On a parallel path, experimental studies were performed. The polymers were synthesised and fully characterised. Then, the formation of drug-free polymer nanoparticles via the method was studied and the properties of these nanoparticles were analysed. Interestingly, when the drug was introduced into the method in the form of drug microparticles suspended in the aqueous region, polymer-coated drug nanoparticles were produced. These nanoparticles were stable, significantly different to the drug-free polymer nanoparticles and were characterised for their size and morphology. Further analysis of the polymer-coated drug nanoparticle suspensions revealed high encapsulation efficiencies and impressive drug loadings. We conclude with some proposed future work on modelling polymer-based drug delivery systems, moving towards a “structure based formulation design” to complement the process of “structure based drug design” which is already very well established in the pharmaceutical industry

Nanoformulation-by-design: an experimental and molecular dynamics study for polymer coated drug nanoparticles

© The Royal Society of Chemistry 2020. This article is licensed under a Creative Commons Attribution 3.0 Unported Licence (https://creativecommons.org/licenses/by/3.0/).The formulation of drug compounds into nanoparticles has many potential advantages in enhancing bioavailability and improving therapeutic efficacy. However, few drug molecules will assemble into stable, well-defined nanoparticulate structures. Amphiphilic polymer coatings are able to stabilise nanoparticles, imparting defined surface properties for many possible drug delivery applications. In the present article we explore, both experimentally and in silico, a potential methodology to coat drug nanoparticles with an amphiphilic co-polymer. Monomethoxy polyethylene glycol–polycaprolactone (mPEG-b-PCL) diblock copolymers with different mPEG lengths (Mw 350, 550, 750 and 2000), designed to give different levels of colloidal stability, were used to coat the surface of indomethacin nanoparticles. Polymer coating was achieved by a flow nanoprecipitation method that demonstrated excellent batch-to-batch reproducibility and resulted in nanoparticles with high drug loadings (up to 78%). At the same time, in order to understand this modified nanoprecipitation method at an atomistic level, large-scale all-atom molecular dynamics simulations were performed in parallel using the GROMOS53a6 forcefield parameters. It was observed that the mPEG-b-PCL chains act synergistically with the acetone molecules to dissolve the indomethacin nanoparticle while after the removal of the acetone molecules (mimicking the evaporation of the organic solvent) a polymer–drug nanoparticle was formed (yield 99%). This work could facilitate the development of more efficient methodologies for producing nanoparticles of hydrophobic drugs coated with amphiphilic polymers. The atomistic insight from the MD simulations in tandem with the data from the drug encapsulation experiments thus leads the way to a nanoformulation-by-design approach for therapeutic nanoparticles.Peer reviewedFinal Published versio

Inhalation Blend Microstructure:Identifying Metrics to Address Q3 Equivalence using Semi-automated X-Ray Microscopy

Assessing the microstructure of inhalation powder blends is important for assessment of Q3 microstructural equivalence, but it remains a challenge to examine a powder in its pre-actuated state. In this work, we demonstrate a robust, user-independent image analysis workflow for using X-ray Computed Tomography (XCT), allowing the fines-rich phase of different blend formulations to be visualized and quantified. The workflow provides qualitative and quantitative information on formulation microstructure. Qualitatively, differences in XCT-characterized microstructure were consistent with differences in aerosolization behavior of carrier lactose blends with micronized lactose, terbutaline sulfate and fluticasone propionate. Quantitatively, metrics for the local thickness of fines-rich phases were derived that quantify the thicker coating of fluticasone propionate fines around carrier lactose particles in a blend, compared to terbutaline sulfate or micronized lactose, which formed agglomerated regions of fines of lower density and a heterogeneous degree of association with carrier lactose particles. This approach links pre-actuated microstructure of inhalation powder blends with product performance and provides the first steps to the application of XCT to a range of dry powder inhalation products