Fabrication of personalised medicines using additive printing technologies

Personalised medicines, tailored to the specific needs of each patient, have emerged as a potential solution for improving therapeutic outcomes. This thesis explores two additive printing technologies using model drugs and polymers stated blow to fabricate drug delivery systems with the potential of personalisation. Additionally, characterisation of the printing parameters of each printing system was performed to understand their influence on the printing volume. The microdispensing technology was used to fabricate personalised orodispersible films by on-demand printing of viscous ink containing paracetamol-hydroxypropyl methylcellulose onto a releasing substrate. Orodispersible films with personalised dosage were fabricated by changing the printing areas, which showed a linear relationship with the drug loading. The tensile strength of the printed film was comparable to that of the cast film and showed good handling propertied compared to the marketed product. The nanoelectrospray (nES) technology was another printing method explored, which enables on-demand and layer-by-layer coating to deposit drug-loaded coatings on contact lenses. Zein, the model polymer, was used to characterise the spraying parameters of the custom-build nES system. This work showed that the contact lenses maintained an excellent vision zone after the nES coating process, and the spray volume was predictable using established scaling laws. Polylactic-co-glycolic acid and three model drugs, ketotifen fumarate, bimatoprost and latanoprost, were coated in the peripheral region on commercially available contact lenses to assess the in vitro drug release and the influence of steam sterilisation to the coating. The drug loading of ketotifen fumarate and bimatoprost, was independent of in vitro drug release. Steam sterilisation was used to sterile the nES-coated contact lenses, and results showed that the method significantly damaged the drug-polymer coating. Gamma rays could be used as an alternative to minimize the damage to the drug-polymer coating

Stability of clay particle-coated microbubbles in alkanes against dissolution induced by heating

We investigated the dissolution and morphological dynamics of air bubbles in alkanes stabilized by fluorinated colloidal clay particles when subjected to temperature changes. A quasi-steady model for bubble dissolution with time-dependent temperature reveals that increasing the temperature enhances the bubble dissolution rate in alkanes, opposite to the behavior in water, due to the differing trends in gas solubility. Experimental results for uncoated air bubbles in decane and hexadecane confirm this prediction. Clay-coated bubbles in decane and hexadecane are shown to be stable in air-saturated oil at constant temperature, where dissolution is driven mainly by the Laplace pressure. When the temperature increases from ambient, the particle-coated bubbles are prone to dissolution as the oil phase becomes under-saturated. The interfacial layer of particles is observed to undergo buckling and crumpling, without shedding of clay particles. Increasing the concentration of particles is shown to enhance the bubble stability by providing a higher resistance to dissolution and buckling. When subjected to complex temperature cycles, the clay-coated bubbles can remain stable in conditions for which uncoated bubbles dissolve completely. These results underpin the design of ultra-stable oil foams stabilized by solid particles with improved shelf life under changing environmental conditions

Precision coating of ocular devices/contact lenses by nanoelectrospray additive printing

Eye drops are widely used for treating ocular diseases, but with poor bioavailability less than 5%. Drug-eluting contact lenses (DECLs) have been proven to improve the efficacy of treatment. For the manufacturing of DECLs, no method can directly deposit drug formulation on commercial lenses. In this work, a novel additive manufacturing approach, nanoelectrospray (nES), and a custom-built nES printing system was developed to directly deposit drug formulations on the surfaces of commercial contact lenses. As a demonstration, nES was used to coat the model biopolymer, zein, onto commercial lenses. Precise deposition of a ring-shaped polymer layer only on the peripheral region was achieved. For printing optimisation, the spraying width is primarily controlled by the nozzle substrate distance. The coating thickness, which can be used to directly control the drug dose, is subject to the polymer concentration in the formulation, dosing speed and the number of rotations. By using the spray current transient and established scaling law, the predicted spray volume is highly correlated to the experimental results. This study built a firm technological foundation for using nES as a novel additive manufacturing method to produce DECLs with drug coating at the surfaces of contact lenses in pre-defined patterns and locations

Does export dependence imply more political support in Sino-Africa relation since 2000?

published_or_final_versionInternational and Public AffairsMasterMaster of International and Public Affair

Suppression of the coffee-ring effect by tailoring the viscosity of pharmaceutical sessile drops

The coffee ring effect (CRE) lies at the heart of droplet-based processing techniques where the drying process of the solute-laden droplet leads to the undesirable formation of a ring-like pattern with uneven distribution of the solidified solute. Although the CRE has been well studied, the practical strategies reported in the literature to prevent CRE are still limited. In this study, we aimed to develop a simple practical solution to minimise CRE by adding polymeric excipients to pharmaceutical solutions containing active pharmaceutical ingredients. We investigated the influence of viscosity on multicomponent sessile droplets containing a polymer (chitosan) and a model drug (paracetamol). When dried on glass, a sessile droplet of an aqueous paracetamol solution was shown to recrystallise into an undesired coffee-ring pattern of drug crystals, due to CRE. This peripheral deposition of crystalline solute was suppressed when the formulation was thickened with chitosan. Increasing the viscosity of the solution prevented the CRE by immobilising solute within the droplet, preventing the radial flow of the solute to the edge of the droplet. This study enriches the mechanistic understanding of a simple practical solution to the suppression of CRE which can have wide applications in many industrial sectors including pharmaceutical

Selectively coated contact lenses by nanoelectrospray (nES) to fabricate drug-eluting contact lenses for treating ocular diseases

Drug-eluting contact lenses (DECLs) incorporated with poly(lactic-co-glycolic acid) (PLGA) and various model drugs (ketotifen fumarate, bimatoprost and latanoprost) were fabricated by using nanoelectrospray (nES) approach. The resulting DECLs demonstrated outstanding optical transmittance within the optical zone, indicating that the employed coating procedure did not compromise visual acuity under the prescribed spraying parameters. In vitro drug release assessments of the model drugs (ketotifen fumarate (KF), bimatoprost (BIM), and latanoprost (LN)) revealed a strong correlation between the model drug's hydrophobicity and the duration of drug release. Changing the drug loading of the more hydrophilic model drugs, BIM and KF, showed no impact on the drug release kinetics of BIM and KF loaded DECLs, whereas for the hydrophobic model drug, LN, the highest LN loading led to the most extended drug release. The conventional steam sterilisation method was found to damage the PLGA coating on the DECLs fabricated by nES. An alternative sterilisation strategy, such as radiation sterilisation may need to be investigated in the future study to minimise potential harm to the coating

Synthesis of calboxamide-containing tranylcypromine analogues as LSD1 (KDM1A) inhibitors targeting acute myeloid Leukemia

Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub-micromolar IC 50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics

Synthesis of Carboxamide-Containing Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors Targeting Acute Myeloid Leukemia

Lysine-specific demethylase 1 (LSD1/KDM1A) oxidatively removes methyl groups from histone proteins, and its aberrant activity has been correlated with cancers including acute myeloid leukemia (AML). We report a novel series of tranylcypromine analogues with a carboxamide at the 4-position of the aryl ring. These compounds, such as 5 a and 5 b with benzyl and phenethylamide substituents, respectively, had potent sub-micromolar IC50 values for the inhibition of LSD1 as well as cell proliferation in a panel of AML cell lines. The dose-dependent increase in cellular expression levels of H3K4me2, CD86, CD11b and CD14 supported a mechanism involving LSD1 inhibition. The tert-butyl and ethyl carbamate derivatives of these tranylcypromines, although inactive in LSD1 inhibition, were of similar potency in cell-based assays with a more rapid onset of action. This suggests that carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics

The socioeconomic burden of SLE.

Systemic lupus erythematosus (SLE) is a chronic, relapsing-remitting, multisystemic autoimmune inflammatory disorder that predominantly affects women of childbearing age. Much has been written about the clinical course and long-term damage associated with SLE, as well as the reduced life expectancy of patients with this condition. In addition, studies have emphasized the socioeconomic and psychosocial impact of SLE, although the monetary cost of caring for patients with the disorder has only been evaluated in a modest number of studies and a restricted number of countries. SLE has a negative impact on quality of life and is associated with high health-care costs and significant productivity loss. Factors associated with increased cost of SLE include long disease duration, high disease activity and damage, poor physical and mental health, and high education and employment levels. Similarly, high disease activity and damage, poor physical health, certain disease manifestations, as well as poor family and social support are associated with poor health-related quality of life outcomes. SLE incurs a great burden on both the patient and society. Long-term prospective studies should be encouraged to monitor the costs and psychosocial impact of this condition, and to better understand the factors that are associated with poor outcomes.postprin

Meta-analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases