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

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

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Drop-on-demand printing of personalised orodispersible films fabricated by precision micro-dispensing

Personalised orodispersible films (ODFs) manufactured at the point of care offer the possibility of adapting the dosing requirements for individual patients. Inkjet printing was extensively explored as a tool to produce personalised ODFs, but it is extensively limited to dispensing liquid with low viscosity and the interaction between ink and edible substrate complicates the fabrication process. In this study, we evaluated the feasibility of using a micro-dispensing (MD) jet system capable of accurately dispensing viscous liquid to fabricate substrate-free ODFs on-demand. The model inks containing hydroxypropyl methylcellulose (HPMC) and paracetamol were used to prepare personalised ODFs by expanding the film area. Cast films were used as the control sample to benchmark the mechanical properties, disintegration time, and dosing accuracy of MD printed ODFs. Both the cast and printed films showed smooth surface morphology without any bubbles. No significant difference was found in the disintegration time of the MD printed films compared to the cast films. High precision in dosing by MD printing was achieved. The dose of paracetamol had a linear correlation with the dimension of the printed films (R 2 = 0.995). The results provide clear evidence of the potential of MD printing to fabricate ODFs and the knowledge foundation of advancing MD printing to a point-of-care small-batch manufacturing technology of personalised ODFs

Synthesis of Carboxamides Tranylcypromine Analogues as LSD1 (KDM1A) Inhibitors for AML

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 5a and 5b, had potent submicromolar 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 t-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 carbamates can act as metabolically labile tranylcypromine prodrugs with superior pharmacokinetics.</p