Inhaled anti-tubercular therapy: Dry powder formulations, device and toxicity challenges

The thesis is comprised of a series of studies that characterise the potential of inhaled therapy for treatment of TB using rifapentine as a model. Novel inhalable dry powder formulations containing efflux pump inhibitors (verapamil or thioridazine) and rifapentine were successfully formulated. These powders demonstrated excellent aerosol performance and enhanced in vitro activity against intracellular growth of M. tuberculosis compared to single drug treatments. Alternatively, rifapentine-PLGA particles regardless of monomer and molecular weight showed good aerosol performance and higher affinity for macrophage uptake. In the following study, a modified Aerolizer® as a low-cost generic device demonstrated promising results for delivery of rifapentine up to a maximum dose of 100 mg in a single capsule. Finally, it was found that intratracheal delivery of rifapentine (20 mg/kg) triggered a transient neutrophil influx in the lungs which resolved by 7 days post-dosing. These findings suggest that the inhaled rifapentine is more suitable for periodic dosing (i.e. weekly) and as an adjunct to the standard oral anti-TB drug regimen

Studies On The Activity Of Isoniazid Derivatives And Their Combinations With Other Anti-TB Drugs On Mycobacterium Tuberculosis

The low permeability of the cell envelope against hydrophilic anti-tuberculosis (TB) drugs especially isoniazid (INH), is one of the crucial factors that contribute to the intrinsic resistance in Mycobacterium tuberculosis. Previous studies have floated the idea that the anti-mycobacterial activity of INH can be enhanced by augmenting the hydrophilic INH into a hydrophobic/lipophilic compound. Therefore, a series of 13 derivatives with different hydrophobicity were synthesized by adding different hydrophobic acyl chain to the parent compound, INH

Fusidic acid/tea-tree oil nanoemulsions : a potentially safe and effective anti MRSA/MSSA topical agent for chronic wound healing

Fusidic acid (FA) is clinically used as an antibacterial agent for the treatment of Gram-positive bacterial infections. It interferes with bacterial protein synthesis, specifically by preventing the translocation of the elongation factor G on the ribosome. In the present work, oil-in-water nanoemulsion (NE) was developed as a carrier for the transdermal delivery of FA. Different oils, surfactants and co-surfactants were screened. The solubility of FA, the emulsifying capacity of the surfactants and phase diagrams for each oil and surfactant mix were constructed. From the analysis, eight stable NE formulations were chosen, and their physicochemical properties were further evaluated. The antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) were also evaluated, and cytotoxicity was conducted on HS-27 cell line to determine the safety of the formula. It was found that the NE produced from tea tree oil has the most optimal stability with promising antibacterial activity against MRSA as compared to a commercially available product. The safety profile of the NE was also comparable to the commercial product; thus, the formulated FA-NE is promising for clinical use

Design, characterization, in vitro antibacterial, antitubercular evaluation and structure–activity relationships of new hydrazinyl thiazolyl coumarin derivatives

Herein, we describe the synthesis of 11new thiazolyl coumarin derivatives and evaluation of their potential role as antibacterial and antituberculosis agents. The structures of the synthesized compounds were established by extensive spectroscopic studies (Fourier transform infrared spectroscopy, 1H-nuclear magnetic resonance, 13C-nuclear magnetic resonance, 2D-nuclear magnetic resonance and liquid chromatography–mass spectrometry) and elemental analysis. All synthesized compounds were assayed for their in vitro antibacterial activity against a few gram positive and gram negative bacteria and antituberculosis activity against Mycobacterium tuberculosis H37Rv ATCC 25618 by using colorimetric microdilution assay method. Nine derivatives showed moderate anti-bacterial and anti-tuberculosis activities against all the tested strains. The highest activity against all the pathogens including Mycobacterium tuberculosis was observed by compound 7c with MIC values ranging between 31.25–62.5 μg/mL, indicating that coumarin skeleton could indeed provide useful scaffold for the development of new anti-microbial drugs

Effect of storage temperature on the stability of spray dried bacteriophage powders

This study aimed to assess the robustness of using a spray drying approach and formulation design in producing inhalable phage powders. Two types of Pseudomonas phages, PEV2 (Podovirus) and PEV40 (Myovirus) in two formulations containing different amounts of trehalose (70% and 60%) and leucine (30% and 40%) were studied. Most of the surface of the produced powders was found to be covered in crystalline leucine. The powders were stored at 4 °C and 20 °C under vacuum. The phage stability and in vitro aerosol performance of the phage powders were examined on the day of production and after 1, 3 and 12 months of storage. A minor titer loss during production was observed for both phages (0.2–0.8 log10 pfu/ml). The storage stability of the produced phage powders was found to be phage and formulation dependent. No further reduction in titer occurred for PEV2 powders stored at 4 °C across the study. The formulation containing 30% leucine maintained the viability of PEV2 at 20 °C, while the formulation containing 40% leucine gradually lost titer over time with a storage reduction of ∼0.9 log10 pfu/ml measured after 12 months. In comparison, the PEV40 phage powders generally had a ∼ 0.5 log10 pfu/ml loss upon storage regardless of temperature. When aerosolized, the total in vitro lung doses of PEV2 were of the order of 107 pfu, except the formulation containing 40% leucine stored at 20 °C which had a lower lung dose. The PEV40 powders also had lung doses of 106–107 pfu. The results demonstrate that spray dried Myoviridae and Podoviridae phage in a simple formulation of leucine and trehalose can be successfully stored for one year at 4 °C and 20 °C with vacuum packaging.The University of Sydney; Australian Research Council; National Institute of Allergy and Infectious Diseases of the National Institutes of Health; National Health and Medical Research Council Centre of Research Excellence in Tuberculosis Contro

<em>Eurycoma longifolia</em>: an overview on the pharmacological properties for the treatment of common cancer

Eurycoma longifolia plant, the so called Tongkat Ali in Malaysia, is a well grown prominent tree in all Southeast Asia. It is well known among traditional medicine practitioners as a curative plant for many diseases and health conditions. The major quassinoid from the plant is eurycomanone, which exhibits many prominent effects on various cancer cell lines. Numerous studies have shown that eurycomanone inhibits cancerous cell growth and encourages cell death both in vitro and in vivo test. Even though analyses of safety and toxicity have been conducted, there is still a substantial knowledge barrier when it comes to providing a scientific foundation for the molecular mechanism as well as intervention strategy in the living people cancer cell. In a way to offer adequate baseline data for future investigations based on molecular mechanism and intervention, the present work seeks to review the researches conducted to date on this herbal plant

Andrographis paniculata Dosage Forms and Advances in Nanoparticulate Delivery Systems: An Overview

Andrographis paniculata is a well-known Asian medicinal plant with a major phytoconstituent of diterpene lactones, such as andrographolide, 14-deoxyandrographolide, and neoandrographolide. A World Health Organization (WHO) monograph on selected medicinal plants showed that A. paniculata extracts and its major diterpene lactones have promising anti-inflammatory, antidiabetic, antimalarial, anticancer, antifungal, antibacterial, antioxidant, and hypoglycemic activities. However, these active phytochemicals have poor water solubility and bioavailability when delivered in a conventional dosage form. These biological barriers can be mitigated if the extract or isolated compound are delivered as nanoparticles. This review discusses existing studies and marketed products of A. paniculata in solid, liquid, semi-solid, and gaseous dosage forms, either as an extract or isolated pure compounds, as well as their deficits in reaching maximum bioavailability. The pharmaceutics and pharmacological activity of A. paniculata as a nano-delivery system are also discussed

Biomedical Applications of Polyhydroxyalkanoate in Tissue Engineering

Tissue engineering technology aids in the regeneration of new tissue to replace damaged or wounded tissue. Three-dimensional biodegradable and porous scaffolds are often utilized in this area to mimic the structure and function of the extracellular matrix. Scaffold material and design are significant areas of biomaterial research and the most favorable material for seeding of in vitro and in vivo cells. Polyhydroxyalkanoates (PHAs) are biopolyesters (thermoplastic) that are appropriate for this application due to their biodegradability, thermo-processability, enhanced biocompatibility, mechanical properties, non-toxicity, and environmental origin. Additionally, they offer enormous potential for modification through biological, chemical and physical alteration, including blending with various other materials. PHAs are produced by bacterial fermentation under nutrient-limiting circumstances and have been reported to offer new perspectives for devices in biological applications. The present review discusses PHAs in the applications of conventional medical devices, especially for soft tissue (sutures, wound dressings, cardiac patches and blood vessels) and hard tissue (bone and cartilage scaffolds) regeneration applications. The paper also addresses a recent advance highlighting the usage of PHAs in implantable devices, such as heart valves, stents, nerve guidance conduits and nanoparticles, including drug delivery. This review summarizes the in vivo and in vitro biodegradability of PHAs and conducts an overview of current scientific research and achievements in the development of PHAs in the biomedical sector. In the future, PHAs may replace synthetic plastics as the material of choice for medical researchers and practitioners

Proof of concept : the effectiveness of disinfectant tunnel as potential measure against COVID-19

Disinfectant tunnels have attracted attention as a potential measure to prevent the spread of COVID-19, but their safety and effectiveness are questionable. Disinfectants such as sodium hypochlorite were used, yet no scientific evidence is available on its effectiveness to eliminate SARS-CoV-2 on the human body through spraying, although this chemical is effective in the elimination of the virus on inanimate surfaces. Since safety issues are of importance, countries have halted the operation of these tunnels. Available literature has suggested several effective disinfectants against SARS-CoV-2, including iodine-based solution, such as povidone-iodine (PVP-I). This report describes the evaluation of the bactericidal activity of PVP-I in comparison to sodium hypochlorite, both in vitro and following spraying under a model tunnel. Two bacteria strains (Pseudomonas aeruginosa ATCC 27853 and Staphylococcus aureus ATCC 12600) were used as model microorganisms. The spraying pattern and droplets distribution from the tunnel are also being described and were correlated with the effectiveness of the disinfectant droplets to eliminate the model bacteria. Results showed that 0.5 % v/v PVP-I and 0.5% v/v sodium hypochlorite are bactericidal (> 5 log10 reduction) in vitro. However, sprayed disinfectants did not show similar activity. Bacterial growth was seen in all cloth samples for 0.5% v/v PVP-I and all cloth samples except right shoulder for 0.5 % v/v sodium hypochlorite. Hence, the design of any disinfectant tunnel is important, and with an effective disinfectant to justify its efficacy

Advances in Polyhydroxyalkanoate Nanocarriers for Effective Drug Delivery: An Overview and Challenges

Polyhydroxyalkanoates (PHAs) are natural polymers produced under specific conditions by certain organisms, primarily bacteria, as a source of energy. These up-and-coming bioplastics are an undeniable asset in enhancing the effectiveness of drug delivery systems, which demand characteristics like non-immunogenicity, a sustained and controlled drug release, targeted delivery, as well as a high drug loading capacity. Given their biocompatibility, biodegradability, modifiability, and compatibility with hydrophobic drugs, PHAs often provide a superior alternative to free drug therapy or treatments using other polymeric nanocarriers. The many formulation methods of existing PHA nanocarriers, such as emulsion solvent evaporation, nanoprecipitation, dialysis, and in situ polymerization, are explained in this review. Due to their flexibility that allows for a vessel tailormade to its intended application, PHA nanocarriers have found their place in diverse therapy options like anticancer and anti-infective treatments, which are among the applications of PHA nanocarriers discussed in this article. Despite their many positive attributes, the advancement of PHA nanocarriers to clinical trials of drug delivery applications has been stunted due to the polymers’ natural hydrophobicity, controversial production materials, and high production costs, among others. These challenges are explored in this review, alongside their existing solutions and alternatives