Philip Chi Lip Kwok

The University of Sydney · Faculty of Pharmacy

Despite significant research progress in substantiating the therapeutic merits of nanomedicines and the emergence of sophisticated nanotechnologies, the translation of this knowledge into new therapeutic modalities has been sluggish, indicating the need for a more comprehensive understanding of how the unique physicochemical properties of nanoparti...

The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the p...

Introduction: Drugs need to enter the systemic circulation efficiently before they can cross the blood-brain barrier and reach the central nervous system. Although the respiratory tract is not a common route of administration for delivering drugs to the central nervous system, it has attracted increasing interest in recent years for this purpose....

Epithelial surfaces protect exposed tissues in the body against the intrusion of foreign materials, including xenobiotics, pollen and microbiota. The relative permeability of the various epithelia reflects their extent of exposure to the external environment and is in the ranking: intestinal≈ nasal ≥ bronchial ≥ tracheal > vaginal ≥ rectal > blood-...

Infections caused by multidrug-resistant (MDR) bacteria have highlighted the importance of the development of new antimicrobial agents. While bacteriophages (phages) are widely studied as alternative agents to antibiotics, combined treatments using phages and antibiotics have exhibited Phage-Antibiotic Synergy (PAS), in which antibiotics promote ph...

Multi-drug-resistant tuberculosis (MDR-TB) is a huge public health problem. The treatment regimen of MDR-TB requires prolonged chemotherapy with multiple drugs including second-line anti-TB agents associated with severe adverse effects. Capreomycin, a polypeptide antibiotic, is the first choice of second-line anti-TB drugs in MDR-TB therapy. It req...

The coronavirus disease 2019 (COVID-19) is an unprecedented pandemic that has severely impacted global public health and the economy. Hydroxychloroquine administered orally to COVID-19 patients was ineffective, but its antiviral and anti-inflammatory actions were observed in vitro. The lack of efficacy in vivo could be due to the inefficiency of th...

In vitro-in vivo correlation is the establishment of a predictive relationship between in vitro and in vivo data. In the context of cascade impactor results of orally inhaled pharmaceutical aerosols, this involves the linking of parameters such as the emitted dose, fine particle dose, fine particle fraction, and mass median aerodynamic diameter to...

Spray drying is a rapid method for converting a liquid feed into dried particles for inhalation aerosols. Lactose is a major inhalation excipient used in spray-dried (SD) formulations. However, SD powders produced from solutions are usually amorphous hence unstable to moisture. This problem can potentially be minimized by spray drying a suspension...

Inhaled drugs are routinely used for the treatment of respiratory-supported patients. To date, pressurized metered dose inhalers and nebulizers are the two platforms routinely employed in the clinical setting. The scarce utilization of the dry powder inhaler (DPI) platform is partly due to the lack of in vivo data that proves optimal delivery and d...

Particles and droplets produced from pharmaceutical inhaler devices are naturally charged. Previous in silico and in vitro studies have shown that the levels of these electrostatic charges may potentially affect deposition in the airways but this has not been confirmed in vivo. Human lung scintigraphic studies using radiolabelled particles with con...

Pulmonary route is the main route of drug delivery for patients with asthma and chronic obstructive pulmonary diseases, offering several advantages over the oral route. Determining the amount of drug deposited onto various parts of the respiratory tract allows for a good correlation to clinical efficacy of inhalation drug devices. However, current...

Lactose is widely used as an approved excipient for dry powder inhaler (DPI) products. Spray drying technique is a rapid method for converting a liquid feed into inhalable dried particles. However, spray-dried (SD) lactose powders produced from solutions are mostly amorphous and particularly unstable when exposed to moisture. In the present study,...

Background: Hydroxychloroquine (HCQ) is one of the repurposed drugs proposed for the treatment of coronavirus disease 2019 (COVID-19). However, all the published clinical trials involve oral administration of the drug, although the disease is primarily a respiratory one. Direct inhaled delivery could reduce the side effects associated with oral use...

Cough is an adverse effect that may hinder the delivery of drugs into the lungs. Chemical or mechanical stimulants activate the transient receptor potential in some airway afferent nerves (C or A fibres) to trigger cough. Types of inhaler device and drug, dose, excipients, formulation characteristics including pH, tonicity, aerosol output and parti...

Spray freeze drying is a particle engineering technique that allows the production of porous particles of low density with excellent aerosol performance for inhalation. There are a number of operating parameters that can be manipulated in order to optimise the powder properties. In this study, a two-fluid nozzle was used to prepare spray freeze dri...

Recent heightened interest in inhaled bacteriophage (phage) therapy for combating antibacterial resistance in pulmonary infections has led to the development of phage powder formulations. Although phages have been successfully bioengineered into inhalable powders with preserved bioactivity, the stabilization mechanism is yet unknown. This paper rep...

A volume-based Monte Carlo simulation describing the distribution of polydisperse particles aerosolized in polydisperse droplets was developed. The algorithm addressed some major limitations found in previous models, particularly when the assumptions of the Poisson distribution, a parametric distribution frequently employed to describe the distribu...

Conventional nebulisation has the disadvantages of low aerosol output rate and potential damage to macromolecules due to high shear (jet nebulisation) or cavitation (ultrasonic nebulisation). HYDRA (HYbriD Resonant Acoustics) technology has been shown to overcome these problems by using a hybrid combination of surface and bulk sound waves to genera...

While nanoparticulate drugs for deep lung delivery hold promise for particular disease treatments, their size-related physical instability and tendency of being exhaled during breathing remain major challenges to their inhaled formulation development. Here we report a viable method for converting drug nanosuspensions into inhalable, stable and redi...

The development of small interfering RNA (siRNA) formulation for pulmonary delivery is a key to the clinical translation of siRNA therapeutics for the treatment of respiratory diseases. Most inhalable siRNA powder formulations published to date were limited by the siRNA content which was often too low to be clinically relevant. This study aimed to...

The manufacture of dry powders for pulmonary drug delivery is complicated by stringent requirements for the aerodynamic size distribution and solid-state properties of the powder. Micronization is often needed after conventional batch crystallization to reduce the particle size, which lowers the process yield and may lead to particles with poor aer...

Cocrystallization represents an emerging approach to tackle the issues associated with pharmaceutical product performance and processing, owing to its capability of modifying a variety of physicochemical properties. In this study, we sought to modify the crystal form of itraconazole (ITZ) with suberic acid (SUB) via rapid solvent removal methods, n...

Antibiotic resistance in pathogenic bacteria has emerged as a big challenge to human and animal health and significant economy loss worldwide. Development of novel strategies to tackle antibiotic resistance is of the utmost priority. In this study, we combined glutathione (GSH), a master antioxidant in all mammalian cells, and nitric oxide, a prove...

Systemic administration of antifungal agents for the treatment of pulmonary aspergillosis is limited by the poor lung deposition and severe adverse effects. In contrast, pulmonary delivery allows a higher amount of drug to be delivered directly to the infection site and therefore a lower dose is required. This study aimed to develop porous and inha...

Deposition of aerosols in the respiratory tract can be quantitatively and qualitatively studied by scintigraphy. The most commonly used radionuclide for this purpose is technetium-99m. The effects of various factors on particle deposition have been investigated by using radiolabeled aerosols in the past decade. Most of these studies were in vivo bu...

Spray freeze drying is an attractive technology to produce powder formulation for inhalation. It can be used to generate large porous particles which tend to aerosolize efficiently and do not aggregate readily. It also avoids material to be exposed to elevated temperature. In this study, we reported the use of two-fluid nozzle to produce spray free...

This review discusses recent developments in the manufacture of inhalable dry powder formulations. Pulmonary drugs have distinct advantages compared with other drug administration routes. However, requirements of drugs properties complicate the manufacture. Control over crystallization to make particles with the desired properties in a single step...

The therapeutic potential of small nucleic acids such as small interfering RNA (siRNA) to treat lung diseases has been successfully demonstrated in many in vivo studies. A major barrier to their clinical application is the lack of a safe and efficient inhaled formulation. In this study, spray freeze drying was employed to prepare dry powder of smal...

Pulmonary delivery of short interfering RNA (siRNA) has been widely studied in both animal and clinical studies to treat various respiratory diseases by gene silencing through RNA interference. Some of these studies showed that the administration of naked siRNA (without the use of any delivery vectors) could achieve satisfactory gene silencing effe...

Aerosols emitted from metered dose inhalers (MDIs) are generally electrically charged and bipolar in nature. While a spacer can effectively dampen the charge magnitude of aerosols, the electrostatic interactions between the positively and negatively charged particles and the spacer have not yet been characterized separately. The Bipolar Charge Anal...

Dexmedetomidine is an alpha 2-adrenoceptor agonist and has been used as a general anesthetic, sedative, and analgesic for about thirty years. The aim of this paper is to review the pharmacokinetics and pharmacodynamics of dexmedetomidine, evaluate physiological factors that may affect the pharmacokinetics of dexmedetomidine, and summarize the pharm...

This study investigated the effect of modifying the Aerolizer® inhaler design and material on bipolar charging of a powder aerosol. The modified inhalers included various grid configurations, mouthpiece lengths, air inlet sizes, and were also constructed of different materials (acrylonitrile butadiene styrene, acetal, low density polyethylene, nylo...

This paper provides a review on key research findings in the rapidly developing area of pharmaceutical aerosol electrostatics. Solids and liquids can become charged without electric fields, the former by contact or friction and the latter by flowing or spraying. Therefore, charged particles and droplets carrying net charges are produced from pharma...

To evaluate the BOLAR™ for measuring bipolar electrostatic charge and mass distributions of powder aerosols generated from a dry powder inhaler. Mannitol powder (5, 10, and 20 mg) was dispersed using an Osmohaler® inhaler into the BOLAR at air flow rates of 30 or 60 L/min. As the aerosol sample was drawn through the BOLAR, the air flow was divided...

Oleanolic acid (OA) is a natural triterpenoid with anticancer property, but its hydrophobic nature and poor aqueous solubility pose challenges in pharmaceutical formulation development. The present study aimed at developing OA-loaded mPEG-PLGA or mPEG-PLA nanoparticles (NPs) to improve the delivery of OA. The NPs were prepared by nanoprecipitation...

Pharmaceutical solids are likely to accumulate electrostatic charge through handling processes encountered both in industry and during clinical use. Important advances in the past decade have continued to improve our understanding and enabled better control of electrostatics. Although certain areas have been studied more extensively than others, mu...

Pulmonary delivery of siRNA has considerable therapeutic potential for treating viral respiratory infectious diseases including influenza. By introducing siRNA that targets the conserved region of viral genes encoding nucleocapsid protein (NP), viral mRNAs can be degraded and viral replication can be inhibited in mammalian cells. To enable siRNA to...

Some protein pharmaceuticals from Chinese medicine have been developed to treat cardiovascular diseases, genetic diseases, and cancer. Bioactive proteins with various pharmacological properties have been successfully isolated from animals such as Hirudo medicinalis (medicinal leech), Eisenia fetida (earthworm), and Mesobuthus martensii (Chinese sco...

This study aimed to characterize inherent charge generated by micron-sized drug-only formulations of amorphous and crystalline salbutamol sulfate (SS). Amorphous SS was produced by spray-drying whilst crystalline SS was produced by conditioning spray-dried SS with supercritical CO2 and menthol. Electrostatic charge of the powders was characterized...

Infants and children constitute a patient group that have unique requirements in pulmonary drug delivery. Since their lungs develop continuously until they reach adulthood, the airways undergo changes in dimensions and number. Computational models have been devised on the growth dynamics of the airways during childhood, as well as the particle depo...

Electrostatics continues to play an important role in pharmaceutical aerosols for inhalation. Despite its ubiquitous nature, the charging process is complex and not well understood. Nonetheless, significant advances in the past few years continue to improve understanding and lead to better control of electrostatics. The purpose of this critical rev...

While most examples of nanoparticle therapeutics have involved parenteral or IV administration, pulmonary delivery is an attractive alternative, especially to target and treat local infections and diseases of the lungs. We describe a successful dry powder formulation which is capable of delivering nanoparticles to the lungs with good aerosolization...

Nucleic acids have the potential to be used as therapies or vaccines for many different types of disease but delivery remains the most significant challenge to their clinical adoption. pH responsive peptides containing either histidine or derivatives of 2,3-diaminopropionic acid (Dap) can mediate effective DNA transfection in lung epithelial cells...

Many newly discovered drug molecules have low aqueous solubility, which results in low bioavailability. One way to improve their dissolution is to formulate them as nanoparticles, which have high specific surface areas, consequently increasing the dissolution rate and solubility. Nanoparticles can be produced via top-down or bottom-up methods. Top-...

Dielectrophoresis (DEP) is the phenomenon in which a particle, such as a living cell, is polarized and moved by electrical gravity in a non-uniform electric field. In the present study, the DEP force is utilized to act on the cells to induce spatial movement for investigating the correlation between the cell adhesion force and activation level of f...

ABSTRACT Preventing obesity could be done by lowering plasma TAG that inhibits adipogenesis. Oat and mushroom beta-glucans in the diet has been reported to lower plasma lipid; however the data focusing on their effects on TAG and obesity are insufficient. In the present study, lowering plasma triacylglycerol, fat deposition, body weight gain (BWG)...

Background: Inhaled dry powder mannitol has established in vivo therapeutic efficacy for enhancing mucociliary function. However, a single dose necessitates multiple inhalations of a sizeable powder mass. Nebulization of mannitol by vibrating mesh devices has recently been shown in vitro to impart similar dosing in a comparable or lesser treatment...

We hypothesize that the USP induction port may de-agglomerate carrier-free powder emitting from dry powder inhalers (DPIs). Aerosols emitting from a range of DPIs (Spinhaler®, Turbuhaler® and Osmohaler™) and induction ports (USP throat, straight tube, Alberta idealized mouth-throat geometry (AG)) were sized by laser diffraction. Total drug recovery...

This work provides a new understanding of critical process parameters involved in the production of inhalation aerosol particles by ultrasonic spray freeze drying to enable precise control over particle size and aerodynamic properties. A series of highly porous mannitol, lysozyme, and bovine serum albumin (BSA) particles were produced, varying only...

While tuberculosis (TB) is a curable intracellular disease, it remains a global health issue with over 1 million deaths reported in 2007. Causes of failed treatment include patient non-compliance and the emergence of drug resistance over the 6 month therapeutic course. Advanced technologies are needed to improve the efficiency of drug delivery to r...

This study aims to improve the dissolution of inhalable cyclosporine A nanoparticles by formulating the drug with mannitol as a hydrophilic nano-matrix former. The effect of mannitol content on the aerosol performance of the nano-matrix particles was also examined. Cyclosporine A nanosuspensions were produced by anti-solvent precipitation using a m...

Mucociliary clearance is compromised by airway surface liquid dehydration in respiratory disease states such as cystic fibrosis. Rehydration by hyperosmolar agents such as nebulised hypertonic saline and dry powder mannitol has demonstrated in vivo safety and efficacy for restoring mucociliary function. Mannitol, delivered as a nebulised formulatio...

This review focuses on bottom-up processes such as precipitation (or crystallisation) and single droplet evaporation to produce nanoparticles containing largely pure therapeutics for pharmaceutical applications. Suitable precipitation techniques involve the use of high-gravity, confined impinging liquid jet mixing, multi-inlet vortex mixing, superc...

After the clinical insertion of a bone biomaterial, the surrounding osteoblasts would migrate and attach to the implant surface and foster a microenvironment that largely determines the differentiation fate of the comigrated mesenchymal stem cells. Whether the fostered microenvironment is suitable for osteogenic differentiation of mesenchymal stem...

To produce and examine the aerosol performance of protein nano-matrix particles with different surface roughness. Aqueous lysozyme solutions were poured into isopropanol during high-shear mixing to produce nanoparticles by precipitation. The size of the nanoparticles was varied by adjusting the precipitation conditions. The resultant suspensions we...

Liquid droplets can be spontaneously charged in the absence of applied electric fields by spraying. It has been shown by computational simulation that charges may influence particle deposition in the airways. The electrostatic properties of jet nebulized aerosols and their potential effects on lung deposition have hardly been studied. A modified el...

This study aims to produce and test the performance of novel crystalline respirable particles containing two low-dose active ingredients and mannitol. This technique overcomes the usual requirement of blending with lactose carriers in formulating combination inhalation products. Ternary powders were produced by co-spray drying solutions containing...

This review focuses on the key findings and developments in the rapidly expanding research area of pharmaceutical aerosol electrostatics. Data from limited in-vivo and computational studies suggest that charges may potentially affect particle deposition in the airways. Charging occurs naturally in the absence of electric fields through triboelectri...

To study if electrostatic charge initially present in mannitol powder plays a role in the generation of aerosols, mannitol was unipolarly charged to varying magnitudes by tumbling the powder inside containers of different materials. The resulting charge in the powder was consistent with predictions from the triboelectric charging theories, based on...

Lactose dry powder inhaler (DPI) carriers, constructed of smaller sub units (composite carriers), were evaluated to assess their potential for minimising drug-carrier adhesion, variability in drug-carrier forces and influence on drug aerosol performance from carrier-drug blends. Lactose carrier particles were prepared by fusing sub units of lactose...

The electrostatic charge properties of drug-free metered dose inhaler (MDI) aerosols containing the propellants HFA-134a and 227ea were studied using a modified electrical low pressure impactor (ELPI) with aerodynamic cutoff diameters ranging from 0.028 to . The MDIs were spiked with various amounts of water and crimped with Hostaform and PBT (poly...

At present, there is no published data examining the effect of relative humidity on the electrostatic charges of dry powder inhaler aerosols. The charging behaviour of two commercial products, Pulmicort and Bricanyl Turbuhalers, were investigated using an electrical low pressure impactor (ELPI). ELPI was successfully modified to disperse the aeroso...

To investigate the influence of storage relative humidity (RH) on the aerosolisation efficiency and tribo-electrification of carrier based dry powder inhaler (DPI) formulations using the next generation impactor (NGI) in vitro methodology and the electrostatic low pressure impactor (ELPI). Micronised salbutamol (d (0.5) 1.48 +/- 0.03 microm) was bl...

The electrostatic charge properties of commercial metered dose inhaler (MDI) aerosols, including Ventolin®, Flixotide®, Tilade® and QVAR®, sampled through new and detergent-coated AeroChamber® Plus spacers were studied using a modified 13-stage electrical low pressure impactor (ELPI) with aerodynamic cutoff diameters ranging from 0.028 to . Aerosol...

This international meeting brought together approximately 250 delegates from the pharmaceutical industry, academia, hospitals and government agencies, to discuss the latest research and development on areas related to inhalation aerosols. Fundamental science and applied research encompassing both the biological and physicochemical aspects were pres...

The electrostatic charge properties of aerosols produced by commercial metered dose inhalers (MDIs), including Ventolin, QVAR, Flixotide, Intal Forte, and Tilade were studied using a modified 13-stage electrical low pressure impactor (ELPI) with aerodynamic diameter cutoff ranging from 0.028 to 10.07 microm. All the stages are electrically insulate...