Browsing by Author "Wang, Ke"
Now showing 1 - 11 of 11
Results Per Page
Sort Options
Item Open Access Artemisinin Cocrystals for Bioavailability Enhancement. Part 1: Formulation Design and Role of the Polymeric Excipient(ACS Publications, 2021-11-01) Kaur, Manreet; Yardley, Vanessa; Wang, Ke; Masania, Jinit; Botana, Adolfo; Arroo, R. R. J.; Li, M.Artemisinin (ART) is a most promising antimalarial agent, which is both effective and well-tolerated in patients, though it has therapeutic limitations due to its low solubility, bioavailability and short half-life. The objective of this work was to explore the possibility of formulating ART cocrystals, i.e., artemisinin-orcinol (ART-ORC) and artemisinin-resorcinol (ART2-RES) as oral dosage forms to deliver ART molecules for bioavailability enhancement. This is the first part of the study, aiming to develop a simple and effective formulation which can then be tested on an appropriate animal model (i.e. mouse selected for in vivo study) to evaluate their preclinical pharmacokinetics for further development. In the current work, the physicochemical properties (i.e., solubility and dissolution rate) of ART cocrystals were measured to collect information necessary for the formulation development strategy. It was found that the ART solubility can be increased significantly by its cocrystals, i.e., 26-fold by ART-ORC and 21-fold by ART2-RES respectively. Screening a set of polymers widely used in pharmaceutical products, including Polyvinylpyrrolidone, Hydroxypropyl Methylcellulose and Hydroxypropyl Methylcellulose Acetate Succinate, based on the powder dissolution performance parameter analysis, revealed that Polyvinylpyrrolidone/vinyl Acetate (PVP-VA) was the most effective crystallisation inhibitor. The optimal concentration of PVP-VA at 0.05 mg/mL for the formulation was then determined by a dissolution/permeability method which represented a simplified permeation model to simultaneously evaluate the effects of a crystallization inhibitor on the dissolution and permeation performance of ART cocrystals. Furthermore, experiments, including surface dissolution of single ART cocrystals monitored by Raman spectroscopy and SEM and diffusion properties of ART in solution measured by 1H and diffusion-ordered spectroscopy (DOSY) nuclear magnetic resonance (NMR) spectroscopy, provided insight into how the excipient affects the ART cocrystal dissolution performance and bioavailability.Item Open Access Artemisinin Cocrystals for Bioavailability Enhancement: Part 2. In-vivo Bioavailability and PBPK Modelling(ACS Publications, 2021-11-08) Kaur, Manreet; Yardley, Vanessa; Wang, Ke; Masania, Jinit; Arroo, R. R. J.; Turner, David B.; Li, M.We report the evaluation and prediction of the pharmacokinetic (PK) performance of artemisinin (ART) cocrystal formulations, i.e., 1:1 Artemisinin-Orcinol (ART-ORC) and 2:1 Artemisinin-Resorcinol (ART2-RES), using in vivo murine animal and PBPK (physiological based pharmacokinetic) models. The efficacy of the ART cocrystal formulations along with the parent drug ART were tested in mice infected with Plasmodium berghei. When given at the same dose, the ART-cocrystal formulation showed a significant reduction in parasitaemia at day 4 post infection compared to ART alone. The PK parameters including Cmax (maximum plasma concentration), Tmax (time to Cmax), AUC (area under the curve) were obtained by determining drug concentrations in the plasma using LC-HRMS (Liquid Chromatography-High Resolution Mass Spectrometry), showing enhanced ART levels after dosage with the cocrystal formulations. The dose-response tests revealed that a significantly lower dose of the ART cocrystals in the formulation was required to achieve a similar therapeutic effect as ART alone. A PBPK model was developed using a PBPK mouse simulator to accurately predict the in vivo behaviour of the cocrystal formulations by combining in vitro dissolution profiles with the properties of the parent drug ART. The study illustrated that information from classical in vitro and in vivo experimental investigations of the parent drug of ART formulation can be coupled with PBPK modelling to predict the PK parameters of an ART cocrystal formulation in an efficient manner. Therefore, the proposed modelling strategy could be used to establish in vitro and in vivo correlations for different cocrystals intended to improve dissolution properties and to support clinical candidate selection, contributing to assessment of cocrystal developability and formulation development.Item Metadata only Assessing Dose‑Exposure–Response Relationships of Miltefosine in Adults and Children using Physiologically‑Based Pharmacokinetic Modeling Approach(Springer Nature, 2023-10-10) Madu, Shadrack J.; Wang, Ke; Chirumamilla, Siri Kalyan; Turner, David B.; Steel, Patrick G.; Li, M.Objectives: Miltefosine is the frst and only oral medication to be successfully utilized as an antileishmanial agent. However, the drug is associated with diferences in exposure patterns and cure rates among diferent population groups e.g. ethnicity and age (i.e., children v adults) in clinical trials. In this work, mechanistic population physiologically-based pharmacokinetic (PBPK) models have been developed to study the dose-exposure–response relationship of miltefosine in in silico clinical trials and evaluate the diferences in population groups, particularly children and adults. Methods: The Simcyp population pharmacokinetics platform was employed to predict miltefosine exposure in plasma and peripheral blood mononuclear cells (PBMCs) in a virtual population under diferent dosing regimens. The cure rate of a simulation was based on the percentage of number of the individual virtual subjects with AUCd0-28>535 µg⋅day/mL in the virtual population. Results: It is shown that both adult and paediatric PBPK models of miltefosine can be developed to predict the PK data of the clinical trials accurately. There was no signifcant diference in the predicted dose-exposure–response of the miltefosine treatment for diferent simulated ethnicities under the same dose regime and the dose-selection strategies determined the clinical outcome of the miltefosine treatment. A lower cure rate of the miltefosine treatment in paediatrics was predicted because a lower exposure of miltefosine was simulated in virtual paediatric in comparison with adult virtual populations when they received the same dose of the treatment. Conclusions: The mechanistic PBPK model suggested that the higher fraction of unbound miltefosine in plasma was responsible for a higher probability of failure in paediatrics because of the diference in the distribution of plasma proteins between adults and paediatrics. The developed PBPK models could be used to determine an optimal miltefosine dose regime in future clinical trials.Item Open Access Cocrystallisation of Daidzein with pyridine-derived molecules: Screening, structure determination and characterisation(Elsevier, 2020-07-13) Bolus, Linzie; Wang, Ke; Pask, Christopher; Lai, Xiaojun; Li, M.Daidzein (7,4' -dihydroxyisoflavone, DAI) is an isoflavone found in soybeans and Pueraria. DAI has potential therapeutic benefits on cancer and osteoporosis yet has quite low solubility, limiting its use. Herein a cocrystal screening of DAI with pyridine-derived molecules, i.e., nicotinamide, isonicotinamide, caffeine, d -Proline, l -Proline and 4,4' -Bipyridine was conducted. A new cocrystal of Daidzein and 4,4' -Bipyridine (DAI-BIP) was successfully generated via grinding and solvent methods. DAI-BIP showed an increased solubility and dissolution rate. In comparison to DAI, there was a 2.03-fold increase of the dissolution performance parameter for DAI-BIP where the concentration observed for DAI quickly reached the equi- librium solubility and continued to reach 1.49 times DAI solubility. A parachute effect was also observed during the dissolution of DAI-BIP, indicating that BIP might be able to maintain the supersaturated state of DAI in solution proving DAI’s ability to form cocrystals of higher solubility and enhanced dissolution properties through co-crystallisationItem Metadata only In Vitro Dissolution Studies of Immediate Release and Extended Release Formulation using Flow-through Cell Apparatus 4. Dissolution technologies(2014-05) Qiu, S.; Wang, Ke; Li, M.The aims of this study were to evaluate the dissolution performance of solid dosage forms using the open and closed modes of the FTC Apparatus 4 under different flow rates and provide examples to demonstrate the advantages of the FTC method, in particular the possibility of changing the pH during experiments, in studying the release mechanisms of extended-release products. Immediate-release (IR) paracetamol and extended-release (ER) theophylline formulations were used in this study. Results from commercially available IR paracetamol tablets using FTC Apparatus 4 have shown similar dissolution behavior in the closed and open systems, reflecting well-maintained apparent sink conditions and controlled hydrodynamics in the test cells. The flow rate of FTC Apparatus 4 significantly affected the disintegration process of IR tablets. This information can be used as a discriminating tool to support formulation development and to set quality control standards and specifications. To mimic the continuous absorption of theophylline during the passage at different pH values through the whole gastrointestinal tract, dissolution tests were conducted using FTC Apparatus 4 with pH-dependent media for three different commercially available theophylline formulations. Two formulations of Uniphyllin 200-mg tablets and Nuelin SA 175-mg tablets provided a constant release rate during the course of medium pH changes, and their release behavior was predicted with accuracy by appropriate mathematical models. However, wide intervariability and biphasic release in the dissolution profiles were found for Slo-Phyllin 125-mg capsules.Item Open Access Insight into Flufenamic Acid Cocrystal Dissolution in the Presence of a Polymer in Solution: from Single Crystal to Powder Dissolution(ACS American Chemical Society, 2017-11-01) Guo, Minshan; Wang, Ke; Qiao, Ning; Fabian, Laszlo; Sadiq, Ghazala; Li, M.Effects of three polymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and copolymer of vinylpyrrolidone/vinyl acetate (PVP-VA), on the dissolution behavior of the cocrystals of flufenamic acid with theophylline (FFA-TP CO) and nicotinamide (FFA-NIC CO) were investigated at multiple length scales. At the molecular level, the interactions of crystal surfaces with a polymer were analyzed by observing etching pattern changes using atomic force microscopy. At the macroscopic scale, dissolution rates of particular faces of a single crystal were determined by measurement of the physical retreat velocities of the faces using optical light microscopy. In the bulk experiments, the FFA concentration in a dissolution medium in the absence or presence of a polymer was measured under both sink and nonsink conditions. It has been found that the dissolution mechanisms of FFA-TP CO are controlled by the defect sites of the crystal surface and by precipitation of the parent drug FFA as individual crystals in the bulk fluid. In contrast, the dissolution mechanisms of FFA-NIC CO are controlled by surface layer removal and by a surface precipitation mechanism, where the parent drug FFA precipitates directly onto the surface of the dissolving cocrystals. Through controlling the dissolution environment by predissolving a polymer, PVP or PVP-VA, which can interact with the crystal surface to alter its dissolution properties, improved solubility, and dissolution rates of FFA-TP CO and FFA-NIC CO have been demonstrated.Item Open Access Investigating Permeation Behavior of Flufenamic Acid Cocrystals Using a Dissolution and Permeation System(ACS Publications, 2018-08-06) Guo, Minshan; Wang, Ke; Qiao, Ning; Yardley, Vanessa; Li, M.Item Open Access Investigating the Influence of Polymers on Supersaturated Flufenamic Acid Cocrystal Solutions(ACS Publications, 2016-08-05) Guo, Minshan; Wang, Ke; Hamill, Noel Anthony; Lorimer, Keith; Li, M.Item Metadata only Investigation of the Effect of Hydroxypropyl Methylcellulose on the Phase Transformation and Release Profiles of Carbamazepine-Nicotinamide Cocrystal(Springer, 2014-09-01) Li, M.; Qiu, Shi; Wang, Ke; Lai, Xiaojun; Rehan, MohammadPurpose The aim of this work was to investigate the influence of hydroxypropyl methylcellulose (HPMC) on the phase transformation and release profile of carbamazepine-nicotinamide (CBZ-NIC) cocrystal in solution and in sustained release matrix tablets. Methods The polymorphic transitions of the CBZ-NIC cocrystal and its crystalline properties were examined by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), Raman spectroscopy, and scanning electron microscopy (SEM). Results The apparent CBZ solubility and dissolution rate of CBZ-NIC cocrystal were constant in different concentrations of HPMC solutions. In a lower percentage of HPMC in the matrix tablets, the CBZ release profile of the CBZ-NIC cocrystal was nonlinear and declined over time. With an increased HPMC content in the tablets, the CBZ-NIC cocrystal formulation showed a significantly higher CBZ release rate in comparison with the other two formulations of CBZ III and the physical mixture. Conclusions Because of a significantly improved dissolution rate of the CBZ-NIC cocrystal, the rate of CBZ entering into solution is significantly faster than the rate of formation of the CBZ-HPMC soluble complex in solution, leading to a higher supersaturation level of CBZ and subsequently precipitation of CBZ dihydrate.Item Metadata only Role of polymers in solution and tablet-based carbamazepine cocrystal formulations(Royal Society of Chemistry, 2016-03-08) Qiu, Shi; Lai, Jumin; Guo, Minshan; Wang, Ke; Lai, Xiaojun; Desai, Unmesh; Juma, Nazmin; Li, M.Item Open Access Understanding the effects of a polymer on the surface dissolution of pharmaceutical cocrystals using combined experimental and molecular dynamics simulation approaches(ACS Publications, 2019-12-30) Li, M.; Kirubakaran, P.; Wang, Ke; Rosbottom, I.; Cross, R. B. M.The molecular interactions between the surfaces of cocrystals [i.e., flufenamic acid and theophylline (FFA-TP), flufenamic acid and nicotinamide (FFA-NIC), and carbamazepine and nicotinamide (CBZ-NIC)] and the polymers [i.e., polyethyleneglycol (PEG), polyvinylpyrrolidone (PVP) and copolymer of vinylpyrrolidone (60%)/vinyl acetate (40%) (PVP-VA)] were investigated through combined experimental and molecular dynamics simulation approaches to resolve the mechanisms of cocrystal dissolution and precipitation. It was found that adsorption of the polymers on the surfaces of cocrystals might prevent the precipitation of the parent drug and alter the dissolution rate. The effect of polymers on precipitation could be determined by the cocrystal dissolution rate, the interactions of polymers with the surfaces of cocrystals, the characters of the noncovalent bonds formed between the polymers and the cocrystal surfaces, and the mobility and conformation of the polymers. The etching experiments of single cocrystals revealed that FFA-NIC and CBZ-NIC appeared as surface precipitation cocrystals while FFA-TP could lead to bulk precipitation. Both PVP and PVP-VA were good precipitation inhibitors for FFA-NIC and they could completely inhibit the recrystallization of FFA III on the surfaces of dissolving cocrystals. In addition, as the adsorption of the polymer was slower than dissolution rate of the cocrystals, PVP and PVP-VA could only partially inhibit the recrystallization of CBZ dihydrate on the surface of CBZ-NIC. While PEG had no inhibitory effect on the surface crystallization of FFA-NIC and CBZ-NIC, due to its weak interactions with the surfaces of the cocrystals, it enhanced the dissolution performance of FFA-TP. In contrast, PVP and PVP-VA reduced the dissolution rate of FFA-TP and subsequently undermined the performance of cocrystals. Taken together, the approach of combining experimental and molecular dynamics simulation provided insights into the mechanisms of cocrystal dissolution as well as the polymers acting as inhibitory excipients for precipitation/recrystallisation, making contribution to the development of novel formulations.