Formulation and Particle Size Reduction Improve Bioavailability of Poorly Water-Soluble Compounds with Antimalarial Activity

Wang, Hongxing; Li, Qigui; Reyes, Sean; Zhang, Jing; Xie, Lijian; Meléndez, Víctor; Hickman, Mark; Kozar, Michael P.

doi:10.1155/2013/769234

Cited by 17 publications

(24 citation statements)

References 21 publications

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“…The oral BA in mice was >20% for RMB041 and -043, and >5% for RMB073, which is substantially longer than that of the parent molecule DQ (Beteck et al, 2016). Efforts have already been made by other groups to enhance the in vivo efficacy of DQ using nanoparticle formulation (Wang et al, 2013). However, our rationale was to synthesize stable and tractable DQ derivatives that can be developed further as potential anti-TB agents.…”

Section: Discussionmentioning

confidence: 99%

An in vitro ADME and in vivo Pharmacokinetic Study of Novel TB-Active Decoquinate Derivatives

2019

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Tuberculosis (TB) is currently the leading cause of mortality due to an infectious disease, despite the existence of multiple effective first-line and second-line drugs. The current anti-TB regimen requires a prolonged treatment period of around 6 months and is only efficacious against drug-sensitive strains of Mycobacterium tuberculosis ( Mtb ). With a rise in cases of multi-drug resistant and extensively drug resistant strains of Mtb , newer treatments comprising compounds with novel mechanisms of action are required. Although decoquinate (DQ) is inactive against Mtb , its derivatives are of interest to anti-TB drug discovery because of their potential to permeate the mycobacterial cell wall, Mtb -infected macrophages, and granulomatous lesions by passive diffusion. The compounds also display mechanisms of action which are unlike those of currently used quinolones, potentially displaying activity against new targets. Three such derivatives bearing an alkyl group at N-1 and an amide group at C-3 (RMB 041, -043, and -073) displayed potent in vitro activities against Mtb H37Rv (90% minimum inhibitory concentrations, MIC90 = 1.61, 4.18, and 1.88 μM, respectively) and high selectivity indices (10–25). In this study, we evaluated the drug-like properties ( in vitro microsomal stability, microsomal/plasma protein binding, kinetic solubility, lipophilicity, and passive permeability) and pharmacokinetic (PK) parameters of these compounds after intravenous and oral administration to male C57BL/6 mice. The compounds showed markedly improved kinetic solubilities compared to that of the parental DQ and were metabolically stable in vitro . The maximum concentrations reached after oral administration were 5.4 ± 0.40, 5.6 ± 1.40, and 2.0 ± 0.03 μM; elimination half-lives were 23.4 ± 2.50, 6.2 ± 0.80, and 11.6 ± 1.30 h; and bioavailabilities were 21.4 ± 1.0, 22.1 ± 2.2, and 5.9 ± 1.3 for RMB041, -043, and -073, respectively. These compounds therefore display promising drug-like properties, and their PK/toxicity profiles (including long half-lives both in vitro and in vivo ) support their potential as candidates for further investigation in animal models of Mtb infection.

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Section: Discussionmentioning

confidence: 99%

An in vitro ADME and in vivo Pharmacokinetic Study of Novel TB-Active Decoquinate Derivatives

2019

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“…It is a water soluble protective colloid that is adsorbed on the particle surface and facilitate formation of small size and stable particles during the size reduction process (Ahmed, 2016 ). The concentration of PVA was found to be critical since, insufficient PVA concentration will not provide adequate coverage of the particles, while at higher PVA concentration polymeric micelles will be formed that affect the thermal stability of the prepared particles (Wang et al., 2013 ). Other studied parameters such as the ratio of methanolic solution, homogenization speed and time of homogenization were also studied, and their optimum levels are presented in Table 1 .…”

Section: Resultsmentioning

confidence: 99%

“…Size reduction is a process of decreasing the large or coarse solid drug particles into small or fine unit masses. This process represents a potentially useful way for enhancing the bioavailability of hydrophobic drugs especially when particles in the nano-size range have been developed (Wang et al., 2013 ). Improving drug bioavailability due to size reduction is attributed to the increase in the drug surface area, solubility and dissolution rate (Jinno et al., 2006 ; Junghanns & Müller, 2008 ; Willmann et al., 2010 ).…”

Section: Introductionmentioning

confidence: 99%

“…Spray and freeze drying, anti-solvent precipitation, crystallization, supercritical fluid technology, high pressure homogenization, ball milling, jet milling, crystal engineering and cryogenic spray process are techniques commonly employed to achieve size reduction (Rogers et al., 2001 ; Blagden et al., 2007 ; Sutradhar et al., 2013 ; Wang et al., 2013 ; Hao et al., 2015 ). The bioavailability and therapeutic activity of wide variety of drugs have been successfully augmented following size reduction of these drug particles (Van Eerdenbrugh et al., 2008 ; Pande & Abhale, 2013 ; Wang et al., 2013 ).…”

Section: Introductionmentioning

confidence: 99%

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Effect of finasteride particle size reduction on its pharmacokinetic, tissue distribution and cellular permeation

Ahmed

Al‐Abd

2018

Drug Delivery

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Finasteride (FSD), a specific competitive inhibitor of the steroid type-II 5α-reductase enzyme, is used in treatment of benign prostate hyperplasia (BPH) and male pattern baldness. The drug is of limited solubility that affect its dissolution and bioavailability. The aim was to study the effect of FSD particle size reduction on the pharmacokinetic, tissue distribution and cellular permeation. An optimized drug micro- and nano-particles were developed, characterized, administered to group of rats, and systemic pharmacokinetic and tissue distribution within target and not-target organs were determined using near-infrared (NIR) spectroscopy technique. Moreover, the cellular permeation of the prepared formulations through normal prostate epithelial cells was assessed and compared to pure FSD. The developed micro- and nano-particles were of 930 and 645 nm, respectively. Plasma maximum drug levels (Cmax) and overall exposure (AUC) of both formulations were not significantly higher than unformulated drug. However, micronized FSD achieved significant higher concentration within the target tissue (prostate) within the current study compared to pure drug and nano-sized formulation as well. Yet, this is explained by the higher sequestration ability of spleen tissue to the nano-sized formula compared to micro-sized FSD. At the cellular level, permeation of nano-sized FSD through prostate epithelial cells was superior to the unformulated FSD as well as the micro-sized drug formulation. FSD particle size reduction significantly influences its cellular permeation and to a lesser extend affect its systemic pharmacokinetics and tissue distribution after oral administration.

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“…Besides its anticoccidial activity, it also has strong antimalarial activity against the blood and liver stages of Plasmodium sp. [ 1 ]. In addition, DQ kills developing gametocytes, the parasite stage responsible for malaria transmission.…”

Section: Introductionmentioning

confidence: 99%

Long-Term Prophylaxis and Pharmacokinetic Evaluation of Intramuscular Nano- and Microparticle Decoquinate in Mice Infected with P. berghei Sporozoites

Xie

Caridha

et al. 2017

Malaria Research and Treatment

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Decoquinate nanoparticle and microparticle suspended in an oily vehicle to retard drug release are evaluated for long-term malaria prophylaxis. Pharmacokinetic studies in normal animals and antimalarial efficacy in liver stage malaria mice were conducted at various single intramuscular-decoquinate doses for 2, 4, 6, or 8 weeks prior to infection with P. berghei sporozoites. The liver stage efficacy evaluation was monitored by using an in vivo imaging system. Full causal prophylaxis was shown in mice with a single intramuscular dose at 120 mg/kg of nanoparticle decoquinate (0.43 μm) for 2-3 weeks and with microparticle decoquinate (8.31 μm) injected 8 weeks earlier than inoculation. The time above MIC of 1,375 hr observed with the microparticle formulation provided a 2.2-fold longer drug exposure than with the nanoparticle formulation (624 hr). The prophylactic effect of the microparticle formulation observed in mice was shown to be 3-4 times longer than the nanoparticle decoquinate formulation.

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Formulation and Particle Size Reduction Improve Bioavailability of Poorly Water-Soluble Compounds with Antimalarial Activity

Cited by 17 publications

References 21 publications

An in vitro ADME and in vivo Pharmacokinetic Study of Novel TB-Active Decoquinate Derivatives

An in vitro ADME and in vivo Pharmacokinetic Study of Novel TB-Active Decoquinate Derivatives

Effect of finasteride particle size reduction on its pharmacokinetic, tissue distribution and cellular permeation

Long-Term Prophylaxis and Pharmacokinetic Evaluation of Intramuscular Nano- and Microparticle Decoquinate in Mice Infected with P. berghei Sporozoites

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