Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration

Murashov, Mikhail D.; Diaz‐Espinosa, Jennifer; LaLone, Vernon; Tan, Joel W. Y.; Laza, Raluca; Wang, Xueding; Stringer, Kathleen A.; Rosania, Gus R.

doi:10.3390/pharmaceutics10040238

Cited by 18 publications

(26 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The weakly dibasic (pK a 3.83, 7.54 at 37 °C, I = 0.15 M [105]) phenazine antibiotic (M W 473.4 g/mol) is used to treat leprosy. The orally-bioavailable molecule has the very unusual characteristic of precipitating and accumulating as easily-visible red microcrystals in macrophages [119]. Figure 5 shows the distribution of properties used by Lipinski et al [120] to define the Rule of 5 as an indicator of "drug-likeness."…”

Section: Physicochemical Properties Of Database Moleculesmentioning

confidence: 99%

Prediction of aqueous intrinsic solubility of druglike molecules using Random Forest regression trained with Wiki-pS0 database

Avdeef¹

2020

ADMET DMPK

125

View full text Add to dashboard Cite

<p class="ADMETkeywordsheading">The accurate prediction of solubility of drugs is still problematic. It was thought for a long time that shortfalls had been due the lack of high-quality solubility data from the chemical space of drugs. This study considers the quality of solubility data, particularly of ionizable drugs. A database is described, comprising 6355 entries of intrinsic solubility for 3014 different molecules, drawing on 1325 citations. In an earlier publication, many factors affecting the quality of the measurement had been discussed, and suggestions were offered to improve ways of extracting more reliable information from legacy data. Many of the suggestions have been implemented in this study. By correcting solubility for ionization (i.e., deriving intrinsic solubility, S<sub>0</sub>) and by normalizing temperature (by transforming measurements performed in the range 10-50 °C to 25 °C), it can now be estimated that the average interlaboratory reproducibility is 0.17 log unit. Empirical methods to predict solubility at best have hovered around the root mean square error (RMSE) of 0.6 log unit. Three prediction methods are compared here: (a) Yalkowsky’s general solubility equation (GSE), (b) Abraham solvation equation (ABSOLV), and (c) Random Forest regression (RFR) statistical machine learning. The latter two methods were trained using the new database. The RFR method outperforms the other two models, as anticipated. However, the ability to predict the solubility of drugs to the level of the quality of data is still out of reach. The data quality is not the limiting factor in prediction. The statistical machine learning methodologies are probably up to the task. Possibly what’s missing are solubility data from a few sparsely-covered chemical space of drugs (particularly of research compounds). Also, new descriptors which can better differentiate the factors affecting solubility between molecules could be critical for narrowing the gap between the accuracy of the prediction models and that of the experimental data.</p>

show abstract

Section: Physicochemical Properties Of Database Moleculesmentioning

confidence: 99%

Prediction of aqueous intrinsic solubility of druglike molecules using Random Forest regression trained with Wiki-pS0 database

Avdeef¹

2020

ADMET DMPK

125

View full text Add to dashboard Cite

show abstract

“…In this study, we explored the differences in the interaction of clofazimine hydrochloride nanoparticles (CFZ-HCl NPs) [19] with normal and tumor bearing prostates, using the transgenic adenocarcinoma of the mouse prostate (TRAMP) animal model [20]. CFZ is a red-pigmented dye and a weakly basic, FDA-approved, orally administered, antimycobacterial agent that is recommended by the World Health Organization as a treatment for leprosy and multidrug resistant tuberculosis [21–29].…”

Section: Introductionmentioning

confidence: 99%

“…In patients, CFZ exhibits atypical pharmacokinetic properties that result in accumulation and stabilization in tissue macrophages of solid drug biocrystals that resemble a hydrochloride (HCl) salt form of the drug [30–35]. These CFZ-HCl biocrystals were determined to be biocompatible, stable, long-lived, relatively non-toxic, and anti-inflammatory [36, 37], which led to the development of a biomimetic formulation of CFZ-HCl NPs for parenteral administration [19]. Importantly, Murashov et al demonstrated that these CFZ-HCl NPs preserved the majority of characteristics of CFZ-HCl biocrystals, including targeting and accumulating inside macrophages in vitro and in vivo [19].…”

Section: Introductionmentioning

confidence: 99%

“…These CFZ-HCl biocrystals were determined to be biocompatible, stable, long-lived, relatively non-toxic, and anti-inflammatory [36, 37], which led to the development of a biomimetic formulation of CFZ-HCl NPs for parenteral administration [19]. Importantly, Murashov et al demonstrated that these CFZ-HCl NPs preserved the majority of characteristics of CFZ-HCl biocrystals, including targeting and accumulating inside macrophages in vitro and in vivo [19]. Thus, the presence of tumor associated macrophages (TAM), including those in prostate tumors [38, 39], make CFZ-HCl NPs a potentially useful targeting agent for prostate cancer detection.…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the functional and therapeutic properties, CFZ-HCl NPs have also been shown to exhibit a strong signal in the Cy5 fluorescence range (650 nm excitation/670 nm emission) and peak optical absorbance at 495 nm [19, 40]. In contrast to the free dye CFZ, CFZ-HCl NPs have a redshifted peak optical absorbance at 495 nm (compared to 450 nm for free dye CFZ), making it more suitable for biological optical applications due to the reduced interference from endogenous chromophores, such as blood at this longer wavelength [41].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Photoacoustic imaging of clofazimine hydrochloride nanoparticle accumulation in cancerous vs normal prostates

et al. 2019

Self Cite

View full text Add to dashboard Cite

Prostate cancer was the most common form and had the second highest death rate of male cancer in the United States in 2015. Current diagnosis techniques, such as prostate-specific antigen tests, transrectal ultrasound scans, and biopsies, are often inconclusive, and in the latter case, invasive. Here, we explore the use of clofazimine hydrochloride nanoparticles (CFZ-HCl NPs), a repurposed formulation from an FDA-approved antimycobacterial agent, as a photoacoustic contrast agent for the evaluation of prostate cancer due to its macrophage-targeting capabilities and high optical absorbance at 495 nm. Using a transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model, our results indicate a preferential accumulation of intravenously injected CFZ-HCl NPs in cancerous prostates over normal prostates. Differences in accumulation of CFZ-HCl NPs between cancerous and normal prostates were determined using a two-wavelength unmixing technique via ex vivo photoacoustic imaging. Thus, intravenous injection of CFZ-HCl NPs leads to differences in the interactions of the particles with cancerous vs normal prostates, while allowing for photoacoustic detection and analysis of prostate cancer. These findings could lead to the development of a new noninvasive technique for the detection and monitoring of prostate cancer progression in an animal model that can potentially be translated to human patients.

show abstract

The Phenazine Scaffold Used as Cytotoxic Pharmacophore Applied in Bactericidal, Antiparasitic and Antitumor Agents

Miksa

2022

Helvetica Chimica Acta

View full text Add to dashboard Cite

Phenazine derivatives are important bactericidal antibiotics and antiparasitic compounds which can be used in synergistic combinations with anticancer drugs in chemotherapy treatments. The development of synthetic phenazines with anticancer activity improves the effectiveness of chemotherapy. Chemical variations introduced at the phenazine core which is known as a chromophore with fluorescent properties provide advanced theranostic agents useful in optical bioimaging techniques and photodynamic anticancer therapy. This review summarizes the field of structural modifications of phenazine derivatives which have been tested against different parasitic and bacterial infections. The report highlights advances in design and biological evaluations of phenazines as anticancer drugs for the development of new chemotherapeutic as well as bio‐imaging reagents.

show abstract

Synthesis and Characterization of a Biomimetic Formulation of Clofazimine Hydrochloride Microcrystals for Parenteral Administration

Cited by 18 publications

References 29 publications

Prediction of aqueous intrinsic solubility of druglike molecules using Random Forest regression trained with Wiki-pS0 database

Prediction of aqueous intrinsic solubility of druglike molecules using Random Forest regression trained with Wiki-pS0 database

Photoacoustic imaging of clofazimine hydrochloride nanoparticle accumulation in cancerous vs normal prostates

The Phenazine Scaffold Used as Cytotoxic Pharmacophore Applied in Bactericidal, Antiparasitic and Antitumor Agents

Contact Info

Product

Resources

About