Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility–Permeability Interplay

Beig, Avital; Miller, Jonathan M.; Lindley, David; Carr, Robert; Zocharski, Philip; Agbaria, Riad; Dahan, Arik

doi:10.1002/jps.24496

Cited by 69 publications

(41 citation statements)

References 35 publications

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“…Amorphous formulations can therefore significantly increase the concentration of drug in solution, while also maintaining a constant effective permeability, giving them a superior solubility-permeability balance. 21,67 The results of this study are therefore in line with those of other researchers, with all of the CIP ASDs enhancing the solubility of the drug in water and FaSSIF, without a subsequent decrease in permeability. The crystalline CIP HCl salt on the other hand significantly reduced the permeability of the drug, most likely due to greater ionization of CIP.…”

Section: Pampa Permeability Studysupporting

confidence: 92%

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Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin

et al. 2017

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Ciprofloxacin (CIP) is a poorly soluble drug that also displays poor permeability. Attempts to improve the solubility of this drug to date have largely focused on the formation of crystalline salts and metal complexes. The aim of this study was to prepare amorphous solid dispersions (ASDs) by ball milling CIP with various polymers. Following examination of their solid state characteristics and physical stability, the solubility advantage of these ASDs was studied, and their permeability was investigated via parallel artificial membrane permeability assay (PAMPA). Finally, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the ASDs were compared to those of CIP. It was discovered that acidic polymers, such as Eudragit L100, Eudragit L100C==, Carbopol and HPMCAS, were necessary for the amorphization of CIP. In each case, the positively charged secondary amine of CIP was found to interact with carboxylate groups in the polymers, forming amorphous polymeric drug salts. Although the ASDs began to crystallize within days under accelerated stability conditions, they remained fully XCray amorphous following exposure to 90% RH at 25 oC, and demonstrated higher than predicted glass transition temperatures. The solubility of CIP in water and simulated intestinal fluid was also increased by all of the ASDs studied. Unlike a number of other solubility enhancing formulations, the ASDs did not decrease the permeability of the drug.Similarly, no decrease in antibiotic efficacy was observed, and significant improvements in the MIC and MBC of CIP were obtained with ASDs containing HPMCASC") and HPMCASCMG. Therefore, ASDs may be a viable alternative for formulating CIP with improved solubility, bioavailability and antimicrobial activity.

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Section: Pampa Permeability Studysupporting

confidence: 92%

“…21,67 According to Miller et al, preparations such as these increase the equilibrium solubility of drugs, which results in a decrease in their apparent cell membrane/intestinal lumen partition coefficient.…”

Section: Pampa Permeability Studymentioning

confidence: 99%

Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin

et al. 2017

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“…22 The effect of SLS on drug absorption has been previously characterized using in vitro systems and preclinical species for various agents including cefadroxil 42 and the poorly soluble agents amiodarone 43 and etoposide. 44 The results in this study represent a clinical example of the role of SLS as a functional excipient and wetting agent used to enhance the bioavailability of a poorly soluble molecule. The observed clinical results showing an impact of reducing the amount of SLS in the formulation suggest that the original in vitro dissolution experiment using the USP Apparatus 2 method for selection of alternate formulations may not be sufficiently discriminatory in revealing in vivo effects (data on file).…”

Section: Discussionmentioning

confidence: 87%

Effect of the Wetting Agent Sodium Lauryl Sulfate on the Pharmacokinetics of Alectinib: Results From a Bioequivalence Study in Healthy Subjects

Morcos

Parrott

Banken

et al. 2016

Clinical Pharm in Drug Dev

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The anaplastic lymphoma kinase (ALK) inhibitor alectinib is an effective treatment for ALK-positive non-small-cell lung cancer. This bioequivalence study evaluated the in vivo performance of test 3 formulations with the reduced wetting agent sodium lauryl sulfate (SLS) content. This randomized, 4-period, 4-sequence, crossover study compared alectinib (600 mg) as 25%, 12.5%, and 3% SLS hard capsule formulations with the reference 50% SLS clinical formulation in healthy subjects under fasted conditions (n = 49), and following a high-fat meal (n = 48). Geometric mean ratios and 90% confidence intervals (CIs) for C , AUC , and AUC of alectinib, its major active metabolite, M4, and alectinib plus M4 were determined for the test formulations versus the reference formulation. Bioequivalence was concluded if the 90%CIs were within the 80% to 125% boundaries. The 25% SLS formulation demonstrated bioequivalence to the reference 50% SLS formulation for C , AUC , and AUC of alectinib, M4, and alectinib plus M4 under both fasted and fed conditions. Further reductions in SLS content (12.5% and 3% SLS) did not meet the bioequivalence criteria. Cross-group comparisons showed an approximately 3-fold positive food effect. Reducing SLS to 25% resulted in a formulation that is bioequivalent to the current 50% SLS formulation used in alectinib pivotal trials.

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“…But, as a P-gp interaction was not evident for petasins, no absorption enhancement is assumed. Other studies referred to PEG 400 as having no effect [19] or a negative effect on absorption of lipophilic substances that induce a decrease of absorption [20,21]. As petasins are classified as lipophilic substances, determined in situ absorptions of petasins might be rather underestimated.…”

Section: Introductionmentioning

confidence: 99%

In Vitro and In Situ Absorption and Metabolism of Sesquiterpenes from Petasites hybridus Extracts

et al. 2018

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extract is used in the treatment of seasonal allergic rhinitis. The aim of this study was to evaluate the active constituent petasin and its isomers isopetasin and neopetasin (petasins) in the extract Ze 339 for liberation, dissolution, absorption, and metabolism. The determination of pH-dependent thermodynamic solubility was performed via the shake-flask method. Petasins exhibited a low solubility that was pH independent., the concentration of solute drugs is decreased continuously by intestinal absorption. Therefore, low solubility is not assumed to be critical for performance. Additionally, dissolution of an herbal medicinal product containing extract Ze 339 was assessed. Furthermore, high permeability through Caco-2 monolayers was evident. Using an rat model, absorption capacity for petasins was found in all tested intestinal segments, namely, duodenum, jejunum, and ileum. Besides, high metabolism was evident both in Caco-2 monolayers and in the rat intestine. To compare intestinal and hepatic metabolism of petasins, enzyme assays using liver and intestinal cytosol and microsomes (S9 fraction) of rats and humans were performed. A significantly higher metabolic rate was found in the liver S9 fraction of both species compared with the intestinal S9 fraction.

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Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility–Permeability Interplay

Cited by 69 publications

References 35 publications

Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin

Amorphous Polymeric Drug Salts as Ionic Solid Dispersion Forms of Ciprofloxacin

Effect of the Wetting Agent Sodium Lauryl Sulfate on the Pharmacokinetics of Alectinib: Results From a Bioequivalence Study in Healthy Subjects

In Vitro and In Situ Absorption and Metabolism of Sesquiterpenes from Petasites hybridus Extracts

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