Production and characterization of spray-dried theophylline powders prepared from fresh milk for potential use in paediatrics

"This is the accepted version of the following article: Production and characterization of spray-dried theophylline powders prepared from fresh milk for potential use in paediatrics (2017). J Pharm Pharmacol, 69: 554–566, which has been published in final form at http://dx.doi.org/10.1111/jphp.12612 . This article may be used for non-commercial purposes in accordance with the Wiley Self-Archiving Policy [http://olabout.wiley.com/WileyCDA/Section/id-820227.html]."Objective: This work evaluates the potential of using fresh milk to deliver theophylline to children.Methods: Theophylline–fresh milk systems were prepared using different solids ratios (0 : 1–1 : 0) and three fat contents in commercial milks (low, medium and high), which were spray-dried at different inlet air temperatures (Tinlet – 105, 130 and 150 °C). The process was evaluated for yield and the resulting powders for moisture content (MC), particle size and shape, density and wettability. Theophylline–milk potential interactions (differential scanning calorimetry (DSC) and FT-IR) and chemical (theophylline content) and microbiological stability of powders (shelf and in-use) were also evaluated.Key Findings: The production yield (13.6–76.0%), MC (0.0–10.3%) and contact angles in water (77.29–93.51°) were significantly (P < 0.05) affected by Tinlet, but no differences were found concerning the mean particle size (3.0–4.3 μm) of the different powders. The milk fat content significantly (P < 0.05) impacted on the density (1.244–1.552 g/cm3). Theophylline content remained stable after 6 months of storage, before extemporaneous reconstitution. After reconstitution in water, low-fat milk samples (stored at 4 °C) met the microbial pharmacopoeia criteria for up to 7 days. No theophylline–milk components interaction was observed.Conclusion: Spray-dried milk-composed powders may be used as vehicles for theophylline delivery in paediatrics following further characterization and in-vivo evaluation.info:eu-repo/semantics/publishedVersio

Power law IVIVC: An application of fractional kinetics for drug release and absorption

Most correlations between in vitro and in vivo data (IVIVC) rely on linear relationships. However, non-linear IVIVC can be also observed, justified and validated. The purpose of the present work was the development of a methodology for power law IVIVC, which mirror power law kinetics under in vitro and in vivo conditions. Fractional calculus was used to justify power law kinetics for zero-order processes in disordered media. Power law kinetics was observed in a large number of in vitro data sets. When &quot; zero-order&quot; release and absorption is considered in terms of fractional calculus the following power law IVIVC between the fraction released Fr and the fraction absorbed Fa, is obtained: Fa=μFrλ-β, where μ is a constant related to the rate constants and the orders of the release/absorption kinetics, λ is the ratio of the orders of the kinetics under in vitro and in vivo conditions and β accounts for a time shift between the in vitro and in vivo processes; We used literature data to develop power law IVIVC and derive estimates for μ, λ and β; the simulated pharmacokinetic profiles using the in vitro release data and the IVIVC developed compared well with the actual in vivo data. © 2010 Elsevier B.V

Novel milk-based oral formulations: Proof of concept

The aim of this study is to develop milk-based formulations for ionized and unionized lipophilic drugs. Solubility studies of the following non-steroidal anti-inflammatory drugs (NSAIDs): mefenamic acid, tolfenamic acid, ketoprofen, meloxicam, tenoxicam and nimesulide in phosphate- and glycine-NaOH buffers at nominal pH 8-12, were performed. The solubilities of cyclosporine and danazol in water-ethanol solutions were studied. NSAIDs-, cyclosporine-, danazol-, aspirin-milk oral liquid formulations were prepared by adding the appropriate volume of (i) NSAIDs-alkaline buffer solutions, (ii) water-ethanol solutions of cyclosporine and danazol and (iii) aspirin aqueous solution to 150-200. ml of milk. All the non-steroidal anti-inflammatory drugs exhibited increased solubility in the alkaline buffers. The actual pH values (range 6.7-7.7) of the final NSAIDs-milk formulations were very close to milk pH. The higher ethanol content in ethanol-water mixtures increased the solubility of danazol and cyclosporine. A 15. mg meloxicam-, a 100. mg cyclosporine- and a 500. mg aspirin-milk formulation was administered orally to healthy volunteers. All these formulations showed a satisfactory in vivo performance. The strong buffering capacity of milk that was observed and the high solubility of unionized drugs in ethanol allow the preparation of drug-milk formulations with enhanced pharmacokinetic properties. © 2010 Elsevier B.V

Novel scaled bioequivalence limits with leveling-off properties

Purpose. (1) To develop novel scaled bioequivalence (BE) limits with levelling-off properties based solely on variability considerations and (2) to evaluate their performance in comparison to the classic unscaled BE limits 0.80-1.25, the expanded BE limits 0.75-1.33 and the recently proposed Geometric Mean Ratio (GMR)-dependent scaled BE limits BELscW (Karalis et al., Eur. J. Pharm. Sci., 26:54-61, 2005). Materials and Methods. Two model functions were used to ensure the gradual change of the BE limits from a starting value towards a predefined plateau value. Plots of the new BE limits and extreme GMR values ensuring BE as a function of the coefficient of variation (CV) were constructed. Two-period crossover BE studies with 12, 24, or 36 subjects were simulated assuming CV values from 10 to 60%. Power curves were constructed by recording the percentage of accepted BE studies as the true GMR was raised from 1.00 to 1.50. The percentage of the true GMR within the simulated BE limits vs. true GMR was used to evaluate the estimation accuracy of the scaled methods. Results. Depending on the parameters&apos; values of the model functions, the scaled BE limits exhibit different performance. Four new scaled BE limits, showing favourable performance for the evaluation of average BE are presented. At low variability levels two of the novel BE limits show similar performance to the 0.80-1.25 criterion, while the other two (as expected from their design) appear to be less permissive. At high CV values (30, 40%) all new BE limits exhibit much higher statistical power than the 0.80-1.25 criterion. They show almost identical behavior with the expanded 0.75-1.33 limits and appear to be less permissive than BELscW. Finally, the percentage of the true GMR within the simulated BE limits vs. true GMR shows a sharp decline. Due to the absence of the GMR factor in the model functions a more accurate estimation of the new scaled BE limits, compared to BELscW, is observed. Conclusions. The new scaled BE limits appear to be highly effective at all levels of variation investigated and present satisfactory estimation accuracy. © 2006 Springer Science+Business Media, LLC

Stability and physicochemical characterization of novel milk-based oral formulations

Purpose: The purpose of this work was to assess the colloidal stability of novel milk-based formulations. Methods: Milk-based formulations were prepared in situ by adding into milk alkaline- or ethanolic-drug solutions containing an array of drugs namely; ketoprofen, tolfenamic acid, meloxicam, tenoxicam and nimesulide, mefenamic acid, cyclosporine A, danazol and clopidogrel besylate. The produced formulations were characterized by means of dynamic lightscattering, ζ-potential studies, atomic force microscopy, fluorescence spectroscopy, Raman spectroscopy complemented with ab initio calculations and stability studies. Results: The presence of the drugs did not induce significant changes in most cases to the particle size and ζ-potential values of the emulsions pointing to the colloidal stability of these formulations. Raman spectroscopy studies revealed interactions of the drugs and the milk at the intermolecular level. Complementary analysis with ab initio calculations confirmed the experimental observations obtained by Raman spectroscopy. Finally the produced drug containing alkaline/ethanolic solutions exhibited stability over a period of up to 12 months. Conclusions: The current data demonstrate that milk is a promising drug carrier. © 2013 Elsevier B.V. All rights reserved