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Title

Investigation and Mathematical Description of the Real Driving Force of Passive Transport of Drug Molecules from Supersaturated Solutions

 

Authors

Enikő Borbás, Bálint Sinkó, Oksana Tsinman, Konstantin Tsinman, Éva Kiserdei, Balázs Démuth, Attila Balogh, Brigitta Bodák, András Domokos, Gergő Dargó, György T. Balogh,
and Zsombor K. Nagy

 

Abstract
The aim of this study was to investigate the impact of formulation excipients and solubilizing additives on dissolution, supersaturation, and membrane transport of an active pharmaceutical ingredient (API). When a poorly water-soluble API is formulated to enhance its dissolution, additives, such as surfactants, polymers, and cyclodextrins, have an effect not only on dissolution profile but also on the measured physicochemical properties (solubility, pKa, permeability) of the drug while the excipient is present, therefore also affecting the driving force of membrane transport. Meloxicam, a nonsteroidal anti-inflammatory drug, was chosen as a poorly water-soluble model drug and formulated in order to enhance its dissolution using solvent-based electrospinning. Three polyvinylpyrrolidone (PVP) derivatives (K30, K90, and VA 64), Soluplus, and (2-hydroxypropyl)-β-cyclodextrin were used to create five different amorphous solid dispersions of meloxicam. Through experimental design, the various formulation additives that could influence the characteristics of dissolution and permeation through artificial membrane were observed by carrying out a simultaneous dissolution−permeation study with a side-by-side diffusion cell, μFLUX. Although the dissolution profiles of the formulations were found to be very similar, in the case of Soluplus containing formulation the flux was superior, showing that the driving force of membrane transport cannot be simplified to the concentration gradient. Supersaturation gradient, the difference in degree of supersaturation (defined as the ratio of dissolved amount of the drug to its thermodynamic solubility) between the donor and acceptor side, was found to be the driving force of membrane transport. It was mathematically derived from Fick’s first law, and experimentally proved to be universal on several meloxicam containing ASDs and DMSO stock solution.

 

Publication

Molecular Pharmaceuticals

 

Link

 

http://pubsdc3.acs.org/articlesonrequest/AOR-FJAmzmwvgfCGXdaEu39C 

 

 

 

 

Title

Utilizing In Vitro Dissolution-Permeation Chamber for the Quantitative Prediction of pH-Dependent Drug-Drug Interactions with Acid-Reducing Agents: a Comparison with Physiologically Based Pharmacokinetic Modeling

 

Authors

Zhu AZ, Ho MD, Gemski CK, Chuang BC, Liao M, Xia CQ.

 

Abstract
For many orally administered basic drugs with pH-dependent solubility, concurrent administration with acid-reducing agents (ARAs) can significantly impair their absorption and exposure. In this study, pH-dependent drug-drug interaction (DDI) prediction methods, including in vitro dissolution-permeation chamber (IVDP) and physiologically based pharmacokinetic (PBPK) modeling, were evaluated for their ability to quantitatively predict the clinical DDI observations using 11 drugs with known clinical pH-dependent DDI data. The data generated by IVDP, which consists of a gastrointestinal compartment and a systemic compartment separated by a biomimic membrane, significantly correlated with the clinical DDI observations. The gastrointestinal compartment AUC ratio showed strong correlation with clinical AUC ratio (R=0.72 and P=0.0056), and systemic compartment AUC ratio showed strong correlation with clinical Cmax ratio (R=0.91 and P=0.0003). PBPK models were also developed for the 11 test compounds. The simulations showed that the predictions from PBPK model with experimentally measured parameters significantly correlated with the clinical DDI observations. Future studies are needed to evaluate predictability of Z-factor-based PBPK models for pH-dependent DDI. Overall, these data suggested that the severity of pH-dependent DDI can be predicted by in vitro and in silico methods. Proper utilization of these methods before clinical DDI studies could allow adequate anticipation of pH-dependent DDI, which helps with minimizing pharmacokinetic variation in clinical studies and ensuring every patient with life-threatening diseases receives full benefit of the therapy.

 

Publication

SpringerLink

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/27600136

 

 

 

 

Title

Kinetics of drug release from ointments: Role of transient-boundary layer

 

Authors

Xiaoming Xu1, Manar Al-Ghabeish1, Yellela S.R. Krishnaiah, Ziyaur Rahman, Mansoor A. Khan

 

Abstract

In the current work, an in vitro release testing method suitable for ointment formulations was developed using acyclovir as a model drug. Release studies were carried out using enhancer cells on acyclovir ointments prepared with oleaginous, absorption, and water-soluble bases. Kinetics and mechanism of drug release was found to be highly dependent on the type of ointment bases. In oleaginous bases, drug release followed a unique logarithmic-time dependent profile; in both absorption and water-soluble bases, drug release exhibited linearity with respect to square root of time (Higuchi model) albeit differences in the overall release profile. To help understand the underlying cause of logarithmic-time dependency of drug release, a novel transient-boundary hypothesis was proposed, verified, and compared to Higuchi theory. Furthermore, impact of drug solubility (under various pH conditions) and temperature on drug release were assessed. Additionally, conditions under which deviations from logarithmic-time drug release kinetics occur were determined using in situ UV fiber-optics. Overall, the results suggest that for oleaginous ointments containing dispersed drug particles, kinetics and mechanism of drug release is controlled by expansion of transient boundary layer, and drug release increases linearly with respect to logarithmic time.

 

Publication

Elsevier B.V.

 

Link

http://www.sciencedirect.com/science/article/pii/S0378517315300958

 

 

 

 

Title

Spectrophotometric pKa determination of ionizable pharmaceuticals: Resolution of molecules with weak pH-dependent spectral shift

 

Authors

Deren Dohoda, Konstantin Tsinman, Oksana Tsinman, Haotian Wang, Kin Y. Tam 

 
Highlights
  • A UV method for measuring pKa of drugs with weak spectral shift is developed.
  • The pKa values determined are in good agreement with literature data (R2 = 0.998).
  • Successful pKa determination even when chromophore and ionizable group are 5 σ bonds apart. 

 

Abstract

The extent of ionization of a drug molecule at different pH values can be characterized by its pKa (acid dissociation constants). It is an important parameter in pharmaceutical development to rationalize the physiochemical and biopharmaceutical properties of the drug molecule. UV titration for pKa determination is one of the popular methods. The success of this method requires the molecule exhibiting strong pH-dependent spectral shift related to the ionization process. Depending on the proximity between the ionizable group and the chromophore, the spectral shift may not be strong enough to warrant a successful determination. In a previous study, it has been reported that a distance of three σ bonds between the chromophore and the ionizable group was the limit for a precise pKa determination. In this work, a UV titration method for pKa determination, with a particular emphasis on molecules with weak pH-dependent spectral shift is investigated. It has been shown that the pKa values determined from this study are in good agreement with those determined using potentiometric method and literature data (R2 = 0.998). Our methodology revealed that successful pKa determination is feasible even with a separation distance of five σ bonds between the chromophore and the ionizable group.

 

Link

http://www.sciencedirect.com/science/article/pii/S0731708515002952

 

 

 

 

Title

In vitro dissolution-permeation evaluation of an electrospun cyclodextrin-based formulation of aripiprazole using µFLUX™

 

Authors

Enikő Borbás, Attila Balogh, Katalin Bocz, Judit Müller, Éva Kiserdei, Tamás Vigh, Bálint Sinkó, Attila Marosi, Attila Halász, Zoltán Dohányos, Lajos Szente, György T. Balogh, Zsombor K. Nagy

Abstract

Since it is a well-known fact that among the newly discovered active pharmaceutical ingredients the number of poorly water soluble candidates is continually increasing, dissolution enhancement of poorly water soluble drugs has become one of the central challenges of pharmaceutical studies. So far the preclinical studies have been mainly focused on formulation methods to enhance the dissolution of active compounds, in many cases disregarding the fact that the formulation matrix not only affects dissolution but also has an effect on the transport through biological membranes, changing permeation of the drug molecules. The aim of this study was to test an electrospun cyclodextrin-based formulation of aripiprazole with the novel μFlux apparatus, which monitors permeation together with dissolution, and by this means better in vitroin vivocorrelation is achieved. It was evinced that a cyclodextrin-based electrospun formulation of aripiprazole has the potential to ensure fast drug delivery through the oral mucosa owing to the ultrafast dissolution of the drug from the formulation and the enhanced flux across membranes as shown by the result of the novel in vitro dissolution and permeation test.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/26117189