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Scientific publication

New biomimetic barrier Permeapad™ for efficient investigation of passive permeability of drugs

In this work the suitability of a newly invented physical patch comprising a biomimetic barrier (named Permeapad™) for drug permeability tests has been investigated. Exemplars of Permeapad™ were adapted to Franz diffusion cells and apparent permeability (Papp) of a series of drugs were measured and compared with calculated partition coefficients (logPcal) of the investigated drugs as well as literature reference values obtained from Parallel Artificial Membrane Permeation Assay (PAMPA) and the cellular based method Caco-2. Moreover, tightness of the barrier to hydrophilic marker’s permeation, resistance of these barriers to proton permeation (pH changes) and shelf-life functionality were also investigated. Comparison with the published data indicated a good correlation between the permeability values measured and partition coefficients (logPcal). Moreover, a good correlation between the permeabilities measured with the new barrier and well-established in vitro permeability methods (PAMPA and Caco-2 respectively) was found for both highly absorbed and poorly permeable compounds. Permeapad™ also proved to maintain high integrity over time and in different pH environments. In conclusion,Permeapad™ as an innovative barrier appears to be a promising tool for fast, cost effective and reliable screening of drugs and chemical entities’ passive permeability.

©2015 Elsevier B.V. All rights reserved

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PermeapadTM for investigation of passive drug permeability: The effect of surfactants, co-solvents and simulated intestinal fluids (FaSSIF and FeSSIF)

The aim of the present work was to investigate the potential of the new and innovative artificial barrier, PermeapadTM, when exposed to surfactants and co-solvents, often employed for poorly water soluble compounds. The barrier was in addition also exposed to fasted and fed state simulated intestinal fluids versions 1 and 2 (FaSSIF and FeSSIF), all of which the PermeapadTM barrier was compatible with based upon relative comparison of the permeability of the hydrophilic marker calcein in phosphate buffer. The new barrier therefore holds a huge potential due to its functional stability and robustness. It can be used as a standard tool to investigate permeability of drugs in the presence of different surfactants and co-solvents, from DMSO stock solutions at even high concentrations and for the evaluation of permeability in the presence of biomimetic media (BMM).

© 2015 Elsevier B.V. All rights reserved

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Use of Permeapad® for prediction of buccal absorption: A comparison to in vitro, ex vivo and in vivo method

The present work explores the usefulness of Permeapad® for prediction of buccal absorption. Permeability studies with themodel drug metoprololwere carried out using the Permeapad® barrier at pH values 7.4; 8.5; 9.0, and 9.5. It was confirmed that Permeapad® can withstand these conditions, and as expected, a clear increase in permeability was found with increasing pH. The permeation results across Permeapad® were compared to published in vitro, ex vivo and in vivo studies for the same formulations. Results showed that the permeability of metoprolol using the Permeapad® barrier correlated very well to both in vitro and ex vivo studies, (r2 = 0.98 and 0.97), respectively. Furthermore, excellent in vitro in vivo correlation IVIVC (r2 = 0.98) was obtained when comparing apparent permeability coefficient to the absolute bioavailability of metoprolol administered buccally to mini-pigs. Results indicate that Permeapad® can be used to mimic the buccal absorption of metoprolol as a faster and less laborious method as compared to any of the other mentioned methods.

© 2016 Elsevier B.V. All rights reserved.

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Evaluation of a dynamic dissolution/permeation model: Mutual influence of dissolution and barrier-flux under non-steady state conditions

Combined dissolution/permeation testing is gaining increasing attention as an in vitro tool for predictive performance ranking of enabling oral formulations. The current aim was to study how in vitro drug permeation evolves under conditions, where the donor concentration is changing (non-steady state). To this end, a model case was construed: compacts of pure crystalline hydrocortisone methanolate (HCMeOH) of slow release rates were prepared, and their dissolution and permeation determined simultaneously in a side-by-side setup, separated by a biomimetic barrier (Permeapad1). This was compared to a corresponding setup for a suspension of micronized hydrocortisone (HC). The HC suspension showed constant dissolved HC concentration and constant flux across the barrier, representing the permeation-limited situation. For the HCMeOH compacts, various dynamic scenarios were observed, where dissolution rate and flux influenced each other. Interestingly, for all the dynamic scenarios, the incremental flux values obtained correlated nicely with the corresponding actual donor concentrations. Furthermore, donor depletion was tested using a HC solution. The dynamic interplay between decrease in donor concentration (down to less than 10% of the initial concentration) and flux was studied. The experiences gained are discussed in terms of further developing combined dissolution/ permeation setups.

© 2017 Elsevier B.V. All rights reserved

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Simultaneous lipolysis/permeation in vitro model, for the estimation of bioavailability of lipid based drug delivery systems

The simultaneous processes of lipid digestion and absorption together determine the oral bioavailability of drugs incorporated into lipid based drug delivery systems (LBDDS). A number of slightly different protocols
for in vitro lipolysis are widely accepted; however, the permeation process has so far not been included into the models due to the harsh conditions of lipid digestion compromising permeation barriers. The present study for the first time combines biomimetic permeation and lipolysis of LBDDS. The focus of the current work was on the functional stability of the barrier - Permeapad during lipid digestion. Using calcein as a marker molecule the investigations demonstrated that the barrier was able to maintain its permeation properties in the presence of the SNEDDS (self-emulsifying drug delivery system) formulation, the lipolysis medium, and the lipolysis medium while digesting the SNEDDS. Furthermore, the permeation of cinnarizine (CINN) from SNEDDS was demonstrated to be lower, if the formulation as such was applied as compared to the digested formulation. This support the general perception that meaningful in vitro evaluation of lipid based formulations requires consideration of both, the digestion and absorption, i.e. lipolysis and permeation.

 2017 Published by Elsevier B.V.

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Drug permeability profiling using cell-free permeation tools: Overview and applications

Cell-free permeation systems are gaining interest in drug discovery and development as tools to obtain a reliable prediction of passive intestinal absorption without the disadvantages associated with cell- or tissue-based permeability profiling. Depending on the composition of the barrier, cell-free permeation systems are classified into two classes including (i) biomimetic barriers which are constructed from (phospho)lipids and (ii) non-biomimetic barriers containing dialysis membranes. This review provides an overview of the currently available cellfree permeation systems including Parallel Artificial Membrane Permeability Assay (PAMPA), Phospholipid Vesicle-based Permeation Assay (PVPA), Permeapad®, and artificial membrane based systems (e.g. the artificial membrane insert system (AMI-system)) in terms of their barrier composition as well as their predictive capacity in relation to well-characterized intestinal permeation systems. Given the potential loss of integrity of cell-based permeation barriers in the presence of food components or pharmaceutical excipients, the superior robustness of cell-free barriers makes them suitable for the combined dissolution/permeation evaluation of formulations. While cell-free permeation systems are mostly applied for exploring intestinal absorption, they can also be used to evaluate non-oral drug delivery by adjusting the composition of the membrane.

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A dynamic in vitro permeation study on solid mono- and diacylphospholipid dispersions of celecoxib

The current study documents enhanced apparent solubility of the BCS class II drug celecoxib (CXB) when formulated as solid phospholipid dispersion (SPD) with either mono- or diacyl-phospholipids by freeze drying from hydro-alcoholic solvent. The enhanced solubility upon dispersion in buffer or fasted state simulated intestinal fluid (FaSSIF) is interpreted to be due to two effects: (1) amorphization of CXB, inducing supersaturation, which is also observed when CXB is freeze dried in the absence of phospholipids and (2) association of CXB with spontaneously forming colloidal structures, such as vesicles and/or micelles, promoting solubilization. The latter effect depended on the CXB-to-phospholipid ratio, where monoacyl-phospholipid was a more efficient solubilizer than diacyl-phospholipid.

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Interpreting non-linear drug diffusion data: Utilizing Korsmeyer-Peppas model to study drug release from liposomes

The aim of this work was to clarify the dynamics behind the influence of ionic strength on the changes in drug release from large unilamellar vesicles (LUVs). For this purpose, we have investigated the transport of two different model drugs (caffeine and hydrocortisone) formulated into liposomes through different types of barriers with different retention properties (regenerated cellulose and the newly introduced biomimetic barrier, Permeapad®). Drug release from liposomes was studied utilizing the standard Franz diffusion cells. LUV dispersions were exposed to the isotonic, hypotonic and hypertonic environment (difference of 300 mOsm/kg between the initial LUVs and the environment) and experimental data treated with both linear and non-linear (Korsmeyer-Peppas) regression models. To alter the rigidity of the liposomal membranes, cholesterol was introduced in the liposomal barriers (up to 25% w/w). Korsmeyer-Peppas model was proven to be suited to analyse experimental data throughout the experimental time frame, providing important additive information in comparison to standard linear approximation. The obtained results are highly relevant as they improve the interpretation of drug release kinetics from LUVs under osmotic stress. Moreover, the findings can be utilized in the development of liposomal formulations intended for nose-to-brain targeted drug delivery.

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PermeaPad® - A new biomimetic tool for drug permeability studies
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The effect of different polymers on the solubility, permeability and distribution of poor soluble 1,2,4-thiadiazole derivative

Solubility and permeability are the main parameters determining the bioavailability of drugs. In this study the increased solubility of novel 1,2,4-thiadiazole derivative (TDZ) proposed for the prevention and treatment of Alzheimer's disease was achieved in the solutions of polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), and pluronic F127 (F127). It was found that solubilizing power of polymers follows the order F127 > PVP > PEG. The mechanism of TDZ solubilization was proposed on the basis of 1H NMR and UV-spectroscopy studies. It was suggested that PEG enhances the TDZ solubility by acting mainly as cosolvent, whereas PVP can be considered as cosolvent and complexing agent. In case of F127, the insertion of TDZ into micelles was detected. The solubilization capacity of pluronic was quantified in terms of average number of TDZ and F127 per micelle and binding constant. In order to reveal the effect of polymers on the TDZ membrane permeability, the distribution coefficients in the 1-octanol/buffer system and permeability coefficients through the novel Permeapad™ barrier were determined. The solubility-permeability and solubility-distribution relationships were discussed.

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Impact of Pluronics of different structure on pharmacologically relevant properties of sulfasalazine and methotrexate

The work was focused on comprehensive evaluation and comparison of the effect of Pluronics of different architecture on the pharmacologically relevant properties of methotrexate and sulfasalazine. Solubility of drugs was measured in buffers pH = 1.6 and pH = 6.8 with variable amount of Pluronics L64, F68, F88 and F127. Solubilization capacity and micelle-water partition coefficients were estimated and analyzed. Influence of the length of poly(ethylene oxide) and poly(propylene oxide) fragments in the polymer structure on the solubilizing effect was revealed. The observed solubility increase in the presence of Pluronics follows the order F127 > F88 > F68 > L64. Interactions of methotrexate and sulfasalazine with Pluronic micelles were characterized. Binding mode and composition of micelle/drug aggregates were proposed. The effect of Pluronics on the permeability of drugs across the model barrier Permeapad™ was investigated. The decrease of the permeability coefficients was discussed in terms of the change of medium viscosity and interactions of the drugs with the micelles.

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Impact of pluronic F127 on aqueous solubility and membrane permeability of antirheumatic compounds of different structure and polarity

Solubilization of the disease modifying antirheumatic drugs (methotrexate, leflunomide and sulfasalazine) in micelles of amphiphilic triblock copolymer Pluronic F127 was studied in buffers with physiological pH. The solubilization follows the order leflunomide ≫ sulfasalazine > methotrexate. It was found that the size and ionization state of the drug molecules play an important role in the binding with the Pruronic F127 micelles. The higher solubilizing effect of Pluronic F127 on leflunomide can be caused by smaller geometrical dimensions and higher hydrophobicity of this drug. The 1D 1H and 2D ROESY NMR, UV-vis spectroscopy and dynamic light scattering experiments were used to get insight into the interaction between Pluronic F127 micelles and antirheumatic drugs in aqueous solutions. Among the drugs under consideration only leflunomide can be located in the micelle core more deeply. Effect of Pluronic F127 on membrane permeability was also examined using Permeapad™ barrier imitating the membranes of the intestinal epithelium. It was found that solubilizing effect of Pluronic F127 is accompanied by decrease of drug permeability.

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Self-emulsifying drug delivery systems: About the fate of hydrophobic ion pairs on a phospholipid bilayer

Purpose To investigate the fate of hydrophobic ion pairs (HIPs) and self-emulsifying drug delivery systems (SEDDS) containing HIPs on a phospholipid bilayer.

Methods HIPs of fluorescein (FL) were formed using the lipophilic cationic counter ion octadecylamine (OCT). HIPs were incorporated into SEDDS comprising 30% Capryol 90, 40% Cremophor RH, 20% Maisine 35-1 and 10% propylene glycol and evaluated regarding log DSEDDS/release medium and dissociation of these complexes at various pH values over time. Furthermore, in vitro permeation studies were carried out in order to evaluate the fate of HIPs and SEDDS containing HIPs on a phospholipid bilayer.

Results HIPs of FL with OCT showed the highest precipitation efficiency at a stoichiometric ratio of 1:1. HIPs (1% v/v) were incorporated into SEDDS pre-concentrate. Log DSEDDS/release medium of incorporated complexes was between 2.5 and 3.5. HIPs dissociated in aqueous media up to 20% at pH 6–7.4 within 4 h. In vitro permeation studies revealed 2.7-fold improved permeation of FL after complex formation and incorporation in SEDDS. Results suggest that SEDDS fuse with the phospholipid bilayer facilitating the permeation of incorporated HIPs.

Conclusion SEDDS enhance the stability of incorporated HIPs and improve their permeation across phospholipid bilayers.

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In vitro digestion models to evaluate lipid based drug delivery systems; present status and current trends

During the past two decades, a range of in vitro models simulating the digestion processes occurring in the stomach and small intestine have been developed to characterize lipid based drug delivery systems (LbDDSs). This review describes the presently existing range of in vitro digestion models and their use in the field of oral drug delivery. The models are evaluated in terms of their suitability to assess LbDDSs, and their ability to produce in vitro - in vivo correlations (IVIVCs).

While the pH-stat lipolysis model is by far the most commonly utilized in vitro digestion model in relation to characterizing LbDDSs, a series of recent studies have shown a lack of IVIVCs limiting its future use. Presently, no single in vitro digestion model exists which is able to predict the in vivo performance of various LbDDSs. However, recent research has shown the potential of combined digestion-permeation models as well as species specific digestion models.

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Estimating the Oral Absorption from Self-Nanoemulsifying Drug Delivery Systems Using an In Vitro Lipolysis-Permeation Method

The aim of this study was to design an in vitro lipolysis-permeation method to estimate drug absorption following the oral administration of self-nanoemulsifying drug delivery systems (SNEDDSs). The method was evaluated by testing five oral formulations containing cinnarizine (four SNEDDSs and one aqueous suspension) from a previously published pharmacokinetic study in rats. In that study, the pharmacokinetic profiles of the five formulations did not correlate with the drug solubilization profiles obtained during in vitro intestinal lipolysis. Using the designed lipolysis-permeation method, in vitro lipolysis of the five formulations was followed by in vitro drug permeation in Franz diffusion cells equipped with PermeaPad® barriers. A linear in vivo–in vitro correlation was obtained when comparing the area under the in vitro drug permeation–time curve (AUC0–3h), to the AUC0–3h of the plasma concentration–time profile obtained from the in vivo study. Based on these results, the evaluated lipolysis-permeation method was found to be a promising tool for estimating the in vivo performance of SNEDDSs, but more studies are needed to evaluate the method further.

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Permeability studies using PermeaPad® Barrier in a Franz-cell set-up

Investigate the permeation of caffeine across the artificial, biomimetic barrier, PermeaPad®
Barrier.

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Permeability studies using PermeaPad® Barrier in a side-by-side set-up

Investigate the permeation of hydrocortisone across the artificial, biomimetic barrier,
PermeaPad® Barrier.

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HPV Lesions and Other Issues in the Oral Cavity Treatment and Removal without Pain

Due to different oral and dental conditions, oral mucosa lesions such as those caused by the human papilloma virus and temporomandibular joint pathologies often have to be treated by surgical, ablative or extractive procedures. The treatment and control of pain and inflammation during these procedures is essential to guarantee the patient’s well-being. For the foregoing reason, a hydrogel based on sodium alginate and hyaluronic acid containing 2% of ketorolac tromethamine has been developed. We characterized it physically, mechanically and morphologically. The rheological results suggest that the formulation can be easily and gently applied. Ex vivo permeation studies show that Ketorolac Tromethamine is able to penetrate through the buccal and sublingual mucosae, in addition to being retained in the mucosae’s structure. Through an in vitro test, we were able to evaluate the role that saliva plays in the bioavailability of the drug, observing that more than half of the applied dose is eliminated in an hour. The histological and cytotoxic studies performed on pigs in vivo showed the excellent safety profile of the formulation, as well as its high tolerability. In parallel, a biomimetic artificial membrane (PermeaPad®) was evaluated, and it showed a high degree of correlation with the oral and sublingual mucosa.

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High-Throughput Dissolution/Permeation Screening —A 96-Well Two-Compartment Microplate Approach

Early formulation screening can alleviate development of advanced oral drug formulations, such as amorphous solid dispersions (ASDs). Traditionally, dissolution is used to predict ASD performance. Here, a high-throughput approach is described that simultaneously screens drug dissolution and permeation employing a two-compartment 96-well plate. Freeze-drying from hydro-alcoholic solutions was used to prepare amorphous formulations. The screening approach was tested on amorphous and crystalline tadalafil formulations with and without Soluplus®. The workflow consisted of: 1) dispersion of the formulations; 2) incubation within the two-compartment plate, where a dialysis membrane separated donor (dispersed formulation) and acceptor; 3) sampling (donor and acceptor), where donor samples were centrifuged to remove non-dissolved material; and 4) quantification by UHPLC-UV. To identify optimal screening conditions, the following parameters were varied: dispersion medium (buffer / biomimetic media), acceptor medium (buffer / surfactant solutions), and incubation time (1, 3, and 6 h). Surfactants (acceptor) increased tadalafil permeation. Biomimetic medium (donor) enhanced dissolution, but not permeation, except for freeze-dried tadalafil, for which the permeated amount increased. The predictiveness was evaluated by comparing dissolution-/permeation-results with in vivo bioavailability. In general, both dissolution and permeation reflected bioavailability, whereof the latter was a better predictor. High-throughput dissolution/permeation is regarded promising for formulation screening.

©2015 Elsevier B.V. All rights reserved

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Drug Permeability Profiling Using the Novel Permeapad® 96-Well Plate

Purpose Here,firstexperienceswithaprototypetoolforhigh throughput (passive) permeability profiling, a 96-well plate comprising the Permeapad® membrane, are reported. The permeabilities of a set of drugs were determined and compared to published measures of oral absorption, such as human fraction absorbed (Fa) and in vitro permeability values obtained using other tools.

Methods The tool consists of a 96-well bottom and screen plate with the artificial, phospholipid-based barrier (Permeapad®) mounted between the plates’ lower and upper compartments. The permeability of 14 model compounds including high- and low-absorption drugs, cationic, anionic, zwitterionic and neutral molecules, was determined by quantifying the compounds’ transport over time, deriving the steady-state flux from the linear part of the cumulative curves and calculating the apparent permeability (Papp). The membrane structure was investigated in a high-resolution digital light microscope.

Results The Permeapad® 96-well plate was found suited to distinguish high and low absorption drugs and yielded a hyperbolic correlation to Fa. The Papp values obtained were congruent with those determined with in-house prepared Permeapad® in the Franz cell set-up. Furthermore, good to excellent correlations were seen with Caco-2 permeability (R2 = 0.70) and PAMPA permeability (R2 =0.89). Microscopic investigation of the Permeapad® barrier
revealed the formation of phospholipid vesicles and myelin figures in aqueous environment.

Conclusion The Permeapad® 96-well plate permeation setup is a promising new tool for rapid and reproducible passive permeability profiling.

Springer Science+Business Media, LLC, part of Springer Nature 2020

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Evaluating the influence of UWL and its composition on permeability profiling of two model drugs by using the PermeaPad®Plate and 2mag MIXdrive 96 MTP magnetic stirrer

New chemical entities (NCE) synthesized in pharmaceutical laboratories across the world must have desirable physicochemical characteristics like solubility, membrane/aqueous partition coefficient etc. (1) before they are investigated in in vitro permeability assays. These assays, as their name imply, will determine the apparent permeability of NCE and decide their further destiny as possible active pharmaceutical ingredients. Apparent permeability as molecule property is a composite of the membrane effect and the unstirred water layer (UWL) adjacent to both sides of the barrier. UWL, as stagnant layer, acts as diffusion barrier and rate-limiting factor for rapidly permeating, highly lipophilic drugs. For hydrophilic drugs, the velocity of permeation process will be determined by the permeability through the membrane since the membrane (not the UWL) is the slow step in permeation for such drugs. Many plate-basedin vitro assays report permeability in water instead the permeability of the membrane itself (2), leading to underestimation of the mitigating effect of UWL on permeability, which leads to poor correlation between experimental values and fraction absorbed (i.e. bioavailability) in humans. Although considerable effort has been put in developing new permeability models with various types of biomimetic barriers, the influence of the unstirred water layer (UWL) remains poorly studied in such assays. UWL is formed in close proximity of any barrier (biologic or artificial) due to insufficient/inefficient stirring, which leads to a concentration gradient between the bulk solution and the barrier. It is believed that UWL acts as an additional permeability barrier by reducing the net flux and, as a consequence, the apparent permeability coefficient (Papp) of drugs through a barrier.The aim of this work was to examine the contribution of UWL as an additional barrier on permeability of two model drugs –caffeine (CAF) and hydrocortisone (HC) using PermeaPad®96-well plate under different experimental conditions. CAF and HC are a water-soluble/highly permeable and a poorly soluble and medium/low permeable compound, respectively. Experiments were conducted with different ratesand types of agitation/stirring pH values and donor solutions with various API concentrations.

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