Biopharmaceutical classification of desloratadine – not all drugs are classified the easy way

The biopharmaceutical classification of drugs was designed as a basis for bio-waivers – a mechanism with the double ethical benefit of delivering new drug formulations to the market with less human testing and lower cost. However, many drugs defy simple classification because in vitro permeability and stability assessment can be challenging as shown in this study for desloratadine. Literature shows that desloratadine is highly soluble, while data on luminal stability and permeability are circumstantial. Combined with borderline bioavailability and not really known fraction of absorbed dose, desloratadine was found to be a good example for showing the innovative in vitro approaches necessary to unambiguously classify desloratadine according to Biopharmaceutical Classification System (BCS) guideline. Presented study undoubtedly confirmed that desloratadine solubility is high and dissolution is very rapid for immediate release reference tablets. We have demonstrated desloratadine stability under legally required conditions and also in more physiologically relevant media. High in vitro desloratadine permeability was confirmed using Caco-2 and Parallel Artificial Membrane Permeability Assay (PAMPA). Well-established in vitro model with rat intestinal tissue could not be used due to reasons elaborated in this paper

Proof-of-concept for a miniaturized shake-flask biopharmaceutical solubility determination by sonic mixing

The solvent volume must be very small to obtain biopharmaceutically relevant drug solubility data with low consumption of the solid sample which is often in low supply during early drug development. However, the adequate and repeatable mixing of a small volume can be challenging. We therefore developed a straightforward technique based on the shake-flask method which employed only sonication for mixing a very small amount of drug in an aqueous solvent at a stable pH and temperature. To test the technique, the solubilities of the model compounds carvedilol, digoxin, propranolol, theophylline, and verapamil were determined. The determined solubility values agreed well with the conventional shake-flask solubility data obtained in our laboratory and previously published literature data. The time necessary for the measurements (24 h), was shown to be similar to the conventional shake-flask method even for the low solubility drugs digoxin and carvedilol. The solubility % pH dependence can be established very well as shown with verapamil and propranolol and confirmed with a pH in-dependent solubility of theophylline

Applicability of RPMI 2650 and Calu-3 cell models for evaluation of nasal formulations

The RPMI 2650 and Calu-3 cell lines have been previously evaluated as models of the nasal and airway epithelial barrier, and they have demonstrated the potential to be used in drug permeation studies. However, limited data exist on the utilization of these two cell models for the assessment of nasal formulations. In our study, we tested these cell lines for the evaluation of in vitro permeation of intranasally administered drugs having a local and systemic effect from different solution- and suspension-based formulations to observe how the effects of formulations reflect on the measured in vitro drug permeability. Both models were shown to be sufficiently discriminative and able to reveal the effect of formulation compositions on drug permeability, as they demonstrated differences in the in vitro drug permeation comparable to the in vivo bioavailability. Good correlation with the available bioavailability data was also established for a limited number of drugs formulated as intranasal solutions. The investigated cell lines can be applied to the evaluation of in vitro permeation of intranasally administered drugs with a local and systemic effect from solution- and suspension-based formulations

Biopharmaceutical classification of desloratadine – not all drugs are classified the easy way

The biopharmaceutical classification of drugs was designed as a basis for bio-waivers – a mechanism with the double ethical benefit of delivering new drug formulations to the market with less human testing and lower cost. However, many drugs defy simple classification because in vitro permeability and stability assessment can be challenging as shown in this study for desloratadine. Literature shows that desloratadine is highly soluble, while data on luminal stability and permeability are circumstantial. Combined with borderline bioavailability and not really known fraction of absorbed dose, desloratadine was found to be a good example for showing the innovative in vitro approaches necessary to unambiguously classify desloratadine according to Biopharmaceutical Classification System (BCS) guideline. Presented study undoubtedly confirmed that desloratadine solubility is high and dissolution is very rapid for immediate release reference tablets. We have demonstrated deslorata-dine stability under legally required conditions and also in more physiologically relevant media. High in vitro desloratadine permeability was confirmed using Caco-2 and Parallel Artificial Membrane Permeability Assay (PAMPA). Well-established in vitro model with rat intestinal tissue could not be used due to reasons elaborated in this paper

Biopharmaceutical classification of desloratadine - not all drugs are classified the easy way

The biopharmaceutical classification of drugs was designed as a basis for bio-waivers % a mechanism with the double ethical benefit of delivering new drug formulations to the market with less human testing and lower cost. However, many drugs defy simple classification because in vitro permeability and stability assessment can be challenging as shown in this study for desloratadine. Literature shows that desloratadine is highly soluble, while data on luminal stability and permeability are circumstantial. Combined with borderline bioavailability and not really known fraction of absorbed dose, desloratadine was found to be a good example for showing the innovative in vitro approaches necessary to unambiguously classify desloratadine according to Biopharmaceutical Classification System (BCS) guideline. Presented study undoubtedly confirmed that desloratadine solubility is high and dissolution is very rapid for immediate release reference tablets. We have demonstrated desloratadine stability under legally required conditions and also in more physiologically relevant media. High in vitro desloratadine permeability was confirmed using Caco-2 and Parallel Artificial Membrane Permeability Assay (PAMPA). Well-established in vitro model with rat intestinal tissue could not be used due to reasons elaborated in this paper

Mechanical properties and drug permeability of the PA6 membranes prepared by immersion precipitation from PA6 - formic acid - water system

The paper presents the effect of polymer solution composition on the morphology, mechanical properties and drug permeability of the asymmetric polyamide 6 (PA6) membranes prepared by immersion precipitation. The effect of polymer solution composition on morphology, mechanical properties and permeability of the produced membrane is considered, since these properties are of relevance for drug delivery applications. PA6-formic acid-deionized water solutions were used to prepare membranes for further characterization with differential scanning calorimetry and scanning electron microscopy for morphology analysis, tensile testing and drug permeability tests. The results show that the amount of PA6 does not significantly affect morphology of the membrane, while having pronounced effect on tensile elastic modulus (50% increase). On the other hand, the concentration of formic acid in solution (dissolution intensity) influences crystallization dynamics and significantly changes the morphology of membrane (in the range of approximately 75-100 wt% of formic acid concentrations), consequently having effect on drug permeability

How azide ion/hydrazoic acid passes through biological membranes

Hydrazoic acid (HN$_3$) and its deprotonated form azide ion (N$_3$$^−$) (AHA) are toxic because they inhibit the cytochrome c oxidase complex IV (CoX IV) embedded in the inner mitochondrial membrane that forms part of the enzyme complexes involved in cellular respiration. Critical to its toxicity is the inhibition of CoX IV in the central nervous system and cardiovascular system. Hydrazoic acid is an ionizable species and its affinity for membranes, and the associated permeabilities, depend on the pH values of aqueous media on both sides of the membranes. In this article, we address the permeability of AHA through the biological membrane. In order to understand the affinity of the membrane for the neutral and ionized form of azide, we measured the octanol/water partition coefficients at pH values of 2.0 and 8.0, which are 2.01 and 0.00034, respectively. Using a Parallel Artificial Membrane Permeability Assay (PAMPA) experiment, we measured the effective permeability through the membrane, which is logP$_e$ − 4.97 and − 5.26 for pH values of 7.4 and pH 8.0, respectively. Experimental permeability was used to validate theoretical permeability, which was estimated by numerically solving a Smoluchowski equation for AHA diffusion through the membrane. We demonstrated that the rate of permeation through the cell membrane of 8.46·10$^4$ s$^{-1}$ is much higher than the rate of the chemical step of CoX IV inhibition by azide of 200 s$^{-1}$. The results of this study show that transport through the membrane does not represent the rate-limiting step and therefore does not control the rate of CoX IV inhibition in the mitochondria. However, the observed dynamics of azide poisoning is controlled by circulatory transport that takes place on a time scale of minutes

8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases

We describe the development of quinolylnitrones (QNs) as multifunctional ligands inhibiting cholinesterases (ChEs: acetylcholinesterase and butyrylcholinesterase–hBChE) and monoamine oxidases (hMAO-A/B) for the therapy of neurodegenerative diseases. We identified QN 19, a simple, low molecular weight nitrone, that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde. Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition, yet unexpectedly showed potent inhibition of hBChE (IC$_{50}$ = 1.06 ± 0.31 nmol/L) and hMAO-B (IC$_{50}$ = 4.46 ± 0.18 μmol/L). The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding, which was further studied by enzyme kinetics. Compound 19 acted as a free radical scavenger and biometal chelator, crossed the blood–brain barrier, was not cytotoxic, and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson’s disease. In addition, in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination. Importantly, chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice, underscoring the disease-modifying effect of QN 19

Echinacea angustifolia DC. lipophilic extract patch for skin application

Dodeca-2E,4E,8Z,10E/Z-tetraenoic isobutylamide (tetraene) is the main component of Echinacea angustifolia DC. lipophilic extract, the bioavailability and immunomodulatory effect after oral administration in soft gel capsules in healthy volunteers of which we have already demonstrated. In the present work, we assessed the transdermal administration as an alternative route of administration of such an alkamide. The first step, therefore, encompassed the preparation of a drug-in-adhesive patch with an area of 868 mm$^2$ and containing a dose of 0.64 mg of tetraene. In vitro skin permeation studies in Franz-type diffusion chambers resulted in a tetraene flux of (103 ± 10) ng × cm$^{−2}$ × h$^{−1}$ with a very good linearity (r = 0.99). The relatively low lag time of just 13 min indicates low binding and the accumulation of tetraene in the skin. Finally, the patch was administered to six healthy volunteers, and the pharmacokinetic analysis was performed by nonlinear mixed effects modelling with soft gel oral capsules serving as the reference formulation. The in vivo results correlated well with the in vitro permeation and indicated an initial burst tetraene absorption from the patch that was in parallel with the zero-order kinetics of absorption. The rate of the latter process was in good agreement with the one estimated in vitro. The tetraene absorption rate was therefore slow and prolonged with time, resulting in a bioavailability of 39% relative to the soft gel capsules and a very flat plasma concentration profile