Background and purpose: Due to their unique application and action, inhalation products require specific quality tests, such as Uniformity of Delivered Dose and Aerodynamic Assessment of Fine Particles. While there's no current official requirement for dissolution tests, new draft guidelines are introducing them as a supportive or required measure; however, a universally accepted methodology for such testing remains elusive. The aim of the present study was to explore the discriminatory ability and in vivo predictability of the newly developed dissolution assembly. Experimental approach: The applied experimental approach to biopharmaceutical characterization of inhalation products involved developing a biorelevant method for testing the dissolution rate of the selected active substances. Seven commercially available products, formulated as pressurized metered dose inhalers, containing either salmeterol xinafoate or beclomethasone dipropionate, have been studied. The research strategy combined in vitro testing within silico simulations. Key results: The developed dissolution method did not detect significant differences in the case of products containing highly soluble salmeterol, but it did reveal differences for products containing poorly soluble beclomethasone dipropionate. Moreover, a correlation was identified between the dissolution test results and absorption constants for beclomethasone dipropionate. Conclusion: The obtained results indicated that the investigated products would not be considered bioequivalent based on the aerodynamic particle size distribution. It was demonstrated that a discriminative dissolution method can be developed through a well-established paradigm of dissolution testing, while taking into account the specificities of the inhalation route of administration.

Abstract The extent and rate of release of active substances from topical products must be sufficient to ensure their effectiveness, which depends on selecting the most appropriate formulation. This study examined allantoin emulsions and gel formulations. In water-in-oil (W/O) and oil-in-water (O/W) emulsions, the main emulsifier was varied, while the same gelling agent was used in all formulations to test the effects of oil phase presence and emulsifier type on allantoin release, as well as the formulations’ rheological and textural characteristics. O/W emulsions exhibited similar release rates and the overall amount released over six hours (11–14.8%), while the highest amount of allantoin (20.9%) was released from the gel formulation. Conversely, the amount of allantoin released from the W/O emulsion (0.77%) was insufficient. Experimental data generally fit best with the Higuchi model kinetics. The formulations demonstrated shear-thinning thixotropic behavior. The greatest deviation from the Newtonian type of flow, with the smallest value of constant n (0.106-0.13) and the largest thixotropic loop area (6602.67-8140 Pas-1) were shown by O/W emulsions. The W/O emulsion exhibited the highest constant n (0.70) and smaller hysteresis area (991.23 Pas-1). Firmness and consistency values increased in the order: gel < W/O emulsion  < O/W emulsions. The O/W emulsions showed similarity in microstructure and textural characteristics, likely explaining their similar release behavior. Graphical Abstract

The aim of the present study is to improve the solubility and antimicrobial activity of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin by formulating its inclusion complexes with 2-hydroxypropyl-β-cyclodextrin in solution and in solid state. The phase solubility study was used to investigate the interactions between 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin and 2-hydroxypropyl-β-cyclodextrin and to estimate the molar ratio between them. The structural characterization of binary systems (prepared by physical mixing, kneading and solvent evaporation methods) was analysed using the FTIR-ATM spectroscopy. The antimicrobial activity of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin and inclusion complexes prepared by solvent evaporation method was tested by the diffusion and dilution methods on various strains of microorganisms. The results of phase solubility studies showed that 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin formed the inclusion complexes with 2-hydroxypropyl-β-cyclodextrin of AP type. The solubility of 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin was increased 64.05-fold with 50% w/w of 2-hydroxypropyl-β-cyclodextrin at 37 o C. The inclusion complexes in solid state, prepared by the solvent evaporation method, showed higher solubility in purified water and in phosphate buffer solutions in comparison with 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin alone. The inclusion complexes prepared by solvent evaporation method showed higher activity on Bacillus subtilis and Staphylococcus aureus compared to uncomplexed 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin due to improved aqueous solubility, thus increasing the amount of available 3-(3-(2-chlorophenyl)prop-2-enoyl)-4-hydroxycoumarin that crosses the bacterial membrane.

The antidiabetic drug gliclazide is partly metabolized by CYP2C19, the main enzyme involved in omeprazole metabolism. The aim of the study was to explore the interaction between omeprazole and gliclazide in relation to CYP2C19 phenotype using physiologically based pharmacokinetic (PBPK) modeling approach. Developed PBPK models were verified using in vivo pharmacokinetic profiles obtained from a clinical trial on omeprazole-gliclazide interaction in healthy volunteers, CYP2C19 normal/rapid/ultrarapid metabolizers (NM/RM/UM). In addition, the association of omeprazole cotreatment with gliclazide-induced hypoglycemia was explored in 267 patients with type 2 diabetes (T2D) from the GoDARTS cohort, Scotland. The PBPK simulations predicted 1.4–1.6-fold higher gliclazide area under the curve (AUC) after 5-day treatment with 20 mg omeprazole in all CYP2C19 phenotype groups except in poor metabolizers. The predicted gliclazide AUC increased 2.1 and 2.5-fold in intermediate metabolizers, and 2.6- and 3.8-fold in NM/RM/UM group, after simulated 20-day dosing with 40 mg omeprazole once and twice daily, respectively. The predicted results were corroborated by findings in patients with T2D which demonstrated 3.3-fold higher odds of severe gliclazide-induced hypoglycemia in NM/RM/UM patients concomitantly treated with omeprazole. Our results indicate that omeprazole may increase exposure to gliclazide and thus increase the risk of gliclazide-associated hypoglycemia in the majority of patients.

The kinetics of passive transport of ketoprofen and metformin, as model substances for high and low permeability, respectively, across the artificial membrane under the influence of the pH of donor solution was investigated. There was an upward trend in the apparent permeation coefficient (Papp) of ketoprofen with the decrease in pH to a value close to pKa. At the pH value below pKa the permeation coefficient had lower value, due to the higher retention of ketoprofen in the artificial membrane. Metformin is a low permeable compound, and the highest permeation values were recorded at pH 7.4. Two dissociation constants determine that metformin at physiological pH exists as a hydrophilic cationic molecule, i.e. predominantly in ionized form. At pH values below 2.8, metformin mainly exists in diprotonated form, and it was, thus, very poorly permeable. The highest retention, i.e. affinity of both ketoprofen and metformin to the membrane, was at the lowest pH values, which is explained by different mechanisms. At higher pH values of donor compartment the substances showed significantly less affinity to the membrane. The obtained values of apparent permeation coefficients at studied pH values showed good correlation with the obtained experimental values by other in vitro methods.

: Medicinal nail lacquers are the most effective topical treatment of nail diseases. These formulations generally are organic solutions of the active substance as well as film-forming polymer and plasticizer, which affects the characteristics of the film formed after application and solvent evaporation. The aim of this work was to test the effects of plasticizer present in nail lacquer formulations on permeation kinetics of fluconazole through the bovine hoof membrane in a novel in vitro test. The formulations contained Eudragit RS100 dis- solved in acetone, and dibutyl-phthalate, PEG 400 or propylene glycol as plasticizers present in two different concentrations. Permeation studies were carried out during the 7-day period, and the obtained permeability pro- files analyzed using similarity and difference factors, and by model-dependent permeation kinetics. When analyzed within the same strength, the highest extent of fluconazole permeation was obtained from the formula- tion with a lower concentration of propylene glycol at 0.9% fluconazole concentration, while for formulations with 1.8% and 2.7% of fluconazole, the highest permeation was achieved from the formulation with the high- er content of PEG400. The permeation profiles showed a greater difference within one formulation of different fluconazole content than with the same plasticizer present in different concentrations, when using dibutyl- phthalate and PEG400. The permeation profiles were similar when using propylene glycol. When comparing formulations with the same concentrations of plasticizers, there were differences in formulations with the high- er fluconazole concentrations. Permeation kinetics depended on fluconazole concentration as well as the path length the active substance had to pass to reach the receptor solution.