Search Results (11)

Riluzole (RLZ), a sodium channel-blocking benzothiazole anticonvulsant BCS class II drug, is very slightly soluble in aqueous medium. To improve aqueous solubility and modulate dissolution rate and membrane permeability, complex formation of RLZ with two cyclodextrin, α-cyclodextrin (α-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), was studied. The stability constants demonstrated a greater affinity of SBE-β-CD towards RLZ compared to α-CD. A solubility growth of 1.7-fold and 3.7-fold with α-CD and SBE-β-CD, respectively, was detected in the solutions of 1% cyclodextrins and accompanied by the permeability reduction. For 1% CD solutions, several biopolymers (1% w/v) were tested for the membrane permeability under static conditions. The synergistic positive effect of α-CD and polymer on the solubility accompanied by unchanged permeability was revealed in RLZ/α-CD/PG, RLZ/α-CD/PEG400, and RLZ/α-CD/PEG1000 systems. Solid RLZ/CD complexes were prepared. Dynamic dissolution/permeation experiments for the solid samples disclosed the characteristic features of the release processes and permeation rate through different artificial membranes. The maximal permeation rate was determined across the hydrophilic semi-permeable cellulose membrane followed by the lipophilic PermeaPad barrier (model of intestinal and buccal absorption) and polydimethylsiloxane-polycarbonate membrane (simulating transdermal delivery way). Different mode of the permeation between the membranes was estimated and discussed. Full article

Cyclodextrin-based delivery systems have been intensively used to improve the bioavailability of drugs through the modification of their pharmaceutically relevant properties, such as solubility, distribution and membrane permeation. The present work aimed to disclose the influence of HP-β-CD and SBE-β-CD on the distribution and permeability of nortriptyline hydrochloride (NTT•HCl), a tricyclic antidepressant drug. To this end, the distribution coefficients in the 1-octanol/buffer and n-hexane/buffer model systems and the coefficients of permeability through the cellulose membrane and lipophilic PermeaPad barrier were determined at several cyclodextrin concentrations. The results demonstrated a dramatic decrease in both the distribution and the permeability coefficients as the cyclodextrin concentration rose, with the decrease being more pronounced in SBE-β-CD due to the charge–charge attraction and electrostatic interactions between NTT and SBE-β-CD. It is these interactions that were shown to be responsible for the greater value of the constant of NTT’s association with SBE-β-CD than that with HP-β-CD. The findings of this study revealed similar trends in the 1-octanol/buffer 6.8 pH distribution and permeability through the PermeaPad barrier in the presence of CDs. These results were attributed to the determinative role of the distribution coefficient (serving as a descriptor) in permeation through the PermeaPad barrier modeling the lipophilic nature of biological barriers. Full article

The main aims of the study were to disclose the influence of the structure on the solubility, distribution and permeability of the parent substances, iproniazid (IPN), isoniazid (INZ) and isonicotinamide (iNCT), at 310.2 K and to evaluate how the presence of cyclodextrins (2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and methylated β-cyclodextrin (M-β-CD)) affects the distribution behavior and diffusion properties of a model pyridinecarboxamide derivative, iproniazid (IPN). The following order of decreasing the distribution and permeability coefficients was estimated: IPN > INZ > iNAM. A slight reduction of the distribution coefficients in the 1-octanol/buffer pH 7.4 and n-hexane/buffer pH 7.4 systems (more pronounced in the first system) was revealed. The extremely weak IPN/cyclodextrins complexes were estimated from the distribution experiments: K_C(IPN/HP-β-CD) > K_C(IPN/M-β-CD). The permeability coefficients of IPN through the lipophilic membrane—the PermeaPad barrier—were also measured with and without cyclodextrins in buffer solution. Permeability of iproniazid was increased in the presence of M-β-CD and reduced by HP-β-CD. Full article

Permeability across cellular membranes is a key factor that influences absorption and distribution. Before absorption, many drugs must pass through the mucus barrier that covers all the wet surfaces of the human body. Cell-free in vitro tools currently used to evaluate permeability fail to effectively model the complexity of mucosal barriers. Here, we present an in vitro mucosal platform as a possible strategy for assessing permeability in a high-throughput setup. The PermeaPad 96-well plate was used as a permeability system and further coupled to a pathological, tridimensional mucus model. The physicochemical determinants predicting passive diffusion were determined by combining experimental and computational approaches. Drug solubility, size, and shape were found to be the critical properties governing permeability, while the charge of the drug was found to be influential on the interaction with mucus. Overall, the proposed mucosal platform could be a promising in vitro tool to model the complexity of mucosal tissues and could therefore be adopted for drug-permeability profiling. Full article

Relationships between the structures of molecules and their properties form the basis of modern chemistry and lay the foundation for structure-based drug design. Being the main two determinants of bioavailability, solubility and permeability of drugs are widely investigated experimentally and predicted from physicochemical parameters and structural descriptors. In the present study, we measure the passive diffusion permeability of a series of new fluconazole derivatives with triazole and thiazolo-pyrimidine moieties connected by different linker bridges through the PermeaPad barrier—a relatively new biomimetic lipophilic membrane that has been increasingly used in recent years. The permeability coefficients of new derivatives are shown to be dependent both on the structure of the linker fragment and on the substituent in the phenyl ring of the thiazolo-pyrimidine moiety. The impact of the compound ionization state on the permeability is revealed. Reliable correlations of the permeability with the antifungal activity and distribution coefficient are found. In addition, the solubility–diffusion approach is shown to be able to successfully predict the permeability of the studied derivatives. The obtained results can be considered another step in the development of permeability databases and design of schemes for in vitro permeability prediction. Full article

Perindopril arginine (PA) as an angiotensin-converting enzyme (ACE) inhibitor is widely used in cardiovascular diseases, especially in systemic hypertension and heart failure. Although the pharmacokinetics of PA are well documented, there is no available detailed data on its permeation in in vitro conditions. The present study aimed to assess the transport of PA across both biological membranes and artificial biomimetic ones. For the determination of PA transport, the Caco-2 cell line was selected as a reliable in vitro model of gastrointestinal biological barriers. Additionally, a novel 96-well plate with phospholipid membrane PermeaPad was used to evaluate the transport of PA by passive diffusion. We confirmed that PA is relatively poorly permeable across the Caco-2 monolayer. The permeability results obtained from the non-cell-based model demonstrated higher transport of PA as compared to that of Caco-2. Thus, PA transport across the biological membranes might be suggested to be regulated by the membrane transporters. Full article

Various types of artificial biomimetic barriers are widely utilized as in vitro tools to predict the passive “transcellular” transport of drug compounds. The current study investigated if the sandwich barrier PermeaPad^®, which is composed of tightly packed phospholipid vesicles enclosed between two support sheets, contributes to a transport mechanism that is paracellular-like, representing one of the alternative pathways of passive transport in vivo, primarily of relevance for hydrophilic drug compounds. To this end, we pretreated the commercial PermeaPad^® barrier with NaCl solutions of either high or low osmolality prior to permeation experiments on reversed Franz cell setups with hydrophilic model compounds calcein and acyclovir and hydrophobic model compounds hydrocortisone and celecoxib. Our starting hypothesis was that the liposomes formed in the barrier during the hydration step should either shrink or swell upon contact with test media (drug solutions) due to osmotic pressure difference as compared to the pretreatment solutions. Apparent permeabilities for calcein and acyclovir across the PermeaPad^® barrier were found to increase approximately 2.0 and 1.7 fold, respectively, upon hypo-osmotic pretreatment (soaking in hypotonic medium, while the permeation of hydrocortisone and celecoxib remained unchanged. A control experiment with lipid-free barriers (support sheets) indicated that the permeation of all the compounds was virtually unchanged upon hypo-osmotic pretreatment. In conclusion, soaking PermeaPad^® in a medium of lower osmotic pressure than that used during the permeation study appears to induce the osmotic shrinking of the lipid vesicles in the barrier, leaving wider water channels between the vesicles and, thus, allowing hydrophilic compounds to pass the barrier in a paracellular-like manner. Full article

The pharmacologically relevant physicochemical properties of the antiandrogen drug bicalutamide (BCL) have been determined for the first time. Solubility in aqueous solution, 1-octanol, n-hexane, and ethanol was measured by the shake flask method in the temperature range of 293.15–313.15 K. The compound was shown to be poorly soluble in aqueous medium and n-hexane; at the same time, an essentially higher solubility in the alcohols was revealed. The following order of molar solubility was determined: ethanol > 1-octanol > water ≈ n-hexane. The solubility was correlated with the Van’t Hoff and Apelblat equations. Evaluation of the Hansen solubility parameters and the atomic group contribution approach of Hoftyzer and Van Krevelen demonstrated consistency with the experimental data and good potential adsorption of bicalutamide. The temperature dependences of the distribution coefficients in the 1-octanol/water and n-hexane/water two-phase systems were measured and discussed in the framework of the thermodynamic approach. The ∆logD parameter determined from the distribution experiment clearly demonstrated the preference of the lipophilic delivery pathways for the compound in the biological media. The overall thermodynamic analysis based on the solubility and distribution results of the present study and the sublimation characteristics published previously has been performed. To this end, the thermodynamic parameters of the dissolution, solvation, and transfer processes were calculated and discussed in view of the solute-solvent interactions. The permeation rate of BCL through the PermeaPad barrier was measured and compared with PAMPA permeability. Full article

The inclusion of a chemical permeation enhancer in a dosage form is considered an effective approach to improve absorption across the nasal mucosa. Herein we evaluated the possibility of exploiting biosurfactants (BS) produced by Lactobacillus gasseri BC9 as innovative natural excipients to improve nasal delivery of hydrocortisone (HC). BC9-BS ability to improve HC solubility and the BS mucoadhesive potential were investigated using the surfactant at a concentration below and above the critical micelle concentration (CMC). In vitro diffusion studies through the biomimetic membrane PermeaPad^® and the same synthetic barrier functionalized with a mucin layer were assessed to determine BC9-BS absorption enhancing properties in the absence and presence of the mucus layer. Lastly, the diffusion study was performed across the sheep nasal mucosa using BC9-BS at a concentration below the CMC. Results showed that BC9-BS was able to interact with the main component of the nasal mucosa, and that it allowed for a greater solubilization and also permeation of the drug when it was employed at a low concentration. Overall, it seems that BC9-BS could be a promising alternative to chemical surfactants in the nasal drug delivery field. Full article

Poor solubility of new antifungal of 1,2,4-triazole class (S-119)—a structural analogue of fluconazole in aqueous media was estimated. The solubility improvement using different excipients: biopolymers (PEGs, PVP), surfactants (Brij S20, pluronic F-127) and cyclodextrins (α-CD, β-CD, 2-HP-β-CD, 6-O-Maltosyl-β-CD) was assessed in buffer solutions pH 2.0 and pH 7.4. Additionally, 2-HP-β-CD and 6-O-Maltosyl-β-CD were proposed as promising solubilizers for S-119. According to the solubilization capacity and micelle/water partition coefficients in buffer pH 7.4 pluronic F-127 was shown to improve S-119 solubility better than Brij S20. Among biopolymers, the greatest increase in solubility was shown in PVP solutions (pH 7.4) at concentrations above 4 w/v%. Complex analysis of the driving forces of solubilization, micellization and complexation processes matched the solubility results and suggested pluronic F-127 and 6-O-Maltosyl-β-CD as the most effective solubilizing agents for S-119. The comparison of S-119 diffusion through the cellulose membrane and lipophilic PermeaPad barrier revealed a considerable effect of the lipid layer on the decrease in the permeability coefficient. According to the PermeaPad, S-119 was classified as a highly permeated substance. The addition of 1.5 w/v% CDs in donor solution moves it to low-medium permeability class. Full article

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 (AUC_0–3h), to the AUC_0–3h 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. Full article