Anti-apoptotic MCL-1 promotes long-chain fatty acid oxidation through interaction with ACSL1.

MCL-1 is essential for promoting the survival of many normal cell lineages and confers survival and chemoresistance in cancer. Beyond apoptosis regulation, MCL-1 has been linked to modulating mitochondrial metabolism, but the mechanism(s) by which it does so are unclear. Here, we show in tissues and cells that MCL-1 supports essential steps in long-chain (but not short-chain) fatty acid ß-oxidation (FAO) through its binding to specific long-chain acyl-coenzyme A (CoA) synthetases of the ACSL family. ACSL1 binds to the BH3-binding hydrophobic groove of MCL-1 through a non-conventional BH3-domain. Perturbation of this interaction, via genetic loss of Mcl1, mutagenesis, or use of selective BH3-mimetic MCL-1 inhibitors, represses long-chain FAO in cells and in mouse livers and hearts. Our findings reveal how anti-apoptotic MCL-1 facilitates mitochondrial metabolism and indicate that disruption of this function may be associated with unanticipated cardiac toxicities of MCL-1 inhibitors in clinical trials.

The Influence of PVP Polymer Topology on the Liquid Crystalline Order of Itraconazole in Binary Systems.

This study presents a novel approach by utilizing poly(vinylpyrrolidone)s (PVPs) with various topologies as potential matrices for the liquid crystalline (LC) active pharmaceutical ingredient itraconazole (ITZ). We examined amorphous solid dispersions (ASDs) composed of ITZ and (i) self-synthesized linear PVP, (ii) self-synthesized star-shaped PVP, and (iii) commercial linear PVP K30. Differential scanning calorimetry, X-ray diffraction, and broad-band dielectric spectroscopy were employed to get a comprehensive insight into the thermal and structural properties, as well as global and local molecular dynamics of ITZ-PVP systems. The primary objective was to assess the influence of PVPs' topology and the composition of ASD on the LC ordering, changes in the temperature of transitions between mesophases, the rate of their restoration, and finally the solubility of ITZ in the prepared ASDs. Our research clearly showed that regardless of the PVP type, both LC transitions, from smectic (Sm) to nematic (N) and from N to isotropic (I) phases, are effectively suppressed. Moreover, a significant difference in the miscibility of different PVPs with the investigated API was found. This phenomenon also affected the solubility of API, which was the greatest, up to 100 µg/mL in the case of starPVP 85:15 w/w mixture in comparison to neat crystalline API (5 µg/mL). Obtained data emphasize the crucial role of the polymer's topology in designing new pharmaceutical formulations.

Requirement for antiapoptotic MCL-1 during early erythropoiesis.

Although BCL-xL is critical to the survival of mature erythrocytes, it is still unclear whether other antiapoptotic molecules mediate survival during earlier stages of erythropoiesis. Here, we demonstrate that erythroid-specific Mcl1 deletion results in embryonic lethality beyond embryonic day 13.5 as a result of severe anemia caused by a lack of mature red blood cells (RBCs). Mcl1-deleted embryos exhibit stunted growth, ischemic necrosis, and decreased RBCs in the blood. Furthermore, we demonstrate that MCL-1 is only required during early definitive erythropoiesis; during later stages, developing erythrocytes become MCL-1 independent and upregulate the expression of BCL-xL. Functionally, MCL-1 relies upon its ability to prevent apoptosis to promote erythroid development because codeletion of the proapoptotic effectors Bax and Bak can overcome the requirement for MCL-1 expression. Furthermore, ectopic expression of human BCL2 in erythroid progenitors can compensate for Mcl1 deletion, indicating redundancy between these 2 antiapoptotic family members. These data clearly demonstrate a requirement for MCL-1 in promoting survival of early erythroid progenitors.

Mesoporous Matrices as a Promising New Generation of Carriers for Multipolymorphic Active Pharmaceutical Ingredient Aripiprazole.

The enhancement of the properties (i.e., poor solubility and low bioavailability) of currently available active pharmaceutical ingredients (APIs) is one of the major goals of modern pharmaceutical sciences. Among different strategies, a novel and innovative route to reach this milestone seems to be the application of nanotechnology, especially the incorporation of APIs into porous membranes composed of pores of nanometric size and made of nontoxic materials. Therefore, in this work, taking the antipsychotic API aripiprazole (APZ) infiltrated into various types of mesoporous matrices (anodic aluminum oxide, native, and silanized silica) characterized by similar pore diameters (d = 8-10 nm) as an example, we showed the advantage of incorporated systems in comparison to the bulk substance considering the crystallization kinetics, molecular dynamics, and physical stability. Calorimetric investigations supported by the temperature-dependent X-ray diffraction measurements revealed that in the bulk system the recrystallization of polymorph III, which next is converted to the mixture of forms IV and I, is visible, while in the case of confined samples polymorphic forms I and III of APZ are produced upon heating of the molten API with different rates. Importantly, the two-step crystallization observed in thermograms obtained for the API infiltrated into native silica templates may suggest crystal formation by the interfacial and core molecules. Furthermore, dielectric studies enabled us to conclude that there is no trace of crystallization of spatially restricted API during one month of storage at T = 298 K. Finally, we found that in contrast to the crystalline and amorphous bulk samples, all examined confined systems show a logarithmic increase in API dissolution over time (very close to a prolonged release effect) without any sign of precipitation. Our data demonstrated that mesoporous matrices appear to be interesting candidates as carriers for unstable amorphous APIs, like APZ. In addition to protecting them against crystallization, they can provide the desired prolonged release effect, which may increase the drug concentration in the blood (resulting in higher bioavailability). We believe that the "nanostructirization" in terms of the application of porous membranes as a novel generation of drug carriers might open unique perspectives in the further development of drugs characterized by prolonged release.

Studying the Intermolecular Interactions, Structural Dynamics, and Non-Equilibrium Kinetics of Cilnidipine Infiltrated into Alumina and Silica Pores.

In the present study, the behavior of the calcium channel blocker cilnidipine (CLN) infiltrated into silica (SiO2) and anodic aluminum oxide (AAO) porous membranes characterized by a similar pore size (d = 8 nm and d = 10 nm, respectively) as well as the bulk sample has been investigated using differential scanning calorimetry, broadband dielectric spectroscopy (BDS), and Fourier-transform infrared spectroscopy (FTIR) techniques. The obtained data suggested the existence of two sets of CLN molecules in both confined systems (core and interfacial). They also revealed the lack of substantial differences in inter- and intramolecular dynamics of nanospatially restricted samples independently of the applied porous membranes. Moreover, the annealing experiments (isothermal time-dependent measurements) performed on the confined CLN clearly indicated that the whole equilibration process under confinement is governed by structural relaxation. It was also found that the ßanneal parameters obtained from BDS and FTIR data upon equilibration of both confined samples are comparable (within 10%) to each other, while the equilibration constants are significantly different. This finding strongly emphasizes that there is a close connection between the inter- and intramolecular dynamics under nanospatial restriction.

Studies on the Vitrified and Cryomilled Bosentan.

In this paper, several experimental techniques [X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry, Fourier transform infrared spectroscopy, and broad-band dielectric spectroscopy] have been applied to characterize the structural and thermal properties, H-bonding pattern, and molecular dynamics of amorphous bosentan (BOS) obtained by vitrification and cryomilling of the monohydrate crystalline form of this drug. Samples prepared by these two methods were found to be similar with regard to their internal structure, H-bonding scheme, and structural (α) dynamics in the supercooled liquid state. However, based on the analysis of α-relaxation times (dielectric measurements) predicted for temperatures below the glass-transition temperature (Tg), as well as DSC thermograms, it was concluded that the cryoground sample is more aged (and probably more physically stable) compared to the vitrified one. Interestingly, such differences in physical properties turned out to be reflected in the lower intrinsic dissolution rate of BOS obtained by cryomilling (in the first 15 min of dissolution test) in comparison to the vitrified drug. Furthermore, we showed that cryogrinding of the crystalline BOS monohydrate leads to the formation of a nearly anhydrous amorphous sample. This finding, different from that reported by Megarry et al. [ Carbohydr. Res. 2011, 346, 1061-1064] for trehalose (TRE), was revealed on the basis of infrared and thermal measurements. Finally, two various hypotheses explaining water removal upon cryomilling have been discussed in the manuscript.

High-Pressure Dielectric Studies-a Way to Experimentally Determine the Solubility of a Drug in the Polymer Matrix at Low Temperatures.

In this work, we employed broad-band dielectric spectroscopy to determine the solubility limits of nimesulide in the Kollidon VA64 matrix at ambient and elevated pressure conditions. Our studies confirmed that the solubility of the drug in the polymer matrix decreases with increasing pressure, and molecular dynamics controls the process of recrystallization of the excess of amorphous nimesulide from the supersaturated drug-polymer solution. More precisely, recrystallization initiated at a certain structural relaxation time of the sample stops when a molecular mobility different from the initial one is reached, regardless of the temperature and pressure conditions. Finally, based on the presented results, one can conclude that by transposing vertically the results obtained at elevated pressures, one can obtain the solubility limit values corresponding to low temperatures. This approach was validated by the comparison of the experimentally determined points with the theoretically obtained values based on the Flory-Huggins theory.

Impact of the Chain Length and Topology of the Acetylated Oligosaccharide on the Crystallization Tendency of Naproxen from Amorphous Binary Mixtures.

The impact of the chain length or dispersity of polymers in controlling the crystallization of amorphous active pharmaceutical ingredients (APIs) has been discussed for a long time. However, because of the weak control of these parameters in the majority of macromolecules used in pharmaceutical formulations, the abovementioned topic is poorly understood. Herein, four acetylated oligosaccharides, maltose (acMAL), raffinose (acRAF), stachyose (acSTA), and α-cyclodextrin (ac-α-CD) of growing chain lengths and different topologies (linear vs cyclic), mimicking the growing backbone of the polymer, were selected to probe the influence of these structural factors on the crystallization of naproxen (NAP)-an API that does not vitrify regardless of the cooling rate applied in our experiment. It was found that in equimolar systems composed of NAP and linear acetylated oligosaccharides, the progress and activation barrier for crystallization are dependent on the molecular weight of the excipient despite the fact that results of Fourier transform infrared studies indicated that there is no difference in the interaction pattern between measured samples. On the other hand, complementary dielectric, calorimetric, and X-ray diffraction data clearly demonstrated that NAP mixed with ac-α-CD (cyclic saccharide) does not tend to crystallize even in the system with a much higher content of APIs. To explain this interesting finding, we have carried out further density functional theory computations, which revealed that incorporation of NAP into the cavity of ac-α-CD is hardly possible because this state is of much higher energy (up to 80 kJ/mol) with respect to the one where the API is located outside of the saccharide torus. Hence, although at the moment, it is very difficult to explain the much stronger impact of the cyclic saccharide on the suppression of crystallization and enhanced stability of NAP with respect to the linear carbohydrates, our studies clearly showed that the chain length and the topology of the excipient play a significant role in controlling the crystallization of this API.

Unique Behavior of Poly(propylene glycols) Confined within Alumina Templates Having a Nanostructured Interface.

Herein we show that the nanostructured interface obtained via modulation of the pore size has a strong impact on the segmental and chain dynamics of two poly(propylene glycol) (PPG) derivatives with various molecular weights (Mn = 4000 g/mol and Mn = 2000 g/mol). In fact, a significant acceleration of the dynamics was observed for PPG infiltrated into ordinary alumina templates (Dp = 36 nm), while bulklike behavior was found for samples incorporated into membranes of modulated diameter (19 nm < Dp < 28 nm). We demostrated that the modulation-induced roughness reduces surface interactions of polymer chains near the interface with respect to the ones adsorbed to the ordinary nanochannels. Interestingly, this effect is noted despite the enhanced wettability of PPG in the latter system. Consequently, as a result of weaker H-bonding surface interactions, the conformation of segments seems to locally mimic the bulk arrangement, leading to bulklike dynamics, highlighting the crucial impact of the interface on the overall behavior of confined materials.

Influence of Annealing in the Close Vicinity of Tg on the Reorganization within Dimers and Its Impact on the Crystallization Kinetics of Gemfibrozil.

In this paper, broadband dielectric spectroscopy (BDS) has been applied to study the molecular dynamics and crystallization kinetics of the antihyperlipidemic active pharmaceutical ingredient (API), gemfibrozil (GEM), as well as its deuterated (dGEM) and methylated (metGEM) derivatives, characterized by different types and strengths of intermolecular interactions. Moreover, calorimetric and infrared measurements have been carried out to characterize the thermal properties of examined samples and to probe a change in the H-bonding pattern in GEM, respectively. We found that the dielectric spectra of all examined compounds, collected below the glass transition temperature (Tg), reveal the presence of two secondary relaxations (ß, γ). According to the coupling model (CM) predictions, it was assumed that the slower process (ß) is of JG type, whereas the faster one (γ) has an intramolecular origin. Interestingly, the extensive crystallization kinetics measurements performed after applying two paths, i.e., the standard procedure (cooling and subsequently heating up to the appropriate temperature, Tc), as well as annealing at two temperatures in the vicinity of Tg and further heating up to Tc, showed that the annealing increases the crystallization rate in the case of native API, while the thermal history of the sample has no significant impact on the pace of this process in the two derivatives of GEM. Analysis of the dielectric strength (Δε) of the α-process during annealing, together with the results of Fourier transform infrared spectroscopy (FTIR) measurements, suggested that the reorganization within dimeric structures formed between the GEM molecules is responsible for the observed behavior. Importantly, our results differ from those obtained by Tominaka et al. (Tominaka, S.; Kawakami, K.; Fukushima, M.; Miyazaki, A.Physical Stabilization of Pharmaceutical Glasses Based on Hydrogen Bond Reorganization under Sub-Tg Temperature Mol. Pharm. 2017 14 264 273 10.1021/acs.molpharmaceut.6b00866.), who demonstrated that the sub-Tg annealing of ritonavir (RTV), which is able to form extensive supramolecular hydrogen bonds, protects this active substance against crystallization. Therefore, based on these contradictory reports, one can hypothesize that materials forming H-bonded structures, characterized by varying architecture, may behave differently after annealing in the vicinity of the glass transition temperature.

The impact of chemical structure on the formation of the medium-range order and dynamical properties of selected antifungal APIs.

In this paper, we have analyzed structural, thermal, and dynamical properties of four azole antifungals: itraconazole (ITZ), posaconazole (POS), terconazole (TER) and ketoconazole (KET), differing mainly in the length of the rod-like backbone and slightly in side groups. Our investigations clearly demonstrated that the changes in the chemical structure result in a different ability to form the medium-range order (MRO) and variation in thermal and dynamical properties of these pharmaceuticals. Direct comparison of the diffractograms collected for glassy and crystalline materials indicated that the MRO observed in the former phases is related to maintaining the local molecular arrangement of the crystal structure. Moreover, it was shown that once the MRO-related diffraction peaks appear, additional mobility (δ- or α' relaxation), slower than the structural (α)-process, is also detected in dielectric spectra. This new mode is connected to the motions within supramolecular nanoaggregates. Detailed analysis of dielectric and calorimetric data also revealed that the variation in the internal structure and MRO of the examined pharmaceuticals have an impact on the glass transition temperature (Tg) shape of the α-process, isobaric fragility, molecular dynamics in the glassy state and number of dynamically correlated molecules. These findings could be helpful in an understanding the influence of different types of intermolecular MRO on the properties of substances having a similar chemical backbone.

The Effect of Different Water Extracts from Platycodon grandiflorum on Selected Factors Associated with Pathogenesis of Chronic Bronchitis in Rats.

The aim of this study was to assess the activity of extracts from Platycodon grandiflorum A. DC (PG) in a model of chronic bronchitis in rats. The research was carried out on three water extracts: E1 - from roots of field cultivated PG; E2 - from biotransformed roots of PG; E3 - from callus of PG. The extracts differed in saponins and inulin levels-the highest was measured in E3 and the lowest in E1. Identification of secondary metabolites was performed using two complementary LC-MS systems. Chronic bronchitis was induced by sodium metabisulfite (a source of SO2). Animals were treated with extracts for three weeks (100 mg/kg, intragastrically) and endothelial growth factor (VEGF), transforming growth factors (TGF-ß1, -ß2, -ß3), and mucin 5AC (MUC5AC) levels were determined in bronchoalveolar lavage fluid, whereas C reactive protein (CRP) level was measured in serum. Moreover, mRNA expression were assessed in bronchi and lungs. In SO2-exposed rats, an elevation of the CRP, TGF-ß1, TGF-ß2, VEGF, and mucin was found, but the extracts' administration mostly reversed this phenomenon, leading to control values. The results showed a strong anti-inflammatory effect of the extracts from PG.

Studies on the internal medium-range ordering and high pressure dynamics in modified ibuprofens.

Broadband dielectric spectroscopy (BDS), combined with the X-ray diffraction (XRD) and Fourier transform infrared (FTIR) techniques, was used to study the dynamics of the primary (α) relaxation process and slow mode (SM), as well as structural properties and intermolecular interactions, in the methyl-, isopropyl-, hexyl-, and benzyl derivative of a well-known pharmaceutical, ibuprofen (IBU). Unexpectedly, the XRD and FTIR methods revealed the formation of medium-range ordering together with some molecular organization, which probably leads to the creation of small aggregates at the scale of several microns at lower temperatures. Moreover, high pressure dielectric experiments revealed that the SM (observed in the ambient pressure data) is not detected in the loss spectra of compressed IBU esters, which is consistent with the results reported previously for propylene carbonate and dioxolane derivatives. This finding can be interpreted as connected to either the comparable time scale of the structural dynamics and slow mode or suppression of the motions responsible for the latter process at elevated pressure. Additionally, it was found that the pressure coefficient of the glass transition temperature (dTg/dp) and activation volume (ΔV) change with molecular weight (Mw) in a non-monotonic way. It might be related to various chemical structures, conformations, and intermolecular interactions, as well as different architecture of supramolecular aggregates in the investigated compounds.

Impact of Intermolecular Interactions, Dimeric Structures on the Glass Forming Ability of Naproxen, and a Series of Its Derivatives.

In this article, thermal properties, molecular dynamics, crystallization kinetics, and intermolecular interactions in pure naproxen (NAP), its amide (NH2-NAP), and four esters (methyl, Met-NAP; isopropyl, Iso-NAP; hexyl, Hex-NAP; and benzyl, Ben-NAP) have been investigated using differential scanning calorimetry as well as broadband dielectric and Fourier transform infrared spectroscopies. We found that the modification of the NAP molecule by substituting a hydrogen atom from the hydroxyl group strongly inhibits the crystallization tendency of this active pharmaceutical ingredient (API) and simultaneously increases its glass forming ability (GFA). In this context, it is worthwhile to stress that pure naproxen and its amide crystallized very quickly, regardless of the cooling rate. Therefore, these compounds cannot be classified as good glass-formers. On the other hand, ester derivatives of API can be easily vitrified. Moreover, dielectric measurements revealed that with an increasing molecular weight of the substituent, the rate of crystallization process slows down significantly. Consequently, Ben-NAP was characterized by the highest GFA among all investigated API esters. Comprehensive FTIR studies clearly indicated that the strong tendency to create dimeric structures in the nonmodified NAP and NH2-NAP is responsible for their enhanced crystallization. At the first sight, our results stay in contrast to most literature data, showing that H-bonds favor the glass formation ability. However, this effect is usually observed for the materials, which form extensive multidirectional hydrogen bonds and associates. In NAP and NH2-NAP, the situation is much different, since both compounds exist mainly as dimers. Therefore, one can postulate that specific intermolecular interactions are an important parameter determining the GFA of different materials, including APIs.

Conformational changes underlying variation in the structural dynamics of materials confined at the nanometric scale.

Broadband dielectric and Raman spectroscopies combined with calorimetric measurements and DFT calculations have been used to investigate the molecular dynamics of the benzyl derivative of ibuprofen (Ben-IBU) incorporated into aluminum oxide (AAO) templates of various pore diameters (d = 20 nm and d = 80 nm). Time-dependent experiments on the material confined in pores of d = 20 nm revealed the occurrence of a low activation barrier kinetic process, that was manifested as a variation in the integral intensities of some characteristic vibrations of carboxylic and benzene moieties as well as a shift of the structural relaxation process. Complementary DFT computations enabled us to identify its molecular nature as originating from cis to trans like conformational change. Our results clearly show that molecular rearrangements enforced by the interactions with the pore walls/substrate may affect the properties of the confined systems. Consequently, these effects must be taken into account to understand the dynamics and variation of the glass transition temperature in high (polymers) and low molecular weight glass formers subjected to spatial restrictions at the nanometer scale.

Studies on dynamics and isomerism in supercooled photochromic compound Aberchrome 670 with the use of different experimental techniques.

Differential Scanning Calorimetry (DSC), X-ray diffraction (XRD), Fourier Transform Infrared (FTIR) and Broadband Dielectric (BD) spectroscopies were applied to investigate the thermal, structural, photochemical and dynamical properties of a fulgide-type photochromic compound, Aberchrome 670 (Ab670). In the original crystals, characterized by a pale yellow color, molecules take the E conformation. However, upon UV irradiation of either the crystalline or glassy compound, it isomerizes to the closed (C) form, characterized by the intense red tone. Although, we have found that such conversion is not complete (far below 100%). It was shown that due to UV irradiation as well as heating of the studied fulgide to high temperature (above the melting point), the Z isomer is formed. Further FTIR measurements performed on the UV irradiated and molten compound indicated that upon annealing of the sample in the vicinity of the glass transition temperature the Z isomer reverts back to the original E form. The final confirmation of this supposition has come from BDS studies, where the strong shift of the structural relaxation process during time-dependent isothermal measurements was noticed. One can add that a similar pattern of behavior has been observed previously by some of us in the case of tautomerism or mutarotation [Z. Wojnarowska et al., J. Chem. Phys., 2010, 133, 094507; W. Kossack et al., J. Chem. Phys., 2014, 140, 215101; P. Wlodarczyk et al., J. Phys. Chem. B, 2009, 113, 4379-4383; P. Wlodarczyk et al., J. Non-Cryst. Solids, 2010, 356, 738-742]. From the analysis of the time variation of the structural relaxation times, the activation barrier, EA = 18 kJ mol-1, for Z to E isomerization in Ab670 was calculated. Interestingly, it agrees well with the one determined for a similar kind of transformation in stilbenes. Therefore, we found that dielectric spectroscopy can be a very useful technique to track Z to E interconversion in the highly viscous supercooled state. Consequently, a unique opportunity to follow this kind of isomerism at high pressures, high electric fields and under nanometric spatial confinement in pure supercooled compounds appeared.

Anhydrosaccharides-A new class of the fragile plastic crystals.

In this paper, 1,6-anhydro-ß-D-glucopyranose (anhGLU), 1,6-anhydro-ß-D-mannopyranose (anhMAN), and 1,6-anhydro-ß-D-galactopyranose (anhGAL), three new materials that form the Orientationally Disordered Crystal (ODIC) phase, have been thoroughly investigated using various experimental techniques. All measurements clearly indicated that these compounds possess a series of very interesting physical properties that are considerably different than those reported for ordinary plastic crystals. X-Ray diffraction investigations have revealed enormously long-range static correlations between molecules, reaching even 120 Å. Moreover, dielectric studies showed that besides Freon 113, the investigated anhydrosaccharides are the most fragile systems that form the ODIC phase. Further analysis of Fourier transform infrared spectra indicated that such peculiar behavior of anhydrosaccharides might be closely related to multidirectional H-bonds of various strengths that most likely affect the number of available conformations, density states, and the potential barriers in the energy landscape of these compounds. This is consistent with the results from previous reports [L. C. Pardo, J. Chem. Phys. 124, 124911 (2006) and Th. Bauer et al., J Chem. Phys. 133, 144509 (2010)] showing that the higher fragility of Freon 112 as well as a mixture of 60% succinonitrile and 40% glutaronitrile (60SN-40GN) can be closely related to the enhanced conformational ability and additional disorder introduced by various substituents, which further make energy landscape more complex. Finally, by studying the properties of 2,3,4-tri-O-acetyl-1,6-anhydro-ß-D-glucopyranose (ac-anhGLU) it was found that besides the shape of the molecules, H-bonds or generally strong intermolecular interactions are extremely important parameters contributing to the ability to form the plastic phase. This is in line with current observations that in most cases the ODIC phase is created in highly interacting compounds.

High-pressure dielectric studies on 1,6-anhydro-ß-D-mannopyranose (plastic crystal) and 2,3,4-tri-O-acetyl-1,6-anhydro-ß-D-glucopyranose (canonical glass).

Broadband Dielectric Spectroscopy was applied to investigate molecular dynamics of two anhydrosaccharides, i.e., 1,6-anhydro-ß-D-mannopyranose, anhMAN (hydrogen-bonded system) and 2,3,4-tri-O-acetyl-1,6-anhydro-ß-D-glucopyranose, ac-anhGLU (van der Waals material), at different thermodynamic conditions. Moreover, the reported data were compared with those recently published for two other H-bonded systems, i.e., 1,6-anhydro-ß-D-glucopyranose (anhGLU) and D-glucose (D-GLU). A direct comparison of the dynamical behavior of the materials with a similar chemical structure but significantly differing by the degrees of freedom, complexity, and intermolecular interactions made it possible to probe the impact of compression on the fragility, Temperature-Pressure Superpositioning and pressure coefficient of the glassy crystal/glass transition temperatures (dTgc/dp ; dTg/dp). Moreover, the correlation between dTgc/dp determined experimentally from the high-pressure dielectric data and the Ehrenfest equation has been tested for the plastic crystals (anhGLU and anhMAN) for the first time. Interestingly, a satisfactory agreement was found between both approaches. It is a quite intriguing finding which can be rationalized by the fact that the studied materials are characterized by the low complexity (lower degrees of freedom with respect to the molecular mobility) as well as ordered internal structure. Therefore, one can speculate that in contrast to the ordinary glasses the dynamics of the plastic crystals might be described with the use of a single order parameter. However, to confirm this thesis further, pressure-volume-temperature (PVT) experiments enabling calculations of the Prigogine Defay ratio are required.

Melts of Octaacetyl Sucrose as Oral-Modified Release Dosage Forms for Delivery of Poorly Soluble Compound in Stable Amorphous Form.

The presented work describes the formulation and characterization of modified release glassy solid dosage forms (GSDFs) containing an amorphous nifedipine, as a model BCS (Biopharmaceutical Classification System) class II drug. The GSDFs were prepared by melting nifedipine together with octaacetyl sucrose. Dissolution profiles, measured under standard and biorelevant conditions, were compared to those obtained from commercially available formulations containing nifedipine such as modified release (MR) tablets and osmotic release oral system (OROS). The results indicate that the dissolution profiles of the GSDFs with nifedipine are neither affected by the pH of the dissolution media, type and concentration of surfactants, nor by simulated mechanical stress of biorelevant intensity. Furthermore, it was found that the dissolution profiles of the novel dosage forms were similar to the profiles obtained from the nifedipine OROS. The formulation of GSDFs is relatively simple, and the dosage forms were found to have favorable dissolution characteristics.

[The role of emollients in atopic dermatitis in children].

Atopic dermatitis is a chronic inflammatory disease characterized by recurrent flares, intense itching, erythema, dry skin resulting from skin barrier defects, and staphylococcal infections. Multiple factors may affect the skin`s normal barrier function, including filaggrin gene mutations, immune dysregulation, altered skin microbiome, altered lipids in stratum corneum, or deficiency of antimicrobial peptides AMPs. The disease mainly affects children, causing a considerable impact on the quality of their life; its first manifestations occur with up to 90% of cases before the age of 5. For years emollients have been known as oily substances used to treat rough, scaling, xerotic conditions to make skin flexible and soft. Recently, we have learned that emollients can also moisten and hydrate dry skin, so the terms "emollient" and "moisturizer" are often used interchangeably. According to current management guidelines on atopic dermatitis prepared by dermatological societies, long-term emollient application direct to the skin and as bath additives are the basic therapy of atopic dermatitis. Emollients may be used in monotherapy or - in the flares - in conjunction with topical corticosteroids or calcineurin inhibitors. Clinical trials proved that regular emollient application moistens and hydrates the skin and helps the skin maintain a defensive barrier effect as well as reduces the amount of topical corticosteroids needed for atopic eczema in infants, children and adult patients. The results of trials and long clinical experience proved that emollients are safe and effective in patients with atopic dermatitis. This paper presents information based on recent knowledge concerning emollients: an overview of emollient components, their properties, mechanism of action, and the role they play in atopic eczema, as well as the results of clinical trials performed in children with atopic dermatitis.