Probing the effectiveness of barrier creams against human skin penetration of nickel powder.

OBJECTIVE: Barrier creams (BCs) are marketed as locally applied medical devices or cosmetic products to protect the skin from exposure to chemicals and irritants. Generally, the mechanism of action of such products is mainly due to the formation of a superficial thin film between the skin and the irritant or sensitizer, thus reducing or totally blocking the cutaneous penetration of such agents. Specifically, studies focusing on the effectiveness of commercial protective creams to prevent nickel cutaneous penetration are extremely scarce. The aim of the current work, therefore, is to evaluate the protective role of a commercially available barrier cream for nickel and compare the results with a simple moisturizing, following exposure to Ni powder. METHODS: Marketed BCs were evaluated and tested. Human skin absorption of Ni was studied in vitro using static Franz diffusion cells. RESULTS: Our results demonstrate that the application of both formulations caused a reduction of Ni inside the skin (8.00 ± 3.35 µg cm-2 for the barrier cream and 22.6 ± 12.6 µg cm-2 for the general moisturizing product), with the specialized barrier cream being statistically (p = 0.015) more efficient on forming a protective barrier, thus evidencing the importance of some ingredients in such formulations on the nickel dermal accumulation. CONCLUSIONS: The composition of the formulations based on film-forming or chelating agents may play an imperative role in reducing the cutaneous penetration of Ni.

OBJECTIF: Les crèmes de barrière (CB) sont commercialisées en tant que dispositifs médicaux ou produits cosmétiques appliqués localement pour protéger la peau contre l'exposition aux produits chimiques et irritants. En général, le mécanisme d'action de ces produits est principalement dû à la formation d'un film mince superficiel entre la peau et l'irritant ou le sensibilisant, réduisant ainsi ou bloquant totalement la pénétration cutanée de ces agents. Plus précisément, les études portant sur l'efficacité des crèmes protectrices commercialisées pour prévenir la pénétration cutanée du nickel sont extrêmement rares. L'objectif du projet en cours est donc d'évaluer le rôle protecteur d'une crème barrière disponible dans le commerce contre le nickel et de comparer les résultats à un simple hydratant après une exposition à la poudre de Ni. MÉTHODES: Des CB commercialisées ont été évaluées et testées. L'absorption cutanée du Ni dans la peau humaine a été étudiée in vitro à l'aide de cellules de diffusion statiques de Franz. RÉSULTATS: Nos résultats démontrent que l'application des deux formulations a entraîné une réduction du taux de Ni à l'intérieur de la peau (8,00 ± 3,35 µg·cm-2 pour la crème barrière et 22,6 ± 12,6 µg·cm-2 pour le produit hydratant ordinaire), la crème barrière spécialisée étant statistiquement (p = 0,015) plus efficace pour former une barrière protectrice, démontrant ainsi l'importance de certains ingrédients dans ces formulations sur l'accumulation dermique du nickel. CONCLUSIONS: La composition des formulations basées sur des agents de formation de film ou de chélation peut jouer un rôle nécessaire pour réduire la pénétration cutanée du Ni.

Modulating Thermal Properties of Polymers through Crystal Engineering.

Crystal engineering has exclusively focused on the development of advanced materials based on small organic molecules. We now demonstrate how the cocrystallization of a polymer yields a material with significantly enhanced thermal stability but equivalent mechanical flexibility. Isomorphous replacement of one of the cocrystal components enables the formation of solid solutions with melting points that can be readily fine-tuned over a usefully wide temperature range. The results of this study credibly extend the scope of crystal engineering and cocrystallization from small molecules to polymers.

Nanostructured Drugs Embedded into a Polymeric Matrix: Vinpocetine/PVP Hybrids Investigated by Debye Function Analysis.

Microcrystalline vinpocetine, coground with cross-linked polyvinylpyrrolidone, affords hybrids containing nanosized drug nanocrystals, the size and size distributions of which depend on milling times and drug-to-polymer weight ratios. Using an innovative approach to microstructural characterization, we analyzed wide-angle X-ray total scattering data by the Debye function analysis and demonstrated the possibility to characterize pharmaceutical solid dispersions obtaining a reliable quantitative view of the physicochemical status of the drug dispersed in an amorphous carrier. The microstructural properties derived therefrom have been successfully employed in reconciling the enigmatic difference in behavior between in vitro and in vivo solubility tests performed on nanosized vinpocetine embedded in a polymeric matrix.

Cocrystal Formation through Mechanochemistry: from Neat and Liquid-Assisted Grinding to Polymer-Assisted Grinding.

Mechanochemistry is an effective method for the preparation of multicomponent crystal systems. In the present work, we propose an alternative to the established liquid-assisted grinding (LAG) approach. Polymer-assisted grinding (POLAG) is demonstrated to provide a new class of catalysts for improving reaction rate and increasing product diversity during mechanochemical cocrystallization reactions. We demonstrate that POLAG provides advantages comparable to the conventional liquid-assisted process, whilst eliminating the risk of unwanted solvate formation as well as enabling control of resulting particle size. It represents a new approach for the development of functional materials through mechanochemistry, and possibly opens new routes toward the understanding of the mechanisms and pathways of mechanochemical cocrystal formation.

Enantiospecific crystallisation behaviour of malic acid in mechanochemical reactions with vinpocetine.

We report an intriguing example of enantioselectivity in the formation of new multicomponent crystalline solid containing vinpocetine and malic acid. Several experimental data sets confirmed that the multicomponent system presents a clear enantiospecific crystallisation behaviour both in the solid-state and in solution: only the system consisting of vinpocetine and L-malic acid produces a free-flowing solid consisting of a new crystalline form, while the experiments with D-malic acid produced an amorphous and often deliquescent material. The new vinpocetine-L-malic system crystallizes in the monoclinic space group of P21 and in a 1:1 molar ratio, where the two molecules are linked through intermolecular hydrogen bonds in the asymmetric unit. The vinpocetine-DL-malic system was partially crystalline (with also traces of unreacted vinpocetine) with diffraction peaks corresponding to those of vinpocetine-L-malic acid. Solid-state NMR experiments revealed strong ionic interactions in all the three systems. However, while vinpocetine-L-malic acid system was a pure and crystalline phase, the other two systems persistently showed the presence of unreacted vinpocetine. This resulted in a significant worsening of the dissolution profile with respect to the pure vinpocetine-L-malic crystalline salt, whose dissolution kinetics appeared superior.

3D human foreskin model for testing topical formulations of sildenafil citrate.

Sildenafil citrate is an approved drug used for the treatment of erectile dysfunction and premature ejaculation. Despite a widespread application, sildenafil citrate shows numerous adverse cardiovascular effects in high-risk patients. Local transdermal drug delivery of this drug is therefore being explored as an interesting and noninvasive alternative administration method that avoids adverse effects arised from peak plasma drug concentrations. Although human and animal skin represents the most reliable models to perform penetration studies, they involve a series of ethical issues and restrictions. For these reasons new in vitro approaches based on artificially reconstructed human skin or "human skin equivalents" are being developed as possible alternatives for transdermal testing. There is little information, however, on the efficiency of such new in vitro methods on cutaneous penetration of active ingredients. The objective of the current study was to investigate the sildenafil citrate loaded in three commercial transdermal vehicles using 3D full-thickness skin equivalent and compare the results with the permeability experiments using porcine skin. Our results demonstrated that, while the formulation plays an imperative role in an appropriate dermal uptake of sildenafil citrate, the D coefficient results obtained by using the 3D skin equivalent are comparable to those obtained by using the porcine skin when a simple drug suspension is applied (1.17 × 10-10 ± 0.92 × 10-10 cm2/s vs 3.5 × 102 ± 3.3 × 102 cm2/s), suggesting that in such case, this 3D skin model can be a valid alternative for ex-vivo skin absorption experiments.

Direct Imaging of Radiation-Sensitive Organic Polymer-Based Nanocrystals at Sub-Ångström Resolution.

Seeing the atomic configuration of single organic nanoparticles at a sub-Å spatial resolution by transmission electron microscopy has been so far prevented by the high sensitivity of soft matter to radiation damage. This difficulty is related to the need to irradiate the particle with a total dose of a few electrons/Å2, not compatible with the electron beam density necessary to search the low-contrast nanoparticle, to control its drift, finely adjust the electron-optical conditions and particle orientation, and finally acquire an effective atomic-resolution image. On the other hand, the capability to study individual pristine nanoparticles, such as proteins, active pharmaceutical ingredients, and polymers, with peculiar sensitivity to the variation in the local structure, defects, and strain, would provide advancements in many fields, including materials science, medicine, biology, and pharmacology. Here, we report the direct sub-ångström-resolution imaging at room temperature of pristine unstained crystalline polymer-based nanoparticles. This result is obtained by combining low-dose in-line electron holography and phase-contrast imaging on state-of-the-art equipment, providing an effective tool for the quantitative sub-ångström imaging of soft matter.

Drug salt formation via mechanochemistry: the case study of vincamine.

In the present research a salt of vincamine, a poorly bioavailable indole alkaloid derived from the leaves of Vinca minor L., was synthesized in the solid state by means of a mechanochemical process employing citric acid as a reagent. The mechanochemical process was adopted as a solvent-free alternative to classical citrate synthetic route that involves the use of solvents. Since the mechanochemical salification is little studied to date and presents the disadvantage of offering a low yield, in this work, the influence of three process and formulation variables on the percentage of vincamine citrate was studied. In particular, the time of mechanical treatment (in planetary mill Fritsch P5) and the amount of citric acid were varied in order to evaluate their effect on the yield of the process, and the introduction of a solid solvent, a common pharmaceutical excipient (sodium carboxymethylcellulose, NaCMC), was considered. Due to the complexity of the resulting samples' matrix, an appropriate experimental design was employed to project the experimental trials and the influence of the three variables on the experimental response was estimated with the help of a statistical analysis. The experimental response, that is, the yield of the process corresponding to the percentage of vincamine in the protonated form, was unconventionally calculated by means of X-ray photoelectron spectroscopy analysis (XPS). Out of 16 samples, the one with the highest yield was the coground sample containing vincamine and citric acid in a 1:2 molar ratio, treated for 60 min in the presence of NaCMC. Under the above conditions the salification reaction was completed highlighting the importance of a proper selection of process and formulation variables of the mechanochemical salification, and emphasizing the crucial role of the solid solvent in facilitating the salification. The second step of the research encompassed the characterization of the citrate salt obtained by solid excipient assisted mechanochemical salification (SEAMS) in comparison with the vincamine citrate obtained by classical synthetic route. The samples were characterized by, besides XPS, high resolution transmission electron microscopy (HRTEM), X-ray powder diffraction (XRPD), in vitro solubilization kinetics and in vivo oral pilot study in rats. Finally, in order to monitor over time possible disproportionation phenomena, stability studies have been performed by repeating XPS analysis after 8 months. As expected, the the SEAMS-vincamine salt consisted of particles both crystalline and amorphous. The solubilization kinetics was superior to the corresponding salt probably thanks to the favorable presence of the hydrophilic excipient although the two salts were bioequivalent in rats after oral administration. Furthermore, no evidence of disporportionation phenomena in the SEAMS-vincamine salt was found after storage. In conclusion, in the case of forming salts of poorly soluble drugs, the SEAMS process may be an interesting alternative to both classical synthetic routes, eliminating the need for solvent removal, and simple neat mechanochemical salification, overcoming the problem of limited process yield.

Praziquantel meets Niclosamide: A dual-drug Antiparasitic Cocrystal.

In this paper we report a successful example of combining drugs through cocrystallization. Specifically, the novel solid is formed by two anthelminthic drugs, namely praziquantel (PZQ) and niclosamide (NCM) in a 1:3 molar ratio, and it can be obtained through a sustainable one-step mechanochemical process in the presence of micromolar amounts of methanol. The novel solid phase crystallizes in the monoclinic space group of P21/c, showing one PZQ and three NCM molecules linked through homo- and heteromolecular hydrogen bonds in the asymmetric unit, as also attested by SSNMR and FT-IR results. A plate-like habitus is evident from scanning electron microscopy analysis with a melting point of 202.89 °C, which is intermediate to those of the parent compounds. The supramolecular interactions confer favorable properties to the cocrystal, preventing NCM transformation into the insoluble monohydrate both in the solid state and in aqueous solution. Remarkably, the PZQ - NCM cocrystal exhibits higher anthelmintic activity against in vitro S. mansoni models than corresponding physical mixture of the APIs. Finally, due to in vitro promising results, in vivo preliminary tests on mice were also performed through the administration of minicapsules size M.

Better and greener: sustainable pharmaceutical manufacturing technologies for highly bioavailable solid dosage forms.

In the last decades, Green Chemistry has been gaining widespread attention within the pharmaceutical field. It is thus very important to bring more sustainable approaches into the design and manufacture of effective oral drug delivery systems. This review focuses on spray congealing and mechanochemical activation, two technologies endorsing different principles of green chemistry, and at the same time, addressing some of the challenges related to the transformation of poorly water-soluble drugs in highly bioavailable solid dosage forms. We therefore present an overview of the basic principles, equipment, and application of these particle-engineering technologies, with specific attention to case studies carried out by the groups working in Italian Universities.

A Safe-by-Design Approach to "Reef Safe" Sunscreens Based on ZnO and Organic UV Filters.

In recent years, the issue of coral bleaching has led to restrictions in some tropical locations (i.e., Palau, Hawaii, etc.) on the use of some organic UV sunscreen filters, such as oxybenzone and ethyl hexyl methoxycinnamate. In contrast, ZnO is considered safe for marine environments and thus is often used without considering its photocatalytic and oxidative activities related to the generation of O2•- and HO•. Moreover, ZnO needs to be used in combination with other filters to reach higher protection factors. Thus, the study of its interaction with formulations and with organic filters is important in sunscreen technology for the development of safer by-design products. In this work, the photocatalytic activity of zinc oxides with different surface areas (30, 25 and 9 m2/g) and their interaction with selected organic sunscreen filters were investigated. In particular, the ZnO photocatalytic kinetics were studied following the photodegradation of Acid Blue 9 (AB9) observing a first-order reaction with a chemical regime. Our evaluations of the selective inhibitions by hvb+ and HO• demonstrated a substantial predominance of the hydroxide radicals in the expression of the photocatalysis, a trend that was also confirmed by the irradiation of ZnO in an ethanolic solution. Indeed, the formulations containing both ZnO and organic filters defined as "safe" for coral reefs (i.e., Diethylamino Hydroxybenzoyl Hexyl Benzoate, DHHB, and Ethylhexyl Triazone, EHT) showed a non-negligible photocatalytic oxidation and thus the combination was underlined as safe to use.

Validation and testing of a new artificial biomimetic barrier for estimation of transdermal drug absorption.

Human skin remains the most reliable model for studying the transdermal permeation of active compounds. Due to the limited source, porcine skin has been used extensively for performing penetration tests. Performing penetration studies by using human and animal skin, however, would also involve a series of ethical issues and restrictions. For these reasons, new biomimetic artificial barriers are being developed as possible alternatives for transdermal testing. If appropriately optimized, such products can be cost-effective, easily standardized across laboratories, precisely controlled in specific experimental conditions, or even present additional properties compared to the human and animal skin models such as negligible variability between replicates. In this current work we use the skin mimicking barrier (SMB) for drug permeability tests. The aim was to evaluate the suitability of the new barrier for studying the percutaneous absorption of the lipophilic extract of the plant Zingiber officinale Roscoe in vitro and compare its permeability ability with the artificial membrane Permeapad® and porcine skin. Our results showed that the permeability values obtained through the SMB are comparable are comparable to those obtained by using the porcine skin, suggesting that the new barrier may be an acceptable in vitro model for conducting percutaneous penetration experiments.

Enhanced oral bioavailability of vinpocetine through mechanochemical salt formation: physico-chemical characterization and in vivo studies.

PURPOSE: Enhancing oral bioavailability of vinpocetine by forming its amorphous citrate salt through a solvent-free mechanochemical process, in presence of micronised crospovidone and citric acid. METHODS: The impact of formulation and process variables (amount of polymer and citric acid, and milling time) on vinpocetine solubilization kinetics from the coground was studied through an experimental design. The best performing samples were characterized by employing a multidisciplinary approach, involving Differential scanning calorimetry, X-ray diffraction, Raman imaging/spectroscopy, X-ray photoelectron spectroscopy, solid-state NMR spectroscopy, porosimetry and in vivo studies on rats to ascertain the salt formation, their solid-state characteristics and oral bioavailability in comparison to vinpocetine citrate salt (Oxopocetine(®)). RESULTS: The analyses attested that the mechanochemical process is a viable way to produce in absence of solvents vinpocetine citrate salt in an amorphous state. CONCLUSION: From the in vivo studies on rats the obtained salt was four times more bioavailable than its physical mixture and bioequivalent to the commercial salt produced by conventional synthetic process implying the use of solvent.

Mechanochemical reactivity inhibited, prohibited and reversed by liquid additives: examples from crystal-form screens.

We demonstrate that liquid additives can exert inhibitive or prohibitive effects on the mechanochemical formation of multi-component molecular crystals, and report that certain additives unexpectedly prompt the dismantling of such solids into physical mixtures of their constituents. Computational methods were employed in an attempt to identify possible reasons for these previously unrecognised effects of liquid additives on mechanochemical transformations.

Mechanochemical Synthesis and Physicochemical Characterization of Previously Unreported Praziquantel Solvates with 2-Pyrrolidone and Acetic Acid.

Two new solvates of the widely used anthelminthic Praziquantel (PZQ) were obtained through mechanochemical screening with different liquid additives. Specifically, 2-pyrrolidone and acetic acid gave solvates with 1:1 stoichiometry (PZQ-AA and PZQ-2P, respectively). A wide-ranging characterization of the new solid forms was carried out by means of powder X-ray diffraction, differential scanning calorimetry, FT-IR, solid-state NMR and biopharmaceutical analyses (solubility and intrinsic dissolution studies). Besides, the crystal structures of the two new solvates were solved from their Synchrotron-PXRD pattern: the solvates are isostructural, with equivalent triclinic packing. In both structures acetic acid and 2-pyrrolidone showed a strong interaction with the PZQ molecule via hydrogen bond. Even though previous studies have shown that PZQ is conformationally flexible, the same syn conformation as the PZQ Form A of the C=O groups of the piperazinone-cyclohexylcarbonyl segment is involved in these two new solid forms. In terms of biopharmaceutical properties, PZQ-AA and PZQ-2P exhibited water solubility and intrinsic dissolution rate much greater than those of anhydrous Form A.

Simultaneous release and ADME processes of poorly water-soluble drugs: mathematical modeling.

The importance of studying oral drug absorption is well recognized by both research facilities/institutions and the pharmaceutical industry. The use of mathematical models can represent a very profitable and indispensable tool to understand oral drug absorption. Indeed, mathematical models can verify the correctness of the mechanisms proposed to describe drug release, absorption, distribution and elimination thus reducing the number of expensive and time-consuming experiments. In this paper we develop a mathematical approach able to model both the polymeric particle mediated delivery and the gastrointestinal absorption-metabolism-excretion (ADME) of a given drug. As a model drug a poorly water-soluble drug (vinpocetine) in both the amorphous and nanocrystalline state is considered. The delivery system is obtained by drug cogrinding with a polymer (cross-linked polyvinilpyrrolidone). As the proposed mathematical model can properly fit the in vivo data on the basis of information obtained in vitro, it represents a powerful theoretical tool connecting in vitro and in vivo behavior.

Echinacea angustifolia DC. Lipophilic Extract Patch for Skin Application: Preparation, In Vitro and In Vivo Studies.

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 mm2 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.

Dissolution of an ensemble of differently shaped poly-dispersed drug particles undergoing solubility reduction: mathematical modelling.

The aim of this theoretical paper is to develop a mathematical model for describing the dissolution process, in a finite liquid environment, of an ensemble of poly-dispersed drug particles, in form of sphere, cylinder and parallelepiped that can undergo solubility reduction due to phase transition induced by dissolution. The main result of this work consists in its simplicity as, whatever the particular particles size distribution, only two ordinary differential equations are needed to describe the dissolution process. This, in turn, reflects in a very powerful and agile theoretical tool that can be easily implemented in electronic sheets, a widespread tool among the research community. Another model advantage lies on the possibility of determining its parameters by means of common independent techniques thus enabling the evaluation of the importance of solid wettability on the dissolution process.

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties.

Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and deposited in the Cambridge Structural Database (CSD). This work adds to the list of multicomponent forms of PZQ a relevant example of a racemic hemihydrate (PZQ-HH), obtainable from commercial PZQ (polymorphic Form A) through mechanochemistry. Noteworthy, the formation of the new hemihydrate strongly depends on the initial polymorphic form of PZQ and on the experimental conditions used. The new PZQ-HH has been fully characterized by means of HPLC, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Hot-Stage Microscopy (SEM), Powder X-Ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), FT-IR, polarimetry, solid-state NMR (SS-NMR), solubility and intrinsic dissolution rate (IDR), and in vitro tests on Schistosoma mansoni adults. The crystal structure was solved from the powder X-ray diffraction pattern and validated by periodic-DFT calculations. The new bioactive hemihydrate was physically stable for three months and showed peculiar biopharmaceutical features including enhanced solubility and a double intrinsic dissolution rate in water in comparison to the commercially available PZQ Form A.

Monitoring polymer-assisted mechanochemical cocrystallisation through in situ X-ray powder diffraction.

Time-resolved mechanochemical cocrystallisation studies have so-far focused solely on neat and liquid-assisted grinding. Here, we report the investigation of polymer-assisted grinding reactions using in situ X-ray powder diffraction, revealing that reaction rate is almost double compared to neat grinding and independent of the molecular weight and amount of the polymer additive used.