Indomethacin co-amorphous drug-drug systems with improved solubility, supersaturation, dissolution rate and physical stability.

In this study, new co-amorphous drug systems were designed using a pharmacologically relevant combination to improve the solubility and dissolution of indomethacin. Combinations of indomethacin-paracetamol (IND-PAR) as an anti-inflammatory/pain killer, and indomethacin-nicotinamide (IND-NCT) for prevention of gastric ulcers caused by IND, were developed for co-amorphization. The effect of PAR and NCT on the solubility, supersaturation, and dissolution of the poorly soluble counterpart, IND, was investigated. PAR and NCT were found to enhance the solubility and supersaturation of IND in biorelevant medium (FaSSIF) and in FaSSIF blank. Differential scanning calorimetry (DSC) showed capability of IND-PAR and IND-NCT binary mixtures to form eutectic mixture. Powder X-ray diffraction and DSC indicated the formation of a homogenous co-amorphous system with single Tg value. Hydrogen bonding between IND and each of PAR and NCT were found to stabilize the co-amorphous systems as supported by FTIR studies. The intrinsic dissolution rate under sink conditions was improved over that of plain amorphous IND both in FaSSIF and FaSSIF blank. IND-PAR 2:1 and IND-NCT 1:1 were extremely stable and remained amorphous for 7 months at 25 °C, while all co-amorphous formulations were stable at least up to one month at 40 °C under dry condition. The present work demonstrates an improved approach to combine IND-PAR and IND-NCT as promising co-amorphous systems for potential therapeutical applications.

Poly(2-oxazoline)s as Smart Bioinspired Polymers.

Poly(2-alkyl-2-oxazoline)s can be regarded as pseudo-peptides or bioinspired polymers, which are available through living/controlled cationic polymerization and polymer ("click") modification procedures. Materials and solution properties may be adjusted via the nature of the side chain (hydrophilic-hydrophobic, chiral, bio-functional, etc.), opening the way to stimulus-responsive materials and complex colloidal structures in aqueous environments. Herein, we give an overview over the macromolecular engineering of polyoxazolines, including the synthesis of biohybrids, and the "smart"/bioinspired aggregation behavior in solution.

Tannic acid as a co-former in co-amorphous systems: Enhancing their physical stability, solubility and dissolution behavior.

Co-amorphous systems have been increasingly investigated to improve the solubility and dissolution rate of poorly soluble drugs. Considering the ability of tannic acid (TA), a polyphenolic compound, to form hydrogen bonds with compounds that contain carbonyl groups, we hypothesized that tannic acid will also be effective in stabilizing amorphous form of drugs in co-amorphous systems. Co-amorphization by TA of two poorly soluble model drugs, carbamazepine (CBZ) and indomethacin (IND) was investigated. Tannic acid facilitated the amorphization of studied drugs and successful co-amorphous systems were obtained as proved by powder X-Ray diffraction (PXRD). Differential scanning calorimetry (DSC) confirmed the homogeneous structure as indicated by the existence of a single Tg for each co-amorphous product. The expected molecular interactions between phenolic groups in TA and carbonyl groups in the studied drugs (CBZ and IND) were confirmed by analyzing their infrared spectra. Drug-TA co-amorphous formulations showed an enhanced equilibrium solubility over the individual drugs. Powder dissolution test under sink conditions showed improved dissolution profiles of drug-TA co-amorphous formulations compared to the corresponding crystalline drugs and physical mixtures. Tannic acid also showed a superior stabilizing effect. CBZ-TA co-amorphous system was physically stable at dry conditions (up to 6 months at 40 °C), under 60% relative humidity (up to one month at 20 °C), and in solution (after 48 h of solubility measurements), as revealed by PXRD examination of the remaining solid after solubility measurement. However, IND-TA co-amorphous formulation remained stable at dry conditions up to 6 months at 4 °C and up to one month at 60% relative humidity at 20 °C. These findings demonstrate the potential of tannic acid as a promising co-former in co-amorphous systems of poorly soluble drugs.

Nisin/polyanion layer-by-layer films exhibiting different mechanisms in antimicrobial efficacy.

Nisin/polyanion Layer-by-Layer (LbL) films are reported to exhibit different mechanisms in antimicrobial efficacy depending on the type of polyanion. LbL films consisting of nisin as the polycationic component were prepared using two different polyanionic constituents: poly acrylic acid (PAA) and dextran sulfate (DX). Due to the weaker interaction strength of carboxylate groups with nisin compared to sulfate/nisin, a larger molecular weight of PAA was needed to achieve LbL assembly. PAA-100K/nisin and DX-15K/nisin multilayer films exhibited significantly different properties. PAA-nisin films grew faster compared to DX-nisin films and showed, for 60 bilayer films, an average bilayer thickness of 21.6 nm compared to that of 6.1 nm in DX-nisin films. The total amount of nisin was found to be 17.1 ± 2.2 µg cm-2 in (PAA-nisin)60 and 6.8 ± 0.4 µg cm-2 in (DX-nisin)60 films. The stability of the films was investigated at three different pH values of 6.0, 7.4 and 9.5. (PAA-nisin)60 films exhibited the release of nisin into the solution which resulted in the disintegration of the film over several hours. A burst release was observed in the first hour followed by a slower release and disintegration over 24 hours with a complete release at pH 9.5. The bacterial growth inhibition test against Staphylococcus epidermidis confirmed the antimicrobial activity of nisin released from PAA-nisin films. PAA was found to stabilize nisin and the film-released nisin retained its antimicrobial activity in the neutral and alkaline pH values. Unlike PAA-nisin films, (DX-nisin)60 films were stable at the physiological conditions up to 14 days with no release of nisin. DX-nisin films were found to inhibit the attachment of Staphylococcus epidermidis and prevent biofilm formation. These results clearly demonstrate the effect of different polyanions on nisin LbL films to achieve different mechanisms in antimicrobial efficacy and show the potential of PAA-nisin multilayer films as promising local delivery systems for treatment of burns and wounds, while DX-nisin multilayer films can be employed as stable coatings against bacterial attachment and biofilm formation.

Motion of single terrylene molecules in confined channels of poly(butadiene)-poly(ethylene oxide) diblock copolymer.

The motion of terrylene probe molecules in confined PB channels of an asymmetric PB-PEO diblock copolymer has been investigated by single molecule tracking. The one-dimensional diffusion coefficients were found to be significantly smaller and had a narrower distribution compared to two-dimensional diffusion coefficients in PB. The trajectories of some single molecules showed unusual behavior of directed motion where mean square displacement had a parabolic dependence on lag time. The likely origin of this behavior is discussed in terms of local variations in the PB channel width and the resulting change in the local density. The results show the effect of nonuniformities and heterogeneities in the channels on the motion of single molecules and demonstrate the sensitivity of single molecule tracking in characterizing self-assembled block copolymer morphologies.

Poly(2-Ethyl-2-Oxazoline) as an Alternative to Poly(Vinylpyrrolidone) in Solid Dispersions for Solubility and Dissolution Rate Enhancement of Drugs.

Poly(2-ethyl-2-oxazoline) (PEOX), a biocompatible polymer considered as pseudopolypeptide, was introduced as a potential alternative to the commonly used polymer, poly(vinylpyrrolidone) (PVP) for the preparation of solid dispersion with a poorly soluble drug. Glipizide (GPZ), a Biopharmaceutical Classification System class II model drug, was selected for solubility and dissolution rate study. GPZ-polymer solid dispersions and physical mixtures were characterized and investigated by X-ray diffractometry, differential scanning calorimetry, scanning electron microscopy, and FTIR spectroscopy. The impact of polymers on crystal nucleation kinetics was studied, and PEOX exhibited strong inhibitory effect compared with PVP. Solubility and dissolution behavior of the prepared solid dispersions and their physical blends were in vitro examined and evaluated. A significant enhancement in GPZ solubility was obtained with PEOX compared with the pure drug and solid dispersion with PVP. A big improvement in the intrinsic dissolution rate (45 times) and dissolved amount of GPZ (58 times) was achieved with PEOX in fasted state simulated intestinal fluid, against comparable enhancement observed with PEOX and PVP in phosphate buffer at pH 6.8. Lower molecular weight of PEOX-5K (5000 g/mol) was found to be superior to higher molecular weight PEOX-50K (50,000 g/mol) in the improvement of dissolution behavior. The findings of this study with GPZ as a model drug introduce lower molecular weight PEOX as a promising polymeric carrier toward better oral bioavailability of poorly soluble drugs.

Nanoparticle and gelation stabilized functional composites of an ionic salt in a hydrophobic polymer matrix.

Polymer composites consisted of small hydrophilic pockets homogeneously dispersed in a hydrophobic polymer matrix are important in many applications where controlled release of the functional agent from the hydrophilic phase is needed. As an example, a release of biomolecules or drugs from therapeutic formulations or release of salt in anti-icing application can be mentioned. Here, we report a method for preparation of such a composite material consisted of small KCOOH salt pockets distributed in the styrene-butadiene-styrene (SBS) polymer matrix and demonstrate its effectiveness in anti-icing coatings. The mixtures of the aqueous KCOOH and SBS-cyclohexane solutions were firstly stabilized by adding silica nanoparticles to the emulsions and, even more, by gelation of the aqueous phase by agarose. The emulsions were observed in optical microscope to check its stability in time and characterized by rheological measurements. The dry composite materials were obtained via casting the emulsions onto the glass substrates and evaporations of the organic solvent. Composite polymer films were characterized by water contact angle (WCA) measurements. The release of KCOOH salt into water and the freezing delay experiments of water droplets on dry composite films demonstrated their anti-icing properties. It has been concluded that hydrophobic and thermoplastic SBS polymer allows incorporation of the hydrophilic pockets/phases through our technique that opens the possibility for controlled delivering of anti-icing agents from the composite.

Effect of anions on the cloud point temperature of aqueous poly(2-ethyl-2-oxazoline) solutions.

Poly(2-alkyl-2-oxazoline)s have recently gained attention in especially biological applications due to their lower critical solution temperature being close to the body temperature and their biocompatibility. The understanding of how cloud point temperature (T(c)) depends on the salt concentration and the molecular mechanisms responsible for such behavior are important to tune T(c) as desired by the applications. In this paper, we report the effect of a series of sodium salts on T(c) of aqueous poly(2-ethyl-2-oxazoline) (PEOX) solutions by dynamic light scattering. PEOX samples having four different molecular weights were investigated, and the results were compared with those of poly(N-isopropylacrylamide) (PNIPAM), the mostly investigated and used thermoresponsive polymer. Kosmotropic anions decreased T(c) linearly while chaotropic anions increased T(c) nonlinearly with salt concentration. The contributions of different mechanisms to T(c) change have been discussed. Our results indicate that the dominant mechanism is the dehydration of PEOX for divalent kosmotropic anions (CO(3)(2-), SO(4)(2-), S(2)O(3)(2-)) and direct binding for chaotropic anions (NO(3)(-), I(-), ClO(4)(-), SCN(-)). For the remaining monovalent kosmotropic anions (H(2)PO(4)(-), F(-), Cl(-), Br(-)), a combination of dehydration and surface tension mechanisms was in effect. The additional contribution of the surface tension mechanism for the monovalent kosmotropic anions was inferred for different molecular weight PEOX samples and also for PNIPAM. With PEOX molecular weight decreasing from 500,000 to 5000 g/mol, T(c) decreased less with salt concentration which was attributed to the contribution of the surface tension mechanism. For PEOX samples, the decrease of T(c) with kosmotropic anion concentration was faster compared to PNIPAM due to differences in their chemical structure. Our results show that the molecular mechanisms of interactions between PEOX chains and specific anions can simply be inferred from determination of T(c) by a common technique-dynamic light scattering.

Effect of structural isomerism and polymer end group on the pH-stability of hydrogen-bonded multilayers.

Association of tannic acid (TA) with structurally isomeric poly(N-isopropylacrylamide) (PNIPAM) and poly(2-isopropyl-2-oxazoline) (PIPOX) has been examined at surfaces to understand the effect of different molecular arrangements in a polymer repeating unit of structural isomers on the construction and pH-stability of hydrogen-bonded multilayers. Films were fabricated using layer-by-layer (LbL) technique through hydrogen-bonding interactions primarily between carbonyl groups of neutral polymers and hydroxyl groups of TA molecules at pH 2. PIPOX and TA formed thinner and more stable films in the pH scale with a critical dissolution pH of 9 when compared to films of PNIPAM and TA with a critical pH of 8. The differences in the thickness and pH-stability were due to different conformational behavior of PNIPAM and PIPOX in water which affects the accessibility of carbonyl groups for participation in the hydrogen bonding and the number of binding sites between the polymer pairs. Addition of electrostatic interactions by introducing amino groups only at the PIPOX chain end shifted the critical dissolution pH to higher values and resulted in gradual dissolution of the films in a wide pH range of 9-12. Such films hold promise for use in biomedical field due to biocompatibility and lower critical solution temperature (LCST) behavior at near physiological temperature of PNIPAM and PIPOX together with the pH-response of the hydrogen-bonded films.

Tuning the surface hydrophobicity of polymer/nanoparticle composite films in the Wenzel regime by composition.

Surface hydrophobicity of composite films containing polymer and nanoparticles has been studied as a function of composition. We show that the hydrophobicity can be tuned by adjusting the amount of particles in the two-component system. A sharp transition from a polymer-rich surface to a nanoparticles-rich surface was observed with increasing mass fraction of particles in spin-coated thin films. Water drops on the films did not slide down even at tilt angles of 90 degrees . Contact angle hysteresis increased with the mass fraction of particles indicating that the surface roughness increased as the surfaces remained in the Wenzel regime. Contact angle hysteresis data were quantitatively consistent with predictions of a recent theory.

Transformation of a simple plastic into a superhydrophobic surface.

Superhydrophobic surfaces are generally made by controlling the surface chemistry and surface roughness of various expensive materials, which are then applied by means of complex time-consuming processes. We describe a simple and inexpensive method for forming a superhydrophobic coating using polypropylene (a simple polymer) and a suitable selection of solvents and temperature to control the surface roughness. The resulting gel-like porous coating has a water contact angle of 160 degrees. The method can be applied to a variety of surfaces as long as the solvent mixture does not dissolve the underlying material.