Hydrogen-bonded multilayer thin films and capsules based on poly(2-n-propyl-2-oxazoline) and tannic acid : investigation on intermolecular forces, stability, and permeability

In recent years, hydrogen-bonded multilayer thin films and capsules based on neutral and nontoxic building blocks have been receiving interest for the design of stimuli-responsive drug delivery systems and for the preparation of thin-film coatings. Capsule systems made of tannic acid (TA), a natural polyphenol, as a hydrogen bonding donor and poly(2-n-propyl-2-oxazoline) (PnPropOx), a polymer with lower critical solution temperature around 25 degrees C, as a hydrogen bonding acceptor are advantageous over other conventional hydrogen-bonded systems because of their high stability in physiological pH range, biocomparibility, good renal clearance, stealth behavior, and stimuli responsiveness for temperature and pH. In this work, investigations on the interactive forces in TA/PnPropOx capsule formation, film thickness, stability, and permeability are reported. The multilayer thin films were assembled on quartz substrates, and the layer-by-layer film growth was investigated by UV-vis spectroscopy, atomic force microscopy, and profilometry. Hollow capsules were fabricated by sequential coating of TA and PnPropOx onto CaCO3 colloidal particles, followed by template dissolution with a 0.2 M ethylenediaminetetraacetic acid solution. The obtained capsules and multilayer thin films were found to be stable over a wide pH range of 2-9. It is found that both hydrogen bonding and hydrophobic interactions are responsible for the enhanced stability of the capsules at higher pH range. Swelling followed by dissolution of the capsules was observed at a pH value lower than 2, while the capsules undergo shrinking at a pH value higher than 8 and finally transform into a particle-like morphology before dissolution. The TA/PnPropOx capsules reported here could be used as a temperature-responsive drug delivery system in controlled drug delivery applications

Comparative study of the potential of poly(2-ethyl-2-oxazoline) as carrier in the formulation of amorphous solid dispersions of poorly soluble drugs

Despite the fact that solid dispersions are gaining momentum, the number of polymers that have been used as a carrier during the past 50 years is rather limited. Recently, the poly(2-alkyl-2-oxazoline) (PAOx) polymer class profiled itself as a versatile platform for a wide variety of applications in drug delivery, including their use as amorphous solid dispersion (ASD) carrier. The aim of this study was to investigate the potential of poly(2-ethyl-2-oxazoline) (PEtOx) by applying a benchmark approach with well-known, commercially available carriers (ie. polyvinylpyrrolidone (PVP) K30, poly(vinylpyrrolidone-co-vinyl acetate) (PVP-VA) 64 and hydro-xypropylmethylcellulose (HPMC)). For this purpose, itraconazole (ITC) and fenofibrate (FFB) were selected as poorly water-soluble model drugs. The four polymers were compared by establishing their supersaturation maintaining potential and by investigating their capability as carrier for ASDs with high drug loadings. Spray drying, as well as hot melt extrusion and cryo-milling were implemented as ASD manufacturing technologies for comparative evaluation. For each manufacturing technique, the formulations with the highest possible drug loadings were tested with respect to in vitro drug release kinetics. This study indicates that PEtOx is able to maintain supersaturation of the drugs to a similar extent as the commercially available polymers and that ASDs with comparable drug loadings can be manufactured. The results of the in vitro dissolution tests reveal that high drug release can be obtained for PEtOx formulations. Overall, proof-of-concept is provided for the potential of PEtOx for drug formulation purposes

Effect of crosslinking stage on photocrosslinking of benzophenone functionalized poly(2-ethyl-2-oxazoline) nanofibers obtained by aqueous electrospinning

In this study, benzophenone was introduced onto partially hydrolyzed poly(2-ethyl-2-oxazoline) (PEtOx-PEI) to prepare a poly(2-ethyl-2-oxazoline)-benzophenone (PEtOx-BP) copolymer, which was used to produce water stable nanofibers via aqueous electrospinning and photocrosslinking. Three different ultraviolet (UV) irradiation methods, i.e. pre-crosslinking before electrospinning, in-situ crosslinking during electrospinning and post-crosslinking after electrospinning, were used to prepare crosslinked nanofibers. The influence of UV-irradiation at these different stages of the nanofiber production process was investigated in terms of alterations in viscosity, nanofiber morphology and water stability of the fibers. It was shown that pre-crosslinking the polymer solutions had a great influence on the solution viscosity which could both positively or negatively alter the stability of the electrospinning process. Whereas the strategy of crosslinking nanofibers during the production process did not lead to uniform nor water-stable nanofibers, the pre-crosslinking and post-crosslinking strategies greatly increased the water stability of the nanofibers. In both techniques the crosslinking density and therefore water solubility can be easily tuned by manipulating the polymer concentration, UV-irradiation time and membrane thickness. Complete insolubility, i.e. the formation of crosslinked networks, was achieved by the post-cross linking strategy. This work provides straightforward methods to increase the water stability of the PEtOx nanofibers, which will definitely be of great value to biomedical applications such as drug delivery and tissue engineering

Nanofibers with a tunable wettability by electrospinning and physical crosslinking of poly(2-n-propyl-2-oxazoline)

This work shows the design of highly porous membranes with tunable wettability based on poly(2-n-propyl-2-oxazoline) (PnPrOx) nanofibers. Wicking and advanced contact angle experiments demonstrate the high potential for applications requiring specific interactions with aqueous media. PnPrOx is a popular member among the biocompatible poly(2-oxazoline)s due to its thermoresponsiveness in aqueous solutions, enabling the production of ‘smart materials’. On material level, however, many interesting properties of this polymer remain undiscovered. Electrospinning is an ideal technique to transfer the properties observed in solutions to end-material properties, as the polymer is processed into highly porous, nanofibrous membranes. PnPrOx' electrospinnability is here investigated in environmentally friendly ethanol/water solvent systems, ensuring industrial scalability. The nanofibrous membranes show increased hydrophobicity exhibiting the rose-petal effect. Upon functionalization with tannic acid, the hydrophobic membranes are transformed into hydrophilic nanofibers showing water-stability in both fresh and salty water, even below the polymer cloud point temperature. By varying the tannic acid amount, the hydrophilicity can be fine-tuned as the contact area between water droplets and surface, the rate and manner of water uptake and the extent of the rose-petal effect can be manipulated easily. Hence an interesting material is designed for applications in which water caption and transport are important

Tannic acid-stabilized self-degrading temperature-sensitive poly(2-n-propyl-2-oxazoline)/gellan gum capsules for lipase delivery

In recent years, stable hydrogen-bonded stimuli-responsive polymer capsules have been receiving great interest for the encapsulation and release of sensitive molecules such as lipase enzymes. Compartmental capsules having a liquid gel core stabilized with temperature-responsive hydrogen-bonded multilayers are advantageous over other conventional systems because of their ability to maintain hydrophilic lipase and other hydrophobic compounds in compatible protected molecular vehide environments and prolong their native properties, e.g., in the body. In this work, we report a methodology to stabilize an aqueous liquid gellan gum (GG) core in a capsule using neutral and nontoxic building blocks, namely, poly(2-n-propyl-2-oxazoline) (PnPrOx) and tannic acid (TA), to fabricate temperature-responsive capsules, comprising both lipase and hydrophobic oil droplets. The capsules were fabricated by adding GG droplets to a PnPrOx suspension at a temperature (T) higher than its cloud point temperature (T-CP). Notably, the formed capsules were not stable in water without TA stabilization via hydrogen bonding. Scanning electron microscopy (SEM) investigations of the GG/building block interphase revealed that the collapsed PnPrOx globules that are present above the T-CP stabilized the GG interphase as a Pickering emulsion, while undergoing a configurational transformation into its linear form by interacting with TA in the next step of capsule formation resulting in a smooth PnPrOx/TA capsule wall. The encapsulation efficiencies of the capsules for model fluorescent molecules were found to be 52, 54, and 24% for FITC-dextran, rhodamine, and Nile red, respectively. The stability experiments exhibited swelling and shell thinning at certain locations followed by complete rupture of the capsules at 37 degrees C, while the capsules were stable for several weeks at temperatures below the T-CP of PnPrOx. The capsules were found to be stable in stimulated gastric fluid (SGF) for several hours at 37 degrees C while successfully releasing the encapsulated lipase and Nile red (model hydrophobic compound) in stimulated intestinal fluid (SIF). The released lipase was found to retain almost 100% of its activity. The reported capsules have high potential for use as carriers for encapsulation and release of a variety of payloads ranging from proteins and vitamin supplements to enzymes and probiotics through the oral route of administration

Detailed Understanding of Solvent Effects for the Cationic Ring-Opening Polymerization of 2-Ethyl-2-oxazoline

Polymerization of 2-ethyl-2-oxazoline (EtOx) has often been in the spotlight for fundamental studies of poly(2-alkyl/aryl-2-oxazoline)s (PAOx) polymerization, especially initiator screening, solvent screening, and copolymerization trends. In this work, we build on previous observations of solvent effects on the cationic ring-opening polymerization (CROP) of EtOx, with additional experimental observations of previously unreported solvents to expand the explored parameter space. Our objective is to find solvents with the lowest activation energy (Ea) and higher Arrhenius preexponential factor (A), which will allow us to produce narrow molar mass distributions at higher molecular weights, in the least time. To achieve this, we examined the various single factors like Dimroth ET(30) values, the Kamlet-Abraham-Taft (KAT) linear free-energy relationship (LFER) equation(s), and the Catalan LFER equations. Only one of Catalan’s equations sufficiently disentangled dipolarity and polarizability to give a good fit due to contradictory effects. It was found that solvent nucleophilicity, electrophilicity, and polarizability affected the Ea, but not dipolarity. All four factors affected the A. This indicates that the Ea is minimized in solvents that do not solvate ions well (i.e. force ion-pairing), and A was minimized in more dipolar solvents that solvate the polymer chains well. A strongly negative activation entropy (ΔS‡) shows that the propagation reaction is associative. The Catalan LFER allows for the prediction of Ea, A, ΔH‡, and ΔS‡, and the derived kp, across a broad range of solvents

Amidation of methyl ester side chain bearing poly(2-oxazoline)s with tyramine : a quest for a selective and quantitative approach

Poly(2-alkyl/aryl-2-oxazoline) s (PAOx) are a class of cytocompatible polymers that have received growing interest over the past decade. This growing interest can mainly be attributed to their greater chemical versatility compared to other cytocompatible polymers, such as poly(ethylene glycol) (PEG), that originate from the diverse set of monomers compatible with the cationic ring-opening polymerization. Within this contribution we focus on the modification of methyl ester functional PAOx, on which we recently reported the quantitative conversion of methyl ester side chain bearing PAOx via direct amidation for a number of amines. While this approach is robust, it can be challenging to introduce certain amines, due to their high cost, poor solubility or additional functionalities. Here we evaluated three alternative amidation approaches of methyl ester side chain bearing PAOx with tyramine in terms of selectivity and quantitative conversion to the respective secondary amides. The amidation proceeded successfully via DMTMM coupling, PFP-activation and TBD catalysis, although only the latter 2 methods selectively yielded the desired product. In summary, we present valuable alternatives to our earlier reported method, contributing further to the biomedical application potential of PAOx