Designing a self-associated cationic polymer for enhanced compatibility, palatability, and gastric release of cefuroxime axetil

Cefuroxime axetil (CA) has exhibited interactions with the polymers hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate, and Eudragit E resulting in the generation of unacceptable amounts of impurities and degradation. Formulations, which mask the bitter taste of CA and release it immediately in the stomach, have therefore not been possible. In an attempt to overcome the interaction with CA, we report a self-associated cationic polymer (NREP) containing methyl methacrylate (MMA), 2-hydroxy ethylmethacrylate (HEMA), and 4-vinyl pyridine (4-VP). The hydrogen bonding between the pyridine nitrogen and the hydroxyl groups of HEMA results in strong intrachain associations, prevents interactions between NREP and CA, and inhibits degradation of CA. This has been validated by differential scanning calorimetry, Fourier transform infrared spectroscopy, NMR, and high-performance liquid chromatography analysis. These self-associations restrict polymer chain motions, enhance biocompatibility, and lead to a higher Tg, which ensures that NREP does not become tacky in processes involving heat. The judicious choice of the hydrophobic and hydrophilic monomers renders the polymer hydrophobic enough as to mask the bitter taste of CA at near neutral pH. Incorporation of the basic monomer 4-VP ensures rapid dissolution of the polymer and release of CA at the acidic pH prevalent in the stomach. The work indicates an approach to design pH-sensitive polymers for dosage forms that meet the pharmacokinetic requirements of the drug.     

Release Mechanisms Behind Polysaccharides-Based Famotidine Controlled Release Matrix Tablets

Polysaccharides, which have been explored to possess gelling properties and a wide margin of safety, were used to formulate single-unit floating matrix tablets by a direct compression technique. This work has the aim to allow continuous slow release of famotidine above its site of absorption. The floating approach was achieved by the use of the low density polypropylene foam powder. Polysaccharides (κ-carrageenan, gellan gum, xyloglucan, and pectin) and blends of polysaccharides (κ-carrageenan and gellan gum) and cellulose ethers (hydroxypropylmethyl cellulose, hydroxypropylcellulose, sodium carboxymethyl cellulose) were tried to modulate the release characteristics. The prepared floating tablets were evaluated for their floating behavior, matrix integrity, swelling studies, in vitro drug release studies, and kinetic analysis of the release data. The differential scanning calorimetry and Fourier transform infrared spectroscopy studies revealed that changing the polymer matrix system by formulation of polymers blends resulted in formation of molecular interactions which may have implications on drug release characteristics. This was obvious from the retardation in drug release and change in its mechanistics.     

A new strategy for the preparation of supramolecular neutral hydrogels

This paper demonstrates that miscible blends from water-insoluble polymers, such as poly(2,4,4-trimethylhexamethylene terephthalamide) (1), methylamine imidized poly(methyl methacrylate) (2), and aromatic poly(ether sulfone) (3) and water-soluble polymers, such as poly(2-ethyl-2-oxazoline) (4) and poly(N-vinyl pyrrolidone) (5), respectively, represent a new class of supramolecular hydrogels. When the degree of polymerization (DP) of the water-soluble polymer is larger than that of water-insoluble polymer, the resulting hydrogels adsorb extremely high amounts of water (i.e., 229 wt % in the case of the hydrogel 1/4) and remain mechanically tough. The high water uptake capability of these blends is explained by a supramolecular network structure generated by H-bonding and/or other noncovalent interactions between the water-insoluble hydrophobic polymer and water-soluble hydrophilic segments as reversible cross-linking points interconnected by hydrophilic water soluble segments. The glass transition temperatures of these hydrogels are tailored via the ratio between the weight percent of the two polymers and by the glass transition temperature of the parent polymers. These supramolecular hydrogels can be processed from melt or solution and maintain excellent mechanical properties both in dry and in the water swollen state. This class of hydrogels is of interest for areas such as membranes, contact lenses, tissue engineering, and other biomedical applications.     

Effect of thiol pendant conjugates on plasmid DNA binding, release, and stability of polymeric delivery vectors

Polymers have attracted much attention as potential gene delivery vectors due to their chemical and structural versatility. However, several challenges associated with polymeric carriers, including low transfection efficiencies, insufficient cargo release, and high cytotoxicity levels have prevented clinical implementation. Strong electrostatic interactions between polymeric carriers and DNA cargo can prohibit complete cargo release within the cell. As a result, cargo DNA never reaches the cell's nucleus where gene expression takes place. In addition, highly charged cationic polymers have been correlated with high cytotoxicity levels, making them unsuitable carriers in vivo. Using poly(allylamine) (PAA) as a model, we investigated how pH-sensitive disulfide cross-linked polymer networks can improve the delivery potential of cationic polymer carriers. To accomplish this, we conjugated thiol-terminated pendant chains onto the primary amines of PAA using 2-iminothiolane, developing three new polymer vectors with 5, 13, or 20% thiol modification. Unmodified PAA and thiol-conjugated polymers were tested for their ability to bind and release plasmid DNA, their capacity to protect genetic cargo from enzymatic degradation, and their potential for endolysosomal escape. Our results demonstrate that polymer-plasmid complexes (polyplexes) formed by the 13% thiolated polymer demonstrate the greatest delivery potential. At high N/P ratios, all thiolated polymers (but not unmodified counterparts) were able to resist decomplexation in the presence of heparin, a negatively charged polysaccharide used to mimic in vivo polyplex-protein interactions. Further, all thiolated polymers exhibited higher buffering capacities than unmodified PAA and, therefore, have a greater potential for endolysosomal escape. However, 5 and 20% thiolated polymers exhibited poor DNA binding-release kinetics, making them unsuitable carriers for gene delivery. The 13% thiolated polymers, on the other hand, displayed high DNA binding efficiency and pH-sensitive release.     

Factors Governing Intercalation of Fullerenes and Other Small Molecules Between the Side Chains of Semiconducting Polymers Used in Solar Cells

While recent reports have established significant miscibility in polymer:fullerene blends used in organic solar cells, little is actually known about why polymers and fullerenes mix and how their mixing can be controlled. Here, X‐ray diffraction (XRD), differential scanning calorimetry (DSC), and molecular simulations are used to study mixing in a variety of polymer:molecule blends by systematically varying the polymer and small‐molecule properties. It is found that a variety of polymer:fullerene blends mix by forming bimolecular crystals provided there is sufficient space between the polymer side chains to accommodate a fullerene. Polymer:tetrafluoro‐tetracyanoquinodimethane (F4‐TCNQ) bimolecular crystals were also observed, although bimolecular crystals did not form in the other studied polymer:non‐fullerene blends, including those with both conjugated and non‐conjugated small molecules. DSC and molecular simulations demonstrate that strong polymer–fullerene interactions can exist, and the calculations point to van der Waals interactions as a significant driving force for molecular mixing.     

Miscibility study of chitosan/2-hydroxyethyl starch blends and evaluation of their effectiveness as drug sustained release hydrogels

Polymeric matrices of chitosan (CS), 2-hydroxyethyl starch (HES) and their blends prepared by solvent evaporation technique, have been tested as sustained release hydrogels of ropinirole drug. X-Ray diffraction (XRD), infrared spectroscopy (FT-IR) and viscometry measurements showed that the two polymers can form miscible blends. This miscibility is owed to formed hydrogen bonds taking place between the reactive groups of CS and HES and one glass transition is recorded in all blends. Neat polymers were used to prepare solid dispersion formulations with ropinirole drug. It was found that drug was released immediately within 15-30 min from HES while the release was slower from CS matrix. Completely different were the release rates from ropinirole with physical mixtures using neat polymers and their blends. Due to the different solubility and swelling behaviour of CS and HES the release rates showed a sustained profile from the blends containing high amounts of CS.     

Theophylline molecularly imprinted polymer dissociation kinetics: a novel sustained release drug dosage mechanism

The template release kinetics of theophylline molecularly imprinted polymers has been examined with a view to determining their potential as a controlled release drug dosage form. The basis for the ligand selectivity of these polymers has been shown through the demonstration of pre-polymerization template-monomer complexation and HPLC studies of the product polymer ligand selectivities. The release kinetics shows a dependence upon template loading and pH. Small differences in release characteristics between imprinted and non-imprinted (reference) polymers have been observed.     

Interpolyelectrolyte Complexes of Eudragit? EPO with Hypromellose Acetate Succinate and Eudragit? EPO with Hypromellose Phthalate as Potential Carriers for Oral Controlled Drug Delivery

The objective of this study was to compare a novel controlled release tablet formulation based on interpolyelectrolyte complex (PEC). Interpolymer interactions between the countercharged polymers like Eudragit® EPO (polycation) and hypromellose acetate succinate (polyanion) and Eudragit® EPO and hypromellose phthalate (polyanion) were investigated with a view to their use in per oral controlled release drug delivery systems. The formation of inter-macromolecular ionic bonds between cationic polymer and anionic polymer was investigated using Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry. The FT-IR spectra of the tested polymeric matrices are characterized by visible changes in the observed IR region indicating the interaction between chains of two oppositely charged copolymers. The performance of the in situ formed PEC as a matrix for controlled release of drugs was evaluated, using acetaminophen as a model drug. The dissolution data of these matrices were fitted to different dissolution models. It was found that drug release followed zero-order kinetics and was controlled by the superposition of the diffusion and erosion. These profiles could be controlled by conveniently modifying the proportion of the polymer ratio, polymer type, and polymer concentration the in the tablets.KEY WORDS: Eudragit E, hypromellose acetate succinate, hypromellose phthalate polyelectrolyte complexation     

Temperature sensitization of liposomes using copolymers of N-isopropylacrylamide.

To obtain liposomes which release the contents in response to ambient temperature, liposomes modified with copolymers of N-isopropylacrylamide with varying lower critical solution temperatures have been designed. Poly(N-isopropylacrylamide-co-acrylamide)s with various compositions were synthesized by free-radical copolymerization. The lower critical solution temperature of the polymer increased with increasing acrylamide content in the polymer. Poly(N-isopropylacrylamide-co-acrylamide-co-N, N-didodecylacrylamide)s were also prepared via the same method as the thermosensitive polymers having anchor groups to the liposome membrane. Calcein-loaded dioleoylphosphatidylethanolamine/egg yolk phosphatidylcholine (6:4, w/w) liposomes were coated with these polymers by incubating the liposomes with aqueous solutions of the polymers. The liposomes hardly released the contents below the lower critical solution temperature of the polymer, but the release was greatly enhanced above that temperature. The liposomes were also made from a mixture of the same lipids and the polymer. The liposome revealed a more drastic release property than the liposomes prepared by the incubation with the polymer solution, because the polymer chains were bound on both surfaces of the membrane. The close relationship between lower critical solution temperatures of the polymers and temperature regions where enhancement of the release from the polymer-fixed liposomes demonstrates that the release was triggered by alteration of the polymers from a hydrophilic state to a hydrophobic state occurring at their lower critical solution temperatures.     

A molecular simulation of the compatibility of chitosan and poly(vinyl pyrrolidone)

The compatibility of chitosan (CS) and poly(vinyl pyrrolidone) was investigated by molecular dynamic (MD) simulations using the Flory–Huggins theory. The specific interactions in blends were studied by the radial distribution function (RDF). The Flory–Huggins interaction parameter, χ, was calculated at 298 K to assess the blend compatibility at different component ratios in the polymers. Miscibility was observed for blends with more than 50% of CS in the molar fraction, while immiscibility was prevalent at the molar fraction of CS between 10 and 50% of CS. Miscibility between poly(N-vinyl-2-pyrrolidone) (PVP) and CS polymers is attributed to the hydrogen bond formation of the –C = O group of PVP and the –CH₂OH groups of CS. This was further confirmed by MD simulations of RDFs for groups or atoms that are involved in interactions. These results are correlated well to obtain more realistic information on interactions involved as a function of blend composition.     

Preparation of solid dispersions of nonsteroidal anti-inflammatory drugs with acrylic polymers and studies on mechanisms of drug-polymer interactions

This work studied the mechanisms of interaction between Eudragit RS100 (RS) and RL100 (RL) polymers with 3 nonsteroidal anti-inflammatory drugs: diflunisal (DIF), flurbiprofen (FLU), and piroxicam (PIR). Solid dispersions of polymers and drugs at different weight ratios were prepared by coevaporation of their ethanol solutions. The resulting coevaporates were characterized in the solid state (Fourier-transformed infrared spectroscopy (FT-IR) IR, differential scanning calorimetry, powder-x-ray diffractometry) as well as by studying the in vitro drug release in a gastroenteric environment. Absorption tests from drug solutions to the solid polymers were also performed to better explain the mechanism of interactions between them. The preparative conditions did not induce changes in the crystalline state of the drugs (amorphization or polymorphic change). Drugs strongly interacted with the ammonium groups present in polymers, giving an electrostatic interaction that reinforced the mere physical dispersion of drug molecules within polymer networks. Such interactions are related to the chemical structure of the drugs and to their dissociated or undissociated state. The dispersion of drugs in the polymer matrices strongly influenced their dissolution rate, which appeared slower and more gradual than those of the pure drugs, when polymer ratios were increased. RL coevaporates usually displayed higher dissolution rates. The kinetic evaluation of the dissolution profile, however, suggested that both the drug solubility in the external medium and its diffusion capacity within the polymer network are involved. In the sorption experiments, RL showed a greater adsorptive capacity than RS, in relation to the greater number of quaternary ammonium functions, which behave as activity sites for the electrostatic interactions. In the presence of Tris-HCl buffer (pH 7.4), drug adsorption was reduced, as a consequence of the competition of the chloride ions with drug anions for the polymer binding sites. In general, DIF and FLU displayed a similar interaction with RS and RL active sites; PIR's was different. The different molecular structures of these agents can justify such findings. The presence of a carboxyl group (instead of another dissociable acidic moiety, like the hydroxy-enolic one in the PIR molecule) could help explain the strong interaction with RS and RL polymers' quaternary ammonium centers. Preliminary studies like ours are important in helping develop better forecasting and increasing the understanding of the incorporation/release behavior of drugs from particulate delivery systems that can be made from these polymers.     

Designing Silk-silk Protein Alloy Materials for Biomedical Applications

Fibrous proteins display different sequences and structures that have been used for various applications in biomedical fields such as biosensors, nanomedicine, tissue regeneration, and drug delivery. Designing materials based on the molecular-scale interactions between these proteins will help generate new multifunctional protein alloy biomaterials with tunable properties. Such alloy material systems also provide advantages in comparison to traditional synthetic polymers due to the materials biodegradability, biocompatibility, and tenability in the body. This article used the protein blends of wild tussah silk (Antheraea pernyi) and domestic mulberry silk (Bombyx mori) as an example to provide useful protocols regarding these topics, including how to predict protein-protein interactions by computational methods, how to produce protein alloy solutions, how to verify alloy systems by thermal analysis, and how to fabricate variable alloy materials including optical materials with diffraction gratings, electric materials with circuits coatings, and pharmaceutical materials for drug release and delivery. These methods can provide important information for designing the next generation multifunctional biomaterials based on different protein alloys.     

Design of mucoadhesive polymeric films based on blends of poly(acrylic acid) and (hydroxypropyl)cellulose

Mixing of aqueous solutions of poly(acrylic acid) and (hydroxypropyl)cellulose results in formation of hydrogen-bonded interpolymer complexes, which precipitate and do not allow preparation of homogeneous polymeric films by casting. In the present work the effect of pH on the complexation between poly(acrylic acid) and (hydroxypropyl)cellulose in solutions and miscibility of these polymers in solid state has been studied. The pH-induced complexation-miscibility-immiscibility transitions in the polymer mixtures have been observed. The optimal conditions for preparation of homogeneous polymeric films based on blends of these polymers have been found, and the possibility of radiation cross-linking of these materials has been demonstrated. Although the gamma-radiation treatment of solid polymeric blends was found to be inefficient, successful cross-linking was achieved by addition of N,N'-methylenebis(acrylamide). The mucoadhesive potential of both soluble and cross-linked films toward porcine buccal mucosa is evaluated. Soluble films adhered to mucosal tissues undergo dissolution within 30-110 min depending on the polymer ratio in the blend. Cross-linked films are retained on the mucosal surface for 10-40 min and then detach.     

Effect of Drying Methods on Swelling,Erosion and Drug Release from Chitosan–Naproxen Sodium Complexes

The purpose of this research was to explore theapplication of ionic interactions between naproxen sodium (NS) and chitosan (CH) in complexes (NSC) prepared by tray drying (TD) and spray drying (SD) methods. Drug–polymer ratio (1:1) in the NSC was optimized on the basis of dialysis studies. The particulate systems of NSC were prepared by tray drying (TD) and spray drying (SD) methods. Release retarding polymers were added to the NSC and to the physical mixtures containing NS–CH and their effects on water uptake, matrix erosion and drug release at different pH were compared. Spray dried complexes (SDC) were spherical, free flowing, light and fine amorphous particles in contrast to the crystalline, hard, tenacious, irregularly shaped, denser tray dried complexes (TDC) with poor flowability. Differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Fourier transform infrared (FTIR) patterns confirm the conversion of crystalline to high energy amorphous phase suitable for ionic interactions in NSC. Presence of release retarding polymers, kappa carrageenan and hydroxypropylmethylcellulose (HPMC) in the NSC compacts retarded the drug release and improved the matrix integrity. Carrageenan matrices exhibited more retardation than HPMC tablets. FTIR patterns, erosion, swelling and drug release from matrices support ionic interactions between NS and CH in NSC. The reasons for retarded drug release from the chitosan matrices at acidic pH include poor solubility of drug at acidic pH, formation of a rate limiting polymer gel barrier along the periphery of matrices and the ionic interactions between oppositely charged moieties.     

Design of polymeric microparticles for pH-responsive and time-sustained drug release

We described the design of uniform microencapsulates with almost 100% encapsulation efficiency, synthesized without organic solvents, via microfluidic spray drying of water-based dispersions of pH-responsive methacrylic acid polymers (Eudragit^® L 30D-55). The effects of incorporating water-based network-forming materials in the formulations on pH-responsiveness and controlled release patterns of enteric microparticles were observed. Acid hydrolysed tetraethoxysilane (TEOS) was used to form an interpenetrating, rigid framework of silica, whereas Eudragit^® NE (a copolymer based on ethyl acrylate and methyl methacrylate) was added to produce a more flexible polymeric network. The spray-dried microparticles generally displayed crumbled or buckled morphologies dependent on drying temperatures, due to large hydrodynamic sizes of solutes in feed dispersions. The drug release kinetics of microparticles were sensitive to the type and the added amount of network-forming materials, due to different colloidal interactions between Eudragit^® L and either silica or the copolymer. This study demonstrated a strategy to design enteric microparticles with different microstructural properties and drug release behaviours through understanding of colloidal interactions between constituents of matrix materials.     

On protein partitioning in two-phase aqueous polymer systems.

The partitioning of proteins between the coexisting phases of two-phase aqueous polymer systems reflects an intricate and delicate balance of interactions between proteins, polymers, salts and water. Experimental investigations have suggested that a large number of factors influence protein partitioning, including the types of polymers, their molecular weight and concentration; the protein sizes, conformation and composition; salt type and concentration, and solution pH; and the presence of ligands attached to the polymer which may interact with surface sites of the protein. Complementary modelling attempts have been successful in illuminating several molecular-level mechanisms influencing protein partitioning using lattice-model techniques, viral expansions and a scaling-thermodynamic approach. In spite of these experimental and modelling approaches, many of the physical phenomena associated with these complex systems are not well understood. Notably, the precise nature of the protein-polymer interactions and the potent effect of inorganic salts on the partitioning of proteins in these systems remains poorly understood.     

Lignin-polymer blends: evaluation of compatibility by image analysis

This paper opens onto a general discussion on the development of new polymeric materials obtained from lignin blends. The aim is (i) to look for good polymer candidates to obtain a good compatibility with lignins (that is among semi polar polymers), and (ii) to look for good lignin candidates to obtain a good compatibility with polymers showing extreme behaviours (very polar, e.g. starch, or apolar, e.g. polypropylene). The compatibility is simply assessed through the blend morphology, as studied by visible microscopy. The morphology of the blends obtained from semi polar polymers is very sensitive to the variation of the solubility parameters. In a low range of polymer solubility parameters (delta delta = 1 cal cm(-3)), both heterogeneous and homogeneous systems are obtained. These blends could be easily improved by a careful choice in the polymer structure (particularly in the family of biodegradable polyesters); it could be possible also to take advantage of lignin variability to improve the compatibility. Only low molecular weight lignins are compatible with apolar and very polar matrixes. These compounds induce interesting specific properties, and original methods have to be looked for in order to improve their production.     

Effect of Polymer–Fullerene Interaction on the Dielectric Properties of the Blend

It is commonly believed that large dielectric constants are required for efficient charge separation in polymer photovoltaic devices. However, many polymers used in high‐performance solar cells do not possess high dielectric constants. In this work, the effect of polymer–fullerene interactions on the dielectric environment of the active layer blend and the device performance for several donor–acceptor conjugated polymer systems is investigated. It is found that, while none of the high‐performing polymers studied has a dielectric constant value larger than 3, all polymer–fullerene blends have a significantly larger dielectric constant compared to their pristine constituents. Additionally, it is found that the blend dielectric constant reaches a maximum value in fully optimized devices. Using PTB7:PC₇₁BM blends as an example, it is showed that, in addition to a small increase in the dielectric constant, devices fabricated using the optimum processing additive concentration exhibit almost 3X larger excited state polarizability. This large increase in excited state polarizability results in a substantial difference in short‐circuit current and ultimately device performance. The results show that the excited state polarizability critically depends on polymer–fullerene interactions, and can be a leading indicator of device performance for a given material system.     

Pairwise Assembly Determines the Intrinsic Potential for Self-Organization and Mechanical Properties of Keratin Filaments

Most type I and II keratin genes are spatially and temporally regulated in a pairwise manner in epithelial tissues, where they represent the major structural proteins. Epithelia can be partitioned into simple (single-layered) and complex (multilayered) types. We compared the structural and mechanical properties of natural keratin polymers occurring in complex (K5-K14) and simple (K8-K18) epithelia. The intrinsic properties of these distantly related keratin filaments, whether dispersed or bundled in vitro, were surprisingly similar in all respects when at high polymer concentration. When type I and II assembly partners were switched to give rise to mismatched polymers (K5-K18; K8-K14), the interfilament interactions, which determine the structural and mechanical properties of keratin polymers, were significantly altered. We also show that a K5-K16 polymer exhibits lesser elasticity than K5- K14, which may help explain the inability of K16 to fully rescue the skin blistering characteristic of K14 null mice. The property of self-interaction exhibited by keratin filaments is likely to assist their function in vivo and may account for the relative paucity of cytoplasmic and keratin-specific cross-linkers. Our findings underscore the fundamental importance of pairwise polymerization and have implications for the functional significance of keratin sequence diversity.     

Novel composite blend microbeads of sodium alginate coated with chitosan for controlled release of amoxicillin

Composite blend microbeads of sodium alginate (NaAlg) with sodium carboxymethyl cellulose (NaCMC) containing magnesium aluminum silicate (MAS) particles and enteric coated with chitosan have been prepared to achieve controlled release (CR) of amoxicillin in stomach environment. The composite beads have been characterized by X-ray diffraction (XRD) to study drug distribution, DSC for understanding thermal stability and Fourier transform infrared (FTIR) spectroscopy to investigate chemical interactions as well as to assess the structure of the drug-loaded formulations. Surface morphology of the beads was investigated by scanning electron microscopy (SEM). The size distribution of beads loaded with drug as studied by particle size analyzer was in the range of 745-889 μm. The beads exhibited quite widely varying encapsulation efficiencies from 52 to 92%. Equilibrium swelling of the beads measured in water and in vitro release of amoxicillin in pH 1.2 medium suggests that drug release depends on polymer blend composition, concentration of MAS and extent of enteric coating.