Release of amoxicillin from polyionic complexes of chitosan and poly(acrylic acid). Study of polymer/polymer and polymer/drug interactions within the network structure

Polyionic complexes of chitosan (CS) and poly(acrylic acid) (PAA) were prepared in a wide range of copolymer composition and with two kind of drugs. Release of amoxicillin trihydrate and amoxicillin sodium from these different complexes were studied. The swelling behavior of and solute transport in swellable hydrogels were investigated to check the effect of polymer/polymer and polymer/drugs interactions. The electrostatic polymer/polymer interactions take place between the cationic groups from CS and the anionic ones from PAA. The diffusion of amoxicillin trihydrate was controlled only by the swelling/eroding ratio of the polyionic complexes. The swelling degree of amoxicillin sodium hydrogels was more extensive when compared to the swelling degree of amoxicillin trihydrate formulations. It was concluded that the water uptake was mainly governed by the degree of ionization. Restriction of amoxicillin sodium diffusion could be achieved by polymer/ionized-drug interaction that retards the drug release. Freeze-dried polyionic complexes could serve as suitable candidates for amoxicillin site-specific delivery in the stomach.     

A novel mucoadhesive polymer prepared by template polymerization of acrylic acid in the presence of chitosan

A novel mucoadhesive polymer was prepared by template polymerization of acrylic acid in the presence of chitosan for transmucosal drug delivery system (TMD). FT-IR results indicated that polymer complex was formed between poly(acrylic acid) (PAA) and chitosan through hydrogen bonding. Glass transition temperature (Tg) of chitosan and PAA in the PAA/chitosan polymer complexes was inner-shifted compared with Tg of chitosan and PAA itself. This may be due to the increased miscibility of PAA with chitosan through the hydrogen bonding. The crystallinity of chitosan in the PAA/chitosan polymer complexes was decreased with polymer complex formation with PAA. The dissolution rate of the PAA/chitosan polymer complex was dependent on pH and ratio of PAA/chitosan. The mucoadhesive force of PAA/chitosan polymer complex was similar to a commericial product, Carbopol 971P NF.     

Chelation properties of polymer complexes of poly(acrylic acid) with poly(acrylamide), and poly(acrylic acid) with poly(N,N-dimethylacrylamide)

The metal-complexing properties of intermolecular complexes of poly(acrylic acid) with poly(acrylamide), and poly(acrylic acid) with poly(N,N-dimethylacrylamide) were studied by means of the liquid-phase polymer based retention (LPR) technique. The metal ion retention ability at pH 5 for 400 μg of Cu(II), Cd(II), Co(II), Cr(III), Hg(II), Ni(II), Pb(II), and Zn(II) was investigated due to their environmental and analytical interest in the presence of 1.1 M of carboxylic acid units and variable amounts of amide groups. The retention profiles of the intermolecular complexes were compared with those of the correspondent homopolymers and copolymers. The retention capacity of poly(acrylic acid) is 100% for all metal ions except for Co(II), Ni(II), and Zn(II) whose values were about 90%, while poly(acrylamide) does not retain any of the metal ion studied. The presence of poly(acrylamide) decreases the retention capacity down to 60% for Co(II) and Ni(II) and to 70% for Zn(II). The decrease on the retention values is dependent on the polymer ratio. A smaller effect is observed by the addition of poly(N,N-dimethylacrylamide) which also decreases the retention capacity down to 80% for Co(II) and Ni(II) for a ratio poly(acrylic acid)/poly(N,N-dimethylacrylamide) = 1/2. The metal ion binding behavior of the interpolymer complexes is very close to that of the copolymers.     

Preparation and characterization of pH-sensitive hydrogel of chitosan/poly(acrylic acid) co-polymer

A pH-sensitive co-polymer hydrogel of chitosan/poly(acrylic acid) (CS/PAAc) was prepared by irradiating the aqueous solution mixture of chitosan and acrylic acid with 60Co gamma-ray irradiation. The effect of the composition of chitosan and AAc on the properties of the hydrogel, such as swelling ratio and pH-sensitivity, were determined. Fourier Transform Infrared (FT-IR) spectrometry was applied in the attenuated total reflectance (ATR) mode for analyzing the structure change of the hydrogels after the treatment in different pH buffer solutions.     

Preparation and characterization of pH-sensitive hydrogel of chitosan/poly(acrylic acid) co-polymer

A pH-sensitive co-polymer hydrogel of chitosan/poly(acrylic acid) (CS/PAAc) was prepared by irradiating the aqueous solution mixture of chitosan and acrylic acid with ⁶⁰Co γ-ray irradiation. The effect of the composition of chitosan and AAc on the properties of the hydrogel, such as swelling ratio and pH-sensitivity, were determined. Fourier Transform Infrared (FT-IR) spectrometry was applied in the attenuated total reflectance (ATR) mode for analyzing the structure change of the hydrogels after the treatment in different pH buffer solutions.     

Superporous hydrogels containing poly(acrylic acid-co-acrylamide)/O-carboxymethyl chitosan interpenetrating polymer networks

Superporous hydrogels containing poly(acrylic acid-co-acrylamide)/O-carboxymethyl chitosan interpenetrating polymer networks (SPH-IPNs) were prepared by cross-linking O-carboxymethyl chitosan (O-CMC) with glutaraldehyde (GA) after superporous hydrogel (SPH) was synthesized. The structures of the SPH-IPNs were characterized with FT-IR, 13C-NMR and DSC. SEM, CLSM and light images revealed that the SPH-IPNs possessed both the IPN network and large numbers of pores and the cross-linked O-CMC molecules were located on the peripheries of these pores. The swelling behavior of SPH-IPNs was dependent on the O-CMC content, GA amount and cross-linking time. Due to the cross-linked O-CMC network, in vitro muco-adhesive force and mechanical properties, including compression and tensile modulus, of the SPH-IPN were greatly improved when compared with the CSPH. An enhanced loading capacity for insulin could be obtained by the SPH-IPNs as compared to non-porous hydrogel and CSPH, and more than 90% of the insulin was released within 1 h. With the improved mechanical properties, in vitro muco-adhesive force and loading capacities, the SPH-IPN may be used as a potential muco-adhesive system for peroral delivery of peptide and protein drugs.     

Hydrogels based on modified chitosan, 1. Synthesis and swelling behavior of poly(acrylic acid) grafted chitosan

A large number of carboxylic groups were introduced onto chitosan by grafting with poly(acrylic acid) as an efficient way of modification. The reactions were carried out in a homogeneous aqueous phase by using potassium persulfate and ferrous ammonium sulfate as the combined redox initiator system. The efficiency of grafting was found to depend on monomer, initiator, and ferrous ion concentrations as well as reaction time and ‐temperature. It was observed that the level of grafting could be controlled to some degree by varying the amount of ferrous ion used as a co‐catalyst in the reaction. Evidence of grafting was obtained by comparison of FTIR spectra of chitosan and the graft copolymer as well as solubility characteristics of the products. The swelling behavior of chitosan samples, grafted with 115% and 524% poly(acrylic acid), was studied as function of pH, in distilled water and in aqueous NaCl solution. The sample that has 115% grafting swells considerably more both in distilled water (pH 5.8) as well as higher pH values than the sample with 524% grafting. In contrast, an inverse swelling behavior at pH 2 was observed. An unusual swelling behavior at pH 2 was found for the sample with 524% grafting, which swells to a greater extent than in distilled water. This was attributed to the amphiphilic nature of the modified chitosan from which complex inter‐ and/or intramolecular interactions could originate.     

Interpolymer complexes of poly(acrylic acid) and chitosan: influence of the ionic hydrogel-forming medium

Non-covalent polyionic complexes were developed for localized antibiotic delivery in the stomach. Freeze-dried interpolymer complexes based on polyacrylic acid (PAA) and chitosan (CS) were prepared in a wide range of copolymer compositions by dissolving both polymers in acidic conditions. The influence of hydrogel-forming medium on the swelling and drug release was evaluated. The properties of these complexes were investigated by using scanning electron microscopy, dynamic swelling/eroding and release experiments in enzyme-free simulated gastric fluid (SGF). The electrostatic polymer/polymer interactions generate polyionic complexes with different porous structures. In a low pH environment, the separation of both polymer chains augmented as the amount of cationic and carboxilic groups increased within the network. However, the presence of higher amount of ions in the hydrogel-forming medium produced a network collapse, decreasing the maximum swelling ratio in SGF. PAA:CS:A (1:2.5:2)-1.75 M complexes released around 54% and 71% of the amoxicillin in 1 and 2 h, respectively, in acidic conditions. A faster drug release from this interpolymer complex was observed when the ionic strength of the hydrogel-forming medium increased. Complexes with a high amount of both polymer chains within the network, PAA:CS:A(2.5:5:2), showed a suitable amoxicillin release without being affected by an increased amount of ions in the hydrogel-forming medium. These freeze-dried interpolymer complexes could serve as potential candidates for amoxicillin delivery in an acidic enviroment.     

Controlled release of anti-diabetic drug Gliclazide from poly(caprolactone)/poly(acrylic acid) hydrogels

Drug Gliclazide (Glz) has limited solubility and low bioavailability. In order to obtain a controlled release of this drug and to improve its bioavailability, the drug has been loaded into poly(caprolactone) (PCL)/poly(acrylic acid) (PAAc) hydrogels, prepared by free radical polymerization of acrylic acid in the presence of poly(caprolactone) in acetone medium using azo-isobutyronitrile as initiator and N,N′ methylene bisacrylamide as cross-linking agent. The swelling behaviour of these hydrogels has been investigated in the physiological gastric and intestinal fluids to obtain an optimum composition suitable for delivery of a biologically active compound. The gels were loaded with anti-diabetic drug Glz and a detailed investigation of release of drug has been carried out. Various kinetic models have been applied on the release data. Finally, the Albino wistar rats were treated for Streptozotocin plus nicotinamide – induced diabetes using a Glz-loaded PCL/PAAc hydrogel. The results indicated a fair reduction in the glucose level of rats.     

Interaction of water-soluble collagen with poly(acrylic acid)

Interactions between poly(acrylic acid) labeled with pyrene (PAA-Py) and succinylated calfskin collagen (type I) (SCSC) were studied by fluorescence spectroscopy. PAA-Py exhibits a strong emission from pyrene monomer (intensity, I(M)) when it exists in an extended conformation. It exhibits another broad emission from pyrene excimer (intensity, I(E)) when it adopts a collapsed globule conformation. At pH 3, a value that is lower than the isoelectric point of SCSC, the ratio I(E)/I(M) value decreased cooperatively with increasing concentration of SCSC at constant PAA-Py concentration, under salt-free condition. On the other hand, this effect was not observed in the presence of 0.1 M NaCl. At pH 7, a value higher than the isoelectric point of SCSC, the ratio I(E)/I(M) was not affected by the presence of SCSC in the absence and presence of salt. From electrophoretic light scattering experiments, it was found that at pH 3 PAA-Py was negatively charged, while SCSC had a positive charge. Thus it is strongly suggested that the two polymers interact by electrostatic attraction at low pH where they are oppositely charged, and that PAA-Py adopts an extended conformation in the complex formed with SCSC. Similar interactions are believed to occur between dentinal collagen and the polycarboxylate component of glass-ionomer cements.     

Biodegradable honeycomb-patterned film composed of poly(lactic acid) and dioleoylphosphatidylethanolamine

Honeycomb-patterned films have been reported to be useful for scaffolds of cell culture in tissue engineering. In the present study, we investigated a new compound, dioleoylphosphatidylethanolamine (DOPE), a naturally derived phospholipid having unsaturated fatty acid moieties, as a surfactant for fabricating honeycomb-patterned poly(d,l-lactide) (PLA) film. Only DOPE among commercially available phospholipids was useful as a surfactant, and it showed good solubility in PLA/chloroform solution and an excellent property for fabricating honeycomb-patterned film (the concentration of DOPE was from 0.2% to 20% by weight based on the weight of PLA). The pore size of the honeycomb was uniform, and all pores were interconnected with each other. The contact angle of water on the honeycomb-patterned film was affected by the amount of DOPE. Time-of-flight secondary ion mass spectrometer (TOF-SIMS) data suggested that DOPE was concentrated on the surface of the honeycomb-patterned film. To investigate cell proliferation and adhesion on the honeycomb-patterned film, NIH3T3 fibroblast cells were cultured on the film. The NIH3T3 cells adhered well on the honeycomb-patterned PLA film with DOPE (PLA-DOPE) and showed good cell proliferation compared to that on honeycomb-patterned PLA film fabricated with a copolymer (CAP) of dodecylacrylamide and omega-carboxyhexylacrylamide (PLA-CAP). These results suggest that the honeycomb-patterned PLA-DOPE can be applicable as a scaffold for cells with better profiles in comparison with PLA-CAP.     

Complexation of polyacrylamide and poly(N-isopropylacrylamide) with poly(acrylic acid). The temperature effect

We present potentiometric and viscometric results on the interpolymer complexation between polyacrylamide (PAAM) and poly(N-isopropylacrylamide) (PNIPAAM) with poly(acrylic acid) (PAA) in dilute aqueous solution. A potentiometric procedure for the determination of the complex stoichiometry in monomeric units has been proposed. The temperature dependence of the strength of the complex formed has been investigated. From the results obtained it has been concluded that hydrogen bonding is the main factor stabilizing the PAAM/PAA complex, strengthened by decreasing the temperature while the much stronger PNIPAAM/PAA complex, strengthened by increasing the temperature, is stabilized by hydrophobic interaction.     

Poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate)-poly(vinyl alcohol)/poly(acrylic acid) interpenetrating polymer networks for improving optrode-neural tissue interface in optogenetics

The field of optogenetics has been successfully used to understand the mechanisms of neuropsychiatric diseases through the precise spatial and temporal control of specific groups of neurons in a neural circuitry. However, it remains a great challenge to integrate optogenetic modulation with electrophysiological and behavioral read out methods as a means to explore the causal, temporally precise, and behaviorally relevant interactions of neurons in the specific circuits of freely behaving animals. In this study, an eight-channel chronically implantable optrode array was fabricated and modified with poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate)-poly(vinyl alcohol)/poly(acrylic acid) interpenetrating polymer networks (PEDOT/PSS-PVA/PAA IPNs) for improving the optrode-neural tissue interface. The conducting polymer-hydrogel IPN films exhibited a significantly higher capacitance and lower electrochemical impedance at 1 kHz as compared to unmodified optrode sites and showed significantly improved mechanical and electrochemical stability as compared to pure conducting polymer films. The cell attachment and neurite outgrowth of rat pheochromocytoma (PC12) cells on the IPN films were clearly observed through calcein-AM staining. Furthermore, the optrode arrays were chronically implanted into the hippocampus of SD rats after the lentiviral expression of synapsin-ChR2-EYFP, and light-evoked, frequency-dependant action potentials were obtained in freely moving animals. The electrical recording results suggested that the modified optrode arrays showed significantly reduced impedance and RMS noise and an improved SNR as compared to unmodified sites, which may have benefited from the improved electrochemical performance and biocompatibility of the deposited IPN films. All these characteristics are greatly desired in optogenetic applications, and the fabrication method of conducting polymer-hydrogel IPNs can be easily integrated with other modification methods to build a more advanced optrode-neural tissue interface.     

Polymeric complexes of lidocaine hydrochloride with poly(acrylic acid) and poly(2-hydroxyethyl vinyl ether)

The specific interactions of local anesthetic lidocaine hydrochloride with poly(acrylic acid) and poly(2-hydroxyethyl vinyl ether), as well as in a triple system composed of the drug and both polymers, have been studied in aqueous solutions by viscometric, turbidimetric, potentiometric, and FTIR spectroscopic methods. The mechanism of the drug binding to the polymers and the structures of the polycomplexes formed are clarified.     

Polymeric complexes of lidocaine hydrochloride with poly(acrylic acid) and poly(2-hydroxyethyl vinyl ether)

The specific interactions of local anesthetic lidocaine hydrochloride with poly(acrylic acid) and poly(2-hydroxyethyl vinyl ether), as well as in a triple system composed of the drug and both polymers, have been studied in aqueous solutions by viscometric, turbidimetric, potentiometric, and FTIR spectroscopic methods. The mechanism of the drug binding to the polymers and the structures of the polycomplexes formed are clarified.     

Biomimetic surface modification of poly(L-lactic acid) with chitosan and its effects on articular chondrocytes in vitro

The objective of this study was to investigate the efficiency of two treatments for poly(L-lactic acid) (PLLA) surface modification with chitosan, via entrapment and coupling by using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and N-hydroxysuccinimide. The properties of original PLLA films, chitosan-entrapped and coupled PLLA films were investigated by water contact angle measurement and electron spectroscopy for chemical analysis (ESCA). The contact angle indicated the change in hydrophilicity and the ESCA data suggested that the modified PLLA films became enriched with nitrogen atoms. The cytocompatibility of modified PLLA films might be improved. Therefore, the attachment and proliferation of bovine articular chondrocyte seeded on modified PLLA films and control one were examined. A whole cell enzyme-linked immunosorbent assay (Cell ELISA) that detects the BrdU incorporation during DNA synthesis and collagen type II secretion was applied to evaluate the chondrocytes on different PLLA films and tissue culture plates. Cell viability was estimated by the MTT assay and cell function were assessed by measuring sulfated glycosaminoglycan secreted by chondrocytes. These results implied that chitosan used to modify PLLA surface through entrapment and coupling could enhance the chondrocyte adhesion, proliferation and function.     

Interpolymer complex between poly(ethylene oxide) and poly(acrylic acid): Viscometric studies in THF-water mixtures

Systematic studies were performed on interpolymer complex formation between Poly(acrylic acid) (PAA) and poly(ethylene oxide) (PEO) in THF-water mixtures of different compositions. Viscosity behaviour during complex formation in mixed solvents was found to be entirely different from that observed by other workers in aqueous and in pure organic solvents. The result are interpreted in terms of, (a) preferential solvation of the polymer, (b) Probable change in conformation of the polyelectrolyte moleculer. (c) association of complex molecules in a medium of low dielectric constant, and (d) expected disordering of bound water molecules around PEO by THF. Irrespective of solvent composition, interpolymer complex of PAA and PEO was always found to have 1:1 unit mole ratio.     

The effect of composition of poly(acrylic acid)-gelatin hydrogel on gentamicin sulphate release: in vitro

Hydrogels based on poly(acrylic acid) and gelatin crosslinked with N,N'-methylene bisacrylamide (0.5mol%) and glutaraldehyde (4%), respectively, forming an interpenetrating network were employed as matrices, for studying the loading and release of gentamicin sulphate. The release kinetics of gentamicin sulphate was evaluated in water (pH approximately 5.8), phosphate buffer (pH 7.4) and citrate buffer (pH 4) at 37+/-0.1 degrees C. The drug release in phosphate buffer was faster as compared to water or citrate buffer. Fitting the data of release studies in Peppas model indicated that the release of drug from full IPNs in phosphate buffer (pH 7.4), water (pH approximately 5.8) and citrate buffer (pH 4) were diffusion controlled. However, semi-IPNs showed both anomalous and Fickian diffusion mechanisms. With increasing gelatin percentage in the polymer, rate of drug release was faster and almost 85% of the loaded drug was released within 7 days in phosphate buffer (pH 7.4).     

Manipulation of nanoneedle and nanosphere apatite/poly(acrylic acid) nanocomposites

Colloidal apatitic nanosphere of 2-5 nm in diameter was synthesized in the presence of poly(acrylic acid), PAA. PAA, which has long been recognized as an inhibitor in the synthesis of hydroxyapatite, is used as a structure-directing agent for the synthesis of calcium-deficient apatite (CDHA) in this study. Experimental observation suggests a critical amount of the low-molecular-weight PAA, above which morphological evolution of CDHA nanoparticles from needle to sphere was observed. This reveals that the PAA acts as an inhibitor for the growth of CDHA crystals. Further incorporation of PAA of high molecular weight formed a highly optically transparent nanocomposite, even with the nanospherical apatite loading up to 35 wt %, suggesting no agglomeration. This was further justified through transmission electron microscopy (TEM), where the CDHA nanospheres were uniformly distributed in the PAA-CDHA nanocomposites. No interfacial crevices were visually observed, indicating a highly compatible interface between the inorganic CDHA and organic PAA phase.     

Poly (acrylic acid) chitosan interpolymer complexes for stomach controlled antibiotic delivery

The aim of this study was to develop a stomach-specific drug delivery system to increase the efficacy of amoxicillin against Helicobacter pylori. Polyacrylic acid (PAA), chitosan (CS), and amoxicillin (A) were employed to obtain polyionic complexes. The design of the hydrogel delivery system was based on the swellable approach; with a floating feature to prolong the Gastric Residence Time (GRT). The polyionic complex (PAA:CS:A 2.5:5:2) showed a sustained drug release profile in enzyme-free simulated gastric fluid (SGF) and pH 4.0. A pH independent swelling-eroding pattern with adequate maximum swelling ratios of 17.76 and 13.42 was obtained at in SGF and pH 4.0, respectively, with similar eroding profiles in both pH media. This network carrier provides an amoxicillin protective effect towards the hydrolytic degradation in SGF. The in vivo study was performed on healthy volunteers, using the [13C] octanoic acid breath test. The proposed hydrogel showed a prolonged GRT of up to 3 h. The preliminary results from this study suggest that amoxicillin polyionic complexes have potential for improving local antibiotic therapy against H. pylori.