Impregnation and release of aspirin from chitosan/poly(acrylic acid) graft copolymer microspheres

The purpose of this study was to produce aspirin-impregnated microspheres of chitosan/poly(acrylic acid) copolymer in order to evaluate the release characteristics as a function of pH, simulating the fluids in the gastrointestinal tract. Chitosan microspheres were obtained by the coacervation-phase separation method, induced by the addition of a non-solvent (NaOH 2.0 M solution). The microspheres were cross-linked with glutaraldehyde, reduced with sodium cianoborohydride and grafted with poly(acrylic acid). The impregnation of aspirin into chitosan/poly(acrylic acid) copolymer microspheres was achieved by the dissolution of the drug in water:ethanol (2:1), which was adsorbed by the microspheres for 24 h at 25 °C. The efficiency of aspirin impregnation was high (~94%). The approach employed herein in the production of aspirin-impregnated microspheres using chitosan/poly(acrylic acid) can be a suitable drug-release control system.     

Impregnation and release of aspirin from chitosan/poly(acrylic acid) graft copolymer microspheres

The purpose of this study was to produce aspirin-impregnated microspheres of chitosan/poly(acrylic acid) copolymer in order to evaluate the release characteristics as a function of pH, simulating the fluids in the gastrointestinal tract. Chitosan microspheres were obtained by the coacervation-phase separation method, induced by the addition of a non-solvent (NaOH 2.0 M solution). The microspheres were cross-linked with glutaraldehyde, reduced with sodium cianoborohydride and grafted with poly(acrylic acid). The impregnation of aspirin into chitosan/poly(acrylic acid) copolymer microspheres was achieved by the dissolution of the drug in water:ethanol (2:1), which was adsorbed by the microspheres for 24h at 25 degrees C. The efficiency of aspirin impregnation was high (approximately 94%). The approach employed herein in the production of aspirin-impregnated microspheres using chitosan/poly(acrylic acid) can be a suitable drug-release control system.     

Enhanced in vitro transdermal delivery of caffeine using a temperature- and pH-sensitive nanogel,poly(NIPAM-co-AAc)

Temperature- and pH-responsive poly(N-isopropylacrylamide) (polyNIPAM) copolymerised with 5% (w/v) of acrylic acid (AAc), termed as poly(NIPAM-co-AAc) nanogel was investigated as a novel multi-responsive topical drug delivery carrier, using caffeine as a model permeant. The role of a pH modulator (citric acid) on the nanogel system was also studied. The loading was carried out in deionised water at two different temperatures, which were 2–4 °C and 25 °C (room temperature, RT) over 3 days. The loading of caffeine into the poly(NIPAM-co-AAc) nanogel was found to be significantly higher at 2–4 °C than at RT (p = 0.0072). As for the control nanogel (polyNIPAM), a similar pattern of loading level can be observed (p = 0.0005). This enhanced loading at low temperatures could be attributed to the hydrophilic behaviour of the polyNIPAM network in response to temperatures lower than its lower critical solution temperature (LCST). In vitro diffusion studies across epidermis porcine skin were carried out at 32 °C for the saturated solution of caffeine as well as caffeine-loaded poly(NIPAM-co-AAc) and polyNIPAM nanogels. The in vitro permeation data of caffeine-loaded poly(NIPAM-co-AAc) at 2–4 °C were shown to enhance the delivery of the loaded caffeine across the epidermis in comparison to the saturated solution of caffeine, by 3.5 orders of magnitude. Additionally, the study demonstrated that the effect of pH modulator on the release of loaded permeant was insignificant.     

Extraction of metal cations by polyterephthalamide microcapsules containing a poly(acrylic acid) gel

Polyterephthalamide microcapsules containing a poly(acrylic acid) gel as a macromolecular ligand (PAA-CAPS) were prepared using an original two step polymerization process in a water-in-oil inverse emulsion system. A polyamide microcapsule containing acrylic acid, initiator and cross-linking agent, is formed by interfacial polycondensation of terephthaloyl dichloride with hexamethylenediamine. In situ radical polymerization of the microcapsule core acrylic acid is initiated to obtain encapsulated poly(acrylic acid) gel. Reference polyamide microcapsules, i.e. without ligand (CAPS), were also synthesized. The mean diameter of synthesized microcapsules was 210 #181;m, and the microcapsule wall thickness was evaluated by SEM and TEM observations of microcapsule cross-section cuts. The microcapsule water content was determined by thermogravimetric experiments. The extractabilities of Cu(II), Ni(II), Co(II) and Zn(II) into PAA-CAPS were examined. The stripping of the various cations can be promoted in diluted hydrochloric acid solutions.     

Drug release from the enzyme-degradable and pH-sensitive hydrogel composed of glycidyl methacrylate dextran and poly(acrylic acid)

Hydrogels composed of glycidyl methacrylate dextran (GMD) and poly(acrylic acid, PAA) were prepared by UV irradiation method for colon-specific drug delivery. GMD was synthesized by coupling of glycidyl methacrylate to dextran in the presence of 4-(N,N-dimethylamino)pyridine. GMD was photo-polymerized by ammonium peroxydisulfate as initiating system in phosphate-buffered solution (0.1 M, pH 7.4). And then, acrylic acid monomer was added and subsequently heat-polymerized by 2,2'-azobisisobutyronitrile as an initiator. The hydrogels exhibited high swelling ratio (about 20) at 37 degrees C, and showed a pH-dependent swelling behavior. In addition, the swelling ratio of the hydrogel was remarkably enhanced to about 45 times in the presence of dextranase at pH 7.4. The swelling-deswelling behavior proceeded reversibly for the GMD/PAA hydrogels between pH 2 and pH 7.4. Release of 5-aminosalicylic acid from the GMD/PAA hydrogels was evaluated in simulated gastrointestinal pH fluids in the absence or presence of dextranase. We concluded that the hydrogels prepared could be used as a dual-sensitive drug carrier for sequential release in gastrointestinal tract.     

Characterization of pH- and temperature-sensitive hydrogel nanoparticles for controlled drug release

Monodispersed poly (N-isopropylacrylamide) (PNIPA) nanoparticles and their derivative poly (N-isopropylacrylamide-co-acrylic acid) (PNIPA-co-AA) nanoparticles were successfully synthesized. Regulation of the size and the lower critical solution temperature (LCST) of the hydrogel nanoparticles was intensively studied. The results showed that the diameters and LCST of the particles can be arbitrarily manipulated according to different application designs. The relationship between the size of the particles and the amount of surfactant were quantitatively disclosed. It was found that the LCST of PNIPA-co-AA nanoparticles ranging from 35-45 degrees C correlated with the molar fraction of acrylic acid which was copolymerized with NIPA. The pH sensitivity of PNIPA-co-AA nanoparticles was displayed by the transmittance transition of their aqueous solution in various pH conditions. Furthermore, the anti-cancer drug 5-fluorouracil (5-Fu) was first loaded into both PNIPA and PNIPA-co-AA hydrogel nanoparticles with an entrapment efficiency larger than 4%. In vitro release of 5-Fu from PNIPA-co-AA nanoparticle hydrogels was shown to be pH- and temperature-dependent, which demonstrated that the PNIPA-co-AA nanoparticles have great potential in the design of controlled drug delivery systems.     

Bioadhesive polymers as platforms for oral controlled drug delivery II: synthesis and evaluation of some swelling, water-insoluble bioadhesive polymers

A series of cross-linked, swellable polymers was sythesized from monomers such as acrylic acid, methacrylic acid, and others with various cross-linking agents to produce a range of polymers differing in charge densities and hydrophobicity. The densities, rate, and extent of hydration of the polymers were determined. An increase in the number of hydrophobic groups in the polymer structure reduced hydration whereas the density of the polymer was unaffected. A sensitive in vitro method for measuring adhesion of polymer to tissue from the rabbit stomach was developed. Polymers of acrylic acid loosely cross-linked (0.3%, w/w) with three different agents, divinyl glycol, 2,5-dimethyl-1,5-hexadiene, and divinylbenzene, showed the same degree of bioadhesion while poly(methacrylic acid-divinylbenzene) showed reduced bioadhesion. The small percent of cross-linking agent, irrespective of physicochemical properties, did not contribute substantially to bioadhesion, whereas the starting monomer had a large effect. The effect of pH on the bioadhesion of poly(acrylic acid-divinyl glycol) was studied at constant temperature, ionic strength, and osmolality. The polymer showed maximum adhesion at pH 5 and 6 and a minimum at pH 7. Gastrointestinal transit studies of cross-linked polymers in rats were studied. Poly(acrylic acid-divinyl glycol) and poly(methacrylic acid-divinylbenzene) were shown to have substantially longer GI transit times than the control, Amberlite 200 resin beads. The delay in transit time was due to bioadhesion of the polymer to the mucin-epithelial cell surface which was clearly observable on animal autopsy. The acrylic acid polymer showed a longer GI transit time than the methacrylic acid polymer, and this in vivo GI transit result is consistent with in vitro bioadhesion test results.     

Extraction of metal cations by polyterephthalamide microcapsules containing a poly(acrylic acid) gel.

Polyterephthalamide microcapsules containing a poly(acrylic acid) gel as a macromolecular ligand (PAA-CAPS) were prepared using an original two step polymerization process in a water-in-oil inverse emulsion system. A polyamide microcapsule containing acrylic acid, initiator and cross-linking agent, is formed by interfacial polycondensation of terephthaloyl dichloride with hexamethylenediamine. In situ radical polymerization of the microcapsule core acrylic acid is initiated to obtain encapsulated poly(acrylic acid) gel. Reference polyamide microcapsules, i.e. without ligand (CAPS), were also synthesized. The mean diameter of synthesized microcapsules was 210 microm, and the microcapsule wall thickness was evaluated by SEM and TEM observations of microcapsule cross-section cuts. The microcapsule water content was determined by thermogravimetric experiments. The extractabilities of Cu(II), Ni(II), Co(II) and Zn(II) into PAA-CAPS were examined. The stripping of the various cations can be promoted in diluted hydrochloric acid solutions.     

An investigation of mucus/polymer rheological synergism using synthesised and characterised poly(acrylic acid)s

A range of poly(acrylic acid)s with different average degrees of polymerisation and cross-linking densities were synthesised using a solution polymerisation process. The rheological characteristics of aqueous dispersions of these materials and those of mixtures with homogenised pigs gastric mucus were investigated using dynamic oscillatory rheology, and compared to the known mucoadhesive Carbopol 934P. From the storage moduli, the rheological synergy and relative rheological synergy were calculated, and the effects of concentration and pH on this considered. Generally, the larger the molecular weight (and degree of cross-linking), the greater the rheological synergy, with Carbopol 934P giving the most pronounced effect. Rheological synergy was seen to be concentration-dependent, and a maximum concentration to produce an optimum effect was evident. Acid pHs were seen to favour synergy, although in marked contrast to previous literature reports, the optimum mucus-polymer interaction was not observed at the half ionised value (pH = pKa) but at pH regimes that were unique to each polymer type. This could be influenced by the structural constrains imposed on potential hydrogen bonded interactions. It was concluded that synthesising poly(acrylic acid)s with better defined physicochemical properties than commercially available polymers will advance the study of the phenomenon of rheological synergy.     

Enhanced nasal retention of hydrophobically modified polyelectrolytes

Hydrophobically modified polyelectrolytes (HMP) are polymers with a high content of ionizable groups bonded to hydrophobic groups. Copolymers of poly(acrylic acid) and Pluronic surfactants constitute a special class of HMP whereby poly(propylene oxide) segments act as hydrophobes. The poly(propylene oxide) segments possess temperature-dependent aqueous solubility and the solutions of the Pluronic-poly(acrylic acid) copolymers (MW > 3,000,000) undergo a sol-gel transition when kept at body temperature. Due to the presence of the poly(acrylic acid) segments, the Pluronic-poly(acrylic acid) copolymers are bioadhesive. We have examined the hypothesis that the in-situ gelling polymer formulations of Pluronic-poly(acrylic acid) copolymers may have an enhanced retention in the nasal cavity. The effects of putative bioadhesive (Carbomer 934P) and thermogelling (Pluronic F127) polymers on nasal clearance were compared with Pluronic-poly(acrylic acid) copolymers using a rat model. The enhancement of the residence time of fluorescent labels by the Pluronic-poly(acrylic acid) copolymers was shown to be 5-8-fold that of Carbomer, and 3-6-fold that of Pluronic F127. The results unequivocally demonstrate the superior retention of the HMP that combines bioadhesive and thermogelling capabilities over either a bioadhesive polyelectrolyte or a polymer of a low molecular weight that undergoes a sol-gel transition.     

Mucoadhesive microspheres prepared by interpolymer complexation and solvent diffusion method

Mucoadhesive microspheres were prepared to increase gastric residence time using an interpolymer complexation of poly(acrylic acid) (PAA) with poly(vinyl pyrrolidone) (PVP) and a solvent diffusion method. The complexation between poly(acrylic acid) and poly(vinyl pyrrolidone) as a result of hydrogen bonding was confirmed by the shift in the carbonyl absorption bands of poly(acrylic acid) using FT-IR. A mixture of ethanol/water was used as the internal phase, corn oil was used as the external phase of emulsion, and span 80 was used as the surfactant. Spherical microspheres were prepared and the inside of the microspheres was completely filled. The optimum solvent ratio of the internal phase (ethanol/water) was 8/2 and 7/3, and the particle size increased as the content of water was increased. The mean particle size increased with the increase in polymer concentration. The adhesive force of microspheres was equivalent to that of Carbopol. The release rate of acetaminophen from the complex microspheres was slower than the PVP microspheres at pH 2.0 and 6.8.     

Temperature and pH-sensitive Polymers for Human Calcitonin Delivery

Purpose. Stimuli-sensitive polymers are suitable candidates for oral peptide drug delivery vehicles since they will prevent gastric degradation in the stomach while providing a controlled release of a peptide drug such as calcitonin later. The purpose of this study was to fabricate polymeric beads from pH/temperature sensitive linear terpolymers (poly(N-isopropylacrylamide-co-butylmethacrylate-co-acrylic acid)) and load them with a peptide drug, human calcitonin, which was dissolved in aqueous phase. Methods. The polymeric beads were formed by solubilizing a cold, aqueous solution of temperature sensitive polymer with human calcitonin. This solution was added dropwise into an oil bath kept at a temperature above the LCST of a polymer, precipitating polymer and entrapping the peptide. The quantity and the physical state of the peptide were analyzed by reverse-phase HPLC, CD and FTIR and its biological activity after loading was determined in vivo. Results. The loading efficiency and stability of human calcitonin into the polymeric beads was studied as a function of pH and ionic strength of the loading buffer and temperature of the oil bath. Final optimal loading conditions were 20 mM glycine/HCl buffer, pH 3.0 containing 0.15 M NaCl as a dissolution medium and 23°C as the oil bath temperature. Loading and release of human calcitonin were also studied as a function of acrylic acid content in the terpolymers. As the acrylic acid content increased from 0 to 10 mol %, the loading efficiency and stability of calcitonin improved significantly. The same trend was observed for the quantity of released calcitonin. In vivo biological activity of the released hormone was preserved. Conclusions. The results showed that the beads made of the polymers with high content of acrylic acid (most hydrophilic) provided better loading, stability and release of human calcitonin. The designed beads represent a new potential system for oral delivery of calcitonin and other peptides.     

Oral gene delivery: Strategies to improve stability of pDNA towards intestinal digestion

Purpose: Gastrointestinal (GI) nucleases are responsible for a rapid presystemic degradation of orally administered transgenes. Within the current study, the activity of these degrading enzymes as well as the effect of various nuclease inhibitors on the degradation process were evaluated in order to assess their potential as auxiliary agents in oral gene delivery.

Methods: Digestion assays of pDNA with DNaseI and in GI juices were performed in absence and presence of inhibitors. Consequently, a chitosan conjugate with covalently bound ethylendiaminetetraacetic acid disodium salt dihydrat (EDTA) was synthesized and its nuclease inhibitory properties were evaluated.

Results: Small intestinal juice was shown to possess a nuclease activity per millilitre corresponding to 0.02 Kunitz units of DNaseI. Inhibition studies revealed that inhibitory activity followed the ranking: EDTA > sodium dodecyl sulfate (SDS) > aurintricarboxylic acid (ATA) > poly (acrylic acid) > cysteine. The chitosan–EDTA conjugate offered good nuclease inhibiting properties.

Conclusion: This study determined the nuclease activity of native porcine small intestinal juice as well as enterocytes homogenate. Moreover, several promising strategies to overcome this enzymatic barrier were identified.     

Eudragit®: a technology evaluation

Introduction: Eudragit is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives.

Areas covered: In this review, the physicochemical characteristics and applications of different grades of Eudragit in colon-specific/enteric-coated/sustained release drug delivery and taste masking have been addressed.

Expert opinion: Eudragits are amorphous polymers having glass transition temperatures between 9 to > 150^oC. Eudragits are non-biodegradable, nonabsorbable, and nontoxic. Anionic Eudragit L dissolves at pH > 6 and is used for enteric coating, while Eudragit S, soluble at pH > 7 is used for colon targeting. Studies in human volunteers have confirmed that pH drops from 7.0 at terminal ileum to 6.0 at ascending colon, and Eudragit S based systems sometimes fail to release the drug. To overcome the shortcoming, combination of Eudragit S and Eudragit L which ensures drug release at pH < 7 has been advocated. Eudragit RL and RS, having quaternary ammonium groups, are water insoluble, but swellable/permeable polymers which are suitable for the sustained release film coating applications. Cationic Eudragit E, insoluble at pH ≥ 5, can prevent drug release in saliva and finds application in taste masking.     

Polynucleotide analogues. Copolymers of vinyl bases with acrylic acid, methylacrylic acid, acrylamide, and 1-vinylpyrrolidone.

Preliminary studies are reported on the synthesis and testing of substituted vinyl polymers that are designed to have sequence specific affinity for polyribonucleic acids. Copolymers of 1-vinyluracil with acrylic acid, 2-methylacrylic acid, or 1-vinyl-2-pyrrolidone were prepared by gamma-irradiation to give the respective polymers 1,3, and 4. Similarly, 9-vinyladenine yielded copolymeric products 5 and 6 with acrylic acid or 2-methylacrylic acid. Radical initiated polymerization of 9-vinyladenine with acrylamide yielded copolymer 7. The products were characterized by elemental analysis and ultraviolet, infrared, and nuclear magnetic resonance spectroscopy. No hypochromicity could be detected on mixing polymers 1-4 with poly(adenylic acid). The acrylic acid copolymer 2 containing a high ratio of vinyluracil was a potent inhibitor of poly(adenylic acid) coded polylysine synthesis in an in vitro system. Polymers 6 and 7, containing a high proportion of vinyladenine, inhibited poly(uridylic acid) coded poly(phenylalanine) synthesis.     

pH-responsive amphiphilic hydrogel networks with IPN structure: a strategy for controlled drug release

A pH-responsive amphiphilic hydrogel with interpenetrating polymer networks (IPN) structure for controlled drug release was proposed. The IPN was constructed with hydrophilic poly(acrylic acid) (PAA) and hydrophobic poly(butyl acrylate) (PBA). Using drug N-acetyl-5-methoxytryptamine (melatonin, MEL) as a model molecule, the controlled drug release behaviors of the IPN were investigated. It is found that not only the release of MEL from the IPN can respond to change in pH, but also the presence of hydrophobic network can overcome disadvantageous burst effect of hydrophilic network. This may be a result of hydrophobic aggregation encapsulating MEL molecules.     

An in vitro model for investigating the gastric mucosal retention of 14C-labelled poly(acrylic acid) dispersions

Polymers that bind from solution onto gastric mucosae can be used as a means of facilitating localised drug delivery, or act as therapeutic agents in their own right (e.g. by forming a protective layer or by inhibiting enzymes). Previous workers have used semi-quantitative methods to identify the ability of commercially available poly(acrylic acid)s to bind to gastric mucosa. In this study, the binding and retention of labelled poly(acrylic acid)s to sections of gastric mucosa from the pyloric region of pigs stomach were evaluated using 'static' and 'dynamic flow' test systems. Dispersions (3%) of 'low', 'high' and 'ultra high' (cross-linked) polymers were seen to adhere to porcine pyloric mucosa after exposure and rinsing in the 'static' system. The high molecular weight polymer showed the greatest retention in the 'dynamic' test system when washing continuously with simulated gastric acid. Changing the pH of the dispersions from 4.3 to 6.2 had little effect on polymer retention. It was concluded that polymers that were sufficiently mobile in solution to spread on, and interact with, the mucosal surface, but had a sufficiently high molecular weight to form viscous solutions and/or bioadhere to the mucosa, may be retained on the mucosal surface for the longest periods.     

Precorneal Clearance of Mucoadhesive Microspheres from the Rabbit Eye

The ocular disposition of hydrated ¹¹¹In-labelled microspheres was investigated in the rabbit by gamma scintigraphy. Microspheres of cross-linked poly(acrylic acid) (Carbopol 907) were prepared by a w/o emulsification process. An in-vitro mucoadhesion test of prehydrated microspheres showed that greater adhesion was achieved to a mucus gel at pH 5·0 compared with pH 7·4. Clearance was a biphasic process with a rapid initial phase preceding a slower basal phase. When hydrated in pH 5·0 phosphate buffered saline, clearance during the basal phase was slower compared with a pH 7·4 buffered preparation. Both prehydrated preparations were retained on the preocular area during the basal phase for longer periods than non-hydrated microspheres. The retention on the ocular surface of approximately 25% of the instilled dose would suggest this technology will have application for controlled ophthalmic drug delivery.     

Oxprenolol-loaded bioadhesive microspheres: preparation and in vitro/in vivo characterization

Biologically adhesive delivery systems offer important advantages over conventional drug-delivery systems. In this paper, microspheres intended as a sustained release carrier for oral or nasal administration have been prepared by associating a known bioadhesive polymer, poly(acrylic acid), in gelatin microspheres. A model drug oxprenolol hydrochloride was chosen. It was found that some of the formulation variables can influence the characteristics of the beads in a controlled manner. The internal structure of the microspheres studied by X-ray diffraction, thermal analysis and optical microscopy showed the absence of drug crystals in microspheres and a lowering in the glass transition temperature. The dynamic swelling of the beads obeyed the square root of time and a shift from the diffusional to the relaxational process dependent on the content of poly(acrylic acid) in gelatin microspheres was observed. As expected, drug release from gelatin/poly(acrylic acid) microspheres was influenced by the poly(acrylic acid) content in beads, by the particle size of microspheres and by the pH of the medium. The mechanism of release was analysed by applying the empirical exponential equation and by calculation of the approximate contribution of the diffusional and relaxational mechanisms to the anomalous release process by fitting the data to the coupled Fickian/Case II equation. In vitro and in vivo experiments in rats showed good adhesive characteristics of the gelatin/poly(acrylic acid) microspheres, which were greater if the poly(acrylic acid) content was greater. A significant retardation in gastric and intestinal emptying time of the beads was observed. This was also suggested by the bioavailability of the model drug after intragastric and intranasal administration of the microspheres. The pharmacokinetic parameters after microsphere administration were more appropriate to a slow release drug-delivery system. The work suggests the potential of this pharmaceutical delivery system as an alternative controlled-release dosage form, either for oral or nasal administration.     

Drug release from pH-sensitive interpenetrating polymer networks hydrogel based on poly (ethylene glycol) macromer and poly (acrylic acid) prepared by UV cured method

Acrylate-terminated poly (ethylene glycol) (PEG) macromer was prepared by the reaction of PEG with acryloyl chloride. Photopolymerization of PEG macromer resulted in the formation of cross-linked PEG network. Interpenetrating polymer networks (IPNs) based on PEG and poly(acrylic acid) (PAA) was obtained via template polymerization of AA to the PEG network by UV curing. The swelling degree of the IPNs hydrogel increased with an increase of pH value due to the association-dissociation between carboxylic acid of PAA and ether of PEG through hydrogen bonding. The swelling-deswelling behavior proceeded reversibly for the IPNs upon changing pH. Release of indomethacin from the IPNs demonstrated “on-off” regulation with pH fluctuation.