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.     

The transport of polymeric microspheres across the ciliated epithelia of the bullfrog

The influence of some hydrophilic polymers on the clearance of particles across the ciliated epithelium of the bullfrog palate has been examined. The polymers studied were Carbopol 907 cross-linked with maltose to provide microspheres of varying cross-link density, Carbopol 934P, hydroxypropylmethylcellulose, chitosan and poly(vinyl alcohol). Transport rates were determined relative to glass spheres. The polymers in dilute solution (0.1 and 0.5% w/v) resulted in a reduction in the transport rate of the glass spheres. For non-cross-linked microspheres, Carbopol 934P exhibited a lower transport rate than the more slowly hydrating chitosan. The cross-linked poly(acrylic acid) microspheres showed clearance rates which were dependent on the cross-link density. Incorporation of some preservatives (EDTA, methylhydroxybenzoate, chlorbutol and chlorocresol), known to reversibly retard clearance, into the cross-linked poly(acrylic acid) microspheres produced effects dependent on cross-link density: lightly cross-linked microspheres were cleared more slowly than the preservative-free microspheres whilst for more heavily cross-linked particles the converse was observed.     

Polymeric microspheres for drug delivery to the oral cavity: an in vitro evaluation of mucoadhesive potential

Polymeric microparticles were fabricated from Carbopol, polycarbophil, chitosan, or Gantrez using a "water-in-oil emulsification" solvent evaporation method. Mean particle sizes, as determined by laser diffraction, were in the range 23-38 microm. Electron microscopy revealed that all microparticles were spherical and of smooth surface morphology. In pH 7.0 phosphate buffered saline, the microspheres exhibited significantly increased swelling ratios and longer half-times of swelling than the corresponding powdered polymers. The relative merits of the potential usefulness of these microspheres as formulation tools for the enhanced retention of a therapeutic entity within the oral mucosa were evaluated by in vitro mucoadhesion tests. Tensile tests showed that all microspheres under consideration were capable of adhering to porcine esophageal mucosa, with particles prepared from the poly(acrylic acid)s exhibiting greater mucoadhesive strength than those constructed from chitosan or Gantrez. However, in elution experiments involving a challenge with artificial saliva, particles of chitosan or Gantrez were retained onto mucosal tissue for longer time periods than those assembled from the poly(acrylic acid)s.     

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.     

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.     

Preparation of mucoadhesive chitosan-poly(acrylic acid) microspheres by interpolymer complexation and solvent evaporation method II

A mucoadhesive microsphere was prepared by an interpolymer complexation and solvent evaporation method, using chitosan and poly(acrylic acid) (PAA), to prolong the gastric residence time of the delivery system. The Fourier transform infrared results showed that microspheres were formed by an electrostatic interaction between the carboxyl groups of the PAA and the amine groups of the chitosan. X-ray diffraction and differential scanning calorimetry analysis showed that the enrofloxacin in the chitosan-PAA microsphere was molecularly dispersed in an amorphous state. Scanning electron microscopy of the surface and the quantity of mucin attached to the microspheres indicated that chitosan-PAA microspheres had a higher affinity for mucin than those of chitosan alone. The swelling and dissolution of the chitosan-PAA microspheres were found to be dependent on the pH of the medium. The rate of enrofloxacin released from the chitosan-PAA microspheres was slower at higher pH; therefore, based on their mucoadhesive properties and morphology, the chitosan-PAA microspheres can be used as a mucoadhesive oral drug delivery system.     

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.     

Preparation and characterization of poly(D,L-lactic-co-glycolic Acid) microspheres containing flurbiprofen sodium

This study aimed to prepare biodegradable microspheres containing flurbiprofen sodium, a nonsteroidal anti-inflammatory drug (NSAID), as the drug delivery system to the periodontal pocket. Microspheres were prepared from biodegradable copolymers of poly (D,L-lactic-co-glycolic acid) (PLGA) using solvent evaporation method. The effects of the different copolymers and amounts of polyvinyl alcohol (PVA) as a dispersing agent on characteristics of the microspheres were evaluated. Although there was no correlation between microsphere size and amount of PVA, an optimum PVA concentration was essential to achieve narrower size distributions of microspheres. As the concentration of PVA increased, the drug loading of the microspheres increased. The effect of PVA on drug loading was found to be statistically significant for those microspheres prepared from PLGA 50:50 (p < 0.05). Regarding copolymer composition, PLGA 85:15 provided higher drug loading into the microspheres than PLGA 50:50 (p < 0.05). The recoveries of microspheres (60-80%) were affected neither by different PVA concentrations nor by copolymer compositions (p > 0.05). According to the first-order release rate constants of the microspheres, the microspheres of PLGA 50:50 released the drug at the highest rate consistently, with the highest hydrophilicity of this copolymer.     

Preparation and evaluation of microparticles from thiolated polymers via air jet milling

Microparticles were formulated by incorporation of the model protein horseradish peroxidase in (thiolated) chitosan and (thiolated) poly(acrylic acid) via co-precipitation. Dried protein/polymer complexes were ground with an air jet mill and resulting particles were evaluated regarding size distribution, shape, zeta potential, drug load, protein activity, release pattern, swelling behaviour and cytotoxicity. The mean particle size distribution was 0.5-12 microm. Non-porous microparticles with a smooth surface were prepared. Microparticles from (thiolated) chitosan had a positive charge whereas microparticles from (thiolated) poly(acrylic acid) were negatively charged. The maximum protein load for microparticles based on chitosan, chitosan-glutathione (Ch-GSH), poly(acrylic acid) (PAA) and for poly(acrylic acid)-glutathione (PAA-GSH) was 7+/-1%, 11+/-2%, 4+/-0.2% and 7+/-2%, respectively. The release profile of all microparticles followed a first order release kinetic. Chitosan (0.5mg), Ch-GSH, PAA and PAA-GSH particles showed a 31.4-, 13.8-, 54.2- and a 42.2-fold increase in weight, respectively. No significant cytotoxicity could be found. Thiolated microparticles prepared by jet milling technique were shown to be stable and to have controlled drug release characteristics. After further optimizations the preparation method described here might be a useful tool for the production of protein loaded drug delivery systems.     

Effects of various granulating systems on the bioavailability of naproxen sodium from polymeric matrix tablets

Naproxen sodium and a cellulose ether derivative were granulated with either water or a poly(meth)acrylic acid ester copolymer aqueous dispersion to make three controlled-release matrix dosage forms. The different polymeric matrix systems contained hydroxypropyl methylcellulose (formulation A), hydroxypropyl cellulose:poly(meth)acrylic acid ester copolymer (formulation B), and hydroxypropyl methylcellulose:poly(meth)acrylic acid ester copolymer (formulation C). All three hydrophilic matrix tablets demonstrated identical in vitro dissolution rates. The three controlled-release formulations were compared with a marketed immediate-release naproxen sodium dosage form (formulation D) in a single-dose crossover study in six healthy volunteers. The AUC values for controlled-release dosage forms A and C were larger than those for formulations B and D. However, the reasons why the AUC for formulations A and C is larger than that for formulations B versus D can be explained differently. Formulations A and C more effectively maintain naproxen plasma levels than formulation D by reducing the amount of naproxen unbound to plasma proteins, therefore reducing naproxen available for urinary excretion. Naproxen sodium delivered from formulations A and C is also probably much better absorbed than from that from formulation B, possibly due to less drug entrapment. More importantly, although all three CR formulations had identical in vitro dissolution profiles, naproxen sodium plasma levels were better maintained (based on AUC) in subjects taking formulations A and C, which contained a lower polymer content and did not use hydroxypropyl cellulose. The tmax values were larger for the three controlled-release dosage forms. Also, the Cmax value for the conventional dosage form was nearly twofold higher than that observed for the controlled-release dosage forms.     

An investigation of the interfacial interaction between poly(acrylic acid) and glycoprotein

The swelling behaviour of poly(acrylic acid) microspheres, produced from poly(acrylic acid) crosslinked with maltose, was investigated as a function of time by using a laser diffraction spectrometer. Swelling was also studied in various pH glycoprotein solutions. Microscopy revealed confirmatory evidence of interfacial film formation when microsphere hydration occurred in a pH 5 glycoprotein solution. ATR-FTIR spectroscopy was used to determine the diffusion coefficient of water through the interfacial film existing at the poly(acrylic acid) glycoprotein solution interface. Both processes exhibited a pH dependency with rates decreasing in the sequence pH 7>6>5=4.     

Preparation and characterization of gelatin surface modified PLGA microspheres

This study optimized conditions for preparing and characterizing gelatin surface modified poly (lactic-co-glycolic acid) (PLGA) copolymer microspheres and determined this systems interaction with fibronectin. Some gelatin microspheres have an affinity for fibronectin-bearing surfaces; these miscrospheres exploit the interaction between gelatin and fibronectin. PLGA copolymer microspheres were selected because they have reproducible and slowrelease characteristics in vivo. The PLGA microspheres were surface modified with gelatin to impart fibronectin recognition. Dexamethasone was incorporated into these microspheres because dexamethasone is beneficial in chronic human diseases associated with extra fibronectin expression (eg, cardiovascular disease, inflammatory disorders, rheumatoid arthritis). The gelatin surface modified PLGA microspheres (prepared by adsorption, conjugation, and spray coating) were investigated and characterized by encapsulation efficiency, particle size, in vitro release, and affinity for fibronectin. The gelatincoated PLGA microspheres had higher interaction with fibronectin compared with the other gelatin surface modified PLGA microspheres (adsorption and conjugation). Dexamethasone was released slowly (over 21 days) from gelatin surface modified PLGA microspheres.     

The role of microsphere fabrication methods on the stability and release kinetics of ovalbumin encapsulated in polyanhydride microspheres

The effect of microsphere fabrication methods on the stability and release kinetics of ovalbumin encapsulated in polyanhydride microspheres was investigated. The polyanhydrides used were poly(sebacic anhydride) (poly(SA)) and a 20:80 random copolymer of poly[1,6-bis(p-carboxyphenoxy)hexane] (poly(CPH)) and poly(SA). Microspheres were fabricated using three double emulsion methods (water/oil/water, water/oil/oil and solid/oil/oil) and cryogenic atomization. The encapsulation efficiency was highest for cryogenic atomization and lowest when the w/o/w technique was used. Microspheres fabricated by the s/o/o method had the largest initial burst of released protein. All the methods resulted in zero-order release of the protein after the burst. The release of ovalbumin from poly(SA) and 20:80 (CPH:SA) microspheres lasted approximately 3 and approximately 6 weeks, respectively. For all fabrication methods the primary structure of released ovalbumin was conserved as determined by gel electrophoresis. The secondary structure of ovalbumin encapsulated in 20:80 (CPH:SA) w/o/w microspheres was not conserved.     

The role of microsphere fabrication methods on the stability and release kinetics of ovalbumin encapsulated in polyanhydride microspheres

The effect of microsphere fabrication methods on the stability and release kinetics of ovalbumin encapsulated in polyanhydride microspheres was investigated. The polyanhydrides used were poly(sebacic anhydride) (poly(SA)) and a 20:80 random copolymer of poly[1,6-bis(p-carboxyphenoxy)hexane] (poly(CPH)) and poly(SA). Microspheres were fabricated using three double emulsion methods (water/oil/water, water/oil/oil and solid/oil/oil) and cryogenic atomization. The encapsulation efficiency was highest for cryogenic atomization and lowest when the w/o/w technique was used. Microspheres fabricated by the s/o/o method had the largest initial burst of released protein. All the methods resulted in zero-order release of the protein after the burst. The release of ovalbumin from poly(SA) and 20:80 (CPH:SA) microspheres lasted ～3 and ～6 weeks, respectively. For all fabrication methods the primary structure of released ovalbumin was conserved as determined by gel electrophoresis. The secondary structure of ovalbumin encapsulated in 20:80 (CPH:SA) w/o/w microspheres was not conserved.     

Bimodal release of theophylline from "seed-matrix" beads made of acrylic polymers

The purpose of this research was to design a "seed-matrix" structure for an in vitro bimodal theophylline release profile and to investigate the mechanism and kinetics of drug release as well as the influence of various factors on the properties of the theophylline-containing microspheres. "Seed" microspheres with high theophylline content were prepared from Eudragit L100 and Eudragit S100, copolymers of methyl methacrylate and methacrylic acid, by the solvent removal process. The seed-matrix beads were subsequently prepared by incorporation of the seed microspheres into Eudragit RL100, a copolymer of acrylic and methacrylic acid esters with a low content of quaternary ammonium group. Increasing the size of encapsulated drug particles and the rate of agitation during the preparation, or decreasing the amount of surfactants led to an increase in the size of the microspheres produced. Scanning electron microscopy revealed porous morphology of the microspheres. The release rate of theophylline was enhanced as the content of methacrylic acid in the copolymer increased and the size of the microspheres decreased. The kinetics of drug release from the microspheres was controlled by swelling at the early stage and by diffusion in the later stage. The drug was released from the matrix of the seed-matrix beads at pH 1.2 and from both the matrix and the seeds at pH 6.8. A bimodal release profile of theophylline was obtained from the seed-matrix beads made of acrylic polymers.     

Chitosan microspheres for encapsulation of alpha-lipoic acid

Encapsulation of alpha-lipoic acid (LA) was carried out using chitosan as an encapsulant matrix. Placebo and LA-loaded chitosan microspheres were prepared by a spray-drying process. Scanning electron microscopy (SEM) studies confirmed the spherical particle geometry and the smooth surface morphology of LA-loaded particles. The particle size distribution (PSD) analysis of the placebo and LA-loaded microspheres has shown that 50% of the microspheres were less than 3.53 and 7.89 microm, respectively. The structural interactions of the chitosan matrix with the encapsulated LA were studied by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) which revealed structural interactions of lipoic acid with the encapsulant matrix. The antioxidant activity of encapsulated lipoic acid was studied using the free-radical scavenging assay. This study demonstrated significant retention of antioxidant activity of lipoic acid (75%) after encapsulation in the chitosan matrix. Encapsulation efficiency of lipoic acid obtained in this study was 55.2% when ethanol and acetic acid (1:1 v/v) was used as incubation/extraction medium.     

Colon-specific delivery of mesalazine chitosan microspheres

Mesalazine (5-ASA) is a cyclo-oxygenase inhibitor and anti-inflammatory drug effective in Crohn's disease and ulcerative-colitis. As 5-ASA is rapidly absorbed from the small intestine and it is necessary to develop a colon-specific delivery system for it. Coated chitosan microspheres were used for this purpose by an emulsion-solvent evaporation technique based on a multiple w/o/w emulsion. Four hundred milligrams of chitosan solution (3%) in dilute acetic acid (0.5 M) containing 12% 5-ASA was dispersed into 2 ml solution of cellulose acetate butyrate (CAB) in methylene chloride. The primary induced w/o emulsion was dispersed into a 1% PVA aqueous solution to produce a w/o/w multiple emulsion and was stirred for approximately 2.5 h. The produced microspheres were separated, washed and dried. Release of 5-ASA from microspheres was studied in different pHs 1.2, 7.4, 6.8 and 6.8 in the presence of caecal contents of rat. The average size of microspheres was 200 microm. The highest yield efficiency (80%) was seen in medium molecular weight (MW) chitosan with a 1 : 2 core/coat ratio and the greatest loading efficiency (85%) related to the microspheres of the same type of chitosan but with a 1 : 1 core/coat ratio. Decreasing the coat content and increasing chitosan Mw increased the bioadhesion significantly (p < 0.05). Microspheres of chitosan with medium Mw and 1 : 1 core/coat that showed the greatest release of drug (near 80%) in the presence of caecal secretions with a zero-order mechanism, near zero per cent in pH 1.2 after 2 h, max 20% in pH 7.4 after 3 h and near 60% in pH 6.8 after 8 h seem suitable for site-specific delivery of 5-ASA in vitro.     

The characterization of paclitaxel-loaded microspheres manufactured from blends of poly(lactic-co-glycolic acid) (PLGA) and low molecular weight diblock copolymers

Paclitaxel-loaded biodegradable drug delivery systems manufactured from poly(lactic-co-glycolic acid) (PLGA) are known to release the drug at extremely slow rates. The objective of this study was to characterize paclitaxel-loaded microspheres composed of blends of PLGA with low molecular weight ampipathic diblock copolymers. The encapsulation and release of a series of poly(epsilon-caprolactone) (PCL)- or poly(D,L-lactic acid) (PDLLA)-co-methoxypolyethylene glycol (MePEG) diblock copolymers was measured using quantitative gel permeation chromatography. Polymeric miscibility was determined by glass transition temperature measurements using differential scanning calorimetry and paclitaxel release was measured using HPLC methods. The PCL- and PDLLA-based diblock copolymers encapsulated at high efficiency and were miscible in PLGA microspheres (30-120m microm size range). The burst phase of paclitaxel release was increased up to 20-fold by the inclusion of diblock copolymers in PLGA microspheres. Approximately 10% of the more hydrophobic PCL-based copolymers released from the microspheres in a short burst over 3 days followed by very slow release over the following 10 weeks. Only the PDLLA-based copolymer released from the PLGA microspheres in a controlled manner over 10 weeks. All microspheres containing PEG were found to have more hydrophilic surfaces (as measured by contact angle) with improved biocompatibility (reduced neutrophil activation) compared to PLGA only microspheres. These results indicate that low molecular weight polyester-based diblock copolymers may be effectively encapsulated in PLGA microspheres to increase paclitaxel release (probably through a micellization process) and improve biocompatibility.     

Preparation of mucoadhesive microspheres containing antimicrobial agents for eradication of H. pylori

Mucoadhesive microspheres containing either amoxicillin or clarithromycin were prepared via the interpolymer complexation of poly(acrylic acid) (PAA) with poly(vinyl pyrrolidone) (PVP) and solvent diffusion method. The complexation between the PAA and PVP in an ethanol/water mixture was confirmed by the change in the transmittance of the solution as a function of repeating PAA and PVP unit ratio. The loading efficiency of clarithromycin in the complex microspheres was higher than that of amoxicillin due to the stronger interaction of clarithromycin with the PAA. The microspheres had a spherical shape with a smooth surface and the inside of the microspheres was completely filled. The dissolution rate of the complex microspheres was significantly slower than that of the PVP microspheres, particularly at pH 2.0. Amoxicillin and clarithromycin degraded significantly during the release study at pH 2.0. Therefore, their release rates were corrected using first order degradation rate constants. The amoxicillin release rates were similar regardless of the pH of the medium, while those of clarithromycin differed depending on the pH. The release mechanism of amoxicillin was mainly by a diffusion process and that of clarithromycin was via a dissolution process. The drug release rate from the complex microspheres was significantly lower than that from the PVP microspheres.     

Preparation and in vitro release behaviour of 5-fluorouracil-loaded microspheres based on poly (L-lactide) and its carbonate copolymers

A modified oil-in-oil (o/o) emulsion solvent evaporation technique was adopted to prepare 5-fluorouracil (5-Fu)-loaded poly (L-lactide) (PLLA) or its carbonate copolymer microspheres. The disperse phase was a drug:polymer solution using a solvent mixture of N,N-dimethylformamide (DMF) and acetonitrile and the continuous phase was liquid paraffin containing 1-10% (w/v) Span 80(R). The effects of preparative parameters, such as the composition of the inner oil phase, drug:polymer ratio, polymer concentration and agitation rate, on 5-Fu entrapment efficiency and microsphere characteristics were investigated. By introducing 25% (v/v) DMF into the inner oil phase, microspheres with high drug entrapment efficiency and an ameliorated burst effect were achieved. Using this modified method, microspheres with various particle sizes could be produced with a high 5-Fu entrapment efficiency (about 80%). In vitro drug release tests showed a burst release of 5-Fu from PLLA microspheres, followed by a sustained release over 50 days. In the case of poly (L-lactide-co-1,3-trimethylene carbonate) (PLTMC) and poly (L-lactide-co-2,2-dimethyl-1,3-trimethylene carbonate) (PLDTMC), the drug release could be continued for over 60 days.