Novel methyl cellulose‐grafted‐acrylamide/gelatin microspheres for controlled release of nifedipine

Naturally available carbohydrate polymers such as methylcellulose (MC) and gelatin (Ge) have been widely studied in the previous literature for controlled release (CR) applications. In this study, methyl cellulose‐g‐acrylamide/gelatin (MC‐g‐AAm/Ge) microspheres were prepared by water‐in‐oil (W/O) emulsion method and crosslinked with glutaraldehyde to encapsulate with nifedipine (NFD), an antihypertensive drug. The microspheres prepared were characterized by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and laser particle size analyzer. DSC thermograms of NFD‐loaded AAm‐MC/Gel microspheres confirmed the molecular level distribution of NFD in the matrix. SEM indicated the formation of spherical particles. Swelling experiments supported the drug diffusion characteristics and release data of the matrices. Cumulative release data were analyzed using an empirical equation to understand the nature of transport of drug through the matrices. Controlled release characteristics of the matrices for NFD were investigated in pH 7.4 media. Drug was released in a controlled manner up to 12 h. Particle size and size distribution of the microspheres as studied by laser light diffraction particle size analyzer indicated their sizes to be around 120 μm. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Inter-polymer complex microspheres of chitosan and cellulose acetate phthalate for oral delivery of 5-fluorouracil

Inter-polymer complexes (IPCs) of chitosan (CS) and cellulose acetate phthalate (CAP) have been prepared to develop spherical microspheres by a novel emulsion-solvent evaporation technique. The microspheres were used for the oral delivery of 5-fluorouracil (5-FU), an antimetabolite and antineoplastic agent, whose release time was extended up to 12 h. Formulations were prepared by varying the concentrations of CS, CAP and 5-FU. FTIR confirmed the formation of IPC, indicating no chemical interactions of 5-FU with the polymer matrix. Scanning electron microscopy suggested spherical shape of the microspheres with smooth surfaces. Average particle size measured by optical microscopy varied between 2.7 and 5.5 μm. Differential scanning calorimetry showed amorphous dispersion of 5-FU particles into the IPC matrix. Encapsulation efficiency as estimated by UV was dependent on polymer composition with the highest value of 96 %. Water uptake by the IPC microspheres was higher at higher concentration of CS in the matrix. In vitro drug release performed in pH 1.2 and pH 7.4 buffer media showed a dependence on compositions of CS, CAP and drug loading. Molar mass between cross-links (M _c) and cross-link density (d _x ) values of the polymer matrix calculated from swelling data indicated the formation of a dense matrix between CS and CAP; the matrix was able to control the release of 5-FU. The in vitro release data have been fitted to empirical equations to understand the nature of drug release mechanism.     

Controlled release of Montelukast Sodium from pH-sensitive injectable hydrogels

pH sensitive hydrogels showed excellent drug release properties, with promise for other biomedical applications. Also, the impact of molecular weight (MW) and degree of deacetylation (DDA) of chitosan on the fabricated chitosan/poly (vinyl alcohol) (3:1 mol ratio) hydrogel with selective silane crosslinker amount was evaluated for controlled drug delivery. The FTIR spectroscopy confirmed the incorporated components and the developed interactions among the polymer chains. The hydrogel characteristics were expressed by their responsive behaviour in different environments (water, ionic media and pH). The hydrogel sample (CH1000) having chitosan with higher MW and DDA exhibited more thermal stability and bacterial growth inhibition against E.coli. All hydrogels exhibited maximum swelling at basic and neutral pH and less swelling was observed in acidic media. For drug release analysis performed in simulated gastric fluid, hydrogel showed controlled drug release in 2 h but it was more than 10%, consequently cannot be used for oral purpose. In simulated intestinal fluid, hydrogels exhibited more than 80% release within 90 min. This characteristic phenomenon at neutral pH empowered hydrogel appropriate towards injectable and targeted controlled release of applicable drug. It was concluded that the prepared hydrogel can be administered directly into the venous circulation through syringe and can be used with better results for biomedical applications.     

Synthesis and characterization of modified chitosan microspheres: Effect of the grafting ratio on the controlled release of nifedipine through microspheres

The grafting of acrylamide onto a chitosan backbone was carried out at three acrylamide concentrations (polymer/monomer ratio = 1:1, 1:2, and 1:3). The synthesis of the grafted polymer was achieved by K₂S₂O₈‐induced free‐radical polymerization. Microspheres of polyacrylamide‐g‐chitosan crosslinked with glutaraldehyde were prepared to encapsulate nifedipine (NFD), a calcium channel blocker and an antihypertensive drug. The microspheres of polyacrylamide‐g‐chitosan were produced by a water‐in‐oil emulsion technique with three different concentrations of glutaraldehyde as the crosslinking agent. Fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetry (DSC) were used to characterize the grafted copolymers, and the microspheres were prepared from them. FTIR and DSC were also used to analyze the extent of crosslinking. The microspheres were characterized by the particle size; the water transport into these microspheres, as well as the equilibrium water uptake, were studied. Scanning electron microscopy confirmed the spherical nature of the particles, which had a mean particle size of 450 μm. Individual particle dynamic swelling experiments suggested that with an increase in crosslinking, the transport became case II. The release of NFD depended on the crosslinking of the network and on the amount of drug loading. Calculating the drug diffusion coefficients with the initial time and later time approximation method further supported this. The drug release in all 27 formulations followed case II transport, and this suggested that the time dependence of the NFD release followed zero‐order kinetics. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 89: 2940–2949, 2003     

Preparation,characterization, and salicylic acid release behavior of chitosan/poly(vinyl alcohol) blend microspheres

Blend microspheres of chitosan (CS) with poly(vinyl alcohol) (PVA) were prepared as candidates for oral delivery system. CS/PVA microspheres containing salicylic acid (SA), as a model drug, were obtained using the coacervation‐phase separation method, induced by addition of a nonsolvent (sodium hydroxide solution) and then crosslinked with glutaraldehyde (GA) as a crosslinking agent. The microspheres were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry (DSC), and scanning electron microscopy. Percentage entrapment efficiency, particle size, and equilibrium swelling degree of the microsphere formulations were determined. The results indicated that these parameters were changed by preparation conditions of the microspheres. Effects of variables such as CS/PVA ratio, pH, crosslinker concentration, and drug/polymer (d/p) ratio on the release of SA were studied at three different pH values (1.2, 6.8, and 7.4) at 37°C. It was observed that SA release from the microspheres increased with decreasing CS/PVA ratio and d/p ratio whereas it decreased with the increase in the extent of crosslinking. It may also be noted that drug release was much higher at pH 1.2 than that of at pH 6.8 and 7.4. The highest SA release percentage was obtained as 100% for the microspheres prepared with PVA/CS ratio of 1/2, d/p ratio of 1/2, exposure time to GA of 5 min, and concentration of GA 1.5% at the end of 6 h. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Preparation and characterization of novel semi‐interpenetrating 2‐hydroxyethyl methacrylate‐g‐chitosan copolymeric microspheres for sustained release of indomethacin

A novel semi‐interpenetrating (semi‐IPN) graft copolymer of 2‐hydroxyethyl methacrylate (HEMA) with chitosan (CS) has been prepared in the form of microspheres, using water‐in‐oil (W/O) emulsion technique. Microspheres were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X‐ray diffractometry (X‐RD) to confirm the crosslinking and polymorphism of indomethacin (IDM). The X‐RD and DSC techniques indicated a molecular‐level dispersion of IDM in the IPN matrix. Scanning electron micrographs (SEM) taken at the cross section of the microspheres have shown rough surfaces around the microspheres. The sustained release characteristics of the matrices for IDM, an anti‐inflammatory drug, were investigated in pH 7.4 media. Particle size and size distribution of the microspheres were studied by laser light diffraction particle size analyzer. The drug was released in a sustained manner for up to 12 h. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci, 2006     

Preparation and characterization of nifedipine-loaded cellulose acetate butyrate based microspheres and their controlled release behavior

Eudragit L100/cellulose acetate butyrate blend microspheres were prepared by solvent evaporation technique using poly(vinyl alcohol) as an emulsifying agent nifedipine (NFD) was successfully loaded into these microspheres. The effect of experimental variables such as ratio of blend ratio on NFD encapsulation efficiency, release rate, size, and morphology of the microspheres has been investigated. Scanning electron micrographs indicated the formation of spherical microspheres. Mean particle size of the microspheres has been measured by the laser light scattering technique ranged between 100 and 120 μm. NFD was successfully encapsulated up to 80% in the polymeric matrices. In vitro dissolution experiments performed in pH 7.4 buffer medium indicated a controlled release of NFD from the blend microspheres up to 12 h.     

Preparation,characterization, and in vitro release of folic acid-conjugated chitosan nanoparticles loaded with methotrexate for targeted delivery

To reduce the toxicity of methotrexate (MTX) and increase the targeting of nanoparticles, the MTX-loaded chitosan (CS) covalently bonded with folic acid (FA) nanoparticles were prepared, and sodium tripolyphosphate was used as the cross-linking agent. FA was successfully conjugated to CS confirmed by ¹H-NMR and Fourier transform infrared spectrometer (FT-IR). The prepared FA–CS nanoparticles were characterized by FT-IR spectroscopy to confirm the cross-linking reaction between FA–CS and cross-linking agent. X-ray diffraction was performed to reveal the crystalline nature of the drug after encapsulation. The average diameters of the nanoparticles ranged from 293.9 ± 24.2 to 401.5 ± 20.4 nm with a narrow particle size distribution. In vitro release pattern in phosphate buffer saline (pH 6.8) indicated that the characteristics of the MTX-loaded nanoparticles appeared to have an initial burst effect and followed by a slow, sustained drug release. FA or low molecular weight FA conjugate fragments were also released from the nanoparticles, which might have potential to reduce toxic effects of MTX within the body.     

Preparation,characterization, and drug‐release properties of pH/temperature‐responsive poly(N‐isopropylacrylamide)/chitosan semi‐IPN hydrogel particles

Novel poly(N‐isopropylacrylamide) (PNIPAAm)/chitosan (CS) semi‐interpenetrating polymer network hydrogel particles were prepared by inverse suspension polymerization. The prepared particles were sensitive to both temperature and pH, and they had good reversibility in solution at different temperatures and pH values. The swelling ratios of PNIPAAm/CS hydrogel particles decreased slightly with the addition of CS, which did not shift the lower critical solution temperature. The drug‐release behavior of the particles was investigated using cyclic adenosine 3′,5′‐monophosphate (cAMP) as a model drug. The release of cAMP from the hydrogel particles was affected by temperature, pH, and the CS content in the particles. These results showed that semi‐IPN hydrogel particles appeared to be of great promise in pH‐ and temperature‐sensitive oral drug release. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

快速膜乳化与热固化法制备粒径均一的pH敏感壳聚糖季铵盐凝胶微球

以具有升温自固化特性的壳聚糖季铵盐/甘油磷酸钠混合溶液为水相,利用快速膜乳化与热固化法制备了粒径均一、pH敏感的壳聚糖季铵盐凝胶微球,考察了跨膜压力、水油相组成、水油相体积比及微孔膜孔径等对微球粒径、结构和药物包埋率的影响. 结果表明,得到粒径698±57.33, 1145±71.48, 2021±53.63及3984±191.72 nm、粒径分布窄(多分散系数<0.1)、药物包埋率高达75.49%±2.62%的凝胶微球. 所制微球生物相容性好,有明显的pH敏感性,中性和碱性环境下结构稳定,药物缓释,pH=7.4时24 h内药物累计释放率为34.6%;酸性环境下微球崩解,药物快速释放,pH=5.5时1 h内药物累计释放率高达79.6%.     

Cumulative release of cefotaxim from interpenetrating networks of poly(vinyl alcohol-g-acrylamide) and chitosan-g-polyacrylamide chains

In this study, novel interpenetrating networks comprising of poly(vinyl alcohol-g-acrylamide) and chitosan-g-polyacrylamide chains were designed by redox polymerization method and their potential for controlled release of an antibiotic drug cefotaxim, and antibacterial and cytotoxic behaviors were evaluated. The polymer matrix hydrogel was loaded with cefotaxim drug by allowing it to swell in the drug solution reservoirs of concentrations varying in the range 0.1–0.5 mg/mL. The polymer network was examined by FTIR, SEM and DSC techniques for structural, morphological and thermal characterization. The FTIR spectra clearly confirmed the presence of functional groups of constituent polymers; the SEM image suggested a mesh-type morphology with approximate mesh dimensions of 10 μm × 20 μm. The DSC studies revealed a fall in glass transition temperature (Tg) of both chitosan and poly(vinyl alcohol) to 50 and 70 °C, respectively, from their native values. The release studies were performed in PBS (pH 7.4) under in vitro conditions and the drug release kinetics was investigated. It was found that the amount of drug released increases from 5.4 to 8.4 mg when the drug loading increases from 5.0 to 16.0 %. It was also found that when the pH rises from 1.8 to 7.4, an increase in drug release was noticed, while a further increase in pH to 8.6 resulted in a fall in the amount of released drug. The polymer matrix also showed fair antibacterial properties against E. coli and no cytotoxicity for L-929 mouse fibroblast cells.     

Drug Release Kinetics of Spray-Dried Chitosan Microspheres

The aim of this article was to investigate the drug release kinetics of spray-dried chitosan microspheres using various kinetic models. The mean particle size and encapsulation efficiency of cross-linked chitosan microspheres was between 3.8 and 4.2 μm and 96.3 and 98.7%, respectively. Spray-dried chitosan microspheres were spherical in shape with smooth surface. The surface morphology of spray-dried chitosan microspheres was affected by the crystallinity of the loaded drug and cross-linking agent. The release data of the spray-dried chitosan microspheres were treated with zero-order, first-order, Higuchi, Korsmeyer, and Kopcha kinetic models and best fit was observed with Higuchi model, indicating the release of drug from spray-dried chitosan microspheres followed Fick's law of diffusion.     

Biodegradable polymeric microspheres of gelatin and carboxymethyl guar gum for controlled release of theophylline

Carboxymethyl guar gum (CMGG) was synthesized by carboxymethylation of guar gum (GG), which was blended with gelatin (GE) to obtain a novel semi-interpenetrating polymer network (semi-IPN) in the form of microspheres prepared by water-in-oil emulsion method to investigate the controlled release of theophylline (THP), an antiasthmatic drug. Electronic spectroscopy revealed the drug encapsulation ranging from 56 to 74 %. Fourier Transform infrared spectroscopy confirmed the carboxymethylation of GG as well as the semi-IPN structure of the blend polymer. Scanning electron microscopy indicated the smooth surfaces with spherical microspheres. Differential scanning calorimetric and X-ray diffraction studies showed the molecular level dispersion of drug in the microspheres. The in vitro drug release profiles were analyzed to study the effect of polymer blend composition, % drug loading and amount of glutaraldehyde added as a crosslinker. The drug release was extended up to 26 h. The in vitro release data performed in acidic and alkaline media were analyzed using the empirical equations to understand the release profiles of THP.     

Characterization of gamma irradiated concentrated aqueous solutions of chitosan/sodium alginate blends and their drug uptake‐release characters

Blends films based on different ratios of concentrated aqueous solutions of chitosan (CS) and sodium alginate (AG) in the presence of 1% of glutaraldehyde, as a cross‐linking agent for chitosan, were prepared by solution casting and then exposed to gamma irradiation. The formed blends were characterized by IR spectroscopic analysis, differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The uptake‐release properties of CS/AG blends, taking ketoprofen as an example for drug, were also investigated. DSC thermograms of CS/AG blends revealed good miscibility was sustained between CS and AG. The water uptake and gel content of CS/AG blends was found to decrease by increasing the ratio of AG in the initial solution. The IR spectra indicated the formation of cross‐linking and hydrogen bonding, while the TGA study showed that the CS/AG blends displayed higher thermal stability than pure CS polymer. Based on Fick's law, it was demonstrated that the main parameters affecting the release of ketoprofen drug from the CS/AG blend hydrogels were composition and pH. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Nanohybrid structure analysis and biomolecule release behavior of polysaccharide-CDHA drug carriers

Nanoscaled polymer composites were prepared from polysaccharide chitosan (CS) and Ca-deficient hydroxyapatite (CDHA). CS-CDHA nanocomposites were synthesized by in situ precipitation at pH 9, and the CS-CDHA carriers were then fabricated by ionic cross-linking methods using tripolyphosphate and chemical cross-linking methods by glutaraldehyde and genipin. Certain biomolecules such as vitamin B₁₂, cytochrome c, and bovine serum albumin were loaded into the CS-CDHA carriers, and their release behaviors were investigated. Furthermore, these CS-CDHA carriers were examined by transmission electron microscopy, electron spectroscopy for chemical analysis, and X-ray diffraction. The release behavior of the biomolecules was controlled by the CS/CDHA ratios and cross-linked agents. By increasing the concentration of CS and the concentration of the cross-linking agents, cross-linking within carriers increases, and the release rate of the biomolecules is decreased. Moreover, the release rate of the biomolecules from the CS-CDHA carriers at pH 4 was higher than that at pH 10, displaying a pH-sensitive behavior. Therefore, these CS-CDHA hydrogel beads may be useful for intelligent drug release and accelerate bone reconstruction.     

Effect of heparin coating on epichlorohydrin cross-linked chitosan microspheres on the adsorption of copper (II) ions

Epichlorohydrin cross-linked chitosan microspheres (CS) and chitosan–heparin polyelectrolyte complex microspheres (CSH) were used in the adsorption of copper (II) ions in aqueous solution. The chitosan microspheres were prepared by the phase inversion method. The use of a cross-linking agent improved the resistance to acidic medium. Polyelectrolyte complex microspheres were prepared by impregnating heparin in cross-linked chitosan microspheres. The microspheres were characterized by IR, TGA and DSC. A study on the effect of the pH on the adsorption of copper (II) ions showed that the optimum pH for both CS and CSH microspheres was 6.0. From a kinetic evaluation, it could be established that the adsorption equilibrium was achieved after 8 h for CS and 25 h for CSH microspheres. The adsorption isotherms were interpreted using Langmuir and Freundlich mathematical models. The results revealed that experimental data of CS was best adjusted by Langmuir model, with maximum capacity of surface saturation equal to 39.31 mg g⁻¹. On the other hand, Langmuir and Freundlich models provided a good fit for adsorption by CSH and the adsorption capacity was 81.04 mg g⁻¹. The interactions between copper (II) ions and both CS and CSH were confirmed by electron paramagnetic resonance spectroscopy, which revealed the formation of a square-planar complex with tetrahedral distortion on the surface of the adsorbents.     

Controlled release of aspirin from pH‐sensitive chitosan/poly(vinyl alcohol) hydrogel

The aim of this study was to develop a cheap, pH‐sensitive enteric coating of aspirin with biocompatible polymers. A novel approach was used to develop enteric coating from chitosan (CS) and poly(vinyl alcohol) (PVA). Solutions of CS and PVA (5 : 1 mol ratio) were mixed and selectively crosslinked with tetraethoxysilane. IR analysis confirmed the presence of the incorporated components and the existence of siloxane linkages between CS and PVA. The crosslinking percentage and thermal stability increased with increasing amount of crosslinker. The response of the developed coating in different media, such as water, pH (nonbuffer and buffer), and ionic media showed hydrogel properties. All hydrogels showed low swelling in acidic and basic pH media, whereas maximum swelling was exhibited at neutral pH. This pH sensitivity of the hydrogel has been exploited as enteric coating for commercial aspirin tablets. The dissolution test of enteric‐coated aspirin tablet in simulated gastric fluid (pH 1.2) showed 7.11% aspirin release over a period of 2 h, whereas a sustained release of remaining aspirin (83.25%) was observed in simulated intestinal fluid (pH 6.8). © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Electroactive polyacrylamide/chitosan/polypyrrole hydrogel for captopril release controlled by electricity

The demand for the development of new therapies and devices for controlled drug release has been continuously increasing, especially those based on materials sensitives to external stimuli, such as electricity. Therefore, in this work, acrylamide was polymerized in the presence of chitosan (CS), using N,N′-methylenebisacrylamide as cross-linking, followed by immersion in pyrrole aqueous solution and chemical polymerization to obtain an electroactive hydrogel of polyacrylamide/CS/polypyrrole (PA/CS/PPy) (67.5/7.5/25% wt.); this electroactive hydrogel was later used in drug delivery controlled by electricity studies. The synthesized PA/CS/PPy hydrogel was characterized by scanning electron microscopy, FTIR spectroscopy, and thermogravimetric analysis. It was observed that the hydrogel presented pores in the range of 50–200 μm with CS and PPy well incorporated to the cross-linked PA. The hydrogel swelling percentage (S) was determined at different pHs. It was observed that S was independent of pH, with S = 700% and a swelling kinetics described by the Fickian diffusion mechanism at alkaline pH. PA/CS/PPy hydrogel was used to absorb captopril (a drug for hypertension control), and its kinetics release at different applied potentials and pH was studied. Release kinetics were described by the Korsmeyer–Peppas model, while release mechanism was a Case-II transport without current at alkaline pH; under electrical stimuli, the mechanism presented an anomalous transport with ON–OFF profile, increasing the release rate with the applied voltage showing its electroactivity in the captopril release.     

Effect of proteolytic enzymes in gastrointestinal fluids on drug release from polyelectrolyte complex microspheres based on partially phosphorylated chitosan

This study investigated the effect of proteolytic enzymes on in vitro release of ibuprofen from phosphorylated chitosan (PCS) microspheres in simulated gastric fluid (SGF) (pH 1.4) and simulated intestinal fluid (SIF) (pH 7.4). To reduce the enzymatic degradability and to enhance the sustained release property, polyelectrolyte complex microspheres based on PCS were developed and characterized. The ibuprofen release from PCS microspheres was found to be sustained more effectively than that from CS microspheres in the medium containing proteolytic enzymes. It was concluded that the PCS microspheres can be used more successfully as sustained oral drug‐delivery vehicles than CS microspheres due to their lesser enzymatic degradability. Copyright © 2004 Society of Chemical Industry     

Temperature-Sensitive Microspheres for Controlled Release of Enalprilmaleate

Poly(N′-isopropylacrylamide-co–methacryl amide) has been prepared by free-radical emulsion polymerization. The copolymer was transformed into thermoresponsive microspheres by chemical crosslinking with N′, N′ Methylenebis-acrylamide (NNMBA). Enalpril maleate (ENAM), an anti-hypertensive drug, was successfully loaded into these microspheres during in-situ polymerization. DSC and X-RD analysis of the drug-loaded and plain microspheres have confirmed partial dispersion of ENAM in the microspheres. SEM confirmed the spherical nature of the particles with a mean particle size of 100 µm. Drug release profiles of these microspheres exhibited a prolonged release of ENAM for more than 12 h.