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.     

Sustained release of ganciclovir from poly(lactide-co-glycolide) microspheres

Biodegradable poly(lactide-co-glycolide) microspheres loaded with ganciclovir were produced using the emulsification/solvent evaporation technique. The effects of drug-to-polymer ratio and dispersion time on the drug content in the microspheres were investigated. The release rate of the drug was studied for 20 weeks in a phosphate buffered solution of pH 7 at 37°C. Data revealed that lower drug content was obtained with increasing drug-to-polymer ratio and decreasing dispersion time. The release of the drug followed a triphasic release pattern, i.e. an initial burst, a diffusive phase and a second burst. The initial burst occurred within the first 2 days of immersion. After the burst, the release was by diffusion for up to 13 weeks, followed by another burst release, which signals the onset of bulk degradation of the polymer. Gel permeation chromatography (GPC), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and ultraviolet spectroscopy (UV) were used to follow the hydrolytic degradation and drug release rate of the microspheres.     

The release of diazepam from poly(hydroxybutyrate-hydroxyvalerate) microspheres

Microspheres based on a poly(hydroxybutyrate-hydroxyvalerate) copolymer (PHBV) (Mw = 630 kD, 21% mol HV) were loaded with diazepam using different emulsion-solvent evaporation processes. Gelatin was used as a strategy to alter the release profile of the incorporated drug. The mean diameter of microspheres was from 30-40 micron. Drug-release from the microspheres over a 30-day period showed a characteristic triphasic release pattern with an initial burst effect, but was linear over the same period and without a burst effect when gelatin was used as a coating agent. Scanning electron microscopy revealed that the microspheres had different structures depending upon their method of preparation.     

Sustained release of ganciclovir from poly(lactide-co-glycolide) microspheres

Biodegradable poly(lactide-co-glycolide) microspheres loaded with ganciclovir were produced using the emulsification/solvent evaporation technique. The effects of drug-to-polymer ratio and dispersion time on the drug content in the microspheres were investigated. The release rate of the drug was studied for 20 weeks in a phosphate buffered solution of pH 7 at 37 degrees C. Data revealed that lower drug content was obtained with increasing drug-to-polymer ratio and decreasing dispersion time. The release of the drug followed a triphasic release pattern, i.e. an initial burst, a diffusive phase and a second burst. The initial burst occurred within the first 2 days of immersion. After the burst, the release was by diffusion for up to 13 weeks, followed by another burst release, which signals the onset of bulk degradation of the polymer. Gel permeation chromatography (GPC), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and ultraviolet spectroscopy (UV) were used to follow the hydrolytic degradation and drug release rate of the microspheres.     

The release of diazepam from poly(hydroxybutyrate-hydroxyvalerate) microspheres

Microspheres based on a poly(hydroxybutyrate-hydroxyvalerate) copolymer (PHBV) (Mw = 630kD, 21% mol HV) were loaded with diazepam using different emulsion-solvent evaporation processes. Gelatin was used as a strategy to alter the release profile of the incorporated drug. The mean diameter of microspheres was from 30-40 micron. Drug-release from the microspheres over a 30-day period showed a characteristic triphasic release pattern with an initial burst effect, but was linear over the same period and without a burst effect when gelatin was used as a coating agent. Scanning electron microscopy revealed that the microspheres had different structures depending upon their method of preparation.     

All-trans-retinoic acid release from core-shell type nanoparticles of poly(epsilon-caprolactone)/poly(ethylene glycol) diblock copolymer

Poly(epsilon-caprolactone)/poly(ethylene glycol) (abbreviated as CE) diblock copolymers were synthesized to make core-shell type nanoparticles for all-trans-retinoic acid (atRA). Fluorescence spectroscopy showed that critical association concentration (CAC) value decreased at higher MW of CE diblock copolymer. Drug loading characteristics were studied under various experimental conditions. Drug contents and loading efficiency increased as the MW of poly(epsilon-caprolactone) (PCL) block of CE and initial drug feeding amount increased. Solvent used and preparation method also affected drug contents and loading efficiency. According to 1H NMR using CDCl3 and D2O, specific peaks of the PCL block and drug appearing in CDCl3, disappeared at D2O, suggesting hydrophobic core with hydrophilic shell formed in water. atRA release was faster at smaller MW of copolymer and lower drug contents. Nanoparticles prepared in DMF showed faster release rate compared with those prepared in THF or acetone. Cytotoxicity of atRA against U87MG, U251MG and U343MG cell lines were increased by nanoencapsulation while empty nanoparticles of CE diblock copolymer were not significantly affected.     

The initial release of cisplatin from poly(lactide-co-glycolide) microspheres

PLGA microspheres loaded with cisplatin were produced using a single emulsion method. A semi-empirical model, with bi-exponential terms, was found to give a better fit to the drug release profiles compared to a mono-exponential model. This model suggests that there are two separate fractions of drug present in the depot. A fraction of the drug is located near/at the surface of the depot, and is readily released during immersion in buffer. A second fraction of drug is entrapped deeper within the depot and is subsequently released. It was also found that the initial release of cisplatin from PLGA microsphere is highly diffusion-controlled and the classical Higuchi model provides a good fit. From studies of water diffusion using PFG-NMR, results suggested that 50:50 PLGA microsphere was most susceptible to swelling and this might have promoted the faster initial drug release. Results from NMR cryoporometry also indicated that the developed PLGA microspheres could have “ink-bottle” pores.     

Controlled transdermal iontophoresis of sulfosalicylic acid from polypyrrole/poly(acrylic acid) hydrogel

A conductive polymer–hydrogel blend between sulfosalicylic acid-doped polypyrrole (PPy) and poly(acrylic acid) (PAA) was used as a carrier/matrix for the transdermal drug delivery under applied electrical field. PAA films and the blend films were prepared by solution casting with ethylene glycol dimethacrylate (EGDMA) as a cross-linking agent, followed by the blending of PPy particles and the PAA matrix. The effects of cross-linking ratio and electric field strength on the diffusion of the drug from PAA and PPy/PAA hydrogels were investigated using a modified Franz-diffusion cell with an acetate buffer of pH 5.5 and at 37 °C, for a period of 48 h. The diffusion coefficient of the drug is calculated using the Higuchi equation, with and without an electric field, at various cross-linking ratios. The drug diffusion coefficient decreases with increasing drug size/mesh size ratio, irrespective of the presence of the conductive polymer as the drug carrier. The diffusion coefficient, at the applied electric field of 1.0 V, becomes larger by an order of magnitude relative to those without the electric field.     

Control of gentamicin release from a calcium phosphate cement by admixed poly(acrylic acid)

The aim of this work was to develop a calcium phosphate cement (CPC) providing controlled release of the antibiotic gentamicin sulfate (GS) over at least 1 week. The CPC was made of beta-tricalcium phosphate [beta-TCP; beta-Ca(3)(PO(4))(2)], monocalcium phosphate monohydrate [MCPM; Ca(H(2)PO(4))(2). H(2)O] and water. Release of GS was controlled by admixture of poly(acrylic acid) (PAA). The effects on the GS release kinetics of the molecular weight of PAA, of the amount of admixed PAA, and of the pH of the release medium were investigated. A typical cement sample weighed 3.6 g and contained 100 mg of GS and between 0 and 150 mg of PAA. In the following, PAA content is expressed as the weight ratio, lambda, with respect to GS. At a low PAA content in the CPC (lambda < 0.7), GS was released over 1-2 days according to a square-root-of-time kinetics, but not all GS was released. The unreleased GS fraction increased from 0 to 58% with an increase of PAA content (up to lambda = 0.7). At high PAA content (lambda > 0.7), GS was released over a period of up to 8 days according to a combination of a square-root-of-time and a zero-order kinetics. The total GS fraction released increased again from 58 to 100% with an increase of the amount of PAA (up to lambda = 1.5). These observations were explained by molecular interaction between PAA and GS resulting in gel formation. The maximum fraction of GS released from the cement was indeed a function of the solubility of the PAA-GS (coacervate) complex in the release medium. Thus, GS release was controlled by two mechanisms: (1) diffusion of free GS molecules through the porous cement (square-root-of-time kinetics); and (2) dissociation of GS from the PAA-GS complex (zero-order kinetics). The first mechanism was predominant at low lambda, whereas the second mechanism became important at high lambda and later release times. As the solubility of the PAA-GS complex decreased with an increase in PAA molecular weight, the higher molecular weight PAA yielded more prolonged release periods of up to 8 days. Interestingly, the use of 450 kDa PAA at lambda = 1.00 provided an almost constant release profile over a period of 7 days. Gel formation between PAA and GS was explained in terms of hydrogen bonding of PAA carboxyl groups with GS amino groups. The molar ratio between carboxyl groups and amino groups in the gel was estimated to be approximately 1.9. In conclusion, admixture of PAA into calcium phosphate cement appeared to be a very elegant tool to control the release of the antibiotic over a period of 7 to 8 days.     

阿司匹林聚乳酸微球的体外加速释放试验

目的:考察不同载药量的阿司匹林聚乳酸微球在不同温度下的体外释药行为,建立体外加速释放试验方法.方法:用紫外分光光度法测定微球中阿司匹林药物含量,由聚乳酸玻璃化温度确定释放介质温度,在pH 7.4磷酸缓冲溶液中,考察温度及载药量对微球释药速度的影响.通过相关性评价建立加速与长期释放度数据的回归方程.结果:加速释放与长期累积释放数据之间线性相关性良好(r=0.999 8).不同载药微球在不同温度下释放动力学均符合一级释药方程,在pH 7.4条件下,55℃的加速释放与在37℃的长期释放相关性好.结论:阿司匹林聚乳酸微球的释放与温度有关.采用高于聚乳酸玻璃化温度2～3℃的体外加速试验方法可适用于快速考察微球的体外释放行为.微球载药量不影响加速释放行为.     

Development of poly(Lactic acid)/chitosan co-matrix microspheres: controlled release of taxol-heparin for preventing restenosis

Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Controlled release of appropriate drugs alone and in combinations is one approach for treating coronary obstructions, balloon angioplasty, restenosis associated with thrombosis, and calcification. We demonstrated the possibility of encapsulating taxol-loaded polylactic acid (PLA) microspheres within heparin-chitosan spheres to develop a prolonged release co-matrix form. The in vitro release profile of taxol and heparin from this co-matrix system was monitored in phosphate buffered saline pH 7.4, using an ultraviolet spectrophotometer. The amount of taxol/heparin release was initially much higher, followed by a constant slow release profile for a prolonged period. The initial burst release of taxol (15.8%) and heparin (32.7%) from the co-matrix was modified with polyethylene glycol coatings (13.5% and 25.4%, respectively, for 24 hr). From scanning electron microscopy studies, it appears that these drugs diffuse out slowly to the dissolution medium through the micropores of the co-matrix. However, the surface micropores were modified with polyethylene glycol (PEG) coatings for a constant slow release profile. This PEG-coated PLA/chitosan co-matrix may target drug combinations having synergestic effects for prolonged periods to treat restenosis.     

Influence of ionic strength on drug adsorption onto and release from a poly(acrylic acid) grafted poly(vinylidene fluoride) membrane

Ion exchange resins have several applications in pharmacy for controlled or sustained release of drugs. In the present study, effects of the ionic strengths of adsorption medium and dissolution medium on drug adsorption onto and release from a acrylic acid grafted poly(vinylidene fluoride) (PAA-PVDF) were studied. Despite their porosity, PAA-PVDF membranes act reasonable well as cation exchange membranes. It was observed, that ionic strength of adsorption medium, degree of grafting and concentration of propranolol-HCl in adsorption medium affect propranolol-HCl adsorption onto the membrane. The fluxes of smaller molecules (MW < 500) across the membrane decreased with ionic strength of buffer solution, whereas the fluxes of the large molecules (FITC-dextran, MW 4400) increased with ionic strength. Release rate of adsorbed propranolol-HCl from the membrane into phosphate buffer was greatly affected by ionic strength of adsorption medium. These results can be explained by a cation exchange process between membrane and cations present in the buffer solution and swelling behavior of the grafted PAA chains.     

Investigations into the structure and composition of β-cyclodextrin/poly(acrylic acid) microspheres

Microspheres composed of the hydrophilic polymer poly(acrylic acid) (PAA), with and without β-cyclodextrin (β-CD), were prepared by a water-in-oil (w/o) solvent evaporation technique. Microspheres were characterised for particle size, β-CD and residual oil content. The type of matrix formed during microsphere synthesis was investigated by solid state carbon ¹³C NMR, in vitro release of β-CD and swelling measurements. A high encapsulation efficiency of the β-CD was observed (>90%). The in vitro release of β-CD in water over 24 h was initially rapid (≈70% in 3 h) with no further loss thereafter, suggesting potential covalent binding of the residual β-CD. NMR indicated that in the presence of β-CD, two concomitant chemical processes occur during microsphere synthesis: (i) esterification of the hydroxyl group(s) of the β-CD with the carboxylic acid groups of the PAA; and (ii) the formation of intra-/inter-polymer acid anhydrides.     

Template-assisted synthesis of nanogels from Pluronic-modified poly(acrylic acid)

A series of novel polymeric nanogels with core-shell morphology was developed. Block ionomer complexes of comb-graft poly(ethylene oxide)-b-poly(polypropylene oxide)-b-poly(ethylene oxide)-g-poly(acrylic acid) copolymers (Pluronic-PAA) and divalent metal cations were utilized as micellar templates for the synthesis of nanogels with sizes ranging from 100 to 200 nm in diameter. The Pluronic-PAA nanogels were confirmed to possess ionic cross-linked PAA cores and flexible hydrophilic shells from the Pluronic copolymer chains. The ionic character of the core provided for pH-dependent swelling/collapse behavior of the nanogels. These prepared nanogels are expected to be of utility as carriers for charged therapeutic or diagnostic agents.     

Template-assisted synthesis of nanogels from Pluronic-modified poly(acrylic acid)

A series of novel polymeric nanogels with core-shell morphology was developed. Block ionomer complexes of comb-graft poly(ethylene oxide)-b-poly(polypropylene oxide)-b-poly(ethylene oxide)-g-poly(acrylic acid) copolymers (Pluronic-PAA) and divalent metal cations were utilized as micellar templates for the synthesis of nanogels with sizes ranging from 100 to 200 nm in diameter. The Pluronic-PAA nanogels were confirmed to possess ionic cross-linked PAA cores and flexible hydrophilic shells from the Pluronic copolymer chains. The ionic character of the core provided for pH-dependent swelling/collapse behavior of the nanogels. These prepared nanogels are expected to be of utility as carriers for charged therapeutic or diagnostic agents.     

Formulation and release characteristics of poly(lactic-co-glycolic acid) microspheres containing chemically modified protein

Chemical modification of proteins may influence their formulation into and release from polymeric microspheres. Three chemical modifications of rat serum albumin (RSA) were effected on the amine groups of this protein: conjugation with a polyanion using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide, intermolecular cross-linking using glutaraldehyde, and reductive alkylation using propyl aldehyde. The modified proteins had different physicochemical properties as well as improved encapsulation efficiencies compared with native RSA microspheres. The microspheres were incubated at 37 degrees C for over one month to investigate the influence of protein modification on the release profiles. Microsphere degradation accelerated from the ninth day of the release studies and this coincided with an increase in the release rates. The degradation rates of poly(lactic-co-glycolic acid) microspheres containing either native or cross-linked RSA were more rapid than those containing either heparin conjugated or propylated RSA. This was in agreement with the release data, since the release of the native and cross-linked RSA were more rapid than those of the other modified proteins. The release profiles of the RSA-heparin conjugates and the propylated RSA were approximately zero rather than first order between the tenth and thirtieth day of study. Chemical modification of protein may be a useful method to increase encapsulation efficiency and to decrease release rates of proteins that are to be used in microsphere formulations of potent therapeutic proteins.     

Controlled release of interleukin-2 from chitosan microspheres

Chitosan microspheres were evaluated for sustained-release of recombinant human interleukin-2 (rIL-2) in this study. In addition, the effects of different formulation factors, such as chitosan and protein concentrations, the volume of sodium sulfate solution, addition technique of rIL-2, and presence of glutaraldehyde during the encapsulation process, on microsphere characteristics were investigated. Chitosan microspheres containing rIL-2 were prepared by using the precipitation technique. The average diameter of microspheres was between 1.11-1.59 microm. Recombinant IL-2 encapsulation efficiency in these microspheres was high (75-98%). Formulation factors had no effect on the microsphere size. Recombinant IL-2 had been released from chitosan microspheres over a period of 3 months. The encapsulated rIL-2 remained biologically active and could be completely recovered from the release medium. Briefly, rIL-2 was released from chitosan microspheres in a sustained manner. The efficacy of rIL-2 loaded chitosan microspheres was studied using two model cells, HeLa and L-strain cell lines. Chitosan microspheres were added to the cells at different concentrations, and the amount of rIL-2 was assayed using the ELISA kit. Cell culture studies indicated that microspheres were uptaken by cells, and rIL-2 was released from the microspheres. Cellular uptake of rIL-2-loaded microspheres was dose dependent. It can be said that chitosan microsphere is a suitable carrier for rIL-2 delivery.     

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.     

Biodegradable poly(DL-lactic-co-glycolic acid) microspheres containing tetracaine hydrochloride. In-vitro release profile

Tetracaine does not result in effective treatment of intractable pain caused by trigeminal neuralgiabecause of its short duration of effect. In asustained release system a controlled delivery of the drug at the site of administration, would avoid successive administrations. Tetracaine hydrochloride (HCl) has been encapsulated using a technique based on the evaporation of solvent from an O/O emulsion, using poly(dl-lactic-co-glycolic acid) (PLGA) 50:50. Microspheres were separated into three fractions: 106-212, 212-300 and 300-425mum. The effects of two variables of the manufacturing method (volume of the inner phase of the emulsion and volume of surfactant added to the external phase) on the drug loading into microspheres, dissolution profiles and SEM characterization of the microspheres were evaluated. Microspheres containing tetracaine hydrochloride (up to94% referred tothe theoretical) released the drug, in-vitro, over 35 days. Tetracaine HCl was delivered according to zero order kinetics from day 5 until the end of the release assay. The rate of drug release depended mainly on the viscosity of the discontinuous phase and on the size of microparticles. Microsphere size resulted more homogeneous when using the highest volume of the surfactant, being almost 80% of microparticles within the range 212-300mum.