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.     

pH-sensitive chitosan/gelatin hybrid polymer network microspheres for delivery of cimetidine

pH responsive chitosan/gelatin hybrid polymer network (HPN) microspheres were prepared via the inverse emulsion crosslinking method. Cimetidine release from the microspheres was studied. The drug only delivers in acidic medium, while the release rate can be controlled by the HPN composition and the degree of deacetylation.     

pH-responsive gelatin microspheres for oral delivery of anticancer drug methotrexate

Multiple unit delivery dosage forms of biodegradable gelatin microspheres containing the anticancer drug methotrexate (GMM) of various mean particle sizes (1–5, 5–10, and 15–20 μm) were prepared by the polymer dispersion technique and were crosslinked with glutaraldehyde. The GMM were coated with biodegradable natural polymers, namely alginate (AGMM) and chitosan (CGMM), which differ in their pH sensitivity, to obtain two different types of pH dependent delivery systems for oral delivery of methotrexate (MTX). The in vitro release profiles of MTX from AGMM and CGMM were determined in simulated gastric medium, intestinal medium, and in media simulating gastrointestinal tract conditions. The effect of the concentration of coating polymer and particle size on the release rate of MTX from both AGMM and CGMM were also studied. Both AGMM and CGMM provided controlled release of MTX following a zero-order release pattern in gastric and intestinal fluids for prolonged periods of time. The release rate of MTX decreased with an increase in concentration of the coating polymer as well as an increase in particle size of the microspheres. Both AGMM and CGMM showed good potential as pH dependent multiple unit delivery systems for the controlled release of MTX in oral administration. © 1995 John Wiley & Sons, Inc.     

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.     

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%.     

Design and development of microparticulate delivery system of metronidazole: Experimental design methodology

This study describes the application of response surface methodology in the optimization of guar gum microspheres for colon‐specific delivery of metronidazole. The effect of varying the relative percent of the four factors used, that is guar gum, glutaraldehyde, swelling time, and stirring speed, has been systematically investigated for identifying their best values to optimize the drug release and encapsulation efficiency as well as to highlight possible interactions among the components. Different batches were prepared according to 2 4 factorial designs and randomly evaluated for drug release and drug encapsulation efficiency. Analysis of response surface plots allowed identification of the best combination of four levels to minimize drug release in upper part of gastrointestinal tract and maximize the encapsulation efficiency. The scanning electron microscopy was used to characterize the surface of these microspheres. Drug polymer interactions were assessed by differential scanning calorimetry and XRD. The good correspondence between calculated and experimental values indicated in the validity of the generated statistical model. Only a small fraction of drug was released at acidic pH; however, the release of drug was found to be higher in the presence of rat cecal contents, indicating the susceptibility of crosslinked guar gum matrix to colonic enzymes released from rat cecal contents. Metronidazole release kinetics corresponds best to zero‐order model and drug release mechanism was diffusion and swelling controlled. The significance of differences was evaluated by analysis of variance (ANOVA). Differences were considered statistically significant at P < 0.05. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Shellac-polyamidoamine: Design of a new polymeric carrier material for controlled release application

The development of a pH sensitive, biodegradable polymer from the combination of Shellac (a natural polymer secreted by lac insect) and polyamidoamine (PAA) (a synthetic polymer) yielded a new biocompatible polymer Shellac-PAA in a photopolymerization process. Scanning electron micrograph of Shellac-PAA shows an interesting heterogeneous surface morphology supported with observation of two different melting temperatures obtained from differential scanning calorimetric measurement. The equilibrium swelling properties of the polymeric material was studied as a function of pH and time in buffer solutions similar to that of gastric and intestinal fluids. The controlled release kinetics of a model colon specific drug 5-aminosalicylic acid showed Fickian diffusion behavior. The new polymer is biocompatible, biodegradable and, hence, projected as a new kind of polymer with improved properties, which can be a potential candidate for controlled release of therapeutic agents in colon specific diseases. © 2012 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

Preparation and characterization of pH sensitive poly(vinyl alcohol)/sodium carboxymethyl cellulose IPN microspheres for in vitro release studies of an anti-cancer drug

Interpenetrating polymeric network microspheres (IPNMs) consisting of poly(vinyl alcohol) and sodium carboxymethylcellulose were prepared by water-in-oil emulsion method and were cross-linked with glutaraldehyde. 5-Fluorouracil (5-FU), an anti-cancer drug, was loaded into IPNMs via in situ method. These IPNMs have been characterized by Fourier transform infrared spectroscopy, which confirms the cross-linking of IPNMs through glutaraldehyde. Differential scanning calorimetry and X-ray diffraction analysis of the drug-loaded IPNMs have confirmed uniform molecular dispersion of 5-FU in the IPNMs. Particle size measured using optical microscopy gave an average size of 80–250 μm. Scanning electron microscopy also confirmed the formation of microspheres with smooth surface and spherical shape. Encapsulation efficiency of 5-FU in these IPNMs was achieved up to 62%. Drug release profiles of the IPNMs at different pH conditions (pH 1.2 and 7.4) confirmed that microspheres formed are pH sensitive, resulting controlled release of drug during in vitro dissolution experiments. It has been analyzed with an empirical equation to understand the diffusion nature of drug through the IPNMs. Both encapsulation efficiency and release patterns are found to depend on the nature of the cross-linking agent as well as amount of drug loading. In vitro release studies indicated the release of 5-FU for more than 10 h.     

Preparation of sodium alginate/poly(vinyl alcohol) blend microspheres for controlled release applications

Sodium alginate (NaAlg)/poly (vinyl alcohol) (PVA) blend microspheres (MS) were prepared by water-in-oil (w/o) emulsion method. These polymer microspheres were crosslinked with glutaraldehyde and loaded with metformin hydrochloride (MHC). The microspheres were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and X-ray diffraction (XRD) analysis to confirm the molecular dispersion of the drug, thermal stability, morphological properties, and crystallinity of the polymer matrix before and after blending. SEM of the microspheres suggested the formation of microspheres in spherical structure. Drug release data were analyzed using an empirical equation to understand the nature of drug transport through polymeric matrices. The controlled release (CR) characteristics of the polymer matrices was investigated in pH 7.4 media and from the results it was obtained that the drug was released in controlled manner up to 10 h. The physico-chemical properties of the microspheres were studied by calculating drug entrapment efficiency and drug release kinetics. Percent of encapsulation efficiency (% EE) decreased with increase in crosslinking agent (GA) and PVA content in the microspheres. The optimum % EE (80%) was observed in case of MS containing 40% of PVA with 15% MHC. The release profiles indicate that the release of MHC decreases with increasing the PVA/NaAlg (w/w) and drug/polymer ratio. At the end of 10 h, the highest release of MHC was found to be 96% for MS containing PVA/NaAlg (40 : 60) and 15 wt % drug loaded. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

The Effect of Polysaccharide Plugs on In Vitro Release Kinetics of Drug From Pulsatile Device and Evaluation of Its In Vivo Targeting Efficiency

The objective was to investigate the effect of different polysaccharide plugs on pulsatile device of Aceclofenac. The Aceclofenac microspheres were prepared in four batches, with Eudragit L-100 and S-100 (1:2) by varying drug to polymer ratio and evaluated for the particle size, drug content, and in vitro release profile and from the obtained results; one better formulation was selected for further fabrication of Pulsatile device. In vitro release mechanism of pulsatile device studied with different kinetics model. The X-ray study on humans pointed out the capability of the system to release drug in colon region.     

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.     

Construction of a sandwich-type wound dressing with pain-reliever and pH-responsive antibiotic delivery system

A multifunctional sandwich type wound dressing was designed in which two types of microspheres, one to alleviate the pain (ibuprofen) and the other to protect the wound from infections (Gentamicin or Ciprofloxacin), were embedded into bilayer chitosan sponge. pH of the wound increases from acidic (pH ~ 5) to basic (pH ~ 8) via infection, so pH-dependent antibiotic release system was designed using gelatin B microspheres to respond to increasing pH. Ibuprofen release from chitosan microspheres, on the other hand, was pH-independent not to intervene with pain management in changing pH conditions. Crosslinking with glutaraldehyde (GA) affected both release profile and size distribution of microspheres and 2.5% GA was chosen to obtain pH-responsive gelatin microspheres with narrow size distribution (80% of microspheres in between 15 and 25 μm). The final system was found to be effective against both Staphylococcus aureus and Escherichia coli and changing pH seemed to affect the antimicrobial agent delivery as desired. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019 , 136, 48252.     

“类乒乓球”状壳聚糖微球对环丙沙星的控制释放性能的研究

以甲醛作为交联剂,通过悬浮交联法得到单分散性的微米级微球。采用分光光度法研究了壳聚糖微球对环丙沙星的载药释药性能,考察了环丙沙星初始浓度、pH、微球粒径大小、载药时间及温度对饱和吸附量的影响。结果表明,在初始浓度为200 mg/L,pH为8.80和时间为65 min,温度为37℃的优化条件下,壳聚糖微球对环丙沙星的载药量最大,最大吸附量为325 mg/g。在pH为7.4,温度为37℃的模拟人体肠胃缓冲溶液(NaH2PO4/NaOH)中研究了初始浓度以及释放时间对释放结果的影响。实验表明,环丙沙星在担载时与环丙沙星的初始浓度有关,浓度越大,担载量越大,但是担载效率和浓度之间无确定的线性关系。在环丙沙星释放初期有明显的释放现象,但是随着时间的推移,药物释放逐渐稳定,释药效率可达97%左右。     

Preparation and Characterization of Carboxymethyl Chitosan and β-Cyclodextrin Microspheres by Spray Drying

Three kinds of carboxymethyl chitosan/β-cyclodextrin microspheres loaded with theophylline were prepared by spray drying intended for pulmonary delivery. Mucociliotoxicity, permeation rate, and drug release characteristics of the product were investigated. The microspheres obtained by spray drying were found to be spherical with smooth or wrinkled surfaces. The mean particle size was between 3.39 and 6.06 µm. The microspheres demonstrated high product yield (43.7-50.2%), high drug loading (13.7-38.1%), and high encapsulation efficiency (86.9-92.8%). FT-IR indicated that there were interactions of theophylline with carboxymethyl chitosan matrix. Further studies on mucociliotoxicity and permeation confirmed that microspheres had better adaptability and high permeation rate. In vitro drug release from the microspheres was not related to the drug/polymer ratios.     

Swelling kinetics,mechanical properties,and release characteristics of chitosan‐based semi‐IPN hydrogels

Two series of pH‐sensitive semi‐interpenetrating network hydrogels (semi‐IPN) based on chitosan (CS) natural polymer and acrylamide (AAm) and/or N‐hydroxymethyl acrylamide (HMA) monomers by varying the monomer and CS ratios were synthesized by free radical chain polymerization. 5‐Fluorouracil (5‐FU), a model anticancer drug, has been added to the feed composition before the polymerization. The characterization of gels indicated that the drug is molecularly dispersed in the polymer matrix. The swelling kinetics of drug‐loaded gels have decreased with increased HMA content at 37°C in both distilled water and buffer solutions with a pH of 2.1 or 7.4. Elastic modulus of the gels increased with the increase in HMA content and higher CS concentration enhanced the elastic modulus positively. Moreover, cumulative release percentages of the gels for 5‐FU were ca. 10% higher in pH 2.1 than those in pH 7.4 media. It was determined that they can be suitable for the use in both gastric and colon environments. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41886.     

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     

Novel blend microspheres of poly(vinyl alcohol) and succinyl chitosan for controlled release of nifedipine

Water-soluble succinyl chitosan (SCS) was synthesized by reacting succinic anhydride with –OH and –NH₂ reactive groups of chitosan (CS). The blend hydrogel microspheres were prepared from SCS with poly(vinyl alcohol) (PVA) by water-in-oil (w/o) emulsion cross-linking using glutaraldehyde (GA) as the cross-linking agent. Nifedipine (NFD), an antihypertensive drug having a plasma half-life of 2 h, was encapsulated giving encapsulation efficiency up to 92 % and its release was extended up to 12 h. Scanning electron microscopy (SEM) confirmed the spherical nature and smooth surfaces of the microspheres, while Fourier transform infrared spectroscopy (FTIR) confirmed succinylation of CS and chemical stability of NFD in the matrix. Thermogravimetry (TGA) and differential scanning calorimetry (DSC) characterized the SCS and the blend hydrogel microspheres. X-ray diffraction (XRD) and DSC were also used to study the crystalline or amorphous nature of NFD. Swelling and in vitro release experiments performed in pH 1.2 and 7.4 buffer media showed a dependence of blend composition, extent of cross-linking and pH of the media. The mechanism of drug release as analyzed by an empirical equation, suggested non-Fickian trends.     

Preparation and Characterization of Carboxymethyl Chitosan and β-Cyclodextrin Microspheres by Spray Drying

Three kinds of carboxymethyl chitosan/β-cyclodextrin microspheres loaded with theophylline were prepared by spray drying intended for pulmonary delivery. Mucociliotoxicity, permeation rate, and drug release characteristics of the product were investigated. The microspheres obtained by spray drying were found to be spherical with smooth or wrinkled surfaces. The mean particle size was between 3.39 and 6.06 µm. The microspheres demonstrated high product yield (43.7–50.2%), high drug loading (13.7–38.1%), and high encapsulation efficiency (86.9–92.8%). FT-IR indicated that there were interactions of theophylline with carboxymethyl chitosan matrix. Further studies on mucociliotoxicity and permeation confirmed that microspheres had better adaptability and high permeation rate. In vitro drug release from the microspheres was not related to the drug/polymer ratios.     

Poly(L‐histidine)‐chitosan/alginate complex microcapsule as a novel drug delivery agent

Novel poly(L ‐histidine)‐chitosan/alginate complex microcapsules were prepared from biodegradable polymers poly(L ‐histidine) (PLHis) in the presence of chitosan at acetate buffer solution pH 4.6. Microcapsules obtained are spherical and well‐dispersed with a smooth surface and a narrow size distribution. The microcapsules can encapsulate the protein model drug hemoglobin (Hb) efficiently. The results show that the complex microcapsules with low, medium, or high molecular weight of chitosan (0.05%, w/v), the highest encapsulation efficiencies obtained are 91.3%, 85.9%, and 94.2% with loading efficiencies of 47.8%, 44.3%, and 39.7%, respectively. The release profiles indicate that Hb‐loaded microcapsules conform to first‐order release kinetic in whole procedure, and 84.8%, 71.4%, and 87.3% of Hb were released during 72‐h incubation in PBS pH6.8 for microcapsules with low, medium, and high molecular weight chitosan (0.05%, w/v), respectively. The results also indicate that particle size and drug loading efficiency have a significant influence on the release profile and encapsulation efficiency. Our results reveal that the PLHis‐chitosan/alginate complex microcapsules are able to encapsulate and release Hb and are potential carriers for protein drugs. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2012     

APPLICATION OF A DISSOLUTION-DIFFUSION MODEL TO THE RELEASE OF 5-FLUOROURACIL FROM POLYMER MICROSPHERES

A theoretical discussion of drug release from microspheres is provided and a model-based predictive algorithm developed. The model verification step includes literature data describing the release profile of 5-fluorouracil (5-FU) from poly(lactic acid) polymer. Material balance equations were written to describe drug transport from a porous sphere. The model included combined effects of dissolution, diffusion, and void fraction on the release of 5-FU and was validated against in vitro experimental data. Analyses, conducted on published 5-FU release test data, revealed that the process was governed by a dissolution-diffusion mechanism. Approximately 1.5 million microspheres were formed; the drug density, diffusivity, and dissolution rate constant were estimated at 1.110 g/cm³, 2.324 × 10^?15 m²/s, and 17.60 g/m³h, respectively. The dissolution rate was faster than the rate of diffusion by a ratio of 12.79 to 1. Manipulation of the microsphere porosity was an effective way to influence the diffusion-controlled process. The procedure, outlined in the study, for estimating process properties will help fabricate microspheres that meet specific requirements.