Study on physiochemical structure and in vitro release behaviors of doxycycline‐loaded PCL microspheres

This study aimed to develop drug delivery system of doxycycline‐loaded polycaprolactone (PCL) microspheres. The investigated microsphere formulation can be considered for local application in bone infections and degenerative joint diseases, which generally require long‐term treatments via systemic drugs. PCL‐14 kDa and 65 kDa were used in microsphere preparation. Before release, the microspheres were characterized by scanning electron microscopy, differential scanning calorimetry, and X‐ray photoelectron spectroscopy. The mean particle size of microspheres was in the range of 74–122 µm and their drug loadings ranged between 10 and 30%. In vitro release profiles were described using the Higuchi and the Korsmeyer–Peppas equations. Diffusion model was applied to experimental data for estimating diffusion coefficients of microspheres; calculated as between 4.5 × 10^?10 and 9.5 × 10^?10 cm²/s. Although long‐term release from microspheres of PCL‐14 kDa obeyed diffusion model, PCL‐65 kDa microspheres showed this tendency only for some period. Modeling studies showed that the drug release mechanism was mainly dependent on loading and molecular weight differences. Release behavior of PCL‐65 kDa microspheres, however, might be better represented by derivation of a different equation to model for the total release period. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41768     

The single-step synthesis of thiol-functionalized phosphazene-based polymeric microspheres as drug carrier

ABSTRACT

Herein, new microspheres were successfully fabricated from pentaerythritol tetrakis(3-mercaptopropionate) as model monomer and hexachlorocyclotriphosphazene as crosslinker using a single-step via precipitation polymerization method. Trimethoprim was chosen as the model antibiotic drug for drug release and antimicrobial activity studies. The percent of drug loading and drug entrapment efficiency of the microspheres was calculated to be 0.85% and 42.2%. According to correlation coefficients, the release kinetic was found to be Higuchi kinetic model and the release mechanism was non-Fickian model for microspheres. The drug-loaded microspheres exhibited excellent bacterial inhibition against gram-positive (Staphylococcus aureus and Bacillus subtilis) and gram-negative (Escherichia coli) bacteria.     

Degradability and antigen-release characteristics of polyester microspheres prepared from polymer blends

Biodegradable microspheres were prepared to function as a depot system for the controlled release of a model protein antigen bovine serum albumin (BSA). As an approach to achieve its controlled release, microspheres were fabricated blending a high-molecular-weight poly-d,l-lactide-co-glycolide (M_w = 61,000) with a low-molecular-weight poly-d,l-lactic acid (M_w = 2000, PLA2000). The effects of PLA2000 on microsphere degradability and release characteristics of BSA from microspheres were investigated. On the basis of the pH change in microsphere suspensions and water uptake of microspheres, the kinetics of microsphere degradation was derived to describe the rate of formation of hydrogen ions due to hydrolysis of ester linkages of polymers. It substantiated that PLA2000-containing microspheres were subject to controlled degradation that was necessary to achieve continuous release profiles of the antigen. Immunization of rabbits by subcutaneous injection of BSA-containing microspheres enhanced the antigenicity of BSA, and significantly increased the duration of humoral immune responses. © 1995 John Wiley & Sons, Inc.     

Influence of microstructure of lactone‐based triblock copolymers on drug release behavior of their microspheres

The current work focuses on the influence of microstructure of different lactone‐based triblock copolymers on drug delivery, where the middle segment was δ‐valerolactone or ?‐caprolactone and the terminal segment was d ,l ‐lactide or cis ‐lactide. Microspheres were fabricated from the triblocks using salicylic acid as the model drug. The microsphere formation and drug release were investigated by scanning electron microscopy, ultraviolet–visible spectroscopy, X‐ray diffraction, and thermogravimetry. The size of the microspheres ranged from 2 to 20 µm in diameter. The diffusion coefficient values showed that replacement of the middle segment, δ‐valerolactone with ?‐caprolactone, retarded the diffusion of the drug molecules. The diffusion coefficient was lowered when d ,l ‐lactide content was decreased in the triblock. Mathematical models were used to predict the drug release from the microspheres of different triblocks. The modeling study on drug release profiles revealed that the biodegradable nature of the triblock played a crucial role in determining the drug release kinetics. The diffusion and degradation reaction justified the drug release from microsphere. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134 , 45284.     

Preparation and the controlled release effect study of graphene oxide-modified poly(ε-caprolactone)

Functionalized graphene oxide-modified poly(ε-caprolactone) composites ((graphene oxide)GO/PCL) were successfully synthesized by Steglich esterification for drug applications of controlled release. Lomefloxacin (LMF) was selected as a model drug to investigate its controlled release properties. The controlled release effect of the LMF-contained pills of the GO/PCL and polylactic acid blend was evaluated. In contrast to the pure PCL, GO/PCL could effectively adjust the time of drug release and release the drug at a constant rate, achieving the controlled release requirements. Furthermore, different additive amounts of graphene oxide have different effects on adjusting the time of controlled release, while the best result obtained under the ratio is 4% GO/PCL as carrier of drug. Thus, high-quality drug carrier materials are obtained which are more suitable for clinical use. Exploring the optimum addition of graphene oxide is very significant for the development of GO/PCL carrier material.     

Preparation of injectable paclitaxel sustained release microspheres by spray drying for inhibition of glioma in vitro

The major aim of this work was to prepare injectable paclitaxel‐loaded poly(D ,L ‐lactide) microspheres for the inhibition of brain glioma. Paclitaxel‐loaded PLA microspheres were prepared by spray drying method employing ethyl acetate as solvent. And the microspheres were characterized by scanning electron microscopy (SEM) for the morphology and differential scanning calorimetry for thermal analysis. The encapsulation efficiency (EE) and in vitro release profiles of paclitaxel‐loaded microspheres were determined by using ultraviolet spectrophotometer. The results showed that the microspheres possess a narrow size distribution with the average diameter of 4.6 μm. The surface of the microspheres was smooth, and the paclitaxel dispersed in microspheres in amorphous state. The solvent residue was 0.03%, and the EE reaches ～ 90%. The microspheres exhibited a sustained release behavior, and the release period last for at least three months, depending on the EE of the microspheres. The γ irradiation sterilization had little effect on the EE and drug release in vitro. Compared with the commercial formulation, the sustained release microsphere showed a stronger inhibition on the tumor cells, suggesting the potential application of long‐term delivery of paclitaxel‐loaded PLA microspheres in clinic tumor therapy. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Development of a novel smart carrier for drug delivery: Ciprofloxacin loaded vaterite/reduced graphene oxide/PCL composite coating on TiO2 nanotube coated titanium

In the field of orthopaedic implants, post-surgery infections and biocompatibility are the most challenging obstacles. Sustained and controlled antibiotic release is a key factor in novel drug delivery systems. A novel drug delivery system combined with vaterite microsphere, graphite oxide (GO), reduced graphene oxide (rGO) incorporated in a polycaprolactone (PCL) matrix on TiO₂ nanotube coated Ti (TNT-Ti) is established. Anodization was employed to develop TiO₂ nanotubular arrays on Ti. Ciprofloxacin hydrochloride (CPF–HCl) loaded vaterite microspheres were synthesized by in situ precipitation method. Deposition of vaterite/PCL, vaterite-GO/PCL and vaterite-rGO/PCL composite coating on TNT-Ti was carried out by dip coating method. The composite coatings were characterized for their phase content, morphological features and functional groups. Among the three types of composite coatings, vaterite-rGO/PCL composite coating is found to be capable of encapsulating CPF-HCl to a level of 75.14 μg. The drug release profile of CPF-HCl from the vaterite-rGO/PCL composite coating exhibits a controlled release amounting to only 35.02 % of release at the end of 120 h. The vaterite-rGO/PCL composite coating exhibits a low dissolution rate and possesses adequate bioactivity in HBSS and SBF solutions at 37 °C for 14 and 10 days, respectively. The in situ loaded CPF-HCL drug on vaterite microspheres, PCL polymer matrix and GO/rGO nanofillers does not affect the cytocompatibility and all the composite coatings supported cell viability and proliferation. The ability of vaterite-rGO/PCL composite coating to provide a slow and steady release of antibiotics with sufficient bioactivity and biocompatibility at the tissue implant interface makes it a promising for osteomyelitis infection of bone tissue implant materials.     

Preparation of carbon dioxide/propylene oxide/ε-caprolactone copolymers and their drug release behaviors

Summary Poly (propylene-ram-ε-caprolactone carbonate) (PPCL) and poly (propylene carbonate) (PPC) were synthesized by ring-opening copolymerization from carbon dioxide, propylene oxide (PO) and ε-caprolactone (CL) using a polymer-supported bimetallic complexes (PBM) as catalyst. PPC and PPCL microspheres containing a 5-alpha reductase inhibitor, finasteride were elaborated by a conventional oil-in-water (O/W) emulsion-solvent evaporation method. The effects of polymer used on microspheres morphology, size, drug loading, encapsulation efficiency and drug release behaviors were examined. In vitro drug release of these microcapsules was performed in a pH 7.4 phosphate-buffered solution. A prolonged in vitro drug release profile was observed. The release profiles of finasteride from PPC and PPCL microcapsules were found to occur with a burst release followed by a gradual release phase. Drug release rates were dependent upon the properties of the polymer in the microspheres, the higher hydrolytic activity of polymer provided faster release rate.     

Span 60 as a Microsphere Matrix: Preparation and in Vitro Characterization of Novel Ibuprofen-Span 60 Microspheres

Microspheres are a potential delivery system for controlled and sustained drug release. Polymeric microspheres are commonly prepared by the solvent evaporation technique whereas waxy microspheres by the melt dispersion technique. The goal of this study was to prepare a surfactant (Span 60)—Ibuprofen microspheres using both techniques. Ibuprofen‐Span 60 microspheres were fabricated with different drug to polymer weight ratios of 3:1, 1:1 and 1:3 and characterized by particle size, in vitro dissolution, infrared spectroscopy, x‐ray diffraction and scanning electron microscopy. The actual drug content increased with increasing the concentration of anti‐aggregating agent (polyvinylpyrolidone). The actual drug content and drug encapsulation efficiency was markedly higher in case of microspheres prepared by a solvent evaporation technique compared to that prepared by a melt dispersion one using the same theoretical drug content. The microspheres were spherical with irregular surfaces. The in vitro release showed no burst effect and incomplete drug release. The rate and total drug released from the microspheres prepared by a solvent evaporation technique are higher than those prepared by using the melt dispersion technique. FTIR rolled out the chemical changes of the drug in Span 60 microspheres. The X‐ray diffraction pattern of the microspheres prepared by using a solvent evaporation technique showed a decrease in the drug crystallinity. The drug crystallinity in microspheres prepared by the melt dispersion technique decreased with increasing the theoretical drug content. The drug entrapment mechanism is responsible for the changes in drug physicochemical properties and in vitro release.     

Fabrication and drug release properties of poly(5‐benzyloxy‐trimethylene‐co‐glycolide) microspheres

Poly(5‐benzyloxy‐trimethylene carbonate‐co‐glycolide) random copolymers were synthesized through the ring‐opening polymerization of 5‐benzyloxy‐trimethylene carbonate and glycolide (GA). The copolymers with different compositions, PBG‐1 with 17% GA units and PBG‐2 with 45% GA units, were obtained. Using these copolymers, microsphere drug delivery systems with submicron sizes were fabricated using an “ultrasonic assisted precipitation method.” The in‐vitro drug release from these microspheres was investigated. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Fabrication and structural regulation of PLLA porous microspheres via phase inversion emulsion and thermally induced phase separation techniques

In this work, a facile, scalable technique was developed to produce biodegradable porous microspheres by combining an oil‐in‐oil (O/O) surfactant‐free phase inversion emulsion technique with thermally induced phase separation (TIPS) method. The effects of PLLA concentration, stirring speed, macromolecule weight, and organic solvents on the size and microstructure of microspheres were investigated by scanning electron microscopy (SEM). The results revealed a highly porous structured microsphere with controllable sizes and morphologies by tuning the synthesis conditions. The typical resulting PLLA microspheres consist of nanoscale topographic structured surface and highly microporous interior. The coarse nanotopography and microcellular inner structure lead to a high drug loading capacity up to 60% for the PLLA microspheres from THF. The cumulative release percentage of the ibuprofen could reach 80% for drug‐loaded microspheres with different microstructures. The fabricated PLLA microspheres would have potential applications in the field of drug delivery and tissue engineering. © 2017 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2017 , 134, 44885.     

PCL/poloxamer 188 blend microsphere for paclitaxel delivery: Influence of poloxamer 188 on morphology and drug release

A novel controlled release system, paclitaxel‐loaded poly (ε‐caprolactone) (PCL)/poloxamer 188 (Pluronic F68, F68) blend microspheres is proposed in the present work. F68 was incorporated into PCL matrices as both a pore‐forming agent and a drug releasing enhancer. Paclitaxel‐loaded PCL/F68 blend microspheres with different amounts of F68 were prepared by the oil‐in water (O/W) emulsion/solvent evaporation method. Characterization of the microspheres followed to examine the particle size, the drug encapsulation efficiency, the surface morphology, and in vitro release behavior. The influences of F68 on microsphere morphology and paclitaxel release are discussed. The porosity of the surface of PCL/F68 blend microspheres and the release rate of paclitaxel from the PCL/F68 blend microspheres increased as the initial amount of blended F68 increased. Faster and controlled release was achieved in comparison with the PCL microspheres. Through this study, the developed microporous PCL/F68 blend microspheres could be used as a drug delivery system to enhance and control drug release in the future. © 2007 Wiley Periodicals, Inc. JAppl Polym Sci 104: 1895–1899, 2007     

Release of indomethacin from a novel chitosan microsphere prepared by a naturally occurring crosslinker: Examination of crosslinking and polycation–anionic drug interaction

Novel chitosan microspheres with lower cytotoxicity were fabricated in this study and their drug release characteristics were investigated. Genipin, a naturally occurring crosslinking reagent that has been used in herbal medicine and in the production of food dye, was used to prepare crosslinked chitosan microspheres by a water‐in‐oil dispersion method. The crosslinking mechanism examined by FTIR and ¹³C–NMR suggests that the crosslinking of chitosan by genipin leads to the formation of secondary amide and heterocyclic amino linkage. The polycation–anionic drug interaction between chitosan and indomethacin was pH dependent and could affect the dissolution property of indomethacin. By examination of the release profiles of the crosslinked chitosan microsphere, it was found that the release of indomethacin from the microsphere was sustainable and influenced by factors such as crosslinking of microsphere and chitosan–indomethacin interaction, thus establishing crosslinked chitosan microsphere as a very promising polymeric carrier for drug release. © 2001 John Wiley & Sons, Inc. J Appl Polym Sci 81: 1700–1711, 2001     

Preparation and evaluation of cellulose acetate butyrate and poly(ethylene oxide) blend microspheres for gastroretentive floating delivery of repaglinide

In this study, hollow microspheres of cellulose acetate butyrate (CAB) and poly(ethylene oxide) (PEO) were prepared by emulsion–solvent evaporation method. Repaglinide was successfully encapsulated into floating microspheres. Various formulations were prepared by varying the ratio of CAB and PEO, drug loading and concentration of poly(vinyl alcohol) (PVA) solution. Encapsulation of the drug up to 95% was achieved. The microspheres tend to float over the simulated gastric media for more than 10 h. The micromeritic properties of microspheres reveal the excellent flow and good packing properties. The % buoyancy of microspheres was found to be up to 87. SEM showed that microspheres have many pores on their surfaces. Particle size ranges from 159 to 601 μm. DSC and X‐RD revealed the amorphous dispersion in the polymer matrix. In vitro release experiments were performed in simulated gastric fluid. In vitro release studies indicated the dependence of release rate on the extent of drug loading and the amount of PEO in the microspheres; slow release was extended up to 12 h. The release data were fitted to an empirical equation to compute the diffusional exponent (n), which indicated that the release mechanism followed the non‐Fickian trend. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007     

Microspheres of copolymeric <Emphasis Type="Italic">N</Emphasis>-vinylpyrrolidone and 2-ethoxyethyl methacrylate for the controlled release of nifedipine

Free radical copolymerization of N-vinyl-2-pyrrolidone (NVP) with 2-ethoxyethyl methacrylate (EOEMA) was carried out with 2,2′-azobisisobutyronitrile (AIBN) initiator in 1,4-dioxane solvent at 60 °C. The resulting copolymers were characterized by FTIR, ¹H-NMR and ¹³C-NMR methods. Microspheres were prepared by varying the amount of NVP with respect to EOEMA. Nifedipine (NFD), a water-insoluble antihypertensive drug, was loaded into these microspheres by the oil in water emulsion technique followed by solvent evaporation. The effect of the proportion of NVP in the NVP/EOEMA copolymer on the controlled release of NFD from the microsphere matrix was investigated. Scanning electron micrographs (SEM) of the microspheres indicated spherical shapes in the size range 17–47 μm, even after loading with NFD. In vitro studies of the release of NFD from the NVP/EOEMA microspheres in pH 7.4 medium showed that the rate of NFD release was enhanced when the NVP content of the copolymer was high; the size of the microspheres also increased with increasing NVP content of the copolymer. Release data were analyzed using an empirical relation in order to elucidate the kinetics of the NFD release. This analysis indicated that a Fickian transport mode operates in this system.     

Chitosan microspheres: modification of polymeric chem‐physical properties of spray‐dried microspheres to control the release of antibiotic drug

Antibiotic drug releasing from chitosan and acylchitosan microspheres was studied. The acylchitosan microspheres were prepared by modifying the microencapsulation process from spray‐drying to spray in‐liquid coagulating process for the improvement of chem‐physical properties of polymer in controlling the release of antibiotic drug. A higher yield of microspheres was recovered by this improved process. Crystallinity, swelling ability, and the morphology of various microspheres were investigated by X‐ray, water adsorption, and scanning electron microscopy studies. Results show that by modifying the microencapsulation process from spray‐drying to spray in‐liquid coagulating process, the chemical properties of the microsphere were varied from a hydrophilic chitosan microsphere to a hydrophobic acylchitosan microsphere, while the physical structure of the microsphere was varied from a porous chitosan microsphere to a dense acylchitosan microsphere. For the reasons, drug release rate of acylchitosan microspheres prepared by the novel spray microencapsulation method were apparently depressed, and the long‐acting release of antibiotic drug was possible to be achieved. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 71: 747–759, 1999     

Amino-Modified Polylactic Acid Nanofibre Microspheres as Drug Sustained Release Carriers for Alendronate

Amino-modified polylactic acid (EPLA) nanofibre microspheres with a high porosity, large specific surface area, strong adsorption capacity, and rich in active amino groups were developed for drug delivery applications. Alendronate, a well-known antiresorptive agent, was chosen as a model drug to evaluate the loading capacity and release properties of the prepared EPLA microspheres. SEM micrographs clearly showed that the drug was loaded into the microspheres within the pores between the nanofibers and as well as being adsorbed on their surface. XRD and FTIR spectra analyses also confirmed drug loading. UV/Vis-absorption spectrophotometry was used to study the impact of various parameters, including adsorption time and initial concentration and pH value of the alendronate solution, on the microsphere drug-loading capacity. Under optimum conditions, EPLA microspheres exhibited a high alendronate adsorption capacity of up to 503?mg/g. In vitro release studies showed that alendronate-loaded EPLA nanofibre microspheres exhibited a perfect release performance, with alendronate being released in a sustained manner for approximately 15 days without any obvious initial burst. Therefore, EPLA nanofibre microspheres hold great potential as efficient, controlled release drug delivery carriers of alendronate.     

Optimization of spray-dried diclofenac sodium-loaded microspheres by screening design

The aim of the present study was to investigate the effect of formulation and operating parameters of the laboratory spray dryer on polymeric microspheres intended to be used for sustaining drug delivery of diclofenac sodium (DS). Four operating and four formulation parameters were investigated by Plackett–Burman design to enhance the encapsulation efficiency (EE). The independent variables were air inlet temperature, aspirator, feed flow rate, spray nozzle diameter, amount of drug, amount of polymers, and volume of organic solvent. The resultant microspheres were characterized for their EE. The microspheres having high EE were further characterized for particle size, morphology, and in vitro drug release. Interaction between the drug and the polymer were investigated by Fourier transform infrared (FTIR) spectroscopy and X-ray powder diffractometry (XRPD). The Pareto chart showed that amount of Eudragit® RS100, amount of ethylcellulose, and aspirator were identified as significant factors. The microspheres showed high EE (47.55?±?0.006% to 67.99?±?0.007%). The microspheres were found to be discrete, spherical with smooth surface. The FTIR analysis confirmed the compatibility of DS with the polymers without interaction. The XRPD revealed the dispersion of drug within microspheres formulation. The in vitro drug release from these DS-loaded microspheres showed sustained release of DS over a period of 12?h and followed the Korsmeyer–Peppas model [R²?=?0.9920 (Run 1) and 0.9957 (Run 13)] with a value of the slope (n)?≤?0.43. This n value, however, appears to indicate that Fickian release is the dominant mechanism of drug release with these formulations.     

In vitro release study of diltiazem hydrochloride from poly(vinyl pyrrolidone)/sodium alginate blend microspheres

Polymeric blend microspheres of poly(vinyl pyrrolidone) (PVP) with sodium alginate (NaAlg) were prepared by cross‐linking with calcium ions and used to deliver a calcium channel blocker drug, diltiazem hydrochloride (DT). The prepared microspheres were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy. Scanning electron microscopy confirmed the spherical nature of the particles. Preparation conditions for the microspheres were optimized by considering the percentage entrapment efficiency, particle size, and swelling capacity. Effects of variables such as PVP/NaAlg ratio, molecular weight of PVP, cross‐linker concentration, and drug/polymer ratio on the release of DT were discussed at two different pH values (1.2, 6.8) at 37°C. It was observed that DT release from the microspheres decreased with increasing molecular weight of PVP and extent of cross‐linking. However, DT release increased with increasing PVP content and drug/polymer ratio (d/p) of the blend microspheres. The highest DT release percentage was obtained as 99% for PVP/NaAlg ratio of 1/2 with d/p ratio of 1/2 at the end of 4 h. It was also observed from release results that DT delivery from the microspheres through the external medium are much higher at low pH (1.2) value than that of high pH (6.8) value. The drug release from the microspheres mostly followed Fickian transport. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Preparation and evaluation of alginate/chitosan microspheres containing pheromones for pest control of Megaplatypus mutatus Chapuis (Platypodinae: Platypodidae)

This work describes the optimization of an alginate/chitosan microsphere preparation for the encapsulation of a sexual pheromone, 6‐methyl‐5‐hepten‐2‐ol (sulcatol), to realize a slow‐release device for the biological control of the Megaplatypus mutatus pest. To evaluate and select the best encapsulation/release conditions three parameters were studied: alginate concentration, pH of gelling solution and Ca²⁺/COO^? ratio. The preparation was optimized using biopolymers with improved mechanical properties and swelling behavior. The obtained microspheres were characterized using Fourier transform infrared spectroscopy, scanning electron and optical microscopies, swelling degree, mechanical properties and in vitro release of encapsulated pheromone. The microspheres performed best when they were synthesized using an alginate concentration of 4% w/v, at pH = 9 and with a Ca²⁺/COO^? ratio of 3.5. The attractiveness of the alginate/chitosan microspheres towards M. mutatus was demonstrated by behavioral bioassay with the completed pheromonal blend of the species (sulcatol, sulcatone and 3‐pentanol). The formulation can be considered as an efficient slow‐release biological control system, with no negative environmental impact. © 2015 Society of Chemical Industry