Polycaprolactone Microspheres Research Articles

Production of CNT-taxol-embedded PCL microspheres using an ammonium-based room temperature ionic liquid: As a sustained drug delivery system

We describe a one-pot method for the mass production of polymeric microspheres containing water-soluble carbon-nanotube (w-CNT)-taxol complexes using an ammonium-based room temperature ionic liquid. Polycaprolactone (PCL), trioctylmethylammonium chloride (TOMAC; liquid state from −20 to 240°C), and taxol were used, respectively, as a model polymer, room temperature ionic liquid, and drug. Large quantities of white colored PCL powder without w-CNT-taxol complexes and gray colored PCL powders containing w-CNT-taxol (1:1 or 1:2 wt/wt) complexes were produced by phase separation between the hydrophilic TOMAC and the hydrophobic PCL. Both microsphere types had a uniform, spherical structure of average diameter 3–5μm. The amount of taxol embedded in PCL microspheres was determined by HPLC and 1H NMR to be 8–12μg per 1.0mg of PCL (loading capacity (LC): 0.8–1.2%; entrapment efficiency (EE): 16–24%). An in vitro HPLC release assay showed sustain release of taxol without an initial burst over 60days at an average rate of 0.003–0.0073mg per day. The viability patterns of human breast cancer cells (MCF-7) for PCTx-1 and -2 showed dose-dependent inhibitory effects. In the presence of PCTx-1 and -2, the MCF-7 cells showed high viability in the concentration level of, respectably, <70 and <5μg/mL.

Incorporation of gold-coated microspheres into embryoid body of human embryonic stem cells for cardiomyogenic differentiation.

Human embryonic stem cells (hESCs) are a useful cell source for cardiac regeneration by stem cell therapy. In this study, we show that incorporation of gold-coated microspheres into hESC-derived embryoid bodies (EBs) enhances the cardiomyogenic differentiation process of pluripotent embryonic stem cells. A polycaprolactone (PCL) microsphere surface was coated with gold. Either gold-coated PCL microspheres (AuMS) or PCL microspheres (MS) were incorporated into hESC-derived EBs. AuMS and MS were not cytotoxic. AuMS promoted the expression of genes for mesodermal and cardiac mesodermal lineage cells, both of which are intermediates in the process of cardiac differentiation of hESCs on day 4 and the expression of cardiomyogenic differentiation markers on day 14 compared to MS. AuMS also enhanced gene expression of cardiac-specific extracellular matrices. Incorporation of gold-coated MS into hESC-derived EBs may provide a new platform for inducing cardiomyogenic differentiation of pluripotent embryonic stem cells.

Vocal Fold Augmentation with Injectable Polycaprolactone Microspheres/Pluronic F127 Hydrogel: Long-Term In Vivo Study for the Treatment of Glottal Insufficiency

There is increasing demand for reconstruction of glottal insufficiency. Several injection materials have been examined for this purpose, but all had limitations, such as poor long-term durability, migration from the injection site, inflammation, granuloma formation, and interference with vocal fold vibration due to viscoelastic mismatch. Here, we developed a novel injection material, consisting of polycaprolactone (PCL) microspheres, which exhibits better viscoelasticity than conventional materials, and Pluronic F127 carrier, which decreases the migration of the injection materials. The material was injected into rabbits with glottal insufficiency and compared with the FDA-approved injection material, calcium hydroxylapatite (CaHA). Endoscopic and histological examinations indicated that PCL/Pluronic F127 remained at the injection site with no inflammatory response or granuloma formation, whereas CaHA leaked out and migrated from the injection site. Therefore, vocal fold augmentation was almost completely retained during the 12-month follow-up period in this study. Moreover, induced phonation and high-speed recording of vocal fold vibration showed decreased vocal fold gap area in the PCL/Pluronic F127 group. Our newly developed injection material, PCL/Pluronic F127, permits efficient augmentation of paralyzed vocal fold without complications, a concept that can be applied clinically, as demonstrated by the successful long-term follow-up.

Functional recovery of urethra by plasmid DNA-loaded injectable agent for the treatment of urinary incontinence

Stress urinary incontinence (SUI) is an embarrassing problem affecting a large number of women and interfering with their quality of life. The injury or weakness of urethral supporting tissues by childbirth and aging has been considered as key factors in the development of the SUI. In this study, plasmid DNA (pDNA; encoding for bFGF) complex-loaded poly(dl-lactic-co-glycolic acid) (PLGA)/Pluronic F127 mixture dispersed with polycaprolactone (PCL) microspheres was prepared as an injectable bioactive bulking agent that may provide bulking effect (by PCL microspheres) and allow stimulation of the defect tissues around urethra (by synthesis of bFGF from cells or tissues transfected by the pDNA complex) for the effective treatment of SUI. From in vitro experiments, the pDNA complex incorporated in the bulking agent was released in a sustained manner over 84 days (≥80% of the initial loading amount). The pDNA complex was effectively transfected into fibroblasts and the cells were continuously producing the target protein, bFGF. From the in vivo study using hairless mice and Sprague–Dawley rats, it was confirmed that the pDNA complex released from the bulking agent is transfected into surrounding cells/tissue, and the cells/tissues synthesize sufficient bFGF to regenerate smooth muscle with biological function around the urethra. Basis on these results, the pDNA (encoding for bFGF) complex-loaded PLGA/Pluronic F127 mixture dispersed with PCL microspheres can be a promising bioactive bulking agent system for the fundamental cure of SUI.

Mild method for the agglomeration of dispersed polycaprolactone microspheres via a genipin‐crosslinked gelatin hydrogel

AbstractMicrosphere systems have been used to deliver drugs, proteins, and cells. However, dispersed microspheres can induce harmful effects after they are introduced into the body. To agglomerate these dispersed microspheres, an in situ forming system was developed to fabricate microsphere/hydrogel composites. Polycaprolactone microspheres with a porous surface and hollow core were physically incorporated into a genipin‐crosslinked gelatin hydrogel. The incorporation of microspheres reduced the swelling capacities and weakened the unexpected volume expansion, which is not favorable for in vivo implants. Additionally, the reacted genipin ratio increased with increasing gelatin concentration. The degradation of the composite was also determined, and it was proposed that the degradation mechanism of the composite was bulk collapse, whereas that for the pure hydrogel was surface erosion. The obtained microsphere/hydrogel composite might have a great potential application as an injectable system for tissue regeneration. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013

Investigation of Physical Properties of a Polycaprolactone Dermal Filler when Mixed with Lidocaine and Lidocaine/Epinephrine

IntroductionIn esthetic treatments with dermal fillers, increasing numbers of physicians are using the technique of mixing an anesthetic agent into the dermal filler before treatment to increase the comfort of the patients. This study aimed at evaluating the effects on the physical properties of a polycaprolactone (PCL)-based dermal filler after mixing with lidocaine.MethodsA range of 2.0% lidocaine and 2.0% lidocaine/epinephrine concentrations was mixed with the PCL dermal filler to evaluate the changes in dynamic viscosity and elasticity, extrusion force, pH, and needle jam rates. The number of passes back to forth for optimal homogeneity of lidocaine and PCL dermal filler was determined.ResultsWith 15 mixing strokes the lidocaine solution can effectively be mixed into dermal filler resulting in a homogenous blend. The viscosity, elasticity, and the extrusion force decrease with increasing lidocaine volume. The viscosity and elasticity of the dermal filler is sufficient to keep the PCL microspheres in suspension. There were no needle jams. The pH of the PCL dermal filler mixed with lidocaine solution is equivalent to that of the original dermal filler.ConclusionIt is concluded that mixing of lidocaine into the PCL-based dermal filler can safely be performed without harmful changes in the physical properties of the original dermal filler.

Erratum to: Studies on the Effect of the Size of Polycaprolactone Microspheres for the Dispersion of Salbutamol Sulfate from Dry Powder Inhaler Formulations

Erratum to: Studies on the Effect of the Size of Polycaprolactone Microspheres for the Dispersion of Salbutamol Sulfate from Dry Powder Inhaler Formulations

Preparation of open porous polycaprolactone microspheres and their applications as effective cell carriers in hydrogel system

Common hydrogel, composed of synthetic polymers or natural polysaccharides could not support the adhesion of anchorage-dependent cells due to the lack of cell affinitive interface and high cell constraint. The use of porous polyester microspheres as cell-carriers and introduction of cell-loaded microspheres into the hydrogel system might overcome the problem. However, the preparation of the open porous microsphere especially using polycaprolactone (PCL) has been rarely reported. Here, the open porous PCL microspheres were fabricated via the combined emulsion/solvent evaporation and particle leaching method. The microspheres exhibited porous surface and inter-connective pore structure. Additionally, the pore structure could be easily controlled by adjusting the processing parameters. The surface pore size could be altered from 20μm to 80μm and the internal porosities were varied from 30% to 70%. The obtained microspheres were evaluated to delivery mesenchymal stem cells (MSCs) and showed the improved cell adhesion and growth when compared with the non-porous microspheres. Then, the MSCs loaded microspheres were introduced into agarose hydrogel. MSCs remained alive and sustained proliferation in microsphere/agarose composite in 5-day incubation while a decrement of MSCs viabilities was found in agarose hydrogel without microspheres. The results indicated that the microsphere/hydrogel composite had a great potential in cell therapy and injectable system for tissue regeneration.

Studies on the Effect of the Size of Polycaprolactone Microspheres for the Dispersion of Salbutamol Sulfate from Dry Powder Inhaler Formulations

To study the effect of the size of the surface-coated polycaprolactone (PCL) microparticle carriers on the aerosolization and dispersion of Salbutamol Sulfate (SS) from Dry Powder Inhaler (DPI) formulations. The microparticles were fabricated using an emulsion technique in four different sizes (25, 48, 104 and 150μm) and later coated with Magnesium stearate (MgSt) and leucine. They were characterized by laser diffraction and SEM. The Fine Particle Fraction (FPF) of SS from powder mixtures was determined by a Twin Stage Impinger (TSI). As the carrier size increased from 25μm to 150μm, the FPF of the SS delivered by the coated PCL particles increased approximately four fold. A linear relationship was found between the FPF and Volume mean Diameter (VMD) of the particles over this range. The dispersion behaviour of SS from PCL carriers was dependent on the inherent size of the carriers and the increased FPF of SS with increased carrier size probably reflects the higher mechanical forces produced due to the carrier-carrier collisions or collisions between the carrier particles and the internal walls of the inhaler during aerosolization.

Collagen adsorption on quercetin loaded polycaprolactone microspheres: Approach for “stealth” implant

We recently experimented with collagen coating on the surface of quercetin loaded polycaprolactone microspheres by simple adsorption technique to mimic extra cellular matrix and reduce immune or inflammatory responses at the site of implants. The collagen immobilization on polymeric scaffold surfaces through various surface modification techniques was the current scenario to improve bio-integration of the polymers with the in vivo system. Nevertheless, it requires other chemicals or processing methods to modify the surface of polymers to immobilize the collagen covalently. Here protein adsorption principle is used for the coating of collagen onto the surface of solid microspheres and characterized. Optical, ATR-FTIR, SEM analysis confirm collagen coating. The reduction in burst release of the quercetin from the PCL microspheres further confirms its presence and role in the controlled release. The results indicate that the adsorption technique can be the simple strategy to coat collagen on the surface of polyester implants to develop stealth implant in shorter time with low cost technology.

Polycaprolactone Microspheres as Carriers for Dry Powder Inhalers: Effect of Surface Coating on Aerosolization of Salbutamol Sulfate

This study reports the factors controlling aerosolization of salbutamol sulfate (SS) from mixtures with polycaprolactone (PCL) microspheres fabricated using an emulsion technique with polyvinyl alcohol (PVA) as stabilizer. The fine particle fraction (FPF) of SS from PCL measured by a twin-stage impinger was unexpectedly found to be zero, although scanning electron microscopy showed that the drug coated the entire microsphere. Precoating the microspheres with magnesium stearate (MgSt) excipient solutions (1%-2%) significantly increased (p < 0.05, n = 5) the FPF of SS (11.4%-15.4%), whereas precoating with leucine had a similar effect (FPF = 11.3 ± 1.1%), but was independent of the solution concentration. The force of adhesion (by atomic force microscopy) between the PCL microspheres and SS was reduced from 301.4 ± 21.7 nN to 110.9 ± 30.5 nN and 121.8 ± 24.6 nN, (p < 0.05, n = 5) for 1% and 2% MgSt solutions, respectively, and to 148.1 ± 21.0 nN when coated with leucine. The presence of PVA on the PCL microspheres (detected by X-ray photoelectron spectroscopy) affected the detachment of SS due to strong adhesion between the two, presumably due to capillary forces acting between them. Precoating the microspheres with excipients increased the FPF significantly by reducing the drug-carrier adhesion.

Preparation, characterization and properties of liposome-loaded polycaprolactone microspheres as a drug delivery system

We reported the preparation and properties of liposome-loaded polycaprolactone microspheres (LPMs) as a drug delivery system for controlling the release of flurbiprofen. LPMs were fabricated using double emulsion solvent extraction/evaporation method and characterized by scanning electron microscopy, Fourier transform infrared spectrum, X-ray diffraction, differential scanning calorimeter and UV–vis spectrum. The results suggest that LPMs have uniform sizes with pores on the external surface. Liposomes are intactly encapsulated in LPMs, which causes slight change of polycaprolactone from semi-crystalline to less-ordered amorphous. The concentrations of polycaprolactone and polyvinyl alcohol (PVA) and the amount of liposomes can affect the diameter, surface morphology and encapsulation efficiency of LPMs. The diameter of LPMs increases from 80 to 200 μm and the encapsulation efficiency of flurbiprofen in LPMs increases from 36.92% to 48.42% when the concentration of polycaprolactone increases from 0.15 to 0.6 g/mL. However, the larger amount of liposomes promotes the aggregation between emulsion droplets and causes more pores on the surface of LPMs, which leads to lower drug encapsulation efficiency. The presence of PVA stabilizes the emulsion droplets against coalescence. With the increase of PVA concentration, the diameter of LPMs decreases and the amount of flurbiprofen encapsulated in LPMs increases. In vitro release studies suggest the structure and morphology of LPMs have close relationship with drug release kinetics. The smaller LPMs with more porous surface have faster cumulative release rate.

Chitosan–polycaprolactone microspheres as carriers for delivering glial cell line-derived neurotrophic factor

Chitosan–polycaprolactone (CH–PCL) copolymers with brush-like chain structures were synthesized. Some CH–PCLs with a PCL content less than 50 wt% were used to build glial cell line-derived neurotrophic factor (GDNF)-loaded microspheres via an emulsification method using genipin as a cross-linker. The resulting microspheres were spherical with a smooth surface and a diameter less than 40 μm; however, their loading efficiency could be higher than 80% if crosslinked properly. These microspheres had various swelling characteristics in lysozyme-containing PBS, which mainly depended on the PCL content, and they did not exhibit significant degradation up to 3 weeks. It is found that the PCL content in the CH–PCLs predominantly governed GDNF releases from some optimal microspheres and that the amount of cross-linker imposed limited impacts on the release behavior. Release kinetics revealed that GDNF release from microspheres was controlled by anomalous mechanisms involving Fickian diffusion and case-II transport. Some microspheres with an initial loading ratio of approximately 5-ng GDNF to 1.0-mg dry microsphere had sustained GDNF release upon addition of a simulant in vivo medium; an approximate linear rate of release was observed, which lasted over 4 weeks, was controllable and did not involve a significant burst release.

Formulation and Evaluation of Quercetin Polycaprolactone Microspheres for the Treatment of Rheumatoid Arthritis

Quercetin had been shown to be effective in the management of arthritis. However, bioavailability of quercetin is a concern for such treatment. This work aims at the development of intra-articular drug delivery system by controlled release of quercetin (loaded in microspheres) for the management of rheumatoid arthritis. Polycaprolactone has been used for the preparation of microspheres (with quercetin) using the solvent evaporation method. The physio-chemical characterisation of polycaprolactone-loaded quercetin microspheres was carried out to obtain information about particle size distribution, drug loading efficiency, morphology, thermal properties, polymorphism and release trends in phosphate-buffered saline at pH 7.4 and 37°C. Quercetin-loaded polycaprolactone microspheres were found to be biocompatible as evidenced from in vitro and in vivo studies using a rabbit synovial cells and Wistar rats, respectively. Quercetin release from microspheres of selected formulations showed biphasic nature due to initial burst effect followed by a controlled release. These results suggest that optimised quercetin-loaded polycaprolactone microspheres may be the viable strategy for controlled release of quercetin in the joint cavity for more than 30 days by intra-articular injection to treat rheumatoid arthritis.

Facile preparation of fluorescence-encoded microspheres based on microfluidic system

The fluorescence-encoded microspheres were prepared by the simple and controllable microfluidic device for the first time. The polycaprolactone (PCL) microspheres were encoded with different quantum dots (QDs) at various ratios, and the fluorescence was decoded successfully. The designed fluorescence encoding method was easily manipulated, and generated the uniform microspheres with different size. This research demonstrated a very facile and promising technique for fluorescence encoding over traditional methods.

Préparation, Characterization in vivo Evaluation of Parenteral Sustained Release Microsphere Formulation of Zopiclone

The aim of this study was to prepare zopiclone-loaded polycaprolactone microspheres by emulsion solvent evaporation technique with different drug-to-carrier ratios {MP 1 (1:1), MP 2 (1:2), MP 3 (1:3), and MP 4 (1:4)}, characterize and evaluate the in vivo performance. The microspheres were characterized for particle size, surface morphology, drug excipient compatibility, percentage yield, drug entrapment, and in vitro release kinetics. Pharmacokinetics and pharmacodynamics were evaluated after parenteral administration so as to determine the sustained action of the drug after one-time administration of the formulation in a rat model. Of four formulations prepared, MP 2, i.e., 1:2 (drug–polymer) ratio was selected as the optimized formulation based on particle size, particle shape, and the release behavior. The size of microspheres was found to be ranging from 5.4 to 12.1 µm. The shape of microspheres was found to be spherical by SEM. Among the four formulations, MP 2 (1:2) showed maximum percentage yield of 75% ± 2.68%. There was no interaction between drug and polymer by FT-IR study. In the in vitro release study, formulation MP 2 (1:2) showed 86.5% drug release and was found to be sustained for 10 days. The microsphere formulations were able to sustain the release of drug both in vitro and in vivo. Pharmacodynamic study (Maze apparatus) indicated that the anxiolytic activity shown by zopiclone microspheres was significant when compared to the zopiclone solution given daily.

Microencapsulation of rosmarinic acid using polycaprolactone and various surfactants

Rosmarinic acid (RA) has a number of interesting biological activities, e.g. anti-viral, anti-bacterial, anti-inflammatory and antioxidant. The antioxidant activity of RA is stronger than that of vitamin E. Despite its strong antioxidant activity, it was limited to use in cosmetics because of the low water solubility, discolouration and chemical instability. The purpose of this study was to prepare RA-loaded polycaprolactone (PCL) microspheres using emulsion solvent evaporation method and characterize them with different surfactants used in the formation process. Finally, long-term stability of RA was evaluated in the cosmetic formulation. As a result, PCL microspheres were found to be spherical in shape, with zwitterionic surfactant-PCL particles being the smallest size distribution and highest entrapment efficiency of RA. Emulsions containing RA-loaded PCL microspheres showed a better long-term stability of the RA compared with those containing only RA. These results suggest that RA may be stably and efficiently encapsulated into polycaprolactone microspheres.

A novel scaffold based on formation and agglomeration of PCL microbeads by freeze‐drying

Polycaprolactone (PCL) scaffolds were prepared by freeze-drying of polymer solutions in tetrahydrofuran. Effects of the polymer composition, which is 10 and 20% (w/v), on the scaffold properties for example, morphology, porosity, mechanical stability, degradability, and so forth were investigated by using suitable methods. Scanning electron microscopy photographs clearly showed the presence of a porous, three-dimensional structure including agglomerated PCL microspheres. Porosity analysis demonstrated that 10 and 20% (w/v) scaffolds have 95.9% and 74.4% porosity, respectively. The microspheres have very narrow size distribution and their diameters increase from 50-70 microm to 90-100 microm with increasing PCL content from 10 to 20% (w/v). The microspheres were highly connected with each other and the scaffolds have superior mechanical properties when compared with the traditional PCL scaffolds. Cell culture experiments showed that periodontal ligament cells (PDL) were able to attach and proliferate on the 20% PCL scaffold. The results demonstrated that this novel PCL structure will be a potential tissue engineering scaffold with its superior properties and simple preparation procedure.

Comparative Study of Some Biodegradable Polymers on the Entrapment Efficiency and Release Behavior of Etoposide from Microspheres

Etoposide-loaded biodegradable microspheres of poly lactic-co-glycolide (PLGA) 50:50, PLGA 75:25, and polycaprolactone (PCL) were prepared by simple o/w emulsification solvent evaparation method and characterized by size analysis and microscopy. The influence of drug to polymer ratio on the entrapment of etoposide was studied. Of all the three types of microspheres, polycaprolactone microspheres (PCL MS) showed the highest entrapment efficiency (94.64%), followed by PLGA 75:25 microspheres (PLGA 75:25 MS) (88.64%) and PLGA 50:50 microspheres (PLGA 50:50 MS) (79.19%). The drug to polymer ratio of 1:20 gave the highest entrapment efficiency for all the three types of microspheres. The in vitro release of etoposide from the three microsphere formulations were studied in phosphate buffer pH 7.4 (pH 7.4 PB) containing 0.1% Tween 80. The microspheres showed an initial burst release, which was highest from the PLGA 50:50 MS and least from the PCL MS. PCL MS microspheres showed the lower and slow drug release than the remaining formulations. The release of etoposide from all the three microsphere formulations followed Higuchi's diffusion pattern. The microspheres in the dissolution medium for 28 days appeared irregular in shape and slightly fragmented.

Changes in cisplatin delivery due to surface-coated poly (lactic acid)-poly(epsilon-caprolactone) microspheres.

Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Local delivery of agents capable of modulating vascular responses, have the potential to prevent restenosis. However, the development of injectable microspheres for sustained drug delivery to the arterial wall is a major challenge. We demonstrated the possibility of entrapping an antiproliferative agent, cisplatin, in a series of surface coated biodegradable microspheres composed of poly(lactic acid)poly(caprolactone) blends, with a mean diameter of 2-10 pm. The microspheres were surface coated with poly ethylene glycol (PEG), chitosan (Chit), or alginate (Alg). A solution of cisplatin and a 50:50 blend of polylactic acid (PLA)-polycaprolactone (PCL) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of PEG (or polyvinyl alcohol or Chit or Alg) with stirring using a high speed homogenizer, for the formation of microspheres. Cisplatin recovery in microspheres ranged from 25-45% depending on the emulsification system used for the preparations. Scanning electron microscopy revealed that the PLA-PCL microspheres were spherical in shape and had a smooth surface texture. The amount of drug release was much higher initially (20-30%), this was followed by a constant slow-release profile for a 30-day period of study. It has been found that drug release depends on the amount of entrapped drug, on the presence of extra cisplatin in the dispensing phase, and on the polymer coatings. This PEG or Alg-coated PLA/PCL microsphere formulation may have potential for the targeted delivery of antiproliferative agents to treat restenosis.