PCL Microspheres Research Articles

Hollow porous poly(ε-caprolactone) microspheres by emulsion solvent extraction

Hollow porous poly (ε-caprolactone) microspheres with different structures were prepared using a solvent/non-solvent emulsion solvent extraction technique. The PCL concentration is an important factor for controlling the structure of hollow PCL microspheres. Hollow PCL microspheres with a porous polymer shell were formed when the polymer concentration was appropriate (12% w/v), whereas porous microspheres were produced when the polymer concentration was too high (20% w/v). The ability to incorporate silica xerogels into the PCL hollow microspheres was examined by scanning electron microscopy. These PCL hollow porous microspheres have potential applications in the local delivery of proteins and drugs.

Preparation of camptothecin-loaded PCEC microspheres for the treatment of colorectal peritoneal carcinomatosis and tumor growth in mice

The aim of this study was to prepare PCL–PEG–PCL (PCEC) microspheres to protect camptothecin from hydrolysis, to extend its release time and to enhance its treatment efficacy on colorectal peritoneal carcinomatosis and tumor growth in mice. Camptothecin (CPT)-loaded PCL–PEG–PCL (PCEC) microspheres were prepared by oil-in-water emulsion solvent evaporation method. The particle size, morphological characteristics, encapsulation efficiency, in vitro drug release studies and in vitro cytotoxicity of CPT-loaded PCEC microspheres have been investigated. In vivo studies were carried out on Balb/c male mice bearing colorectal peritoneal carcinomatosis. CPT-loaded PCEC microspheres were applied to abdominal cavity of mice once a week. Free CPT was used as a positive control. On 14th day of treatment, mice were sacrificed and antitumor activities of CPT-loaded PCEC microspheres were evaluated. Compared with control group, a significant decrease in the number of tumor nodes was observed in group treated with CPT-loaded PCEC microspheres. Immunohistochemistry staining of tumor tissues with CD34 revealed that MVD positive cells were significantly reduced in CPT-loaded PCEC microspheres treated group in contrast to other groups ( P < 0.05). The CPT-loaded PCEC microspheres were considered potentially useful to treat the abdominal metastases of colon carcinoma.

Silk coating on poly(ε-caprolactone) microspheres for the delayed release of vancomycin

The treatment of osteomyelitis remains a challenge for orthopaedic surgeons. Controlled release of vancomycin from biodegradable microspheres is a promising method for eliminating infection. However, the large initial burst release may make it difficult to maintain the local vancomycin concentration superior to minimum inhibitory concentration for several weeks. The aims of this study were to explore applications of the silk fibroin (SF) as an aqueous coating material for vancomycin-loaded poly(ε-caprolactone) (PCL) microspheres, and investigate the effects of silk coating on in vitro drug release. Examinations of particle size analyses, vancomycin content, Fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy and in vitro drug release were performed. The results showed that silk coating could reduce the large initial burst release and retard the vancomycin release. Therefore, we suggest that the SF could be used as an aqueous coating material for vancomycin-loaded PCL microspheres and prolonged the drug release. SF coating on vancomycin-loaded PCL microspheres may be considered as an effective approach to prolong the drug release and improve the anti-infection effects.

Porous biomedical composite microspheres developed for cell delivering scaffold in bone regeneration

Microspherical particles have attracted great interest as a delivery system of tissue cells in regenerative engineering. For hard tissue regeneration, here we exploited porous biomedical composite microspheres of hydroxyapatite–polycaprolactone (HA–PCL). The pore channels within the microsphere was facilitated by using camphene as the porogen, where the initial HA–PCL–camphene mixture in chloroform was solidified and the camphene was then sublimed to leave pore channels within the HA–PCL microspheres. The pore size increased with increasing camphene concentration, resulting in the generation of macropores (> 50 μm). Rat bone marrow mesenchymal stem cells were shown to proliferate actively on the porous microspheres penetrating deeply into the pore channels. Results suggest future applications of the porous composite microsphere as a cell delivery scaffold for bone tissue regeneration.

Development characterizations and evaluation of Poly(-ϵ-caprolactone)-based microspheres for hepatitis B surface antigen delivery

The major disadvantage of several currently available vaccines is the need for repeated administrations. The aim of the study was to develop long-acting microspheres based on poly(-ϵ-caprolactone) (PCL) for delivery of recombinant hepatitis B surface antigen (rHBsAg). PCL microspheres were prepared for induction of humoral and cellular immunity by intramuscular administration. Microspheres were characterized for their size, shape, incorporation efficiency, zeta potential, antigen integrity, antigen conformation and immunogenicity. DSC (Differential Scanning Calorimetry) studies revealed that better encapsulation efficiency between high and low mol wt polymer. The Circular Dichorism spectroscopy (CD) of antigen, released from PCL microspheres revealed that the secondary structure of antigen was unperturbed. Antigen integrity was evaluated by SDS-PAGE. Immunization with HBsAg PCL microspheres resulted in upregulation of specific cellular (IFN-γ and IL-2) as well as IgG response in BALB/c mice. Immune responses were found significantly higher than the conventional alum adjuvant following a single intramuscular immunization. These results highlight the enhanced efficiency of these PCL microspheres as an adjuvant and their prospective use in the prevention of hepatitis B.

Optimization of preparation conditions of poly(ε-caprolactone) microspheres for controlled release of carbamazepine

Poly (?-caprolactone), PCL, is an aliphatic polyester suitable for controlled drug release due to its biodegradability, biocompatibility, non-toxicity and high permeability to many therapeutic drugs. This study investigates the effect of the preparation parameters on the size and the morphology of the PCL microspheres and on the release profile of carbamazepine from these microspheres. The PCL microspheres were prepared using oil-in-water (o/w) emulsion solvent evaporation method with the poly(vinyl alcohol), PVA, as the emulsion stabilizer. The influence of the stirring rate applied during the emulsion formation, the homogenization time and the emulsifier concentration on diameter and size distribution of the microspheres was analyzed by scanning electron microscope (SEM). The initial emulsion was formed applying high stirring rates of 10000, 18000 and 23000 rpm, for homogenization times: 5, 10 and 15 min. The diameter was strongly influenced by the stirring rate, and the average particle size decreased from 9.2 to 2.8 ?m with the increase of the stirring rate. Increasing the amount of PVA in the water phase from 0.2 to 1 mass% improved stabilization of the oil droplets and led to a slight decrease of the average particle diameter. Drug-loaded microspheres were prepared by the same technique using different amounts of carbamazepine (10 and 15 mass%), under given conditions (1 mass% PVA, stirring rate of 18000 rpm for a period of 5 min of emulsion formation). Additionally, microspheres were prepared by applying low stirring rate of 1000 rpm with 10 and 15 mass% of the drug. The SEM analysis showed that microspheres created with 18000 rpm stirring rate, had average diameters of 3-4 ?m, and the microspheres prepared with 1000 rpm stirring rate were larger than 100 ?m. It was also observed that, in the case of the large microspheres, carbamazepine was deposited on their surfaces, while the small microspheres had smooth surfaces without observable drug crystals. The encapsulation efficiency and the release behavior of the carbamazepine were examined using high performance liquid chromatography-ultraviolet spectroscopy (HPLC-UV). The drug encapsulation efficiencies were in the range from 69 to 81%, and were increasing with the increase of the amount of carbamazepine in both series. In vitro release experiments were carried out in the phosphate buffer solution (pH 7) at 37?C. The release rate was influenced by the microspheres size and morphology. The larger microspheres released more carbamazepine (85-95%) compared to the small ones (50-65%) for the same period. This behavior was attributed to the different drug distribution in the PCL matrix. Different mathematical models were used to describe drug release kinetics. It was concluded that the mechanism of the carbamazepine release from the microspheres was diffusion-controlled, independent on the type of microspheres. The kinetic parameters showed that the release of carbamazepine was slower from the smaller microspheres, probably as a result of more even distribution of the drug in the polymer matrix.

Determination of poly(ɛ-caprolactone) solubility parameters: Application to solvent substitution in a microencapsulation process

The evolution of regulation on chemical substances (i.e. REACH regulation) calls for the progressive substitution of toxic chemicals in formulations when suitable alternatives have been identified. In this context, the method of Hansen solubility parameters was applied to identify an alternative solvent less toxic than methylene chloride used in a microencapsulation process. During the process based on a multiple emulsion (W/O/W) with solvent evaporation/extraction method, the solvent has to dissolve a polymer, poly(ɛ-caprolactone) (PCL), which forms a polymeric matrix encapsulating or entrapping a therapeutic protein as the solvent is extracted. Therefore the three partial solubility parameters of PCL have been determined by a group contribution method, swelling experiments and turbidimetric titration. The results obtained allowed us to find a solvent, anisole, able to solubilize PCL and to form a multiple emulsion with aqueous solutions. A feasibility test was conducted under standard operating conditions and allowed the production of PCL microspheres.

Tissue Engineering Polymeric Microcarriers with Macroporous Morphology and Bone‐Bioactive Surface

PCL microspheres featuring a macroporous morphology and a bone-bioactive surface have been prepared. 'Camphene' was introduced to generate pores within the microsphere network. The pore size was variable from a few to tens to hundreds of microm depending on the Camphene/PCL ratio. Macropores (with sizes >50 microm) could be obtained with a Camphene/PCL ratio exceeding 6. The microsphere surface was further tailored with apatite mineral phase through solution-mediated precipitation, to endow the interface with bone bioactivity. Rat bone marrow stromal cells attached and spread actively on microspheres and populated well within their macropores. The developed microspheres may be potentially applicable as a cell delivery scaffold for bone tissue engineering.

Tyrosine kinase inhibitor loaded PCL microspheres prepared by S/O/W technique using ethanol as pretreatment agent

A new tyrosine kinase inhibitor (denoted as CH331) and its poly(ɛ-caprolactone) (PCL) microspheres were studied. The CH331 particles were pretreated with ethanol and then used to prepare CH331 loaded PCL microspheres by S/O/W solvent evaporation technique. Solubility values of CH331 in several organic and aqueous media were measured. The amount of ethanol and CH331 solubility play a significant role in drug loading, encapsulation efficiency, mean diameter and morphology of the microspheres, crystallinity and in vitro drug release. The treatment with a suitable amount of ethanol leads to more uniform sizes, better appearance and higher encapsulation efficiency for the microspheres. Compared with 0.5% PVA phosphate buffer solution (pH 7.4), 0.5% PVA aqueous solution as outer aqueous phase lowers encapsulation efficiency of microspheres, however, improves the drug release behavior.

Synthesis of Biodegradable Poly-ε-caprolactone Microspheres by Dispersion Ring-Opening Polymerization in Supercritical Carbon Dioxide

A series of fluorinated diblock and triblock copolymers of poly(epsilon-caprolactone) and poly(heptadecafluorodecylacrylate) were prepared by combining ring-opening polymerization of epsilon-CL and atom transfer radical polymerization of the acrylate. These copolymers with well-controlled molecular weight and composition were characterized by (1)H NMR spectroscopy and used as stabilizers for the dispersion ring-opening polymerization of epsilon-CL in supercritical carbon dioxide. The effect of composition and architecture of the polymeric stabilizers on the stabilization of PCL microspheres was investigated. Finally, purification of PCL was successfully implemented by reactive supercritical fluid extraction of the tin catalyst.

PCL microspheres based functional scaffolds by bottom-up approach with predefined microstructural properties and release profiles

Advanced tissue engineering approaches rely upon the employment of biomaterials that integrate biodegradable scaffolds with growth factor delivery devices to better guide cellular activities and enhance tissue neogenesis. Along these lines, here we proposed a bottom-up approach for the realization of bioactive scaffolds with controllable pore size and interconnection, combined with protein-loaded polymeric microcarriers acting as local chrono-programmed point source generation of bioactive signals. Bioactive scaffolds are obtained through the thermal assembly of protein activated poly(ɛ-caprolactone) (PCL) microspheres prepared by double emulsion and larger protein free PCL microspheres obtained by single emulsion. It is shown that the pore dimension, interconnectivity and mechanical properties in compression of the scaffold could be predefined by an appropriate choice of the size of the protein-free microparticles and process conditions. Protein-loaded microparticles were successfully included within the scaffold and provided a sustained delivery of a model protein (BSA). These matrices offer the possibility to concurrently modulate and control the size and extension of the porosity, mechanical properties and the spatial-temporal distribution of multiple bioactive signals.

Disodium norcantharidate loaded poly(ɛ-caprolactone) microspheres: I. Preparation and evaluation

Poly(ɛ-caprolactone) (PCL) microspheres encapsulating disodium norcantharidate (DSNC), a drug in salt form and with high water solubility, were prepared by s/o/w solvent evaporation technique and characterized in terms of size, morphology, encapsulation efficiency and drug release. The viscosity of s/o dispersion was crucial to the successful encapsulation of DSNC. Scanning electron microscopy (SEM) studies showed that the drug-loaded microspheres had coarse surface and porous internal structure. The analysis of X-ray diffraction (XRD) indicated that there was no interaction between DSNC and PCL, but the degree of crystallinity of PCL decreased with the introduction of the drug. The drug release profiles indicated an initial burst release followed by a slow release, and a further investigation into the release mechanism implied that the release of DSNC from PCL microspheres was caused by a combination of diffusion and osmotic pressure.

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

AbstractA 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

Microspheres Made of Poly(ε‐caprolactone)‐Based Amphiphilic Copolymers: Potential in Sustained Delivery of Proteins

Microspheres of amphiphilic multi-block poly(ester-ether)s (PEE)s and poly(ester-ether-amide)s (PEEA)s based on poly(epsilon-caprolactone) (PCL) were investigated as delivery systems for proteins. The interest was mainly focused on the effect of their molecular structure and composition on the overall properties of the microspheres, encapsulating bovine serum albumin (BSA) as a model protein. PEEs and PEEAs were prepared using a alpha,omega-dihydroxy-terminated PCL macromer (Mn= 2.0 kDa) as a hydrophobic component. Hydrophilic oxyethylene sequences were generated using poly(ethylene oxide)s (PEO)s of different molecular mass (Mn= 300-600 Da) in the case of PEEs, or 4,7,10-trioxa-1,13-tridecanediamine (Trioxy) and PEO150 (Mn= 150 Da) in the case of PEEAs. The copolymers showed a decrease of Tm and crystallinity values as compared with PCL. Within each class of copolymers, the bulk hydrophilicity increased with increasing the number of oxyethylene groups in the chain repeat unit. PEEAs were more hydrophilic than PEEs with a similar number of oxyethylene groups. Discrete spherical particles were prepared by both PEEs and PEEAs and their BSA encapsulation efficiency related to copolymer properties. Interestingly, the insertion of short hydrophilic segments is enough to significantly affect protein distribution inside microspheres and its release profiles, as compared to PCL microspheres. Different degradation rates and mechanisms were observed for copolymer microspheres, mainly depending on the distribution of oxyethylene units along the chain. The results highlight that a fine control over the structural parameters of amphiphilic PCL-based multi-block copolymers is a key factor for their application in the field of protein delivery.

Characterization of polymeric poly(ϵ‐caprolactone) injectable implant delivery system for the controlled delivery of contraceptive steroids

Contraceptive steroids levonorgestrel (LNG) and ethinyl estradiol (EE) have been encapsulated with poly(epsilon-caprolactone) (PCL) microspheres using a w / o /w double emulsion method. The microspheres prepared were smooth and spherical, with a mean size from 8-25 microm. In vitro release profiles of microspheres showed a trend of increasing initially at the first week, and thereafter the release was sustained. At the end of the seventh week LNG/EE from 1:5 and 1:10 PCL microspheres were 60 and 48%, 52 and 46%, respectively. An in vitro degradation study shows that at the 20th week the microspheres maintained the surface integrity. The PCL microspheres showed a triphasic in vivo release profile with an initial burst effect due to the release of the steroid adsorbed on the microsphere surface, a second sustained release phase due to the steroid diffusion through the pores or channels formed in the polymer matrix, and third phase due to polymer bioerodible. Histological examination of PCL microspheres injected intramuscularly into thigh muscle of a rat showed a minimal inflammatory reaction demonstrating that contraceptive steroid-loaded microspheres were biocompatible. The level of inflammatory cytokines determined by immunostaining for IL-1alpha, the tissue response to formulations at the first week was considered mild, whereas at the end of the 20th week the inflammatory response ceased. Thus, this study helped us to evaluate the feasibility of using these microspheres as a long-acting biodegradable drug delivery system for contraceptive steroids.

Effect of Vitamin E TPGS on immune response to nasally delivered diphtheria toxoid loaded poly(caprolactone) microparticles

The nasal mucosa has many advantages as a potential site for drug and vaccine delivery. The present study has sought to exploit this route of delivery using microparticles composed of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as a matrix material blended with poly(caprolactone) for nasal immunisation with diphtheria toxoid. Particles were prepared by a double emulsion method, followed by spray drying and the effect of TPGS on size, zeta potential, loading and release of antigen was assessed. Particles composed of TPGS–PCL blends were spherical, smooth and monodisperse, displaying increasing yields after spray drying with increasing concentrations of TPGS. The immune response to diphtheria toxoid loaded PCL-TPGS microspheres after nasal administration was shown to be higher than that achieved using PCL microspheres alone. We conclude that TPGS shows significant potential as a novel adjuvant either alone or in combination with an appropriate delivery system.

Preparation, characterization and in vitro release properties of ibuprofen-loaded microspheres based on polylactide, poly(϶-caprolactone) and their copolymers

In this paper, ibuprofen was encapsulated into microspheres by oil-in-water (o/w) emulsion solvent evaporation method. Biodegradable polymers with certain compositions and characteristics such as polylactide (PLA), poly(ϵ-caprolactone) (PCL) and their block copolymer were used to prepare the microspheres. The results indicate that, under the same processing conditions, the drug entrapment efficiency was similar (∼80%) for microspheres prepared with PLA and P(LA-b-CL) (78.7/21.3 by mole), but it was only 25.4% for PCL microspheres. The in vitro drug release rate decreased in the order of PCL, P(LA-b-CL) (78.7/21.3 by mole) and PLA microspheres. PCL microspheres showed more serious burst release during the first day (almost 80%) than P(LA-b-CL) (50%) and PLA microspheres (18%). The complete ibuprofen release duration from the last two kinds of microspheres exceeded 1 month. Characterization of the microspheres by differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and polarized optical microscope (POM) revealed that ibuprofen was amorphous in PCL microspheres and partially crystalline in P(LA-b-CL) and PLA microspheres. The different release behaviour of ibuprofen from the three kinds of microspheres could be attributed to the different crystallinity of the studied polymers and drug dispersion state in polymer matrices. All the above results suggest that the copolymer with a certain ratio of lactide to ϵ-caprolactone could have potential applications for long-term ibuprofen release.

Preparation and characterization of 5‐fluorouracil‐loaded poly(ϵ‐caprolactone) microspheres for drug administration

AbstractMicrospheres of 5‐fluorouracil‐loaded poly(ϵ‐caprolactone) (PCL) were prepared by spray‐drying procedure. The degradation characteristics and 5‐fluorouracil release in vitro as well as in vivo were investigated. The average molecular weight, weight loss, crystallinity, and morphology of microspheres were determined using GPC, DSC, and SEM, at different times during the in vitro degradation process. The size distribution of the microspheres indicated that most of the particles were smaller than 3 µm. A 30% weight loss as well as an increase of crystallinity were observed on day 330 of incubation. The percentage of entrapment efficiency of 5‐FU was 49% (44 µg of drug/mg of microspheres). The in vitro total release of 5‐FU took place in 8 days. Determination of plasma 5‐FU concentration in vivo using s.c. injection of 5‐FU‐loaded microspheres in Wistar rats by HPLC with analysis of data using a non‐compartmental model showed drug in plasma 18 days after administration with a maximum drug concentration of 1.5 µg/ml at 96 h. Pharmacokineticallly, a significant increase of AUC and MRT of 5‐FU with regard to the administration of the drug in solution. Scanning electron microscopy and histological studies indicated that the microspheres were surrounded by connective tissue and inflammatory processes were not evident. As a result of these characteristics, the 5‐FU‐loaded PCL microspheres could be used for drug delivery. Drug Dev Res 63:41–53, 2004. © 2004 Wiley‐Liss, Inc.

Contribution of Supercritical CO2 to the Preparation of Aliphatic Polyesters and Materials Thereof

AbstractThis paper is a short review of the most recent achievments of CERM in the synthesis of poly (ϵ‐caprolactone) (PCL) and polylactides (PLA) in supercritical carbon dioxide (sc CO2). In addition to the macromolecular engineering of these aliphatic polyesters, nanocomposites and PCL microspheres have been prepared with the assistance of this supercritical fluid.

Preparation and characterization of injectable microspheres of contraceptive hormones

Present study describes the development of a new formulation of levonorgestrel and ethinylestradiol based on double emulsion-solvent evaporation technique using poly(ε-caprolactone) (PCL) as biodegradable polymer. The effect of polymer concentration on microspheres and entrapment of drug into microspheres were studied. PCL was selected because of its hydrophobicity and advantages over other biodegradable polymers. Characterization of biodegradable polymer used for controlled drug delivery is essential to ensure reproducibility of in vitro and in vivo performances. The selected characterisation techniques established for PCL microspheres include its loading and entrapment efficiencies, DSC to analyse thermal behaviour, SEM to observe surface morphology, drug content of microspheres and in vitro release of drugs from microspheres. The SEM reports showed that microspheres were with smooth surface and DSC thermograms revealed no interaction between drug and polymer. The entrapment was found to be 58 and 47% for 1:10 and 1:5 batches and in vitro release studies showed that about 69.7% of LNG and 66.7% of EE from 1:10 batch and about 80% of LNG and 75.5% of EE from 1:5 batch for 150 days.