Biomedical subjects

C Evora

Publications and source records attributed to C Evora.

16 recordsLinked to original sources

PubMed2006

Biodegradable implantable fluconazole delivery rods designed for the treatment of fungal osteomyelitis: influence of gamma sterilization.

Fluconazole poly(D,L-lactic) acid (PLA) and poly(L-lactic) acid (L-PLA) implantable delivery rods were studied, in vitro and in vivo, as an alternative treatment of fungal osteomyelitis. Implantable rods loaded with 5% fluconazole (FLU) were prepared by the injection-molding method and sterilized by gamma-irradiation at a dose of 25 kGy. Loading efficiency, physical chemistry (high performance liquid chromatography, X-ray diffraction, gel permeation chromatography), and in vitro and in vivo release assays were performed to evaluate the novel delivery systems and the sterilization effect on implant characteristics. In spite of polymer degradation after gamma-irradiation, the loading efficiency, chemical stability, and crystallographic structure of FLU were not affected. In vivo studies were carried out in femoral bone marrow of rabbits. Approximately 85 and 80% of the total dose were released within 12 and 4 weeks from PLA and L-PLA rods, respectively. This showed a faster release rate of FLU in vivo than in vitro, showing almost zero-order kinetics from PLA rods.

Animals↗

PubMed2005

PLA-PEG particles as nasal protein carriers: the influence of the particle size.

Previous studies have shown that PLA-PEG nanoparticles (NP) are able to enhance the transport of the encapsulated model protein, tetanus toxoid (TT), across the rat nasal mucosa. The aim of this work was to study if the size of PLA-PEG particles affects the nasal transport of the encapsulated protein and, also, the potential contribution of blank nanoparticles to the transport of the free protein. To achieve this purpose, 125I-TT was encapsulated into PLA-PEG particles of different sizes (200 nm, 1.5, 5 and 10 microm) prepared by the water-in-oil-in-water solvent evaporation technique. Firstly, in order to investigate the carrier role of the particles, two series of either conscious or anaesthetized rats were nasally treated with 125I-TT-loaded NP, free 125I-TT, and a physical mixture of blank NP and free 125I-TT. Secondly, the influence of the particle size on the nasal transport of TT encapsulated into PLA-PEG particles was evaluated in conscious rats. The amount of radioactivity recovered in the blood compartment, lymph nodes and other relevant tissues was monitored for up to 24h. Finally, the nasal bioavailability of 125I-TT-loaded PLA-PEG NP was calculated. The results indicated that the use of anaesthesia enhances the transport of 125I-TT and that the physical presence of PLA-PEG NP does not affect the transport of the toxoid. In contrast, when TT was encapsulated into the particles its transport across the nasal mucosa of conscious rats was significantly enhanced. Furthermore, the efficacy of this transport was related to the particle size, reaching the most important transport for the smallest particle size. The intensity of this transport was also illustrated by the high nasal bioavailability of TT encapsulated into nanoparticles (200 nm) (F = 70-80%). These results led us to conclude that PLA-PEG NP can be accepted as nasal protein carriers for nasal administration.

Administration, Intranasal↗

PubMed2005

Two-month ciprofloxacin implants for multibacterial bone infections.

A ciprofloxacin implant formulation composed of 12% hydroxyapatite, 36% tricalcium phosphate, 12% poly(DL-lactide) (PLA) and 40% ciprofloxacin was characterized in vivo for use in treatment of multibacterial bone infection. After the implant was inserted in the femur of rabbits, approximately 90% of the total ciprofloxacin was released within 8 weeks, maintaining therapeutic levels in the femur and tibia. Throughout the femoral cortex and marrow these remained higher than the minimum inhibitory concentrations (MIC) against the most common pathogens causing osteomyelitis. Levels in tibia cortex were also above MIC for 6 weeks. The implant was characterized in terms of polymer degradation and morphological and crystallographic changes. X-ray analyses confirmed the osteoconductivity and biocompatibility of these materials. The sequential changes in the femur were those of a normal surgical trauma reaction followed by a repair process. All the results confirmed that ciprofloxacin release is limited by its low solubility, and that implant erosion and bone ingrowth into the implants enhance the antibiotic release.

Animals↗

PubMed2004

Methadone implants for methadone maintenance treatment. In vitro and in vivo animal studies.

Methadone implant formulations elaborated with polylactide-co-glycolide (PLGA) and polylactic acid (PLA) for 1 week and 1 month release duration, respectively, were evaluated in vitro and in vivo. One-week implants prepared with methadone clorhydrate, methadone clorhydrate/methadone base blend or methadone base were tested in vitro. Results showed that the methadone release rate decreased as the methadone base increased. The best release profile was achieve when the methadone base implants, made by compression of a 50:50 PLGA (12 kDa) and methadone base mix, were coated with PLA (30 kDa). For 1-month implants, the methadone base load was increased to 65% and PLA of 30 kDa was used as a matrix component. In this case the implants were coated with the same polymer. Deconvolution methods could not be used for in vivo release estimation because an increase in methadone clearance was observed with methadone clorhydrate solution multiple-dose treatment. Therefore the amount of drug remaining within the implants was evaluated and the deconvolution was only used to establish the release profile range. The upper limit was estimated applying the absorption-disposition function obtained after multiple-dose administrations while the lower curve was estimated using the single-dose function. Methadone serum levels were maintained around 200 ng/ml during 1 week and approximately 5 weeks with the optimised implants. In vivo-in vitro correlations were always very good with slopes near 1.

Animals↗

PubMed2004

PEG-PLA nanoparticles as carriers for nasal vaccine delivery.

This report presents an overview of the potential of nanoparticles as nasal carriers for drug/vaccine administration. In addition, this report shows, for the first time, the efficacy of polylactic acid nanoparticles coated with a hydrophilic polyethyleneglycol coating (PEG-PLA nanoparticles) as carriers for the nasal transport of bioactive compounds. For this purpose, tetanus toxoid (TT), a high molecular weight protein (Mw 150,000 Da), was chosen as a model antigen and encapsulated in the PEG-PLA nano- and microparticles (200 nm and 1.5 microm respectively). These nanosystems were first characterized for their stability in the presence of lysozyme and also for their size, electrical charge, loading efficiency, in vitro release of antigenically active toxoid and afterwards, these formulations were administered intranasally to mice and the systemic and mucosal anti-tetanus responses were evaluated for up to 24 weeks. Additionally, PEG-PLA particles labeled with rhodamine 6G were administered intranasally to rats in order to visualize their interaction with the nasal mucosae by fluorescence microscopy. Their behavior was compared with that of the well known PLA nanoparticles (200 nm). The results showed that PLA nanoparticles suffered an immediate aggregation upon incubation with lysozyme, whereas the PEG-coated nanoparticles remained totally stable. The antibody levels elicited following i.n. administration of PEG-coated nanoparticles were significantly higher than those corresponding to PLA nanoparticles. Furthermore, PEG-PLA nanoparticles generated an increasing and a long lasting response. The qualitative fluorescence microscopy studies revealed that PEG-PLA particles are able to cross the rat nasal epithelium. These studies indicate that the PEG coating around the particles has a role in stabilizing PLA particles in mucosal fluids and that it facilitates the transport of the nanoencapsulated antigen, hence eliciting a high and long lasting immune response.

Administration, Intranasal↗

PubMed2003

Ciprofloxacin implants for bone infection. In vitro-in vivo characterization.

To elucidate the antibiotic release mechanism from implants composed of calcium phosphates (hydroxyapatite [HAP] and tricalcium phosphate [TCP]), 30 kDa poly(DL-lactide) (PLA-30) and ciprofloxacin (CFX), nine formulations were prepared. In vitro results show that the release rate decreased as compression load and PLA/phosphates ratio increased. In contrast, a slower percent release rate was observed with higher drug loading. Swelling-erosion-disintegration of the implants was observed during the release assays, due to CFX swelling. Two CFX implant formulations were selected for implantation in the femur of rabbits, according to in vitro results. The implant drug loads tested were 10% and 40% of CFX. The in vivo results showed that the antibiotic concentrations achieved throughout the femur were higher for 4 weeks than the minimum inhibitory concentrations (MIC) against the most common of the pathogens that cause osteomyelitis. The CFX-10% implant was considered the best formulation as CFX was totally released within 6 weeks, and therapeutic bone levels were achieved, and the histological and radiographic analyses showed the osteoconductive properties of the materials. All these results showed that CFX release is limited by its solubility, and the erosion-disintegration and bone ingrowth into the implants enhanced the antibiotic release.

Animals↗

PubMed2002

In vitro-in vivo characterization of gentamicin bone implants.

A gentamicin carrier system composed of calcium phosphates, poly(DL-lactide) (PLA) and gentamicin was developed and characterized in vitro and in vivo for use in the prevention and treatment of bone infection. Four formulations were prepared according to an experimental design based on the Hadamard matrix. The technological variables included in the design were: gentamicin loading with respect to the implant weight, weight average molecular weight (M(w)) of the PLA as a compound of the matrix and the presence or absence of a PLA coating of 200 kDa. The variable to be optimized in vitro was the gentamicin release level during the first week. According to this goal, the selected formulation was F-D which was composed of 80% phosphates (25% hydroxyapatite, HAP and 75% tricalcium phosphate, TCP), 20% PLA (M(w), 30 kDa) and 3.5% gentamicin sulfate (GS) and was coated with PLA (M(w), 200 kDa). To elucidate the in vitro release mechanism of this implant, another implant lot (F-X) uncoated, but with identical matrix composition, was prepared. Results showed that the PLA coating delay the gentamicin release, indicating that part of the antibiotic released from the matrix diffuses through the polymer coating film. The selected formulation was tested in the femur of rabbits and showed a faster release rate in vivo than in vitro. This is due to a greater degree of PLA degradation, changes in the phosphate blend, and bone tissue invading the implant. Gentamicin concentration in the areas of the bone closest to the implant was higher than the minimum inhibitory concentration (MIC) against Staphylococcus aureus.

Animals↗

PubMed2001

In vivo-in vitro study of biodegradable methadone delivery systems.

Three one-week controlled-release methadone formulations: polylactic acid microspheres (F-PLA) and poly(lactide-co-glycolide) microspheres (F-PLGA) with 24 and 30% methadone content, respectively, and an implant of 50:50 poly(lactide-co-glycolide): methadone, were evaluated in vitro and in vivo. The implant released the total amount of methadone in vitro while microsphere formulations released the methadone incompletely, 63% from F-PLA and 85% from F-PLGA in a week. Methadone release in vivo was estimated by deconvolution, F-PLGA giving a bioavailability >99% (methadone was totally released in 48h), while the estimated bioavailability of F-PLA was lower than expected. The bioavailability of the implant by deconvolution was around 60%, but absence of methadone in the implant indicated its complete release. These differences are due to an increase in methadone clearance after 72 h of the in vivo experimental period had passed, disturbing a good in vivo-in vitro correlation. A linear correlation between in vitro methadone release and in vivo release calculated from the amount of drug remaining within the implant, was found until the drug was completely released.

Animals↗

PubMed2001

In vivo-in vitro study of biodegradable and osteointegrable gentamicin bone implants.

Three implants composed of phosphate (25% hydroxyapatite, 75% tricalcium phosphate), 20% poly(DL-lactide) (DL-PLA; weight-average molecular weight (Mw), 30 kD) and 3% gentamicin sulphate (GS) were assayed in vitro and in vivo to study their release profiles as potential drug delivery systems to prevent or treat osteomyelitis. To prolong GS release, some implants were coated with poly(lactide-co-glycolide) (PLGA; Mw, 100 kD; I-PLGA) or DL-PLA (Mw, 200 kD; I-PLA). GS levels were measured in bone, kidney and blood after implantation into the femur of rats. The release profiles show a burst in the first few days, followed by a slower release rate. After I-PLA implantation, bone antibiotic concentrations higher than the minimum bactericidal concentration were maintained for 4 weeks. A linear correlation between in vitro and in vivo GS release was found to continue until complete drug release. Histological and radiological analysis showed that the implants were well tolerated and gradual new bone formation was observed.

Absorbable Implants↗

PubMed2000

The role of PEG on the stability in digestive fluids and in vivo fate of PEG-PLA nanoparticles following oral administration.

The aim of the present work was to evaluate if the presence of a polyethylenglycol (PEG) coating around PLA nanoparticles would affect their interaction with biological surfaces, following oral administration to rats. For this purpose, a model antigen, 125I-radiolabeled tetanus toxoid, was encapsulated in PLA and PLA-PEG nanoparticles by a modified water-in-oil-in-water solvent evaporation technique. Firstly, the stability of the nanoparticles in simulated gastrointestinal fluids was evaluated. Results showed an interaction between the nanoparticles and the enzymes of the digestive fluids, this interaction being considerably reduced by the PEG coating around the particles. On the other hand, the PLA forming the nanoparticles was found to be only slightly degraded (9% converted to lactate for PLA nanoparticles and 3% for PLA-PEG nanoparticles) and that the encapsulated tetanus toxoid remained mostly associated to the nanoparticles upon incubation in the digestive fluids for up to 4 h. Finally, the in vivo experiments showed that, after oral administration to rats, the levels of encapsulated radioactive antigen in the blood stream and lymphatics were higher for PLA-PEG nanoparticles than for PLA nanoparticles. In conclusion, the PLA-PEG nanoparticles have a promising future as protein delivery systems for oral administration.

Journal Article↗

PubMed2000

Formulation of calcium phosphates/poly (d,l-lactide) blends containing gentamicin for bone implantation.

Implants to prevent or treat osteomyelitis are described, composed of phosphate/poly(d,l-lactide) blends containing the antibiotic gentamicin. Seven formulations of implants containing 3% gentamicin sulfate (GS) were prepared at 433 MPa and 693 MPa of compression pressure. The blends contained phosphates (25% hydroxyapatite (HAP), 75% tricalcium phosphate (TCP)) and 20% dl-PLA (weight average molecular weight, M(w): 30 kD). To prolong GS release, implants were coated with PLGA (M(w):100 kD) or dl-PLA (M(w): 200 kD). Various durations of GS release from these devices were demonstrated as feasible. Release times of more than 10 weeks were attained with implants coated with dl-PLA (M(w): 200 kD), greatly exceeding the performance of the commercial formulation.

Absorbable Implants↗

PubMed2000

Radiolabelled biodegradable microspheres for lung imaging.

The effect on lung accumulation of modifying the surface compositions of (99m)Tc poly(lactide-co-glycolide) (PLGA) and (99m)Tc poly(ethylene glycol)-poly(lactide-co-glycolide) (PEG-PLGA) microspheres with different surfactants was assessed after intravenous injection into rats. Microspheres were prepared with PLGA or PEG-PLGA by the emulsion solvent evaporation method using polyvinyl alcohol (PVA), polyethylene glycol (PEG), albumin (BSA) or poloxamer 188 as surfactant, in the external aqueous phase. Commercial human albumin microspheres (Sferotec((R)), HAM) were used as reference. According to the European Pharmacopeia, >80% of (99m)Tc-HAM in the size range 10-50 microm, must be accumulated in the lung 15 min after intravenous administration. By modifying the surfactant, the resulting lung accumulation was 99% for (99m)Tc-HAM, and more than 50% for PLGA microspheres prepared with poloxamer 188 (1 and 4%), reaching 67% with 8% Poloxamer 188 and around 30-39% for PLGA and PEG-PLGA microspheres prepared with the other surfactants. PLGA microspheres made with 8% poloxamer 188 gave good quality lung images under a gamma camera for the first few minutes, subsequently liver radioactivity masked lung images.

Animals↗

PubMed1999

One-month sustained release microspheres of 125I-bovine calcitonin. In vitro-in vivo studies.

To obtain a 1-month release formulation of 125I-bovine calcitonin, microspheres were prepared with three different PLA copolymers, PLGA I (mol. wt. [MW]=30000), polyethyleneglycol (PEG)-PLGA (MW=34000) and PLGA II (MW=12000) using the double emulsion method. The release of 125I-bovine calcitonin was assayed in vitro using dialysis bags at 37 degrees C in isotonic phosphate buffer (pH 7.4). The in vitro release results indicated a very slow release rate for an optimal 1-month sustained release formulation. 125I-bovine calcitonin microspheres were administered under the skin on the back of Wistar rats and the radioactivity at the injection site was subsequently measured over a 4-week period. The in vitro and in vivo profiles were affected by the weight average molecular weight of the copolymers. The 125I-bovine calcitonin release rate was faster from microspheres prepared with PLGA II (MW=12000) than from microspheres prepared with higher molecular weight copolymers (PLGA I and PEG-PLGA). Microspheres prepared with PLGA II (MW=12000) release 100% of the dose in 1 month, in vivo release profiles presented two phases, during the first 2 weeks approximately 70% of the 125I-bovine calcitonin injected was released, followed by a second slower phase.

Animals↗

PubMed1998

Relating the phagocytosis of microparticles by alveolar macrophages to surface chemistry: the effect of 1,2-dipalmitoylphosphatidylcholine.

This study examines the potential of 1,2-dipalmitoylphosphatidylcholine (DPPC), a major component of lung surfactant, to reduce the phagocytosis of microspheres by altering the cellular interactions occurring in the alveoli. These microspheres could be designed to act as a controlled delivery system for small molecules, peptides or proteins for pulmonary administration. Microspheres were prepared using poly (lactic-co-glycolic acid) (PLGA, 50/50 and encapsulated peroxidase as a model protein. DPPC was included in some formulations. The interaction of PLGA and DPPC-PLGA microspheres with phagocytic cells was evaluated using lung macrophages in culture. X-ray Photoelectron Spectra (XPS) results indicate that the inclusion of DPPC in the microspheres alters the microsphere surface chemistry, with the DPPC covering a large portion of the microsphere surface. The dominance of DPPC on the microsphere surface is highly beneficial in moderating the interaction occurring between the microspheres and phagocytic cells in the lung. Fluorescent confocal microscopy indicates that only 25% of cells internalized DPPC-coated particles, whereas 70% of those cells exposed to particles without the DPPC coating internalized particles after one hour of incubation.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1997

The Adsorption of Poly(vinyl alcohol) to Biodegradable Microparticles Studied by X-Ray Photoelectron Spectroscopy (XPS)

The design of biodegradable microparticle drug delivery systems with precisely tailored surface properties requires surface analytical methods that can relate polymer chemistry and fabrication parameters to the final surface chemistry of the microparticles. We demonstrate using X-ray photoelectron spectroscopy (XPS) that it is possible to identify significant variations in the surface chemistry of microparticles composed of poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), or block copolymers of PLA or PLGA with poly(ethylene glycol) (PEG). These variations are related to the mechanism by which the microparticle/water interface is stabilized. This, in turn, is controlled by the interfacial surface tensions of the polymers within aqueous environments. For PEG containing block copolymers, adsorption of a surfactant, poly(vinyl alcohol) (PVA), from the aqueous medium onto the polymer is reduced compared with the PLA and PLGA polymers. This reduction is achieved because the PEG segments, within the copolymer structure, stabilize the polymer/water interface. Estimates of the relative amounts of lactide, lactide-co-glycolide, vinyl alcohol, and ethylene glycol monomer units at the microparticle surfaces are presented based on curve-fitting analysis of the XPS data.

Journal Article↗

PubMedDate not supplied

[The bioavailability of drugs administered via a minimal jejunostomy catheter. A clinico-experimental study].

For the evaluation of the bioavailability of drugs administered through a minimal jejunostomy catheter (MJC) postoperatively, ampicillin and metronidazol were administered via this route. The study with ampicillin consisted of a first cross-over experimental trial, in which six dogs were used, and a second based on the experience with four human volunteers. As a measure of the absorption of the drug, the serum levels of the lower plasma area are monitored. The statistical analysis was done by means of logarithmic transformation of the areas, and two-way analysis of variance. The posterior distribution of the relative bioavailability of the drug was obtained by applying a bayesian method. The results showed an important decrease of the ampicillin absorption, while the expected bioavailability when administered through MJC was 0.24, and the 95% interval (0.19, 0.30). The expected bioavailability of metronidazol when administered through MJC was 0.84, and the 95% interval (0.66, 1.07). This new route of drug administration in patients who undergo abdominal surgery, is shown to be of great importance from a clinical point of view, and should be kept in mind.

Adult↗