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Dive into the research topics where Matías Llabrés is active.

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Featured researches published by Matías Llabrés.


Journal of Chromatography B: Biomedical Sciences and Applications | 2000

Development of two high-performance liquid chromatographic methods for the analysis and characterization of insulin and its degradation products in pharmaceutical preparations

Alexis Oliva; José B. Fariña; Matías Llabrés

Two high-performance liquid chromatography methods either in reversed-phase or as size exclusion separation mode were developed and validated for the analysis of insulin and its degradation products in pharmaceutical preparations. The results show the reliability of the analytical methods for the intended used. The static and dynamic light scattering were used to characterize the insulin and its derivatives. The absolute molecular weight of human insulin monomer and dimer were 5800 and 12400 Da respectively whereas its z-average root mean square radius were 21.6+/-0.4 and 40.5+/-0.7 nm, respectively. In contrast, the hydrodynamic diameter varied between 2.69 and 5.50 nm, depending of the association behavior of insulin.


Journal of Pharmaceutical and Biomedical Analysis | 2001

Comparative study of protein molecular weights by size-exclusion chromatography and laser-light scattering.

Alexis Oliva; Matías Llabrés; José B. Fariña

High-performance size-exclusion chromatography (SEC) based on UV-Vis detection is a relative technique for molecular weight determination whereas procedure based on multi-angle laser light scattering (MALLS) is both rapid and absolute. The two methods using recombinant human growth hormone (rHGH) and beta-lactoglobulin samples were compared. A calibration curve for the chromatographic system was generated based on standard proteins and the data were fitted by least squares to a third order polynomial model. The molecular weight from the conventional SEC method for both proteins was higher than the reported values. The molecular weight of rHGH from MALLS was 23.1+/-0.57 and 21.2+/-0.80 kDa using differential refractive index (SEC-MALLS/RI) and UV (SEC-MALLS/UV-Vis) detectors as mass detectors. Both values agree, within experimental error with the molecular weight sequence of rHGH, 22.1 kDa. In contrast, the molecular weight from LS for beta-lactoglobulin was 22.5+/-0.55 kDa by SEC-MALLS/RI and 23.0+/-1.22 kDa by SEC-MALLS/UV-Vis, respectively, values always higher than those supplied by the manufacturer, 18.4 kDa. The reproducibility of the SEC-MALLS/UV-Vis method versus the SEC-MALLS/RI method was performed using the concordance correlation coefficient. The methods reproducibility was accepted by assuming a precision of 98% and a 1% loss in precision.


International Journal of Pharmaceutics | 2003

New approach to stability assessment of protein solution formulations by differential scanning calorimetry

Madaisy Cueto; M. Jesús Dorta; Obdulia Munguía; Matías Llabrés

A central composite rotate second order design was used to evaluate chicken egg-white lysozyme (lysozyme) thermal stability at different pH, and lysozyme, sucrose and 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) concentrations, by means of differential scanning calorimetry (DSC). Four measurements were used to characterize the thermogram: the calorimetric enthalpy (DeltaH(cal)), the temperature at maximum heat flux (T(m)), the ratio of maximum heat flux over thermogram area (C(pT(m))/area), and the ratio of calorimetric enthalpies from the second heating cycle to the first enthalpy (R(DeltaH(cal))). These parameters were interpreted using the three step equilibrium model for protein degradation (irreversible degradation following reversible unfolding). In addition to degradation, increased lysozyme concentration leads to a sizeable decrease in DeltaH(cal) and area ratio, showing how it causes protein aggregation; which in turn promotes protein degradation. DeltaH(cal) and T(m) reach maxima at pH 5, R(DeltaH(cal)) at pH 4.19, while C(pT(m))/area increases linearly with pH, revealing a specific base catalysis of the irreversible degradation step. The role of sucrose concentration in lysozyme stabilization is linked to the stabilization of the unfolded moiety; it neither affects DeltaH(cal) nor C(pT(m))/area, but increases both T(m) and R(DeltaH(cal)). No influence of HPbetaCD on the stability of lyzozyme was observed, probably due to low concentrations employed.


Journal of Pharmaceutical and Biomedical Analysis | 2003

Effect of high shear rate on stability of proteins: kinetic study.

Alexis Oliva; Ana Santoveña; José B. Fariña; Matías Llabrés

Size-exclusion chromatography (SEC) was used to monitor the time-course of protein degradation induced by high shear rates during the formulation and manufacture of controlled-release pharmaceutical dosage forms. SEC with multi-angle laser light-scattering (MALLS) detection was used to characterize the aggregation products, determining their absolute molecular weight. A stability-indicating method was developed and validated to obtain reliable drug degradation data. The results obtained according to the ICH guidelines confirm that the system and methods proposed are suitable for their intended use. The degradation kinetics are influenced by the type of protein and the effect of the shear rate on their stability. Reversible pseudo-first order degradation kinetics were observed for bovine beta-lactoglobulin, whereas for human (HSA) and bovine serum albumin (BSA), a monomer-dimer transition was observed, independently of the rate of shear. However, trimer formation was also observed for HSA, especially at high shear rates. The kinetic model may thus be described as a two-step process: a monomer-dimer, and dimer-trimer transition.


International Journal of Pharmaceutics | 2002

Potential applications of PLGA film-implants in modulating in vitro drugs release

M. J. Dorta; Ana Santoveña; Matías Llabrés; José B. Fariña

In this work we evaluate poly(lactic/glycolic) acid (PLGA) film-implants as potential biodegradable devices for controlled release of two different drugs: 5-Fluorouridine (5-FUR), a conventional low molecular weight water-soluble compound and SPf66 malaria vaccine, a therapeutic synthetic polypeptide. Three types of devices were prepared by solvent-casting techniques alone or combined with compression method: simple monolithic discs (SMD), multilayer discs with a central monolithic layer (MLDM), and multilayer discs with a central drug-reservoir (MLDR). For the highly water-soluble drug, 5-FUR, in vitro release from SMD showed an initial burst (24% in 2 h) followed by prolonged release over 20 days. In contrast, from a MLDM (two drug-free PLGA discs were added to the SMD) showed an initial lag-time of 12 days followed by a very fast second release phase. Finally, when the load of this system was increased from 3 to 9%, an extended release over 20 days with a low burst effect was obtained. For SPf66, the central reservoir containing the synthetic polypeptide MLDR reduces the possibility of degradation due to peptide contact with polymer solution. When four layers were added, 10 days sustained-release was obtained without any burst effect. With six layers a moderate pulse was obtained, 18-22 days from the beginning of the release. The results show the suitability of the proposed devices to control release and avoid the burst effect with highly water-soluble drugs; as well as modulate in vitro peptide release.


Biomaterials | 2001

In vivo}in vitro study of biodegradable methadone delivery systems

C.M Negrı́n; Araceli Delgado; Matías Llabrés; Carmen Évora

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.


International Journal of Pharmaceutics | 1996

Influence of temperature and shaking on stability of insulin preparations: Degradation kinetics

Alexis Oliva; JoséB. Fariña; Matías Llabrés

Abstract Two commercial human insulin preparations were stored at different conditions in order to study the influence of temperature and shaking on their stability. Deamidation was the predominant degradation process in the case of the suspension, while dimerization prevailed for the solution, mainly when shaking was applied. The formation process of desamido B3 insulin follows first order kinetics; the dimer formation fit better the Prout-Thompkins nucleation model. Results obtained for suspension confirm the suitability of Arrhenius plot for both storage conditions. However, in the case of solution, the Arrhenius relationship was only valid when it was stored without shaking, since with shaking no linearity was observed in the temperature range studied.


Journal of Controlled Release | 1999

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

R.V Diaz; Matías Llabrés; Carmen Évora

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.


International Journal of Pharmaceutics | 1996

Preparation and evaluation of insulin-loaded poly(dl-lactide) microspheres using an experimental design

I. Soriano; Carmen Évora; Matías Llabrés

Twenty formulations of bovine insulin in poly(dl-lactide) (dl-PLA) microspheres were elaborated to study the influence of polymer molecular weight, insulin content and polyvinylalcohol (PVA) concentration on microsphere characteristics and in vitro release profile. Ten of them released nearly all the incorporated insulin in 24 h. Of the rest, four were porous, presenting a burst effect over 40% and releasing 70% in 48 h. The other six formulations were non-porous; four released the insulin in 1 week and the other two only released 28% in 15 days. None of these 10 formulations were able to release the total amount of incorporated insulin, probably due to the adsorption of insulin by the polymer. From the results obtained with the experimental design, one more lot was prepared and tested in vitro and in vivo. The in vitro release profile was much slower than the in vivo one; 16% and 28% were released in vitro on the first day and in the following 10 days, respectively, while the corresponding figures for in vivo release were 60% and 90%.


Journal of Pharmacy and Pharmacology | 1999

Stability Study of Human Serum Albumin Pharmaceutical Preparations

Alexis Oliva; Ana Santoveña; Matías Llabrés; José B. Fariña

The influence of temperature on the stability of human serum albumin (HSA) pharmaceutical preparations has been studied by size‐exclusion high‐performance liquid chromatography with multi‐angle laser‐light‐scattering detection and by particle‐size analysis.

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Alexis Oliva

University of La Laguna

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Angel Concheiro

University of Santiago de Compostela

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Carmen Alvarez-Lorenzo

University of Santiago de Compostela

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M. J. Dorta

University of La Laguna

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