Nuestros investigadores

María del Carmen Dios Viéitez

Farmacia y Tecnología Farmacéutica
Facultad de Farmacia y Nutrición. Universidad de Navarra
Departamento de Tecnología y Química Farmacéuticas
Facultad de Farmacia y Nutrición. Universidad de Navarra
Líneas de investigación
Nuevas formas farmacéuticas ; estudios biofarmacéuticos, farmacocinéticos y farmacocinéticos-farmacodinámicos (inmunosupresores, antitumorales, etc)., Tecnología Farmacéutica, Biofarmacia y Farmacocinética

Publicaciones científicas más recientes (desde 2010)

Autores: Guada Ramírez, Melissa; Beloqui, A.; Kumar, M. N. ; et al.
ISSN 0168-3659  Vol. 225  2016  págs. 269 - 282
Cyclosporine A (CsA) is a well-known immunosuppressive agent that gained considerable importance in transplant medicine in the late 1970s due to its selective and reversible inhibition of T-lymphocytes. While CsA has been widely used to prevent graft rejection in patients undergoing organ transplant it was also used to treat several systemic and local autoimmune disorders. Currently, the neuro-and cardio-protective effects of CsA (CiCloMulsion (R); NeuroSTAT (R)) are being tested in phase II and III trials respectively and NeuroSTAT (R) received orphan drug status from US FDA and Europe in 2010. The reformulation strategies focused on developing Cremophor (R) EL free formulations and address variable bioavailability and toxicity issues of CsA. This reviewis an attempt to highlight the progressmade so far and the roomavailable for further improvements to realize the maximum benefits of CsA.
Autores: Guada Ramírez, Melissa; Lana Vega, Hugo; Gil Royo, Ana Gloria; et al.
ISSN 0939-6411  Vol. 101  2016  págs. 112 - 118
The pharmacodynamic effect and the safety of cyclosporine A lipid nanoparticles (CsA LN) for oral administration were investigated using Sandimmune Neoral as reference. First, the biocompatibility of the unloaded LN on Caco-2 cells was demonstrated. The pharmacodynamic response and blood levels of CsA were studied in Balb/c mice after 5 and 10days of daily oral administration equivalent to 5 and 15mg/kg of CsA in different formulations. The in vivo nephrotoxicity after 15days of treatment at the high dose was also evaluated. The results showed a significant decrease in lymphocyte count (indicator of immunosuppression) for the CsA LN groups which was not observed with Sandimmune Neoral. CsA blood levels remained constant over the time after treatment with LN, whereas a proportional increase in drug blood concentration was observed with Sandimmune Neoral. Therefore, CsA LN exhibited a better pharmacological response along with more predictable pharmacokinetic information, diminishing the risk of toxicity. Moreover, a nephroprotective effect against CsA related toxicity was observed in the histopathological evaluation when LN containing Tween 80 were administered. Therefore, our preliminary findings suggest LN formulations would be a good alternative for CsA oral delivery, enhancing efficacy and reducing the risk of nephrotoxicity.
Autores: Guada Ramírez, Melissa; Lasa Saracíbar, Beatriz; Lana Vega, Hugo; et al.
ISSN 0378-5173  Vol. 500  Nº 1 - 2  2016  págs. 154 - 161
In the present work, the feasibility of cyclosporine A lipid nanoparticles (CsA LN) for oral administration was investigated. Three CsA LN formulations were developed using Precirol as lipid matrix, one stabilized with Tween(®) 80 (Tw) and the other two with mixtures of phosphatidylcholine or Pluronic(®) F127 with taurocholate (Lec:TC and PL:TC, respectively). The physical characteristics of the LN were studied under gastrointestinal pH and their integrity was found to be dependent on the stabilizers. The in vitro intestinal permeability was assessed with a human colon adenocarcinoma cell model and in vivo pharmacokinetic and biodistribution studies were performed in Balb/c mice using Sandimmune Neoral(®) as reference. In vitro results showed the highest CsA permeability with the LN containing Lec:TC. In contrast, the best in vivo performance was achieved from the LN containing Tw. The bioavailability of CsA was matched and even enhanced with Precirol nanoparticles. This study suggests the suitability of LN as promising vehicles for CsA oral delivery.
Autores: Guada Ramírez, Melissa; Beloqui, A.; Alhouayek, M.; et al.
ISSN 0378-5173  Vol. 503  Nº 1 - 2  2016  págs. 196 - 198
Cyclosporine A (CsA) is a well-known immunosuppressive agent used as rescue therapy in severe steroid-refractory ulcerative colitis (UC). However, toxicity issues associated with CsA when administered in its commercially available formulations have been reported in clinical practice. Since nanotechnology has been proposed as a promising strategy to improve safety and efficacy in the treatment of inflammatory bowel disease (IBD), the main purpose of this study was to evaluate the effect of oral administration of CsA-loaded lipid nanoparticles (LN) in the dextran sodium sulfate (DSS)-induced colitis mouse model using Sandimmune Neoral (R) as reference. The results showed that the formulations used did not decrease colon inflammation in terms of myeloperoxidase activity (MPO), tumor necrosis factor (TNF)-alpha expression, or histological scoring in the acute stage of the disease. However, further studies are needed in order to corroborate the efficacy of these formulations in the chronic phase of the disease.
Autores: Guada Ramírez, Melissa; Sebastian, V.; Irusta, S.; et al.
ISSN 1176-9114  Vol. 10  2015  págs. 6541 - 6553
Cyclosporine A (CsA) is an immunosuppressant commonly used in transplantation for prevention of organ rejection as well as in the treatment of several autoimmune disorders. Although commercial formulations are available, they have some stability, bioavailability, and toxicity related problems. Some of these issues are associated with the drug or excipients and others with the dosage forms. With the aim of overcoming these drawbacks, lipid nanoparticles (LN) have been proposed as an alternative, since excipients are biocompatible and also a large amount of surfactants and organic solvents can be avoided. CsA was successfully incorporated into LN using the method of hot homogenization followed by ultrasonication. Three different formulations were optimized for CsA oral administration, using different surfactants: Tween(®) 80, phosphatidylcholine, taurocholate and Pluronic(®) F127 (either alone or mixtures). Freshly prepared Precirol nanoparticles showed mean sizes with a narrow size distribution ranging from 121 to 202 nm, and after freeze-drying were between 163 and 270 nm, depending on the stabilizer used. Surface charge was negative in all LN developed. High CsA entrapment efficiency of approximately 100% was achieved. Transmission electron microscopy was used to study the morphology of the optimized LN. Also, the crystallinity of the nanoparticles was studied by X-ray powder diffraction and differential scanning calorimetry. The presence of the drug in LN surfaces was confirmed by X-ray photoelectron spectroscopy. The CsA LN developed preserved their physicochemical properties for 3 months when stored at 4°C. Moreover, when the stabilizer system was composed of two surfactants, the LN formulations were also stable at room temperature. Finally, the new CsA formulations showed in vitro dose-dependent immuno-suppressive effects caused by the inhibition of IL-2 levels secreted from stimulated Jurkat cells. The findings obtained in this paper suggest that new lipid nanosystems are a good alternative to produce physicochemically stable CsA formulations for oral administration.
Autores: Pecchio, M.; Renedo Omaechevarria, María Jesús; Sanz Ramos, Patricia; et al.
ISSN 2167-9312  Vol. 2  Nº 2  2014  págs. 161 - 168
Conventional marketed formulations of cyclosporine A (CsA) have considerable limitations owing to poor drug bioavailability and extensive inter- and intrapatient variability. Nanoparticles are currently used as an alternative to solve these issues, but attainment of an effective nanoformulation loaded with CsA is a significant challenge. In this study, we described the preparation and characterization of poly[methyl vinyl ether-co-maleic anhydride (PVM/MA) nanoparticles loaded with CsA and examined in vitro release of the drug from the novel formulation. Derivatives of cyclodextrin were used to improve drug loading in the nanoparticles and modulate the CsA release profile. Nanoparticles were prepared using a solvent displacement method, and characterized based on particle size, zeta potential, encapsulation efficiency, product yield, X-ray and thermal analyses. Our results showed that the nanoparticles are ~100¿243 nm in size and the amount of CsA loaded is higher when the nanoformulation contains hydroxypropyl-ß-cyclodextrin than hydroxypropyl-¿-cyclodextrin. Furthermore, these nanoparticles showed biphasic release behaviour in physiological media, consistent with characteristics of nanoparticle drug delivery systems in general. This biphasic profile indicates that CsA is released from nanoparticles through diffusion in the initial phase and subsequent time-period. The in vitro release profile of CsA from nanoformulations with hydroxypropyl-¿-cyclodextrin additionally showed a higher initial burst effect in all simulated physiological media used. Our results collectively support the potential utility of a nanoformulation with hydroxypropyl-ß-cyclodextrin in improving the bioavailability of CsA in vivo.
Autores: Pecchio González, Marisin; Salman, Hesham; Irache Garreta, Juan Manuel; et al.
ISSN 0250-474X  Vol. 76  Nº 2  2014  págs. 132 - 137
A simple and reliable high performance liquid chromatography method was developed and validated for the rapid determination of cyclosporine A in new pharmaceutical dosage forms based on the use of poly (methylvinylether¿co¿maleic anhydride) nanoparticles. The chromatographic separation was achieved using Ultrabase C18 column (250×4.6 mm, 5 ¿m), which was kept at 75°. The gradient mobile phase consisted of acetonitrile and water with a flow rate of 1 ml/min. The effluent was monitored at 205 nm using diode array detector. The method exhibited linearity over the assayed concentration range (22¿250 ¿g/ml) and demonstrated good intraday and interday precision and accuracy (relative standard deviations were less than 6.5% and the deviation from theoretical values is below 5.5%). The detection limit was 1.36 ¿g/ml. This method was also applied for quantitative analysis of cyclosporine A released from poly (methylvinylether¿co¿maleic anhydride) nanoparticles. Key words: Cyclosporine A, HPLC¿UV, nanoparticles, poly (methylvinylether¿co¿maleic anhydride), oral administration
Autores: Guada Ramírez, Melissa; Imbuluzqueta Iturburua, Edurne; Estella Hermoso de Mendoza, Ander; et al.
ISSN 1570-0232  Vol. 927  2013  págs. 164 - 172
Cyclosporine A (CyA) is an immunosuppressant cyclic undecapeptide used for the prevention of organ transplant rejection and in the treatment of several autoimmune disorders. An ultra high performance liquid chromatography tandem mass spectrometry method (UHPLC-MS/MS) to quantify CyA in lipid nanosystems and mouse biological matrices (whole blood, kidneys, lungs, spleen, liver, heart, brain, stomach and intestine) was developed and fully validated. Chromatographic separation was performed on an Acquity UPLC (R) BEH C18 column with a gradient elution consisting of methanol and 2 mM ammonium acetate aqueous solution containing 0.1% formic acid at a flow rate of 0.6 mL/min. Amiodarone was used as internal standard (IS). Retention times of IS and CyA were 0.69 min and 1.09 min, respectively. Mass spectrometer operated in electrospray ionization positive mode (ESI+) and multiple reaction monitoring (MRM) transitions were detected, m/z 1220.69 -> 1203.7 for CyA and m/z 646 -> 58 for IS. The extraction method from biological samples consisted of a simple protein precipitation with 10% trichloroacetic acid aqueous solution and acetonitrile and 5 mu L of supernatant were directly injected into the UHPLC-MS/MS system. Linearity was observed between 0.001 mu g/mL-2.5 mu g/mL (r >= 0.99) in all matrices. The precision expressed in coefficient of variation (CV) was below 11.44% and accuracy in bias ranged from -12.78% to 7.99% including methanol and biological matrices. Recovery in all cases was above 70.54% and some matrix effect was observed. CyA was found to be stable in post-extraction whole blood and liver homogenate samples exposed for 6h at room temperature and 72 h at 4 degrees C. The present method was successfully applied for quality control of lipid nanocarriers as well as in vivo studies in BALB/c mice.
Autores: Lasa Saracíbar, Beatriz; Estella Hermoso de Mendoza, Ander; Guada Ramírez, Melissa; et al.
ISSN 1742-5247  Vol. 9  Nº 10  2012  págs. 1245 - 1261
Introduction: Cancer is a leading cause of death worldwide and it is estimated that deaths from this disease will rise to over 11 million in 2030. Most cases of cancer can be cured with surgery, radiotherapy or chemotherapy if they are detected at an early stage. However, current cancer therapies are commonly associated with undesirable side effects, as most chemotherapy treatments are cytotoxic and present poor tumor targeting. Areas covered: Lipid nanoparticles (LN) are one of the most promising options in this field. LN are made up of biodegradable generally recognized as safe (GRAS) lipids, their formulation includes different techniques, and most are easily scalable to industrial manufacture. LN overcome the limitations imposed by the need for intravenous administration, as they are mainly absorbed via the lymphatic system when they are administered orally, which improves drug bioavailability. Furthermore, depending on their composition, LN present the ability to cross the blood-brain barrier, thus opening up the possibility of targeting brain tumors. Expert opinion: The drawbacks of chemotherapeutic agents make it necessary to invest in research to find safer and more effective therapies. Nanotechnology has opened the door to new therapeutic options through the design of formulations that include a wide range of materials and formulations at the nanometer range, which improve drug efficacy through direct or indirect tumor targeting, increased bioavailability and diminished toxicity.
Autores: Pecchio González, Marisin; Renedo Omaechevarria, María Jesús; Dios Viéitez, María del Carmen
ISSN 0973-8916  Vol. 5  Nº 4  2011  págs. 1383 - 1396