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Coimbra, Portugal

Mendonca P.V.,University of Coimbra | Moreno M.J.,University of Coimbra | Serra A.C.,University of Coimbra | Simoes S.,Industria Farmaceutica SA | Coelho J.F.J.,University of Coimbra
RSC Advances

This work reports the synthesis of tailor-made polymeric bile acid sequestrants (BAS) by supplemental activator and reducing agent atom transfer radical polymerization (SARA ATRP) using ecofriendly conditions. The new materials were based on amphiphilic poly(methyl acrylate)-b-poly((3-acrylamidopropyl)trimethylammonium chloride) (PMA-b-PAMPTMA) star block copolymers and cationic hydrogels (PAMPTMA). The in vitro sequestration ability of the polymers was investigated in simulated intestinal fluid using sodium cholate (NaCA) as the bile salt model molecule. Both polymeric structures investigated showed higher affinity towards NaCA micelles than unimers. The cationic hydrogels proved to be attractive BAS candidates, with binding parameters similar to those of the most effective commercial BAS: Colesevelam hydrochloride. Several polymer features were investigated for the star block copolymers in order to understand the structure/performance relationship. It was found that the binding parameters can be tuned by targeting different compositions of the block copolymers and, typically, longer cationic arms led to enhanced binding capacity. © 2016 The Royal Society of Chemistry. Source

Borges A.F.,Industria Farmaceutica SA | Borges A.F.,University of Coimbra | Silva C.,Industria Farmaceutica SA | Coelho J.F.J.,University of Coimbra | And 2 more authors.
Journal of Controlled Release

Polymers are the most common excipients used in pharmaceutical dosage forms, and often new applications and innovative polymers appear aiming to overcome unmet needs in the drug formulation field. Orodispersible dosage forms based on polymeric matrices have currently demonstrated their prominence in accordance with the actual market requirements and patients' demands. The versatility of the polymeric oral films had proven their high value as suitable technological platforms for extension and adjustment to different delivery routes and promising markets. These are the main reasons for the increasing investment of several companies in this technology and their applicability in different therapeutic segments. This pharmaceutical form with a blustering beginning as a breath freshener had an emergent entrance in the Rx market proving its reliable value. This review describes and explores the oral film technology from its main component, the polymeric matrices, to the new and possible market applications, highlighting all the critical and important points of its development. © 2015 Elsevier B.V. All rights reserved. Source

Pinto A.C.,University of Coimbra | Pinto A.C.,Industria Farmaceutica SA | Moreira J.N.,University of Coimbra | Simoes S.,University of Coimbra | Simoes S.,Industria Farmaceutica SA

Background Mitoxantrone plus prednisone is a palliative treatment for hormone-refractory prostate cancer (HRPC) but without survival benefit. Imatinib has shown activity against HRPC but only in the preclinical setting. Our previous in vitro cytotoxicity screening study established that their free combination act additively to inhibit proliferation of PC-3 cells. We aim to develop a liposomal imatinib-mitoxantrone (LIM) formulation with improved in vivo therapeutic activity. Methods Imatinib and mitoxantrone were simultaneously co-loaded into DSPC/Chol liposomes by means of a (NH4) 2SO4-generated proton gradient method. The optimized formulation was characterized in terms of mean size diameter, loading parameters and drug retention in human serum. In vivo antitumor activity of developed LIM formulation was evaluated in a nude mice bearing subcutaneous PC-3 xenograft model. Results LIM formulation exhibited maximal encapsulation efficiency (>95%) and enhanced drug retention for both drugs. Additionally, this LIM formulation, administered at a low mitoxantrone dose (0.5 mg/kg), showed a tumor inhibition activity (TGI = 66.7% and 4.0-fold tumor volume increase) slightly superior to that of liposomal mitoxantrone (LM) at 2 mg/kg (TGI = 53.0% and 4.2-fold volume increase). Therefore, therapeutic activity of mitoxantrone was significantly improved by co-loading with imatinib since a four times lower dose was needed to achieve an equivalent growth inhibition effect. Conclusions The loading parameters and drug retention properties of our LIM formulation, combined with its in vivo antitumor activity, make this formulation an excellent strategy to improve the therapeutic index of mitoxantrone and a promising candidate for clinical development in prostate cancer therapy. © 2010 Wiley-Liss, Inc. Source

Pinto A.C.,Industria Farmaceutica SA | Angelo S.,Industria Farmaceutica SA | Moreira J.N.,University of Coimbra | Simoes S.,Industria Farmaceutica SA | Simoes S.,University of Coimbra
Journal of Nanoscience and Nanotechnology

Mitoxantrone-based combinations are a standard palliative treatment in hormone-refractory prostate cancer (HRPC) but with no survival benefit. Imatinib has shown preclinical activity against HRPC although minimal clinical therapeutic efficacy. Our previous in vitro studies demonstrated that simultaneous combination of imatinib with mitoxantrone yielded additive growth inhibition effects against PC-3 cell line. The main aim of the work was to develop novel liposomal formulations comprising imatinib co-encapsulated with mitoxantrone, by different loading methods and experimental conditions, in order to achieve the highest drug loading and maximum physical stability. In the optimized formulations, imatinib and mitoxantrone were actively co-loaded by means of a (NH 4) 2SO 4 transmembrane gradient. Encapsulation efficiency, mean size diameter and drug retention in storage and in biological conditions were characterized. Our study presented for the first time an active loading method for imatinib and suggests that the optimized liposomal formulation co-encapsulates both drugs with high encapsulation efficiency (>95%), shows enhanced drug retention under tested conditions and delivers a drug:drug ratio capable of improving tumor cell growth inhibition with a mitoxantrone dose reduction of 2.6-fold as compared to single liposomal formulation. Therefore, our nanotechnology-based drug combined platform may constitute a promising strategy in prostate cancer therapy. Copyright © 2012 American Scientific Publishers. Source

Mendonca P.V.,University of Coimbra | Serra A.C.,University of Coimbra | Silva C.L.,Industria Farmaceutica SA | Simoes S.,Industria Farmaceutica SA | And 2 more authors.
Progress in Polymer Science

Polymeric bile acid sequestrants have received increasing attention as therapeutic agents for the treatment of hypercholesterolemia. These materials are usually cationic hydrogels that selectively bind and remove bile acid molecules from the gastrointestinal tract, decreasing plasma cholesterol levels. Due to their high molecular weight, the action of bile acid sequestrants can be limited to the gastrointestinal tract, avoiding systemic exposure, which constitutes an advantage over conventional small-molecule drugs. Different polymers, such as vinyl polymers, acrylic polymers and allyl polymers have been used to prepare potential bile acid sequestrants based on conventional polymerization techniques. Also, much effort has been devoted to understanding the structure-property relationships between these polymers and their ability to bind bile acid molecules. The efficacy of these polymeric drugs can be ascribed to five major variables: (i) the density of cationic charges, (ii) the length and distribution of the hydrophobic chains, (iii) the polymer backbone flexibility, (iv) the degree of cross-linking and (v) the polymer shape. This review summarizes the major synthesis pathways that are employed in the preparation of this type of polymer therapeutics and the polymer structural key factors that are of relevance to enhanced therapeutic efficacy. Herein, new synthesis approaches, based on "controlled"/living radical polymerization techniques, are highlighted. © 2012 Elsevier B.V. All rights reserved. Source

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