Utilize este identificador para referenciar este registo: http://hdl.handle.net/10451/20231
Título: Investigation of new formulations of acrylic bone cement containing antibiotics
Autor: Matos, Ana Cristina Mendes Correia de, 1968-
Orientador: Bettencourt, Ana Francisca de Campos Simão
Almeida, António José Leitão das Neves, 1963-
Vaz, Mário Augusto Pires
Palavras-chave: Teses de doutoramento - 2015
Data de Defesa: 2015
Resumo: Antibiotic-loaded bone cement (ALABC), is the common designation for polymethylmethacrylate bone cement (BC), used as drug-delivery system to prevent or to treat bone related-infections. Although presenting some disadvantages, the use of ALABC is still considered the standard of care for patients with chronic bone and joint infection, providing local delivery of high levels of antibiotics for an extended period without exceeding systemic toxicity, while being a more costeffective procedure when compared to cementless implants. Described and reported ALABCs drawbacks include the inadequate release of the loaded antibiotic, the lack of bioactivity and the poor diversity of antibiotics available in commercial premixed formulations. The base-concept of this study was to develop a novel ALABC with improved antibiotic release through the inclusion of particulate drug delivery systems and a release modulator without hampering the antibacterial activity of antibiotics or the BC mechanical and biocompatibility properties. Levofloxacin, a 3rd generation fluoroquinolone, and minocycline, a tetracycline, were the elected antibiotics to load into BC. The rationale behind this choice was related to their adequate microbiological and physicochemical characteristics. Both antibiotics present a broad-spectrum of activity against the main organisms responsible for bone and joint infections, namely Staphylococcus spp. Physicochemically, both are molecules with amphiphilic characteristics - greater for levofloxacin; soluble in acidic aqueous media; with high melting points (over 200ºC) and available in powder form; the latter two characteristics being restrictive when choosing for antibiotics to load into BC. Two main strategies were explored for the inclusion of antibiotics into particulate systems previous to incorporation into BC: 1) by encapsulation into PMMA; 2) by adsorption into calciumphosphate particles (CaPs). To improve drug release from the matrix, a pharmaceutical excipient was used as release modulator, lactose, and loaded into the BC powder component. A step-by-step approach was pursued: 1st. Assessment of antibiotics encapsulation into PMMA particles and of antibiotics in vitro release followed by loading antibiotic-loaded-particles into BC; The PMMA biopolymer was chosen to prepare PMMA-particles (PMMAp) foreseeing a mechanical reinforcement of the final ALABC matrix, because PMMA is the base-polymer of both systems. Plain, levofloxacin- and minocycline-loaded particles were successfully prepared using the double-emulsion solvent evaporation method. Since only minocycline-PMMAp registered an interesting in vitro release profile, studies proceeded with these particles and 15% (wparticles/wBC) were loaded into BC, which, on the other hand, hindered BC setting. 2nd. Effect of the inclusion of lactose into BC, monitoring antibiotics in vitro release, quasi-static mechanical properties and biocompatibility of the resultant matrices; Each powdered antibiotic was directly loaded into BC, and lactose, was added to each formulation. The amount of antibiotic loaded corresponded to the low-dose currently used in commercial ALABCs formulations - 2.5% (w/wBC) - in order to provide an effective antimicrobial activity and preserve the mechanical properties. As to lactose, 10% (wL/wBC) resulted in the optimised amount to be loaded into BC. This lactose-modified BC matrix allowed total release of the minocycline after a one-week period, and a 3.5-fold increase of levofloxacin release compared to control without lactose, over a 7-week period. 3rd. Inclusion of levofloxacin-adsorbed doped CaPs into BC and monitoring of the antibiotics in vitro release, quasi-static mechanical properties and biocompatibility of the resultant matrices; Intending to improve antibiotic release and bioactivity calcium-phosphate particles (CaPs) were tested as drug delivery system. Mg- and Sr-doped CaPs were prepared as levofloxacin carriers and were loaded into the 10% (wL/wBC) lactose-modified acrylic BC at 2.5% (wCaPs/wBC). This novel BC composite revealed a sustained release of levofloxacin over an 8-week period, with concentrations over the Staphylococcus spp. minimum inhibitory concentration values after 48 h. The novel 10% (wL/wBC) lactose-loaded ALABC, independently of the antibiotic or CaPs loaded, followed the same release mechanistic based on dissolution and subsequent diffusion of the antibiotic from the matrix. Both minocycline and levofloxacin maintained antibacterial activity against the Staphylococcus spp. after being released from ALABC matrix. Though this result suggest that polymerization setting did not affect these antibiotics, a novel in silico approach revealed the existence of covalent and non-covalent interactions between the levofloxacin and the BC matrix. Evaluation of the antibiotic-lactose-modified BC matrices regarding the quasi-static mechanical properties according to standard ISO 5833, clearly demonstrated that the mechanical performance was not compromised. Biocompatibility was also successfully evaluated following standard ISO 10993-5 with fibroblasts and osteoblasts cell lines incubated with extracts or in direct contact with BC composites, respectively. Results have shown that neither lactose nor the loaded antibiotics compromised the biocompatibility of the BC. All considered, these features justify the potential of lactose-loaded BC as a valuable step forward on the development of novel BC composites, namely with lactose, as release modulator, and doped CaP particles, as antibiotic carriers, for the control of bone and joint infections.
Descrição: Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2015
URI: http://hdl.handle.net/10451/20231
Designação: Doutoramento em Farmácia
Aparece nas colecções:FF - Teses de Doutoramento

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