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Projeto de investigação
Integrated Manufacture of Liposomal Dry Powder Formulations
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Cu, Zn- Superoxide dismutase liposomal dry powder formulations production using supercritical CO2-assisted spray-drying
Publication . Costa, Clarinda; Casimiro, Teresa; Corvo, M. Luísa; Aguiar-Ricardo, Ana; LAQV@REQUIMTE; DQ - Departamento de Química; Elsevier
Enzyme-based inhalable therapeutics for lung inflammation are gaining interest as an alternative to long-term corticosteroids treatments. However, enzymes have poor pharmacokinetics. Encapsulating enzymes in liposomes can increase their half-live and modify their biodistribution. But both liposomes and enzymes are susceptible to destabilization during storage. This drawback can be surpassed, by converting liposomal suspension into solid dosage forms for different administration routes, including inhalation. In this study, Cu, Zn- superoxide dismutase (SOD) was encapsulated in liposomes, then dried using supercritical CO2-assisted spray-drying to make SOD-loaded liposomal dry powder formulations (SOD_Lip-DPFs). Upon resuspension in water, liposomes maintained structural integrity, with 99% SOD encapsulation efficiency and preserved enzymatic activity. Stability studies showed that SOD_Lip-DPFs maintained liposomal and enzyme stability for 50 days at 40% relative humidity. This offers a stable and efficient delivery system for enzyme-based inhalable therapeutics.
Integrated manufacture of Liposomal dry powder formulations
Publication . Sequeira, Clarinda Isabel da Silva e Costa; Ricardo, Ana; Corvo, Maria Luísa; Fernandes, Eduarda
Chronic respiratory diseases (CRDs) affect the airways and other structures of the lungs. CRDs are not curable, and it is estimated by the World Health Organization, 70 % of deaths under 70 years of age occur in low- and middle-income countries. Anti-inflammatory-based therapies may result in several adverse side effects. To address this problem, a synergy between pharmaceutical and supercritical carbon dioxide techniques is established for the manufacturing of inhaled enzyme and natural products-based anti-inflammatory therapies. In this work, enzyme (SOD)/quercetin (Quer) - loaded liposomal formulations were converted into liposomal dry powder formulations (Lip-DPFs) for the treatment of inflammatory lung diseases, using supercritical CO2-assisted spray-drying (SASD). First, liposomal formulations were produced using distinct methods - microfluidics and thin-film method hydration. Microfluidics showed to be able to encapsulate both low and high molecular weight proteins, while pre-serving the conformational structure and enzyme activity. Secondly, a quality-by-design approach was applied towards the Lip-DPFs optimization using a low molecular weight hydrophilic dye as a model molecule. Stability studies proved that powders remain stable for 30 days at a relative humidity of 4 %. Translating the knowledge, the optimized parameters and formulations were applied to the production of SOD-loaded liposomal dry powder formulations (SOD_Lip-DPFs) for inhalation. Resuspended SOD-loaded liposomes showed structural maintenance and enzyme protection, regarding the SOD encapsulation efficiency and enzyme activity retention. SOD_Lip-DPFs showed to be able to inhalation, reaching the respiratory region, namely terminal bronchi. Finally, hydrophobic molecule-loaded liposomal dry powder formulations (Quer_Lip-DPFs) were produced with suitable aerodynamic properties. Overall, the work herein detailed represents an innovative, robust, upscaling, and time-efficient technique for drying liposomes, keeping them stable during storage and overcoming the common drawbacks of current drying and storage methods.
Optimization of quercetin
Publication . Costa, Clarinda; Grenho, Liliana; Casimiro, Teresa; Gomes, Pedro Sousa; Fernandes, Maria Helena; Corvo, M. Luisa; Aguiar-Ricardo, Ana; LAQV@REQUIMTE; DQ - Departamento de Química; Elsevier
Quercetin exhibits anti-inflammatory and antioxidant properties. Incorporating quercetin into liposomes can overcome its limited water solubility and poor oral bioavailability, making it a promising candidate for treating inflammatory diseases. For pulmonary administration, supercritical CO2-assisted spray drying can be used to convert liposomal suspensions into dry powder formulations suitable for inhalation. However, the extraction power of scCO2 can pose challenges on retaining the incorporation efficiency (IE) of this flavonoid in the lipid bilayer. This study focuses on optimizing quercetin's IE after drying using different liposomal lipid compositions with varying surface charges. The IE of quercetin into positively charged liposomes was 57 %. Additionally, the resulting powders had a mass median aerodynamic diameter of 1.7 µm and a fine particle fraction (particle size < 5 µm) of 63 %, indicating their suitability for inhalation. Cytotoxicity assays also revealed that both reconstituted liposomes and dry powder formulations were non-toxic to areolar fibroblast cells.
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Fundação para a Ciência e a Tecnologia
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COVID/BD/152744/2022