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Projeto de investigação
Integrated Manufacture of Liposomal Dry Powder Formulations
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Solid dosage forms of biopharmaceuticals in drug delivery systems using sustainable strategies
Publication . Costa, Clarinda; Casimiro, Teresa; Corvo, Maria Luísa; Aguiar-Ricardo, Ana; LAQV@REQUIMTE; DQ - Departamento de Química; MDPI - Multidisciplinary Digital Publishing Institute
Drug delivery systems (DDS) often comprise biopharmaceuticals in aqueous form, making them susceptible to physical and chemical degradation, and therefore requiring low temperature storage in cold supply and distribution chains. Freeze-drying, spray-drying, and spray-freeze-drying are some of the techniques used to convert biopharmaceuticals-loaded DDS from aqueous to solid dosage forms. However, the risk exists that shear and heat stress during processing may provoke DDS damage and efficacy loss. Supercritical fluids (SCF), specifically, supercritical carbon dioxide (scCO2), is a sustainable alternative to common techniques. Due to its moderately critical and tunable properties and thermodynamic behavior, scCO2 has aroused scientific and industrial interest. Therefore, this article reviews scCO2-based techniques used over the year in the production of solid biopharmaceutical dosage forms. Looking particularly at the use of scCO2 in each of its potential roles—as a solvent, co-solvent, anti-solvent, or co-solute. It ends with a comparison between the compound’s stability using supercritical CO2-assisted atomization/spray-drying and conventional drying.
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.
Dry Dosage Forms of Add-Value Bioactive Phenolic Compounds by Supercritical CO2-Assisted Spray-Drying
Publication . Costa, Clarinda; Anselmo, Hugo; Ferro, Rita; Matos, Ana Sofia; Aguiar-Ricardo, Ana; Casimiro, Teresa; LAQV@REQUIMTE; DQ - Departamento de Química; UNIDEMI - Unidade de Investigação e Desenvolvimento em Engenharia Mecânica e Industrial; DEMI - Departamento de Engenharia Mecânica e Industrial; MDPI - Multidisciplinary Digital Publishing Institute
Every year, grapevine pruning produces huge amounts of residue, 90% of which are from vine shoots. These are a rich source of natural antioxidants, mostly phenolic compounds, which, when properly extracted, can give rise to added-value products. However, their lack of solubility in aqueous media and high susceptibility to thermal and oxidative degradation highly limit their bioavailability. Encapsulation in suitable carriers may have a positive impact on their bioavailability and bioactivity. Previous data on vine-shoot extraction have identified gallic acid (GA) and resveratrol (RSV) as the main phenolic compounds. In this work, model dry powder formulations (DPFs) of GA and RSV using hydroxypropyl cellulose (HPC) as carriers were developed using Supercritical CO2-Assisted Spray Drying (SASD). A 32 full factorial Design of Experiments investigated the solid and ethanol contents to ascertain process yield, particle size, span, and encapsulation efficiency. Amorphous powder yields above 60%, and encapsulation efficiencies up to 100% were achieved, representing excellent performances. SASD has proven to be an efficient encapsulation technique for these phenolic compounds, preserving their antioxidation potential after three months in storage with average EC50 values of 30.6 µg/mL for GA–DPFs and 149.4 µg/mL for RSV–DPF as assessed by the scavenging capacity of the DPPH radical.
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.
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Fundação para a Ciência e a Tecnologia
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PD/BD/142880/2018