Publicação
Dissolution of Dry Powder Inhaler formulations : in vitro / in vivo correlations
| datacite.subject.fos | Ciências Médicas::Medicina Básica | pt_PT |
| dc.contributor.advisor | Corvo, Maria Luísa Teixeira de Azevedo Rodrigues | |
| dc.contributor.advisor | Costa, Eunice Margarida Santos | |
| dc.contributor.author | Noriega-Fernandes, Beatriz | |
| dc.date.accessioned | 2022-10-26T14:25:09Z | |
| dc.date.available | 2025-06-01T00:31:14Z | |
| dc.date.issued | 2022-05 | |
| dc.date.submitted | 2022-02 | |
| dc.description.abstract | Orally inhaled drug delivery has been the preferred route to deliver locally acting drug substances (DS) to the lung for conditions such as asthma, chronic obstructive pulmonary disease (COPD) or infections, as the local delivery allows for rapid onset action while minimizing side effects. More recently, inhalation to the lung has been used as a path for systemic delivery for small and large molecules due to the large surface area of absorption and the avoidance of first path metabolism. The development of formulations for pulmonary delivery relies on aerodynamic performance in vitro characterization by cascade impaction, with output parameters such as the total emitted dose from the device or the dose capable of reaching the deep lung, the fine particle dose, with an aerodynamic diameter below 5 μm. It is acknowledged the DS action is dependent not only on the delivered dose, but also on dissolution and absorption kinetics of the deposited particles, nonetheless there is not a standardized globally accepted method to assess dissolution and/or absorption on the lung, mostly due the challenges of mimicking such environment – particle agglomerates deposition on an extremely large area of stagnant and thin lining fluid with a complex composition. Hence, the present research aims to develop, optimize, and explore different strategies to assess the dissolution and absorption kinetics of dry powder inhaler (DPI) formulations, from a quality control – QC – perspective, with strategies based on pre-existing compendial methodologies, and from a biorelevant performance prediction perspective, with the application of a newly developed breath simulator coupled with a biorelevant dissolution system. Several combinations of standard cascade impactors and the United States Pharmacopeia (USP) dissolution apparatus are analyzed regarding critical method parameters. Ultimately, these resulted in reproducible methods capable of differentiating carrier-based and carrier-free DPI formulations of low and high solubility DS. In particular, the combination of the fast screening impactor with the USP apparatus II was validated by testing DS of different solubilities, and although far from mimicking the particle deposition and dissolution in the lung, was rendered suitable as a QC and formulation screening strategy at an early development stage. Aiming for a more biorelevant approach capable to predict in vivo therapeutic effect more reliably, a more complex system combination, the breath simulator PreciseInhale® and the dissolution apparatus DissolvIt®, is optimized and used. This methodology proved to differentiate distinct particle engineering technologies, formulation approaches and used excipients by assessing particle deposition, dissolution, and absorption for low and high solubility DS, using a commercial product as benchmark. Moreover, the DissolvIt® system generates pharmacokinetic-like dissolution profiles which can be used as input parameters for physiologically based pharmacokinetic (PBPK) modelling. Hence, this biorelevant approach is suitable for formulation selection in later stages of pre-clinical or early clinical development and for de-risking generic development. Overall, the present work suggests deposition and dissolution testing can be an essential tool for DPI development, but collaborative efforts of academia, pharmaceutical industry and regulatory bodies are still required to overcome remaining challenges. | pt_PT |
| dc.description.provenance | Submitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2022-10-26T11:24:05Z No. of bitstreams: 1 scnd_td_Beatriz_Fernandes.pdf: 6326486 bytes, checksum: 697e8fea06da1acb5d0106d0c5f7a60b (MD5) | en |
| dc.description.provenance | Made available in DSpace on 2022-10-26T14:25:09Z (GMT). No. of bitstreams: 1 scnd_td_Beatriz_Fernandes.pdf: 6326486 bytes, checksum: 697e8fea06da1acb5d0106d0c5f7a60b (MD5) Previous issue date: 2022-05 | en |
| dc.identifier.tid | 101540914 | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10451/54920 | |
| dc.language.iso | eng | pt_PT |
| dc.relation | UID/DTP/04138/2020 | pt_PT |
| dc.relation | Research Institute for Medicines | |
| dc.subject | inaladores de pó seco | pt_PT |
| dc.subject | dissolução no pulmão | pt_PT |
| dc.subject | administração de fármacos pulmonares | pt_PT |
| dc.subject | métodos de dissolução in vitro | pt_PT |
| dc.subject | formulação com/sem transportadores | pt_PT |
| dc.subject | dry powder inhaler | pt_PT |
| dc.subject | lung dissolution | pt_PT |
| dc.subject | pulmonary drug delivery | pt_PT |
| dc.subject | in vitro dissolution method | pt_PT |
| dc.subject | carrier-based formulation | pt_PT |
| dc.subject | carrier-free formulation | pt_PT |
| dc.title | Dissolution of Dry Powder Inhaler formulations : in vitro / in vivo correlations | pt_PT |
| dc.type | doctoral thesis | |
| dspace.entity.type | Publication | |
| oaire.awardNumber | UIDP/04138/2020 | |
| oaire.awardTitle | Research Institute for Medicines | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT | |
| oaire.fundingStream | 6817 - DCRRNI ID | |
| person.familyName | Noriega Fernandes | |
| person.givenName | Beatriz | |
| person.identifier.ciencia-id | DE1F-1F1A-92F4 | |
| person.identifier.orcid | 0000-0002-3749-103X | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.contributor.authoremail | repositorio@reitoria.ulisboa.pt | |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | doctoralThesis | pt_PT |
| relation.isAuthorOfPublication | f3d01441-1dff-466a-aa76-6e9f3ebab4ac | |
| relation.isAuthorOfPublication.latestForDiscovery | f3d01441-1dff-466a-aa76-6e9f3ebab4ac | |
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| thesis.degree.name | Tese de doutoramento, Farmácia (Tecnologia Farmacêutica), Universidade de Lisboa, Faculdade de Farmácia, 2022 | pt_PT |