Publicação
Drug release and transdermal permeation studies in composite ceramic microdevices
| Resumo: | Transdermal drug administration represents an interesting strategy, avoiding first-pass hepatic metabolism and enzymatic degradation via the gastrointestinal route. Recently, microneedles (MN) have revealed the ability to deliver a variety of molecules to the skin, including drugs and vaccines. MN is an emerging technology that offers a minimally invasive and practically painless system for the patient. From metals to polymers, MN are fabricated with a wide variety of materials, although with some constraints regarding mechanical strength (limitations related to skin perforation). Additionally, the incorporation of drugs represents a challenge due to the effect on the material properties and the optimization of its release. In this context, the main objective of this dissertation was to assess the potential interest of incorporating an anti-inflammatory drug, diclofenac (DCF), in apatitic MN. For this purpose, different studies were carried out using, in a first stage, cylindrical samples with different compositions, based on a calcium phosphate cement (α-TCP) and citric acid to accelerate the cement setting reaction. Three different compositions were evaluated: i) base cement, ii) base cement added with chitosan and iii) base cement added with chitosan and genipin. Cylindrical samples containing DCF were evaluated in release tests at two pH (7.4 and 5.5), and the kinetics that best described the release profiles and the associated mechanism were determined. In parallel, drug content, stability and material characterization studies were carried out (phase quantification by Rietveld refinement method, porosity, compressive strength, Fourier transform infrared spectroscopy and scanning electron microscopy). It was demonstrated that the DCF release profiles obtained with the cylindrical samples were related to the composition as well as the porosity. From the results obtained on the drug content assays of the samples, it was found that although the amount of drug present in the samples decreased after the release assays, it did not release completely at the pre-determinated time. After the release tests, the structures of the cylindrical samples were again characterized, showing a smaller amount of α-TCP that turned into hydroxyapatite (HA) and the presence of DCF. Based on the results of the characterization in terms of mechanical properties (compressive strength) and the evaluation of in vitro release profiles and kinetics at two different pH values (7.4 and 5.5) the composition containing chitosan and genipin was selected to study the influence of the liquid-to-powder ratio (LPR = 0.33, 0.40 and 0.45 m/m) in these same parameters. With the variation of LPR, a selection was conducted again, based on the results of compressive strength and drug release profiles, to carry out the studies in MN with the chosen composition (LPR = 0.33 m/m). In MN with the selected composition (with chitosan and genipin, LPR = 0.33 m/m) and with two different quantities of DCF, 2.5 and 5 wt% (m/m), drug release and compressive strength assays were performed. The best composition was chosen based on drug release profiles and compressive strength results. With the selected composition incorporated with 5 wt% (m/m) of DCF, MN arrays with a rigid support were produced by micromoulding and studied for the drug permeation profile with in vitro drug permeation and retention studies in newborn pig skin and pig skin from the ear. In these assays the cession of the DCF from the MN was confirmed. Additionally, it was observed that the drug permeation results depend on the penetration of the MN into the skin and the thickness of the skin used in each assay. In summary, ceramic composite MN tested in this work have potential to be used for transdermal administration of DCF. However, further studies must be carried out, namely, obtaining a matrix of MN fixed on a flexible support that provides a better contact with the skin, preserving a certain perforation of the MN into the skin. It is also suggested to improve the permeation protocol when using MN in pig skin and perform a safety assessment of MN before in vivo testing. |
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| Autores principais: | Oliveira, Joana Cartaxo Pinto |
| Assunto: | Microneedles Self-setting composite ceramic Diclofenac α-TCP Drug release assays Permeation studies |
| Ano: | 2021 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Aveiro |
| Idioma: | inglês |
| Origem: | RIA - Repositório Institucional da Universidade de Aveiro |
| Resumo: | Transdermal drug administration represents an interesting strategy, avoiding first-pass hepatic metabolism and enzymatic degradation via the gastrointestinal route. Recently, microneedles (MN) have revealed the ability to deliver a variety of molecules to the skin, including drugs and vaccines. MN is an emerging technology that offers a minimally invasive and practically painless system for the patient. From metals to polymers, MN are fabricated with a wide variety of materials, although with some constraints regarding mechanical strength (limitations related to skin perforation). Additionally, the incorporation of drugs represents a challenge due to the effect on the material properties and the optimization of its release. In this context, the main objective of this dissertation was to assess the potential interest of incorporating an anti-inflammatory drug, diclofenac (DCF), in apatitic MN. For this purpose, different studies were carried out using, in a first stage, cylindrical samples with different compositions, based on a calcium phosphate cement (α-TCP) and citric acid to accelerate the cement setting reaction. Three different compositions were evaluated: i) base cement, ii) base cement added with chitosan and iii) base cement added with chitosan and genipin. Cylindrical samples containing DCF were evaluated in release tests at two pH (7.4 and 5.5), and the kinetics that best described the release profiles and the associated mechanism were determined. In parallel, drug content, stability and material characterization studies were carried out (phase quantification by Rietveld refinement method, porosity, compressive strength, Fourier transform infrared spectroscopy and scanning electron microscopy). It was demonstrated that the DCF release profiles obtained with the cylindrical samples were related to the composition as well as the porosity. From the results obtained on the drug content assays of the samples, it was found that although the amount of drug present in the samples decreased after the release assays, it did not release completely at the pre-determinated time. After the release tests, the structures of the cylindrical samples were again characterized, showing a smaller amount of α-TCP that turned into hydroxyapatite (HA) and the presence of DCF. Based on the results of the characterization in terms of mechanical properties (compressive strength) and the evaluation of in vitro release profiles and kinetics at two different pH values (7.4 and 5.5) the composition containing chitosan and genipin was selected to study the influence of the liquid-to-powder ratio (LPR = 0.33, 0.40 and 0.45 m/m) in these same parameters. With the variation of LPR, a selection was conducted again, based on the results of compressive strength and drug release profiles, to carry out the studies in MN with the chosen composition (LPR = 0.33 m/m). In MN with the selected composition (with chitosan and genipin, LPR = 0.33 m/m) and with two different quantities of DCF, 2.5 and 5 wt% (m/m), drug release and compressive strength assays were performed. The best composition was chosen based on drug release profiles and compressive strength results. With the selected composition incorporated with 5 wt% (m/m) of DCF, MN arrays with a rigid support were produced by micromoulding and studied for the drug permeation profile with in vitro drug permeation and retention studies in newborn pig skin and pig skin from the ear. In these assays the cession of the DCF from the MN was confirmed. Additionally, it was observed that the drug permeation results depend on the penetration of the MN into the skin and the thickness of the skin used in each assay. In summary, ceramic composite MN tested in this work have potential to be used for transdermal administration of DCF. However, further studies must be carried out, namely, obtaining a matrix of MN fixed on a flexible support that provides a better contact with the skin, preserving a certain perforation of the MN into the skin. It is also suggested to improve the permeation protocol when using MN in pig skin and perform a safety assessment of MN before in vivo testing. |
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