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Transdermal Delivery of Pharmaceuticals with Ionic Systems and Nanomaterials
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A administração transdérmica de fármacos constitui uma alternativa promissora às vias convencionais. No entanto, a maioria dos antibióticos, devido à sua elevada polaridade e baixa lipofilicidade, apresenta limitações significativas na capacidade de atravessar eficazmente a barreira cutânea. Esta tese explora a utilização de sais e líquidos iónicos derivados do próprio fármaco (API-OSILs) como estratégia química para melhorar a solubilidade, lipofilicidade e permeabilidade cutânea de antibióticos. Avalia-se ainda a sua integração em plataformas avançadas de administração, incluindo nanopartículas lipídicas e microagulhas dissolúveis. A cefuroxima e a estreptomicina foram selecionadas como sistemas modelo para investigar como a conjugação com iões orgânicos poderá potenciar a administração transdérmica. O trabalho está organizado em quatro estudos principais: (1) síntese e avaliação de sais de cefuroxima (CFX-OSILs), (2) desenho e triagem de sais orgânicos de estreptomicina (STP-OS), (3) formulação destes compostos em nanopartículas lipídicas sólidas e (4) incorporação em dispositivos de microagulhas dissolúveis.
Para explorar o potencial da modificação iónica na melhoria da administração transdérmica de antibióticos, a tese inicia-se com a síntese de sais orgânicos de cefuroxima utilizando catiões de piridínio e imidazólio. Estes sais aumentaram a solubilidade original, até 200 vezes superior à do fármaco de base a 37 °C, e modificaram o comportamento de partição, sendo que catiões mais lipofílicos aumentaram a afinidade pela fase orgânica. Entre eles, [PyC10Py][CFX]2 manteve atividade antibacteriana, enquanto outros apresentaram eficácia reduzida. Os ensaios de citotoxicidade revelaram maior toxicidade apenas em sais contendo cadeias longas de alquilo. Embora não fossem candidatos finais à administração transdérmica, este estudo forneceu contributos metodológicos relevantes para a modificação iónica e estabeleceu uma base para aplicar esta estratégia a antibióticos mais desafiantes e clinicamente relevantes.
Dando seguimento a esta abordagem, o segundo estudo aplicou uma estratégia semelhante de modificação iónica à estreptomicina, um antibiótico aminoglicosídeo particularmente desafiante. Foram sintetizados oito sais orgânicos de estreptomicina (STP-OS), contendo contra-iões sulfonato e carboxilato, que originaram sólidos estáveis e foram caracterizados sistematicamente. Em estudos de permeação através de bicamadas fosfolipídicas, [STPH3][p-TolSO3]3 apresentou a maior permeabilidade cutânea, [STPH3][C6SO3]3 exibiu um equilíbrio entre permeabilidade e solubilidade, enquanto [STPH3][GlyCOO]3 mostrou maior solubilidade mas permeação negligenciável. Os ensaios antimicrobianos confirmaram a manutenção da atividade contra estirpes suscetíveis. Em conjunto, estes resultados demonstram que a modificação iónica pode ser uma ferramenta versátil para ajustar a solubilidade, lipofilicidade e interação com membranas da estreptomicina, estabelecendo uma base química para a sua incorporação em sistemas avançados de administração transdérmica.
Com base nos resultados promissores da modificação iónica, o terceiro estudo investigou a incorporação de STP-OS selecionados: [STPH3][p-TolSO3]3, [STPH3][C6SO3]3 e [STPH3][GlyCOO]3, em paralelo com o sal convencional de sulfato, em nanopartículas lipídicas sólidas (NLS) utilizando Softisan® como matriz lipídica. As nanopartículas resultantes apresentaram cerca de 150 nm de diâmetro, índices de polidispersidade baixos (~0,2) e potenciais zeta negativos (~–30 mV), indicadores de estabilidade coloidal. As eficiências de encapsulação variaram entre 35 e 62%, com cargas de fármaco entre 4-6%, demonstrando que todos os sais eram globalmente compatíveis com o veículo lipídico. Géis liofilizados obtidos a partir destas NLS mostraram-se adequados para aplicação dérmica, com manuseamento e consistência favoráveis. Os ensaios de CIM revelaram maior potência antimicrobiana das formulações em NLS comparativamente aos sais livres, reforçando o valor da encapsulação em nanopartículas. Importa salientar que a formulação bem-sucedida de sais com perfis distintos de solubilidade e permeabilidade demonstrou que a identidade do OSIL não comprometeu a formulação, permitindo ainda afinar o comportamento de administração.
O quarto e último estudo incorporou os mesmos três STP-OS em microdispositivos dissolúveis (MAPs) compostos por PVP/PVA. O sal de sulfato convencional apresentou menor solubilidade na matriz polimérica, resultando em menor carga de fármaco quando comparado com os dispositivos contendo STP-OS. Apesar destas diferenças, todos os MAPs apresentaram excelentes propriedades mecânicas, com >99% de inserção confirmada por tomografia de coerência ótica e microscopia. Estudos ex vivo em pele de leitão de espessura total revelaram que, embora a carga total de fármaco variasse, os perfis de libertação e deposição foram comparáveis entre formulações. Curiosamente, os OSILs apresentaram ligeiramente maior retenção nas camadas cutâneas. Estes resultados evidenciam a importância da solubilidade na matriz de formulação e demonstram como a modificação iónica pode expandir as opções de formulação em sistemas de administração transdérmica.
Em conjunto, os quatro estudos desta tese demonstram que os API-OSILs representam uma plataforma química para modular a solubilidade, lipofilicidade, permeabilidade e perfis de administração de antibióticos. Além disso, estas modificações podem ser com sucesso transpostas para sistemas avançados de administração, como nanopartículas lipídicas e microagulhas dissolúveis. Embora a extensão da melhoria dependa da molécula, como observado na modulação limitada da estreptomicina altamente hidrofílica, os resultados fornecem uma prova de conceito de que a modificação iónica constitui uma estratégia viável e adaptável para potenciar e otimizar a administração transdérmica de fármacos.
Transdermal drug delivery offers a promising alternative to conventional administration routes. However, most antibiotics, due to their high polarity and low lipophilicity, exhibit limitations to cross the skin barrier effectively. This thesis explores the use of Active Pharmaceutical Ingredient based Organic Salts & Ionic Liquids (API-OSILs) as a chemical strategy to enhance antibiotic solubility, lipophilicity, and skin permeability of antibiotics. It further evaluates their integration into advanced delivery platforms, including lipid nanoparticles and dissolving microneedles. Cefuroxime and streptomycin were selected as model systems to investigate whether conjugation with organic ions can improve transdermal delivery. The work is organized into four key studies: (1) synthesis and evaluation of cefuroxime salts (CFX-OSILs), (2) design and screening of streptomycin organic salts (STP-OS), (3) formulation of these compounds into solid lipid nanoparticles, and (4) incorporation into dissolving microneedle patches. To explore the potential of ionic modification for enhancing transdermal antibiotic de-livery, the thesis begins with the synthesis of cefuroxime organic salts using pyridinium and imidazolium cations. These salts increased the original solubility, up to 200 times higher than the parent drug at 37 °C, and modified partitioning behavior, with more lipophilic cations increasing affinity towards the organic phase. Among them, [PyC10Py][CFX]2 retained antibacterial activity, while others showed reduced efficacy. Cytotoxicity assays showed higher toxicity only in salts containing long-alkyl cations. Although not intended as final candidates for transdermal delivery, this study provided valuable methodological insights into ionic modification and established a foundation for applying this strategy to more challenging and clinically relevant antibiotics. Building on this framework, the second study applied a similar ionic modification strategy to streptomycin, a more challenging aminoglycoside antibiotic. Eight streptomycin organic salts (STP-OS) were synthetized, containing sulfonate and carboxylate counterions, yielding stable solids that were systematically characterized. In phospholipid bilayer permeation studies, [STPH3][p-TolSO3]3 showed the highest skin permeability, [STPH3][C6SO3]3 exhibited a balanced permeability and solubility, while [STPH3][GlyCOO]3 displayed increased solubility but negligible permeation. Antimicrobial testing confirmed preserved activity against susceptible strains. Together, these studies demonstrate that ionic modification can be a versatile tool for tuning the solubility, lipophilicity, and membrane interaction of streptomycin, establishing a chemical basis for their incorporation into advanced transdermal delivery systems. Expanding on the promising results of the ionic modification strategy, the third study investigated incorporation of selected STP-OS: [STPH3][p-TolSO3]3, [STPH3][C6SO3]3, and [STPH3][GlyCOO]3, alongside the conventional sulfate salt, were formulated into solid lipid nanoparticles (SLNs) using Softisan® as lipid matrix. The resulting nanoparticles were ~150 nm in diameter, exhibited low polydispersity indices (~0.2), maintained negative zeta potential (~–30 mV), indicating colloidal stability. Encapsulation efficiencies ranged from 35 to 62%, with drug loadings between 4-6% showing that all salts were broadly compatible with the lipid carrier. Lyophilized gels formed from these SLNs were suitable for dermal application offering favorable handling and consistency. MIC testing revealed enhanced antimicrobial potency of the SLN-formulated salts when compared to free salts, supporting the value of nano-particle encapsulation, importantly, the inclusion of salts. Crucially, the successful formulation of salts with diverse solubility and permeability profiles demonstrated that OSIL identity did not hinder nanoparticle formulation, while offering scope to fine-tuning delivery behavior. The fourth and final study incorporated the same three streptomycin OS into dissolving Micro Array Patches (MAPs) composed of PVP/PVA. The conventional sulfate salt exhibited lower solubility in the polymer matrix, resulting in reduced drug loading in comparison with the devices loaded with STP-OS. Despite these differences, all MAPs demonstrated excellent mechanical properties, with >99% insertion confirmed via optical coherence tomography and microscopy. Ex vivo permeation studies across full-thickness piglet skin revealed that, although total drug loading varied, the release and deposition profiles were comparable among the formulations. Interestingly, OSILs showed slightly higher retention within the skin layers. These results highlight the importance of solubility within the formulation matrix and demonstrate how ionic modification can broaden formulation options for transdermal delivery systems. Taken together, the four studies in this thesis establish that API-OSILs represent a chemical platform for modulating solubility, lipophilicity, permeability, and delivery profiles of antibiotics. Furthermore, these modifications can be successfully carried through to advanced delivery systems such as lipid nanoparticles and dissolving microneedles. While the extent of enhancement is molecule-dependent, as seen in the limited modulation of highly hydrophilic streptomycin, the results provide a proof of concept that ionic modification is a viable and adaptable strategy for enabling and optimizing transdermal delivery of pharmaceuticals.
Transdermal drug delivery offers a promising alternative to conventional administration routes. However, most antibiotics, due to their high polarity and low lipophilicity, exhibit limitations to cross the skin barrier effectively. This thesis explores the use of Active Pharmaceutical Ingredient based Organic Salts & Ionic Liquids (API-OSILs) as a chemical strategy to enhance antibiotic solubility, lipophilicity, and skin permeability of antibiotics. It further evaluates their integration into advanced delivery platforms, including lipid nanoparticles and dissolving microneedles. Cefuroxime and streptomycin were selected as model systems to investigate whether conjugation with organic ions can improve transdermal delivery. The work is organized into four key studies: (1) synthesis and evaluation of cefuroxime salts (CFX-OSILs), (2) design and screening of streptomycin organic salts (STP-OS), (3) formulation of these compounds into solid lipid nanoparticles, and (4) incorporation into dissolving microneedle patches. To explore the potential of ionic modification for enhancing transdermal antibiotic de-livery, the thesis begins with the synthesis of cefuroxime organic salts using pyridinium and imidazolium cations. These salts increased the original solubility, up to 200 times higher than the parent drug at 37 °C, and modified partitioning behavior, with more lipophilic cations increasing affinity towards the organic phase. Among them, [PyC10Py][CFX]2 retained antibacterial activity, while others showed reduced efficacy. Cytotoxicity assays showed higher toxicity only in salts containing long-alkyl cations. Although not intended as final candidates for transdermal delivery, this study provided valuable methodological insights into ionic modification and established a foundation for applying this strategy to more challenging and clinically relevant antibiotics. Building on this framework, the second study applied a similar ionic modification strategy to streptomycin, a more challenging aminoglycoside antibiotic. Eight streptomycin organic salts (STP-OS) were synthetized, containing sulfonate and carboxylate counterions, yielding stable solids that were systematically characterized. In phospholipid bilayer permeation studies, [STPH3][p-TolSO3]3 showed the highest skin permeability, [STPH3][C6SO3]3 exhibited a balanced permeability and solubility, while [STPH3][GlyCOO]3 displayed increased solubility but negligible permeation. Antimicrobial testing confirmed preserved activity against susceptible strains. Together, these studies demonstrate that ionic modification can be a versatile tool for tuning the solubility, lipophilicity, and membrane interaction of streptomycin, establishing a chemical basis for their incorporation into advanced transdermal delivery systems. Expanding on the promising results of the ionic modification strategy, the third study investigated incorporation of selected STP-OS: [STPH3][p-TolSO3]3, [STPH3][C6SO3]3, and [STPH3][GlyCOO]3, alongside the conventional sulfate salt, were formulated into solid lipid nanoparticles (SLNs) using Softisan® as lipid matrix. The resulting nanoparticles were ~150 nm in diameter, exhibited low polydispersity indices (~0.2), maintained negative zeta potential (~–30 mV), indicating colloidal stability. Encapsulation efficiencies ranged from 35 to 62%, with drug loadings between 4-6% showing that all salts were broadly compatible with the lipid carrier. Lyophilized gels formed from these SLNs were suitable for dermal application offering favorable handling and consistency. MIC testing revealed enhanced antimicrobial potency of the SLN-formulated salts when compared to free salts, supporting the value of nano-particle encapsulation, importantly, the inclusion of salts. Crucially, the successful formulation of salts with diverse solubility and permeability profiles demonstrated that OSIL identity did not hinder nanoparticle formulation, while offering scope to fine-tuning delivery behavior. The fourth and final study incorporated the same three streptomycin OS into dissolving Micro Array Patches (MAPs) composed of PVP/PVA. The conventional sulfate salt exhibited lower solubility in the polymer matrix, resulting in reduced drug loading in comparison with the devices loaded with STP-OS. Despite these differences, all MAPs demonstrated excellent mechanical properties, with >99% insertion confirmed via optical coherence tomography and microscopy. Ex vivo permeation studies across full-thickness piglet skin revealed that, although total drug loading varied, the release and deposition profiles were comparable among the formulations. Interestingly, OSILs showed slightly higher retention within the skin layers. These results highlight the importance of solubility within the formulation matrix and demonstrate how ionic modification can broaden formulation options for transdermal delivery systems. Taken together, the four studies in this thesis establish that API-OSILs represent a chemical platform for modulating solubility, lipophilicity, permeability, and delivery profiles of antibiotics. Furthermore, these modifications can be successfully carried through to advanced delivery systems such as lipid nanoparticles and dissolving microneedles. While the extent of enhancement is molecule-dependent, as seen in the limited modulation of highly hydrophilic streptomycin, the results provide a proof of concept that ionic modification is a viable and adaptable strategy for enabling and optimizing transdermal delivery of pharmaceuticals.
Descrição
Palavras-chave
cefuroxime salts lipid nanoparticles microneedle array patches transdermal delivery streptomycin salts