Publicação
Deep eutectic solvent formulations for the development of drug delivery systems
| Resumo: | The pharmaceutical industry is characterized by constant changes and demands, driven by the need to develop new drugs, or drug formulations of existing drugs, that are more efficient and safer. In this context, strategies such as drug reformulation are frequently applied to overcome many of the drawbacks associated with the existing pharmaceuticals, given the lower cost of this approach. Approaches to enhance drug solubility, stability, and permeation are crucial to improve their therapeutic efficacy. Therefore, understanding the problems associated with the existing active pharmaceutical ingredients, developing more effective strategies for their solubilization and administration, as well as to select proper solvents or excipients, are main aspects to improve therapeutic efficacy. Additionally, the possibility to incorporate these components, namely the solvents, in the drug delivery system, to tune their properties is appealing. Recently, alternative solvents, such as deep eutectic solvents (DES), have been explored in the pharmaceutical field, showing high solvation ability and high drug permeation across biological membranes, as well as drug stabilization. Furthermore, the versatility displayed by these solvents enables their incorporation into different drug delivery systems, being even possible the use of hydrophilic biopolymers. This partnership results in positive effects in the properties of biopolymer-based materials, allowing to particularly tune the mechanical properties and the respective drug release profiles. In this context, the main goal of this thesis is focused on the development of DES formulations of existing drugs and their incorporation in delivery systems, envisioning the improvement of their efficacy. The works developed involved the rational design of these formulations and the evaluation of their impact on system’s performance. Given the rising concerns associated with antimicrobial agents, including antibiotics, this was the class mainly studied. The first study focused on the development of DES aqueous solutions of cholinium chloride:urea:malonic acid, proline:urea:malonic acid and citric acid:xylitol, to remarkably improve the solubility, stability, and therapeutic efficacy of the antibiotic ciprofloxacin. The developed formulations enhanced the drug solubility up to 430-fold, in comparison to water, and the susceptibility of Gram-negative and Gram-positive bacteria to ciprofloxacin by 2- to 4-fold, respectively, while being non-toxic to human cells at the studied concentrations. The ability to improve the therapeutic efficacy of the antibiotic while avoiding the development of antimicrobial tolerance was demonstrated. The following study aimed to use betaine-based DES aqueous solutions, such as betaine:glycerol and betaine:xylitol, in the development of ocular drug delivery systems, namely thermo-responsive microemulsions that increase their viscosity upon contact with the ocular environment. These systems allowed a sustained-release and a higher permeation of the antibiotic chloramphenicol through the cornea. Finally, a higher antimicrobial activity and faster action in case of infection caused by multi-resistant bacteria was demonstrated using these microemulsions in comparison to a commercialized formulation. The versatility of DES formulations was also explored in the development of biopolymer-based drug delivery systems. In this sense, pullulan-based adhesive films were developed for application in antimicrobial photodynamic therapy (aPDT). For this purpose, betaine-based DES (betaine:levulinic acid) were applied to improve the solubility and photostability of the natural photosensitizer, curcumin. The incorporation of the DES formulations in the films, permitted to tune pullulan’s properties, obtaining systems with higher extensibility than the pristine materials. These films also present capability to absorb skin moisture and transit into a hydrogel with and higher adhesiveness than commercial hydrogels. The use of these systems in combination with an aPDT approach, allowed to eradicate common drug-resistant strains below the detection limit in ex vivo skin samples while being non-toxic to skin cells. The partnership between DES and biopolymers was also investigated for the transdermal delivery of anti-inflammatory drugs. DES aqueous solutions, based on arginine:glycerol, were used to increase the solubility of ibuprofen (up to 7917-fold, in comparison to water). These formulations were non-cytotoxic to macrophages and shown to preserve the anti-inflammatory action of the drug. Their incorporation into alginate-based hydrogels resulted in materials with higher flexibility, that presented a sustained release of the drug. Additionally, these hydrogels promoted an enhancement in the drug permeation across human skin in comparison to their counterpart containing only ibuprofen. In conclusion, the present thesis demonstrates the versatility and advantages of DES formulations in the improvement of drug delivery and therapeutic efficacy of known drugs. |
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| Autores principais: | Pedro, Sónia Isabel Neto |
| Assunto: | Active pharmaceutical ingredients Drug reformulation Deep eutectic solvents Biopolymers Drug delivery systems Therapeutic efficacy |
| Ano: | 2023 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Aveiro |
| Idioma: | inglês |
| Origem: | RIA - Repositório Institucional da Universidade de Aveiro |
| Resumo: | The pharmaceutical industry is characterized by constant changes and demands, driven by the need to develop new drugs, or drug formulations of existing drugs, that are more efficient and safer. In this context, strategies such as drug reformulation are frequently applied to overcome many of the drawbacks associated with the existing pharmaceuticals, given the lower cost of this approach. Approaches to enhance drug solubility, stability, and permeation are crucial to improve their therapeutic efficacy. Therefore, understanding the problems associated with the existing active pharmaceutical ingredients, developing more effective strategies for their solubilization and administration, as well as to select proper solvents or excipients, are main aspects to improve therapeutic efficacy. Additionally, the possibility to incorporate these components, namely the solvents, in the drug delivery system, to tune their properties is appealing. Recently, alternative solvents, such as deep eutectic solvents (DES), have been explored in the pharmaceutical field, showing high solvation ability and high drug permeation across biological membranes, as well as drug stabilization. Furthermore, the versatility displayed by these solvents enables their incorporation into different drug delivery systems, being even possible the use of hydrophilic biopolymers. This partnership results in positive effects in the properties of biopolymer-based materials, allowing to particularly tune the mechanical properties and the respective drug release profiles. In this context, the main goal of this thesis is focused on the development of DES formulations of existing drugs and their incorporation in delivery systems, envisioning the improvement of their efficacy. The works developed involved the rational design of these formulations and the evaluation of their impact on system’s performance. Given the rising concerns associated with antimicrobial agents, including antibiotics, this was the class mainly studied. The first study focused on the development of DES aqueous solutions of cholinium chloride:urea:malonic acid, proline:urea:malonic acid and citric acid:xylitol, to remarkably improve the solubility, stability, and therapeutic efficacy of the antibiotic ciprofloxacin. The developed formulations enhanced the drug solubility up to 430-fold, in comparison to water, and the susceptibility of Gram-negative and Gram-positive bacteria to ciprofloxacin by 2- to 4-fold, respectively, while being non-toxic to human cells at the studied concentrations. The ability to improve the therapeutic efficacy of the antibiotic while avoiding the development of antimicrobial tolerance was demonstrated. The following study aimed to use betaine-based DES aqueous solutions, such as betaine:glycerol and betaine:xylitol, in the development of ocular drug delivery systems, namely thermo-responsive microemulsions that increase their viscosity upon contact with the ocular environment. These systems allowed a sustained-release and a higher permeation of the antibiotic chloramphenicol through the cornea. Finally, a higher antimicrobial activity and faster action in case of infection caused by multi-resistant bacteria was demonstrated using these microemulsions in comparison to a commercialized formulation. The versatility of DES formulations was also explored in the development of biopolymer-based drug delivery systems. In this sense, pullulan-based adhesive films were developed for application in antimicrobial photodynamic therapy (aPDT). For this purpose, betaine-based DES (betaine:levulinic acid) were applied to improve the solubility and photostability of the natural photosensitizer, curcumin. The incorporation of the DES formulations in the films, permitted to tune pullulan’s properties, obtaining systems with higher extensibility than the pristine materials. These films also present capability to absorb skin moisture and transit into a hydrogel with and higher adhesiveness than commercial hydrogels. The use of these systems in combination with an aPDT approach, allowed to eradicate common drug-resistant strains below the detection limit in ex vivo skin samples while being non-toxic to skin cells. The partnership between DES and biopolymers was also investigated for the transdermal delivery of anti-inflammatory drugs. DES aqueous solutions, based on arginine:glycerol, were used to increase the solubility of ibuprofen (up to 7917-fold, in comparison to water). These formulations were non-cytotoxic to macrophages and shown to preserve the anti-inflammatory action of the drug. Their incorporation into alginate-based hydrogels resulted in materials with higher flexibility, that presented a sustained release of the drug. Additionally, these hydrogels promoted an enhancement in the drug permeation across human skin in comparison to their counterpart containing only ibuprofen. In conclusion, the present thesis demonstrates the versatility and advantages of DES formulations in the improvement of drug delivery and therapeutic efficacy of known drugs. |
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