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Advisor(s)
Abstract(s)
Ciclodextrinas são oligossacarídeos com 6, 7 ou 8 anéis de D-(+)-glucopiranose unidos em ligações glicosídicas α-1,4. São moléculas ocas, capazes de formar complexos de inclusão com moléculas-hóspede de tamanho adequado, em que o hóspede é incluído na ciclodextrina. Em soluções aquosas, moléculas-hospede em complexos de inclusão estão em equilíbrio com moléculas-hóspede livres. Na indústria farmacêutica, as ciclodextrinas são usadas para aumentar a solubilidade de fármacos pouco solúveis em água, diminuir toxicidade, aumentar a biodisponibilidade, evitar degradação, evitar incompatibilidades na forma farmacêutica, e mascarar odores ou sabores desagradáveis dos fármacos.
Nesta tese é revisto o estatuto regulamentar das ciclodextrinas usadas como excipientes, bem como o seu perfil de segurança.
As ciclodextrinas são usadas mundialmente como excipientes. A Agência Europeia do Medicamento e a Food and Drug Administration estabeleceram o uso seguro – dentro de certas dosagens/concentrações – das ciclodextrinas alfadex, betadex, gammadex, hidroxipropil betadex, sulfobutileter betadex, e betadex aleatoriamente metilada.
Foram consideradas três fontes para análise da segurança das ciclodextrinas: informação determinada pela Agência Europeia do Medicamento, informação da literatura publicada, e informação do EudraVigilance Data Analysis System.
A Agência Europeia do Medicamento avaliou as ciclodextrinas como relativamente seguras dentro de certos limites abaixo dos quais não se esperam reações adversas. Algumas ciclodextrinas não são adequadas a uso parentérico devido ao risco de nefrotoxicidade. Em insuficientes renais há risco de acumulação de ciclodextrinas, por isso o uso prolongado nestes doentes deve ser feito com precaução.
A pesquisa bibliográfica reforçou a avaliação feita pela Agência Europeia do Medicamento. Riscos adicionais incluíram ototoxicidade e aumento dos marcadores inflamatórios (em que as ciclodextrinas foram administradas em doses elevadas como substância ativa) e possíveis interações farmacocinéticas.
Apenas seis casos individuais de segurança foram selecionados para análise da EudraVigilance; destes, três foram considerados não-relacionados com as ciclodextrinas implicadas, um foi considerado como possivelmente relacionado, e dois eram relacionados com o uso de ciclodextrina em dose elevada administrada como substância ativa.
Concluiu-se que dentro dos limites estabelecidos pelas autoridades, as ciclodextrinas são seguras. Novas ciclodextrinas ou utilização de ciclodextrinas existentes em doses elevadas – como acontece quando são utilizadas como substância ativa – podem exigir uma avaliação de segurança completa.
Cyclodextrins are cyclic oligosaccharides containing six, seven or eight linked D-(+)-glucopyranose units by α-1,4-glycosidic bonds. They are hollow molecules, able to form inclusion complexes with guest molecules of adequate size, where the guest molecule is enveloped by the cyclodextrin. In aqueous solutions, guest molecules bound within the cyclodextrin inclusion complex are in dynamic equilibrium with free guest molecules. In the pharmaceutical industry, cyclodextrins are used to increase solubility of drugs poorly soluble in water, decrease drug toxicity, increase drug bioavailability, prevent drug lability, prevent drug formulation incompatibilities, and mask unpleasant odors/taste. In this thesis, the regulatory status of cyclodextrins as excipients was reviewed and their safety profile was analyzed. Cyclodextrins are used worldwide as excipients. The European Medicines Agency and the Food and Drug Administration have stablished the safe use – within certain dosages/concentrations – of alfadex, betadex, gammadex, hydroxypropyl betadex, sulfobutylether betadex, and randomly methylated betadex. For the analysis of cyclodextrins safety profile, three sources were considered: information established by the European Medicines Agency, information from the published literature and information from the EudraVigilance Data Analysis System. The European Medicines Agency found that cyclodextrins are relatively safe to use within certain thresholds, below which no adverse reaction is expected. Some cyclodextrins are not suitable for parenteral use due to the risk of nephrotoxicity. Prolonged use must also warrant caution in renally impaired patients as it may lead to accumulation of cyclodextrins. The literature search confirmed the previous assessment made by the European Medicines Agency. Other raised safety concerns included ototoxicity and increased inflammatory markers (where cyclodextrins were administered in high doses as active ingredients) and possible pharmacokinetic interactions. Only six individual safety cases were selected for analysis from EudraVigilance; of these, three cases were considered unrelated to the implicated cyclodextrins, one was assessed as possibly related, and the other two were related to use of high dose of cyclodextrin as active ingredient. It was concluded that within the thresholds established by the authorities, cyclodextrins are safe to use. Developing new cyclodextrins or using existing cyclodextrins in high concentrations – as when used as an active ingredient – may warrant a full safety evaluation.
Cyclodextrins are cyclic oligosaccharides containing six, seven or eight linked D-(+)-glucopyranose units by α-1,4-glycosidic bonds. They are hollow molecules, able to form inclusion complexes with guest molecules of adequate size, where the guest molecule is enveloped by the cyclodextrin. In aqueous solutions, guest molecules bound within the cyclodextrin inclusion complex are in dynamic equilibrium with free guest molecules. In the pharmaceutical industry, cyclodextrins are used to increase solubility of drugs poorly soluble in water, decrease drug toxicity, increase drug bioavailability, prevent drug lability, prevent drug formulation incompatibilities, and mask unpleasant odors/taste. In this thesis, the regulatory status of cyclodextrins as excipients was reviewed and their safety profile was analyzed. Cyclodextrins are used worldwide as excipients. The European Medicines Agency and the Food and Drug Administration have stablished the safe use – within certain dosages/concentrations – of alfadex, betadex, gammadex, hydroxypropyl betadex, sulfobutylether betadex, and randomly methylated betadex. For the analysis of cyclodextrins safety profile, three sources were considered: information established by the European Medicines Agency, information from the published literature and information from the EudraVigilance Data Analysis System. The European Medicines Agency found that cyclodextrins are relatively safe to use within certain thresholds, below which no adverse reaction is expected. Some cyclodextrins are not suitable for parenteral use due to the risk of nephrotoxicity. Prolonged use must also warrant caution in renally impaired patients as it may lead to accumulation of cyclodextrins. The literature search confirmed the previous assessment made by the European Medicines Agency. Other raised safety concerns included ototoxicity and increased inflammatory markers (where cyclodextrins were administered in high doses as active ingredients) and possible pharmacokinetic interactions. Only six individual safety cases were selected for analysis from EudraVigilance; of these, three cases were considered unrelated to the implicated cyclodextrins, one was assessed as possibly related, and the other two were related to use of high dose of cyclodextrin as active ingredient. It was concluded that within the thresholds established by the authorities, cyclodextrins are safe to use. Developing new cyclodextrins or using existing cyclodextrins in high concentrations – as when used as an active ingredient – may warrant a full safety evaluation.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2022, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Cyclodextrins Excipient Regulatory status Safety profile Pharmacovigilance Mestrado Integrado - 2022