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Avaliação da estabilidade físico-química de um colutório hospitalar destinado ao tratamento da mucosite oral
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Authors
Abstract(s)
A mucosite oral é uma doença inflamatória e ulcerativa que afeta doentes submetidos a
tratamentos oncológicos, comprometendo de forma significativa a sua qualidade de vida.
Apesar da elevada incidência e do impacto clínico, as opções terapêuticas efetivas são limitadas,
o que reforça a necessidade de explorar novos medicamentos. Neste contexto, o Instituto
Português de Oncologia do Porto Francisco Gentil, E.P.E (IPO-Porto) desenvolveu duas
formulações de um colutório inovador: a formulação A, contendo fosfato sódico de
dexametasona (DSP), ácido ascórbico (AA) e hialuronato de sódio (HS); e a formulação B, que
inclui, além destes componentes, bicarbonato de sódio (BC).
O objetivo deste trabalho consistiu em avaliar a estabilidade físico-química destas formulações,
assegurando a sua qualidade e segurança para utilização como medicamento manipulado
hospitalar. Foram realizados estudos exploratórios em condições de envelhecimento acelerado
(40 ± 2 °C), seguidos de um estudo de estabilidade em condições de tempo real (20 ± 2 °C) e
condições de refrigeração (4 ± 2 °C). Para avaliar o impacto da exposição ao ar na estabilidade
do fármaco, foram realizados estudos envolvendo a simulação do uso (“in use stability”). Todas
as formulações foram armazenadas em frasco de vidro âmbar tipo III. Em cada tempo de
amostragem foi efetuada a caracterização físico-química (pH e características organolépticas:
cor, odor e formação de precipitados) e o doseamento do DSP através de cromatografia líquida
de alta eficiência, recorrendo ao método de referência descrito na Farmacopeia Europeia 11.0.
Os resultados mostraram que a formulação B apresentava alterações precoces e progressivas
da cor, devido ao seu carácter alcalino associado à presença de BC, pelo que não foi submetida
a qualquer estudo de estabilidade. Por outro lado, os ensaios realizados com a formulação A a
40 °C permitiram concluir que exposições curtas (≤ 6 h) a esta temperatura não afetavam a sua
estabilidade, já que não se observaram alterações significativas do teor de DSP. Em condições
de refrigeração (4 °C), verificou-se que a formulação se mantinha estável, com teor de DSP
superior a 90 % após 30 dias de armazenamento em frasco fechado. Durante o estudo in use de
mais 7 dias, o teor permaneceu acima de 90 %. A extensão do armazenamento até 2 meses, em
condições de refrigeração, permitiu concluir que a formulação deixa de ser considerada estável,
apresentando partículas em suspensão e uma diminuição do teor de DSP superior a 10 %. O
armazenamento da formulação A em condições de tempo real (20 °C) originou resultados
inconsistentes para os 3 lotes testados, pelo que não permitiu obter dados concludentes.
Assim, este estudo revelou que a formulação A poderá ser utilizada como alternativa
terapêutica para o tratamento da mucosite oral, desde que conservada sob condições de
refrigeração (4 °C). Nestas condições, mantém-se estável durante 30 dias em frasco fechado e
até 7 dias de utilização (3 aplicações diárias) após a abertura.
Oral mucositis is an inflammatory and ulcerative disease that affects patients undergoing cancer treatment, significantly compromising their quality of life. Despite its high incidence and clinical impact, effective therapeutic options are limited, which reinforces the need to explore new drugs. In this context, the Instituto Português de Oncologia do Porto Francisco Gentil, E.P.E (IPOPorto) has developed two formulations of an innovative mouthwash: formulation A, containing dexamethasone sodium phosphate (DSP), ascorbic acid (AA) and sodium hyaluronate (HS); and formulation B, which includes, in addition to these components, sodium bicarbonate (BC). The aim of this work was to assess the physicochemical stability of these formulations, ensuring their quality and safety for use as a manipulated hospital drug. Exploratory studies were carried out under accelerated ageing conditions (40 ± 2 °C), followed by stability studies under real time conditions (20 ± 2 °C) and refrigeration conditions (4 ± 2 °C). To assess the impact of exposure to air on the stability of the drug, studies involving simulated use (‘in use stability’) were carried out. All formulations were stored in type III amber glass vials. At each sampling time, physicochemical characterisation was carried out (pH and organoleptic characteristics: colour, odour and precipitate formation) and the DSP was assayed using high-performance liquid chromatography, using the reference method described in European Pharmacopoeia 11.0. The results showed that formulation B had early and progressive colour changes due to its alkaline character associated with the presence of BC, so it was not subjected to any stability study. On the other hand, the tests carried out on formulation A at 40 °C led to the conclusion that short exposures (≤ 6 h) at this temperature did not affect its stability, since no significant changes in the DSP content were observed. Under refrigeration conditions (4 °C), the formulation was found to be stable, with a DSP content of over 90 % after 30 days of storage in a closed bottle. During the 7-day in-use study, the content remained above 90 %. Extending storage to 2 months under refrigeration conditions led to the conclusion that the formulation was no longer considered stable, with particles in suspension and a decrease in DSP content of more than 10 %. Storing formulation A under real time conditions (20 °C) gave inconsistent results for the 3 batches tested, so it was not possible to obtain conclusive data. This study has therefore shown that formulation A can be used as a therapeutic alternative for the treatment of oral mucositis, as long as it is kept refrigerated (4 °C). Under these conditions, it remains stable for 30 days in a closed bottle and up to 7 days of use (3 daily applications) after opening.
Oral mucositis is an inflammatory and ulcerative disease that affects patients undergoing cancer treatment, significantly compromising their quality of life. Despite its high incidence and clinical impact, effective therapeutic options are limited, which reinforces the need to explore new drugs. In this context, the Instituto Português de Oncologia do Porto Francisco Gentil, E.P.E (IPOPorto) has developed two formulations of an innovative mouthwash: formulation A, containing dexamethasone sodium phosphate (DSP), ascorbic acid (AA) and sodium hyaluronate (HS); and formulation B, which includes, in addition to these components, sodium bicarbonate (BC). The aim of this work was to assess the physicochemical stability of these formulations, ensuring their quality and safety for use as a manipulated hospital drug. Exploratory studies were carried out under accelerated ageing conditions (40 ± 2 °C), followed by stability studies under real time conditions (20 ± 2 °C) and refrigeration conditions (4 ± 2 °C). To assess the impact of exposure to air on the stability of the drug, studies involving simulated use (‘in use stability’) were carried out. All formulations were stored in type III amber glass vials. At each sampling time, physicochemical characterisation was carried out (pH and organoleptic characteristics: colour, odour and precipitate formation) and the DSP was assayed using high-performance liquid chromatography, using the reference method described in European Pharmacopoeia 11.0. The results showed that formulation B had early and progressive colour changes due to its alkaline character associated with the presence of BC, so it was not subjected to any stability study. On the other hand, the tests carried out on formulation A at 40 °C led to the conclusion that short exposures (≤ 6 h) at this temperature did not affect its stability, since no significant changes in the DSP content were observed. Under refrigeration conditions (4 °C), the formulation was found to be stable, with a DSP content of over 90 % after 30 days of storage in a closed bottle. During the 7-day in-use study, the content remained above 90 %. Extending storage to 2 months under refrigeration conditions led to the conclusion that the formulation was no longer considered stable, with particles in suspension and a decrease in DSP content of more than 10 %. Storing formulation A under real time conditions (20 °C) gave inconsistent results for the 3 batches tested, so it was not possible to obtain conclusive data. This study has therefore shown that formulation A can be used as a therapeutic alternative for the treatment of oral mucositis, as long as it is kept refrigerated (4 °C). Under these conditions, it remains stable for 30 days in a closed bottle and up to 7 days of use (3 daily applications) after opening.
Description
Keywords
Stability studies HPLC Oral mucositis Mouthwash Dexamethasone sodium phosphate Estudos de estabilidade Mucosite oral Colutório Fosfato sódico de dexametasona