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Publication
Challenges in the development of high concentration protein formulations for subcutaneous route
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Abstract(s)
A administração por via subcutânea de biofármacos tem vindo a demonstrar ser uma
alternativa significativa e rentável face à administração intravenosa no tratamento de
vários grupos de doenças. Esta via de administração demonstrou ser segura, poupar
tempo, reduzir custos e aumentar a satisfação dos doentes.
No entanto, embora a via SC ofereça diversas vantagens, esta apresenta alguns obstáculos,
principalmente quando é necessário desenvolver formulações proteicas que requeiram
dosagem elevada (mg/kg) e com um volume de administração limitado. Além disso, o
comportamento das soluções a altas concentrações de proteína pode diferir marcadamente
daquele previsto com base na análise da mesma solução diluída, isto devido
principalmente às interações proteína-proteína. Isso leva a alguns problemas de produção,
estabilidade, análise e administração.
Tendo tudo isto em conta, o objetivo deste trabalho de investigação é compreender melhor
os desafios que estão inerentes à administração subcutânea de formulações de proteína
altamente concentradas, quando e como acontecem.
Utilizou-se a Albumina de soro bovina (BSA) como proteína modelo e foram preparadas
e estudadas 16 soluções com diferentes concentrações de albumina (4, 5, 6, 8, 10, 20, 30,
40, 50, 100, 200 and 300 mg/mL) e com 2 valores de pH distintos (4,1 e 6,8).
O parâmetro de interação (kD) e o índice de polidispersibilidade (PDI) foram obtidos a
partir da técnica de espalhamento de luz dinâmico (DLS). Além disso, recorreu-se a
estudos reológicos, tanto oscilatórios como rotacionais, para caraterizar as soluções
concentradas de proteína quanto à sua viscoelasticidade.
As soluções estudadas apresentaram estabilidade sem agregação de partículas para
concentrações de BSA abaixo de 100 mg/mL, na presença de um agente tensioativo
(Tween®20), o qual demonstrou ser um fator bastante importante. Para as soluções de
BSA com concentração acima de 100mg/mL, não foi possível a sua caracterização pelo
que há que desenvolver futuros estudos que incluam este intervalo de concentrações.
Subcutaneous (SC) delivery of biotherapeutics has become a significant and profitable alternative to intravenous administration for the treatment of several diseases. This administration route shown to be safe, to save time, to reduce costs and to increase the satisfaction of the patients. However, while SC route offers several advantages it is not without some obstacles, especially, when its needed to develop formulations for protein drugs requiring high dosing (mg/kg) and within a limited administration volume. On the other hand, the solutions behaviour at high protein concentrations can markedly differ from the ones that are predicted based on dilute solutions analysis, mainly due to the protein–protein interactions(PPI). This will lead to a few manufacturing, stability, analytical, and delivery adversities. Having all of this in mind, the purpose of this research work is to better understand the challenges that are inherent to the subcutaneous deliver of highly concentrated protein formulations, why and at what moment they happen. Bovine serum albumin (BSA) was used as a model protein and 16 samples with different concentrations of BSA (4, 5, 6, 8, 10, 20, 30, 40, 50, 100, 200 and 300 mg/mL) and with two different pH values ( 4.1 and 6.8) were prepared and studied. Interaction parameter (kD) and polydispersity index (PDI) were obtained from dynamic light scattering technique. Furthermore, rheological studies, including rotational and oscillatory tests, characterized the viscoelasticity of the samples. The results shown that the albumin solutions were stable and no particles aggregation occurred for the samples with a concentration under 100 mg/mL in the presence of a tensioactive agent (Tween®20), which was a determinant factor. For BSA solutions with a concentration over 100mg/mL no conclusive results were obtained, thus, further investigation is needed for this range of concentrations.
Subcutaneous (SC) delivery of biotherapeutics has become a significant and profitable alternative to intravenous administration for the treatment of several diseases. This administration route shown to be safe, to save time, to reduce costs and to increase the satisfaction of the patients. However, while SC route offers several advantages it is not without some obstacles, especially, when its needed to develop formulations for protein drugs requiring high dosing (mg/kg) and within a limited administration volume. On the other hand, the solutions behaviour at high protein concentrations can markedly differ from the ones that are predicted based on dilute solutions analysis, mainly due to the protein–protein interactions(PPI). This will lead to a few manufacturing, stability, analytical, and delivery adversities. Having all of this in mind, the purpose of this research work is to better understand the challenges that are inherent to the subcutaneous deliver of highly concentrated protein formulations, why and at what moment they happen. Bovine serum albumin (BSA) was used as a model protein and 16 samples with different concentrations of BSA (4, 5, 6, 8, 10, 20, 30, 40, 50, 100, 200 and 300 mg/mL) and with two different pH values ( 4.1 and 6.8) were prepared and studied. Interaction parameter (kD) and polydispersity index (PDI) were obtained from dynamic light scattering technique. Furthermore, rheological studies, including rotational and oscillatory tests, characterized the viscoelasticity of the samples. The results shown that the albumin solutions were stable and no particles aggregation occurred for the samples with a concentration under 100 mg/mL in the presence of a tensioactive agent (Tween®20), which was a determinant factor. For BSA solutions with a concentration over 100mg/mL no conclusive results were obtained, thus, further investigation is needed for this range of concentrations.
Description
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, 2020, Universidade de Lisboa, Faculdade de Farmácia.
Keywords
Rheological DLS Aggregation Subcutaneous route Highly concentrated protein formulations Mestrado integrado - 2020