TY - JOUR
T1 - Impact of simulated lung fluid components on the solubility of inhaled drugs and predicted in vivo performance
AU - Radivojev, Snezana
AU - Luschin-Ebengreuth, Gerfried
AU - Pinto, Joana T.
AU - Laggner, Peter
AU - Cavecchi, Alessandro
AU - Cesari, Nicola
AU - Cella, Massimo
AU - Melli, Fabrizio
AU - Paudel, Amrit
AU - Fröhlich, Eleonore
N1 - Funding Information:
This work was funded through the Austrian COMET Program by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT), the Austrian Federal Ministry of Economy, Family and Youth (BMWFJ) and by the State of Styria (Styrian Funding Agency SFG). The authors would also like to thank Per Gerde for his support and fruitful discussions regarding this work.
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/9/5
Y1 - 2021/9/5
N2 - Orally inhaled products (OIPs) are gaining increased attention, as pulmonary delivery is a preferred route for the treatment of various diseases. Yet, the field of inhalation biopharmaceutics is still in development phase. For a successful correlation between various in vitro data obtained during formulation characterization and in vivo performance, it is necessary to understand the impact of parameters such as solubility and dissolution of drugs. In this work, we used in vitro-in silico feedback-feedforward approach to gain a better insight into the biopharmaceutics behavior of inhaled Salbutamol Sulphate (SS) and Budesonide (BUD). The thorough characterization of the in vitro test media and the impact of different in vitro fluid components such as lipids and protein on the solubility of aforementioned drugs was studied. These results were subsequently used as an input into the developed in silico models to investigate potential PK parameter changes in vivo. Results revealed that media comprising lipids and albumin were the most biorelevant and impacted the solubility of BUD the most. On the contrary, no notable impact was seen in case of SS. The use of simple media such as phosphate buffer saline (PBS) might be sufficient to use in solubility studies of the highly soluble and permeable drugs. However, its use for the poorly soluble drugs is limited due to the greater potential for interactions within in vivo environment. The use of in silico tools showed that the model response varies, depending on the used media. Therefore, this work highlights the relevance of carefully selecting the media composition when investigating solubility and dissolution behavior, especially in the early phases of drug development and of poorly soluble drugs.
AB - Orally inhaled products (OIPs) are gaining increased attention, as pulmonary delivery is a preferred route for the treatment of various diseases. Yet, the field of inhalation biopharmaceutics is still in development phase. For a successful correlation between various in vitro data obtained during formulation characterization and in vivo performance, it is necessary to understand the impact of parameters such as solubility and dissolution of drugs. In this work, we used in vitro-in silico feedback-feedforward approach to gain a better insight into the biopharmaceutics behavior of inhaled Salbutamol Sulphate (SS) and Budesonide (BUD). The thorough characterization of the in vitro test media and the impact of different in vitro fluid components such as lipids and protein on the solubility of aforementioned drugs was studied. These results were subsequently used as an input into the developed in silico models to investigate potential PK parameter changes in vivo. Results revealed that media comprising lipids and albumin were the most biorelevant and impacted the solubility of BUD the most. On the contrary, no notable impact was seen in case of SS. The use of simple media such as phosphate buffer saline (PBS) might be sufficient to use in solubility studies of the highly soluble and permeable drugs. However, its use for the poorly soluble drugs is limited due to the greater potential for interactions within in vivo environment. The use of in silico tools showed that the model response varies, depending on the used media. Therefore, this work highlights the relevance of carefully selecting the media composition when investigating solubility and dissolution behavior, especially in the early phases of drug development and of poorly soluble drugs.
KW - Budesonide
KW - Dissolution
KW - Oral inhalation
KW - PBPK modelling
KW - Salbutamol Sulphate
KW - Solubility
UR - http://www.scopus.com/inward/record.url?scp=85111063698&partnerID=8YFLogxK
U2 - 10.1016/j.ijpharm.2021.120893
DO - 10.1016/j.ijpharm.2021.120893
M3 - Article
C2 - 34274456
AN - SCOPUS:85111063698
SN - 0378-5173
VL - 606
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
M1 - 120893
ER -