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Projects / Programmes source: ARIS

Development of highly concentrated protein formulations and evaluation of absorption kinetics after subcutaneous administration

Research activity

Code Science Field Subfield
1.09.00  Natural sciences and mathematics  Pharmacy   

Code Science Field
3.01  Medical and Health Sciences  Basic medicine 
Keywords
subcutaneous protein delivery; high-concentration formulation; monoclonal antibodies; viscosity-reducers; computational screening; excipient synthesis; proline; in situ depot system; in vitro absorption model; in vivo study; pharmacokinetic model; in vitro – in vivo relation; absorption prediction
Evaluation (rules)
source: COBISS
Points
9,254.68
A''
1,080.29
A'
4,238.5
A1/2
6,241.35
CI10
12,062
CImax
362
h10
51
A1
32.18
A3
9.97
Data for the last 5 years (citations for the last 10 years) on July 13, 2024; A3 for period 2018-2022
Data for ARIS tenders ( 04.04.2019 – Programme tender, archive )
Database Linked records Citations Pure citations Average pure citations
WoS  645  14,428  12,649  19.61 
Scopus  686  15,719  13,806  20.13 
Researchers (19)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  15490  PhD Pegi Ahlin Grabnar  Pharmacy  Researcher  2021 - 2024  214 
2.  38497  PhD Maja Bjelošević Žiberna  Pharmacy  Researcher  2021 - 2024  82 
3.  32694  PhD Katarina Bolko Seljak  Pharmacy  Researcher  2022 - 2024  55 
4.  52168  Tjaša Felicijan  Pharmacy  Researcher  2021 - 2024  27 
5.  11789  PhD Mirjana Gašperlin  Pharmacy  Researcher  2021 - 2024  605 
6.  15284  PhD Stanislav Gobec  Pharmacy  Researcher  2021 - 2024  849 
7.  29887  PhD Mirjam Gosenca Matjaž  Pharmacy  Researcher  2021 - 2024  144 
8.  16107  PhD Iztok Grabnar  Pharmacy  Head  2021 - 2024  442 
9.  32036  PhD Martina Hrast Rambaher  Pharmacy  Researcher  2022 - 2024  142 
10.  36438  PhD Damijan Knez  Pharmacy  Researcher  2021 - 2024  208 
11.  33908  PhD Urban Košak  Pharmacy  Researcher  2021 - 2024  59 
12.  53673  Nika Kržišnik  Pharmacy  Researcher  2021 - 2024  40 
13.  56839  Monika Prašnikar  Pharmacy  Junior researcher  2023 - 2024  10 
14.  52376  PhD Matic Proj  Pharmacy  Junior researcher  2021 - 2023  67 
15.  23549  PhD Robert Roškar  Pharmacy  Researcher  2021 - 2024  309 
16.  23420  PhD Jurij Trontelj  Pharmacy  Researcher  2021 - 2024  263 
17.  51148  Jurij Zdovc  Pharmacy  Researcher  2021 - 2023  40 
18.  26226  PhD Alenka Zvonar Pobirk  Pharmacy  Researcher  2021 - 2024  217 
19.  22659  PhD Simon Žakelj  Pharmacy  Researcher  2021 - 2024  162 
Organisations (1)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,412 
Abstract
Over the past several decades, protein therapeutics, and monoclonal antibodies (MAbs) have contributed to better therapeutic success in a wide range of diseases. Especially formulations for subcutaneous administration are gaining in importance and represent one of the most significant areas in the field of pharmaceutical industry. Subcutaneous administration presents with many advantages compared to intravenous administration, however, there are many lingering technological challenges in terms of preparation of highly concentrated protein formulations intended for subcutaneous dosing. Particularly the protein stability and appropriate viscosity should not be overlooked, considering it may otherwise result in a limited syringeability. Thus, the initial objective of the proposed research work, will be the identification of novel excipients for reducing the viscosity of formulations for subcutaneous administration. At the beginning, promising new excipients will first be identified through the computational screening and subsequently synthesized. The most suitable excipients will then be incorporated in highly concentrated formulations and evaluated in terms of protein stability and viscosity. Simultaneously, new depot systems for controlled release of proteins with limited duration of action will be established and characterized for physico-chemical properties and biological acceptability. In addition, a novel in vitro absorption model will be developed for the purpose of studying the subcutaneous absorption kinetics of selected highly concentrated formulations. The bioavailability and absorption rate constant will be predicted based on the estimated in vitro diffusion and convection processes, which were highlighted as two main biological mechanisms of the subcutaneous protein absorption. The best performing in vitro formulations will be chosen for the in vivo study, which will be the basis for the extensive in silico modeling of the pharmacokinetics (PK) of subcutaneously administered MAbs. Through the development of a population PK model, the most important factors governing PK of protein drugs will be identified. A more detailed model of subcutaneous absorption of macromolecules will be developed through mechanistic physiologically-based pharmacokinetic modeling. The in vivo absorption data analyzed by PK modelling will be related with the results from in vitro testing. Namely, the diffusion and convection parameters of the same formulations obtained in the in vitro study will be compared with the absorption rate constants and fraction of the absorbed dose in vivo. The predictive in vitro in vivo correlation will be established for future forecasting of protein absorption kinetics. We anticipate that the study will have an academic, as well as practical and economic impact, with the direct applicability into the current setting of the pharmaceutical industry. The results will contribute to a deeper understanding about protein formulations for subcutaneous administration, as well as mechanisms of subcutaneous absorption process. Our project will contribute to optimized production costs through the enhanced absorption screening for new potential lead drugs, upgraded predictive ability of the absorption models, and reduced necessary animal testing. This project will be a steppingstone for the future development of increasingly complex drug formulation systems.
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