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Projects / Programmes source: ARRS

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

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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
8,113.86
A''
1,175.23
A'
3,861.74
A1/2
5,473.83
CI10
10,523
CImax
341
h10
47
A1
28.56
A3
20.07
Data for the last 5 years (citations for the last 10 years) on May 29, 2023; A3 for period 2017-2021
Data for ARRS tenders ( 04.04.2019 – Programme tender, archive )
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Database Linked records Citations Pure citations Average pure citations
WoS  614  12,960  11,295  18.4 
Scopus  654  14,063  12,270  18.76 
Researchers (18)
no. Code Name and surname Research area Role Period No. of publications
1.  15490  PhD Pegi Ahlin Grabnar  Natural sciences and mathematics  Researcher  2021 - 2023  191 
2.  38497  PhD Maja Bjelošević Žiberna  Natural sciences and mathematics  Researcher  2021 - 2023  61 
3.  32694  PhD Katarina Bolko Seljak  Natural sciences and mathematics  Researcher  2022 - 2023  52 
4.  52168  Tjaša Felicijan  Natural sciences and mathematics  Researcher  2021 - 2023  23 
5.  11789  PhD Mirjana Gašperlin  Natural sciences and mathematics  Researcher  2021 - 2023  583 
6.  15284  PhD Stanislav Gobec  Natural sciences and mathematics  Researcher  2021 - 2023  800 
7.  29887  PhD Mirjam Gosenca Matjaž  Natural sciences and mathematics  Researcher  2021 - 2023  122 
8.  16107  PhD Iztok Grabnar  Natural sciences and mathematics  Principal Researcher  2021 - 2023  425 
9.  32036  PhD Martina Hrast Rambaher  Natural sciences and mathematics  Researcher  2022 - 2023  110 
10.  36438  PhD Damijan Knez  Natural sciences and mathematics  Researcher  2021 - 2023  176 
11.  33908  PhD Urban Košak  Natural sciences and mathematics  Researcher  2021 - 2023  53 
12.  53673  Nika Osel  Natural sciences and mathematics  Researcher  2021 - 2023  36 
13.  52376  Matic Proj  Natural sciences and mathematics  Junior researcher  2021 - 2023  53 
14.  23549  PhD Robert Roškar  Natural sciences and mathematics  Researcher  2021 - 2023  287 
15.  23420  PhD Jurij Trontelj  Natural sciences and mathematics  Researcher  2021 - 2023  242 
16.  51148  Jurij Zdovc  Natural sciences and mathematics  Researcher  2021 - 2023  38 
17.  26226  PhD Alenka Zvonar Pobirk  Natural sciences and mathematics  Researcher  2021 - 2023  196 
18.  22659  PhD Simon Žakelj  Natural sciences and mathematics  Researcher  2021 - 2023  155 
Organisations (1)
no. Code Research organisation City Registration number No. of publications
1.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,107 
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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