ECTS: 15
Faglige nøgleord: lægemiddelformulering, analyse
Antal Studerende: 1-2
Vejleder: René Holm
Beskrivelse: Through their molecular structure, cyclodextrins (CDs) can form inclusion complexes through molecular encapsulation with a wide range of organic compounds. This special characteristic makes CDs valuable in a number of disciplines, including pharmaceutics, where the increased solubility of complexes can be used to increase the apparent solubility of poorly soluble drugs (Carrier et al., 2007; Davis and Brewster, 2004; Brewster and Loftsson, 2007; Loftsson et al., 2005; Szejtli, 1994; Rajewski and Stella, 1996; Uekama and Otagiri, 1987; Challa et al., 2005; Arima et al., 2002; Thompson, 1997; Uekama, 2004; Kurkov and Loftsson, 2013; Loftsson and Brewster, 2012; Jambhekar and Breen, 2016; Loftsson, 2021).
CDs have been applied in formulations for a number of different administration routes. In a recent review Loftsson (2021) report eight commercial pharmaceutical products for parenteral administration containing CDs either for intracavitary, intravenous or intramuscular administration. Other reviews provide overview of the many different administration routes where CDs have been applied, including transdermal, buccal, ocular and nasal (e.g. Jacob and Nair, 2018; Puskás et al., 2023).
Ditzinger and coworkers (2019) analysed the compounds included in commercial formulations containing CDs across all administration routs and reported that the compounds had an average molecular weight of 369 ± 130 g/mol. The distribution in molecular weight was not associated with the type of CD used in the formulation, i.e., the lower molecular weight molecules were not predominantly formulated with α-CD and the larger compounds with γ-CD (Ditzinger et al., 2019). The log P of the molecules were reported to be 3.2 ± 1.8 with a distribution from -0.4 to 7.8, with most of the compounds having a log P of 2–4. CDs therefore seems best suited in the mid-range of log P with a not to large molecular weight, as would seem logical, provided that there needs to be both a chemical and physical fit into the CD molecule. Since the analysis by Ditzinger and coworkers (2019) more compounds have been brought to the market formulated with cyclodextrins and in a recent review from 2023 the total number of CD-formulated APIs in marketed drug products was reported to be as many as 129 (Puskás et al., 2023). While additional compounds are therefore added to the list compared to the analysis may by Ditzinger et al. (2018), the previous analysis also had a number of elements not investigated that can help us fully understand the potential of cyclodextrins, such as dose link, concentration CD applied etc.
The purpose of this project is therefore to analysis all relevant compounds formulated with cyclodextrins and provide theoretical insights into the application of the excipient.
Metoder: Extensive literature analysis
Referencer:
Carrier RL, Miller LA, Ahmed I. The utility of cyclodextrins for enhancing oral bioavailability. J Control Release. 2007;123:78-99.
Davis ME, Brewster ME. Cyclodextrin-based pharmaceutics: past, present and future. Nat Rev Drug Discov 2004;3:1023–1035.
Brewster ME, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev. 2007;59:645-666.
Loftsson T, Jarho P, Másson M, Järvinen T. Cyclodextrins in drug delivery. Expert Opin Drug Deliv. 2005;2:335-351.
Szejtli J. Medicinal applications of cyclodextrins. Med Res Rev. 1994;14:353–386.
Rajewski RA, Stella VJ. Pharmaceutical applications of cyclodextrins. 2. In vivo drug delivery. J Pharm Sci. 1996;85:1142–1169.
Uekama K, Otagiri M. Cyclodextrins in drug carrier systems. Crit Rev Ther Drug Carrier Syst. 1987;3:1–40.
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Loftsson T, Brewster ME. Cyclodextrins as functional excipients: methods to enhance complexation efficiency. J Pharm Sci. 2012;101:3019-3032.
Jambhekar SS, Breen P. Cyclodextrins in pharmaceutical formulations II: solubilization, binding constant, and complexation efficiency. DrugDiscov Today 2016;21:363–368.
Loftsson T. Cyclodextrins in parenteral formulations. J Pharm Sci. 2021;110:654-664.
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Puskás I, Szente L, Szocs L, Fenyvesi É. Recent list of cyclodextrin-containing drug products. Period Polytech Chem Eng. 2023;67:11–17.
Ditzinger F, Price DJ, Ilie AR, Köhl NJ, Jankovic S, Tsakiridou G, Aleandri S, Kalantzi L, Holm R, Nair A, Saal C, Griffin B, Kuentz M. Lipophilicity and hydrophobicity considerations in bio-enabling oral formulations approaches - a PEARRL review. J Pharm Pharmacol. 2019;71:464-482.