Recent List of Cyclodextrin-Containing Drug Products

The number of the cyclodextrin-containing drug formulations on the market has been continuously growing since the first drug (prostaglandin E1 formulated with α -cyclodextrin) was launched in Japan in 1976. We have collected a list of drugs from various sources available on the internet to find 130 approved pharmaceutical ingredients formulated with either parent cyclodextrins or their hydroxypropyl, sulfobutyl, random methylated or sulfolipo derivatives. We have sorted the drug products according to the cavity size of the cyclodextrins, the administration route and dosage forms


Introduction
Cyclodextrins (CDs) are cyclic carbohydrates consisting of usually 6, 7 or 8 glucopyranose units (called α-, β-and γ-CDs, respectively) able to form non-covalent host-guest inclusion complexes with other molecules such as drugs. Their beneficial effects (enhancement of solubility and bioavailability, improvement of stability and taste, etc.) on various pharmaceuticals have been reviewed several times [1][2][3][4]. The very first drug marketed in the form of a CD complex was a prostaglandin produced by Ono Pharmaceutical Co. (Japan) as injection containing α-CD/ prostaglandin E1 and later tablets of β-CD/prostaglandin E2 [5]. In Europe at first β-CD/piroxicam, the product of Chiesi Pharmaceutici (Italy), was introduced to the market in 1988 with a brand name Brexin [6]. The first drug in the US market appeared in 1997; it was the hydroxypropyl-β-CD/itraconazol solution (Sporanox) produced by Janssen Pharmaceutical Co. (Belgium) [7].
The list of the CD-containing pharmaceutical products approved and marketed has been continuously increasing since then. The first list collected by Davis and Brewster in 2004 contained 24 active pharmaceutical ingredients (APIs) [8]. This list was enlarged to 35 items in 2007 by Brewster and Loftsson [9]. A bit longer list was published in the Cyclodextrin News in 2013 with 48 APIs [10]. This list has been continuously enlarged by the data available from internet e.g. from drugs.com, a platform on marketed drugs informing also on the excipients [11]. More recently a similar webpage on the drugs marketed in Japan has been also explored [12]. In September 2022 the total number of CD-formulated active ingredients in the marketed drugs -we found so far -is as much as 129. Further data are expected from China and India. Table 1 gives a summary of the number of active ingredients in marketed drugs formulated with various CDs showing that most of them contain β-CD or its derivatives. Among the derivatives hydroxypropyl β-and γ-CDs (HP-β-CD and HP-γ-CD), sulfobutyl ether (SBECD), random methyl (RAMEB) and sulfolipo-β-CDs can be found in drug formulations. Their abundance follows this order.

List of pharmaceutical actives marketed in CDcontaining formulations
From Table 2 one can get an overview on the administration routes, showing that the native CDs are utilized n.s.: not specified mostly in oral formulations, while the soluble sulfobutyl CD derivative is used only parenterally. The hydroxypropyl β-CD is applied both in oral and parenteral formulations as well as in ocular solutions. In Table 3, the drugs are sorted according to the dosage forms. The complete list is given in Tables 4-7.
We have to note that these tables do not show the drugs where the active ingredient is a CD itself: Bridion (Sugammadex) and HP-β-CD, which are used for reversal of neuromuscular block in anesthesia and for the treatment of fatal genetic Niemann Pick Type C disease, a cholesterol metabolism disorder, respectively. There is available also a tablet for atherosclerosis regression to prevent stroke and heart disease, which contains α-CD as active (Belytrim, Maxcure Nutravedics Ltd.).
Vitamins, various herbal compositions, phytosterols, carotenoids, unsaturated fatty acids, fish oil, etc. usually marketed as nutraceuticals have not been taken into account although they are on the borderline between drugs and healthy foods. The nutrition supplements with steroids for body builders have not been included either.

Conclusions
We have collected via internet and several scientific reports the list of CD-formulated drugs available on the market. Although this list is not complete due to the difficulties in finding the relevant information, it shows that more than 120 active ingredients are already marketed in drug formulations containing also CDs as excipients. Some of them are already generic produced by several manufacturers under different trade names.
It can be concluded that β-CD and its hydroxypropylated and sulfobutylated derivatives (HP-β-CD and SBECD) are dominating the market. HP-β-CD was the first semi synthetic cyclodextrin derivative that was used in final dosage forms, however SBECD is also a powerful solubilizing and stabilizing agent, especially for weak bases and is used in more and more products.

Acknowledgement
The Support for the market-driven RDI project (2020-1.1.2-PIACI-KFI-2020-00092) of National Research, Development and Innovation Office is greatly acknowledged.