55
1987, Sébille showed that cyclodextrin chemistry offered various possibilities to synthetize derivatives with different functions for various industrial uses, e.g., sulfurand nitrogen- and imidazole- or histamine-containing derivatives, alkylated and acyl
derivatives, halogenated products, polymers from cyclodextrins, etc. (Sébille 1987).
By working in carefully controlled conditions, mono-, di-, and poly- substitution
were possible and opened the way to several functional derivatives with catalytic or
biological activity, for instance. One of the most popular derivative was mono-substituted 6-O-p-toluenesulfonyl-cyclodextrin, used as starting material to prepare
modified cyclodextrins (Saenger 1980; Szejtli 1982a; Sébille 1987). Jicsinszky et al.
(1996) published a comprehensive chapter (137 pages, 865 references) on cyclodextrin derivatives. In 1998, Khan et al. (1998) proposed a global schema for the modification of cyclodextrins. These two last publications are still reference today.
Thousands of derivatives containing cyclodextrin have been proposed in the literature, particularly for pharmaceutical uses. Szejtli (2004) estimated that over 15,000
derivatives had been studied. In reality, most of these derivatives will never find applications, especially for reasons of production costs and essentially lengthy and difficult
synthesis involving complicated steps. Among industrially produced, standardized,
and available derivatives, the most important ones are the methylated β-cyclodextrins
such as RAMEB (randomly methylated-β-cyclodextrin; considered as a mixture) and
DIMEB (a particular methylated cyclodextrin: heptakis(2,6-di-O- methyl-βcyclodextrin), considered a single isomer; its solubility decreases with an increase in
temperature), the 2-hydroxypropylated β-cyclodextrins or HPBCD (the real advantage of this derivative over the methylated derivatives is the lower affinity for cholesterol binding), and the sulfobutylether-β-cyclodextrins or SBEBCD (Fig. 1.24).
Brauns and Müller (1983) and Pitha (1984) registered the first patents on
2-hydroxypropyl-β-cyclodextrin. This compound called hydroxypropylbetadex was
the first commonly applied cyclodextrin derivative, used as pharmaceutical excipient in drug formulations in the 1990s (Szente and Strattan 1991). Rapidly, a monograph for this substance has been published in both the US Pharmacopeia and
European Pharmacopeia (Brewster and Loftsson 2002, 2007; Brewster et al. 2004).
Nowadays, 2-hydroxypropyl-β-cyclodextrin is the most versatile excipient among
the cyclic oligosaccharides (Malanga et al. 2016). It can be used in oral, rectal, dermal, ocular, and parenteral formulations, and several pharmaceutical products are
marketed, e.g., Indocid
®
(eye drop), Vorzu
®
(tablet for fungal infection), Strepfen
®
(oromucosal spray with flurbiprofen), Vibativ
®
(i.v. infusion with telavancin), and
Lubion
®
(injection with progesterone as active ingredient). This substance is used as
excipient and/or as active component, e.g., at the end of the 2000s, it was discovered
that it had beneficial effects for patients in Niemann-Pick type C disease (Liu et al.
2009). Stella and Rajewski (1992) patented the sulfobutylether-β-cyclodextrin
product as a potential alternate solubilizing excipient to 2-hydroxypropyl-βcyclodextrin. This derivative, developed by CyDex under the brand name Captisol
®
,
was found a more efficient complex-forming host than parent cyclodextrins with no
apparent toxicity and very high water solubility. Captisol
®
became generic worldwide in 2011, e.g., Dexolve
®
developed by CycloLab Ltd. (Hungary). It is used not
only as a solubilizing agent but also as an osmotic agent (Puskás et al. 2015).
1 History of Cyclodextrins
1987, Sébille showed that cyclodextrin chemistry offered various possibilities to synthetize derivatives with different functions for various industrial uses, e.g., sulfurand nitrogen- and imidazole- or histamine-containing derivatives, alkylated and acyl
derivatives, halogenated products, polymers from cyclodextrins, etc. (Sébille 1987).
By working in carefully controlled conditions, mono-, di-, and poly- substitution
were possible and opened the way to several functional derivatives with catalytic or
biological activity, for instance. One of the most popular derivative was mono-substituted 6-O-p-toluenesulfonyl-cyclodextrin, used as starting material to prepare
modified cyclodextrins (Saenger 1980; Szejtli 1982a; Sébille 1987). Jicsinszky et al.
(1996) published a comprehensive chapter (137 pages, 865 references) on cyclodextrin derivatives. In 1998, Khan et al. (1998) proposed a global schema for the modification of cyclodextrins. These two last publications are still reference today.
Thousands of derivatives containing cyclodextrin have been proposed in the literature, particularly for pharmaceutical uses. Szejtli (2004) estimated that over 15,000
derivatives had been studied. In reality, most of these derivatives will never find applications, especially for reasons of production costs and essentially lengthy and difficult
synthesis involving complicated steps. Among industrially produced, standardized,
and available derivatives, the most important ones are the methylated β-cyclodextrins
such as RAMEB (randomly methylated-β-cyclodextrin; considered as a mixture) and
DIMEB (a particular methylated cyclodextrin: heptakis(2,6-di-O- methyl-βcyclodextrin), considered a single isomer; its solubility decreases with an increase in
temperature), the 2-hydroxypropylated β-cyclodextrins or HPBCD (the real advantage of this derivative over the methylated derivatives is the lower affinity for cholesterol binding), and the sulfobutylether-β-cyclodextrins or SBEBCD (Fig. 1.24).
Brauns and Müller (1983) and Pitha (1984) registered the first patents on
2-hydroxypropyl-β-cyclodextrin. This compound called hydroxypropylbetadex was
the first commonly applied cyclodextrin derivative, used as pharmaceutical excipient in drug formulations in the 1990s (Szente and Strattan 1991). Rapidly, a monograph for this substance has been published in both the US Pharmacopeia and
European Pharmacopeia (Brewster and Loftsson 2002, 2007; Brewster et al. 2004).
Nowadays, 2-hydroxypropyl-β-cyclodextrin is the most versatile excipient among
the cyclic oligosaccharides (Malanga et al. 2016). It can be used in oral, rectal, dermal, ocular, and parenteral formulations, and several pharmaceutical products are
marketed, e.g., Indocid
®
(eye drop), Vorzu
®
(tablet for fungal infection), Strepfen
®
(oromucosal spray with flurbiprofen), Vibativ
®
(i.v. infusion with telavancin), and
Lubion
®
(injection with progesterone as active ingredient). This substance is used as
excipient and/or as active component, e.g., at the end of the 2000s, it was discovered
that it had beneficial effects for patients in Niemann-Pick type C disease (Liu et al.
2009). Stella and Rajewski (1992) patented the sulfobutylether-β-cyclodextrin
product as a potential alternate solubilizing excipient to 2-hydroxypropyl-βcyclodextrin. This derivative, developed by CyDex under the brand name Captisol
®
,
was found a more efficient complex-forming host than parent cyclodextrins with no
apparent toxicity and very high water solubility. Captisol
®
became generic worldwide in 2011, e.g., Dexolve
®
developed by CycloLab Ltd. (Hungary). It is used not
only as a solubilizing agent but also as an osmotic agent (Puskás et al. 2015).
1 History of Cyclodextrins