60
understanding of molecular encapsulation, several inclusion complexes appeared on
the market (Davis and Brewster 2004; Brewster and Loftsson 2007).
In 1976, the first product, i.e., prostaglandin E2/β-cyclodextrin Prostarmon E™
sublingual tablet, was marketed in Japan (Ono Co.) (Uekama and Hirayama 1978;
Hirayama et al. 1980). Prostaglandin E2, a substance with potent oxytocin-like
effects, was of interest as a possible agent for the induction of labor in childbirth
(Davis and Brewster 2004). However, this substance was highly unstable, and this
feature complicated its formulation and development. The solution was to encapsulate it using β-cyclodextrin, resulting in a significant increase in its solid- state stability. This led to spectacular progress in pharmaceutical domain. The second
prostaglandin marketed was Prostavasin
®
, a complex between prostaglandin E1 and
α-cyclodextrin. In 1979, this product was approved for the treatment of peripheral
vascular complications. Uekama’s group studied the molecular motions of prostaglandin F 2α -cyclodextrin inclusion compounds (Uekama and Hirayama 1978;
Hirayama et al. 1980; Uekama et al. 1984). As a consequence of the inclusion, the
internal motion of the ϖ-side alkyl chain of the prostaglandin is selectively reduced
by α-cyclodextrin, while the internal motion around the five-membered ring, as well
as the overall motion, is decreased by β-cyclodextrin. In the case of the γ-cyclodextrin
inclusion compound, total motion of the prostaglandin is reduced. The inclusion of
prostaglandin E 1 in γ-cyclodextrin increased its heat stability and slowed down its
conversion to prostaglandin A 1 (Uekama et al. 1984). The structures proposed by
Uekama’s group and illustrated in Fig. 1.25 were demonstrated using NMR data
(Uekama and Hirayama 1978; Hirayama et al. 1980).
Another interesting formulation was the complex β-cyclodextrin/piroxicam,
used, e.g., in the treatment of acute pain of rheumatic disease. In 1988, Chiesi
Farmaceutici, Italy, has put on the market this complex Brexin
®
or Cycladol
®
(Fig. 1.26). Nine years later, the first US-approved product, 2-hydroxypropyl-βcyclodextrin/itraconazole oral solution (Sporanox
®
Janssen), was introduced
(Fig. 1.26). Itraconazole is an orally active triazole antifungal agent to inhibit most
human fungal pathogens but is practically insoluble in water at physiological pH. In
2002, two formulations containing sulfobutylether β-cyclodextrin were introduced
by Pfizer in the USA and Europe: an intravenous formulation of the antifungal agent
voriconazole (Vfend
®
) and an intramuscular dosage form for the antipsychotic
agent ziprasidone (Geodon
®
).
All these formulations are preformed prior to be administrated. There are also
some cases when the complexes are formed within the body. The best-known example is the one containing the active compound sugammadex (Bridion
®
): it is a modified γ-CD used as an antidote to certain curare-like muscle relaxants in anesthesia
since 2008. After intravenous administration, it neutralizes steroid curare-like
agents such as rocuronium and vecuronium by forming an inactive complex
(Fig. 1.26) in the plasma which is then eliminated in the urine.
Actually, more than 80 pharmaceutical products can be found (CycloLab Ltd.,
Hungary). In these formulations, native cyclodextrins and their derivatives, such as the
hydroxypropyl derivatives of β- and γ-cyclodextrins, sulfobutylether β-cyclodextrin,
and maltosyl-β-cyclodextrin (this derivative might be a component of several drugs
N. Morin-Crini et al.
understanding of molecular encapsulation, several inclusion complexes appeared on
the market (Davis and Brewster 2004; Brewster and Loftsson 2007).
In 1976, the first product, i.e., prostaglandin E2/β-cyclodextrin Prostarmon E™
sublingual tablet, was marketed in Japan (Ono Co.) (Uekama and Hirayama 1978;
Hirayama et al. 1980). Prostaglandin E2, a substance with potent oxytocin-like
effects, was of interest as a possible agent for the induction of labor in childbirth
(Davis and Brewster 2004). However, this substance was highly unstable, and this
feature complicated its formulation and development. The solution was to encapsulate it using β-cyclodextrin, resulting in a significant increase in its solid- state stability. This led to spectacular progress in pharmaceutical domain. The second
prostaglandin marketed was Prostavasin
®
, a complex between prostaglandin E1 and
α-cyclodextrin. In 1979, this product was approved for the treatment of peripheral
vascular complications. Uekama’s group studied the molecular motions of prostaglandin F 2α -cyclodextrin inclusion compounds (Uekama and Hirayama 1978;
Hirayama et al. 1980; Uekama et al. 1984). As a consequence of the inclusion, the
internal motion of the ϖ-side alkyl chain of the prostaglandin is selectively reduced
by α-cyclodextrin, while the internal motion around the five-membered ring, as well
as the overall motion, is decreased by β-cyclodextrin. In the case of the γ-cyclodextrin
inclusion compound, total motion of the prostaglandin is reduced. The inclusion of
prostaglandin E 1 in γ-cyclodextrin increased its heat stability and slowed down its
conversion to prostaglandin A 1 (Uekama et al. 1984). The structures proposed by
Uekama’s group and illustrated in Fig. 1.25 were demonstrated using NMR data
(Uekama and Hirayama 1978; Hirayama et al. 1980).
Another interesting formulation was the complex β-cyclodextrin/piroxicam,
used, e.g., in the treatment of acute pain of rheumatic disease. In 1988, Chiesi
Farmaceutici, Italy, has put on the market this complex Brexin
®
or Cycladol
®
(Fig. 1.26). Nine years later, the first US-approved product, 2-hydroxypropyl-βcyclodextrin/itraconazole oral solution (Sporanox
®
Janssen), was introduced
(Fig. 1.26). Itraconazole is an orally active triazole antifungal agent to inhibit most
human fungal pathogens but is practically insoluble in water at physiological pH. In
2002, two formulations containing sulfobutylether β-cyclodextrin were introduced
by Pfizer in the USA and Europe: an intravenous formulation of the antifungal agent
voriconazole (Vfend
®
) and an intramuscular dosage form for the antipsychotic
agent ziprasidone (Geodon
®
).
All these formulations are preformed prior to be administrated. There are also
some cases when the complexes are formed within the body. The best-known example is the one containing the active compound sugammadex (Bridion
®
): it is a modified γ-CD used as an antidote to certain curare-like muscle relaxants in anesthesia
since 2008. After intravenous administration, it neutralizes steroid curare-like
agents such as rocuronium and vecuronium by forming an inactive complex
(Fig. 1.26) in the plasma which is then eliminated in the urine.
Actually, more than 80 pharmaceutical products can be found (CycloLab Ltd.,
Hungary). In these formulations, native cyclodextrins and their derivatives, such as the
hydroxypropyl derivatives of β- and γ-cyclodextrins, sulfobutylether β-cyclodextrin,
and maltosyl-β-cyclodextrin (this derivative might be a component of several drugs
N. Morin-Crini et al.