131
2.5.3 Cyclodextrin and Drugs
The first studies on the complex formation of cyclodextrins with pharmaceuticals
were carried out in the middle of the 1950s in Germany, e.g., with the important
contributions made by Professors Cramer and Frömming, in Japan in the 1970s,
e.g., with the works by Professors Nagai and Uekama, and also in Hungary. Indeed,
Professor Szejtli made a significant contribution on the use of cyclodextrins in pharmacy (Pitha et al. 1983; Szente and Fenyvesi 2016).
In 1977, Professor Szejtli, reviewing the possible applications of β-cyclodextrin
in pharmaceutical industries, pointed out the enhancement of drug bioavailability
by β-cyclodextrin due to the molecular encapsulation, e.g., indomethacin, hydrocortisone, progesterone, lidocaine, etc. (Szejtli 1977a). The poorly soluble drug became
molecularly dispersed in a hydrophilic matrix; therefore the drug became more
soluble and dissolved with an increased dissolution rate in aqueous medium. The
improved solubility led to higher blood level of the drug, which was manifested also
in the biological response (Szejtli et al. 1980h; Szejtli 1981; Szente et al. 1984a).
Two years later, in 1979, Professor Szejtli unambiguously proved that orally
applied β-cyclodextrin was not toxic (Szejtli and Sebestyén 1979). Further metabolic studies delivered explanation for the safety of cyclodextrin consumption
(Gerlóczy et al. 1982; Gergely et al. 1982; Szabo et al. 1982).
For instance,
14
C-β-cyclodextrin or
14
C-glucose were given orally to rats, and the
radioactivity was measured in the blood by liquid scintillation method. The results
showed that the peak of radioactivity appeared in the blood within 10 min in the
case of labelled glucose, while a rather protracted and low maximum was found
between 2 and 10 h in the case of labelled β-cyclodextrin. The values of respiration
of
14
CO 2 proved that β-cyclodextrin was metabolized in rat. 8 hours after oral administration of 313 mg/kg
14
C-β-cyclodextrin, a very small amount (3 μg) was detected
in 1000 μg of the blood. On the basis of investigations of radioactivity distribution,
it was claimed that β-cyclodextrin was excreted by the feces after high dose of
cyclodextrin treatment.
During the First International Symposium organized in Budapest in 1981,
Professor Szejtli stated: “Some years ago, cyclodextrins seemed to be expensive and
highly toxic substances of very limited accessibility, representing more scientific
curiosity than industrial tangibility. The recent years however brought about dramatic change… We are entering a new era.”
At the beginning of the 1980s, several patents on highly soluble cyclodextrin
derivatives including DIMEB and polymers were patented by Professor Szejtli and
his collaborators (Szejtli et al. 1980d, e, 1980g, h, 1981b, 1982b). The DIMEB was
an interesting substance in drug formulation due to the fact that it was very soluble
in cold water and also in organic solvents (Szejtli et al. 1980g). In such aqueous
solutions, many insoluble and/or poorly soluble compounds can be easily dissolved,
e.g., the solubility of steroids in water increased by a factor of 40–1200; 13 mg/mL
progesterone or 20 mg/mL hydrocortisone can be dissolved in a 100 mg/mL DIMEB
solution (Szejtli et al. 1980g).
2 Professor József Szejtli: The Godfather of Cyclodextrins
2.5.3 Cyclodextrin and Drugs
The first studies on the complex formation of cyclodextrins with pharmaceuticals
were carried out in the middle of the 1950s in Germany, e.g., with the important
contributions made by Professors Cramer and Frömming, in Japan in the 1970s,
e.g., with the works by Professors Nagai and Uekama, and also in Hungary. Indeed,
Professor Szejtli made a significant contribution on the use of cyclodextrins in pharmacy (Pitha et al. 1983; Szente and Fenyvesi 2016).
In 1977, Professor Szejtli, reviewing the possible applications of β-cyclodextrin
in pharmaceutical industries, pointed out the enhancement of drug bioavailability
by β-cyclodextrin due to the molecular encapsulation, e.g., indomethacin, hydrocortisone, progesterone, lidocaine, etc. (Szejtli 1977a). The poorly soluble drug became
molecularly dispersed in a hydrophilic matrix; therefore the drug became more
soluble and dissolved with an increased dissolution rate in aqueous medium. The
improved solubility led to higher blood level of the drug, which was manifested also
in the biological response (Szejtli et al. 1980h; Szejtli 1981; Szente et al. 1984a).
Two years later, in 1979, Professor Szejtli unambiguously proved that orally
applied β-cyclodextrin was not toxic (Szejtli and Sebestyén 1979). Further metabolic studies delivered explanation for the safety of cyclodextrin consumption
(Gerlóczy et al. 1982; Gergely et al. 1982; Szabo et al. 1982).
For instance,
14
C-β-cyclodextrin or
14
C-glucose were given orally to rats, and the
radioactivity was measured in the blood by liquid scintillation method. The results
showed that the peak of radioactivity appeared in the blood within 10 min in the
case of labelled glucose, while a rather protracted and low maximum was found
between 2 and 10 h in the case of labelled β-cyclodextrin. The values of respiration
of
14
CO 2 proved that β-cyclodextrin was metabolized in rat. 8 hours after oral administration of 313 mg/kg
14
C-β-cyclodextrin, a very small amount (3 μg) was detected
in 1000 μg of the blood. On the basis of investigations of radioactivity distribution,
it was claimed that β-cyclodextrin was excreted by the feces after high dose of
cyclodextrin treatment.
During the First International Symposium organized in Budapest in 1981,
Professor Szejtli stated: “Some years ago, cyclodextrins seemed to be expensive and
highly toxic substances of very limited accessibility, representing more scientific
curiosity than industrial tangibility. The recent years however brought about dramatic change… We are entering a new era.”
At the beginning of the 1980s, several patents on highly soluble cyclodextrin
derivatives including DIMEB and polymers were patented by Professor Szejtli and
his collaborators (Szejtli et al. 1980d, e, 1980g, h, 1981b, 1982b). The DIMEB was
an interesting substance in drug formulation due to the fact that it was very soluble
in cold water and also in organic solvents (Szejtli et al. 1980g). In such aqueous
solutions, many insoluble and/or poorly soluble compounds can be easily dissolved,
e.g., the solubility of steroids in water increased by a factor of 40–1200; 13 mg/mL
progesterone or 20 mg/mL hydrocortisone can be dissolved in a 100 mg/mL DIMEB
solution (Szejtli et al. 1980g).
2 Professor József Szejtli: The Godfather of Cyclodextrins