Szejtli J. (szerk.): Proceedings of the First International Symposium on Cyclodextrins. Budapest, 1981 (Budapest, 1982)
5. Cyclodextrins in pharmaceuticals
I want to consider the following three points in my lecture : 1) Why have the Cyclodextrin (CD)-inclusion compounds the greatest pharmaceutical significance in comparison to other inclusion compounds? 2) I'll give a survey about the most important previous results of pharmaceutical applications of CD-inclusion compounds . 3) What could be the future development of the pharmaceutical use of CD-inclusion compounds? Urea, thiourea, deoxycholeic acid, the cyclodextrins, and amylose are the most important chemical compounds which can act as host molecules for the formation of inclusion compounds for pharmaceutical purposes. Why have the CD complexes among these five host molecules the greatest pharmaceutical interest? There are three reasons to consider: 1) The size of the channel diameter 2) Good stability 3) Absence of toxicological side effects Regarding the size of the channel diameter. The diameter of the ring molecule or of the channel determines which compounds or compound classes can be included. The guest molecule neither must be too big, nor too small. The approximate cavity dimension (internal diameter) have the following values: Urea 5'1 8 Thiourea 6,1 8 Deoxycholeic acid 6,0 8 a-Cyclodextrin 4,5 8 ß-Cyclodextrin 7,0 8 y-Cyclodextrin 8,5 8 Amylose 5,0 8 Diameters of approximately 5 8 result in a too.great limitation of the interesting pharmaceutical compounds to be included. Only long-chain, unbranched molecules like fatty acids may be accomodated within the cavity of the urea channel. This is not the case with the (3- and y-CD, Regarding the stability problems. Urea, thiourea, deoxycholeic acid and CD can form stable solid complexes. This allows us to use them generally in solid drug formulations. But the stability problems after mixing with other additives are different. As pure complexes the urea adducts with fatty acids can be stored up to a relative humidity of 70 to 75 percent without deterioration. Mixtures with water containing solid pharmaceutical additives like starch, can have a reduced stability. Examples are the addition of starches. The manufacture of the urea complexes is only possible with water-free excipients (1_) . This is not necessary with the CD-complexes; CD inclusion compounds are quite stable. They can be recrystallized from water. Higher humidity and higher water contents of added additives in solid formulations have no negative influences. 368