"Back to the Future": A New Look at Hydroxypropyl Beta-Cyclodextrins.
Since the discovery about 30 years ago (2-hydroxypropyl) beta-cyclodextrin, a highly soluble derivative of beta-cyclodextrin, has become an approved excipient of drug formulations included both in the United States and European Pharmacopoeias. It is recommended to use as solubilizer and stabilizer for oral and parenteral formulations. Recently, its pharmacological activity has been recognized in various diseases. The increasing applications require a closer look to the structure-activity relationship. As (2-hydroxypropyl) beta-cyclodextrin (HPBCD) is always a mixture of isomers with various degrees and pattern of hydroxypropylation, no wonder that the products of different manufacturers are often different. Several HPBCDs were compared applying a battery of analytical tools including thin layer chromatography, high performance liquid chromatography (HPLC), HPLC-mass spectrometry (MS), and matrix-assisted laser desorption MS. We studied how the average degree of substitution affects the aggregation behavior, the toxicity, and the solubilizing effect on poorly soluble drugs. We found that the products with low average degree of substitution are more prone to aggregation. The samples studied are nontoxic to Caco-2 cells and have low hemolytic activity. The solubility enhancement of poorly soluble drugs decreases or increases with increasing degree of substitution or shows a maximum curve depending on the properties of the guest.
CycloLab Cyclodextrin Research & Development Ltd, Budapest, Hungary H-1097.
Milo
M
Malanga
CycloLab Cyclodextrin Research & Development Ltd, Budapest, Hungary H-1097.
Julianna
J
Szemán
CycloLab Cyclodextrin Research & Development Ltd, Budapest, Hungary H-1097. Electronic address: fenyvesi.e@cyclolab.hu.
Éva
É
Fenyvesi
CycloLab Cyclodextrin Research & Development Ltd, Budapest, Hungary H-1097.
István
I
Puskás
CycloLab Cyclodextrin Research & Development Ltd, Budapest, Hungary H-1097.
Katalin
K
Csabai
Inorganic and Analytical Chemistry, Faculty of Sciences and Technology, University of Debrecen, Hungary, H-4032.
Gyöngyi
G
Gyémánt
Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Debrecen, Debrecen, Hungary.
Ferenc
F
Fenyvesi
CycloLab Cyclodextrin Research & Development Ltd, Budapest, Hungary H-1097.
Lajos
L
Szente
D000073738:2-Hydroxypropyl-beta-cyclodextrin / Q000737:chemistry* / Q000494:pharmacology*; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D005079:Excipients; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008422:Materials Testing; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship
D005079:Excipients; D000073738:2-Hydroxypropyl-beta-cyclodextrin
HPLC; NMR; biocompatibility; cyclodextrins; drug delivery; inclusion compounds; light scattering; solubility