Sugar-branched-cyclodextrins as injectable drug carriers in mice.
The purpose of this study was to investigate stable complexation of drug in blood by sugar-branched-beta-cyclodextrins (beta-CDs) such as glucose (glu)- or galactose (gal)-branched-beta-CDs and the pharmacokinetic disposition of drug in sugar-branched-beta-CD complex. Complexation of steroidal drugs in sugar-branched-beta-CDs and their replacement by cholesterol were measured. The complexes of dexamethasone/glucosyl-beta-CDs (dexamethasone/glu-beta-CD or dexamethasone/glu-glu-beta-CD) were not replaced by cholesterol, which is a representative endogenous compound, whereas the complex of dexamethasone/beta-CD was replaced by cholesterol. The same results were obtained in steroidal drugs such as hydrocortisone, triamcinolone, and prednisolone. Thus, the use of glu-beta-CD and glu-glu-beta-CD permitted the stable complexation of the drug in water. Stability constants of dexamethasone/glu-glu-beta-CD and dexamethasone/gal-glu-beta-CD complexes are the same, which means that the sugar moiety of the side chain in beta-CD has little effect on stability constants. After the dexamethasone/gal-glu-beta-CD complex or the dexamethasone/glu-glu-beta-CD complex (dexamethasone: 1 mg/body) was administered intravenously to mice, dexamethasone concentrations in liver tissue and blood were measured. The dexamethasone/gal-glu-beta-CD complex (66.1 +/- 1.7 micrograms as dexamethasone/gram of liver tissue) was distributed to liver tissue significantly more than the dexamethasone/glu-glu-beta-CD (beta-CD) complex (59.9 +/- 1.0 micrograms as dexamethasone/gram of liver) at 30 min after administration (p < .05). Sugar-branched-beta-CD gave a water-soluble and stable complex for dexamethasone and changed the disposition of dexamethasone. Sugar-branched-beta-CDs are potentially excellent carriers for a steroidal injectable formulation.
Shinoda
T
T
Novel Pharmaceutical Laboratories, Yamanouchi Pharmaceutical Company, Limited, Shizuoka, Japan. shinoda@yamanouchi.co.jp
Kagatani
S
S
Maeda
A
A
Konno
Y
Y
Hashimoto
H
H
Hara
K
K
Fujita
K
K
Sonobe
T
T
D000818:Animals; D002241:Carbohydrates / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry; D003505:Cyclodextrins / Q000737:chemistry*; D003907:Dexamethasone / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D051379:Mice; D012995:Solubility; D013256:Steroids / Q000737:chemistry
D002241:Carbohydrates; D003505:Cyclodextrins; D004337:Drug Carriers; D013256:Steroids; D003907:Dexamethasone; D002784:Cholesterol