Methylated beta-cyclodextrins are able to improve the nasal absorption of salmon calcitonin.
The absorption enhancing effect of methylated beta-cyclodextrins on the nasal absorption of salmon calcitonin (sCT) was studied in rats and rabbits. The nasal absorption of sCT following administration without additives was low in both species. The absorption in rats could be largely improved by coadministration of cyclodextrins as apparent from the effect on serum calcium concentrations. Trimethyl-beta-cyclodextrin (TM beta CD), at a concentration of 5% (w/v), was the least potent enhancer. Randomly methylated-beta-cyclodextrin (RM beta CD) and dimethyl-beta-cyclodextrin (DM beta CD), all at a concentration of 5% (w/v), were almost equally effective in decreasing serum calcium levels, and the hypocalcemic responses were similar to those of i.v. and s.c. injected sCT. Absorption enhancement was already achieved with 1% DM beta CD added to the nasal formulations. In rabbits, only the effect of DM beta CD on the nasal sCT absorption was investigated. A total serum calcium decrement in 4 hours of 9.4 +/- 3.9% (mean +/- SD) was observed following nasal administration of 12.6 IU/kg sCT with 5% DM beta CD, comparable to that of i.v.-injected sCT. In conclusion, the methylated cyclodextrins DM beta CD and RM beta CD are suitable absorption enhancers for nasal sCT administration, which is expected to have a clinical impact on the therapy with calcitonin.
Schipper
N G
NG
Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.
Verhoef
J C
JC
Romeijn
S G
SG
Merkus
F W
FW
D000042:Absorption; D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage / Q000494:pharmacology*; D000281:Administration, Intranasal; D000818:Animals; D002116:Calcitonin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002118:Calcium / Q000097:blood; D003505:Cyclodextrins / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D008297:Male; D008745:Methylation; D009297:Nasal Mucosa / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D047392:beta-Cyclodextrins
D000277:Adjuvants, Pharmaceutic; D003505:Cyclodextrins; D047392:beta-Cyclodextrins; C028815:salmon calcitonin; D002116:Calcitonin; C031215:betadex; D002118:Calcium