Excipients and their role in absorption: Influencing bioavailability of cyclosporine by triglycerides and polyglycerol esters.
OBJECTIVE
The goal of the experiment was to verify bioavailability of immunosuppressive drug cyclosporine after oral administration, to determine, in particular, effect of triglycerides and polyglycerol esters on bioavailability of this lipophilic, poorly soluble drug.


METHODS
1) Absorption of cyclosporine A from soya oil and polyglycerol-3-oleate was tested after intra-duodenal application to rats. This method enable to administer dispersion directly to the site of absorption and avoid problems with potential precipitation of active substances in the stomach. Samples were pre-dispersed in water and diluted on concentration 1mg/ml prior administration. In defined time intervals a blood sample was taken in a volume of 0.5 ml from the cannuled carotid. Blood was sampled in time 5, 15, 30, 45, 60, 90, 120, 180 and 240 minutes after application. For the comparison, Equoral oral solution diluted and pre-dispersed in the same manner was used. 2) 100 mg of cyclosporin in form of 1% dispersion in water was administered orally to dogs under fasting condition. The blood level of cyclosporine was evaluated from samples taken in time 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, 12 and 24 hours following application. Formulations containing different ratio of polyglycerol esters / olive oil were compared.


RESULTS
The experiments conducted indicate that cyclosporine is 19x more available from polyglycerol-3-oleate than from soya oil. When applying cyclosporine in polyglycerol-3-oleate the average maximum blood level is 10x higher then in application of cyclosporine in oil. If polyglycerols are fully substituted with plant oils in the formula observed, its pharmacokinetic parameters decrease to 1/10 of the initial values.


CONCLUSIONS
The right selection of a type of excipient accompanying cyclosporine affects significantly cyclosporine availability and thus its efficiency.
Andrysek
Tomas
T
Generic Pharmaceutical RD Department, IVAX Pharmaceuticals Ltd., Ostravska 29, Opava 9, Czech Republic. tomas_andrysek@ivax-cz.com
D000042:Absorption / Q000187:drug effects; D000818:Animals; D001682:Biological Availability; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004285:Dogs; D016503:Drug Delivery Systems; D005079:Excipients / Q000494:pharmacology*; D005990:Glycerol / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D011108:Polymers / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013024:Soybean Oil / Q000494:pharmacology; D014280:Triglycerides / Q000494:pharmacology*
D005079:Excipients; D007166:Immunosuppressive Agents; D011108:Polymers; D014280:Triglycerides; C043941:polyglycerol; D013024:Soybean Oil; D016572:Cyclosporine; D005990:Glycerol