Bioavailability of seocalcitol II: development and characterisation of self-microemulsifying drug delivery systems (SMEDDS) for oral administration containing medium and long chain triglycerides.
By constructing ternary phase diagrams it was possible to identify two self-microemulsifying drug delivery systems (SMEDDS) containing either medium chain triglycerides (MC-SMEDDS) or long chain triglycerides (LC-SMEDDS), with the same ratio between lipid, surfactant and co-surfactant. The SMEDDS ended up having a composition of 25% lipid, 48% surfactant and 27% co-surfactant, MC-SMEDDS: viscoleo, cremophor RH40, akoline MCM and LC-SMEDDS: sesame oil, cremophor RH40, peceol. Upon dilution with water both SMEDDS resulted in clear to bluish transparent microemulsions with a narrow droplet size of 30nm. The industrial usefulness of the developed SMEDDS was evaluated with regard to bioavailability and chemical stability using the vitamin D analogue, seocalcitol, as model compound. The absorption and bioavailability of seocalcitol in rats were approximately 45% and 18%, respectively, from both the MC-SMEDDS and LC-SMEDDS indicating similar in vivo behavior of the two formulations, despite the difference in nature of lipid component. There was no improvement in bioavailability by the use of SMEDDS, compared to the bioavailability achieved from simple MCT and LCT solutions (22-24%) (Grove, M., Pedersen, G.P., Nielsen, J.L., Mullertz, A., 2005. Bioavailability of seocalcitol. I. Relating solubility in biorelevant media with oral bioavailability in rats-effect of medium and long chain triglycerides. J. Pharm. Sci. 94, 1830-1838.). After 3 months' storage at accelerated conditions (40 degrees C/75% RH), a decrease in concentration of seocalcitol of 10-11% was found in MC-SMEDDS and LC-SMEDDS compared with a degradation of less than 3% for the simple lipid solutions of MCT and LCT. In this study the simple lipid solutions seem to be a better choice compared with the developed SMEDDS due to a slightly higher bioavailability and a better chemical stability of seocalcitol.
Grove
Mette
M
Pharmaceutical Formulation, LEO Pharma A/S, Industriparken 55, DK-2750 Ballerup, Denmark.
Müllertz
Anette
A
Nielsen
Jeanet Løgsted
JL
Pedersen
Gitte Pommergaard
GP
D000284:Administration, Oral; D001682:Biological Availability; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D002626:Chemistry, Pharmaceutical; D016503:Drug Delivery Systems; D004355:Drug Stability; D004655:Emulsions; D007408:Intestinal Absorption; D015394:Molecular Structure; D009829:Oleic Acids / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D012715:Sesame Oil / Q000737:chemistry*; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D014280:Triglycerides / Q000737:chemistry*
D004655:Emulsions; D009829:Oleic Acids; C482692:Peceol; D013501:Surface-Active Agents; D014280:Triglycerides; C022131:cremophor; D011092:Polyethylene Glycols; D012715:Sesame Oil; D002117:Calcitriol; C078903:seocalcitol