An investigation into the structure and bioavailability of alpha-tocopherol dispersions in Gelucire 44/14.
In this investigation we describe the preparation, physical characterisation and in vivo behaviour of solid dispersions of a liquid nutraceutical, alpha-tocopherol, in Gelucire 44/14 with a view to establishing whether dispersion in this matrix may provide a means of formulating a liquid drug in a solid dosage form while also improving the oral bioavailability. Using Vitamin E Preparation USP as the source of alpha-tocopherol, dispersions were prepared using a melt-fusion method with active loadings up to 50% (w/w) and characterised using differential scanning calorimetry and optical microscopy. Capsules containing 300 IU alpha-tocopherol were manufactured and the absorption profiles compared to a commercial soft gelatin capsule preparation in healthy human volunteers. Confocal laser scanning microscopy (CLSM) studies were performed in order to elucidate the mechanism by which drug release may be occurring. Differential scanning calorimetry studies indicated that the presence of the active had a negligible effect on the melting profile of the carrier, indicating limited miscibility between the two components, a conclusion supported by the microscopy studies. Similarly, the dispersions were shown to exhibit a glass transition corresponding to the incorporated drug, indicating molecular cooperativity and hence phase separation from the lipid base. Despite the phase separation, it was noted that capsules stored for 18 months under ambient conditions showed no evidence of leakage. Bioavailability studies in six healthy male volunteers indicated that the Gelucire 44/14 formulation showed an approximately two-fold increase in total alpha-tocopherol absorption compared to the commercial preparation. Confocal laser scanning microscopy studies indicated that, on contact with water, the dispersions formed two interfacial layers, from which the Gelucire 44/14 disperses in the liquid medium as small particles. Furthermore, evidence was obtained for the dispersed material becoming incorporated into the hydrated lipid. In conclusion, the dispersion of the liquid drug in Gelucire 44/14 appears to allow the dual advantages of the preparation of a solid formulation and improved bioavailability of this material.
Barker
S A
SA
The School of Pharmacy, The Queen's University of Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK.
Yap
S P
SP
Yuen
K H
KH
McCoy
C P
CP
Murphy
J R
JR
Craig
D Q M
DQ
D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000493:pharmacokinetics*; D012995:Solubility / Q000187:drug effects; D013329:Structure-Activity Relationship; D024502:alpha-Tocopherol / Q000737:chemistry* / Q000493:pharmacokinetics*
C104509:gelucire 44-14; D011092:Polyethylene Glycols; D024502:alpha-Tocopherol