Enhanced in-Vitro Release of Glibenclamide from Drug-in-Adhesive Silicone Layers Using Solid-Dispersions of Glibenclamide with Solutol-Hs15

Objectives To prepare and compare the properties of solid dispersions of
glibenclamide with a non-ionic surfactant (Solutol-HS15) using two different
methods and to examine how solid-dispersion properties affect the in vitro
glibenclamide release from drug-in-adhesive layers.
Methods Solid dispersions of glibenclamide (melting point = 169C) with
Solutol-HS15 (melting point = 30C) in glibenclamide/Solutol-HS15 weight ratios
of 1:9 and 3:7 were prepared using melting and solvent methods. In the melting
method (MM), glibenclamide and the surfactant were melted in an oven and the
molten products were left to cool at ambient temperature. For the solvent method
(SM), glibenclamide and the surfactant were dissolved in ethanol which was
evaporated by heating at 40C (in a controlled-temperature oven) until constant
product weight was obtained. Solid dispersions prepared by MM or SM were semisolid in nature. Solid dispersions were examined for their solubility in phosphate
buffer (pH = 5.4), drug content uniformity, microscopic appearance via polarized
microscopy, enthalpy changes and melting point using differential scanning
calorimetry (DSC) and solid-state interaction using Fourier-transform infrared
(FTIR) spectroscopy. Saturation solubility of glibenclamide in a silicone adhesive
(BIO-PSA 7-4302) was examined using microscopy. Solid dispersions were then
used in the preparation of drug-in-adhesive layers with a target glibenclamide
loading of 5 mg and a supersaturated glibenclamide concentration of 2% w/w.
Layers containing only glibenclamide were also prepared. Glibenclamide release
from each set of layers was tested over 6 hours in a paddle dissolution apparatus
using 1 L phosphate buffer (pH = 5.4) under sink conditions at 32C. The UV
spectrophotometric analysis was performed at 224 nm.
Results MM binary mixtures demonstrated better content uniformity
compared with SM binary mixtures (intimate contact between glibenclamide and (ii) 3:7 SM, 42.2 ± 4.2 mg/mL and (iii) pure drug, 0.95 ± 0.1 mg/mL (P < 0.001).
Microscopic analysis revealed that all formulations had crystalline structure but
crystal morphology was different. DSC data demonstrated that glibenclamide
crystals in the 1:9 MM solid dispersion had the lowest melting point (100.8C)
versus 132.5, 137.8, 141.2 and 177.1C for 1:9 SM, 3:7 MM, 3:7 SM and pure
glibenclamide, respectively. There was an additional peak at 207C for binary
mixtures 3:7 MM and SM, suggesting formation of a new crystalline form. This
was confirmed by FTIR results. The solubility of glibenclamide in the silicone
adhesive was found to be less than 2% w/w. Glibenclamide cumulative percentage
release from the drug-in-adhesive layers at 6 hours was 19.5 ± 4.4, 6.9 ± 0.58,
5.1 ± 1.75, 4.9 ± 1.3% and 5.37 ± 0.88% from the 1:9 MM, 1:9 SM, 3:7 MM,
3:7 SM and pure drug, respectively. Glibenclamide release was highest (P < 0.001)
from the layers containing 1:9 MM and there was insignificant difference in drug
release among the rest of the layers.
Conclusions Drug-in-adhesive layers containing the 1:9 MM solid dispersion
showed the highest in vitro drug release. This indicates that the enhanced dissolution
of glibenclamide in the adhesive is a result to the melting point suppression, but it
could also be attributed to the higher aqueous solubility of 1:9 MM.
Solutol-HS15, MM): 100.9 ± 3.5, 85.5 ± 10.5, 99.7 ± 2.7 and 91.3 ± 8.9% for
1:9 MM, 1:9 SM, 3:7 MM and 3:7 SM, respectively. Solid dispersion of 1:9 MM
exhibited a significant higher solubility (91.2 ± 9.1 mg/mL) in phosphate buffer
compared with: (i) 1:9 SM, 79.1 ± 7.9 mg/mL (P < 0.05, analysis of variance);