Bioavailability enhancement of a poorly water-soluble drug by solid dispersion in polyethylene glycol-polysorbate 80 mixture.
Oral bioavailability of a poorly water-soluble drug was greatly enhanced by using its solid dispersion in a surface-active carrier. The weakly basic drug (pK(a) approximately 5.5) had the highest solubility of 0.1mg/ml at pH 1.5, < 1 microg/ml aqueous solubility between pH 3.5 and 5.5 at 24+/-1 degrees C, and no detectable solubility (< 0.02 microg/ml) at pH greater than 5.5. Two solid dispersion formulations of the drug, one in Gelucire 44/14 and another one in a mixture of polyethylene glycol 3350 (PEG 3350) with polysorbate 80, were prepared by dissolving the drug in the molten carrier (65 degrees C) and filling the melt in hard gelatin capsules. From the two solid dispersion formulations, the PEG 3350-polysorbate 80 was selected for further development. The oral bioavailability of this formulation in dogs was compared with that of a capsule containing micronized drug blended with lactose and microcrystalline cellulose and a liquid solution in a mixture of PEG 400, polysorbate 80 and water. For intravenous administration, a solution in a mixture of propylene glycol, polysorbate 80 and water was used. Absolute oral bioavailability values from the capsule containing micronized drug, the capsule containing solid dispersion and the oral liquid were 1.7+/-1.0%, 35.8+/-5.2% and 59.6+/-21.4%, respectively. Thus, the solid dispersion provided a 21-fold increase in bioavailability of the drug as compared to the capsule containing micronized drug. A capsule formulation containing 25 mg of drug with a total fill weight of 600 mg was subsequently selected for further development. The selected solid dispersion formulation was physically and chemically stable under accelerated storage conditions for at least 6 months. It is hypothesized that polysorbate 80 ensures complete release of drug in a metastable finely dispersed state having a large surface area, which facilitates further solubilization by bile acids in the GI tract and the absorption into the enterocytes. Thus, the bioavailability of this poorly water-soluble drug was greatly enhanced by formulation as a solid dispersion in a surface-active carrier.
Joshi
Hemant N
HN
Bristol-Myers Squibb Pharmaceutical Research Institute, New Brunswick, NJ 08903, USA.
Tejwani
Ravindra W
RW
Davidovich
Martha
M
Sahasrabudhe
Vaishali P
VP
Jemal
Mohammed
M
Bathala
Mohinder S
MS
Varia
Sailesh A
SA
Serajuddin
Abu T M
AT
D000284:Administration, Oral; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry / Q000493:pharmacokinetics*; D001647:Bile Acids and Salts / Q000378:metabolism; D001682:Biological Availability; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D003460:Crystallization; D004285:Dogs; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D019999:Pharmaceutical Solutions; D011092:Polyethylene Glycols / Q000737:chemistry / Q000493:pharmacokinetics*; D011136:Polysorbates / Q000737:chemistry / Q000493:pharmacokinetics*; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D014867:Water / Q000737:chemistry
D001562:Benzimidazoles; D001647:Bile Acids and Salts; D002214:Capsules; D019999:Pharmaceutical Solutions; D011136:Polysorbates; D013501:Surface-Active Agents; D014867:Water; C104509:gelucire 44-14; D011092:Polyethylene Glycols