Product formulation of phenylbutazone, theophylline, tolbutamide and pharmacokinetics-toxicities of theophylline injections in pigs Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/3r074z63b

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  • A two-part study was conducted with three poorly water soluble drugs (phenylbutazone, tolbutamide, theophylline) to develop two new drug delivery systems based on physical-chemical approaches. In the first part, tolbutamide and phenylbutazone were made into solid dispersions with various excipients using a lyophilization technique. In vitro dissolution studies of these solid dispersions at pH's 5.4 and 7.4 showed a marked increase in dissolution rates of both drugs in freeze-dried dispersions containing polyethylene glycol 20,000, compared to those of lecithin or combinations of polyethylene glycol 20,000, lecithin, and theobroma oil. Solid dispersions of either drug in polyethylene glycol 20,000 obtained using freeze-drying techniques showed greater dissolution at both pH's (5.4 and 7.4) compared to those prepared using solvent method, direct melting, and physical mixtures. Dissolution rates of both drugs were greater as the ratio of drug to polyethylene glycol 20,000 was reduced. In the second part, theophylline was solubilized in a ternary solvent system of ethyl lactate, ethyl alcohol, and water to produce a concentrated intravenous theophylline injection. Theophylline solubilities across a range of mixed solvents studied were predicted by a regression method based on an extension of the Scatchard-Hildebrand equation of regular solution theory and compared to experimental values. The injectable solution was compatible with other parenteral solutions and can be diluted by them. Pharmacokinetics and toxicity of the theophylline injections were studied in two normal, white 4-month-old Yorkshire pigs weighing 68.2 and 72.7 kg, respectively. Each pig received two doses of theophylline, 350 mg, then 700 mg 3 days later as a continuous (15-minute) intravenous infusion. The pharmacokinetics of theophylline were described by a two-compartment open model with constant intravenous infusion. The means for biological half-life were 8.52 and 8.82 hours. No evidence of dose-dependent clearance for theophylline in pigs was found at the doses given. No side effects or toxicities in the pigs were seen due to the theophylline or the mixed solvents. The pure mixed solvent system had very mild hemolytic activity compared to extensive hemolytic activity observed for available aminophylline products.
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