PART 1. A BIOADHESIVE POLYMER-DRUG SYSTEM AS A NEW RECTAL DOSAGE FORM. PART 2. BIOAVAILABILITY ANALYSIS OF CHLORPROMAZINE AND THIORIDAZINE IN RATS USING A PHARMACOLOGICAL RESPONSE

JAMES LOWELL YEAGER, Purdue University

Abstract

Rectal dosage forms made from a cellulose acetate phthalate pseudolatex interacted with the analgetic drug dextropropoxyphene were evaluated in male white rats. Polymer-drug products, made to contain 30% and 60% drug, were shown to be retained in the rectums of fasted animals for 8 to 10 hours after dosing, when the products were administered in the form of a dry 60/80 mesh powder. Bioavailability analysis of the rectally dosed polymer-drug products in powder form demonstrated the feasibility of this dosage form as a sustained effect, rectal bioretention system for systemic drug delivery. Polymer-drug formulations having polymer to drug ratios of 70:30 and 40:60 were found to have relative systemic bioavailabilities approximately equal to an aqueous solution control when given at a dose level of 15 mg/kg. The same polymer-drug formulations produced total systemic bioavailabilities at least 20% higher than a dextropropoxyphene hydrochloride in lactose powder mixture control. The polymer-drug rectally dosed material also produced sustained dextropropoxyphene plasma levels for eight hours when administered to fasted rats at a dose level of 15 mg/kg. The effect of the polymer-drug ratio on the in-vivo performance of the rectally dosed material was found to be insignificant as indicated by the similarity of the plasma profiles and approximately equal relative systemic bioavailabilities. Pharmacokinetic analysis of blood levels and analgetic tail-flick responses obtained from the same intravenous dosing experiment demonstrated that the pharmacological response and the drug in blood levels have different pharmacokinetics. Elimination of dextropropoxyphene from the blood was much faster than elimination of the pharmacological response. A classical dose-effect, semilogarithmic relationship was shown to exist between the blood levels and the analgetic tail-flick response. The response of rats to a light-beam initiated heat stimulus on the tail was used as quantitative pharmacological data for the bioavailability analysis of chlorpromazine and thioridazine. Chlorpromazine administered by the rectal route as a polyethylene glycol base suppository was 1.5 times more available than by the oral route. The oral route of administration was the least available for both chlorpromazine and thioridazine. Chlorpromazine was shown to be more potent in producing a large tail-flick response intensity than thioridazine.

Degree

Ph.D.

Subject Area

Pharmaceuticals

COinS