Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories

• Published in: International journal of pharmaceutics Vol. 189; no. 2; pp. 147 - 160
• Main Authors: Chicco, D., Grabnar, I., Škerjanec, A., Vojnovic, D., Maurich, V., Realdon, N., Ragazzi, E., Belič, A., Karba, R., Mrhar, A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 05.11.1999; Elsevier
• Subjects: Acetaminophen - chemistry; Acetaminophen - pharmacokinetics; Acetaminophen - urine; Administration, Rectal; Adult; Analgesics, Non-Narcotic - chemistry; Analgesics, Non-Narcotic - pharmacokinetics; Animals; Area Under Curve; Biological and medical sciences; Biological Availability; Cross-Over Studies; Delayed-Action Preparations; Diffusion; Drug Compounding; Excipients - chemistry; Excipients - pharmacokinetics; Female; General pharmacology; Humans; In Vitro Techniques; Male; Medical sciences; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Rats; Rats, Wistar; Rectum - metabolism; Statistics as Topic; Suppositories; Time Factors; Viscosity; Human; Urine; Viscosity; Pharmaceutical technology; Healthy subject; Vehicle(excipient); Slow release form; Partition coefficient; Layer; In vitro; Rectal administration; Glyceride; Blood; Blood plasma; In vivo; Monoglyceride; Paracetamol; Absorption; Immediate release form; Dosage form; Pharmacokinetics; Suppository; Physicochemical properties
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/S0378-5173(99)00247-1

An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro–in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.