Pharmacology & Toxicology Poster Session
Phenobarbital has poor aqueous solubility. Cosolvents are therefore necessary to formulate an aqueous solution. In the US, oral preparations include tablets and an elixir which contains phenobarbital in an alcohol and sucrose base. For neonates there is need for an easy to administer liquid oral dosage form of phenobarbital without cosolvents like alcohol. A suspension may be considered, but has some practical disadvantages.
Recently much attention has been given to the use of lipid microemulsions and monoglycerides in drug delivery [1,2]. To formulate a liquid oral delivery system for phenobarbital we used Myvacet 9-08 as a solvent, without addition of any other excipient. Myvacet 9-08 is an acetic ester of monoglycerides made from hydrogenated coconut oil. The acceptable daily intake for man (ADI) is unlimited. [3,4] We performed an open randomized single dose cross-over study in healthy volunteers to determine the relative bioavailabilty of a solution of phenobarbital in Myvacet 9-08, and a suspension, in comparison with a tablet.
Materials and Methods
Analysis of Phenobarbital
Other than some mild transient drowsiness no adverse reactions were reported. Most volunteers disliked the taste of phenobarbital in Myvacet 9-08.
Figure 1 shows the serum concentration-versus time profiles of one subject during the initial 10 h after administration of the medication.
Table 1 summarizes the mean pharmacokinetic parameters of phenobarbital after administration of the three preparations.
Table 2 shows the statistical analysis on Cmax and AUC0-48. All three oral dosage forms of phenobarbital are bioequivalent.
The results of the statistical analysis of Tmax of phenobarbital from the doasge froms are shown in Table 3.
Discussion and Conclusion
Previous pharmacokinetic studies in healthy volunteers showed, that phenobarbital administered as a tablet has almost complete bioavailability. Literature is sparse on the pharmacokinetics after oral administration of a suspension. Our study has demonstrated, that the suspension and the tablet are bioequivalent. The individual data show, that in most subjects the absorption of phenobarbital from the suspension is faster than from the tablet with a smaller Cmax and AUC0-48. Besides the disadvantages of using a suspension, for patients who find it difficult to swallow tablets, the formulation of the suspension of phenobartbital as we studied it, could be a good alternative.
For drugs with a low aqueous solubility microemulsions or self-emulsifying drug delivery systems may be considered as a formulation for oral administration. We showed, that phenobarbital dissolved in Myvacet 9-08 and formulated without addition of an emulsifier, has a good oral absorption profile and is bioequivalent to a tablet and the suspension. Myvacet 9-08 might prove to be an excellent vehicle to enhance the intestinal absorption of a co-formulated drug, therefore it should be studied with other drugs with a known bioavailability problem.
1. Constantinides P.P.
2. Shah N.H., Carvajal M.T., Patel C.I., Infeld M.H., Malick A.W. Self-emulsifying drug delivery systems (SEDDS) with polyglycolyzed glycerides for improving in vitro dissolution and oral absorption of lipophilic drugs. Int J.Pharm. 1994; 106: 7-14.
3. Acetic and fatty acid esters of glycerol. In: Toxicological evaluation of some food additives. FAO Nutrition meetings report series no. 53A; Rome, 1974: pp 210-213.
4. Mono- and di-acetylated monoglycerides.
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|Yska, JP.; Essink, AWG.; Bosch, FH.; Lankhaar, G.; van Sorge, AA.; (1998). Phenobarbital: Comparable Oral Bioavailability from a Solution in Myvacet 9-08, a Suspension, and a Tablet. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Available at URL http://www.mcmaster.ca/inabis98/pharmtox/yska0351/index.html|
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