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Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Enalapril
Roger K Verbeeck1, Isadore Kanfer2, Raimar Löbenberg3
1School of Pharmacy, University of Namibia, Windhoek, Namibia; Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa.
Journal of Pharmaceutical Sciences
|April 25, 2017
Summary
A biowaiver for enalapril maleate (a prodrug) is acceptable for immediate-release dosage forms. This applies if in vitro dissolution is rapid and the active ingredient is identical, avoiding extensive in vivo bioequivalence testing.
Area of Science:
- Pharmaceutical Sciences
- Drug Development
- Regulatory Science
Background:
- Enalapril maleate is a Biopharmaceutics Classification System class III substance, with 60-70% oral absorption.
- Enalapril, a prodrug, is converted to its active form, enalaprilat, via hydrolysis.
- The drug does not possess a narrow therapeutic index, simplifying regulatory considerations.
Purpose of the Study:
- To review literature data for granting a waiver of in vivo bioequivalence testing for enalapril maleate.
- To establish criteria for the marketing authorization of generic immediate-release, solid oral dosage forms of enalapril maleate.
- To assess the suitability of in vitro dissolution testing as a surrogate for in vivo bioequivalence.
Main Methods:
- Literature review of pharmacokinetic and biopharmaceutic properties of enalapril maleate.
- Analysis of Biopharmaceutics Classification System (BCS) classification and therapeutic index.
- Evaluation of in vitro dissolution profiles at various pH levels (1.2, 4.5, and 6.8).
Main Results:
- Enalapril maleate is highly soluble but exhibits limited gastrointestinal absorption, classifying it as BCS class III.
- A biowaiver is deemed acceptable for enalapril maleate products meeting specific dissolution criteria.
- Rapid in vitro dissolution (≥85% in 15 min) at multiple pH values is a key requirement.
Conclusions:
- A biowaiver procedure is acceptable for enalapril maleate immediate-release products, streamlining generic drug approval.
- Stringent in vitro dissolution testing can ensure bioequivalence, reducing the need for in vivo studies.
- Ensuring the identical active pharmaceutical ingredient in test and reference products is crucial for biowaiver acceptance.
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