Category: Formulation and Quality
Purpose: Topical cream and gel products containing both lidocaine (2.5%) and prilocaine (2.5%) have a eutectic mixture of these drugs that forms a dispersed phase in the product. The use of an emulsifier in the creams vs. a polymerizing agent in the gel gives each dosage form a different microstructure. To elucidate how physicochemical differences between the cream and gel alter the bioavailability of lidocaine and prilocaine from each product, we characterized and compared physical and structural properties of the cream and gel products as well as the cutaneous pharmacokinetics (PK) of lidocaine and prilocaine using an in vitro permeation test (IVPT).
Methods: The reference cream (Actavis Laboratories UT Inc.) was compared with a generic cream (Fougera Pharmaceuticals Inc.), as well as with a gel (Dentsply Pharmaceutical Inc.). Rheological assessments characterized the response of viscosity to shear. The loss of water and volatiles was assessed gravimetrically. Drug deposition on the skin was assessed by tape stripping. IVPT studies were performed with a replicate study design (six skin donors with six replicates per donor) using heat separated human epidermis and a flow through diffusion system (PermeGear®, Hellertown, PA). Bioequivalence to the reference cream was evaluated based upon cutaneous PK endpoints for both lidocaine and prilocaine, and the statistical power was compared for a reference scaled average BE (SABE) and average BE (ABE) analysis of the IVPT study results.
Results: The evaporative rate, rheological results, and cutaneous PK of lidocaine and prilocaine were comparable for the reference and generic creams. By contrast, compared to the creams, the gel’s evaporative rate was substantially higher, its shear stress trend was substantially lower, and the cutaneous PK of lidocaine and prilocaine was substantially lower. Despite the relatively small number of donors, the creams were bioequivalent for both PK endpoints for both drugs, except when comparing the cumulative amount permeated for prilocaine. The gel was not bioequivalent to the reference cream for any PK endpoint for either drug. The SABE analysis provided greater statistical power than the ABE analysis.
Conclusion: These results demonstrate the impact of the composition, and ultimately, the physical and structural arrangement of matter on dosage form performance. Despite compositional differences, the structural properties and cutaneous PK of the creams are comparable for lidocaine and prilocaine. By contrast, the gel has a fundamentally different arrangement of matter than the creams and it also exhibits a different cutaneous PK for both drugs.
Maryam Dabbaghi– Brisbane, Queensland, Australia
Sarika Namjoshi– Brisbane, Queensland, Australia
Krishna Telaprolu– Brisbane, Queensland, Australia
Tannaz Ramezanli– Pharmacologist, Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA, Silver Spring, Maryland
Elena Rantou– Division of Biostatistics VIII, Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland
Sam Raney– Lead for Topical & Transdermal Drug Products, U.S. FDA, Silver Spring, Maryland
Jeffrey Grice– Brisbane, Queensland, Australia
Michael Roberts– Professor Clinical Pharmacology & Therapeutics, University of Queensland, Brisbane, Queensland, Australia