Purpose: Rivastigmine is used to treat mild to moderate dementia related to Alzheimer’s and Parkinson’s disease and is available in oral capsules and transdermal delivery systems (TDS). Exposure to heat (elevated temperature) may alter the bioavailability of rivastigmine from a TDS. Such changes in bioavailability may be heavily dependent on the design and composition of the TDS. Therefore, the effect of controlled heat on the comparative bioavailability of rivastigmine from a reference and generic rivastigmine TDS, which are different in composition, was investigated in this study. The primary goal of the present exploratory study was to explore the feasibility of using an in vitro permeation test (IVPT) to characterize the rate and extent of rivastigmine permeation. This was explored using skin from a single Yucatan miniature pig, assessed using a normal skin surface temperature (32°C) and an elevated skin surface temperature (42°C). A related goal was to optimize the IVPT study conditions for evaluating the delivery of rivastigmine across human skin using an IVPT study, and to characterize the effects of heat on the transdermal delivery of rivastigmine through human skin in vitro.
Methods: Exelon® (rivastigmine) TDS, 9.5 mg/24 h (reference listed drug (RLD)), and a generic rivastigmine TDS, 9.5 mg/24 h (Alvogen) were evaluated in the study. The IVPT studies were conducted using a PermeGear® In-Line flow-through diffusion cell system. Dermatomed pig skin samples with transepidermal water loss values below 15.0 g/m2/h were used in the IVPT studies. 0.97 cm2 discs of each TDS over an active diffusional area of a 0.95 cm2 area of skin were used. Studies were performed either at a normal skin surface temperature (32 ± 2°C), or under continuous or transient exposure to elevated skin surface temperature (42 ± 2°C). Temperature at the surface of the skin was maintained using a circulating water bath. Isotonic phosphate buffer (pH 7.4 ± 0.1) was used as the receiver solution at a flow rate of 1.0 mL/h and samples were collected at pre-determined time intervals. Concentrations of rivastigmine in the receiver solution were analyzed using a validated high performance liquid chromatography (HPLC) method. Flux profiles were generated based on the concentration of rivastigmine in the receiver solution collected across the 24 h study duration. Each study condition was evaluated using four replicate skin sections per TDS. Statistical analyses were conducted using an unpaired t test (GraphPad Prism 7).
Results: The reference and generic TDS both exhibited an enhanced delivery of rivastigmine when exposed to continuous heat for 24 h, with a rate and to an extent that was higher compared to their respective baseline delivery at normal skin temperature (Figure 1 and Figure 2). The maximum flux (Jmax) for both TDS under continuous heat exposure were significantly higher compared to the corresponding baseline condition for each TDS (43.46 ± 4.56 µg/cm2h (heat) and 15.85 ± 9.12 µg/cm2h (baseline), enhancement ratio=2.74, p= 0.0026 for Exelon TDS, and 55.94 ± 6.16 µg/cm2h (heat) and 24.63 ± 5.48 µg/cm2h (baseline), enhancement ratio=2.27, p=0.0001 for Alvogen TDS). The total cumulative amount of rivastigmine delivered through porcine skin under elevated temperature exposure was also significantly higher compared to the baseline conditions (685.9 ± 23.74 µg (heat) and 273.8 ± 66.74 µg (baseline), p=0.0053 for Exelon TDS, and 917.5 ± 30.47 µg (heat) and 433 ± 43.71 µg (baseline), p=0.0002 for Alvogen TDS). Similar results were also obtained following exposure of the TDS to transient heat for 1.5 h.
Conclusion: In the present exploratory study, both the generic and reference TDS exhibited an increase in the rate and extent of drug delivery in vitro when exposed to an elevated temperature, involving continuous or transient heat. The time to reach Jmax was also shorter for both TDS relative to the baseline condition when heat was applied (Figures 1 and 2). The results suggest that carefully designed and optimized IVPT studies using excised human skin may have the potential to compare the changes in the rate and extent of drug delivery from generic and reference rivastigmine TDS under the influence of heat. Additional studies using human skin and an identical study design are currently underway. The data could be used to evaluate whether there exists an in vitro in vivo correlation between IVPT and plasma pharmacokinetic data from human subjects, and could help evaluate the effectiveness of an IVPT study as a tool for comparing the bioavailability of rivastigmine from different rivastigmine TDS under the influence of heat.
Acknowledgment. Funding for this project was made possible, in part, by the Food and Drug Administration through grant U01FD004955. The views expressed in this abstract do not reflect the official policies of the U.S. Food and Drug Administration or the U.S. Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.
Priyanka Ghosh– Pharmacologist, US Food and Drug Administration
Sameersing Raney– Scientific lead for topical and transdermal drug products, U.S. Food and Drug Adminstration
Dana Hammell– Research Fellow, University of Maryland, Baltimore
Hassan Hazem– Clinical Pharmacologist, U S Food and Drug Adminstration
Audra Stinchcomb– Professor, University of Maryland Baltimore, Baltimore, Maryland