📄 medicine

Sticking to therapy: bioequivalence assessment and adhesion performance of rivastigmine transdermal patch formulations

This open-label, randomized crossover study demonstrated that the branded generic rivastigmine transdermal patch (Rivazich) is bioequivalent to the reference product (Exelon Patch 10) and exhibits non-inferior adhesion performance in healthy subjects following a single 24-hour application.

Original authors: Thalita Martins da Silva, Jessica Meulman, Débora Renz Barreto Vianna, Miguel Fortuny, Alejandro Scasso, Karini Bruno Bellorio, Ana Carolina Costa Sampaio Mendes Caçula, Leonardo Souza Teixeira, Ferna

Published 2026-08-11

📖 6 min read🧠 Deep dive

CC BY 4.0

Original authors: Thalita Martins da Silva, Jessica Meulman, Débora Renz Barreto Vianna, Miguel Fortuny, Alejandro Scasso, Karini Bruno Bellorio, Ana Carolina Costa Sampaio Mendes Caçula, Leonardo Souza Teixeira, Fernando Costa, Celso Francisco Pimentel Vespasiano

Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). ✨ This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer

Imagine your body as a bustling city where messages need to be delivered to keep the lights on and the traffic moving. In conditions like Alzheimer's disease, the messengers carrying these vital instructions start to vanish, causing the city to slow down and forget its own rhythm. To help, doctors use special drugs called cholinesterase inhibitors, which act like a traffic cop, slowing down the cleanup crew so the remaining messengers can stick around longer and do their job.

But here's the catch: getting these drugs into the city is tricky. If you swallow a pill, it hits the system all at once, like a firehose blasting water into a garden hose. This sudden rush can cause the "garden" (your stomach) to get upset, leading to nausea and other grumpy side effects. To fix this, scientists invented a "slow-drip" system: a patch you stick to your skin. This patch acts like a gentle, steady faucet, releasing the medicine slowly over 24 hours. This keeps the levels smooth, avoiding the scary spikes that upset the stomach, and keeps the city running steadily.

Now, imagine a new company wants to make their own version of this "slow-drip" patch. They can't just copy the design; they have to prove their patch works exactly the same way as the famous original one. They need to show that their patch releases the medicine at the same speed, sticks to the skin just as well, and doesn't cause any new problems. This is where a new study comes in, acting like a rigorous quality control inspector to see if a new patch, called Rivazich, is truly the same as the gold-standard Exelon Patch.

The Great Patch Showdown

In this study, researchers set up a head-to-head battle between two rivastigmine patches. On one side was the famous reference patch, Exelon® Patch 10, which contains 18 mg of medicine but delivers 9.5 mg every 24 hours. On the other side was the new challenger, Rivazich, which is a bit smaller and lighter, containing only 13.68 mg of medicine but promising to deliver that same 9.5 mg every 24 hours.

The scientists recruited 74 healthy volunteers for a two-part adventure. Each person wore both patches at different times, separated by a week of rest. It was a "crossover" game: some wore the new patch first, then the old one; others did the reverse. While wearing the patches on their upper arms, the volunteers stayed in a clinic for two days. The researchers were very strict about the rules: no showers for a while after putting the patch on (to make sure it didn't peel off from water), no tight clothes rubbing against it, and no touching it with their hands. They wanted to see how the patches behaved in real-world conditions, but with zero interference.

The Blood Test: Did the Medicine Flow the Same?

The main question was: Did the new patch put the same amount of medicine into the bloodstream as the old one? To find out, the researchers took 21 blood samples from each volunteer over 48 hours, creating a detailed map of how the drug moved through the body.

The results were a resounding "yes." The study found that the new Rivazich patch and the old Exelon patch were bioequivalent. This is a fancy scientific way of saying they are twins in terms of performance. The amount of medicine in the blood (measured as Cmax and AUC) was nearly identical for both. The new patch didn't release the drug too fast or too slow; it matched the reference patch perfectly.

Even more impressive, the researchers looked at the "partial" flow of the drug—checking the first 12 hours and the last 12 hours separately. They wanted to make sure the new patch didn't have a weird start or a weird finish. The data showed that the new patch maintained a steady, smooth flow from the moment it was stuck on until the moment it was peeled off, just like the original. The statistical confidence in this result was incredibly high, with the data falling well within the safe zone (80% to 125%) that regulators require.

The Stick Test: Will It Stay Put?

A patch is only good if it stays stuck to your skin. If it peels off, the medicine stops flowing, and the treatment fails. The researchers checked the adhesion of both patches every few hours for 24 hours. They used special see-through templates to measure exactly how much of the patch was still touching the skin.

Here, the results were a bit more nuanced but still a victory for the new patch. The reference patch (Exelon) stayed stuck about 80% of the time after 24 hours. The new patch (Rivazich) stayed stuck about 77.5% of the time. While the new patch was slightly less sticky in raw numbers, the difference was so small that it didn't matter. The study proved that the new patch was non-inferior, meaning it was "good enough" to be considered just as effective as the original. It didn't fall off any more often than the famous brand, and the difference was well within the acceptable margin of error.

The Safety Check: Did Anyone Get Sick?

Finally, the team asked: Did the new patch cause any new or scary side effects? Out of the 74 people who started the study, 42 reported some minor issues, but nothing serious. The most common complaints were headaches and nausea, which are known to happen with this type of medicine. Interestingly, the new patch caused very few stomach upsets compared to what you might expect from a pill. This confirms that the "slow-drip" method is still doing its job of keeping the stomach happy. No one had to drop out of the study because of a severe reaction, and no one had a dangerous medical event.

The Verdict

So, what's the bottom line? The study concludes that the new Rivazich patch is a perfect match for the original Exelon patch. It delivers the same steady stream of medicine, it sticks to the skin just as well (even though it's a smaller, more compact patch), and it is just as safe.

The researchers found that the new patch is a "branded generic," meaning it's a high-quality copy that has passed every test. It offers the same therapeutic benefits as the original, potentially with the added bonus of being a smaller, less noticeable patch on the skin. For patients and doctors, this means there is now another reliable option available that works just as well as the one they have trusted for years. The "slow-drip" faucet is working perfectly, and the city of the brain can keep running smoothly.

Technical Summary: Bioequivalence and Adhesion Performance of a Rivastigmine Transdermal Patch

Problem Statement
Rivastigmine is a cornerstone treatment for Alzheimer's disease and Parkinson's disease dementia, acting as a dual inhibitor of acetylcholinesterase and butyrylcholinesterase. While transdermal drug delivery systems (TDDS) offer a smoother pharmacokinetic profile and improved tolerability compared to oral formulations by minimizing peak-to-trough fluctuations, the physical performance of the patch—specifically adhesion—remains a critical variable. Detachment can alter drug flux and compromise therapeutic efficacy. Although clinical utility is established, most regulatory bioequivalence studies for rivastigmine patches have focused on multiple-dose steady-state conditions. There is a need for rigorous single-dose characterization to detect potential differences in initial drug release and skin permeation kinetics that might be masked by accumulation at steady-state, as well as to validate adhesion performance under controlled conditions.

Methodology
The study was an open-label, randomized, balanced, two-period crossover trial conducted in healthy subjects (aged 18–50) under fasting conditions.

Formulations: The test formulation was Rivazich (13.68 mg nominal content, delivering 9.5 mg/24 h; patch area 7.6 cm²), manufactured by Amarin Technologies S.A. The reference product was Exelon Patch 10 (18 mg nominal content, delivering 9.5 mg/24 h; patch area 10.0 cm²), manufactured by Lohmann Therapie-Systeme AG. Both products were confirmed to be pharmaceutically equivalent via in vitro assays prior to the clinical study.
Design: 74 participants were enrolled, with 58 completing the study. Subjects received a single 24-hour application of either the test or reference patch on the deltoid region, followed by a 7-day washout period.
Bioanalysis: Plasma concentrations of rivastigmine were quantified up to 48 hours post-application using a validated HPLC–MS/MS method.
Endpoints:
- Pharmacokinetics (PK): Primary endpoints included maximum plasma concentration ( $C_{max}$ ), total exposure ( $AUC_{0-t}$ ), and partial areas under the curve ( $AUC_{0-12}$ and $AUC_{12-t}$ ) to assess absorption rates and release profiles. Bioequivalence was established if the 90% confidence intervals (CI) for the geometric mean ratios (GMR) fell within 80–125%.
- Adhesion: Adhesion was assessed at predefined intervals (0, 4, 8, 12, 16, 20, and 24 hours) using custom templates. Non-inferiority was assessed at 24 hours with a margin of -10%, following EMA guidelines.
- Safety: Vital signs, laboratory tests, and adverse events (AEs) were monitored throughout the confinement period.

Key Results

Bioequivalence: The test formulation demonstrated bioequivalence to the reference product. The 90% CIs for all pharmacokinetic parameters ( $C_{max}$ , $AUC_{0-t}$ , $AUC_{0-12}$ , $AUC_{12-t}$ , and $AUC_{0-inf}$ ) were within the 80–125% acceptance range. Specifically, the GMR for $C_{max}$ was 100.78% (90% CI: 92.83–109.41), and for $AUC_{0-t}$ it was 98.35% (90% CI: 92.24–104.86). The study achieved high statistical power (>95%) for all parameters.
Adhesion Performance: The reference product exhibited a mean adhesion of 79.97% at 24 hours, falling below the 90% threshold that would trigger an equivalence test; therefore, a non-inferiority analysis was applied. The test formulation showed a mean adhesion of 77.53%. The mean difference (Test - Reference) was -2.44%, with a 90% CI lower bound of -7.24%. As this lower bound exceeded the pre-specified non-inferiority margin of -10%, adhesion non-inferiority was demonstrated.
Safety: Both formulations were well tolerated. Of 74 enrolled subjects, 42 reported 92 adverse events, all classified as mild and non-serious. The most frequent events were headache (25%) and leukocyturia (15.2%). Gastrointestinal events, such as nausea (12%) and vomiting (4.3%), occurred at low frequencies, consistent with the known tolerability profile of transdermal rivastigmine compared to oral formulations. No serious adverse events were reported.

Significance and Claims
The paper concludes that the Rivazich transdermal patch is bioequivalent to the reference Exelon Patch 10 in healthy subjects following a single 24-hour application. The study highlights that the test formulation achieves the same therapeutic dose (9.5 mg/24 h) through a smaller patch area (7.6 cm² vs. 10.0 cm²), indicating a superior delivery efficiency (Patch Area Activity of 9.14%/cm² vs. 5.28%/cm²) without compromising systemic exposure or adhesion performance.

The authors assert that the demonstration of bioequivalence, coupled with non-inferior adhesion and a comparable safety profile, supports the therapeutic interchangeability of the test formulation with the reference product in medical practice. The study emphasizes that the use of partial AUCs as primary endpoints in a single-dose design provides a rigorous assessment of the initial drug release and absorption kinetics, filling a gap in the literature where most studies rely on steady-state data. The paper notes that while the safety profile was favorable in this single-dose study, ongoing pharmacovigilance is necessary for long-term cumulative tolerability.

The Great Patch Showdown

The Blood Test: Did the Medicine Flow the Same?

The Stick Test: Will It Stay Put?

The Safety Check: Did Anyone Get Sick?

The Verdict

More like this