Transdermal technology has been around for a very long time. The popularity of patches, consisting of plant, animal or mineral extracts, dates back to the building of the pyramids in ancient Egypt and in Babylonian medicine, around 3000 BC. 1 So why are transdermal patches so effective?
Each day, transdermal patches help millions to decrease the risk to the gastrointestinal system from drugs that may be hard to tolerate. Transdermel patches bring four key advantages over pills and other oral delivery systems. Transdermal patches offer a sustained delivery for up to seven days, improve patient compliance, and help avoid the peaks, like many experience with their first cup of coffee in the morning and troughs that come at the end of an exhaustive day. Peaks typically happen with oral products and allow drug administration in a continuous stable-interval manner.
Unlike oral delivery systems, transdermal patches also come with five other key safety benefits, including:
Adheres to both wet and dry surfaces.
Flexibility with natural skin movement.
Improved drug bioavailability.
Offers patent protection.
Avoids the stomach and first pass liver metabolism.
To work best, transdermal patches require medicines that adhere to several key principles, according to the NIH’s National Library of Medicine. Among the principles are low molecular weight (less than 600 g/mol), the ability to pass through the epidermis, absorbable by the blood vessels, active drug must be chemically and physically stable, and active substance must have a low daily dose for patient comfort and adhesive propensity.
Patches can be as small as a circle of 1.5 cm sq. in diameter, placed under or behind the ear, to almost upwards of 100 cm sq. of lidocaine for back pain. Patches may be in a matrix form where the drug resides in a nonreactive polymer matrix or a reservoir when the drug diffuses through a drug controlling-layer, allowing transport at a sustained rate. One can also envision a multi-layered system such as the world’s first seven-day patch for Alzheimer’s. These internal designs differ from each other depending on the drug, its stability, how much is required for it to be effective, and the desired duration of deliverability.
History of the Patch
The transdermal patch has made great progress over the years. In December, the United States marks the 45th anniversary of FDA approval of the first prescription patch for motion sickness. To help move the science of transdermal patches forward nearly 25 years ago, Dr. Gary Cleary, Adrian Faasse and their teams set out to use cutting-edge science and engineering to create a bold new world of drug-delivery technologies. These researchers pioneered the first transdermal patches for motion sickness, diabetes, contraception and smoking cessation before joining Grand Rapids, MI-based Corium Innovations.
Nearly a quarter of a century of transdermal innovations has led Corium Innovations to develop nearly 100 patents covering a wide range of scientific research in drug delivery, including applications for transdermal, polymer, and permeation enhancement technologies, as well as 35 published scientific papers and more than 40 partnerships with different clients.
And in so doing, the Corium Innovations team advanced the science of transdermal technology with Corplex®, a flexible, groundbreaking transdermal drug-delivery innovation platform with a proprietary mix of adhesives, polymers, and liners that can be adjusted for almost any use situation.
Corplex, helping millions of consumers and patients, is used in Crest White Strips, Clonidine for hypertension for Dr. Reddy’s, Twirla for contraception for Agile Therapeutics, and Adlarity, the first and only seven-day continuous treatment patch for Alzheimer’s disease. Corium Innovations joins a 45-year short list of indications available in a transdermal patch form. The list includes:
Hypertension
Local anesthesia
Angina pectoris
Motion sickness
Pain
Smoking control
Migraine
Major depression
Parkinson disease
Alzheimer disease
ADHD
Adlarity: Instantly Converting Hydrophilic Into Hydrophobic
Unlike most transdermal products, which can only deliver only hydrophobic drugs, Corplex is made by Corium Innovations, the only company that can deliver HCl salts through the skin. Corplex makes it possible for hydrophilic drugs, which are otherwise impossible to deliver transdermally, to be successfully delivered by in-situ-free-base conversion into hydrophobic drugs, which are transdermally delivered with high drug utilization, enhanced skin absorption and low COGs.
The Corplex technology advance makes it possible to treat mild, moderate, or severe dementia of the Alzheimer’s type with Adlarity®, the first and only FDA-approved once-weekly transdermal system that consistently delivers the molecule Donepezil-hydrochloride. Because Corplex converts the molecule Donepezil-hydrochloride in-situ into a freebase, Corplex enables the bioavailability or the absorption of that particular drug. to shoot up like a rocket.
Corplex and other conventional transdermal patches that are made for hydrophobic drugs can go through the skin more effectively. Corplex can control that flux or plasma concentration can control the permeation by using permission enhancers and adjusting pH, etc. So, there’s a design aspect that is relevant that the company can potentially pursue in hydrophobic moieties, but in addition to that, Corplex can handle hydrophilic drugs that others can’t.
Administering Drugs via Patch
So how best to determine whether a patch system will work for a certain drug? It starts with a feasibility program, which takes about four weeks to complete. Corium Innovations, for example, has a program called the 1-2-3 Transdermal Development that is implemented in three stages:
Stage 1. The first stage takes a customer-provided molecule and assesses it against different models through a one-to-two-week paper screening exercise that defines the probability of success.
Assess key drug properties.
Determine partner/patient clinical demand.
Model potential for skin irritation.
Source quantitative likelihood of formulation success.
Stage 2. The next stage involves understanding and generating data on the solubility and incompatibility of the drug with respect to specific components that are typically used in transdermal application during a two-to-three-week period for a Solubility Study that determines:
Drug solubility in multiple-GRAS excipients and process aids.
Gross compatibility of multiple adhesive mixes.
Map prototype formulation from combined results.
Stage 3. The final stage is to design a prototype that generates flux data to a cadaver skin of a human that demonstrates through evidence that the drug will be delivered and be able to be absorbed through a suitable three-to-four-week skin flux testing that includes:
Produce 3–5 patch prototypes.
Run skin flux testing (N=3) on all test patch systems.
Perform physical and chemical testing of the systems.
Issue report of generated data and recommendations.
For scientists, there are screening processes that are based on several properties such as molecular weight, predictive bioavailability, permeation or log P values, log S values, or partitioning, plus additional properties. If four or five of these attributes are met, then it is considered a viable transdermal option from a low- and manageable-risk standpoint.
Six-Layer Patch for Alzheimer’s
To see how patch technology works best, a good example is Adlarity, the first and only once-weekly treatment for Alzheimer’s. Approved by the FDA in 2022 at 5 mg and 10 mg daily doses, the Adlarity patch comes in six layers:
Layer 1: Overlay backing with adhesive.
Layer 2: Separating layer.
Layer 3: Drug matrix.
Layer 4: Microporous membrane.
Layer 5: Contract adhesive.
Layer 6: Release liner.
The seven-day multi-layer Adlarity patch delivers in a dose-proportional manner, which means that there is a 5-mg strength and the proportional-dose 10-mg strength product that is protected by Corium Innovations intellectual property till 2042. Other products are expected to be developed based on this platform as well.
Right now, Ozanimod for multiple sclerosis is under development. Ozanimod has cardiovascular side effects such as bradycardia, which is the lowering of the heart rate to significantly low levels that could lead to a cardiac event or acute prolongation concerns.
TRANSDERMAL SYSTEMS
Transdermal patches are medicated adhesive patches applied to the skin to deliver a specific dose of medication through the skin and continuously into the bloodstream for periods of 1–7 days per patch. It provides a sustained, controlled release of the drug, via bypassing the digestive system and first pass metabolism, which minimizes the drug plasma peaks/troughs observed with multiple oral doses of drug and therefore potentially reducing side effects.
Delivery Advantages
Bypass first pass metabolism.
Potential for fewer side effects.
Sustained delivery for up to seven days with a single patch.
Improved patient compliance.
No fed-fast effects.
Easier drug administration — no food effect, eliminates dosing/timing issues.
Avoids swallowing issues prevalent with certain diseases/population.
Added Benefits
Excellent adhesion/ease of removal.
Adheres to both wet and dry surfaces.
Flexibility with natural skin movement.
Improved drug bioavailability.
Finding a Patch Partner
Look for a company that can deliver HCI salts through the skin, has patent-protect platform technologies, manages complex development issues, and provides experts in product development and commercial manufacturing.
There are at least three ways to work with a patch partner. The first, moving a product from ground zero, or as an idea of a drug molecule, involves taking early-stage molecules from concept across multiple different therapeutic areas. This can involve:
Product concepts across multiple therapeutic areas.
Feasibility and prototyping work through commercial manufacturing.
Exclusive use of patented formulation solutions for intellectual property protection through the year 2042 or beyond.
The second way to work together with a patch partner is for companies with a clinical asset that have demonstrated product opportunities but require manufacturing and development support and access to the intellectual property, patents and innovation.
The third and final method works for companies with the opportunity to transfer technology or need a secondary manufacturing source so as to mitigate the risk in terms of supply chain.
Wherever a company is in the development of a delivery-system process, a transdermal patch should be considered when patient compliance and efficacy are required.
This article was written by Niraj Vasisht, PhD, Chief Technology Officer of Corium Innovations, Grand Rapids, MI. Corium Innovations, a full-service contract development and manufacturing organization, focusing on the development and manufacturing of transdermal patches and transmucosal films. With more than 30 years’ experience in the pharmaceutical industry, For more information, e-mail Kevin Ostrander at
Reference
- M Pastore, et al., “Transdermal patches: history, development and pharmacology,” Br J Pharmacol., 2015 May; 172 (9): 2019: 2179– 2209.