Next-generation transdermal drug delivery

Medherant, a spin-out from the University of Warwick, is developing new applications for patch technology that have not been possible before, including high-dose drug delivery systems with a constant rate of drug release

Medherant, a developer of next generation transdermal drug delivery patches, is using its world-leading expertise in bioadhesives and polymer chemistry to create new adhesive transdermal patches to expand and advance the library of drugs that can be delivered using patches. The TEPI Patch technology, developed by Medherant, improves upon existing patches by significantly increasing their drug loading capability, efficacy and the patient user experience.

The company is currently developing an ibuprofen transdermal patch, and has also had significant results testing their breakthrough TEPI Patch design with lidocaine. Dr Kevin Robinson caught up with CEO, Nigel Davis, to find out more.

If you know about patches, says Nigel, there have been a number of different varieties and designs during the past few years, starting with simple poultices and reservoir patches comprising a gel or a bag-like structure with a semi-permeable membrane containing a drug, and an adhesive component to hold it in place. These were generally quite cumbersome and difficult to manufacture, and uncomfortable to wear.

To improve on this, industry looked into developing a matrix-like system wherein the drug, or even the drug and the adhesive, were incorporated into a matrix-based patch. Currently, most patches, such as hormone and nicotine patches for example, follow this model. They work, they’re quite good … but there are limitations to what you can do with currently available adhesives, which is why patch-based delivery systems are not as ubiquitous as oral solid dosage (OSD) forms. You have to have an adhesive that’s capable of carrying an appropriate payload to deliver an adequate dose and achieve the required therapeutic effect through the skin.

If you can’t put a significant volume of drug into the patch, then you’re limited to high potency actives, and they have to be compatible with the adhesive that you’re using. And, of course, formulation issues have to be considered; it’s important that the drug doesn’t crystallise within the patch, leak out or diffuse into the backing material. The range of products that you can use with current adhesives is relatively small. Some formulations cause the adhesive to lose their stickiness, so they don’t remain in place, which affects both user compliance and efficacy.

So, we looked at this and realised that there must be a way of getting more products into patches. We looked at using micro-needles to make little holes, so that product could better penetrate the skin, or electroporation, using an electric current to transport the drug into the dermis. Both of these techniques are valid and in use, and are very appropriate for specific drugs. But, the real issue is that there have been no new adhesives for, perhaps, more than 20 years. Sure, there have been subtle variations on existing versions, but no new classes of adhesive.

A new adhesive

There are only a limited number of existing polymers that have the right characteristics to be used for transdermal patches — that will stick securely to the skin and can be removed easily without leaving residues. Furthermore, there are also only a limited number of drugs that will dissolve into these existing polymers.

So, the long and the short of it was that the pharmaceutical industry needed a new adhesive … and we happened to know Bostik very well! They happened to have created a new class of adhesive that, they thought, might have medical applications. We agreed, we tested it and then spent some time exploring how we could use this new product for transdermal drug delivery systems.

The critical differentiator, and what makes it stand out from the competition, is its high payload capacity. It enables us to incorporate greater amounts of drug and/or excipients such as permeation enhancers (which are normally used in creams and gels) while still sticking well for 24 hours or more! So, we can make a more comfortable patch, that’s user friendly with a high level of active ingredient.

Beyond the increased drug loading capacity, we can now also accommodate a wider range of drugs and formulate certain drugs that haven’t previously been administered in a transdermal format. There remain some actives — such as insulin — that will not penetrate the skin. However, Medherant’s new patch technology may enable some drugs to be delivered through the skin that, in the past, were incompatible with extant patch technology. Even when applied as creams or gels, they were messy, difficult to use and it is/was almost impossible to accurately control the dose. Our patches solve these issues, while providing exactly the same unit dose control as an OSD.

Medherant has worked with a variety of candidate drugs to date and, of these, 75–80% are fully soluble. All of those that dissolve are subsequently tested in permeation studies. We can vary their rate of permeation by either changing their concentration or adding excipients to alter how they leave the adhesive and cross the skin, notes Nigel. Other drugs that yield dispersions rather than fully dissolving can also still be delivered.

We tried a number of different drugs and now have a portfolio of 40 actives that are compatible with the new technology. Some have been used in patches before, but we can now offer a smaller version; some were only available as creams or gels; and some have been formulated into a patch for the first time.

Targeting pain

We have taken a few of the drugs from our portfolio into the clinic and focused on pain as a medical condition. So, we’ve looked at ibuprofen, lidocaine and methyl salicylate. We wanted to select a product that, we hoped, would be relatively quick to get through the regulatory system and onto the market. Because we’re working with a new adhesive, it’s defined in pharma terms as a novel excipient, and it has to be approved as such. And, to get a novel excipient approved, you have to get a drug product approved that actually contains your excipient.

With studies under way, the company is looking to target Europe with an ibuprofen patch, and the US with a lidocaine version. The ibuprofen patch will fill a conspicuous gap in the market, which is currently worth more than $4 billion. The transparent adhesive patch can deliver a prolonged high dose of ibuprofen at a consistent dose rate for up to 24 hours.

Significant amounts of the drug (up to 30% weight) are incorporated into the polymer matrix that sticks the patch to the patient’s skin with the drug then being delivered at a steady rate for at least 12 hours. This opens the way for the development of a range of novel long-acting over-the-counter pain relief products, which can be used to treat common painful conditions such as chronic back pain, neuralgia and arthritis without the need to take potentially damaging doses of the drug orally.

Further benefits

Another benefit that we’ve observed with TEPI Patch technology is that, compared with existing technologies, much less drug remains in the patch after use. Drugs dissolve directly in the pre-cured adhesive, but are not “penned in.” Once cross-linked, the adhesive acts as a solid-phase solvent. As such, the high drug load and consistent drug release profile means that the TEPI Patch outperforms other patches and gels in its ability to deliver a consistent and significant dose of drug during a prolonged time, offering significant new opportunities for the development of a wide range of drug delivery products.

Unlike other patch adhesives, there are no organic solvents in the TEPI Patch polymer matrix, so there is no need for a costly solvent removal step during manufacture, and curing (cross-linking the polymer chains for added stability) is done with water. These characteristics make for an environmentally friendly production process.

In summary, the TEPI Patch technology can be used for many other therapeutic areas and provides an excellent platform for the development of a wide range of drug delivery products. This excludes biologics, but includes drugs such as nicotine that are already delivered through a patch, in addition to others for which patch delivery was not previously viable.