According to data from Kalorama, the global market for transdermal patch drug delivery topped $7 billion in 2015. Patches are most familiar in the pain relief market and for the delivery of sex hormones, wherein the ability to provide a continuous low dose offers significant patient benefits.
Other marketed transdermal patch products include those that deliver nicotine as part of a smoking cessation programme, and products for hypertension and motion sickness. These formulations can also give improved patient compliance, thanks to the stick-it-on-and-forget-it potential of a patch.
There are other advantages. By delivering the active directly to the bloodstream, first-pass metabolism in the liver is avoided, potentially reducing the side-effects caused by metabolites created by liver enzymes. Avoiding the harsh environment of the gastrointestinal tract may be beneficial for acid-sensitive active pharmaceutical ingredients (APIs). For opiate analgesics, the potential for abuse is lower and, as a patch is far less appealing for addicts, it may reduce the amount of diversion of prescription opiates into the black market. Furthermore, it is easy to discontinue dosing by the simple action of removing the patch.
Innovative patch technology
Most transdermal patches contain the API in some form of reservoir, with an impermeable outer layer, and adhesives on the inner surface to attach the patch to the skin. The adhesive can be spread across the entire patch or just around the edges. Simple patches are ideal for the delivery of low doses of small, lipophilic APIs. More recently, products that use chemical enhancers, iontophoresis and microneedles to aid delivery have been created. It is now even possible to deliver macromolecules and biologics using innovative patch technology.
Two different transdermal delivery systems have been developed by California-based Corium International, which are manufactured at its own GMP production facility in Grand Rapids (MI, USA). MicroCor is a biodegradable microstructure patch technology designed for the delivery of biologics, including proteins, peptides and vaccines, whereas Corplex is an adhesive system and patch technology for the delivery of otherwise difficult small molecules.
Microcor is a biodegradable microstructure patch that was designed to deliver large molecule therapeutics and vaccines in a non-parenteral manner. In the past, the company says, transdermal delivery was limited to small and potent drug molecules using conventional patch technology and passive diffusion mechanisms and, for the most part, large molecules and vaccines required delivery by injection or infusion. Microcor integrates the drug active or vaccine directly into arrays of biodegradable microstructures — or ‘microneedles’ — that penetrate the outer layers of the skin and release the drug for local or systemic absorption.
As MicroCor patches are solid state, they should be stable at room temperature, removing the need for cold chain distribution and storage. Plus, there are no sharps to get rid of. The microstructures on the patches are typically 200µm long, but this length can be varied, allowing the drug to be delivered anywhere from the stratum corneum to the dermis, and both bolus and sustained delivery are possible. The technology is also applicable to small molecules, giving faster skin permeation than a traditional patch.
Corium claims it is the first company to achieve clinical success with a biodegradable microstructure delivery system, after positive results were obtained in a Phase I study with a formulation of the parathyroid hormone teriparatide in healthy women, in which it was safe, well tolerated and exhibited good pharmacokinetics. The patch achieved rapid systemic delivery of the hormone with equivalent exposure to administration via subcutaneous injection.
Corium claims it is the first company to achieve clinical success with a biodegradable microstructure delivery system
Corplex patches, meanwhile, are constructed using a combination of traditional pressure-sensitive adhesives and bioadhesives. Careful selection of polymer blends allows the patches’ properties to range from hydrophilic to hydrophobic, enabling adhesion to both wet and dry surfaces. Wear times range from seconds to days, thus enabling both fast-acting and extended-release products to be formulated.
The company claims this type of patch is compatible with a wide range of drugs, vehicles and enhancers to facilitate passive transdermal delivery, including actives that were previously thought to be incompatible with delivery through the skin. The technology has already been commercialised in the consumer products area, being used in Crest Advanced Seal tooth whitening strips. The adhesive properties are not weakened or destroyed by exposure to moisture or humidity; they are resistant to accidental removal but are easy to remove without damaging the skin or leaving a residue.
Clinical projects include a formulation of the cholinesterase Alzheimer’s drug donepezil (Eisai’s Aricept). Earlier this year, following a successful Phase I pharmacokinetic study, FDA advised that if bioequivalence can be demonstrated between the patch and oral Aricept in the pharmacokinetic study planned for 2017, they will not require further clinical efficacy studies to demonstrate bioequivalence. If this is the case, the company anticipates filing for approval in mid-2018.
Transdermal contraceptives
New Jersey-based Agile Therapeutics is using its Skinfusion transdermal patch technology to develop a portfolio of prescription contraceptives. Its lead product candidate, Twirla, is a once-weekly contraceptive patch that is currently in Phase III. It combines the common contraceptive ingredients ethinyl oestradiol and levonorgestrel, which are delivered during a 7-day period at levels comparable with currently marketed low dose oral contraceptives.
It is worn weekly for 3 weeks, followed by a week without a patch. These patches comprise several layers of material that contain the active and inactive ingredients, plus adhesives to attach it to the skin. The visible top layer is made from a thin, silky adhesive-backed material. Underneath this is a set of concentric layers with a smaller diameter — leaving adhesive exposed around the outer ring of the patch — which contain the ingredients in a matrix adhesive system that delivers the ingredients through the skin at the desired rate.
A barrier prevents the ingredients migrating to the outer edges of the patch, and stops them breaking down the adhesive at the edge. The six layers of the patch are compressed together to create an unobtrusive patch that is less than 1mm thick. The company says its new technology should facilitate the optimisation of patch adherence and patient acceptability and, therefore, compliance.
Several more products are in earlier stages of the pipeline, including AG200-ER, which is designed to allow a woman to extend the length of her cycle; AG200-SP, with a shortened hormone-free interval, for which a Phase II trial recently got under way; and AG890, a progestin-only patch for those who cannot or do not want to take oestrogen.
Extended delivery
Another company specialising in transdermal patches is Californian biotech Durect. Its Transdur transdermal technology enables the topical treatment of disorders localised to discrete areas of the skin, or the efficient delivery of drugs with poor oral bioavailability or a short duration of action. Large patches are designed for topical treatment, and smaller ones are optimised for comfort and long wear times; continuous drug delivery for up to a week is possible.
Several products are under development. These include Eladur, a bupivacaine patch designed to treat post-herpetic neuralgia. It is formulated to deliver the local anaesthetic to the affected area for up to 3 days, compared with the 12-hour delivery of existing patches. It is also thinner and lighter; and, with a sweat- and water-resistant adhesive, the company claims it causes less skin irritation. The product is currently in Phase II trials.
A second product is a patch containing the opioid sufentanil. This delivers the drug during a period of 7 days to treat moderate to severe chronic pain. The patches are smaller and longer-lasting than those containing fentanyl, and the company believes there is the potential for fewer side-effects than are seen with alternative opioids. Eight Phase I trials and one Phase II have been completed, and the company is now looking for a development and commercialisation partner.
Wound dressings
UK-based Edixomed is developing a nitric oxide-generating technology that has the potential to permit the passage of molecules across the skin that, under normal conditions, would not be able to cross the barrier as they are too large, or not lipophilic enough. Nitric oxide is produced in many tissues in the body, acting as a signalling mechanism between cells.
It can improve transdermal delivery potential by causing local vasodilation, regulating intercellular adhesion and increasing the porosity of blood vessels. Clinical investigation has shown that it can indeed facilitate the passage of larger molecules across the skin. The company has several wound dressing products that generate nitric oxide in the pipeline, including one to treat diabetic foot ulcers that is in Phase III. The ‘active’ that is being delivered here is nitric oxide itself, combined with a hydrogel top layer that absorbs exudate and protects the wound. Drug delivery is still in its early stages, however, and a product to deliver a local anaesthetic is in Phase I.
Added heat and hydrophilic adhesives
Japanese company Teikoku Pharma has developed Hydrohesive and Matrix patch technologies. Hydrohesive patches use skin-friendly hydrophilic adhesives, and are primarily used for topical application. The patches can delivery up to 1mg/day, with application once or twice a day. The formulation contains high levels of water, providing a cooling sensation on the skin. A lidocaine formulation is already on the market. A further product is in the earlier stages of development, for the treatment of chronic pruritus.
Its Matrix technology uses hydrophobic adhesives or a rate-controlled membrane to deliver APIs through the skin. In contrast with Hydrohesive patches, this facilitates systemic delivery, and extended release for up to 7 days is possible. A maximum of 10mg/day can be delivered. The API is incorporated into a liquid or semisolid polymer matrix. The rate of delivery can be regulated using a rate-controlling membrane for a high flux API.
The Medicines Company, based in New Jersey, has developed a patient-controlled iontophoretic transdermal system
Canada’s Nuvo Pharmaceuticals has developed a patch technology that uses heat to improve delivery. Its Controlled Heat-Assisted Drug Delivery technology was used to formulate a patch that combines lidocaine and tetracaine, which provide local analgesia prior to needle-based procedures such as dialysis, paediatric immunisations and phlebotomy. The patch produces long, dense analgesic and vasodilatory effects after 20–30 minutes. It is now being sold by Galen with the brand name Synera in the US, and Eurocept in the EU as Rapydan.
The heat is provided by an oxygen-activated heating component. When the patch is removed from its pouch, exposure to atmospheric oxygen activates the heating element. The skin temperature under the patch increases by about 5°C, promoting faster dermal absorption of the anaesthetic molecules; skin temperature should not exceed 40°C.
In a clinical trial, pain intensity scores were about a third lower with the heated patch compared with those treated with a patch containing the same anaesthetics but no heating element. The most common side-effects were redness or paleness of the skin and swelling, but these effects were generally mild and resolved after the patch was removed.
Iontophoretic delivery
The Medicines Company, based in New Jersey, has developed a patient-controlled iontophoretic transdermal system. This is designed to give on-demand systemic delivery of analgesia for the short-term management of acute post-operative pain in a hospital setting. The patient presses the button on the credit-card sized device, which is attached to their chest or upper arm, and an aliquot of ionised drug will be delivered transdermally. It was approved in the US and EU in 2015, and has been licensed to SymBio in Japan, where a further Phase III trial is under way.
Ionsys delivers 40µg of fentanyl in each dose. As no intravenous lines are required, it facilitates patient mobility during recovery. When the button is pressed, a 62µA/cm2 current, usually imperceptible to the patient, actively transports fentanyl into the bloodstream during a period of 10 minutes. The drug reservoir is in the anode, and the current transports the drug through the epidermis and dermis into the blood vessels beneath.
The device is programmable, and can deliver up to six doses an hour, and 80 during a 24-hour period. It should not be used for more than 3 days. Serum concentrations of fentanyl are more constant using the device than with intravenous dosing. Six placebo-controlled trials have been done to establish efficacy and safety, plus four more active-controlled trials. Several drug delivery products are under development, including a formulation of the Parkinson’s disease drug rasagiline, which is in Phase I. Another product, an as-yet-undisclosed non-narcotic, non-NSAID analgesic, is being developed as a 3-day patch for chronic pain management.
