Transdermal drug delivery looks for new frontiers

NuPathe’s Zecuity ionotophoretic patch (left) and a Theraject application (right). Credit: NuPathe, Theraject

The skin, the largest organ, effectively prevents passage of many foreign substances into the body. Passive transdermal products, such as patches and gels, creams, and sprays are able to pass some drugs through the skin at therapeutic rates to deliver drugs systemically. Drugs that are lipophilic, with low molecular weights and low dosages, can pass through the skin most easily. Not all small-molecule drugs, however, can do so; e.g., charged molecules. To enable delivery, products often use various passive technologies, including:

• Particulate systems, such as liposomes, transfersomes (synthetic vesicles), microemulsions, or solid lipid nanoparticles
• Chemical penetration enhancers, such as glycols and terpenes

The skin provides an effective barrier as well to large-molecule drugs, such as proteins and peptides, and this obstacle has led to efforts to develop physical or active methods of overcoming the skin barrier, including:

• Microneedles—sharp microprojections, frequently in patch form
• Iontophoresis—a weak, continuous electrical current
• Electroporation—short, high-voltage pulses
• Magnetophoresis—a magnetic field
• Ultrasound—low intensity ultrasound

Passive patches still dominate the transdermal market. Despite years of effort, the movement of active technologies into the market has been slow, and few have reached the market or been successful. In May 2011, FDA approved Sanofi Pasteur’s microneedle-based product, an influenza-virus vaccine called Fluzone Intradermal. In January, FDA approved Zecuity (sumatriptan), a single-use, battery-powered, iontophoretic patch for treatment of migraine in adults, developed by NuPathe Inc. (Conshohocken, PA). These achievements may open the way for development of more drugs using active technologies.

Fig. 1. Transdermal drug and technology market, 2010—2017. Credit: Kalorama Information

Historically, many transdermal products have delivered drugs that provide treatment for hormonal deficiencies, help with smoking cessation, or manage pain. In addition to Sanofi and NuPathe, two other pharmaceutical companies have recently developed new products that treat other types of medical conditions. In January 2009, FDA approved Watson Pharmaceuticals’ Gelnique (oxybutynin), a gel for the treatment of overactive bladder. Last April, FDA approved UCB’s Neupro (rotigotine), a transdermal patch, for treatment of Parkinson’s disease and restless legs syndrome.

In a market study published in September, Kalorama Information (New York) puts the current market for transdermal and transmucosal products at about $8.4 billion, with around $700 million being spent on the delivery technology. By 2017, the product value will be just over $10 billion, with delivery technology at $900 million (Fig. 1).

Pharmaceutical companies initially became interested in transdermal technology for systemic drug delivery because it: 1) avoids problems related to gastrointestinal passage and hepatic first-pass metabolism in which absorption in the liver and the gut wall reduces the amount of drug available for systemic delivery; i.e., its bioavailability; 2) offers a controlled, continuous delivery of drugs; 3) provides the option of delivery once or twice weekly; and 4) facilitates easy termination of the drug.

In addition to those benefits, companies have used the introduction of transdermal products as a method of extending the life cycle of products originally introduced in another form, such as capsules. Prior to entry of generic competitors into the market, a company can move the revenue base for its product from the original form to a transdermal solution. If patient acceptance is high, a barrier is created for generic products stuck with the original form of delivery.

Systemic and topical delivery

Transdermal technologies not only provide benefits for systemic drug delivery but also for local delivery of dermatological and cosmeceutical products, the latter not being subject to FDA’s stringent requirements regarding therapeutic effects. Transdermal delivery includes topical products such as gels that deliver drugs systemically, and many topical products are available for dermatological and cosmeceutical purposes. The skin is the common thread that unites systemic transdermal and local dermatological and cosmeceutical development, and many technology companies have sought partnerships with companies in all three fields. The cosmeceutical industry actually developed some of the technologies, and pharmaceutical companies later adopted them.

Given the benefits of passive and active technologies for local and systemic delivery, companies will continue to develop pharmaceutical, dermatological, and cosmeceutical products, and both passive and active technologies provide opportunities for development of marketable transdermal drugs.

Passive technologies

Nanotechnologies

Nanotechnologies seem to hold some hope of expanding the transdermal market. In 2010, NewGen BioPharma (Titusville, NJ) bought a transdermal platform, Micellar Nanoparticulates (MNP), from Novavax. That company had developed one transdermal product using MNP, Estrasorb (estradiol), which is currently on the market for treatment of symptoms of menopause. The platform improves the solubility and bioavailability of topically delivered products. Providing an increased residence time for an active pharmaceutical ingredient (API), the technology can reduce the dosage or the number of applications per day.

MNP offers a solution for delivery not only of systemic transdermal products but also of topical local, oral, injectable, and ophthalmic products. Navdeep Jaikaria, NewGen’s CEO, indicates that MNP gives NewGen the ability to reformulate 60% of all small-molecule drugs. The company also has a platform for delivery of inhaled products and is developing a technology for large-molecule peptides. These peptides must have a stable conformation that withstands the high pressure under which formulations are produced; Jaikaria adds that only GRAS-listed (Generally Recognized As Safe) additives are used.

Jaikaria has indicated that NewGen’s MNP platform holds promise for transdermal technology because it may improve patient acceptance of transdermal products. While common and well accepted in Asia, transdermal products such as patches can cause irritation and itching, and US consumers have not been as tolerant. NewGen’s nanoformulated, medicated lotions are nonirritating and are moisturizing rather than dehydrating, unlike patches in the first instance and gels in the second.

NewGen is developing its own pipeline of drugs, currently 20 APIs that it has reformulated using the MNP platform. This year NewGen plans to launch an ophthalmic and a topical drug in India as well as a reformulation of Estrasorb that keeps estrogen in the skin longer. NewGen has used its technology to develop cosmeceutical products as well, one for hair regrowth and an anti-aging cream.

The company will work with partners as a contract service provider, developing drugs using the platform. Jaikaria indicates that hormonal (steroidal) conditions, pain, urinary incontinence, erectile dysfunction, and smoking cessation are examples of the types of conditions that drugs using the platform can treat. The technology primarily permits delivery of small-molecule drugs, but Jaikaria says that it also will function with small peptides as long as conformation is not an issue. He says that any drug listed as BCS Class 2 (a measure of drug absorption), or that is poorly water-soluble, is a possibility for delivery.

Like NewGen, Particle Sciences, a Bethlehem, PA, contract development and manufacturing organization, sees nanoparticles as a standard drug-delivery option. The company can incorporate APIs into particles using its proprietary technologies, with the possibilities ranging from an emulsion droplet to a nanoparticle of the API itself, from tens of microns down to several nanometers. Particle Sciences also uses an in-licensed technology, LyoCell, which combines a lipid-based approach with nanoparticles, with the particles having unique solubilization properties.

Particle Sciences has focused on technologies for passive delivery of small-molecule drugs but has also developed a proprietary system for targeting large molecules. Rob Lee, VP, says that Particle Sciences has worked on all routes of drug delivery, including transdermal patches, but especially on topical, local and systemic formulations in creams, lotions and gels, and on mucosal formulations. Products have ranged from contraceptives to a head lice shampoo recently launched by a major pharma company. “Lately, we’ve seen a lot of interest in patches, beyond the typical amount,” he says. “Most are for typical transdermal products, such as drugs for hormonal products and pain management, but a few are for unusual, proprietary APIs.”

Lee adds that active technologies will be necessary for the delivery of other types of drugs, such as proteins and peptides. He believes that active technologies hold a lot of promise, in particular the use of them for development of antibody-based therapeutics and vaccines.

Chemical penetration enhancers

Xel™ Pharmaceuticals (Draper, UT) develops systemic transdermal drug systems (patches and topical formulations) that incorporate proprietary skin penetration enhancers (SPEs). The topical products also can provide local delivery of dermatological or cosmeceutical products. The company often works with partners for development of proprietary formulations.

Danyi Quan, Xel’s chief scientific officer (CSO), believes that local delivery of drugs and cosmeceuticals offers many prospects for marketable products currently, including new drugs that treat dermatological conditions, such as acne, psoriasis, and minor skin irritations, itching, and rashes caused by eczema. For example, topical hydrocortisone has been successful in treating skin irritation.

She indicates that some topical transdermal products have provided systemic drug delivery and have been successful in the marketplace, such as the testosterone gels that provide treatment of hormonal deficiencies. She thinks that pain management and hormonal treatments continue to be good areas for systemic transdermal delivery, whether in patches or creams and gels.

To grow the market for transdermal products, Quan believes that pharmaceutical companies must focus their efforts on three areas. “First, transdermal drugs offer many benefits over other methods of delivery, and we need to do drug discovery specifically to fit transdermal technology. Second, an opportunity exists to use botanical compounds to create new transdermal drugs (a specialty of Xel). Finally, scientists can use transdermal technologies to improve the efficacy of dermatological products.”

Active technologies

Microneedles

TheraJect, Inc. (Fremont, CA) has developed two patches with microneedles, DrugMat and VaxMat, intended for topical, transbuccal and transdermal delivery. The company manufactures the microneedles from a sugar polysaccharide, combining it with the drug and molding these components into sharp needles. The resulting product is inert and safe, and the needles dissolve with use, thereby avoiding issues of disposal and contamination. TheraJect will license its technologies to interested partners for both topical and transdermal products.

The company’s products first entered the market through the cosmeceutical industry. Sung-Yun Kwon, TheraJect’s CEO, indicates that a cosmeceutical product called ARTPE, an antiwrinkle eye patch, is using the company’s technology and is now selling in Malaysia and Hong Kong. TheraJect is looking for a distributor in the US. It is also currently negotiating with a Korean cosmetic company that plans to make 10 million patches per year using its technology.

TheraJect is currently developing a transdermal product for systemic delivery that appears likely to enter the marketplace, Sumatriptan for migraines. The National Science Foundation (NSF) has funded that development through small business grants in two phases, feasibility and commercialization. In the first phase, the NSF provided $150,000 for feasibility studies and accepted the product as feasible, making it one of only four products accepted in that funding cycle. The company is now in phase 2, for which the NSF has provided a half-million dollars for two years to move the product into commercialization. TheraJect is looking for a company to partner with them in this phase, and the NSF will match whatever amount the company is willing to invest.

Microneedles offer a solution for overcoming the barrier that the skin creates to delivery of drugs such as proteins, peptides and vaccines, which would mean that many more drugs could be formulated for transdermal delivery. “Protein drugs are very potent but permit use of a lower dosage,” Kwon says. “We can easily load drugs on microneedles that will penetrate the skin or buccal barrier.

Other companies are working on products that use microprojection systems. Zosano Pharma (Fremont, CA) is working with the ZP Patch, a sheet with metal microneedles to deliver select drug products with a similar pharmacokinetic profile as a subcutaneous injection. In October 2011, Zosano entered into collaboration with Asahi Kasei Pharma Corp. for the development, commercialization, and supply of Teribone (teriparatide acetate), an osteoporosis therapy. Zosano develops its own products and also will contract with partners to develop drugs that use the ZP Patch technology. The company indicates that the ZP Patch is capable of delivering a broad range of compounds, including peptides, proteins, small molecules, and vaccines.

In December 2012, 3M Drug Delivery announced a partnership for development and commercialization of a proprietary peptide analog to treat patients with osteoporosis at high risk of fracture. 3M has developed a microneedle platform, its Microstructured Transdermal Systems (MTS), and partners with companies to develop products.

Theraject’s technology as used in a cosmetic patch. Credit: Theraject

Iontophoresis and electroporation

Unlike TheraJect, Xel, and NewGen, NuPathe has not ventured into the cosmeceutical market. A small company, its primary focus since its inception eight years ago has been development of its iontophoretic system, SmartRelief. NuPathe’s Zecuity uses that proprietary, battery-powered technology, which involves application of a mild current to the skin through two pads. With FDA’s recent approval of Zecuity for the treatment of acute migraine, NuPathe’s priority is on scale-up for manufacturing, with the drug’s projected launch to be in the fourth quarter of 2013. The company is currently seeking partners to commercialize the product. NuPathe owns worldwide rights to Zecuity.

Jerry McLaughlin, NuPathe VP, says that iontophoresis best fits the delivery of drugs where the treatment demands building sufficient blood levels in a short time: “Passive delivery just doesn’t provide that capacity.” Zecuity delivers the migraine drug over a four-hour period and at a specified rate with low patient-to-patient variability. The microprocessor continuously monitors skin resistance and can adjust the current to deliver predefined doses.

McLaughlin believes that success for iontophoretic technologies requires choosing the right disease area and the right molecule, one that is difficult to deliver by other methods, has poor absorption in the gut, and can benefit from the use of an electric current to increase the speed or rate of delivery. McLaughlin says, “NuPathe’s eight years of experience creating SmartRelief and developing Zecuity has taught us that everything matters in product development—current, density, size, shape, and contact with the skin. Getting to this point has required a lot of experimentation.”

McLaughlin indicates that drugs that require delivery on a daily basis over an extended period of time (e.g., 24 hours per day) may not be ideal for iontophoretic technologies. Daily delivery in the same spot likely would not be good for the skin. The possible exception is a microdose. If the user can rotate the delivery site or if delivery occurs only once or twice per week, the drug may be a candidate for iontophoresis. As an example of an appropriate use, McLaughlin suggests development of drugs for treatment of rheumatoid arthritis as an alternative to the drugs currently delivered as injections every week or two. Iontophoretic technology may be a noninvasive option that could eliminate patients’ anxiety about self-administration of injections.

Other electrical devices are in development or on the market to provide treatment of specific diseases, including Travanti Medical’s Iontopatch (low voltage, continuous), an alternative to injection for treatment of tendinitis and Inovio’s electroporation (high voltage, short duration) for vaccine delivery. Those companies don’t currently license their technologies.