Evolution has designed the human body like a fortress with heavily guarded entrances. Our physical well-being relies on keeping pathogens and other detrimental substances at bay. While the facial apertures — mouth, nose, eyes, ears — and the anal and uro-genital openings have their own defenses, the epidermis constitutes the body’s main guardian against invasion, simply because it is so extensive in surface area and so interactive. Possessing at least half a dozen properties and strategies for repelling invaders, our skin stops a vast spectrum of unwanted agents.

Lucky for us, the skin can also be convinced to pass beneficial things, such as drugs, directly into the body where they can be readily utilized with distinct advantages over other modes of delivery. (The mucosal membranes offer a similar entryway, although they are a bit trickier to employ, as we shall see.) When injections and pills are counter-indicated, transdermal and transmucosal delivery systems may get drugs into the body with great efficacy and beneficial results.

Today’s pharmaceutical companies are continually enhancing and improving a wide range of patches and topical drugs, as well as lozenges, sprays, films, tablets and wafers, which offer physicians the maximum range of treatment options. With the help of CMOs, bioanalytical and clinical testing firms, and packagers, the future of these delivery systems looks bright, with significant growth projected straight through 2015.

Transmucosal Delivery Systems
The body’s mucous membranes occur primarily in the mouth and the nose. Their permeability — estimated at four to 4000 times that of the epidermis — allows for the systemic uptake of drugs painlessly and at a steady rate of delivery, bypassing the stomach environment and first-pass liver metabolism.

The Mouth
In the mouth, the areas beneath the tongue (“sublingual”) and in the cheek are most useful for these transfer purposes, whereas drugs for locally bounded oral treatment may be applied elsewhere as needed in the mouth. But the unique nature of the mucosal membranes in comparison to the epidermis means that special polymer bioadhesives with different properties other than those employed in epidermal patches must be formulated and tested. Polymer chemist Dr Vitaliy Khutoryanskiy, in a recent interview with the magazine Pharmaceutical Market Europe, characterized the state of the art in this fashion: “Despite several decades of research, muco-adhesion is still not fully understood.”¹ But this has not stopped various companies from producing highly valuable oromucosal products.

For the treatment of pain relief, there is Subutex from Reckitt Benckiser, Onsolis from Valeant Pharma, and Actiq/Fentora from Cephalon. Sativex from GW Pharma is used in the treatment of multiple sclerosis. Angina is addressed by NovaDel’s Nitromist, Pfizer’s Nitrostat, and Suscard from Forest Laboratories. BioAlliance offers an antifungal with Loramyc. There are two smoking cessation products in Nicorette from GlaxoSmithKline and Nicotinell from Novartis. Nausea and vomiting are treated with Alliance Pharma’s Buccastem and GlaxoSmithKline’s Zofran, while Columbia Labs features a testosterone replacement with Striant SR, and NovaDel appeals to insomnia patients with Zolpimist.

The Nose
Uptake of drugs via nasal sprays is so common as to seem old hat at times. GSK’s anti-inflammatory preparation Flonase and MedImmune’s anti-influenza drug FluMist are well known in healthcare circles, but this familiarity conceals some other novel applications.

Miacalcin from Novartis Pharmaceuticals and Fortical from Upsher-Smith Laboratories both treat osteoporosis; Pfizer’s Nicotrol addresses nicotine addiction; Nascobal from Strativa Pharmaceuticals is used to treat vitamin B deficiency; Ferring Pharmaceuticals produces Desmospray, which fights the dehydration associated with diabetes; Lazanda is a nasally administered opiate from Archimedes Pharma used for pain management; and Novartis delivers Syntocinon, which addresses several conditions associated with pregnancy.

But beyond the perfected mode of sprays comes the truly exciting realm of adhesives particularly formulated for the conditions in the nasal mucosa that permit a steady-state administration of drugs. For instance, Arindam Das and his colleagues from the Faculty of Pharmacy at the Lincoln University College in Malaysia are experimenting with mucoadhesive polymeric hydrogels that facilitate the nasal delivery of penciclovir.

And SRI International’s recent 21st century, multi-purpose nasal adhesive offers a host of applications. According to the company’s press information, the product consists of “a two-component polymeric solution: one is responsive to pH and the other to temperature. On mixing and application to the physiological site, the two components form an adhesive gel that attaches to the mucosa, creating a platform for drug release.” SRI postulates that the adhesive will be useful for deploying “vaccines . . . and contraceptive formulations or to provide topical microbicides that protect against sexually transmitted diseases, such as HIV and genital herpes.” Usage in poorer countries where injections are problematical is a further attraction.

The Future
On the horizon are newly formulated mucosal adhesives that would allow drug delivery through the eyes, lungs, and intestinal tract, the latter occurring after oral ingestion of a protective capsule and passage through the stomach, ending in attachment in the intestines. Also of interest is an oral prosthetic device featuring an exchangeable cartridge system delivering an anti-Parkinson’s drug via saliva-triggered osmosis, being perfected by Simon Herrlich of HSG-IMIT and colleagues. Likewise, tests are being made on the utility of delivering interferon through oromucosal channels also.

It could be quite a lucrative area. In the beginning of 2012, Endo Pharmaceuticals and BioDelivery Sciences International (BDSI) former a partnership to develop and commercialize a treatment of chronic pain. The drug uses BDSI’s patented BioErodible MucoAdhesive (BEMA) technology to deliver the opioid analgesic buprenorphine. BDSI stands to gain $180 million (with $30 million upfront) if all milestones are met, along with a tiered mid- to upper-teen royalty on U.S. net sales.

Epidermal Delivery Systems
Delivery systems that take advantage of the skin’s selective permeability to administer non-local doses of drugs come in two types: dispensing patches that encapsulate the drugs and are affixed to the skin by adhesives; and creams and gels applied topically, without any apparatus. The range of conditions treatable by such technology parallels the treatments discussed above for mucosal routes, while being perhaps even more extensive.

Patches
After nearly 35 years of FDA-approved use, patches are such a well-known and mature technology that they have come to facilitate the delivery of a wide variety of drugs. A number of conditions are currently addressed by transdermal patches, including:

• Transderm Scop (Novartis) for motion sickness
• Transderm Nitro (Novartis) for angina
• Estraderm and CombiPatch (Novartis) for menopausal symptoms
• Exelon (Novartis) for Alzheimer’s
• Catapres-TTS (Boehringer Ingelheim) for hypertension
• Duragesic (Janssen Pharmaceutica) for pain
• Lidoderm (Endo Pharmaceuticals) for pain relief
• Daytrana (Noven Therapeutics) for ADHD
• Neupro (Schwarz Pharma) for Parkinson’s sufferers
• Emsam (Bristol-Myers Squibb) for cases of major depressive disorder
• Oxytrol (Watson Pharma) for overactive bladder condition

Even with all these applications, improvements are still being made to extend their remit further. Employing iontophoresis — the transmission of an electrical current across the epidermis to improve migration of drug molecules — is one such refinement.

Travanti Medical’s IontoPatch family is a leader in the field, with four products that treat large and small areas, offer multiple wear times, and include a stronger dose. Its wearability is marked by its small, self-contained battery, requiring neither external charger nor controller, according to the company.

Additionally, changing the structure of the drug itself — fabricating microemulsions or nanoemulsions — results in better rates of uptake. And engineering the very material of the patches with new technologies leads to “smart patches,” programmable by the physician.

Creams and Gels
Generally speaking, topical transdermals can convey as wide a variety of drugs as patches. But in practical terms, the main products seem to center around pain relief and hormone replacement. For instance, Endo and Novartis have teamed up to offer Voltaren Gel, an NSAID for relief of osteoarthritis pain. Similarly, Pfizer markets Feldene; Tillomed Laboratories makes Tiloket; and Pennsaid is produced by Nuvo Research. In the realm of hormone replacement therapy, we find such products as EstroGel from Ascend Therapeutics and AndroGel from Abbott Laboratories.

One fascinating new kind of cream that seems to offer a feature not available in patches is Lipoderm from PCCA. This substrate can contain and deliver as many as four different drugs simultaneously.

However, topical creams must be used carefully, compared to transdermal patches: accidental contact with the cream by non-users can produce unintended effects in the bodies of the accidental recipients. Tapemark has worked to protect against such mishaps with its proprietary Snap!^® packaging, which dispenses a precisely-measured single dose of a cream in an easy-to-use disposable format.

The Future
Tom Martin, the Microstructured Transdermal Systems Global Business Leader for 3M Drug Delivery Systems, told Contract Pharma of exciting developments in his company’s product line. 3M technology is already employed in 60% of transdermal products in the U.S., and the division also develops and manufactures microneedle delivery systems that can deliver molecules, such as vaccines, to the intradermal space. In the latest case, 3M’s microneedle technology is being used in the treatment of osteoporosis.

Mr. Martin explained, “[We] have entered an exclusive partnership with Radius Health, Inc. to develop and commercialize the BA058-transdermal (TD), a synthetic peptide analog of human parathyroid hormone related protein (hPTHrP), a bone building anabolic compound, for the potential treatment of osteoporosis. Upon a successful Phase I trial that demonstrated the ability of the BA058-transdermal patch to safely and rapidly deliver the drug over a short wear time, BA058 is currently being studied in a Phase II trail. We believe the final product for Radius Health will increase efficacy, improve therapeutic outcomes and offer their patients an easy-to-use solution.”

Mr. Martin believes that microneedle technology can help answer the need in the industry for alternatives to injections and options for improved pharmacokinetic profiles and dose-sparing possibilities. He pointed out, “3M has developed one of the first high volume intradermal delivery systems with our hollow MTS (hollow microstructure transdermal system) device, which delivers up to 2mL of formulation. Currently, we are prioritizing the development of our hMTS device and our testing has shown that this single-use microneedle device is easy to use and requires a minimal number of steps for patients to perform.”

NuPathe’s Zecuity, a development-stage migraine treatment patch using iontophoresis, is attracting much interest. If approved, it will be the first transdermal treatment for migraine, delivering sumatripan by iontophoresis to bypass the GI tract and moderate peak plasma levels for more effective relief.

Drug Development and Clinical Studies
Identifying a useful drug, perfecting it and getting it into the marketplace is a long and intricate process, and several firms specialize in helping new transdermal and transmucosal products down this route. We spoke with Mike Peel, executive director of Discovery Research at Scynexis, about his company’s involvement in this area. After many years of helping to bring orally delivered drugs to market, Mr. Peel sees a wide future for transdermals, and has built up Scynexis’s DMPK capabilities to meet selection and testing needs. He remarked, “We have everything that a company would need to be able to take its compound set and test for stability toward skin metabolism or skin enzymes, and ability to penetrate through mimics of skin, by utilizing the Franz Diffusion Cell. We have a very strong analytical capability. We use mass spectrometry for almost everything we do, a much more sensitive and reproducible analysis [than UV].”

Mr. Peel also emphasized Scynexis’s expertise in chemistry, particularly the realm of prodrugs, which are temporarily attached molecular adjuncts that allow formerly non-penetrative drugs to be delivered, the union of the two parts generating new intellectual properties. Furthermore, Scynexis’s deployment of “reconstructed human epidermal models,” or artificially cultured human skin, allows for a greater and faster volume of testing, and meets regulatory demands for non-animal test subjects, he remarked.

Paul A. Lehman, vice president of Dermal and Transdermal Research at PRACS Institute, took time to converse with Contract Pharma and outline his firm’s vast experience, centering around the company’s Fargo, ND, facility. Mr. Lehman said, “We do both laboratory and clinical studies. Our clients bring us different patch designs and we put them on skin mounted in Franz Diffusion Cells. We can then predict how much of the drug will be absorbed through the skin. We can then screen prototypes — preliminary designs — on their ability to deliver. When they go to clinical trials, they’ll have a heads-up on what to expect.”

Mr. Lehman focuses on three essential patch qualities that PRACS can assess: adhesion, absorption and stability. Reports on these qualities from in vitro testing lead straight into PRACS’ main division, the clinical testing realm. Applying new patches to human volunteer subjects — both at its Fargo facility of more than 500 beds and elsewhere — PRACS looks for drug delivery, skin safety and systemic (absorption) safety. Subjects are monitored over a period ranging from several hours to several days. PRACS also performs “Twenty-one Day Cumulative Irritation Studies” and “Sensitization Studies on transdermal delivery systems.”

Finally, Mr. Lehman explained one physiological fact that makes development of transmucosal drugs more difficult, as we alluded to earlier: “It’s extremely difficult to do laboratory research [on transmucosals] because mucous membranes do not survive well off the body. Skin can be stored for long period of time and retain its barrier functions.”

Another expert in this area is Ken Phelps, chief executive officer and president of Camargo Pharmaceutical Services, who told Contract Pharma that his firm devotes special attention to one particular route of approval.

“The 505(b)(2) development pathway provides U.S. Food and Drug Administration approval of an existing drug based on publicly available data supplemented by sponsor studies,” Mr. Phelps remarked. “Pharma companies are using this pathway to change the route of administration of drugs to transdermal/transmucosal systems. Changing the route of administration is desirable when the safety or efficacy of the current route is less than optimal.” He gave the example of oxybutynin, where the change from oral tablets to transdermal gel reduces the extensive first-pass metabolism, reducing the levels of dry-mouth causing metabolite. Transdermal/transmu-cosal systems may also better target the affected tissues, reducing systemic exposure and the attendant adverse effects.

“505(b)(2) drugs are developed less costly, faster and have less risk than de novo drugs developed under the 505(b)(1) process. Cost and time savings arise due to having much of the usual new drug application (NDA) requirements satisfied using information gleaned from the pioneer drug. For instance, a transdermal may only need animal and human sensitivity and irritation studies, as well as pharmacokinetics studies, for approval. Considering that the pioneer drug already has a known safety and efficacy profile, risks are vastly reduced in 505(b)(2) development compared to new drug development where only 1 in 10,000 new discoveries are approved.”

Contract Development & Manufacturing
Andy Rensink, president and chief operating officer of Tapemark, told Contract Pharma that upon its 60th anniversary, Tapemark recently invested heavily in expanding both its capabilities and its physical facilities in the realm of transdermals. Receiving batches of approved drugs from other companies, Tapemark gets the pharmaceuticals into the forms a patient can use. Long practiced in the creation of medical devices and reservoir transdermals such as Travanti Medical iontophoretic patches and reservoir transdermals, Tapemark has responded to client demands for matrix patches as well, where the drug formula is compounded with the adhesive.

“Responding to customer demand for full vertical integration, we’re adding formulation, blending, and coating to our existing superior converting and packaging capabilities. Now we’re a soup-to-nuts provider in the transdermal space,” said Mr. Rensink. Producing oral dissolvable films for transmucosal drug delivery is also part of Tapemark’s new armory. “With our new investment we will be able to be fully integrated into that new technology as well.”

Mr. Rensink foresees great things for smart patches, and Tapemark’s leveraging of its engineering expertise in this area. “It’s going to become a really interesting area. Because electronics have become so capable, you can not only deliver drugs but collect drugs and do analytical work [through the patches]. Patches could regulate the delivery of drugs and have different delivery cycles.”

Tapemark also prides itself on its global reach, being certified in the EU and Asia, as well as North America.

Secondary Packaging and Shipping
Of course, no transdermal device, however wonderful, is of any real use until it reaches the patients, and Aesica is a firm that ensures such deliveries. Franz-Josef Kohlenberg, Operations Director, Monheim at Aesica, and Christian Gross, head of Packaging Technology and Artwork Services at Aesica, were kind enough to outline their work to us. 

Mr. Kohlenberg revealed, “In Monheim we have a packaging facility with 10 different packaging lines that turn out approximately 30 million boxes per year. One of our main competencies is the packaging of patches into pouches. In 2013, we will extend our capabilities to more than 150 million pouches per year. We have a high flexibility in our capacity, and huge experience in patch-packaging technology.”

Mr. Gross emphasized the role that strong project management plays: “We can launch customers and monitor their status with our project management tool, Aspire. Our technology for secondary packaging is quite sophisticated. We do a 100% barcode inspection [of the patches] for assurance of identity, and up to 800 pouches per minute are packed.”

Designing specialty boxes, such as easy-to-open ones containing Parkinson’s drugs, are no problem. And from dealing with over seventy global markets, Aesica has developed fluid interfaces with regulatory processes everywhere.

If the experts we spoke to agreed on just one thing, it was the relevance of transdermal and transmucosal technology for the manufacturers of generic drugs. Tom Martin of 3M says, “The generics market is ripe for passive transdermal technology as large and small companies search for ways to differentiate themselves from competitors. An enhanced delivery system can positively influence the life-cycle management of a drug — especially if it appeals to patients and caregivers.”

Andy Rensink of Tapemark agreed, saying, “There’s a large scramble for a number of companies to come out with generic versions of those [formerly patented] transdermals.”

Franz-Josef Kohlenberg at Aesica observed, “I am sure that patches are a target of generic companies. There will be a lot of generic competition in the next year. The market for patch therapeutics is big and increasing.”

Paul Lehman at PRACS noted one major attraction of transdermals and transmucosals: “The elderly and children may have difficulty in taking tablets, and keeping track of taking tablets. To be able to apply a patch to a child or elderly person is a much easier dosing mechanism. And if adverse effects appear, you can quickly discontinue the dose by removing the patch.”

But perhaps Tom Martin of 3M summed up the potential of these types of drug delivery systems best when he said, “With the industry currently facing a patent cliff approaching $100 billion over the next few years, there will be a continued need to innovate to offer a real alternative to injections, and we believe transdermal patches and microneedle technologies will play a major role. The patient-friendly nature of transdermal and microneedle technologies makes them a very attractive alternative to injections, and as the technology matures we expect enthusiastic adoption of these products.” 

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Reference

1. http://www.pmlive.com/pharma_news/mucosal_drug_delivery_beyond_buccal_382500

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Paul Di Filippo is a contributor to Contract Pharma. He can be reached at pgdf@cox.net.