New technologies and markets abound
The human body can be its own worst enemy. Not only does its operating system frequently go on the fritz, with deadly results, but the human organism also maintains stout defenses against any attempts to introduce agents from outside itself that might alleviate the crisis situation. The epidermis, the mucosal membranes and the gastric system are mighty barriers against Active Pharmaceutical Ingredients (APIs).
But those three somatic avenues can also be co-opted for the patient’s own good, enlisted in the desirable and programmatic uptake of meds, either as immediate doses or controlled-release loads. Since the dawn of medicine, APIs have been administered through the skin (topically or via mechanical penetration), orally, and through inhalation. Science and technology continue to refine and improve on these three methods of getting desired compounds into the human body — sometimes even by dramatically changing the properties of the actives themselves — as we shall see in our survey below.
“Smart inhalers” sounds like a bit of an oxymoron. What could be simpler or “dumber” than a device that delivers an aerosol blast upon the push of a button? And yet as with so many formerly non-cybernetic appliances, vehicles and gadgets, inhalers stand to benefit from an upgrade in intelligence via embedded chips.
Clement Kleinstreuer and Stefan Seelecke, experts in biomechanics and fluid dynamics employed at North Carolina State University, Raleigh, are busy perfecting an inhaler which responds to an individual’s personal “inhalation waveform” in such a manner that precise dosages are delivered to targeted areas of the lung. Their invention has not yet emerged from the lab, but shows promise.
Certain patents seem to indicate that Jones Medical Instruments, a leader in spirometry equipment, is planning to incorporate spirometric feedback and reportage directly into an inhaler, allowing its device to modulate dosage delivery.
SiliconSky GPS has demonstrated a prototype of its GPS-enabled inhaler, a device intended to accumulate valuable data on environmental factors relating to asthma incidence — data that will aid in determining individual treatment. Similarly, Cambridge Consultants has equipped a prototype inhaler with its Vena wireless technology, allowing for collection and transmission of important usage stats.
A device currently on the market, now functioning almost as a toy, yet holding the potential for serious results, is Le Whif, the brainchild of Harvard’s David Edwards. This lipstick-sized inhaler device currently offers mere taste sensations such as chocolate, but is going to be repurposed by Prof. Edwards and his Medicine in Need foundation to deliver TB vaccine in Third World settings.
But other innovations along these lines are available without waiting.
In December 2009, Boehringer Ingleheim Pharmaceuticals received expanded FDA approval for its Spiriva HandiHaler, a sleek, futuristic looking device that delivers its powdered API in the treatment of COPD.
Also receiving approval that month for use in the U.S., after previous distribution in New Zealand, land of its birth, was the Nexus6 Smartinhaler, from Nexus6, Ltd. The device records usage in its onboard chip, and the data can then be uploaded to generate useful reports to tailor subsequent treatments.
The simple inhaler, equipped with chip-based brains, stands ready to deliver APIs with increased efficiency and cleverness, while accumulating valuable research data all the while.
Topical and Implant Applications
Sometimes rethinking or reformulating existing compounds can constitute a major advance. Such is the case with Quinnova’s Proderm Technology. By eliminating alcohol from its transdermal creams and foams, and replacing that ingredient with a patented mix of lipids and water, Quinnova has succeeded in increasing drug absorption and lessening skin irritation. Its latest product, Neosalus Cream, takes advantage of all these properties to treat a variety of chronic inflammatory skin conditions like atopic dermatitis, contact dermatitis, and hand eczema in a novel fashion.
Harnessing together a new API with just the right delivery method often constitutes a breakthrough, and such is the case with the partnership between NuPathe and SurModics, regarding their new treatment for Parkinson’s. Having formulated NP201, a dopamine agonist which can provide one to three months of relief for Parkinson’s sufferers, NuPathe turned to SurModics’s biodegradable polymer matrix implant technology. As Bruce Barclay, president and chief executive officer of SurModics, put it, “The use of SurModics’ biodegradable implant technology is an ideal match in this clinical area, as maintaining desired drug levels are critical for achieving the optimal clinical outcome.”
Additionally, NuPathe is developing Zelrix, “the first and only transdermal treatment for acute migraine.” Delivering the API sumatriptan through its SmartRelief Iontophoretic System, Zelrix offers “fast, consistent, and controlled delivery of migraine medication regardless of nausea, vomiting, or other gastric symptoms associated with migraine.”NuPathe successfully completed a pivotal Phase III clinical trial for Zelrix in July 2009 and expects to submit an NDA to the FDA in 4Q10. Subject to FDA approval, NuPathe plans to build its own specialty sales force in the U.S. to launch Zelrix in the 1H12.
Another firm with vast expertise in the field of drug delivery silicones is NuSil Technology, and Contract Pharma was privileged to speak with the company’s technical sales spokesperson, Nathan Wolfe. He brought us up to speed on NuSil’s philosophy toward rapid custom tailoring of its adhesives, elastomers and tacky gels, both for topical patches and implants.
Said Mr. Wolfe, “In the last few years we’ve really realized that probably our most important asset is our ability to modify our formulations and our ability to assay those formulations to target specified drug elution rates. We’ve seen an explosion in demand. We have the facilities and the expertise with modifying our formulations to meet a client’s basic goals and evaluate the product in-house.”
And although NuSil also splits its talent and Resources among other non-health lines of business such as aerospace and electronics, it remains confident that “we have the capacity and willingness to grow in every direction we choose to, without sacrificing any existing product lines or services,” according to Mr. Wolfe.
A conversation with Martha Sloboda, business manager for ARx, LLC, a subsidiary of Adhesives Research (AR), and Mary Lawson, AR’s Pharmaceutical Business Manager, brought to light several exciting developments. Ms. Lawson highlighted the fact that extended-wear systems are a growth region. “In the past, we might have worked with people on one-day or three-day wears, but now people are looking for seven-day-wear systems. You can imagine that there are additional challenges there. There’s the issue of showers, and systems need to be more breathable.”
Ms. Sloboda emphasized that taking existing systems and making them multifunctional is of growing interest to their clients. There’s a growing demand for patches that detach only upon application of a trigger catalyst, are conducive to iontophoretic processing, or that give feedback about amounts of API released. As with the advanced inhalers cited above, added intelligence makes these devices almost into programmable computers. AR is also managing to incorporate its products into wound treatment therapies.
And like NuSil, Adhesives Research and ARx place a high value on carefully tailoring formulations for different APIs, as well as producing both small and large batches at will and in multiple formats. “We have the ability to use the same types of processing techniques to create distinctly different dosage formats,” said Ms. Sloboda.
Another novel drug-device combo, explained Diane Burgess of the Controlled Release Society (whose other work is explicated below), involves drug-eluting stents and scaffolding that are seeded with anti-fibrosis or antibiotic agents.
Convincing the gastric and intestinal systems to perform as desired is a tricky business. Once swallowed, APIs are at the mercy of a host of biological forces. Ms. Sloboda of ARx informed us, “New technology is being embedded in capsules whereby they can be retained in different parts of the body for more efficacious treatment and potentially lower dose-loading.”
Certainly the firm of Encap, even after 20 years of pill formulation, has managed to add a new twist to oral meds, specifically in the delivery of drugs associated with such colon-centric ailments as Crohn's disease, ulcerative colitis, colorectal cancer and irritable bowel syndrome. (The new technology can also facilitate oral delivery of peptides, proteins, oligonucleotides and vaccines.) Known as ENCODE, Encap’s invention incorporates the Phloral system devised by the School of Pharmacy in London.
ENCODE will bring various types of API past the acids and enzymes of the stomach and safely to the target area, where release will be triggered by sensitivity to specific pH levels, and a breakdown reaction linked to the unique microbiota in the colonic region.
NuSil’s Simethecone, on the market since 2004, continues to be employed in novel ways, said Mr. Wolfe, who added, “Many people are using our Simethecone products for defoaming or degassing.” But producing products for human ingestion and consequent FDA approval required upgrading NuSil’s manufacturing facilities to strict clean-room status, a not-inconsiderable investment.
Peter Ciano, vice president for Corporate Development at Tris Pharma, shared information with us on his company’s unique OralXR+ technology, which allows for sustained release of APIs across a number of formats: liquid, tablets (chewable or otherwise), capsules and filmstrips.
Older, organic solvent- (i.e., acetone, methylene chloride, etc.) based methods of sequestering APIs into time-release form suffered from several drawbacks. The manufacturing process produced environmentally hazardous wastes, the resulting product retained some negative physiological consequences, and the coating was not particularly robust, resulting in large variations of potency across batches and over shelf life.
After several years of R&D, Tris managed to come up with an extremely durable water-based coating that solved all these problems. The encapsulated particles are able to withstand mechanical crushing and even alcohol-degradation. Said Mr. Ciano, “We have created a particulate-based technology that delivers drugs over time — suspended in liquid, tablets, filmstrips or even chewed. There’s never been a chewable sustained-release! There’s a big benefit there for pediatric or geriatric applications.” One final bonus: the new technology locks opioids into a form that cannot be easily abused.
The first approved product using OralXR+ is Clonidine ER Suspension and once-daily Clonidine ER tablets.
One of the most astonishing new technologies in this realm is that dubbed “microneedles.” Employing highly advanced miniaturization fabrication techniques known as MEMS, the companies that offer microneedles have brought one of the most ancient drug delivery modes into the 21st century. Carving a matrix of incredibly tiny tips into a substrate, MEMS fabrication carries engineering of three-dimensional structures down to new extremes.
NanoPass of Israel is one of the leaders in this area, with its MicronJet product line, and Contract Pharma had the opportunity to speak with Dr. Yotam Levin, the company’s chief executive officer. He informed us that his company had been working in this area since the year 2000, and had created a product with many benefits.
He said, “Because our microneedles are about half a millimeter long, we can inject to the shallow layers of the skin without leakage — something that conventional needles cannot accomplish. Our injection method is simple to implement, unlike the conventional needle approach for injecting into the skin (the so-called Mantoux technique). Unlike Mantoux, our device allows for consistent delivery to the same depth every time, and is not user-dependent. Regular Mantoux is quoted to cause high prevalence of leakage, as well as too-deep delivery into the subcutaneous fat. [And] our clinical trials suggest that the needles are nearly painless and preferred over conventional needles.
“They are designed as regular needles, and are attached to disposable syringes for injection. Unlike patches (including microneedle patches), we are able to deliver relatively large quantities of the drug or vaccine, immediately. There is no passive delivery. Thus, we are not limited by molecular weight or construct of the drug, and are able to deliver proteins, DNA, cells and viscous drugs.”
The utility and allure of NanoPass’s microneedles is confirmed by a partnership with the Infectious Disease Research Institute, which plans to employ MicronJet technology “for the intradermal delivery of products against a number of diseases including tuberculosis, HIV, malaria, leishmaniasis and leprosy, among others.”
Debiotech and their Nanoject system are another player in this area.
Also in the forefront of needle improvements is West Pharmaceuticals Services. Graham Reynolds, vice-president Marketing and Innovation at West, reminds us that his firm has traditionally been renowned for the vital but unglamorous business of “primary drug containers and packaging systems for injectable products: vials, syringes and various other systems.” But during the past three to five years, West has evolved a Delivery Systems division, incorporating various extramural acquisitions, to focus on next-generation delivery devices.
“One of the largest growth areas for delivery systems,” said Mr. Reynolds, “is self-administration, or treatment at home.” Meeting this need is West’s ConfiDose Auto-Injector System. Ideally incorporating the Daikyo Crystal Zenith syringe discussed below, but also quite tolerant of glass syringes, this mechanical injector is remarkable for the safety of its completely hidden needle, both pre- and post-injection.
Such a user-friendly device also lends itself to improving distribution of vaccines in Third World environments, an area of some concern for West.
Taking the glass out of traditional syringes and bulk containers is another innovative avenue West has followed, relying on their Daikyo Crystal Zenith technology. Not only is their revolutionary plastic less subject to breakage, it also eliminates the need for silicone-oil lubrication in the plunger and barrel, a possible source of API contamination and aggregation.
“We want to make needles more user-friendly and safe, to provide protection to healthcare workers and patients at home,” Mr. Reynolds said. NovaGuard, another of West’s solutions to accidental sticks, keeps used needle tips safely shielded after deployment.
But from the perspective of the university laboratory, all the injectable drugs currently on the market are still old-fashioned. Researchers are working on APIs of surpassing smartness, where the drug, once delivered by injection or IV, takes over as practically a delivery device in its own right.
Diane Burgess — who wears three hats, as president of the Controlled Release Society, board of trustees Distinguished Professor at the University of Connecticut, and editor for the International Journal of Pharmaceutics — shared with us some of her insights, as well as reports from her lab at UConn, where atomic-force microscopy and MEMS technology are helping to produce marvels.
Having just attended a conference in India, she observed that both India and China are leapfrogging over old-school manufacturing of drugs into techniques for active gene delivery and siRNA therapy. “SiRNA is a very hot topic, and it’s probably the first place we are going to see some products entering clinical trials,” she commented.
Because naked genes and siRNAs are subject to unwanted degradation inside the body, they need to be protected by carriers, and that’s the topic Prof. Burgess’s lab is addressing.
“The typical carriers are liposomes and cationic polymers, with liposomes being ahead of the game a little. Cationic liposomes interact very nicely with DNA and siRNA, offering easier release once in the cell plasma. [We can also] add targeting ligands onto the surface of the liposome, as well as stealth coatings — a layer of gene-length polymer polyetheylene oxide,” she remarked, citing the work of Vladimir P. Torchilin at Northeastern University as cutting-edge, and prophesizing efficacy of the technique against AIDS and cancer.
The key feature across all these innovations is adding intelligence: inhalers that know their users; implants that release APIs just where and when they are needed; adhesives that recognize action prompts; patches that diagnose; stents and scaffolding that can protect themselves and foster their own mission; needles that penetrate to precise depths; smart APIs that ignore certain somatic sites and zero in on others, or degrade according to a built in timetable.
Humans are transferring some of their fabled intelligence to actives and their delivery methods, eliminating guesswork, brute force, chance and costly monitoring.
Paul Di Filippo is the author of numerous science fiction novels and short fiction collections, and his criticism has appeared in The Washington Post. He can be reached at firstname.lastname@example.org.