With a groundswell of innovation under way in noninvasive drug-delivery solutions, a new era in patient convenience and improved therapy seems to beckon. For instance, companies developing new technologies and drug formulations for needleless dosing gained a burst of momentum in January when FDA approved Exubera for pulmonary delivery of insulin.
New therapies that deliver drugs via the lungs, nose, and mouth, and through the skin, for an array of local and systemic drugs promise increased patient use and compliance. Systems may provide faster drug delivery by targeting oral and nasal tissues and the alveoli of the deep lung.
Pfizer said that Exubera, codeveloped with Sanofi-Aventis and Nektar Technologies (San Carlos, CA), will be available to diabetes patients this summer. Pfizer has acquired from Sanofi-Aventis the worldwide Exubera rights and Aventis’s insulin production facilities in Frankfurt, Germany, for $1.3 billion.
The Tech Group (Scottsdale, AZ) injection molds and assembles the Exubera delivery device. Bespak (Milton Keynes, United Kingdom) is a second supplier of the molded components.
“We are building inventory at the moment. Nektar developed the device and the technology for powderizing insulin. Pfizer’s Terre Haute, IN, facility blister packs the drug and kits the product for distribution,” says Mike Treadaway, general manager, drug-delivery device division, The Tech Group.
The Tech Group, a division of West Pharmaceutical Services Inc. (Lionsville, PA), is a custom injection molder offering contract manufacturing to the consumer and healthcare markets. The company has recently focused on the drug-delivery segment. “We want to take advantage of the growth in drug delivery. Many of the major OEMs are looking to subcontract manufacturing. As pharmaceutical companies look for innovative ways to deliver their drugs, we are seeing intranasal delivery and transdermal systems expand quite rapidly. Our injectables business is growing significantly, with the alarming growth rate of diabetes. As more [patients] address symptoms earlier and maintain compliance with more-convenient devices, the overall insulin device market will expand,” Treadaway says.
ImageTherm (Sudbury, MA) has worked with companies testing oral sprays and nasal devices for locally acting and systemic drug dosing. “There is new interest in developing systemic nasal drug-delivery products, particularly for treating brain-related conditions and pain management. Biopharmaceutical companies are exploring nasal delivery for large peptide molecules for a variety of indications. Additionally, companies have contacted us for testing nasal delivery of drugs, such as narcotics, for controlled pain management for patients suffering from migraines and other debilitating ailments. In those cases, we work with partner companies that have facilities for handling these controlled substances,” says Dino Farina, president.
In some cases, innovator companies are vying to enter the market with new drug-delivery systems and drug formulations. For large pharmaceutical firms, patient convenience and improved drug therapy are not the only issues. New devices provide a route for extending the life of top-selling drugs.
“Locally acting nasal sprays have been shown to be very effective for treating seasonal rhinitis, hay fever, and allergies. Given this success, drug companies are investigating the feasibility of reformulating existing drugs for nasal spray delivery, partnering with smaller biopharmaceutical companies to assist in bringing new drugs to the market,” Farina says.
Schering-Plough Corp. has forged an agreement with Kurve Technology Inc. (Bothell, WA), the companies announced. And Kurve has partnered with DARA BioSciences Inc., a company that focuses on treating metabolic diseases and central nervous system disorders.
Kurve’s controlled particle dispersion (CPD) technology delivers drugs via the nose. CPD creates a controlled vortical, or turbulent airflow, to propel the drug into the nasal cavity. Tailoring vortex characteristics depending on the therapy, its pocket-sized ViaNase device saturates the whole nasal cavity or targets beyond the nasal vestibule to the paranasal sinuses and olfactory region.
“A turbulent airflow is crucial for crossing the natural airstream in the nasal cavity that tends to funnel everything to the lungs,” says Kurve chairman and CEO Marc Giroux.
Vortices are created using the air generated by the patient and through diverting the system’s compressed air. This is done by “running a line of air to the dispenser in the chamber to put the action on the droplets just as they exit the device,” Giroux says.
Comar is converting its Oral Dispenser and dosage cup line to a new material that supports gamma sterilization.
Topical, systemic, and nose-to-brain drugs are delivered using unit-dose ampules of liquid, suspension, or powder. ViaNase adjusts droplet sizes in increments of 1 µm in a range of sizes from 3 to 50 µm. Gentle handling of large molecules during atomization prevents their degradation. “Instead of running the liquid against a barrier, we run it against air, sort out the large particles postatomization, and reintroduce them, so only the correct droplet sizes pass through,” he says.
NovaDel Pharma Inc. (Flemington, NJ) hopes to launch its first product shortly, an oral spray nitroglycerin called NitroMist, which Par Pharmaceuticals will sell. First Horizon Pharmaceutical Corp. was first to market with a nitroglycerin oral spray for angina treatment with its Nitrolingual pump spray.
“We received an approvable letter for NitroMist last year from FDA in which [the agency] requested to see release data from our process validation batches. We believe a full approval letter is possible within the next two months,” says Barry Cohen, vice president of business and new product development. NovaDel converts currently marketed drugs into its proprietary oral transmucosal spray formulation. Since it is offering a new form of delivery for an existing drug, the new drug application (NDA) 505 (b)(2) drug approval pathway can be used. Using the 505 (b)(2) route, companies can leverage existing clinical studies, and thereby avoid the extensive research required of a new chemical entity.
“This is not a generic version of the drug we are replicating, because we are changing the route of administration and enhancing the performance of the drug versus the tablet,” says Cohen. The company is also developing an oral spray alternative to GlaxoSmithKline’s migraine medication Imitrex (sumatriptan succinate). GSK provides an Imitrex nasal spray.
With Zensana, NovaDel, along with its U.S. partner Hana Biosciences, is targeting a bigger prize. Zensana is an oral spray version of GSK’s nausea medication Zofran (ondansetron hydrochloride). With worldwide sales of $1.3 billion, Zofran loses patent protection on its active ingredient in December. “If approved, we will have the only spray version of this drug,” says Cohen, noting that a spray promises treatment benefits because patients suffering from nausea and vomiting have difficulty swallowing and holding down pills. In pilot pharmacokinetic studies, Zensana achieved detectable blood levels faster than the Zofran tablet. Targeting a 2007 commercial launch, Hana Biosciences will submit a 505 (b)(2) NDA this year, Cohen says.
Approved by FDA and the European Commission for treating type 1 and type 2 diabetes in adults, Exubera will create a new market in pulmonary insulin delivery that some analysts say could reach blockbuster proportions. Companies lining up to offer alternative lung-delivered insulin systems are watching closely to see how Exubera will be accepted by doctors and patients.
LUNG DELIVERY OF INSULIN
“All of the pharmaceutical companies that are big players in the diabetes market have products in the pipeline. The key issue to acceptance will be patients’ perspectives on the products, and how the market will meet these needs. There is a lot of good news so far, but these products won’t be considered successful until people start using them on a daily basis,” says Steven White, senior director, product development, Epic Therapeutics (Norwood, MA), a subsidiary of Baxter Healthcare Corp.
One pressing question is the cost-versus-benefit ratio to patients and the healthcare system of lung-delivered insulin. White notes that noninvasive delivery technologies must feature sufficient molecule bioavailability to be affordable. Pfizer reported to the FDA advisory committee that Exubera’s bioavailability—the amount and duration of drug in the bloodstream—is about 10% that of regular injected insulin. With 10% bioavailability, a patient would have to deliver 10 times more insulin to get the same effect, probably resulting in a higher cost per dose.
“This becomes a cost-benefit issue. We are waiting anxiously to hear what the Exubera economics are and how successful it will be,” White says.
In reporting on lung-delivery insulin systems in the pipeline, many companies are emphasizing the bioavailability of their formulations and products.
BioSante Pharmaceuticals Inc. (Lincolnshire, IL) says its inhaled insulin product—based on calcium phosphate nanoparticles—provides 60% absolute bioavailability, or equivalent bioavailability compared with insulin injection.
Emisphere Technologies Inc. (Tarrytown, NY) is developing its eligen technology for oral delivery of proteins, peptides, macromolecules, and charged organics. Preclinical data have “demonstrated that the bioavailability of insulin via pulmonary delivery with an eligen carrier was approximately twofold higher than pulmonary dosing of insulin alone and had a bioavailability of greater than 70% when compared with subcutaneous dosing,” the company reports.
Recently, Exubera’s cost versus that of injected insulin, as well as its relative efficacy, were challenged by the National Institute for Health and Clinical Excellence (NICE), the drug assessment body for the national health service in England and Wales.
In issuing preliminary guidance, NICE said that Exubera “cannot be recommended” for diabetes treatment, as it cannot be proven as more clinically effective and more cost-effective than existing treatments. In response, Pfizer said NICE’s decision “appears perverse and shortsighted” and dismisses “robust scientific and medical evidence” used in granting approval in the United States and Europe.
“The choice here is quite simple: force patients to keep enduring the burden of multiple daily injections and poor compliance, as they have since the 1920s, or give them an alternative. In clinical trials, three times as many patients chose to start on insulin therapy when the inhaled option was made available,” Pfizer said.
Novo Nordisk is pursing additional clinical Phase III trials of Aradigm Corp.’s AERx inhaled insulin system, funding AERx’s development and commercialization. Eli Lilly & Co. (Indianapolis), in a partnership with Alkermes Inc. (Cambridge, MA), is developing and selling Alkermes’ AIR pulmonary delivery insulin system. Phase III studies began in 2005. The companies are also studying inhaled formulations of parathyroid and human growth hormones. And MannKind (Valencia, CA) is in Phase III trials of its Technosphere dry powder formulation.
Epic Therapeutics has generated Phase I data in feasibility studies of its ProMaxx microsphere technology for the pulmonary delivery of powdered proteins. “There will be a second generation of these products, and we expect that Epic’s ProMaxx technology is going to be a part of that,” says White.
“We have found that by controlling the process of protein precipitation from a polymer solution, we can make microspheres of a precise size and small enough for deep lung delivery, down to 1 µm,” White says.
ProMaxx technology offers several potential advantages over other inhaled insulin systems, he says. Insulin is delivered in a particle without excipients, “essentially as a pure protein.” And the formulation can be used with simpler devices such as those used for inhaled asthma drugs.
TARGETING THE MOUTH
The rapid drug onset provided by these pulmonary systems is an advantage for many diabetic patients who need to control blood sugar spikes during and after meals.
With its Oral-lyn/RapidMist aerosolized liquid-insulin-delivery product, Generex Biotechnology Corp. (Toronto) provides fast drug delivery by targeting the tissues of the mouth.
Insulin molecules in the Oral-lyn formulation are incorporated into bubbles that protect the protein from being destroyed before it can reach the blood system, says Anna Gluskin, Generex’s president and CEO.
“There are 142 blood vessels in the mucosa of the mouth that provide tremendous availability of vascularity, so the drug gets into the bloodstream very quickly. When you are injecting insulin, it can stay in the muscle for a half hour to 40 minutes,” Gluskin says.
Generex is forging ahead with development after the dissolution in 2003 of a development and license agreement with Eli Lilly. The company gained approval last year to sell the product in Ecuador, where Generex partner PharmaBrand will make and distribute the devices. It’s planning large-scale clinical trials in the United States, Canada, and Europe.
The RapidMist metered-dose valve system allows doses to be divided for convenient use. “You can’t ask patients to inject twice before and after meals, yet there is always a pocket of glucose left after a meal. We are addressing an unmet need—the risk of postprandial hyperglycemia. The insulin can be administered in small increments throughout the day, so it is always available to the patient, which is the way it works in a healthy individual.”
ON THE MARKET
Precise dosing, safety, and convenience are being addressed by other forms of drug delivery that are available for marketplace use today.
Cardinal Health (Dublin, OH, and Somerset, NJ) says it has commercialized its proprietary DelStrip unit-dose delivery system. The thin-film-strip technology for packaging oral medicine is senior friendly, and Cardinal Health says it is the first child-resistant oral thin-film strip on the market.
Used for drug delivery in infant care, the Oral Dispenser two-piece liquid-dispensing syringe by Comar Inc. (Buena, NJ) has found new uses in topical delivery. “We have realigned the syringe and dosage cup lines to address the broader application market of ‘liquid dispensing,’” says Dennis Paris, director of marketing.
Target pharmacies have recently adopted the syringe system. A single-piece plunger design features a lubricant engineered into the cylinder that blooms to the surface after each washing. A flexible wiper blade expands proportionally with the pressure applied to maintain a perfect seal. Used with Comar molded bottles, a press-in bottle adapter facilitates fluid control. Comar is converting its two-piece Oral Dispenser product line to a new resin material that supports gamma sterilization while maintaining its seal integrity, Paris says.
Ampac Flexibles–Converted Products, a unit of Ampac Packaging LLC (Carey, IL), developed the Flexi 6833 flexible pouch for use with a handheld pulmonary delivery system. Advanced Scientifics (Millersburg, PA) manufactures the plastic fitment or spout and then attaches it to the small drug-delivery pouch that inserts into the reusable drug-delivery device, says Doug Andersen, account manager, Ampac Flexibles.
In a typical size of 1.5 × 1.5 in., the lightweight pouch avoids the headspace gases inherent with glass containers and the production cost of aerosols. Full collapsibility supports full evacuation and prevents air reentry.