Medical Device Link.

Originally Published PMPN May 2004

Drug Delivery

Kassandra Kania

Accuspray from BD Medical–Pharmaceutical Systems is a single-use nasal sprayer for monodose or bidose administration

Nasal drug delivery is a popular way to treat respiratory ailments and administer OTC drugs for sinus conditions, such as congestion and allergies. But companies are also beginning to explore the benefits of nasal delivery as an alternative to oral or injectable methods of delivering systemic drugs for a variety of diseases. Prescription drugs for pain management, migraine headaches, and osteoporosis, to name a few, have benefited from this alternate route of administration. And companies are working on technologies and delivery devices that will overcome some of the challenges of delivering prescription drugs nasally, such as delivering the correct dosage, as well as ensuring that enough of the drug is absorbed by the nasal mucosa. The benefits of this delivery method include faster onset of action, im-proved compliance, and avoidance of any degradation and/or unwanted metabolism of the drug, which can change the drug’s molecular structure. 

Through the Nose

Nasal sprays, squeeze bottles, and liquid droppers are some of the more common delivery methods that consumers are likely to see both on drugstore shelves and in prescription medications for colds and allergies. Dey L.P. (Napa, CA), a company focused on products for the treatment of respiratory diseases and allergies, offers a prescription multidose nasal spray to treat allergic rhinitis. Dey also markets a variety of prescription respiratory medications that are administered through nebulization, a delivery method that allows patients to breathe in their medicine as a fine mist through a face mask or a mouth inhaler. This method of administration can be particularly helpful for young children and some elderly patients who find it challenging to coordinate their intake of a drug with the actuation of the dry powder or metered dose inhaler, says Ray Joske, senior vice president for marketing and business development. Dey offers proprietary drugs to treat emphysema (DuoNeb) and pediatric asthma (AccuNeb) through nebulization as well as a line of respiratory generic products that are also administered through nebulization. This mode of drug delivery can serve as an alternative for patients who are unable to manage inhalers, as it allows them to breathe the product in naturally through their nose or mouth. “Even for patients who use inhalers correctly, they receive a very fast, sharp intake of the active. That harshness can be difficult for some patients who may be physically compromised,” explains Joske.

For patients who don’t like the idea of spraying something into their nose or for whom nebulization therapy is unavailable to treat their condition, a premedicated unit-dose swab can serve as a welcome alternative. Some companies are exploring the use of single-dose applicators, such as those developed by Innovative Swab Technologies (Antioch, IL), to coat the nostrils with a liquid or gel. “We’ve had a good response for cold remedy–type applications,” says Bill Casey, president of Innovative Swab Technologies. While the swabs are currently being used to treat common colds, they could also be an option for other chemistries that are absorbed through the nasal passages, says Casey. 

Beyond the Nose
Dino Farina, president of Image-Therm (Sudbury, MA), says that companies are starting to expand their horizons and look at nasal drug delivery for a variety of prescription medications. “The primary motivation for nasal delivery is that, typically, you can deliver a much lower actual dose of a drug because, compared to oral dosing, the first pass metabolism in the liver is avoided,” he explains. The rapid onset of action and the noninvasive nature of this delivery method are also advantageous. Diabetes patients, for example, could benefit from delivering insulin to the upper airways, allowing them to do away with needle injections. 

Alex Theodorakis, vice president of sales and marketing for Valois (France), says that 15 to 20 years ago, there was significant interest in delivering insulin via the nose, before companies started looking at delivery via the lungs. “Development slowed down because you have to use enhancers to allow the drug to penetrate the nose,” he says. “[Nasal delivery] was effective at getting the insulin in, but the enhancers were very irritating to the nose.” The pulmonary route is being examined more closely, he says; however, that too has its challenges. “The lung is a very sensitive organ. Even though you aren’t using additives or enhancers, you’re still blowing significant amounts of powder into the lungs on a regular basis. People are concerned about the long-term effects of doing this.” The development of nasal insulin has picked up again, says Theodorakis, thanks in part to the development of enhancers that are better tolerated and safer.

Vaccines are also a growing area of interest for nasal drug delivery. BioSante Pharmaceuticals (Lincolnshire, IL) was recently awarded a subcontract with DynPort Vaccine Co. to develop anthrax vaccines using nanotechnology-based alternative delivery systems, including nasal delivery systems. Steve Bell, vice president of R&D for BioSante, says that the company has a number of contracts with the U.S. Department of Defense and the National Institutes of Health. “They are particularly interested in mass immunizations and easy delivery and storage of formulations,” he says. “When you have masses of fighting forces, ease of administration is important.” 

West Pharmaceutical Services’ chitosan-based technology, ChiSys, increases the residence time of drugs on mucosal surfaces and may improve bioavailability.

FluMist, developed by MedImmune Inc. and Wyeth, is another example of a successful nasal vaccine. The vaccine is administered with the BD Accuspray nasal spray system from BD Medical–Pharmaceutical Systems (Franklin Lakes, NJ). According to Glenn Thorpe, director, marketing and business development, the company conducted extensive market research in the product development stage to find out what was important to end-users. “Accuspray is a single-use nasal spray for monodose or bidose administration,” he explains. “Unit dose is important because it discourages the possibility of misuse, and there is no need to use a preservative. The system is also easy to handle, and there is no contact between the administrator’s hands and the patient’s nostrils.” It was also important for the product to be visible so that it could be inspected prior to use. 

“Since the launch of FluMist, we’ve done some follow-up research with nurses who have used the product, and 93% said Accuspray was convenient to use,” says Thorpe. The study also showed that among those who received FluMist, half received an influenza vaccine for the first time. “For some people with needle phobia, nasal delivery has the ability to grow a market,” says Thorpe. The biggest advantage of Accuspray, he adds, is that it’s fully compatible with BD Hypak filling lines, making the processing simple and cost-effective.

Getting it Right

The use of nasal drug-delivery options for systemic drugs introduces certain challenges. “For proper ab-sorption, you need to have a particular droplet size or particle size distribution associated with the spray,” says ImageTherm’s Farina. The magic number is between 20 and 50 µm in diameter, he says. “Anything smaller goes right through the nose into the trachea area and you inhale it. You want the spray to be deposited into the nasal cavity. If the droplet size is greater than 50 µm, the spray contents tend to flow out of the nasal cavity and may be swallowed.”

Actuation of the device becomes an important factor in determining the spray formation. “If you take a traditional nasal spray and have adolescents actuate it, they have hand ergonomics different from someone who is much older,” explains Farina. ImageTherm offers testing equipment that simulates the actuation of the spray and measures it. “One of the company’s customers chose to enhance its propriety position in the respiratory products marketplace by requesting approval of a new drug application (NDA),” says Dr. Frank Bales, senior regulatory consultant for worldwide regulatory affairs at Parexel International (Waltham, MA). The drug was for the treatment of nasal symptoms of seasonal and perennial allergic rhinitis in adults and children 12 years of age or older. “FDA reviewers of the NDA pointed out that the particle size distribution appeared to indicate the presence of two different compositions or viscosities of the liquid because the particle size distribution of the spray seemed to show the presence of two different distributions and two different average particle sizes,” says Bales. FDA reviewers suggested that this might be traced to inadequate mixing during the bulk liquid manufacturing process. “ImageTherm equipment enabled us to see (literally) that misfiring of the pump, due to improper actuation when using a pneumatic actuator, caused this. When actuated correctly, a single particle size distribution and average size was obtained. It was submitted and accepted, thus avoiding a fruitless investigation of the bulk liquid manufacturing practices.”

The development of the formulation itself can also be challenging, says Farina. “If you were to look at a regular nasal spray, the bulk of the fluid is a carrier. The drug constitutes a small percentage of the total fluid. The challenge is finding a formulation that won’t bother the patient and will be well absorbed by the nose, but still be effectively pumped by a regular mechanical pump.” 

Companies are meeting this challenge with additives that help the drug adhere to the nasal mucosa. West Pharmaceutical Services’ ChiSys formulation technology—based on chitosan, a naturally occurring substance derived from crustacean shells—enhances formulations for nasal delivery and acts as a bioadhesive to help drugs adhere to the linings of the nasal mucosa. “With conventional sprays, you get very little of the drug into the systemic circulation,” says Bruce Morra, PhD, president of West Pharmaceutical Services’ drug delivery division (Lionville, PA). “Our ChiSys formulation enables us to get enough of the drug into the body through the nasal route.” The company is developing drugs for pain relief, including a fentanyl product, and nasally delivered vaccines. It is also preparing for Phase II clinical trials for its ChiSys-Leuprolide product, which will provide a nasal-delivery alternative to subcutaneous injection and implant methods for leuprolide to treat endometriosis and other gynecological disorders.

New Devices

While nasal delivery devices have—for the most part—remained unchanged, companies are realizing the need for more-sophisticated devices and technologies to meet the challenges of systemic delivery—such as accessing the blood-brain barrier to target delivery to the brain. “Traditional nasal spray bottles generally deliver only to the first third of your nasal mucosa,” says Marc Giroux, CEO of Kurve Technology Inc. (Bothell, WA). Kurve’s controlled particle dispersion technology applies formulations to the entire nasal mucosa and delivers drugs into the paranasal sinuses. The technology has the potential to offer deeper penetration of topical drugs and greater drug absorption of systemic drugs. The ViaNase is a cartridge system that uses unit-dose ampules. It works with multiple drugs, and reusable cartridges are custom-designed for different drug formulations.

There is also talk about a new generation of pumps that allow for preservative free formulations. “There’s some fear that if the preservatives are used every day, they will damage the nose and mucosa,” says Valois’ Theodorakis. “Preservative-free systems either filter the air going back into the bottle or prevent air from going into it.” This could present some challenges in the design and manufacture of these devices. 

Mike Sheckler, director of business development for Intra Nasal Technology (Lexington, KY), agrees that preservative-free pumps are an important step forward. However, for some acute and chronic situations, he believes that single and bidose pumps are preferable because they reduce the risk of introducing contaminants.

Some companies are also looking at new designs to ease administration, such as devices that dispense the drug using a side actuator. “Part of the reason for having the actuation on the side of the device is for the aging population,” says Sheckler. “It may be easier for them to grasp the side and push in rather than up.” He sees the aging population as one of the drivers for considering alternative routes of administration, such as nasal. “Companies are looking for ways to deliver a drug that are less invasive but will still deliver it in a timely manner and will not be affected by metabolism like oral drugs are. This drives the interest in making nasal delivery devices better.”

With the development of new technologies and devices, companies are looking more closely at reformulation of drugs for nasal delivery. “The pipeline for nasal drug delivery is fairly full,” notes Sheckler, particularly in the areas of pain management and vaccines. “Companies are being innovative about the formulations they have and the devices themselves to meet the requirements of cost and patient compliance,” adds Farina. Improvements in these areas will establish nasal delivery as a viable alternative to injectable and oral delivery methods in the future. 

Copyright ©2004 Pharmaceutical & Medical Packaging News