Drug Delivery: Packaging Drug Delivery

Drug manufacturers are turning to packaging to provide stable, effective product delivery.

 

by Christina Elston
Contributing Editor

On StarTrek: Enterprise, hyposprays deliver instantaneous relief, without needles. Today’s patients won’t have to wait until the 22nd century for similar technology. High-tech devices currently in development deliver drugs via novel pathways, including the nasal and pulmonary routes, as alternatives to systemic injection. For injectable drugs, pens and autoinjectors ease the process for the needle-phobic self-injector. How will these diverse delivery vehicles be packaged?

PULMONARY ROUTE

In March 2005, Pfizer Inc. (New York City) and the Sanofi-Aventis Group (Paris) announced that FDA had accepted their new drug application for Exubera, a dry-powder form of insulin inhaled into the lungs. Nektar (San Carlos, CA) manufactures the specialized inhalers and the powdered insulin for the Exubera product. Even back in August 2001, CNN.com called Exubera “one of the most-anticipated drugs in development” and reported that “analysts said it could be a blockbuster.”

Excitement about the prospect of a U.S. launch of a commercial pulmonary drug-delivery system was apparent everywhere at the Ninth Annual Drug Delivery Partnerships conference January 24–26, 2005, in San Diego. Representatives of Pfizer and Nektar spoke about their partnership at the event.

John Patton, founder and chief scientific officer of Nektar, spoke about the firm’s technology to PMP News. “Nektar achieves long-term stability of its drug powders partially by using individual blister packaging to provide a strong moisture barrier. Unit-dose packaging also enables very precise dosing and the ability to deliver blister-packed doses of different strengths, important for certain drugs, such as insulin. To automate the filling of the individual blister packs, Nektar developed a proprietary filling machine to accurately fill very small amounts of the fine powder into the small containers.”

“This product is going to validate inhalable insulin for the United States, which is just the Holy Grail,” says Hedden Miller, Health Care Marketing Specialist for Ticona (Florence, KY). Ticona makes FDA-compliant engineering resins that are used for mechanical internal components in dry-powder inhalers and nebulizers. Ticona’s medical technology engineering polymers include seven resin families: Celcon and Hostaform acetal copolymer; Celanex polybutylene terephthalate; Fortron polyphenylene sulfide; GUR ultra-high-molecular-weight polyethylene; Riteflex copolyester thermoplastic elastomer; Topas cyclic olefin copolymer; and Vectra liquid crystal polymer.

“Now what’s going to happen with Pfizer coming out with this inhalable insulin this year is all the people at these competing companies are going to ask, ‘How are we going to get to market faster?’ And it’s also going to put another positive spin on pulmonary drug delivery for all types of medications,” Miller says.

Dry powders for pulmonary delivery present a particular engineering challenge because of the tiny particle size—1 to 4 µm—required for pulmonary delivery, Miller adds. “A particle that size tends to develop a lot of static electricity. This causes the powders to adhere to the walls of the delivery chamber. One of the ways we’re getting around that is by using our antistatic Celcon resins. We’re offering these to people who have seen powder holdup as a problem.”

DEPOT FORMULATIONS

The OptiNose single-dose disposable device delivers a drug to the posterior two-thirds of the nose, speeding the onset of action.

Microparticles formulated of lactide-glycolide polymers and an active drug have been used for decades in depot formulations, but their uses are expanding. Thomas Tice attended the Drug Delivery Partnerships conference to publicize the creation of two new companies, Brookwood Pharmaceuticals (Birmingham, AL) and Lakeshore Biomaterials, to commercialize depot formula- tions and biodegradable polymers. Brookwood is the for-profit spin-off of the not-for-profit Southern Research Institute, where the first commercial injectable microsphere product was developed. Tice is now executive vice president and chief scientific officer of Brookwood. Lakeshore arose when Brookwood acquired the external polymer manufacturing business of Alkermes Inc. (Cincinnati).

These depot microparticles are usually packaged in a vial as a dry powder, Tice says, and mixed with diluent just before administration. Some are supplied in prefilled syringes. Keeping the microparticles dry is paramount. “Water hydrolyzes the polymer, and that will modify the release. It can also, on the microparticle side, cause their polymeric excipient to decrease molecular weight; they start sticking, and they become difficult to inject,” he stresses.

Depot formulations, Tice says, are always packaged in a kit. “There are some very sophisticated packages,” he adds. “For instance, we are going to be putting these microparticles in the brain, or in the eye, so that kit probably can have more value than the small amount of drug delivery formulation that is in there. Packaging is very important.”

Novel drugs often demand moisture barrier. As a result, high-barrier packaging materials such as Aclar are finding their way into new laminates and films for new applications. “Aclar is a polychlorotrifluorethylene film that has been used for decades in pharmaceutical packaging due to its excellent moisture barrier and other critical properties,” said Rick Knight, global business manager for Honeywell Specialty Films. “Honeywell continues to demonstrate innovaton through new offerings from market-leading product lines that target adjacent markets. Our new Aclar Flex film, for example, is designed specifically for medical flexible packaging where transparency, moisture barrier, and flex-crack resistance is key.”

Ticona, too, offers products to meet the need for high barrier. “Vectra is a liquid-crystal polymer that has both water and oxygen barrier properties, so if somebody needs to have a super barrier that's injection molded, we can do it,” Miller asserts.

NASAL ROUTE

Ypsomed AG offers a reusable autoinjector for use with the Ultra Safe Drug Delivery
System.

Blazing a trail on the nasal route is OptiNose, a tiny company started by three people in Oslo, Norway, four years ago. OptiNose has already signed an agreement with German drug-delivery powerhouse Pfeiffer (Radolfzell, Germany) for the commercialization of its lead single-dose disposable device.

The OptiNose device delivers drug to the posterior two-thirds of the nose, where the olfactory bulb region is. In that region, explains Rod Hafner, OptiNose’s director of operations, “a mechanism allows transfer of a drug from the nose into the brain, bypassing the systemic circulation.

“We have the opportunity to improve the speed of onset of action and potentially also lower the dose in the systemic circulation,” he adds. This route offers particular promise for drugs that have undesirable side effects when broadcast throughout the body by traditional methods of administration. One such product the company is fast-tracking is a treatment for migraine headaches.

Hafner attended the Drug Delivery Partnerships conference to scout pharmaceutical manufacturers for whose products the OptiNose device might be suitable. “If you can provide a meaningful clinical benefit, you can justify the pricing. What we can’t afford to do is put generic drugs in and get ‘me too’ performance, because you’d never justify the cost of the device,” he adds.

The primary package for the drug inside this sophisticated device is actually quite familiar: a glass vial with an elastomeric stopper. The breath-actuated device, however, is an elaborate contraption. A priming button compresses a spring, which is held in place by a tether. When the user actuates the device by blowing into it, a membrane flips forward and cuts the tether, releasing the spring. The stored energy in the spring forces the vial stopper onto a needle, which penetrates it to release the drug for delivery. “It’s a bit like a prefilled syringe working in reverse,” Hafner explains.

Packaging the drug inside in a tried-and-true container facilitates stability studies, but the device also requires testing. “It’s true that the device has no direct contact with the drug substance. But we will, of course, need to show that the breath actuation mechanism will still work efficiently over the shelf life of the product,” Hafner says.

The BD Accuspray nasal spray delivery system developed by BD Medical-Pharmaceutical Systems, a unit of Becton, Dickinson, and Co., (BD; Franklin Lakes, NJ), is based on BD Hypak SCF technology. The BD Accuspray has been selected to deliver FluMist since its launch in 2003. To further improve the delivery system, BD will offer a new bidose BD Accuspray holder that allows customization and provides a unique delivery design in an easy-to-fill BD SCF format.

Pens—Mightier Than the Syringe?

The Norditropin NordiFlex is a prefilled, multidose disposable pen for administration of liquid growth hormone.

Injection pens might be considered the pioneer drug-delivery devices for injectables; they have been used for administration of human growth hormone, insulin, and heparin for more than a decade. The latest models, however, are technological marvels.

In January, Novo Nordisk (Copenhagen, Denmark) announced the U.S. launch of Norditropin NordiFlex, a prefilled, multidose disposable pen for administration of liquid growth hormone. The pen is available in two sizes, 5 mg and 15 mg. Electronic dosing mechanisms allow fine and flexible dosing, with a total of 100 dose settings possible between the two pen sizes.

Ypsomed AG (Burgdorf, Switzerland), a leading multinational injection pen manufacturer, announced the availability of a reusable autoinjector for use with the UltraSafe Drug Delivery System developed by Safety Syringes Inc. (Carlsbad, CA). Ian Thompson, Ypsomed’s manager, business development, while attending the Drug Delivery Partnerships conference in January, told PMP News about the collaboration. “To date, you have no autoinjector, reusable or single-use, that has needle safety on the market. We had a reusable autoinjector platform, and we fast-tracked development to cover the Safety Syringes system. Because the market for autoinjectors is really self-injection, it just made sense, rather than to develop a reusable autoinjector for a bare syringe, which is intrinsically not safe after the injection has been given. In terms of the complete package, we are offering added value for particular therapies, especially in the areas where patients have not self-injected but in the future they will, such as cancer therapy. For the home-care market, the autoinjector is an ideal add-on,” Thompson says.

Jeffrey Turns, of Vetter Pharma-Turm Inc. (Yardley, PA), explains the appeal of the multidose pen. “The user can carry around the pen and one cartridge for a whole week. The drug manufacturer may be able to have 8 or 9 days of therapy in one cartridge. There’s a cost savings and a drug savings and a convenience factor. By using a multidose pen with a dual-chamber cartridge, the convenience is even given for products that are stable only in the lyophilized state,” he says. Vetter Pharma-Turm, a subsidiary of Vetter Pharma-Fertigung GmbH & Co. KG (Ravensburg, Germany), is a major international contract packager of injectable drugs in prefilled syringes and cartridges.

Injector pens and their components illustrate the labyrinthine packaging paths often required for novel drug delivery devices. Vetter does not make cartridges; it fills cartridges made to its specifications. On the other hand, Baxter Pharmaceutical Solutions (Bloomington, IL), a major contract packager, has recently begun to manufacture and fill cartridges but does not make the pens, according to Michael Akers, director, pharmaceutical research and development. “Our cartridge filling equipment is from Bausch + Stroebel,” says Akers. “We can fill 1.5-, 2.7-, and 3.0-ml cartridge sizes. The standard filling speed is up to 300 cartridges per minute. We also have the capability of assembling the cartridge with the pen, meaning that we can do all the secondary packaging as long as the pen delivery device is provided by the client.”

BD Medical-Pharmaceutical Systems has developed a range of injector pens and pen needles. Users must replace the pen needle after each use.

Glenn Thorpe, director, marketing and business development, at BD Medical-Pharmaceutical Systems explains that BD pens are custom designed to fit the unique needs of the drug and particular patient population. BD can deliver pens in disposable or reusable formats; the company does not make cartridges. The disposable format allows the patient to dispose of the pen once the medication has been dispensed, whereas reusable format allows the patient to keep the pen and just insert a new cartridge. Disposable pens are assembled with a drug-filled cartridge inside. Reusable pens, on the other hand, are supplied without drug, and the cartridges are dispensed via a pharmacy. Some drug manufacturers, Thorpe adds, rely on pharmacies to distribute the pen needles as well; others supply pen needles with the pens.

BD can develop systems that deliver the same exact dose volume each time (fixed dose) or that can be tailored to the unique volume needs of each patient (variable dose). For example, BD developed a variable-dose pen for Organon’s Puregon/ Follistim pen. The dose volume is different from patient to patient and potentially from week to week, and the BD variable-dose pen allows patients to easily change the dosage according to their doctor’s instructions without changing pens.

New frontiers for drug delivery

Every orifice of the body, and the skin as well, may be a novel drug-delivery route to a pharmaceutical scientist with imagination. Transmucosal delivery, intraocular delivery, and nanotechnology are just a few of the many other ideas floated at the Drug Delivery Partnerships conference. As each moves from the realm of science fiction to commercialization, packaging engineers will face the challenges of ensuring stable, effective delivery.

 

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