New routes in drug delivery

Package formats hold promise for patient therapy adherence.

Many new drug packaging and delivery solutions feature attributes that promote ease of use and convenience for patients and caregivers. As these solutions stream into the marketplace, some bring inherent advantages for drug regimen compliance.

While emerging categories such as dermal patches and nasal sprays seem to offer obvious improvements for medication delivery, their success to some extent rests with vendors’ ability to prove their value as cost-effective alternatives to existing methods. Morecomprehensive data on compliance benefits as well as impacts on treatment outcomes may be needed to prove value to manufacturers, caregivers, and healthcare payers.

“We need to see more compliance studies with broader scope,” says Thani Jambulingam, chairman, associate professor of pharmaceutical marketing, Saint Joseph University (Philadelphia). “There is a lack of good, comprehensive compliance studies demonstrating real-world use of medications in which there might be multiple interventions by caregivers.”

An Ohio State University (OSU; Columbus) study examining blister packs for delivery of solid doses showed that a calendared blister format encouraged patients to follow drug regimens and refill prescriptions. Patients receiving lisinopril in compliance packaging showed significantly lower blood pressure than a control group supplied with medication in bottles.

However, “There are not that many studies,” says Phillip Schneider, the study’s author and clinical professor of pharmacy, OSU. “Compliance studies are very difficult to do in a real-world setting, which is the only way to evaluate [packaging’s impact] in the real world. Barriers include finding one condition to study that has objective treatment outcomes, limiting the number of medications that are packaged a certain way, and enlisting pharmacies to ensure feasibility and follow-up,” he says.

Transdermal patches seem to offer inherent compliance advantages, as caregivers can confirm adherence by visually inspecting that the patches are in place. Dermatrends Inc. (Minneapolis) offers proprietary patch technology that can deliver compounds such as nonsteroidal antiinflammatory drugs (NSAIDs).

“There are no public-domain studies that show [that better patient compliance] would be the case [with transdermal NSAID delivery],” says Ted Schwarzrock, CEO, Dermatrends. However, “We expect that, over time, as the therapeutic benefits of patches are demonstrated, insurers will want to support transdermal solutions, because their long-term costs will drop.”

Akan Oton is global marketing director, commercial and clinical packaging, pharmaceutical technologies and services group, for Cardinal Health Inc. (Philadelphia). Oton says that manufacturers will increasingly realize that they can gain preferred formulary positions with payers by marketing drugs with clinically proven compliance-enhancing tools. “Pharmacy benefit managers tell us that they are willing to pay for compliance benefits. As manufacturers develop creditable data in clinical studies on drugs with compliance designs, payers will be influenced to accord preferential formulary treatment to packaging that drives real clinical outcomes. This is particularly the case in categories with known compliance issues. As these packages start to gain preferential reimbursement, you will see compliance packaging tip to a broader range of categories,” says Oton.

Though controlled trials may provide valuable insights, Schneider notes that “some have suggested that randomized controlled trials may be neither necessary nor feasible for certain practices that clearly make sense.” Schneider points to a paper published in the July 2002 issue of the Journal of the American Medical Association titled, “What Practices Will Most Improve Safety.”

“There will never be complete evidence for everything that must be done in medicine,” the authors write. “Evidence from randomized trials is important information, but it is neither sufficient nor necessary for acceptance of a practice. Policymakers must consider the entire experience with safety practices when deciding which practices should be recommended for widespread use,” the authors state.

Speaking last year at the Healthcare Compliance Packaging Council’s Annual Symposium on Patient Compliance, Jambulingam said that drug manufacturers should view packaging that reinforces consistent medication as an investment rather than as a cost.

Jambulingam says that the Centers for Medicare and Medicaid Services (CMS; Baltimore) will collect huge amounts of patient data in the Medicare Part D drug-benefit program that the agency could use to drive packaging design. “CMS will have the ability to accurately track information such as refill behavior for millions of patients. They will have the outpatient data [along with] the data derived from Medicare inpatient coverage. The agency will be able to correlate the outpatient compliance data with hospitalization rates,” he says.

“They might identify high-risk populations such as those with diabetes for which there is a high cost of treatment in later stages and set compliance goals for those populations. They have tremendous potential to use the data to influence pharmaceutical packaging that delivers outcomes or push prescription drug plans to cover packaging demonstrated to work better,” Jambulingam says.

GAUGING INJECTION PENS

Use of injection pens for insulin therapy is accelerating in the United States, and pens and autoinjection systems for prefilled syringes have gained increasing popularity for other drugs.

In Europe, 80% of diabetics treat themselves with pens. A Schering-Plough study in France found high levels of patient satisfaction for those using injection pens for treating chronic viral hepatitis C with Peg IFN alfa-2b. Noting that the number of patients adopting the pen doubled during a 12-week follow-up period, the study concluded that the device can be expected to promote good treatment adherence.

“One weakness of this study is the lack of a control group. A prospective comparative evaluation of syringe versus pen device would have been more rigorous,” the study notes.

While many diabetes patients in the United States are accustomed to using vials and syringes and are less willing to move to a new technology, new patients will adopt pens for their ease of use and
convenience, says Michael Ratigan, worldwide business platform leader for self-injection, BD Medical—Pharmaceutical Systems (Franklin Lakes, NJ).

“We believe there will be a very high adoption rate as insulin patients are introduced to pen solutions. Pens provide a self-contained system that is conveniently used in public,” says Ratigan.

Companies are looking to differentiate themselves by marketing their drugs with drug-delivery systems that offer patients more features and benefits. “The focus on home administration for therapies in areas such as osteoporosis, multiple sclerosis, and rheumatoid arthritis will provide real growth opportunities for pens and autoinjection devices,” he adds.

Disposable pens that eliminate the need for replacing the cartridge and minimize the potential for human error are gaining ground. Eli Lilly (Indianapolis) provides Humalog in a disposable prefilled-pen format. “We believe strongly in both prefilled and reusable pen systems, since both formats are favored by patients,” says Scott Mac-Gregor, senior communications associate, Humalog brand, Eli Lilly.

Pens are becoming more advanced with the use of autoinsertion and autoinjection functions. “Cartridgebased pens are moving most significantly in the direction of spring-assisted injection, in particular because of the use of finer pen needles. For prefilled syringes, there is growth in demand for autoinjectors where the patient simply pushes a button to autoinsert and autodeliver the drug,” says Ian Thompson, manager, business development, Ypsomed AG (Burgdorf, Switzerland). The firm announced in May that it has granted a nonexclusive license to use certain autoinjector patents to a global pharmaceutical company.

Autoinjectors automatically insert the needle and perform the injection. Reusable autoinjection systems have been comarketed with drugs treating arthritis, anemia, and multiple sclerosis, and drugs for hormone replacement. These reusable systems require the patient to load and then activate the device.

Fully disposable autoinjectors are providing a new level of ease of use and safety by eliminating the need for syringe handling. In these systems, the syringe is supplied preassembled with the injection device for single fixed-dose delivery.

“With single-use disposable autoinjectors, you press a button and the dose is automatically delivered. Disposable autoinjectors can use the BD Hypak 1-ml-long prefilled syringe as the primary container,” Ratigan says. BD is developing a disposable autoinjector for 2009 commercialization, he adds.

Amgen (Thousand Oaks, CA) and Abbott Labs have recently launched drugs in disposable autoinjector format with preassembled, prefilled syringes.

Amgen provides its anemia drug AranespA (darbepoetin alfa) in the single-dose disposable SureClick auto-injector. The SureClick features a safety cover that limits needle exposure, audible clicks announcing the start and finish of the injection, and a large inspection window for confirming the delivery of the complete injection.

After offering Humira in a specially designed prefilled syringe, Abbott debuted the Humira Pen for rheumatoid and psoriatic arthritis patients self-administering Humira (adalimumab). An Abbott survey reported that almost all patients found the one-time-use device easier to use, more convenient, and less painful, when compared with manual injection using prefilled syringes.

HIDING THE NEEDLE

Thompson says that Ypsomed is performing patient-handling studies with its disposable autoinjector solution and also pen devices with springassisted auto delivery. The increasing number of biotech drugs in freeze-dried states has opened opportunities for new dual-chamber cartridge pens for self-injection.

“Many of these new lyophilized drugs are in monodose formulations, injected immediately after reconstitution. If the dose needs to be varied, a pen-like dosing device used with a safety pen needle is ideal,” he says.

Pens and autoinjectors are addressing patient needle phobia—such as with needle hiders—and needle safety. Disposable autoinjectors provide the most safety and comfort with integrated needle safety features. Thompson notes that needle safety is also addressed by safety syringes and safety needles on pens, while finer needles are making self-administration more acceptable to patients.

Ratigan says that “BD is focused on next-generation pen needle safety as well as on enhancements to needle safety guards that are currently available in autoinjectors.”

The HumaPen Memoir pen from Eli Lilly aims to ease the day-to-day burden of diabetes management with a high-tech device that helps patients keep track of their multiple daily injections. The chip-based, battery-operated pen developed by Lilly with Batelle Medical Device Solutions (Columbus, OH) features a push-to-know digital display for reviewing the time, date, and amount of the last 16 doses.

“The Memoir Pen moves diabetes management into the electronic age,” says Lilly’s MacGregor, noting that it is Lilly’s first reusable pen format launched in the United States.

Using the Memoir pen, the patient can more systematically match dosing with food intake and blood sugar readings, without having to write the dosing history down. The doctor can use the logged data to fine-tune treatment with the right insulin dose, MacGregor says.

“Patients can test their blood sugar levels, but that doesn’t necessarily tell them if they took enough insulin at their last dose, or if they remembered to take it at all. If they are taking insulin at each meal, the right insulin dose has to be balanced with their food intake,” MacGregor adds.

The dialed-in Memoir dosage is shown via digital display. For patients who need smaller insulin amounts, Lilly has launched the HumaPen Luxura HD reusable pen. The patient tracks the dosing through a hash-marked window display and audible clicks. Four clicks is the equivalent of two units of insulin, given in half-unit increments.

“Pens are more accurate than vials and syringes. We have demonstrated through testing data the dose accuracy time after time. We think this will move the U.S. market toward pens, because patients are telling us they would rather use a pen,” he says.

EDIBLE FILMS

In providing premeasured doses in an easy-to-ingest form, edible film strips would seem to have inherent compliance advantages. Products such as vitamins and breath fresheners are offered in unitof- use strips in cassette formats.

OTC drugs, notably for cough and cold remedies, have emerged in film-strip formats where they offer advantages that include portability, convenience, and a child-friendly dosage form. Novartis Consumer Health’s Theraflu and Triaminic cold remedies are examples of products marketed in unit-dose strip formats.

“Almost all OTC manufacturers with edible films will opt for unit-dose packaging as a better way to ensure that the patient takes only one dose at a time. OTC marketers are gaining market share with a format that is innovative and convenient for the consumer,” says Cardinal Health’s Oton.

“A lot of the targets for dissolvable films have been in pediatric applications and categories where patients are best served by a fast-dissolving product. Films lend themselves nicely to special populations such as schizophrenia patients where caregivers want a fast-dissolving dosage form,” Oton says.

In developing its patented DelStrip unit-dose package for film strips, Cardinal refined the design to ensure that user convenience isn’t compromised. “Childresistance functionality cannot detract from package convenience. We saw that many customers were unable to open the primary packaging without ripping the packaged medicated strip. If you have a 1% consumer complaint rate, you are shooting yourself in the foot,” says Oton.

After an initial configuration to prove the technology, Cardinal redesigned the package and the strip, replacing a chevron package seal with a razor-tooth design that allows a more-consistent tear on opening, which avoids damaging the edible film.

Thin films promise enhanced patient convenience for prescription drug delivery, but the format has been limited in this application by a number of factors. These factors include drug firms’ conservatism
and the fact that companies have other delivery options, such as fast-dissolve tablets, says Oton.

Also, “OTC products have been first to get to market because the approval process for new packaging is much faster. With prescription drugs, a company’s first concern is to get to market as fast as possible with a known technology. Development time for a new format may be three to five years. [And] for most molecules, film does not add to the treatment efficacy,” Oton says.

The number of drugs that can be delivered with film are limited because of the dosage amount. “Films can deliver 50 mg or less. But we are seeing new drugs coming down the pipeline with highly potent actives. Perhaps 30% of these compounds can be delivered in an under 50-mg dosage,” he says.

“You have to identify the right drug at the right dosage for the right delivery format. We are actively working with several pharmaceutical companies developing unit-dose film-strip applications for prescription drugs,” Oton adds.

Tim Notter, vice president, sales and marketing, CWS Contract Packaging (Norwich, NY), says that film-strip technology has to improve to promote prescription-drug delivery.

Besides accommodating enough active ingredient, films must address masking of the flavor. “Strips are generally able to supply 50 mg of active product with OTCs and vitamins. Prescription drugs may require 200 mg or more per dose. Strips must be made to immediately dissolve in a palatable form, without grittiness,” Notter says. “Edible films will emerge as a major factor in oral-dose administration as the technology advances. Children and seniors account for most oral dosing, and both of these groups have an aversion to taking pills,” says Notter.

CWS converts edible films in unit-of-use format for products including vitamins, caffeine strips, cold medications, and homeopathic remedies. CWS sources preinfused films from a number of companies and then converts the films and places them into cassettes that are injection molded by Moldieco Plastics Products Inc. (Fords, NJ). CWS cuts and stacks the film into the cassettes and then caps, labels, and lot codes the filled cassettes. Typically, cassettes are blister packaged on a form-fill-seal machine, with the blister then sandwiched between two blister cards and sealed on an Alloyd unit. CWS recently packaged an edible film in a PET/Aclar blister, eliminating the standard two-piece blister card format by sealing the blister to a foil-faced blister card supplied by Dot Packaging (Batavia, IL). “This has resulted in a better package, with the same properties, and less material,” Notter says.

PATCHING IN

Besides promising compliance benefits, transdermal patches offer advantages for some therapies. Patches have been used for testosterone (Watson Pharmaceutical’s Androderm), shingles pain (the Lidoderm patch from Endo Pharmaceuticals), and birth control (the Ortho Evra patch from Ortho Women’s Health and Urology division of Ortho-McNeil Pharmaceuticals Inc. (Raritan, NJ).

“You can put the patch between the patient’s shoulder blades and confirm the patch is in place. In treatments with antipsychotic medications, for example, caregivers and pharmaceutical companies universally believe that a patch offers compliance advantages,” says Dermatrends’ Schwarzrock.

Dermatrends has teamed with Teikoku Pharma USA to develop a prototype patch for a Teikoku antipsychotic drug, using Dermatrends hydroxide-releasing agent (HRA) technology. MINRAD International Inc. (Buffalo, NY) licensed the technology to develop a conscious-sedation product.

The drug-in-adhesive-patch system delivers therapeutic quantities of a range of drugs of different molecular sizes and composition, with larger doses in smaller patch sizes supplied with acceptable skin-irritation levels, says Schwarzrock.

“We think we are in a unique position because we have demonstrated the ability to deliver many different molecules in useful quantities that have not been available transdermally,” he says.

Patches provide therapeutic advantages for drugs such as proton pump inhibitors (PPIs) and NSAIDs.

“PPIs have short half-lives. Even if you are taking the drug twice a day, there are moments when there is not enough drug in the bloodstream. After two hours, half the therapeutic level of the drug in the blood is gone. Doctors want to ensure a stomach pH of above 4 for up to 24 hours,” Schwarzrock says.

“No one has demonstrated the ability to deliver a PPI with a patch. With HRA technology, we can deliver the PPI continuously at therapeutic levels throughout the day,” he says.

HRA delivers NSAIDs in therapeutic quantities, allowing the circumvention of the gastrointestinal (GI) tract for patients with NSAID intolerance. “We surveyed 1600 rheumatologists and internists that write the majority of NSAID prescriptions. [Findings show that] 85% of physicians said they would use the transdermal solution with the same label tomorrow because it would improve compliance with patients susceptible to GI upset,” he says.

SOLID DOSES

The DosePak by Meadwestvaco (Mebane, NC) has earned adoption in numerous cartoned blister applications where companies have sought to implement compliance features and child resistance in packaging.

Some years ago, Anderson Packaging (Rockford, IL) was the first to develop an automated assembly process to deliver Meadwestvaco’s design with an acceptable unit cost for pharmaceutical trade packaging.

“We recently launched a large-scale commercial program for a major pharmaceutical customer using our sixthgeneration packaging process for DosePak,” says Peter Belden, vice president, sales, Anderson Packaging.

“The configuration of the package, the volume, and the quality system requirements pushed us to an even higher level of integration and automation for the multiple steps involved in assembling the DosePak. We have been told our line is one of a kind for this type of package,” says Belden.

In this case, the customer was interested in delivering a high level of compliance with packaging that keeps the patient on the regimen and wanted F-1 child resistance.

Compliance projects in development and soon to launch at Anderson include multiple packaging options. “We have experienced tremendous growth in compliance-prompting packaging that requires a high level of child-resistant and senior-friendly features,” says Belden.

Aiming for a first-quarter 2008 opening, Anderson is adding 260,000 sq ft to a 148,000-sq-ft contract packaging facility that opened in Rockford, IL, in 2005. That expansion will enable the company to keep up with demand for its primary and secondary packaging services.

Packagers are focusing on driving costs out of compliance package solutions with designs that can be assembled with standard blister packaging equipment.

Cardinal Health’s HingePak is a patent-pending child-resistant, seniorfriendly format that can be produced and assembled with conventional blister card sealing equipment. Its design could be used to create a cost-effective F-1 package, says Oton. Cardinal Health also produces the Rx Barrier Plus package, named the 2006 Innovative Design of the Year by the Healthcare Compliance Packaging Council in its annual Compliance Package of the Year competition. (See sidebar.)

Designed specifically to make small tablets more easily accessible to seniors, the child-resistant package provides superior ease of use by employing a thermoformed cover on the blisters that self-seats fingers to the pill cavities, says Oton.

“Our customers are telling us they want to move to compliance designs in therapeutic areas where compliance issues are most pronounced. But at the end of the day, we have to deliver a cost that makes it harder to justify the repackaging and bottling model. We have been developing proprietary compliance packaging vehicles that meet high senior friendliness and child resistance standards, with a focus on the design of the packaging execution so that assembly is increasingly more costeffective,” he says.

Stora Enso (Helsinki, Finland) is developing a new carton design for a carded blister. The scalable design will yield a “discrete, pocketable package,” complementing Stora Enso’s pharmaceutical solution offerings, says Ralph Mendoza, sales manager, pharmaceutical solutions, Stora Enso (Morris Plains, NJ).

Last year, TestPak (Whippany, NJ) launched the Pharma SHR packaging system developed by Stora Enso and Bosch Packaging.

The new carton will be produced with existing off-the-shelf cartoners,” says Mendoza.

“The package will be an option for products that will require high compliance and convenience of use on top of child resistance. We expect to launch the new design this fall,” he adds.

Developed by Chesapeake Corp.’s (Richmond, VA) European subsidiary Field Boxmore (Nottingham, UK), the Kid Key is a seal-end bottom, tuck-top carton with a fifth panel to incorporate a “key,” or tear-away piece that is inserted to open the box. The key features a hole for convenient hanging on a key chain. The child-resistant carton is manufactured with standard printing, die-cutting, and gluing equipment, says Matt Ramsdell, manager of package engineering and development, Chesapeake Pharmaceutical Packaging–North America (Lake Success, NY).

“The benefit behind the Kid Key is that it’s designed to run on existing packaging lines. Making the carton out of laminated board or polypropylene provides superior tear resistance, but regular paperboard works as well. The Kid Key also provides excellent tamper evidence,” says Ramsdell.

Chesapeake’s Kid Stop is a pressuresensitive label that can be offered with multiple adhesive options that provides a senior-friendly alternative to paperboard for blister peel-push formats. Packagers can apply the labels in-line using equipment manufactured by Chesapeake subsidiary Field Packaging Systems (Thatcham, UK), or use an off-line solution from the company for smaller volume requirements, Ramsdell says.

Alcoa Flexible Packaging (AFP; Richmond, VA) continues to work on improving the senior friendliness of child-resistant blister package lidding. At Interphex, the company showcased its three styles of child-resistant Safety-Pak Plus blister lidding. Safety-Pak Plus PP opens in the traditional peel-push manner; however, the external-polyesterfilm-based specification, used in place of an exterior paper-based design, allows for a full-panel peel without tearing. Safety-Pak Plus PL is AFP’s peel-only version of the polyester-film-based lidding for fragile tablets that cannot be pushed through lidstock. Safety-Pak Plus LT, AFP’s lock-tight lidding, is an option when seeking to package products requiring low F ratings as the package can only be opened with a tool, such as scissors.

“Total child resistance is challenging,” says Bill Sharpless, global market director for AFP’s pharmaceutical packaging group. “It has traditionally only been achieved with a paper-based lidding solution or bulky boardstock overwraps. Our film-based solution, however, has been easier for seniors to use. In recent tests, seniors were able to open peelpush packages with our Safety-Pak Plus material faster than with traditional paper-based lidstock.” Alcoa’s presentation at Interphex pointed out that the traditional heat-seal-coated paper/film/foil lidstock technology is more than 30 years old.

TAKING A FRESH LOOK

Alcan Global Pharmaceutical Packaging (Kirkland, QC, Canada) has sought insights on patient compliance in a program in which company departments collaborate to develop packaging based on user needs discovered in the marketplace through research and fieldwork.

A project that examined physician samples has led to the development of new packaging solutions at the company, says Nina Goodrich, director of innovation, Alcan Global Pharmaceutical Packaging.

The value innovation process (VIP) “reinvents” the approach to innovation with a focus on “human-centered packaging needs.” (See the Viewpoint column.)

Cross-departmental teams initiate exploratory research to define questions such as the components of a value chain, and the requirements of parties along the chain. Research may include interviews with end-users, and direct observation of package usage.

Researchers develop insights about how product is used, and what performance features are most important to key customers and potential customers. These may include pharmacists, insurers, or resellers.

Goodrich notes that she once rode in an ambulance for a day to watch how Alcan Packaging materials, vials, and swabs were employed by EMTs. “Easy-open with dry hands is completely different from opening with wet gloves in a stressful environment in a bouncing vehicle.”

“The majority of innovation that takes place at many companies responds to companies’ current customers and current products. VIP is designed for game-changing solutions, not evolutionary products. You are exploring the requirements of the entire value chain, including the needs of parties that might not be current customers. Ideally, you are creating a product that meets the needs at more than one level of the chain,” Goodrich says.

“In the pharmaceutical space, noncompliant patients are one new group of customers you could be reaching. You might need to look at how a package is delivered, as opposed to how it is made,” she says.

An Alcan team targeted doctor samples as a good entrée into the compliance issue, given that samples are patients’ first exposure to a medicine. Doctors, patients, pharmacists, drug reps, and drug companies were interviewed so Alcan could better understand what was important to them. One group collected sample packages used for different products, including cosmetics, paint, and wine, “to sample other sample experiences. You can’t get more sophisticated than cosmetics sampling,” Goodrich says.

“The idea that one size fits all was quickly dispelled. Different groups of patients with different diseases have different needs. Our findings have changed our approach to samplepackage development. We are prepared to share these results with our customers when they want to embark on a physician sample redesign project,” she says.