Discovering New Capabilities for Packaging

Mega Pumps support prescriptive dosing for topical applications.

While making it easier for clinicians and patients to prepare and administer therapies, advances in drug-delivery systems for premeasured single doses also support precise dosing and hold the promise of reducing medical errors.

As innovation grows apace in areas such as dissolvable films, pumps for topical dosing, and unit-dose pouches, packaging manufacturers foresee growing adoption of convenient, unit-of-use packaging systems for OTCs and prescription drugs.

ARx LLC (Glen Rock, PA), a subsidiary of Adhesives Research Inc., tripled manufacturing capacity and lab space with the opening of a new 25,000-sq-ft pharmaceutical manufacturing facility in 2007. The new capacity will quadruple potential output of dissolvable film strips to 1.4 billion strips per year.

Created as a wholly owned subsidiary of Adhesives Research in 2005 to address growing demand globally for alternative delivery formats, ARx supplies dissolvable films used in Novartis Consumer Health’s Triaminic Thin Strips cough and cold products, the Theraflu Thin Strips cold and flu products, and the Gas-X Thin Strips for anti-gas relief.

A new line accommodates producing either dissolvable films or transdermal patches. The equipment train along with a second line will also support development of newer applications and serve existing customers, says Martha Sloboda, business manager, ARx.

ARx develops custom formulations for each customer, then sends the film to converters for unitized or cassette-style packaging, Sloboda says.

New capabilities for oral film strip applications, as well as more-complex transdermal constructions are under development. The company is also working on topical applications for dissolvable films.

“Film strips are used now only for immediate-release oral drug delivery,” she says. “We are developing controlled release systems in thicker and thinner films.”

Sloboda says dissolvable films are amenable for prescription products, although they have not to date been used in this area. ARx is working on applications in gastrointestinal and allergy medications.

“We say the only limitation is that the compound itself can only be about 50% of the mass of the final strip before you start trading off on the properties of the film,” she says.

ARx broke the 50-mg load barrier in dissolvable films with Gas-X where 62.5 mg of the drug is contained in a 120-mg strip.

“Most allergy medications are under 10-mg doses” she says. “I think we will be seeing a lot [on the prescription side] in the next 18 months.”

REAGENT DELIVERY IN IVDS

In Tapemark�s SoluStrip Pak, multiple film strips are each separated by barrier protection.

Adhesives Research is offering dissolvable film technology for reagents used in in vitro devices (IVDs). Reagents are incorporated directly into a dissolvable film, replacing the standard technique of impregnating the reagent onto an insoluble absorbent carrier.

“The formulation of dissolvable films from aqueous polymer matrices across a wide molecular weight range provides the flexibility to achieve various physical properties that can be tailored to the IVD manufacturer’s specific design needs,” the company reports. “The intrinsic benefit of dissolvable film technology to the device manufacturer is the ability to completely customize the polymer base [for uniquely configured systems for each application].”

Unlike the conventional method of spraying or coating test strips, reagents are homogeneously loaded into the film. The dissolving films ensure more-consistent dispersion of the active component, which supports delivering accurate results, as well as increased yield of the active component.

“The reagent is uniformly concentrated in the dissolvable film which allows the dosage per area to be consistent from strip to strip,” says William Meathrel, PhD, medical and pharmaceutical senior research scientist, Adhesives Research.

Film characteristics can be tailored, for example, to manage a film’s dissolution rate for a controlled release of a reagent. Films can be used as barrier layers where a controlled flow of the sample being tested is required to flow from one reagent area to another, or to a designated test area in the device.

“You have more flexibility for precisely controlling the reagents to allow a reaction to occur,” Meathrel says. “One example is the controlled dissolution of the film for controlled release of a reagent for an influenza test. The film can hold back a sputum sample allowing the enzyme to reduce the sample’s viscosity before dissolving to allow the sample to move by lateral flow to the detection area.”

In assays where fine powders are used as reagents, the accurate dispensing of the powders may be affected by static effect on plastic and glass components.

Tapemark�s SoluStrip Pak provides multiple dissolvable film doses in a small footprint.

“It’s difficult to control the exact dosage when you are dispensing the reagent as a powder,” he says. “You can dispense it very accurately by putting the powdered reagent into a dissolvable film format.”

Another advantage is that the technology allows continuous web processing. Conventionally, a process is required for spotting reagents onto membranes, onto conjugate pads, or into microwells. The spotted reagents then have to be dried.

“With a dissolvable film you have a continuous strip with one or more reagents that is die-cut or punched and deposited directly into a test strip or reagent well in the device,” Meathrel says. “You avoid the drying process and the process of dispensing the liquids onto the strips. Costly losses from overspraying are avoided.”

Meathrel adds that the dry films improve reagent stability.

“Reagents have to be stored in low relative-humidity conditions, often under desiccation, and in some cases refrigerated. We have found that if you put the reagent into the film, it improves the stability of the reagent,” he says. As an added step, finished rolls can be wrapped in foil packaging for protection during storage and handling.

WATSON ADOPTS MIXJECT DEVICE

Devices that support the reconstitution of lyophilized drugs at the point of use can reduce medical errors, and avoid the need for overfilling that is common with standard vial and needle systems. West’s MixJect and Clip ’n’ Ject plastic transfer devices that link to existing drug vial packaging provide convenient and safe dosing for both caregivers in clinical settings and patients at home. MixJect, for example, has been adopted for home administration of multiple sclerosis medication.

Watson Pharma Inc., a subsidiary of Watson Pharmaceuticals Inc., has selected the MixJect as the new drug-delivery system for Trelstar (triptorelin pamoate for injectable suspension), a treatment for advanced prostate cancer. Clinics will receive kits including the drug, the MixJect device, prefilled syringe with diluent, and alcohol swabs, for delivery of the drug by the doctor, says Graham Reynolds, vice president, innovation strategic marketing, West Pharmaceutical Services Inc. (Lionville, PA) .

For Trelstar, Watson is using a MixJect modified to include an attached safety needle.

“Watson was using the Clip ’n’ Ject which is also a reconstitution system but with a regular needle attached,” Reynolds says. “They found that in certain markets customers were requesting an integrated safety solution. They wanted safety not only in the reconstitution and mixing process, but also after the injection process.”

In the Clip ’n’ Ject system, a syringe barrel with an attached needle is pressed into place and seated to a connector that has been seated to the drug vial.

The MixJect device used by Watson features a 21-gauge needle that can be covered by a snap-back shield for ensuring safety both before and after the drug is administered. In the MixJect system, the drug vial is attached to the MixJect with a plastic spike. After that, the diluent syringe with luer lock is attached to the MixJect, for injecting the diluent through the device into the vial. After the reconstituted drug is pulled back into the syringe, the vial and vial adapter are removed from the assembly, leaving the mixed drug in the syringe with safety needle attached.

“Twisting the vial and adapter [during removal] turns a three-way stopcock that changes the flow path of the liquid so it can be injected directly from the needle,” Reynolds says.

MixJect is a registered trademark of Medimop Medical Projects Ltd. Clip ’n’ Ject is a registered trademark of West Pharmaceutical Services Inc. in the United States and other jurisdictions.

MULTIPLE STRIPS TO A POUCH

Tapemark (West St. Paul, MN) converts soluble films for packaging single or multiple film strips in its SoluStrip pouches. The company has developed the SoluStrip Pak, a multilayer pouch for individual packaging of multiple soluble film strip doses.

In the system, each strip is separated by its own barrier protection. When the patient peels off one dose, the others remained sealed.

“The SoluStrip Pak is a totally unique package that will help drive acceptance of soluble films as the dosage format of choice,” says Julie Karlson, marketing manager. “The system provides a convenient, portable format that, for example, is very applicable for medications that patients have to carry with them because of the dosage timing.”

The package delivers dosage control, and product stability, Karlson says.

Dosage control is a challenge in formats where multiple soluble film strips are packaged together because patients can inadvertently grab several strips at a time. Although this is avoided when strips are packaged individually, the packaging cost mounts.

“Packaging one strip to a pouch requires two layers of packaging for every strip, or, for 10 strips, 20 layers,” she says. “The SoluStrip Pak will package 10 strips in 11 layers of packaging.”

A bellows and dual-value system keeps the Mega Pump air-free. (click to enlarge)

Packaging layers can be printed for identifying each dose, such as with days of the week. The soluble film itself also can be printed with edible inks. The SoluStrip Pak could be put in a child-resistant master pouch.

“We have very strong confidence in this system after completing feasibility work to prove the concept. We are now looking for a pharmaceutical company to partner with us to commercialize the technology,” Karlson says.

Tapemark has expanded its commitment to the Snap! single-use, fold-and-squeeze package that it has manufactured for pharmaceutical and consumer applications under a license agreement with Smyth Companies. Last month, Tapemark acquired the Snap! intellectual property, equipment, inventory, and customer base from Smyth, becoming the exclusive manufacturer of Snap! for all markets worldwide.

In moving Smyth’s Snap! production line to its West St. Paul facility, Tapemark will have two lines supporting production and R&D work on Snap! formats, Karlson says.

The Snap! product line has grown to include the “Snapplicator” applicator for supporting the format’s “no-touch” dispensing. A flat Snapplicator feature is a pad of medical-grade foam or nonwoven material adhered to the side of the pouch. A pop-up version presents the pad three-dimensionally for applying ointments with the pad’s full surface.

Snap! Array delivers multiple Snaps! in perfed sheets supporting multidose regimens. Two products for two-step applications, or daytime/nighttime regimens, are packaged side by side in the Snap! Duet. For two formulas that must remain separate until use, the Snap! Dual Chamber features a hard center seal.

PRECISE TOPICAL DOSING

Mega Pumps (Eatontown, NJ) is focusing on pharmaceutical topical dosing applications in the United States following the 2006 submission of a drug master file (DMF) on the technology and manufacturing processes for Mega Pumps’ airless dispensers.

Contract research and contract manufacturing organizations have since placed numerous projects on stability with plans for commercializing products using the system, says Russell Haines, pharmaceutical sales rep, Mega Pumps.

“The DMF opened the door for development of pharmaceutical applications,” Haines says. “We now have a DMF for our entire product line, with great expectations for drug product commercialization in 2009.”

The company has introduced smaller dosage styles suitable for dosing of pharmaceutical ointments, creams, and gels.

“Most recently we added a 0.5-ml dosage to our intermediate-sized packages, the Mezzo and Mini formats, offering a new choice in our range of dosage sizes from 0.3 to 1.5 ml. In addition, we added two new actuator styles, including a very prescriptive style for the Micro series,” says Janis Swindlehurst, VP and general manager, Mega Pumps.

Mega Pumps offers top and bottom fill systems, with a top-fill system that simplifies filling on standard tube and bottle lines.

The Mega Pump protects the product from exposure to air for extending product shelf life. The device features an accordion-like bellows situated between two valves. The bellows serves as a dosage chamber, and as a plastic spring for raising the actuator. A vacuum created in the bellows after a dosing is dispensed pulls the next dose into the bellows chamber, pulling a piston below the product up for maintaining airless conditions.

When the user presses the actuator, the upper valve opens releasing the dosage from the bellows, and the lower valve closes to keep the remaining product air-free. With release of the actuator, the upper valve closes to prevent air ingress, and the lower valves opens to allow the next dose to fill the bellows. A unique option is a self sealing actuator that moves the upper valve to the opening of the orifice to keep product protected from air at the orifice spout.

Although applications in the United States to date have been for personal care and cosmetic products, MegaPlast (Pfaffenweiler, Germany), Mega Pumps’ affiliate company, has been producing the dispenser for use in the European market. Applications include use for antiinflammatory drugs and drugs treating skin conditions such as psoriasis and acne, says Swindlehurst.

The all-plastic device allows dispensing with one hand, in any position.

“Precise topical dosing has been a huge challenge for the pharma industry,” Swindlehurst says. “For dispensing highly viscous products in tubes, a dosage ruler is often required for controlling the dosage. In some cases, products need to be packaged with extensive dosing instructions. With full actuation of a fully primed pump, the Mega Pump delivers a very precise, repeatable dose. And there is absolutely no contact of product with the air.”