Dialing in stable packaging for sensitive drugs

Custom sorbent solutions target product degradation in drug and device combination products.

Drug and device combination products often require advanced desiccant solutions to prevent physical and chemical degradation of the drug and preserve efficacy on the shelf and through use by the patient.

In packaging of respiratory drug delivery (RDD) devices and transdermal patches, standard desiccating silica-based desiccants designed to take head space or device reservoir moisture levels down to zero are often too aggressive.

RDD devices include aerosol pressurized metered dose inhalers (pMDI) and dry powder inhalers (DPI), both in premeasured dose and reservoir formats.

In aerosol-based pMDI systems such as metered dose inhalers, the hydrofluoroalkane (HFA) propellant creates moisture management issues. HFA is very hydroscopic, tending to adsorb moisture into the device’s dosing chamber, says Adrian Possumato, global director, healthcare packaging, Multisorb Technologies (Buffalo, NY).

“In all cases with DPI devices, you are regulating moisture. If the product gets too wet you get particle agglomeration—particles become too big to evacuate through breath activation or aerosolize properly for delivery into the lungs,” says Adrian Possumato, global director, healthcare packaging, Multisorb Technologies (Buffalo, NY).

Over drying, however, must also be avoided. Too-dry environments can affect the amount of dose going into the lungs, when electrostatic charges are generated.

“Whether it’s a premeasured dose packaged outside the device, or inside the device, or a device with a reservoir for the drug product, in any of these cases, going too dry can create a static charge on the materials, the device, or in the capsules. This causes the powder to cling to the capsules or to the plastic components inside the device, which affects the dosing performance,” Possumato says.

“Well before you have any chemical instability issues with moisture in dry powder inhaler devices, you have these physical stability issues, which affects the delivery of the product into the lungs,” he adds.

Multisorb’s Intellisorb sorbent solutions are engineered for regulating specific levels of moisture, oxygen, and hydrocarbons. “There is a sweet spot for most lactose carrier dry powder inhaler formulations with regard to moisture regulation. We can manufacture a customized formulation of an intelligent sorbent for moisture regulation to a specific level.

“We can then model that in our Simulsorb program and show the client exactly how hydrated their product will become [with a specific package and desiccant solution],” Possumato says.

FORMAT CHOICES

Multisorb intelligent sorbent formulations are available in three formats. StripPax systems are “dropped in” to packaging for the devices or separately packaged drugs used with the devices. Engineered to fit into device cavities or bottle closures, its Multiform Coated Solid Form CSF features compressed density technology enabling higher utility per unit volume. PolySorb desiccant polymers are molded into component parts, in a “built in” approach.

“The fit-in solution is often selected because you can load more desiccant than with a built-in. It becomes more cost-effective, and it is also the most flexible in the regulation of moisture. The primary mission for a desiccant thermoplastic built-in solution is one of an active moisture barrier system,” Possumato says.

Süd-Chemie Performance Packaging (Belen, NM) has launched a new line of sorbents designed for maintaining specified humidity levels in packaging. The EQ-Can and EQ-Pak canister and packet sorbents simultaneously perform as desiccants and humectants, or desorbers, to achieve a particular equilibrium relative humidity.

“Sensitive inhalation remedies in dry powder inhalers and other novel drug delivery devices often need to maintain a specific range of relative humidity. Given a set condition, we can calibrate the EQ products to provide a specific RH based on the customer’s needs,” says Mark Florez, global marketing manager.

“We see an increasing need from customers to control package environments not only from excessive humidity but also from excessive dryness,” adds Robert Crossno director of sales and marketing.

Excessive humidity can cause an API to adsorb moisture, resulting in deliquescence, decomposition, or overall instability of the drug. Overly dry environments on the other hand can accelerate efflorescence in some products, or cause cracking of gelatin coatings, Crossno says.

Solutions need to address secondary stability or the efficacy of the drug during consumer use.

CONSUMER USE PROFILE

“FDA is looking at secondary stability for all devices to protect for the consumer use profile. Can you demonstrate that it will work for the 30 days you are asking the consumer to use the product? (The agency’s) Center for Devices and Radiological Health (CDRH) and Drug Evaluation and Research (CDER) will be asking very specific questions about flow characteristics of the powder through the device into the lungs from day one to day 30,” Possumato says.

Device manufacturers need to ensure the product can be reliably dispensed days after it has been removed from the secondary packaging.

A soon to launch device for which Multisorb developed the sorbent solution will employ as Intellisorb sorbent in CFS solid form designed to fit into a cavity in the device. The single solution will provide for both primary and secondary stability over 30 days of consumer use.

When device designs don’t allow for enough sorbent to maintain efficacy through two years of shelf life and 30 days of use, a fit-in or built-in solution can be augmented with a drop-in solution. In such cases, “the drop-in packet is tuned to behave equal to or faster than the desiccant inside the device, because we want it to carry the load for the primary protection, preserving the fit-in sorbent for handling the 30 days of consumer use,” Possumato says.

Secondary stability can be addressed in the engineering of the device component parts.

CSP Technologies Inc. (Auburn, AL) offers desiccant-entrained polymers that use its Active-Polymer technology. Polymers can be extruded into sheets or injection molded into device components.

In injection molded components for inhalers and other devices, the active polymer can be engineered to maintain a target water activity level. In addition, CSP Technologies designs and engineers device components and subassemblies.

“We are involved in multiple programs at various stages of development and commercialization. One of our areas of expertise is the development of tightly sealed devices,” says Billy Abrams, vice president, business development. “In addition to providing relative humidity control, we are able to help companies minimize the rate of moisture ingress into the device. This promotes the useful life of the desiccant on the shelf and after during use by the patient.”

In desiccating polymer solutions, Süd-Chemie offers its Advanced Desiccant Polymer (ADP) technology. ADP’s major application has been in injection molded flip-top test strip tubes for the diagnostics industry. “We are poised to offer the diagnostic, medical device, and pharmaceutical industries innovative packaging systems and components made with our highly advanced desiccant polymer. There are countless options to (use this technology) in customized solutions,” says Crossno.

CSP Technologies’ Activ-Film family of desiccant films can adsorb a variety of gases including moisture and oxygen. CSP films can also adsorb multiple gases simultaneously.

PATCH PACKAGING

“We are very active today in transdermal patch packaging where our “combo” moisture and oxygen scavenging film is applied like a label directly to the inside of the foil pouch. It is a very elegant way to seamlessly introduce a scavenging solution into a pouch,” Abrams says.

Films with 0.3 to 0.6 mm thickness are applied adhesively or heat staked to the seal layer of the foil. Harro Höfliger and Siebler-Romaco are among companies that have built modules for automatically applying the film to the foil on high-speed pouching lines.

Multisorb has developed solutions for passive matrix transdermal patches and active transdermal systems using iontophoresis for delivering the drug. Customers use the solutions for passive transdermal systems for removal of moisture and volatilized hydrocarbons, and to prevent oxidation.

Noven Pharmaceutical’s Daytrana methylphenidate ADHA passive transdermal system uses Multisorb StripPax Desiccant Packets for preventing physical and chemical degradation in 30-count bulk packs. A leading estrogen replacement transdermal system uses the Multisorb DesiMax Sorbent Label for physical and chemical degradation prevention, Possumato says.

As systems with electrical components and often gel-based reservoirs, active transdermal patches present more complex challenges. “Active transdermal systems have unique moisture management requirements. The electronics can be oxygen sensitive, and you have a wet ionized formulation in the reservoir,” Possumato says.

Multisorb developed a solution for an active transdermal system that addressed multiple requirements in “the most comprehensive intelligent sorbent solution we’ve ever done.”

Specially formulated MiniPax and StripPax Intellisorb Packets were dropped into the pouch packaging.

“In this case, the client had an inotophoretic, gel-reservoir-based transdermal system with a desire to adsorb a volatilized hydrocarbon, regulate relative humidity to a specific steady-condition, and remove oxygen from the package headspace.

“Conventional sorbents used in the adsorption of volatilized hydrocarbons would have been too drying, destroying the gel reservoir system. The StripPax Intellisorb Packet easily managed moisture, oxygen and the hydrocarbon to provide an extended shelf life to allow for successful global distribution,” Possumato says.

BOTTLE BARRIER

For high barrier protection from oxygen degradation, Süd-Chemie has launched Oxy-Guard extrusion blow molded bottles. Bottles are featured with up to six layers. A black resin layer can be incorporated for UV protection.

Oxy-Guard bottles with EVOH barrier layer offer up to 100 times the oxygen protection barrier of standard HDPE bottles and also provide a high level of moisture barrier protection. The bottles can be used along with the PharmaKeep sorbents. As a supplemental oxygen scavenger, the packets and canisters absorb head space oxygen and any oxygen that permeates during shelf life, says Florez.

“Some of the innovative new drugs are extremely sensitive to oxygen. Manufacturers can use protective packaging, rather than address oxidation in the formulation of the drug, which prolongs development,” Florez says.