Sensing the Effectiveness of a Drug-Delivery System

A pressure-sensitive film records a device's pressure on a blister to ensure effective drug delivery.

 

Photo of an AERx strip (top). The red area (bottom) shows the region where tactile pressure sensor film was used to determine clamping pressure uniformity on the dosage form.

Aradigm Corp. (Hayward, CA) wants patients to breathe easier. Seeking to replace lengthy nebulizer treatments with drug delivery making use of the lungs' ability to rapidly absorb molecules into the bloodstream, the firm has developed AERx, a trademarked product. This electromechanical device delivers breathable aerosol from disposable single-use dosage forms called AERx Strips. These multilaminate strips consist of a blister reservoir with approximately 50 µl of the liquid drug formulation (sufficient for a single inhalation), a micromachined array of microscopic nozzles, and a peelable layer that seals the reservoir area until dispensing.

AERx delivers the dosage form contents by driving a piston against the exterior surface of the blister reservoir. This action causes a rapid pressure increase inside the reservoir until the peel/seal layer opens between the reservoir and the nozzle array. Activation of the piston also causes the drug to be forced from the reservoir through the nozzle array as a stream of jets. The nozzle array's hole size changes this stream into a breathable aerosol, allowing drug inhalation.

During delivery, pressure within the reservoir is on the order of several hundred kg/cm2. To ensure that the peel/seal layer does not open anywhere except in the specific region between the reservoir/nozzle array, the device uses a clamp fitting around the periphery of the reservoir and nozzle array during delivery. "This clamp is designed to create a pressure around the periphery far in excess of the hydraulic pressure within the reservoir," says Eric Johansson, director of electrical engineering and project leader at Aradigm. "This ensures that the peel seal cannot open in the clamped regions."

To assess clamping uniformity and confirm the predicted clamping pressure, Johansson turned to a tactile pressure sensor film (TPSF) called Pressurex from Sensor Products Inc. (East Hanover, NJ). TPSF comes in the form of thin sheets, ranging in thickness from 0.1016 mm to 0.2032 mm, structurally affixed to a Mylar substrate for stiffness. The films come in various pressure sensitivities ranging from 2 to 1300 kg/cm2 (28 to 18,500 psi).

Pressurex is a single-use system capturing maximal pressure loading at a specific moment in time. TPSF reveals a very high resolution image of pressure distribution and pressure magnitude. Microcapsules embedded in the film rupture at precise pressure levels, releasing chemical contents which then interact with a developer component to produce a visible color change. This quantifiable color change is directly proportional to the amount of pressure applied. The user can also visually inspect the film for significant variations and general uniformity. Spatial resolution of the TPSF system is 0.005 to 0.015 mm, yielding ultra-high-definition imagery of force profile. The color change of the film is both instantaneous and permanent, allowing for the film to be both immediately analyzed and then saved for archival purposes.

In Aradigm's case, Pressurex was used "in place of the dosage form to obtain clamping impressions during drug delivery," says Johansson. While the average pressure exerted by the clamp on the dosage form was easily calculated, the uniformity of pressure along the clamping surface proved more difficult to determine.

Before its AERx program, Aradigm used TPSF on the advice of Elform Inc. (Reno, NV). The film helped Aradigm determine proper alignment of a production component for a different product line. "Because the objective of the heat-seal application was very similar to measuring pressure uniformity along a surface for AERx, we felt the sensor film would be a very useful tool during the development of the AERx clamp design," Johansson says.

As part of the device design (the only time the film was used for this particular project), Aradigm "used standard sheet stock, which we then cut to the approximate dimensions of our dosage form," Johansson explained. "Because the combined thickness of the two sensor film layers was several mils less than that of our dosage form, two layers of adhesive tape were used to increase the thickness of the surrogate pressure sensor film dosage form. The tape used to increase the thickness of the pressure-indicating-film assembly had the added benefit of keeping the two film layers together as the surrogate dosage form was loaded into the device. During actual measurement, the film assembly was held securely in place by the device's clamping surface. For this particular project, we needed to ensure that during delivery the clamping pressure would exceed the drug's hydraulic pressure along the entire length of the clamping surface."

Using the film provided a direct measurement of clamping pressure uniformity. "This tool allowed our engineers to quickly assess design iterations targeted toward improving clamping reliability," Johansson concluded.

Once Aradigm had the pressure data, it used an optical imaging tool called Topaq for analysis. Consisting of Windows-based software and a specially calibrated scanner system, Topaq renders images that are accurate to ±2 or ±3% full-scale (kg/cm2) and are accompanied by statistical data about the clamping-force pressure test. Key features of the system include the ability to produce histogramic data. The optical image-analysis system not only allows for the analysis of the entire interfacial surface, but small and problematic areas can also be enlarged, enhanced, and carefully scrutinized.

Rob Clark, principal mechanical engineer at Aradigm, says, "the Topaq analysis provided a quantitative measure of clamping-pressure distribution that allowed for a direct comparison to the pressure distribution predicted by FEA. The generally good agreement between the Topaq measurement and the FEA prediction gave us confidence that both techniques were giving reasonable results, and that the system was performing as intended." His final comment on the interpretation techniques employed by Aradigm during the design phase of their AERx pulmonary drug-delivery system reflected, in his opinion, a view that the "combination Pressurex/Topaq [method] helped improve product quality insofar as it provided assurance" that their design system met performance and production standards.

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