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Dissolvable films can be die-cut and placed in a testing device or test strip used in immunoassays, food testing, environmental analysis, and emergency response test kits.

Dissolvable films were first introduced to consumers in 2001 as a novel breath freshener. Pharmaceutical companies quickly followed suit by developing oral strip formats of popular over-the-counter cold and antacid drugs to promote easy and accurate dosing for children and the elderly.¹ Manufacturers of cosmetic teeth whiteners, personal grooming products, and dishwashing detergents are also adopting ways to take advantage of the premeasured, single-dose benefits of dissolvable film technologies.

As IVD manufacturers explore new platform technologies, applications and cost reductions for next generation devices, dissolvable films can offer viable design and manufacturing benefits. The formulation of dissolvable films from aqueous polymer matrices across a wide molecular weight (Mw) range provides the flexibility to achieve various physical properties that can be tailored to the IVD manufacturer’s specific design needs. Reagents can be integrated directly into a dry, dissolvable film that may be die-cut and placed in a testing device or test strip used in immunoassays, cell separations, food testing, environmental analysis, and emergency response test kits.

Designers can use a single dissolvable film with one or multiple reagents. Alternatively, multiple dissolvable films with one or multiple reagents may also be considered for diagnostic test devices.²

This article will review the formulation, properties, benefits, and potential applications of dissolvable films for manufacturers of diagnostic tests such as biosensors, lateral-flow devices, test strips, and test cards.

Formulating Dissolvable Films

Single-layer dissolvable films are produced by combining water-soluble components and additives to attain the desired dissolution rate of less than 60 seconds when exposed to aqueous biological and environmental fluids. Various polymers can be used if they are water soluble, impart sufficient film strength, and enable the desired film disintegration properties.3 The optimal properties of film strength and disintegration are obtained when the water-soluble components include a combination of hydrophilic polymers.

Once a homogeneous solution is formed, reagents and plymers can be added to control the film’s strength and flexibility. The film can also include filler, which is a dispersed phase within the film to modify its dissolution profile. For cases in which combinations of additives are included, making the ingredients compatible with the polymer base formula can be challenging.

Other components such as starches and polysaccharides can promote or delay the film’s disintegration.² Plasticizers or humectants can be added during manufacturing to increase its overall flexibility, while preventing brittleness or breakage. Thickeners, buffers, stabilizers, and other additives can also be added to deliver the desired capabilities of the product design.

Some applications may require films to demonstrate variable dissolution times in order to perform in different conditions (e.g., elevated pH), which would require altering film thickness or adding materials with different solubility parameters. Dispersed phase filler particles can be included to add bulk to the film, increase the solids portion to aid in the coating process, or alter dissolution rates with an aqueous sample. Air or other gases can also change the dissolution time. A surface energy modifier can stabilize the gaseous bubbles as a dispersed phase within a solution to allow it to be processed.

A reagent or combination of reagents that may be either soluble in the solution, suspended, or dispersed is further processed into a film by one of many casting, drawing, or extruding techniques. For example, the solution or dispersion may be roll-coated onto a release-treated paper or film substrate.

After coating the solution or dispersion onto a support surface, the solvent is removed by drying, which produces a film containing one or more homogenously dispersed reagents. In addition, reagents may be homogenously dispersed in the film during extrusion processing. The preferred range for finished films is 0.4-2.0 mil, although various thicknesses are possible to meet the needs of a particular application.

The film is wound into a roll format prior to being processed into single, measured doses of films for specific IVD devices.

As a precaution, the finished rolls of dry film are wrapped in foil packaging to ensure environmental protection during handling and storage. Exposing test strips containing dissolvable films to high humidity should be avoided since hydrophilic water-soluble polymers are used. Because IVD manufacturers process their test strips under low humidity conditions, no changes in the manufacturing environment would be anticipated.

Figure 1. After coating, the film is dried and wound into a roll format prior to being processed into single, measured doses of films for specific IVD devices.

The dry film can be further processed by any suitable technique to achieve the desired outcome for the device, including die cutting or cutting across the width of a single, narrow roll. Continuous processing of rolls containing reagents can be less wasteful than conventional processes (see Figure 1).

Physical Properties

Figure 2. (click to enlarge) Disintegration photo series: (a) start of test; (b) three seconds; (c) five seconds; (d) ten seconds.

Characteristics such as thickness, dissolution rate, surface characteristics (e.g., texture), and mechanical properties (e.g., film strength) can be tailored for dissolvable films. Such physical attributes are affected by the Mw of the water-soluble polymers in the film base. High concentrations of nonfilm-forming additives will also decrease film strength and compromise dissolution time. Consequently, there is a balance that exists between film strength and disintegration rate (see Figure 2).³

Table I. (click to enlarge) Effect of polymer selection on dissolution time. Note: Test average of n = 4; Polymer content provided as ratio.

In addition, thickness and mass play a role in determining the dissolvable film’s physical properties. Constructions comprised predominantly of low-Mw, water-soluble polymers at different thicknesses will result in a range of disintegration rates and mechanical strengths. Table I illustrates the influence of Mw on film solubility. A combination of low-Mw cellulose and a low-Mw polymer reduces disintegration time. The effect appears substantial as an additional low-Mw polymer is added. The opposite effect is observed with a combination of high-Mw cellulose polymers; although they tend to impart good mechanical properties, disintegration time is increased.

Benefits of Dissolvable Films

Benefits of dissolvable films to IVD devices include the ability to do the following:

• Utilize premeasured, preservative-free single doses.
• Enable concentrated doses.
• Improve reagent stability.
• Allow efficient use of reagents.
• Enable continuous web processing.
• Increase device design options.
• Enable separation of reactive components.
• Utilize films as protective barriers to dissolve and expose active components.
• Improve cost-effectiveness.

As discussed previously, dissolvable films offer formulation flexibility for achieving the desired physical properties of an IVD’s specific application. Because these cast films are manufactured in a continuous web format, they can also offer significant manufacturing and cost efficiencies.

Conventional preparation techniques for test strips such as spraying, coating, or striping can result in reagent loss, which is expensive. Such methods can also be limiting in their effectiveness to distribute active components evenly throughout a membrane or conjugate pad. Since dissolvable films are formulated as a homogeneous mixture of a film former and reagents, consistent dispersion of the active component is a benefit of such films, translating to increased yield and reduced costs.²

The coating and processing of the film product can be customized by application. For example, the film may be cut into any size or shape to fit the end design, or may be provided in a continuous reel if needed. Each die-cut film component is a premeasured, single dose that is easier and safer to handle than aqueous solutions of reagents. Higher-dose concentrations can be obtained by increasing either the loadings in the film or the film’s overall mass and thickness.

Reagent-loaded dry films do not require refrigeration or preservatives. When the reagent is integrated into a film format, its increased stability results in less waste and requires fewer resources for IVD manufacturers to store and handle the fragile reagents properly.

Diagnostic Applications

Useful for many diagnostic applications, dissolvable film technologies can do the following:

• Facilitate incorporating reagents into devices such as lateral flow, microfluidics, and microplates.
• Allow controlled release of reagents through tailored dissolution rates.
• Create isolation barriers to separate components or reagents within a device.
• Enable multilayered film constructions, including vertical-flow configurations.

The unique physical properties of dissolvable films make them well suited to meet the specific design challenges of today’s IVD devices. Because a reagent may be incorporated directly into the film versus being sprayed or dispensed in droplet form by conventional methods, dispersion of a reagent within a dissolvable film is more consistent in delivering accurate results. Some appropriate reagents for integrating with dissolvable film technology may include proteins, enzymes, fluorescent markers, ferro fluids, and dyes for disease detection.

For diagnostic applications requiring controlled timing of a reaction, dissolvable films can also be incorporated as isolation barriers formulated with longer disintegration rates to delay a reaction. Alternatively, the films can be used in multiple-layer constructions containing or separating one or more reagents for their controlled release when exposed to an analyte in a device. The patent application for “Disintegratable Films for Diagnostic Devices” describes several theoretical device constructions and applications utilizing dissolvable film technology.²

Reagents can be formulated directly into a dissolvable film’s composition in place of the existing technique of impregnating a reagent onto an insoluble absorbent carrier. Reagents prepared by the latter technique are not readily extracted or diffused into a sample fluid because the insoluble carrier must be wetted in order for the reagents to dissolve prior to the reaction. By substituting a dissolvable film loaded with reagents in place of the coated carrier, IVD manufacturers can control analyte exposure to a reagent. Improved control and dosing of reagents becomes important in IVD devices using multiple reagents.

In test strips that measure blood glucose levels, a blood sample flows through a fluidic channel to a reaction zone where the glucose reacts with a reagent such as an oxidizing enzyme to produce a signal proportional to the glucose concentration. A dissolvable film containing the reactive components improves the stability of the reagents. In addition, a dissolvable film with reagents can improve the efficiency of the test strip manufacturing process by the continuous processing of rolls of reagents through die-cutting and reagent placement in the glucose test strip.

Multilayer Reagent Separation Constructions. Some devices may require reactants to be separated due to incompatibility or a required sequencing of reactants. In such cases, dissolvable films containing different reagents may be positioned adjacent to one another in the device on either a vertical or horizontal plane. As the sample fluid flows from one area to the next, sequential reactions can occur.

Figure 3. (click to enlarge) Dissolvable films may be loaded with reagents and utilized as a component for the conjugate pad or the area designated for capturing reagents.

Figure 3 illustrates how a dissolvable film can be integrated as part of a multilayer device to form fluidic channels for lateral-flow test strip designs. This example incorporates multiple dissolvable films, each containing two reagents for multiple reactions. This type of construction is suitable for use in hCG test strips, since multiple films are desired for the complex reactions.⁴ The first film contains an organic acid and an inorganic base, and the second film contains an organic salt and an organic amine.

Films as Barrier Layers. Some IVD devices require a controlled flow of a sample fluid from one reagent area to another, or to a designated test area in the device. If a time delay is required for a reaction between an analyte and one or more reagents, a dissolvable film can create a barrier for enabling the required reaction time. For example, a test may require saliva samples to be exposed to the first of two reagents for a period of time either to allow a reaction with an analyte or to break down the fluid to a less viscous form. In this case, a dissolvable film acts as a barrier to contain the fluid in a location of the device for a period of time. After sufficient contact time, the barrier film will disintegrate, allowing the analyte reactant or reagents to flow to a second reagent zone or detection area. The disintegration time of the dissolvable film barrier can be controlled through polymer selection, film components, and other physical properties of film.

Figure 4. (click to enlarge) By customizing disintegration times, dissolvable films may be used as barriers to control the flow of a sample fluid from one reagent to another.

Figure 4 shows how dissolvable films can function as an isolation barrier to separate various reactive components or act as a protective coating that dissolves to expose one reagent or reaction area to another. This feature would be advantageous for applications requiring a timed manual action, such as a valve release, in which multiple reactions are required. The interaction between reactive components in the device can be controlled by a choice of dissolution time and conditions, such as pH, temperature, or ionic strength.²

The use of ferro fluids such as iron oxide in IVD testing techniques, including immunoassays, cell separation, toxicity testing, food testing, and environmental analysis, has been ongoing for some time. In such assays, biochemical complexes are separated and isolated based on magnetic properties.⁵ While the use of magnetic particles in such tests is effective, it is difficult to control the concentration of such particles due to static effects of the glass and plastic containers used in conventional diagnostic techniques. Because dissolvable films offer a stable, dry reagent composition, this technology can provide IVD manufacturers with design capabilities that can mini- mize or eliminate such problems. Reagent-containing dissolvable films can be die-cut, and the reagent part can be dispensed directly into the diagnostic container or device.

Test Methods

Testing methods to characterize dissolvable films include dissolution time and film strength to assure that the dissolution rate needed for the application is met. Testing will also ensure that the films demonstrate the appropriate strength required to withstand the rigors of processing and packaging without breakage.

The disintegration test method calls for the sample to be placed in a basket that is repeatedly dunked into a fluid. The dissolution test immerses the film sample into a bath liquid that is mechanically agitated. Alternate testing methods may be developed to specifically suit the film’s polymer system. Other testing methods to simulate a desired environmental influence (e.g., disintegration in varying fluid temperatures) can also be applied.

Film strength properties are measured through tensile and burst tests, which measure the force required to break or puncture the film. Tensile strength can be measured on any standard tensile tester. 

Conclusion

As IVD manufacturers evaluate ways to meet the growing demand for better, faster, and more cost-effective constructions, dissolvable film technologies should be considered as a viable component in new applications and in the evolution of existing devices into their next generation.

A proven technology in a growing number of pharmaceutical and personal care products, dissolvable films can offer advantages to IVD devices, including improved reagent stability, higher manufacturing efficiency due to continuous web processing, precise dosing, increased choice of device designs (including lateral and vertical flow), and the controlled release of reagents. The precise placement of a reagent in a dissolvable film can translate to lower costs due to reduced waste. In addition, the benefit of dissolvable film technologies to an IVD device designer is the ability to customize the polymeric base to develop a system configured for the specific performance requirements of each diagnostic application.

 

William Meathrel, PhD, is the medical and pharmaceutical R&D group leader at Adhesives Research (Glen Rock, PA). He can be reached at bmeathrel@arglobal.com.	Cathy Moritz is a product development chemist for the ARcare medical division at Adhesives Research (Glen Rock, PA). She can be reached at cmoritz@arglobal.com.

 

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