Manufacturing prescription drugs with distinct markings, colors, shapes or packaging isn’t enough to protect them from counterfeiting, U.S. Drug Enforcement Administration reports have shown.
Purdue University researchers are aiming to stump counterfeiters with an edible “security tag” embedded into medicine.
To imitate the drug, a counterfeiter would have to uncrack a complicated puzzle of patterns not fully visible to the naked eye.
The work is published in the journal Nature Communications.
Fake medicine is a thriving business, making up at least 10% of global pharmaceutical commerce while also claiming thousands of lives each year.
In the U.S., counterfeit drugs range from cancer and diabetes treatment to erectile dysfunction medication. Counterfeit opioids have caused deaths in 46 states.
Tagging drugs would not only guard against fakery, but also help pharmacies better verify the legitimacy of a drug before selling to consumers.
“Every single tag is unique, offering a much higher level of security,” said Young Kim, an associate professor in Purdue’s Weldon School of Biomedical Engineering.
The tag acts as a digital fingerprint for each drug capsule or tablet, using an authentication technique called “physical unclonable functions,” or PUF, that was originally developed for information and hardware security.
Purdue University researchers are aiming to stump counterfeiters with an edible “security tag” embedded into medicine. Credit: Purdue University/Erin Easterling
PUFs have the ability to generate a different response each time that they are stimulated, rendering them unpredictable and extremely difficult to duplicate. Even the manufacturer wouldn’t be able to re-create an identical PUF tag.
Kim’s group is the first to create an edible PUF – a thin, transparent film made of silk proteins and fluorescent proteins genetically fused together.
Because the tag is easily digestible and made entirely of proteins, it can be consumed as part of a pill or tablet.
Shining various LED light sources on the tag excites the fluorescent silk microparticles, causing them to generate a different random pattern each time. The microparticles emit cyan, green, yellow or red fluorescent colors.
Digital bits can then be extracted from an image of those patterns to produce a security key, which a pharmacy or patient would use to confirm that a drug is authentic.
The researchers are currently converting this process to a smartphone app for both pharmacies and consumers.
“Our concept is to use a smartphone to shine an LED light on the tag and take a picture of it. The app then identifies if the medicine is genuine or fake,” said Jung Woo Leem, a postdoctoral associate in biomedical engineering at Purdue.
The tag also has the potential to hold much more information than simply a confirmation of what the drug is, Leem said, such as the dose and expiration date.
Leem found that the tag works for at least a two-month period without the proteins degrading. Next, the team will need to confirm that the tag could last as long as a drug does and that it doesn’t affect a medicine’s key ingredients or potency.
Results
Protein-based PUFs
Figure 1 shows that the photoluminescent properties of fluorescent silk proteins are used to realize multiple challenge-response pairs in an edible PUF platform with heightened security for on-dose authentication and anti-counterfeiting of medicines. Importantly, challenge-response pairs differentiate our protein-based PUFs from other common unique objects and tags29,63.
In reaction to optical challenges, defined by a unique set of excitation and emission bands of different fluorescent proteins, the edible PUF made of silk protein (i.e., fibroin) and fluorescent proteins generates distinct output responses, which are used to extract digitized keys (Fig. 1a). The source of entropy is randomly distributed fluorescent silk microparticles seamlessly embedded in a covert thin transparent silk film.
First, we take advantage of four different fluorescent proteins (i.e., eCFP, eGFP, eYFP, and mKate2) that have specific excitation and emission peaks in the visible wavelength range (Supplementary Table 1).
Specifically, we utilize fluorescent protein-expressed silk produced by transgenic silkworms as recombinant proteins via the piggyBac transposase method (Supplementary Methods and Supplementary Fig. 1a).
Silk proteins are an excellent biopolymer to be genetically hybridized with fluorescent protein genes46,55,57,59.
Second, to fabricate fluorescent silk microparticles (Supplementary Fig. 2), fluorescent silk fibroin is regenerated into an aqueous solution with a low-temperature process, is freeze-dried, and is gently ground into zeolite-shaped microparticles with sizes of 99.3 ± 7.9 μm (mean ± standard deviation) (Fig. 2a, b and Supplementary Fig. 3).
Third, an admixture of the fluorescent silk microparticles is broadcast on a large flat surface and a white silk fibroin solution is poured on top. After an ambient drying process in the dark, this thin transparent silk film with a thickness of 150 μm is punched into 7 × 7 mm2 squares, resulting in all protein-based edible PUF devices (Methods and Supplementary Figs. 2 and 4). eCFP, eGFP, eYFP, and mKate2 silk cocoons possess bluish, greenish, yellowish, and reddish colors under white light illumination (Supplementary Fig. 1b).
However, after the regeneration of the fluorescent silk, each type of fluorescent silk microparticles are not distinguishable in the naked eye, while maintaining their fluorescent properties (Fig. 2 and Supplementary Fig. 5).
This fabrication process is scalable for mass production without using any sophisticated equipment and is safe for oral consumption without any organic solvents or synthetic polymers (e.g., methanol, ethanol, isopropanol, or polyvinyl alcohol) (Methods and Supplementary Fig. 6a).
Analyses of mass spectroscopy, energy-dispersive X-ray spectroscopy, and in vitro cytotoxicity (cell viability test) assays support the overall nontoxicity of the edible PUF devices (Supplementary Methods and Supplementary Figs. 7–9).
More information: Jung Woo Leem et al, Edible unclonable functions, Nature Communications (2020). DOI: 10.1038/s41467-019-14066-5
