- Email: [email protected]
Drug-laden 3D biodegradable label using QR code for anti-counterfeiting of drugs
Materials Science and Engineering C 63 (2016) 657–662
Contents lists available at ScienceDirect
Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec
Drug-laden 3D biodegradable label using QR code for anti-counterfeiting of drugs Jie Fei 1, Ran Liu ⁎,1 Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China
a r t i c l e
i n f o
Article history: Received 15 December 2015 Received in revised form 1 February 2016 Accepted 1 March 2016 Available online 4 March 2016 Keywords: Anti-counterfeiting QR code Drug-laden biodegradable label Identification
a b s t r a c t Wiping out counterfeit drugs is a great task for public health care around the world. The boost of these drugs makes treatment to become potentially harmful or even lethal. In this paper, biodegradable drug-laden QR code label for anti-counterfeiting of drugs is proposed that can provide the non-fluorescence recognition and high capacity. It is fabricated by the laser cutting to achieve the roughness over different surface which causes the difference in the gray levels on the translucent material the QR code pattern, and the micro mold process to obtain the drug-laden biodegradable label. We screened biomaterials presenting the relevant conditions and further requirements of the package. The drug-laden microlabel is on the surface of the troches or the bottom of the capsule and can be read by a simple smartphone QR code reader application. Labeling the pill directly and decoding the information successfully means more convenient and simple operation with nonfluorescence and high capacity in contrast to the traditional methods. © 2016 Elsevier B.V. All rights reserved.
1. Introduction With the rapid development of pharmaceutical industry, counterfeit products have emerged in the field of medical science. Fake drugs bring about an enormous damage, not only destroying the health and consumer-finances, but also decreasing public's trust of government facility system and sales revenue of the pharmaceutical companies, even condoning more criminal behaviors. According to the world health organization (WHO) and the United Nations Office (UNO on Drugs and Crime), worldwide counterfeits account of nearly 10%, with a higher proportion in sub-Saharan African and Southeast Asian regions. [1–3]The counterfeit market annual trade volume reaches $7.5 billion, rising by almost 90% in 5 years [4], with over $16,680,000 fake drugs being intercepted in 2011 by the US Customs and Border Protection (CBP) [5]. Although $400 million has been injected into the West African anti-malarial market, so far [6], fake meningitis vaccine took 2500 people's lives in Niger, of which 64% were forged [7,8]. Furthermore, numbers of people were killed due to illegal channels of mixing up cough medicine and drugs with diethylene glycol in Niger, 2008 [9,10]. Apart from security power and the rules of law, we should concentrate more on the anti-counterfeiting technology. Radio Frequency Identification (RFID) is a wireless use of electromagnetic fields to transfer data, for the purpose of automatically identifying and tracking the tags attached to objects, which was firstly applied during the establishment of the drug supply chain, 1996 [11]. It is reported that Pfizer initially ⁎ Corresponding author. E-mail address: [email protected] (R. Liu). 1 Jie Fei and Ran Liu contributed equally to this work.
http://dx.doi.org/10.1016/j.msec.2016.03.004 0928-4931/© 2016 Elsevier B.V. All rights reserved.
used RFID tags for the security of bottled medicines in 2005. [12] But during the RFID system pilot project, the US Food and Drug Administration (FDA) found that there were some problems in its applications, such as it influences the quality, safety and efficacy, and in addition to its flaw by technical standards in its accuracy of identification through various processes. Unmatched frequency could cause interference and insufficiency of the readable distance [13,14]. Pharmaceutical packaging technology is the alternative solution, which includes fluorescent inks, watermarks, and micro-printing, through which it's still hard to escape from the doom of counterfeit criminals' [15], for various reasons of uncomplicated measures and materials [16]. Although printing anticounterfeiting codes on the pharmaceutical package or blister card is possible and applicable, replacing them with fake ones is still a piece of cake for criminals. Besides that, fingerprint-like encoding strategies [17, 18], organic electronic devices [19], nanopillar array paper [20], 3D microstructure films [21], and invisible photonic printings [22] can make their ways into anti-counterfeiting authentication. Encoding polymer microparticles [23] and luminescent QR codes [24] are attractive as information carriers. Even DNA codes can be scanned directly by a smartphone [25]. Sunghoon Kwon and Wook Park's team from Kyung Hee University attempted to introduce lithographically encoded polymer microtaggants into capsules, which significantly improved the efforts to combat counterfeiting compared with the traditional methods [26]. However, this micro polymer was mixed with a fluorescent acrylic monomer, methacryloxyethyl thiocarbamoyl rhodamine B, which further complicates the fabrication in materials, as well as the identification under a fluorescence microscope. Furthermore, the approach that microtaggants are still required to be taken out of capsules, which means separating drugs and codes, seems not
658
J. Fei, R. Liu / Materials Science and Engineering C 63 (2016) 657–662
rigorous enough to come to terms of anti-counterfeiting. Also it is obviously inconvenient and costly for most public consumers. Since counterfeit drugs pose a growing threat to our live because they can deliver hazardous treatment or even cause death, we propose an encoded three dimensional drug-laden biodegradable label without fluorescence labeling for anti-counterfeiting of drugs. The technologies include the process of laser etching [27], micro machining and micro molding, as well as the designing and arrangement of identification. The experiments for screening of biodegradable material have been conducted, ensuring the safety of the drug labels. Using high-capacity and error-correctable QR code makes point-of-care testing convenient with smartphones. The developing ways of pharmaceutical packaging and storage are further discussed in this paper, which are being planned for further research. 2. Materials and methods 2.1. Materials and devices Polymethyl methacrylate (PMMA) sheets (2.0 mm thick) were purchased from Sunjin Electronics Co., Ltd. (Taiwan, China). Polydimethylsiloxane (PDMS) was purchased from Dow Corning Co., Ltd. (Midland, MI, USA). Polyvinyl alcohol (PVA) including 30,000 – 70,000 MW and 80,000 – 124,000 MW were purchased from Sigma-Aldrich Co., Ltd. (St. Louis, MO, USA). Hyaluronic acid (HA) including 400,000 – 1,000,000 MW and 1,800,000 – 2,200,000 MW were purchased from Shanghai Jiao Yuan Industry Co., Ltd. (Shanghai, China). Pharmaceutical gelatin (PG) including 50,000 – 60,000 MW and 150,000 – 250,000 MW were purchased from Aladdin Industrial Co., Ltd. (Shanghai, China). Laser cutting system (speedy 100) was purchased from Trobec Co., Ltd. (Wels, Austria). Vacuum pump and oven were purchased from Shanghai Boxun Industry & Commerce Co., Ltd. (Shanghai, China). An iPhone 5 (Apple Inc., Cupertino, CA, USA) was also used. 2.2. Design and fabrication of drug-laden biomaterial label with QR code The QR code has high-capacity and error-correctability, and also has comprehensive reading and fast generational abilities. A traditional bar code only enables to carry 12 to 20 characters [28], which is inadequate for drug security. To obtain the drug-laden QR code label, it is indispensable to prepare the encoding mold. We attempted to adopt PMMA plastic as the mold
on account of its excellent transparency, insulative resistance, aging resistance, corrosive resistance, easy processing, light weight and other good characteristics. Firstly, we need to require a QR code carrying production information, such as the drug name, manufacturer and its expiry date, through a two-dimensional code generator from a common website. In our laser cutting system, the light propagates along the vertical direction and spreads horizontally when the image plane is engraved over the PMMA sheet by a commercial software (Job control, Trobec Inc.), which is applicable for industrial production with high efficiency (Fig. 1a). Before laser engraving, the 2.0 mm thick PMMA sheet was ultrasonically washed for 10 min in deionized water, and then rinsed by a lot of distilled water to remove minor impurities attached to its surface. After drying it with compressed nitrogen, the desired template is engraved on the platform under the following conditions: laser energy density of 7.26 J/cm2, infrared wavelength of 10.6 μm and the maximum power of 1300 W. Focal distance from the substrate surface was maintained at 61.64 mm, under the processing speed of 180– 280 cm/s. The pattern of the template size was designed according to a commercial software (AutoCAD 2012, Autodesk Inc.) which was 4.35 mm long × 4.35 mm wide × 2.0 mm thick, with power of 12.66 W and its pace 189 cm/s. The laser parameters which are highly relevant with the clarity of QR code would be analyzed later in the results. Secondly, the code patterns are planned to be replicated from PMMA sheets to biocompatible materials (Fig. 1b). The liquid PDMS is cast over the patterned PMMA, and cured under oven with 70 °C for 1.5 h. The PDMS replica with QR code functional microstructures was removed from the PMMA master. The biomaterials, which we selected to make the drug capsule, were cast over PDMS mold with microstructures and allowed to dry in room temperature, and were removed from the PDMS mold. Another package was that the drug pill with QR code. We used the biomaterials to mix with drug content, and the mixed solution was cast over the PDMS mold with QR code. Then, the drug carrying QR code label was obtained after separation with the PDMS mold. We selected three kinds of materials (HA, PG and PVA) consisting of different molecular weight owning to their good biocompatibility, degradability and edibility. There were solutions including 1 wt.% HA, 10 wt.% PG and 15 wt.% PVA prepared for further use. These solutions were separately dropped over the PDMS mold with a pipette then ventilated them at room temperature (25 °C) for 1 day. Obviously increasing the temperature and more ventilation can be effective to decrease the time of solidification. After polymerization, three polymers were
Fig. 1. Design and fabrication processing of drug-laden biodegradable label. (a) Schematic diagram of the process of engraving QR codes over PMMA. (b) Schematic diagram of the micro mold processing of the drug-laden biodegradable label. The code patterns are replicated from PMMA sheets to biocompatible materials. The “A” represents encoded PMMA is poured by a layer of PDMS, then the PDMS is peeled off after drying and we get the “B” which is a replica of PDMS mold with QR code functional microstructure. The “C” means the biomaterials are poured over the “B” and produces the label film “D”; the “E” is a cylindrically shaped process over B and results into a capsule F.
J. Fei, R. Liu / Materials Science and Engineering C 63 (2016) 657–662
659
Fig. 2. The photos of the results of our fabrications. (a) The encoded label film was compared with a Chinese coin. (b) The film could stick perfectly over the pills with clear code (scale bar: 1 mm). (c) The capsule we fabricated and could load other granular or powder of medicines (scale bar: 1 mm). (d) Smartphone scanned the code directly upon the capsule and the information was then obtained and showed over the screen.
produced with functional QR code microstructures. These polymers could be bonded on the surface of the pills or be make of the capsules of the drugs. 2.3. Experiments on properties of biodegradable materials We would like to demonstrate the properties of solubility and stability in various biomaterials we selected after we had obtained the encoded biodegradable label successfully. We designed several experiments with three kinds of labeling films with different molecular weights were dissolved respectively in 10 ml of distilled water under the temperature of 25 °C. We observed the phenomena and recoded the times when the code structure and the whole label were completely dissolved.
3. Results 3.1. Biodegradable drug-laden QR code label After the experiments which we have described above, the biodegradable label film was accomplished with a thickness of 0.05 mm, smaller than a Chinese coin (diameter: 22.5 mm) (Fig. 2a). The encoded label films could attach closely to the pills with little adhesives (Fig. 2b). Another approach, fabricating to the drug capsules, was more capable of loading granules or powder form of medicine (Fig. 2c). Finally, the decoding was successful through the QR code reader application in iPhone 5 (Fig. 2d). Furthermore, it was possible to retrieve most of the information by directly connecting to the websites via links within the QR code. 3.2. Laser engraving parameters
2.4. Decoding steps of QR code Rapid and easy recognition of information in this label is essential for the anti-counterfeiting of drugs. Overall decoding of QR code was achieved using a simple reading application in a smartphone. Scanning directly is an obvious solution that the label lays vertically below the camera in the phone so as to be recognized without any magnification. In response to the interference of environmental diversity and human factors, a more efficient method is proposed to raise the identification rate of the image. Aiming to improve the contrast of the image which is acquired by camera, firstly the extracted gray levels are manipulated according to the threshold extension. Next, median filtering and dilation were important for the purpose of unnecessary noise distractions. All programming processes were realized and operated through MATLAB software. Finally, the processed image was scanned and our identification was accomplished.
In the process of engraving, we found that the mechanical parameters of laser power and pace significantly affected the quality of products. So we performed divergent parameters to acquire the optimal PMMA template with the same size of 4.35 mm × 4.35 mm. The results are summarized in Table 1.
Table 1 The relationship between laser parameters and product qualities. Power (W)
Pace (cm/s)
Aspect ratio
Articulation
Definition
12.33 12.495 12.66 12.66 12.66
188 188 188 188.5 189
0.33 0.36 0.39 0.35 0.30
Vague Vague Vague Vague Vague
ˣ ˣ ˣ √ √
660
J. Fei, R. Liu / Materials Science and Engineering C 63 (2016) 657–662
Fig. 3. The influence of aspect ratio. (a) The schematic of the structure (aspect ratio: 0.30), and the material object of the structure (scale bar: 1 mm) (b) The schematic of the structure (aspect ratio: 0.39), and the material object of the structure (scale bar: 1 mm).
The data in Table 1 could be fitted with the curve between two parameters on the aspect ratio. We could draw a conclusion that laser parameters influenced the aspect ratio, which was closely related with the clarity of QR code. Furthermore, power parameter drived inversely proportional to the pace parameter. The accuracy depended on capabilities of the device, which could search for further research. The principle that divergence in reflectivity caused by variety of roughness in PMMA surface after engraving brought about difference of gray values made possible for us to fabricate and identify the QR code (Fig. 3a), and the structures of the QR code were three dimensional. To test continuously by adjusting the parameters, we could find that within an appropriate range under certain conditions, the lesser the aspect ratio, the more the difference in roughness (reflectivity) was present, which meant the identification needed an upper limitation of aspect ratio (Fig. 3b).
1,800,000 – 220,000, PVA 80,000 – 124,000. During the material solubility experiments, we drew conclusions that HA and PG dissolved readily in the wet condition, whereas PVA was not prone to swelling with high humidity. The molecular weight of the material had a certain relationship with its moisture. Typically, the higher molecular weight demonstrated the better stability towards deliquescence. It was optimistic that these labels degraded in the body within a short period of time. The biomaterial screening results also tells us that dry storage should be marked to retain the information for HA and PG, in the production and commercialization of drugs, on account of their disposed deliquescence. But PVA could preserve well under a general environment, without increasing the complexity of the package and storage. According to their characteristics, the storage stability of PVA is better than HA and PG which can only maintain the integrity and efficiency of labels in dry circumstance. 3.4. Image analysis and processing
3.3. Biomaterial screening The results of the whole experiment could be observed in Fig. 4. Using 15 wt.% PVA 30,000 – 70,000 label as an example, the label film was fully dissolved within 60 min (shown as Fig. 5). Relatively low molecular weight represented HA 40,000 – 1,000,000, PG 50,000 – 60,000, PVA 30,000 – 70,000; while relatively high molecular weight stood HA
Usually we let the label lay vertically below the camera so as to be recognized in normal circumstances (Fig. 2d). Aiming to ensure the success rate of recognition, we shot a photograph under a CCD camera (Fig. 6a). For the purpose of strengthening the contrast, algorithms comprising threshold extension and noise reduction (dilation and erosion plus median filtering) were added to ensure the identification faster over
Fig. 4. The bar graphs of the dissolution time of the experiments of biomaterials (HA, PG, and PVA). (a) The dissolution time of the part with the QR code microstructure. (b) The dissolution time of the whole label.
J. Fei, R. Liu / Materials Science and Engineering C 63 (2016) 657–662
661
Fig. 5. The photos of dissolution phenomena at different time period (0, 1 min, 10 min, 60 min). The label dissolved was the 30,000 – 70,000 PVA.
the MATLAB platform. As a result of collecting gray values between segment AB (Fig. 6b), it was obvious that the QR code becomes amiable to be recognized after image processing (Fig. 6c,d). 4. Discussions and conclusions In conclusion, we developed a drug-laden encoded 3D biodegradable polymer micro label by laser engraving and micro molding of a QR code suitable for anti-counterfeiting of drugs, which is suitable for multiple states of drugs, such as troche, powder, and granule. This simple fabrication processing method used the laser cutter to achieve the roughness over different surface which causes the difference in the gray levels on the translucent material to form the micro pattern of the QR code. The laser parameter optimization could achieve the micro scale size of the QR code to be used to carry bio-information in smaller biological samples. This technique needs not the fluorescein recognition device. The polymer we used to load the code had good biocompatibility and even could be dissolved fast, which could mix with the drug contents or be as a drug capsule. So labeling each pill directly prevents from replacing the pharmaceutical package or blister card
illegally. We also demonstrated the complete process of drug authentication using QR-coded micro label, from the formulation of the pill itself and capsule to the decoding step directly using a QR code reader application on a simple smartphone without the image processing and other devices. The bioactivity of the drugs including aspirin, glucose, glucuronolactone and ziprasidone hydrochloride (antineoplastic drugs would be validated soon) with encoding QR code would not be damaged. Furthermore, the pharmacokinetic and pharmacodynamic experiments of drug release would be designed and implemented systematically for further research. Besides, we would observe the dissolution of drug labels in the digestive juice by mimicking the gastrointestinal environment for oral drug delivery in the future work. In terms of information recorder, QR code is an excellent opportunity because of its high-capacity and error-correctability, its comprehensive reading ability, and its rapid and easy generation. Considering the perspectives of industrial products, the packaging of medicine restricts and burdens less to its storage, which brings high acceptance to patients as well. We anticipate broad applications of the current platform for the establishment of databases of drugs in the fields of high-throughput
Fig. 6. The image processing section. (a) The anti-counterfeiting drug-laden label with QR code under CCD(scale bar: 1 mm). (b) The value of gray from A to B before processing. (c) The successfully identified image after processing. (d) The value of gray from A to B after processing.
662
J. Fei, R. Liu / Materials Science and Engineering C 63 (2016) 657–662
screening and drug delivery [29,30]. In food security areas, validation of expired time can be a future work by adjusting the temperature parameters and controlling the degradation rate of the label. We can also make a lot of small interesting toys and foods for children with microstructures of these safe biodegradable materials. As for the design inspiration of smart home and wearable devices, a smart label would play an increasingly important role in the future of humanity. Acknowledgements This research was supported by the National Natural Science Foundation of China under Grant 81471749, the Tsinghua University Initiative Scientific Research Program 20131089190, the National Scientific Equipment Development Special Foundation of China under Grant No. 2011YQ030134, the Tsinghua-Salubris Joint Center for Cancer and Infection Diseases Drug Discovery and Development, and the Foundation of Beijing Laboratory in Biomedical Technology and Instruments. References [1] M.L.N. Gaurvika, G.B. Joel, N.N. Paul, H. James, Poor quality antimalarial drugs in Southeast Asia and sub-Saharan Africa, Lancet Infect. Dis. 12 (6) (2012) 488. [2] D. Reddy, J. Banerji, Commentary: counterfeit antimalarial drugs, Lancet Infect. Dis. 12 (11) (2012) 829. [3] World Health Organization, The Sixty-fourth World Health Assembly the Report of the Working Group of Member States on Substandard/Spurious/Falsely-Labelled/ Falsified/Counterfeit Medical Products. established by decision WHA63(10), Geneva, 28 February to 2 March, 2011. [4] World Health Organization, Growing threat from counterfeit medicines, Bull. World Health Organ. 88 (2010) 247. [5] E.C. Peggy, A.S. Stephen, The challenge of curbing counterfeit prescription drug growth: preventing the perfect storm, Bus. Horiz. 56 (2013) 189. [6] T.K. Mackey, B.A. Liang, Improving global health governance to combat counterfeit medicines: a proposal for a UNODC-WHO-Interpol trilateral mechanism, BMC Med. 11 (2013) 233. [7] K. Theodore, K. Iosif, I.R. Petros, E.F. Matthew, Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence, Anti. Chem. 60 (2007) 214. [8] The Economist. Fake pharmaceuticals: bad medicine [online]. http://www.economist.com/node/21564546/2012 (accessed Apr 17, 2014). [9] A. Olusegun, Counterfeit drugs in Nigeria: a threat to public health, Afr. J. Pharm. Phamacol. 7 (36) (2013) 2571. [10] E.D. Rentz, L. Lewis, B.B. Dana, G.S. Joshua, W. Gayanga, P. Kuklenyik, M. McGeehin, J. Osterloh, J. Wamsley, C. Rubin, O.J. Mujica, W.C. Alleyne, N. Sosa, J. Motta, Outbreak of acute renal failure in Panama in 2006: a case–control study, Bull. World Health Organ. 86 (2008) 749–756. [11] T. Douglas, RFID in pharmaceutical industry: addressing counterfeits with technology, Med. Syst. 38 (2014) 141.
[12] M. Attaran, RFID: an enabler of supply chain operations, J. Supply Chain Manag. 4 (2007) 249–257. [13] F. Chen, X. Hong, Application of wireless radio frequency identification technology in drug security and tracking, Prog. Pharm. Sci. 3 (2006) 34. [14] A.M. Wicks, J.K. Visich, S. Li, Radio frequency identification applications in hospital environments, Hosp. Top. 84 (2006) 3–8. [15] C. Su, Status quo and development of drugs packaging for anti-counterfeiting, China Anti-counterfeiting Report, 6 2008, p. 76. [16] Y. Wu, Current situation and development of anti-counterfeit packaging of drugs, Food Drug 8 (2006) 31–33. [17] H.J. Bae, S. Bae, C. Park, S. Han, J. Kim, L.N. Kim, K. Kim, S.-H. Song, W. Park, S. Kwon, Biomimetic microfingerprints for anti-counterfeiting strategies, Adv. Mater. 27 (2015) 2083–2089. [18] J. Yin, M.C. Boyce, Materials science: unique wrinkles as identity tags, Nature 520 (2015) 164–165. [19] L. Zhang, H. Wang, Y. Zhao, Y. Guo, W. Hu, G. Yu, Y. Liu, Substrate-free ultra-flexible organic field-effect transistors and five-stage ring oscillators, Adv. Mater. 23 (2013) 5455–5460. [20] K.G. Lee, B.G. Choi, B.I. Kim, T. Shyu, M.S. Oh, S.G. Im, S.-J. Chang, T.J. Lee, N.A. Kotov, S.J. Lee, Transferring flexible and scalable nanopillar arrays, Adv. Mater. 26 (2014) 6119–6124. [21] T.S. Shim, S.-M. Yang, S.-H. Kim, Dynamic designing of microstructures by chemical gradient-mediated growth, Nat. Commun. 6 (2015) 6584. [22] H. Hu, J. Tang, H. Zhong, Z. Xi, C. Chen, Q. Chen, Invisible photonic printing: computer designing graphics, UV printing and shown by a magnetic field, Sci. Rep. 3 (2013) 1484. [23] J. Lee, P.W. Bisso, R.L. Srinivas, J.J. Kim, A.J. Swiston, P.S. Doyle, Universal processinert encoding architecture for polymer microparticles, Nat. Mater. 13 (2014) 524–529. [24] S. Armstrong, O. Graydon, D. Pile, R. Won, Squeeze with care, Nat. Photonics 6 (2012) 801. [25] D.-H. Park, C.J. Han, Y.-G. Shul, J.-H. Choy, Avatar DNA nanohybrid system in chipon-a-phone, Sci. Rep. 4 (2014) 4879. [26] S. Han, H.J. Bae, J. Kim, S. Shin, S. Choi, S.H. Lee, S. Kwon, W. Park, Lithographically encoded polymer microtaggant using high-capacity and error-correctable QR code for anti-counterfeiting of drugs, Adv. Mater. 24 (2012) 5924. [27] R.J. Jackman, D.C. Duffy, E. Ostuni, J.C. McDonald, O.J. Schueller, G.M. Whitesides, Fabricating large arrays of microwells with arbitrary dimensions and filling them using discontinuous dewetting, Anal. Chem. 70 (11) (1998) 2280–2287. [28] J.J. Lou, G. Andrechak, M. Riben, W.H. Yong, A review of radio frequency identification technology for the anatomic pathology or biorepository laboratory: much promise, some progress, and more work needed, J. Pathol. Inform. 2 (2011) 34. [29] A.E. Kusi-Appiah, N. Vafai, P.J. Cranfill, M.W. Davidson, S. Lenhert, Lipid multilayer microarrays for in vitro liposomal drug delivery and screening, Biomaterials 33 (2012) 4187–4194. [30] S. Zhang, W. Tong, B. Zheng, T.A.K. Susanto, L. Xia, C. Zhang, A. Ananthanarayanan, X. Tuo, R.B. Sakban, R. Jia, C. Iliescu, K.-H. Chai, M. McMillian, S. Shen, H. Leo, H. Yu, A robust high-throughput sandwich cell-based drug screening platform, Biomaterials 32 (2011) 1229–1241.
Contents lists available at ScienceDirect
Materials Science and Engineering C journal homepage: www.elsevier.com/locate/msec
Drug-laden 3D biodegradable label using QR code for anti-counterfeiting of drugs Jie Fei 1, Ran Liu ⁎,1 Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China
a r t i c l e
i n f o
Article history: Received 15 December 2015 Received in revised form 1 February 2016 Accepted 1 March 2016 Available online 4 March 2016 Keywords: Anti-counterfeiting QR code Drug-laden biodegradable label Identification
a b s t r a c t Wiping out counterfeit drugs is a great task for public health care around the world. The boost of these drugs makes treatment to become potentially harmful or even lethal. In this paper, biodegradable drug-laden QR code label for anti-counterfeiting of drugs is proposed that can provide the non-fluorescence recognition and high capacity. It is fabricated by the laser cutting to achieve the roughness over different surface which causes the difference in the gray levels on the translucent material the QR code pattern, and the micro mold process to obtain the drug-laden biodegradable label. We screened biomaterials presenting the relevant conditions and further requirements of the package. The drug-laden microlabel is on the surface of the troches or the bottom of the capsule and can be read by a simple smartphone QR code reader application. Labeling the pill directly and decoding the information successfully means more convenient and simple operation with nonfluorescence and high capacity in contrast to the traditional methods. © 2016 Elsevier B.V. All rights reserved.
1. Introduction With the rapid development of pharmaceutical industry, counterfeit products have emerged in the field of medical science. Fake drugs bring about an enormous damage, not only destroying the health and consumer-finances, but also decreasing public's trust of government facility system and sales revenue of the pharmaceutical companies, even condoning more criminal behaviors. According to the world health organization (WHO) and the United Nations Office (UNO on Drugs and Crime), worldwide counterfeits account of nearly 10%, with a higher proportion in sub-Saharan African and Southeast Asian regions. [1–3]The counterfeit market annual trade volume reaches $7.5 billion, rising by almost 90% in 5 years [4], with over $16,680,000 fake drugs being intercepted in 2011 by the US Customs and Border Protection (CBP) [5]. Although $400 million has been injected into the West African anti-malarial market, so far [6], fake meningitis vaccine took 2500 people's lives in Niger, of which 64% were forged [7,8]. Furthermore, numbers of people were killed due to illegal channels of mixing up cough medicine and drugs with diethylene glycol in Niger, 2008 [9,10]. Apart from security power and the rules of law, we should concentrate more on the anti-counterfeiting technology. Radio Frequency Identification (RFID) is a wireless use of electromagnetic fields to transfer data, for the purpose of automatically identifying and tracking the tags attached to objects, which was firstly applied during the establishment of the drug supply chain, 1996 [11]. It is reported that Pfizer initially ⁎ Corresponding author. E-mail address: [email protected] (R. Liu). 1 Jie Fei and Ran Liu contributed equally to this work.
http://dx.doi.org/10.1016/j.msec.2016.03.004 0928-4931/© 2016 Elsevier B.V. All rights reserved.
used RFID tags for the security of bottled medicines in 2005. [12] But during the RFID system pilot project, the US Food and Drug Administration (FDA) found that there were some problems in its applications, such as it influences the quality, safety and efficacy, and in addition to its flaw by technical standards in its accuracy of identification through various processes. Unmatched frequency could cause interference and insufficiency of the readable distance [13,14]. Pharmaceutical packaging technology is the alternative solution, which includes fluorescent inks, watermarks, and micro-printing, through which it's still hard to escape from the doom of counterfeit criminals' [15], for various reasons of uncomplicated measures and materials [16]. Although printing anticounterfeiting codes on the pharmaceutical package or blister card is possible and applicable, replacing them with fake ones is still a piece of cake for criminals. Besides that, fingerprint-like encoding strategies [17, 18], organic electronic devices [19], nanopillar array paper [20], 3D microstructure films [21], and invisible photonic printings [22] can make their ways into anti-counterfeiting authentication. Encoding polymer microparticles [23] and luminescent QR codes [24] are attractive as information carriers. Even DNA codes can be scanned directly by a smartphone [25]. Sunghoon Kwon and Wook Park's team from Kyung Hee University attempted to introduce lithographically encoded polymer microtaggants into capsules, which significantly improved the efforts to combat counterfeiting compared with the traditional methods [26]. However, this micro polymer was mixed with a fluorescent acrylic monomer, methacryloxyethyl thiocarbamoyl rhodamine B, which further complicates the fabrication in materials, as well as the identification under a fluorescence microscope. Furthermore, the approach that microtaggants are still required to be taken out of capsules, which means separating drugs and codes, seems not
658
J. Fei, R. Liu / Materials Science and Engineering C 63 (2016) 657–662
rigorous enough to come to terms of anti-counterfeiting. Also it is obviously inconvenient and costly for most public consumers. Since counterfeit drugs pose a growing threat to our live because they can deliver hazardous treatment or even cause death, we propose an encoded three dimensional drug-laden biodegradable label without fluorescence labeling for anti-counterfeiting of drugs. The technologies include the process of laser etching [27], micro machining and micro molding, as well as the designing and arrangement of identification. The experiments for screening of biodegradable material have been conducted, ensuring the safety of the drug labels. Using high-capacity and error-correctable QR code makes point-of-care testing convenient with smartphones. The developing ways of pharmaceutical packaging and storage are further discussed in this paper, which are being planned for further research. 2. Materials and methods 2.1. Materials and devices Polymethyl methacrylate (PMMA) sheets (2.0 mm thick) were purchased from Sunjin Electronics Co., Ltd. (Taiwan, China). Polydimethylsiloxane (PDMS) was purchased from Dow Corning Co., Ltd. (Midland, MI, USA). Polyvinyl alcohol (PVA) including 30,000 – 70,000 MW and 80,000 – 124,000 MW were purchased from Sigma-Aldrich Co., Ltd. (St. Louis, MO, USA). Hyaluronic acid (HA) including 400,000 – 1,000,000 MW and 1,800,000 – 2,200,000 MW were purchased from Shanghai Jiao Yuan Industry Co., Ltd. (Shanghai, China). Pharmaceutical gelatin (PG) including 50,000 – 60,000 MW and 150,000 – 250,000 MW were purchased from Aladdin Industrial Co., Ltd. (Shanghai, China). Laser cutting system (speedy 100) was purchased from Trobec Co., Ltd. (Wels, Austria). Vacuum pump and oven were purchased from Shanghai Boxun Industry & Commerce Co., Ltd. (Shanghai, China). An iPhone 5 (Apple Inc., Cupertino, CA, USA) was also used. 2.2. Design and fabrication of drug-laden biomaterial label with QR code The QR code has high-capacity and error-correctability, and also has comprehensive reading and fast generational abilities. A traditional bar code only enables to carry 12 to 20 characters [28], which is inadequate for drug security. To obtain the drug-laden QR code label, it is indispensable to prepare the encoding mold. We attempted to adopt PMMA plastic as the mold
on account of its excellent transparency, insulative resistance, aging resistance, corrosive resistance, easy processing, light weight and other good characteristics. Firstly, we need to require a QR code carrying production information, such as the drug name, manufacturer and its expiry date, through a two-dimensional code generator from a common website. In our laser cutting system, the light propagates along the vertical direction and spreads horizontally when the image plane is engraved over the PMMA sheet by a commercial software (Job control, Trobec Inc.), which is applicable for industrial production with high efficiency (Fig. 1a). Before laser engraving, the 2.0 mm thick PMMA sheet was ultrasonically washed for 10 min in deionized water, and then rinsed by a lot of distilled water to remove minor impurities attached to its surface. After drying it with compressed nitrogen, the desired template is engraved on the platform under the following conditions: laser energy density of 7.26 J/cm2, infrared wavelength of 10.6 μm and the maximum power of 1300 W. Focal distance from the substrate surface was maintained at 61.64 mm, under the processing speed of 180– 280 cm/s. The pattern of the template size was designed according to a commercial software (AutoCAD 2012, Autodesk Inc.) which was 4.35 mm long × 4.35 mm wide × 2.0 mm thick, with power of 12.66 W and its pace 189 cm/s. The laser parameters which are highly relevant with the clarity of QR code would be analyzed later in the results. Secondly, the code patterns are planned to be replicated from PMMA sheets to biocompatible materials (Fig. 1b). The liquid PDMS is cast over the patterned PMMA, and cured under oven with 70 °C for 1.5 h. The PDMS replica with QR code functional microstructures was removed from the PMMA master. The biomaterials, which we selected to make the drug capsule, were cast over PDMS mold with microstructures and allowed to dry in room temperature, and were removed from the PDMS mold. Another package was that the drug pill with QR code. We used the biomaterials to mix with drug content, and the mixed solution was cast over the PDMS mold with QR code. Then, the drug carrying QR code label was obtained after separation with the PDMS mold. We selected three kinds of materials (HA, PG and PVA) consisting of different molecular weight owning to their good biocompatibility, degradability and edibility. There were solutions including 1 wt.% HA, 10 wt.% PG and 15 wt.% PVA prepared for further use. These solutions were separately dropped over the PDMS mold with a pipette then ventilated them at room temperature (25 °C) for 1 day. Obviously increasing the temperature and more ventilation can be effective to decrease the time of solidification. After polymerization, three polymers were
Fig. 1. Design and fabrication processing of drug-laden biodegradable label. (a) Schematic diagram of the process of engraving QR codes over PMMA. (b) Schematic diagram of the micro mold processing of the drug-laden biodegradable label. The code patterns are replicated from PMMA sheets to biocompatible materials. The “A” represents encoded PMMA is poured by a layer of PDMS, then the PDMS is peeled off after drying and we get the “B” which is a replica of PDMS mold with QR code functional microstructure. The “C” means the biomaterials are poured over the “B” and produces the label film “D”; the “E” is a cylindrically shaped process over B and results into a capsule F.
J. Fei, R. Liu / Materials Science and Engineering C 63 (2016) 657–662
659
Fig. 2. The photos of the results of our fabrications. (a) The encoded label film was compared with a Chinese coin. (b) The film could stick perfectly over the pills with clear code (scale bar: 1 mm). (c) The capsule we fabricated and could load other granular or powder of medicines (scale bar: 1 mm). (d) Smartphone scanned the code directly upon the capsule and the information was then obtained and showed over the screen.
produced with functional QR code microstructures. These polymers could be bonded on the surface of the pills or be make of the capsules of the drugs. 2.3. Experiments on properties of biodegradable materials We would like to demonstrate the properties of solubility and stability in various biomaterials we selected after we had obtained the encoded biodegradable label successfully. We designed several experiments with three kinds of labeling films with different molecular weights were dissolved respectively in 10 ml of distilled water under the temperature of 25 °C. We observed the phenomena and recoded the times when the code structure and the whole label were completely dissolved.
3. Results 3.1. Biodegradable drug-laden QR code label After the experiments which we have described above, the biodegradable label film was accomplished with a thickness of 0.05 mm, smaller than a Chinese coin (diameter: 22.5 mm) (Fig. 2a). The encoded label films could attach closely to the pills with little adhesives (Fig. 2b). Another approach, fabricating to the drug capsules, was more capable of loading granules or powder form of medicine (Fig. 2c). Finally, the decoding was successful through the QR code reader application in iPhone 5 (Fig. 2d). Furthermore, it was possible to retrieve most of the information by directly connecting to the websites via links within the QR code. 3.2. Laser engraving parameters
2.4. Decoding steps of QR code Rapid and easy recognition of information in this label is essential for the anti-counterfeiting of drugs. Overall decoding of QR code was achieved using a simple reading application in a smartphone. Scanning directly is an obvious solution that the label lays vertically below the camera in the phone so as to be recognized without any magnification. In response to the interference of environmental diversity and human factors, a more efficient method is proposed to raise the identification rate of the image. Aiming to improve the contrast of the image which is acquired by camera, firstly the extracted gray levels are manipulated according to the threshold extension. Next, median filtering and dilation were important for the purpose of unnecessary noise distractions. All programming processes were realized and operated through MATLAB software. Finally, the processed image was scanned and our identification was accomplished.
In the process of engraving, we found that the mechanical parameters of laser power and pace significantly affected the quality of products. So we performed divergent parameters to acquire the optimal PMMA template with the same size of 4.35 mm × 4.35 mm. The results are summarized in Table 1.
Table 1 The relationship between laser parameters and product qualities. Power (W)
Pace (cm/s)
Aspect ratio
Articulation
Definition
12.33 12.495 12.66 12.66 12.66
188 188 188 188.5 189
0.33 0.36 0.39 0.35 0.30
Vague Vague Vague Vague Vague
ˣ ˣ ˣ √ √
660
J. Fei, R. Liu / Materials Science and Engineering C 63 (2016) 657–662
Fig. 3. The influence of aspect ratio. (a) The schematic of the structure (aspect ratio: 0.30), and the material object of the structure (scale bar: 1 mm) (b) The schematic of the structure (aspect ratio: 0.39), and the material object of the structure (scale bar: 1 mm).
The data in Table 1 could be fitted with the curve between two parameters on the aspect ratio. We could draw a conclusion that laser parameters influenced the aspect ratio, which was closely related with the clarity of QR code. Furthermore, power parameter drived inversely proportional to the pace parameter. The accuracy depended on capabilities of the device, which could search for further research. The principle that divergence in reflectivity caused by variety of roughness in PMMA surface after engraving brought about difference of gray values made possible for us to fabricate and identify the QR code (Fig. 3a), and the structures of the QR code were three dimensional. To test continuously by adjusting the parameters, we could find that within an appropriate range under certain conditions, the lesser the aspect ratio, the more the difference in roughness (reflectivity) was present, which meant the identification needed an upper limitation of aspect ratio (Fig. 3b).
1,800,000 – 220,000, PVA 80,000 – 124,000. During the material solubility experiments, we drew conclusions that HA and PG dissolved readily in the wet condition, whereas PVA was not prone to swelling with high humidity. The molecular weight of the material had a certain relationship with its moisture. Typically, the higher molecular weight demonstrated the better stability towards deliquescence. It was optimistic that these labels degraded in the body within a short period of time. The biomaterial screening results also tells us that dry storage should be marked to retain the information for HA and PG, in the production and commercialization of drugs, on account of their disposed deliquescence. But PVA could preserve well under a general environment, without increasing the complexity of the package and storage. According to their characteristics, the storage stability of PVA is better than HA and PG which can only maintain the integrity and efficiency of labels in dry circumstance. 3.4. Image analysis and processing
3.3. Biomaterial screening The results of the whole experiment could be observed in Fig. 4. Using 15 wt.% PVA 30,000 – 70,000 label as an example, the label film was fully dissolved within 60 min (shown as Fig. 5). Relatively low molecular weight represented HA 40,000 – 1,000,000, PG 50,000 – 60,000, PVA 30,000 – 70,000; while relatively high molecular weight stood HA
Usually we let the label lay vertically below the camera so as to be recognized in normal circumstances (Fig. 2d). Aiming to ensure the success rate of recognition, we shot a photograph under a CCD camera (Fig. 6a). For the purpose of strengthening the contrast, algorithms comprising threshold extension and noise reduction (dilation and erosion plus median filtering) were added to ensure the identification faster over
Fig. 4. The bar graphs of the dissolution time of the experiments of biomaterials (HA, PG, and PVA). (a) The dissolution time of the part with the QR code microstructure. (b) The dissolution time of the whole label.
J. Fei, R. Liu / Materials Science and Engineering C 63 (2016) 657–662
661
Fig. 5. The photos of dissolution phenomena at different time period (0, 1 min, 10 min, 60 min). The label dissolved was the 30,000 – 70,000 PVA.
the MATLAB platform. As a result of collecting gray values between segment AB (Fig. 6b), it was obvious that the QR code becomes amiable to be recognized after image processing (Fig. 6c,d). 4. Discussions and conclusions In conclusion, we developed a drug-laden encoded 3D biodegradable polymer micro label by laser engraving and micro molding of a QR code suitable for anti-counterfeiting of drugs, which is suitable for multiple states of drugs, such as troche, powder, and granule. This simple fabrication processing method used the laser cutter to achieve the roughness over different surface which causes the difference in the gray levels on the translucent material to form the micro pattern of the QR code. The laser parameter optimization could achieve the micro scale size of the QR code to be used to carry bio-information in smaller biological samples. This technique needs not the fluorescein recognition device. The polymer we used to load the code had good biocompatibility and even could be dissolved fast, which could mix with the drug contents or be as a drug capsule. So labeling each pill directly prevents from replacing the pharmaceutical package or blister card
illegally. We also demonstrated the complete process of drug authentication using QR-coded micro label, from the formulation of the pill itself and capsule to the decoding step directly using a QR code reader application on a simple smartphone without the image processing and other devices. The bioactivity of the drugs including aspirin, glucose, glucuronolactone and ziprasidone hydrochloride (antineoplastic drugs would be validated soon) with encoding QR code would not be damaged. Furthermore, the pharmacokinetic and pharmacodynamic experiments of drug release would be designed and implemented systematically for further research. Besides, we would observe the dissolution of drug labels in the digestive juice by mimicking the gastrointestinal environment for oral drug delivery in the future work. In terms of information recorder, QR code is an excellent opportunity because of its high-capacity and error-correctability, its comprehensive reading ability, and its rapid and easy generation. Considering the perspectives of industrial products, the packaging of medicine restricts and burdens less to its storage, which brings high acceptance to patients as well. We anticipate broad applications of the current platform for the establishment of databases of drugs in the fields of high-throughput
Fig. 6. The image processing section. (a) The anti-counterfeiting drug-laden label with QR code under CCD(scale bar: 1 mm). (b) The value of gray from A to B before processing. (c) The successfully identified image after processing. (d) The value of gray from A to B after processing.
662
J. Fei, R. Liu / Materials Science and Engineering C 63 (2016) 657–662
screening and drug delivery [29,30]. In food security areas, validation of expired time can be a future work by adjusting the temperature parameters and controlling the degradation rate of the label. We can also make a lot of small interesting toys and foods for children with microstructures of these safe biodegradable materials. As for the design inspiration of smart home and wearable devices, a smart label would play an increasingly important role in the future of humanity. Acknowledgements This research was supported by the National Natural Science Foundation of China under Grant 81471749, the Tsinghua University Initiative Scientific Research Program 20131089190, the National Scientific Equipment Development Special Foundation of China under Grant No. 2011YQ030134, the Tsinghua-Salubris Joint Center for Cancer and Infection Diseases Drug Discovery and Development, and the Foundation of Beijing Laboratory in Biomedical Technology and Instruments. References [1] M.L.N. Gaurvika, G.B. Joel, N.N. Paul, H. James, Poor quality antimalarial drugs in Southeast Asia and sub-Saharan Africa, Lancet Infect. Dis. 12 (6) (2012) 488. [2] D. Reddy, J. Banerji, Commentary: counterfeit antimalarial drugs, Lancet Infect. Dis. 12 (11) (2012) 829. [3] World Health Organization, The Sixty-fourth World Health Assembly the Report of the Working Group of Member States on Substandard/Spurious/Falsely-Labelled/ Falsified/Counterfeit Medical Products. established by decision WHA63(10), Geneva, 28 February to 2 March, 2011. [4] World Health Organization, Growing threat from counterfeit medicines, Bull. World Health Organ. 88 (2010) 247. [5] E.C. Peggy, A.S. Stephen, The challenge of curbing counterfeit prescription drug growth: preventing the perfect storm, Bus. Horiz. 56 (2013) 189. [6] T.K. Mackey, B.A. Liang, Improving global health governance to combat counterfeit medicines: a proposal for a UNODC-WHO-Interpol trilateral mechanism, BMC Med. 11 (2013) 233. [7] K. Theodore, K. Iosif, I.R. Petros, E.F. Matthew, Counterfeit or substandard antimicrobial drugs: a review of the scientific evidence, Anti. Chem. 60 (2007) 214. [8] The Economist. Fake pharmaceuticals: bad medicine [online]. http://www.economist.com/node/21564546/2012 (accessed Apr 17, 2014). [9] A. Olusegun, Counterfeit drugs in Nigeria: a threat to public health, Afr. J. Pharm. Phamacol. 7 (36) (2013) 2571. [10] E.D. Rentz, L. Lewis, B.B. Dana, G.S. Joshua, W. Gayanga, P. Kuklenyik, M. McGeehin, J. Osterloh, J. Wamsley, C. Rubin, O.J. Mujica, W.C. Alleyne, N. Sosa, J. Motta, Outbreak of acute renal failure in Panama in 2006: a case–control study, Bull. World Health Organ. 86 (2008) 749–756. [11] T. Douglas, RFID in pharmaceutical industry: addressing counterfeits with technology, Med. Syst. 38 (2014) 141.
[12] M. Attaran, RFID: an enabler of supply chain operations, J. Supply Chain Manag. 4 (2007) 249–257. [13] F. Chen, X. Hong, Application of wireless radio frequency identification technology in drug security and tracking, Prog. Pharm. Sci. 3 (2006) 34. [14] A.M. Wicks, J.K. Visich, S. Li, Radio frequency identification applications in hospital environments, Hosp. Top. 84 (2006) 3–8. [15] C. Su, Status quo and development of drugs packaging for anti-counterfeiting, China Anti-counterfeiting Report, 6 2008, p. 76. [16] Y. Wu, Current situation and development of anti-counterfeit packaging of drugs, Food Drug 8 (2006) 31–33. [17] H.J. Bae, S. Bae, C. Park, S. Han, J. Kim, L.N. Kim, K. Kim, S.-H. Song, W. Park, S. Kwon, Biomimetic microfingerprints for anti-counterfeiting strategies, Adv. Mater. 27 (2015) 2083–2089. [18] J. Yin, M.C. Boyce, Materials science: unique wrinkles as identity tags, Nature 520 (2015) 164–165. [19] L. Zhang, H. Wang, Y. Zhao, Y. Guo, W. Hu, G. Yu, Y. Liu, Substrate-free ultra-flexible organic field-effect transistors and five-stage ring oscillators, Adv. Mater. 23 (2013) 5455–5460. [20] K.G. Lee, B.G. Choi, B.I. Kim, T. Shyu, M.S. Oh, S.G. Im, S.-J. Chang, T.J. Lee, N.A. Kotov, S.J. Lee, Transferring flexible and scalable nanopillar arrays, Adv. Mater. 26 (2014) 6119–6124. [21] T.S. Shim, S.-M. Yang, S.-H. Kim, Dynamic designing of microstructures by chemical gradient-mediated growth, Nat. Commun. 6 (2015) 6584. [22] H. Hu, J. Tang, H. Zhong, Z. Xi, C. Chen, Q. Chen, Invisible photonic printing: computer designing graphics, UV printing and shown by a magnetic field, Sci. Rep. 3 (2013) 1484. [23] J. Lee, P.W. Bisso, R.L. Srinivas, J.J. Kim, A.J. Swiston, P.S. Doyle, Universal processinert encoding architecture for polymer microparticles, Nat. Mater. 13 (2014) 524–529. [24] S. Armstrong, O. Graydon, D. Pile, R. Won, Squeeze with care, Nat. Photonics 6 (2012) 801. [25] D.-H. Park, C.J. Han, Y.-G. Shul, J.-H. Choy, Avatar DNA nanohybrid system in chipon-a-phone, Sci. Rep. 4 (2014) 4879. [26] S. Han, H.J. Bae, J. Kim, S. Shin, S. Choi, S.H. Lee, S. Kwon, W. Park, Lithographically encoded polymer microtaggant using high-capacity and error-correctable QR code for anti-counterfeiting of drugs, Adv. Mater. 24 (2012) 5924. [27] R.J. Jackman, D.C. Duffy, E. Ostuni, J.C. McDonald, O.J. Schueller, G.M. Whitesides, Fabricating large arrays of microwells with arbitrary dimensions and filling them using discontinuous dewetting, Anal. Chem. 70 (11) (1998) 2280–2287. [28] J.J. Lou, G. Andrechak, M. Riben, W.H. Yong, A review of radio frequency identification technology for the anatomic pathology or biorepository laboratory: much promise, some progress, and more work needed, J. Pathol. Inform. 2 (2011) 34. [29] A.E. Kusi-Appiah, N. Vafai, P.J. Cranfill, M.W. Davidson, S. Lenhert, Lipid multilayer microarrays for in vitro liposomal drug delivery and screening, Biomaterials 33 (2012) 4187–4194. [30] S. Zhang, W. Tong, B. Zheng, T.A.K. Susanto, L. Xia, C. Zhang, A. Ananthanarayanan, X. Tuo, R.B. Sakban, R. Jia, C. Iliescu, K.-H. Chai, M. McMillian, S. Shen, H. Leo, H. Yu, A robust high-throughput sandwich cell-based drug screening platform, Biomaterials 32 (2011) 1229–1241.