Changes in the quality of medicines during storage under LED lighting and consideration of countermeasures

Changes in the quality of medicines during storage under LED lighting and consideration of... Background: In recent years, the popularity of LED lighting has rapidly increased, owing to its many advantages, including economic benefits. We examined the change in the quality of drugs during storage under LED and fluorescent lighting and found that some medicines exhibited a different degree of color change depending on the light source. The purpose of this study was to investigate the effects of different plastic storage bags on the color change over time when various medicines were stored under LED and fluorescent lighting conditions. Methods: Photostability tests were conducted on several types of target drugs. Subsequently, subjective evaluation by ten evaluators and objective evaluation by image analysis software were carried out regarding color change. Results: A similar change in color tone was observed after all types of illumination. Subjective evaluation by 10 evaluators revealed that “change in color tone” occurred in the order of bulb-color LED lighting < daylight-color LED lighting < fluorescent lighting, regardless of the type of plastic bags. A similar tendency was observed also in objective evaluation. In this study, it was considered that a brown light-shielding plastic bag was more effective than a normal plastic bag for the prevention of the color change of medicines stored under LED lighting. Conclusions: The above results suggested that the most appropriate combination of plastic bag and light source for medicine storage was a brown light-shielding plastic bag and bulb-color LED lighting. Keywords: LED lighting, Fluorescent lighting, Photostability, Color change, Medicines Background “International Conference on Harmonization of Technical Medicines are affected by external factors, such as Requirements for Registration of Pharmaceuticals for temperature, humidity, and light, during storage in med- Human Use”. ical institutions and patient homes. These cause physical Sometimes medicines are stored in a plastic bag at the and chemical changes; a change in appearance and a de- dispensing room of a medical institution or the patient’s crease in titer have been reported [1–3]. For this reason, home. Polybags are made of various materials, but in according to the test results based on the “Guidelines for general they often refer to those made of polyethylene. Photostability Test of New Media and New Products” [4], In addition, various additives are likely added in the pharmacists agreed on the need to maintain a consistent manufacturing process in order to impart various func- storage environment for medicines in the dispensing tions such as light shielding, antistatic and antimicrobial. room, ensure the quality of medicines, and to instruct Fluorescent lighting is a light source expected to be patients about appropriate storage methods at the widely encountered in the dispensing room of a medical institution or a patient’s home. However, owing to the * Correspondence: tsugi@gifu-pu.ac.jp advantages of energy conservation, such as less power Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical consumption and lower heat generation, and the reduc- University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan tion of the burdens on the natural environment, such as Department of Community Healthcare Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan long energy-saving period and low emission of ultraviolet Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yamashita et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:12 Page 2 of 6 light, LED lighting has been increasingly used in both or- Corp., EFA 15 EN 10 H 2, Tokyo, Japan). The color dinary households and medical institutions. The light temperature of each light was 6700 K, 2700 K, and source color of a bulb-type LED lamp is divided into five 5000 K, respectively. The wavelength spectrum of each kinds of daylight color, day white color, white color, warm lighting was measured with an LED meter (UPRtek white color and light bulb color based on Japanese Indus- Corp., MK 350, Miaoli, Taiwan). trial Standards [5]. The difference in light source color de- pends on the difference in correlated color temperature Polybag with seal (K), which affects not only the impression given to the When storing the target drugs, UV-cut plastic bags room but also the energy consumption efficiency. (Kinshi Seisakujo Co., Ltd., 200 mm × 140 mm (G-5), We examined the differences in the degree of the color Tokyo, Japan), brown light-shielding plastic bags (Kinshi change of various medicines after exposure to LED and Seisakujo Co., Ltd., 100 mm × 70 mm (C), Tokyo, Japan), fluorescent lighting. A noticeable degree of color change and normal plastic bags (SHIMOJIMA Co., Ltd., SWAN was observed for the Lasix® 20 mg Tab. and Parlodel® Chakkupori (120 mm × 170 mm (F-4)), Tokyo, Japan) 2.5 mg Tab. [6, 7]. However, the differences in the were used (Fig. 1). stability of medicines stored in different plastic bag types under LED lighting have not been examined so Test of photostability of target medicines and evaluation far. Therefore, the purpose of this study was to assess A total of five medicines (Lasix®20 mg Tab., Parlodel® the effect of different plastic bag types on the color 2.5 mg Tab., Fluitran® 2 mg Tab., Nipolazin® 3 mg Tab., change of medicines over time after storage under and Calonal® 200 mg Tab.) were placed in several types of LED lighting and fluorescent lighting. plastic bags with a seal (UV-cut function; brown with light-shielding function; normal without light-shielding Methods function) and exposed for up to 28 days (approximately Pharmaceuticals 670,000 lx·h) to daylight-color LED lighting, bulb-color The target drugs were furosemide (Sanofi KK, Lasix® LED lighting, fluorescent lighting, and in the dark. 20 mg Tab., Tokyo, Japan), bromocriptine mesylate (Sun The color change of the exposed medicine was evalu- Pharmaceutical Industries Ltd., Parlodel® 2.5 mg Tab., ated subjectively by the evaluators, who were 10 prac- Mumbai, India), trichlormethiazide (Shionogi & Co, tical interns accepted at this facility, between May 9 and Fluitran® 2 mg Tab., Osaka, Japan), mequitazine (Alfresa July 22, 2016. They were students of the 22–25 year old Pharma Corp., Nipolazin® 3 mg Tab., Osaka, Japan), and pharmaceutical department, 4 men and 6 females. We paracetamol (Ayumi Pharmaceutical Corp., Ltd., instructed the evaluators to observe the medicines after Calonal® 200 mg Tab., Tokyo, Japan), which represented different exposure periods. Thereafter, the evaluators five types of medicine. reported whether there was a color change between the medicine exposed to the different illumination condi- Lighting conditions and LED meter tions and the medicine left in the dark. The target The lighting conditions were daylight-color LED bulb medicine was described as “change in color tone” or “no (Panasonic Corp., LDA 11 DG, Tokyo, Japan), bulb-color change in color tone”. LED (Panasonic Corp., LDA 10 LG/Z 60 W, Tokyo, Changes in color tone of the target drug after the test Japan), and bulb type fluorescent lighting (Panasonic of photostability were analyzed using image analysis Fig. 1 Pictures of various polybag with seal in this study. UV-cut plastic bags (a), brown light-shielding plastic bags (b), and normal plastic bags (c) Yamashita et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:12 Page 3 of 6 software ImageJ (version 1.51, National Institutes of fluorescent lamp had many peaks due to mercury emis- Health, USA). The mean gray value of the relevant part sion line accompanied by discharge and light obtained of the image (Additional file 1) obtained by photograph- by synthesizing the emission spectrum of the phosphor. ing the object drug after the test of photostability was measured. In addition, mean gray value was measured Changes in the quality of medicines under each condition for each medicine at three places, and the average value Additional file 1 shows the results of exposing each of the mean gray value calculated respectively was used. medicine at 1000 lx for up to 28 days under LED and fluorescent lighting. During different exposure condi- Results tions, the temperature was maintained at 24.8 ± 4 °C and Measurement result of wavelength spectrum the humidity was 56 ± 16%. The white LED employs the blue LED and the yellow Figure 2 shows the total number of evaluators evalu- phosphor to obtain white light, so the peak appeared in ated as “change in color tone”. After 7 days, all 10 evalu- two places. Bulb color and daylight color were the same ators reported “change in color tone” for Lasix®20 mg LED lighting, but differences in spectrum were seen due Tab., Parlodel® 2.5 mg Tab., and Fluitran® 2 mg Tab. to different light colors. On the other hand, the white stored in UV-cut polybags or normal plastic bags ab c d ef g h ij k l Fig. 2 Subjective evaluation of the color change of various medicines. Indicates the number of evaluators who evaluated “change in color tone” for each medicine after the test of photostability. The color change of various medicines was evaluated after storage for 1 day to 28 days in three lighting conditions (Daylight-color LED lighting (△), bulb-color LED lighting (□) and fluorescent lighting (○)) in UV-cut plastic bags (a-d), brown light-shielding plastic bags (e-h), and normal plastic bags (i-l) Yamashita et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:12 Page 4 of 6 without a light-shielding function under fluorescent light color tone were observed under any storage conditions (Fig. 2a, b, i, and j). Similar color tone changes were ob- (Fig. 2d, h and l). served under all illumination conditions. After 14 days, Figure 3 shows the results of evaluating the color tone all 10 evaluators reported “change in color tone” for change after the test of photostability of each pharma- Nipolazin® 3 mg Tab. in normal plastic bags stored ceutical product using ImageJ software. In Lasix®20 mg under fluorescent lighting (Fig. 2k). After 28 days, five Tab., Parlodel® 2.5 mg Tab., and Nipolazin® 3 mg Tab., evaluators indicated a “change in color tone” for Nipola- the mean gray value decreased under any light source, zin® 3 mg Tab. stored in UV-cut plastic bags and four and a change in color tone was time dependent (Fig. 3). evaluators indicated this for the Nipolazin® 3 mg Tab. The condition that caused the largest color tone change stored in brown light-shielding plastic bag under fluores- was that the mean gray value was reduced by 34.9 when cent lighting (Fig. 2c, g). The number of evaluators Parlodel® 2.5 mg Tab. was normal plastic bags under who reported “change in color tone” showed the fol- fluorescent lighting (Fig. 3j). lowing trend: bulb-color LED lighting < daylight-color LED lighting < fluorescent lighting (Fig. 2). For brown Discussion light-shielding plastic bags, the number of evaluators In this study, color changes were observed for many of who reported “change in color tone” tended to be the target medicines stored under LED lighting in both smaller for the target medicines in comparison with normal plastic bags and UV-cut plastic bags (Fig. 2a-d, i-l). that observed for the other types of plastic bags (Fig. However, when the target medicines were placed in 2). For Calonal® 200 mg Tab., almost no changes in brown light-shielding plastic bags, a smaller degree of ab c d ef g h ij k l Fig. 3 Objective evaluation of color change of various medicines. The results of objectively evaluating the color change of various medicines after the test of photostability was shown. Mean gray value was estimated using ImageJ. The color change of various medicines was evaluated after storage for 1 day to 28 days in three lighting conditions (Daylight-color LED lighting (△), bulb-color LED lighting (□) and fluorescent lighting (○)) in UV-cut plastic bags (a-d), brown light-shielding plastic bags(e-h), and normal plastic bags (i-l) Yamashita et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:12 Page 5 of 6 change in the color tone was observed, suggesting they with LED lighting. In the UV-cut plastic bag and the could be more effective than normal plastic bags (Fig. brown light-shielding plastic bag, there was no signifi- 2). Therefore, it was indicated that, depending on the cant difference in the degree of color change among the conditions, shielding by UV-cut plastic bags may be in- lighting conditions. One explanation for this was that sufficient to prevent the color changes that result from the relative emission intensity in the ultraviolet region, LED lighting (Fig. 2). where Nipolazin® 3 mg Tab. mainly absorbs light, was The color change was slower than in other light lower than that of fluorescent lighting and the light- sources when stored under bulb-color LED lighting, re- shielding performance in this wavelength region of the gardless of the target medicine or the plastic bags used UV-cut plastic bag and the brown light-shielding plastic in this study (Fig. 2). Moreover, the gentlest light source bag was sufficient in LED lighting. for medicine was thought to be bulb-color LED lighting; The same tendency as the result of subjective evalu- this agreed with our previous reports [6, 7]. ation was also observed in objective evaluation using Lasix®20 mg Tab. showed almost no color change ImageJ. Regarding Nipolazin® 3 mg Tab., the difference when exposed to light in the wavelength region of in each light source was not as clear as the result of sub- 420 nm or more, but was reported to undergo a remark- jective evaluation. Even taking this into consideration, able color change after irradiation with light in the wave- we believed that the results obtained by objective length region below 420 nm [8]. In general, it is known evaluation support the results obtained by subjective that the photolytic degradation of medicines is evaluation. wavelength-dependent; when the absorbed light energy The reason for choosing five drugs in this study was as is larger than binding energy of the substance, photolytic follows: two drugs that were reported to exhibit a color degradation occurs. If the decomposition product is col- change by the patient after dispensing and delivery at ored, the color change can be visually observed. It is our facility (Lasix® 20 mg Tab. and Fluitran® 2 mg Tab.), known that light of different wavelengths is easily medicines listed as having a color change in the inter- absorbed by medicines owing to their differences in view form (Parlodel® 2.5 mg Tab. and Nipolazin® 3 mg structure; even for identical illuminance, irradiation with Tab.), as a control for these, and a white medicine not light sources of different spectra produces different ef- described to exhibit a change in color tone (Calonal® fects on medicines [9, 10]. In general, a white LED emits 200 mg Tab.). white light through a combination of a blue LED elem- The degree of color change tended to become small ent and a yellow phosphor; therefore, the peak appears when stored in brown light-shielding plastic bags for all in two places. The difference in the emission spectrum combinations of medicines and light sources used in this of each type was attributed to the difference in the ratio study. We reported that subjective tendency to feel a of the peak of the blue emission spectrum of the elem- sense of resistance to medication tended to be felt so ent and the yellow emission spectrum of the phosphor. that a change in color tone was felt [6]. Regardless of the As shown in Figs. 2a, e and i, the degree of color change decomposition of the principal component, changes in in Lasix®20 mg Tab. stored under the bulb-color LED the appearance of medicines were easy to understand for lighting, in any type of bag, was the smallest. One ex- the patient, and it was thought that it affected compli- planation for this was that the total energy of 420 nm or ance as well. For this reason, we focused attention on less of the bulb-color LED lighting was lower than that the subjective color change of the evaluator and exam- of other LED lighting. ined it from the PTP which seemed to be easier to It is known that Parlodel® 2.5 mg Tab. showed a understand color change than the PTP state. However, change in color tone after light irradiation [11]. The de- the effect on safety and efficacy owing to changes in the gree of color change in bulb-color LED lighting condi- principal component and additives was also considered tions (Fig. 2b, f and Additional file 1)was thesmallest, to be an important item to be evaluated. Therefore, we even in Parlodel® 2.5 mg Tab., regardless of the type of intend to quantitatively and qualitatively examine the plastic bags. Although the cause was unknown, refer- changes in the principal component and additives of ence to the past reports [11]and themeasurement of each subject drug and establish evidence for the proper the wavelength spectrum indicated that photosensitivity storage of medicinal products. occurred over a small wavelength range, like that for Lasix®20 mg Tab. It was been reported that Nipolazin® 3 mg Tab. Conclusion absorbed light in the wavelength range 300–350 nm The above results suggested that the most appropriate [12]. When Nipolazin® 3 mg Tab. was stored for 28 days combination of the plastic bag and light source for in normal plastic bags, a distinct color change was ob- medicine storage was brown light-shielding plastic bags served under fluorescent lighting as compared to that and bulb-color LED lighting. Yamashita et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:12 Page 6 of 6 Additional file and colour rendering property, JIS Z 9112. Tokyo: Japanese Standards Association; 2012. 6. Yamashita S, Noguchi Y, Kubota M, Iguchi K, Aoki S, Tanei S, et al. Color Additional file 1: Figure S1. The color change of various medicines for change of various medicines under LED lighting and fluorescent lighting. 1 day to 28 days in three lighting conditions in UV-cut plastic bag (A), Jpn J Pharm Health Care Sci. 2015;41:198–204. brown light-shielding plastic bag (B),normal plastic bags (C). (PPTX 23261 kb) 7. Yamashita S, Iguchi K, Noguchi Y, Sakai C, Yokoyama S, Ino Y, et al. Study on selecting the most suitable lighting application for medicines in dispensary of medical institution. Jpn J Pharm Health Care Sci. 2016;42:512–7. Abbreviations 8. Teraoka R, Yokoyama I, Sugimoto I, Ushio M, Kitagawa S. Effect of colored LED: Light emitting diode; PTP: Press through package; UV: Ultra violet press-through package (PTP) materialon photostability of furosemide tablets. Jpn J Pharm Health Care Sci. 2009;35:395–402. Acknowledgements 9. Sugimoto I, Tohgo K, Sasaki K, Nakagawa H, Matsuda Y, Masahara R. Department of Community Healthcare Pharmacy is an endowment department, Wavelength dependency of the photodegradation of nifedipine tablets. supported with an unrestricted grant from WELCIA YAKKYOKU CO., LTD. Yakugaku Zasshi. 1981;101:1149–53. 10. Matsuda Y, Masahara R. Comparative evaluation of coloration of Availability of data and material photosensitive solid drugs under various light sources. Yakugaku Zasshi. The dataset supporting the conclusions of this article is included within the article. 1980;100:953–7. 11. Phakinee P, Jankana B. Development and validation of a stability-indicating Funding HPLC method for determination of bromocriptine mesylate in bulk drug There are no funding sources for this report. and tablets. Curr Pharm Anal. 2013;9:92–101. 12. Teraoka R, Sugimoto I, Kakinoki K, Matsuda Y. Photostability of mequitazine Authors’ contributions in a syrup and isotonic buffer solution -effects of various prescription ShuY carried out the experiments and drafted the manuscript. KI advised the bottles and photostabilizing effect of additives. Jpn J Pharm Health Care Sci. methods of experiments and helped to draft the manuscript. YN, CS, SaY and 2005;31:701–6. YI helped the experiments. HH and HT helped to draft the manuscript. MS advised the methods of experiments. TS coordinated this project and helped to draft the manuscript. All authors read and approved the final manuscript. Ethics approval and consent to participate Not applicable. Competing interests Department of Community Healthcare Pharmacy is an endowment department, supported with an unrestricted grant from WELCIA YAKKYOKU CO., LTD. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan. Gifu Pharmaceutical University Pharmacy, 1-108-3 Daigaku-nishi, Gifu, Gifu 501-1113, Japan. Laboratory of Community Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan. Laboratory of Clinical Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan. Department of Community Healthcare Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan. Research and Development Department, Ohara Pharmaceutical Co. Ltd., 121-15 Toriino, Koka-cho, Koka-shi, Shiga 520-3403, Japan. Received: 13 October 2017 Accepted: 8 May 2018 References 1. Kakinoki K, Yamane K, Teraoka R, Otsuka M, Matsuda Y. Effect of relative humidity on the photocatalytic activity of titanium dioxide and photostability of famotidine. J Pharm Sci. 2004;93:582–9. 2. Matsuda Y, Akazawa R, Teraoka R, Otsuka M. Pharmaceutical evaluation of carbamazepine modifications: comparative study for photostability of carbamazepine polymorphs by using fourier-transformed reflection- absorption infrared spectroscopy and colorimetric measurement. J Pharm Pharmacol. 1994;46:162–7. 3. Matsuda Y, Teraoka R, Sugimoto I. Comparative evaluation of photostability of solid-state nifedipine under ordinary and intensive light irradiation conditions. Int J Pharm. 1989;54:211–21. 4. ICH guideline Q1B “Guideline for Stability Testing: Photostability Testing of New Drug Substances and Products” (PAB/PCD Notification No. 422 dated May 28, 1997). Tokyo, Japan. 5. Japanese Industrial Standard Committee. Japanese industrial standard, classification of fluorescent lamps and light emitting diodes by chromaticity http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Pharmaceutical Health Care and Sciences Springer Journals

Changes in the quality of medicines during storage under LED lighting and consideration of countermeasures

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Abstract

Background: In recent years, the popularity of LED lighting has rapidly increased, owing to its many advantages, including economic benefits. We examined the change in the quality of drugs during storage under LED and fluorescent lighting and found that some medicines exhibited a different degree of color change depending on the light source. The purpose of this study was to investigate the effects of different plastic storage bags on the color change over time when various medicines were stored under LED and fluorescent lighting conditions. Methods: Photostability tests were conducted on several types of target drugs. Subsequently, subjective evaluation by ten evaluators and objective evaluation by image analysis software were carried out regarding color change. Results: A similar change in color tone was observed after all types of illumination. Subjective evaluation by 10 evaluators revealed that “change in color tone” occurred in the order of bulb-color LED lighting < daylight-color LED lighting < fluorescent lighting, regardless of the type of plastic bags. A similar tendency was observed also in objective evaluation. In this study, it was considered that a brown light-shielding plastic bag was more effective than a normal plastic bag for the prevention of the color change of medicines stored under LED lighting. Conclusions: The above results suggested that the most appropriate combination of plastic bag and light source for medicine storage was a brown light-shielding plastic bag and bulb-color LED lighting. Keywords: LED lighting, Fluorescent lighting, Photostability, Color change, Medicines Background “International Conference on Harmonization of Technical Medicines are affected by external factors, such as Requirements for Registration of Pharmaceuticals for temperature, humidity, and light, during storage in med- Human Use”. ical institutions and patient homes. These cause physical Sometimes medicines are stored in a plastic bag at the and chemical changes; a change in appearance and a de- dispensing room of a medical institution or the patient’s crease in titer have been reported [1–3]. For this reason, home. Polybags are made of various materials, but in according to the test results based on the “Guidelines for general they often refer to those made of polyethylene. Photostability Test of New Media and New Products” [4], In addition, various additives are likely added in the pharmacists agreed on the need to maintain a consistent manufacturing process in order to impart various func- storage environment for medicines in the dispensing tions such as light shielding, antistatic and antimicrobial. room, ensure the quality of medicines, and to instruct Fluorescent lighting is a light source expected to be patients about appropriate storage methods at the widely encountered in the dispensing room of a medical institution or a patient’s home. However, owing to the * Correspondence: tsugi@gifu-pu.ac.jp advantages of energy conservation, such as less power Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical consumption and lower heat generation, and the reduc- University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan tion of the burdens on the natural environment, such as Department of Community Healthcare Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan long energy-saving period and low emission of ultraviolet Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yamashita et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:12 Page 2 of 6 light, LED lighting has been increasingly used in both or- Corp., EFA 15 EN 10 H 2, Tokyo, Japan). The color dinary households and medical institutions. The light temperature of each light was 6700 K, 2700 K, and source color of a bulb-type LED lamp is divided into five 5000 K, respectively. The wavelength spectrum of each kinds of daylight color, day white color, white color, warm lighting was measured with an LED meter (UPRtek white color and light bulb color based on Japanese Indus- Corp., MK 350, Miaoli, Taiwan). trial Standards [5]. The difference in light source color de- pends on the difference in correlated color temperature Polybag with seal (K), which affects not only the impression given to the When storing the target drugs, UV-cut plastic bags room but also the energy consumption efficiency. (Kinshi Seisakujo Co., Ltd., 200 mm × 140 mm (G-5), We examined the differences in the degree of the color Tokyo, Japan), brown light-shielding plastic bags (Kinshi change of various medicines after exposure to LED and Seisakujo Co., Ltd., 100 mm × 70 mm (C), Tokyo, Japan), fluorescent lighting. A noticeable degree of color change and normal plastic bags (SHIMOJIMA Co., Ltd., SWAN was observed for the Lasix® 20 mg Tab. and Parlodel® Chakkupori (120 mm × 170 mm (F-4)), Tokyo, Japan) 2.5 mg Tab. [6, 7]. However, the differences in the were used (Fig. 1). stability of medicines stored in different plastic bag types under LED lighting have not been examined so Test of photostability of target medicines and evaluation far. Therefore, the purpose of this study was to assess A total of five medicines (Lasix®20 mg Tab., Parlodel® the effect of different plastic bag types on the color 2.5 mg Tab., Fluitran® 2 mg Tab., Nipolazin® 3 mg Tab., change of medicines over time after storage under and Calonal® 200 mg Tab.) were placed in several types of LED lighting and fluorescent lighting. plastic bags with a seal (UV-cut function; brown with light-shielding function; normal without light-shielding Methods function) and exposed for up to 28 days (approximately Pharmaceuticals 670,000 lx·h) to daylight-color LED lighting, bulb-color The target drugs were furosemide (Sanofi KK, Lasix® LED lighting, fluorescent lighting, and in the dark. 20 mg Tab., Tokyo, Japan), bromocriptine mesylate (Sun The color change of the exposed medicine was evalu- Pharmaceutical Industries Ltd., Parlodel® 2.5 mg Tab., ated subjectively by the evaluators, who were 10 prac- Mumbai, India), trichlormethiazide (Shionogi & Co, tical interns accepted at this facility, between May 9 and Fluitran® 2 mg Tab., Osaka, Japan), mequitazine (Alfresa July 22, 2016. They were students of the 22–25 year old Pharma Corp., Nipolazin® 3 mg Tab., Osaka, Japan), and pharmaceutical department, 4 men and 6 females. We paracetamol (Ayumi Pharmaceutical Corp., Ltd., instructed the evaluators to observe the medicines after Calonal® 200 mg Tab., Tokyo, Japan), which represented different exposure periods. Thereafter, the evaluators five types of medicine. reported whether there was a color change between the medicine exposed to the different illumination condi- Lighting conditions and LED meter tions and the medicine left in the dark. The target The lighting conditions were daylight-color LED bulb medicine was described as “change in color tone” or “no (Panasonic Corp., LDA 11 DG, Tokyo, Japan), bulb-color change in color tone”. LED (Panasonic Corp., LDA 10 LG/Z 60 W, Tokyo, Changes in color tone of the target drug after the test Japan), and bulb type fluorescent lighting (Panasonic of photostability were analyzed using image analysis Fig. 1 Pictures of various polybag with seal in this study. UV-cut plastic bags (a), brown light-shielding plastic bags (b), and normal plastic bags (c) Yamashita et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:12 Page 3 of 6 software ImageJ (version 1.51, National Institutes of fluorescent lamp had many peaks due to mercury emis- Health, USA). The mean gray value of the relevant part sion line accompanied by discharge and light obtained of the image (Additional file 1) obtained by photograph- by synthesizing the emission spectrum of the phosphor. ing the object drug after the test of photostability was measured. In addition, mean gray value was measured Changes in the quality of medicines under each condition for each medicine at three places, and the average value Additional file 1 shows the results of exposing each of the mean gray value calculated respectively was used. medicine at 1000 lx for up to 28 days under LED and fluorescent lighting. During different exposure condi- Results tions, the temperature was maintained at 24.8 ± 4 °C and Measurement result of wavelength spectrum the humidity was 56 ± 16%. The white LED employs the blue LED and the yellow Figure 2 shows the total number of evaluators evalu- phosphor to obtain white light, so the peak appeared in ated as “change in color tone”. After 7 days, all 10 evalu- two places. Bulb color and daylight color were the same ators reported “change in color tone” for Lasix®20 mg LED lighting, but differences in spectrum were seen due Tab., Parlodel® 2.5 mg Tab., and Fluitran® 2 mg Tab. to different light colors. On the other hand, the white stored in UV-cut polybags or normal plastic bags ab c d ef g h ij k l Fig. 2 Subjective evaluation of the color change of various medicines. Indicates the number of evaluators who evaluated “change in color tone” for each medicine after the test of photostability. The color change of various medicines was evaluated after storage for 1 day to 28 days in three lighting conditions (Daylight-color LED lighting (△), bulb-color LED lighting (□) and fluorescent lighting (○)) in UV-cut plastic bags (a-d), brown light-shielding plastic bags (e-h), and normal plastic bags (i-l) Yamashita et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:12 Page 4 of 6 without a light-shielding function under fluorescent light color tone were observed under any storage conditions (Fig. 2a, b, i, and j). Similar color tone changes were ob- (Fig. 2d, h and l). served under all illumination conditions. After 14 days, Figure 3 shows the results of evaluating the color tone all 10 evaluators reported “change in color tone” for change after the test of photostability of each pharma- Nipolazin® 3 mg Tab. in normal plastic bags stored ceutical product using ImageJ software. In Lasix®20 mg under fluorescent lighting (Fig. 2k). After 28 days, five Tab., Parlodel® 2.5 mg Tab., and Nipolazin® 3 mg Tab., evaluators indicated a “change in color tone” for Nipola- the mean gray value decreased under any light source, zin® 3 mg Tab. stored in UV-cut plastic bags and four and a change in color tone was time dependent (Fig. 3). evaluators indicated this for the Nipolazin® 3 mg Tab. The condition that caused the largest color tone change stored in brown light-shielding plastic bag under fluores- was that the mean gray value was reduced by 34.9 when cent lighting (Fig. 2c, g). The number of evaluators Parlodel® 2.5 mg Tab. was normal plastic bags under who reported “change in color tone” showed the fol- fluorescent lighting (Fig. 3j). lowing trend: bulb-color LED lighting < daylight-color LED lighting < fluorescent lighting (Fig. 2). For brown Discussion light-shielding plastic bags, the number of evaluators In this study, color changes were observed for many of who reported “change in color tone” tended to be the target medicines stored under LED lighting in both smaller for the target medicines in comparison with normal plastic bags and UV-cut plastic bags (Fig. 2a-d, i-l). that observed for the other types of plastic bags (Fig. However, when the target medicines were placed in 2). For Calonal® 200 mg Tab., almost no changes in brown light-shielding plastic bags, a smaller degree of ab c d ef g h ij k l Fig. 3 Objective evaluation of color change of various medicines. The results of objectively evaluating the color change of various medicines after the test of photostability was shown. Mean gray value was estimated using ImageJ. The color change of various medicines was evaluated after storage for 1 day to 28 days in three lighting conditions (Daylight-color LED lighting (△), bulb-color LED lighting (□) and fluorescent lighting (○)) in UV-cut plastic bags (a-d), brown light-shielding plastic bags(e-h), and normal plastic bags (i-l) Yamashita et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:12 Page 5 of 6 change in the color tone was observed, suggesting they with LED lighting. In the UV-cut plastic bag and the could be more effective than normal plastic bags (Fig. brown light-shielding plastic bag, there was no signifi- 2). Therefore, it was indicated that, depending on the cant difference in the degree of color change among the conditions, shielding by UV-cut plastic bags may be in- lighting conditions. One explanation for this was that sufficient to prevent the color changes that result from the relative emission intensity in the ultraviolet region, LED lighting (Fig. 2). where Nipolazin® 3 mg Tab. mainly absorbs light, was The color change was slower than in other light lower than that of fluorescent lighting and the light- sources when stored under bulb-color LED lighting, re- shielding performance in this wavelength region of the gardless of the target medicine or the plastic bags used UV-cut plastic bag and the brown light-shielding plastic in this study (Fig. 2). Moreover, the gentlest light source bag was sufficient in LED lighting. for medicine was thought to be bulb-color LED lighting; The same tendency as the result of subjective evalu- this agreed with our previous reports [6, 7]. ation was also observed in objective evaluation using Lasix®20 mg Tab. showed almost no color change ImageJ. Regarding Nipolazin® 3 mg Tab., the difference when exposed to light in the wavelength region of in each light source was not as clear as the result of sub- 420 nm or more, but was reported to undergo a remark- jective evaluation. Even taking this into consideration, able color change after irradiation with light in the wave- we believed that the results obtained by objective length region below 420 nm [8]. In general, it is known evaluation support the results obtained by subjective that the photolytic degradation of medicines is evaluation. wavelength-dependent; when the absorbed light energy The reason for choosing five drugs in this study was as is larger than binding energy of the substance, photolytic follows: two drugs that were reported to exhibit a color degradation occurs. If the decomposition product is col- change by the patient after dispensing and delivery at ored, the color change can be visually observed. It is our facility (Lasix® 20 mg Tab. and Fluitran® 2 mg Tab.), known that light of different wavelengths is easily medicines listed as having a color change in the inter- absorbed by medicines owing to their differences in view form (Parlodel® 2.5 mg Tab. and Nipolazin® 3 mg structure; even for identical illuminance, irradiation with Tab.), as a control for these, and a white medicine not light sources of different spectra produces different ef- described to exhibit a change in color tone (Calonal® fects on medicines [9, 10]. In general, a white LED emits 200 mg Tab.). white light through a combination of a blue LED elem- The degree of color change tended to become small ent and a yellow phosphor; therefore, the peak appears when stored in brown light-shielding plastic bags for all in two places. The difference in the emission spectrum combinations of medicines and light sources used in this of each type was attributed to the difference in the ratio study. We reported that subjective tendency to feel a of the peak of the blue emission spectrum of the elem- sense of resistance to medication tended to be felt so ent and the yellow emission spectrum of the phosphor. that a change in color tone was felt [6]. Regardless of the As shown in Figs. 2a, e and i, the degree of color change decomposition of the principal component, changes in in Lasix®20 mg Tab. stored under the bulb-color LED the appearance of medicines were easy to understand for lighting, in any type of bag, was the smallest. One ex- the patient, and it was thought that it affected compli- planation for this was that the total energy of 420 nm or ance as well. For this reason, we focused attention on less of the bulb-color LED lighting was lower than that the subjective color change of the evaluator and exam- of other LED lighting. ined it from the PTP which seemed to be easier to It is known that Parlodel® 2.5 mg Tab. showed a understand color change than the PTP state. However, change in color tone after light irradiation [11]. The de- the effect on safety and efficacy owing to changes in the gree of color change in bulb-color LED lighting condi- principal component and additives was also considered tions (Fig. 2b, f and Additional file 1)was thesmallest, to be an important item to be evaluated. Therefore, we even in Parlodel® 2.5 mg Tab., regardless of the type of intend to quantitatively and qualitatively examine the plastic bags. Although the cause was unknown, refer- changes in the principal component and additives of ence to the past reports [11]and themeasurement of each subject drug and establish evidence for the proper the wavelength spectrum indicated that photosensitivity storage of medicinal products. occurred over a small wavelength range, like that for Lasix®20 mg Tab. It was been reported that Nipolazin® 3 mg Tab. Conclusion absorbed light in the wavelength range 300–350 nm The above results suggested that the most appropriate [12]. When Nipolazin® 3 mg Tab. was stored for 28 days combination of the plastic bag and light source for in normal plastic bags, a distinct color change was ob- medicine storage was brown light-shielding plastic bags served under fluorescent lighting as compared to that and bulb-color LED lighting. Yamashita et al. Journal of Pharmaceutical Health Care and Sciences (2018) 4:12 Page 6 of 6 Additional file and colour rendering property, JIS Z 9112. Tokyo: Japanese Standards Association; 2012. 6. Yamashita S, Noguchi Y, Kubota M, Iguchi K, Aoki S, Tanei S, et al. Color Additional file 1: Figure S1. The color change of various medicines for change of various medicines under LED lighting and fluorescent lighting. 1 day to 28 days in three lighting conditions in UV-cut plastic bag (A), Jpn J Pharm Health Care Sci. 2015;41:198–204. brown light-shielding plastic bag (B),normal plastic bags (C). (PPTX 23261 kb) 7. Yamashita S, Iguchi K, Noguchi Y, Sakai C, Yokoyama S, Ino Y, et al. Study on selecting the most suitable lighting application for medicines in dispensary of medical institution. Jpn J Pharm Health Care Sci. 2016;42:512–7. Abbreviations 8. Teraoka R, Yokoyama I, Sugimoto I, Ushio M, Kitagawa S. Effect of colored LED: Light emitting diode; PTP: Press through package; UV: Ultra violet press-through package (PTP) materialon photostability of furosemide tablets. Jpn J Pharm Health Care Sci. 2009;35:395–402. Acknowledgements 9. Sugimoto I, Tohgo K, Sasaki K, Nakagawa H, Matsuda Y, Masahara R. Department of Community Healthcare Pharmacy is an endowment department, Wavelength dependency of the photodegradation of nifedipine tablets. supported with an unrestricted grant from WELCIA YAKKYOKU CO., LTD. Yakugaku Zasshi. 1981;101:1149–53. 10. Matsuda Y, Masahara R. Comparative evaluation of coloration of Availability of data and material photosensitive solid drugs under various light sources. Yakugaku Zasshi. The dataset supporting the conclusions of this article is included within the article. 1980;100:953–7. 11. Phakinee P, Jankana B. Development and validation of a stability-indicating Funding HPLC method for determination of bromocriptine mesylate in bulk drug There are no funding sources for this report. and tablets. Curr Pharm Anal. 2013;9:92–101. 12. Teraoka R, Sugimoto I, Kakinoki K, Matsuda Y. Photostability of mequitazine Authors’ contributions in a syrup and isotonic buffer solution -effects of various prescription ShuY carried out the experiments and drafted the manuscript. KI advised the bottles and photostabilizing effect of additives. Jpn J Pharm Health Care Sci. methods of experiments and helped to draft the manuscript. YN, CS, SaY and 2005;31:701–6. YI helped the experiments. HH and HT helped to draft the manuscript. MS advised the methods of experiments. TS coordinated this project and helped to draft the manuscript. All authors read and approved the final manuscript. Ethics approval and consent to participate Not applicable. Competing interests Department of Community Healthcare Pharmacy is an endowment department, supported with an unrestricted grant from WELCIA YAKKYOKU CO., LTD. Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan. Gifu Pharmaceutical University Pharmacy, 1-108-3 Daigaku-nishi, Gifu, Gifu 501-1113, Japan. Laboratory of Community Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan. Laboratory of Clinical Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan. Department of Community Healthcare Pharmacy, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu, Gifu 501-1196, Japan. Research and Development Department, Ohara Pharmaceutical Co. Ltd., 121-15 Toriino, Koka-cho, Koka-shi, Shiga 520-3403, Japan. Received: 13 October 2017 Accepted: 8 May 2018 References 1. Kakinoki K, Yamane K, Teraoka R, Otsuka M, Matsuda Y. Effect of relative humidity on the photocatalytic activity of titanium dioxide and photostability of famotidine. J Pharm Sci. 2004;93:582–9. 2. Matsuda Y, Akazawa R, Teraoka R, Otsuka M. Pharmaceutical evaluation of carbamazepine modifications: comparative study for photostability of carbamazepine polymorphs by using fourier-transformed reflection- absorption infrared spectroscopy and colorimetric measurement. J Pharm Pharmacol. 1994;46:162–7. 3. Matsuda Y, Teraoka R, Sugimoto I. Comparative evaluation of photostability of solid-state nifedipine under ordinary and intensive light irradiation conditions. Int J Pharm. 1989;54:211–21. 4. ICH guideline Q1B “Guideline for Stability Testing: Photostability Testing of New Drug Substances and Products” (PAB/PCD Notification No. 422 dated May 28, 1997). Tokyo, Japan. 5. Japanese Industrial Standard Committee. Japanese industrial standard, classification of fluorescent lamps and light emitting diodes by chromaticity

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Journal of Pharmaceutical Health Care and SciencesSpringer Journals

Published: Jun 1, 2018

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