Thai Journal of Pharmaceutical Sciences (TJPS)

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1 Thai Journal of Pharmaceutical Sciences (TJPS) 34 th International Annual Meeting in Pharmaceutical Sciences and 2 nd CU FPhS - RIKEN CDB Symposium (IAMPS34 and 2 nd CU FPhS - RIKEN CDB) The Effectiveness of Localized Intradermal Microinjection of 50 mg/ml of Tranexamic Acid for Melasma Treatment in Thai Patients: A Pilot Study Prapalpitch Wongwicharn 1, Punyaphat Sirithanabadeekul 1,* 1 Division of Dermatology Chulabhorn International college of medicine, Thammasat University * Corresponding author: Tel. +66(0) ; address: punyaphats.cicm@gmail.com Keywords: melasma, tranexamic acid, intradermal microinjection Introduction Melasma is a common cosmetic problem displaying facial hyperpigmentation among Asians. It is a chronic acquired pigmentary disorder. The characteristics are symmetrically distributed light to dark brown macules and patches in the sun exposed areas, mostly on the face(2). Women are more susceptible than men, particularly those at reproductive ages and those with darker skin types (Fitzpatrick skin type IV-VI)(3).Even though the pathogenesis of melasma remains unknown, some studies confirmed that increased numbers of melanocyte as well as increased production of melanin (melanogenesis) play a role in the hyperpigmentation in melasma. Common predisposing factors include genetic predisposition, ultraviolet radiation, pregnancy, oral contraceptives, thyroid disease, cosmetics, nutrition and drugs(4). The greatest aggravating factor is UV radiation. It can induce melanocytosis and melanogenesis by inducing plasminogen activator synthesis and increasing plasmin activity in keratinocyte(5)(6). There are studies which revealed that tranexamic acid (TA) is a plasmin inhibitor. It is a lysine analog and works by reversibly blocking lysine binding sites on plasminogen molecules, which ultimately results in decreased melanocyte activity(7). Therefore, TA has recently been a popular choice in melasma treatments as it can reduce the hyperpigmentation effect. Many studies discussed the use of topical and oral tranexamic acid in melasma treatment. The outcome of the topical treatment is still not satisfactory while the oral tranexamic acid is quite dangerous due to the systemic side effects of the drugs when given in high dosage and taken for long durations(8). Recently, there has been growing interest in clinical trial studies using localized intradermal microinjection of tranexamic acid (TA). The goal of this treatment is to apply an adequate amount of medication directly to the problem point and avoid oral medication(9). Therefore, the study aims to evaluate the efficacy and side effect of intradermal microinjection of 50 mg/ml of TA for treatment of melasma. Methods Study design and subject This is a prospective open label study. Ten patients aged with melasma with malar distribution were recruited into trial by the clinic of dermatology at tobacco Monopoly Hospital, Thailand. The total duration of the study was 16 weeks. The study was approved by the Ethics Committee of Thammasat University Hospital. Informed consents were obtained. Exclusion criteria included those who were pregnant or nursing; on hormonal therapy or contraceptive pill; with any history of bleeding disorders or the concomitant use of anticoagulants; with any known allergic to TA; with a history of any topical cream, oral medication or laser for melasma in the past 1 month. Method and drug preparation A topical anaesthetic cream (EMLA ; 2.5% lidocaine and 2.5% prilocaine) was applied on the face for 45 minutes under occlusion. A 30-gauge, 1 ml syringe with 50 mg/ml tranexamic acid (Transamin, Daiichi Sankyo CO., LTD, Tokyo, Japan). was prepared under sterile conditions. Injection of about 0.05 ml was applied intradermally on the melasma lesion at 1 cm intervals. This was repeated every two weeks for 12 weeks. The patients were advised to avoid excessive sun exposure and to apply a broad-spectrum 140

2 sunscreen with a sun protection factor of 50, and avoid the use of any topical preparation agents on the lesion during the study period. Outcome measurement Clinical evaluation of melasma severity was performed at the baseline, week 4 th, 8 th, 12 th and 16 th (a day of follow up) which involved measuring the melanin index with a skin analysis camera (Antera3D ) and modified Malasma Area and Severity Index (mmasi) and the patients self-assessment was conduct at the week 16 th, the end of the study. The patient s self-assessment of melasma improvement was graded along four scales: more than 75% lightening (excellent); 51 to 75% as (good); 26 to 50%; (fair); and 0 to 25% (poor). After treatment in every session the patients were asked about the pain score and any immediate side effects. Any other side effects were also noted during the study period. Data analysis Data analysis and statistics were analysed with SPSS statistics version 22 for windows. A repeated ANOVA was used to evaluate the changes in melanin index and mmasi score before and after treatment. The side effects were performed with Wilcoxon signed ranks. Outcome with a P-value < 0.05 were considered to be statistically significant differences. Results A total of 10 patients successfully completed the trial. The mean melanin index and mmasi score at the baseline, week 4 th, 8 th, 12 th and 16 th are shown in table 1. The mean melanin index after treatment ranged from 0.66±0.076 at the baseline to 0.662±0.072, 0.647±0.064, 0.642±0.061, and 0.619±0.058 at week 4 th, 8 th, 12 th and 16 th, respectively (table 1). It is demonstrated that the melanin index gradually decreased at week 8 th after the fourth session of the treatment. At week 12 of the study, the last week of treatment, the melanin index decreased or 2.72% from the baseline but it was not a statistically significant difference (p=0.103). However, the reduction of melanin index is statistically significant at week 16 (a day of follow up) (P-value < 0.05). For the mean modified MASI score after treatment, a decrease was shown from 2.73±1.07 at baseline to 2.16±1.07, 1.74±0.94, 1.17±0.82 and 1.23±0.79 at week 4 th, 8 th, 12 th, 16 th, respectively (Figure 2). Changes in the mmasi score slightly decreased since week 4 th and showed statistically significant difference at week 8 th (p < 0.05). At the end of the study, week 16 th, the mmasi score slightly increased, However it was still statistically significant decrease when compare with baseline(p=0.002). Table 1 Melanin Index and modified MASI score mmasi score p-value Melanin Index p-value week ± 1.07 Reference 0.66 ± Reference week ± ± week ± * ± week ± * ± week ± * ± * Figure1. Melanin index before and after treatment Figure 2. The modified MASI score before and after treatment 141

3 The average pain score is 2.01.The patients self-assessment of melasma improvement was evaluated at week 16 th ; 90% as excellent improvement and 10% as good improvement (table 2). For the side effects, the patients reported burning sensation, wheal immediately after injection, redness, local bruising. The side effect was mild and patients well tolerated. Table 2. Patients self-assessment of melasma improvement at week 16 th Melasma Improvement Grading No. Percent (%) 0 No change 0-25% (slightly improvement) 26-50% (Fair improvement) 51-75% 1 10 (good improvement) % (excellent improvement) 9 90 Figure 3. Photo before and after 16 weeks of the study (A) and melanin index before and after 16 week of the treatment (B) Discussion Although, many treatment modalities have been tried, no treatment has achieved satisfactory results. Therefore, treating melasma remains a challenging hyperpigmented condition that still needs a new effective treatment modality. Tranexamic acid, a plasmin inhibitor, had been previously used as an antifibrinolytic agent through oral or intraveneous admistration of 0.5 to 2.0 g three or four times a day(9). Recently, research suggested that TA suppresses the formation of melanin by blocking the communication of melanocyte and keratinocyte via plasmin/plasminogen complex(7). There was a study that showed a reduction of pigment after application of topical TA on guinea pigs as a result of reduction in arachidonic acid and prostaglandins which have plasmin as a precursor(10). About topical TA for melasma treatment, Kanechorn Na Ayuthaya et al(11), they assessed the efficacy of topical 5% TA versus vehicle for melasma treatment for 12 weeks. The 142

4 lightening of pigmentation was not statistic significant difference between the two regimens. Another study from Chung JY et al(12), a study which evaluated the efficacy and safety of topical TA combine with intense pulsed light (IPL) treatment in Asian melasma. Four monthly sessions of IPL to both sides of face, Topical TA or vehicle was applied to a randomly assigned side during and after IPL treatment. The result showed the topical TA side was significant decrease in melanin index and mmasi score from baseline to the end of the treatment. Also the efficacy of topical TA in preventing rebound pigmentation after IPL treatment was also statistically significant. Recently there is a study about intradermal injection of TA for melasma. A pilot study done by Lee et al, in Korea (9). They evaluated the efficacy of intralesional TA injection in melasma treatments. It showed a significant reduction in MASI score from baseline to week 12 th. The above provide a good result of topical and localized injection of TA in the treatment of melasma. In this study, we sought an adequate dosage of TA intradermal injection for melasma treatment. The mean dose of TA in our patients was mg/session, which is lower than the usual dose used for antifibrinolytic effect. Thus, no significant systemic side effects related to TA were noted. The melanin index, gradual improvement was seen at week 8 th but a statistically significant decrease was observed in week 16 th. For the mmasi score, a decrease was seen in week 4 th, but there was a statistically significant reduction in mmasi score at week 8 th, 12 th, and 16 th. The decrease in mmasi score was 0.99 at week 8 th, 1.56 at week 12 th, and 1.50 at week 16 th (36.26%, 57.14% and 54.95%, respectively). During follow ups at week 16 th, both mmasi score and melanin index were observed to have a statistically significant decrease when compared with the baseline. However, the mmasi score is slightly increased at week 16 but the repigmentation was still less than the initial hyperpigmentation. As for the patients selfassessment, 90% of them graded the improvement as excellent. A limitation of this study is the small sample size which may not be able to see the real outcome of TA intradermal injection for melasma. The weather and surrounding environment such as heat and sun light may also have affected the result of the treatment. Conclusion Intralesional microinjection of 50 mg/ml of TA was effective. It can demonstrate the improvement of melasma without significant side effects. Therefore, 50 mg/ml of TA apprear to be promising therapeutic option for melasma. References 1. Kang-Rotondo CH, Miller CC, Morrison AR, Pentland AP. Enhanced keratinocyte prostaglandin synthesis after UV injury is due to increased phospholipase activity. Am J Physiol Feb;264(2 Pt 1):C Budamakuntla L, Loganathan E, Suresh D, Shanmugam S, Dongare A, Prabhu N, et al. A randomised, open-label, comparative study of tranexamic acid microinjections and tranexamic acid with microneedling in patients with melasma. J Cutan Aesthet Surg. 2013;6(3): Rathi S, Achar A. Melasma: A clinico-epidemiological study of 312 cases. Indian J Dermatol. 2011;56(4): Shankar K, Godse K, Aurangabadkar S, Lahiri K, Mysore V, Ganjoo A, et al. Evidence-Based Treatment for Melasma: Expert Opinion and a Review. Dermatol Ther (Heidelb). 2014;4(2): Takashima A, Yasuda S, Mizuno N. Determination of the action spectrum for UV-induced plasminogen activator synthesis in mouse keratinocytes in vitro. J Dermatol Sci Jul;4(1): Cejková J, Lojda Z. The damaging effect of UV rays (with the wavelength shorter than 320 nm) on the rabbit anterior eye segment. I. Early changes and their prevention by catalase-aprotinin application. Acta Histochem Sep;96(3): Tse TW, Hui E. Tranexamic acid: An important adjuvant in the treatment of melasma. J Cosmet Dermatol. 2013;12(1): Rodrigues M, Pandya AG. Melasma: Clinical diagnosis and management options. Australas J Dermatol. 2015;56(3): Lee JH, Park JG, Lim SH, Kim JY, Ahn KY, Kim MY, et al. Localized intradermal microinjection of tranexamic acid for treatment of melasma in Asian patients: A preliminary clinical trial. Dermatologic Surg. 2006;32(5):

5 10. Maeda K, Naganuma M. Topical trans-4-aminomethylcyclohexanecarboxylic acid prevents ultraviolet radiation-induced pigmentation. J Photochem Photobiol B Biol. 1998;47(2 3): Ayuthaya PKN, Niumphradit N, Manosroi A, Nakakes A. Topical 5% tranexamic acid for the treatment of melasma in Asians: A double-blind randomized controlled clinical trial. J Cosmet Laser Ther. 2012;14(3): Chung JY, Lee JH, Lee JH. Topical tranexamic acid as an adjuvant treatment in melasma: Side-byside comparison clinical study. J Dermatolog Treat. 2016;27(4):