Passion fruit purple variant (Passiflora edulis Sims var. edulis) seeds extract 10% cream in acne vulgaris treatment: an open-label pilot study
Nani K. Dewi, MD, Imam B. Putra, MD, PhD and Nelva K. Jusuf, MD, PhD

Department of Dermatology and Venereology Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia

Correspondence Imam B. Putra, MD, PHD
Department of Dermatology and Venereology Faculty of Medicine Universitas Sumatera Utara
Jln. Dr. Mansur No. 5
Medan, North Sumatera 20155 Indonesia
E-mail: [email protected] Conflict of interest: None. Funding source: None.

doi: 10.1111/ijd.15178
Background Purple variant of passion fruit (Passiflora edulis Sims var. edulis) is a tropical plant commonly used in the beverage industry. The seeds have high content of linoleic
acid and piceatannol which has been reported and showed antibacterial, anti-inflammatory, and antioxidant activities. However, there is no report regarding its effect on acne vulgaris. Objective To determine the efficacy of topical use of Passiflora edulis Sims var. edulis seeds extract on acne vulgaris.
Methods In this open-label uncontrolled trial, 45 subjects with acne vulgaris were given passion fruit purple variant seeds extract 10% cream for 8 weeks. Noninflammatory, inflammatory, and total acne lesions count along with ultraviolet-induced red fluorescence (UVRF) measurement were done at weeks 0, 2, 4, 6, and 8. All reported adverse events were documented, and patient satisfaction rates were determined at week 8. Paired T-test and Wilcoxon test were done with P ≤ 0.05 indicating significance.
Results There were significant reductions in noninflammatory (80.9%), inflammatory (71.1%), and total (73%) lesion count after 8 weeks of the cream application (P < 0.001). Significant reduction in UVRF spot quantity (36%) and percentage area (45.9%) were found at week 8 (P < 0.001). Only 2.2% of subjects experienced an adverse event of mild and transient peeling. Most of the subjects (77.8%) noticed significant improvement in their acne vulgaris and expressed good satisfaction rate. Conclusion Topical use of passion fruit purple variant seeds extract improves acne vulgaris with reduction in lesion counts and UVRF, minimal adverse events, and good satisfaction rate. Additional prospective studies are required. Introduction Acne vulgaris is a chronic pilosebaceous inflammatory disorder that has varied manifestations from noninflammatory open and closed comedones, inflammatory papules, pustules, nodules, or protoporphyrin IX (PPIX), that appeared as orange-red fluores- cence under ultraviolet A (UVA) illumination, known as UV-in- duced red fluorescence (UVRF). One of the commonly used devices to evaluate this follicular fluorescence is Visiopor PP34ti camera, which is equipped with UVA 375 nm.10 Some 1–3 cysts. It commonly presents during adolescence. Despite its studies reported the proportional correlation between UVRF and self-healing nature, the sequelae of acne vulgaris such as scars and pigmentary changes can remain for a lifetime.1,2,4 This dis- ease does not only cause permanent physical complication but also psychosocial effect and affects quality of life.5 Worldwide, acne vulgaris affects 9.4% of the population and ranks as the eighth most common disease.6 About 90% of adolescents suf- fered from acne vulgaris, and more than half retained it until adulthood.1,6,7 The pathogenesis includes four factors: inflammation, follicu- lar hyperproliferation of epidermis, increase in sebum production density of C. acnes, and it can be used to evaluate C. acnes suppression effect of a particular treatment.11 In general, Asian skin is more prone to irritation from topical agents and postinflammatory hyperpigmentation. Relatively higher neurosensory response to stimulus and melanin content in Asian skin compared to Caucasian are the primary cause.5 Topical acne treatment has the potential for irritations such as dry skin, erythema, scaling, sore skin, burning sensation, and itchiness. As a result, poor compliance to treatment was found high in the Asian group, with a proportion of 48%.12 Hence, skin and activities of Cutibacterium acnes.1,2,8,9 Follicular coloniza- care is essential to decrease those risks by maintaining the skin tion of C. acnes and accumulation of sebum stimulate produc- tion of porphyrins, mostly coproporphyrin III (CPPIII) and moisture, and cosmeceuticals have become a key element in the maintenance therapy of acne vulgaris. Several nonmedical 1 raw or natural materials are considered cosmeceuticals because of their functional effects to skin and can be used as adjuvant therapy in acne vulgaris.5 In recent years, there is a trend in exploring the use of natural resources because of their vast availability in nature, promising results, and minimal side effects. Passion fruit purple variant (Passiflora edulis Sims var. edu- lis) is a prominent plant in the agricultural sector and commer- cially farmed in Indonesia since its pulp is used in syrup and the refreshment beverages industry. North Sumatera is one of the largest plantation of this plant in Indonesia, with plateau topographic areas such as Karo, Simalungun, Dairi, and North Tapanuli.13 Passiflora edulis Sims var. edulis has been used as a traditional remedy for stimulant (fruit), anxiolytic (leaves), and cough reliever (flowers).14,15 Potential anti-inflammatory, antimi- crobial, and antioxidant activities have been reported on P. edu- lis stem and leaves extract.16,17 Currently, only the pulp is commercially used in juice production because of its high multi- vitamin, mineral, and antioxidant contents which are beneficial for skin health.18,19 The rind and seeds are not used in the food industry and considered as waste. Reports on the benefit of passion fruit purple variant seeds was not vastly published. Nyanzi et al. reported that P. edulis Sims var. edulis seeds extract contains the high concentration of linoleic acid.20 In conjunction with acne vulgaris, a decrease in this essential fatty acid was found in the sebum of acne patients, and it returned to normal level after resolution.21 Fur- thermore, piceatannol was found vastly in the seeds, and this polyphenol has good antibacterial activity against C. acnes as well as good anti-inflammatory, and antioxidant properties.22,23 Based on these findings, it is hypothesized that the use of pas- sion fruit purple variant seeds extract might affect the develop- ment of acne vulgaris lesions. The aim of this study is to evaluate the effect of passion fruit purple variant seeds extract topical application on acne vulgaris patients. Materials and methods Plant material The purple variant of passion fruit used in this study was harvested from Brastagi, Karo, North Sumatera, Indonesia, and has been authorized by the Department of Biology, Faculty of Mathematics and Natural Science, Universitas Sumatera Utara. The seeds were separated from their pulps and dried at 40°C, then mashed with a blender into powder prior to extraction. Extraction and preparation of topical cream The grounded powder of purple variant passion fruit seeds was soaked in 96% ethanol for 5 days, and extraction was done by rotary evaporation at 40°C–50°C. The obtained extract was brown in color with thick consistency. It was collected in aglass container with light protection cover and stored in the refrigerator at 4°C. Prior to topical cream preparation, a pre- experimental in vitro study was done to determine the antibacterial concentration against C. acnes. According to the results of the in vitro study, a 10% cream was prepared by mixing the extract with cream base that contained 12% stearic acid, 0.5% cetyl alcohol, 5% sorbitol, 3% propylene glycol, and 1% triethanolamine. This formulation was kept in a 20 g nontransparent plastic jar and stored at a temperature <30°C. Study design and ethical issues This is an open-label uncontrolled clinical trial that was conducted from April 2019 until September 2019 at the Outpatient Department of Dermatology and Venereology, General Hospital of Universitas Sumatera Utara. The study protocol was approved by the Research Ethics Committee of the Faculty of Medicine, Universitas Sumatera Utara (no. 354/ TGL/KEPK FK USU-RSUP HAM/2019). This study was conducted according to the ethical considerations of the Declaration of Helsinki and Good Clinical Practice (GCP). All subjects provided informed written consent before entering the study. Subjects and intervention Forty-five patients with a clinical diagnosis of acne vulgaris, aged ≥18 years old, who had noninflammatory and inflammatory lesions on the face, were included in this study. The exclusion criteria were pregnancy and lactating mothers, prior acne treatment within the last one month, acute infection, other dermatoses, and autoimmune diseases. Subjects who did not apply the cream for seven consecutive days and duration of treatment less than 6 weeks were dropped out of the study. The eligible subjects signed written consent form and applied passion fruit purple variant seeds extract 10% cream on the face once a day for 8 weeks. Sodium lauryl sulphate containing soap was given as daily facial wash. All the subjects were required to come for a follow-up visit every 2 weeks until week 8.Concurrent use of any topical or oral anti-acne medications was not allowed during the study. A pre-trial safety study of 8- hour application of the extract cream with patch cover on each participant’s lower arm was done prior to the start of the clinical trial and showed no signs and symptoms of irritation. Outcome measurement The demographic data were collected initially, including identity, age, and gender. The primary outcome of this study was acne lesion count, including noninflammatory, inflammatory, and total lesions on the face. Photography documentation of the face (front, right, and left side) was done at each visit. Fluorescence photography was performed using Visiopor PP34ticamera (C & K, Courage-Khazaka, K€oln, Germany) with UVA 375 nm and measured area of 6 9 8 mm on five divided facial areas (forehead, nose, right cheek, left cheek, chin). The secondary outcomes were mean of UVRF spot quantity and percentage area from all the examined areas. Adverse events during the study were evaluated and documented in the scales of 0 (none), 1 (mild), 2 (moderate), and 3 (severe). All the evaluations were done independently by three different examiners. At the end of the study, every subject was required to give satisfaction rate based on their acne improvement in the following scales: 0 (none), 1 (minimal), 2 (moderate), 3 (good), and 4 (worsen). Statistical analysis All collected data from weeks 0, 2, 4, 6, and 8 were analyzed using normality test by Saphiro–Wilk. Paired T-test was performed on noninflammatory lesion counts, UVRF spot quantity, and percentage area data. Wilcoxon test was done to compare inflammatory and total lesion counts data before and after intervention. In all analysis, P value ≤ 0.05 was considered statistically significant. Results There were 45 subjects who fulfilled inclusion and exclusion crite- ria. Among all participants, female proportion (62.2%) was found higher than male (37.8%). The majority of subjects (84.5%) belonged to the 18 to 25-year-old age group (Table 1). Initially, mean of the baseline noninflammatory, inflammatory, and total acne lesion counts were 88.22 ti 41.94, 22.44 ti 15.83, and 110.67 ti 49.56, respectively. After 8 weeks of passion fruit pur- ple variant seeds extract topical use, there was significant reduc- tion in noninflammatory lesion counts to 24.91 ti 17.58% (71.1%, P < 0.001). The number of inflammatory lesions was reduced 80.9% to 4.78 ti 5.09, which was statistically significant (P < 0.001). Furthermore, total acne lesion counts decreased 73% to 29.69 ti 18.52 (P < 0.001) at the end of the study (Fig. 1). There was significant reduction in UVRF spot quantity (36%, P < 0.001), from 39.98 ti 11.45 to 25.69 ti 10.96, after 8 weeks of the cream extract application. In UVRF spot percent- age area, 45.9% reduction (P < 0.001), from 4.39 ti 1.72 to 2.39 ti 2.09, was found on week 8 (Table 2). Follow-up evaluation on weeks 2, 4, 6, and 8 revealed that mean reduction percentage of noninflammatory lesions occurred more rapidly, as much as 49.7% on the second week. On the other hand, 50% reduction of inflammatory and total acne lesion Table 1 Demographic data Figure 1 Photograph comparison of acne vulgaris condition at week 0 and week 8 counts was achieved in week 4 of passion fruit purple variant seeds extract topical application (Fig. 2). Furthermore, reduction in UVRF spot quantity and percentage area was found as early as week 2 in consecutive 20.7 and 20.1%. These changes gradually escalated with mean reduction percentage of UVRF spot quantity and percentage area 36 and 45.9%, respectively, at the end of the study (Fig. 3). Characteristic Subject Drop out n (%) 45 (100) 0(0) Adverse events evaluation of the passion fruit purple variant seeds extract topical application for 8 weeks revealed that only 1 of 45 subjects experienced mild and transient peeling for 1 week, and no limitation of cream application was needed. At Gender Male 17 (37.8) Female 28 (62.2) Age (year) 18–25 38 (84.5) 26-30 6 (13.3) >30 1 (2.2)
the end of the study, all subjects were required to evaluate satisfaction rate according to the improvement of their acne condition. Majority of the subjects expressed good satisfaction rate (77.8%), followed by moderate 20%, and minimal 2.2% (Table 3). It can be concluded that the topical use of passion fruit purple variant seeds extract provides good satisfaction

Table 2 Comparison of non-inflammatory, inflammatory, total acne lesion counts, UVRF spot quantity, and percentage area covered before and after topical application of Passiflora edulis Sims var. edulis seeds extract

Outcomes Week Mean ti SD Median Minimum Maximum P
Acne lesions

Non-inflammatory Inflammatory Total
UVRF spot
88.22 ti 41.94 24.91 ti 17.58 22.44 ti 15.83
4.78 ti 5.09 110.67 ti 49.56
29.69 ti 18.52
<0.001 <0.001 <0.001 Quantity Percentage area 0 8 0 8 39.98 ti 11.45 25.69 ti 10.96 4.39 ti 1.72 2.39 ti 2.09 41 26.6 4.36 2.14 12.2 8.4 1.27 0.44 67.6 51.8 10.78 8.14 <0.001 <0.001 Figure 2 Comparison of mean reduction percentage in lesion counts of noninflammatory, inflammatory, and total lesions of acne vulgaris on weeks 2, 4, 6, and 8 after topical application of Passiflora edulis Sims var. edulis seeds extract 10% cream rate and minimal risk of adverse events in acne vulgaris patients. Discussion Topical use of passion fruit purple variant seeds extract on acne vulgaris has not been reported yet. This is a pilot study that reports the effect of Passiflora edulis Sims var. edulis seeds development of inflammatory acne lesions can be achieved with its topical use. In vitro study by Jusuf et al. reported antibacterial effect of Passiflora edulis Sims seeds extract against C. acnes at mini- mum concentration of 5% and increase parallel with concentra- tion.25 Piceatannol, the predominant polyphenol of passion fruit seeds, has been reported to have comparable antibacterial activity on C. acnes with benzoyl peroxide (BPO) that is widely extract in improving acne vulgaris. Clinical evaluation revealed 23,26 used as first line topical antibiotic in acne vulgaris. This that mean counts of inflammatory acne lesions were found reduced earlier than noninflammatory. In week 2, almost 50% reduction of inflammatory lesions has been found. On the other hand, noninflammatory lesions have just shown 50.3% reduc- tion in week 4. Passiflora edulis Sims seeds extract is known to have a high content of piceatannol that has inhibition activity on TNF-aand IL-6, proinflammatory cytokines in acne vulgaris pathogenesis.24 Because of this anti-inflammatory effect of pas- sion fruit purple variant, rapid improvement and reduction in the anaerobic gram negative bacteria may promote inflammation reaction through stimulation of lipase, protease, hyaluronidase, and chemotactic factors production. C. acnes cell wall can induce antibody production because of its carbohydrate antigen, leading to the progression of inflammation through complement cascade activation.1 With this antibacterial activity, topical use of passion fruit purple variant seeds extract can reduce C. acnes colonization on the skin of acne vulgaris patients. As a result, the development of an inflammation reaction, turned into Figure 3 Comparison of mean reduction percentage of UVRF spot quantity and percentage area after application of Passiflora edulis Sims var. edulis seeds extract 10% cream on weeks 2, 4, 6, 8 Table 3 Subject’s satisfaction rate on the use of Passiflora edulis Sims var. edulis seeds extract in acne vulgaris Subject and this essential fatty acid level in sebum returns to normal after successful therapy with isotretinoin and oral antiandro- gen.28,29 Therefore, Passiflora edulis Sims var. edulis seeds extract topical application can reduce and inhibit the develop- ment of comedonal lesion in acne vulgaris. Satisfaction rate 0(none) 1(minimal) 2(moderate) 3(good) n 0 1 9 35 % 0 2.2 20 77.8 As a result, total acne lesion counts also found a decrease of 73% after 8 weeks of passion fruit purple variant seeds extract containing cream application. This is certain because of reduc- tion and inhibition effect of the extracts in the development of both inflammatory and noninflammatory acne lesions. The topi- 4(worsen) Total 0 45 0 100 cal use of this extract can be recommended as an adjuvant therapy. However, further studies with randomized controlled trial design are required to evaluate its efficacy in comparison to lesions, can be inhibited and prevented with the use of Passi- flora edulis Sims seeds extract cream. Noninflammatory acne lesions developed through several pathogenetic pathways. Hyperproliferation of keratinocyte and increased sebum production play an important role in the devel- opment of comedonal lesions. Excess sebum results in dilution effect, leading to decrease in linoleic acid level. This low level of linoleic acid stimulates the release of IL-1a, a proinflamma- tory cytokine that promotes follicular keratinocyte hyperprolifera- tion and microcomedones.1 Furthermore, the decrease in this essential fatty acid leads to reduction in lineoyl ceramide, which regulates barrier function and follicular permeability, and may result in comedonal rupture.27 In this study, the topical use of passion fruit purple variant seeds extract can reduce 71.1% of noninflammatory lesion counts. High content of linoleic acid in the seeds extract might play an important role. Nyanzi et al. reported that oil extract of Passiflora edulis Sims seeds contains a large amount of essen- tial fatty acid, predominantly linoleic acid (72.26%).20 Further- more, some studies have reported that the topical use of 2.5% linoleic acid results in reduction of comedones size in 4 weeks, the standard therapy of acne vulgaris. Cutibacterium acnes colonization plays a crucial role in pro- moting inflammation by releasing porphyrins, mostly in the form of coproporphyrin III and protoporphyrin IX. These metabolites have stimulation effect on perifollicular inflammation via ker- atinocyte derived IL-8 and cytotoxic squalene production.11,30,31 As an indicator of the presence of porphyrins, indirectly C. acnes colonization, UVRF examination is often used in treat- ment evaluation of acne vulgaris. Pagnoni et al. reported the use of UVRF examination using fluorescence photography (Canfield Clinical Systems, Cedar Grove, NJ) on the nose and right cheek in the evaluation of BPO therapy. Ninety seven per- cent reduction in total area of UVRF spot was found in just 3 days, from 0.693 ti 0.278 to 0.018 ti 0.026.32 In this passion fruit study, mean reduction of UVRF spot quantity and percent- age area was 36 and 45.9%, using Visiopor PP34ti camera on five divided facial areas. This variety of results might be because of the different tools, parameters, and areas of obser- vation that were used in the two studies. Besides C. acnes colo- nization, sebum level was found to have a positive correlation with porphyrins fluorescence rate especially on the cheeks and 33,34 chin. In this study, sebum level of acne vulgaris patients with reduction in noninflammatory, inflammatory, and total acne was not evaluated. With the reduction in UVRF, topical use of passion fruit purple variant seeds extract might have an inhibi- tion effect on sebum production, and further studies are neces- sary to evaluate this effect in acne vulgaris patients. Poor treatment compliance to the standard acne therapy was found in the Asian group because of higher risk of side effects. Babayeva et al. reported peeling as the most frequent adverse event (60.9%) found in the use of tretinoin 0.05% + clindamycin combination therapy, followed by dry skin (52.2%), erythema (34.8%), burning sensation (30.4%), and itchiness (21.1%). In the 3% salicylic acid + clindamycin group, dry skin was found as the most frequent adverse event (60.9%), followed by peel- ing (43.5%), burning sensation (34.8%), erythema (30.4%), and itchiness (13.1%).35 Gold et al. also reported the use of ada- palene and BPO combination has moderate to severe side effects such as erythema, peeling, dry skin, and burning sensa- tion.36 In comparison, topical application of passion fruit purple variant seeds extract 10% cream for 8 weeks was found to have mild and transient peeling adverse event only in one out of 45 subjects (2.2%). This result is in accordance with a prelim- inary study by Lourith et al. that reported patch test result of 20 µl passion fruit purple variant seeds extract single application on 20 volunteers and found low irritation index on a par with water and sodium lauryl sulphate.37 Therefore, Passiflora edulis Sims var. edulis seeds extract topical application has only mini- mal adverse event risk. At the end of the study period, 77.8% of subjects expressed a good satisfaction rate, based on their significant acne improvement. In comparison with the Gold et al. study results, significant improvement was found only in 44.6% of participants with adapalene and BPO combination therapy, followed by moderate (36.3%), minimal (5.9%), no improvement (2.9%), and worsen (0.5%).36 As a result, passion fruit purple variant seeds extract containing cream has a good safety profile, and satisfaction rate, thus, might be considered to be used as adju- vant therapy in acne vulgaris. This is a non-controlled trial in which no standard treatment or placebo group has been included in the study analysis. Thus, it limits the study capability to compare the efficacy of P. edulis seeds extract 10% cream with the available acne treatment. With this study design, we are also unable to exclude the poten- tial effect of sodium lauryl sulphate soap, in addition to the P. edulis seeds extract 10% cream, in the improvement of acne vulgaris on study participants. Therefore, further studies with randomized controlled trial design are necessary to determine the safety and efficacy of Passiflora edulis Sims var. edulis seeds extract topical application on acne vulgaris. Conclusion Topical use of passion fruit purple variant (Passiflora edulis Sims var. edulis) seeds extract improves acne vulgaris condition lesion counts, and also UVRF spot quantity and percentage area. 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