Clinical Evaluation of a Sunscreen Cream (AK-UV ) Containing Glycoceramide in Sensitive Skin of Atopic Dermatitis or Contact Dermatitis

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1 Clinical Evaluation of a Sunscreen Cream (AK-UV ) Containing Glycoceramide in Sensitive Skin of Dermatitis or Dermatitis Toshinori Bito, Masahiro Oka, Yoko Funasaka, Tatsuya Horikawa Masamitsu Ichihashi and Chikako Nishigori Division of Dermatology, Clinical Molecular Medicine, Faculty of Medicine, Kobe University Graduate School of Medicine 7-5-, Kusunoki-cho Chuo-ku, Kobe 65-7, Japan Clinical evaluation of a sunscreen cream (AK-UV ) containing glycoceramide was performed in 6 patients with sensitive skin found in atopic or contact. The sunscreen has been developed as hypo-irritant and hypo-allergic for the sensitive skin such as atopic. The products were evaluated for the safety and the usefulness on dry skin. Dryness of the skin and erythema at the end of week s application were observed. The results of the clinical trial of the products on the sun-exposed area for weeks indicated that AK-UV improved dry skin and erythema with atopic or contact. No adverse effect was observed throughout the study. In conclusion, these results suggest that AK-UV is a safe and useful sunscreen for the patients with sensitive skin. Skin Research, : 6-, Key words: sensitive skin, sunscreen, ceramide Introduction In recent years, it is increasingly understood that ultraviolet rays have adverse actions including facilitation of skin photo-aging and induction of skin cancers. It has been demonstrated that skin cancers and precancers presumably caused by ultraviolet rays have greatly increased in Japan, and this appears to be associated with various factors, such as aging of the society and increased exposure to ultraviolet rays due to the changes in people s lifestyle ). In such situations, the use of sunscreen agents is becoming very popular as ultraviolet protection. However, people with sensitive skin, such as atopic patients, seem to be less willing to use sunscreens because of anxiety about skin exposure to unknown chemicals. Although a variety of hypoallergenic cosmetic products have recently been developed for such customers with sensitive skin, there are still only limited options in sunscreen agents. In this study, we conducted a clinical trial to evaluate a sunscreen cream (AK-UV ) containing natural glycoceramide in patients with sensitive skin including atopic patients. This product is free from parabens and aroma chemicals, and ultraviolet absorbers are encapsulated in microcapsules to reduce allergenicity ). We he re report the excellent results with this sunscreen agent. Participants and methods. Participants This study included the patients with a history of definite diagnosis of contact or with mild to moderate atopic who attended the outpatient unit of the Department of Dermatology of Kobe University Hospital between January and August. These patients were in need of sunscreen agents. Prior to the clinical trial, the patients were fully informed by the dermatologists about the aim and the detailed method of study, and written informed consent was obtained from each patient. The following patients were excluded: () those with severe atopic, () those with acute accompanied by exudate or severe flares in the test area, and () those who were judged to be ineligible for entry by the investigators because of complications that would possibly affect the study results and other reasons. The details and the age distribution of the subjects are shown in Table and Fig., respectively.. Test material The sunscreen AK-UV used in this study contains ultraviolet absorbers encapsulated in microcapsules to avoid direct contact with skin. The microcapsules are made spherical for pleasant feeling and smoothness. The other ingredients include tamarind polysaccharide, which prevents ultraviolet-induced immune suppression ), an antioxidative vitamin E derivative, olive oil and natural glycoceramide, which is an intracellular lipid component. No ultraviolet-scattering agents are contained. The sunscreen can be washed out with a normal facial wash or soap easily, and no cleansing is necessary.

2 Table. Background of patients and summary of study result Background of patients Dryness Erythema Adverse Target After After After After Complications No. Sex Severity reactions disease weeks weeks weeks weeks Concomitant drugs Male IPD Mild None, Zyrtec, Kenacort-A Ointment Female Moderate None Azunol Ointment Female IPD Moderate None, Myser Ointment Male Mild None Myser Zaditen 5 Female None Ebastel, Protopic Ointment 6 Female Mild None Locoid Ointment 7 Male None Atarax P 8 Female None Hythiol 9 Female Mild None Zyrtec, Protopic Ointment Female Mild None Topsym Nipolazin Female Mild None Allegra, Protopic Ointment Female Mild None Allegra, Lidomex Ointment Female None None Female Mild None Ebastel 5 Male Claritin Moderate None, Voalla Protopic Ointment 6 Female Moderate None Claritin, Protopic Ointment 7 Female Azunol Moderate None Kenacort-A Ointment 8 Female Mild None Protopic Ointment 9 Female Mild None None Female Mild None None Male Mild None None Male Propaderm Moderate None Protopic Ointment Female Propaderm Mild None Protopic Ointment Female None None 5 Female Mild None None 6 Male Mild None None 7 Male Mild None None 8 Male Mild None Rinderon-VG Ointment 9 Female Mild None Talion Male Moderate None Allegra Female None None Female Allegra Mild None, Myser Lidomex Ointment Female Azunol Mild None Kenacort-A Ointment Female Mild None None 5 Female None None 6 Female None None : no visit to hospital, no data

3 Number of patients to to to to 5 5 to 6 Total Male Female 6 to 7 7 to 8 Table. Ingredients of AK-UV Capsules of organic ultraviolet absorbers (wall material: silicone resin-polypeptide) -Ethylhexyl p-methoxycinnamate -tert-butyl- -methoxydibenzoylmethane Gel matrix Hydroxyethyl acrylate/sodium acryloyldimethyl taurate copolymer Plant squalane Olive oil dl-α-tocopherol acetate Cerebroside (ceramide) Tamarind polysaccharide, -Butylene glycol Phenoxyethanol Purified water Age Aroma chemicals, colorants or parabens are not included in this product. SPF is 5 and PA is ++. The ingredients are listed in Table.. Methods The participants were asked to apply an appropriate amount ( mg/cm ) of the test agent to the face and forearms to be exposed to sunlight once before going out and at least every four hours while being outdoors. In case of sweating and wetting, the sunscreen was reapplied. The concomitant use of other sunscreens, including ultraviolet-protective cosmetics, was prohibited. However, toilet waters, milky lotions and creams that the patients had continuously used in the test area since the pretrial period were permitted and applied prior to the test agent. a. Study period The patients were asked to use the test materials for four weeks before final evaluation. b. Examination schedule The patients were examined on the first day of the trial, two weeks ( to 7 days) and four weeks (5 to days) after the start of the trial in principle. c. Items recorded At the start of the trial, the following items were recorded for each participant: initials, sex, age, chart number, institution, dermatologist in charge, date of informed consent, target disease, cause of the target disease (for contact ), severity of the target disease (for atopic ), summary of history of the target disease, previous diseases, complications, drugs for the target disease and their dosing period, and use of sunscreen agents before the trial. Foundations and makeup bases with a light-blocking effect were regarded as sunscreens. Medications for the target diseases were not modified during the trial in principle, but the discontinuation due to remission of the diseases was recorded. The frequency of use of the test agent was examined by inquiry and classified into four grades; : everyday, : every other day (-6 days a week), : - days a week, : no use.. Evaluation items a. Dermatological findings Dryness/desquamation and erythema in the test area attributed to the underlying disease were examined on each observation day, and the severity was evaluated as follows; 5: severe, : moderate, : mild, : slight, : none. b. Adverse reactions In the event of adverse reactions, the following items were recorded in detail on the survey sheets; types of adverse reactions (state specifically), time of onset (date of onset and elapsed days since the start of the trial), symptom (: mild, : moderate, : severe), treatment (: continued, : discontinued [date of discontinuation], : other [specify]), outcome (: cure [date of cure], : remission [date of remission], : not changed, : worsened, 5: unknown), and causality. Comments from the attending dermatologists were also stated. c. Safety of the test material At the end of the trial, the safety of the test material was assessed by the following three grades based on the time-related changes in dermatological findings and adverse reactions; : safe (no adverse reactions), : almost safe (transient adverse reactions occurred but the patient continued to use the test agent without intervention, or some interventions, such as temporal discontinuation, was required but the patient resumed the application of the agent), : problematic (the use of the agent was discontinued due to adverse reactions). d. Discontinuation of the trial When a patient was not able to continue the trial for any reasons, "discontinuation" was stated together with a reason, i.e., : therapeutic purpose, : poor response, : adverse reactions, : onset of other disease, 5: exacerbation, 6: impossible to visit the hospital, 7: patient s self-judgment, 8: other. Comments from the attending doctor were also added. e. Questionnaire survey At the end of the trial, we carried out a questionnaire survey about the patients feelings of the use of the test agent. The patients were asked to fill the questionnaire during examination in principle, and unclear points were explained orally by the doctors. The questions included: (a) adhesion to skin, (b) sticky sensation, (c) moist sensation, (d) spreadability, (e) overall feeling, and (f) ease of use. Each of these was assessed as; : good, : normal, : poor.

4 5 No use % Everyday % Everyday Every other day Number of patients 5 5 Mild atopic Moderate atopic 66% - days a week n = 5 % Every other day (-6 days a week) (-6 days a week) - days a week No use Fig.. Diseases of participants Fig.. Average frequency of use during the study period.5 p<.5 p< After weeks n = 5 After weeks n = 5 Fig..Comparison of erythema scores before and after study Fig. 5. Comparison of dryness scores before and after study - days a week (erythema) p<.5 Every other day (erythema) p<.5 Every day (erythema) After weeks After weeks After weeks n = n = 7 n = 5 Fig. 6. Comparison of erythema scores according to the frequency of use

5 - days a week (dryness) Every other day (dryness) p<.5 Every day (dryness) p<. After weeks After weeks After weeks n = n = 7 n = 5 Fig. 7. Comparison of dryness scores according to the frequency of use Without concomitant medications With concomitant medications P< After weeks After weeks n = n = Fig. 8. Comparison of erythema scores in the presence and absence of concomitant medications Without concomitant medications P<. With concomitant medications After weeks After weeks n = n = Fig. 9. Comparison of dryness scores in the presence and absence of concomitant medications f. Statistical analysis The dryness and erythema scores at the start and after four weeks of the study were statistically compared by using t-tests. Results Background of patients The participants in this study were 6 patients aged to 79 years (mean,.9 years) who met the inclusion criteria. They consisted of males (mean age, 5.5 5

6 Table. Results of the questionnaire survey on patients feelings after trial Evaluation items Good Normal Poor Adhesion to skin Sticky sensation 7 5 Moist sensation 6 9 Spreadability 6 9 Overall feeling Ease of use 6 8 years) and 6 females (mean age,.5 years). The participants classified by disease are shown in Fig.. More than half of the patients had mild atopic, and seven had moderate atopic. No patients received oral immunosuppressants or steroids. Nine patients had contact in the remission stage. Table shows the previous drugs and concomitant drugs given during the study period. Of the 6 participants, 5 were analyzed in this study except for one patient who did not visit the hospital in the fourth week. The frequency of use of the test agent is presented in Fig.. About half of the participants used the sunscreen every other day, and the rest half used it one to three days a week. The severity of erythema and dryness after four weeks of topical application was compared with that before use. The mean erythema and dryness scores significantly decreased from.6 to.66 and from.59 to.7, respectively (p<.5) (Figs. and 5). The results were analyzed in more details. In terms of the frequency of use, the erythema score in the "everyday" group decreased from. to. showing 7% improvement, which was no significant difference (p>.5). The "every other day" and "- days a week" groups showed 5% and % improvement, respectively, with significant differences (p<.5). This result indicates that the improvement of erythema would not correlate with the frequency of use. On the contrary, the dryness scores in the "everyday" and "every other day" groups showed % (from to.) and 6% improvement, respectively, indicating significant changes (p<. and p<.5, respectively). The patients who used the agent - days a week achieved % improvement, which was not significant (p>.5). This result suggests that the improvement of dryness would depend on the frequency of use (Figs. 6 and 7). With regard to the continuing use of the previous medications, the patients who received concomitant medications showed % improvement in erythema, indicating a significant change (p<.). The improvement was % and not statistically significant (p>.5) in the patients receiving the test agent alone, including those who discontinued their previous medications or sunscreens and those who had received no previous treatment (Fig. 8). In contrast, dryness was significantly improved by 7% (p<.) in the patients using AK-UV alone, whereas those who continued the previous medications achieved only % improvement with no significant change (p>.5). Thus, the use of AK-UV alone resulted in marked improvement in dry skin (Fig. 9). In the safety evaluation, no adverse reactions were reported in any of the participants during the four-week 6 trial, which gave a conclusion that the product is safe. The results of the questionnaire survey performed after four weeks are shown in Table. Regarding the adhesion to skin and spreadability of the product, 68% and 7%, respectively, of the participants answered "good", indicating that the sunscreen was highly evaluated. In addition, 57% gave a response of "good" to the question about overall feeling. However, three, one and one participants chose "poor" to the questions about sticky sensation, overall feeling and ease of use, respectively. Discussion "Sensitive skin" is not a technical term of dermatology. This has been widely used in the field of cosmetic science and among cosmetic users, and has subsequently come into the clinical field of dermatology. "Sensitive skin" has no clear dermatological definition but is understood as a skin type that is susceptible to exogenous stimulants to cause disadvantageous and adverse reactions despite the absence of appreciable skin lesions ). In this clinical trial, we included patients with atopic or with a history of contact so that the subjects could be objectively regarded as having sensitive skin, although skin lesions are not essential for "sensitive skin" in its definition as described above. Sunscreen agents with an SPF of or more usually contain various ultraviolet absorbers as chief ingredients for their ultraviolet-protective capacity. Since these absorbers are known as the potential causes of irritation in sensitive skin, as seen in the present participants, and also of contact and photocontact 5), many patients with sensitive skin seem to hesitate to use sunscreens, even though they understand the adverse effects of ultraviolet rays. Recently, sunscreen products containing no ultraviolet absorbers have been developed and have produced excellent results with sensitive skin in clinical studies 6). Thus, sunscreens for sensitive skin is increasingly attracting attention, but still there are only limited options and further development is desired. AK-UV, a cosmetic sunscreen product used in this study, contains no ultraviolet-scattering agent. In addition, the ultraviolet absorbers are encapsulated in microcapsules to avoid direct contact with skin for reducing the risk of contact or photocontact. Moreover, the sunscreen contains the vitamin E derivative, olive oil, glycoceramide of natural origin, which constitutes the intracellular lipids, and other ingredients so that it could function as a moisturizing agent that is not only hypoallergenic but also curative of damaged skin. Therefore, we evaluated the improvement of the underlying diseases as well as the safety of the product in this study. It has been suggested that dry skin in atopic should be associated with decreased levels of ceramides, a class of sphingolipids 7-8). We have previously reported that the glycoceramide-containing topical agent, a sister product of this sunscreen, is effective for the improvement of dry skin in atopic ). The present product is endowed with an additional ultraviolet-protective effect, and has been expected to be not only safe to sensitive skin but also effective in improving dry skin. Indeed, no adverse reactions were observed throughout the study, suggesting

7 the safety of this product. Furthermore, the improvement of dry skin was dependent on the frequency of use of this product, and the marked improvements were observed in the patients who had received no previous medications and those who had switched from the other products to this sunscreen. These findings support the notion that AK-UV improves dry skin. Taken together, the present results suggest that AK-UV is a safe sunscreen with a moisturizing effect suitable for patients with sensitive skin, such as atopic patients showing relatively mild symptoms. Reference. Ichihashi M, Bito, Bito T, Watanabe E et al : Epidemiological study on the prevalence and incidence of skin tumors of Japanese, Japanese Committee for Sunlight Protection () : -9,. Yuka Ueda, Masato Yoshioka : The characteristic and application of microcapsule involving UV absorber, Fragrance Journal ; 7 : Strickland FM, Darvill A, Albersheim P, Eberhard S, Pauly M, Pelley RP : Inhibition of UV-induced immune suppression and interleukin- production by plant oligosaccharides and polysaccharides, Photochem Photobiol 999 ; 69 : -7. Berardesca E, Maibach HI : Sensitive and ethnic skin. A need for special skin-care agents? Dermatol Clin 99 ; 9 : Dromgoole SH, Maibach HI, sensitization and photocontact sensitization of sunscreening agents in sunscreens. Eds by Lowe NJ, Shaath NA, Marcel Dekker, New York and Basel. pp Fnasaka Y, Utsuki A, Ichihashi M : Clinical evaluation of NOV UV stick (sunscreen product) on its safety and utility. Skin Res : 5-6, 7. Imokawa G, Abe A, Jin K, Higaki Y, Kawashima M, Hidano A : Decreased level of ceramides in stratum corneum of atopic : an etiologic factor in atopic dry skin? J Invest Dermatol 99 ; 96 : Yamamoto A, Serizawa S, Ito M, Sato Y : Stratum corneum lipid abnormalities in atopic. Arch Dermatol Res 99 ; 8 : 9-9. Jin K, Higaki Y et al : Analysis of b-glucocerebrosidase and ceramidase actives in atopic and aged dry skin. Acta Derm Venereol 99 ; 7 : 7-. Tatsuya Horikawa, Tsutomu Takashima, Susumu Harada, Toshiya Chihara, Masamitsu Ichihashi : An open clinical trial of glycoceramide-containing cream and lotion on dry skin of atopic 998 ; : 5-9 7