Retinoic acid – Abatacept0

The efficacy and safety of multilamellar vesicle containing retinaldehyde: A double- blinded, randomized, split- face controlled study

Abstract

Background: Retinaldehyde is one of the major members of the retinoid family, which has potential skin rejuvenating effects on photoaged skin and has a good safety profile.
Aims: The study aimed to evaluate the efficacy and safety of multilamellar vesicle containing retinaldehyde (MLV- RAL) 0.05% and 0.1% used to treat photoaged skin. Patients and methods: A randomized, prospective, investigator- blinded, split- face comparison study was conducted. We enrolled 23 Korean volunteers who applied MLV- RAL 0.05%/0.1% cream on one randomized side of their face and retinol 0.05%/0.1% cream on the opposite side. Wrinkle depth on both crow’s feet was assessed by the Antera 3D system. Skin hydration, elasticity, facial curved length, and dermal density were also evaluated.
Results: After an 8- week application, all objective parameters, including wrinkle depth, were significantly improved in both MLV- RAL 0.05%/0.1% and retinol 0.05%/0.1% treated sides. Compared with the retinol- treated side, MLV- RAL- treated side showed a significant improvement of objective assessments except for dermal density. Additionally, there was no adverse event associated with the use of either MLV- RAL 0.05%/0.1% or retinol 0.05%/0.1% cream.
Conclusion: The application of MLV- RAL 0.05%/0.1% cream improved wrinkle, facial contour, and biophysical parameters associated with skin aging.

K E Y W O R D S
cosmeceuticals, photoaged skin, retinaldehyde, retinoic acid

1 | INTRODUCTION

Photoaging of skin is characterized by fine and coarse wrinkling, loss of skin laxity, a rough texture, and pigmentation.1 These phenotypes are associated with epidermal atrophy, dermal elastosis, collagen degradation, and inflammatory cell influx from blood vessels.2 Retinoids, which are defined as a class of natural or synthetic form of vitamin A (retinol), could reverse some photoaging phenotypes.3 The retinoid family comprises vitamin A (retinol) and its oxidized forms, such as retinoic acid and retinaldehyde (RAL). The most oxidized and biologically active form of all vitamin A derivative is the retinoic acid, but its topical application causes local skin irritation.3,4 irritation but weak retinoid- like activity due to the slow and rate- limiting oxidation process.5
Retinaldehyde is the natural precursor of retinoic acid, which exerts the similar biologic activity of retinoic acid.3,5 Retinaldehyde has potential skin rejuvenating actions; in vitro data suggest that incubation of human skin explants with retinaldehyde led to increased dermal collagen synthesis and stimulated the keratinocyte proliferation and epidermal hyperplasia.6,7 Moreover, retinaldehyde is less irritative and better tolerated than retinoic acid when used as a topical agent.8 The purpose of this study is to assess the efficacy and safety of multilamellar vesicle containing retinaldehyde (MLV- RAL) for photoaged skin.

2 | MATERIAL AND METHODS

2.1 | Subjects

Healthy female adults who have wrinkles on the face were considered eligible for this study. The Institutional Review Board of the Global Medical Research Center approved this study (IRB No. GIRB- ETP- 035), and informed consent was obtained from each subject. The exclusion criteria were history of active facial dermatosis, pregnancy, known allergy or hypersensitivity to cosmetic ingredients, and the history of wrinkle removal, peeling, or laser treatment within the prior 6 months. The study was performed according to the principles of Good Clinical Practices and the Declaration of Helsinki.

2.2 | Study design and randomization

We conducted a randomized, prospective, investigator- blinded, split- face trial. The sides of the face were randomized before performing the study. A random number generator was used to generate 0’s and 1’s by Microsoft Excel (2016 version; Microsoft). Each random assignment was sealed separately in a non- transparent envelope. Allocations were made consecutively, with subjects applying the MLV- RAL 0.05%/0.1% or retinol 0.05%/0.1% cream on either the left or right side of the face.
The subjects were instructed to apply MLV- RAL 0.05% or retinol 0.05% cream for the first four weeks and MLV- RAL 0.1% or retinol 0.1% cream for the next four weeks on the designated side once a day. The participants were advised not to use any other pharmaceutical products or emollients other than the study products during the study. The study duration was 8 weeks and included three assessment visits: an inclusion visit in week 0 (baseline), and two follow- up visits at 4 and 8 weeks.

2.3 | Efficacy assessment

We quantitatively assessed the treatment effects. We evaluated both crow’s feet’ wrinkle depth by using a 3D skin analysis camera system (Antera 3D®, Miravex, UK) at weeks 0, 4, and 8. The facial curved length was obtained from measuring curvature distances from the tragus to ala of nose by the 3D surface scanning system (Morpheus 3D® scanner, Morpheus Co., Seoul, Korea). Other objective biophysical skin properties such as skin hydration, skin elasticity, and dermal density were assessed on each of the three visits. Skin hydration was measured by a Corneometer® CM825 (Courage Khazaka electronic, Germany); skin elasticity employing a Cutometer® Dual MPA580 (Courage Khazaka electronic, Germany); and dermal density using an Ultrascan® UC22 (Courage Khazaka electronic, Germany), which is measuring the density of the skin by generating a short electric pulse using a 22 MHz ultrasonic transducer.

2.4 | Safety and tolerability assessment

Subjects underwent a physical examination to assess safety outcomes at every visit. Participants also were asked to report side effects during the study period. Additionally, the participants were questioned to score their rates of satisfaction using following scale: 1 = unsatisfied, 2 = no change, 3 = slightly satisfied, 4 = satisfied, and 5 = very satisfied.

2.5 | Statistical analysis

Data within the group were compared using the paired Student’s t test and are presented as the mean ± standard error of the mean. Repeated measures analysis of variables (RM- ANOVA) was conducted to incorporate data from all time points, analyze differences in time, treatment group, and incorporate these factors. Post hoc analysis of each time point was done by using the independent t test with Bonferroni’s correction. All statistical analyses were performed using SPSS version 25.0 (SPSS Inc). P <.05 was considered statistically significant in all cases. 3 | RESULTS 3.1 | Patient characteristics We enrolled the twenty- three female subjects (mean age, 49.6; range, 40- 60 years) with wrinkles on the face. Among the 23 participants, one dropped out from the clinical trial due to follow- up loss and retracted their consent. Therefore, the per- protocol analysis was conducted on data obtained from 22 participants. 3.2 | Objective assessment of efficacy Compared to baseline, wrinkle depth was significantly reduced by 23.7% in the MLV- RAL 0.05/0.1% treated side and 10.27% in the retinol 0.05/0.1% treated side after 8 weeks of application (Figure 1). groups. *p- value < 0.05, **p- value < 0.001 Also, skin hydration, skin elasticity, facial curved length, and dermal density increased significantly in both MLV-R AL 0.05/0.1% and retinol 0.05/0.1% treated side after 8 weeks of application (Figure 2, Table 1). We then conducted the inter- group comparison between MLV- RAL 0.05/0.1% and retinol 0.05/0.1% treated side of the total 8- week study period using the RM- ANOVA (Table 1). Significant improvement of wrinkle depth (P =.001), skin hydration (P <.001), skin elasticity (P <.001), and the facial curved length (P <.001) was noted in the MLV- RAL 0.05/0.1% treated side compared to the retinol 0.05/0.1% treated side. Only dermal density showed no statistical difference between the two groups. Notably, post hoc analysis at a 4- week of application revealed that skin elasticity (8.47% vs. 6.78%, P =.004) and facial curved length (0.50% vs. 0.14%, P <.001) were more improved in the MLV- RAL 0.05/0.1% group than in the retinol 0.05/0.1% group. 3.3 | Patient satisfaction Overall, the average percentage of patients who responded “very satisfied” and “satisfied” was 76.6% in the MLV- RAL group and 74.5% in the retinol group. On comparing the MLV- RAL- treated side with the retinol used side, no significant difference in patient satisfaction levels was noted after 8 weeks. 3.4 | Adverse events Both study products were well tolerated without significant skin irritation. No subject reported any serious adverse event during the study period. No side effects such as erythema, itching, hyperpigmentation, or hypopigmentation were noted. 4 | DISCUSSION In this prospective, randomized, split- face controlled study, significant improvement of wrinkle depth and biophysical properties of skin was noted, with an overall better outcome in the MLV- RAL- treated side than the retinol- treated side. Skin hydration was most remarkably improved (57.4%) with the MLV- RAL application, followed by wrinkle depth (23.7%) and skin elasticity (20.4%), whereas the improvement effects of MLV- RAL for facial contour and dermal density were modest, which were less than 10%. The preparations used in this study were very safe; no subject reported any adverse effects while applying the MLV- RAL 0.05/0.1% or retinol 0.05/0.1% cream. Topical retinoic acid, such as tretinoin, has long demonstrated its efficacy in treating photoaged skin.9 However, cutaneous irritation caused by an “overload” of the retinoic acid– dependent pathway with excess, non- physiologic amounts of exogenous retinoic acid is a limiting factor of compliance.10 The topical application of retinaldehyde may prevent such overload by controlled oxidation toward the active retinoic acid form in the epidermal cells on the pertinent stage of differentiation.5,10 Due to the biochemical advantages mentioned above, several clinical trials existed to utilize retinaldehyde as an active ingredient for skin anti- aging.3,11,12 However, none of the studies have directly compared the effectiveness and tolerability of retinaldehyde with another retinoid derivative by a half split design. Our study product also contained retinaldehyde in the multilamellar vesicles, which are known to be beneficial for drug delivery and cellular uptake.13 By efficiently delivering retinaldehyde into the skin in a stable form through multilamellar vesicles, the overall bioavailability increases; thus, the MLV- RAL can exhibit profound effects in improving skin wrinkles and elasticity (Figure 3). The present study demonstrated the superior efficacy of MLV- RAL compared to retinol in multiple objective parameters of skin aging. Moreover, MLV- RAL showed at least a similar degree of safety and tolerability as retinol during the study period. There are a few limitations to the present study. An 8- week study period may not be sufficient to evaluate the improvement of facial contour and enhance the dermal density by the MLV- RAL. Thus, long- term evaluation is required to clarify the potential rejuvenating effect of the MLV- RAL. Also, this study lacks the histologic evaluation of whether the microscopic alterations of epidermis and dermis were achieved in the MLV- RAL applied subjects. However, in the prior study, only four weeks of retinol treatments were sufficient to show the increased epidermal thickness and up- regulated genes for collagen synthesis. Also, these histologic changes preceded the clinical improvements, such as reduction of facial wrinkles.14 Thus, we expect that our MLV- RAL could reverse the microscopic properties of photoaged skin before clinical improvement. 5 | CONCLUSION Our study suggests that MLV- RAL cream was effectively improved the photoaged skin while showed a good safety profile. Further studies are needed to analyze the long- term clinical and microscopic effects of MLV- RAL in various cosmetic indications. REFERENCES 1. Krutmann J, Bouloc A, Sore G, Bernard BA, Passeron T. The skin aging exposome. J Dermatol Sci. 2017;85(3):152- 161. 2. 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