Retrospective Analysis of Combined Treatment with Triple Combination Cream and Hyaluronic Acid Microneedle Patch for Benign Pigmented Skin Lesions

Background : Triple Combination Cream (TCC), which is a combination of retinoic acid, hydroquinone, and a corticosteroid at fixed ratios, is an economical option for treating common pigmented skin lesions, although it can elicit some discomfort, including redness, dryness, and itching. Objective : We evaluated the clinical usefulness of combining TCC with a dissolvable microneedle hyaluronic acid patch (TCC+HA-DMN) to achieve the therapeutic effects of TCC while avoiding its side effects when treating pigmented skin lesions. Methods & Materials : We retrospectively analyzed the results of 25 patients (mean age, 48.2 years, range 27–72 years, SD = 13.078) with pigmented lesions along the face (e.g., solar lentigines and seborrheic keratoses) who received TCC+HA-DMN between March 1, 2018 and June 30, 2019. For 4 weeks, patients were asked to apply TCC and an HA-DMN patch daily only to the pigmented area and to wash their face after 3 hours. Results : A UV and polarized LED light source and CMOS (Complementary metal–oxide– semiconductor) sensor integrated digital analysis system revealed significant reductions in pigmentation and melanin level in lesions 4 and 8 weeks after initiating TCC+HA-DMN, respectively. Visual analog scale scores also highlighted marked improvements in lesion appearance at 4 and 8 weeks (min = 1, max = 5, mean = 2.48 (4weeks), 3.76 (8 weeks); standard deviation at 4 and 8 weeks = 0.871 and 1.051, respectively). Conclusion : TCC+HA-DMN is effective in treating pigmented skin lesions. Retrospective Analysis of Combined Treatment with Triple Combination Cream and Hyaluronic Acid Microneedle Patch for Benign Pigmented Skin Lesions.

has indicated that solar lentigines show structural changes in the epidermis that are accompanied by increases in the expression of genetic markers associated with melanin synthesis, such as proopiomelanocortin, tyrosinase, tyrosinase-related protein 1, dopachrome tautomerase, Pmel-17, and microphthalmiaassociated transcription factor [1]. These changes in the skin are permanent and do not recover by avoiding exposure to UV light.
Thus, clinical intervention is necessary to remove solar lentigines. Solar lentigine treatment can be broadly divided into two categories: physical removal and topical applications. Topical therapy is relatively cost-effective and primarily relies on the use of triple combination cream (TCC), which is a combination of retinoic acid, hydroquinone, and corticosteroid at fixed ratios [2].
Hydroquinone suppresses tyrosinase and reduces the formation of melanin pigment; retinoic acid promotes keratinocyte loss and the downregulation of tyrosinase; and the steroid suppresses tyrosinase gene transcription, thus providing an anti-inflammatory effect. Altogether, they provide a skin lightening effect [2]. In a review of clinical studies conducted over the past 20 years, the Pigmentary Disorders Academy has recommended TCC as the first option for treating patients with pigmented blemishes [3].
The typical drawbacks of topical TCC treatment include irritant dermatitis with keratin, dryness, and erythema caused by retinoic acid [4]. An irritant to the skin, retinoic acid has low solubility in water, is unstable in light, and has low permeability in the skin. Interestingly, in a study of lentigo and seborrheic keratosis treatment, [5] noted an improvement in treatment results when using a microneedle patch loaded with retinoic acid to overcome the drawbacks of monotherapy with retinoic acid. In another study, [6] indicated that the use of hydroquinone ointment and silicone sheets containing retinoic acid to treat epidermal melanosis elicited less skin irritation and had equivalent treatment effects, compared to when using hydroquinone ointment alone. Thus, TCC treatment for pigmented lesions may also benefit from the application of similar transdermal drug delivery systems. Accordingly, in this study, we sought to evaluate the effectiveness of combined treatment of TCC and a dissolvable microneedle patch loaded with hyaluronic acid (TCC + HA-DMN patch) for localized, benign, pigmented skin lesions. Through a retrospective review of medical records and results from digital analyses of the skin before and at 4 and 8 weeks after initiating treatment, we assessed potential reductions in both pigmentation and the common side effects of TCC (e.g., redness, dryness, and itching).

Study Design and Subjects
This retrospective study was approved by the Public Institutional Bioethics Committee, which is designated by the Patients were excluded if they met any of the following criteria:

Procedures
Instead of the conventional method of applying TCC at night before bedtime and washing it off the next day, we asked all 25 patients to apply the cream only to the pigmented area and to then put the HA-DMN patch on top, as described in Figure 2. After 3 hours, they were to then wash their face. Patients were to apply the combined treatment only on solar lentigines lesions, even if other melasma or acquired bilateral nevus of Ota-like macule lesions were present. The treatment was to be applied once daily for up to 4 weeks.

Figure 2:
Image of a Thera-Pass® RMD-6.5A microneedle patch and an illustration of how the patch ought to be applied to the skin. Image is the courtesy of the RAPHAS Corporation.

Clinical Assessment
Melanin

Results
Patient characteristics and their diagnoses are listed in Table  the average age was 48.2 Table 2). The changes in epidermal pigmentation had an F value of 11.838 and a significance probability of 0.002 (Table 3).
Generally, symptoms gradually subsided with continued use and naturally disappeared approximately 1 week after treatment was completed.'       Note: All symptoms resolved naturally within 1 week after the treatment was discontinued.

Discussion
In this study, we aimed to determine whether adding an HA-DMN patch to TCC would be beneficial for simple treatment of benign pigmented lesions in the skin. Indeed, we found that the   [11].
In a study of an HA-DMN patch loaded with retinoic acid for the treatment of seborrheic keratosis and senile lentigo, Hirobe et al.
9 explained that the penetrating hyaluronic acid microneedles weakened the stratum corneum by inducing edema, allowing retinoic acid to permeate the epidermis.
As an added benefit, the hyaluronic acid component helped to moisturize the epidermis as the microneedles dissolved 9; when moisture levels increase and percutaneous moisture loss decreases, dryness, wrinkles, and pruritus generally improve. In another study, the HA-DMN patch alone was found to improve the appearance of eye wrinkles, [12] while further research indicated that the use of a combination of adenosine wrinkle cream and an HA-DMN patch elicited superior treatment results, above and beyond using each treatment separately, without any notable side effects [13]. Additionally, an in vivo study of a microneedle patch in humans demonstrated that local skin side effects, such as erythema, mostly disappeared within 7 days after patch application and that skin returned to normal within 30 days [14][15][16]. This study has a few limitations that warrant consideration. First, due to the retrospective nature of this study and the small number of patients, we were unable to draw definitive conclusions regarding the efficacy of the combined treatment presented herein [17]. Finally, there may be some recall bias in the reporting of side effects by the patients [18].

Conclusion
In light of the present results, we suggest that combined TCC and HA-DMN patch treatment, as described in this study, which shortens the length of time that TCC is applied to the skin (3 hours vs. overnight), may be beneficial for treating benign pigmented skin lesions in patients who are prone to discomfort when they apply cream and to adverse effects of laser treatment. The intermittent application of TCC in combination with an HA-DMN patch showed therapeutic effects equivalent to conventional all-day application of TCC, with fewer side effects, and the effects of the combined treatment were more pronounced 4 weeks after treatment was completed. Further research is needed to devise an optimal treatment regimen for combining TCC with an HA-DMN patch.