Use of a pharmaceutical composition associated with a co 2 laser with cold pulse for the treatment of melasma

Abstract

The present invention relates to the use of a mixture of tranexamic acid, hydroquinone, arbutin and a concentrated extract solution of the brown seaweed Ascophyllum nodosum in the preparation of a medicament for treating melasma, wherein said medicament is associated with the use of a CO2 laser with cold pulse for the treatment of melasma.

Description

"USE OF A PHARMACEUTICAL COMPOSITION ASSOCIATED WITH A CO2 LASER WITH COLD PULSE FOR THE TREATMENT OF MELASMA" Field of Application:

[0001] The present invention falls within the field of medical science, more specifically, in the area of ​​radiation therapy, since it refers to the use of a pharmaceutical composition comprising a mixture of tranexamic acid, hydroquinone, arbutin and a concentrated extract solution of the brown algae Ascophyllum nodosum associated with the use of a cold-pulse CO2 laser for the treatment of melasma. Background of the Invention:

[0002] Melasma is a condition characterized by the appearance of dark spots on the skin, most commonly on the face, but it can also occur on other areas such as the arms, neck, and chest. It more frequently affects women, but can also be seen in men.

[0003] Melasma has historically been difficult to treat, and its therapy remains a challenge due to its chronic nature. Clinical studies demonstrate that various treatments can alleviate this dermatological condition to varying degrees; however, to date, there is no cure for melasma, and it is rare for all lesions to be completely cleared.

[0004] Furthermore, since melasma is a recurring condition, there is a real need to act in order to maintain the effectiveness achieved after acute treatment.

[0005] Therefore, although there are currently many treatment options, there is still no definitive solution. Effective therapy with satisfactory results, causing negative psychological impact and disapproval from those affected.

[0006] The products and methods currently on the market for eliminating melasma, despite their efforts, often achieve results ranging from 50% to 80% reduction. This causes discomfort for the patient, as even with use, a significant percentage of the melasma remains visible.

[0007] Furthermore, the rebound effect (the spot lightens, but returns stronger after the treatment ends) of synthetic products available for the treatment of melasma is a major problem that needs to be solved.

[0008] In order to solve the existing technical problem, the present invention proposes an effective treatment protocol comprising the use of a pharmaceutical composition containing a mixture of the active ingredients tranexamic acid, hydroquinone, arbutin and a concentrated extract solution of the brown algae Ascophyllum nodosum associated with the use of a cold pulse CO2 laser for the treatment of melasma.

[0009] The combination of CO2 laser with the aforementioned pharmaceutical composition used in the melasma protocol of the present invention is capable of optimizing the result for melasma treatment, with effective gradual lightening (90-98% improvement in melasma) after a few weeks of use, without rebound effect. Background of the Invention:

[0010] Some prior art documents describe protocols for the treatment of melasma.

[0011] International patent application No. PCT / IL2022 / 050148, published under No. WO 2022 / 168093 on August 11, 2022, in the name of Ariel Scientific Innovations, entitled: “Active agent-releasing hyaluronic acid vehicle,” describes a molecular structure comprising a hyaluronic acid moiety and a plurality of bioactive agents selected from the group consisting of tranexamic acid, kojic acid, cysteamine, cystamine, azelaic acid, hydroquinone, mequinol, flutamide, CBD, arbutin, vitamin A, vitamin C, vitamin E, ellagic acid, glutathione, biotin, mandelic acid, an alpha-hydroxy acid, tretinoin, an alpha-lipoic acid, glutathione, salicylic acid, and fluocinolone, for use in the treatment of skin diseases, such as melasma.However, the document deviates from the present invention, since it does not mention the use of cold pulsed CO2 laser with radiofrequency in the treatment of melasma in association with the pharmaceutical composition of the present invention, which also includes a solution of concentrated extract of the brown algae Ascophyllum nodosum and active adjuvants that are not mentioned in the aforementioned international application.

[0012] Korean patent application No. KR1020150012785, published on February 4, 2015, in the name of LG H&H Co., Ltd., entitled: “Composition comprising polydatin and tranexamic acid for whitening skin” describes a skin-whitening composition that includes polydatin and tranexamic acid. as active ingredients, promoting notable effects in inhibiting the creation of the pigment melanin, compared to the use of isolated active ingredients, for the treatment of skin pigmentation such as melasma, blemishes, and freckles. However, the document differs from the present invention, since it does not mention the use of cold pulse CO2 laser with radiofrequency in the treatment of melasma in association with the pharmaceutical composition of the present invention, which also includes a concentrated extract solution of the brown algae Ascophyllum nodosum and active adjuvants that are not mentioned in the aforementioned Korean application.

[0013] International patent application No. PCT / EP2016 / 055873, published under No. WO 2016 / 146778A1 on September 22, 2016, in the name of Inderm, entitled: “Methods of providing skin care using phototherapy,” describes a method for treating a skin-related disorder, such as melasma, using a composition that may comprise various depigmenting agents, including Ascophyllum nodosum extract, hydroquinone, and arbutin, and adjuvants. However, the document differs from the present invention, since it does not mention the use of cold pulse CO2 laser with radiofrequency in the treatment of melasma in association with the pharmaceutical composition of the present invention, which also comprises tranexamic acid and active adjuvants that are not mentioned in the aforementioned international application.

[0014] O artigo intitulado “Combination of Hydroquinone and Fractional CO2 Laser versus Hydroquinone Monotherapy in Melasma Treatment: A Randomized, Single- The study, titled "blinded, Split-face Clinical Trial," published in March 2019 under DOI number 10.4103 / ijd.IJD_240_17, authored by Nourmohammadi Abadchi S, Fatemi Naeini F, and Beheshtian E, reveals a study that aimed to compare the efficacy of fractional CO2 laser in combination with topical therapy versus topical therapy alone in the treatment of melasma. More specifically, the study reveals the use of CO2 laser associated with the depigmenting active ingredient hydroquinone in the treatment of melasma. However, the study concluded that the two methods were not statistically significant in the short-term follow-up with respect to clinical response to treatment, patient satisfaction, and overall physician assessment. Thus, considering the results obtained and the high cost of laser therapy, the study considered this approach not to be cost-effective. In contrast, the present invention proposes an effective melasma treatment protocol without rebound effect.

[0015] The article entitled “Assessment of combined fractional CO2 and tranexamic acid in melasma treatment. Lasers”, published on November 15, 2018, under DOI number 0.1002 / lsm.23032, authored by Tawfic SO, Abdel Halim DM, Albarbary A, and Abdelhady M, reveals a study that aimed to compare the efficacy of fractional CO2 laser in combination with topical therapy versus topical therapy alone in the treatment of melasma. More specifically, the study reveals the use of CO2 laser associated with the depigmenting active ingredient tranexamic acid in topical form in the treatment of melasma. In contrast, the present invention proposes a composition comprising a mixture of more than... A depigmenting agent and active adjuvants for use in conjunction with a specific cold pulse CO2 laser with radiofrequency and PSD technology in the treatment of melasma. This composition describes more than one depigmenting agent and adjuvants for use in conjunction with a specific cold pulse CO2 laser with radiofrequency and PSD (pulse shape design) technology in the treatment of melasma, achieving effective results without rebound effect.

[0016] Therefore, based on the aforementioned state of the art, the need for an effective treatment for melasma is a common technical problem. In this sense, the present invention is an alternative solution to the existing technical problem of the state of the art, since no document in the state of the art proposes the use of a pharmaceutical composition comprising a mixture of tranexamic acid, hydroquinone, arbutin and a concentrated extract solution of the brown algae Ascophyllum nodosum associated with the use of a CO2 laser with cold pulse and PSD (pulse shape design) technology for the treatment of melasma. Summary of the invention:

[0017] The present invention will provide significant advantages for the treatment of melasma.

[0018] In one aspect, the present invention relates to the use of a mixture of tranexamic acid, hydroquinone, arbutin and a concentrated extract solution of the brown algae Ascophyllum nodosum in the preparation of a medication to treat melasma, wherein said medication is associated with the use of cold pulse CO2 laser for the treatment of melasma.

[0019] In a second aspect, the present invention relates to a method for treating melasma comprising the topical administration of a pharmaceutical composition comprising a mixture of tranexamic acid, hydroquinone, arbutin, and a concentrated extract solution of the brown algae Ascophyllum nodosum after application of a cold-pulse CO2 laser to a patient in need.

[0020] In a third aspect, the present invention relates to a pharmaceutical composition comprising a mixture of tranexamic acid, hydroquinone, arbutin, and a concentrated extract solution of the brown algae Ascophyllum nodosum for use in the treatment of melasma, wherein the pharmaceutical composition is associated with the use of a cold-pulse CO2 laser. Brief description of the figures:

[0021] The present invention, along with its additional advantages, can be better understood by referring to the attached images and the following description.

[0022] Figures 1 AE present photographs illustrating the before and after of a patient with normal skin type who was treated with the melasma protocol described here, in which the patient presented with severe melasma and after treatment presented with mild recurrence, with no rebound effect.

[0023] Figures 2 AC present photographs illustrating the before and after of a patient with sensitive skin who was treated with the melasma protocol described here, in which the patient presented with mild melasma and after treatment presented with mild recurrence, with no rebound effect.

[0024] Figures 3 AE present photographs illustrating the before and after of a patient with normal skin who was treated with the melasma protocol described here, in which the patient presented with moderate melasma and after treatment presented with no melasma, with no recurrence and no rebound effect.

[0025] Figures 4 AE present photographs illustrating the before and after of a patient with normal skin who was treated with the melasma protocol described here, in which the patient presented with mild melasma and after treatment presented with no melasma, with no recurrence and no rebound effect.

[0026] Figures 5 AE present photographs illustrating the before and after of a patient with sensitive skin who was treated with the melasma protocol described here, in which the patient presented with mild melasma and after treatment presented with mild recurrence, with no rebound effect.

[0027] Figures 6 AD present photographs illustrating the before and after of a patient with normal skin who was treated with the melasma protocol described here, in which the patient presented with moderate melasma and after treatment presented with no melasma, with no recurrence and no rebound effect.

[0028] Figures 7 AC present photographs illustrating the before and after of a patient with normal skin who was treated with the melasma protocol described here, in which the patient presented with mild melasma. and after treatment, no melasma appeared, with no recurrence and no rebound effect.

[0029] Figures 8 AF present photographs illustrating the before and after of a patient with normal skin who was treated with the melasma protocol described here, in which the patient presented with mild melasma and after treatment presented with no melasma, with no recurrence and no rebound effect.

[0030] Figures 9 AE present photographs illustrating the before and after of a patient with normal skin who was treated with the melasma protocol described here, in which the patient presented with moderate melasma and, after treatment, presented with mild recurrence, with no rebound effect.

[0031] Figure 10 represents the topographic division used in the Melasma Area and Severity Index (MASI).

[0032] Figure 11 refers to a photograph of the three cold-pulse CO2 laser devices used, where A = SmartXide Punto®; B = Hybrid CO2®; and C = Fraxel® re:pair CO2.

[0033] Figures 12A-C show photographs of participant 1 (P1) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0034] Figures 13A-C show photographs of participant 2 (P2) from the comparative study, in which A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0035] Figures 14A-C show photographs of participant 3 (P3) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0036] Figures 15A-C show photographs of participant 4 (P4) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0037] Figures 16A-C show photographs of participant 5 (P5) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0038] Figures 17A-C show photographs of participant 6 (P6) from the comparative study, where A is the initial photograph (left) and reassessment (right). A is the initial photograph (left) and reassessment (right) in a frontal position; B is the initial photograph (left) and reassessment (right) in a right lateral position; and C is the initial photograph (left) and reassessment (right) in a left lateral position.

[0039] Figures 18A-C show photographs of participant 7 (P7) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0040] Figures 19A-C show photographs of participant 8 (P8) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0041] Figures 20A-C show photographs of participant 9 (P9) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0042] Figures 21A-C show photographs of participant 10 (P10) from the comparative study, where A is the initial photograph (left) and reassessment photograph (right) in a frontal position; B is the initial photograph. (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0043] Figures 22A-C show photographs of participant 11 (P11) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0044] Figures 23A-C show photographs of participant 12 (P12) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0045] Figures 24A-C show photographs of participant 13 (P13) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0046] Figures 25A-C show photographs of participant 14 (P14) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in lateral position. right; and C is the initial photograph (left) and reassessment (right) in left lateral position.

[0047] Figures 26A-C show photographs of participant 15 (P15) from the comparative study, where A is the initial photograph (left) and reassessment (right) in frontal position; B is the initial photograph (left) and reassessment (right) in right lateral position; and C is the initial photograph (left) and reassessment (right) in left lateral position. Detailed description of the invention:

[0048] Although the present invention may be susceptible to different embodiments, a preferred embodiment is shown in the following detailed discussion, with the understanding that the present embodiment should be considered an exemplification of the principles of the invention and is not intended to limit the present invention to what has been described in this report.

[0049] The present invention relates to the use of a mixture of tranexamic acid, hydroquinone, arbutin and a concentrated extract solution of the brown algae Ascophyllum nodosum in the preparation of a medication to treat melasma, wherein said medication is associated with the use of cold pulse CO2 laser for the treatment of melasma.

[0050] The aforementioned medication refers to a pharmaceutical composition comprising a mixture of tranexamic acid, hydroquinone, arbutin, and a concentrated extract solution of the brown algae Ascophyllum nodosum.

[0051] Additionally, the aforementioned pharmaceutical composition also includes selected active adjuvants. from the group consisting of hyaluronic acid, green tea glycolic extract, niacinamide, ceramides, resveratrol (nanovits), aloe vera glycolic extract, orchid glycolic extract, clobetasol, γ-glutamyltranspeptidase (GGT) inhibitor (kawaii kirei), plant extract derived from dormant bulbs of the Narcissus plant (telodormim), Scutellaria baicalensis root extract / propanediol / water (scutaline), Physalis angulata plant extract (physavie), and a combination thereof.

[0052] In one embodiment, the pharmaceutical composition comprises 3% w / w tranexamic acid, 4 to 7% w / w, preferably 4 or 7% w / w hydroquinone, 2% w / w arbutin and 2% w / w of a concentrated extract solution of the brown algae Ascophyllum nodosum.

[0053] In a preferred embodiment, the pharmaceutical composition further comprises 5% w / w hyaluronic acid, 2% w / w green tea glycolic extract, 5% w / w niacinamide, 5% w / w ceramides, 1% w / w resveratrol (nanovits), 2% w / w aloe vera glycolic extract, 3% w / w orchid glycolic extract, 0 to 0.05% w / w, preferably 0 or 0.05% w / w clobetasol, 2% w / w γ-glutamyltranspeptidase (GGT) inhibitor (kawaii kirei), 3% w / w plant extract derived from dormant bulbs of the Narcissus plant (telodormim), 2% w / w Scutellaria baicalensis root extract / propanediol / water (scutaline), 0 to 0.5% w / w, preferably 0 or 0.5% w / w of plant extract of Physalis angulata (physalis).

[0054] Additionally, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle (q.s.p.). Preferably, the aforementioned pharmaceutical composition is in gel form (q.s.p.) for topical application.

[0055] The laser used in this treatment is a CO2 laser with radio frequency, cold pulse, and PSD (pulse shape design) technology.

[0056] In one embodiment, with a spacing of 950µm and power of 2.5W, the laser application uses a fluence of approximately 0.33 J / cm². 2 , DOT energy of approximately 5.5 mJ and density of approximately 5.7%.

[0057] Thus, the treatment protocol involves applying the aforementioned laser, followed by the use of the aforementioned pharmaceutical composition.

[0058] Preferably, the aforementioned treatment protocol comprises the following steps: i) After laser use, the composition is applied to the skin, preferably twice a day, for about 45 days; ii) After step “i”, a new laser session is performed and the composition is applied to the skin, preferably twice a day, for about 45 days; iii) After step “ii”, the composition is applied to the skin, preferably once a day, for about 4 months.

[0059] The combination of the aforementioned CO2 laser with the composition used in this melasma protocol is capable of optimizing the results for melasma treatment, with gradual but effective lightening (90 to 98% improvement in the condition) after a few weeks of use.

[0060] After completing the treatment following steps “i” to “iii”, there is no rebound effect of melasma.

[0061] It is important to emphasize that the CO2 laser, under the parameters used in this melasma protocol, when used in isolation, performs a laser "peeling" without downtime, improves skin texture in a few days, but is incapable of producing lightening on its own.

[0062] The isolated use of the composition used in this protocol produces a slight lightening of the skin as a whole after a few days of use, but it is not possible to effectively remove melasma due to its poor penetration, since it does not contain any acid among its active ingredients that breaks the cohesion of cells in the epidermis.

[0063] Given this, the use of the pharmaceutical composition comprising a mixture of tranexamic acid, hydroquinone, arbutin, and a concentrated extract solution of the brown algae Ascophyllum nodosum, combined with the use of a cold-pulse CO2 laser, presents a surprising synergistic effect, which is not achieved when they are used in isolation.

[0064] The synergistic effect achieved promotes an effective result of 90 to 98% improvement in melasma, without rebound effect.

[0065] Additionally, it is worth emphasizing that the pharmaceutical composition described here comprises a mixture of depigmenting agents and active adjuvants that was surprisingly effective when used in conjunction with cold-pulse CO2 laser. It is important to highlight that the aforementioned mixture included in the pharmaceutical composition promotes a... a supra-additive effect in lightening blemishes, which would not be achieved with the use of only one or even three depigmenting agents, which may have good lightening results but not effective for lightening indices obtained with the complete pharmaceutical composition of the present invention, or even a high chance of recurrence.

[0066] In this sense, additionally, the aforementioned invention relates to a method for treating melasma comprising topically administering a pharmaceutical composition comprising a mixture of tranexamic acid, hydroquinone, arbutin, and a solution of concentrated extract of the brown algae Ascophyllum nodosum after application of a cold-pulse CO2 laser to a needy individual.

[0067] Additionally, the aforementioned invention relates to the aforementioned pharmaceutical composition for use in the treatment of melasma, wherein the pharmaceutical composition is associated with the use of a cold-pulse CO2 laser and comprises a mixture of tranexamic acid, hydroquinone, arbutin, and a solution of concentrated extract of the brown algae Ascophyllum nodosum.

[0068] Therefore, in order to elucidate the present invention, experimental results and embodiments of the invention are presented below to demonstrate the inventive step of using the pharmaceutical composition associated with the use of CO2 laser for the treatment of melasma in the present invention. Embodiments of the invention

[0069] In one embodiment of the present invention, the pharmaceutical composition is formulated for patients with skin Normal. Thus, the pharmaceutical composition for post-laser use in gel form (30 grams) comprises the following formulation: Formulation for normal skin – post-laser use Hydroquinone..................... 7% Clobetasol....................... 0.05% Hyaluronic Acid................ 5% Algo White....................... 2% Green Tea Glycolic Extract... 2% Niacinamide...................... 5% Ceramides........................ 5% Nanovits......................... 1% Aloe Vera Glycolic Extract...... 2% Orchid Glycolic Extract... 3% Tranexamic Acid................ 3% Kawaii Kirei..................... 2% Telodormin....................... 3% Scutaline........................ 2% Arbutin.......................... 2% Gel.............................. qsp

[0070] Additionally, the pharmaceutical composition is for use in gel form (30 grams) for normal skin. The maintenance phase includes the following formulation: Formulation for normal skin – maintenance Hydroquinone....................... 4% Hyaluronic Acid.................. 5% Algo White......................... 2% Green Tea Glycolic Extract..... 2% Niacinamide........................ 5% Ceramides.......................... 5% Nanovits........................... 1% Aloe Vera Glycolic Extract........ 2% Orchid Glycolic Extract..... 3% Tranexamic Acid.................. 3% Kawaii Kirei....................... 2% Telodormin......................... 3% Scutaline.......................... 2% Arbutin............................ 2% Gel................................ qsp

[0071] Thus, the melasma treatment protocol for normal skin comprises the following steps: (i) Post-laser: Apply 1 pump to the face every morning and night until the bottle is finished (approximately 45 days); (ii) Maintenance: Repeat the procedure from cycle “i” until the bottle is finished (approximately 45 days); (iii) Maintenance: After cycle “ii”, apply only at night for 4 months.

[0072] In one embodiment of the present invention, the pharmaceutical composition is formulated for patients with sensitive skin. Thus, the pharmaceutical composition for post-laser use in gel form (30 grams) comprises the following formulation: Formulation for sensitive skin – post-laser use Hydroquinone......................... 7% Physavie............................. 0.05% Hyaluronic Acid.................... 5% Algo White........................... 2% Green Tea Glycolic Extract....... 2% Niacinamide.......................... 5% Ceramides............................ 5% Nanovits............................. 1% Aloe Vera Glycolic Extract.......... 2% Orchid Glycolic Extract....... 3% Tranexamic Acid.................... 3% Kawaii Kirei......................... 2% Telodormin........................... 3% Scutaline............................ 2% Arbutin.................................. 2% Gel.................................. qsp

[0073] Additionally, the aforementioned pharmaceutical composition for use in gel form (30 grams) for sensitive skin for maintenance purposes comprises the following formulation: Formulation for sensitive skin – maintenance Hydroquinone......................... 4% Physavie............................. 0.5% Hyaluronic Acid.................... 5% Algo White........................... 2% Green Tea Glycolic Extract........ 2% Niacinamide.......................... 5% Ceramides............................ 5% Nanovits.............................. 1% Aloe Vera Glycolic Extract........... 2% Orchid Glycolic Extract........ 3% Tranexamic Acid..................... 3% Kawaii Kirei.......................... 2% Telodormin............................ 3% Scutaline............................. 2% Arbutin............................... 2% Gel................................... qsp

[0074] Thus, the melasma treatment protocol for sensitive skin comprises the following steps: (i) Post-laser: Apply 1 pump to the face every morning and night until the bottle is finished (approximately 45 days); (ii) Maintenance: Repeat the procedure from cycle “i” until the bottle is finished (approximately 45 days); (iii) Maintenance: After cycle “ii”, apply only at night for 4 months.

[0075] At the end of both treatments (for both sensitive and normal skin), an effective result of 90 to 98% improvement in melasma was achieved, without rebound effect. Figures 1 to 9 show the results achieved before and after the aforementioned treatment. Overall melasma severity indices

[0076] The investigator assesses the severity of the subject's melasma (disease severity) at each visit. The overall severity assessment is shown in the following table: Table 1 - Overall severity assessment

[0077] The time to relapse is defined as the duration between the Initial Maintenance Phase Measurement and the visit in which the relapse occurs. Melasma recurrence is derived from the global severity index. Any subject who enters the Maintenance Phase is permitted [(with a global severity index of 0 (before the end of the 90-day period (Initial Treatment Phase)) or a global severity index of 0 or 1 (during the 90 days)] and who obtains a global severity index of at least 2 during that Maintenance Phase is considered a relapser. This is further transformed into a dichotomized variable (no relapse = 0 and relapse = 1).

[0078] It is important to highlight that over the course of 10 years, approximately 1400 patients have been treated following the melasma protocol of the present invention, in which several adaptations have been made over the years until reaching the current treatment described herein. Surprisingly, the combination of the aforementioned pharmaceutical composition described herein with CO2 laser with radiofrequency, cold pulse, and PSD (pulse shape design) technology provided an effective treatment with 90-98% improvement in melasma, obtaining results with gradual lightening after a few weeks of use, as shown in Figures 1 to 9, and in Table 2 below: Table 2 - Assessment of overall severity before and after treatment with the present invention.

[0079] Therefore, as shown in Figures 1 to 9 and in the aforementioned melasma severity index before and after treatment, the present invention solved the existing problem and obtained results with gradual and effective lightening (90-98% improvement in the condition) after a few weeks. In use, the combination of CO2 laser with the pharmaceutical composition used in the present invention is capable of optimizing the result for the treatment of melasma. Comparative Studies

[0080] A comparative study was conducted to evaluate and compare the therapeutic response for melasma of the following treatment options: (i) after the use of CO2 laser with cold pulse alone; (ii) after the use of the pharmaceutical composition alone; and (iii) after the use of CO2 laser with cold pulse combined with the use of the pharmaceutical composition. This study was conducted and performed by Dermatologist Dr. Paula Nicole Tigre.

[0081] The three therapeutic modalities for melasma were evaluated and compared, based on data previously collected and stored in electronic medical records and medical imaging software. The three treatments analyzed were isolated cold pulse CO2 laser; the use of an isolated topical pharmaceutical composition; and the combination of cold pulse CO2 laser and the topical pharmaceutical composition. First, the therapeutic response of each therapy was analyzed individually, based on a comparison of the severity of melasma before and after the intervention. The severity of melasma was quantified using a widely used and validated assessment tool for this purpose, the Melasma Area and Severity Index (MASI) - (PANDYA, AG. et al. Reliability assessment and validation of the Melasma Area and Severity Index (MASI) and a new modified MASI scoring method. J Am Acad Dermatol., n. 64, v. 1, p. 78-83, Apr. 2010. DOI: 10.1016 / j.jaad.2009.10.051).

[0082] The previously collected data were stored in a licensed electronic medical record (ComAmigo®, Brazilian Center for Medical Informatics – CEBIM, version 25.2.5). Photographs from two distinct moments (before and after treatment) of the participants were used and analyzed. The photographs were stored in licensed medical imaging software (Mirror®, Canfield Scientific Inc., version 7.5.11). The study was conducted at CD Clínica Dermatológica, a private clinic specializing in the treatment of melasma, on patients of dermatologists Cyro Hirano and Denise Barcelos, located in Rio de Janeiro / RJ, Brazil.

[0083] The personal information used in the study was age and sex. Names were omitted throughout the study to ensure participant confidentiality. Other data used relate to melasma treatment and follow-up.

[0084] In total, fifteen participants were selected. They were divided into three groups, based on the therapy performed, with each group including five participants. The inclusion criteria were: diagnosis of melasma; having undergone one of the three melasma treatments included in this study; possessing photographs from at least two distinct moments, including the moment immediately prior to the start of therapy (initial assessment) and the day of reassessment (post-treatment); and having completed adequate post-intervention follow-up, as per oral and written medical instructions.

[0085] Among the researchers, one evaluator was chosen to measure the MASI of all participants, to avoid possible measurement bias. Each participant received two distinct MASI measurements: an initial MASI (which will be named MASI1) and a reassessment MASI (which will be named MASI2).

[0086] According to Hammerschmidt (2012), the Melasma Area and Severity Index (MASI) “has been the most widely used method in the literature to assess treatment response” (HAMMERSCHMIDT, M. et al. Evaluation of melasma classification methods based on response to treatment. Surg cosmet dermatol., v. 4, n. 2, p. 155-158, Apr. 2012). The final MASI score ranges from 0 to 48, and the higher the score, the more severe the melasma. The MASI assesses three parameters (area, hyperpigmentation, and skin color homogeneity) per region (forehead, right malar, left malar, and chin, shown in Figure 10). The MASI formula is as follows: Formula 1: MASI = 0.3A(D+H) + 0.3A(D+H) + 0.3A(D+H) + 0.1A(D+H) right forehead left cheekbone chin (Formula 1)

[0087] In Formula 1, the abbreviations mean: A = area, D = darkness, and H = homogeneity.

[0088] Participants who underwent CO2 laser treatment with a cold pulse alone for melasma were identified numerically from 1-5 (e.g., “participant 1 or P1”), forming Group 1 (G1). Intervention. All participants used a moisturizing formula on their face morning and night in the post-laser period and continued using it until reassessment. No participant was undergoing any other treatment for melasma during this period.

[0089] Because this is a clinic specializing in melasma treatment, there is a high demand for procedures, and three cold-pulse CO2 laser devices are currently in use: SmartXide Punto® (Deka MELA Srl.); Hybrid CO2® (LMG - Laser Medical Group); and Fraxel® re:pair CO2 (Solta Medical). All three devices were used in this study and are shown in Figure 11.

[0090] The parameters used for each laser will be presented below and aim to establish equivalence between the technologies. For the SmartXide Punto® laser, an energy of 5.5 mJ and a density of approximately 5.7% were used. For the Hybrid CO2® laser, an energy of 5 mJ and a density of 100 points / cm² were used. 3 In cold laser mode, for the Fraxel® re:pair CO2 laser, an energy of 5mJ and a density of 5% were used.

[0091] The five participants who used the topical pharmaceutical composition for the treatment of melasma were identified numerically from 6-10 (example: “participant 6 or P6”), forming Intervention Group 2 (G2). All were instructed to apply one pump of the topical pharmaceutical composition to the face in the morning and one pump at night, until the bottle was finished. All participants in G2 were using the topical pharmaceutical composition at the time of reassessment. No participant was undergoing another treatment for melasma concurrently.

[0092] The topical pharmaceutical composition used is presented as a gel (30g) and comes in two distinct formulations (for normal and sensitive skin). The formulation for normal skin contains hydroquinone 7%, clobetasol 0.05%, hyaluronic acid 5%, algo white 2%, green tea glycolic extract 2%, niacinamide 5%, ceramides 5%, nanovits 1%, aloe vera glycolic extract 2%, orchid glycolic extract 3%, tranexamic acid 3%, kawaii kirei 2%, telodormin 3%, scutaline 2%, and arbutin 2%. The formulation for sensitive skin contains hydroquinone 7%, physavie 0.05%, hyaluronic acid 5%, algo white 2%, green tea glycolic extract 2%, niacinamide 5%, ceramides 5%, nanovits 1%, aloe vera glycolic extract 2%, orchid glycolic extract 3%, tranexamic acid 3%, kawaii kirei 2%, telodormin 3%, scutaline 2%, and arbutin 2%.

[0093] The five participants who underwent CO2 laser treatment with a cold pulse combined with the use of a topical pharmaceutical composition formed Intervention Group 3 (G3) and were identified numerically from 11-15 (e.g., “participant 11 or P11”). Participants initially used a moisturizing formula on their face morning and night for the first seven days after the laser treatment. After this period, they began applying one pump of the topical pharmaceutical composition to their face in the morning and one pump at night until the bottle was empty. All participants in G3 were using the topical pharmaceutical composition at the time of reassessment. No participant was undergoing another treatment for melasma concurrently.

[0094] The licensed Excel® software for Mac (Microsoft, version 16.95.1) was used for storing and organizing the collected data and information. For statistical evaluation, the licensed SPSS Statistics® software for Mac (IBM Corp., version 29.0.2.0) was used. The non-parametric Mood median test and the non-parametric Kruskal-Wallis test were used in the statistical analysis of the data.

[0095] The photographs used in the study are shown in the following images (Figures 12A-C to 26A-C). - Results and analysis of results:

[0096] This study evaluated fifteen participants, belonging to three distinct treatment groups for melasma, analyzed the therapeutic response of each group, and then compared the results between the groups. The response to treatment was measured by the difference in melasma severity (in %) before and after the intervention.

[0097] Table 3 contains general participant data, such as treatment group, age (in years), sex, interval between initial and reassessment (days), MASI score at initial assessment (MASI1), MASI score at reassessment (MASI2), improvement in melasma severity after treatment (expressed as a percentage), and identification of the laser used (valid for Groups 1 and 3). Table 3 – General Data F= female; H= Hybrid CO; R= Fraxel re:pair CO; S= SmartXide Punto

[0098] All participants (100%) were female, although male sex was not an exclusion criterion. The average age was 43 years. The interval between the initial assessment (pre-treatment) and the reassessment (post-treatment) was on average 33 days – similar to the medical recommendation of reassessment in 30 days.

[0099] Participants P1-5 correspond to Treatment Group 1 (G1), i.e., they underwent cold pulse CO2 laser treatment. Participants P6-10 correspond to Treatment Group 2 (G2), the group that used a topical pharmacological composition. Participants P11-15 correspond to Treatment Group 3 (G3), the group that underwent cold pulse CO2 laser treatment combined with a topical pharmacological composition.

[0100] The average improvement in melasma severity was, respectively: 6.9% for Group 1; 13.6% for Group 2; and 90.1% for Group 3. These results demonstrate the superiority of the combination of cold pulse CO2 laser with the topical pharmaceutical composition when compared The two therapies were tested in isolation. Statistical analysis was performed using non-parametric tests.

[0101] The Kruskal-Wallis test was used, with a 95% confidence interval, as shown in Table 4. Table 4 – Summary of the hypothesis test

[0102] The Mood median test, with a 95% confidence interval, was also used, as shown in Table 5. Table 5 - Summary of hypothesis testing

[0103] Therefore, the study concluded that, in the samples analyzed, the treatment for melasma with CO2 laser with cold pulse associated with the use of a composition was superior. Topical pharmaceutical treatment. The reduction in melasma severity was 90.1%.

[0104] In summary, the invention relates to the following aspects, as defined in the following numbered items: 1. Use of a mixture of tranexamic acid, hydroquinone, arbutin and a solution of concentrated extract of the brown algae Ascophyllum nodosum associated with a cold-pulse CO2 laser in the preparation of a medicament to treat melasma. 2. Method of treating melasma comprising topically administering a pharmaceutical composition comprising a mixture of tranexamic acid, hydroquinone, arbutin and a solution of concentrated extract of the brown algae Ascophyllum nodosum associated with the application of a cold-pulse CO2 laser to an individual in need.3. Pharmaceutical composition for use in the treatment of melasma, wherein the pharmaceutical composition is associated with the use of CO2 laser with cold pulse and comprises a mixture of tranexamic acid, hydroquinone, arbutin and a solution of concentrated extract of the brown algae Ascophyllum nodosum. 4. Use, according to item 1, wherein the said medicine refers to a pharmaceutical composition that further comprises selected active adjuvants from the group consisting of hyaluronic acid, glycolic extract of green tea, niacinamide, ceramides, resveratrol (nanovits), glycolic extract of aloe vera, glycolic extract of orchids, clobetasol, γ-glutamyl transpeptidase (GGT) inhibitor (kawaii kirei), plant extract derived from the bulbs. Dormant stems of the Narcissus plant (telodormine), Scutellaria baicalensis root extract / propanediol / water (scutaline), Physalis angulata plant extract (physavius), and a combination thereof. 5. Method or pharmaceutical composition for use according to claim 2 or 3, in accordance with items 2 or 3, wherein said pharmaceutical composition further comprises active adjuvants selected from the group consisting of hyaluronic acid, green tea glycolic extract, niacinamide, ceramides, resveratrol (nanovits), aloe vera glycolic extract, orchid glycolic extract, clobetasol, γ-glutamyltranspeptidase (GGT) inhibitor (kawaii kirei), plant extract derived from dormant bulbs of the Narcissus plant (telodormim), Scutellaria baicalensis root extract / propanediol / water (scutaline), Physalis angulata plant extract (physavie), and a combination thereof. 6. Use or method or pharmaceutical composition for use according to any of items 1 to 5.wherein the pharmaceutical composition comprises 3% by weight of tranexamic acid, 4 to 7% w / w, preferably 4 or 7% hydroquinone, 2% by weight of arbutin and 2% by weight of a concentrated extract solution of the brown algae Ascophyllum nodosum. 7 Use or method or pharmaceutical composition for use, according to any of items 1 to 6, wherein the pharmaceutical composition further comprises 5% by weight of hyaluronic acid, 2% by weight of green tea glycolic extract, 5% by weight of niacinamide, 5% by weight of ceramides, 1% by weight of resveratrol (nanovits), 2% by weight of extract, Aloe vera glycolic extract, 3% by weight of orchid glycolic extract, 0 to 0.05% by weight, preferably 0 or 0.05% clobetasol, 2% by weight of γ-glutamyltranspeptidase (GGT) inhibitor (kawaii kirei), 3% by weight of plant extract derived from dormant bulbs of the Narcissus plant (telodormim), 2% by weight of Scutellaria baicalensis root extract / propanediol / water (scutaline), 0 to 0.5% by weight, preferably 0 or 0.5% by weight of Physalis angulata plant extract (physavie); and q.s.p. of a pharmaceutically acceptable carrier. 8. Use or method or pharmaceutical composition for use, according to any of items 1 to 7, wherein the CO2 laser is a cold pulse laser and additionally with radio frequency and PSD (pulse shape design) technology. 9. Use or method or pharmaceutical composition for use, according to any of items 1 to 8, wherein the laser application is performed first, followed by the use of said medicine or pharmaceutical composition.10. Use or method or pharmaceutical composition for use, according to any of items 1 to 9, which provides gradual and effective lightening of melasma with 90 to 98% improvement after use, without rebound effect of melasma. 11. Use or method or pharmaceutical composition for use, according to any of items 1 to 10, in which the association of the medicine or pharmaceutical composition with the aforementioned laser presents a synergistic effect. 12. Use or method or pharmaceutical composition for use, according to any of items 1 to 11, in which a. The pharmaceutical composition is presented in topical form, preferably in gel form. 13 Method, according to item 2, which preferably comprises the following steps: i) After laser use, the composition is applied to the skin, preferably twice a day, for about 45 days; ii) After step “i”, a new laser session is performed and the composition is applied to the skin, preferably twice a day, for about 45 days; iii) After step “ii”, the composition is applied to the skin, preferably once a day, for about 4 months.

[0105] Thus, the embodiments presented in the present invention do not limit the totality of possibilities, and it will be understood that various omissions, substitutions and alterations may be made by a person skilled in the art, without departing from the scope of the present invention.

[0106] It is expressly provided that all combinations of elements that perform the same function substantially in the same way to achieve the same results are within the scope of the invention. Substitutions of elements from one described embodiment for another are also fully intended and contemplated.

[0107] Skilled individuals will appreciate the knowledge presented here and will be able to reproduce the invention in the embodiments shown and in other variants covered by the claims.

Claims

CLAIMS 1. Use of a mixture of tranexamic acid, hydroquinone, arbutin and a solution of concentrated extract of the brown algae Ascophyllum nodosum associated with a cold-pulse CO2 laser, characterized in that the mixture is in the preparation of a medicine to treat melasma.

2. Method of treating melasma characterized in that it involves the topical administration of a pharmaceutical composition comprising a mixture of tranexamic acid, hydroquinone, arbutin and a solution of concentrated extract of the brown algae Ascophyllum nodosum after the application of a cold-pulse CO2 laser to an individual in need.

3. Pharmaceutical composition for use characterized in that it is in the treatment of melasma, wherein the pharmaceutical composition is associated with the use of a cold-pulse CO2 laser and comprises a mixture of tranexamic acid, hydroquinone, arbutin and a solution of concentrated extract of the brown algae Ascophyllum nodosum. 4.Use, according to claim 1, characterized in that said medicine refers to a pharmaceutical composition that further comprises selected active adjuvants from the group consisting of hyaluronic acid, green tea glycolic extract, niacinamide, ceramides, resveratrol (nanovits), aloe vera glycolic extract, orchid glycolic extract, clobetasol, γ-glutamyltranspeptidase (GGT) inhibitor (kawaii kirei), plant extract derived from dormant bulbs of the Narcissus plant (telodormim), Scutellaria root extract.

5. A pharmaceutical method or composition for use according to claim 2 or 3, characterized in that said pharmaceutical composition further comprises active adjuvants selected from the group consisting of hyaluronic acid, green tea glycolic extract, niacinamide, ceramides, resveratrol (nanovits), aloe vera glycolic extract, orchid glycolic extract, clobetasol, γ-glutamyl transpeptidase (GGT) inhibitor (kawaii kirei), plant extract derived from the dormant bulbs of the Narcissus plant (telodormim), Scutellaria baicalensis root extract / propanediol / water (scutaline), Physalis angulata plant extract (physavie), and a combination thereof. 6.Use or method or pharmaceutical composition for use, according to any one of claims 1 to 5, characterized in that the pharmaceutical composition comprises 3% by weight of tranexamic acid, 4 to 7% w / w, preferably 4 or 7% hydroquinone, 2% by weight of arbutin and 2% by weight of a concentrated extract solution of the brown algae Ascophyllum nodosum.

7. Use or method or pharmaceutical composition for use, according to any one of claims 1 to 6, characterized in that the pharmaceutical composition further comprises 5% by weight of hyaluronic acid, 2% by weight of green tea glycolic extract, 5% by weight of niacinamide, 5% by weight of ceramides, 1% by weight of resveratrol (nanovits), 2% by weight of aloe vera glycolic extract, 3% by weight of orchid glycolic extract, 0 to 0.05% w / w. Preferably 0 or 0.05% clobetasol, 2% by weight of γ-glutamyltranspeptidase (GGT) inhibitor (kawaii kirei), 3% by weight of plant extract derived from the dormant bulbs of the Narcissus plant (telodormim), 2% by weight of Scutellaria baicalensis root extract / propanediol / water (scutaline), 0 to 0.5% w / w, preferably 0 or 0.5% of Physalis angulata plant extract (physavie); and q.s.p. of a pharmaceutically acceptable carrier.

8. Use or method or pharmaceutical composition for use, according to any of claims 1 to 7, characterized in that the CO2 laser is a cold pulse laser and additionally with radio frequency and PSD (pulse shape design) technology.

9. Use or method or pharmaceutical composition for use, according to any of claims 1 to 8, characterized in that first the laser is applied, followed by the use of said medicine or pharmaceutical composition. 10.Use or method or pharmaceutical composition for use, according to any one of claims 1 to 9, characterized in that it provides gradual and effective lightening of melasma with 90 to 98% improvement after use, without rebound effect of melasma.

11. Use or method or pharmaceutical composition for use, according to any one of claims 1 to 10, characterized in that the association of the medicine or pharmaceutical composition with said laser presents a synergistic effect.

12. Use or method or pharmaceutical composition for use, according to any one of claims 1 to 11, characterized in that the pharmaceutical composition is presented in topical form, preferably in gel form.

13. Method, according to claim 2, characterized in that it preferably comprises the following steps: i) After laser use, the composition is applied to the skin, preferably twice a day, for about 45 days; ii) After step “i”, a new laser session is performed and the composition is applied to the skin, preferably twice a day, for about 45 days; iii) After step “ii”, the composition is applied to the skin, preferably once a day, for about 4 months.

Images