Nutraceutical composition of hyaluronic acid for treatment of melasma

Abstract

The current invention describes a liquid oral formulation containing a synergistic combination of hyaluronic acid or nutraceutically acceptable salt thereof and Methylsulfonylmethane or pharmaceutically acceptable salt thereof. The formulation of the invention is effective in alleviating symptoms of melasma. Optionally, the formulation of the invention can be preservative-free composition. The invention further describes the method for manufacturing the formulation of the invention

Description

[0001] NUTRACEUTICAL COMPOSITION OF HYALURONIC ACID

[0002] FOR TREATMENT OF MELASMA

[0003] Field of Invention:

[0004] The current invention is in field of skin care. More particularly, the present invention relates to a nutraceutical composition containing hyaluronic acid for reducing skin pigmentation.

[0005] Background of Invention:

[0006] The one’s skin tone is determined by the level of melanin pigmentation. Changes in melanin production can cause pigment disorders, such as hyperpigmentation (dark spots), hypopigmentation (light spots), depigmentation (white spots or patches).

[0007] Hyperpigmentation is a common skin problem that causes tanning, dark spots, melasma, blemishes, post-inflammatory acne marks, and dark circles that make your skin appear darker than its normal skin tone. Melasma is a common, acquired, circumscribed hypermelanosis of the sun-exposed skin, It presents as symmetric, hyperpigmented macules having irregular, serrated, and geographic borders, The most common locations are the cheeks, upper lips, the chin and the forehead, but other sun-exposed areas may also be occasionally involved Commonly used topical agents for the treatment of melasma include hydroquinone, azelaic acid, kojic acid, glycolic acid, salicylic acid and tretinoin. Of these treatments, hydroquinones are most preferred option. Second-line treatments, such as chemical peels and lasers, are efficacious in some patients.

[0008] Hyaluronic acid is a naturally occurring mucopolysaccharide generally present in all vertebrates, including humans. Hyaluronic acid (HA) is also known as hyaluronan, hylan, hyaluronate. It can include several thousand sugar molecules in the backbone to form a long chain. It is a hydrophilic molecule which binds to water to give a viscous, gelatine-like molecule which hydrates, lubricates, cushions movable part of the body and hence it is also named as “nature’s moisturizer” or natural humectant. Although HA was discovered in 1934 (Meyer and Palmer), it was first commercialised in 1942 by Endre Balazs as a substitute for egg white in bakery products.

[0009] Dimethyl sulfone or Methylsulfone methane (MSM) is natural form of bioavailable sulphur. MSM stimulates synthesis of collagen, elastin, proteoglycans and hyaluronic acid. It is an anti-inflammatory, antioxidant, detoxifier of body and is used mostly in the treatment of arthritis, degenerative bone and joint diseases, bursitis, tendonitis, tenosynovitis, gum diseases, eye inflammation, chronic pain. Further, MSM has also shown effectiveness in clearing arteries of heart, interstitial cystitis, promotes wound healing, improves collagen production, raise energy levels, cartilage preservation, improves joint pain, treats digestive problems, improves skin health and complexion, strengthens hairs and nails, relieves allergy symptoms, boost immunity, anticancer, scleroderma, fibromyalgia, autoimmune disorders, chronic venous insufficiency, bacterial prostatitis, obesity induced metabolic disorder, reduce muscle soreness associated with exercise, rosacea, gastric ulcers, hemorrhoids etc.

[0010] The effectiveness of Hyaluronic acid in treatment of melasma was established vide article titled “Advantages of Hyaluronic Acid and Its Combination with Other Bioactive Ingredients in Cosmeceuticals” by Juncan, A.M.; et al published in Molecules 2021, 26, 4429.

[0011] Another article by Michael Anthonavage, titled “Effects of Oral Supplementation with Methylsulfonylmethane on Skin Health and Wrinkle Reduction” (published in Natural Medicine Journal, dated 04.11.2015) assess the effectiveness of methyl sulfonylmethane (MSM) as an oral supplement on skin health, particularly in context of wrinkle reduction.

[0012] However, there are not many published studies that focus solely on use of hyaluronic acid for melasma treatment. However, a study by Zeinab A Ibrahim et al, titled “Evaluation of the efficacy and safety of combinations of hydroquinone, glycolic acid, and hyaluronic acid in the treatment of melasma”, published in J Cosmet Dermatol. 2015 Jun; 14(2): 113-23, demonstrated that when hyaluronic acid is combined with hydroquinone and glycolic acid showed positive results in treating melasma in patients.

[0013] Therefore, in view of above, the current inventors venture to provide a formulation which has improved effectiveness against pigmentation disorders of skin.

[0014] Summary of Invention:

[0015] In view of above it is an aspect of the invention to provide a nutraceutical composition containing a synergistic combination of Hyaluronic acid or salt thereof and methyl sulfonylmethane (MSM) or a salt thereof for alleviating symptoms of melasma.

[0016] The composition of the invention is a preservative-free composition.

[0017] The said composition is effective in treating symptoms of melasma.

[0018] The composition of the invention is effective in treating melasma of sub epidermal tissue.

[0019] The composition of the invention is an oral composition. Detailed Description of the Invention:

[0020] The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. As used herein, the following terms and phrases shall have the meaning set forth below.

[0021] Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.

[0022] Unless stated to the contrary, any of the words “contains”, “containing”, "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention. Further, words like “a”, “an”, “at least” and “the” should be construed to not only cover singular quantities but also plural quantities of the elements immediately following them.

[0023] Described herein is a nutraceutical formulation containing a synergistic combination of Hyaluronic acid or a nutraceutically acceptable salt thereof and methyl sulfonylmethane (MSM) or a nutraceutically acceptable salt thereof.

[0024] The formulation of the invention has been found effective in treating symptoms of sub epidermal melasma. Further, the formulation of the invention is, preferably, an oral formulation.

[0025] In an embodiment, the formulation of invention comprises of nutraceutically effective amount of hyaluronic acid or salt thereof and methylsulfonylmethane (MSM) or salt thereof. The formulation in accordance with this embodiment is a liquid formulation in distilled water.

[0026] The hyaluronic acid or salt thereof, in accordance with above embodiment, has a molecular weight in range of 1.4 to 2 MDa

[0027] In an additional embodiment, the composition of the invention further comprises a chelating agent. Said chelating agent has antioxidant properties, its concentration in the formulation is judiciously chosen to stabilize hyaluronic acid or salt thereof and methyl sulfonylmethane (MSM) or salt thereof by maintaining proper pH of the solution. In a preferred embodiment the chelating agent is Ethylenediaminetetraacetic acid disodium salt dihydrate

[0028] The invention further provides a process for synthesis of the nutraceutical formulation in accordance with above embodiment. The process comprises of:

[0029] Step A: Measuring of purified water (pH 7.6-7.7) in a pharma grade stainless steel tank;

[0030] Step B: adding potassium sorbate and sodium benzoate in the tank of Step A containing water and stirring to dissolve;

[0031] Step C: transferring a part of the solution of Step B in a second tank and adding weighed amount of sodium hyaluronate and stirring said solution till sodium hyaluronate is completely dissolved;

[0032] Step D: dissolving weighed amount of MSM and Ethylenediaminetetraacetic acid disodium salt dihydrate in the remaining portion of the solution of step B, and

[0033] Step E: mixing the solution of Step D and Step C and stirring said solution to obtain the liquid formulation of the invention.

[0034] In a subsequent embodiment, the liquid formulation of the invention is a preservative-free formulation using 0.9% saline as vehicle. The formulation in accordance with this embodiment, the formulation is completely devoid of any preservative.

[0035] In an embodiment, the invention further provides a process for synthesis of a preservative-free composition containing hyaluronic acid or salt thereof and methyl sulfonylmethane (MSM) or salt thereof, whereby the process consists of:

[0036] Step A: Measuring 0.9% Sodium Chloride solution in a pharma grade stainless steel tank;

[0037] Step B: adding weighed amount of hyaluronic acid or salt thereof in tank of Step A and stirring the mixture with axial impeller (45°) at 1200 rpm for 12- 15 min;

[0038] Step C: keeping mixture overnight (8 hours) in a covered tank for soaking to ensure complete dissolution of sodium hyaluronate;

[0039] Step D: adding weighed amount of Ethylenediaminetetraacetic acid disodium salt dihydrate in the mixture of Step C with stirring for lOmin at 1600 rpm;

[0040] Step E: adding Methylsulfonylmethane or salt thereof in the mixture of Step D and stirring the mixture for 20 min, at 1200 rpm, after complete dissolution of Ethylenediaminetetraacetic acid disodium salt dihydrate (mixture will become clear).

[0041] EXAMPLES:

[0042] Several examples are set forth below to further illustrate the nature of the invention and the manner of carrying it out. However, the invention should not be considered as being limited to the details thereof. Example 1

[0043] Table 1: Oral liquid solution of Hyaluronic acid (Purified water) Process for manufacturing

[0044] Procedure:

[0045] 1) Measure 1000 mL of purified water (pH 7.6-7.7) in a pharma grade stainless steel tank.

[0046] 2) Add potassium sorbate and sodium benzoate in a tank containing water and stir to dissolve (stir for 10 min). 3) After complete dissolution of potassium sorbate and sodium benzoate, transfer

[0047] 750 mL of that water in a main mixing tank and add weighed amount of sodium hyaluronate in it and stir the mixture with axial impeller (45°) at 1200 rpm till sodium hyaluronate completely dissolved. 4) Dissolve weighed amount of MSM & Ethylenediaminetetraacetic acid disodium salt dihydrate in the remaining 250 mL of water separately and transfer that into a main mixing tank.

[0048] 5) Stir the final mixture for 30 min. Example 2:

[0049] Table 2: Preservative free oral liquid solution of Hyaluronic acid (0.9% saline solution)

[0050] Process for manufacturing Procedure: 1) Measure 750 mL of 0.9% saline water in a pharma grade main mixing stainless steel tank.

[0051] 2) Add the weighted amount of sodium hyaluronate in the main mixing tank and stir till it completely dissolved.

[0052] 3) Dissolve weighed amount of MSM & Ethylenediaminetetraacetic acid disodium salt dihydrate in the remaining 250 mL of 0.9% saline water separately and transfer that into a main mixing tank.

[0053] 4) Stir the final mixture for 30 min.

[0054] Example 3:

[0055] 20 female participants with moderate to severe melasma conditions were studied to establish the effectiveness of the formulation of the invention. All participants were treated with the same dose (6 mL) of oral hyaluronic acid solution (purified / saline) with variable duration.

[0056] Eligibility criteria:

[0057] Number of participants: 20

[0058] Ages accepted for study: 30-65 years

[0059] Sexes accepted for study: Female

[0060] Accepted healthy volunteers: 0

[0061] Inclusion Criteria:

[0062] A. Feminine gender

[0063] B. Age between 30 to 65 years C. Subjects presented with melasma.

[0064] D. Facial melasma

[0065] E. Melasma persisting for more than 6 months that has failed to respond to conventional treatment.

[0066] Exclusion Criteria:

[0067] • Pregnancy and lactation.

[0068] • Subjects with local inflammatory skin disorder or active herpes infection at the site of procedure.

[0069] • Subjects with history of medical diseases which contraindicate cryosurgery such as cold intolerance, cold urticaria, Raynaud's disease and history of allergic reactions to cryosurgery.

[0070] • Undertakes any treatment for topical or oral Melasma at the time of the research or less than 3 months ago.

[0071] • Uses retinoic acid, vitamin A derivatives, photosensitizing drugs.

[0072] • Skin pathologies on the face

[0073] • Glaucoma, cataract, cancer patients, pregnant women, lactating women

[0074] • Uses oral or intrauterine contraceptives (IUD)

[0075] • Thyroid disorders

[0076] • Use of hormone replacement

[0077] • Bacterial, viral, and fungal infections Table 3: Observations: Around 45% of participants showed a very good response (MASI 4 out of 5) for the novel oral hyaluronic acid solution. While 55% of participants showed a good response (MASI 3 out of 5). The average duration of treatment for all the participants was approximately 4 weeks.

Claims

We Claim,1. A nutraceutical formulation comprising a synergistic combination of: a. Hyaluronic acid or nutraceutically acceptable salt thereof; b. Methylsulfonylmethane or nutraceutically acceptable salt thereof, and c. a chelating agent or nutraceutically acceptable salt thereof, wherein, the formulation is effective in alleviating symptoms of melasma.

2. The formulation as claimed in Claim 1, wherein the formulation, optionally, further comprises of preservative selected from potassium benzoate, sodium benzoate or combinations thereof.

3. The formulation as claimed in Claim 1, wherein the hyaluronic acid has a molecular weight in range of 1.4 to 2 MDa.

4. The formulation as claimed in Claim 1, wherein the nutraceutically acceptable salt of hyaluronic acid is sodium hyaluronate.

5. The formulation as claimed in Claim 1, wherein sodium hyaluronate is present in range of 0.2 - 5%.

6. The formulation as claimed in Claim 1, wherein Methyl sulfonylmethane or nutraceutically acceptable salt thereof is present in range of 0.2 - 5%.

7. The formulation as claimed in Claim 1, wherein the chelating agent is Ethylenediaminetetraacetic acid.

8. The formulation as claimed in Claim 7, wherein Ethylenediaminetetraacetic acid is present in range of 0.01 - 0.1%.

9. The formulation as claimed in Claim 1, wherein the formulation is an oral liquid formulation containing a vehicle.

10. The formulation as claimed in Claim 9, wherein the vehicle is purified water.

11. The formulation as claimed in Claim 9, wherein the vehicle is 0.9% Sodium Chloride Solution or a saline solution.

12. A method for manufacturing the formulation as claimed in Claims 1 and 10, wherein the process comprises following steps:A. Measuring of purified water (pH 7.6-7.7) in a pharma grade stainless steel tank;B. adding potassium sorbate and sodium benzoate in the tank of Step A containing water and stirring to dissolve;C. transferring a part of the solution of Step B in a second tank and adding weighed amount of sodium hyaluronate and stirring said solution till sodium hyaluronate is completely dissolved;D. dissolving weighed amount of Ethylenediaminetetraacetic acid disodium salt dihydrate in the remaining portion of the solution of step B, andE. mixing the solution of Step D and Step C and stirring said solution to obtain the liquid formulation of the invention13. A method for manufacturing the formulation as claimed in Claims 1 and 11, wherein the process comprises following steps:A. Measuring 0.9% Sodium Chloride solution in a pharma grade stainless steel tank;B. adding weighed amount of hyaluronic acid or salt thereof in tank of Step A and stirring the mixture with axial impeller (45°) at 1200 rpm for 12-15 min;C. keeping mixture overnight (8 hours) in a covered tank for soaking to ensure complete dissolution of sodium hyaluronate;D. adding weighed amount of Ethylenediaminetetraacetic acid disodium salt dihydrate in the mixture of Step C with stirring for lOmin at 1600 rpm;E. adding Methyl sulfonylmethane or salt thereof in the mixture of Step D and stirring the mixture for 20 min, at 1200 rpm.

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