Azelaic acid-cyclodextrin complex based hydrogel formulations for acne treatment

Abstract

The present invention relates to hydrogel formulations comprising azelaic acid-cyclodextrin complex for use in the treatment of acne.

Description

[0001] AZELAIC ACID-CYCLODEXTRIN COMPLEX BASED HYDROGEL FORMULATIONS FOR ACNE TREATMENT

[0002] Technical Field

[0003] The present invention relates to hydrogel formulations comprising azelaic acid-cyclodextrin complex for use in the treatment of acne.

[0004] State of the Art

[0005] Acne is an inflammatory disorder of the pilosebaceous unit with a lifetime incidence of approximately 85%, usually occurring in the form of inflammatory or non-inflammatory lesions. It deeply affects people's quality of life not only in terms of physical appearance but also due to its negative psychological and social effects. Stopping the scarring caused by acne and shortening the treatment period are the main objectives of acne treatment.

[0006] In the state of the art, active ingredients such as azelaic acid, benzoyl peroxide, isotretinoin or erythromycin are used in the treatment of acne. These active ingredients are generally formulated in semisolid drug carrier compositions such as gel, cream, and lotion suitable for topical use.

[0007] Azelaic acid, one of the active ingredients used in the treatment of acne, is an active ingredient with a very low solubility in water. Therefore, azelaic acid can be formulated in different solvents to penetrate the skin and show therapeutic effectiveness. However, some of the solvents used cause irritation to the skin, leading to side effects and reducing patient compliance. Likewise, oil-based formulations have low patient compliance. For this reason, water-based hydrogel formulations and / or complex -based formulations in which the active ingredient can be solubilized become very attractive.

[0008] Brief Description of the Invention Based on the problems existing in the prior art, the inventors aim to develop water-based azelaic acid formulations with effective skin penetration.

[0009] For this purpose, the inventors have prepared a hydrogel formulation containing azelaic acid- beta-cyclodextrin complex. As a result of the tests conducted, it has been surprisingly observed that the hydrogel formulation comprising azelaic acid-beta-cyclodextrin complex according to the invention provides a much higher release profile than the commercially available product named Azelderm, which contains azelaic acid as the active ingredient.

[0010] Descriptions of the Figures

[0011] Figure 1: Cumulative drug release graph of the formulations (Fl and F2) according to the invention comprising azelaic acid-beta-cyclodextrin complex with Azelderm commercial product. When the graph is examined, it is seen that less than 50% azelaic acid is released from the product named Azelderm within 12 hours, while almost 100% azelaic acid is released in the Fl and F2 formulations according to the invention.

[0012] Figure 2: Total azelaic acid release graph of the formulations (Fl and F2) according to the invention comprising azelaic acid-beta-cyclodextrin complex with Azelderm commercial product within 12 hours.

[0013] Figure 3: (a) Viscosity and spreadability test results of the Fl and F2 hydrogels according to the invention, (b) Viscometer measurement results showing the flow characterization of the Fl and F2 hydrogels according to the invention shows that the gels according to the invention have non-Newtonian type pseudoplastic flow characteristics.

[0014] Detailed Description of the Invention

[0015] As mentioned above, the present invention relates to topical formulations comprising azelaic acid-beta-cyclodextrin complex for use in the treatment of acne.

[0016] The formulations of the invention are as follows:

[0017] Azelaic acid and beta-cyclodextrin, preferably hydroxypropyl beta-cyclodextrin (1 : 1.17 molar ratio),

[0018] Cellulose-derived water-soluble polymer as the gel-forming agent,

[0019] - Humectant Antimicrobial agent and

[0020] - Distilled water

[0021] Within the scope of the invention, the expression "azelaic acid and beta-cyclodextrin, preferably hydroxypropyl beta-cyclodextrin (1 :1.17 molar ratio)" refers to the azelaic acid- beta-cyclodextrin or preferably azelaic acid-hydroxypropyl-beta-cyclodextrin inclusion complex.

[0022] The cellulose-derived soluble polymer used as the gel-forming agent in the formulation according to the invention can be selected from a group consisting of methylcellulose, hydroxy propyl methyl cellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose. Hydroxy propyl methyl cellulose is preferably used as the gel-forming cellulose-derived soluble polymer in the formulation according to the invention.

[0023] The hydroxy propyl methyl cellulose used as the gel-forming cellulose-derived soluble polymer in the formulation according to the invention is preferably of medium molecular weight.

[0024] The gel-forming cellulose-derived soluble polymer in the formulation according to the invention is used at a rate of 0. l%-3.5% (w / w) compared to the total weight.

[0025] The humectant used in the formulation according to the invention can be selected from a group consisting of glycerin, propylene glycol, PEG 400.

[0026] A humectant in the range of l%-10% (w / w) compared to the total weight is used in the formulation according to the invention.

[0027] Benzalkonium chloride is used as the antimicrobial agent in the formulation according to the invention.

[0028] An antimicrobial agent in the range of 0.001%-0.1% (w / w) compared to the total weight is used in the formulation according to the invention.

[0029] Accordingly, an element of the invention relates to topical formulations comprising azelaic acid-beta-cyclodextrin complex, characterized in that it comprises the following:

[0030] Azelaic acid and beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin, in 1 : 1.17 molar ratios, The gel-forming water-soluble polymer at a rate of 0. l%-3.5% (w / w), HPMC, preferably medium molecular weight,

[0031] - Humectant selected from 1%- 10% (w / w) glycerin, propylene glycol, PEG 400

[0032] - Benzalkonium chloride at a rate of 0.001%-0.1% (w / w),

[0033] - Distilled water.

[0034] Another element of the invention is the method used in the preparation of topical formulations comprising azelaic acid-beta-cyclodextrin complexes according to the invention. Accordingly, said method comprises the following:

[0035] - Dissolving beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin (1.17 molar ratio) in water,

[0036] Obtaining azelaic acid-beta-cyclodextrin complex (1 : 1.17 molar ratio) by adding 1 molar of azelaic acid to the resulting mixture,

[0037] Obtaining the hydrogel formulation by adding the gel-forming cellulose-derived water- soluble polymer, preferably HPMC, and then the antimicrobial agent, preferably benzalkonium chloride, to the resulting mixture.

[0038] In another aspect, the invention relates to topical formulations comprising azelaic acid-beta- cyclodextrin complex according to the invention for use as a drug in the treatment of acne and similar skin problems (e.g. rosacea).

[0039] In another aspect, the invention relates to topical formulations comprising azelaic acid-beta- cyclodextrin complex according to the invention for use in cosmetic applications such as reducing hyperpigmentation in the skin, opening pores, and reducing pore sizes.

[0040] EXAMPLES:

[0041] Example 1: Preparation of azelaic acid-hydroxypropyl-beta-cyclodextrin-inclusion complexes

[0042] Dissolve hydroxypropyl-beta-cyclodextrin (1.17 molar ratio) in water, mix by adding 1 molar of azelaic acid to the resulting solution, and the azelaic acid-hydroxypropyl-beta-cyclodextrin complex (1 : 1.17 molar ratio) is obtained. Monitor the solubility and complex formation of azelaic acid by visual and HPLC analysis. Example 2: Preparation of hydrogel formulations containing azelaic acid- hydroxypropyl-beta-cyclodextrin-inclusion complexes

[0043] Dissolve hydroxypropyl-beta-cyclodextrin (1.17 molar ratio) in water, mix by adding 1 molar of azelaic acid to the resulting solution, and the azelaic acid-hydroxypropyl-beta-cyclodextrin complex (1 : 1.17 molar ratio) is obtained. Then, add 2.5% or 3% by weight (w / w) of hydroxy propyl methyl cellulose (HPMC) to this mixture and mix until dissolved. Then, add benzalkonium chloride (0.1%, w / w) to the mixture as a humectant (5%, w / w) and antimicrobial agent, respectively, and the final hydrogel formulation is obtained.

[0044] The gel obtained by adding 2.5% HPMC is called Fl in the experiments.

[0045] The gel obtained by adding 3% HPMC is called F2 in the experiments.

[0046] In Figures 1, 2 and 3, various characterization results of the Fl and F2 formulations according to the invention and the comparative release profile with the commercial product Azelderm are given.

[0047] As a result, it is seen that the Fl and F2 formulations according to the invention have significantly higher release characteristics than the commercial product Azelderm, especially considering the test results given in Figures 1 and 2. As can be seen from these data, the release problem arising from the hydrophobic structure of azelaic acid and the oil-based cream formulation was solved by forming the inclusive beta-cyclodextrin complex according to the present invention and preparing the hydrogel formulation, and a formulation that is much superior to the commercial product of the known art, has higher therapeutic effectiveness and is easier to use by patients and increases patient compliance due to its waterbased nature.

Claims

CLAIMS1. A hydrogel formulation comprising azelaic acid, characterized in that it comprises the following:• Azelaic acid-beta-cyclodextrin or azelaic acid-hydroxypropyl-beta-cyclodextrin inclusion complex,• Cellulose-derived water-soluble polymer as a gel-forming agent,• Humectant,• Antimicrobial agents and• Water.

2. A hydrogel formulation according to claim 1, characterized in that it is selected from the group consisting of gel-forming cellulose-derived polymer methylcellulose, hydroxy propyl methyl cellulose (HPMC), hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose.

3. A hydrogel formulation according to any one of claims 1 or 2, characterized in that the hydroxy propyl methyl cellulose is used as the gel-forming cellulose-derived polymer.

4. A hydrogel formulation according to any one of claims 1 or 2, characterized in that the hydroxy propyl methyl cellulose, which is equipped as the gel-forming cellulose-derived polymer is of medium molecular weight.

5. A hydrogel formulation according to any one of claims 1-4, characterized in that the gel- forming cellulose-derived polymer is 0. l%-3.5% (w / w) relative to the total weight.

6. A hydrogel formulation according to any one of claims 1-5, characterized in that the humectant is selected from a group consisting of glycerin, propylene glycol, PEG 400.

7. A hydrogel formulation according to any one of claims 1-6, characterized in that the humectant is 1%- 10% (w / w) relative to the total weight.

8. A hydrogel formulation according to any one of claims 1-7, characterized in that benzalkonium chloride is used as the antimicrobial agent.

9. A hydrogel formulation according to any one of claims 1-8, characterized in that the antimicrobial agent is 0.001%-0.1% (w / w) relative to the total weight.

10. A hydrogel formulation according to any one of claims 1-9, characterized in that the azelaic acid-beta-cyclodextrin or azelaic acid-hydroxypropyl-beta-cyclodextrin inclusion complex is in a molar ratio of 1 : 1.17.

11. A method for preparing a hydrogel formulation according to any one of claims 1-10, characterized in that it comprises the following steps:- Dissolving beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin (in 1.17 molar ratio) in water,- Obtaining azelaic acid-beta-cyclodextrin complex by adding azelaic acid (in 1 molar ratio) to the resulting mixture,- Obtaining the hydrogel formulation by adding the gel-forming cellulose-derived water-soluble polymer, preferably HPMC, and then an antimicrobial agent, preferably benzalkonium chloride, to the resulting mixture.

12. A hydrogel formulation according to any one of claims 1-10 for use as a medicament in the treatment of acne and similar skin problems.

13. A hydrogel formulation according to any one of claims 1-10 for use in cosmetic applications such as reducing hyperpigmentation in the skin, unclogging pores, and reducing pore sizes.

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