Adapalene gel

Abstract

A formula of the adapalene gel comprises glabridin serving as a high humectant, glycerol and butanediol, and further comprises propylene glycol, a carbomer homopolymer type C, poloxamer, disodium ethylene diamine tetraacetate, methyl p-hydroxybenzoate, a pH regulator and purified water. The content of glabridin is 1%-3%, preferably 2%. During preparation, the carbomer homopolymer C is dispersed in a uniform dispersion of propylene glycol, butanediol and glycerol under stirring, and then is hydrated with purified water under stirring. The adapalene mask has the advantages that the formula and the preparation method are reasonable in design, irritation to the skin can be effectively reduced on the premise that the treatment effect of adapalene is guaranteed, and the skin is helped to keep moisture.

Description

Technical Field

[0001] The present invention relates to an adapalene gel and a preparation method thereof. Background Art

[0002] according to Product label information of Adapalene Gel: Adapalene Gel can cause local skin irritation. Specifically, during a 12-week clinical study of 258 acne subjects using the gel once a day, a high incidence of local skin irritation was observed. Among subjects who experienced skin allergies (erythema, scaling, dryness, and / or burning / stinging), most cases were mild to moderate in severity and occurred at the beginning of treatment. 26.1% of the subjects experienced different types of erythema, 13.0% of the subjects experienced moderate erythema, and 0.4% of the subjects experienced severe erythema. 43.5% of the subjects experienced mild scaling, 18.6% of the subjects experienced moderate scaling, and 1.2% of the subjects experienced severe scaling. 44.7% of the subjects experienced mild dryness, 17.0% of the subjects experienced moderate dryness, and 0.8% of the subjects experienced severe dryness. 28.5% of the subjects experienced mild burning and stinging, 14.2% of the subjects experienced moderate burning and stinging, and 3.6% of the subjects experienced severe burning and stinging.

[0003] CN105411999A discloses a method for preparing adapalene gel, CN103462882A discloses an adapalene gel and a method for preparing the same, CN103417473B discloses an adapalene gel and a method for preparing the same, CN101878022B discloses a method for preparing adapalene gel, and CN103830163B discloses a method for preparing adapalene gel, but none of them solves the problem of irritation to the patient's skin.

[0004] Based on the above results, it can be seen that the incidence of dry skin and desquamation after use of the prior art adapalene gel is very high, and it is considered to improve the formula by using high moisturizing ingredients in the formula to reduce the incidence of local skin irritation.

[0005] CN117018225A discloses a method for preparing a high-drug-loaded adapalene gel, which uses microsponge technology to encapsulate adapalene in porous microspheres, thereby increasing the drug-load of the adapalene preparation without increasing irritation. However, this technology requires various modern production equipment, resulting in additional production costs, which in turn affects the selling price.

[0006] Glabridin, chemical formula:

[0007]

[0008] Glabridin is the main component of licorice root (Glycyrrhiza glabra), accounting for 0.1% to 0.4% of the dry weight of licorice root. The B ring hydroxyl group provides a powerful sink for free radical electrons. The effect of glabridin on the skin is to reduce facial redness, acne scars, aging and skin blemishes caused by age, environmental factors or inflammation such as acne. In addition, the effects of glabridin on acne skin also include inhibiting the activity of cyclooxygenase, reducing inflammation, controlling the production of melanin, and inhibiting the production of melanin, a pigment that causes acne. Glabridin is extracted from the root extract of the licorice plant.

[0009] Glabridin helps soften or smooth the skin because it can help support the skin's natural outer barrier, making it a good choice for dry and irritated skin as it has been shown to help calm redness and inflammation. Glabridin is non-comedogenic and is suitable for use on dry or sensitive skin, but is generally suitable for all skin types. Specifically, dry, irritated, or sensitive skin will benefit best from using glabridin, but almost all skin types can benefit from this skincare ingredient. Glabridin was introduced to help regulate the amount of sebum produced by the body. One of its most notable benefits, which has been well-studied, is strengthening the skin barrier.

[0010] Glabridin’s anti-inflammatory properties make it an effective anti-irritant in skin care, too. In addition, according to some studies, glabridin can block superoxide anions, a major mediator of irritation, helping to calm and soothe the skin.

[0011] Glabridin hydrates the skin by acting as an emollient, meaning it helps lock in moisture and makes it harder for it to evaporate. Glabridin hydrates the skin without irritating it - a win-win for those suffering from dryness and acne, and it can also soothe certain symptoms of eczema, such as dryness, cracking and flaking. Glabridin helps reduce transepidermal water loss (TEWL), restoring suppleness and elasticity to the skin, without leaving a greasy residue. It is highly biocompatible, non-irritating and can be used at concentrations up to 100%. Summary of the invention

[0012] The present invention provides an adapalene gel, the purpose of which is to overcome the above-mentioned shortcomings of the prior art and reduce skin irritation at a relatively low cost while ensuring the therapeutic effect.

[0013] The technical solution of the present invention is an adapalene gel, the formula of which includes glabridin, a high moisturizing agent.

[0014] Preferably, high moisturizing agents glycerin and butylene glycol are also included.

[0015] Preferably, the preparation further comprises auxiliary materials: propylene glycol, carbomer homopolymer type C, poloxamer, disodium edetate, methyl paraben, pH regulator and purified water.

[0016] Preferably, the formula comprises, by weight percentage: 0.05%-0.5% adapalene, 0.5%-5% glabridin, 1-10% glycerol, and 1-5% butylene glycol.

[0017] Preferably, the formula specifically includes, by weight percentage: 0.1%-0.3% adapalene, 1%-3% glabridin, 3% glycerol, 3% butylene glycol, 3% propylene glycol, 1.1% carbomer homopolymer type C, 0.1%-0.3% poloxamer, 0.1% disodium ethylenediaminetetraacetate, and 0.2% methylparaben.

[0018] Preferably, the formula contains 2% glabridin.

[0019] Preferably, the pH adjuster is sodium hydroxide or sodium hydroxide and hydrochloric acid, which is used to adjust the pH value of the gel to 5.0±0.2.

[0020] Preferably, a method for preparing adapalene gel comprises dispersing carbomer homopolymer type C in a uniform dispersion of propylene glycol, butylene glycol and glycerol under stirring, and then hydrating with purified water under stirring. This can solve the problem that carbomer homopolymer type C easily forms lumps when dispersed in water, and forms fish eyes in the dispersion, making it difficult to disperse again.

[0021] Preferably, a method for preparing adapalene gel comprises the following steps:

[0022] (a) Water phase: Add purified water to the main mixing container, add the formulated amount of disodium ethylenediaminetetraacetate and mix;

[0023] (b) Preservative phase: Add the formulated amounts of propylene glycol, butylene glycol and glycerin to a stainless steel container, add the formulated amount of methyl paraben and mix until completely dissolved, heat as needed and cool to room temperature, add the formulated amount of glabridin, stir and mix, heat as needed and cool to room temperature;

[0024] (c) Gel Phase: Add the formulated amount of Carbomer Homopolymer Type C to the preservative phase under stirring, continue stirring until a uniform dispersion is formed, transfer the dispersion to the main mixing vessel containing the water phase and mix under stirring, and hydrate under stirring for 40 minutes.

[0025] (d) Drug phase: In another stainless steel container, add purified water and add the formulated amount of poloxamer under stirring until a transparent solution is formed, add the formulated amount of adapalene and disperse under stirring until uniform;

[0026] (e) Adding drug phase: Transfer the drug phase dispersion into the gel phase and mix under stirring.

[0027] (f) adjusting the pH value: preparing a sodium hydroxide solution with purified water in another container and adding it to the mixture to adjust the pH value to within the range of 4.8-5.2;

[0028] (g) If the pH value is within the specified range, add the remaining amount of purified water. If the pH value is lower or higher than the specified range, adjust the pH value to 5.0 ± 0.2 with hydrochloric acid or sodium hydroxide solution.

[0029] The invention has the advantages that the formula and the preparation method are reasonably designed, and can effectively reduce the irritation to the skin and help the skin retain moisture while ensuring the therapeutic effect of adapalene. DETAILED DESCRIPTION

[0030] The present invention is further described in detail below with reference to examples and specific implementation methods.

[0031] Disclosed is an adapalene gel and an industrial preparation method thereof. The adapalene gel can effectively reduce the incidence of local skin irritation.

[0032] As an example, adapalene gel includes a high humectant.

[0033] As a further example, the high moisturizing agent is glabridin.

[0034] As a further example, the adapalene gel also includes high moisturizing agents such as glycerin and butylene glycol.

[0035] As a further embodiment, the adapalene gel further comprises other excipients, specifically propylene glycol, carbomer homopolymer type C, poloxamer, disodium edetate, methyl paraben, pH adjuster and purified water.

[0036] By weight percentage, the formula includes: 0.05%-0.5% adapalene (preferably 0.1%-0.3%), 0.5%-5% glabridin (preferably 1%-3%), 1-10% glycerol (preferably 3%), 1-5% butylene glycol (preferably 3%), 3% propylene glycol, 1.1% carbomer homopolymer type C, 0.1%-0.3% poloxamer, 0.1% disodium ethylenediaminetetraacetic acid, and 0.2% methyl paraben.

[0037] As a further example, the pH adjuster is sodium hydroxide and / or hydrochloric acid.

[0038] The hydration of polymers is an important aspect of production process design, which affects the safety and efficacy of the preparation. Carbomer homopolymer type C tends to form lumps when dispersed in water, and once fish eyes are formed in the dispersion, it is difficult to disperse again. Therefore, an insoluble solvent such as propylene glycol, butylene glycol, glycerin, etc. is added and dispersed under stirring to form a uniform dispersion.

[0039] As a further example, a method for preparing adapalene gel comprises dispersing carbomer homopolymer type C in a uniform dispersion of propylene glycol, butylene glycol and glycerol under stirring, and then hydrating with purified water under stirring.

[0040] Example 1: Commercially available adapalene gel

[0041] Table 1: Example 1 formulation composition

[0042] Serial number Ingredient name Effect of ingredients %w / w 1 Adapalene active 0.3 2 Disodium EDTA Chelating agents 0.1 3 Propylene glycol Moisturizer 4.0 4 Methylparaben preservative 0.2 5 Poloxamer 182 Surfactants 0.2 6 Carbomer Homopolymer Type C Gelling Agent 1.10 7 Sodium hydroxide Neutralizer pH 5.0 ± 0.2 8 hydrochloric acid Neutralizer pH 5.0 ± 0.2 9 Purified water Carrier qsto100

[0043] Preparation method:

[0044] (a) Water Phase: Add purified water (88.92%) to the main mixing vessel, add pre-weighed disodium EDTA (0.10%) and mix.

[0045] (b) Preservative Phase: Add pre-weighed propylene glycol (4%) to a stainless steel container, add methylparaben (0.2%) and mix until completely dissolved. Heat if necessary and cool to room temperature.

[0046] (c) Gel Phase: Add pre-weighed Carbomer Homopolymer Type C (1.10%) to the preservative phase under stirring and continue stirring until a uniform dispersion is formed. Transfer the dispersion to the main mixing vessel containing the water phase and mix under stirring and hydrate under stirring for 40 minutes.

[0047] (d) Drug phase: In another stainless steel container, add a specified amount of purified water (1%), and add pre-weighed Poloxamer 182 (0.2%) under stirring until a transparent solution is formed, add Adapalene (0.3%), and disperse under stirring until uniform.

[0048] (e) Adding drug phase: Transfer the drug phase dispersion into the gel phase and mix under stirring.

[0049] (f) Adjusting pH: Prepare a pre-weighed solution of sodium hydroxide (0.18%) with purified water (1%) in a separate container and add to the mixture to adjust the pH to within the range of 4.8-5.2.

[0050] (g) If the pH value is within the specified range, add the remaining amount of purified water to make the formula 100%. If the pH value is lower or higher than the specified range, adjust the pH value to 5.0 ± 0.2 with hydrochloric acid or sodium hydroxide solution.

[0051] Example 2: Improved Adapalene Gel 1

[0052] Table 2: Example 2 formulation composition

[0053]

[0054]

[0055] Preparation method:

[0056] (a) Water Phase: Add purified water (84%) to the main mixing vessel, add pre-weighed disodium EDTA (0.10%) and mix.

[0057] (b) Preservative Phase: Add pre-weighed propylene glycol (3%), butylene glycol (3%) and glycerin (3%) to a stainless steel container. Add methyl paraben (0.1%) and mix until completely dissolved. Heat if necessary and cool to room temperature. Add glabridin (2%) and stir to mix. Heat if necessary and cool to room temperature.

[0058] (c) Gel Phase: Add pre-weighed Carbomer Homopolymer Type C (1.10%) to the preservative phase under stirring and continue stirring until a uniform dispersion is formed. Transfer the dispersion to the main mixing vessel containing the water phase and mix under stirring and hydrate under stirring for 40 minutes.

[0059] (d) Drug phase: In another stainless steel container, add a specified amount of purified water (1%), and add pre-weighed Poloxamer 182 (0.2%) under stirring until a transparent solution is formed, add Adapalene (0.3%), and disperse under stirring until uniform.

[0060] (e) Adding drug phase: Transfer the drug phase dispersion into the gel phase and mix under stirring.

[0061] (f) Adjusting pH: Prepare a pre-weighed solution of sodium hydroxide (0.18%) with purified water (1%) in a separate container and add to the mixture to adjust the pH to within the range of 4.8-5.2.

[0062] (g) If the pH value is within the specified range, add the remaining amount of purified water to make the formula 100%. If the pH value is lower or higher than the specified range, adjust the pH value to 5.0 ± 0.2 with hydrochloric acid or sodium hydroxide solution.

[0063] Example 3: Improved Adapalene Gel 2

[0064] The difference from Example 2 is that Adapalene accounts for 0.1% w / w in the formula, and Poloxamer 182 is replaced by Poloxamer 124.

[0065] Example 4: Improved Adapalene Gel 3

[0066] The difference from Example 2 is that glabridin accounts for 1% w / w in the formula.

[0067] Example 5: Improved Adapalene Gel 4

[0068] The difference from Example 2 is that glabridin accounts for 3% w / w in the formula.

[0069] Example 6: Physical and Chemical Studies

[0070] The apparent viscosity, assay and evaluation of organic impurities of adapalene in the finished product were performed on each example sample using validated analytical methods. All formulations showed similar stability in terms of physical and chemical parameters, as shown in the following table.

[0071] Table 3

[0072]

[0073] Example 7: Porcine Transepidermal Water Loss Study (TWEL)

[0074] In a controlled laboratory environment, the animal transepidermal water loss test was conducted on the formulations of each example, and the test subjects were 10 mini pig models. The samples of each example formulation were applied to the specific marked areas of two handprints for 4 weeks, and the TWEL values ​​were measured at 0, 2 and 4 weeks respectively.

[0075] Table 4: Percutaneous loss results from the porcine study

[0076]

[0077]

[0078] As shown in the table above, Example 1 showed almost no change in transepidermal water loss from week 0 to week 4. Example 4 contained a lower concentration of 1% glabridin, and showed little change in transepidermal water loss from week 0 to week 4. While Examples 2 and 3, which contained 2% glabridin, showed similar significant changes in transepidermal water loss despite the different concentrations of adapalene. Finally, the results of Example 5 were similar to those of Examples 2 and 3. Therefore, when the concentration of glabridin was 2%, the formula showed stronger hydrating properties and helped the skin retain moisture.

[0079] Example 8: Human clinical study

[0080] A clinical study of the formulations of Examples 1 and 2 was conducted on 40 subjects aged 12-40 years with mild to moderate acne vulgaris. The commercially available adapalene gel of Example 1 and the modified adapalene gel of Example 2 were applied to the face and optionally to the trunk once a day for 12 weeks. Success was defined as "none" or "essentially none" in the Investigator's Global Assessment (IGA).

[0081] In addition, subjects were found to have adverse reactions such as skin allergies (erythema, scaling, dryness and / or burning / stinging), most of which were mild to moderate in severity and occurred in the early stages of treatment. The following table lists the success rate, mean reduction and percentage reduction in the number of acne lesions compared to baseline after 12 weeks of treatment, as well as the incidence of local skin irritation and transepidermal water loss:

[0082] Table 5: Safety and efficacy clinical study results

[0083]

[0084]

[0085] According to the above clinical research results, compared with Example 1, the efficacy of the preparation of Example 2 is improved, and the adverse reactions are significantly reduced. The therapeutic effects of Examples 1 and 2 are: inflammatory skin lesions (%) are reduced by 55% and 70%, non-inflammatory skin lesions (%) are reduced by 45% and 60%, and total skin lesions (%) are reduced by 50% and 65%. Compared with the formulation of Example 1, the adverse reactions of the formulation of Example 2, such as erythema, desquamation, dryness, and burning / stinging, are significantly reduced. The transepidermal water loss rate of Example 1 is reduced from 20.16 in week 0 to 18.45, while the transepidermal water loss rate of Example 2 is reduced from 21.95 to 15.24, which is a large reduction, which is also the main reason for the reduction of adverse reactions of the formulation of Example 2.

[0086] Therefore, the formula of Example 2 has better therapeutic effect, reduces adverse reactions of patients, helps to continue treatment, and cures acne as thoroughly as possible.

[0087] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. An adapalene gel, characterized in that: The formula includes the highly humectant glabridin.

2. An adapalene gel as claimed in claim 1, characterized in that The formula also includes high humectants glycerin and butylene glycol.

3. An adapalene gel as claimed in claim 2, characterized in that, The formulation also includes excipients: propylene glycol, carbomer homopolymer type C, poloxamer, disodium edetate, methylparaben, pH adjuster and purified water.

4. An adapalene gel as claimed in claim 3, characterized in that, Calculated by weight percentage, the formula specifically includes: 0.05%-0.5% adapalene, 0.5%-5% glabridin, 1-10% glycerol, and 1-5% butylene glycol.

5. An adapalene gel as claimed in claim 4, characterized in that, Calculated by weight percentage, the formula specifically includes: 0.1%-0.3% adapalene, 1%-3% glabridin, 3% glycerol, 3% butylene glycol, 3% propylene glycol, 1.1% carbomer homopolymer type C, 0.1%-0.3% poloxamer, 0.1% disodium ethylenediaminetetraacetate, and 0.2% methyl paraben.

6. An adapalene gel as claimed in claim 5, characterized in that: The formula contains 2% glabridin.

7. An adapalene gel as claimed in claim 6, characterized in that: The pH regulator is sodium hydroxide or sodium hydroxide and hydrochloric acid, which is used to adjust the pH value of the gel to 5.0±0.

2.

8. A method for preparing an adapalene gel as claimed in any one of claims 3 to 7, characterized in that: The method comprises dispersing carbomer homopolymer type C in a uniform dispersion of propylene glycol, butylene glycol and glycerin under stirring, and then hydrating with purified water under stirring.

9. The method for preparing adapalene gel according to claim 8, characterized in that: The following steps are involved: (a) Water phase: Add purified water to the main mixing container, add the formulated amount of disodium ethylenediaminetetraacetate and mix; (b) Preservative phase: Add the formulated amounts of propylene glycol, butylene glycol and glycerin to a stainless steel container, add the formulated amount of methyl paraben and mix until completely dissolved, heat as needed and cool to room temperature, add the formulated amount of glabridin, stir and mix, heat as needed and cool to room temperature; (c) Gel Phase: Add the formulated amount of Carbomer Homopolymer Type C to the preservative phase under stirring, continue stirring until a uniform dispersion is formed, transfer the dispersion to the main mixing vessel containing the water phase and mix under stirring, and hydrate under stirring for 40 minutes. (d) Drug phase: In another stainless steel container, add purified water and add the formulated amount of poloxamer under stirring until a transparent solution is formed, add the formulated amount of adapalene and disperse under stirring until uniform; (e) Adding drug phase: Transfer the drug phase dispersion into the gel phase and mix under stirring. (f) adjusting the pH value: preparing a sodium hydroxide solution with purified water in another container and adding it to the mixture to adjust the pH value to within the range of 4.8-5.2; (g) If the pH value is within the specified range, add the remaining amount of purified water. If the pH value is lower or higher than the specified range, adjust the pH value to 5.0 ± 0.2 with hydrochloric acid or sodium hydroxide solution.

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