Benzoyl peroxide external composition containing non-volatile solvent

Abstract

The invention relates to a benzoyl peroxide external composition containing a non-volatile solvent, the formula of the benzoyl peroxide external composition comprises benzoyl peroxide and the non-volatile solvent, the non-volatile solvent is dicapryl carbonate, ethyoxyl diethylene glycol or polyethylene glycol, and the weight percentage of the non-volatile solvent in the formula is more than 30%. The weight percentage of benzoyl peroxide in the formula is 0.5%-5.0%, preferably 1%-2.5%, and the composition also comprises a combination of an antioxidant butylated hydroxytoluene, propyl gallate and tocopherol. The benzoyl peroxide composition has the advantages that the formula and the preparation method are reasonable in design, long-term stability of the benzoyl peroxide composition can be guaranteed, benzoyl peroxide in a solution can be prevented from being degraded by arranging a proper stabilizer in the formula, and the benzoyl peroxide composition has a good practical treatment effect.

Description

Technical Field

[0001] The present invention relates to a benzoyl peroxide external composition, specifically to a benzoyl peroxide external composition containing a non-volatile solvent. Background Art

[0002] Benzoyl peroxide [(C 6 H 5 CO) 2 O 2 ] is an organic compound belonging to the peroxide family, which consists of two benzyl rings coupled to a peroxide group. It is a colorless crystalline solid with a melting point between 104°C and 106°C and an explosive boiling point of 107°C. Benzoyl peroxide is one of the most widely used compounds for the treatment of acne due to its significant antimicrobial activity, mild keratolytic and duct-opening properties, and low cost. The effects of benzoyl peroxide include topical antimicrobial properties, exfoliation of the epidermal stratum corneum, and removal of thick sebum and other debris that clog the pores of the hair follicles.

[0003] At room temperature, benzoyl peroxide is a white crystalline powder that appears as an aggregate of tetragonal crystals under a microscope. Although benzoyl peroxide is a stable solid at room temperature, it decomposes after being dissolved or at temperatures exceeding 66°C. Decomposition when heated may cause an explosion. Because the pure product is oxidizing and pyrophoric, it is sold in mixtures of varying concentrations containing inert fillers. Pharmaceutical grade benzoyl peroxide contains 25% water (by weight).

[0004] Benzoyl peroxide, especially in suspension, has the potential to irritate the skin when used in concentrations suitable for effective acne treatment. In addition, the hardness of benzoyl peroxide can be abrasive to the skin, thereby increasing skin irritation. The solubility of benzoyl peroxide in aqueous media is extremely low, which has prompted researchers to develop dissolving formulations that deliver high concentrations of the oxidant at the point of action (i.e., the clogged follicle or blemish).

[0005] In addition, benzoyl peroxide forms very hard agglomerates that are difficult to break up during formulation, requiring lengthy homogenization, grinding, and related handling. However, these steps are unable to reduce the agglomeration of particles in the finished product.

[0006] Benzoyl peroxide forms a clear solution, but requires high concentrations of volatile organic solvents (such as acetone, ethanol, and isopropyl alcohol) to achieve this. The resulting solution must be kept refrigerated. After the solution is applied to the epidermis, evaporation of the solvent may cause the drug to crystallize on the skin surface.

[0007] Although there are few disclosed benzoyl peroxide preparation compositions, their carriers generally include isosorbide and water, and contain surfactants, hydroxy acids and polyvinylpyrrolidone carboxylates to improve solubility and reduce irritation. Currently known benzoyl peroxide topical preparations do not have the best combination of effective anti-acne properties, non-irritating ingredients and formulation stability. They can neither effectively treat acne nor remain stable for a long time under high temperature. There is still a need for a stable benzoyl peroxide dissolving preparation to improve the treatment effect and reduce skin irritation.

[0008] Compared to existing formulations of suspended ground or micronized materials, a formulated composition of benzoyl peroxide in dissolved form has significant advantages in that it is more effective as an oxidizing agent and is less irritating when applied to the skin because it does not produce crystalline precipitation. However, there are serious obstacles to dissolving benzoyl peroxide and maintaining a stable solution for an extended period of time. First, the solubility of benzoyl peroxide in commonly used solvents is relatively low. In addition, dissolving benzoyl peroxide in a suitable solvent accelerates the irreversible degradation of benzoyl peroxide. In addition, water-soluble solvents will produce a large amount of precipitation when increasing the concentration of water. When the water content increases from 0% to 25%, the solubility decreases by 2-4 orders of magnitude. In addition, the evaporation of volatile solvents may also trigger the precipitation and crystallization of peroxide, resulting in local skin irritation due to contact with the precipitated peroxide crystals. Summary of the invention

[0009] The present invention provides a benzoyl peroxide external-use composition containing a non-volatile solvent, the purpose of which is to overcome the above-mentioned shortcomings of the prior art and stabilize benzoyl peroxide in a solubilized form.

[0010] The technical solution of the present invention is a benzoyl peroxide external-use composition containing a non-volatile solvent, wherein the formula of the composition comprises benzoyl peroxide and the non-volatile solvent.

[0011] Preferably, the non-volatile solvent is dicaprylyl carbonate, ethoxydiglycol or polyethylene glycol.

[0012] Preferably, the weight percentage of the non-volatile solvent in the formulation exceeds 30%.

[0013] Preferably, the weight percentage of the benzoyl peroxide in the formula is 0.5%-5.0%.

[0014] Preferably, the weight percentage of the benzoyl peroxide in the formula is 1%-2.5%.

[0015] Preferably, the formulation also includes a combination of the antioxidants butylated hydroxytoluene, propyl gallate and tocopherol.

[0016] Preferably, the formulation further comprises disodium edetate, docusate sodium, poloxamer, carbomer, glycerin, propylene glycol and colloidal silicon dioxide.

[0017] Preferably, the formulation comprises, by weight percentage, 0.01%-0.2% butylated hydroxytoluene, 0.01-0.2% tocopherol, 0.01%-0.2% propyl gallate, 0.01-0.2% disodium edetate, 0.01-0.1% docusate sodium, 0.1-0.5% poloxamer, 0.5-1.2% carbomer, 2-6% glycerol, 2-6% propylene glycol, and 0.005-0.1% colloidal silicon dioxide.

[0018] A method for preparing a benzoyl peroxide external-use composition containing a non-volatile solvent comprises the following steps:

[0019] [1] Aqueous phase: Add purified water, disodium edetate, propylene glycol and glycerin to a container and stir to mix for 10 minutes. Add and dissolve poloxamer while stirring. Add sodium polyformate and dissolve while stirring. Add acrylate copolymer and mix while stirring. Add colloidal silica and stir to mix.

[0020] [2] Polymer phase: Add carbomer under stirring and continue stirring for 40±20 minutes to allow the polymer to be fully hydrated. Homogenize for 5-10 minutes and cool to a temperature of 10-20°C.

[0021] [3] Drug phase: Add a non-volatile solvent to a container. Add and dissolve butylated hydroxytoluene, propyl gallate and tocopherol in sequence while stirring. Add benzoyl peroxide and homogenize at 20±5℃. Check the clarity of the solution and re-homogenize as needed.

[0022] [4] Add drug phase: Add drug phase to polymer phase, rinse drug phase container with propylene glycol, transfer rinsed solution to slurry, homogenize at 20±5℃ for 30±10 minutes,

[0023] [5] pH adjustment and mixing: Adjust the pH to 5.0 using sodium hydroxide solution under stirring, homogenize at an appropriate speed for 30 minutes at a temperature of 20±5°C, and mix under stirring for 30±10 minutes.

[0024] The invention has the advantages that the formula and the preparation method are reasonably designed, the long-term stability of the benzoyl peroxide composition can be ensured, and the degradation of benzoyl peroxide in the solution can be prevented by setting a suitable stabilizer in the formula, and the invention has good therapeutic and practical effects. DETAILED DESCRIPTION

[0025] The present invention is further described in detail below with reference to examples and specific implementation modes.

[0026] The invention discloses a benzoyl peroxide external composition containing a non-volatile solvent, wherein the suitable dosage form ensures that the dissolved concentration of benzoyl peroxide is high enough to provide effective therapeutic effect in treating acne while minimizing skin irritation.

[0027] As an embodiment, benzoyl peroxide is dissolved in a non-volatile solvent, and the weight percentage of benzoyl peroxide in the formula is 0.5%-20% to prevent degradation of the dissolved form, preferably 0.5%-10%, more preferably 0.5%-5.0%, and most preferably 1%-2.5%.

[0028] As a further example, the formulation also includes pharmaceutically acceptable concentrations of solvents, antioxidants, chelating agents, surfactants, gelling agents, humectants, and the like.

[0029] As a further embodiment, the solvent is selected from dicaprylyl carbonate, ethoxydiglycol and polyethylene glycol 400; the antioxidant is selected from butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, propyl gallate; the chelating agent is selected from disodium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, calcium disodium ethylenediaminetetraacetate, diethylenetriaminepentaacetic acid and sodium glutamate diacetate; the surfactant is selected from sodium docusate, poloxamer, polysorbate and span; the gelling agent is selected from carbomer, cellulose derivatives, acrylate polymers and copolymers; the humectant is selected from glycerin, propylene glycol and butylene glycol.

[0030] As a further example, the formulation includes dicaprylyl carbonate, butylated hydroxytoluene, tocopherol, propyl gallate, disodium edetate, docusate sodium, poloxamer, carbomer, glycerin, propylene glycol, and colloidal silicon dioxide.

[0031] As a further example, the formulation includes, by weight percentage, 0.5%-5% benzoyl peroxide, more than 30% dicaprylyl carbonate, 0.01%-0.2% butylated hydroxytoluene, 0.01-0.2% tocopherol, 0.01%-0.2% propyl gallate, 0.01-0.2% disodium edetate, 0.01-0.1% docusate sodium, 0.1-0.5% poloxamer, 0.5-1.2% carbomer, 2-6% glycerin, 2-6% propylene glycol, and 0.005-0.1% colloidal silicon dioxide.

[0032] As a further example, the formulation includes, by weight percentage, 1%-2% benzoyl peroxide, 50% dicaprylyl carbonate, 0.1% tocopherol, 0.1% propyl gallate, 0.1% disodium edetate, 0.1% docusate sodium, 0.2% poloxamer, 0.8% carbomer, 4% glycerol, 4% propylene glycol and 0.02% colloidal silicon dioxide.

[0033] As another embodiment, the formula includes, by weight percentage, 1%-2% benzoyl peroxide, 50% ethoxydiglycol, 0.1% butylated hydroxytoluene, 0.1% propyl gallate, 0.1% disodium edetate, 0.05% docusate sodium, 0.2% polyoxyethylene ether, 0.8% carbomer, 4% glycerol, 4% propylene glycol, and 0.02% colloidal silicon dioxide.

[0034] As another example, the formula includes, by weight percentage, 1%-2% benzoyl peroxide, 50% polyethylene glycol 400, 0.1% tocopherol, 0.1% propyl gallate, 0.1% disodium edetate, 0.05% docusate sodium, 0.2% polyhydroxylamine, 0.8% carbomer, 4% glycerol, 4% propylene glycol and 0.02% colloidal silicon dioxide.

[0035] A method for preparing a benzoyl peroxide external composition containing a non-volatile solvent comprises the steps of preparing a water phase, preparing a polymer phase, preparing a benzoyl peroxide drug phase, adding the drug phase, adjusting the pH value and mixing.

[0036] As a further example, all unit processes are carried out under stirring, homogenizing or a combination of both conditions.

[0037] As a further example, drug phase preparation is the most critical step in the formulation process, followed by addition and mixing stages. Drug phase preparation can be performed under stirring, homogenization, or a combination of both, more preferably under stirring, and most preferably homogenization.

[0038] In another aspect of the invention, the preparation of the drug phase involves dissolution of disodium EDTA with stirring, homogenization, or a combination of both.

[0039] Example 1: Commercially available benzoyl peroxide topical composition

[0040]

[0041]

[0042] Preparation steps:

[0043] [1] Aqueous Phase: Add purified water, disodium EDTA, propylene glycol, and glycerin to a container of suitable size and stir for 10 minutes. Add and dissolve Poloxamer 182 while stirring. Add acrylate copolymer and mix while stirring. Add colloidal silica and stir to mix.

[0044] [2] Polymer phase: Add Carbomer 980 while stirring and continue stirring for 40±20 minutes to allow the polymer to fully hydrate. Homogenize for 5-10 minutes and cool to a temperature of 10-20°C.

[0045] [3] Drug phase: Dissolve docusate sodium in 15% purified water and dissolve under stirring. Cool the phase to 10-20°C. Add benzoyl peroxide and homogenize at high speed at 10-20°C for 90±30 minutes. Check the fineness of the benzoyl peroxide and re-homogenize if necessary.

[0046] [4] Add drug phase: Add drug phase to polymer phase. Rinse drug phase container with purified water and rinse dispersion until lumps form. Homogenize at 10-20°C for 30±10 minutes.

[0047] [5] pH adjustment and mixing: Adjust the pH to 5.0 using 10% sodium hydroxide solution under stirring. After pH adjustment, mix under stirring for 30 ± 10 minutes.

[0048] Example 2: Benzoyl peroxide topical composition 1

[0049]

[0050]

[0051] Preparation steps:

[0052] [1] Aqueous Phase: Add purified water, disodium EDTA, 2% propylene glycol, and glycerin to a container of suitable size and stir for 10 minutes. Add and dissolve Poloxamer 182 while stirring. Add sodium polyformate and dissolve while stirring. Add acrylate copolymer and mix while stirring. Add colloidal silica and stir to mix.

[0053] [2] Polymer phase: Add Carbomer 980 while stirring and continue stirring for 40±20 minutes to allow the polymer to fully hydrate. Homogenize for 5-10 minutes and cool to a temperature of 10-20°C.

[0054] [3] Drug phase: Add dicaprylyl carbonate to a container of appropriate size. Add and dissolve butylated hydroxytoluene, propyl gallate and tocopherol in sequence while stirring. Add benzoyl peroxide and homogenize at an appropriate speed and temperature (20±5℃). Check the clarity of the solution and re-homogenize if necessary.

[0055] [4] Add drug phase: Add drug phase to polymer phase. Rinse drug phase container with 2% propylene glycol and transfer rinsed solution to slurry. Homogenize at 20±5℃ for 30±10 minutes.

[0056] [5] pH adjustment and mixing: Adjust the pH of the formulation to 5.0 using 10% sodium hydroxide solution under stirring. Homogenize at an appropriate speed for 30 minutes at a temperature of 20±5°C. Mix under stirring for 30±10 minutes.

[0057] Example 3: Benzoyl peroxide topical composition 2

[0058] The difference from Example 2 is that dicaprylyl carbonate is replaced by ethoxydiglycol, and the weight percentage of benzoyl peroxide is changed to 2%.

[0059] Example 4: Benzoyl peroxide topical composition 3

[0060] The difference from Example 2 is that dicaprylyl carbonate is replaced by polyethylene glycol 400.

[0061] Example 5: Stability Study

[0062] The efficacy of benzoyl peroxide and benzoyl peroxide degradation products was analyzed. The results are shown in the following table. Although benzoyl peroxide is in solution form, the results are comparable to those of the commercial product in Example 1, and impurities are also controlled.

[0063]

[0064] ACC refers to accelerated storage conditions.

[0065] Example 6: Skin penetration study

[0066] 300 mg of the product of Example 1-3 was accurately weighed and applied to the pig skin of a single donor and used immediately after separation. The skin thickness measured with a cassette micrometer was 0.501 to 0.661 mm. The subcutaneous part of the skin contains the stratum corneum and epidermis and a small part of the dermis.

[0067] The percutaneous absorption was evaluated using the skin mounted in a Franz diffusion cell maintained at 32 ± 0.5 °C using a circulating water bath.

[0068] The receptor medium used fresh receptor solution (phosphate buffered saline [PBS], pH 7.4, containing 0.1% sodium azide and 4% bovine serum albumin).

[0069] Samples at the receptor stage were collected in pre-weighed scintillation vials and weighed again at the end of the study.

[0070] After 24 hours of contact, the preparation remaining on the stratum corneum was collected and the stratum corneum was stripped with tape.Topically applied benzoyl peroxide is rapidly metabolized by the skin to benzoic acid.

[0071] When evaluating the skin penetration of benzoyl peroxide, benzoic acid levels were used rather than benzoyl peroxide levels.

[0072] Epidermal, dermal, and receptor phase samples were labeled and frozen before analysis of benzoic acid content using liquid chromatography-tandem mass spectrometry (LC / MS / MS).

[0073] formula About the stratum corneum epidermis Dermis Receptor medium Example 1 958.1±10.4μg 765.6±56.7μg 450.3±23.4μg 259.5±20.4μg Example 2 7.7±4.5μg 754.9±10.6μg 224.5±8.5μg 9.4±2.5μg Example 3 567.4±8.5μg 798.2±34.5μg 355.3±28.4μg 212.3±13.8μg

[0074] As shown in the table above, all formulations have good skin permeability, while the formulations of Examples 1 and 3 enter the receptor fluid. In contrast, the amount of penetration of the sample of Example 2 is negligible. The amount of Examples 1 and 3 entering the receptor fluid may have side effects on the whole body, while Example 2 will not have any side effects on the whole body because the amount entering the receptor fluid is negligible.

[0075] The retention of benzoyl peroxide on the skin was also higher for Examples 1 and 3, indicating that the penetration was due to the higher concentration of benzoyl peroxide. Example 2 had a lower concentration of benzoyl peroxide, but its concentration levels in the epidermis and dermis were similar to those of the 2% and 2.5% formulations.

[0076] Therefore, Example 2 is more preferable because its level in the skin is comparable to that of Example 1, it does not enter the receptor fluid, and has the lowest retention rate on the skin.

[0077] Example 7: Animal toxicity studies

[0078] The compositions of Example 2 and Example 3 were topically injected with semi-closed doses twice a day for 12 consecutive weeks into the Gottingen miniature pigs (4 in each group). The results are shown in the following table. All groups (including the drug control group) developed erythema, edema, and skin desquamation. After 12 weeks of the study, no erythema, edema, or desquamation was observed.

[0079]

[0080] 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. A benzoyl peroxide external-use composition containing a non-volatile solvent, characterized in that: The formula includes benzoyl peroxide and non-volatile solvents.

2. A benzoyl peroxide external-use composition containing a non-volatile solvent as claimed in claim 1, characterized in that: The non-volatile solvent is dicaprylyl carbonate, ethoxydiglycol or polyethylene glycol.

3. A benzoyl peroxide external-use composition containing a non-volatile solvent as claimed in claim 2, characterized in that: The weight percentage of the non-volatile solvent in the formulation is more than 30%.

4. A benzoyl peroxide external-use composition containing a non-volatile solvent as claimed in claim 3, characterized in that: The weight percentage of the benzoyl peroxide in the formula is 0.5%-5.0%.

5. A benzoyl peroxide external-use composition containing a non-volatile solvent as claimed in claim 4, characterized in that: The weight percentage of the benzoyl peroxide in the formula is 1%-2.5%.

6. A benzoyl peroxide external-use composition containing a non-volatile solvent as claimed in claim 5, characterized in that: The formula also includes a combination of the antioxidants butylated hydroxytoluene, propyl gallate, and tocopherol.

7. A benzoyl peroxide external-use composition containing a non-volatile solvent as claimed in claim 6, characterized in that: The formula also includes EDTA disodium, docusate sodium, poloxamer, carbomer, glycerin, propylene glycol, and colloidal silicon dioxide.

8. A benzoyl peroxide external-use composition containing a non-volatile solvent as claimed in claim 7, characterized in that: In terms of weight percentage, the formula includes 0.01%-0.2% butylated hydroxytoluene, 0.01-0.2% tocopherol, 0.01%-0.2% propyl gallate, 0.01-0.2% disodium edetate, 0.01-0.1% docusate sodium, 0.1-0.5% poloxamer, 0.5-1.2% carbomer, 2-6% glycerol, 2-6% propylene glycol, and 0.005-0.1% colloidal silicon dioxide.

9. A method for preparing a benzoyl peroxide external-use composition containing a non-volatile solvent as claimed in claim 7 or 8, characterized in that: The following steps are involved: [1] Aqueous phase: Add purified water, disodium edetate, propylene glycol and glycerin to a container and stir to mix for 10 minutes. Add and dissolve poloxamer while stirring. Add sodium polyformate and dissolve while stirring. Add acrylate copolymer and mix while stirring. Add colloidal silica and stir to mix. [2] Polymer phase: Add carbomer under stirring and continue stirring for 40±20 minutes to allow the polymer to be fully hydrated. Homogenize for 5-10 minutes and cool to a temperature of 10-20°C. [3] Drug phase: Add a non-volatile solvent to a container. Add and dissolve butylated hydroxytoluene, propyl gallate and tocopherol in sequence while stirring. Add benzoyl peroxide and homogenize at 20±5℃. Check the clarity of the solution and re-homogenize as needed. [4] Add drug phase: Add drug phase to polymer phase, rinse drug phase container with propylene glycol, transfer rinsed solution to slurry, homogenize at 20±5℃ for 30±10 minutes, [5] pH adjustment and mixing: Adjust the pH to 5.0 using sodium hydroxide solution under stirring, homogenize at an appropriate speed for 30 minutes at a temperature of 20±5°C, and mix under stirring for 30±10 minutes.

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