A tretinoin and benzoyl peroxide composition and methods of making and using the same

Abstract

The present invention provides a tretinoin and benzoyl peroxide composition, its preparation method and use, which comprises component (i) benzoyl peroxide; component (ii) tretinoin; and (iii) a lipid material. The composition has excellent stability, and the preparation process is simple and easy to scale up production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of composition preparation, and particularly relates to a composition of tretinoin and benzoyl peroxide as well as a preparation method and use thereof. BACKGROUND

[0002] Acne is a chronic inflammatory skin disease of the pilosebaceous unit mainly involving the face in adolescence. The pathogenesis of acne has not been fully elucidated. It is related to the excessive secretion of lipids induced by hormones under genetic background, abnormal keratinization of pilosebaceous duct, proliferation of microorganisms such as Propionibacterium acnes in the pilosebaceous unit, and inflammation and immune response.

[0003] Topical retinoids can improve the keratinization of pilosebaceous duct, dissolve microcomedones and comedones, have anti-inflammatory effect, prevent and improve post-inflammatory hyperpigmentation and acne scars, etc. In addition, topical retinoids can also increase skin permeability and increase the efficacy of topical antibacterial and anti-inflammatory drugs in combination therapy. Topical retinoids can be used as a single first-line drug for mild acne, a combination drug for moderate acne, and the first choice for maintenance therapy of acne. Commonly used retinoids include tretinoin and isotretinoin.

[0004] Benzoyl peroxide can slowly release nascent oxygen and benzoic acid, has the effect of killing Propionibacterium acnes, anti-inflammatory and mild comedolytic effect, and no drug resistance to Propionibacterium acnes has been found so far. It can be used as the first choice of topical antibacterial drugs for inflammatory acne, and can be used alone or in combination with topical retinoids or topical antibiotics. The drug has different concentrations of 2.5% to 10% and different dosage forms such as lotion, emulsion or gel.

[0005] Tretinoin and benzoyl peroxide show good effects in the treatment of acne, but tretinoin and benzoyl peroxide have a compatibility contraindication. Tretinoin is a reducing agent, while benzoyl peroxide is an oxidizing agent, which will cause redox reaction and degradation of the two drugs in the same prescription.

[0006] Existing literature has reported formulations of retinoic acid and benzoyl peroxide. For example, patent application CN101754677B discloses a method for coating solid water-insoluble particulate matter with metal oxides. The solid water-insoluble particles include retinoic acid, benzoyl peroxide, and other APIs. The method includes (1) grinding: high-speed grinding of APIs and cationic surfactants to form a suspension, with the cationic surfactant covering the API surface and the particle size controlled to be tens of nanometers; (2) coating: adding sodium silicate solution, stirring at 500 rpm, adjusting the pH to allow silicate anions to combine with cations, adsorb onto the drug surface, and polymerize to form a silica layer; (3) repeated coating: repeating the coating process, adding cationic surfactants and silicates in sequence to form a silica shell, 5-100 times; (4) aging: stirring at room temperature and under certain pH conditions for 24-96 hours. Since the combination of silicate anions and cations is a passive adsorption process, the silica shells formed by repeated coating have poor reproducibility. In addition, the aging process of 24-96 hours is extremely time-consuming. Formulations produced using this method, whether through repeated coating or prolonged aging processes, are difficult to commercialize due to the challenges of quality control, high equipment requirements, and high costs.

[0007] Therefore, there is a need to develop a stable, safe, non-irritating composition of retinoic acid and benzoyl peroxide that is suitable for industrial production. Summary of the Invention

[0008] To address the problems existing in the prior art, in a first aspect, the present invention provides a composition comprising component (i) benzoyl peroxide; component (ii) retinoic acid; and (iii) a lipid material.

[0009] According to an embodiment of the present invention, the lipid material is selected from one, two or more of the following: carnauba wax, behenate glycerol, cholesterol, β-sitosterol, palmitate glycerol, cholesterol stearate, and castor oil wax.

[0010] According to an embodiment of the present invention, the composition further comprises a gelling agent. The gelling agent is selected from one, two, or more of HPMC, carbomer, cellulose derivatives such as HPMC, MC, CMC-Na, and chitosan.

[0011] According to an embodiment of the present invention, the composition further comprises an antioxidant selected from one, two or more of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), and ascorbyl palmitate.

[0012] According to an embodiment of the invention, the component (i) accounts for about 2.0% to about 10.0% (w / w) of the total composition, for example 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, preferably, the component (i) accounts for about 2.0% to about 3.0% (w / w) of the total composition.

[0013] According to an embodiment of the invention, component (ii) accounts for about 0.01% to about 0.30% (w / w) of the total composition, for example 0.01%, 0.025%, 0.05%, 0.1%, 0.15%, 0.20% (w / w), preferably, component (ii) accounts for about 0.025% to about 0.20% (w / w) of the total composition.

[0014] According to embodiments of the present invention, the gelling agent accounts for about 5% to 30% (w / w) of the total composition, for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, preferably, the gelling agent accounts for about 15% to about 25% (w / w) of the total composition.

[0015] According to an embodiment of the invention, the antioxidant accounts for about 0.01% to about 0.50% (w / w) of the total composition, for example, 0.01%, 0.02%, 0.025%, 0.05%, 0.1%, 0.15%, 0.20% (w / w). Preferably, the component (i) accounts for about 0.02% to about 0.30% (w / w) of the total composition.

[0016] According to embodiments of the present invention, components (i) and (ii) are dispersed in the lipid material. In some embodiments, components (i) and (ii) are each dispersed in the lipid material. In some embodiments, the mass ratio of the dispersed component (i) to the lipid material is 0.5-3:1, for example, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.5:1, 3:1; preferably 0.9-1.1:1. In some embodiments, the mass ratio of the lipid material of the dispersing component (ii) to component (ii) is 6-15:1, for example 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1, 15:1; preferably 7-9:1.

[0017] According to an embodiment of the present invention, the preparation steps of dispersing component (i) in the lipid material are as follows: mixing BPO and the lipid material, heating and melting while stirring until homogeneous, and cooling to room temperature. In some embodiments, the heating and melting temperature is 60-100°C, preferably 75-85°C; in some embodiments, after cooling to room temperature, the resulting material is ground and passed through a 40-100 mesh sieve, preferably a 60 mesh sieve.

[0018] According to an embodiment of the present invention, the preparation steps of dispersing component (ii) in the lipid material are as follows: mixing RA and the lipid material, heating to melt and stirring until homogeneous, and cooling to room temperature. In some embodiments, the heating and melting temperature is 70-110°C, preferably 85-95°C; in some embodiments, after cooling to room temperature, the resulting material is ground and passed through a 60-mesh sieve; in some embodiments, an antioxidant is further added after mixing RA and the lipid material.

[0019] In a second aspect, the present invention provides a method for preparing the composition, comprising the following steps:

[0020] (a) Disperse components (i) and (ii) in the lipid material, respectively;

[0021] (b) Dissolve the gelling agent in water, heat it, and add the component (i) and the component (ii) dispersed by the lipid material.

[0022] According to an embodiment of the present invention, the preparation steps of dispersing the components (i) and (ii) in the lipid material are as described above.

[0023] According to an embodiment of the present invention, the gelling agent is dissolved in water at a mass percentage of 15-25%, for example 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, preferably 18-22%.

[0024] According to an embodiment of the present invention, in step (b), the heating temperature is 60-100°C, preferably 75-85°C.

[0025] Thirdly, the present invention provides the use of the composition in the preparation of medicaments for the prevention / alleviation / treatment of skin diseases. These skin diseases include acne, psoriasis, ichthyosis, lichen planus, pityriasis rubra pilaris, keratosis pilaris, squamous cell carcinoma, and melanoma, among others.

[0026] Beneficial effects

[0027] This invention provides a compositional formulation of retinoic acid and benzoyl peroxide, which has excellent stability and a simple formulation process that is easy to scale up for production. Detailed Implementation

[0028] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0029] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0030] Abbreviations for materials and reagents

[0031] RA: Retinoic acid

[0032] BPO: Benzoyl peroxide

[0033] BHT: Butylated hydroxytoluene

[0034] CW: Carnauba Wax, Brazilian Carnauba Wax

[0035] GB: Glyceryl Behenate

[0036] GT: Glycerol Tristearate (stearyl)

[0037] GM: Glyceryl Monostearate

[0038] Unless otherwise stated, "%" in the following examples refers to mass percentage.

[0039] Example 1: Preparation of RA / CW + BPO / CW Composition

[0040] 1. Preparation of RA and BPO intermediates using carnauba wax as a lipid material

[0041] I. Take appropriate amounts of RA and BPO, grind them appropriately to make the drugs as fine as possible, and pass them through a 100-mesh sieve.

[0042] II. Take 0.1g of the above RA, weigh the raw materials and excipients in a ratio of RA:carnauba wax:butylated hydroxytoluene = 1:8:1 and put them into a 50ml EP tube. Mix them appropriately, heat at 90℃ to melt and stir evenly, cool to room temperature, grind and pass through a 60-mesh sieve to obtain 0.1g of coated RA intermediate (RA / CW), in which the theoretical content of RA is 10%.

[0043] III. Take 0.4285g of the above BPO (BPO raw material content is labeled as 70%), weigh the raw materials and auxiliary materials with BPO:carnauba wax = 1:1 and put them into a 50ml EP tube, mix them appropriately, heat at 80℃ to melt and stir evenly, cool to room temperature, grind and pass through a 60-mesh sieve to obtain 0.857g of coated BPO intermediate (BPO / CW), of which the theoretical content of BPO is 1*0.7 / (1+1)=35%.

[0044] 2. Preparation of gel composition

[0045] Weigh 20g HPMC + 80g water, heat to 80℃, and you will get 100g of 20% HPMC blank gel.

[0046] 3. Preparation of RA / BPO gel

[0047] Take RA raw material (or RA / CW) and BPO raw material (or BPO / CW) according to the formula in Table A-1 below, add the formula amount of blank gel, and stir evenly to obtain 10g of gel. In this gel composition, the theoretical contents of RA and BPO are 0.1% and 3.0%, respectively.

[0048] Table A-1

[0049]

[0050] Example 2 Preparation of RA / GB+BPO / GB composition

[0051] 1. Preparation of RA and BPO intermediates using behenyl glycerol as lipid material

[0052] I. Take appropriate amounts of RA and BPO, grind them appropriately to make the drugs as fine as possible, and pass them through a 100-mesh sieve.

[0053] II. Take 0.1g of the above RA, weigh the raw materials and excipients with RA: glyceryl behenate: butylated hydroxytoluene = 1:8:1 and put them into a 50ml EP tube. Mix them appropriately, heat at 90℃ to melt and stir evenly, cool to room temperature, grind and pass through a 60-mesh sieve to obtain 0.1g of coated RA intermediate (RA / GB), of which the theoretical content of RA is 10%.

[0054] III. Take 0.4285g of the above BPO (BPO raw material content is 70%), weigh the raw materials and excipients with BPO: glyceryl behenate = 1:1 and put them into a 50ml EP tube, mix them appropriately, heat to 80℃ to melt and stir evenly, cool to room temperature, grind and pass through a 60-mesh sieve to obtain 0.857g of coated BPO intermediate (BPO / GB), of which the theoretical content of BPO is 1*0.7 / (1+1)=35%.

[0055] 2. Preparation of gel composition

[0056] Weigh 20g HPMC + 80g water, heat to 80℃, and you will get 100g of 20% HPMC blank gel.

[0057] 3. Preparation of RA / BPO gel

[0058] Take RA raw material (or RA / GB) and BPO raw material (or BPO / GB) according to the prescription in Table B-1 below, add the prescribed amount of blank gel, and stir evenly to obtain 10g of gel. In this gel composition, the theoretical contents of RA and BPO are 0.1% and 3.0%, respectively.

[0059] Table B-1

[0060]

[0061] Example 3: Stability testing of RA and BPO content

[0062] 1. Sample preparation methods

[0063] This operation requires complete protection from light. Take 100mg of gel sample, add 20mg of sodium sulfite, then add 1ml of water, vortex for 10min to break the gel and react to remove BPO, then add 2ml of isopropanol and sonicate for 20min to extract, add 4ml of methanol, sonicate for 4min, centrifuge at 13000rpm to precipitate, and then take the supernatant for RA detection.

[0064] The extraction of BPO was performed without the addition of sodium sulfite, and the remaining procedures were the same as before. The BPO was then injected for detection.

[0065] 2. Retinoic acid (RA) detection method

[0066] The HPLC detection method for RA was based on the Chinese Pharmacopoeia (2020 edition): Column: C18 column (150 mm × 4.6 mm, 5 μm); Mobile phase: methanol-2% glacial acetic acid solution (81:19); Column temperature: 30℃; Detection wavelength: 350 nm; Flow rate: 1 mL / min; Injection volume: 20 μL. Two replicates of the same sample were prepared, and the average value was taken.

[0067] 3. Benzoyl peroxide (BPO) detection method

[0068] The HPLC detection method for BPO was as follows: Column: C18 column (150 mm × 4.6 mm, 5 μm); Mobile phase: acetonitrile-water (1:1); Column temperature: 30℃; Detection wavelength: 254 nm; Flow rate: 1 mL / min; Injection volume: 10 μL. Two replicates of the same sample were prepared, and the average value was taken.

[0069] 4. Test on the coating effect of carnauba wax: The RA / BPO gel prepared according to the prescription in Table A-1 of Example 1 was used, and the content of its active ingredients is shown in Table A-2 below.

[0070] Table A-2 Mass of active ingredients in the formulation (g)

[0071]

[0072] Note: The superscript 'a' indicates the quality of the theoretical calculation.

[0073] The stability results are shown in Tables A-3 and A-4 below, where the ratio of the change in active ingredient content with the detection time point is expressed as w / w%.

[0074] Table A-3. Stability at room temperature

[0075]

[0076] Table A-4. Accelerated stability at 40℃

[0077]

[0078] 5. Coating effect test of behenicol glyceride

[0079] The RA / BPO gel prepared according to the formulation in Table B-1 of Example 2 has the active ingredient content shown in Table B-2 below.

[0080] Table B-2

[0081]

[0082] Note: The superscript 'a' indicates the quality of the theoretical calculation.

[0083] The stability results are shown in B-3 and B-4 below:

[0084] Table B-3. Stability at room temperature

[0085]

[0086] Table B-4. Accelerated stability at 40℃

[0087]

[0088] Example 4. Determination of gel properties

[0089] For the RA-BPO compound composition coated with carnauba wax and glyceryl behenate, appearance, color, viscosity, uniformity, and coating performance were measured, and the results are shown below:

[0090]

[0091] Comparative Example 1

[0092] Referring to Example 1, only the lipid material was replaced with glyceryl tristearate (stearin) to prepare RA intermediates (RA / GT) coated with glyceryl tristearate as the lipid material and BPO intermediates (BPO / GT) coated with glyceryl tristearate as the lipid material. Following the RA / BPO gel preparation method of Example 1, four groups of samples were prepared: Rx1-H, Rx2-H, Rx3-H, and a control group. The active ingredient contents are shown in Table C-1 below.

[0093] Table C-1

[0094]

[0095] Note: The superscript 'a' indicates the quality of the theoretical calculation.

[0096] The stability of the RA and BPO content in the sample was tested according to Example 3, and the results are shown in Tables C-2 and C-3 below:

[0097] Table C-2. Stability at room temperature

[0098]

[0099]

[0100] Table C-3. Accelerated stability at 40℃

[0101]

[0102] Conclusion: After the active ingredient was coated with stearin, the composition showed rapid degradation of RA in the accelerated stability test at 40℃, resulting in significant changes in appearance and color, with the color changing from the initial pale yellow to nearly white.

[0103] Comparative Example 2

[0104] Referring to Example 1, only the lipid material was replaced with glyceryl monostearate to prepare RA intermediates (RA / GM) coated with glyceryl monostearate as the lipid material and BPO intermediates (BPO / GM) coated with glyceryl monostearate as the lipid material. Following the gel composition preparation method of Example 1, four groups of samples were prepared: Rx1-M, Rx2-M, Rx3-M, and a control group. The active ingredient contents are shown in Table D-1 below.

[0105] Table D-1

[0106]

[0107] Note: The superscript 'a' indicates the quality of the theoretical calculation.

[0108] The stability of the RA and BPO content in the sample was tested according to Example 3, and the results are shown in Tables D-2 and D-3 below:

[0109] Table D-2 Stability at room temperature

[0110]

[0111] Table D-3. Accelerated stability at 40℃

[0112]

[0113] Conclusion: After the active ingredient was coated with glyceryl monostearate, the RA in the formulation rapidly degraded in the accelerated test at 40℃, and the color changed from the initial pale yellow to nearly white.

[0114] The exemplary embodiments of the present invention have been described above. However, the scope of protection of the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A composition, characterized in that, The composition comprises component (i) benzoyl peroxide; component (ii) retinoic acid; and (iii) a lipid material, wherein components (i) and (ii) are dispersed in the lipid material; The mass ratio of the lipid material to component (i) in the dispersion component (i) is 0.5-3:1; the mass ratio of the lipid material to component (ii) in the dispersion component (ii) is 6-15:1; the lipid material is selected from one or two of carnauba wax and behenicol glyceride; the composition contains a gelling agent selected from one, two or more of HPMC, carbomer, MC, CMC-Na, and chitosan; the preparation steps of dispersing component (i) in the lipid material are as follows: mixing BPO and lipid material, heating to melt and stirring evenly, and cooling to room temperature; the preparation steps of dispersing component (ii) in the lipid material are as follows: mixing RA and lipid material, heating to melt and stirring evenly, and cooling to room temperature.

2. The composition according to claim 1, characterized in that, The composition further comprises an antioxidant.

3. The composition according to claim 2, characterized in that, The antioxidant is selected from one, two or more of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tert-butylhydroquinone (TBHQ), and ascorbyl palmitate.

4. The composition according to claim 1, characterized in that, The component (i) accounts for 2.0% to 10.0% (w / w) of the total composition. The component (ii) comprises 0.01% to 0.30% (w / w) of the total composition. The gelling agent comprises 5% to 30% (w / w) of the total composition.

5. The composition according to claim 1, characterized in that, The component (i) accounts for 2.0% to 3.0% (w / w) of the total composition. The component (ii) comprises 0.025% to 0.20% (w / w) of the total composition. The gelling agent comprises 15% to 25% (w / w) of the total composition.

6. The composition according to claim 2, characterized in that, The antioxidant accounts for 0.01% to 0.50% (w / w) of the total composition.

7. The composition according to claim 2, characterized in that, The antioxidant accounts for 0.02% to 0.30% (w / w) of the total composition.

8. The composition according to claim 1, characterized in that, The mass ratio of lipid material to component (i) in the dispersion component (i) is 0.9-1.1:1; the mass ratio of lipid material to component (ii) in the dispersion component (ii) is 7-9:

1.

9. A method for preparing the composition according to any one of claims 1-8, characterized in that, Includes the following steps: (a) Disperse components (i) and (ii) in the lipid material, respectively; (b) Dissolve the gelling agent in water, heat it, and add the component (i) and the component (ii) dispersed by the lipid material.

10. Use of the composition according to any one of claims 1-8 in the preparation of a medicament for the prevention / alleviation / treatment of acne.

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