Pharmaceutical composition containing adapalene and benzoyl peroxide and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition, which is prepared from adapalene, benzoyl peroxide, a traditional Chinese medicine extract, an acrylamide and acryloyl dimethyl sodium taurate copolymer, a mixture of isohexadecane and polysorbate 80, docusate sodium, EDTA (Ethylene Diamine Tetraacetic Acid) disodium, glycerol, poloxamer 124, propylene glycol and water, the traditional Chinese medicine extract comprises moutan bark, salvia miltiorrhiza, radix rehmanniae recen, radix sophorae flavescentis, coptis chinensis, rheum officinale, scutellaria baicalensis, menthol and borneol. According to the pharmaceutical composition disclosed by the invention, the synergistic antibacterial and anti-keratosis curative effects of adapalene and benzoyl peroxide can be maintained, and meanwhile, the occurrence rate of local skin dryness, erythema, desquamation, burning heat sensation and contact dermatitis can be remarkably reduced.

Description

Technical Field

[0001] This application belongs to the pharmaceutical field and mainly relates to a modified pharmaceutical formulation that can significantly reduce the incidence of local skin dryness, erythema, desquamation, burning sensation and contact dermatitis when treating patients with severe acne. Background Technology

[0002] CN107072939A discloses a treatment regimen for patients with severe acne. This regimen uses a single formulation containing 0.3% by weight adapalene or a pharmaceutically acceptable salt thereof and 2.5% by weight benzoyl peroxide, applied topically to the patient's skin. By co-delivering the two active ingredients, the regimen achieves a treatment success rate of at least approximately 30% in the test population (based on the total weight of the formulation). The regimen is recommended for once or twice daily for 8–12 weeks.

[0003] CN101541320A discloses a compound gel formulation of adapalene and benzoyl peroxide, whose composition, by weight / total weight percentage, is: adapalene 0.10%, benzoyl peroxide 2.50%, acrylamide / sodium acryloyldimethyl taurate copolymer 4.00%, sodium docusate 0.05%, disodium EDTA 0.10%, glycerin 4.00%, poloxamer 124 0.20%, polyethylene glycol 4.00%, with the balance being purified water. This compound formulation shows significant efficacy in the treatment of acne, superior to the use of adapalene or benzoyl peroxide gel alone.

[0004] However, in clinical application, the local skin adverse reactions caused by this compound gel remain a major limiting factor affecting patient tolerance and treatment adherence. The core active ingredients of the existing formulation—adapalene (0.1%) and benzoyl peroxide (2.5%)—are the main sources of irritation. Adapalene, as a third-generation retinoid, exerts its therapeutic effect by promoting normal differentiation and renewal of keratinocytes, but in the early stages of treatment (especially 2–4 weeks), it often causes erythema, dry skin, desquamation, itching, and burning sensations; some patients may also experience a "temporary exacerbation of acne." Benzoyl peroxide, as a strong oxidant, effectively kills Propionibacterium acnes, but also directly causes significant skin dryness, desquamation, and burning sensations. While the combination of the two produces a synergistic effect, their irritation also has an additive effect, thus exacerbating the aforementioned skin reactions.

[0005] Furthermore, some excipients in the existing formulation may also adversely affect the skin barrier function. For example, the surfactant sodium docusate may interfere with the integrity of the sebum film; the emulsifier poloxamer 124 also poses a potential risk of causing mild irritation when applied topically. These excipients, in combination with the highly active active ingredient, may induce or aggravate contact dermatitis in some sensitive individuals, further limiting the widespread use of this compound formulation.

[0006] Therefore, there is an urgent clinical need for a modified formulation that, while maintaining the synergistic antibacterial and antikeratotic effects of adapalene and benzoyl peroxide, can significantly reduce the incidence of local skin dryness, erythema, desquamation, burning sensation, and contact dermatitis. Developing such a formulation is of great significance for improving patient comfort and long-term medication adherence. Summary of the Invention

[0007] To address the aforementioned technical problems, the present invention provides a pharmaceutical composition and its preparation method, wherein the composition comprises adapalene, benzoyl peroxide, a traditional Chinese medicine extract, a copolymer of acrylamide and sodium acryloyl dimethyl taurate and a mixture of isohexadecane and polysorbate 80, sodium docusate, disodium EDTA, glycerol, poloxamer 124, propylene glycol, and water.

[0008] Preferably, the mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 is SIMULGEL 600.

[0009] In a first aspect, the present invention provides a pharmaceutical composition comprising, based on 100 parts by weight, 0.05-0.5 parts adapalene, 1-7 parts benzoyl peroxide, 3-15 parts a traditional Chinese medicine extract, 2-10 parts a mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80, 0.01-0.2 parts sodium docusate, 0.02-0.5 parts disodium EDTA, 1-8 parts glycerin, 0.05-1 part poloxamer 124, 1-8 parts propylene glycol, and the balance being water.

[0010] Preferably, the mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 is SIMULGEL 600.

[0011] As an example, the pharmaceutical composition of the present invention, calculated on a 100-part weight basis, may include the following component amounts: adapalene may be 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5 parts; benzoyl peroxide may be 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7 parts; and the amount of traditional Chinese medicine extract may be... The amount of the mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 can be 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 parts, and the amount of sodium docusate can be 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.11, or 15 parts. The dosages are 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.2 parts; the dosage of disodium EDTA can be 0.02, 0.03, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, or 0.5 parts; and the dosage of glycerol can be 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, or 7 parts. The dosage of poloxamer 124 can be 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, or 1 part, and the dosage of propylene glycol can be 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 parts. The point values ​​of each component can be independently selected and combined according to actual preparation needs to constitute the specific formulation of the pharmaceutical composition.

[0012] Preferably, the present invention relates to a pharmaceutical composition comprising, by weight, 0.2-0.5 parts adapalene, 2-4 parts benzoyl peroxide, 5-10 parts traditional Chinese medicine extract, 3-8 parts a mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80, 0.02-0.1 parts sodium docusate, 0.05-0.3 parts disodium EDTA, 2-6 parts glycerin, 0.1-0.5 parts poloxamer 124, 2-6 parts propylene glycol, and the balance being water.

[0013] Preferably, the mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 is SIMULGEL 600.

[0014] Furthermore, as a preferred embodiment, this application relates to a pharmaceutical composition comprising, on a weight basis of 100 parts, 0.3 parts adapalene, 2.5 parts benzoyl peroxide, 6 parts traditional Chinese medicine extract, 4 parts a mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80, 0.05 parts sodium docusate, 0.1 parts disodium EDTA, 4 parts glycerin, 0.2 parts poloxamer 124, 4 parts propylene glycol, and the balance being water.

[0015] The herbal extract of the present invention is made from the following raw materials in parts by weight: 8-20 parts of peony bark, 6-12 parts of salvia miltiorrhiza, 6-12 parts of rehmannia glutinosa, 2-10 parts of sophora flavescens, 2-10 parts of coptis chinensis, 2-10 parts of rhubarb, 1-6 parts of scutellaria baicalensis, 0.5-4 parts of menthol, and 0.5-4 parts of borneol.

[0016] Furthermore, the traditional Chinese medicine extract of the present invention is made from the following raw materials in parts by weight: 8-20 parts of peony bark, 6-12 parts of salvia miltiorrhiza, 6-12 parts of rehmannia glutinosa, 2-10 parts of sophora flavescens, 2-10 parts of coptis chinensis, 2-10 parts of rhubarb, 1-6 parts of scutellaria baicalensis, 0.5-4 parts of menthol, and 0.5-4 parts of borneol.

[0017] As an example, the herbal extract of the present invention, calculated by weight, may include the following component amounts: Moutan bark may be 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 parts; Salvia miltiorrhiza may be 6, 7, 8, 9, 10, 11, or 12 parts; Rehmannia glutinosa may be 6, 7, 8, 9, 10, 11, or 12 parts; and Sophora flavescens may be 2, 3, 4, 5, 6, 7, 8, or 9 parts. The dosage of Coptis chinensis can be 2, 3, 4, 5, 6, 7, 8, 9, or 10 parts; the dosage of Rheum palmatum can be 2, 3, 4, 5, 6, 7, 8, 9, or 10 parts; the dosage of Scutellaria baicalensis can be 1, 2, 3, 4, 5, or 6 parts; the dosage of Menthol can be 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0 parts; the dosage of Borneol can be 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, or 4.0 parts. The concentration values ​​of each component can be independently selected and combined according to actual preparation needs to form the specific formula of the herbal extract.

[0018] As a preferred embodiment, the traditional Chinese medicine extract of the present invention is made from the following raw materials in parts by weight: 10-15 parts of peony bark, 8-10 parts of salvia miltiorrhiza, 8-10 parts of rehmannia glutinosa, 3-6 parts of sophora flavescens, 3-6 parts of coptis chinensis, 3-6 parts of rhubarb, 2-5 parts of scutellaria baicalensis, 1-3 parts of menthol, and 1-3 parts of borneol.

[0019] Furthermore, the traditional Chinese medicine extract of the present invention is made from the following raw materials in parts by weight: 10-15 parts of peony bark, 8-10 parts of salvia miltiorrhiza, 8-10 parts of rehmannia glutinosa, 3-6 parts of sophora flavescens, 3-6 parts of coptis chinensis, 3-6 parts of rhubarb, 2-5 parts of scutellaria baicalensis, 1-3 parts of menthol, and 1-3 parts of borneol.

[0020] Furthermore, as a preferred embodiment, the traditional Chinese medicine extract of the present invention is made from the following raw materials in parts by weight: 12 parts of peony bark, 9 parts of salvia miltiorrhiza, 9 parts of rehmannia glutinosa, 5 parts of sophora flavescens, 5 parts of coptis chinensis, 5 parts of rhubarb, 3 parts of scutellaria baicalensis, 2 parts of menthol, and 2 parts of borneol.

[0021] Furthermore, the herbal extract of the present invention is made from the following raw materials in parts by weight: 12 parts of peony bark, 9 parts of salvia miltiorrhiza, 9 parts of rehmannia glutinosa, 5 parts of sophora flavescens, 5 parts of coptis chinensis, 5 parts of rhubarb, 3 parts of scutellaria baicalensis, 2 parts of menthol, and 2 parts of borneol.

[0022] This invention also provides a method for preparing the above-mentioned traditional Chinese medicine extract, comprising the following steps:

[0023] (1) Pretreatment: Peony bark, Salvia miltiorrhiza, Rehmannia glutinosa, Sophora flavescens, Coptis chinensis, Rheum palmatum and Scutellaria baicalensis are crushed and sieved separately and then mixed in proportion to obtain mixed medicinal materials;

[0024] (2) Extraction: The mixed medicinal materials are extracted with ethanol solvent, the extracts are combined and filtered;

[0025] (3) Concentration: The solvent is recovered from the filtrate under low temperature and reduced pressure to obtain a thick extract;

[0026] (4) Blending and drying: Dissolve menthol and borneol in ethanol and mix them evenly with the thick extract. After drying, crushing and sieving, the Chinese medicine extract is obtained.

[0027] Preferably, the extraction method in step (2) is reflux extraction; the concentration of ethanol is 50-90%; the amount of ethanol used is 3-7 times the amount; and the number of extractions is 2-5 times.

[0028] In step (4), the concentration of ethanol is 70-95%.

[0029] Furthermore, as a preferred embodiment, the method for preparing the traditional Chinese medicine extract of the present invention includes the following steps:

[0030] (1) Pretreatment: Peony bark, Salvia miltiorrhiza, Rehmannia glutinosa, Sophora flavescens, Coptis chinensis, Rheum palmatum and Scutellaria baicalensis are crushed separately, passed through a 20-mesh sieve, and mixed in proportion to obtain mixed medicinal materials.

[0031] (2) Extraction: Place the mixed medicinal materials in a reflux extraction device, add 5 times the amount (w / v) of 70% ethanol solution, heat and reflux twice, 1.5 hours each time. Combine the extracts, filter, and obtain the filtrate.

[0032] (3) Concentration: The filtrate is subjected to reduced pressure to recover ethanol at a temperature below 50°C and a vacuum of -0.08 MPa to obtain a thick extract (until no alcohol odor is detected).

[0033] (4) Blending and drying: Dissolve menthol and borneol in a small amount of 95% ethanol and mix thoroughly with the above thick extract. Then, vacuum dry at low temperature (temperature ≤50℃) or spray dry the mixture, pulverize, and sieve to obtain the Chinese herbal extract.

[0034] In the traditional Chinese medicine composition of this invention, peony bark extract clears heat and cools blood, promotes blood circulation and removes blood stasis, inhibits inflammation, and reduces erythema and swelling; salvia miltiorrhiza extract promotes blood circulation and removes blood stasis, quickly relieving redness, swelling, and burning sensation; rehmannia glutinosa extract nourishes yin and moistens dryness, nourishes blood and moisturizes the skin, enhances skin's moisturizing ability, and relieves dryness and peeling; sophora flavescens extract clears heat and dries dampness, has anti-inflammatory and antipruritic effects, inhibits pruritus mediators, and reduces the incidence of contact dermatitis; coptis chinensis extract has antibacterial, anti-inflammatory, and astringent effects; rhubarb clears heat and detoxifies, cools blood and stops bleeding, and assists in anti-inflammatory treatment and reduces redness and swelling; scutellaria baicalensis clears heat and detoxifies, has antioxidant and anti-inflammatory effects; menthol has a cooling sensation, instantly relieves burning, stinging, and has a mild local anesthetic effect; borneol promotes transdermal penetration, clears heat and detoxifies, and cools and relieves itching.

[0035] The traditional Chinese medicine composition of this invention uses peony bark and salvia miltiorrhiza to invigorate blood circulation and cool the blood, improving local heat stagnation; and rehmannia glutinosa to nourish yin and moisturize the skin. These three ingredients work together to regulate the skin, repair the damaged skin barrier, and prevent recurrence. Sophora flavescens, coptis chinensis, scutellaria baicalensis, and rhubarb are used as important auxiliary ingredients to concentrate on clearing heat and drying dampness, detoxifying, and reducing inflammation, thereby reducing local skin dryness, erythema, desquamation, burning sensation, and the incidence of contact dermatitis. Furthermore, borneol and menthol, as classic transdermal penetration enhancers, can significantly improve the transdermal absorption of other active ingredients, greatly enhancing the bioavailability of the entire compound. Therefore, the combination of this application treats the root cause by clearing heat and drying dampness, cooling blood and invigorating blood circulation, targeting the core pathogenesis of inflammatory skin diseases; it treats the symptoms by using antibacterial and anti-inflammatory agents and immediate itch relief, quickly controlling symptoms; and it nourishes yin and moisturizes the skin to strengthen the foundation, focusing on the repair and consolidation of the skin barrier.

[0036] A second aspect of the present invention also provides a method for preparing a pharmaceutical composition, the method comprising the following steps:

[0037] (1) Preparation of aqueous phase: Mix the Chinese herbal extract, water, glycerin and disodium EDTA, and stir until dissolved and clear to obtain the aqueous phase;

[0038] (2) Preparation of the first active phase: Dissolve poloxamer 124 in water, stir until dissolved, add benzoyl peroxide, and homogenize at high speed to form a homogeneous dispersion;

[0039] (3) Preparation of the second active phase: Sodium docusate and adapalene are added sequentially or together to propylene glycol and homogenized to form a homogeneous mixture;

[0040] (4) Mixing and emulsification: Add part or all of the mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 to the aqueous phase for a first stage of mixing; then add the first active phase and perform a second stage of mixing; next, add the second active phase and perform a third stage of mixing; then transfer all the drug solution to an emulsification device, add the remaining part of the mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80, and perform homogenization emulsification to obtain a homogeneous drug composition.

[0041] Preferably, the material temperature is controlled between 10°C and 40°C throughout the preparation process. In step (2), the homogenization speed is not less than 8000 rpm; in step (4), the stirring speed of the second and third mixing stages is not less than 2000 rpm.

[0042] In step (4), when homogenizing emulsification is carried out in the emulsification equipment, it is operated under vacuum conditions, and the vacuum degree is not lower than -0.06 MPa.

[0043] In step (4), the acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 are added to the mixing system in at least three separate additions, with at least one addition before mixing the aqueous phase and the active phase, and at least one addition after mixing all the active phases. Preferably, the addition is done in two separate additions after mixing all the active phases.

[0044] The preparation method of this invention first employs a phase-separation pretreatment of the active ingredients, namely, preparing an aqueous phase by mixing a traditional Chinese medicine extract, water, glycerol, and disodium EDTA; then, homogenizing an aqueous solution of benzoyl peroxide and poloxamer 124 at high speed to form a uniform dispersion (first active phase); and finally, homogenizing adapalene and sodium docusate in propylene glycol to form a uniform mixture (second active phase). This step ensures that each active ingredient achieves a highly dispersed state in its optimal medium, avoiding mutual interference or aggregation that may be caused by direct mixing.

[0045] Secondly, sequential mixing and stepwise emulsification are employed. First, a portion of the acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 (emulsion / gel matrix) are premixed with the aqueous phase to construct a preliminary gel. Then, the first and second active phases are sequentially incorporated, with high-speed shear mixing applied after each incorporation to ensure thorough integration of the phases and uniform distribution of the active ingredients. Finally, the remaining acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 are added in stages in the main emulsification unit, and final homogenization emulsification is completed under a preferred vacuum atmosphere, resulting in a final product with a fine texture and stable structure.

[0046] In a third aspect of the invention, the dosage form of the pharmaceutical composition is a topical preparation, preferably a gel. The application of the drug obtained by the preparation method of the present invention in the preparation of a drug for treating acne, preferably, is in the case of severe acne.

[0047] The present invention has achieved the following beneficial technical effects:

[0048] (1) The gel containing Chinese herbal extracts of the present invention exhibits pharmacological activity equivalent to that of conventional gels without Chinese herbal extracts in an in vitro antibacterial (MIC / MBC) model.

[0049] (2) In the safety evaluation of animals (rabbits, mice) and human skin, the incidence and severity of local irritation reactions (dryness, erythema, edema, desquamation, burning sensation, etc.) caused by the gel of the present invention were significantly lower than those of gels without the addition of Chinese herbal extracts.

[0050] (3) By comparing the individual prescriptions, it was found that the complete Chinese herbal formula (peony bark, salvia miltiorrhiza, rehmannia root, sophora flavescens, coptis chinensis, rhubarb, and scutellaria baicalensis) showed the best effect in reducing irritation. In long-term use scenarios, the absence of any herbal material will lead to a decrease in protective effect, which emphasizes the necessity and synergy of the complete formula described in this invention.

[0051] (4) The pharmaceutical composition of the present invention is an improved pharmaceutical preparation that can significantly reduce the incidence of local skin dryness, erythema, desquamation, burning sensation and contact dermatitis while maintaining the synergistic antibacterial and antikeratotic effects of adapalene and benzoyl peroxide. Detailed Implementation

[0052] Example 1

[0053] A method for preparing a traditional Chinese medicine extract includes the following steps:

[0054] (1) Pretreatment: 12g of peony bark, 9g of salvia miltiorrhiza, 9g of rehmannia glutinosa, 5g of sophora flavescens, 5g of coptis chinensis, 5g of rhubarb, and 3g of scutellaria baicalensis are crushed separately, passed through a 20-mesh sieve, and mixed in proportion to obtain mixed medicinal materials.

[0055] (2) Extraction: Place the mixed medicinal materials in a reflux extraction device, add 5 times the amount (w / v) of 70% ethanol solution, heat and reflux twice, 1.5 hours each time. Combine the extracts, filter, and obtain the filtrate.

[0056] (3) Concentration: The filtrate is subjected to reduced pressure to recover ethanol at a temperature below 50°C and a vacuum of -0.08 MPa to obtain a thick extract (until no alcohol odor is detected).

[0057] (4) Blending and drying: Dissolve 2g of menthol and 2g of borneol in a small amount of 95% ethanol, and stir thoroughly with the above thick extract. Then, vacuum dry at low temperature (temperature ≤50℃) or spray dry the mixture, pulverize it, and sieve it to obtain the Chinese herbal extract.

[0058] Example 2

[0059] A method for preparing a traditional Chinese medicine extract includes the following steps:

[0060] (1) Pretreatment: 10g of peony bark, 8g of salvia miltiorrhiza, 8g of rehmannia glutinosa, 3g of sophora flavescens, 3g of coptis chinensis, 3g of rhubarb, and 2g of scutellaria baicalensis are crushed separately, passed through a 20-mesh sieve, and mixed in proportion to obtain mixed medicinal materials.

[0061] (2) Extraction: Place the mixed medicinal materials in a reflux extraction device, add 5 times the amount (w / v) of 70% ethanol solution, heat and reflux twice, 1.5 hours each time. Combine the extracts, filter, and obtain the filtrate.

[0062] (3) Concentration: The filtrate is subjected to reduced pressure to recover ethanol at a temperature below 50°C and a vacuum of -0.08 MPa to obtain a thick extract (until no alcohol odor is detected).

[0063] (4) Blending and drying: Dissolve 1g of menthol and 1g of borneol in a small amount of 95% ethanol, and stir thoroughly with the above thick extract. Then, vacuum dry at low temperature (temperature ≤50℃) or spray dry the mixture, pulverize, and sieve to obtain the Chinese herbal extract.

[0064] Example 3

[0065] A method for preparing a traditional Chinese medicine extract includes the following steps:

[0066] (1) Pretreatment: 15g of peony bark, 10g of salvia miltiorrhiza, 10g of rehmannia glutinosa, 6g of sophora flavescens, 6g of coptis chinensis, 6g of rhubarb, and 5g of scutellaria baicalensis are crushed separately, passed through a 20-mesh sieve, and mixed in proportion to obtain mixed medicinal materials.

[0067] (2) Extraction: Place the mixed medicinal materials in a reflux extraction device, add 5 times the amount (w / v) of 70% ethanol solution, heat and reflux twice, 1.5 hours each time. Combine the extracts, filter, and obtain the filtrate.

[0068] (3) Concentration: The filtrate is subjected to reduced pressure to recover ethanol at a temperature below 50°C and a vacuum of -0.08 MPa to obtain a thick extract (until no alcohol odor is detected).

[0069] (4) Blending and drying: Dissolve 3g of menthol and 3g of borneol in a small amount of 95% ethanol, and stir thoroughly with the above thick extract. Then, vacuum dry at low temperature (temperature ≤50℃) or spray dry the mixture, pulverize it, and sieve it to obtain the Chinese herbal extract.

[0070] Example 4

[0071] A method for preparing a gel containing adapalene and benzoyl peroxide

[0072] Table 1 Drug Prescription

[0073]

[0074] The preparation method includes the following steps:

[0075] (1) Preparation of aqueous phase: Mix about 530g of purified water, the Chinese herbal extract prepared in Example 1, glycerol and disodium EDTA, and stir until completely dissolved to form a clear aqueous phase.

[0076] (2) Preparation of the first active phase: Poloxamer 124 was added to the remaining purified water and stirred to dissolve. Benzoyl peroxide was then added and homogenized using a high-speed homogenizer at a speed of about 9000 rpm until a uniform dispersion was formed.

[0077] (3) Preparation of the second active phase: Sodium docusate is added to propylene glycol and stirred or heated slightly to dissolve it. After cooling, adapalene is added and homogenized using a high-speed homogenizer until a uniform mixture is formed.

[0078] (4) Mixing and emulsification:

[0079] a) Add approximately 12g of SIMULGEL 600 to the aqueous phase and mix thoroughly at approximately 1500 rpm.

[0080] b) The first active phase is added to the above system and sheared and mixed at a speed of about 2800 rpm.

[0081] c) Add the second active phase to the above system and shear mix again at a speed of about 2800 rpm.

[0082] d) Transfer the mixed drug solution to a vacuum emulsifier. While stirring, add the remaining SIMULGEL600 in two batches, each time about 35% of the total amount (i.e., 14g). Under a vacuum of not less than -0.06 MPa, perform final emulsification at a homogenization speed of about 1500 rpm to obtain a uniform gel composition.

[0083] The material temperature is controlled between 10-40℃ throughout the entire preparation process.

[0084] Comparative Example 1

[0085] A method for preparing a gel containing adapalene and benzoyl peroxide (excluding traditional Chinese medicine extracts).

[0086] Table 2 Drug Prescription

[0087]

[0088] The preparation method includes the following steps:

[0089] (1) Preparation of aqueous phase: Mix about 565g of purified water, glycerol and disodium EDTA and stir until completely dissolved to form a clear aqueous phase.

[0090] (2) Preparation of the first active phase: Poloxamer 124 was added to the remaining purified water and stirred to dissolve. Benzoyl peroxide was then added and homogenized using a high-speed homogenizer at a speed of about 9000 rpm until a uniform dispersion was formed.

[0091] (3) Preparation of the second active phase: Sodium docusate is added to propylene glycol and stirred or heated slightly to dissolve it. After cooling, adapalene is added and homogenized using a high-speed homogenizer until a uniform mixture is formed.

[0092] (4) Mixing and emulsification:

[0093] a) Add approximately 12g of SIMULGEL 600 to the aqueous phase and mix thoroughly at approximately 1500 rpm.

[0094] b) The first active phase is added to the above system and sheared and mixed at a speed of about 2800 rpm.

[0095] c) Add the second active phase to the above system and shear mix again at a speed of about 2800 rpm.

[0096] d) Transfer the mixed drug solution to a vacuum emulsifier. While stirring, add the remaining SIMULGEL600 in two batches, each time about 35% of the total amount (i.e., 14g). Under a vacuum of not less than -0.06 MPa, perform final emulsification at a homogenization speed of about 1500 rpm to obtain a uniform gel composition.

[0097] The material temperature is controlled between 10-40℃ throughout the entire preparation process.

[0098] Comparative Examples 2-4

[0099] The composition was prepared using the preparation method of Example 4, wherein the traditional Chinese medicine extract was prepared using the formulation in Table 3 below and the method of Example 1.

[0100] Table 3 Raw material compositions for preparing traditional Chinese medicine extracts (dosage in g)

[0101]

[0102] Experimental Example 1

[0103] In vitro pharmacodynamic experiments

[0104] 1. Specific grouping of the test samples

[0105] (1) Experimental group: Gel prepared in Example 4.

[0106] (2) Positive control group: gel prepared in Comparative Example 1.

[0107] (3) Blank control group: gel containing only the matrix (without any active ingredients adapalene, benzoyl peroxide and traditional Chinese medicine extracts).

[0108] 2. Experimental Methods

[0109] Methods and results for determining minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC)

[0110] (1) Sample pretreatment: Accurately weigh 1.0 g of each gel sample, dissolve it in 9.0 mL of sterile physiological saline containing 0.5% Tween-80, vortex to mix, prepare a 10% (w / v) stock solution, sonicate for 10 minutes, and set aside. Then perform serial dilution with the corresponding liquid culture medium.

[0111] (2) Preparation of bacterial culture: Propionibacterium acnes (cultured anaerobically at 37°C for 48 hours) and Staphylococcus aureus (cultured aerobically at 37°C for 24 hours) were inoculated into fresh liquid culture medium, and the bacterial culture concentration was adjusted to approximately 1×10⁻⁶. 8 CFU / mL, then diluted with culture medium to 1×10⁻⁶. 6CFU / mL was used as the working bacterial solution.

[0112] (3) Determination of MIC: The MIC value was determined using the microbroth dilution method. 100 μL of a series of concentration gradients of sample diluent was added to each well of a 96-well plate. 100 μL of working bacterial culture (approximately 5 × 10⁻⁶ bacteria) was added to each well. 5 (CFU / well). A negative control was set up using culture medium, and the absorbance was measured at 600 nm using a microplate reader. The lowest drug concentration with absorbance close to that of the negative control was taken as the MIC for that sample. Each sample and each strain was tested independently in triplicate.

[0113] (4) MBC determination: Take 100 μL of liquid from 2-3 wells with sterile growth above the MIC value in the MIC determination, spread it evenly on the corresponding solid agar plate, and incubate under suitable conditions. The lowest drug concentration corresponding to less than 5 colonies on the plate (killing rate ≥99.9%) is defined as the MBC.

[0114] 3. Experimental Results

[0115] Table 4. MIC and MBC values ​​of each gel group against Propionibacterium acnes and Staphylococcus aureus

[0116]

[0117] The experimental results showed that the blank control group had no antibacterial activity. Compared with the positive control group, the experimental group was slightly better than the positive control group, but there was no statistically significant difference between the two groups, proving that the addition of traditional Chinese medicine extract did not weaken the core antibacterial activity.

[0118] Experimental Example 2

[0119] Skin irritation test: Single and multiple skin irritation tests on rabbits

[0120] 1. Specific grouping of the test samples

[0121] (1) Experimental group: Gel prepared in Example 4.

[0122] (2) Positive control group: gel prepared in Comparative Example 1.

[0123] (3) Control group 1: Gel prepared in comparative example 2.

[0124] (4) Control group 2: Gel prepared in comparative example 3.

[0125] (5) Control group 3: Gel prepared in comparative example 4.

[0126] (6) Blank control group: gel containing only the matrix (without any active ingredients adapalene, benzoyl peroxide and traditional Chinese medicine extracts).

[0127] 2. Experimental Methods

[0128] Twenty-four hours prior to the experiment, the fur on symmetrical areas (approximately 10 cm × 15 cm) on both sides of the spine on the back of rabbits was shaved using an animal-specific shaver to avoid skin damage. The left side of each rabbit was designated as the experimental area, and the right side as the control area (applied to the blank group B). Rabbits were randomly divided into 6 groups of 4. 0.5 g of the test gel was evenly applied to the skin of the experimental area (approximately 2.5 cm × 2.5 cm), covered with sterile gauze, and secured with non-irritating adhesive tape.

[0129] (1) Single-dose administration method: After applying the patch for 4 hours, carefully remove the residual sample with warm water. Observe the skin reaction at the application site at 1, 24, 48 and 72 hours after sample removal.

[0130] (2) Multiple administration method: Apply once daily to the same site for 14 consecutive days. Record the irritation on the 14th day.

[0131] Skin reaction score: Erythema and edema are scored, and dryness, desquamation, crusting and other conditions are recorded in detail.

[0132] 3. Experimental Results

[0133] (1) Results of a single dose

[0134] The experimental results showed that the positive control group, which did not contain traditional Chinese medicine, exhibited significant acute irritation after a single exposure, with a score of 3.5. In contrast, the experimental group containing complete traditional Chinese medicine extracts showed extremely low irritation, with a score of only 0.8. This is the first direct demonstration that traditional Chinese medicine extracts can provide significant immediate protection from the first use, reducing the "initial impact" of active ingredients on the skin.

[0135] Secondly, the acute stimulation scores of all the incomplete prescription groups (i.e., control groups 1-3) were significantly higher than those of the experimental group, but lower than those of the positive control group. This indicates that even incomplete traditional Chinese medicine prescriptions have a certain immediate effect in reducing stimulation, but the complete prescriptions have the best effect.

[0136] (2) Results of multiple administrations

[0137] Table 5. Cumulative irritation scores of rabbits after multiple skin irritation tests (14 days, n=4)

[0138]

[0139] Note: P-values ​​are compared with the experimental group. **P<0.01; *P<0.05. A higher stimulation index indicates a stronger stimulation.

[0140] Experimental results showed that the experimental group had the best effect, significantly better than the positive control group. The cumulative stimulus scores of the control group from 1 to 3 were all higher than those of the experimental group, indicating that the combinations of peony bark, salvia miltiorrhiza, and rehmannia glutinosa, and the combinations of sophora flavescens, coptis chinensis, rhubarb, and scutellaria baicalensis all affected the efficacy and are all essential components of the traditional Chinese medicine composition. This suggests that in long-term use, the absence of any medicinal material will lead to a decrease in protective effect, emphasizing the necessity and synergy of the complete formulation described in this invention.

[0141] Experimental Example 3

[0142] Skin irritation test: Mouse ear stimulation model

[0143] 1. Specific grouping of the test samples

[0144] Same as Experiment 2.

[0145] 2. Experimental Methods

[0146] Mice were randomly divided into 6 groups of 8 mice each. 20 μL of the test gel was precisely pipetted and evenly applied to both sides of the right auricle of each mouse. An equal amount of the blank control (group B) was applied to the left ear as a self-control. Application was performed once daily for 5 consecutive days. Six hours after the last administration, mice were euthanized after being anesthetized with carbon dioxide. Immediately afterward, the thickness of the mid-section of both ears was measured at the same location on the auricle using calipers, and the difference (Δear thickness) was calculated.

[0147] Both ears were cut off, fixed in 10% neutral formalin, embedded in paraffin, sectioned (5 μm thick), and stained with hematoxylin and eosin (HE). The epidermal integrity, degree of edema, and infiltration of inflammatory cells (neutrophils and lymphocytes) in the dermis of the auricle skin were observed and compared under an optical microscope (200×), and a semi-quantitative score (0-3 points) was performed.

[0148] 3. Experimental Results

[0149] The experimental results showed that the ear thickness difference (Δear thickness, mm) was as follows: the positive control group caused significant auricular swelling (0.42 ± 0.05 mm); the experimental group showed significantly reduced swelling (0.18 ± 0.03 mm, P < 0.05 compared with the positive control group). The Δear thickness of the control groups 1-3 was between the two (0.25-0.35 mm).

[0150] In the positive control group, partial necrosis and parakeratosis were observed in the epidermis, and neutrophil infiltration was present in the dermis. The epidermal structure of the experimental group was largely intact, with only mild edema and a small amount of lymphocyte infiltration. The degree of inflammatory cell infiltration in control groups 1-3 was higher than that in the experimental group.

[0151] Experiment Example 4

[0152] Human skin occlusive patch test

[0153] 1. Specific grouping of the test samples

[0154] (1) Experimental group: Gel prepared in Example 4.

[0155] (2) Positive control group: gel prepared in Comparative Example 1.

[0156] (3) Blank control group: gel containing only the matrix (without any active ingredients adapalene, benzoyl peroxide and traditional Chinese medicine extracts).

[0157] 2. Experimental Methods

[0158] Ninety eligible healthy volunteers (half male and half female, aged 18-45 years, with no active skin diseases and no history of drug allergies) were recruited and randomly assigned to three groups. A standard Finn Chamber patch applicator and hypoallergenic adhesive tape were used. Approximately 15 mg of the test gel (experimental group and positive control group) and a placebo (blank control group) were added to the respective compartments of the patch applicator. The sample-loaded patch applicator was applied to healthy skin on the volunteers' backs for 48 hours. After removing the patch applicator, a 30-minute waiting period was allowed for the elimination of pressure erythema, and then the skin reaction at the application site was observed by the same experienced dermatologist for 48 hours.

[0159] Reaction score: The score is based on the International Contact Dermatitis Study Group (ICDRG) criteria: 0 points (negative reaction), 1 point (weak positive, only erythema), 2 points (strong positive, erythema, infiltration, possibly with papules), 3 points (very strong positive, erythema, infiltration, papules, vesicles).

[0160] 3. Experimental Results

[0161] Table 6 Results of human skin occlusive patch test

[0162]

[0163] Experimental results show that, on human skin, the irritant reactions (subjective discomfort such as erythema, infiltration, papules, and blisters) induced by gels containing complete Chinese herbal extracts are significantly lower than those induced by conventional gels without Chinese herbal extracts.

[0164] The specific embodiments described above further illustrate the technical problems, technical solutions, and beneficial effects of the present invention. It should be understood that the above descriptions are merely specific embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, Based on 100 parts by weight, it contains 0.05-0.5 parts adapalene, 1-7 parts benzoyl peroxide, 3-15 parts traditional Chinese medicine extract, 2-10 parts a mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80, 0.01-0.2 parts sodium docusate, 0.02-0.5 parts disodium EDTA, 1-8 parts glycerin, 0.05-1 part poloxamer 124, 1-8 parts propylene glycol, and the balance being water; The herbal extract is made from the following raw materials in parts by weight: 8-20 parts of peony bark, 6-12 parts of salvia miltiorrhiza, 6-12 parts of rehmannia glutinosa, 2-10 parts of sophora flavescens, 2-10 parts of coptis chinensis, 2-10 parts of rhubarb, 1-6 parts of scutellaria baicalensis, 0.5-4 parts of menthol, and 0.5-4 parts of borneol; preferably, the mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 is SIMULGEL 600.

2. The pharmaceutical composition according to claim 1, characterized in that, Based on 100 parts by weight, it contains 0.2-0.5 parts adapalene, 2-4 parts benzoyl peroxide, 5-10 parts traditional Chinese medicine extract, 3-8 parts a mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80, 0.02-0.1 parts sodium docusate, 0.05-0.3 parts disodium EDTA, 2-6 parts glycerin, 0.1-0.5 parts poloxamer 124, 2-6 parts propylene glycol, and the balance being water.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, Based on 100 parts by weight, it contains 0.3 parts adapalene, 2.5 parts benzoyl peroxide, 6 parts traditional Chinese medicine extract, 4 parts a mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80, 0.05 parts sodium docusate, 0.1 parts disodium EDTA, 4 parts glycerin, 0.2 parts poloxamer 124, 4 parts propylene glycol, and the balance being water.

4. The pharmaceutical composition according to claim 1 or 2, characterized in that, The herbal extract is made from the following raw materials in parts by weight: 10-15 parts of peony bark, 8-10 parts of salvia miltiorrhiza, 8-10 parts of rehmannia glutinosa, 3-6 parts of sophora flavescens, 3-6 parts of coptis chinensis, 3-6 parts of rhubarb, 2-5 parts of scutellaria baicalensis, 1-3 parts of menthol, and 1-3 parts of borneol.

5. The pharmaceutical composition according to claim 4, characterized in that, The herbal extract is made from the following raw materials in parts by weight: 12 parts of peony bark, 9 parts of salvia miltiorrhiza, 9 parts of rehmannia glutinosa, 5 parts of sophora flavescens, 5 parts of coptis chinensis, 5 parts of rhubarb, 3 parts of scutellaria baicalensis, 2 parts of menthol, and 2 parts of borneol.

6. A method for preparing the pharmaceutical composition according to any one of claims 1-5, characterized in that, The preparation method of the traditional Chinese medicine extract includes the following steps: (1) Pretreatment: Peony bark, Salvia miltiorrhiza, Rehmannia glutinosa, Sophora flavescens, Coptis chinensis, Rheum palmatum and Scutellaria baicalensis are pulverized and sieved respectively, and then mixed in proportion to obtain mixed medicinal materials; (2) Extraction: The mixed medicinal materials are extracted with ethanol solvent, the extracts are combined and filtered; (3) Concentration: The solvent is recovered from the filtrate under low temperature and reduced pressure to obtain a thick extract; (4) Blending and drying: Dissolve menthol and borneol in ethanol and mix them evenly with the thick extract. After drying, crushing and sieving, the Chinese medicine extract is obtained.

7. The preparation method according to claim 6, characterized in that, In step (2), the extraction method is reflux extraction; and / or the concentration of the ethanol is 50-90%; and / or the amount of the ethanol used is 3-7 times; and / or the number of extractions is 2-5 times; and / or in step (4), the concentration of the ethanol used to dissolve menthol and borneol is 70-95%.

8. A method for preparing the pharmaceutical composition according to any one of claims 1-5, characterized in that, Includes the following steps: (1) Preparation of aqueous phase: Mix the Chinese herbal extract, water, glycerin and disodium EDTA, and stir until dissolved and clear to obtain the aqueous phase; (2) Preparation of the first active phase: Dissolve poloxamer 124 in water, stir until dissolved, add benzoyl peroxide, and homogenize at high speed to form a homogeneous dispersion; (3) Preparation of the second active phase: Sodium docusate and adapalene are added sequentially or together to propylene glycol and homogenized to form a homogeneous mixture; (4) Mixing and emulsification: Add part or all of the mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 to the aqueous phase for the first stage of mixing; Subsequently, the first active phase is added and a second stage of mixing is performed; then, the second active phase is added and a third stage of mixing is performed; after that, all the drug solution is transferred to an emulsification device, and the remaining mixture of acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 is added, and homogenized emulsification is performed to obtain a homogeneous drug composition.

9. The preparation method according to claim 8, characterized in that, The material temperature is controlled between 10°C and 50°C throughout the preparation process; and / or the homogenization speed in step (2) is not less than 8000 rpm; and / or the stirring speed of the second and third mixing stages in step (4) is not less than 2000 rpm; and / or in step (4), when homogenizing emulsification is carried out in the emulsification equipment, it is operated under vacuum conditions, and the vacuum degree is not less than -0.06 MPa; and / or in step (4), the acrylamide and sodium acryloyl dimethyl taurate copolymer and isohexadecane and polysorbate 80 are added to the mixing system at least three times, of which at least one is added before the aqueous phase and the active phase are mixed, and at least one is added after all the active phases are mixed.

10. Use of the pharmaceutical composition according to any one of claims 1-5 in the preparation of a medicament for treating acne, preferably, the acne being severe acne.

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