A compound ointment formulation containing calcipotriol and betamethasone dipropionate and a process for its preparation

Abstract

The application belongs to the field of pharmaceutical preparations, and particularly relates to a calcipotriol betamethasone ointment and a preparation method thereof. The ointment comprises calcipotriol, betamethasone dipropionate, propyl gallate, polyglyceryl-3-diisostearate, a solvent and a base. The application uses propyl gallate and polyglyceryl-3-diisostearate as a stabilizer system, which significantly improves the chemical stability and physical stability of the ointment. Accelerated test results show that the ointment of the application is significantly superior to prior art in terms of stability, and the properties and coatability of the ointment remain good, and no physical instability phenomena such as delamination, thinning, hardening and the like occur. Pharmacodynamic experiments show that the ointment of the application is significantly superior to prior art in terms of improvement of psoriasis. The preparation process of the application is simple and suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, specifically relates to a compound ointment preparation containing calcipotriol and betamethasone dipropionate and a preparation method thereof, and particularly relates to a calcipotriol-betamethasone ointment with excellent stability. Background Art

[0002] Psoriasis (commonly known as psoriasis vulgaris) is a chronic inflammatory skin disease with a long course and high recurrence tendency, which seriously affects the quality of life of patients. Calcipotriol is a derivative of vitamin D3 that can inhibit the proliferation of keratinocytes and induce their differentiation; betamethasone dipropionate is a highly potent glucocorticoid drug with anti-inflammatory, antipruritic and immunosuppressive effects. The two have complementary mechanisms of action, and the clinical efficacy of their combination is significantly better than that of monotherapy. The combination therapy has become a first-line option for the treatment of stable plaque psoriasis.

[0003] However, preparing stable compound preparations of calcipotriol and betamethasone dipropionate faces many technical challenges. Calcipotriol is sensitive to oxidizing agents and acidic substances, and has the best stability in an alkaline environment (pH>8); while betamethasone dipropionate contains an ester bond in its molecular structure, is sensitive to alkaline substances, and is more stable under weakly acidic conditions (pH 4 to 6). The opposite requirements of the two active ingredients for pH value make it a pharmaceutical challenge to balance the stability of both in a single preparation.

[0004] To improve the stability of calcipotriol-betamethasone compound preparations, many attempts have been made in the art. Chinese patent CN104666312A uses triethanolamine to neutralize acidic impurities and adjust pH to 6.8-7.5, but the addition of triethanolamine has potential adverse effects on the stability of betamethasone dipropionate, and the high dosage of benzyl alcohol may bring the risk of skin irritation; Chinese patent CN105708842A uses medium-chain triglycerides to dissolve calcipotriol and uses racemic α-tocopherol as an antioxidant, but a single antioxidant alone lacks a comprehensive stabilization protection mechanism, and the increase of related substances is still significant; Chinese patent CN106344589A uses caprylic capric polyethylene glycol glyceride of specific specification and vitamin E-TPGS as stabilizers. Although the stability is improved, the source of the auxiliary materials used is limited and the cost is high, which is not conducive to industrial popularization.

[0005] In summary, the chemical stability and / or physical stability of calcipotriol-betamethasone compound ointment in the prior art is still not ideal, and there is an urgent need to develop a calcipotriol-betamethasone ointment preparation with better stability, wide sources of auxiliary materials and reasonable cost. Summary of the Invention

[0006] This invention addresses the technical deficiency of insufficient stability in existing calcipotriol betamethasone compound ointments by providing a calcipotriol betamethasone ointment with significantly improved stability and its preparation method. This invention achieves simultaneous improvement in both the chemical and physical stability of the ointment through a specific combination of excipients, particularly the synergistic use of propyl gallate and polyglycerol-3-diisostearate.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution: In a first aspect, the present invention provides a calcipotriol betamethasone ointment, the ointment comprising calcipotriol, betamethasone dipropionate, propyl gallate, polyglycerol-3-diisostearate, solvent, and matrix.

[0008] Preferably, the content of calcipotriol is 0.005%, and the content of betamethasone dipropionate is 0.0643%.

[0009] Preferably, the content of propyl gallate is 0.02% to 0.2%, and the content of polyglycerol-3-diisostearate is 1.5% to 3%.

[0010] More preferably, the content of propyl gallate is 0.05% to 0.1%, and the content of polyglycerol-3-diisostearate is 2% to 2.5%.

[0011] Preferably, the solvent is a medium-chain triglyceride, and the matrix comprises liquid paraffin and nephrite.

[0012] More preferably, the content of the medium-chain triglycerides is 4% to 6%, the content of the liquid paraffin is 2% to 4%, and the balance is nephrite.

[0013] Secondly, the present invention provides a method for preparing the above-mentioned calcipotriol betamethasone ointment, comprising the following steps: (1) Heat the solid matrix until it melts and keep it at that temperature for later use; (2) Dissolve calcipotriol in a solvent, add propyl gallate and polyglycerol-3-diisostearate to dissolve, and obtain a drug-containing mixed solution; (3) Disperse betamethasone dipropionate in a liquid matrix to obtain a dispersion; (4) Under stirring conditions, the drug-containing mixed solution from step (2) and the dispersion from step (3) are added to the molten solid matrix from step (1), mixed evenly, cooled, and then filled to obtain the final product.

[0014] Preferably, the solid matrix is ​​white paraffin, the solvent is a medium-chain triglyceride, and the liquid matrix is ​​liquid paraffin.

[0015] Preferably, the heating and melting temperature in step (1) is 75-80°C, and the heat preservation temperature is 55-65°C; the dispersion in step (3) is carried out under ultrasonic conditions, and the dispersion time is 2-5 minutes.

[0016] Preferably, the amount of liquid matrix used in step (3) is 80% of the liquid matrix prescription amount, and the remaining 20% ​​of the liquid matrix is ​​used for rinsing.

[0017] Beneficial effects Compared with the prior art, the present invention has the following significant advantages: (1) Excellent chemical stability: The present invention constructs an efficient stabilization and protection system by using propyl gallate and polyglycerol-3-diisostearate in synergy. Under accelerated testing and high temperature extreme conditions, the content of the main drug and related substance indicators are significantly better than the existing technical solutions.

[0018] (2) Good physical stability: The ointment of the present invention maintained a uniform paste state and good spreadability during the accelerated test, and did not exhibit physical instability phenomena such as layering, thinning, or hardening. In contrast, existing technical solutions showed different degrees of physical stability problems under the same conditions.

[0019] (3) Excellent pharmacodynamic effects: The mouse model experiment of psoriasis showed that the ointment of the present invention has a significantly better effect on improving skin lesion symptoms and epidermal hyperplasia than the existing technical solutions and positive control drugs. Detailed Implementation

[0020] The embodiments of the present invention will be clearly and completely described below with reference to the examples. These embodiments are merely some, not all, of the embodiments of the present invention. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention. Those skilled in the art should understand that modifications or substitutions to the details and form of the technical solutions of this application can be made without departing from the spirit and scope of this application, but such modifications and substitutions all fall within the scope of protection of this application.

[0021] Furthermore, to better illustrate the present invention, numerous specific details are set forth in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In some embodiments, materials, methods, and means well-known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0022] Unless otherwise specified, the instruments and materials used in the following embodiments are all commonly used laboratory equipment, and the technical solutions described are all conventional technologies in the field.

[0023] Example 1 A calcipotriol betamethasone ointment, with the following formulation and dosage: Preparation process of calcipotriol betamethasone ointment: Prepared according to a dosage of 15g per vial.

[0024] (1) Substrate preparation: Take the prescribed amount of white paraffin, heat it in a water bath to 80°C to melt it, then cool it to 60°C and keep it warm for later use.

[0025] (2) Preparation of calcipotriol solution: Take the prescribed amount of medium-chain triglycerides and add the prescribed amount of calcipotriol (anhydrous). Stir at room temperature until the calcipotriol is completely dissolved to obtain a clear solution. Add the prescribed amounts of propyl gallate and polyglycerol-3-diisostearate to the above solution and continue stirring until completely dissolved to obtain a mixed solution containing calcipotriol for later use.

[0026] (3) Preparation of betamethasone dipropionate dispersion: Take the prescribed amount of betamethasone dipropionate and add it to 80% of the prescribed amount of liquid paraffin. Disperse the mixture ultrasonically in an ultrasonic cleaner for 5 minutes to ensure uniform dispersion of betamethasone dipropionate in the liquid paraffin, obtaining a homogeneous betamethasone dipropionate dispersion. Reserve the remaining 20% ​​of the liquid paraffin for rinsing purposes.

[0027] (4) Preparation of ointment: While stirring at 500 rpm, the calcipotriol mixture obtained in step (2) and the betamethasone dipropionate dispersion obtained in step (3) were slowly added to the white paraffin wax kept at 60°C in step (1). The containers were rinsed with the remaining liquid paraffin wax from step (3) before being added together.

[0028] (5) Homogeneous: After the ingredients are added, homogenize the mixture for 15 minutes at 10,000 rpm using a high-speed homogenizer to obtain a uniform paste. Maintain the paste temperature at 60℃ during the homogenization process.

[0029] (6) Cooling and filling: Stop heating and homogenizing, and while stirring, reduce the temperature until the paste cools to 30~35℃. Take a sample for intermediate testing. After passing the test, fill the paste into aluminum tubes at a temperature controlled at 30±5℃. After filling, fold the end and seal the tube for packaging.

[0030] Example 2 A calcipotriol betamethasone ointment, with the following formulation and dosage: Preparation process of calcipotriol betamethasone ointment: Prepared according to a dosage of 15g per vial.

[0031] (1) Substrate preparation: Take the prescribed amount of white paraffin wax, heat it in a water bath to 75°C to melt it, then cool it to 60°C and keep it warm for later use.

[0032] (2) Preparation of calcipotriol solution: Take the prescribed amount of medium-chain triglycerides and add the prescribed amount of calcipotriol (anhydrous). Stir at room temperature until the calcipotriol is completely dissolved to obtain a clear solution. Add the prescribed amounts of propyl gallate and polyglycerol-3-diisostearate to the above solution and continue stirring until completely dissolved to obtain a mixed solution containing calcipotriol for later use.

[0033] (3) Preparation of betamethasone dipropionate dispersion: Take the prescribed amount of betamethasone dipropionate and add it to 80% of the prescribed amount of liquid paraffin. Disperse the mixture ultrasonically in an ultrasonic cleaner for 4 minutes to ensure uniform dispersion of betamethasone dipropionate in the liquid paraffin, obtaining a homogeneous betamethasone dipropionate dispersion. Reserve the remaining 20% ​​of the liquid paraffin for rinsing purposes.

[0034] (4) Preparation of ointment: While stirring at 400 rpm, the calcipotriol mixture obtained in step (2) and the betamethasone dipropionate dispersion obtained in step (3) were slowly added to the white paraffin wax kept at 60°C in step (1). The containers were rinsed with the remaining liquid paraffin wax from step (3) before being added together.

[0035] (5) Homogeneous: After the ingredients are added, homogenize the mixture for 12 minutes at 9000 rpm using a high-speed homogenizer to obtain a uniform paste. Maintain the paste temperature at 60℃ during the homogenization process.

[0036] (6) Cooling and filling: Stop heating and homogenizing, and while stirring, reduce the temperature until the paste cools to 30~35℃. Take a sample for intermediate testing. After passing the test, fill the paste into aluminum tubes at a temperature controlled at 30±5℃. After filling, fold the end and seal the tube for packaging.

[0037] Example 3 A calcipotriol betamethasone ointment, with the following formulation and dosage: Preparation process of calcipotriol betamethasone ointment: Prepared according to a dosage of 15g per vial.

[0038] (1) Substrate preparation: Take the prescribed amount of white paraffin, heat it in a water bath to 80°C to melt it, then cool it to 65°C and keep it warm for later use.

[0039] (2) Preparation of calcipotriol solution: Take the prescribed amount of medium-chain triglycerides and add the prescribed amount of calcipotriol (anhydrous). Stir at room temperature until the calcipotriol is completely dissolved to obtain a clear solution. Add the prescribed amounts of propyl gallate and polyglycerol-3-diisostearate to the above solution and continue stirring until completely dissolved to obtain a mixed solution containing calcipotriol for later use.

[0040] (3) Preparation of betamethasone dipropionate dispersion: Take the prescribed amount of betamethasone dipropionate and add it to 80% of the prescribed amount of liquid paraffin. Disperse the mixture ultrasonically in an ultrasonic cleaner for 5 minutes to ensure uniform dispersion of betamethasone dipropionate in the liquid paraffin, obtaining a homogeneous betamethasone dipropionate dispersion. Reserve the remaining 20% ​​of the liquid paraffin for rinsing purposes.

[0041] (4) Preparation of ointment: While stirring at 300 rpm, the calcipotriol mixture obtained in step (2) and the betamethasone dipropionate dispersion obtained in step (3) were slowly added to the white paraffin wax kept at 65°C in step (1). The containers were rinsed with the remaining liquid paraffin wax from step (3) before being added together.

[0042] (5) Homogeneous: After the ingredients are added, homogenize the mixture for 15 minutes at 8000 rpm using a high-speed homogenizer to obtain a uniform paste. Maintain the paste temperature at 65℃ during the homogenization process.

[0043] (6) Cooling and filling: Stop heating and homogenizing, and while stirring, reduce the temperature until the paste cools to 30~35℃. Take a sample for intermediate testing. After passing the test, fill the paste into aluminum tubes at a temperature controlled at 30±5℃. After filling, fold the end and seal the tube for packaging.

[0044] Example 4 A calcipotriol betamethasone ointment, with the following formulation and dosage: Preparation process of calcipotriol betamethasone ointment: Prepared according to a dosage of 15g per vial.

[0045] (1) Substrate preparation: Take the prescribed amount of white paraffin, heat it in a water bath to 80°C to melt it, then cool it to 65°C and keep it warm for later use.

[0046] (2) Preparation of calcipotriol solution: Take the prescribed amount of medium-chain triglycerides and add the prescribed amount of calcipotriol (anhydrous). Stir at room temperature until the calcipotriol is completely dissolved to obtain a clear solution. Add the prescribed amounts of propyl gallate and polyglycerol-3-diisostearate to the above solution and continue stirring until completely dissolved to obtain a mixed solution containing calcipotriol for later use.

[0047] (3) Preparation of betamethasone dipropionate dispersion: Take the prescribed amount of betamethasone dipropionate and add it to 80% of the prescribed amount of liquid paraffin. Disperse the mixture ultrasonically in an ultrasonic cleaner for 5 minutes to ensure uniform dispersion of betamethasone dipropionate in the liquid paraffin, obtaining a homogeneous betamethasone dipropionate dispersion. Reserve the remaining 20% ​​of the liquid paraffin for rinsing purposes.

[0048] (4) Preparation of ointment: While stirring at 600 rpm, the calcipotriol mixture obtained in step (2) and the betamethasone dipropionate dispersion obtained in step (3) were slowly added to the white paraffin wax kept at 65°C in step (1). The containers were rinsed with the remaining liquid paraffin wax from step (3) before being added together.

[0049] (5) Homogeneous: After the ingredients are added, homogenize the mixture for 10 minutes at 10,000 rpm using a high-speed homogenizer to obtain a uniform paste. Maintain the paste temperature at 60℃ during the homogenization process.

[0050] (6) Cooling and filling: Stop heating and homogenizing, and while stirring, reduce the temperature until the paste cools to 30~35℃. Take a sample for intermediate testing. After passing the test, fill the paste into aluminum tubes at a temperature controlled at 30±5℃. After filling, fold the end and seal the tube for packaging.

[0051] Example 5 Calcipotriol betamethasone ointment was prepared according to the formula and preparation process in CN106344589A. The formula composition and dosage are as follows: Preparation process of calcipotriol betamethasone ointment: Prepared according to a dosage of 15g per vial.

[0052] Weigh out the following ingredients according to the prescription: calcipotriol, betamethasone dipropionate, vitamin E-TPGS, caprylic / capric acid PEG-glyceryl ester, light liquid paraffin, propylene glycol, and nephrite, and set aside. Matrix preparation: Take the prescribed amount of white paraffin, heat it to 80℃ to melt it, cool it to 65±5℃ and keep it warm for later use; Solution preparation: Add the prescribed amount of calcipotriol to 80% of the prescribed amount of octanoic acid, caprylic acid, PEG-1, and propylene glycol, and sonicate until completely dissolved to obtain a clear calcipotriol solution I for later use. Preparation of dispersion medium: Add the prescribed amount of betamethasone dipropionate to 80% of the prescribed amount of light liquid paraffin, and sonicate until uniformly dispersed to obtain betamethasone dipropionate dispersion II, for later use. Ointment preparation: Slowly add the above clear solution I to the molten white paraffin, rinse with the remaining caprylic / capric acid / polyethylene glycol glycerol ester solution before adding; Slowly add the above dispersion II and the prescribed amount of vitamin E-TPGS to the molten white paraffin, rinse with the remaining light liquid paraffin before adding; Homogenization: After the ingredients are added, use a high-speed homogenizer at 10,000 rpm for 15 minutes to obtain a uniform paste. Maintain the paste temperature at 60℃ during the homogenization process.

[0053] Cooling and Filling: Stop heating and homogenization, and cool down while stirring. When the paste cools to 30~35℃, take a sample for intermediate testing. After passing the test, fill the paste into aluminum tubes, controlling the filling temperature at 30±5℃. After filling, fold the end and seal the tube for packaging.

[0054] Example 6 Calcipotriol betamethasone ointment was prepared according to the formula and preparation process in CN104666312A. The formula composition and dosage are as follows: Preparation process of calcipotriol betamethasone ointment: Prepared according to a dosage of 15g per vial.

[0055] Melt the prescribed amount of white petrolatum in a water bath at 75–85°C, cool it to 55–60°C and keep it warm for later use.

[0056] The prescribed amount of betamethasone dipropionate with a D90 of less than 15 μm was added to the prescribed amount of liquid paraffin and ultrasonicated in an ultrasonic cleaner for 2 minutes to disperse the betamethasone dipropionate evenly, thus obtaining a uniformly dispersed betamethasone dipropionate dispersion.

[0057] Add the prescribed amount of triethanolamine to the prescribed amount of benzyl alcohol, stir well, and then add the prescribed amount of calcipotriol. Stir until the calcipotriol is completely dissolved to obtain a calcipotriol solution.

[0058] Add the calcipotriol solution and betamethasone dipropionate dispersion to white petrolatum kept at 55-60°C, stir at 500 rpm for 5 minutes, and then homogenize at 10,000 rpm for 15 minutes using a high-speed homogenizer to obtain a uniform paste.

[0059] Stop heating and homogenizing, and while stirring, reduce the temperature until the paste cools to 30~35℃. Take a sample for intermediate testing. After passing the test, fill the paste into aluminum tubes at a temperature controlled at 30±5℃. After filling, fold the end and seal the tube for packaging.

[0060] Example 7 Calcipotriol betamethasone ointment was prepared according to the formula and preparation process in CN105708842A. The formula composition and dosage are as follows: Preparation process of calcipotriol betamethasone ointment: Prepared according to a dosage of 15g per vial.

[0061] (1) Weigh out the prescribed amount of white petrolatum, heat it in a water bath at 60°C until it is completely melted, and then cool it down to 45-50°C for later use; (2) Weigh the prescribed amount of liquid paraffin, add the prescribed amount of racemic α-tocopherol, and stir until completely dissolved; add the prescribed amount of betamethasone dipropionate (90% of the particles are <15μm), and stir until evenly dispersed, and set aside. (3) Weigh out the prescribed amount of medium-chain triglycerides, add the prescribed amount of calcipotriol, heat in a 50°C water bath until completely dissolved, and set aside. (4) Add the products from steps (2) and (3) to the product from step (1) and emulsify at 4000 rpm for 15 min. (5) After emulsification, cool down to 25-35℃ and take samples for intermediate testing. After passing the test, fill the ointment into aluminum tubes. The filling temperature is controlled at 30±5℃. After filling, fold the end and seal the tube. The product is then packaged.

[0062] Experimental Example 1: Stability Study of Calcipotriol Betamethasone Ointment Accelerated testing was conducted on the calcipotriol betamethasone ointment prepared in Examples 1-7. The ointment was placed at 40℃±2℃ and 75%±5% relative humidity for 6 months. Samples were taken on day 0 and at months 1, 3, and 6 for analysis to determine the sample properties, spreadability, content, and related substances (total impurities). The results are shown in Tables 1-3.

[0063] Table 1. Changes in the properties and spreadability of calcipotriol betamethasone ointment Table 2. Changes in calcipotriol content and related substances (total impurities) Table 3. Changes in betamethasone dipropionate content and related substances (total impurities) As can be seen from the results in Tables 1-3 above, the calcipotriol betamethasone ointment prepared in Examples 1-4 of this invention maintained good physical properties and spreadability after being placed under accelerated conditions of 40℃±2℃ and RH75%±5% for 6 months, without any physical instability phenomena such as layering, thinning, or hardening. The contents of the two main drugs remained at a high level (calcipotriol ≥98%, betamethasone dipropionate ≥97%), and the increase of related substances was significantly lower than that in Examples 5-7.

[0064] The above results indicate that the excipient combination described in this invention, especially the synergistic use of propyl gallate and polyglycerol-3-diisostearate, can significantly improve the chemical and physical stability of calcipotriol betamethasone ointment, providing a feasible technical solution for developing compound ointment formulations with superior performance compared to existing technologies.

[0065] Experiment Example 2: Evaluation of the therapeutic effect of calcipotriol betamethasone ointment on a mouse model of psoriasis. 1. Experimental Methods After one week of acclimatization, male SPF-grade BALB / c mice had their back hair (approximately 2.5cm × 3.0cm area) carefully removed using an electric shaver. 62.5 mg of 5% imiquimod cream was applied to the balded area daily for 7 consecutive days. Skin changes on the back of the mice were observed and recorded daily. Around day 3 after application, thickened skin, erythema, and scaling began to appear on the back of the mice. By day 7, the skin lesions were obvious, characterized by significant thickening of the skin, increased silvery-white scaling, and pronounced erythema, consistent with psoriasis-like lesions, indicating successful modeling.

[0066] Mice that successfully developed the model were randomly divided into the following six groups, ensuring that there were no significant differences in baseline PASI scores among the groups, with 8 mice in each group: Model group: After successful modeling, continue to apply 62.5 mg of 5% imiquimod cream daily, and no other treatment will be given; Positive control group: After successful modeling, 62.5 mg of 5% imiquimod cream was applied daily, and commercially available calcipotriol betamethasone ointment (approximately 0.2 g / vial) was administered once daily from the date of successful modeling. Examples 1 and 5-7: After successful modeling, 62.5 mg of 5% imiquimod cream was applied daily, and 0.2 g of calcipotriol betamethasone ointment prepared in Examples 1, 5, 6 and 7 was administered once daily from the date of successful modeling.

[0067] Eight age-matched BALB / c mice that were not treated in any way were used as a blank control group, with only an equal amount of petroleum jelly applied to their backs.

[0068] Each group was administered the drug continuously for 7 days. The body weight and changes in skin lesions on the back of the mice were observed and recorded daily.

[0069] 2. Detection Indicators Referring to the Psoriasis Area and Severity Index (PASI) scoring criteria, the degree of erythema, scaling, and infiltration of the skin lesions on the backs of mice was independently scored daily. The scoring criteria are as follows: 0 points = asymptomatic; 1 point = mild; 2 points = moderate; 3 points = severe; 4 points = very severe. The sum of the three scores is the total PASI score.

[0070] Mice were sacrificed after the last administration, and skin tissue (approximately 0.5 cm × 0.5 cm) from the dorsal lesion area was harvested. Subcutaneous fat was removed, and the tissue was fixed in 4% paraformaldehyde for 48 h. After dehydration with graded ethanol, clearing with xylene, and embedding in paraffin, serial sections with a thickness of 4 μm were prepared. After dewaxing and rehydration with graded ethanol, the sections were stained with hematoxylin and eosin (HE), mounted, and observed for histopathological changes in the skin tissue under an optical microscope. Five non-overlapping fields of view were randomly selected from each section, and the epidermal thickness (vertical distance from the basement membrane to the bottom of the stratum corneum) was measured using ImageJ image analysis software. The average value was taken as the epidermal thickness of the sample.

[0071] 3. Experimental Results The experimental results are shown in Tables 4 and 5 below.

[0072] Table 4. Effects of calcipotriol betamethasone ointment on skin PASI scores ( ±s ) Note: Comparison with model group. a P <0.01; compared with Example 5 group, b P <0.01; compared with Example 6 group, c P <0.01; compared with Example 7 group, d P <0.05; compared with the positive control group, e P <0.05 Table 5. Effect of calcipotriol betamethasone ointment on epidermal thickness in psoriasis patients ( ±s ) Note: Compared with the blank control group, a P <0.01; compared with the model group, b P <0.01; compared with Example 5 group, c P <0.01; compared with Example 6 group, d P <0.01; compared with Example 7 group, e P <0.01; compared with the positive control group, f P <0.05 As shown in Tables 4 and 5, the PASI score and epidermal thickness of the skin lesions in the model group mice were significantly higher than those in the blank control group, indicating that the psoriasis model was successfully established.

[0073] Compared with the model group, all treatment groups showed significant reductions in PASI scores and epidermal thickness. Among them, the ointment of Example 1 showed the most significant improvement, with its PASI score and epidermal thickness being significantly lower than those of the positive control group and Examples 5-7, and the differences were statistically significant (P<0.05 or P<0.01). This indicates that the ointment of Example 1 of the present invention has a significantly better effect on improving skin lesions and epidermal hyperplasia in psoriatic mice than existing technical solutions.

[0074] The above results indicate that the calcipotriol betamethasone ointment prepared by the excipient combination described in this invention has excellent anti-psoriasis efficacy, which is superior to the disclosed prior art formulations.

[0075] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0076] As used in this invention, the terms "comprising" and "including" are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0077] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.

[0078] The scope of protection of this invention is not limited to the above embodiments. Any variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of this invention are included in this invention and are protected by the appended claims.

Claims

1. A calcipotriol betamethasone ointment, characterized in that, The ointment comprises calcipotriol, betamethasone dipropionate, propyl gallate, polyglycerol-3-diisostearate, solvent, and matrix.

2. The calcipotriol betamethasone ointment according to claim 1, characterized in that, The content of calcipotriol is 0.005%, and the content of betamethasone dipropionate is 0.0643%.

3. The calcipotriol betamethasone ointment according to claim 1, characterized in that, The content of propyl gallate is 0.02-0.2%, and the content of polyglycerol-3-diisostearate is 1.5-3%.

4. The calcipotriol betamethasone ointment according to claim 3, characterized in that, The content of propyl gallate is 0.05~0.1%, and the content of polyglycerol-3-diisostearate is 2~2.5%.

5. The calcipotriol betamethasone ointment according to claim 1, characterized in that, The solvent is a medium-chain triglyceride, and the matrix includes liquid paraffin and nephrite.

6. The calcipotriol betamethasone ointment according to claim 5, characterized in that, The content of the medium-chain triglycerides is 4-6%, the content of the liquid paraffin is 2-4%, and the balance is nephrite.

7. A method for preparing calcipotriol betamethasone ointment as described in any one of claims 1-6, characterized in that, Includes the following steps: (1) Heat the solid matrix until it melts and keep it at that temperature for later use; (2) Dissolve calcipotriol in a solvent, add propyl gallate and polyglycerol-3-diisostearate to dissolve, and obtain a drug-containing mixed solution; (3) Disperse betamethasone dipropionate in a liquid matrix to obtain a dispersion; (4) Under stirring conditions, the drug-containing mixed solution from step (2) and the dispersion from step (3) are added to the molten solid matrix from step (1), mixed evenly, cooled, and then filled to obtain the final product.

8. The method for preparing calcipotriol betamethasone ointment according to claim 7, characterized in that, The solid matrix is ​​white paraffin, the solvent is medium-chain triglycerides, and the liquid matrix is ​​liquid paraffin.

9. The method for preparing calcipotriol betamethasone ointment according to claim 7, characterized in that, The heating and melting temperature in step (1) is 75-80°C, and the heat preservation temperature is 55-65°C; the dispersion in step (3) is carried out under ultrasonic conditions, and the dispersion time is 2-5 minutes.

10. The method for preparing calcipotriol betamethasone ointment according to claim 7, characterized in that, The amount of liquid matrix used in step (3) is 80% of the liquid matrix prescription amount, and the remaining 20% ​​of the liquid matrix is ​​used for rinsing.

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