A method for preparing tacrolimus ointment by nitrogen purging and sequential dilution

Abstract

The present application relates to a method for preparing a tacrolimus ointment by nitrogen purging and sequentially diluting the ointment, comprising the following steps: mixing an emollient, an emulsifier, a hardener, and an ointment base, heating and melting them, blowing nitrogen into the melted ointment base to obtain an ointment base A; adding purging nitrogen into a solvent, adding tacrolimus into the solvent, dissolving it, purging nitrogen, and heating to obtain a drug phase; adding the drug phase into the ointment base A, homogenizing to obtain an emulsified ointment; mixing an emollient, an emulsifier, a hardener, and an ointment base, heating and melting them, and blowing nitrogen to obtain an ointment base B; adding the ointment base B into the emulsified ointment, and homogenizing to obtain a mixed ointment; mixing an emollient, an emulsifier, a hardener, and an ointment base, heating and melting them, and blowing nitrogen to obtain an ointment base C; adding the ointment base C into the mixed ointment, and homogenizing to obtain an ointment block; cooling; and stirring and mixing the cooled ointment block to obtain the tacrolimus ointment. This application has the effect of improving the performance of tacrolimus ointment products.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical products, and in particular to a method for preparing tacrolimus ointment by nitrogen purging and sequential dilution. Background Art

[0002] Atopic dermatitis is a common chronic, recurrent, inflammatory skin disease, also known as atopic eczema, formerly known as atopic dermatitis and hereditary allergic dermatitis.

[0003] Tacrolimus ointment is mainly used to treat severe atopic dermatitis and can improve symptoms. It is suitable for second-line therapy for short-term and non-continuous chronic treatment of moderate to severe atopic dermatitis in non-immunocompromised adults and children who are ineffective or inappropriate for other topical prescription treatments for atopic dermatitis.

[0004] Chinese patent with publication number CN116077421A discloses tacrolimus ointment and its preparation method, which solves the problem of tacrolimus impurities in the ointment matrix.

[0005] The Chinese patent with the publication number CN114028325A discloses the formula of tacrolimus ointment and its preparation method. Although the ointment base is melted at a temperature of 65-85°C, the drug solution is added at a temperature of 35-45°C. At this temperature, the ointment structure is relatively hard and the distribution of tacrolimus in the ointment base is poor, which also leads to the separation of the drug solution from the ointment base.

[0006] Chinese patent publication number CN110403902A discloses a method for preparing tacrolimus ointment, which specifically solves the problem that the ointment is prone to form small lumps when rapidly cooled.

[0007] The Chinese patent with the publication number CN109820814A discloses a tacrolimus ointment and a preparation method thereof, wherein the claimed formula composition and process can make the ointment have better stability and uniformity. However, the formula contains titanium dioxide, which makes the ointment more greasy than the original ointment, and the titanium dioxide particles are clearly visible when applied, resulting in poor patient compliance.

[0008] The skin of people with atopic dermatitis can become dry, itchy and inflamed, so special care is needed for the affected skin, so the formula should be more emollient than other products. Summary of the invention

[0009] In order to improve the performance of tacrolimus and provide a better moisturizing effect, the present application provides a method for preparing tacrolimus ointment by nitrogen purging and sequential dilution.

[0010] The present application provides a method for preparing tacrolimus ointment by nitrogen purging and sequential dilution, which adopts the following technical scheme: A method for preparing tacrolimus ointment by nitrogen purging and sequential dilution, comprising the following steps: Preparation of ointment base A: mixing an emollient, an emulsifier, a hardener, and an ointment base in an ointment mixer, heating and heating the components to melt the components, and blowing nitrogen into the melted ointment base to obtain ointment base A; preparing a drug phase: purging a solvent with nitrogen, adding tacrolimus into the solvent, dissolving it, then purging nitrogen, and heating to obtain a drug phase; Emulsification: Add the drug phase to the ointment base A and homogenize to obtain; Preparation of ointment base B: mixing an emollient, an emulsifier, a hardener, and an ointment base in an ointment mixer, heating to melt the above components, and blowing nitrogen into the melted ointment base to obtain ointment base B; Mixing: adding the melted ointment base B to the emulsified ointment, and homogenizing to obtain a mixed ointment; Preparation of ointment base C: mixing an emollient, an emulsifier, a hardener, and an ointment base in an ointment mixer, heating and heating the components to melt the components, and blowing nitrogen into the melted ointment base to obtain ointment base C; Mixing: adding the melted ointment base C to the mixed ointment and homogenizing to obtain an ointment block; Cooling: Allow the ointment mass to cool; Mixing: Stir and mix the cooled ointment blocks to obtain tacrolimus ointment.

[0011] Preferably, the emollient comprises isopropyl myristate and medium chain triglycerides.

[0012] Preferably, the solvent comprises propylene glycol monolaurate.

[0013] Preferably, in terms of weight percentage, the concentration of tacrolimus is 0.03-0.1% w / w.

[0014] Preferably, the emulsifier includes glyceryl behenate, and the hardener includes hard paraffin and white wax.

[0015] Preferably, the ointment base comprises liquid paraffin and white soft paraffin.

[0016] In summary, the present application includes at least one of the following beneficial technical effects: 1. The formulation composition of the present application has better stability in terms of impurity spectrum and can maintain the effectiveness of tacrolimus throughout the shelf life. After adding an emollient, the emollient effect of tacrolimus in the skin can be further improved to further improve the performance of the tacrolimus ointment. At the same time, due to the nitrogen purging during the processing, the impurity concentration of the prepared ointment can be reduced; 2. Isopropyl myristate is a colorless, transparent, oily liquid that can moisturize and nourish the skin. It has good absorbability and can effectively contact the hair follicles in the cortex, penetrate deep into the cortex, and replace the active components in the preparation to give full play to the effective ingredients. Medium-chain triglycerides are naturally present in foods such as palm kernel oil and coconut oil. They have good moisturizing and humidifying properties and can form a protective film on the skin surface to reduce water loss, keeping the skin moisturized and soft, refreshing and easy to absorb. When added with isopropyl myristate as an emollient, it can synergistically improve the overall emollient properties of the preparation and promote the absorption of the effective ingredients, further improving the permeability of tacrolimus in the skin and the emollient effect of the matrix on dry, itchy and inflamed skin. 3. When propylene glycol monolaurate is added as a penetration enhancer, it increases skin permeability and retention in the skis without entering the blood circulation, thereby further improving the safety and effectiveness of the prepared preparation. DETAILED DESCRIPTION

[0017] The embodiments of the present application will be described in detail below in conjunction with the examples, but it will be appreciated by those skilled in the art that the following examples are only used to illustrate the present application and should not be considered as limiting the scope of the present application. In the examples, if specific conditions are not specified, they are carried out according to normal conditions or the conditions recommended by the manufacturer. If the manufacturer is not specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0018] Example 1 The material dosage is shown in Table 1; Table 1 Formula composition Serial number Ingredient name Effect of ingredients %w / w 1 Tacrolimus active 0.03 2 Propylene glycol monolaurate Solvents 5.00 3 Isopropyl myristate Emollients 2.00 4 Medium Chain Triglycerides Emollients 3..00 5 Glyceryl Behenate Emulsifier 2.00 6 Hard paraffin Hardener 3.00 7 white wax Hardener 3.50 8 Liquid paraffin Ointment base 11.00 9 White soft paraffin Ointment base qsto 100 Preparation steps: Preparation of ointment base A: isopropyl myristate, medium chain triglyceride, glyceryl hydrochloride, dietetic acid, white wax, liquid paraffin and white soft paraffin are charged into an ointment mixer of suitable size, the ingredients are heated and melted at a temperature of 60 to 65° C. using a nozzle speed of 0.5 to 2 m / s, nitrogen is blown into the melted ointment base at a nozzle speed of 0.5 to 2 m / s for 10 min at a temperature of 60 to 65° C. to obtain ointment base A; Preparing a drug phase: purging nitrogen in a solvent propylene glycol monolaurate at a needle tip speed of 0.5 to 2 m / s for 10 minutes at room temperature, then adding tacrolimus to the propylene glycol monolaurate, dissolving at a nozzle speed of 0.5 to 2 m / s at room temperature, purging nitrogen in the drug solution at a tip speed of 0.5 to 2 m / s for 10 minutes at room temperature, and heating the drug solution to 60 to 6° C. at a nozzle speed of 0.5 to 2 m / s to obtain a drug phase; Emulsification: Add the drug phase to the ointment base A, homogenize at a low shear rate of 0.5 to 0.75 m / s for 10 min at a temperature of 60 to 65°C to obtain an emulsified ointment; Preparation of ointment base B: isopropyl myristate, medium chain triglyceride, glyceryl hydrochloride, dietetic acid, white wax, liquid paraffin and white soft paraffin are charged into an ointment mixer of suitable size, the ingredients are heated and melted at a temperature of 60 to 65° C. using a nozzle speed of 0.5 to 2 m / s, nitrogen is blown into the melted ointment base at a nozzle speed of 0.5 to 2 m / s for 10 min at a temperature of 60 to 65° C. to obtain ointment base B; Mixing: adding the lubricated ointment base B to the emulsified ointment, homogenizing at a shear rate of 0.5 to 0.75 m / s and a temperature of 60 to 65° C. for 10 min to obtain a mixed ointment; Preparation of ointment base C: adding isopropyl myristate, medium chain triglyceride, glyceryl hydrochloride, dietary fiber, white wax, liquid paraffin and white soft paraffin into an ointment mixer of suitable size, heating and melting the ingredients at a temperature of 60 to 65° C. using a nozzle speed of 0.5 to 2 m / s, blowing nitrogen into the melted ointment base at a nozzle speed of 0.5 to 2 m / s for 10 min at a temperature of 60 to 65° C. to obtain ointment base C; Mixing: Add the melted ointment base C to the mixed ointment, and homogenize at a shear rate of 0.5 to 0.75 m / s and a temperature of 60 to 65° C. for 10 min to obtain an ointment block; Cooling: Cool the ointment mass to a target temperature of 38-40°C at a homogenizer head speed of 0.1-0.25 m / s; Mixing: Stir the cooled ointment mass at a temperature of 38-40° C. and a stirring speed of 0.01-0.1 m / s for 30 minutes to obtain tacrolimus ointment.

[0019] Example 2 The material usage is shown in Table 2; Table 2 Formulation Serial number Ingredient name Effect of ingredients %w / w 1 Tacrolimus active 0.1 2 Propylene glycol monolaurate Solvents 5.00 3 Isopropyl myristate Emollients 2.00 4 Medium Chain Triglycerides Emollients 3..00 5 Glyceryl Behenate Emulsifier 2.00 6 Hard paraffin Hardener 3.00 7 white wax Hardener 3.50 8 Liquid paraffin Ointment base 11.00 9 White soft paraffin Ointment base qsto 100 Preparation steps: Preparation of ointment base A: isopropyl myristate, medium chain triglyceride, glyceryl hydrochloride, dietetic acid, white wax, liquid paraffin and white soft paraffin are charged into an ointment mixer of suitable size, the ingredients are heated and melted at a temperature of 60 to 65° C. using a nozzle speed of 0.5 to 2 m / s, nitrogen is blown into the melted ointment base at a nozzle speed of 0.5 to 2 m / s for 10 min at a temperature of 60 to 65° C. to obtain ointment base A; Preparing a drug phase: purging nitrogen in a solvent propylene glycol monolaurate at a needle tip speed of 0.5 to 2 m / s for 10 minutes at room temperature, then adding tacrolimus to the propylene glycol monolaurate, dissolving at a nozzle speed of 0.5 to 2 m / s at room temperature, purging nitrogen in the drug solution at a tip speed of 0.5 to 2 m / s for 10 minutes at room temperature, and heating the drug solution to 60 to 6° C. at a nozzle speed of 0.5 to 2 m / s to obtain a drug phase; Emulsification: Add the drug phase to the ointment base A, homogenize at a low shear rate of 0.5 to 0.75 m / s for 10 min at a temperature of 60 to 65°C to obtain an emulsified ointment; Preparation of ointment base B: isopropyl myristate, medium chain triglyceride, glyceryl hydrochloride, dietetic acid, white wax, liquid paraffin and white soft paraffin are charged into an ointment mixer of suitable size, the ingredients are heated and melted at a temperature of 60 to 65° C. using a nozzle speed of 0.5 to 2 m / s, nitrogen is blown into the melted ointment base at a nozzle speed of 0.5 to 2 m / s for 10 min at a temperature of 60 to 65° C. to obtain ointment base B; Mixing: adding the lubricated ointment base B to the emulsified ointment, homogenizing at a shear rate of 0.5 to 0.75 m / s and a temperature of 60 to 65° C. for 10 min to obtain a mixed ointment; Preparation of ointment base C: adding isopropyl myristate, medium chain triglyceride, glyceryl hydrochloride, dietary fiber, white wax, liquid paraffin and white soft paraffin into an ointment mixer of suitable size, heating and melting the ingredients at a temperature of 60 to 65° C. using a nozzle speed of 0.5 to 2 m / s, blowing nitrogen into the melted ointment base at a nozzle speed of 0.5 to 2 m / s for 10 min at a temperature of 60 to 65° C. to obtain ointment base C; Mixing: Add the melted ointment base C to the mixed ointment, and homogenize at a shear rate of 0.5 to 0.75 m / s and a temperature of 60 to 65° C. for 10 min to obtain an ointment block; Cooling: Cool the ointment mass to a target temperature of 38-40°C at a homogenizer head speed of 0.1-0.25 m / s; Mixing: Stir the cooled ointment mass at a temperature of 38-40° C. and a stirring speed of 0.01-0.1 m / s for 30 minutes to obtain tacrolimus ointment.

[0020] Comparative Example 1 The material usage is shown in Table 3; Table 3 Formula composition Preparation steps: Preparation of ointment base: Put all the hard paraffin, white paraffin, liquid paraffin and white paraffin into an ointment mixer of suitable size, heat and melt the ingredients at a temperature of 60 to 65°C, and the speed of the stirring head is 50-100 rpm; Preparation of drug phase: adding tacrolimus to 5% w / w propylene carbonate, dissolving at room temperature at a speed of 500-1000 r / min, heating the drug solution to 60-65° C. at a speed of 500-1000 r / min to obtain a drug phase; Emulsification: Add the drug phase to the molten ointment base, homogenize at a high shear rate of 2000-4000 for 30 minutes at a temperature of 60-65°C to obtain an ointment; Cooling: Cool the ointment to the target temperature of 38-40°C at a speed of 500-100 r / min to obtain an ointment mass; Mixing: Mix the ointment mass for 30 minutes at a temperature of 38-40° C. and a stirring speed of 500-1000 r / min to obtain tacrolimus ointment.

[0021] Comparative Example 2 The material usage is shown in Table 4; Table 4 Formula composition Serial number Ingredient name Effect of ingredients %w / w 1 Tacrolimus active 0.1 2 Propylene glycol monolaurate Solvents 5.00 3 Hard paraffin Hardener 3.00 4 white wax Hardener 3.50 5 Liquid paraffin Ointment base 11.00 6 White soft paraffin Ointment base qsto 100 Preparation steps: Preparation of ointment base: Put all the hard paraffin, white paraffin, liquid paraffin and white paraffin into an ointment mixer of suitable size, heat and melt the ingredients at a temperature of 60 to 65°C, and the speed of the stirring head is 50-100 rpm; Preparation of drug phase: adding tacrolimus to 5% w / w propylene carbonate, dissolving at room temperature at a speed of 500-1000 r / min, heating the drug solution to 60-65° C. at a speed of 500-1000 r / min to obtain a drug phase; Emulsification: Add the drug phase to the molten ointment base, homogenize at a high shear rate of 2000-4000 for 30 minutes at a temperature of 60-65°C to obtain an ointment; Cooling: Cool the ointment to the target temperature of 38-40°C at a speed of 500-100 r / min to obtain an ointment mass; Mixing: Mix the ointment mass for 30 minutes at a temperature of 38-40° C. and a stirring speed of 500-1000 r / min to obtain tacrolimus ointment.

[0022] Bulk uniformity studies: Six samples were collected from each of the top, middle and bottom locations of the sample, and the samples were tested for tacrolimus and spherical particle size distribution [D90] using an effective analytical method, and the test results were filled in Table 5.

[0023] Table 5 Bulk uniformity study results The bulk uniformity study results show that the Examples have excellent volume uniformity and a constant spherical size distribution [D90] compared to the Comparative Examples.

[0024] Impurity studies: The samples were analyzed for impurities under initial and accelerated stable storage conditions using a validated analytical method and the test results are reported in Table 6.

[0025] Table 6 Impurity research results The results of the impurity study show that, compared with the comparative examples, the impurity concentration in the examples was significantly reduced due to nitrogen purging during the processing; the tacrolimus concentration in comparative example 1 was lower, while the degradation rate was higher, while the tacrolimus concentration in comparative example 2 was higher, while the degradation rate was lower, but the degradation rate of tacrolimus in the examples did not change with the concentration, and since the degradation product was controlled, the efficacy of the preparation was maintained within a certain range.

[0026] In vitro drug release studies: Using artificial membrane and 20% tetrahydrofuran aqueous solution as receptor medium, an in vitro release study was conducted in a vertical Franz diffusion cell at a temperature of 32±0.5°C and a stirring speed of 600 rpm for 8 hours, and the test results are entered in Table 7.

[0027] Table 7 In vitro drug release study results time Example 1 Example 2 Comparative Example 1 Comparative Example 2 0.5h 18.7 17.1 19.1 18.1 1h 32.5 29.4 34.7 30.6 2h 48.4 45.6 44.9 44.6 3h 60.8 59.6 64.1 58.9 4h 78.9 80.3 80.4 79.2 6h 86.3 89.3 84.5 88.4 8h 89.6 94.5 88.7 93.5 The results of in vitro drug release studies showed that the release amounts of the embodiments and comparative examples were the same throughout the entire process.

[0028] In vitro drug permeation studies: The in vitro permeation study was conducted in a vertical Franz diffusion cell at a temperature of 32 ± 0.5 °C and a rotation speed of 600 r / min using porcine anterior abdominal skin and 20% ethanol aqueous solution as the receptor medium for 24 hours, and the test results are entered in Table 8.

[0029] Table 8 In vitro drug permeation study results Sample Residue on the skin surface Skin retention rate Skin permeability Mass balance Example 1 70.85±3.82％ 27.92±2.56％ 1.0±0.50％ 99.77±2.29％ Example 2 59.22±2.59％ 38.16±0.89％ 1.52±0.69％ 98.90±1.39％ Comparative Example 1 73.42±3.82％ 15.82±1.31％ 10.73±3.84％ 99.97±2.99％ Comparative Example 2 60.15±4.80％ 21.16±0.89％ 18.26±4.05％ 99.57±3.25％ The results of in vitro drug permeation studies show that although the drug release of the embodiment is higher, its permeability and skin retention rate are much higher than those of the comparative example, which indicates that the preparation has better drug efficacy than the comparative example. In addition, the amount of the embodiment entering the receptor medium is negligible, which means that it will not enter the blood circulation, thereby avoiding adverse reactions.

[0030] Skin Irritation Studies: Guinea pigs (400-500 g), of either sex, were used for the skin irritation test. The animals were fed with standard animal feed and had free access to water. The animals were housed under standard conditions. They were divided into two groups of four, namely Group 1: Example 1 and Group 2: Example 2.

[0031] The back hair was shaved with a razor, and a 4 cm2 area was marked. The sample (500 mg / guinea pig) was applied twice a day for 15 days, 30 days, and 90 days, and the site was observed for any sensitivity and reaction. The sensitivity was divided into 0, 1, 2, and 3 levels, representing no reaction, mild patchy erythema, patchy erythema, and severe erythema with or without edema, respectively, and the test results were filled in Table 9.

[0032] Table 9 Skin irritation study results This specific embodiment is only an explanation of the present application, and it is not a limitation of the present application. Through the above description, relevant staff can make various changes and modifications without deviating from the technical idea of ​​the present application. The technical scope of the present application is not limited to the content in the specification, and its technical scope must be determined according to the scope of the claims.

Claims

1. A method for preparing a tacrolimus dye paste by nitrogen purging and sequential dilution, characterized in that: The steps include: Preparation of ointment base A: mixing an emollient, an emulsifier, a hardener, and an ointment base in an ointment mixer, heating and heating the components to melt the components, and blowing nitrogen into the melted ointment base to obtain ointment base A; preparing a drug phase: purging a solvent with nitrogen, adding tacrolimus into the solvent, dissolving it, then purging nitrogen, and heating to obtain a drug phase; Emulsification: Add the drug phase to the ointment base A and homogenize to obtain; Preparation of ointment base B: mixing an emollient, an emulsifier, a hardener, and an ointment base in an ointment mixer, heating to melt the above components, and blowing nitrogen into the melted ointment base to obtain ointment base B; Mixing: adding the melted ointment base B to the emulsified ointment, and homogenizing to obtain a mixed ointment; Preparation of ointment base C: mixing an emollient, an emulsifier, a hardener, and an ointment base in an ointment mixer, heating and heating the components to melt the components, and blowing nitrogen into the melted ointment base to obtain ointment base C; Mixing: adding the melted ointment base C to the mixed ointment and homogenizing to obtain an ointment block; Cooling: Allow the ointment mass to cool; Mixing: Stir and mix the cooled ointment blocks to obtain tacrolimus ointment.

2. The method for preparing tacrolimus ointment by nitrogen purging and sequential dilution according to claim 1, characterized in that: The emollients include isopropyl myristate and medium chain triglycerides.

3. The method for preparing tacrolimus ointment by nitrogen purging and sequential dilution according to claim 1, characterized in that: The solvent includes propylene glycol monolaurate.

4. The method for preparing tacrolimus ointment by nitrogen purging and sequential dilution according to claim 1, characterized in that: In terms of weight percentage, the concentration of tacrolimus is 0.03-0.1% w / w.

5. The method for preparing tacrolimus ointment by nitrogen purging and sequential dilution according to claim 1, characterized in that: The emulsifier includes glyceryl behenate, and the hardener includes hard paraffin and white wax.

6. The method for preparing tacrolimus ointment by nitrogen purging and sequential dilution according to claim 1, characterized in that: The ointment base comprises liquid paraffin and white soft paraffin.

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