A kind of crisaborole ointment and preparation method thereof

Abstract

The present invention relates to a crisaborole ointment, comprising the following raw materials in parts by mass: 1-3 parts of crisaborole, 68-76 parts of white vaseline, 7-12 parts of propylene glycol, 2.5-4 parts of polyols, 4-6 parts of mono- and distearic glycerides, 1-2 parts of 2-hexyldecanoic acid, 2-4 parts of cetearyl glucoside, 0.1-0.4 parts of stearate, 0.05-0.3 parts of antioxidant and 0.003-0.006 parts of chelating agent. The crisaborole ointment prepared by the present invention has good mixing uniformity; through the reasonable compatibility of auxiliary materials, especially the compounding of 2-hexyldecanoic acid, cetearyl glucoside and stearate, the ointment droplet particle size span can be controlled between 1.3-1.6, D 90 About 20 μm, D 50 About 8μm, easier to squeeze out and apply, uniform particle size is conducive to treatment comfort and compliance, and can better restore the structure after application to maintain the original properties of the ointment.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a crisaborole ointment and a preparation method thereof. Background Art

[0002] Clisborole is a nonsteroidal phosphodiesterase 4 (PDE-4) inhibitor. PDE4 inhibitors can reduce PDE levels, increase cAMP, activate protein kinase A, inhibit NFκB and NF-AT pathways, inhibit the production of proinflammatory cytokines, and participate in regulating inflammatory responses mediated by a variety of immune cells. The specific mechanism of action of Clisborole in the treatment of atopic dermatitis is still unclear.

[0003] Atopic dermatitis (AD) is one of the most common chronic inflammatory itch diseases in the field of autoimmune diseases. It has a variety of clinical manifestations, ranging from mild symptoms such as simple pityriasis (dry hypopigmented spots) or hand eczema to severe symptoms of erythrodermic eczema. At present, the prevalence of AD is mainly focused on children and adolescents. Epidemiological surveys show that the prevalence of infants aged 1-12 months is 30%, and the prevalence of children aged 1-7 years is 13%; most children with AD are mild (74.6%), followed by moderate (23.96%), and severe cases are rare. There are a large number of patients with atopic dermatitis in my country, and the vast majority of them are mild to moderate AD. Most of the patients who seek medical treatment are under 12 years old, and the prevalence of AD is on the rise.

[0004] Clisborole is unstable in water and light conditions. It is dissolved in a solvent of a non-aqueous polyol and protected with a metal chelating agent. The raw material solution is dispersed in a matrix composed of a hardener, an ointment base, and an antioxidant to make an ointment, which can fully guarantee the stability and effectiveness of Clisborole. However, Clisborole ointment is currently very easy to stratify and has poor mixing uniformity. Therefore, the problem of content uniformity restricts the large-scale production of Clisborole ointment. From the perspective of quality by design, it is crucial to uniformly dissolve and mix the early materials prepared by Clisborole ointment. In addition, due to the lack of uniformity and stability of emulsification and the use of a hardener, the uniformity of the droplet size of the obtained Clisborole ointment is poor and relatively dispersed, which is not conducive to the distribution of the active ingredients of the product ointment and the application of patients, thereby affecting the efficacy of Clisborole ointment and the comfort and compliance of treatment.

[0005] CN117398332A discloses a crisaborole ointment, comprising crisaborole or a pharmaceutically acceptable salt or hydrate or solvate thereof, propylene glycol and propylene glycol monocaprylate. The patented crisaborole ointment shows lower impurity content than commercially available preparations under long-term and accelerated conditions, i.e., has higher stability.

[0006] CN114767623A discloses a crisaborole ointment, which is composed of crisaborole, fatty alcohol, metal chelating agent, oil antioxidant, white vaseline, wax hardener and surfactant; the cone penetration of the white vaseline is 160-240 units, and the impurity absorbance at a wavelength of 290nm is ≤0.07. The patent uses specific white vaseline as petrolatum to prepare crisaborole ointment, and the raw material phase droplets are smaller and easier to be absorbed by the skin; the yield stress is smaller, and it is easier to squeeze out and apply during use, and the structure can be restored after application to maintain the original properties of the ointment; the chemical stability of crisaborole is better guaranteed; the droplets can stably maintain the dispersed particle size and uniform distribution under the premise of ensuring homogeneity, thereby ensuring the physical stability of the ointment.

[0007] CN111658602A discloses a method for preparing a stable crisaborole ointment, comprising the following steps: preparing an oil phase: preparing an oil phase at a temperature of 70-80°C, the oil phase being made of one or more bases, and maintaining the temperature of the oil phase at 70-80°C; preparing an active phase: preparing an active phase at a temperature of 30-60°C, the active phase being made of one or more solvents and one or more complexing agents, and maintaining the temperature of the active phase at 30-60°C; crisaborole is also added to the active phase; emulsification: adding the active phase to the oil phase at a temperature of 70-80°C, stirring for 5-20 minutes to complete emulsification to obtain an ointment; cooling: cooling the ointment to 35-45°C at a rate of 0.5 to 2°C / min to obtain an ointment. This patent improves the stability of the ointment, avoids large viscosity changes in the ointment, and prevents the ointment from having oil droplet particle sizes that are not tightly and evenly dispersed.

[0008] CN110464702A discloses a crisaborole ointment, comprising 2% crisaborole, 60-90% cream base, 5-20% solvent, transdermal enhancer, 0.5-8% emulsifier, 0.05-0.5% chelating agent, and 0.05-0.5 antioxidant.

[0009] However, the above-mentioned prior art disclosed crisaborole ointment still has the defect of poor uniformity of droplet size, which will affect the distribution of the active ingredients of the ointment and the application by the patient, thus possibly affecting the safety and effectiveness of the product. After a large number of experiments, the inventor found that the main reason for the poor uniformity of droplet size in the ointment is the excessively fast stirring rate and the presence of conventional wax hardeners, such as paraffin and beeswax. Summary of the invention

[0010] In order to solve the defect of poor uniformity of droplet particle size in the prior art crisaborole ointment preparation, the primary purpose of the present invention is to provide a method for preparing crisaborole ointment so as to have good stability, content uniformity and droplet particle size uniformity.

[0011] To achieve this object, the present invention provides a crisaborole ointment, comprising the following raw materials in parts by mass: 1-3 parts of crisaborole, 68-76 parts of white vaseline, 7-12 parts of propylene glycol, 2.5-4 parts of polyols, 4-6 parts of mono- and distearic glyceryl, 1-2 parts of 2-hexyldecanoic acid, 2-4 parts of cetearyl glucoside, 0.1-0.4 parts of stearate, 0.05-0.3 parts of antioxidant and 0.003-0.006 parts of chelating agent.

[0012] Preferably, the crisaborole ointment comprises the following raw materials in parts by mass: 2 parts of crisaborole, 76-80 parts of white vaseline, 8-9 parts of propylene glycol, 2.7-3.5 parts of polyols, 4.6-5.3 parts of mono- and distearic glyceryl, 1.3-1.8 parts of 2-hexyldecanoic acid, 2.8-3.4 parts of cetearyl glucoside, 0.22-0.32 parts of stearate, 0.1-0.2 parts of antioxidant and 0.003-0.004 parts of chelating agent.

[0013] In a preferred technical solution of the present invention, the crisaborole ointment comprises the following raw materials in parts by mass: 2 parts of crisaborole, 76.0365 parts of white vaseline, 9 parts of propylene glycol, 3.1 parts of polyols, 4.9 parts of mono- and distearic glyceryl, 1.5 parts of 2-hexyldecanoic acid, 3.1 parts of cetearyl glucoside, 0.26 parts of stearate, 0.1 parts of antioxidant and 0.0035 parts of chelating agent.

[0014] Furthermore, the stearate is selected from at least one of sodium stearate, potassium stearate, magnesium stearate and calcium stearate.

[0015] Furthermore, the polyol is selected from at least one of polyethylene glycol, polypropylene glycol and polytetrahydrofuran, and the number average molecular weight of the polyol is 400-600.

[0016] The present invention does not need to use a hardener such as paraffin wax, thereby avoiding the phenomenon of uneven droplet size caused by conventional wax hardeners during the emulsification process. The present invention uses a compound of 2-hexyldecanoic acid, cetearyl glucoside and stearate, which can also play the role of a hardener, but the compounding and use in a specific ratio can significantly improve the uniformity of the particle size of the prepared crisaborole ointment.

[0017] The chelating agent is selected from at least one of calcium sodium edetate and disodium edetate; the antioxidant is selected from at least one of butylated hydroxytoluene, ascorbic acid, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, thiodipropionic acid, dilauryl thiodipropionate, and tert-butylhydroquinone.

[0018] The second object of the present invention is to provide a method for preparing the above-mentioned crisaborole ointment, comprising the following steps:

[0019] (S1) under stirring conditions, white vaseline is heated to 70-80° C. and melted into a transparent liquid, mono- and distearic acid glyceryl, 2-hexyldecanoic acid, cetearyl glucoside, and an antioxidant are added, and stirred evenly until clear, and stirring is maintained, and vacuum is evacuated. The temperature is lowered to 40-50° C. under vacuum conditions, and maintained at 40-50° C. to keep the system clear, thereby obtaining an oil phase;

[0020] (S2) mixing propylene glycol, polyol, chelating agent and stearate under heating and stirring conditions, adding the crisaborole raw material, and stirring until dissolved and clarified to obtain an active phase;

[0021] (S3) slowly transferring the oil phase and the active phase to an emulsifying tank through a valve, mixing the oil phase and the active phase evenly under vacuum conditions and maintaining the temperature at 40-50° C. and stirring, and then homogenizing; after homogenizing, maintaining the vacuum degree, cooling to 25-35° C., and filling to obtain crisaborole ointment.

[0022] Furthermore, the vacuum condition is a vacuum degree of -0.01 MPa to -0.1 MPa (relative vacuum degree). Multiple operations under vacuum conditions ensure that the product is free of bubbles, and the produced product is delicate and has a good appearance.

[0023] Furthermore, in steps (S1) and (S3), the stirring speed is 30-60 rpm,

[0024] Further, in step (S2), the heating temperature is 45-60°C, and the stirring speed is 50-75rpm. Propylene glycol is added twice, the first time is 80-90% of propylene glycol and polyol, chelating agent and stearate are prepared together with the active phase, and the second time is after the active phase is transferred to the emulsification tank, the active phase tank is rinsed with the remaining propylene glycol and also transferred to the emulsification tank.

[0025] Further, in step (S3), the homogenization parameters are: homogenization speed 1000~2500rpm, stirring speed 30rpm~60rpm, homogenization time 20~60min; then adjust the cooling rate to cool down gradually, slowly pass 20~25℃ cooling water, and keep it at 40℃, 36℃, and 32℃ for 10min~20min, so that the product will not produce agglomeration during the cooling process. The filling specifications are 30g / piece to 90g / piece, and the heat sealing temperature during filling is 260-360℃.

[0026] Compared with the prior art, the present invention has the following advantages:

[0027] 1. The coefficient of variation CV% of the mixing uniformity of the crisaborole ointment prepared by the present invention is low, and the uniformity is good; through the reasonable compatibility of the excipients, especially the compounding of 2-hexyldecanoic acid, cetearyl glucoside and stearate, the ointment droplet size span can be controlled between 1.3-1.6, D 90 About 20μm, D 50 About 8μm, easier to squeeze out and apply, uniform particle size is conducive to treatment comfort and compliance, and can better restore structure after application to maintain the original properties of the ointment;

[0028] 2. The preparation process of the crisaborole ointment of the present invention is simple, easy to control, convenient to operate, suitable for industrial production, with little growth of impurities during the preparation process and good stability. DETAILED DESCRIPTION

[0029] The specific implementation modes of the present invention are further described below in conjunction with embodiments, but the present invention is not limited thereto.

[0030] Example 1

[0031] The raw materials are shown in Table 1.

[0032] Table 1 Criborol ointment formula

[0033] .

[0034] The preparation method is as follows:

[0035] (S1) Add white vaseline to the oil phase tank, set the stirring speed to 30 rpm, turn on heating and stirring, control the material temperature to 70-80°C, until the white vaseline melts and clarifies into a transparent liquid; add mono- and distearic acid glyceryl, 2-hexyldecanoic acid, cetearyl glucoside, and butylated hydroxytoluene, set the stirring speed to 30 rpm, control the material temperature to 70-80°C, until it is visually melted and clear; turn on the cooling water, adjust the cooling water temperature to 25±2°C, set the vacuum degree to -0.1Mpa, the stirring speed to 30rpm, reduce the material temperature in the emulsification tank to 45°C, observe that there is no wall sticking, the overall fluidity is good, and transfer to the emulsification tank to form the oil phase.

[0036] (S2) Add 80% propylene glycol, PEG400, sodium calcium edetate, and sodium stearate to the active phase tank, turn on the heating, control the material temperature in the range of 45-50°C, stir at a speed of 300 rpm, and stir until dissolved and clarified; add the criborol API to the active phase tank, control the material temperature in the range of 45-50°C, until dissolved and clarified, and set aside; after the active phase is transferred to the vacuum emulsification tank, rinse the active phase tank with the remaining propylene glycol and also transfer it to the vacuum emulsification tank.

[0037] (S3) Open the valves of the active phase and oil phase tanks, transfer the active phase and oil phase materials to the vacuum emulsification tank, control the material temperature at 40-50°C, set the stirring speed to 30rpm, the vacuum degree to -0.1MPa, mix evenly, and visually observe that the material is in good stirring state; after mixing, homogenize: set the homogenization speed to 1000rpm, set the stirring speed to 40rpm, and the homogenization time to 60min. Stir continuously during the entire homogenization process, and maintain the material temperature at 40-50°C to obtain an ointment; turn on the cooling water, adjust the cooling water temperature to 25°C, the vacuum degree to -0.1MPa, cool the ointment under vacuum conditions, set the stirring speed to 30rpm, cool to 25°C, take samples and detect the content. Fill according to the packaging specification of 30g / piece. Set the temperature of the insulation circulating water of the filling machine hopper to 35°C, and add the material to the filling machine hopper. Set the filling speed to ≤100 pieces / min, the heat sealing temperature to 300°C, and run the equipment for filling.

[0038] Example 2

[0039] The other conditions are the same as those in Example 1, except that the formula of Example 2 is shown in Table 2 below.

[0040] Table 2 Criborol ointment formula

[0041] .

[0042] Example 3

[0043] The other conditions are the same as those in Example 1, except that the formula of Example 3 is shown in Table 3 below.

[0044] Table 3 Criborol ointment formula

[0045] .

[0046] Example 4

[0047] The other conditions were the same as those in Example 1, except that PEG400 was replaced by PEG800.

[0048] Example 5

[0049] The other conditions were the same as those in Example 1, except that PEG400 was replaced by PEG200.

[0050] Comparative Example 1

[0051] Other conditions are the same as those in Example 1, except that the formula of Comparative Example 1 is shown in Table 4 below.

[0052] Table 4 Criborol ointment formula

[0053] .

[0054] That is, in Comparative Example 1, PEG400 is not added, and propylene glycol, glyceryl mono- and distearate, 2-hexyldecanoic acid, and cetearyl glucoside are used to supplement the mixture in a certain proportion.

[0055] Comparative Example 2

[0056] Other conditions are the same as those in Example 1, except that the formula of Comparative Example 2 is shown in Table 5 below.

[0057] Table 5 Criborol ointment formula

[0058] .

[0059] That is, in Comparative Example 2, 2-hexyldecanoic acid is not added, and is supplemented by mono- and distearic acid glyceryl and cetearyl glucoside in a certain ratio.

[0060] Comparative Example 3

[0061] Other conditions are the same as those in Example 1, except that the formula of Comparative Example 3 is shown in Table 6 below.

[0062] Table 6 Criborol ointment formula

[0063] .

[0064] That is, comparative example 3 does not add cetearyl glucoside, and is supplemented by PEG400, 2-hexyldecanoic acid, mono- and distearic glyceryl, and cetearyl glucoside in a certain proportion.

[0065] Application Example 1

[0066] The final mixing uniformity of the crisaborole ointment prepared in the embodiment and the comparative example was tested respectively (the testing method was referred to the 2020 edition of the Chinese Pharmacopoeia); and the particle size of the droplets of crisaborole ointment was tested to calculate the span. The span SPAN calculation formula was as follows: SPAN = [( D 90 - D 10 ) / D 50 ]× 100% calculation, the results are shown in Table 7 below.

[0067] Table 7 Test results of mixing uniformity and droplet size dispersion of crisaborole ointment

[0068] .

[0069] Application Example 2

[0070] The stability test of the crisaborole ointment prepared in the preferred embodiment 1 was carried out. The test method was based on the 2020 edition of the Chinese Pharmacopoeia General Principles 9001 Guidelines for Stability Tests of Raw Materials and Preparations (II) Accelerated Test Section. The sample was placed in a constant temperature and humidity incubator at a temperature of 40°C ± 2°C and a relative humidity of 75% RH ± 5% RH for 6 consecutive months, and samples were taken and sent for inspection at 0, 1, 2, 3, and 6 months. The results are shown in Table 8 below. All samples met the requirements, indicating that the samples obtained by the present invention have good stability and reliable quality.

[0071] Table 8 Accelerated stability test results of the crisaborole ointment prepared in Example 1

[0072] .

[0073] From the results of Tables 7 and 8 above, it can be seen that the ointment mixing uniformity and droplet particle size results of each step of Examples 1-3 are good, especially the ointment particle size distribution obtained in Example 1 is the most uniform. The accelerated stability test results of the crisaborole ointment prepared in the preferred embodiment 1 show good stability, indicating that the preparation process of the crisaborole ointment of the present invention has good stability.

Claims

1. A crisaborole ointment, characterized in that: The invention comprises the following raw materials in parts by weight: 2 parts of crisaborole, 76-80 parts of white vaseline, 8-9 parts of propylene glycol, 2.7-3.5 parts of polyols, 4.6-5.3 parts of mono- and distearic glyceryl, 1.3-1.8 parts of 2-hexyldecanoic acid, 2.8-3.4 parts of cetearyl glucoside, 0.22-0.32 parts of stearate, 0.1-0.2 parts of antioxidant and 0.003-0.004 parts of chelating agent; the polyols are selected from polyethylene glycol and polypropylene glycol, and the number average molecular weight of the polyols is 400-600.

2. The crisaborole ointment according to claim 1, characterized in that The invention comprises the following raw materials in parts by mass: 2 parts of crisaborole, 76.0365 parts of white vaseline, 9 parts of propylene glycol, 3.1 parts of polyols, 4.9 parts of mono- and distearic glyceryl, 1.5 parts of 2-hexyldecanoic acid, 3.1 parts of cetearyl glucoside, 0.26 parts of stearate, 0.1 parts of antioxidant and 0.0035 parts of chelating agent.

3. The crisaborole ointment according to claim 1, characterized in that The stearate is selected from at least one of sodium stearate, potassium stearate, magnesium stearate and calcium stearate.

4. The crisaborole ointment according to claim 1, characterized in that The chelating agent is selected from at least one of calcium sodium edetate and disodium edetate; the antioxidant is selected from at least one of butylated hydroxytoluene, ascorbic acid, 2,4,5-trihydroxybutyrophenone, 4-hydroxymethyl-2,6-di-tert-butylphenol, thiodipropionic acid, dilauryl thiodipropionate, and tert-butylhydroquinone.

5. The method for preparing the crisaborole ointment according to any one of claims 1 to 4, characterized in that: The steps include: (S1) under stirring conditions, white vaseline is heated to 70-80° C. and melted into a transparent liquid, mono- and distearic acid glyceryl, 2-hexyldecanoic acid, cetearyl glucoside, and an antioxidant are added, and stirred evenly until clear, and stirring is maintained, and vacuum is evacuated. The temperature is lowered to 40-50° C. under vacuum conditions, and maintained at 40-50° C. to keep the system clear, thereby obtaining an oil phase; (S2) mixing propylene glycol, polyol, chelating agent and stearate under heating and stirring conditions, adding the crisaborole raw material, and stirring until dissolved and clarified to obtain an active phase; (S3) slowly transferring the oil phase and the active phase to an emulsifying tank through a valve, mixing the oil phase and the active phase evenly under vacuum conditions and maintaining the temperature at 40-50° C. and stirring, and then homogenizing; after homogenizing, maintaining the vacuum degree, cooling to 25-35° C., and filling to obtain crisaborole ointment.

6. The preparation method according to claim 5, characterized in that: The vacuum condition is a vacuum degree of -0.01 MPa to -0.1 MPa.

7. The preparation method according to claim 5, characterized in that: In steps (S1) and (S3), the stirring speed is 30-60 rpm; In step (S2), the heating temperature is 45-60°C and the stirring speed is 50-75 rpm.

8. The preparation method according to claim 5, characterized in that: In step (S3), the homogenization parameters are: homogenization speed 1000~2500rpm, stirring speed 30rpm~60rpm, homogenization time 20~60min; when cooling, the cooling rate is adjusted to perform gradient cooling, and 20~25℃ cooling water is slowly passed, and the temperatures at 40℃, 36℃, and 32℃ are maintained for 10min~20min.