Pharmaceutical composition for treating inflammatory dermatosis

Abstract

The invention provides a pharmaceutical composition for treating inflammatory skin diseases, and particularly relates to an O / W cream containing trifarotene. The pharmaceutical composition provided by the invention has proper viscosity and elasticity, and the trifarotene composition preferably contains diethylene glycol monoethyl ether. The pharmaceutical composition can be directly applied to skin.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical composition for treating inflammatory skin diseases. More particularly, the present application relates to a pharmaceutical composition comprising the active ingredient tretinoin. BACKGROUND

[0002] The incidence of chronic inflammatory skin diseases (especially acne) varies by race and country. Cross-sectional statistics of Chinese population show that the incidence of acne is 8.1%, but research shows that more than 95% of people will have different degrees of acne, and 3% to 7% of acne patients will leave scars. Changes in living environment and habits today have led to a certain extension of the age of onset of acne, showing a trend of youth and old age. In summary, the incidence of acne has increased, the age of onset has shown a polarization trend, and the degree of attention has also increased significantly. Retinoids show excellent clinical effects in the treatment of acne, especially the fourth-generation retinoid tretinoin, which has good effects and low irritation.

[0003] Tretinoin belongs to the fourth generation of retinoids, has super receptor selectivity, and the dose is only one-twentieth of the previous three generations. Tretinoin cream, trade name AKLIEF, was developed and marketed by Galderma in the United States in 2019, and is mainly used for acne vulgaris in patients aged 9 years and older. The prescription composition includes allantoin, acrylamide and acryloyldimethyl sodium taurate copolymer, 40% isohexadecane dispersion, cyclomethicone, ethanol, medium-chain triglyceride, phenoxyethanol, propylene glycol, purified water, etc. SUMMARY

[0004] Tretinoin cream has the following problems: through research, the compatibility of phenoxyethanol in the prescription with tretinoin is not good, tretinoin is dissolved in phenoxyethanol, and the influence factor result shows that the related substances increase significantly. In view of this, we surprisingly found that the compatibility of tretinoin with diethylene glycol monoethyl ether is good, tretinoin is dissolved in diethylene glycol monoethyl ether, and the influence factor result shows that the related substances are significantly reduced compared with phenoxyethanol. Therefore, it is considered to replace phenoxyethanol with diethylene glycol monoethyl ether to enhance the chemical stability of the tretinoin pharmaceutical composition.

[0005] The purpose of the present application is to provide a pharmaceutical composition for treating inflammatory skin diseases (especially acne) to treat chronic inflammatory skin diseases of the pilosebaceous unit, mainly manifested as comedones, papules, pustules, cysts, nodules and scars, etc., and often accompanied by sebum excretion, and specifically relates to an O / W type cream containing tretinoin.

[0006] The cream provided by the present application has appropriate viscosity and elasticity.

[0007] The active pharmaceutical ingredients in the cream of the present application are in a dissolved state in the composition, which is defined herein as the active pharmaceuticals existing in a molecular form in the oil solution, having good stability during preparation, transportation, storage and use, and not aggregating or precipitating.

[0008] The technical solution to achieve the above-mentioned object of the present application is:

[0009] According to the embodiment of the present application, the pharmaceutical composition is a cream, comprising an active pharmaceutical ingredient, roflumilast, an oil phase solvent and diethylene glycol monoethyl ether, the roflumilast being in a dissolved state in the oil phase solvent, and the amount of diethylene glycol monoethyl ether being 0.1-10% w / w, preferably 0.5-5% w / w.

[0010] According to the embodiment of the present application, the pharmaceutical composition comprises a polar solvent, diethylene glycol monoethyl ether and ethanol, wherein the amount of ethanol is 1-10% w / w, preferably 2-8% w / w, and the amount of diethylene glycol monoethyl ether is 0.1-10% w / w, preferably 0.5-5% w / w. The polar solvent is a good solvent for roflumilast, allowing it to exist in a molecular state in the preparation, and not precipitating crystals during long-term storage, which is crucial for maintaining the quality and efficacy of the product.

[0011] According to the embodiment of the present application, the oil phase solvent in the pharmaceutical composition comprises a low-polarity ester oil and a non-polar liquid oil, the low-polarity ester oil being selected from one or more of isopropyl myristate, isopropyl palmitate, caprylic capric triglyceride, medium-chain triglyceride, preferably isopropyl myristate and medium-chain triglyceride; and the non-polar liquid oil being selected from one or more of liquid paraffin, dimethicone, cyclopentasiloxane, cyclomethicone, sesame oil, preferably liquid paraffin and cyclomethicone. The content of the low-polarity ester oil is 0.5-25% w / w, preferably 1-15% w / w, and the content of the non-polar liquid oil is 0.1-25% w / w, preferably 0.5-20% w / w.

[0012] Furthermore, the ratio of the low-polarity ester oil to the non-polar liquid oil is 10:1-1:10.

[0013] According to the embodiment of the present application, the composition further comprises a bacteriostatic agent selected from one or more of chlorobutanol, benzoic acid, sodium benzoate, dichlorobenzyl alcohol, methylparaben, diazolidinyl urea, and propylene glycol, in an amount of 0.05-35% w / w. Among them, propylene glycol with a content of more than 10% w / w in external use preparations can be used as a bacteriostatic agent.

[0014] According to the embodiment of the present application, the pharmaceutical composition comprises a gelling agent, which mainly functions to impart a certain viscosity to the product, so that it has good stability during storage and transportation, and is easy to apply and wipe off. The gelling agent is selected from one or more of carbomer, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, and SEPINEO P600, preferably carbomer homopolymer, SEPINEO P600, and further preferably SEPINEO P600. SEPINEO P600 is a new type of high molecular mixture for topical preparations, and its ingredients include acrylamide, acryloyldimethyltaurate sodium copolymer, and polysorbate 80, and its content can be 1-10% w / w, preferably 2-5% w / w.

[0015] According to the embodiment of the present application, the pharmaceutical composition comprises a humectant, which is selected from glycerol, propylene glycol, butylene glycol, allantoin, and sodium hyaluronate, and the content of the humectant is 0.01-50% w / w.

[0016] According to the embodiment of the present application, the pharmaceutical composition further comprises ethanol and purified water, and the content of the ethanol is 2-8% w / w, and the content of the purified water is 40-60% w / w.

[0017] The present application provides a pharmaceutical composition for treating inflammatory skin diseases, and the mass percentage of each component in the pharmaceutical composition is as follows:

[0018]

[0019] According to the embodiment of the present application, the average particle size of the droplets in the pharmaceutical composition is between 0.1 and 20 μm.

[0020] According to the embodiment of the present application, the pH of the pharmaceutical composition is between 4.5 and 7.5.

[0021] The present application also provides a preparation method of a pharmaceutical composition, and the composition is a cream containing an active pharmaceutical ingredient, i.e., crisaborole, which comprises the following steps:

[0022] 1) At room temperature, weigh the crisaborole and add it to diethylene glycol monoethyl ether, and magnetically stir to dissolve. Weigh the low-polarity ester oil in a beaker, and stir until it is uniformly mixed.

[0023] 2) Weigh the purified water in a beaker, and add the humectant and stir to dissolve.

[0024] 3) Weigh the gelling agent, and add it to 2) under low-speed stirring until it is uniformly mixed.

[0025] 4) Weigh the non-polar liquid oil, and slowly add 1) to 3) under low-speed stirring, and stir to emulsify to obtain the pharmaceutical composition.

[0026] The pharmaceutical composition described in the present application is used for preventing or treating inflammatory skin diseases, especially acne.

[0027] Advantages:

[0028] The active pharmaceutical ingredient turoefurone in the pharmaceutical composition prepared in the present application is dissolved in diethylene glycol monoethyl ether, which maintains its chemical stability while existing in the final preparation in a dissolved state. Through stability investigation, turoefurone has good compatibility with diethylene glycol monoethyl ether. And after being placed at 40℃ / 75%RH for 6 months, no significant changes in the size and distribution of the emulsion droplets are observed under a microscope, and the changes in the content and related substances are superior to those of the control preparation (“Preparation 2” in CN104507469B). BRIEF DESCRIPTION OF DRAWINGS

[0029] Figure 1 Microscope pictures of the sample prepared for Example 3 at 0 days (left) and 40℃-180 days (right).

[0030] Figure 2 High performance liquid chromatogram of the sample prepared for Example 3 at 40℃-180 days when the content is determined. DETAILED DESCRIPTION

[0031] The technical solutions of the present application will be further described in detail below in combination with specific test examples and embodiments. It should be understood that the following test examples and embodiments are only used to illustrate and explain the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is covered within the scope of protection intended by the present application.

[0032] Unless otherwise specified, the raw materials and reagents used in the following test examples and embodiments are commercially available or can be prepared by known methods.

[0033] The main detection methods involved in the present application are as follows:

[0034] I. High performance liquid chromatography (HPLC):

[0035] 1. The content of turoefurone is measured according to the following method (operation in the dark):

[0036] Chromatographic column YMC-Triart C18 4.6*150mm, 5um or equivalent performance chromatographic column Mobile phase 0.1% acetic acid solution: acetonitrile (75:25) Flow rate 1.0 ml / min Detection wavelength 254 nm Injection volume 50 μl Column temperature 30℃ Run time 10 min

[0037] 2. The related substances of turoefurone are measured according to the following method (operation in the dark):

[0038] Chromatographic column: Intersil ODS-34.6*250mm, 5um or a chromatographic column with equivalent performance

[0039] Mobile phase A: 0.005%phosphoric acid

[0040] Mobile phase B: Acetonitrile

[0041]

[0042]

[0043] Flow rate: 1.0 ml / min Column temperature: 30 °C Detection wavelength: 254 nm Injection volume: 100 μl

[0044] II. Viscosity Determination

[0045] The sample was subjected to a shear rate scanning test at 25 °C using a constant shear mode, and the viscosity and shear rate relationship was determined. Before the test, the sample was equilibrated at the test temperature for 3 min, the rotation time scanning was selected, the shear rate was set to 501 / s, the test time was 30 s, and the gap was set to 1 mm.

[0046] III. Appearance and Stability Study

[0047] The appearance and physical stability of the paste were evaluated as the evaluation index, and the standard score was used for comprehensive evaluation, with a full score of 90 points. The appearance accounted for 30 points (luster 10 points, fineness 10 points, and spreadability 10 points), and the stability accounted for 60 points (centrifugal stability 20 points, freeze-thaw stability 40 points).

[0048] 1. Appearance

[0049] It mainly includes luster, fineness, and spreadability. The scoring standard is "9-10 points" for luster, uniformity, no particle feeling, easy to spread, no whitening, and refreshing; "6-8 points" for moderate luster, small particles, moderate spreadability; and "6 points or less" for no luster, large particles, bubbles, difficult to spread, whitening, and obvious greasy feeling.

[0050] 2. Freeze-thaw stability

[0051] The sample was divided into colorless transparent vials, sealed, and stored at -20 °C for 48 h, then taken out and stored at 40 °C for 48 h. Four days constituted one cycle, and three cycles were observed for oil and water layering.

[0052] 3. Centrifugal stability

[0053] An appropriate amount of paste was taken into a centrifugal tube, centrifuged at 5000 rpm for 30 min, and observed for oil and water separation.

[0054] 4. Chemical stability

[0055] The sample was subjected to a shear rate scanning test at 25 °C using a constant shear mode, and the viscosity and shear rate relationship was determined. Before the test, the sample was equilibrated at the test temperature for 3 min, the rotation time scanning was selected, the shear rate was set to 501 / s, the test time was 30 s, and the gap was set to 1 mm.

[0056] IV. Skin Toxicity and Irritation

[0057] The rabbit abdomen hair is shaved, the intact skin is selected, the local toxicity and irritation test for 4 weeks is carried out, and whether the red spot, edema and the like appear in the administration site is observed and recorded.

[0058] The compound structure involved in the application is as follows:

[0059]

[0060] Test Example 1

[0061] The solubility of the raw material drug trilostane in different polar solvents is measured at 25 DEG C and 32 DEG C respectively, that is, an appropriate excess of the raw material drug is weighed into different solvents, in a constant temperature incubation oscillator, 200 rpm oscillation for 48 hours, each sample is measured three times to take the average value, and the results are shown in Table 1.

[0062] Table 1 solubility of trilostane in different media (n = 3)

[0063] Name Equilibrium solubility 25°C (mg / g) Equilibrium solubility 32°C (mg / g) Diethylene glycol monoethyl ether 4.01±0.03 5.27±0.05 Medium-chain triglyceride 0.003±0.001 0.02±0.005 Phenoxyethanol 2.93±0.04 3.24±0.14 1,3-Butylene glycol 0.40±0.05 0.54±0.09

[0064] The above results show that under the condition of 32 DEG C, the saturated solubility of trilostane in diethylene glycol monoethyl ether is the largest, followed by phenoxyethanol and 1, 3-butanediol, and it is almost insoluble in medium-chain triglyceride. The solubility value under the condition of 32 DEG C is slightly higher than that under the condition of 25 DEG C, and there is no significant difference.

[0065] Test Example 2

[0066] An appropriate amount of trilostane is weighed into diethylene glycol monoethyl ether, phenoxyethanol and 1, 3-butanediol respectively, and its chemical stability is investigated at 40 DEG C and 50 DEG C respectively, and the results are shown in Table 2, Table 3 and Table 4 respectively.

[0067] Table 2 stability investigation results of trilostane in diethylene glycol monoethyl ether

[0068]

[0069] Table 3 stability investigation results of trilostane in 1, 3-butanediol

[0070]

[0071]

[0072] Table 4 stability investigation results of trilostane in phenoxyethanol

[0073]

[0074] The above results show that: the larger impurities appear at RRT 0.39 in the solution of trofinarate in phenoxyethanol under the conditions of 40℃-30 days and 50℃-30 days; the larger impurities appear at RRT 1.39 in the solution of trofinarate in 1,3-butanediol under the conditions of 40℃-30 days and 50℃-30 days; the compatibility of trofinarate and diethylene glycol monoethyl ether is the best among the three.

[0075] Test Example 3

[0076] In order to screen the types of excipients (such as polar solvents, low-polarity ester oils, and non-polar liquid oils) directly contacted with trofinarate, the compatibility of the raw and auxiliary materials was studied. After mixing trofinarate with the corresponding excipients, they were placed at 25℃ and 40℃ for 21 days, respectively, and then the change of related substances was determined. Some experimental data are shown in Table 6.

[0077] Table 6: Test and results of the compatibility of raw and auxiliary materials in the composition of trofinarate

[0078]

[0079]

[0080] The above results show that: the larger impurities appear at RRT 0.39 in the solution of trofinarate in phenoxyethanol under the conditions of 40℃-30 days and 50℃-30 days; the larger impurities appear at RRT 1.39 in the solution of trofinarate in 1,3-butanediol under the conditions of 40℃-30 days and 50℃-30 days; the compatibility of trofinarate and diethylene glycol monoethyl ether is the best among the three.

[0081] The technical solutions of the present application will be further described in detail below in combination with specific prescription examples.

[0082] Example 1

[0083] The prescription of the pharmaceutical composition described in the present application is as follows, and the total prescription is 500g:

[0084] Ingredient Prescription amount Content (%) Trifarotene 25.00 mg 0.005 Diethylene glycol monoethyl ether 5.16g 1.03 Allantoin 1.08g 0.22 Cyclo-methicone 10.88g 2.17 Ethanol 25.37g 5.05 Medium-chain triglyceride 41.90g 8.34 Propylene glycol 150.43g 29.95 SEPINEOP 600 15.57g 3.10 Purified water 252.56g 50.29 Total weight 502.00g 100

[0085] The preparation method of the pharmaceutical composition described in the present application comprises the following steps:

[0086] 1) At room temperature, weigh trofinarate and add it to diethylene glycol monoethyl ether, magnetically stir to dissolve, weigh medium-chain triglyceride in a beaker, and stir until mixed uniformly;

[0087] 2) Weigh purified water in a beaker, heat to 50℃ in a water bath, add allantoin and stir until dissolved, cool to room temperature, stir to add propylene glycol and ethanol.

[0088] 3) At room temperature, weigh SEPINEO P 600 and add it to 2) under low-speed stirring until uniform.

[0089] 4) room temperature, weighing cyclo-methicone, low speed stirring slowly add 1) to 3), stirring emulsification to obtain a pharmaceutical composition.

[0090] Example 2

[0091] The prescription of the pharmaceutical composition described in the present application is as follows, total prescription 500g:

[0092]

[0093]

[0094] The preparation method of the pharmaceutical composition described in the present application comprises the following steps:

[0095] 1) room temperature, weighing curcumin, add to diethylene glycol monoethyl ether, magnetic stirring to dissolve, weighing medium chain triglyceride in a beaker, stirring until mixed evenly;

[0096] 2) weighing purified water in a beaker, heated to a certain temperature in a water bath, add allantoin stirring until dissolved, cool to room temperature stirring add propylene glycol and ethanol.

[0097] 3) room temperature, weighing SEPINEO P 600, add to 2) under low speed stirring, until uniform.

[0098] 4) room temperature, weighing cyclo-methicone, low speed stirring slowly add 1) to 3), stirring emulsification to obtain a pharmaceutical composition.

[0099] Example 3

[0100] The prescription of the pharmaceutical composition described in the present application is as follows, total prescription 500g:

[0101] Ingredient Prescription amount Content (%) Trifarotene 25 mg 0.005 Diethylene glycol monoethyl ether 5.50g 1.1 Allantoin 1.10g 0.22 Liquid paraffin 11.65g 2.33 Ethanol 25.55g 5.11 Isopropyl myristate 43.75g 8.75 Propylene glycol 152.80g 30.56 SEPINEOP 600 15.20g 3.04 Sodium hyaluronate 5.00 1.0 Purified water 239.42g 47.885 Total weight 500.225g 100

[0102] The preparation method of the pharmaceutical composition described in the present application comprises the following steps:

[0103] 1) room temperature, weighing curcumin, add to diethylene glycol monoethyl ether, magnetic stirring to dissolve, weighing isopropyl myristate in a beaker, stirring until mixed evenly;

[0104] 2) weighing purified water in a beaker, heated to a certain temperature in a water bath, add allantoin, sodium hyaluronate stirring until dissolved, cool to room temperature stirring add propylene glycol and ethanol.

[0105] 3) room temperature, weighing SEPINEO P 600, add to 2) under low speed stirring, until uniform.

[0106] 4) room temperature, weighing liquid paraffin, low speed stirring slowly add 1) to 3), stirring emulsification to obtain a pharmaceutical composition.

[0107] Control preparation

[0108] The prescription of the control preparation described in the present application is as follows, total prescription 500 g:

[0109] Ingredient Prescription amount Content (%) Trifarotene 25 mg 0.005 Phenoxyethanol 5.06g 1.0 Allantoin 1.06g 0.21 Cyclopentasiloxane 10.48g 2.07 Ethanol 25.57g 5.05 Medium-chain triglyceride 42.18g 8.33 Propylene glycol 154.04g 30.42 SEPINEOP 600 16.20g 3.20 Purified water 251.93g 49.725 Total weight 506.38g 100

[0110] The preparation method of the control preparation described in the present application comprises the following steps:

[0111] 1) Room temperature, weigh the trofan, add to the phenoxyethanol, magnetically stir to dissolve, weigh the medium-chain triglyceride in a beaker, stir until uniform;

[0112] 2) Weigh purified water in a beaker, heat to a certain temperature in a water bath, add allantoin and stir until dissolved, cool to room temperature and stir to add propylene glycol and ethanol.

[0113] 3) Room temperature, weigh SEPINEO P 600, add to 2) under low speed stirring until uniform.

[0114] 4) Room temperature, weigh cyclopentasiloxane, slowly add 1) to 3) under low speed stirring, stir to emulsify to obtain the control preparation.

[0115] The samples prepared in the above examples 1-3 and the control preparation are placed at 40℃ / 75% RH for 180 days, and their advantages and disadvantages are comprehensively evaluated from the aspects of appearance and physical stability, chemical stability and skin irritation, etc. The results are shown in Tables 7, 8, 9 and 10.

[0116] Table 7 Appearance and physical stability results

[0117]

[0118] Table 8 Physical stability test results

[0119]

[0120] Table 9 Chemical stability test results

[0121]

[0122] Table 10 Skin irritation test results

[0123] Prescription Erythema Edema Ulceration Pigmentation Skin roughness Skin thinning Example 1 No No No No No No Example 2 No No No No No No Example 3 No No No No No No Control preparation No No No No No No

[0124] The above describes the embodiments of the present application. However, the present application is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A pharmaceutical composition for treating inflammatory skin diseases, characterized in that, The pharmaceutical composition is an ointment containing the active pharmaceutical ingredient trefaridine, an oil phase solvent, and diethylene glycol monoethyl ether. The trefaridine is present in a dissolved form in the oil phase solvent, and the amount of diethylene glycol monoethyl ether is 0.1-10% w / w, preferably 0.5-5% w / w.

2. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition comprises an antibacterial agent selected from one or more of chlorobutanol, benzoic acid, sodium benzoate, dichlorobenzyl alcohol, methylparaben, diazolidinyl urea, and propylene glycol; the antibacterial agent content is 0.05-35% w / w.

3. The pharmaceutical composition according to any one of claims 1 to 2, characterized in that, The oil phase solvent comprises low-polarity ester oil and non-polar liquid oil. The low-polarity ester oil is selected from one or more of isopropyl myristate, isopropyl palmitate, caprylic / capric triglyceride, and medium-chain triglycerides, preferably isopropyl myristate and medium-chain triglycerides. The non-polar liquid oil is selected from one or more of liquid paraffin, polydimethylsiloxane, cyclopentasiloxane, cyclomethylsilicon, and sesame oil, preferably liquid paraffin and cyclomethylsilicon.

4. The pharmaceutical composition according to claim 3, characterized in that, The low-polarity ester oil content is 0.5-25% w / w, preferably 1-15% w / w, and the non-polar liquid oil content is 0.1-25% w / w, preferably 0.5-20% w / w.

5. The pharmaceutical composition according to claim 3 or 4, characterized in that, The mass ratio of the low-polarity ester oil to the non-polar liquid oil is 10:1 to 1:

10.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that, It also contains a gelling agent selected from carbomer homopolymers, SEPINEO P 600, preferably SEPINEO P 600; the gelling agent content is 2-5% w / w.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that, The composition further comprises a humectant selected from glycerin, propylene glycol, butylene glycol, allantoin, and sodium hyaluronate; the humectant content is 0.01 to 50% w / w.

8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that, The pharmaceutical composition further comprises ethanol and purified water; the ethanol content is 2-8% w / w, and the purified water content is 40-60% w / w.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that, The formulation composition and mass percentage of the pharmaceutical composition are as follows: Trafarotine 0.005% Low polarity ester oil 1-15% 10. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that, The average droplet size in the pharmaceutical composition is between 0.1 and 20 μm; the pH of the pharmaceutical composition is between 4.5 and 7.5.

Images