High-stability fluticasone propionate suspension type cream and preparation method thereof

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a high-stability fluticasone propionate suspension type cream and a preparation method thereof. The fluticasone propionate suspension type cream comprises fluticasone propionate, a liquid oil phase, a solid oil phase, an emulsifier, a humectant, an acid-base regulator, a preservative and a stabilizer, wherein the stabilizer is carbomer and / or xanthan gum. By exploring a product prescription and a process route, emulsion droplets and suspension type active ingredients are uniformly and lastingly wrapped in an emulsifiable paste system, the stability of the product can be obviously improved, key quality indexes such as rheology of the product are not obviously changed, meanwhile, the suspension type active ingredients can be kept in a uniform and stable distribution state for a long time, and the stability of the product is improved. And the cream product quality is further ensured.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a high-stability fluticasone propionate suspension type cream and a preparation method thereof. BACKGROUND

[0002] Skin is the first physiological defense line and the largest organ of the human body, and participates in various physiological functions of the body. Skin diseases have high incidence and are complex and diverse. It is estimated that the prevalence of skin diseases in China is as high as 40% to 70%, and the health life loss caused thereby ranks fourth among all diseases. Skin diseases are one of common diseases and frequently-occurring diseases that seriously affect people's health, and have a very high incidence in clinic. The population affected by the diseases ranges from infants to the elderly. Skin diseases are various in types, and the disease types and clinical manifestations mainly include skin inflammation, eczema, dermatophytosis, itching and the like. Some skin diseases are not easy to cure, and are prone to recurrence after cure, which seriously affects the physical and mental health of human beings.

[0003] Fluticasone propionate cream is an external use glucocorticoid preparation, which is developed by GlaxoSmithKline Company, and is suitable for various inflammatory and pruritic skin diseases that can be relieved by corticosteroids. Existing researches show that fluticasone propionate cream has multiple effects such as secretion inhibition, anti-inflammatory, anti-allergic, anti-infection and the like, and can effectively relieve the skin symptoms of patients and improve the life quality of patients. At present, the prescription composition of the foreign marketed generic drug is basically the same as that of the original research product, and the drug composition product often faces the following problems: (1) poor high-temperature stability, obvious oil-water separation phenomenon occurs after 12 hours of 50℃ investigation, and the phenomenon cannot be restored after reduction to room temperature; (2) poor centrifugal stability, obvious stratification phenomenon occurs after centrifugation of the sample. Since the temperature changes greatly in most regions of China throughout the year, the basic properties of the product cannot be guaranteed under the conventional use and storage conditions, thereby greatly reducing the convenience of use of patients and increasing the use risk.

[0004] In the prior art, the patent for invention with publication number CN102885762B discloses a preparation method of fluticasone propionate cream, which adopts a prescription similar to the original preparation and foreign generic drugs, and the preparation method comprises the following steps: 1) preparation of an oil phase: mix and heat to melt cetyl alcohol, liquid paraffin and peregal-20, and keep at 75 DEG C for standby; 2) preparation of an aqueous phase: mix and heat to melt citric acid, sodium citrate, imidazolidinyl urea and purified water, and keep at 75 DEG C for standby; 3) weigh a propylene glycol solution, heat to 65 DEG C for standby, and add fluticasone propionate into the prepared propylene glycol solution and stir to dissolve; 4) quickly add the aqueous phase into the oil phase, and use a vacuum homogenizing emulsifier to homogenize and emulsify at 75 DEG C for 10 minutes with a rotating speed of 2400 r / min, continuously stir in the same direction until complete emulsification, and then cool the emulsified solution to 65 DEG C under stirring; 5) add the fluticasone propionate solution into the emulsion, stir uniformly, and place at room temperature to condense into a cream. In the method, fluticasone propionate is added after being dissolved, the particle size control of API is relatively poor, and the product stability is poor.

[0005] Therefore, it is necessary to optimize the prescription and preparation method of fluticasone propionate cream, and improve the product stability and uniformity. SUMMARY

[0006] In order to overcome the defects in the prior art, the present application is found through prescription research that a certain amount of stabilizer suitable for the prescription system is added, and the preparation process of the suspension type fluticasone propionate cream is optimized based on the new prescription, so that the emulsion droplets and the suspension type active ingredient are uniformly and durably wrapped in the cream system, the physical stability of the suspension type fluticasone propionate cream can be effectively improved without obvious changes in the key indicators such as physicochemical indicators, rheology and IVRT, and the suspension type active ingredient can be kept in a uniform and stable distribution state for a long time. The present application has important significance for improving the quality of fluticasone propionate drugs.

[0007] Therefore, one of the purposes of the present application is to provide a fluticasone propionate pharmaceutical composition with high stability.

[0008] In order to achieve the above-mentioned purposes, the present application adopts the following technical solutions:

[0009] The fluticasone propionate pharmaceutical composition with high stability is composed of the main drug fluticasone propionate and excipients; the excipients contain a stabilizer, and the stabilizer is any one or more of carbomer and xanthan gum.

[0010] Further, the content of the stabilizer in the pharmaceutical composition is 0.05%-0.5%.

[0011] Further, the adjuvant contains stabilizer, liquid oil phase, solid oil phase, emulsifier, humectant, acid-base regulator and preservative, the liquid oil phase is any one or more of light liquid paraffin, liquid paraffin, isopropyl myristate, the solid oil phase is any one or more of cetyl alcohol, stearyl alcohol, cetylstearyl alcohol, the emulsifier is any one or more of polyoxyethylene 18-alkyl ether, ceteth-20, cetomacrogol 1000, the humectant is one or more of propylene glycol, sorbitol, glycerol, the acid-base regulator is composed of citric acid and disodium hydrogen phosphate or disodium hydrogen phosphate dodecahydrate, and the preservative is any one or more of hydroxybenzoic acid ester, hydroxybenzoic acid propyl ester or imidazolidinyl urea.

[0012] Preferably, the liquid oil phase is composed of light liquid paraffin or liquid paraffin and isopropyl myristate; the weight ratio of the light liquid paraffin or liquid paraffin and isopropyl myristate is 30-45.

[0013] Preferably, the weight ratio of the citric acid and the disodium hydrogen phosphate or disodium hydrogen phosphate dodecahydrate is 0.05:0.05-0.15.

[0014] Further, the content of the liquid oil phase in the pharmaceutical composition is 30%-55%, the content of the solid oil phase in the pharmaceutical composition is 3%-9%, the content of the emulsifier in the pharmaceutical composition is 0.5%-3%, the content of the humectant in the pharmaceutical composition is 5%-20%, the content of the acid-base regulator in the pharmaceutical composition is 0.1%-0.3%, and the content of the preservative in the pharmaceutical composition is 0.1%-0.3%.

[0015] The second object of the present application is to provide a high-stability fluticasone propionate suspension type cream.

[0016] To achieve the above object, the present application adopts the following technical scheme:

[0017] The high-stability fluticasone propionate suspension type cream contains the aforementioned pharmaceutical composition.

[0018] The present application adjusts the prescription on the basis of the original research prescription, and the stability of the product after prescription optimization is obviously improved compared with the original research preparation product.

[0019] Further, the suspension type cream includes the following components in terms of weight parts: fluticasone propionate 0.05 parts, liquid oil phase 30-55 parts, solid oil phase 3-9 parts, emulsifier 0.5-3 parts, humectant 5-20 parts, acid-base regulator 0.1-0.3 parts, physical stabilizer 0.05-0.5 parts, preservative 0.1-0.3 parts, and purified water to 100 parts.

[0020] Further, the liquid oil phase is any one or more of light liquid paraffin, liquid paraffin, isopropyl myristate.

[0021] Further, the acid-base regulator consists of citric acid and disodium hydrogen phosphate or disodium hydrogen phosphate dodecahydrate.

[0022] Further, the solid oil phase is any one or more of cetyl alcohol, stearyl alcohol, cetostearyl alcohol.

[0023] Further, the emulsifier is any one or more of polyoxyl 16-18 glycerides, ceteth-20, cetomacrogol 1000.

[0024] Further, the humectant is one or more of propylene glycol, sorbitol, glycerin.

[0025] Further, the preservative is any one or more of methylparaben, propylparaben, or imidurea.

[0026] Preferably, the suspension cream comprises the following components by weight: fluticasone propionate 0.05 parts, light liquid paraffin or liquid paraffin 30-45 parts, isopropyl myristate 4-8 parts, solid oil phase 3-8 parts, emulsifier 0.5-3 parts, humectant 5-20 parts, citric acid 0.05 parts, disodium hydrogen phosphate or disodium hydrogen phosphate dodecahydrate 0.05-0.15 parts, stabilizer 0.05-0.5 parts, preservative 0.1-0.25 parts, and purified water to 100 parts.

[0027] Preferably, the suspension cream comprises the following components by weight: fluticasone propionate 0.05 parts, light liquid paraffin 30-45 parts, isopropyl myristate 4-8 parts, cetostearyl alcohol 3-8 parts, ceteth-20 or polyoxyl 16-18 glycerides 0.5-3 parts, humectant 5-20 parts, citric acid 0.05 parts, disodium hydrogen phosphate dodecahydrate 0.15 parts, stabilizer 0.05-0.5 parts, methylparaben or imidurea 0.1-0.25 parts, and purified water to 100 parts.

[0028] The third object of the present application is to provide a preparation method of fluticasone propionate suspension cream, which avoids the significant influence of the dissolution and precipitation of the raw material drug on the particle size of API after the dissolution of the raw material drug, effectively controls the particle size of the raw material drug in the finished product, and improves the product quality.

[0029] To achieve the above object, the present application adopts the following technical solutions:

[0030] The preparation method of fluticasone propionate suspension cream comprises the following steps:

[0031] (1) Preparation of the water phase: the humectant, acid-base regulator and emulsifier are added to purified water, stirred and heated to dissolve, and then the stabilizer is added or not, heated and stirred to obtain the water phase;

[0032] (2) Preparation of the oil phase: the liquid oil phase and solid oil phase are heated and stirred to melt, to obtain the oil phase;

[0033] (3) Stabilizer solution: the stabilizer is added to purified water, stirred and swelled completely to obtain the stabilizer solution;

[0034] (4) The fluticasone propionate is added to the stabilizer solution, and dispersed by high-speed stirring or homogenization to obtain a suspension;

[0035] (5) The suspension obtained in step (4) is added to the water phase, heated and stirred to disperse, to obtain a fluticasone propionate suspension base;

[0036] (6) The fluticasone propionate suspension base obtained in step (5) is mixed with the oil phase obtained in step (2) to perform emulsification reaction, and then cooled to about 31℃ to obtain a suspension-type fluticasone propionate cream.

[0037] The addition of API by dissolution and the addition of API by dispersion are two obviously different processes, and the consequences are also completely different: the addition of API by dispersion is obviously more uniform in particle size control.

[0038] Further, the prepared water phase, oil phase, fluticasone propionate suspension base and the like are kept at 65-85℃ for standby use.

[0039] Further, in step (1), the heating temperature is 60-90℃, and the stirring speed is 120-400 rpm; the pH of the water phase is 4.0-6.5.

[0040] Preferably, in step (1), the heating temperature is 65-85℃, and the stirring speed is 150-300 rpm; the pH of the water phase is 4.0-6.5.

[0041] Further, in step (1), the amount of stabilizer is 0-0.45 parts by weight.

[0042] Further, in step (3), the stabilizer is heated and stirred to swell completely, and the stirring speed is 300-800 rpm.

[0043] Further, in step (3), the concentration of the stabilizer solution is preferably 0.5%.

[0044] Further, in step (4), the stirring speed is 500-800 rpm, and the stirring time is 20-40 min; or the homogenization speed is 4000-10000 rpm, and the homogenization time is 5-30 min.

[0045] Preferably, in step (4), the homogenization speed is 6000 rpm and the homogenization time is 5 min.

[0046] Further, in step (5), the stirring speed is 150-350 rpm and the stirring time is 10-30 min.

[0047] Preferably, in step (5), the stirring speed is 250 rpm and the stirring time is 10 min.

[0048] Further, in step (6), the emulsification reaction conditions are: stirring emulsification at 150-300 rpm for 10-30 min at 60-85℃; homogenization emulsification at a homogenization intensity of 6000-10000 rpm for 1-4 min.

[0049] Preferably, in step (6), the emulsification reaction conditions are: stirring emulsification at 250 rpm for 10 min at 75℃; homogenization emulsification at a homogenization intensity of 6000 rpm for 2 min.

[0050] Further, in step (6), the cooling is carried out under stirring at 150-300 rpm to about 30-35℃.

[0051] Preferably, in step (6), the cooling is carried out under stirring at 250 rpm to about 31℃.

[0052] As a preferred technical solution, the preparation method of the fluticasone propionate suspension type cream comprises the following steps:

[0053] (1) Preparation of water phase: add humectant, acid-base regulator and emulsifier into purified water, stir and heat to dissolve, heat to 65-85℃, stirring speed 150-300 rpm, to obtain water phase;

[0054] (2) Preparation of oil phase: heat and stir the liquid oil phase and solid oil phase to melt, to obtain oil phase;

[0055] (3) Stabilizer solution: add stabilizer into purified water, stir to swell completely, to obtain stabilizer solution with a concentration of 0.5%;

[0056] (4) Slowly add fluticasone propionate into the stabilizer solution under homogenization, homogenization speed is 6000 rpm, homogenization time is 5 min; to obtain suspension;

[0057] (5) Add the suspension obtained in step (4) into the water phase, heat and stir to disperse, stirring speed is 250 rpm, stirring time is 10 min, to obtain fluticasone propionate suspension base;

[0058] (6) the fluticasone propionate suspension base obtained in step (5) is mixed with the oil phase obtained in step (2), and emulsified at 75 DEG C and 250 rpm for 10 min, and homogenized at a homogenizing intensity of 6000 rpm for 2 min; and then cooled to about 31 DEG C under stirring at 250 rpm to obtain the fluticasone propionate suspension cream.

[0059] As a preferred technical scheme, the preparation method of the fluticasone propionate suspension cream comprises the following steps:

[0060] (1) preparation of the water phase: the humectant, the acid-base regulator and the emulsifier are added into purified water, stirred and heated to dissolve; then the stabilizer is added and stirred to swell completely, and heated to 65-85 DEG C under stirring at a stirring speed of 150-300 rpm to obtain the water phase;

[0061] (2) preparation of the oil phase: the liquid oil phase and the solid oil phase are heated and stirred to melt to obtain the oil phase;

[0062] (3) stabilizer solution: the stabilizer is added into purified water, stirred and swelled completely to obtain a stabilizer solution with a concentration of 0.5%;

[0063] (4) the fluticasone propionate is slowly added into the stabilizer solution under homogenization, and the homogenization speed is 6000 rpm, and the homogenization time is 5 min to obtain the suspension;

[0064] (5) the suspension obtained in step (4) is added into the water phase, heated and stirred to disperse, and the stirring speed is 250 rpm, and the stirring time is 10 min to obtain the fluticasone propionate suspension base;

[0065] (6) the fluticasone propionate suspension base obtained in step (5) is mixed with the oil phase obtained in step (2), and emulsified at 75 DEG C and 250 rpm for 10 min, and homogenized at a homogenizing intensity of 6000 rpm for 2 min; and then cooled to about 31 DEG C under stirring at 250 rpm to obtain the fluticasone propionate suspension cream.

[0066] The fluticasone propionate suspension cream prepared by the method has the following advantages:

[0067] 1. The present application provides a new type of fluticasone propionate suspension cream composition, compared with the reference preparation and the same kind of product on the market, the physical stability of the new type composition provided by the present application is improved significantly; the physical stability of the reference preparation is poor, and obvious oil-water separation is observed at 50℃ for 12 hours; the physical stability of the fluticasone propionate suspension cream of the present application is good, and there is no oil-water separation at 50℃ for 240 hours. The present application significantly widens the storage conditions of such cream products (sealed storage at 20-25℃→ sealed storage), thereby increasing the safety of use by patients and the convenience of storage and transportation; and through optimization of the process, a product with superior physical stability and consistent key quality indicators (physicochemical indicators, rheology, IVRT, etc.) with the reference preparation is obtained.

[0068] 2. The present application achieves the effect of stabilizing the suspended drug substance in the cream by increasing the physical stabilizer and optimizing the process, thereby more favorably ensuring the content uniformity of the cream product during high-temperature storage and long-term storage, and the suspended drug substance can maintain stable and uniform existence under various severe conditions (freeze-thaw cycle, 40℃, 50℃ investigation, etc.), thereby fully ensuring the long-term effectiveness of the product.

[0069] 3. The present application avoids the significant influence of the precipitation of the dissolved drug substance on the particle size of the API, effectively controls the particle size of the drug substance in the finished product, and the suspension cream prepared by the method of the present application has uniform and controllable particle size of the active ingredient, superior physical stability, and stable and uniform product quality. BRIEF DESCRIPTION OF DRAWINGS

[0070] Fig. 1 Figure 4 is a comparison of the appearance of the self-prepared product and the control product after 1 day of 50℃ investigation;

[0071] Fig. 2 Figure 5 is a cream droplet morphology diagram of the sample of Example 1 investigated for 0 days;

[0072] Fig. 3 Figure 6 is a cream droplet morphology diagram of the sample of Example 1 after 10 days of 50℃ investigation;

[0073] Fig. 4 Figure 7 is an API distribution state diagram of the sample of Example 1 investigated for 0 days;

[0074] Fig. 5 Figure 8 is an API distribution state diagram of the sample of Example 1 after 10 days of 50℃ investigation;

[0075] Fig. 6 Figure 9 is an API distribution state diagram of the sample of Comparative Example 2 investigated for 0 days. DETAILED DESCRIPTION

[0076] The technical solutions of the present application will be described further in detail below in combination with specific embodiments. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Therefore, all other embodiments obtained by those skilled in the art based on the embodiments in the present application without creative effort shall fall within the protection scope of the present application.

[0077] Embodiment 1

[0078] 1. Formulation prescription

[0079] Fluticasone propionate 0.5 g, light liquid paraffin 400 g, isopropyl myristate 50 g, cetostearyl alcohol 60 g, cetyl alcohol polyether-20 10 g, glycerol 100 g, citric acid 0.5 g, disodium hydrogen phosphate dodecahydrate 1.5 g, xanthan gum 0.5 g, imidazole alkyl urea 2.0 g, purified water to 1000 g.

[0080] 2. Formulation process

[0081] (1) Preparation of the water phase: add glycerol, citric acid, disodium hydrogen phosphate dodecahydrate, cetyl alcohol polyether-20 and imidazole alkyl urea into part of water, stir and heat to dissolve, heat to 75℃, stirring speed 300 rpm, stir and dissolve and keep warm for standby;

[0082] (2) Preparation of the oil phase: heat and stir light liquid paraffin, cetostearyl alcohol and isopropyl myristate to melt, keep warm at 75℃ for standby;

[0083] (3) Preparation of the stabilizer solution: take a certain amount of purified water, add xanthan gum and stir to swell, prepare a 0.5% solution, stirring speed 500 rpm;

[0084] (4) Slowly add fluticasone propionate into the stabilizer solution under homogenization, homogenization speed 6000 rpm, homogenization for 5 min;

[0085] (5) Add the suspension obtained in (4) into (1) and stir uniformly, stirring speed 250 rpm, stir for 10 min, keep warm at 75℃ for standby;

[0086] (6) Mix the water phase with the oil phase, emulsify at 75℃ under 250 rpm stirring for 10 min, then homogenize emulsify under 6000 rpm homogenization intensity for 2 min, then cool to about 31℃ under 250 rpm stirring and discharge.

[0087] Embodiment 2

[0088] 1. Formulation prescription

[0089] Fluticasone propionate 0.5 g, light liquid paraffin 350 g, isopropyl myristate 60 g, cetostearyl alcohol 70 g, cetostearyl ether 10 g, propylene glycol 150 g, citric acid 0.5 g, disodium hydrogen phosphate 12-hydrate 1.5 g, xanthan gum 1.0 g, hydroxybenzoate 1 g, purified water to 1000 g.

[0090] 2. Preparation process

[0091] (1) Preparation of the water phase: add propylene glycol, citric acid, disodium hydrogen phosphate 12-hydrate, cetostearyl ether and hydroxybenzoate into part of water, stir and heat to dissolve, then add 0.5 g of xanthan gum and stir to swell completely, heat to 75 °C, stirring speed 300 rpm, and stir to dissolve and keep warm for standby;

[0092] (2) Preparation of the oil phase: heat and stir light liquid paraffin, cetostearyl alcohol and isopropyl myristate to melt, keep warm at 75 °C for standby;

[0093] (3) Preparation of the stabilizer solution: take a certain amount of purified water, add 0.5 g of xanthan gum and stir to swell, prepare a 0.5% solution, stirring speed 500 rpm;

[0094] (4) Slowly add fluticasone propionate into the stabilizer solution under homogenization, homogenization speed 6000 rpm, homogenization time 5 min;

[0095] (5) Add the suspension obtained in (4) into (1) and stir uniformly, stirring speed 250 rpm, stirring time 10 min, keep warm at 75 °C for standby;

[0096] (6) Mix the water phase and the oil phase, emulsify at 75 °C, 250 rpm for 10 min, then homogenize at 6000 rpm for 2 min, and cool to about 31 °C under 250 rpm to discharge.

[0097] Example 3

[0098] 1. Preparation prescription

[0099] Fluticasone propionate 0.5 g, light liquid paraffin 400 g, isopropyl myristate 70 g, cetostearyl alcohol 50 g, cetyl alcohol polyether-20 10 g, sorbitol 100 g, citric acid 0.5 g, disodium hydrogen phosphate 12-hydrate 1.5 g, xanthan gum 2.5 g, hydroxybenzoate 1.5 g, purified water to 1000 g.

[0100] 2. Preparation process

[0101] (1) Preparation of the water phase: sorbitol, citric acid, disodium hydrogen phosphate dodecahydrate, ceteth-20 and hydroxypropyl methylcellulose were added to part of the water and stirred to dissolve, then 2.0 g of xanthan gum was added and stirred to swell completely, heated to 75°C, the stirring speed was 300 rpm, and the stirring solution was kept warm for standby;

[0102] (2) Preparation of the oil phase: light liquid paraffin, cetyl alcohol and isopropyl myristate were heated and stirred to melt, and kept warm at 75°C for standby;

[0103] (3) Preparation of the stabilizer solution: a certain amount of purified water was taken, 0.5 g of xanthan gum was added and stirred to swell, and a 0.5% solution was prepared, the stirring speed was 500 rpm;

[0104] (4) Under the condition of homogenization, fluticasone propionate was slowly added to the stabilizer solution, the homogenization speed was 6000 rpm, and the homogenization time was 5 min;

[0105] (5) The suspension obtained in (4) was added to (1) and stirred uniformly, the stirring speed was 250 rpm, the stirring time was 10 min, and the temperature was kept at 75°C for standby;

[0106] (6) The water phase and the oil phase were mixed, emulsified at 75°C and 250 rpm for 10 min, then homogenized at 6000 rpm for 2 min, and finally cooled to about 31°C under the condition of 250 rpm stirring to discharge.

[0107] Example 4

[0108] 1. Formulation prescription

[0109] Fluticasone propionate 0.5 g, light liquid paraffin 450 g, isopropyl myristate 50 g, cetyl alcohol 40 g, cetostearyl alcohol 10 g, glycerol 150 g, citric acid 0.5 g, disodium hydrogen phosphate dodecahydrate 1.5 g, xanthan gum 3.0 g, imidazolidinyl urea 1 g, and purified water were added to 1000 g.

[0110] 2. Formulation process

[0111] (1) Preparation of the water phase: glycerol, citric acid, disodium hydrogen phosphate dodecahydrate, cetostearyl alcohol and imidazolidinyl urea were added to part of the water and stirred to dissolve, then 2.5 g of xanthan gum was added and stirred to swell completely, heated to 65°C, the stirring speed was 300 rpm, and the stirring solution was kept warm for standby;

[0112] (2) Preparation of the oil phase: light liquid paraffin, cetyl alcohol and isopropyl myristate were heated and stirred to melt, and kept warm at 75°C for standby;

[0113] (3) Stabilizer solution preparation: Take a certain amount of purified water, add 0.5 g of xanthan gum and stir to swell, prepare a 0.5% solution, the stirring speed is 500 rpm;

[0114] (4) Slowly add fluticasone propionate to the stabilizer solution under homogenization, the homogenization speed is 6000 rpm, and homogenization is performed for 5 min;

[0115] (5) Add the suspension obtained in (4) to (1) and stir uniformly, the stirring speed is 250 rpm, stirring is performed for 10 min, and 65°C is kept for standby;

[0116] (6) Mix the water phase and the oil phase, emulsify at 65°C under stirring at 250 rpm for 10 min, then homogenize emulsification under 6000 rpm homogenization intensity for 2 min, and then cool to about 31°C under stirring at 250 rpm and discharge.

[0117] Example 5

[0118] 1. Formulation prescription

[0119] Fluticasone propionate 0.5 g, light liquid paraffin 450 g, isopropyl myristate 60 g, cetostearyl alcohol 70 g, cetyl alcohol polyether-20 10 g, propylene glycol 50 g, citric acid 0.5 g, disodium hydrogen phosphate dodecahydrate 1.5 g, xanthan gum 4.0 g, hydroxybenzyl methyl ester 2.5 g, and purified water are added to 1000 g.

[0120] 2. Formulation process

[0121] (1) Preparation of water phase: add propylene glycol, citric acid, disodium hydrogen phosphate dodecahydrate, cetyl alcohol polyether-20 and hydroxybenzyl methyl ester to part of water, stir and heat to dissolve, then add 3.5 g of xanthan gum and stir to swell completely, heat to 85°C, the stirring speed is 300 rpm, and stirring and dissolving are kept for standby;

[0122] (2) Preparation of oil phase: heat and stir light liquid paraffin, cetostearyl alcohol and isopropyl myristate to melt, and keep at 85°C for standby;

[0123] (3) Stabilizer solution preparation: Take a certain amount of purified water, add 0.5 g of xanthan gum and stir to swell, prepare a 0.5% solution, the stirring speed is 500 rpm;

[0124] (4) Slowly add fluticasone propionate to the stabilizer solution under homogenization, the homogenization speed is 6000 rpm, and homogenization is performed for 5 min;

[0125] (5) Add the suspension obtained in (4) to (1) and stir uniformly, the stirring speed is 250 rpm, stirring is performed for 10 min, and 85°C is kept for standby;

[0126] (6) Mix the water phase with the oil phase, emulsify at 85°C temperature, 250 rpm stirring for 10 min, then homogenize at 6000 rpm for 2 min, and cool to about 31°C under 250 rpm stirring and discharge.

[0127] Example 6

[0128] 1. Formulation prescription

[0129] Fluticasone propionate 0.5 g, light liquid paraffin 350 g, isopropyl myristate 70 g, cetostearyl alcohol 50 g, cetostearyl ether 10 g, sorbitol 150 g, citric acid 0.5 g, disodium hydrogen phosphate 0.5 g, xanthan gum 5.0 g, hydroxypropyl benzyl ester 1.5 g, purified water to 1000 g.

[0130] 2. Formulation process

[0131] (1) Preparation of water phase: add sorbitol, citric acid, disodium hydrogen phosphate, cetostearyl ether and hydroxypropyl benzyl ester into part of water, stir and heat to dissolve, then add 4.0 g of xanthan gum and stir to swell completely, heat to 75°C, stirring speed 150 rpm, and stir to dissolve and keep warm for standby;

[0132] (2) Preparation of oil phase: heat and stir light liquid paraffin, cetostearyl alcohol and isopropyl myristate to melt, keep warm at 75°C for standby;

[0133] (3) Preparation of stabilizer solution: take a certain amount of purified water, add 1.0 g of xanthan gum and stir to swell, prepare 0.5% solution, stirring speed 800 rpm;

[0134] (4) Slowly add fluticasone propionate to the stabilizer solution under homogenization, homogenization speed 6000 rpm, homogenization for 5 min;

[0135] (5) Add the suspension obtained in (4) to (1) and stir evenly, stirring speed 250 rpm, stir for 10 min, keep warm at 75°C for standby;

[0136] (6) Mix the water phase with the oil phase, emulsify at 75°C temperature, 250 rpm stirring for 10 min, then homogenize at 6000 rpm for 2 min, and cool to about 31°C under 250 rpm stirring and discharge.

[0137] Example 7

[0138] 1. Formulation prescription

[0139] Fluticasone propionate 0.5 g, light liquid paraffin 300 g, isopropyl myristate 80 g, cetyl alcohol 30 g, stearyl alcohol 30 g, cetyl alcohol polyether-20 10 g, glycerin 150 g, citric acid 0.5 g, disodium hydrogen phosphate dodecahydrate 1.5 g, xanthan gum 2.0 g, hydroxybenzyl propyl ester 1.5 g, purified water to 1000 g.

[0140] 2. Preparation process

[0141] (1) Preparation of the water phase: add glycerin, citric acid, disodium hydrogen phosphate dodecahydrate, cetyl alcohol polyether-20 and hydroxybenzyl propyl ester into part of water, stir and heat to dissolve, then add 1.0 g of xanthan gum to stir and swell completely, heat to 75°C, stirring speed 150 rpm, stir and dissolve and keep warm for standby;

[0142] (2) Preparation of the oil phase: heat and stir light liquid paraffin, cetyl alcohol, stearyl alcohol and isopropyl myristate to melt, keep warm at 75°C for standby;

[0143] (3) Preparation of the stabilizer solution: take a certain amount of purified water, add 1.0 g of xanthan gum to stir and swell, prepare a 0.5% solution, stirring speed 800 rpm;

[0144] (4) Slowly add fluticasone propionate into the stabilizer solution under homogenization, homogenization speed 6000 rpm, homogenization for 5 min;

[0145] (5) Add the suspension obtained in (4) into (1) to stir uniformly, stirring speed 250 rpm, stir for 10 min, keep warm at 75°C for standby;

[0146] (6) Mix the water phase with the oil phase, emulsify at 75°C under 250 rpm stirring for 10 min, then homogenize emulsify under 6000 rpm homogenization intensity for 2 min, then cool to about 31°C under 250 rpm stirring to discharge.

[0147] Example 8

[0148] 1. Preparation prescription

[0149] Fluticasone propionate 0.5 g, light liquid paraffin 500 g, isopropyl myristate 40 g, cetyl alcohol and stearyl alcohol 50 g, polyoxyethylene cetylstearyl ether 15 g, propylene glycol 150 g, citric acid 0.5 g, disodium hydrogen phosphate dodecahydrate 1.5 g, carbomer 2.5 g, hydroxybenzyl methyl ester 1.5 g, purified water to 1000 g.

[0150] 2. Preparation process

[0151] (1) Preparation of the water phase: add propylene glycol, citric acid, disodium hydrogen phosphate dodecahydrate, polyethylene glycol hexadecyl ester and hydroxybenzyl methyl ether into part of water, stir and heat to dissolve, then add 2.0 g carbomer, stir to swell completely, heat to 75 °C, stirring speed is 300 rpm, stir and dissolve, keep warm for standby;

[0152] (2) Preparation of the oil phase: heat and stir light liquid paraffin, cetyl alcohol and isopropyl myristate to melt, keep warm at 75 °C for standby;

[0153] (3) Preparation of the stabilizer solution: take a certain amount of purified water, add 0.5 g carbomer, stir to swell, prepare 0.5% solution, stirring speed is 800 rpm;

[0154] (4) Slowly add fluticasone propionate into the stabilizer solution under homogenization, homogenization speed is 6000 rpm, homogenization for 5 min;

[0155] (5) Add the suspension obtained in (4) into (1) and stir uniformly, stirring speed is 250 rpm, stir for 10 min, keep warm at 75 °C for standby;

[0156] (6) Mix the water phase with the oil phase, emulsify at 75 °C under 250 rpm stirring for 10 min, then homogenize emulsify under 6000 rpm homogenization intensity for 2 min, then cool to about 31 °C under 250 rpm stirring and discharge.

[0157] Example 9

[0158] 1. Formulation prescription

[0159] Fluticasone propionate 0.5 g, liquid paraffin 400 g, isopropyl myristate 50 g, cetyl alcohol 40 g, cetyl alcohol polyether-20 15 g, propylene glycol 200 g, citric acid 0.5 g, disodium hydrogen phosphate dodecahydrate 1.5 g, xanthan gum 2.5 g, hydroxybenzyl methyl ether 1.5 g, purified water to 1000 g.

[0160] 2. Formulation process

[0161] (1) Preparation of the water phase: add propylene glycol, citric acid, disodium hydrogen phosphate dodecahydrate, cetyl alcohol polyether-20 and hydroxybenzyl methyl ether into part of water, stir and heat to dissolve, then add 1.5 g xanthan gum, stir to swell completely, heat to 75 °C, stirring speed is 150 rpm, stir and dissolve, keep warm for standby;

[0162] (2) Preparation of the oil phase: heat and stir light liquid paraffin, cetyl alcohol and isopropyl myristate to melt, keep warm at 75 °C for standby;

[0163] (3) Stabilizer solution preparation: Take a certain amount of purified water, add 1.0 g of xanthan gum and stir to swell, prepare a 0.5% solution, the stirring speed is 800 rpm;

[0164] (4) Slowly add fluticasone propionate to the stabilizer solution under homogenization, the homogenization speed is 6000 rpm, and homogenization is performed for 5 min;

[0165] (5) Add the suspension obtained in (4) to (1) and stir uniformly, the stirring speed is 250 rpm, stirring is performed for 10 min, and 75°C is kept for standby;

[0166] (6) Mix the water phase and the oil phase, emulsify at 75°C under stirring at 250 rpm for 10 min, then homogenize emulsification under 6000 rpm homogenization intensity for 2 min, and then cool to about 31°C under stirring at 250 rpm and discharge.

[0167] Example 10

[0168] 1. Formulation prescription

[0169] Fluticasone propionate 0.5 g, light liquid paraffin 500 g, isopropyl myristate 40 g, cetostearyl alcohol 80 g, poloxamer 1000 10 g, propylene glycol 100 g, citric acid 0.5 g, disodium hydrogen phosphate dodecahydrate 1.5 g, carbomer 1.5 g, imidazole alkyl urea 3.0 g, and purified water are added to 1000 g.

[0170] 2. Formulation process

[0171] (1) Preparation of water phase: add propylene glycol, citric acid, disodium hydrogen phosphate dodecahydrate, poloxamer 1000 and imidazole alkyl urea to part of water, stir and heat to dissolve, then add 1.0 g of carbomer and stir to swell completely, heat to 75°C, the stirring speed is 300 rpm, and the stirring and dissolving are kept for standby;

[0172] (2) Preparation of oil phase: heat and stir light liquid paraffin, cetostearyl alcohol and isopropyl myristate to melt, and keep at 65-85°C for standby;

[0173] (3) Stabilizer solution preparation: Take a certain amount of purified water, add 0.5 g of carbomer and stir to swell, prepare a 0.5% solution, the stirring speed is 800 rpm;

[0174] (4) Slowly add fluticasone propionate to the stabilizer solution under homogenization, the homogenization speed is 6000 rpm, and homogenization is performed for 5 min;

[0175] (5) Add the suspension obtained in (4) to (1) and stir uniformly, the stirring speed is 250 rpm, stirring is performed for 10 min, and 75°C is kept for standby;

[0176] (6) Mix the water phase with the oil phase, emulsify at 75°C temperature, 250 rpm stirring for 10 min, then homogenize at 6000 rpm homogenization intensity for 2 min, and then cool to about 31°C under 250 rpm stirring and discharge.

[0177] Example 11

[0178] 1. Formulation prescription

[0179] Fluticasone propionate 0.5 g, liquid paraffin 400 g, isopropyl myristate 60 g, cetostearyl alcohol 60 g, cetyl alcohol polyether-20 30 g, glycerol 100 g, citric acid 0.5 g, disodium hydrogen phosphate dodecahydrate 1.5 g, carbomer 0.5 g, hydroxybenzyl ester 1.5 g, purified water to 1000 g.

[0180] 2. Formulation process

[0181] (1) Preparation of water phase: add glycerol, citric acid, disodium hydrogen phosphate dodecahydrate, cetyl alcohol polyether-20 and hydroxybenzyl ester into part of water, stir and heat to dissolve, then add 0.2 g of carbomer and stir to swell completely, heat to 75°C, stirring speed 300 rpm, and stir to dissolve and keep warm for standby;

[0182] (2) Preparation of oil phase: heat and stir liquid paraffin, cetostearyl alcohol and isopropyl myristate to melt, keep warm at 75°C for standby;

[0183] (3) Preparation of stabilizer solution: take a certain amount of purified water, add 0.3 g of carbomer and stir to swell, prepare 0.5% solution, stirring speed 800 rpm;

[0184] (4) Slowly add fluticasone propionate to the stabilizer solution under homogenization, homogenization speed 6000 rpm, homogenization for 5 min;

[0185] (5) Add the suspension obtained in (4) to (1) and stir evenly, stirring speed 250 rpm, stir for 10 min, keep warm at 75°C for standby;

[0186] (6) Mix the water phase with the oil phase, emulsify at 75°C temperature, 250 rpm stirring for 10 min, then homogenize at 6000 rpm homogenization intensity for 2 min, and then cool to about 31°C under 250 rpm stirring and discharge.

[0187] Example 12

[0188] 1. Formulation prescription

[0189] Fluticasone propionate 0.5 g, light liquid paraffin 350 g, isopropyl myristate 50 g, cetostearyl alcohol 70 g, cetostearyl ether 5.0 g, sorbitol 100 g, citric acid 0.5 g, disodium hydrogen phosphate dodecahydrate 1.5 g, carbomer 5.0 g, imidazolidinyl urea 2.0 g, purified water to 1000 g.

[0190] 2. Preparation process

[0191] (1) Preparation of water phase: sorbitol, citric acid, disodium hydrogen phosphate dodecahydrate, cetostearyl ether and imidazolidinyl urea were added to part of water and stirred to dissolve, then 4.5 g of carbomer was added and stirred to swell completely, heated to 75℃, the stirring speed was 200 rpm, and the stirring solution was kept warm for standby;

[0192] (2) Preparation of oil phase: light liquid paraffin, cetostearyl alcohol and isopropyl myristate were heated and stirred to melt, and kept warm at 75℃ for standby;

[0193] (3) Preparation of stabilizer solution: a certain amount of purified water was taken, 0.5 g of carbomer was added and stirred to swell, and a 0.5% solution was prepared, the stirring speed was 600 rpm;

[0194] (4) Fluticasone propionate was slowly added to the stabilizer solution under homogenization, the homogenization speed was 6000 rpm, and the homogenization time was 5 min;

[0195] (5) The suspension obtained in (4) was added to (1) and stirred uniformly, the stirring speed was 250 rpm, and the stirring time was 10 min, and it was kept warm at 75℃ for standby;

[0196] (6) The water phase and the oil phase were mixed, emulsified at 75℃ and 250 rpm for 10 min, then homogenized at 6000 rpm for 2 min, and finally cooled to about 31℃ under stirring at 250 rpm and discharged.

[0197] Comparative Example 1

[0198] Perrigo. Cream preparation (0.05% fluticasone propionate cream,

[0199] Comparative Example 2

[0200] Fluticasone propionate cream was prepared according to the method in CN 102885762B.

[0201] (1) Preparation of water phase: citric acid, disodium hydrogen phosphate dodecahydrate, cetostearyl alcohol polyether-20 and imidazolidinyl urea were added to water and stirred to dissolve, heated to 65-85℃, the stirring speed was 150-300 rpm, and the stirring solution was kept warm for standby;

[0202] (2) Oil phase preparation: liquid paraffin, cetostearyl alcohol and isopropyl myristate were heated and stirred to melt, and then kept at 65-85 °C for standby;

[0203] (3) Fluticasone propionate solution preparation: the prescribed amount of propylene glycol solution was weighed, and the prescribed amount of fluticasone propionate was added and stirred or homogenized (with appropriate heating) to prepare a fluticasone propionate solution, which was kept at 65 °C for standby;

[0204] (4) The water phase and the oil phase were mixed, and emulsified at 65-85 °C and 250 rpm for 10 min, and then homogenized at 6000 rpm for 2 min. Then the fluticasone propionate solution prepared in step (3) was added under stirring, and then continued to stir at 65-85 °C for 10 min, and then homogenized at 6000 rpm for 2 min, and then cooled to about 31 °C under 250 rpm stirring to discharge.

[0205] Comparative Example 3

[0206] 1. Formulation prescription

[0207] Fluticasone propionate 0.5 g, liquid paraffin 400 g, isopropyl myristate 50 g, cetostearyl alcohol 60 g, cetyl alcohol polyether-20 10 g, propylene glycol 100 g, citric acid 0.5 g, disodium hydrogen phosphate dodecahydrate 1.5 g, imidazole alkyl urea 2.0 g, and purified water were added to 1000 g.

[0208] 2. Formulation process

[0209] (1) Water phase preparation: propylene glycol, citric acid, disodium hydrogen phosphate dodecahydrate, cetyl alcohol polyether-20 and imidazole alkyl urea were added to water and stirred and heated to dissolve, and then heated to 65-85 °C and stirred to dissolve and kept for standby;

[0210] (2) Oil phase preparation: liquid paraffin, cetostearyl alcohol and isopropyl myristate were heated and stirred to melt, and then kept at 65-85 °C for standby;

[0211] (3) The water phase and the oil phase were mixed, and emulsified at 65-85 °C and 250 rpm for 10 min, and then homogenized at 6000 rpm for 5 min;

[0212] (4) Fluticasone propionate was slowly added to the blank cream base under stirring for 10 min, and then homogenized for 5 min (homogenization speed was 6000 rpm);

[0213] (5) The temperature was cooled to about 31 °C under 250 rpm stirring to discharge.

[0214] Example 13

[0215] The products of Examples 1-12 and Comparative Examples 1-3 were investigated, including physical stability, API distribution, rheological properties of the products, and product release. Details are as follows:

[0216] 1. Physical stability

[0217] The above examples and reference formulations were subjected to freeze-thaw cycles (-20°C / 40°C, investigated for 12 days), 40°C investigation, and 50°C investigation (1 day, 3 days, 5 days, 10 days) under the same investigation conditions.

[0218] The investigation results are shown in Tables 1-3, Figs. 1-3 and the results show that the cream products prepared according to the present method have good physical stability, and do not show oil-water separation and delamination after 10 days of 50°C investigation.

[0219] Table 1. Properties of products after investigation under different conditions (cooled to room temperature)

[0220]

[0221] Table 2. Results of centrifugation of products after investigation under different conditions (cooled to room temperature)

[0222]

[0223]

[0224] Note: “—” indicates that the product is oil-water separated, and centrifugation is not necessary.

[0225] Table 3. Microscopic results of products after investigation under different conditions (cooled to room temperature)

[0226]

[0227] Note: “—” indicates that the product is oil-water separated, and microscopic observation is not necessary.

[0228] 2. API distribution

[0229] The API distribution of the creams prepared in the above examples and comparative examples was investigated after room temperature storage and high temperature investigation. The results are shown in Table 4, Figs. 4-6 and the results show that the creams prepared according to the present method have uniform API distribution and can stably exist after relatively severe condition investigation and long-term room temperature storage. In the formulation prepared by the method of Comparative Example 2, the API particle size is obviously rod-shaped, and the particle size difference is large.

[0230] Table 4. API distribution of products after investigation under different conditions

[0231]

[0232] 3. Rheological properties of the products

[0233] The samples prepared in the above examples and comparative examples were subjected to rheological index determination. The results are shown in Table 5, and the rheological properties of the creams prepared according to the present method were not significantly different from those of the control product, Perrigo (Comparative Example 1).

[0234] Table 5. Rheological properties of the products

[0235]

[0236]

[0237] 4. Release of the products

[0238] In combination with the physical properties, rheological indexes, microscopic state, and dispersion state of the raw drug of the above cream products, the release of the cream prepared according to the present method was investigated. The results are shown in Table 6, and the release of the cream product prepared according to the present method was similar to that of the control product. This indicates that the quality of the present product is consistent with that of the control product (Corresponding to Comparative Example 1).

[0239] Table 6. Release of the products

[0240]

Claims

1. A highly stable fluticasone propionate pharmaceutical composition, characterized in that, The pharmaceutical composition is composed of the main drug fluticasone propionate and the auxiliary materials; the auxiliary materials contain the stabilizer, which is any one or more of carbomer, xanthan gum.

2. The pharmaceutical composition of claim 1, wherein, The content of the stabilizer in the pharmaceutical composition is 0.05%-0.5%.

3. The pharmaceutical composition of claim 1, wherein, The auxiliary materials contain the liquid oil phase, the solid oil phase, the emulsifier, the humectant, the acid-base regulator and the preservative, the liquid oil phase is any one or more of light liquid paraffin, liquid paraffin, isopropyl myristate, the solid oil phase is any one or more of cetyl alcohol, stearyl alcohol, cetylstearyl alcohol, the emulsifier is any one or more of polyoxyethylene 18 cetylstearyl ether, ceteth-20, cetomacrogol 1000, the humectant is one or more of propylene glycol, sorbitol, glycerol, the acid-base regulator is composed of citric acid and disodium hydrogen phosphate or disodium hydrogen phosphate dodecahydrate, and the preservative is any one or more of hydroxybenzoic acid ester, hydroxybenzoic acid propyl ester or imidazolidinyl urea.

4. The pharmaceutical composition of claim 3, wherein, The content of the liquid oil phase in the pharmaceutical composition is 30%-55%, the content of the solid oil phase in the pharmaceutical composition is 3%-9%, the content of the emulsifier in the pharmaceutical composition is 0.5%-3%, the content of the humectant in the pharmaceutical composition is 5%-20%, the content of the acid-base regulator in the pharmaceutical composition is 0.1%-0.3%, and the content of the preservative in the pharmaceutical composition is 0.1%-0.3%.

5. A suspension-type cream of fluticasone propionate with high stability, characterized in that, The fluticasone propionate suspension type cream contains the pharmaceutical composition of any one of claims 1-4.

6. The suspending cream of claim 5, wherein, The suspension type cream comprises the following components by weight: 0.05 parts of fluticasone propionate, 30-55 parts of the liquid oil phase, 3-9 parts of the solid oil phase, 0.5-3 parts of the emulsifier, 5-20 parts of the humectant, 0.1-0.3 parts of the acid-base regulator, 0.05-0.5 parts of the physical stabilizer, 0.1-0.3 parts of the preservative, and purified water to 100 parts.

7. The suspending cream of claim 6, wherein, The suspension type cream comprises the following components by weight: 0.05 parts of fluticasone propionate, 30-45 parts of light liquid paraffin or liquid paraffin, 4-8 parts of isopropyl myristate, 3-8 parts of the solid oil phase, 0.5-3 parts of the emulsifier, 5-20 parts of the humectant, 0.05 parts of citric acid, 0.05-0.15 parts of disodium hydrogen phosphate or disodium hydrogen phosphate dodecahydrate, 0.05-0.5 parts of the stabilizer, 0.1-0.25 parts of the preservative, and purified water to 100 parts.

8. Process for the preparation of a suspension of fluticasone propionate cream according to any one of claims 5 to 7, characterized in that, The method comprises the following steps: (1) Preparation of the water phase: the humectant, the acid-base regulator and the emulsifier are added to the purified water, stirred and heated to dissolve, the stabilizer is added or not, heated and stirred to obtain the water phase; (2) Preparation of the oil phase: the liquid oil phase and the solid oil phase are heated and stirred to melt, to obtain the oil phase; (3) Stabilizer solution: the stabilizer is added to the purified water, stirred and swelled completely to obtain the stabilizer solution; (4) Fluticasone propionate is added to the stabilizer solution, high-speed stirring or homogenization dispersion to obtain the suspension. (5) The suspension obtained in step (4) is added into the water phase, and dispersed by heating and stirring to obtain a fluticasone propionate suspension base; (6) The fluticasone propionate suspension base obtained in step (5) is mixed with the oil phase obtained in step (2) to perform an emulsification reaction, and the temperature is lowered to obtain a fluticasone propionate suspension cream.

9. The method of claim 8, wherein, In step (1), the heating temperature is 60-90°C, and the stirring speed is 120-400 rpm; the pH of the water phase is 4.0-6.

5.

10. The method of claim 8, wherein, In step (6), the emulsification reaction conditions are as follows: emulsification at 60-85°C under stirring at 150-300 rpm for 10-30 min; homogenization emulsification under a homogenization intensity of 6000-10000 rpm for 1-4 min.

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