Desonide composition with improved stability

Abstract

The invention relates to a desonide composition with improved stability, which is an emulsion type topical pharmaceutical preparation composition with a pH value of 3.7-4.5, and comprises 0.005-0.5% w / w of desonide, an oil phase comprising a surfactant and a combination of a self-emulsifier and a surface active emulsifier, and a water phase comprising a humectant, a preservative and a chelating agent. By reducing the pH value, the stability of the composition can be effectively improved. The composition has the advantages that the components and the preparation method are reasonable in design, the stability of the composition can be effectively improved by adjusting the pH value on the basis of improving skin conditions (such as inflammation and pruritus) of skin diseases, and the composition has equivalence with commercially available products.

Description

TECHNICAL FIELD

[0001] The present application relates to a stable betamethasone composition, in particular to a stable betamethasone emulsion liquid preparation composition and a preparation method thereof, and belongs to the technical field of betamethasone composition preparation. BACKGROUND

[0002] Pruritus patients have an uncomfortable feeling on the skin, causing the desire to scratch. Pruritus not only has a negative impact on the quality of life of patients, but also aggravates skin and skin diseases. Compared with other skin diseases, the incidence of pruritus is higher in patients with prurigo, urticaria and inflammatory skin diseases (such as acne, eczematous dermatitis and psoriasis). The incidence of pruritus in female patients is higher than that in male patients.

[0003] Desowen® betamethasone lotion is approved for marketing in many countries, and its ingredients include cetyl alcohol, sodium ethylenediaminetetraacetate, glyceryl monostearate, light mineral oil, methyl paraben, propylene glycol, propyl paraben, water, sodium lauryl sulfate (SLS), sorbitol monostearate, stearyl alcohol, anhydrous citric acid and sodium hydroxide, and the pH value of the final formula is maintained at about 5.7-5.8. However, the pH value of the final product has been adjusted to 4.5-5.0. The higher the pH value range of the emulsion preparation, the lower the stability, resulting in an increase in the degradation of the active ingredient of betamethasone lotion within the shelf life.

[0004] The composition disclosed in US6387383B1 contains 0.5mg of betamethasone, and the hydrogel matrix is pure water, glycerol, propylene glycol, disodium ethylenediaminetetraacetate dihydrate, methyl paraben, propyl paraben, sodium hydroxide and Carbopol® 981, and the pH value range is 4.5 to 7.0, which is also relatively high.

[0005] If the pH value range of the betamethasone emulsion can be further reduced, the stability can be effectively improved. SUMMARY

[0006] The present application provides a stable betamethasone composition, which aims to overcome the above-mentioned deficiencies in the prior art, further reduce the pH value range of the betamethasone emulsion, and improve the stability.

[0007] The technical solution of the present application: a stable betamethasone composition is an emulsion type topical pharmaceutical preparation composition with a pH value of 3.7-4.5, containing 0.005%-0.5%w / w of betamethasone, an oil phase containing a surfactant and a combination of self-emulsifying agents and surface active emulsifiers, and an aqueous phase containing a humectant, a preservative and a chelating agent. By reducing the pH value, the stability of the composition can be effectively improved.

[0008] Preferably, during preparation, the oil phase and the aqueous phase are emulsified, then mixed with the drug phase containing desonide, and then the pH value is adjusted to 3.7-4.5 by a pH adjuster.

[0009] Preferably, the desonide content is 0.01%-0.1% w / w, the surfactant in the oil phase is selected from sodium dodecyl sulfate, the self-emulsifier is selected from multi-grade glyceryl stearate SE containing 30-90% monoglyceride, and the surfactant emulsifier is selected from polyoxyethylene sorbitan fatty acid ester of any chain length; the preparation includes dispersing desonide in pure water and adding or not adding surfactant to obtain a drug phase, and adding the drug phase to the emulsion at 45-50°C.

[0010] Preferably, the surfactant emulsifier in the oil phase is sorbitol fatty acid ester, the humectant in the aqueous phase is selected from glycerol, propylene glycol, sorbitol, and mannitol, and the chelating agent is selected from disodium ethylenediaminetetraacetate, nitrotriacetic acid, diethylenetriaminepentaacetic acid, and triethylenetetraaminehexaacetic acid. During preparation, the oil phase and aqueous phase are homogenized and emulsified at 70°C. Desonide is dispersed in pure water, and the surfactant, which may or may not be added, is sodium dodecyl sulfate. The pH adjuster is a combination of acetic acid, phosphoric acid, or citric acid and sodium hydroxide, potassium hydroxide, or ammonia. The pH value is adjusted to 4.0-4.5 by the pH adjuster.

[0011] Preferably, the self-emulsifier is selected from glyceryl multi-grade stearate SE containing 40% monoglyceride, the surfactant is sorbitan monostearate, the humectant in the aqueous phase is propylene glycol, the chelating agent is disodium ethylenediaminetetraacetate, and the pH adjuster is a combination of citric acid and sodium hydroxide.

[0012] Preferably, the oil phase and the aqueous phase are prepared at 70°C.

[0013] Preferably, during preparation, desonide is dispersed in purified water and 0.01%-0.2% w / w sodium dodecyl sulfate is added.

[0014] Preferably, the sodium dodecyl sulfate content is 0.05-0.1% w / w.

[0015] Preferably, the oil phase further comprises cetyl alcohol, stearyl alcohol and liquid paraffin, and the aqueous phase further comprises methylparaben and propylparaben.

[0016] Preferably, the concentration of sodium dodecyl sulfate in the oil phase is 0.01-0.50% w / w, the concentration of the self-emulsifier is 0.1-0.50% w / w, and the concentration of the oil phase in the emulsion is 10-30% w / w.

[0017] Advantages of this invention: The components and preparation method are rationally designed. While ensuring the improvement of skin conditions (such as inflammation and itching), the stability of the composition can be effectively improved by adjusting the pH value, and it is equivalent to commercially available products. Detailed Implementation

[0018] The present invention will be further described in detail below with reference to embodiments and specific implementation methods.

[0019] As one embodiment, a desonide composition with improved stability is an emulsion-based topical pharmaceutical formulation composition with a pH of 3.7-4.5, comprising about 0.005%-0.5% w / w desonide, an oil phase containing surfactants and a combination of self-emulsifiers and surfactant emulsifiers, and an aqueous phase containing humectants, preservatives, and chelating agents. The preparation method includes a suitable emulsification method and a suitable desonide addition method, and the pH of the final formulation is adjusted to 3.7-4.5 using a pH adjuster.

[0020] Based on this, as a more preferred embodiment, the desonide content is about 0.01%-0.1% w / w, the surfactant in the oil phase is selected from sodium dodecyl sulfate, the self-emulsifier is selected from multi-grade glyceryl stearate SE containing 30-90% monoglycerides, and the surfactant emulsifier is selected from polyoxyethylene sorbitan fatty acid esters of any chain length. The desonide addition method in the preparation method involves dispersing desonide in purified water and adding or not adding a surfactant to obtain the drug phase, and then adding the drug phase to the emulsion at about 45-50°C.

[0021] Based on this, as a more preferred embodiment, the surfactant emulsifier in the oil phase is selected from sorbitol fatty acid esters, the humectant in the aqueous phase is selected from glycerol, propylene glycol, sorbitol, and mannitol, and the chelating agent is selected from disodium ethylenediaminetetraacetate, nitrotriacetic acid, diethylenetriaminepentaacetic acid, and triethylenetetraaminehexaacetic acid. In the preparation method, the emulsification method involves homogenizing and emulsifying the oil and aqueous phases at approximately 70°C. In the desonide addition method, the surfactant is sodium dodecyl sulfate, and the pH adjuster is a combination of acetic acid, phosphoric acid, or citric acid with sodium hydroxide, potassium hydroxide, or ammonia. The pH of the final formulation is adjusted to 4.0-4.5 using the pH adjuster.

[0022] Based on this, as a more preferred embodiment, the self-emulsifier is selected from glyceryl multi-grade stearate SE containing 40% monoglyceride, the surfactant emulsifier is selected from sorbitan monostearate, the humectant in the aqueous phase is selected from propylene glycol, the chelating agent is selected from disodium ethylenediaminetetraacetate, and the pH adjuster is a combination of citric acid and / or sodium hydroxide.

[0023] Based on this, as a more preferred embodiment, the oil phase and the aqueous phase are prepared at approximately 70°C.

[0024] Based on this, as a more preferred embodiment, in the desonide addition method of the preparation method, desonide is dispersed in purified water containing 0.01%-0.2% sodium dodecyl sulfate.

[0025] Based on this, as a more preferred embodiment, the sodium dodecyl sulfate content in the purified water is 0.05-0.1%.

[0026] Based on this, as a more preferred embodiment, the oil phase further comprises cetyl alcohol, stearyl alcohol and liquid paraffin, and the aqueous phase further comprises methylparaben and propylparaben.

[0027] Based on this, as a more preferred embodiment, the concentration of sodium dodecyl sulfate in the oil phase is 0.01-0.50%, the concentration of self-emulsifier is 0.1-0.50%, and the concentration of oil phase in the emulsion is 10-30%.

[0028] To demonstrate the equivalence of the composition of the present invention compared with commercially available products, an in vitro release test method was designed, comprising: combining an organic solvent and an aqueous solvent in the receptor medium; selecting a vertical diffusion cell or an immersion sample cell as the instrument; using a nylon membrane with a pore size of 0.2-0.45 μm; maintaining the temperature of the receptor medium and the membrane-containing sample at 32±0.5℃; and stirring the receptor medium at a speed of 200-800 r / min.

[0029] Based on this, as a more preferred embodiment, the organic solvent is methanol, ethanol, isopropanol or butanol, the aqueous solvent is purified water, propylene glycol or phosphate buffer, and the nylon membrane has a pore size of 0.25 μm or 0.45 μm.

[0030] Based on this, as a more preferred embodiment, the organic solvent accounts for 10%-80% by volume and is methanol or ethanol.

[0031] Based on this, as a more preferred embodiment, the organic solvent accounts for 30-60% of the volume.

[0032] Based on this, as a more preferred embodiment, the organic solvent accounts for 40% of the volume.

[0033] Based on this, as a more preferred embodiment, the water solvent is pure water, which accounts for 60% by volume.

[0034] Based on this, as a more preferred embodiment, the nylon membrane has a pore size of 0.45 μm.

[0035] Example 1 (SLS oil phase, drug slurry) Preparation of the oil phase: Cetyl alcohol, stearyl alcohol, glyceryl stearate SE, and sorbitan monostearate are heated and melted together with liquid paraffin at approximately 70-75°C. Sodium dodecyl sulfate is then added and dispersed at approximately 70-75°C.

[0036] Preparation of the aqueous phase: Heat a mixture of propylene glycol and purified water. Add and dissolve disodium ethylenediaminetetraacetate at approximately 70-75°C.

[0037] Emulsification: Add the oil phase to the aqueous phase, stir until homogeneous and emulsify at approximately 70-75°C. Cool the emulsion to approximately 45-50°C.

[0038] Preparation of the drug phase: Dissolve 0.05% w / w sodium dodecyl sulfate in a portion of water. Add and disperse dessonide under homogenization, and continue high-speed homogenization for 20 min until a uniform dispersion of dessonide is formed.

[0039] Adding the drug phase: At approximately 45-50°C, add the drug phase to the emulsified and cooled powder, and stir under homogenization conditions for 20 minutes. Cool the powder to approximately 36-40°C.

[0040] pH adjustment: Adjust the pH of the powder to 4.0-4.5, and then mix the powder with stirring to form the dessonide composition.

[0041] Example 2 (SLS aqueous phase, drug slurry) The difference from Example 1 is that sodium dodecyl sulfate is not added to the oil phase; instead, sodium dodecyl sulfate is added and dispersed at about 70-75°C after dissolving disodium ethylenediaminetetraacetate in the aqueous phase. Example 3 (SLS and drug are both in the oil phase)

[0042] Preparation of the oil phase: Cetyl alcohol, stearyl alcohol, glyceryl stearate SE, and sorbitan monostearate were melted together with liquid paraffin at approximately 70-75°C. Sodium dodecyl sulfate was added and dispersed at approximately 70-75°C. Desonide was added under high-speed homogenization conditions, and homogenization was continued for 20 min.

[0043] Preparation of the aqueous phase: Heat a mixture of propylene glycol and purified water. Add and dissolve disodium ethylenediaminetetraacetate at approximately 70-75°C.

[0044] Emulsification: Add the oil phase to the aqueous phase, stir until homogeneous and emulsify at approximately 70-75°C. Cool the emulsion to approximately 36-40°C.

[0045] pH adjustment: Adjust the pH of the emulsion to 4.0-4.5, and then mix with stirring to obtain the desinede composition.

[0046] Example 4 (SLS oil phase, drug aqueous phase) Preparation of the oil phase: Cetyl alcohol, stearyl alcohol, glyceryl stearate SE, and sorbitan monostearate are heated and melted together with liquid paraffin at approximately 70-75°C. Sodium dodecyl sulfate is then added and dispersed at approximately 70-75°C.

[0047] Preparation of the aqueous phase: Heat a mixture of propylene glycol and purified water. Add and dissolve disodium ethylenediaminetetraacetate at approximately 70-75°C. Add desonide under high-speed homogenization conditions and continue homogenization for 20 min.

[0048] Emulsification: Add the oil phase to the aqueous phase, stir until homogeneous and emulsify at approximately 70-75°C. Cool the emulsion to approximately 36-40°C.

[0049] pH adjustment: Adjust the pH of the emulsion to 4.0-4.5, and then mix with stirring to obtain the desinede composition.

[0050] Example 5 (SLS oil phase, drug in emulsion) Preparation of the oil phase: Cetyl alcohol, stearyl alcohol, glyceryl stearate SE, and sorbitan monostearate are heated and melted together with liquid paraffin at approximately 70-75°C. Sodium dodecyl sulfate is then added and dispersed at approximately 70-75°C.

[0051] Preparation of the aqueous phase: Heat a mixture of propylene glycol and purified water. Add and dissolve disodium ethylenediaminetetraacetate at approximately 70-75°C. Add and disperse sodium dodecyl sulfate at approximately 70-75°C.

[0052] Emulsification: Add the oil phase to the aqueous phase, stir until homogeneous and emulsify at approximately 70-75°C. Cool the emulsion to approximately 44-46°C.

[0053] Add the drug: Add desonide at the optimal rate under homogenization conditions, and continue homogenization for 20 minutes. Cool the emulsion to approximately 36-40°C.

[0054] pH adjustment: Adjust the pH of the emulsion to 4.0-4.5, and then mix with stirring to obtain the desinede composition.

[0055] Example 6 (In vitro release study) In vitro release studies were conducted at 32±0.2℃ using a fixed ratio of ethanol and water, a 0.45μm nylon membrane, a vertical diffusion cell, or an immersion sample cell, with stirring. The results comparing the desonide compositions of Examples 1-5 with the comparative example Desowen® desonide lotion are shown in the table below.

[0056]

[0057] According to the table above, Examples 1, 3, and 5, which added SLS to the oil phase and the drug slurry to the emulsion, had release rates comparable to the comparative example, Desowen® Desonide Lotion, while Examples 2 and 4 had significantly faster release rates than the comparative example. Example 7 (In vitro release study)

[0058] In vitro release studies were conducted using 20%, 40%, and 60% ethanol or methanol as media, at 32±0.2°C, with a 0.45μm nylon membrane, a vertical diffusion cell, or an immersion sample cell. The results comparing the desonide composition of Example 1 with the comparative example Desowen® desonide lotion are shown in the table below.

[0059]

[0060]

[0061] Example 8 (Stability Study) Stability studies were conducted under pressure conditions to understand the degradation patterns of impurities as the pH of the corresponding desonide composition changed. The results of comparing the desonide composition of Example 1 with the comparative example Desowen® desonide lotion are shown in the table below.

[0062]

[0063]

[0064] According to the table above, under accelerated storage conditions, the degradation of the desonide composition showed a correlation with pH stability over a period of time. The most stable pH was around 4.0-4.5. At pH values ​​above 5.50, impurities increased significantly.

[0065] Example 9 (In vitro permeation study) In vitro permeation studies of the optimized formulation were conducted on porcine skin using a vertical diffusion cell with 0.9% sodium chloride solution as the medium. The permeability of the desonide composition of Example 1 was studied for 24 hours at 2, 4, 8, 12, and 24 hours at 32 ± 0.2 °C. The results are shown in the table below.

[0066]

[0067] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A desonide composition for improving stability, characterized in that, It is an emulsion-type topical drug formulation composition with a pH of 3.7-4.5, comprising 0.005%-0.5% w / w desonide, an oil phase containing surfactants and a combination of self-emulsifiers and surfactant emulsifiers, and an aqueous phase containing humectants, preservatives and chelating agents.

2. The desonide composition for improving stability as described in claim 1, characterized in that, During preparation, the oil and aqueous phases are emulsified and then mixed with the drug phase containing desonide. The pH value is then adjusted to 3.7-4.5 using a pH adjuster.

3. The desonide composition for improving stability as described in claim 2, characterized in that, During preparation, the desonide content is 0.01%-0.1% w / w, the surfactant in the oil phase is selected from sodium dodecyl sulfate, the self-emulsifier is selected from multi-grade glyceryl stearate SE containing 30-90% monoglyceride, and the surface-active emulsifier is selected from polyoxyethylene sorbitan fatty acid ester of any chain length. The preparation includes dispersing desonide in pure water and adding or not adding surfactant to obtain the drug phase, and adding the drug phase to the emulsion at 45-50°C.

4. The desonide composition for improving stability as described in claim 3, characterized in that, In the preparation process, the surface-active emulsifier in the oil phase is sorbitol fatty acid ester, the humectant in the aqueous phase is selected from glycerol, propylene glycol, sorbitol, and mannitol, and the chelating agent is selected from disodium ethylenediaminetetraacetate, nitrotriacetic acid, diethylenetriaminepentaacetic acid, and triethylenetetraaminehexaacetic acid. In the preparation process, the oil phase and the aqueous phase are homogenized and emulsified at 70°C. Desonide is dispersed in pure water, and the surfactant added or not added is sodium dodecyl sulfate. The pH adjuster is a combination of acetic acid, phosphoric acid, or citric acid and sodium hydroxide, potassium hydroxide, or ammonia. The pH value is adjusted to 4.0-4.5 by the pH adjuster.

5. The desonide composition for improving stability as described in claim 4, characterized in that, In preparation, the self-emulsifier is selected from glyceryl multi-stage stearate SE containing 40% monoglyceride, the surface-active emulsifier is sorbitan monostearate, the humectant in the aqueous phase is propylene glycol, the chelating agent is disodium ethylenediaminetetraacetate, and the pH adjuster is a combination of citric acid and sodium hydroxide.

6. The desonide composition for improving stability as described in claim 5, characterized in that, During preparation, the oil phase and the aqueous phase were prepared at 70°C respectively.

7. The desonide composition for improving stability as described in claim 6, characterized in that, During preparation, desonide is dispersed in purified water and 0.01%-0.2% w / w sodium dodecyl sulfate is added.

8. The desonide composition for improving stability as described in claim 7, characterized in that, The sodium dodecyl sulfate content is 0.05-0.1% w / w.

9. The desonide composition for improving stability as described in claim 8, characterized in that, The oil phase further comprises cetyl alcohol, stearyl alcohol and liquid paraffin, and the aqueous phase further comprises methylparaben and propylparaben.

10. The desonide composition for improving stability as described in claim 9, characterized in that, The concentration of sodium dodecyl sulfate in the oil phase is 0.01-0.50% w / w, the concentration of self-emulsifier is 0.1-0.50% w / w, and the concentration of oil phase in the emulsion is 10-30% w / w.

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