Dapsone gel and preparation method thereof

Abstract

The invention provides dapsone gel. The gel is prepared from the following components in percentage by weight: 7.5 percent of dapsone, 30 percent to 34 percent of diethylene glycol monoethyl ether, 1.9 percent to 2.4 percent of hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer, 0.1 percent to 0.3 percent of methylparaben and 56 percent to 60 percent of purified water. According to the dapsone gel disclosed by the invention, the hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer is selected as a thickening agent, and a specific dissolution promoter, an oil phase and a surfactant are added, so that the dapsone gel which is more stable in bulk drug particle size and better in smearing feeling is prepared.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dapsone gel and a preparation method thereof. Background Art

[0002] Dapsone gel is a topical medication for the treatment of acne vulgaris, with antibacterial and anti-inflammatory effects, capable of reducing the number of bacteria on the skin and alleviating inflammation, thereby improving acne symptoms.

[0003] The dapsone gel Aczone produced by Allergan, Inc. in the United States has been successively marketed in the United States, Canada, and EU countries. However, the active pharmaceutical ingredient (API) in this product exists in a suspension state, which will cause problems such as the growth of the API particle size after the product is stored, affecting the quality of the product, and also resulting in a gritty feeling during the application process, affecting the user experience of patients.

[0004] Therefore, there is a need in the art to provide a dapsone gel with better patient compliance and more stable quality. Summary of the Invention

[0005] To solve the above technical problems, the present invention selects poly (hydroxyethyl acrylate / sodium acryloyldimethyltaurate) as a thickening agent, and adds specific solubilizers, oil phases, and surfactants to prepare a dapsone gel with more stable API particle size and better application feeling.

[0006] On the one hand, the present invention provides a dapsone gel, which comprises the following components by weight percentage: 7.5% dapsone, 30% - 34% diethylene glycol monoethyl ether, 1.9% - 2.4% poly (hydroxyethyl acrylate / sodium acryloyldimethyltaurate), 0.1% - 0.3% methylparaben, and 56% - 60% purified water.

[0007] The percentage content of diethylene glycol monoethyl ether is 30% - 34%, for example, it can be 30%, 31%, 32%, 33% or 34%, as well as the specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively list the specific point values included in the above range.

[0008] The percentage content of poly (hydroxyethyl acrylate / sodium acryloyldimethyltaurate) is 1.9% - 2.4%, for example, it can be 1.9%, 2.1%, 2.2% or 2.4%, as well as the specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively list the specific point values included in the above range.

[0009] The percentage content of methylparaben is 0.1% - 0.3%, for example, it can be 0.1%, 0.2%, 0.3% or 0.4%, as well as the specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively list the specific point values included in the said range.

[0010] The percentage content of purified water is 56% - 60%, for example, it can be 56%, 57%, 58%, 59% or 60%, as well as the specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively list the specific point values included in the said range.

[0011] In some embodiments, the gel further comprises 0.5% - 1.6% of a solubilizer, and the solubilizer comprises polyethylene glycol 400 and / or propylene glycol.

[0012] The percentage content of the solubilizer is 0.8% - 1.6%, for example, it can be 0.5%, 1.0%, 1.4% or 1.6%, as well as the specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively list the specific point values included in the said range.

[0013] It can be understood that adding a solubilizer to the dapsone gel can increase the solubility of dapsone raw material drug in the gel, reduce the particle size of the raw material drug, reduce the granular feeling of the preparation and increase the smoothness.

[0014] In some embodiments, the gel further comprises 0 - 1.0% of an oil phase, and the oil phase comprises one or more of liquid paraffin, cetane, and light liquid paraffin.

[0015] The percentage content of the oil phase is 0 - 1.0%, for example, it can be 0%, 0.5%, 0.8% or 1.0%, as well as the specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively list the specific point values included in the said range.

[0016] It can be understood that adding an oil phase to the dapsone gel is beneficial to the dispersion of dapsone raw material drug, making the particle size of dapsone raw material drug more uniform.

[0017] In some embodiments, the gel further comprises 0 - 0.4% of a surfactant, and the surfactant comprises one or more of Tween, Span, and polyoxyethylene (35) castor oil.

[0018] The percentage content of the surfactant is 0 - 0.4%, for example, it can be 0%, 0.1%, 0.3% or 0.4%, as well as the specific point values between the above point values. Due to space limitations and for the sake of simplicity, the present invention does not exhaustively list the specific point values included in the said range.

[0019] It is understandable that adding a surfactant to the dapsone gel helps the uniform mixing of the oil and water phases in the gel preparation and contributes to the long-term storage of the preparation.

[0020] In some embodiments, the gel comprises the following components by weight percentage: 7.5% dapsone, 30% - 34% diethylene glycol monoethyl ether, 1.9% - 2.4% hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer, 0.5% - 1.6% polyethylene glycol 400, 0 - 1.0% liquid paraffin, 0 - 0.4% polyoxyl 35 castor oil, 0.1% - 0.3% methylparaben, 56% - 60% purified water.

[0021] On the other hand, the present invention also provides a method for preparing a dapsone gel, comprising:

[0022] Step 1: Optionally, mix a solubilizer, an oil phase, a surfactant with purified water, and then add a hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer to obtain a first mixture;

[0023] Step 2: Mix dapsone, methylparaben and diethylene glycol monoethyl ether to obtain a second mixture;

[0024] Step 3: Mix the first mixture with the second mixture to obtain the product.

[0025] The dapsone gel of the present invention has the following advantages:

[0026] The present invention selects a hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer as a thickener, and adds specific solubilizers, oil phases and surfactants to prepare a dapsone gel with more stable particle size of the active pharmaceutical ingredient and better spreading feel.

[0027] 1. The present invention adds an appropriate amount of solubilizer to the dapsone gel, which promotes the dissolution of the dapsone active pharmaceutical ingredient in the gel preparation, reduces the particle size of the dapsone active pharmaceutical ingredient during the storage of the preparation, reduces the graininess of the dapsone gel preparation and increases the smoothness of the preparation during use;

[0028] 2. The present invention adds an oil phase to the dapsone gel, which helps the dispersion of the dapsone active pharmaceutical ingredient in the preparation and further reduces the particle size of the dapsone active pharmaceutical ingredient during the storage of the preparation;

[0029] 3. The present invention adds a surfactant to the dapsone gel, which helps the uniform mixing of the oil and water phases in the dapsone gel preparation and contributes to the long-term storage of the preparation. Description of the Drawings

[0030] Figure 1 The external view of the dapsone gel prepared in Example 15;

[0031] Figure 2 Appearance diagram of the dapsone gel prepared as Comparative Example 1. Detailed implementation manners

[0032] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific implementations disclosed below.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this invention belongs. The terms used in the description of the present invention are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0034] Preparation of dapsone gel in Example 1

[0035] Table 1 Prescription table of Example 1

[0036]

[0037]

[0038] Preparation method:

[0039] 1. Matrix preparation: Weigh the prescribed amounts of polyethylene glycol 400 and propylene glycol, add an appropriate amount of purified water, mix evenly, and then add the prescribed amount of carbomer, stir and mix evenly to obtain the matrix for standby;

[0040] 2. Dapsone solution preparation: Weigh the prescribed amounts of dapsone and methylparaben and dissolve them all in diethylene glycol monoethyl ether to obtain the solution for standby;

[0041] 3. Mixing to prepare the gel: Mix the dapsone solution and the above matrix evenly to obtain the dapsone gel.

[0042] Preparation of dapsone gel in Example 2

[0043] Table 2 Prescription table of Example 2

[0044] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 30 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2 Polyethylene glycol 400 1.6 Methylparaben 0.2 Purified water Make up to 100

[0045] Preparation method:

[0046] 1. Matrix preparation: Weigh the prescribed amount of polyethylene glycol 400, add an appropriate amount of purified water, mix evenly, and then add the prescribed amount of carbomer, stir and mix evenly to obtain the matrix for standby;

[0047] 2. Preparation of dapsone solution: Weigh the prescribed amounts of dapsone and methylparaben and dissolve them completely in diethylene glycol monoethyl ether to obtain the matrix for standby.

[0048] 3. Preparation of gel by mixing: Mix the dapsone solution with the above matrix evenly to obtain dapsone gel.

[0049] Preparation of dapsone gel in Examples 3 - 6

[0050] Table 3 Prescription table of Example 3

[0051] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 30 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2 Polyoxyl 35 castor oil 0.4 Methylparaben 0.2 Purified water Make up to 100

[0052] Table 4 Prescription table of Example 4

[0053] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 30 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2.0 Tween 80 0.4 Methylparaben 0.2 Purified water Make up to 100

[0054] Table 5 Prescription table of Example 5

[0055] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 30 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2 Polyoxyl 35 castor oil 0.2 Tween 80 0.2 Methylparaben 0.2 Purified water Make up to 100

[0056] Table 6 Prescription table of Example 6

[0057]

[0058]

[0059] Preparation method:

[0060] 1. Matrix preparation: Weigh the prescribed amounts of polyethylene glycol 400, polyoxyethylene (35) castor oil / Tween 80 / glycerol, add an appropriate amount of purified water, mix evenly, and then add the prescribed amount of polyacrylate copolymer of hydroxyethyl acrylate / sodium acryloyldimethyltaurate, stir and mix evenly to obtain the matrix for standby;

[0061] 2. Preparation of dapsone solution: Weigh the prescribed amounts of dapsone and methylparaben and dissolve them completely in diethylene glycol monoethyl ether to obtain the matrix for standby;

[0062] 3. Preparation of gel by mixing: Mix the dapsone solution with the above matrix evenly to obtain dapsone gel.

[0063] Preparation of dapsone gel in Examples 7 - 10

[0064] Table 7 Prescription table of Example 7

[0065] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 30 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2.0 Liquid paraffin 0.8 Methylparaben 0.2 Purified water Make up to 100

[0066] Table 8 Prescription table of Example 8

[0067] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 30 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2.0 Hexadecane 0.8 Methylparaben 0.2 Purified water Make up to 100

[0068] Table 9 Prescription table of Example 9

[0069]

[0070]

[0071] Table 10 Prescription Table of Example 10

[0072] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 30 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2.0 Hexadecane 0.4 Liquid paraffin 0.4 Methylparaben 0.2 Purified water Make up to 100

[0073] Preparation method:

[0074] 1. Matrix preparation: Weigh the prescribed amounts of polyethylene glycol 400, liquid paraffin / cetane / dimethicone, add an appropriate amount of purified water, mix evenly, and then add the prescribed amount of carbomer 940, stir and mix evenly to obtain the matrix for standby;

[0075] 2. Dapsone solution preparation: Weigh the prescribed amounts of dapsone and methylparaben, dissolve them all in diethylene glycol monoethyl ether to obtain the solution for standby;

[0076] 3. Mixing to prepare the gel: Mix the dapsone solution with the above matrix evenly to obtain dapsone gel.

[0077] Preparation of Dapsone Gel in Example 11

[0078] Table 11 Prescription Table of Example 11

[0079] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 31.5 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2 Polyethylene glycol 400 0.8 Liquid paraffin 0.4 Polyoxyl 35 castor oil 0.2 Methylparaben 0.2 Purified water 57.4

[0080] Preparation method:

[0081] 1. Matrix preparation: Weigh the prescribed amounts of polyethylene glycol 400, liquid paraffin, polyoxyl 35 castor oil, add the prescribed amount of purified water, mix evenly, and then add the prescribed amount of carbomer 940, stir and mix evenly to obtain the matrix for standby;

[0082] 2. Dapsone solution preparation: Weigh the prescribed amounts of dapsone and methylparaben, dissolve them all in diethylene glycol monoethyl ether to obtain the solution for standby;

[0083] 3. Mixing to prepare the gel: Mix the dapsone solution with the above matrix evenly to obtain dapsone gel.

[0084] Preparation of Dapsone Gel in Examples 12 - 15

[0085] Table 12 Prescription Table of Example 12

[0086] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 30 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2 Polyethylene glycol 400 0.8 Liquid paraffin 0.4 Polyoxyl 35 castor oil 0.2 Methylparaben 0.2 Purified water 58.9

[0087] Table 13 Prescription Table of Example 13

[0088] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 33 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2 Polyethylene glycol 400 0.8 Liquid paraffin 0.4 Polyoxyl 35 castor oil 0.2 Methylparaben 0.2 Purified water 55.9

[0089] Table 14 Prescription Table of Example 14

[0090] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 31.5 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 1.9 Polyethylene glycol 400 0.8 Liquid paraffin 0.4 Polyoxyl 35 castor oil 0.2 Methylparaben 0.2 Purified water 57.5

[0091] Table 15 Prescription Table of Example 15

[0092] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 31.5 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2.4 Polyethylene glycol 400 0.8 Liquid paraffin 0.4 Polyoxyl 35 castor oil 0.2 Methylparaben 0.2 Purified water 57.0

[0093] The preparation method is the same as that of Example 11.

[0094] Preparation of Dapsone Gel for Examples 16 - 18

[0095] Table 16 Prescription Table of Example 16

[0096] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 31.5 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2 Polyethylene glycol 400 1.6 Liquid paraffin 0 Polyoxyl 35 castor oil 0 Methylparaben 0.2 Purified water 57.2

[0097] Table 17 Prescription Table of Example 17

[0098] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 31.5 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2 Polyethylene glycol 400 0.8 Liquid paraffin 0.8 Polyoxyl 35 castor oil 0 Methylparaben 0.2 Purified water 57.2

[0099] Table 18 Prescription Table of Example 18

[0100] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 31.5 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2 Polyethylene glycol 400 0.6 Liquid paraffin 0 Polyoxyl 35 castor oil 0.4 Methylparaben 0.2 Purified water 57.8

[0101] Preparation of Dapsone Gel for Comparative Example 1

[0102] Table 19 Prescription Table of Comparative Example 1

[0103] Ingredient Ratio (%) Dapsone 7.5 Diethylene glycol monoethyl ether 30 Hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer 2 Methylparaben 0.2 Purified water Make up to 100

[0104] Preparation method:

[0105] 1. Matrix preparation: Weigh the prescribed amount of poly (acrylic acid - co - sodium acryloyldimethyltaurate) and put it into an appropriate amount of purified water, stir and mix evenly to obtain the matrix for standby;

[0106] 2. Dapsone solution preparation: Weigh the prescribed amounts of dapsone and methylparaben and dissolve them all in diethylene glycol monoethyl ether to obtain the solution for standby;

[0107] 3. Mixing to prepare the gel: Mix the dapsone solution with the above - mentioned matrix evenly to obtain dapsone gel.

[0108] Effect experiment of Example 19

[0109] Particle size detection was carried out using a transdermal cream particle size analyzer. Take a small amount of the sample on a glass slide, cover it with a cover slip and gently press the cover slip, then observe the gel microscopically under a 10× magnification lens and count the particle size.

[0110] Table 20 Particle Size Detection Results of the Gel Agents of Comparative Example 1, Example 1 and Example 2

[0111] Particle size Control Example 1 Example 1 Example 2 D10 (μm) 50.03 33.94 32.65 D50 (μm) 113.93 80.50 81.70 D95 (μm) 214.93 153.60 141.78

[0112] From the results of particle size detection on the dapsone gels prepared according to Comparative Example 1, Example 1 and Example 2, it can be seen that by adding the solubilizers polyethylene glycol 400 and / or propylene glycol, the particle size of the active pharmaceutical ingredient in the preparation was significantly improved, and it was found that the granular feeling of the preparation was reduced during use.

[0113] Table 21 Particle size detection results of the gels of Comparative Example 1, Examples 3 - 6

[0114] Particle size Comparative Example 1 Example 3 Example 4 Example 5 Example 6 D10 (μm) 50.03 34.51 37.01 31.20 83.81 D50 (μm) 113.93 84.35 80.12 65.71 101.50 D95 (μm) 214.93 168.71 161.24 158.19 276.24

[0115] From the results of particle size detection on the dapsone gels prepared according to Comparative Example 1, Examples 3 - 6, it can be seen that after adding Tween 80 and polyoxyl 35 castor oil as surfactants, the particle size of the active pharmaceutical ingredient in the preparation was improved, and it was found that the smoothness was increased during use.

[0116] Table 22 Particle size detection results of the gels of Comparative Example 1, Examples 7 - 10

[0117] Particle size Comparative Example 1 Example 7 Example 8 Example 9 Example 10 D10 (μm) 50.03 36.41 35.10 78.90 35.03 D50 (μm) 113.93 100.74 87.30 121.34 67.40 D95 (μm) 214.93 158.47 161.67 265.90 153.24

[0118] From the results of particle size detection on the dapsone gels prepared according to Comparative Example 1, Examples 7 - 10, it can be seen that after adding liquid paraffin and cetane as the oil phase, the particle size of the active pharmaceutical ingredient in the preparation was effectively improved, and it was found that the smoothness was increased during use.

[0119] Table 23 Particle size detection results of the gels of Example 11, Examples 16 - 18

[0120] Particle size Example 11 Example 16 Example 17 Example 18 D10 (μm) 45.52 36.11 38.31 34.25 D50 (μm) 85.97 80.90 81.90 93.03 D95 (μm) 149.70 143.52 146.07 166.10

[0121] From the results of particle size detection on the dapsone gels prepared according to Example 11, Examples 16 - 18, it can be seen that adding 0.5% - 1.6% of solubilizer, 0 - 1.0% of oil phase, and 0 - 0.4% of surfactant in the formulation can improve the particle size of the active pharmaceutical ingredient in the preparation. Among them, compared with the commercially available preparation (Aczone, 7.5%), the particle size distribution of Example 11 is closer to that of the commercially available preparation, and there is no obvious granular feeling and it is consistent with the commercially available preparation, and the smoothness is better.

[0122] Table 24 Particle size detection results of the gels of Example 11 - 13

[0123] Particle size Example 11 Example 12 Example 13 D10 (μm) 45.52 29.22 28.89 D50 (μm) 85.97 69.67 71.25 D95 (μm) 149.70 142.39 152.50

[0124] From the results of particle size detection on the dapsone gels prepared according to Example 11 - 13, it can be seen that there is no obvious difference in the particle size of the preparations prepared with the dosage range of diethylene glycol monoethyl ether of 30% - 34%, and they all have good smoothness and no granular feeling.

[0125] Table 25 Detection results of the particle size of the gel in Examples 14 - 15

[0126] Particle size Example 11 Example 14 Example 15 D10 (μm) 45.52 40.15 36.11 D50 (μm) 85.97 92.10 80.90 D95 (μm) 149.70 159.52 143.52

[0127] From the results of the particle size detection of the dapsone gel prepared according to Examples 14 - 15, it can be seen that there is no obvious difference in the particle size of the preparations prepared with the dosage range of hydroxyethyl acrylate / sodium acryloyldimethyltaurate copolymer of 1.9% - 2.4%, and there is no particle feeling and they all have good smoothness.

Claims

1. A dapsone gel, characterized in that: The gel comprises the following components by weight percentage: 7.5% dapsone, 30% to 34% diethylene glycol monoethyl ether, 1.9% to 2.4% hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer, 0.1% to 0.3% methylparaben, and 56% to 60% purified water.

2. The dapsone gel according to claim 1, characterized in that The gel also includes 0.5% to 1.6% of a solubilizing agent.

3. The dapsone gel according to claim 2, characterized in that Dissolution enhancers include polyethylene glycol 400 and / or propylene glycol.

4. The dapsone gel according to claim 1, characterized in that The gel also includes 0-1.0% oil phase.

5. The dapsone gel according to claim 4, characterized in that The oil phase includes one or more of liquid paraffin, hexadecane, and light liquid paraffin.

6. The dapsone gel according to claim 1, characterized in that The gel also includes 0-0.4% surfactant.

7. The dapsone gel according to claim 6, characterized in that The surfactant includes one or more of Tween 80, Span 80, and polyoxyethylene (35) castor oil.

8. The dapsone gel according to claim 1, characterized in that The gel comprises the following components by weight percentage: 7.5% dapsone, 30% to 34% diethylene glycol monoethyl ether, 1.9% to 2.4% hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer, 0.5% to 1.6% polyethylene glycol 400, 0 to 1.0% liquid paraffin, 0 to 0.4% polyoxyethylene (35) castor oil, 0.1% to 0.3% methylparaben, and 56% to 60% purified water.

9. A method for preparing the dapsone gel according to any one of claims 1 to 8, characterized in that: include: Step 1: Mix an optional solvent promoter, an oil phase, a surfactant and purified water, and then add hydroxyethyl acrylate / sodium acryloyldimethyl taurate copolymer to obtain a first mixture; Step 2: mixing dapsone, methylparaben and diethylene glycol monoethyl ether to obtain a second mixture; Step 3: Mix the first mixture and the second mixture.

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