Iguratimod gel and preparation method thereof

Abstract

The invention discloses iguratimod gel and a preparation method thereof. In the disclosed gel, iguratimod is dissolved in light liquid paraffin, and the light liquid paraffin, a water-based gel matrix carbomer and a pH regulator are stirred, homogenized and dispersed to form milk white gel which is uniform and fine in texture. The Iguratimod gel disclosed by the invention is simple and feasible in process, stable in property, relatively good in reproducibility, very good in extrusion performance, easy to coat and use, free of local irritation, and convenient and rapid in clinical application.

Description

Technical Field

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

[0002] Ailamod is a new type of anti-rheumatic drug for disease relief, which can relieve joint damage and immune abnormalities in chronic arthritis and autoimmune diseases, and inhibit the production of inflammatory cytokines and immunoglobulins. It has significant effects and safety in the treatment of rheumatoid arthritis, and it shows anti-inflammatory and analgesic effects on acute and chronic inflammation. At present, the only drug available on the market in China is tablets. In clinical applications, tablets are often used at a dose of 25 mg / time, twice a day; but tablets have compliance problems for some patients with dysphagia. Considering the main medication population and pathological characteristics of rheumatic diseases, compared with tablets, local external preparations are more convenient to use. At present, there is no related technology disclosure of Ailamod external pharmaceutical composition or preparation in the field. Therefore, the inventor invented an Ailamod external gel, which is more targeted to the lesion site and easy to apply and clean, so as to achieve better clinical application effects.

[0003] Gels refer to thick liquid or semisolid preparations made of auxiliary materials that form gels and drugs into suspension or emulsion type. They have sustained-release and controlled-release effects on drugs, increase the local concentration of drugs, and prolong the release or diffusion process of drugs. They are widely used in clinical practice. Gels are divided into aqueous and lipophilic types. Compared with lipophilic gels, aqueous gels have the characteristics of biocompatibility, bioadhesion, and biodegradability, and have better spreading effects. They are easy to wash off and basically have no greasy feeling. They can easily absorb tissue exudate without interfering with the normal physiological function of the skin, making them more suitable for clinical applications. However, literature reports that elamod is a fat-soluble compound that is difficult to dissolve in water. Therefore, when preparing topical preparations, under the premise of not changing its chemical structure, it is necessary to disperse it in the matrix when preparing aqueous gels to prepare suspension gels. In order to ensure uniform and delicate properties and no granular feeling after application, suspension gels generally have higher requirements on the particle size distribution of raw materials. The conventional particle size distribution is D 90 The particle size distribution of elamod is below 20 μm, but due to the light weight, easy generation of static electricity and poor fluidity of the raw material of elamod, the current pulverization process is difficult to control the particle size distribution within an appropriate range. The larger particle size makes it impossible to ensure the uniformity of the content of elamod in the suspension gel. Summary of the invention

[0004] The purpose of the present invention is to solve the problem that iguratimod is insoluble and difficult to disperse in conventional aqueous gel matrices in the prior art, and to provide a iguratimod gel with high compliance and good transdermal effect and a preparation method thereof.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is as follows: The invention discloses iguratimod gel and a preparation method thereof. The gel consists of iguratimod, a solvent aqueous gel matrix carbomer 980, glycerol and a pH regulator.

[0006] According to the embodiment of the present invention, the inventors have experimentally verified that iguratimod is insoluble in conventional aqueous gel matrices: carbomer, poloxamer, hydroxypropyl methylcellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, and polyvinyl alcohol; while it can be dissolved in fat-soluble gel matrices such as monostearate glyceryl, fatty oil, and light liquid paraffin. However, the inventors have found in the experiment that after being dissolved in monostearate glyceryl and fatty oil, the prepared gel has a strong greasy feeling and is difficult to remove after application. If it is combined with an aqueous gel matrix, a gel with a smooth appearance and uniform texture cannot be prepared. The inventors have found in the study that iguratimod has a strong greasy feeling after being dissolved in monostearate glyceryl and fatty oil. 90 The particle size distribution range is 20 to 80 μm, and it can be dissolved in a small amount of liquid paraffin. By controlling the pH range, after mixing with the carbomer 980 aqueous gel matrix, stirring and homogenizing can be made into a gel, and compared with other commonly used fat-soluble matrices or solvents, the viscosity is moderate after dissolving in light liquid paraffin; the appearance, spreadability and viscosity after mixing and homogenizing with the carbomer 980 matrix are good; therefore, the inventor creatively dissolves Ailamod in a small amount of light liquid paraffin, and then stirs and homogenizes with the carbomer 980 gel matrix to prepare a gel, which has the advantages of both aqueous and lipophilic gels: smooth and delicate appearance, good spreadability, easy to wash off, no greasy feeling, moderate viscosity, and good lubrication effect. And light liquid paraffin has a certain permeability-promoting effect, which can promote the transdermal absorption of drugs and make the drugs work better. Preferably, the solvent selected for the gel of the present invention is selected from light liquid paraffin.

[0007] According to an embodiment of the present invention, the amount of iguratimod in the iguratimod gel disclosed in the present invention is 50-200 mg, the weight ratio of carbomer 980 is 0.5-1.5%, and the weight ratio of light liquid paraffin is 0.1-0.2%. The inventors tested the appearance, spreadability (score 1→5) and viscosity of the prepared gel at different amounts of carbomer 980 and light liquid paraffin, and the results are shown in Table 1: Table 1 Properties of gels prepared at different dosages of Carbomer 980 and light liquid paraffin

[0008] Light liquid paraffin is commonly used in ointments, creams and eye preparations. The dosage reported in the literature is generally above 0.2%, and the maximum dosage can be up to 50%. In the present invention, the light liquid paraffin mainly acts as a solvent for dissolving elamod, and the dosage is only 0.1-0.2%, which is lower than the conventional dosage in the field. The experimental results show that the amount of carbomer is 0.5-1.5%, and the amount of light liquid paraffin is in the range of 0.1-0.2%. The gel is smooth, delicate, uniform in texture, stable at room temperature, better in spreadability, no greasy feeling after application, moderate viscosity, can stay on the skin for a certain period of time after application, and is easy to clean.

[0009] Preferably, the amount of iguratimod is 100-150 mg, the weight ratio of carbomer 980 is 0.8-1.2%, and the weight ratio of light liquid paraffin is 0.15%.

[0010] Further, according to an embodiment of the present invention, the particle size distribution D of iguratimod in the iguratimod gel disclosed in the present invention is 90 The inventors have found that the particle size distribution of iguratimod is D 90 When the particle size is less than 20 μm, due to its light weight and large volume, when it is dissolved in light liquid paraffin, a large amount of raw materials will float on the surface of the solvent and be difficult to dissolve. 90 When the particle size is greater than 80 μm, the amount of light liquid paraffin needs to be increased during dissolution, and a higher amount makes the prepared gel feel greasy after application.

[0011] Preferably, the particle size distribution of iguratimod is 90 The preferred particle size distribution range can make iguratimod with a prescription amount of 100-150 mg easily dissolved in light liquid paraffin with a dosage range of 0.1-0.2%.

[0012] The present invention also discloses a method for preparing iguratimod gel, comprising: 1) Add 60% of the prescribed amount of water to Carbomer 980 and stir until it swells evenly to obtain a gel matrix. 2) Dissolve iguratimod in light liquid paraffin, add to the carbomer gel matrix, adjust the pH to 5-7, and stir to make it uniform; 3) Add the prescribed amount of water and stir to make it uniform.

[0013] Data show that elamod is easily distributed to the organic layer in acidic and neutral conditions, and to the water layer in alkaline conditions. The distribution coefficient between 1-octanol and various pH aqueous solutions at 25°C is 131-149 below pH 6, 46 at pH 7, 3.0 at pH 8, and 0.68 at pH 9. According to an embodiment of the present invention, the pH value of the gel is adjusted to 5-7, so that elamod can remain dissolved in the organic phase (light liquid paraffin) in a mixed system of aqueous matrix carbomer and light liquid paraffin, making the gel properties more stable. This pH range has low irritation to the skin and is safer as a topical preparation. The pH regulator in the gel disclosed in the present invention is selected from sodium hydroxide.

[0014] Furthermore, other addible external preparation excipients, such as wetting agents and antibacterial agents, can be added to the iguratimod gel of the present invention to improve the moisturizing performance and storage stability of the preparation during use; Specifically, the wetting agent includes glycerin and propylene glycol; the antibacterial agent includes sorbic acid, potassium sorbate, benzyl alcohol, methylparaben, ethylparaben, propylparaben, etc.; Furthermore, an appropriate amount of emulsifier and surfactant may be added to the iguratimod gel of the present invention to prepare an emulsion gel; Specifically, the emulsifier includes stearin, stearic acid, etc.; Specifically, the surfactant includes sodium lauryl sulfate, polysorbates, poloxamers and the like.

[0015] Aiming at the indication characteristics of iguratimod, the present invention creatively invents an iguratimod external gel preparation, which technically solves the problems that iguratimod is poorly soluble in water, has poor fluidity, cannot be dissolved in a conventional aqueous gel matrix and is difficult to disperse. Iguratimod is dissolved in a small amount of light liquid paraffin, and carbomer 980 is used as a gel matrix to prepare an iguratimod gel. The gel composition has a smooth and delicate appearance, good spreadability, easy washing, moderate viscosity after application, no greasy feeling, directly acts on the lesion site through the skin, has a fast onset of action, is convenient and quick in clinical application, and has a good transdermal absorption effect after administration under the promoting penetration of the light liquid paraffin. DETAILED DESCRIPTION

[0016] The present invention will be further described in detail below by combining the preparation method of iguratimod gel with examples.

[0017] Example 1: Iguratimod gel, specification 50 mg Prescription composition dosage (g) Ailamode (D 90 40~60μm) 5.0 Carbomer 980 5.0 Light liquid paraffin 1.0 Sodium hydroxide 20mg Add purified water to 1000g Batch 100 pieces, 10g / piece Preparation process: add 60% of the prescribed amount of water to Carbomer 980, stir while adding until it is evenly swollen to obtain a gel matrix; dissolve Iguratimod in light liquid paraffin, add it to the Carbomer gel matrix, adjust the pH to 5-7 with sodium hydroxide, stir and homogenize to make it uniform; finally add water to the prescribed amount, stir and homogenize to make it uniform.

[0018] Example 2: Iguratimod gel, specification 100 mg Prescription composition dosage (g) Ailamode (D 90 40~60μm) 10.0 Carbomer 980 8 Light liquid paraffin 1.25 Sodium hydroxide 32mg Add purified water to 1000g Batch 100 pieces, 10g / piece Preparation process: add 60% of the prescribed amount of water to Carbomer 980, stir while adding until it is evenly swollen to obtain a gel matrix; dissolve Iguratimod in light liquid paraffin, add it to the Carbomer gel matrix, adjust the pH to 5-7 with sodium hydroxide, stir and homogenize to make it uniform; finally add water to the prescribed amount, stir and homogenize to make it uniform.

[0019] Example 3: Iguratimod gel, specification 150 mg Prescription composition dosage (g) Ailamode (D 90 40~60μm) 15.0 Carbomer 980 12.0 Light liquid paraffin 1.8 Sodium hydroxide 48mg Add purified water to 1000g Batch 100 pieces, 10g / piece Preparation process: add 60% of the prescribed amount of water to Carbomer 980, stir while adding until it is evenly swollen to obtain a gel matrix; dissolve Iguratimod in light liquid paraffin, add it to the Carbomer gel matrix, adjust the pH to 5-7 with sodium hydroxide, stir and homogenize to make it uniform; finally add water to the prescribed amount, stir and homogenize to make it uniform.

[0020] Example 4: Iguratimod gel, specification 200 mg Prescription composition dosage (g) Ailamode (D 90 40~60μm) 20.0 Carbomer 980 15.0 Light liquid paraffin 2.0 Sodium hydroxide 60mg Add purified water to 1000g Batch 100 pieces, 10g / piece Preparation process: add 60% of the prescribed amount of water to Carbomer 980, stir while adding until it is evenly swollen to obtain a gel matrix; dissolve Iguratimod in light liquid paraffin, add it to the Carbomer gel matrix, adjust the pH to 5-7 with sodium hydroxide, stir and homogenize to make it uniform; finally add water to the prescribed amount, stir and homogenize to make it uniform.

[0021] Example 5: Iguratimod gel, specification 100 mg Prescription composition dosage (g) Ailamode (D 90 40~60μm) 10.0 Carbomer 980 10.0 Light liquid paraffin 1.5 Glycerol 100.0 Methylparaben 1.0 Sodium hydroxide 50mg Add purified water to 1000g Batch 100 pieces, 10g / piece Preparation process: Take 60% of the prescribed amount of water, heat it to 70°C, add methylparaben, stir to completely dissolve it, and cool it to room temperature; add carbomer 980 to glycerin and disperse it, add it to the methylparaben aqueous solution, stir while adding until it is evenly swollen to obtain a gel matrix; dissolve ilamod in light liquid paraffin, add it to the carbomer gel matrix, adjust the pH to 5-7 with sodium hydroxide, stir and homogenize it to make it uniform; finally, add water to the prescribed amount, stir and homogenize it to make it uniform.

[0022] Example 6: Iguratimod gel, specification 100 mg Prescription composition dosage (g) Ailamode (D 90 40~60μm) 10.0 Carbomer 980 10.0 Light liquid paraffin 1.5 Glycerol 100.0 Methylparaben 1.0 Hard fat 10.0 Sodium hydroxide 40mg Add purified water to 1000g Batch 100 pieces, 10g / piece Preparation process: Take 60% of the prescribed amount of water, heat it to 70°C, add methylparaben, stir to completely dissolve, and cool to room temperature; add carbomer 980 to glycerin and disperse it, add it to the methylparaben aqueous solution, stir while adding until it is evenly swollen to obtain a gel matrix; dissolve ilamod in light liquid paraffin, add it to the carbomer gel matrix, adjust the pH to 5-7 with sodium hydroxide, add an appropriate amount of purified water, stir and homogenize it to make it uniform; melt stearin at 50-60°C, add it to the gel, stir and homogenize it to obtain.

Claims

1. An iguratimod gel, characterized in that: The gel consists of iguratimod, a solvent, an aqueous gel matrix carbomer 980 and a pH regulator.

2. The iguratimod gel according to claim 1, characterized in that: The solvent is selected from light liquid paraffin.

3. The iguratimod gel according to claim 2, characterized in that: The amount of iguratimod in the iguratimod gel is 50-200 mg, the weight ratio of carbomer 980 is 0.5-1.5%, and the weight ratio of light liquid paraffin is 0.1-0.2%.

4. The iguratimod gel according to claim 3, characterized in that: The amount of iguratimod in the iguratimod gel is 100-150 mg, the weight ratio of carbomer 980 is 0.8-1.2%, and the weight ratio of light liquid paraffin is 0.15%.

5. The iguratimod gel according to any one of claims 1 to 4, characterized in that: The particle size distribution D of iguratimod in the iguratimod gel 90 20~80μm.

6. The iguratimod gel according to claim 5, characterized in that: The particle size distribution D of iguratimod in the iguratimod gel 90 40~60μm.

7. The iguratimod gel according to claim 1, characterized in that: The pH regulator is selected from sodium hydroxide.

8. The iguratimod gel according to claim 1, characterized in that: The method for preparing the iguratimod gel comprises: 1) Add 60% of the prescribed amount of water to Carbomer 980, stirring until it is evenly swollen to obtain a gel matrix; 2) Dissolve iguratimod in light liquid paraffin, add to the carbomer gel matrix, adjust the pH to 5-7, and stir to make it uniform; 3) Add the prescribed amount of water and stir to make it uniform.

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