A flurbiprofen gel and a method for preparing the same

Abstract

The application belongs to the technical field of antipyretic analgesic drug preparation, and relates to a flurbiprofen gel and a preparation method thereof. The flurbiprofen gel comprises flurbiprofen, sodium carboxymethyl cellulose, tragacanth gum, glutamine, glycerol, a bacteriostatic agent, ethanol, a pH buffer solution and water. The application optimizes a prescription to construct a stable gel structure, improves the physical stability of the flurbiprofen gel, reduces impurity content and enhances the transdermal absorption effect.

Description

Technical Field

[0001] This invention belongs to the field of antipyretic and analgesic drug formulation technology, specifically relating to a flurbiprofen gel and its preparation method. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Flurbiprofen is a nonsteroidal anti-inflammatory drug (NSAID) with strong analgesic, anti-inflammatory, and antipyretic effects. Due to its excellent efficacy, flurbiprofen is widely used to relieve pain and inflammation caused by arthritis, rheumatism, and soft tissue injuries. However, oral flurbiprofen may cause some side effects during treatment, such as gastrointestinal discomfort and liver and kidney damage, especially with long-term use.

[0004] To avoid the side effects of oral flurbiprofen, topical administration has become a more ideal option. Topical administration, by directly applying the drug to the lesion site, not only increases the local drug concentration and enhances efficacy but also reduces systemic absorption, thereby decreasing the occurrence of systemic side effects. However, traditional topical formulations of flurbiprofen (such as oral medications or tablets dissolved in a solution for external application) suffer from poor drug penetration, high local irritation, and short duration of action, necessitating the development of more effective and comfortable topical application methods.

[0005] In recent years, drug gel formulations have become one of the most popular dosage forms for topical medications due to their advantages such as good skin permeability, sustained release, low irritation, and ease of application. Gel formulations not only promote drug penetration through effective solubilization but also provide a stable and continuous release platform, avoiding adverse reactions caused by excessively rapid drug release.

[0006] Chinese Patent Publication No. CN111012737A discloses a flurbiprofen sodium gel formulation and its application. The flurbiprofen sodium gel formulation includes, by total weight of the pharmaceutical preparation, 0.5-5% flurbiprofen sodium, 0.5-5% matrix, 50-95% solvent, 0.1-1.0% preservative, 0-5% pH adjuster, and 0.1-20% transdermal absorption enhancer.

[0007] Chinese Patent Publication No. CN115969776A discloses a flurbiprofen sodium gel composition, which, by weight percentage, comprises: 0.5-4% flurbiprofen sodium (calculated as flurbiprofen), 0.75-2% carbomer 980, 12-25% propylene glycol, 5-10% isopropanol, 0.2-1% menthol, 1-3% pH adjuster, 0.1-0.5% preservative, and the balance being water. Summary of the Invention

[0008] Overcoming the shortcomings of existing technologies, this invention provides a flurbiprofen gel with stable physicochemical properties and good transdermal absorption by optimizing the formulation.

[0009] Specifically, the flurbiprofen gel, by weight, comprises 20 parts flurbiprofen, 50-100 parts sodium carboxymethyl cellulose, 5-10 parts tragacanth gum, 2-5 parts glutamine, 50-100 parts glycerin, 0.5-2 parts antibacterial agent, 10-20 parts ethanol, pH buffer solution, and water to a total of 1000 parts.

[0010] Furthermore, the antibacterial agent is selected from at least one of phenylmercuric nitrate, chlorobutanol, chlorphenesin, and sodium benzoate; the pH buffer solution is selected from one of carbonate buffer solution, citrate buffer solution, phosphate buffer solution, and acetate buffer solution; the buffer solution is adjusted to pH = 5.0 to 6.5.

[0011] The present invention also provides a method for preparing the above-mentioned flurbiprofen gel, the method comprising the following steps:

[0012] (1) Sodium carboxymethyl cellulose, tragacanth gum, and glutamine are dissolved in water and swollen to form a gel matrix;

[0013] (2) Mix flurbiprofen, glycerin and ethanol, add buffer solution to adjust pH, and obtain drug loading solution;

[0014] (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

[0015] Compared with the prior art, the technical advantages of the present invention are as follows:

[0016] The flurbiprofen gel of this invention incorporates a certain proportion of tragacanth gum and glutamine. The tragacanth gum and glutamine form a stable gel structure with sodium carboxymethyl cellulose, which improves the physical stability of the flurbiprofen gel, reduces the impurity content, and enhances the transdermal absorption effect. Attached Figure Description

[0017] Figure 1 Accelerated test of impurity I content in flurbiprofen gels of Examples 1-4 and Comparative Examples 1-5.

[0018] Figure 2 Accelerated test of total impurity content in flurbiprofen gels of Examples 1-4 and Comparative Examples 1-5.

[0019] Figure 3 Dehydration of flurbiprofen gels in Examples 1-4 and Comparative Examples 1-5 stored at 30±2℃. Detailed Implementation

[0020] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0021] Example 1 Flurbiprofen Gel

[0022] formula:

[0023]

[0024] Preparation method:

[0025] (1) Dissolve sodium carboxymethyl cellulose, tragacanth gum, and glutamine in 200 ml of water and let them swell to form a gel matrix;

[0026] (2) Mix flurbiprofen, glycerin and ethanol, add buffer solution to adjust pH to 5.5, and obtain drug loading solution;

[0027] (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

[0028] Example 2 Flurbiprofen Gel

[0029] formula:

[0030]

[0031]

[0032] Preparation method:

[0033] (1) Dissolve sodium carboxymethyl cellulose, tragacanth gum, and glutamine in 250 ml of water and let them swell to form a gel matrix;

[0034] (2) Mix flurbiprofen, glycerin, and ethanol, and add buffer solution to adjust pH to 6.0 to obtain a drug-loaded solution;

[0035] (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

[0036] Example 3 Flurbiprofen Gel

[0037] formula:

[0038]

[0039] Preparation method:

[0040] (1) Dissolve sodium carboxymethyl cellulose, tragacanth gum, and glutamine in 200 ml of water and let them swell to form a gel matrix;

[0041] (2) Mix flurbiprofen, glycerin and ethanol, add buffer solution to adjust pH to 5.0, and obtain drug loading solution;

[0042] (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

[0043] Example 4 Flurbiprofen Gel

[0044] formula:

[0045]

[0046] Preparation method:

[0047] (1) Dissolve sodium carboxymethyl cellulose, tragacanth gum, and glutamine in 300 ml of water and let them swell to form a gel matrix;

[0048] (2) Mix flurbiprofen, glycerin, and ethanol, and add buffer solution to adjust pH to 6.5 to obtain a drug-loaded solution;

[0049] (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

[0050] Comparative Example 1: Flurbiprofen Gel

[0051] formula:

[0052]

[0053]

[0054] Preparation method:

[0055] (1) Dissolve sodium carboxymethyl cellulose and glutamine in 200 ml of water and swell to form a gel matrix;

[0056] (2) Mix flurbiprofen, glycerin and ethanol, add buffer solution to adjust pH to 5.5, and obtain drug loading solution;

[0057] (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

[0058] Comparative Example 2: Flurbiprofen Gel

[0059] formula:

[0060]

[0061] Preparation method:

[0062] (1) Dissolve sodium carboxymethyl cellulose and tragacanth gum in 200 ml of water and let them swell to form a gel matrix;

[0063] (2) Mix flurbiprofen, glycerin and ethanol, add buffer solution to adjust pH to 5.5, and obtain drug loading solution;

[0064] (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

[0065] Comparative Example 3 Flurbiprofen Gel

[0066] formula:

[0067]

[0068]

[0069] Preparation method:

[0070] (1) Dissolve sodium carboxymethyl cellulose, tragacanth gum, and glutamic acid in 200 ml of water and let them swell to form a gel matrix;

[0071] (2) Mix flurbiprofen, glycerin and ethanol, add buffer solution to adjust pH to 5.5, and obtain drug loading solution;

[0072] (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

[0073] Comparative Example 4: Flurbiprofen Gel

[0074] formula:

[0075]

[0076] Preparation method:

[0077] (1) Dissolve sodium carboxymethyl cellulose, tragacanth gum, and glutamine in 200 ml of water and let them swell to form a gel matrix;

[0078] (2) Mix flurbiprofen, glycerin and ethanol, add buffer solution to adjust pH to 5.5, and obtain drug loading solution;

[0079] (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

[0080] Control Example 5 Flurbiprofen Gel

[0081] Formula:

[0082]

[0083] Preparation method:

[0084] (1) Dissolve sodium carboxymethylcellulose, tragacanth gum, and glutamine in 200 ml of water and swell to form a gel matrix;

[0085] (2) Mix flurbiprofen, glycerol, and ethanol, add a buffer solution to adjust the pH to 7.5 to obtain a drug-loaded solution;

[0086] (3) Slowly add the drug-loaded solution to the gel matrix, add an antibacterial agent, and add water to obtain the product.

[0087] Stability of Flurbiprofen Gel

[0088] After packaging the flurbiprofen gels of Examples 1 to 4 and Control Examples 1 to 5, place them at 40 ± 2°C and a relative humidity of 75% ± 5% for 6 months. Samples are taken at the end of the 1st month, 2nd month, 3rd month, and 6th month during the test period, and impurity inspection is carried out by the high performance liquid chromatography method (General Principles 0512) of the Chinese Pharmacopoeia.

[0089] Figure 1 For the content of Impurity I in the accelerated test of the flurbiprofen gels of Examples 1 to 4 and Control Examples 1 to 5, Figure 2 For the total impurity content in the accelerated test of the flurbiprofen gels of Examples 1 to 4 and Control Examples 1 to 5, it can be seen that the flurbiprofen gels of Examples 1 to 4 of the present invention have high stability. In a high temperature and high humidity environment, the flurbiprofen gel can still remain stable with low impurity content.

[0090] Transdermal permeability test

[0091] Prepare several SD rats, SPF grade, 180 - 220 g, experimental animal license number: SYXK (Lu) 20180008, and adaptively raise them for one week before the experiment. Depilate with 8% sodium sulfide solution, wash, raise for 24 h, decapitate and sacrifice the rats, take the abdominal skin, remove subcutaneous fat, wash repeatedly with physiological saline, absorb the surface moisture with filter paper, fix the processed rat abdominal skin between the supply pool and the receiving pool, with the stratum corneum facing the supply pool. The supply pool contains equal doses of the flurbiprofen gels of Example 1, Example 2, Example 3, Example 4, Control Example 1, Control Example 2, Control Example 3, Control Example 4, and Control Example 5, and the receiving solution is 20% ethanol - pH 7.4 phosphate buffer solution. Samples are taken at 0.5 h and 6 h, and the content of flurbiprofen in the receiving solution is measured, and the cumulative permeation amount of each example is calculated according to the formula.

[0092]

[0093] Where V is the total volume of the receiving liquid, Cn is the drug concentration (μg / mL) measured at the nth sampling point, C is the drug concentration (μg / mL) measured at the i-th sampling point, V is the sampling volume, and A is the diffusion and penetration area (cm²). 2 ).

[0094] Table 1. Cumulative permeation of flurbiprofen gel

[0095]

[0096] Table 1 shows the cumulative permeation of flurbiprofen gels in Examples 1-4 and Comparative Examples 1-5. The data shows that the cumulative permeation of flurbiprofen gels in Examples 1-4 is significantly higher than that in Comparative Examples 1-5, indicating that the flurbiprofen gel of the present invention has strong skin permeability, can increase the local drug concentration in the skin, and is conducive to the therapeutic effect of drug treatment on local diseases.

[0097] Dehydration of flurbiprofen gel

[0098] The flurbiprofen gels of Examples 1-4 and Comparative Examples 1-5 were packaged and stored at 30±2℃ for 30 days. They were weighed before the experiment and on the 7th, 14th and 30th days of the experiment to calculate the water loss rate and verify the water loss of the flurbiprofen gel.

[0099] Figure 3 The water loss of flurbiprofen gels in Examples 1-4 and Comparative Examples 1-5 after storage at 30±2℃ for 7 days, 14 days, and 30 days demonstrates that the formulation or structure of the flurbiprofen gel of the present invention has high stability, strong hydration, and can effectively lock in moisture to prevent evaporation or loss of moisture at high temperatures.

Claims

1. A flurbiprofen gel, characterized in that, The flurbiprofen gel, by weight, comprises 20 parts flurbiprofen, 50-100 parts sodium carboxymethyl cellulose, 5-10 parts tragacanth gum, 2-5 parts glutamine, 50-100 parts glycerin, 0.5-2 parts antibacterial agent, 10-20 parts ethanol, buffer solution, and water to a final volume of 1000 parts. The preparation method of the flurbiprofen gel includes the following steps: (1) Dissolve sodium carboxymethyl cellulose, tragacanth gum, and glutamine in water and let them swell to form a gel matrix; (2) Mix flurbiprofen, glycerin, and ethanol, and add buffer solution to adjust the pH to 5.0~6.5 to obtain a drug-loaded solution; (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

2. The flurbiprofen gel according to claim 1, characterized in that, The antibacterial agent is selected from at least one of phenylmercuric nitrate, chlorobutanol, chlorphenesin, and sodium benzoate.

3. The flurbiprofen gel according to claim 1, characterized in that, The antibacterial agent is phenylmercuric nitrate.

4. The flurbiprofen gel according to claim 1, characterized in that, The pH buffer solution is selected from one of the following: carbonate buffer solution, citrate buffer solution, phosphate buffer solution, and acetate buffer solution.

5. The flurbiprofen gel according to claim 1, characterized in that, The pH buffer solution is a citrate buffer solution.

6. The flurbiprofen gel according to claim 1, characterized in that, By weight, the flurbiprofen gel comprises 20 parts flurbiprofen, 70 parts sodium carboxymethyl cellulose, 8 parts tragacanth gum, 3 parts glutamine, 60 parts glycerin, 1 part antibacterial agent, 15 parts ethanol, pH buffer solution, and water to a total of 1000 parts.

7. A method for preparing the flurbiprofen gel of claim 1, characterized in that, The method includes the following steps: (1) Dissolve sodium carboxymethyl cellulose, tragacanth gum, and glutamine in water and let them swell to form a gel matrix; (2) Mix flurbiprofen, glycerin and ethanol, add buffer solution to adjust pH, and obtain drug loading solution; (3) Slowly add the drug-loaded solution to the gel matrix, add the antibacterial agent, and add water to obtain the final product.

8. The method according to claim 7, characterized in that, The buffer solution is adjusted to pH 5.0~6.

5.

9. The method according to claim 7, characterized in that, The buffer solution is adjusted to pH 5.5.

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