Flurbiprofen gel and preparation method thereof

Abstract

The invention belongs to the technical field of antipyretic and analgesic medicinal preparations, and relates to flurbiprofen gel and a preparation method thereof. The flurbiprofen gel is prepared from flurbiprofen, sodium carboxymethyl cellulose, tragacanth, glutamine, glycerol, a bacteriostatic agent, ethanol, a pH buffer solution and water. According to the flurbiprofen gel, a stable gel structure is constructed by optimizing a prescription, the physical stability of the flurbiprofen gel is improved, the impurity content is reduced, and the transdermal absorption effect is enhanced.

Description

Technical Field

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

[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Flurbiprofen is a nonsteroidal anti-inflammatory drug 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, soft tissue injuries, etc. However, oral flurbiprofen may cause some side effects during treatment, such as gastrointestinal discomfort, liver and kidney damage, etc., especially in the case of long-term use.

[0004] In order to avoid the side effects of oral flurbiprofen, topical administration becomes a more ideal choice. Topical administration can not only increase the local concentration of the drug and enhance the efficacy by directly acting on the lesion site, but also reduce systemic absorption, thereby reducing the occurrence of systemic side effects. However, traditional flurbiprofen topical dosage forms (such as oral medications or tablets dissolved into solution for external use) have problems such as poor drug permeability, large local irritation, and short duration of drug effect, and it is urgent to develop a more effective and comfortable topical form of medication.

[0005] In recent years, drug gel dosage forms have become one of the most popular dosage forms in topical drug preparations due to its good skin permeability, sustained release, low irritation, and easy application. Gel dosage forms can not only promote drug penetration through the skin through effective solubilizers, but also provide a sustained and stable release platform for drugs, avoiding adverse reactions caused by too rapid drug release.

[0006] Chinese patent with publication number CN111012737A discloses a flurbiprofen sodium gel preparation prescription and its application. The flurbiprofen sodium gel preparation comprises: based on the total weight of the drug preparation, 0.5-5% of flurbiprofen sodium, 0.5-5% of a matrix, 50-95% of a solvent, 0.1-1.0% of a preservative, 0-5% of a pH adjuster, and 0.1-20% of a percutaneous absorption enhancer.

[0007] Chinese patent with publication number CN115969776A discloses a sodium flurbiprofen gel composition, which comprises, by weight percentage: sodium flurbiprofen (calculated as flurbiprofen) 0.5-4%, carbomer 980 0.75-2%, propylene glycol 12-25%, isopropanol 5-10%, menthol 0.2-1%, pH regulator 1-3%, preservative 0.1-0.5%, and the balance is water. Summary of the invention

[0008] The disadvantages of the prior art are overcome, and the invention provides a flurbiprofen gel with stable physicochemical properties and good transdermal absorption by optimizing the formula.

[0009] Specifically, the flurbiprofen gel is calculated by weight and includes 20 parts of flurbiprofen, 50-100 parts of sodium carboxymethyl cellulose, 5-10 parts of tragacanth gum, 2-5 parts of glutamine, 50-100 parts of glycerol, 0.5-2 parts of antibacterial agent, 10-20 parts of ethanol, pH buffer solution, and water added to 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; and the buffer solution is adjusted to pH=5.0-6.5.

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

[0012] (1) dissolving sodium carboxymethylcellulose, tragacanth gum, and glutamine in water and allowing them to swell to form a gel matrix;

[0013] (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH, and obtaining a drug-loaded solution;

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

[0015] Compared with the prior art, the technical effects of the present invention are:

[0016] The flurbiprofen gel of the invention is added with a certain proportion of tragacanth gum and glutamine, and the tragacanth gum, glutamine and sodium carboxymethyl cellulose form a stable gel structure, thereby improving the physical stability of the flurbiprofen gel, reducing the impurity content and enhancing the transdermal absorption effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 : Accelerated test of impurity I content of flurbiprofen gel in Examples 1 to 4 and Comparative Examples 1 to 5.

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

[0019] Figure 3 : The water loss of flurbiprofen gel of Examples 1 to 4 and flurbiprofen gel of Comparative Examples 1 to 5 when stored in an environment of 30±2°C. DETAILED DESCRIPTION

[0020] In order to make the purpose and technical solution of the present invention clearer, the present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited to these embodiments, and the embodiments are only used to explain the present invention. It should be understood by those skilled in the art that any changes or equivalent substitutions that do not deviate from the concept of the present invention are included in the protection scope of the present invention.

[0021] Example 1 Flurbiprofen gel

[0022] formula:

[0023]

[0024] Preparation method:

[0025] (1) dissolving sodium carboxymethylcellulose, tragacanth gum and glutamine in 200 ml of water and allowing them to swell to form a gel matrix;

[0026] (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH to 5.5, and obtaining a drug-loaded solution;

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

[0028] Example 2 Flurbiprofen gel

[0029] formula:

[0030]

[0031]

[0032] Preparation method:

[0033] (1) dissolving sodium carboxymethylcellulose, tragacanth gum and glutamine in 250 ml of water and allowing them to swell to form a gel matrix;

[0034] (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH to 6.0, and obtaining a drug-loaded solution;

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

[0036] Example 3 Flurbiprofen gel

[0037] formula:

[0038]

[0039] Preparation method:

[0040] (1) dissolving sodium carboxymethylcellulose, tragacanth gum and glutamine in 200 ml of water and allowing them to swell to form a gel matrix;

[0041] (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH to 5.0, and obtaining a drug-loaded solution;

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

[0043] Example 4 Flurbiprofen gel

[0044] formula:

[0045]

[0046] Preparation method:

[0047] (1) dissolving sodium carboxymethylcellulose, tragacanth gum and glutamine in 300 ml of water and allowing them to swell to form a gel matrix;

[0048] (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH to 6.5, and obtaining a drug-loaded solution;

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

[0050] Comparative Example 1 Flurbiprofen Gel

[0051] formula:

[0052]

[0053]

[0054] Preparation method:

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

[0056] (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH to 5.5, and obtaining a drug-loaded solution;

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

[0058] Comparative Example 2 Flurbiprofen Gel

[0059] formula:

[0060]

[0061] Preparation method:

[0062] (1) dissolving sodium carboxymethylcellulose and tragacanth gum in 200 ml of water and allowing them to swell to form a gel matrix;

[0063] (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH to 5.5, and obtaining a drug-loaded solution;

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

[0065] Comparative Example 3 Flurbiprofen Gel

[0066] formula:

[0067]

[0068]

[0069] Preparation method:

[0070] (1) dissolving sodium carboxymethylcellulose, tragacanth gum, and glutamic acid in 200 ml of water and allowing to swell to form a gel matrix;

[0071] (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH to 5.5, and obtaining a drug-loaded solution;

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

[0073] Comparative Example 4 Flurbiprofen Gel

[0074] formula:

[0075]

[0076] Preparation method:

[0077] (1) dissolving sodium carboxymethylcellulose, tragacanth gum and glutamine in 200 ml of water and allowing them to swell to form a gel matrix;

[0078] (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH to 5.5, and obtaining a drug-loaded solution;

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

[0080] Comparative Example 5 Flurbiprofen Gel

[0081] formula:

[0082]

[0083] Preparation method:

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

[0085] (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH to 7.5, and obtaining a drug-loaded solution;

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

[0087] Flurbiprofen gel stability

[0088] The flurbiprofen gels of Examples 1 to 4 and the flurbiprofen gels of Comparative Examples 1 to 5 were packaged and placed under conditions of a temperature of 40±2° C. and a relative humidity of 75%±5% for 6 months. Samples were taken at the end of the first, second, third and sixth months of the test period, and impurity inspection was performed according to the high performance liquid chromatography method (General Rule 0512) of the Chinese Pharmacopoeia.

[0089] Figure 1 The content of impurity I in the accelerated test of flurbiprofen gel in Examples 1 to 4 and flurbiprofen gel in Comparative Examples 1 to 5, Figure 2 The total impurity content of the flurbiprofen gel of Examples 1 to 4 and the flurbiprofen gel of Comparative Examples 1 to 5 was accelerated. It can be seen that the flurbiprofen gel of Examples 1 to 4 of the present invention has high stability. In a high temperature and high humidity environment, the flurbiprofen gel can still remain stable with a low impurity content.

[0090] Percutaneous permeability test

[0091] Prepare several SD rats, SPF grade, 180-220g, experimental animal license number: SYXK (Lu) 20180008, and feed them for one week before the experiment. Depilate with 8% sodium sulfide solution, wash, feed for 24h, take abdominal skin after cervical dislocation, remove subcutaneous fat, wash repeatedly with physiological saline, absorb surface moisture with filter paper, fix the treated rat abdominal skin between the supply pool and the receiving pool, the stratum corneum faces the supply pool, and the supply pool contains equal doses of flurbiprofen gel in Example 1, Example 2, Example 3, Example 4, Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4, and Comparative Example 5, and the receiving solution is 20% ethanol-pH7.4 phosphate buffer, and samples are taken at 0.5h and 6h, and the flurbiprofen content in the receiving solution is determined, and the cumulative permeation amount of each embodiment is calculated according to the formula.

[0092]

[0093] Where V is the total volume of the receiving solution, Cn is the drug concentration measured at the nth sampling point (μg / mL), C is the drug concentration measured at the ith sampling point (μg / mL), V is the sampling volume, and A is the diffusion permeation area (cm 2 ).

[0094] Table 1 Cumulative permeation of flurbiprofen gel

[0095]

[0096] Table 1 shows the cumulative permeation amounts of the flurbiprofen gels of Examples 1 to 4 and Comparative Examples 1 to 5. The data show that the cumulative permeation amounts of the flurbiprofen gels of Examples 1 to 4 are significantly higher than those of the flurbiprofen gels of Comparative Examples 1 to 5, indicating that the flurbiprofen gels of the present invention have strong skin permeability, can increase the local drug concentration in the skin, and are beneficial to the efficacy of drug treatment of local diseases.

[0097] Water loss from flurbiprofen gel

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

[0099] Figure 3 The water loss conditions of the flurbiprofen gels of Examples 1 to 4 and Comparative Examples 1 to 5 on the 7th, 14th and 30th days of storage in an environment of 30±2°C are shown, which proves that the formula 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 comprises flurbiprofen, sodium carboxymethylcellulose, tragacanth gum, glutamine, glycerol, an antibacterial agent, ethanol, a pH buffer solution and water.

2. The flurbiprofen gel according to claim 1, characterized in that Calculated by weight, the flurbiprofen gel includes 20 parts of flurbiprofen, 50-100 parts of sodium carboxymethyl cellulose, 5-10 parts of tragacanth gum, 2-5 parts of glutamine, 50-100 parts of glycerol, 0.5-2 parts of antibacterial agent, 10-20 parts of ethanol, pH buffer solution, and water is added to 1000 parts.

3. 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.

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

5. The flurbiprofen gel according to claim 1, characterized in that The pH buffer solution is selected from one of a carbonate buffer solution, a citrate buffer solution, a phosphate buffer solution and an acetate buffer solution.

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

7. The flurbiprofen gel according to claim 1, characterized in that Calculated by weight, the flurbiprofen gel includes 20 parts of flurbiprofen, 70 parts of sodium carboxymethyl cellulose, 8 parts of tragacanth gum, 3 parts of glutamine, 60 parts of glycerol, 1 part of antibacterial agent, 15 parts of ethanol, pH buffer solution, and water is added to 1000 parts.

8. A method for preparing the flurbiprofen gel according to claim 1, characterized in that: The method comprises the following steps: (1) dissolving sodium carboxymethylcellulose, tragacanth gum, and glutamine in water and allowing them to swell to form a gel matrix; (2) mixing flurbiprofen, glycerol and ethanol, adding a buffer solution to adjust the pH, and obtaining a drug-loaded solution; (3) Slowly add the drug-loaded solution into the gel matrix, add the antibacterial agent, and add water to obtain the product.

9. The method according to claim 8, characterized in that The buffer solution is adjusted to pH=5.0-6.

5.

10. The method according to claim 8, characterized in that The buffer solution was adjusted to pH=5.5.

Images