Diclofenac diethylamine latex and preparation method thereof

Abstract

The invention belongs to the technical field of analgesic pharmaceutical preparations, and particularly relates to a diclofenac diethylamine latex agent and a preparation method thereof. The diclofenac diethylamine latex agent disclosed by the invention is prepared from diclofenac diethylamine, phospholipid, isopropanol, glutamine, propylene glycol, poloxamer 188, tragacanth gum, a buffer solution and a preservative. The diclofenac diethylamine latex agent is high in stability, the effective component diclofenac is basically not degraded under the conditions of high temperature, high humidity and illumination, and the phenomena of layering, condensation or precipitation do not occur. In addition, the diclofenac diethylamine latex disclosed by the invention is small in skin irritation and has a wide product market application value.

Description

Technical Field

[0001] The invention belongs to the technical field of analgesic drug preparations, and particularly relates to a diclofenac diethylamine emulsion 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] Diclofenac diethylamide is a commonly used non-steroidal anti-inflammatory drug first developed by Honeywell in 1966. It has significant anti-inflammatory and analgesic effects and is widely used to relieve the symptoms of various inflammatory-related diseases, such as osteoarthritis, rheumatoid arthritis, soft tissue injuries, muscle pain, etc.

[0004] Diclofenac diethylamine is a derivative of diclofenac, which improves the solubility and skin penetration of the drug by reacting with diethylamine. The mechanism of action of diclofenac diethylamine is mainly to reduce the synthesis of prostaglandins by inhibiting cyclooxygenase (COX-2), thereby reducing inflammation, relieving pain, and reducing fever. Because it has certain selective COX-2 inhibition properties, it reduces the inhibitory effect on COX-1 while reducing the inflammatory response, which may reduce the risk of gastrointestinal adverse reactions. Compared with ordinary diclofenac, diclofenac diethylamine is more suitable for external use due to its structural improvements. It can not only promote the absorption of drugs on the skin, but also better achieve therapeutic effects and reduce adverse reactions.

[0005] The commercially available diclofenac diethylamine emulsion contains diclofenac diethylamine, isopropyl alcohol, propylene glycol, carbomer 974P, cetumagogue 1000, capric / caprylic acid fatty alcohol esters, diethylamine, liquid paraffin, fragrance emulsion 45, pure water and other excipients. It is a white to light yellow creamy gel.

[0006] A Chinese patent with publication number CN102525886A discloses a diclofenac diethylamine emulsion, which uses a combination of isopropyl myristate, isopropyl alcohol and propylene glycol as a transdermal absorption enhancer, carbomer 980 as an aqueous gel matrix, liquid paraffin as an oil phase matrix, polysorbate 80 and mono- and di-stearate glyceryl as emulsifiers, thereby improving the in vitro transdermal absorption rate and the onset of action, which is conducive to timely relief of the patient's pain.

[0007] However, diclofenac shows a tendency to degrade under certain conditions such as light, and therefore, the stability problem of diclofenac diethylamine emulsion in the prior art needs to be solved urgently. Summary of the invention

[0008] In order to overcome the shortcomings of the prior art, the present invention provides a diclofenac diethylamine emulsion with high stability and low irritation. Specifically, the diclofenac diethylamine emulsion comprises, by mass ratio, 0.8-1.6 parts of diclofenac diethylamine, 30-45 parts of phospholipids, 10-15 parts of isopropanol, 1.2-3.5 parts of glutamine, 15-30 parts of propylene glycol, 5-15 parts of poloxamer 188, 1.5-5.5 parts of tragacanth gum, 15-35 parts of buffer solution and 0.1-0.3 parts of preservative.

[0009] Furthermore, the preservative is selected from at least one of phenoxyethanol, methylparaben, ethylparaben, and sodium benzoate; the phospholipid is soybean lecithin and / or egg yolk lecithin; and the buffer solution is selected from at least one of phosphate buffer solution, carbonate buffer solution, citrate buffer solution, and acetate buffer solution.

[0010] The present invention also provides a method for preparing the above-mentioned diclofenac diethylamine emulsion, comprising the following steps:

[0011] (1) Preparation of oil phase: melt phospholipids and poloxamer 188 in a water bath at 70-80° C., add diclofenac diethylamine, and stir to obtain an oil phase;

[0012] (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative to a buffer solution, heating in a water bath at 70 to 80° C., and stirring to obtain an aqueous phase;

[0013] (3) Emulsification: Slowly add the oil phase into the water phase and stir using a high-speed homogenizer to form an emulsion;

[0014] (4) Post-treatment: The emulsion is cooled, and glutamine and tragacanth gum are added, and stirring is continued to obtain diclofenac diethylamine emulsion.

[0015] The stirring speed of the high-speed homogenizer is 1000-1500 rpm for 20-30 minutes; the emulsion is cooled to 20°C-30°C; the oil phase is slowly added to the water phase at a speed of about 0.5-5 ml / min.

[0016] Compared with the prior art, the technical effects of the present invention are:

[0017] The diclofenac diethylamine emulsion of the invention has high chemical stability, can still maintain relatively high stability under high temperature, high humidity and light conditions, and the effective ingredient diclofenac is substantially not degraded.

[0018] The diclofenac diethylamine emulsion of the invention has high indoor stability and emulsification stability, and will not cause stratification, coagulation or precipitation under high temperature, high humidity and light conditions.

[0019] In addition, the diclofenac diethylamine emulsion of the present invention has little irritation to the skin and has wide product market application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The changes in the content of the active ingredient in the diclofenac diethylamine emulsion of Examples 1 to 4 and Comparative Example 6 are shown.

[0021] Figure 2 The figures are the changes in the active ingredient content in the diclofenac diethylamine emulsions of Comparative Examples 1 to 5. DETAILED DESCRIPTION

[0022] 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.

[0023] Example 1 Diclofenac diethylamine emulsion

[0024]

[0025] Preparation method:

[0026] (1) Preparation of oil phase: melt phospholipids and poloxamer 188 in a water bath at 75° C., add diclofenac diethylamine, and stir to obtain an oil phase;

[0027] (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative to a pH = 5.2 buffer solution, heating in a 75° C. water bath, stirring evenly, to obtain an aqueous phase;

[0028] (3) Emulsification: slowly add the oil phase into the water phase and stir using a high-speed homogenizer at a stirring speed of 1200 rpm for 25 min to form an emulsion;

[0029] (4) Post-treatment: The emulsion was cooled to 25° C., glutamine and tragacanth gum were added, and stirring was continued to obtain diclofenac diethylamine emulsion.

[0030] Embodiment 2 Diclofenac diethylamine emulsion

[0031]

[0032] Preparation method:

[0033] (1) Preparation of oil phase: melt phospholipids and poloxamer 188 in a water bath at 75° C., add diclofenac diethylamine, and stir to obtain an oil phase;

[0034] (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative into a pH = 5.5 buffer solution, heating in a 75° C. water bath, stirring evenly, to obtain an aqueous phase;

[0035] (3) Emulsification: slowly add the oil phase into the water phase and stir using a high-speed homogenizer at a stirring speed of 1300 rpm for 25 min to form an emulsion;

[0036] (4) Post-treatment: The emulsion was cooled to 25° C., glutamine and tragacanth gum were added, and stirring was continued to obtain diclofenac diethylamine emulsion.

[0037] Example 3 Diclofenac diethylamine emulsion

[0038]

[0039]

[0040] Preparation method:

[0041] (1) Preparation of oil phase: melt phospholipids and poloxamer 188 in a water bath at 70° C., add diclofenac diethylamine, and stir to obtain an oil phase;

[0042] (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative into a pH = 4.5 buffer solution, heating in a 70° C. water bath, stirring evenly, to obtain an aqueous phase;

[0043] (3) Emulsification: slowly add the oil phase into the water phase and stir using a high-speed homogenizer at a stirring speed of 1000 rpm for 20 min to form an emulsion;

[0044] (4) Post-treatment: The emulsion was cooled to 20° C., glutamine and tragacanth gum were added, and stirring was continued to obtain diclofenac diethylamine emulsion.

[0045] Embodiment 4 Diclofenac diethylamine emulsion

[0046]

[0047] Preparation method:

[0048] (1) Preparation of oil phase: melt phospholipids and poloxamer 188 in a water bath at 80° C., add diclofenac diethylamine, and stir to obtain an oil phase;

[0049] (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative into a pH = 6.0 buffer solution, heating in a water bath at 80° C., stirring evenly, to obtain an aqueous phase;

[0050] (3) Emulsification: slowly add the oil phase into the water phase and stir using a high-speed homogenizer at a stirring speed of 1500 rpm for 30 minutes to form an emulsion;

[0051] (4) Post-treatment: The emulsion was cooled to 30° C., glutamine and tragacanth gum were added, and stirring was continued to obtain diclofenac diethylamine emulsion.

[0052] Comparative Example 1 Diclofenac diethylamine emulsion

[0053]

[0054] Preparation method:

[0055] (1) Preparation of oil phase: melt phospholipids and poloxamer 188 in a water bath at 75° C., add diclofenac diethylamine, and stir to obtain an oil phase;

[0056] (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative to a pH = 5.2 buffer solution, heating in a 75° C. water bath, stirring evenly, to obtain an aqueous phase;

[0057] (3) Emulsification: slowly add the oil phase into the water phase and stir using a high-speed homogenizer at a stirring speed of 1200 rpm for 25 min to form an emulsion;

[0058] (4) Post-treatment: The emulsion was cooled to 25° C., tragacanth gum was added, and stirring was continued to obtain diclofenac diethylamine emulsion.

[0059] Comparative Example 2 Diclofenac diethylamine emulsion

[0060]

[0061]

[0062] Preparation method:

[0063] (1) Preparation of oil phase: melt phospholipids and poloxamer 188 in a water bath at 75° C., add diclofenac diethylamine, and stir to obtain an oil phase;

[0064] (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative to a pH = 5.2 buffer solution, heating in a 75° C. water bath, stirring evenly, to obtain an aqueous phase;

[0065] (3) Emulsification: slowly add the oil phase into the water phase and stir using a high-speed homogenizer at a stirring speed of 1200 rpm for 25 min to form an emulsion;

[0066] (4) Post-treatment: The emulsion is cooled to 25° C., glutamine and xanthan gum are added, and stirring is continued to obtain diclofenac diethylamine emulsion.

[0067] Comparative Example 3 Diclofenac diethylamine emulsion

[0068]

[0069]

[0070] Preparation method:

[0071] (1) Preparation of oil phase: melt phospholipids and poloxamer 188 in a water bath at 75° C., add diclofenac diethylamine, and stir to obtain an oil phase;

[0072] (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative to a pH = 5.2 buffer solution, heating in a 75° C. water bath, stirring evenly, to obtain an aqueous phase;

[0073] (3) Emulsification: slowly add the oil phase into the water phase and stir using a high-speed homogenizer at a stirring speed of 1200 rpm for 25 min to form an emulsion;

[0074] (4) Post-treatment: The emulsion was cooled to 25° C., xanthan gum was added, and stirring was continued to obtain diclofenac diethylamine emulsion.

[0075] Comparative Example 4 Diclofenac diethylamine emulsion

[0076]

[0077] Preparation method:

[0078] (1) Preparation of oil phase: melt phospholipids and poloxamer 188 in a water bath at 75° C., add diclofenac diethylamine, and stir to obtain an oil phase;

[0079] (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative to a pH = 5.2 buffer solution, heating in a 75° C. water bath, stirring evenly, to obtain an aqueous phase;

[0080] (3) Emulsification: slowly add the oil phase into the water phase and stir using a high-speed homogenizer at a stirring speed of 1200 rpm for 25 min to form an emulsion;

[0081] (4) Post-treatment: The emulsion was cooled to 25° C., L-asparagine and tragacanth gum were added, and stirring was continued to obtain diclofenac diethylamine emulsion.

[0082] Comparative Example 5 Diclofenac diethylamine emulsion

[0083]

[0084] Preparation method:

[0085] (1) Preparation of oil phase: melt liquid paraffin and poloxamer 188 in a water bath at 75° C., add diclofenac diethylamine, and stir to obtain an oil phase;

[0086] (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative to a pH = 5.2 buffer solution, heating in a 75° C. water bath, stirring evenly, to obtain an aqueous phase;

[0087] (3) Emulsification: slowly add the oil phase into the water phase and stir using a high-speed homogenizer at a stirring speed of 1200 rpm for 25 min to form an emulsion;

[0088] (4) Post-treatment: The emulsion was cooled to 25° C., glutamine and tragacanth gum were added, and stirring was continued to obtain diclofenac diethylamine emulsion.

[0089] Comparative Example 6 Commercially available diclofenac diethylamine emulsion (approval number H20181225)

[0090] Quality evaluation of diclofenac diethylamine emulsion

[0091] Content stability test

[0092] The diclofenac diethylamine emulsions of Examples 1 to 4 and the diclofenac diethylamine emulsions of Comparative Examples 1 to 6 were packaged as commercially available, placed at a temperature of 40°C ± 2°C, a relative humidity of 75% ± 5%, and an illumination of 4500xl ± 500xl for 6 months, and samples were taken on the 1st day, 30th day, 90th day, and 180th day during the test, and the diclofenac content was detected according to the high performance liquid chromatography method of the Chinese Pharmacopoeia.

[0093] Figure 1 The changes in the content of the active ingredient in the diclofenac diethylamine emulsion of Examples 1 to 4 and Comparative Example 6 are shown. Figure 2 The content of the active ingredient in the diclofenac diethylamine emulsion of comparative examples 1 to 5 is changed. The experiment shows that the diclofenac diethylamine emulsion of the present invention can still maintain a high stability under high temperature, high humidity and light conditions, and the active ingredient diclofenac is basically not degraded.

[0094] Emulsion stability test

[0095] The diclofenac diethylamine emulsions of Examples 1 to 4 and the diclofenac diethylamine emulsions of Comparative Examples 1 to 6 were packaged as sold on the market, placed at a temperature of 40°C ± 2°C, a relative humidity of 75% ± 5%, and an illumination of 4500xl ± 500xl for 6 months, and samples were taken on the 1st day and the 180th day during the test, and the emulsification stability of the emulsions was checked by centrifugation to ensure that the emulsions did not show stratification, coagulation or precipitation during storage.

[0096] Table 1 Emulsion stability test

[0097]

[0098] As shown in Table 1, the diclofenac diethylamine emulsions of Examples 1 to 4 of the present invention have stable properties, and no stratification, coagulation or precipitation occurs before and after the test.

[0099] Irritation test of diclofenac diethylamine emulsion

[0100] Intact skin irritation test: Take a number of ordinary New Zealand rabbits (experimental animal license number: SYXK (Lu) 20180008), half male and half female, and randomly divide them into a negative control group (normal saline), groups 1 to 4 of Examples, and 6 groups of comparative examples, with 6 rabbits in each group. Remove hair in the middle of the back 24 hours before the test, and the removal range is about 3cm×3cm for each rabbit. Before administration, check that the depilated skin is not damaged and conduct the test. Apply normal saline, diclofenac diethylamine emulsion of Examples 1 to 4, and diclofenac diethylamine emulsion of Comparative Example 6 on the depilated skin of New Zealand rabbits in the corresponding groups, respectively, once every 1h, for a total of 6 times, observe the skin reaction under natural light, and take whether the skin is red and swollen as the investigation index to observe the local skin reaction 0.1h, 0.2h, 0.5h, 1h, and 2h after administration. The results are as follows:

[0101] Table 2 Diclofenac diethylamine emulsion intact skin irritation test

[0102]

[0103] As shown in Table 2, the diclofenac diethylamine emulsion of the present invention has little irritation to the skin, does not cause skin redness and swelling, and has a wide range of product market application value.

Claims

1. A diclofenac diethylamine emulsion, characterized in that, The diclofenac diethylamine emulsion comprises, by mass ratio, 0.8 to 1.6 parts of diclofenac diethylamine, 30 to 45 parts of phospholipids, 10 to 15 parts of isopropanol, 1.2 to 3.5 parts of glutamine, 15 to 30 parts of propylene glycol, 5 to 15 parts of poloxamer 188, 1.5 to 5.5 parts of tragacanth gum, 15 to 35 parts of buffer solution, and 0.1 to 0.3 parts of preservative.

2. Diclofenac diethylamine emulsion according to claim 1, characterized in that, The preservative is selected from at least one of phenoxyethanol, methylparaben, ethylparaben and sodium benzoate.

3. The diclofenac diethylamine emulsion according to claim 1, characterized in that The phospholipids are soybean lecithin and / or egg yolk lecithin.

4. The diclofenac diethylamine emulsion according to claim 1, characterized in that The buffer solution is selected from at least one of a phosphate buffer solution, a carbonate buffer solution, a citrate buffer solution, and an acetate buffer solution.

5. The diclofenac diethylamine emulsion according to claim 1, characterized in that The diclofenac diethylamine emulsion comprises, by mass fraction, 1 part of diclofenac diethylamine, 33.2 parts of phospholipids, 12 parts of isopropanol, 2.6 parts of glutamine, 18 parts of propylene glycol, 8 parts of poloxamer 1885, 2.2 parts of tragacanth gum, 25 parts of buffer solution, and 0.2 parts of preservative.

6. A method for preparing the diclofenac diethylamine emulsion according to claim 1, characterized in that: The method is: (1) Preparation of oil phase: melt phospholipids and poloxamer 188 in a water bath at 70-80° C., add diclofenac diethylamine, and stir to obtain an oil phase; (2) Preparation of aqueous phase: adding isopropanol, propylene glycol and preservative to a buffer solution, heating in a water bath at 70 to 80° C., and stirring to obtain an aqueous phase; (3) Emulsification: Slowly add the oil phase into the water phase and stir using a high-speed homogenizer to form an emulsion; (4) Post-treatment: The emulsion is cooled, and glutamine and tragacanth gum are added, and stirring is continued to obtain diclofenac diethylamine emulsion.

7. The method according to claim 6, characterized in that The pH of the buffer solution is 4.5-6.

0.

8. The method according to claim 6, characterized in that The pH of the buffer solution is 5.

2.

9. The method according to claim 6, characterized in that The high-speed homogenizer has a stirring speed of 1000 to 1500 revolutions per minute and a stirring time of 20 to 30 minutes.

10. The method according to claim 6, characterized in that The emulsion is cooled to 20°C to 30°C.

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