Dichlorfenac diethylamine emulsion and method for preparing the same

Abstract

This invention provides a diclofenac diethylamine latex, belonging to the field of topical pharmaceutical preparations. By adding polyoxyethylene (10) oil-based ether, propylene carbonate, and a natural penetration enhancer to the diclofenac diethylamine latex, this invention obtains a latex with good skin permeability, high bioavailability, and good quality stability, which has significant clinical advantages over existing technologies. The preparation process of the diclofenac diethylamine latex of this invention is simple and very suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of topical pharmaceutical preparations, specifically relating to a diclofenac diethylamine latex and its preparation method. Background Technology

[0002] Pain relief is one of the most important treatment goals for improving quality of life, and drug therapy is the most basic and commonly used method in pain management. Based on the patient's condition and cause, appropriate medications are selected, and careful consideration is given to drug compatibility and rational application to achieve the best clinical efficacy. Diclofenac diethylamine is a nonsteroidal anti-inflammatory analgesic with anti-inflammatory and analgesic effects. When applied topically, its active ingredient can penetrate the skin to reach the inflamed area, relieving acute and chronic inflammatory responses, reducing inflammatory swelling, and alleviating pain.

[0003] Diclofenac diethylamine gel and latex are already available in China. However, due to the strong hydrophilicity of diclofenac diethylamine, ordinary topical formulations have poor skin penetration, slow onset of action, and unsatisfactory bioavailability. Emulsification technology can increase the lipid solubility of diclofenac diethylamine to some extent, as seen in the diclofenac diethylamine latex (trade name Voltaren) currently available in China. However, the transdermal efficiency of this latex is still not ideal, and its onset of action still fails to meet the clinical requirement of rapid analgesia. Furthermore, isopropanol is added to this latex to improve bioavailability. However, isopropanol is a volatile irritant with toxicity between methanol and ethanol. Long-term inhalation may affect the central nervous system, leading to symptoms such as dizziness, headache, and slowed reaction time. High-concentration exposure can even cause loss of consciousness or death. In addition, as a topical formulation, long-term skin contact with isopropanol can cause discomfort such as dry and cracked skin.

[0004] Therefore, there is a need to develop a stable diclofenac diethylamine latex formulation that is free of isopropanol, has better transdermal drug penetration, and higher bioavailability. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a diclofenac diethylamine latex, which has good skin permeability and bioavailability, and avoids the harm to the human body or skin caused by the addition of isopropanol to the latex; moreover, the diclofenac diethylamine latex of this invention has stable quality, a simple preparation method, and is very suitable for industrial production.

[0006] To achieve the above objectives, the present invention adopts the following solution:

[0007] A diclofenac diethylamine latex comprising the active ingredient diclofenac diethylamine, an oily matrix, an aqueous matrix, polyoxyethylene (10) oil-based ether, propylene carbonate, a natural penetration enhancer, and purified water.

[0008] The diclofenac diethylamine latex of the present invention uses a natural penetration enhancer selected from one or more of peppermint oil, eucalyptus oil, and oleic acid.

[0009] The diclofenac diethylamine latex of the present invention comprises an oily matrix selected from one or more of caprylic / capric cocoate, hydrocarbon matrix, and mono- and di-stearate glycerides; wherein the hydrocarbon substance is selected from one or more of liquid paraffin, white petrolatum, and octadecyl alcohol.

[0010] The diclofenac diethylamine latex of the present invention has an aqueous matrix selected from one or more of hydroxypropyl methylcellulose, carboxymethyl cellulose, chitosan, and hydroxypropyl chitosan.

[0011] In one embodiment of the present invention, the diclofenac diethylamine latex comprises the following components in weight percentage: 1.16% diclofenac diethylamine, 25.0%–45.0% oily matrix, 0.5%–4.0% aqueous matrix, 1.0%–3.0% polyoxyethylene (10) oil-based ether, 0.5%–1.5% propylene carbonate, 0.3%–1.3% natural penetration enhancer, and 42.0%–68.0% purified water.

[0012] The diclofenac diethylamine latex of the present invention further includes a pH adjuster; preferably, the pH adjuster is selected from one or more of diethylamine, sodium carbonate and sodium hydroxide.

[0013] In one embodiment of the present invention, the diclofenac diethylamine latex comprises the following components by weight percentage: 1.16% diclofenac diethylamine, 25.0%–45.0% oily matrix, 0.5%–4.0% aqueous matrix, 1.0%–3.0% polyoxyethylene (10) oil-based ether, 0.5%–1.5% propylene carbonate, 0.3%–1.3% natural penetration enhancer, 42.0%–68.0% purified water, and 0.1%–2.1% pH adjuster.

[0014] Another aspect of the present invention provides a method for preparing diclofenac diethylamine latex, specifically comprising the following steps:

[0015] 1) Aqueous phase preparation: The purified water and aqueous matrix are stirred evenly to obtain the aqueous phase.

[0016] 2) Preparation of oil phase: The oily matrix, polyoxyethylene (10) oil-based ether and propylene carbonate are heated and stirred until dissolved to obtain the oil phase;

[0017] 3) Preparation of the active pharmaceutical ingredient solution: Add diclofenac diethylamine to the aqueous phase and stir to dissolve to obtain the active pharmaceutical ingredient solution;

[0018] 4) Total mixing: Add the main drug solution and natural penetration enhancer to the oil phase, mix evenly, and cool to obtain diclofenac diethylamine emulsion.

[0019] The natural penetration enhancer is selected from one or more of peppermint oil, eucalyptus oil, and oleic acid.

[0020] The preparation method of diclofenac diethylamine latex of the present invention further includes step (3) of adding a pH adjuster; preferably, the pH adjuster is selected from one or more of diethylamine, sodium carbonate and sodium hydroxide.

[0021] Technical effects of the present invention:

[0022] (1) By adding polyoxyethylene (10) oil-based ether, propylene carbonate and natural penetration enhancer to diclofenac diethylamine latex, this invention obtains a latex with good skin permeability, high bioavailability and good quality stability, which has obvious clinical advantages over the prior art; moreover, the latex of this invention does not contain isopropanol, which can avoid the side effects of isopropanol on the human body.

[0023] (2) The diclofenac diethylamine latex of the present invention, which uses polyoxyethylene (10) oil-based ether, propylene carbonate and natural penetration enhancer in combination, has better transdermal absorption performance than the latex obtained by using penetration enhancer alone, or in combination with other penetration enhancers, or in combination with other emulsifiers, or without using propylene carbonate. This shows that the specific combination of polyoxyethylene (10) oil-based ether, propylene carbonate and natural penetration enhancer of the present invention plays a crucial role in improving the bioavailability of diclofenac diethylamine latex, ensuring the safety and effectiveness of the formulation.

[0024] (3) The preparation process of the diclofenac diethylamine latex of the present invention is simple and very suitable for industrial production. Detailed Implementation

[0025] The technical solution of the present invention will be further described below with reference to specific embodiments, but this does not limit the present invention.

[0026] Example 1

[0027]

[0028] Preparation method:

[0029] 1) Preparation of aqueous phase: Purified water and carboxymethyl cellulose are stirred evenly to obtain aqueous phase.

[0030] 2) Preparation of oil phase: Coccal ethyl ester, liquid paraffin, white petrolatum, polyoxyethylene (10) oil-based ether and propylene carbonate were heated and stirred to 75°C until dissolved to obtain oil phase;

[0031] 3) Preparation of the active pharmaceutical ingredient solution: Diclofenac diethylamine was added to the aqueous phase and stirred to dissolve, thus obtaining the active pharmaceutical ingredient solution;

[0032] 4) Total mixing: Add the main drug solution and oleic acid to the oil phase, mix evenly, and cool to obtain diclofenac diethylamine emulsion.

[0033] Example 2

[0034] composition Dosage (kg) Diclofenac diethylamine 1.39 Glyceryl monostearate and glyceryl distearate 12.00 Stearyl alcohol 18.00 Hydroxypropyl methylcellulose 4.80 Polyoxyethylene (10) oil-based ether 2.00 Acrylic carbonate 0.60 peppermint 1.56 Sodium carbonate 0.12 Purified water 79.53

[0035] Preparation method:

[0036] 1) Preparation of aqueous phase: Purified water and hydroxypropyl methylcellulose were stirred evenly to obtain an aqueous phase.

[0037] 2) Preparation of the oil phase: Glyceryl mono- and di-stearate, octadecyl alcohol, polyoxyethylene (10) oleyl ether and propylene carbonate were heated and stirred to 75°C until dissolved to obtain the oil phase;

[0038] 3) Preparation of the active pharmaceutical ingredient solution: Diclofenac diethylamine and sodium carbonate were added to the aqueous phase and stirred to dissolve, thus obtaining the active pharmaceutical ingredient solution;

[0039] 4) Total mixing: Add the main drug solution and peppermint oil to the oil phase, mix evenly, and cool to obtain diclofenac diethylamine emulsion.

[0040] Example 3

[0041] composition Dosage (kg) Diclofenac diethylamine 1.39 Coconut oil ester caprylate 15.00 Vaseline 28.00 Chitosan 0.60 Polyoxyethylene (10) oil-based ether 2.40 Acrylic carbonate 1.20 Eucalyptus oil 1.20 Purified water 70.21

[0042] Preparation method:

[0043] 1) Preparation of aqueous phase: Purified water and chitosan are stirred evenly to obtain aqueous phase.

[0044] 2) Preparation of oil phase: Cocyl octanoate, white petrolatum, polyoxyethylene (10) oil-based ether and propylene carbonate were heated and stirred to 75°C until dissolved to obtain oil phase;

[0045] 3) Preparation of the active pharmaceutical ingredient solution: Diclofenac diethylamine was added to the aqueous phase and stirred to dissolve, thus obtaining the active pharmaceutical ingredient solution;

[0046] 4) Total mixing: Add the main drug solution and eucalyptus oil to the oil phase, mix evenly, and cool to obtain diclofenac diethylamine emulsion.

[0047] Example 4

[0048] composition Dosage (kg) Diclofenac diethylamine 1.39 Glyceryl monostearate and glyceryl distearate 15.00 Liquid paraffin 9.00 Vaseline 30.00 Hydroxypropyl chitosan 4.80 Polyoxyethylene (10) oil-based ether 1.20 Acrylic carbonate 1.50 Oleic acid 1.50 Purified water 55.61

[0049] Preparation method:

[0050] 1) Preparation of aqueous phase: Purified water and hydroxypropyl chitosan were stirred evenly to obtain an aqueous phase.

[0051] 2) Preparation of oil phase: Glyceryl mono- and di-stearyl esters, liquid paraffin, white petrolatum, polyoxyethylene (10) oil-based ether and propylene carbonate were heated and stirred to 75°C until dissolved to obtain the oil phase;

[0052] 3) Preparation of the active pharmaceutical ingredient solution: Diclofenac diethylamine was added to the aqueous phase and stirred to dissolve, thus obtaining the active pharmaceutical ingredient solution;

[0053] 4) Total mixing: Add the main drug solution and oleic acid to the oil phase, mix evenly, and cool to obtain diclofenac diethylamine emulsion.

[0054] Example 5

[0055] composition Dosage (kg) Diclofenac diethylamine 1.39 Coconut oil ester caprylate 15.00 Liquid paraffin 9.00 Vaseline 30.00 Carboxymethyl cellulose 4.73 Polyoxyethylene (10) oil-based ether 3.60 Acrylic carbonate 1.80 Oleic acid 1.56 Sodium hydroxide 2.52 Purified water 50.40

[0056] Preparation method:

[0057] 1) Preparation of aqueous phase: Purified water and carboxymethyl cellulose are stirred evenly to obtain aqueous phase.

[0058] 2) Preparation of oil phase: Coccal ethyl ester, liquid paraffin, white petrolatum, polyoxyethylene (10) oil-based ether and propylene carbonate are heated and stirred to 75°C and stirred until dissolved to obtain oil phase;

[0059] 3) Preparation of the active pharmaceutical ingredient solution: Diclofenac diethylamine and sodium hydroxide were added to the aqueous phase and stirred to dissolve, thus obtaining the active pharmaceutical ingredient solution;

[0060] 4) Total mixing: Add the main drug solution and oleic acid to the oil phase, mix evenly, and cool to obtain diclofenac diethylamine emulsion.

[0061] Example 6

[0062] composition Dosage (kg) Diclofenac diethylamine 1.39 Coconut oil ester caprylate 14.05 Vaseline 20.00 Chitosan 0.80 Polyoxyethylene (10) oil-based ether 1.20 Acrylic carbonate 0.60 Eucalyptus oil 0.36 Purified water 81.60

[0063] Preparation method:

[0064] 1) Preparation of aqueous phase: Purified water and chitosan are stirred evenly to obtain aqueous phase.

[0065] 2) Preparation of oil phase: Cocyl octanoate, white petrolatum, polyoxyethylene (10) oil-based ether and propylene carbonate were heated and stirred to 75°C until dissolved to obtain oil phase;

[0066] 3) Preparation of the active pharmaceutical ingredient solution: Diclofenac diethylamine was added to the aqueous phase and stirred to dissolve, thus obtaining the active pharmaceutical ingredient solution;

[0067] 4) Total mixing: Add the main drug solution and eucalyptus oil to the oil phase, mix evenly, and cool to obtain diclofenac diethylamine emulsion.

[0068] control group

[0069]

[0070] The preparation methods of Comparative Examples 1-6 are the same as those of Example 1.

[0071] Compared with Example 3 of the present invention, Comparative Examples 1 and 4 used different emulsifiers, namely polyethylene glycol hexadecyl ether and sodium hexadecyl sulfate, respectively; Comparative Examples 2 and 3 used different penetration enhancers, namely ethanol and urea, respectively; no penetration enhancer was used in Comparative Example 5; and no propylene carbonate was used in Comparative Example 6.

[0072] Example of effect

[0073] Transdermal absorption study:

[0074] In vitro transdermal tests were conducted on the diclofenac diethylamine latex products of Examples 1-6 and Comparative Examples 1-6 of this invention, as well as commercially available products. The drug content of specific fractions in the test samples was determined by HPLC to obtain the subcutaneous drug permeation amount. Based on the test results, the transdermal permeation performance of the latex products was evaluated.

[0075] Table 1. Subcutaneous drug penetration (%) of diclofenac diethylamine emulsion

[0076] sample 1 2 3 4 5 6 average value Example 1 23.5656 24.0123 23.8569 23.7764 23.6432 24.0110 23.8109 Example 2 24.2133 24.1256 24.0288 23.9910 24.0188 24.5698 24.1579 Example 3 24.2289 24.5699 24.0188 23.0189 24.5532 23.0211 23.9018 Example 4 24.3312 24.2103 23.1987 25.0011 24.1255 23.9987 24.1443 Example 5 23.1655 23.3456 23.5597 25.0122 23.1259 24.2526 23.7436 Example 6 25.3236 25.8823 24.5678 25.0123 24.2289 24.6678 24.9471 Comparative Example 1 17.3244 17.3584 17.2466 16.3245 17.1001 16.8479 17.0337 Comparative Example 2 14.3244 14.6678 14.3211 15.1632 14.7979 14.2213 14.5826 Comparative Example 3 10.1233 9.8988 10.1233 9.7789 9.1516 10.1233 9.8665 Comparative Example 4 16.1233 17.3234 17.0110 17.6678 17.7701 16.3634 17.0432 Comparative Example 5 7.6833 8.0102 7.5633 7.5987 7.8988 7.6543 7.7348 Comparative Example 6 6.8821 6.1259 5.9988 6.1328 6.3324 6.3577 6.3050 Comparison Example 18.8553 19.1446 18.8904 18.7773 19.1036 18.8741 18.9409

[0077] As can be seen from Table 1, the subcutaneous drug permeation of the diclofenac diethylamine latex formulations of Examples 1-6 of the present invention is significantly higher than that of Comparative Examples 1-6; moreover, compared with commercially available products, the subcutaneous drug permeation of the latex formulations of Examples 1-6 of the present invention still has an advantage; indicating that the diclofenac diethylamine latex formulation of the present invention, which contains polyoxyethylene (10) oil-based ether, propylene carbonate and natural penetration enhancer, has a significant advantage in terms of subcutaneous drug permeation, that is, the diclofenac diethylamine latex formulation of the present invention has better bioavailability.

[0078] Stability assessment:

[0079] The properties and physical characteristics of the diclofenac diethylamine latex from Examples 1-6 and Comparative Examples 1-6 of this invention, as well as commercially available products, were studied. The specific results are shown in Table 2.

[0080] Table 2 Properties and physical stability of diclofenac diethylamine latex samples

[0081]

[0082]

[0083] As shown in Table 2, the diclofenac diethylamine latex formulations of Examples 1-6 of this invention exhibit good stability, maintaining stable latex shape in both low-temperature and high-temperature tests, achieving product quality stability comparable to commercially available products. In contrast, the diclofenac diethylamine latex formulations of Comparative Examples 1-6 show poor stability, exhibiting centrifugal stratification in low-temperature tests, and even showing liquid seepage, thinning, and a bean curd-like appearance in high-temperature tests in Comparative Examples 2-4, severely impacting the safety and efficacy of the formulation. This demonstrates that the diclofenac diethylamine latex formulation of this invention, containing polyoxyethylene (10) oil-based ether, propylene carbonate, and a natural penetration enhancer, exhibits a significant advantage in quality stability.

[0084] It should be understood that the specific embodiments described above are merely illustrative or explanatory of the principles of the invention and do not constitute a limitation thereof. Therefore, any modifications, equivalent substitutions, improvements, etc., made without departing from the spirit and scope of the invention should be included within the protection scope of the invention. Furthermore, the appended claims are intended to cover all variations and modifications falling within the scope and boundaries of the appended claims, or equivalent forms of such scope and boundaries.

Claims

1. A diclofenac diethylamine latex, characterized in that, The latex contains the active ingredient diclofenac diethylamine, an oily matrix, an aqueous matrix, polyoxyethylene (10) oil-based ether, propylene carbonate, a natural penetration enhancer, and purified water.

2. The diclofenac diethylamine latex of claim 1, characterized in that, The natural penetration enhancer is selected from one or more of peppermint oil, eucalyptus oil, and oleic acid.

3. The diclofenac diethylamine latex of claim 1, characterized in that, The oily matrix is ​​selected from one or more of the following: caprylic / capric cocoate, hydrocarbon matrix, and mono- and di-stearate glycerides.

4. The diclofenac diethylamine latex of claim 3, characterized in that, The hydrocarbons are selected from one or more of liquid paraffin, white petrolatum, and octadecyl alcohol.

5. The diclofenac diethylamine latex of claim 1, characterized in that, The aqueous matrix is ​​selected from one or more of hydroxypropyl methylcellulose, carboxymethyl cellulose, chitosan, and hydroxypropyl chitosan.

6. The diclofenac diethylamine latex of claim 1, characterized in that, The diclofenac diethylamine latex comprises the following components by weight percentage: 1.16% diclofenac diethylamine, 25.0%–45.0% oily matrix, 0.5%–4.0% aqueous matrix, 1.0%–3.0% polyoxyethylene (10) oil-based ether, 0.5%–1.5% propylene carbonate, 0.3%–1.3% natural penetration enhancer, and 42.0%–68.0% purified water.

7. The diclofenac diethylamine latex of claim 1, characterized in that, The diclofenac diethylamine latex also includes a pH adjuster.

8. The diclofenac diethylamine latex of claim 7, characterized in that, The pH adjuster is selected from one or more of diethylamine, sodium carbonate, and sodium hydroxide.

9. The diclofenac diethylamine latex of claim 1, characterized in that, The diclofenac diethylamine latex comprises the following components by weight percentage: 1.16% diclofenac diethylamine, 25.0%–45.0% oily matrix, 0.5%–4.0% aqueous matrix, 1.0%–3.0% polyoxyethylene (10) oil-based ether, 0.5%–1.5% propylene carbonate, 0.3%–1.3% natural penetration enhancer, 42.0%–68.0% purified water, and 0.1%–2.1% pH adjuster.

10. The method for preparing diclofenac diethylamine latex according to any one of claims 1-9, characterized in that, The preparation method specifically includes the following steps: 1) Aqueous phase preparation: The purified water and aqueous matrix are stirred evenly to obtain the aqueous phase. 2) Preparation of oil phase: The oily matrix, polyoxyethylene (10) oil-based ether and propylene carbonate are heated and stirred until dissolved to obtain the oil phase; 3) Preparation of the active pharmaceutical ingredient solution: Add diclofenac diethylamine to the aqueous phase and stir to dissolve to obtain the active pharmaceutical ingredient solution; 4) Total mixing: Add the main drug solution and natural penetration enhancer to the oil phase, mix evenly, and cool to obtain diclofenac diethylamine emulsion.

11. The method for preparing the diclofenac diethylamine latex of claim 10, characterized in that, Step (3) further includes the step of adding a pH adjuster; preferably, the pH adjuster is selected from one or more of diethylamine, sodium carbonate and sodium hydroxide.

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