Pharmaceutical composition containing 2-((2, 6-dichlorophenyl) amino) phenylacetic acid diethylamine

Abstract

The invention discloses a pharmaceutical composition containing 2-((2, 6-dichlorophenyl) amino) phenylacetic acid diethylamine, which comprises the following components in percentage by mass: 1.5-3% of 2-((2, 6-dichlorophenyl) amino) phenylacetic acid diethylamine, 0.5-2% of 2-((2, 6-dichlorophenyl) amino) phenylacetic acid diethylamine and the balance of water. The hydrogel is prepared from the following components in percentage by weight: 40 to 50 percent of (2, 6-dichlorophenyl) amino) phenylacetic acid diethylamine, 40 to 50 percent of an organic solvent system, 1 to 2 percent of a hydrogel matrix, 0.5 to 1.5 percent of a pH regulator, 4 to 5.5 percent of an oil phase matrix, 0.1 to 1.0 percent of a transdermal absorption enhancer, 0.01 to 0.035 percent of an antioxidant, 1.5 to 3 percent of an emulsifier and the balance of purified water. The composition disclosed by the invention has the advantages of high permeation rate, quick response, good safety, stable property and the like.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical compositions, and in particular to a pharmaceutical composition containing 2-((2,6-dichlorophenyl)amino)phenylacetic acid diethylamine. Background Art

[0002] Diclofenac diethylamine, chemically named 2-((2,6-dichlorophenyl)amino)phenylacetic acid diethylamine, is a non-steroidal anti-inflammatory drug with anti-inflammatory and analgesic effects. It is widely used in topical drug delivery products. Compared with oral administration, it can avoid gastrointestinal irritation and first-pass effect, and reduce adverse reactions. For example, the diclofenac diethylamine emulsion gel currently on the market in China is an oil-in-water emulsion with a jelly-like aqueous phase. Its active ingredients can penetrate the skin and eventually reach the inflamed area, reducing inflammatory swelling and relieving pain. Two specifications of products have been launched. Specification 1 (containing 1.16% w / w diclofenac diethylamine) has a low penetration rate and unsatisfactory bioavailability, which is difficult to meet the needs of patients; Specification 2 (containing 2.32% w / w diclofenac diethylamine) increases the amount of active ingredients on this basis, and the penetration rate has increased compared to Specification 1, but the penetration rate of this product is still low, and it cannot effectively relieve patients' acute inflammatory reactions and quickly relieve patients' pain.

[0003] CN111904926A discloses a topical diclofenac sodium composition. The ternary solvent system composed of water, a volatile organic solvent and a non-volatile organic solvent in a specific ratio can effectively dissolve diclofenac sodium with a concentration higher than 1%, and can improve the permeability of diclofenac sodium without adding a permeation enhancer. However, it can be seen that the permeation amount before 6 hours is still relatively low, which is not conducive to improving the product's onset speed.

[0004] CN102525886A discloses a diclofenac diethylamine emulsion and a preparation method thereof, which uses a combination of isopropyl myristate, isopropyl alcohol and propylene glycol as a transdermal absorption enhancer to improve the transdermal absorption effect of diclofenac diethylamine. The content of isopropyl myristate is as high as 10%. Although the patent records that it is non-irritating within 72 hours, the inventors found that 10% isopropyl myristate still irritates after 72 hours in the process of screening penetration enhancers. And other types of penetration enhancers also face the problem of poor penetration enhancement effect at low concentrations and irritation at high concentrations.

[0005] In addition, the ambient temperature used in the above two patents when testing the transdermal efficiency is 37°C. Although it can theoretically simulate human body temperature, the actual temperature of human exposed skin is lower than 37°C, and the decrease in temperature will inevitably affect the penetration efficiency of the drug. Therefore, it is necessary to develop a pharmaceutical composition containing 2-((2,6-dichlorophenyl)amino)phenylacetic acid diethylamine, which can accelerate the penetration rate of active ingredients and achieve rapid onset of effect under conditions closer to the actual use temperature (lower than 37°C), and also meet quality and safety requirements, which has more practical significance for quickly relieving patients' pain. Summary of the invention

[0006] The invention aims to provide a high-concentration diclofenac diethylamine composition which has good skin permeability, fast drug onset speed and is safe and non-irritating.

[0007] The technical scheme of the present invention is: a pharmaceutical composition containing 2-((2,6-dichlorophenyl)amino)phenylacetic acid diethylamine, which comprises, by mass percentage, 1.5-3% of diclofenac diethylamine, 40-50% of an organic solvent system, 1-2% of an aqueous gel matrix, 0.5-1.5% of a pH regulator, 4-5.5% of an oil phase matrix, 0.1-1.0% of a transdermal absorption enhancer, 0.01-0.035% of an antioxidant, 1.5-3% of an emulsifier, and the balance is purified water.

[0008] Furthermore, the organic solvent system includes a volatile solvent and a non-volatile solvent, the volatile solvent is selected from ethanol, isopropanol or a combination thereof, and the non-volatile solvent is selected from propylene glycol, glycerol or a combination thereof.

[0009] Furthermore, the organic solvent system preferably comprises ethanol, isopropanol and propylene glycol, wherein the mass percentage of ethanol is 10%-15%, the mass percentage of isopropanol is 15%-20%, and the mass percentage of propylene glycol is 13%-17%. If the content of ethanol or isopropanol is too low, the volatilization rate will be affected. After application, the volatilization rate of the solvent is slow, and the active ingredient content in the product cannot be maintained at a high concentration, resulting in a low penetration rate, which affects the product's onset speed; if the content of isopropanol is too high, the product will be stratified during quality inspection, which is not conducive to product stability; if the content of ethanol is too high, the volatilization rate is too fast, resulting in the precipitation of active ingredients, which in turn reduces the transdermal rate; if the content of non-volatile solvent propylene glycol is too low, the active ingredients will not be absorbed in time after the volatile solvent evaporates and will be precipitated, resulting in incomplete absorption; and if the content of propylene glycol is too high, it will be greasy and the skin feel will be poor.

[0010] Furthermore, the aqueous gel matrix is ​​selected from carbomer, chitosan graphene hydrogel, cellulose derivatives, gelatin, alginate, and polyvinyl alcohol.

[0011] Furthermore, the aqueous gel matrix is ​​preferably chitosan graphene hydrogel. Compared with ordinary hydrogels (such as carbomer), chitosan graphene hydrogel also has excellent thermal conductivity, can evenly transfer body temperature to drugs, increase the evaporation rate of volatile solvents, and keep the active ingredient content in the product at a high concentration; and chitosan graphene hydrogel has a porous nature, can evenly disperse drugs, increase the contact area between the active ingredient and the skin, can make the high concentration of active ingredients enriched on the skin surface due to solvent volatilization quickly absorbed, and prevent the active ingredients from being precipitated before being absorbed; in addition, chitosan graphene hydrogel also has antibacterial and anti-inflammatory effects, and is more suitable for wound surface analgesia.

[0012] Furthermore, the pH adjuster is selected from alkaline agents such as sodium hydroxide, potassium hydroxide, diethylamine, triethanolamine, etc., preferably diethylamine.

[0013] Furthermore, the oil phase matrix is ​​selected from white vaseline, liquid paraffin, triglyceride, coconut oil alcohol caprylate caprate, isopropyl myristate, isopropyl palmitate, preferably a mixture of liquid paraffin and coconut oil alcohol caprylate caprate, and the weight ratio of liquid paraffin to coconut oil alcohol caprylate caprate is 1:1.

[0014] Furthermore, the transdermal absorption enhancer is selected from azone, oleyl alcohol, oleic acid, menthol, etc., preferably oleyl alcohol.

[0015] Furthermore, the antioxidant is selected from butylated hydroxytoluene (BHT), α-tocopherol, sodium thiosulfate, sodium sulfite, preferably butylated hydroxytoluene (BHT).

[0016] Furthermore, the emulsifier is selected from glyceryl monostearate, sodium lauryl sulfate, sodium dodecyl sulfate, cetumab 1000, polysorbate, preferably cetumab 1000.

[0017] Compared with the prior art, the beneficial effects of this application are:

[0018] (1) The present invention adopts a ternary organic solvent system consisting of ethanol, isopropanol and propylene glycol, and controls the volatilization rate of the organic solvent by reasonably controlling the ratio of non-volatile organic solvent to volatile organic solvent, so that the content of active ingredients in the product can be continuously maintained at a higher concentration that is more conducive to transdermal penetration.

[0019] (2) The present invention also uses chitosan graphene hydrogel as an auxiliary means, using its excellent thermal conductivity to evenly transfer body temperature to the drug, ensuring that the evaporation rate of volatile solvents is further increased under the actual temperature (below 37°C) environment, so that the active ingredient content in the product continues to maintain a high concentration, and uses its porous properties to evenly disperse the drug, increasing the contact area between the active ingredient and the skin, so that the high concentration of active ingredients enriched on the skin surface due to solvent evaporation can be quickly absorbed, preventing the active ingredients from being precipitated before being absorbed, and further improving the rapid penetration rate of the drug.

[0020] (3) In addition, the inventors unexpectedly discovered that under the premise of ensuring safety and non-irritation, the combination of chitosan graphene hydrogel and a small amount of permeation enhancer (oleyl alcohol) can also play a synergistic role in improving the transdermal penetration rate in a short period of time. Compared with the existing technology products, the transdermal onset time is shorter and more conducive to timely relief of patients' pain. DETAILED DESCRIPTION

[0021] The present application is further illustrated by specific examples. It should be understood that the examples of the present application are only used to illustrate the present application, rather than to limit the present application. The experimental methods for which specific conditions are not specified in the following examples are usually carried out under conventional conditions or under conditions recommended by the manufacturer. The raw and auxiliary materials for which specific sources are not specified in the following examples are usually conventional products available on the market. Technical solutions obtained by simple improvements to the present application or by equivalent replacement of conventional means or components based on the technical solutions of the present application belong to the protection scope of the present application.

[0022] The prescriptions of Examples 1-3 and Comparative Examples 1-7 are shown in Table 1.

[0023] Table 1 Diclofenac diethylamine compositions of different prescriptions

[0024]

[0025] The preparation method of the diclofenac diethylamine composition sample in Table 1 is prepared according to the following steps:

[0026] Step (1): weigh propylene glycol and partially purified water according to the prescribed amount, add chitosan graphene hydrogel or carbomer hydrogel, and swell completely for later use;

[0027] Step (2): taking the prescribed amount of isopropanol, ethanol and the remaining purified water, adding diclofenac diethylamine, mixing to dissolve it completely, and then mixing it evenly with step (1), adjusting the pH to 6.5-8.0 with diethylamine, mixing evenly, and keeping warm at 60-80° C. for later use;

[0028] Step (3): Take the prescribed amount of liquid paraffin, coconut oil caprylate and caprate, oleyl alcohol, BHT, and cetumagogue 1000, heat to dissolve at 60-80° C., and homogenize with step (2) until emulsification is complete;

[0029] Step (4): Stir to room temperature and fill.

[0030] Comparative Example 8 Sample

[0031] A topical diclofenac sodium composition (2% specification) was prepared with reference to prescription No. 38 of Example 1 of CN111904926A.

[0032] Comparative Example 9 Sample

[0033] Commercially available product: Voltaren (2% specification).

[0034] Comparative Example 10 Sample

[0035] Diclofenac diethylamine emulsion (1% specification) was prepared with reference to Example 5 of CN102525886A.

[0036] Test Example 1: In vitro transdermal results

[0037] The samples of Examples 1-3 were used as the experimental group, and the samples of Comparative Examples 1-2 and Comparative Examples 5-10 were used as the control group to conduct a weight loss test and a transdermal test. The specific method is as follows:

[0038] Skin for test: Bama miniature pigs were selected and the ex vivo skin of the back trunk was taken. The same donor skin was used in the experimental group and the control group, and each sample was measured in parallel 6 times.

[0039] Test receptor medium: physiological saline, the volume of the receptor medium is 18 ml.

[0040] Test temperature: 32℃.

[0041] The stirring speed during the test was 600 rpm.

[0042] Sampling time (hours): 0.5, 1, 2, 4, 6, 8.

[0043] Sampling volume: 5 ml. Fresh receiving phase liquid should be added after sampling at each sampling point to ensure that the lower surface of the pigskin always remains in contact with the receiving phase during the entire experiment.

[0044] Determination method: HPLC was used to determine the content of diclofenac in the receiving solution.

[0045] Test method: Fix the stratum corneum of Bama miniature pig skin upward on a Franz vertical diffusion cell equipped with a magnetic stirrer, install a quantitative ring, cover the upper half of the cell and clamp it with an iron clamp, weigh about 500 mg of the test sample, and place it evenly on the pig skin. Add preheated physiological saline to the receiving cell so that the lower surface of the Bama miniature pig skin contacts the receiving liquid, and take samples for testing at 0.5h, 1h, 2h, 4h, 6h, and 8h. Calculate the cumulative permeation per unit area at each time point, and the results are shown in Tables 2-1, 2-2, 2-3, and 2-4 below.

[0046] Table 2-1 Comparison of transdermal test results of the present invention and the prior art

[0047]

[0048] It can be seen from Table 2-1 that the samples of Examples 1-3 of the present invention have higher transdermal efficiency in a short period of time than the samples of Comparative Examples 8-10 of the prior art solution (i.e., the samples of Example CN111904926A, the commercially available product Voltaren, and the samples of Example CN102525886A), indicating that the present invention has a faster onset rate and analgesic effect, and can accelerate the penetration rate of the active ingredient under the actual use temperature (below 37°C) to achieve rapid onset of effect.

[0049] Table 2-2 Effects of different organic solvent systems on transdermal experiments

[0050]

[0051] It can be seen from Table 2-2 that the weight loss rate of the samples of Examples 1-3 is in the range of 40%-50%, and the transdermal effect is the best in a short time; the low content of volatile organic solvents (ethanol and isopropanol) in the sample of Comparative Example 2 affects the volatilization rate, which is not conducive to increasing the drug concentration in a short time, so the transdermal efficiency is low; and the sample of Comparative Example 1 has a high volatile solvent content, so the volatilization rate is fast, but the transdermal rate is not high in a short time, which may be because when the content of non-volatile organic (propylene glycol) is low, the volatilization rate is too fast and active components are easily precipitated, which affects the drug absorption.

[0052] Table 2-3 Effects of different gel matrices on transdermal testing results

[0053]

[0054] It can be seen from Table 2-3 that under the same organic solvent ratio conditions, the weight loss rate (volatilization efficiency) of chitosan graphene hydrogel is higher than that of carbomer hydrogel, and the transdermal efficiency in a short time is also higher.

[0055] Table 2-4 Effect of adding penetration enhancers on transdermal test results

[0056]

[0057] As shown in Tables 2-4, the weight loss rate of each group did not change when a small amount of oleyl alcohol was added, but the short-time skin penetration rate of Example 1 (1.5% chitosan graphene hydrogel + 0.3% oleyl alcohol) was further improved compared with that of Comparative Example 6 (1.5% chitosan graphene hydrogel), while the short-time skin penetration rate of Comparative Example 5 (1.5% carbomer hydrogel + 0.3% oleyl alcohol) was unchanged compared with that of Comparative Example 7 (1.5% carbomer hydrogel). This shows that the combination of chitosan graphene hydrogel and a small amount of oleyl alcohol can play a synergistic role in improving the skin penetration rate in a short time.

[0058] Test Example 2: Animal irritation test

[0059] The samples of Examples 1-3 were used as the experimental group, and the samples of Comparative Examples 8-10 were used as the control group, each group including 2 New Zealand white rabbits with normal skin and 2 New Zealand white rabbits with damaged skin. The samples of the experimental group and the control group were continuously administered to the normal skin and damaged skin of the New Zealand white rabbits according to the maximum concentration to be used clinically (administered twice a day for 7 consecutive days), and the results of daily cage observation showed that there was no abnormality in the state, behavior, and physical signs of the experimental group and the control group.

[0060] The results of visual observation of the administration site of the normal skin group showed that the samples of Examples 1-3 in the experimental group and the samples of Comparative Examples 8-9 in the control group did not show any irritation reaction within 7 days, and no obvious visual abnormalities were observed at the administration site, and the histopathological phenomena were basically the same. The sample of Comparative Example 10 did not show any irritation reaction after administration for the first 4 days, but one rabbit began to show skin redness and swelling after administration on the 5th day.

[0061] The results of visual observation of the administration part of the damaged skin group showed that no irritation reaction occurred when the samples of Examples 1-3 of the experimental group were administered at various time points for 7 days, and the damaged skin wounds healed well; after administration of the samples of Comparative Examples 8-9 of the control group on the 7th day, it was found that the damaged skin wounds of 2 rabbits were slightly red and swollen, and the wounds healed generally; after administration of the sample of Comparative Example 10 on the 5th day, it was found that the damaged skin wounds of 2 rabbits were slightly red and swollen, and the wounds healed generally.

[0062] In summary, the samples of Examples 1-3 of the present invention are non-irritating to normal skin and damaged skin and can also promote wound healing of damaged skin, and the effects are significantly better than those of Comparative Examples 8-10 (i.e., the samples of Example CN111904926A, the commercially available product Voltaren, and the samples of Example CN102525886A).

[0063] Test Example 3: Stability Study

[0064] The samples of Examples 1-3 were subjected to stability tests respectively and placed in a stability test box at 40°C / 75%RH (accelerated conditions) for 6 months. The results of the key indicators tested are shown in Table 3.

[0065] Table 3 Accelerated stability test results

[0066]

[0067] The above results show that after being placed under accelerated conditions for 6 months, the key indicators of Examples 1-3 of the present invention are relatively stable, with no significant differences compared with 0 month.

[0068] Test Example 4: Investigating the effects of different amounts of organic solvents on product quality

[0069] The properties, skin feel, microscopic characteristics, centrifugal stability, heat and cold resistance, and weight loss of the topical diclofenac diethylamine compositions prepared in Examples 1-3 and Comparative Examples 1-4 were investigated, respectively. The results are shown in Table 4 below.

[0070] Table 4 Effect of different amounts of organic solvents on product quality

[0071]

[0072] As shown in Table 4, samples of Examples 1-3 of the present invention and samples of Comparative Examples 1-2 have no obvious quality problems, but samples of Comparative Examples 3 and 4 show non-uniformity during the hot and cold cycle and fail the quality inspection.

[0073] Test Example 5: Effects of different hydrogels on product quality

[0074] The properties, skin feel, microscopic characteristics, centrifugal stability, heat and cold resistance, and weight loss of the topical diclofenac diethylamine compositions prepared in Example 1 and Comparative Example 5 were investigated respectively. The results are shown in Table 5 below.

[0075] Table 5 Effect of different hydrogels on product quality

[0076]

[0077] It can be seen from Table 5 that there is basically no difference in quality between the hydrogel matrices using chitosan graphene and carbomer, but the weight loss rate of chitosan graphene hydrogel is higher than that of carbomer hydrogel, indicating that it is more conducive to the volatilization of organic solvents.

[0078] The above specific implementation methods are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to examples, a person skilled in the art should understand that the technical solution of the present invention can be modified or replaced by equivalents without departing from the scope of the technical solution of the present invention, which should be included in the scope of the claims of the present invention.

Claims

1. A pharmaceutical composition containing 2-((2,6-dichlorophenyl)amino)phenylacetic acid diethylamine, characterized in that: Calculated by mass percentage, the composition comprises: 1.5-3% diclofenac diethylamine, 40-50% organic solvent system, 1-2% aqueous gel matrix, 0.5-1.5% pH regulator, 4-5.5% oil phase matrix, 0.1-1.0% transdermal absorption enhancer, 0.01-0.035% antioxidant, 1.5-3% emulsifier, and the balance is purified water.

2. The pharmaceutical composition according to claim 1, characterized in that The organic solvent system comprises a volatile solvent and a non-volatile solvent, wherein the volatile solvent is selected from ethanol, isopropanol or a combination thereof, and the non-volatile solvent is selected from propylene glycol, glycerol or a combination thereof.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The organic solvent system is preferably ethanol, isopropanol and propylene glycol, wherein the mass percentage of ethanol is 10%-15%, the mass percentage of isopropanol is 15%-20%, and the mass percentage of propylene glycol is 13%-17%.

4. The pharmaceutical composition according to claim 1, characterized in that The aqueous gel matrix is ​​selected from carbomer, chitosan graphene hydrogel, cellulose derivatives, gelatin, alginate, and polyvinyl alcohol.

5. The pharmaceutical composition according to claim 1 or 5, characterized in that The aqueous gel matrix is ​​preferably chitosan graphene hydrogel.

6. The pharmaceutical composition according to claim 1, characterized in that The pH regulator is selected from sodium hydroxide, potassium hydroxide, diethylamine, triethanolamine, preferably diethylamine.

7. The pharmaceutical composition according to claim 1, characterized in that The oil phase matrix is ​​selected from white vaseline, liquid paraffin, triglyceride, coconut caprylate caprate, isopropyl myristate, isopropyl palmitate, preferably a mixture of liquid paraffin and coconut caprylate caprate, and the weight ratio of the liquid paraffin to coconut caprylate caprate is 1:

1.

8. The pharmaceutical composition according to claim 1, characterized in that The transdermal absorption enhancer is selected from azone, oleyl alcohol, oleic acid, menthol, preferably oleyl alcohol.

9. The pharmaceutical composition according to claim 1, characterized in that The antioxidant is selected from butylated hydroxytoluene, α-tocopherol, sodium thiosulfate, sodium sulfite, preferably butylated hydroxytoluene.

10. The pharmaceutical composition according to claim 1, characterized in that The emulsifier is selected from glyceryl monostearate, sodium lauryl sulfate, sodium dodecyl sulfate, cetumab 1000, polysorbate, and cetumab 1000 is preferred.

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