A kind of ketoprofen gel and preparation method thereof

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and in particular to a ketoprofen gel and a preparation method thereof. The ketoprofen gel of the present invention is composed of ketoprofen, tragacanth gum, thioglycerol, L-phenylalanine, glycerol triacetate, ethanol, an antibacterial agent, and water. By optimizing the prescription and improving the preparation process, the transdermal effect is improved, the skin irritation is small, and the moisture retention performance and content stability of the ketoprofen gel are significantly improved.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a ketoprofen 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] Ketoprofen is a nonsteroidal anti-inflammatory analgesic, also known as ibuprofen ketone. Its functions and indications include: (1) Analgesic effect: Ketoprofen can effectively relieve mild to moderate pain, including headache, toothache, joint pain, muscle pain, etc. It reduces the synthesis of prostaglandins, including prostaglandin E2 (PGE2), by inhibiting COX. This prostaglandin can sensitize nerve endings and cause pain. Ketoprofen reduces the synthesis of prostaglandins and thus reduces the pain. (2) Anti-inflammatory effect: Ketoprofen can relieve pain and discomfort caused by inflammation. It is suitable for inflammatory diseases such as arthritis and rheumatoid arthritis. Ketoprofen exerts its anti-inflammatory effect by inhibiting the activity of cyclooxygenase (COX). COX is a key enzyme involved in the synthesis of arachidonic acid (arachidonic acid). (3) Antipyretic effect: Ketoprofen also has the effect of lowering body temperature and is suitable for discomfort caused by fever. During fever, white blood cells release prostaglandin E2 (PGE2). PGE2 causes body temperature to rise by affecting the hypothalamic temperature regulation center. Ketoprofen reduces the stimulation of PGE2 on the hypothalamic temperature regulation center by inhibiting the synthesis of PGE2, thereby alleviating the symptoms of fever.

[0004] Transdermal drug delivery is a non-invasive way to deliver drugs into the body through the skin. Unlike traditional direct drug delivery routes, transdermal drug delivery does not require the use of needle injections and does not involve passing through the gastrointestinal tract. Small molecule drugs can usually use intracellular pathways to pass through the epidermal stratum corneum, so there will be no first-pass metabolism that leads to drug loss, and drugs can be delivered without interference from pH, enzymes, and intestinal bacteria.

[0005] Ketoprofen gel is a topical medication that contains ketoprofen as the main active ingredient. It acts directly on the skin surface and local tissues through application and massage, thereby penetrating the skin and releasing ketoprofen at the site of inflammation. It is used for local treatment of pain and inflammation, and can be used specifically to treat inflammatory diseases such as arthritis and rheumatoid arthritis.

[0006] Chinese patent publication number CN103156803A discloses a ketoprofen gel and a preparation method thereof, which is prepared from the following components: 2% to 5% ketoprofen, 0.5% to 2% matrix material, 2% to 4% transdermal enhancer, 0.5% to 5% neutralizer, 0.05% to 0.2% antioxidant, 20% to 50% ethanol, and the remainder is water.

[0007] Chinese patent publication number CN110693860A discloses a ketoprofen-containing gel patch and a preparation method thereof, wherein the prescription includes ketoprofen or a pharmaceutically acceptable salt thereof, an aqueous polymer compound, a moisturizer, a thickener, and the like.

[0008] The existing ketoprofen gels all have the disadvantages of poor transdermal effect and easy decomposition of the main components, especially under light, making them more unstable. Summary of the invention

[0009] The disadvantages of the prior art are overcome, and the present invention provides a ketoprofen gel with good transdermal effect, low irritation, stable content and good quality.

[0010] Specifically, the ketoprofen gel provided by the present invention is composed of the following components: 2 to 4 parts by weight of ketoprofen, 1 to 3 parts by weight of tragacanth gum, 0.5 to 1.5 parts by weight of thioglycerol, 0.5 to 1 parts by weight of L-phenylalanine, 1 to 5 parts by weight of glycerol triacetate, 10 to 15 parts by weight of ethanol, 0.01 to 0.2 parts by weight of an antibacterial agent, and water.

[0011] It should be noted that the antibacterial agent in the gel plays the role of maintaining the sterility of the product, preventing cross infection, extending the service life of the product and enhancing the safety of the product. It can be selected from one or more of benzyl alcohol, chlorobutanol, ethylparaben, benzalkonium bromide, propylparaben, sorbic acid, chlorocresol, hydroxypropylmethyl ester and phenylmercuric nitrate. It is a routine experimental operation for those skilled in the art to ensure that it is within the safe dosage range.

[0012] In one embodiment, the ketoprofen gel is composed of the following components: 3 parts by weight of ketoprofen, 2.5 parts by weight of tragacanth gum, 1 part by weight of monothioglycerol, 0.7 parts by weight of L-phenylalanine, 2.5 parts by weight of glycerol triacetate, 12 parts by weight of ethanol, 0.1 parts by weight of ethylparaben, and water.

[0013] In one embodiment, the ketoprofen gel is composed of the following components: 2 parts by weight of ketoprofen, 2 parts by weight of tragacanth gum, 0.8 parts by weight of thioglycerol, 0.8 parts by weight of L-phenylalanine, 2 parts by weight of glycerol triacetate, 13 parts by weight of ethanol, 0.05 parts by weight of phenylmercuric nitrate, and water.

[0014] According to the dosage and specifications of the medicine, the mass fraction of the ketoprofen gel is 2.0% to 3.0%.

[0015] In order to improve the stability of ketoprofen gel, the present invention also provides a method for preparing the above ketoprofen gel:

[0016] (1) Mix tragacanth gum, thioglycerol, glycerol triacetate, and L-phenylalanine, add an appropriate amount to swell, add disodium hydrogen phosphate-citric acid buffer with a pH of 2.5 to 4.5, stir, and keep warm in a water bath at 35° C. to 50° C. for 4 to 8 hours to obtain a colloid intermediate;

[0017] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding a buffer to adjust the pH to 5.5-6.5, and adding a preservative to obtain a gel matrix;

[0018] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the gel matrix.

[0019] The buffer solution in step (2) is selected from at least one of carbonate buffer, phosphate buffer and citrate buffer, which is a routine operation for those skilled in the art.

[0020] In one embodiment, the method for preparing ketoprofen gel comprises the following steps:

[0021] (1) Mix tragacanth gum, thioglycerol, glycerol triacetate, and L-phenylalanine, add an appropriate amount to swell, add disodium hydrogen phosphate-citric acid buffer with a pH of 3.5, stir, and keep in a water bath at 40° C. for 6 hours to obtain a colloid intermediate;

[0022] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding citrate buffer to adjust the pH to 5.0, and adding a preservative to obtain a gel matrix;

[0023] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the product. The pH in step (1) is 3.5.

[0024] Compared with the prior art, the technical effects of the present invention are:

[0025] The ketoprofen gel of the present invention has good transdermal effect and low irritation through optimized prescription and improved preparation process, and animal experiments prove that the active ingredient content is stable in accelerated tests. In particular, L-phenylalanine in a certain dosage range is added to the prescription to effectively stabilize the active ingredient ketoprofen, and the innovative improved preparation method significantly improves the moisture retention performance and content stability of the ketoprofen gel by adjusting pH twice. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1It is the cumulative penetration amount of the active ingredients of the ketoprofen gels of Examples 1 to 4 and Comparative Examples 1 to 6.

[0027] Figure 2 It is the transdermal absorption rate of the active ingredient of the ketoprofen gel of Examples 1 to 4 and Comparative Examples 1 to 6.

[0028] Figure 3 The skin retention amounts of the ketoprofen gels of Examples 1 to 4 and Comparative Examples 1 to 6.

[0029] Figure 4 This is the water loss of ketoprofen gel A~H.

[0030] Figure 5 The water loss of ketoprofen gel in groups I to K.

[0031] Figure 6 This is the content change chart of ketoprofen gel in groups A to K in the accelerated test.

[0032] Figure 7 This is the effect of L-phenylalanine on the content of active ingredients in ketoprofen gel. DETAILED DESCRIPTION

[0033] 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.

[0034] Example 1 Ketoprofen gel

[0035] formula:

[0036]

[0037]

[0038] Add water to 100ml

[0039] Preparation method:

[0040] (1) Mix tragacanth gum, thioglycerol, glycerol triacetate, and L-phenylalanine, add an appropriate amount to swell, add disodium hydrogen phosphate-citric acid buffer with a pH of 3.5, stir, and keep in a water bath at 40° C. for 6 hours to obtain a colloid intermediate;

[0041] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding citrate buffer to adjust the pH to 5.0, and adding a preservative to obtain a gel matrix;

[0042] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the gel matrix.

[0043] Embodiment 2 Ketoprofen gel

[0044] formula:

[0045]

[0046] Add water to 100ml

[0047] Preparation method:

[0048] (1) Mix tragacanth gum, thioglycerol, glycerol triacetate, and L-phenylalanine, add an appropriate amount to swell, add disodium hydrogen phosphate-citric acid buffer with a pH of 3.5, stir, and keep in a water bath at 40° C. for 6 hours to obtain a colloid intermediate;

[0049] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding citrate buffer to adjust the pH to 5.0, and adding a preservative to obtain a gel matrix;

[0050] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the gel matrix.

[0051] Example 3 Ketoprofen gel

[0052] formula:

[0053]

[0054]

[0055] Add water to 100ml

[0056] Preparation method:

[0057] (1) Mix tragacanth gum, thioglycerol, glycerol triacetate, and L-phenylalanine, add an appropriate amount to swell, add disodium hydrogen phosphate-citric acid buffer with a pH of 2.5, stir, and keep in a water bath at 30°C for 4 hours to obtain a colloid intermediate;

[0058] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding carbonate buffer to adjust the pH to 5.5, and adding a preservative to obtain a gel matrix;

[0059] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the gel matrix.

[0060] Embodiment 4 Ketoprofen gel

[0061] formula:

[0062]

[0063] Add water to 100ml

[0064] Preparation method:

[0065] (1) Mix tragacanth gum, thioglycerol, glycerol triacetate, and L-phenylalanine, add an appropriate amount to swell, add disodium hydrogen phosphate-citric acid buffer with a pH of 4.5, stir, and keep in a water bath at 50°C for 8 hours to obtain a colloid intermediate;

[0066] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding phosphate buffer to adjust the pH to 6.5, and adding a preservative to obtain a gel matrix;

[0067] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the gel matrix.

[0068] Comparative Example 1 Ketoprofen gel

[0069] formula:

[0070]

[0071] Add water to 100ml

[0072] Preparation method:

[0073] (1) Mix tragacanth gum, thioglycerol, and glycerol triacetate, add an appropriate amount to swell, add disodium hydrogen phosphate-citric acid buffer with a pH of 3.5, stir, and keep in a water bath at 40° C. for 6 hours to obtain a colloid intermediate;

[0074] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding citrate buffer to adjust the pH to 5.0, and adding a preservative to obtain a gel matrix;

[0075] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the gel matrix.

[0076] Comparative Example 2 Ketoprofen Gel

[0077] formula:

[0078]

[0079] Add water to 100ml

[0080] Preparation method:

[0081] (1) Mix tragacanth gum, thioglycerol, glycerol triacetate, and tryptophan, add an appropriate amount to swell, add disodium hydrogen phosphate-citric acid buffer with a pH of 3.5, stir, and keep in a water bath at 40° C. for 6 hours to obtain a colloid intermediate;

[0082] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding citrate buffer to adjust the pH to 5.0, and adding a preservative to obtain a gel matrix;

[0083] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the gel matrix.

[0084] Comparative Example 3 Ketoprofen Gel

[0085] formula:

[0086]

[0087] Add water to 100ml

[0088] Preparation method:

[0089] (1) Mix tragacanth gum, thioglycerol, glycerol triacetate, and L-phenylalanine, add an appropriate amount to swell, add disodium hydrogen phosphate-citric acid buffer with a pH of 3.5, stir, and keep in a water bath at 40° C. for 6 hours to obtain a colloid intermediate;

[0090] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding citrate buffer to adjust the pH to 5.0, and adding a preservative to obtain a gel matrix;

[0091] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the gel matrix.

[0092] Comparative Example 4 Ketoprofen Gel

[0093] formula:

[0094]

[0095] Add water to 100ml

[0096] Preparation method:

[0097] (1) Mix tragacanth gum, thioglycerol, glycerol triacetate, and L-phenylalanine, add an appropriate amount of swelling agent, stir, and keep in a water bath at 40° C. for 6 hours to obtain a colloid intermediate;

[0098] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding citrate buffer to adjust the pH to 5.0, and adding a preservative to obtain a gel matrix;

[0099] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the gel matrix.

[0100] Comparative Example 5 Ketoprofen Gel

[0101]

[0102] Add water to 100ml

[0103] Preparation method:

[0104] (1) Mix tragacanth gum, thioglycerol, glycerol triacetate, and L-phenylalanine, add an appropriate amount to swell, add disodium hydrogen phosphate-citric acid buffer solution with a pH of 3.5, and stir to obtain a colloid intermediate;

[0105] (2) adding ethanol to the colloid intermediate to dilute it, cooling it to room temperature, adding citrate buffer to adjust the pH to 5.0, and adding a preservative to obtain a gel matrix;

[0106] (3) Add ketoprofen to the gel matrix and stir evenly to obtain the gel matrix.

[0107] Comparative Example 6 Commercially available ketoprofen gel (approval number H20150425)

[0108] Transdermal permeation experiment of ketoprofen gel

[0109] Experimental animals

[0110] SD rats, SPF grade, 180-220 g, experimental animal license number: SYXK(Lu)20180008, were adaptively raised for one week before the experiment.

[0111] Experimental procedure: 8% sodium sulfide solution was used to depilate rats, and the rats were fed for 24 hours and then killed. The abdominal skin was taken, subcutaneous fat was removed, and the rats were washed with physiological saline. The surface moisture was removed by filter paper. The skin was fixed between the receiving pool and the supply pool. The supply pool was precisely measured with equal volumes of ketoprofen gels of Examples 1 to 5 and ketoprofen gels of Comparative Example 6, and evenly applied to the skin. The application area and time were the same to ensure the consistency of the experiment. The stratum corneum of the skin was facing upward, and the physiological saline in the receiving pool was the receiving solution, and the receiving solution just contacted the dermis of the skin, and the rats were placed in a (37±0.5)°C constant temperature water bath and stirred at a speed of 200r / min. 5mL samples were taken at 2, 4, 8, 12, and 24h, and equal volumes of physiological saline were added at the same time. The taken out receiving solution was filtered through a microporous filter membrane, 20 μL was injected, the peak area was recorded, the ketoprofen concentration was calculated, and the cumulative permeation amount (Q) was calculated. The cumulative permeation amount of ketoprofen was used as an indicator to study the transdermal absorption rate of ketoprofen gel through a transdermal absorption test.

[0112]

[0113] 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 ).

[0114] After the in vitro permeation test, the rat skin was removed, the surface was washed, dried, cut into pieces, 5 mL of pH 7.4 phosphate buffer was added, homogenized, centrifuged at 5000 r·min-1 for 5 min, the supernatant was taken, filtered with a 0.22 μm filter membrane, and the filtrate was taken and the ketoprofen content in the skin was determined by high performance liquid chromatography, and the skin retention of ketoprofen gel was determined.

[0115] Figure 1 It is the cumulative penetration amount of the active ingredients of the ketoprofen gels of Examples 1 to 4 and Comparative Examples 1 to 6. Figure 2 It is the transdermal absorption rate of the active ingredient of the ketoprofen gel of Examples 1 to 4 and Comparative Examples 1 to 6. Figure 3 The skin retention amount of ketoprofen gel of Examples 1 to 4 and Comparative Examples 1 to 6. The experimental results show that the ketoprofen gel of Examples 1 to 4 of the present invention can improve the transdermal efficiency of the active ingredient ketoprofen, increase the concentration of the drug in the target tissue, increase the retention amount of the active ingredient in the skin, and are more conducive to its continuous good therapeutic effect in the skin and its deep tissues, thereby improving the therapeutic effect.

[0116] Irritation test of ketoprofen gel

[0117] Experimental animals: SD rats, SPF grade, 180-220g, experimental animal license number: SYXK (Lu) 20180008, adaptive feeding for one week before the experiment. Skin irritation test method: Rats were randomly divided into a negative control group, ketoprofen gel of Examples 1 to 5, and ketoprofen gel of comparative example 6, with 10 rats in each group. The hair was removed in the middle of the back 24 hours before the test, and the hair removal range was about 5cm×5cm for each rat. Before administration, the depilated skin was checked for damage and tested. Each group of drugs was applied to the depilated skin, applied continuously for 8 hours, and the skin reaction was observed under natural light. Whether the skin was red and swollen was used as the investigation index, and the local skin reaction was observed 0.5h, 1h, 6h, 12h, 24h, 48h, and 72h after administration. The results are as follows:

[0118] Table 1 Ketoprofen gel skin irritation test

[0119]

[0120] The results showed that the ketoprofen gels of Examples 1 to 5 of the present invention did not cause erythema and edema after application, had little irritation to the skin, and had market application value.

[0121] Experimental study on the preparation method of ketoprofen gel of the present invention

[0122] The other parameters in the prescription and preparation method are the same as those in Example 1. The following are the variables in each group:

[0123] Group A: Add sodium hydrogen phosphate-citric acid buffer with a pH of 2.2 in step (1)

[0124] Group B: Add sodium hydrogen phosphate-citric acid buffer with a pH of 2.5 in step (1)

[0125] Group C: Add sodium hydrogen phosphate-citric acid buffer with a pH of 3.0 in step (1)

[0126] Group D: Add sodium hydrogen phosphate-citric acid buffer with a pH of 4.0 in step (1)

[0127] Group E: Add sodium hydrogen phosphate-citric acid buffer with a pH of 4.5 in step (1)

[0128] Group F: Add sodium hydrogen phosphate-citric acid buffer with a pH of 5.0 in step (1)

[0129] Group G: Add sodium hydrogen phosphate-citric acid buffer with a pH of 5.5 in step (1)

[0130] Group H: Add sodium hydrogen phosphate-citric acid buffer with a pH of 6.0 in step (1)

[0131] Group I: Same as Example 4

[0132] Group J: Same as Example 5

[0133] Group K: The water bath temperature in step (1) was 60°C

[0134] The ketoprofen gel prepared in groups A to H was stored in an oven at (30±1)°C, room temperature at (23±1)°C, and refrigerator at (5±1)°C for 7 days, respectively. The gel was weighed before and after the experiment, and the water loss rate was calculated to determine the water loss of the ketoprofen gel. Figure 4 The water loss of A~H ketoprofen gel, Figure 5 The water loss of ketoprofen gel in groups I to K. The analysis shows that the first pH adjustment and heat preservation measures in the preparation method have an impact on the moisture retention stability of ketoprofen gel.

[0135] The ketoprofen gel prepared by the above-mentioned groups A to K was packaged in commercial packaging and subjected to an accelerated test at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5%. The ketoprofen content was tested by sampling at the first day, the end of the second month, the end of the third month, and the end of the sixth month. The test was performed according to the high performance liquid chromatography method (General Rule 0512) of the Chinese Pharmacopoeia. Test solution: Accurately measure an appropriate amount of this product and quantitatively dilute it with the mobile phase to prepare a solution containing about 0.1 mg of ketoprofen per 1 ml. Reference solution: Take an appropriate amount of ketoprofen reference substance, accurately weigh it, dissolve it in the mobile phase, and quantitatively dilute it to prepare a solution containing about 0.1 mg per 1 ml. Chromatographic conditions: octadecylsilane bonded silica gel is used as filler; phosphate buffer (6.8g potassium dihydrogen phosphate is taken, dissolved in water and diluted to 100ml, and the pH value is adjusted to 3.5+0.1 with phosphoric acid)-acetonitrile-water (2:43:55) is used as mobile phase; detection wavelength is 255nm; injection volume is 10μl. System suitability requirements: The number of theoretical plates calculated based on the ketoprofen peak is not less than 2000. Determination method: Accurately measure the test solution and the reference solution, inject them into the liquid chromatograph respectively, and record the chromatogram. Calculate by peak area according to the external standard method. Figure 6 This is the content change chart of ketoprofen gel in groups A to K in the accelerated test.

[0136] It should be noted that the results of the water loss test and the accelerated test of the effective ingredient content change test of the ketoprofen gel in Examples 1 to 4 are similar to the experimental results of Groups B to E, and all have good stability, low water loss rate, and high content stability. Only some experimental data are listed below:

[0137] Figure 7 The graphs are the changes in the content of the active ingredient of the ketoprofen gel in the accelerated test of Example 1, Comparative Example 1 and Comparative Example 2. It shows that the addition of an appropriate amount of L-phenylalanine can stabilize ketoprofen.

Claims

1. A ketoprofen gel, characterized in that: The ketoprofen gel is composed of the following components: 2-4 parts by weight of ketoprofen, 1-3 parts by weight of tragacanth gum, 0.5-1.5 parts by weight of thioglycerol, 0.5-1 parts by weight of L-phenylalanine, 1-5 parts by weight of glycerol triacetate, 10-15 parts by weight of ethanol, 0.01-0.2 parts by weight of an antibacterial agent, and water.

2. Ketoprofen gel according to claim 1, characterized in that, The antibacterial agent is selected from benzyl alcohol, chlorobutanol, ethylparaben, benzalkonium bromide, propylparaben, sorbic acid, chlorocresol, hydroxypropylmethyl ester, and phenylmercuric nitrate.

3. Ketoprofen gel according to claim 1, characterized in that, The ketoprofen gel is composed of the following components: 3 parts by weight of ketoprofen, 2.5 parts by weight of tragacanth gum, 1 part by weight of thioglycerol, 0.7 parts by weight of L-phenylalanine, 2.5 parts by weight of glycerol triacetate, 12 parts by weight of ethanol, 0.1 parts by weight of ethylparaben, and water.

4. The ketoprofen gel according to claim 1, characterized in that The ketoprofen gel is composed of the following components: 2 parts by weight of ketoprofen, 2 parts by weight of tragacanth gum, 0.8 parts by weight of thioglycerol, 0.8 parts by weight of L-phenylalanine, 2 parts by weight of glycerol triacetate, 13 parts by weight of ethanol, 0.05 parts by weight of phenylmercuric nitrate, and water.

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