Dexketoprofen trometamol nasal spray and preparation method thereof

Abstract

The invention discloses a dexketoprofen trometamol nasal spray and a preparation method thereof, a buffering agent is used as a stabilizer, and the dexketoprofen trometamol nasal spray which is good in stability, small in irritation, convenient, rapid in effect taking and extremely small in side effect is provided, so that the medication compliance of patients and the convenience of clinical medication are improved; after being administrated, the nasal spray can be quickly absorbed through nasal mucosa, the absorption speed is equivalent to that of intramuscular injection, the nasal spray can quickly reach the peak concentration as intramuscular injection, and the curative effect can be quickly exerted; the preparation has the advantages of no first-pass effect during nasal mucosa administration, high bioavailability and rapid absorption, is suitable for self-rapid analgesia, and is stable in process and suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a dexketoprofen tromethamine nasal spray and a preparation method. BACKGROUND

[0002] Dexketoprofen tromethamine is an organic compound with a chemical formula of C 20 H 25 NO6, which is mainly used as an antipyretic analgesic and non-steroidal anti-inflammatory drug, and is used for all pain, the mechanism of action of which is mainly to reduce the synthesis of prostaglandins by non-selectively inhibiting cyclooxygenase (COX), and is suitable for short-term elimination of trauma and postoperative pain, swelling pain, severe pain and pain caused by various reasons.

[0003] At present, only dexketoprofen tromethamine tablets and injections are available on the domestic and foreign markets, and there is no nasal spray on the market. Tablets and injections can be used to relieve moderate to severe postoperative pain, including abdominal, chest, gynecological, oral, orthopedic and urological surgery. In addition, it can also relieve acute renal colic, biliary colic, toothache, trauma pain, trigeminal neuralgia, cancer visceral pain, and all previous pain that requires morphine or pethidine to be effective.

[0004] Intravenous injection is the first choice for relieving pain, however, intravenous injection must be administered by professional medical staff in a medical institution, and it is difficult for patients with sudden pain at home or other places to receive timely treatment on site.

[0005] Therefore, it is urgent to develop a stable pharmaceutical composition of dexketoprofen tromethamine suitable for immediate treatment of patients with sudden pain at home or in a simple condition, and a simple and easy preparation process, and the nasal administration route can avoid the degradation and metabolism of the drug by the gastrointestinal tract, avoid the liver first-pass effect, and is more beneficial to children, people who cannot swallow or are prone to vomiting, and has unique advantages and broad market prospects. The development of dexketoprofen tromethamine nasal spray can improve patient compliance, reduce morphine dosage, and reduce gastrointestinal complications. SUMMARY

[0006] In view of the deficiencies of traditional dexketoprofen tromethamine tablets and injections, the present application develops a new dosage form of dexketoprofen tromethamine nasal spray. The development of the product aims to provide a convenient, effective and rapid-acting analgesic choice for outpatients with acute moderate and severe pain. It provides a non-narcotic and easy-to-use product for outpatients with acute pain to replace commonly used opioid prescription drugs.

[0007] The purpose of the present application is to provide a dexketoprofen tromethamine nasal spray and a preparation method thereof on the basis of the prior art, so as to overcome the above-mentioned defects in the prior art.

[0008] To achieve the above object, the present application provides the following technical scheme.

[0009] The present application provides a dexketoprofen tromethamine nasal spray, characterized in that it contains 18%-50% of dexketoprofen tromethamine, 0.006%-0.012% of complexing agent, 0.1%-0.2% of buffer and 0.06%-0.8% of pH regulator, in terms of percentage by weight.

[0010] The percentages in the present application are all percentage by weight.

[0011] The dexketoprofen tromethamine nasal spray of the present application preferably contains 30%-40% of dexketoprofen tromethamine, 0.006%-0.012% of complexing agent, 0.13%-0.19% of buffer and 0.07%-0.3% of pH regulator.

[0012] Further, the complexing agent in the present application is sodium nitrilotriacetate, disodium edetate or diethylenetriaminepentaacetate, preferably disodium edetate.

[0013] Further, the buffer in the present application is one or more of anhydrous or crystalline water-containing phosphate, acetate, citrate, triethylamine and borax, preferably phosphate.

[0014] Further, the phosphate is one or more of phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, ammonium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate and zinc phosphate, preferably sodium phosphate, sodium dihydrogen phosphate, potassium phosphate and potassium dihydrogen phosphate, which can or can not contain crystalline water.

[0015] Further, the pH regulator is one or more of organic base, sodium hydroxide, potassium hydroxide, sodium citrate, diethanolamine and sodium bicarbonate, preferably sodium hydroxide.

[0016] Further, the pH value of the dexketoprofen tromethamine nasal spray of the present application is 7.0-8.0, preferably 7.0-7.5, most preferably 7.5.

[0017] In addition to dexketoprofen tromethamine, buffer and pH regulator, the dexketoprofen tromethamine nasal spray of the present application can also contain other additives contained in conventional dexketoprofen tromethamine injection.

[0018] The composition and content of the dexketoprofen tromethamine nasal spray of the present application are as follows:

[0019] Dexketoprofen tromethamine 18-50%

[0020] Sodium edetate 0.006 - 0.012%

[0021] Potassium phosphate monobasic 0.1 - 0.2%

[0022] Sodium hydroxide 0.06 - 0.8%

[0023] Water q.s. 100%

[0024] The pH of the above nasal spray is 7.0-8.0.

[0025] Further, the composition and content of the dexketoprofen tromethamine nasal spray of the present application are as follows:

[0026] Dexketoprofen tromethamine 30 - 40%

[0027] Sodium edetate 0.006 - 0.012%

[0028] Potassium phosphate monobasic 0.13 - 0.19%

[0029] Sodium hydroxide 0.07 - 0.3%

[0030] Water q.s. 100%

[0031] The pH of the above nasal spray is 7.0-7.5.

[0032] Further, the composition and content of the dexketoprofen tromethamine nasal spray of the present application are as follows:

[0033] Dexketoprofen tromethamine 34%

[0034] Sodium edetate 0.012%

[0035] Potassium phosphate monobasic 0.14%

[0036] Sodium hydroxide 0.3%

[0037] Water q.s. 100%

[0038] The pH of the above nasal spray is 7.5.

[0039] The present application also provides a method for preparing the dexketoprofen tromethamine nasal spray, characterized in that the specific operation steps of the dexketoprofen tromethamine nasal spray are as follows:

[0040] 1) Take dexketoprofen tromethamine, complexing agent, and buffer and add them into an appropriate amount of water, stir until dissolved, take pH adjuster and prepare an alkali solution with an appropriate amount of water, and reserve;

[0041] 2) Take the prepared alkali solution to adjust the pH of the prepared dexketoprofen tromethamine solution: add purified water to the prescribed amount, mix uniformly, filter the solution, fill, install the quantitative spray pump;

[0042] 3) Test the spray mode, spray shape and particle size distribution; routine foreign matter inspection; pH value inspection; content and related substance determination; labeling; packaging.

[0043] Further, the present application also provides a method for preparing the dexketoprofen tromethamine nasal spray, characterized in that the specific operation steps of the dexketoprofen tromethamine nasal spray are as follows:

[0044] 1) Take dexketoprofen tromethamine, complexing agent and buffer and add them into a proper amount of purified water, stir until dissolved, prepare an alkali solution with a proper amount of purified water using the pH value adjusting agent, and reserve;

[0045] 2) Take the prepared alkali solution to adjust the pH of the prepared dexketoprofen tromethamine solution to 7.5: add purified water to the prescribed amount, mix uniformly, filter the solution with 0.22 μm sterile filter, fill in the nasal spray device, and install the quantitative spray pump;

[0046] 3) Use Spray VIEW spray mode and spray shape analyzer and STP5315 spray particle size instrument to test the spray mode, spray shape and particle size distribution; perform routine foreign matter inspection including clarity, insoluble particle detection; pH value inspection; content and related substance determination; labeling; packaging.

[0047] Beneficial effects

[0048] The technical scheme of the present application has the following advantages:

[0049] 1. In view of the above-mentioned shortcomings of traditional dexketoprofen tromethamine injection and oral tablets, the present application provides a dexketoprofen tromethamine nasal spray with good stability, small irritation, convenience, rapid onset and minimal side effects by taking a buffer as a stabilizer, thereby improving patient medication compliance and clinical medication convenience.

[0050] 2. After nasal spray administration of the product, it can be rapidly absorbed through the nasal mucosa, and the absorption speed is equivalent to intramuscular injection, and the peak concentration can be reached as fast as intramuscular injection, so that the therapeutic effect can be rapidly exerted.

[0051] 3. The present application is a nasal mucosa administration without preservative and bacteriostatic agent sterile preparation, which avoids the damage of preservative and bacteriostatic agent to the nasal mucosa, and the product exerts local or systemic therapeutic or prophylactic effect through nasal mucosa absorption, and the nasal mucosa administration has no first-pass effect, high bioavailability, rapid absorption and is suitable for self rapid analgesia. BRIEF DESCRIPTION OF DRAWINGS

[0052] Figure 1 Mean plasma concentration-time curves of dexketoprofen tromethamine formulation after intranasal administration and intravenous injection DETAILED DESCRIPTION

[0053] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively and explain the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technical solutions achieved based on the above description of the present application are covered within the scope of the present application.

[0054] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0055] Example 1:

[0056] A: Spray composition

[0057]

[0058] B: Preparation method

[0059] Dexketoprofen tromethamine, disodium edetate, potassium dihydrogen phosphate were added into a beaker in sequence, and a part of purified water was added to dissolve and stir, and the amount of purified water was recorded. After dissolution, 25% sodium hydroxide solution was used to adjust the pH value of the solution to 7.50, and the amount of 25% sodium hydroxide solution was recorded. Then the solution was transferred to a volumetric flask, purified water was added to the beaker to constant volume, and the amount of purified water was recorded.

[0060] Example 2:

[0061] A: Spray composition

[0062]

[0063]

[0064] B: Preparation method

[0065] Dexketoprofen tromethamine, disodium edetate, potassium dihydrogen phosphate were added into a beaker in sequence, and a part of purified water was added to dissolve and stir, and the amount of purified water was recorded. After dissolution, 25% sodium hydroxide solution was used to adjust the pH value of the solution to 7.00, and the amount of 25% sodium hydroxide solution was recorded. Then the solution was transferred to a volumetric flask, purified water was added to the beaker to constant volume, and the amount of purified water was recorded.

[0066] Example 3:

[0067] A: Spray composition

[0068]

[0069] B: Preparation method

[0070] Into a beaker, add dexketoprofen tromethamine, edetate disodium, potassium dihydrogen phosphate in turn, and add a part of purified water to dissolve and stir, record the amount of purified water; after dissolving, use 25% sodium hydroxide solution to adjust the pH value of the solution to 8.00, record the amount of 25% sodium hydroxide solution; and transfer the solution to a volumetric flask, add purified water to the beaker to constant volume, record the amount of purified water.

[0071] Example 4:

[0072] A: Spray composition

[0073]

[0074] B: Preparation method

[0075] Into a beaker, add dexketoprofen tromethamine, edetate disodium, potassium dihydrogen phosphate in turn, and add a part of purified water to dissolve and stir, record the amount of purified water; after dissolving, use 25% sodium hydroxide solution to adjust the pH value of the solution to 7.50, record the amount of 25% sodium hydroxide solution; and transfer the solution to a volumetric flask, add purified water to the beaker to constant volume, record the amount of purified water.

[0076] Example 5:

[0077] A: Spray composition

[0078]

[0079] B: Preparation method

[0080] Into a beaker, add dexketoprofen tromethamine, edetate disodium, potassium dihydrogen phosphate in turn, and add a part of purified water to dissolve and stir, record the amount of purified water; after dissolving, use 25% sodium hydroxide solution to adjust the pH value of the solution to 7.50, record the amount of 25% sodium hydroxide solution; and transfer the solution to a volumetric flask, add purified water to the beaker to constant volume, record the amount of purified water.

[0081] Example 6:

[0082] A: Spray composition

[0083]

[0084] B: Preparation method

[0085] Into a beaker, add dexketoprofen trometamol, disodium edetate, potassium dihydrogen phosphate, and a portion of purified water to dissolve and stir. Record the amount of purified water used. After dissolving, use 25% sodium hydroxide solution to adjust the pH of the solution to 7.50. Record the amount of 25% sodium hydroxide solution used. Transfer the solution to a volumetric flask, add purified water to the beaker to the mark, and record the amount of purified water used.

[0086] Example 7:

[0087] A: Spray composition

[0088]

[0089]

[0090] B: Preparation method

[0091] Into a beaker, add dexketoprofen trometamol, disodium edetate, potassium dihydrogen phosphate, and a portion of purified water to dissolve and stir. Record the amount of purified water used. After dissolving, use 25% sodium hydroxide solution to adjust the pH of the solution to 7.51. Record the amount of 25% sodium hydroxide solution used. Transfer the solution to a volumetric flask, add purified water to the beaker to the mark, and record the amount of purified water used.

[0092] Example 8: Analgesic effect of dexketoprofen trometamol nasal spray on writhing test in rats

[0093] Intravenous administration and nasal administration:

[0094] The model control group was intravenously injected with the solvent and then intraperitoneally injected with 0.6% acetic acid solution. The test substance intravenous administration group was intravenously administered with different concentrations of compound solution and then immediately intraperitoneally injected with 0.6% acetic acid solution. The test substance nasal administration group was administered with different concentrations of compound solution by nose drop and then intraperitoneally injected with 0.6% acetic acid solution after 10 min. The administration volume of intravenous and nose drop administration was 10 mL / kg and 20 μL / kg, respectively, and the administration volume of intraperitoneal injection of 0.6% acetic acid solution was 5 mL / kg. Intraperitoneal injection of acetic acid would cause abdominal depression, stretching of the body and hind limbs, and writhing in rats, etc. The number of writhing within 30 min was observed and recorded. The writhing inhibition rate of the test compound and the IC 50 of the test substance for inhibiting the number of writhing were calculated. % of writhing inhibition rate = (number of writhing of the model group - number of writhing of the administration group) / number of writhing of the model group x 100%.

[0095] Results:

[0096]

[0097] Example 9: Spray test of dexketoprofen trometamol nasal spray

[0098] 1 Instruments and reagents

[0099] 1.1 Instruments

[0100] XPR404S / A electronic balance (METTLER TOLEDO); BT124S electronic balance (Beijing Sartorius Instrument System Co., Ltd.); Orion 3Star pH meter (Thermo SCIENTIFIC); Agilent 1260 high performance liquid chromatograph (Agilent Technology); Spray VIEW spray pattern and spray morphology analyzer (Proveris); STP5313 Spraytec spray particle size analyzer (MALVERN PANALYTICAL LIMITED); NSx automatic press trigger (Proveris); Triple Quad TM 5500 + - Ready liquid chromatograph-mass spectrometer (SCIEX Company).

[0101] 1.2 Reagents

[0102] Droxicam tromethamine; disodium edetate; potassium dihydrogen phosphate; sodium hydroxide; isoflurane; sodium chloride injection; acetic acid.

[0103] 2 Methods and results

[0104] 2.1 Formulation and process

[0105] 2.1.1 Formulation

[0106] The active ingredient in the formulation is droxicam tromethamine, and the inactive ingredients include disodium edetate, potassium dihydrogen phosphate, sodium hydroxide, and purified water. The formulation is shown in Table 1:

[0107] Table 1 Formulation of droxicam tromethamine nasal spray

[0108]

[0109] 2.1.2 Process

[0110] The prescribed amount of droxicam tromethamine, disodium edetate, potassium dihydrogen phosphate, and purified water was precisely weighed into a beaker, and ultrasonic was used to dissolve it. A 25% (w / w) sodium hydroxide solution was added to adjust the pH value to 7.0, 7.5, or 8.0, obtaining an intermediate liquid. Then, a certain amount of the intermediate liquid was filled into a quantitative spray pump to obtain the finished product of droxicam tromethamine nasal spray.

[0111] 2.2 Characterization of spray properties

[0112] 2.2.1 Number of discarded sprays

[0113] 2.2.1.1 Preparation of test solution

[0114] Each quantitative spray pump was filled with 2 ml of the test solution, and was placed upright on the automatic press trigger. The trigger was activated to spray vertically into a 100 ml volumetric flask. Water was immediately added to dilute to the calibration mark, and the mixture was shaken to obtain the test solution for the first spray. The test solution for the second spray was prepared in the same manner. The interval between each spray was at least 5 seconds, and the sprays were collected continuously up to the 20th spray.

[0115] 2.2.1.2 Preparation of control solution

[0116] About 3.69 mg of the dexketoprofen tromethamine control sample was accurately weighed into a 10 ml volumetric flask, and was dissolved and diluted with water to the calibration mark. The mixture was shaken to obtain the control solution.

[0117] 2.2.1.3 Chromatographic conditions

[0118] The filler was octadecylsilane-bonded silica gel (Agilent Eclipse XDB-C18, 4.6 mm x 150 mm, 5 μm or a chromatographic column with equivalent performance); the mobile phase was phosphate buffer-acetonitrile-water (2:43:55); the flow rate was 1 ml per minute; the detection wavelength was 255 nm; and the column temperature was 30°C.

[0119] 2.2.1.4 Detection method and results

[0120] Ten μl of each of the test solution and the control solution described above was injected into the liquid chromatograph, and the chromatogram was recorded. The detection results are shown in Table 2.

[0121] Table 2 Drug content per spray of dexketoprofen tromethamine nasal spray

[0122]

[0123] As shown in Table 2, the dexketoprofen content in the 4th spray was 95.8%. To ensure that the amount of drug delivered per spray is sufficient, the product was discarded for 5 sprays before use, and the filling amount was adjusted to 1.7 g per pump, and the number of labeled sprays was 6.

[0124] 2.2.2 Spray pattern

[0125] 2.2.2.1 Parameters for setting the spray pattern and spray pattern analyzer

[0126] Camera parameters: camera position 5.0 cm, camera height 24.0 cm, lens aperture 2.0; laser parameters: laser position 9.0 cm, laser depth 5.5 cm; spray distance 30 mm.

[0127] 2.2.2.2 Automatic press trigger setting parameters

[0128] Contact force: 0.3 kg; driving speed: 70 mm / s; driving acceleration: 3000 mm / s 2 ; holding time 100 ms.

[0129] 2.2.2.3 Detection method and results

[0130] Take one of each prescription dexketoprofen tromethamine nasal spray (1.7 g of liquid medicine is filled in each fixed dose spray pump) on the automatic press trigger, discard the first 5 sprays, detect the spray pattern at a distance of 30 mm from the driver nozzle, detect continuously for three times, take the average of the three times as the detection result, the results are shown in Table 3.

[0131] Table 3 Spray pattern detection results of dexketoprofen tromethamine nasal spray of each prescription

[0132]

[0133] From Table 3, the spray pattern of each prescription dexketoprofen tromethamine nasal spray at a distance of 30 mm from the driver nozzle is an oval with relatively uniform density, and the ovality is between 1.250-1.389, among which the D max The detection results are basically consistent, the D max of prescription 6 is relatively small, and the D max of prescription 7 is relatively large.

[0134] 2.2.3 Spray pattern

[0135] 2.2.3.1 Spray pattern and spray pattern analyzer setting parameters

[0136] Camera parameters: camera position 30.0 cm, camera height 10.0 cm, lens aperture 2.0; laser parameters: laser position 9.0 cm, laser height 13.3 cm, laser depth 5.5 cm; spray distance 60 mm.

[0137] 2.2.3.2 Automatic press trigger setting parameters

[0138] Contact force: 0.3 kg; driving speed: 70 mm / s, driving acceleration: 3000 mm / s 2 , holding time: 100 ms.

[0139] 2.2.3.3 Detection method and results

[0140] Take each prescription dexketoprofen tromethamine nasal spray (1.7 g of liquid medicine per branch of the metered dose pump) 1 branch on the automatic press trigger, discard the first 5 spray, detect its spray pattern at a distance of 60 mm from the driver nozzle, detect three times in succession, take the average of three times as the detection result, the results are shown in Table 4.

[0141] Table 4 Spray pattern detection results of dexketoprofen tromethamine nasal spray of each prescription

[0142]

[0143] Table 4 shows that the spray angle of dexketoprofen tromethamine nasal spray of prescription 1-5 at a distance of 60 mm from the driver nozzle is between 16.7-19.4 deg, and the spray width is between 18.54-20.64 mm. Compared with prescription 1-5, the spray angle and spray width of prescription 6 are smaller, and the spray angle and spray width of prescription 7 are larger.

[0144] 2.2.4 Droplet size distribution

[0145] 2.2.4.1 Spray particle size instrument setting parameters

[0146] Acquisition frequency: 2.5 KHz; lens: 30 mm; test time: 400 ms; measurement trigger: transmittance drops to a certain value; light transmittance: 90%; nozzle to lens distance: 15 cm; spray distance: 40 mm; spray angle: 20°; analysis window: stable period.

[0147] Drive parameters: contact force 0.3 kg; drive speed 70 mm / s; drive acceleration 3000 mm / s 2 ; holding time 100 ms.

[0148] 2.2.4.3 Detection method and results

[0149] Take each prescription dexketoprofen tromethamine nasal spray (1.7 g of liquid medicine per branch of the metered dose pump) 1 branch on the automatic press trigger, discard the first 5 spray, detect its droplet size distribution at a distance of 40 mm from the driver nozzle, detect three times in succession, analyze the data in the spray stable period, take the average of three times as the detection result, the results are shown in Table 5:

[0150] Table 5 Droplet size distribution detection results of dexketoprofen tromethamine nasal spray of each prescription

[0151]

[0152] As shown in Table 5, the droplet size distribution Dv10 of the formulations 1-5 at a distance of 40 mm from the driver orifice is between 34.1-39.3 μm, Dv50 is between 105.9-130.2 μm, Dv90 is between 290.7-334.1 μm, and Span is between 2.3-2.4; compared with the formulations 1-5, the droplet size of the formulation 6 is larger, and the droplet size of the formulation 7 is smaller.

[0153] Example 10: In vivo pharmacokinetic study and in vivo pharmacodynamic study of dexketoprofen tromethamine nasal spray

[0154] Formulation 1 is selected as the test drug formulation.

[0155] 1.1.2 Test animals

[0156] Male SD rats, weighing in the range of 200-250 g, 4 in each of the nasal administration group and the intravenous administration group, SPF level, Shanghai Jihui Experimental Animal Breeding Co., Ltd.

[0157] 1.1.3 Test design and results

[0158] Eight male SD rats are selected and randomly divided into two groups. After being anesthetized with isoflurane, dexketoprofen tromethamine formulations are administered by nasal administration and intravenous injection respectively, and the dose is 2 mpk. Plasma is collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 7 h and 24 h after administration, and the concentration of dexketoprofen in the plasma is detected. The average plasma concentration-time curves of dexketoprofen tromethamine formulations after nasal administration and intravenous injection are shown in Figure 1 Table 6 shows the pharmacokinetic parameters.

[0159] Table 6: Pharmacokinetic parameters of dexketoprofen tromethamine formulations after nasal administration and intravenous injection

[0160] Parameters Nasal instillation Intravenous injection T max (h)]]> 0.08±0.00 / C max (ng / mL) 11130.00±24.06 15650.60±7.75 t 1 / 2 (h)]]> 20.77±46.68 17.70±25.00 AUC (inf) (ng·h / mL) 75214.92±34.10 62690.27±16.20 AUC (0-t) (ng·h / mL)]]> 40772.23±14.70 39875.01±14.88

[0161] It can be seen that, after nasal administration of dexketoprofen tromethamine, T max is only 0.08 h, absorption is rapid, and the bioavailability is close to that of intravenous injection.

[0162] 1.2 In vivo pharmacodynamic study

[0163] 1.2.1 Test drug formulation

[0164] Formulation 1 is selected as the test drug formulation.

[0165] 1.2.2 Test animals

[0166] SD rats, body weight range 250-300g, 12 in each of control group, intranasal administration group and intragastric administration group, half male and half female.

[0167] 1.2.3 Test design and results

[0168] Control group: intravenous injection of sodium chloride injection, followed by intraperitoneal injection of 0.6% acetic acid solution (dose: 5 mL / kg) ;

[0169] Intragastric administration group: intragastric administration of different doses of dexketoprofen tromethamine preparation 30 min before intraperitoneal injection of 0.6% acetic acid solution (dose: 5 mL / kg) ;

[0170] Intranasal administration group: intranasal administration of different doses of dexketoprofen tromethamine preparation 10 min before intraperitoneal injection of 0.6% acetic acid solution (dose: 5 mL / kg).

[0171] Intraperitoneal injection of acetic acid will cause rats to have abdominal depression, body and hind limb stretching and peristalsis, etc. Twisting reaction, observe and record the number of writhing within 30 min. Calculate the writhing inhibition rate of dexketoprofen tromethamine

writhing inhibition rate % = (control group writhing times - administration group writhing times) / control group writhing times × 100%

[0172] Table 7: Results of dexketoprofen tromethamine writhing inhibition rate and IC50 under different administration routes

[0173]

[0174] From the above test results, the IC50 under intragastric administration route is 0.78 mg / kg, and the IC50 under intranasal administration route is 0.37 mg / kg. Compared with intragastric administration, intranasal administration has better analgesic effect, the main reasons are as follows: dexketoprofen tromethamine needs to be metabolized by the liver after intragastric administration, and part of the active ingredients is degraded, while intranasal administration directly enters the systemic circulation, avoiding the first pass effect and reducing metabolic loss. In addition, the nasal spray is specially designed to be evenly distributed on the surface of the nasal mucosa, which can also improve the absorption efficiency of the drug.

[0175] The formulation of the present application has a good fitting image ellipticity of spray mode, the sample is stable and uniform, and the repeatability is good; the spray angle and width of the fitting image at 60mm of the spray form are good, the sample is stable and uniform, and the repeatability is good; the droplet size results measured by using the Aptar multi-dose nasal spray pump show that the DV(10), DV(50) and DV(90) particle size distributions of different samples of the same batch are uniform, the Span has no obvious change, the sample is stable and uniform; the clarity (Chinese Pharmacopoeia 2020 edition four chapters 0901, 0902) is clear and colorless; the insoluble particles meet the requirements; the pH value is between 7.0-8.0; the content and related substances determined by high performance liquid chromatography (Chinese Pharmacopoeia 2020 edition four chapters 0512) meet the requirements.

[0176] The above is a description of specific embodiments of the present application. It should be understood that the present application is not limited by the above embodiments, and the above embodiments and descriptions in the specification are only to illustrate the principles of the present application.

[0177] The present application also has various non-essential changes and improvements without departing from the concept of the present application, which fall within the scope of the present application.

Claims

1. A dexketoprofen tromethamine nasal spray, characterized by, It contains 18%-50% dexketoprofen tromethamine, 0.006%-0.012% complexing agent, 0.1%-0.2% buffer and 0.06%-0.8% pH regulator by weight percentage.

2. The dexketoprofen tromethamine nasal spray according to claim 1, wherein, It contains 30-40% dexketoprofen tromethamine, 0.006%-0.012% complexing agent, 0.13%-0.19% buffer and 0.07%-0.3% pH regulator by weight percentage.

3. The dexketoprofen atrometica nasal spray according to claim 1, characterized in that, The complexing agent is sodium nitrilotriacetate, disodium edetate or diethylenetriamine pentaacetate, preferably disodium edetate.

4. The dexketoprofen atrometica nasal spray according to claim 1, wherein, The buffer is one or more of anhydrous or crystalline water-containing phosphate, acetate, citrate, triethylamine or borax, preferably phosphate.

5. The dexketoprofen atrometica nasal spray according to claim 4, characterized by, The phosphate is one or more of phosphoric acid, sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, ammonium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate, zinc phosphate, preferably sodium phosphate, sodium dihydrogen phosphate, potassium phosphate or potassium dihydrogen phosphate, which can or can not contain crystalline water.

6. The dexketoprofen tromethamine nasal spray of claim 1, wherein, The pH regulator is one or more of organic base, sodium hydroxide, potassium hydroxide, sodium citrate, diethanolamine or sodium bicarbonate, preferably sodium hydroxide.

7. The dexketoprofen tromethamine nasal spray according to claim 1, wherein, The pH regulator adjusts the pH to 7.0-8.0, preferably 7.0-7.5, most preferably 7.

5.

8. The dexketoprofen atsuginol nasal spray according to any one of claims 1 to 7, wherein, The composition and content are as follows:

9. The dexketoprofen atsuginol nasal spray according to any one of claims 1 to 8, wherein, The composition and content are as follows:

10. The dexketoprofen atsuginol nasal spray according to any one of claims 1 to 9, wherein, The specific operation steps of the dexketoprofen tromethamine nasal spray are as follows: 1) Take dexketoprofen tromethamine, complexing agent and buffer, add an appropriate amount of water, stir to dissolve, take pH regulator, prepare alkali solution with an appropriate amount of water, and reserve; 2) Take the prepared alkali solution to adjust the pH of the prepared dexketoprofen tromethamine solution: add water to the prescribed amount, mix evenly, filter the solution, fill, and install a quantitative spray pump; 3) Test the spray mode, spray shape and particle size distribution; routine foreign matter inspection; pH test; content and related substance determination; labeling; packaging.

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