A kind of ketorolac tromethamine injection

Abstract

The invention discloses a ketorolac tromethamine injection; specifically, the invention provides a pharmaceutical composition, which includes ketorolac tromethamine, L-cysteine, an osmotic pressure regulator, a pH regulator and water; the concentration of the L-cysteine ​​is ≥0.2 mg / mL; the pH of the pharmaceutical composition is 7.0-8.5. The injection of the invention is non-allergenic, non-hemolytic, low irritant, comparable to negative control saline, has higher stability and lower irritation, and has a wider range of applications.

Description

Technical Field

[0001] The invention relates to ketorolac tromethamine injection. Background Art

[0002] Currently, there are a variety of ketorolac tromethamine preparations on the market, including injections, tablets, eye drops, and nasal sprays. The normal treatment regimen for ketorolac tromethamine injection for moderate to severe postoperative or postoperative pain, acute musculoskeletal pain, chronic pain states, postpartum or labor pain, and post-traumatic pain includes two to three injections per day. Ketorolac tromethamine injection is the first nonsteroidal injectable analgesic approved for the treatment of acute pain. It can be administered systemically in the form of intramuscular injection (30–60 mg) or intravenous injection (15–30 mg). Since its launch, it has been widely used due to its excellent antipyretic, analgesic and anti-inflammatory effects.

[0003] The existing ketorolac tromethamine injections available in China and abroad contain 10% (w / w) ethanol in their prescriptions. However, ethanol is highly irritating in clinical use, especially when injected intramuscularly. When used in combination with morphine and other injections, it affects the absorption and metabolism of morphine. When used in combination with cephalosporin antibiotics, disulfiram reaction may occur. At the same time, patients who are allergic to ethanol cannot use this injection. These problems greatly limit the clinical application of this injection. Summary of the invention

[0004] The technical problem to be solved by the present invention is that the prescription of ketorolac tromethamine injection currently marketed at home and abroad has the defects of high irritation, poor stability and limited clinical application. The present invention provides a ketorolac tromethamine injection, which has lower irritation and higher stability than the marketed product.

[0005] The present invention solves the above technical problems through the following technical methods.

[0006] The present invention provides a pharmaceutical composition, which comprises ketorolac tromethamine, L-cysteine, an osmotic pressure regulator, a pH regulator and water;

[0007] The concentration of L-cysteine ​​is ≥0.2 mg / mL;

[0008] The pH of the pharmaceutical composition is 7.0-8.5;

[0009] The concentration refers to the ratio of the mass of a component in a pharmaceutical composition to the volume of the pharmaceutical composition.

[0010] The concentration of ketorolac tromethamine is the conventional dosage of such pharmaceutical compositions in the art. Preferably, the concentration of ketorolac tromethamine is 20-50 mg / mL, and more preferably, the concentration of ketorolac tromethamine is 30 mg / mL.

[0011] In some embodiments, the concentration of L-cysteine ​​is 0.2-1 mg / mL, preferably, the concentration of L-cysteine ​​is 0.25 mg / ml, 0.5 mg / mL, 0.75 mg / mL or 1 mg / ml.

[0012] The osmotic pressure regulator can be a conventional one of this type of pharmaceutical composition in the art. Preferably, the osmotic pressure regulator is selected from one or more of mannitol, glucose, sodium chloride and sodium bicarbonate. More preferably, the osmotic pressure regulator is sodium chloride.

[0013] The concentration of the osmotic pressure regulator may be the conventional concentration of such pharmaceutical compositions in the art. Preferably, the concentration of the osmotic pressure regulator is 4-5 mg / ml; more preferably, the concentration of the osmotic pressure regulator is 4.35 mg / ml.

[0014] The pH adjuster can be conventional for such pharmaceutical compositions in the art. Preferably, the pH adjuster is selected from one or more of sodium acetate, sodium hydroxide, disodium hydrogen phosphate and sodium bicarbonate. More preferably, the pH adjuster is sodium hydroxide.

[0015] In some embodiments, the pH adjuster is used to adjust the pH of the pharmaceutical composition to between 7.5 and 8.5. Preferably, the pH adjuster is used to adjust the pH of the pharmaceutical composition to 8.0.

[0016] The water can be conventional water for such pharmaceutical compositions in the art. Preferably, the water is distilled water or water for injection; more preferably, the water is water for injection.

[0017] In some embodiments, the pharmaceutical composition is an injection, preferably, the injection is for intravenous injection or intramuscular injection.

[0018] In some embodiments, the pharmaceutical composition comprises or consists of any of the following:

[0019] Option 1:

[0020]

[0021] Option 2:

[0022]

[0023] Option 3:

[0024]

[0025] Option 4:

[0026]

[0027] Option 5:

[0028]

[0029] Option 6:

[0030]

[0031] Option 7:

[0032]

[0033] The present invention also provides a pharmaceutical composition, the raw materials of which include ketorolac tromethamine, L-cysteine, an osmotic pressure regulator, a pH regulator and water;

[0034] Wherein, the concentration of L-cysteine ​​is ≥0.2 mg / mL;

[0035] The pH of the pharmaceutical composition is 7.0-8.5.

[0036] In some embodiments, the pharmaceutical composition is prepared by the following preparation method, which comprises the following steps:

[0037] Ketorolac tromethamine is added to the aqueous solution in which L-cysteine ​​and an osmotic pressure regulator are dissolved, the pH is adjusted to 7.0-8.5 using a pH regulator, and then diluted with water.

[0038] In some embodiments, the preparation method comprises the following steps:

[0039] (1) weighing the L-cysteine, the osmotic pressure regulator and a portion of the water for injection and dissolving them;

[0040] (2) adding the ketorolac tromethamine and dissolving it;

[0041] (3) adding a pH adjuster to adjust the pH to 7.0-8.5;

[0042] (4) Fixed volume;

[0043] (5) Filter

[0044] (6) Filling, nitrogen filling and sealing;

[0045] (7) Sterilization;

[0046] (8) Packaging.

[0047] The sterilization method used for the sterilization can be a conventional sterilization method in the art. Preferably, the sterilization method used for the sterilization includes one or more of filtration sterilization, overkilling method (F0≥12) and residual probability method (8≤F0<12). More preferably, the sterilization method used for the sterilization is overkilling method, such as heating at 121°C for 15 minutes.

[0048] In some embodiments, the nitrogen filling method is headspace nitrogen filling or full nitrogen filling. Preferably, the nitrogen filling method is headspace nitrogen filling.

[0049] In some embodiments, the nitrogen-filled sealing method is to control the residual oxygen level in the headspace to be less than 2% and then seal immediately.

[0050] In some embodiments, the filtering method is filtering through a 0.22 μm PES microporous filter.

[0051] In some embodiments, the injection inner packaging container is made of brown glass; preferably, the injection inner packaging container is selected from one or more of a brown ampoule, a brown cartridge and a brown controlled injection bottle, and more preferably, the injection inner packaging container is a brown ampoule.

[0052] In some embodiments, the preparation method of the pharmaceutical composition is the following steps:

[0053] (1) Prepare a solution by taking an appropriate amount of water for injection, adding sodium chloride and L-cysteine ​​and stirring to dissolve, adding ketorolac tromethamine and stirring until dissolved, and finally adding water for injection to make up the volume, and adjusting the pH to between 7.0 and 8.5 with sodium hydroxide;

[0054] (2) Filtration: The drug solution is filtered through a 0.22 μm PES microporous filter;

[0055] (3) Nitrogen filling and sealing: the filtered liquid intermediate is quantitatively filled into a Cangzhou Sixing ampoule (brown) at a volume of 1.1 mL, and the headspace nitrogen filling method is adopted to control the headspace residual oxygen level within 2%, and the ampoule is immediately sealed;

[0056] (4) Sterilization: terminal sterilization is performed by overkilling method of heating at 121°C for 15 minutes.

[0057] In some embodiments, the pharmaceutical composition is used for antipyretic, analgesic or anti-inflammatory purposes.

[0058] The present invention also provides a pharmaceutical composition, the raw materials of which include ketorolac tromethamine, L-cysteine, an osmotic pressure regulator, a pH regulator and water;

[0059] Wherein, the concentration of L-cysteine ​​is ≥0.2 mg / mL;

[0060] The pH of the pharmaceutical composition is 7.0-8.5.

[0061] In some embodiments, the amounts and definitions of ketorolac tromethamine, L-cysteine, osmotic pressure regulator, pH regulator and water are as described in any of the preceding items.

[0062] In some embodiments, the method for preparing the pharmaceutical composition is as described in any of the preceding items.

[0063] In some embodiments, the pharmaceutical composition is used for antipyretic, analgesic or anti-inflammatory purposes.

[0064] The present invention also provides a method for preparing a pharmaceutical composition, wherein the conditions and operations are as described in any of the preceding items; preferably, the raw materials of the pharmaceutical composition are as described in any of the preceding items.

[0065] The present invention also provides a use of any of the above-mentioned pharmaceutical compositions in preparing an injection.

[0066] In some embodiments, the injection is for intravenous or intramuscular injection.

[0067] In some embodiments, the injection is used for antipyretic, analgesic or anti-inflammatory purposes.

[0068] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0069] The reagents and raw materials used in the present invention are commercially available.

[0070] The positive and progressive effects of the present invention are as follows: the present invention discloses a low-irritation ketorolac tromethamine injection, the injection of the present invention is non-allergenic, non-hemolytic, low-irritating, comparable to negative control physiological saline, has higher stability and lower irritation, and has a wider range of applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0071] Figure 1 This is a photo of muscle tissue section two days after intramuscular injection. DETAILED DESCRIPTION

[0072] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0073] Example 1 Preparation of injection

[0074] Prescription 1:

[0075]

[0076] The preparation method comprises the following steps:

[0077] (1) Weigh the prescribed amount of L-cysteine, osmotic pressure regulator and part of the prescribed amount of water for injection and dissolve them;

[0078] (2) adding the prescribed amount of ketorolac tromethamine and dissolving;

[0079] (3) adding an aqueous solution of an alkalizing agent to adjust the pH to 8.5;

[0080] (4) Add distilled water to make up to 1 ml;

[0081] (5) Filling, nitrogen filling and sealing: The liquid medicine obtained in (4) is quantitatively filled into a Cangzhou Sixing ampoule bottle (brown), and the headspace nitrogen filling method is adopted to control the headspace residual oxygen level within 2%, and the ampoule is immediately sealed;

[0082] (6) Sterilization: terminal sterilization is performed by overkilling by heating at 121°C for 15 min;

[0083] (7) Leak detection and light inspection;

[0084] (8) Packaging.

[0085] Example 2

[0086] Using the same preparation method as in Example 1, injections were prepared according to prescriptions E1-E5;

[0087]

[0088] Example 3

[0089] Using the same preparation method as in Example 1, injections were prepared according to prescriptions F1-F6;

[0090]

[0091] Comparative Example 1

[0092] Using the same preparation method as in Example 1, the following injections were prepared according to the following prescriptions: Prescription 2:

[0093]

[0094] Prescription 3:

[0095]

[0096] Prescription 4:

[0097]

[0098] Prescription 5

[0099]

[0100] Prescription 6

[0101]

[0102] Prescription 7

[0103]

[0104] Effect Example 1

[0105] The test sample was dissolved in a solvent and diluted to make a solution containing about 0.4 mg per 1 ml for detection. The HPLC related substance detection method of ketorolac tromethamine raw material is as follows:

[0106]

[0107] The structural formula and limits of impurities in ketorolac tromethamine injection are as follows:

[0108]

[0109] The injections prepared in Example 1 and Comparative Example 1 were placed under light (5000 Lx, 83 uw / cm 2 , 10D) and 100℃ for 24h, then take out and detect related substances. The results of prescriptions 1-7 are shown in the following table:

[0110]

[0111]

[0112] The only difference between prescription 7 and prescriptions 2-6 is the stabilizer. Prescription 7 contains L-cysteine. The results show that in the stability tests of the preparations of prescription 7 under light for 10 days and at 60℃ for 30 days, the growth of the maximum single impurity content and the total impurity content are much smaller than those of prescriptions 2-6, which proves that L-cysteine ​​is better than stabilizers such as citric acid and ethanol as a stabilizer. Prescription 1 adjusts the pH, reduces the basic impurity content in the preparation, and obtains a stable ketorolac tromethamine injection formula suitable for industrial production.

[0113] The test results of prescriptions E1-E5 are as follows:

[0114]

[0115]

[0116] The test results of prescriptions F1-F6 are as follows:

[0117]

[0118] The only difference between prescriptions F1-F6 is the different pH values ​​adjusted by sodium hydroxide. The results show that the quality of the prescription is stable when the pH of the preparation is 7.0-8.5.

[0119] Effect Example 2

[0120] According to the Technical Guidelines for Drug Irritation, Allergy and Hemolysis Research, rats (SD rats, male, Shanghai Bikaikoyi Biotechnology Co., Ltd.) were selected as experimental animals, and a normal saline control group was set up. The same body left and right side self-comparison method was used. The observation time was selected according to the characteristics of the test substance and the irritation reaction. At the end of the observation period, some animals should be subjected to histopathological examination. The drugs were injected into the quadriceps femoris and upper limb muscles on both sides, respectively, with 0.5 ml of prescription 2 injection (prescription 2 group), 1.0 ml of positive control preparation (1.7w / v% acetic acid solution) (acetic acid solution group), 0.5 ml of prescription F4 injection (prescription F4 group) and 0.5 ml of 0.9% sodium chloride solution (normal saline group), and local reactions at different times after administration, such as congestion, redness and swelling, were observed. 48 hours and 14 days after administration, the irritation reaction at the injection site was observed by autopsy, and the corresponding reaction level was calculated. Local tissue pathology examination was performed, and the muscle tissue at the injection site was placed in 4% paraformaldehyde solution, embedded in paraffin, sliced, and then stained with hematoxylin and eosin for pathological examination and photographed under a microscope. Pay attention to observe whether there is irritation reaction at the injection site, and organize pathological examination.

[0121] Observation was performed 2 days after intramuscular injection of each group of injection solutions. The muscle tissue slices were shown in the following figure. Figure 1 shown.

[0122] The observation results showed that the cross-section of the muscle tissue in the normal saline group showed several muscle fiber bundles with clear boundaries. The muscle fibers in the muscle bundles were closely arranged, most of them had an angular appearance, and typical light and dark alternating striations were visible, with no obvious abnormalities. In the muscle tissue of the prescription 2 group, small areas of necrosis, nuclear dissolution, and decreased cytoplasmic eosinophilia (black arrows) were visible, and mild edema was visible in the interstitium, the distance between muscle cells increased, and the connective tissue was loosely arranged (yellow arrows), accompanied by a small amount of lymphocyte infiltration (blue arrows). The cross-section of the muscle tissue in the prescription F4 group showed several muscle fiber bundles with clear boundaries. The muscle fibers in the muscle bundles were closely arranged, most of them had an angular appearance, and typical light and dark alternating striations were visible, with no obvious abnormalities. In the control group of the 1.7w / v% acetic acid solution group, mild edema was visible in the interstitium of the muscle tissue, the connective tissue was loosely arranged (black arrows), mild bleeding was visible (red arrows), a small amount of vascular congestion was visible (orange arrows), and a small amount of scattered lymphocyte infiltration (blue arrows).

[0123] The results showed that the ketorolac tromethamine injection of prescription 2 had obvious muscle irritation after injection, while the ketorolac tromethamine injection of prescription 1 had no obvious muscle irritation. Therefore, the ketorolac tromethamine injection of prescription F4 is safer and less irritating.

[0124] Effect Example 3 Allergy Evaluation

[0125] Take mice (BALB / c mice, SPF grade, female, Shanghai Bikeway Biotechnology Co., Ltd.) 2 were randomly divided into 3 groups, 4 in each group, including ketorolac tromethamine injection group, 0.9% sodium chloride injection group (negative control group), and ovalbumin group (positive control group).

[0126] Allergy establishment: The ketorolac tromethamine injection group was given prescription F4 ketorolac tromethamine injection, with a single dose of 0.5 ml (30 mg / ml) per mouse, the ovalbumin group was given ovalbumin, with a single dose of 0.5 ml of 10% ovalbumin solution, and the sodium chloride injection group was given 0.5 ml of 0.9% sodium chloride solution per mouse. Sensitization was induced by intraperitoneal injection every other day, for a total of 3 times.

[0127] Allergic attack: The attack was performed by a single rapid intravenous injection of double doses of injection solution on the 14th and 21st days after the last administration. The animal symptoms were observed daily during the sensitization period, and the animals were weighed before the first administration, the last sensitization, and the challenge. The animal reaction was observed immediately after the challenge for 30 minutes, including the time when the symptoms appeared and disappeared, and the observation was at least 3 hours for evaluation and grading. The evaluation criteria for allergic reaction are shown in the following table.

[0128]

[0129] The results of the allergy test are shown in the following table:

[0130]

[0131] The mice in the normal saline group and the ketorolac tromethamine group had no obvious reaction, and all the mice in the ovalbumin group died. The experiment showed that the prescription F4 ketorolac tromethamine injection had no sensitization phenomenon and was evaluated as safe.

[0132] Effect Example 4 Hemolytic Test

[0133] Take 10ml of rat (SD rat, male, Shanghai Bikekeyi Biotechnology Co., Ltd.) heart blood, put it into a beaker rinsed with 0.9% sodium chloride injection, stir the blood with a glass rod to remove fibrinogen, and make it defibrinated blood. Add about 10 times the amount of physiological saline to the defibrinated blood, centrifuge at 1000rmp for 10min, remove the supernatant, and wash the precipitated red blood cells with physiological saline repeatedly according to the above method until the supernatant is no longer red. Take 4ml of precipitated red blood cells, add it to a 200ml volumetric flask, and dilute to the scale with physiological saline for use.

[0134] Add the corresponding reagents according to the table below and repeat three times.

[0135] Place in a 37°C oven and take out after 1h, 2h, and 3h respectively.

[0136] Centrifuge at 1200 rpm for 15 min, take the supernatant, and measure the absorbance at a wavelength of 545 nm.

[0137] Table of dosage of different components in hemolysis test (n=3):

[0138]

[0139] Observe the colors of different test tubes. The saline group should not have hemolysis, and the solution color should be colorless to light pink. The pure water group has complete hemolysis, and the solution color should be red. The test group should not have hemolysis, and the color should be close to the color of the saline group.

[0140] The absorbance of the supernatant after centrifugation was measured at 545 nm, and the measurement was repeated three times to obtain the average value. The hemolysis rate was calculated according to the formula.

[0141] Hemolysis rate = (A t -A nc ) / (A pc -A nc )×100%

[0142] A t is the sample absorbance, A nc is the absorbance of the negative control, i.e. the absorbance of the saline test tube, A pc is the absorbance of the positive control, that is, the absorbance of the pure water test tube.

[0143] The judgment standard is that the hemolysis rate is less than 5%, which means that the drug is safe and does not produce hemolysis.

[0144] Experimental results:

[0145] According to naked eye observation, the 1h result shows that the test tubes added with ketorolac tromethamine solution all show that the red blood cells sink, and the supernatant is transparent, and the test tube added with pure water is a red solution, showing complete hemolysis. The 2h result shows that the test tubes added with ketorolac tromethamine solution all show that the red blood cells sink, and the supernatant is transparent, and the test tube added with pure water is a red solution, showing complete hemolysis. The 3h result shows that the test tubes added with ketorolac tromethamine solution all show that the red blood cells sink, and the supernatant is transparent, and the test tube added with pure water is a red solution, showing complete hemolysis.

[0146] The absorbance under different conditions was measured and the hemolysis rate was calculated. The specific test results are shown in the following table.

[0147] Hemolysis rate of different added amounts of ketorolac tromethamine injection (n=3):

[0148]

[0149] The hemolysis rates of different ketorolac tromethamine additions were compared and compared with the normal saline group and the pure water group. The experimental results showed that the prescription F4 ketorolac tromethamine solution was not hemolytic.

Claims

1. A pharmaceutical composition, characterized in that It includes ketorolac tromethamine, L-cysteine, an osmotic pressure regulator, a pH regulator and water; The concentration of L-cysteine ​​is ≥0.2 mg / mL; The pH of the pharmaceutical composition is 7.0-8.

5.

2. The pharmaceutical composition according to claim 1, characterized in that It meets one or more of the following conditions: (1) The concentration of ketorolac tromethamine is 20-50 mg / mL; for example, 30 mg / mL; (2) The osmotic pressure regulator is selected from one or more of mannitol, glucose, sodium chloride and sodium bicarbonate. Preferably, the osmotic pressure regulator is sodium chloride; (3) The concentration of the osmotic pressure regulator is 4-5 mg / ml; preferably, the concentration of the osmotic pressure regulator is 4.35 mg / ml; (4) The pH adjuster is selected from one or more of sodium acetate, sodium hydroxide, disodium hydrogen phosphate and sodium bicarbonate. Preferably, the pH adjuster is sodium hydroxide; (5) The water is distilled water or water for injection; preferably, the water is water for injection; (6) The pharmaceutical composition is an injection, preferably, the injection is for intravenous injection or intramuscular injection; (7) The pharmaceutical composition is used for antipyretic, analgesic or anti-inflammatory purposes.

3. The pharmaceutical composition according to claim 1, characterized in that The concentration of L-cysteine ​​is 0.2-1 mg / mL, preferably, the concentration of L-cysteine ​​is 0.25 mg / ml, 0.5 mg / mL, 0.75 mg / mL or 1 mg / ml.

4. The pharmaceutical composition according to claim 1, characterized in that The pH of the pharmaceutical composition is between 7.5 and 8.5, preferably, the pH of the pharmaceutical composition is 8.

0.

5. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition comprises or consists of any of the following: Solution 1: Option 2: Option 3: Option 4: Option 5: Option 6: Option 7:

6. A pharmaceutical composition, characterized in that Its raw materials include ketorolac tromethamine, L-cysteine, an osmotic pressure regulator, a pH regulator and water; Wherein, the concentration of L-cysteine ​​is ≥0.2 mg / mL; The pH of the pharmaceutical composition is 7.0-8.

5.

7. The pharmaceutical composition according to claim 6, characterized in that The concentrations of the ketorolac tromethamine, L-cysteine, osmotic pressure regulator, pH regulator and water are independently as described in any one of claims 1-3; the definitions of the osmotic pressure regulator, pH regulator and water are independently as described in any one of claims 1-3.

8. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition is prepared by the following preparation method, which comprises the following steps: Ketorolac tromethamine is added to the aqueous solution in which L-cysteine ​​and an osmotic pressure regulator are dissolved, the pH is adjusted to 7.0-8.5 using a pH regulator, and then diluted with water.

9. The pharmaceutical composition according to claim 8, characterized in that The preparation method comprises the following steps: (1) weighing the L-cysteine, the osmotic pressure regulator and a portion of the water and dissolving them; (2) adding the ketorolac tromethamine and dissolving it; (3) Add a pH adjuster to adjust the pH to 7.0-8.5 and dilute with water.

10. A method for preparing a pharmaceutical composition, characterized in that: The conditions and operations of the preparation method of the pharmaceutical composition are as described in claim 8 or 9; preferably, the raw materials of the pharmaceutical composition are as described in claim 6 or 7.

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