Pharmaceutical composition of levoketorolac and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition of levoketorolac and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The pharmaceutical composition comprises levoketorolac or pharmaceutically acceptable salts thereof, a stabilizer, a pH regulator and an excipient, preferably freeze-dried powder injection. After the freeze-dried powder injection prepared by the method disclosed by the invention is placed for 6 months under a long-term stability test condition, the optical purity of the active ingredients is greater than or equal to 95%; after the freeze-dried powder injection is placed for 6 months under an accelerated stability test condition, the optical purity of the active component is greater than or equal to 90%. The freeze-dried powder injection has important application in preparation of non-steroidal anti-inflammatory drugs with the effects of easing pain, diminishing inflammation, relieving fever and the like.

Description

Technical Field

[0001] The invention relates to a levoketorolac pharmaceutical composition and a preparation method thereof, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Ketorolac Tromethamine is a nonsteroidal antipyretic analgesic with a special structure of pyrrolic acid derivatives. It was first developed and marketed by Syntex Corporation in the United States. It achieves analgesic, anti-inflammatory and antipyretic effects by inhibiting the synthesis of prostaglandins (PGs), rather than acting on opioid receptors or stimulating the release of opioid peptides in the body. Ketorolac Tromethamine can relieve poisoning pain in various muscles, soft tissues and joints. It is suitable for short-term treatment of acute and severe pain that requires opioid analgesics. It is usually used for postoperative analgesia, but not for the treatment of mild or chronic pain. The drug is non-addictive. In a standard analgesic activity animal model, the analgesic activity of ketorolac Tromethamine is 800 times that of aspirin, much stronger than indomethacin and naproxen, and better than phenylbutazone. Compared with opioid analgesics, ketorolac has the advantages of rapid onset, no addiction, no central nervous system damage, no adverse reactions such as respiratory depression or constipation, and long duration of action. The combined use of ketorolac and morphine can reduce the dosage of morphine and reduce the adverse reactions and addiction caused by morphine.

[0003] The dosage forms of ketorolac tromethamine used in clinical practice in China mainly include tablets, capsules, injections and eye drops. There is also a nasal spray on the market in the United States. In addition, the topical preparations of ketorolac, such as gels, have gradually attracted the attention of researchers.

[0004] Ketorolac tromethamine injection has been widely used in clinical postoperative analgesia and other fields due to its rapid analgesic effect. There are two main formulations of ketorolac tromethamine injection currently available at home and abroad: one is potassium dihydrogen phosphate as a pH regulator, represented by the products of Yongxin Pharmaceutical Industry (Kunshan) Co., Ltd.; the other is ethanol as a stabilizer, which is used by most companies. However, ketorolac tromethamine injection contains ethanol as a cosolvent and stabilizer in the traditional prescription. During long-term storage, with the inevitable volatility of ethanol, white spots or crystals still precipitate, affecting quality indicators such as visible foreign matter and insoluble particles, and there are safety hazards in clinical use. In addition, when used in combination with cephalosporin antibiotics, a disulfiram reaction may occur, resulting in a decrease in blood pressure, an accelerated heartbeat, or partial changes in the electrocardiogram of the patient. Therefore, ketorolac tromethamine injection containing ethanol has safety hazards.

[0005] Chinese patent CN101199514A improves the clarity of ketorolac tromethamine injection by adding 10-60% propylene glycol to the traditional prescription, and improves the white spots after sterilization. However, the preparation uses propylene glycol as a solvent, and the adverse stimulation caused by the current use of propylene glycol cannot be avoided, which is not conducive to the promotion and application of the drug, and the related substances increase rapidly.

[0006] Chinese patent CN102846542A improves the clarity of the injection after placement by adding glycerol to the prescription, and also adds poloxamer 188, hoping to improve both the clarity and placement stability of the injection. However, since cholesterol, oleic acid, sodium oleate, glycerol or poloxamer 188 are selected as stabilizers, cholesterol, oleic acid, etc. are easily oxidized; poloxamer, as a surfactant, has certain hemolytic and sensitizing properties and has the risk of hemolysis and sensitization, which can easily cause safety issues.

[0007] The active pharmaceutical ingredients reported in the marketed preparations and open literature are all ketorolac tromethamine, and its acid radical ketorolac is a racemate, which is composed of equal amounts of left ketorolac and right ketorolac. Ketorolac easily causes serious adverse reactions such as systemic allergy, gastrointestinal perforation, gastric bleeding, asthma, pulmonary edema, and renal failure. These serious side effects limit the dosage and medication time of ketorolac in pain treatment. As its effective single isomer, left ketorolac can reduce the renal metabolic burden brought by right ketorolac without analgesic effect, which may be a development exploration to reduce adverse reactions.

[0008] The optical rotation value of levoketorolac is negative, and the stereo configuration is the S-type enantiomer. The structure is shown in the following formula I compound. Levoketorolac exerts the main analgesic effect. The optical rotation value of dexketorolac is positive, and the stereo configuration is the R-type enantiomer. Dexketorolac has almost no analgesic effect, which may be one of the reasons why ketorolac causes more adverse reactions. The structure is shown below.

[0009] The search and development of single isomer drugs of ketorolac has also attracted increasing attention from researchers.

[0010]

[0011] Studies have shown that the efficacy of left ketorolac is much stronger than that of right ketorolac. The analgesic efficacy of left ketorolac is 230 times that of right ketorolac, and the anti-inflammatory efficacy of left ketorolac is 60 times that of right ketorolac. Therefore, if a single S-isomer is used for administration, the dosage can be reduced by nearly half compared with the administration of the racemic body under the condition of producing the same efficacy, thereby reducing toxic and side effects. Therefore, it is meaningful to obtain an optically active S-isomer. Left ketorolac undergoes conversion to different degrees between left and right ketorolac in mice and rats, and the proportion of left ketorolac converted to right ketorolac in the human body is less than or equal to 6.5% (see document J Cln Pharmacol 1996; 36: 521-539). A single preparation of left ketorolac has the advantages of reduced dosage, better efficacy and better safety, and has broad development prospects.

[0012] Ketorolac has a unique chemical structure, namely the pyrrolopyrrolidine heterocycle, which is different from common aromatic propionic acid non-steroidal anti-inflammatory drugs, such as ibuprofen. The chiral center of levoketorolac is located on this special pyrrolopyrrolidine heterocycle, which makes the molecule very easy to racemize when the temperature rises, especially in solution, to produce more isomeric impurities, dextroketorolac.

[0013] Chinese patent CN108451909A reports that "ketorolac tromethamine is unstable to light, heat, acid and alkali, and is prone to decarboxylation and oxidation reactions to produce impurities, which to a certain extent affects the safety of clinical medication." Gu et al. (International Journal of Pharmaceutics, 1988, 41, 105-113) reported that ketorolac tromethamine generates an oxidized intermediate (originally marked as impurity 2) through the mechanism of photolysis of free radicals under light conditions, and further generates 1-ketoketorolac (originally marked as impurity 3) and 1-hydroxyketorolac (originally marked as impurity 1). The structures of the related compounds are shown below:

[0014]

[0015] There are no reports or suggestions on how to maintain optical stability in the injection of levoketorolac in the existing public literature. After literature review and experimental exploration, we found that it is difficult to maintain the chiral optical purity of the raw material in the preparation of levoketorolac. Therefore, how to use preparation technology to maintain the optical stability of levoketorolac in the preparation is a challenging issue that needs to be solved urgently. Summary of the invention

[0016] Levoketorolac is the active optical isomer in ketorolac tromethamine that exerts its pharmacological effects. Separating it from the racemic form to prepare a preparation of levoketorolac is beneficial for improving the pharmacological effect per unit dosage and reducing the more obvious adverse reactions of ketorolac tromethamine, and has broad prospects for clinical application.

[0017] In view of the fact that: 1) the drug ingredients in the ketorolac preparations currently on the market are all racemic ketorolac, and there is no single stereoisomer on the market as a drug substance; 2) due to the special position of the chiral center of levoketorolac, the chiral center is very likely to undergo racemization under high temperature and high humidity conditions or in a high temperature solution state; 3) the current public literature and information have not reported any precedents for the preparation of levoketorolac injection and maintaining optical stability.

[0018] Therefore, in order to solve the technical gaps and technical defects in the prior art regarding maintaining optical stability of levoketorolac injection, the purpose of the present invention is to provide a pharmaceutical composition of levoketorolac, which comprises: ① a compound of formula I, i.e., levoketorolac or a pharmaceutically acceptable salt or solvate thereof; ② a pH regulator; and ③ a pharmaceutically acceptable excipient. The chemical structure of levoketorolac is shown in the compound of formula I,

[0019]

[0020] In the pharmaceutical composition of the present invention, the pharmaceutically acceptable salt is selected from: one or more of levoketorolac sodium salt, levoketorolac tromethamine salt, levoketorolac diethylamine salt, levoketorolac ethylenediamine salt, levoketorolac lysine salt, levoketorolac arginine salt, levoketorolac histidine salt and levoketorolac meglumine salt.

[0021] The pharmaceutical composition of the present invention is in the form of a freeze-dried powder injection, or a solution injection, or a sterile powder obtained by uniformly mixing various components.

[0022] The pharmaceutical composition of the present invention is preferably a lyophilized powder injection; the optical purity of the active ingredient of the lyophilized powder injection is greater than or equal to 95% after being placed under the conditions of 25°C±2°C / 60%RH±5%RH for 6 months in a long-term stability test; the optical purity of the active ingredient of the lyophilized powder injection is greater than or equal to 90% after being placed under the conditions of 40°C±2°C / 75%RH±5%RH for 6 months in an accelerated stability test; and the moisture content of the lyophilized powder injection is less than or equal to 5%, preferably less than or equal to 3%, and more preferably less than or equal to 2%.

[0023] In a preferred embodiment of the present invention, the raw material used in the preparation is selected from the group consisting of levoketorolac, levoketorolac sodium salt, levoketorolac tromethamine salt, levoketorolac diethylamine salt, levoketorolac ethylenediamine salt, levoketorolac lysine salt, levoketorolac arginine salt, levoketorolac histidine salt, and levoketorolac meglumine salt;

[0024] The pH adjuster includes two parts: "buffer" and "constant pH adjuster". The "buffer" is anhydrous or crystalline water-containing phosphate and its solution, acetate and its solution, citrate and its solution, triethylamine buffer solution, borax buffer solution, or a mixture thereof; preferably phosphate and its solution, or acetate and its solution, or citrate and its solution; wherein the anhydrous or crystalline water-containing phosphate is selected from one or more of sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, tripotassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, ammonium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate or zinc phosphate;

[0025] The “constant pH value adjusting agent” is selected from sodium hydroxide, potassium hydroxide, tromethamine, triethanolamine, diethanolamine, ethanolamine, sodium citrate, potassium citrate, sodium carbonate, sodium bicarbonate, anhydrous or crystalline hydrate of disodium hydrogen phosphate, anhydrous or crystalline hydrate of sodium dihydrogen phosphate, anhydrous or crystalline hydrate of dipotassium hydrogen phosphate, anhydrous or crystalline hydrate of potassium dihydrogen phosphate, sodium phosphate, phosphoric acid, hydrochloric acid, tartaric acid, lactic acid; preferably anhydrous or crystalline hydrate of disodium hydrogen phosphate, anhydrous or crystalline hydrate of sodium dihydrogen phosphate, phosphoric acid, or an aqueous solution thereof;

[0026] The excipient is selected from mannitol, dextran, sucrose, maltose, lactose, glycine, maltodextrin, or povidone K30; preferably mannitol or maltodextrin. In the present invention, mannitol or / and maltodextrin are preferably used as freeze-drying excipients. Compared with other excipients, mannitol or / and maltodextrin have the most stable compatibility and the best application effect.

[0027] In a preferred embodiment of the present invention, the constant volume pH regulator is used to adjust the pH value of the lyophilized stock solution during the preparation of the lyophilized powder injection to 6.5-7.5, preferably 6.8-7.2; more preferably 6.9-7.0.

[0028] In a preferred embodiment of the present invention, in the freeze-dried stock solution during the preparation of the freeze-dried powder injection, levoketorolac C 15 H 13 The drug concentration in terms of NO3 is 2 to 30 mg / ml, preferably 5 to 10 mg / ml.

[0029] The pharmaceutical composition obtained by the present invention can also be used after being diluted with a diluent. Preferably, the lyophilized powder injection can be used after being diluted with a diluent commonly used in clinical practice; the diluent is selected from 5% glucose injection, 10% glucose injection, glucose sodium chloride injection, 0.9% sodium chloride injection, compound sodium chloride injection, lactated sodium Ringer's injection, compound glucose sodium lactate injection, sterile injection water, xylitol injection, fructose injection; and after dilution, the lyophilized powder injection is diluted with levoketorolac C 15 H 13 The drug concentration measured by NO3 is 0.05-5 mg / ml.

[0030] In a preferred embodiment of the present invention, in the lyophilized powder injection, the raw material drug is selected from levoketorolac, or levoketorolac tromethamine salt, or levoketorolac arginine salt; in the pH regulator, the buffer is selected from anhydrous or crystalline water-containing phosphate, which can be one or more of disodium hydrogen phosphate anhydrous or crystalline water, sodium dihydrogen phosphate anhydrous or crystalline water; the constant volume pH value regulator is selected from disodium hydrogen phosphate anhydrous or crystalline water, sodium dihydrogen phosphate anhydrous or crystalline water, phosphoric acid, sodium hydroxide, or aqueous solutions prepared thereof; the excipient is selected from mannitol; and the drug concentration in the lyophilized stock solution when preparing the lyophilized powder injection is 5-7.5 mg / ml in terms of levoketorolac; and the pH value of the lyophilized stock solution before freeze drying is 6.8-7.2.

[0031] The raw material used in the preparation of the present invention, taking levoketorolac as an example, is an off-white to light yellow solid powder, which is almost insoluble or insoluble in water; slightly soluble in dichloromethane; slightly soluble in anhydrous ethanol; soluble in methanol; and easily soluble in dimethylformamide.

[0032] Through physical and chemical experiments, it was found that the solubility of levoketorolac is pH-dependent, and its solubility increases with the increase of pH. Under acidic conditions, a pH value below 6.0 is not conducive to the dissolution of the active ingredient levoketorolac, and the product molding and re-dissolution effects are not good. The solubility is higher when the pH is above 6.8; when the pH is in the range of 6.0 to 7.5, as the pH increases, the rate at which levoketorolac undergoes conformational flip to generate dexketorolac is very low, indicating that the optical stability of the levoketorolac lyophilized preparation is better; and when the pH is greater than 7.5, the rate at which levoketorolac undergoes conformational flip to generate dexketorolac increases, the dexketorolac content in the lyophilized preparation increases, and the optical stability of the reconstituted solution decreases.

[0033] In a preferred embodiment of the present invention, the molar concentration of phosphate used as a pH regulator in the freeze-dried powder injection is 0.01 to 0.1 mmol / ml, preferably 0.05 to 0.06 mmol / ml; and the molar ratio of levoketorolac:phosphate in the freeze-dried stock solution is 1:1 to 1:3, preferably 1:2.5 to 1:2.8; the mass percentage of the excipient mannitol in the freeze-dried stock solution is 3% to 7%, preferably 5%.

[0034] Visible foreign matter and insoluble particles inspection is an important inspection item of quality control of lyophilized powder injection, which is directly related to the drug safety of injection. These two items are closely related to the properties of the re-dissolution of lyophilized powder injection. After prescription screening, combined with the indexes such as re-dissolution properties and water control, we surprisingly found that by adding components such as meglumine, tromethamine, arginine, etc., it is beneficial to improve the quality of the re-dissolution of the obtained lyophilized powder injection after being placed for a period of time, including the inspection indexes of visible foreign matter and insoluble particles can be stably guaranteed to be qualified. Preferred meglumine or arginine. We define such components as "stabilizers" in the present invention, which are used to prevent the precipitation of drugs during the re-dissolution of lyophilized powder injection, and effectively improve the detection indexes of visible foreign matter and insoluble particles. Looking back at the prior art, most of them use organic solvents such as ethanol and propylene glycol as cosolvents to dissolve the drug component ketorolac, which can improve the clarity of the injection to a certain extent, and the white spots after sterilization are improved, but the use of organic alcohols inevitably brings greater irritation during administration, which is not conducive to the promotion and application of drugs.

[0035] In a preferred embodiment of the present invention, the lyophilized powder injection further contains a stabilizer, which is selected from one or more of meglumine, arginine, lysine, and tromethamine, preferably meglumine or arginine, and the mass percentage of the stabilizer in the lyophilized stock solution is 0.1% to 5%, preferably 0.5% to 1%.

[0036] Ketorolac is prone to excessive decarboxylation and oxidation through the form of oxidized free radical intermediates under light and / or high temperature, thereby generating 1-ketoketorolac and 1-hydroxyketorolac. The generation of oxidized free radicals can be reduced or prevented by adding antioxidants such as sodium bisulfite, thereby reducing the generation of decarboxylation and oxidation impurities. At the same time, oxidation reaction is a very complex type of degradation in stability. Oxidation reactions generally include self-oxidation reactions of free radicals. Oxidative degradation reactions are greatly affected by light, metal ions (copper ions, iron ions), temperature and humidity, solutions or solids. For example, some drug API solids are not sensitive, but the solution state is very sensitive. Therefore, by adding an appropriate amount of metal ion chelating agents such as disodium edetate, the catalytic acceleration of metal ions on oxidation can be weakened, and thus the generation of impurities can be inhibited to a certain extent.

[0037] In a preferred embodiment of the present invention, the freeze-dried powder injection further contains one or two of a metal ion chelator and an antioxidant; wherein the metal ion chelator is selected from one or more of disodium edetate, sodium calcium edetate, sodium citrate, and citric acid, preferably disodium edetate or sodium calcium edetate, and its weight percentage in the freeze-dried stock solution is 0.05% to 1%; the antioxidant is selected from one or more of sodium thiosulfate, sodium sulfite, sodium pyrosulfite, sodium bisulfite, vitamin C, sodium citrate, citric acid, and L-cysteine, preferably sodium bisulfite or vitamin C, and its weight percentage in the freeze-dried stock solution is 0.02% to 2%.

[0038] The present invention preferably uses disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, and potassium dihydrogen phosphate without water or crystal water as pH regulators to maintain a balance between dissolving the main drug and maintaining optical stability.

[0039] Since phosphate buffer salts are usually divided into anhydrous substances and various numbers of hydrates, the following is specially explained: the disodium hydrogen phosphate mentioned in the content of the invention and the embodiments of the present application can use anhydrous disodium hydrogen phosphate, disodium hydrogen phosphate dodecahydrate, disodium hydrogen phosphate monohydrate, disodium hydrogen phosphate dihydrate, disodium hydrogen phosphate pentahydrate, and disodium hydrogen phosphate heptahydrate. If not specifically stated, disodium hydrogen phosphate dodecahydrate is usually used. Similarly, sodium dihydrogen phosphate can use anhydrous sodium dihydrogen phosphate, or sodium dihydrogen phosphate monohydrate, or sodium dihydrogen phosphate dihydrate. The application of the above reagents should be understood as using anhydrous substances or other numbers of hydrates with the same molar number, that is, the same amount of substance, to achieve the same buffering and pH adjustment effect. Because the molecular weight of anhydrous substances or different numbers of hydrates is different, it only reflects a slight difference in the weight of the feed. In addition, dipotassium hydrogen phosphate and potassium dihydrogen phosphate have similar situations and descriptions. If other reagents have similar situations, by analogy, they will not be repeated.

[0040] In a preferred embodiment of the present invention, the freeze-dried powder injection comprises the raw material of levoketorolac; in the pH adjusting agent, the buffer is disodium hydrogen phosphate in anhydrous or crystalline water; the constant volume pH adjusting agent is disodium hydrogen phosphate in anhydrous or crystalline water, or an aqueous solution thereof; the freeze-dried powder injection further comprises a stabilizer, meglumine, the mass percentage of the stabilizer in the freeze-dried stock solution is 0.1% to 5%, preferably 0.5% to 1%; and the freeze-dried powder injection, in a long-term stability test, i.e., after being placed under the conditions of 25°C ± 2°C / 60% RH ± 5% RH for 6 months, the light release rate of the active ingredient is The optical purity of the active ingredient is greater than or equal to 95%; after being placed under the conditions of 40°C±2°C / 75%RH±5%RH for 6 months in an accelerated stability test, the optical purity of the active ingredient is greater than or equal to 90%; more preferably, the optical purity of the lyophilized powder injection is greater than or equal to 98% after being placed under the conditions of 25°C±2°C / 60%RH±5%RH for 6 months in a long-term stability test; the optical purity of the active ingredient is greater than or equal to 95% after being placed under the conditions of 40°C±2°C / 75%RH±5%RH for 6 months in an accelerated stability test.

[0041] In a preferred embodiment of the present invention, the freeze-dried powder injection comprises the raw material of levoketorolac; the buffer of the pH regulator comprises sodium phosphate or sodium dihydrogen phosphate hydrate; the constant volume pH regulator comprises sodium hydroxide, phosphoric acid, or an aqueous solution thereof; the freeze-dried powder injection further comprises a stabilizer, and the mass percentage of the stabilizer in the freeze-dried stock solution is 0.1% to 5%, preferably 0.5% to 1%; and the optical purity of the active ingredient of the freeze-dried powder injection after being placed under the conditions of 25°C ± 2°C / 60% RH ± 5% RH for 6 months in a long-term stability test is as follows: The optical purity of the active ingredient is greater than or equal to 95%; after being placed under the conditions of 40°C±2°C / 75%RH±5%RH for 6 months in an accelerated stability test, the optical purity of the active ingredient is greater than or equal to 90%; more preferably, the optical purity of the lyophilized powder injection is greater than or equal to 98% after being placed under the conditions of 25°C±2°C / 60%RH±5%RH for 6 months in a long-term stability test; the optical purity of the active ingredient is greater than or equal to 95% after being placed under the conditions of 40°C±2°C / 75%RH±5%RH for 6 months in an accelerated stability test.

[0042] In a preferred embodiment of the present invention, the freeze-dried powder injection comprises the raw material of levoketorolac tromethamine salt; the buffering agent in the pH adjusting agent is anhydrous or crystalline water dipotassium hydrogen phosphate, anhydrous or crystalline water potassium dihydrogen phosphate; the constant volume pH value adjusting agent is sodium bicarbonate, hydrochloric acid, or an aqueous solution prepared therefrom; the freeze-dried powder injection further comprises a stabilizer arginine, the mass percentage of the stabilizer in the freeze-dried stock solution is 0.1% to 5%, preferably 0.5% to 1%; and the freeze-dried powder injection, in a long-term stability test, i.e., after being placed under 25°C ± 2°C / 60% RH ± 5% RH for 6 months, , the optical purity of the active ingredient is greater than or equal to 95%; in an accelerated stability test, i.e., after being placed under 40°C ± 2°C / 75% RH ± 5% RH conditions for 6 months, the optical purity of the active ingredient is greater than or equal to 90%; more preferably, the lyophilized powder injection, in a long-term stability test, i.e., after being placed under 25°C ± 2°C / 60% RH ± 5% RH conditions for 6 months, the optical purity of the active ingredient is greater than or equal to 98%; in an accelerated stability test, i.e., after being placed under 40°C ± 2°C / 75% RH ± 5% RH conditions for 6 months, the optical purity of the active ingredient is greater than or equal to 95%

[0043] In a preferred embodiment of the present invention, the freeze-dried powder injection further contains a metal ion chelating agent selected from disodium edetate or sodium calcium edetate, and the weight percentage of the metal ion chelating agent in the freeze-dried stock solution is 0.05% to 1%.

[0044] In a preferred embodiment of the present invention, the freeze-dried powder injection further contains an antioxidant selected from sodium bisulfite or vitamin C, and the weight percentage of the antioxidant in the freeze-dried stock solution is 0.02% to 2%.

[0045] As a preferred embodiment of the present invention, the weight percentage of each component in the freeze-dried stock solution during the preparation of the freeze-dried powder injection is as follows:

[0046] Levoketorolac: 0.5% to 0.7%

[0047] Disodium hydrogen phosphate dodecahydrate: 1.8% to 2.0%

[0048] Mannitol: 6% to 9%

[0049] Edetate disodium: 0.05% to 0.1%

[0050] Disodium hydrogen phosphate aqueous solution: appropriate amount, adjust the pH value to 6.8-7.2;

[0051] Add water for injection to: 100%;

[0052] Furthermore, the lyophilized stock solution is aseptically filtered, packaged, and freeze-dried to obtain the lyophilized powder injection.

[0053] As a preferred embodiment of the present invention, the weight percentage of each component in the freeze-dried stock solution during the preparation of the freeze-dried powder injection is as follows:

[0054] Levoketorolac: 0.5% to 1%

[0055] Disodium hydrogen phosphate dodecahydrate: 1.8% to 2.5%

[0056] Mannitol: 5% to 15%

[0057] Meglumine: 1% to 2%

[0058] Disodium hydrogen phosphate aqueous solution: appropriate amount, adjust the pH value to 6.8-7.2;

[0059] Add water for injection to: 100%;

[0060] Furthermore, the lyophilized stock solution is aseptically filtered, packaged, and freeze-dried to obtain the lyophilized powder injection.

[0061] As a preferred embodiment of the present invention, the weight percentage of each component in the freeze-dried stock solution during the preparation of the freeze-dried powder injection is as follows:

[0062] Levoketorolac tromethamine salt: 0.8% to 1.5%

[0063] Potassium dihydrogen phosphate: 0.5% to 1.5%

[0064] Mannitol: 5% to 10%

[0065] Arginine: 1% to 2%

[0066] Potassium hydrogen phosphate aqueous solution, appropriate amount, adjust the pH value to 6.8-7.2;

[0067] Add water for injection to: 100%;

[0068] Furthermore, the lyophilized stock solution is aseptically filtered, packaged, and freeze-dried to obtain the lyophilized powder injection.

[0069] The second object of the present invention is to provide a method for preparing a lyophilized powder injection of levoketorolac, comprising the following steps:

[0070] 1) using 70-80% water for injection at room temperature and under stirring conditions to dissolve all excipients except the API and the constant volume pH adjuster, wherein the excipient is one or more of a buffer, an excipient, a stabilizer, a metal ion chelating agent, and an antioxidant, to obtain a clear solution;

[0071] 2) adding levoketorolac or a pharmaceutically acceptable salt thereof and stirring to dissolve;

[0072] 3) preparing a volume-fixing pH adjusting agent, and slowly adding it to the solution obtained in step 2 to adjust the pH to 6.5 to 7.5, preferably 6.8 to 7.2, and more preferably 6.9 to 7.0;

[0073] 4) Make up the total volume with water for injection, sterile filter the drug solution through 0.45 μm, 0.22 μm, and 0.22 μm pore size polyethersulfone filter elements in sequence, and perform quality control on the content of the intermediate solution;

[0074] 5) The drug solution is divided into neutral borosilicate glass tube injection bottles, and the freeze-drying process is performed using freeze-drying equipment. Finally, the bottle is plugged, taken out of the cabinet, and the cap is rolled to obtain the finished product of levoketorolac freeze-dried powder injection.

[0075] The third object of the present invention is to provide a freeze-dried powder injection of levoketorolac for use in the preparation of analgesics, wherein the analgesic indication is specifically: short-term treatment of acute and severe pain requiring analgesics at the opioid level, usually for postoperative analgesia. After evaluation and judgment, the freeze-dried powder injection of levoketorolac of the present invention can relieve moderate pain and severe pain after surgery, including the abdomen, chest, gynecology, oral cavity and urology. It can also be used to relieve renal colic, biliary colic, toothache, trigeminal neuralgia and cancer pain.

[0076] The present invention reports for the first time a freeze-dried powder injection preparation of levoketorolac or a pharmaceutically acceptable salt thereof (including levoketorolac tromethamine salt and levoketorolac sodium salt) and a preparation method thereof. The freeze-dried powder injection preparation has an important use in the preparation of analgesic drugs, and the analgesic indication is specifically: short-term treatment of acute and severe pain requiring analgesics at the opioid level, usually for postoperative analgesia.

[0077] Compared with the prior art, the present invention has the following significant advantages:

[0078] (1) The analgesic activity of ketorolac comes from levoketorolac, and its enantiomer dextroketorolac has almost no analgesic effect. Ketorolac tromethamine sold in domestic and foreign markets is a racemic body, which has the disadvantages of frequent administration, gastrointestinal adverse reactions common to non-steroidal drugs, and poor patient compliance; the daily dose is 60-120 mg, and multiple doses are required to maintain the efficacy. Our research found that levoketorolac can be directly prepared into a lyophilized powder injection, or the raw material can be first made into tromethamine salt, arginine salt, sodium salt and other salt forms of levoketorolac and then formed into a lyophilized preparation, which can reduce the traditional dosage to about 50%, and has the advantages of stable properties, high efficacy and high safety.

[0079] (2) The present invention has further studied the properties of the active ingredient ketoconazole, or its pharmaceutically acceptable salts (including ketoconazole tromethamine salt, ketoconazole sodium salt, etc.), and found that it is degraded and racemized in aqueous solution, and the content of ketoconazole increases with time, so it is necessary to strictly control the external conditions to ensure that the isomeric impurities do not exceed the limit. We found that directly preparing ketoconazole into a lyophilized powder injection is beneficial to maintaining the optical purity of ketoconazole itself. We controlled the content of the isomeric impurity ketoconazole within the quality limit by adjusting the formulation and process of the preparation. We used the optimized formulation and process of the lyophilized powder injection to solve the technical difficulties and bottlenecks of maintaining the optical stability of ketoconazole injection.

[0080] (3) During the screening of pH regulators, we were pleasantly surprised to find that although the water solubility of ketoconazole is poor, it can be dissolved to obtain a clear solution after a short period of stirring under the coexistence of an appropriate proportion of phosphate buffer, and the pH value at this time is measured to be 6.6-6.9, which is lower than the neutral pH value of 7.0. Phosphates are preferably anhydrous or crystalline water phosphates, including but not limited to: disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium phosphate. The above scheme not only improves the water solubility and dissolution rate of ketoconazole, but also ensures the optical stability of the finished product under storage conditions during the dissolution process, the process of preparing freeze-dried powder injection, and the conditions of storage, and plays a positive role in avoiding the excessive growth of the isomer impurity ketoconazole and slowing down the racemization rate. At the same time, the technical scheme reported for the first time avoids the use of organic solvents such as ethanol and propylene glycol as cosolvents, avoids the use of inclusion compounds such as cyclodextrin or non-ionic surfactants such as poloxamer 188, reduces the irritation of blood vessels and muscles during the application of injections, and reduces the risks of drug safety such as hemolysis. In a preferred embodiment of the present invention, after being placed under the conditions of 25°C ± 2°C / 60% RH ± 5% RH for 6 months in a long-term stability test, the optical purity of the active ingredient is greater than or equal to 98%; after being placed under the conditions of 40°C ± 2°C / 75% RH ± 5% RH for 6 months in an accelerated stability test, the optical purity of the active ingredient is greater than or equal to 95%.

[0081] (4) We also explored the effect of solution pH on the stability of the main drug: acidic conditions are not conducive to the dissolution of active ketoconazole, and the appearance, uniformity and resolubility of the finished preparation are not good. Under alkaline conditions (pH greater than 7.5), the degradation and racemization of ketoconazole will be aggravated, and the content of right ketoconazole will increase significantly. Therefore, the final suitable pH is determined to be between 6.0 and 7.5, and more preferably between 6.8 and 7.2. The physicochemical stability of ketoconazole or its pharmaceutically acceptable salts (including ketoconazole tromethamine salt, ketoconazole sodium salt, and ketoconazole arginine salt) under this pH condition is the best.

[0082] (5) We have conducted in-depth research on the freeze-drying process and moisture control of finished products. We focus on the two stages of pre-freezing and sublimation drying, and reasonably set the temperature and time parameters of each stage to ensure the quality of the freeze-dried product. The moisture content of the freeze-dried product obtained by the modified method is controlled at ≤2%. In the prior art, the moisture content of freeze-dried powder injection is generally higher than 2%, usually 3% to 5%. It is well known that ketorolac itself is easily degraded and its color deepens when it encounters high temperature, light and acid-base conditions. It is easy to undergo decarboxylation oxidation reaction to produce impurities, which affects the safety of clinical medication to a certain extent. The degradation rate in the solution state is significantly faster than that in the solid state. In addition to the chemical instability brought by ketorolac, the optical stability of levoketorolac also needs to be paid great attention to, as the chiral atoms are very easy to racemize. Therefore, controlling the moisture content of the levoketorolac freeze-dried preparation within a reasonable range is conducive to increasing the chemical stability and optical stability during the sample placement process.

[0083] (6) The levoketorolac or its pharmaceutically acceptable salt (including levoketorolac tromethamine salt, levoketorolac sodium salt, levoketorolac arginine salt) of the present invention is a raw material drug with stable process and convenient operation, which meets the requirements of large-scale industrial production.

[0084] (7) In a preferred embodiment of the present invention, a "stabilizer" such as arginine or meglumine is added to effectively improve the clarity test results of the reconstituted solution of the lyophilized powder injection after being left for a period of time, such as visible foreign matter and insoluble particles.

[0085] (8) In a preferred embodiment of the present invention, a metal ion chelator or an antioxidant is added to help reduce the decarboxylation and oxidation impurities generated by the drug components during the preparation and sample storage process, such as "1-ketoketorolac" and "1-hydroxyketorolac" and other impurities, and can also inhibit the stereoconversion of levoketorolac to a certain extent. BRIEF DESCRIPTION OF THE DRAWINGS

[0086] Figure 1 This is the H NMR spectrum of levoketorolac.

[0087] Figure 2 This is a high-resolution mass spectrum of levoketorolac.

[0088] Figure 3 It is a schematic diagram of the main effect of the formulation on the isomeric impurity dexketorolac (%).

[0089] Figure 4 It is a schematic diagram of the interaction of the formulation on the isomeric impurity dexketorolac (%).

[0090] Figure 5 This is a representative graph of the stability test of the lyophilized powder injection described in the present invention stored at 25°C for 6 months.

[0091] Figure 6It is a representative graph of the stability test of the lyophilized powder injection described in the present invention stored at 40°C for 6 months. DETAILED DESCRIPTION

[0092] In order to make the above-mentioned purposes, features and advantages of the present disclosure more obvious and easy to understand, the specific implementation methods of the present disclosure are described in detail below in conjunction with the accompanying drawings and specific embodiments. In the following description, many specific details are set forth to facilitate a full understanding of the present disclosure, but the present disclosure can also be implemented in other ways different from those described herein, and those skilled in the art can make similar generalizations without violating the connotation of the present disclosure, so the present disclosure is not limited by the specific embodiments disclosed below.

[0093] Experimental Example 1 Preparation and Structural Confirmation of Levoketorolac

[0094] The preparation of levoketorolac has been mentioned in the existing literature. Fulling et al. (J.Am.Chem.Soc., 1987, 109, 2845) obtained S-ketorolac by selectively catalyzing the hydrolysis of ketorolac esters with an enzyme, and the product had high optical purity. Guzman et al. (J.Med.Chem., 1986, 29, 589-591) used L-cinchonidine to react with ketorolac to form a salt, and then separated the ketorolac by a crystallization method. Angel et al. (Tetrahydron: Asymmetry, 1992, 3(11), 1455) reacted ketorolac with an optically active alcohol to form an ester, which was separated by high pressure liquid chromatography (HPLC) and then hydrolyzed to obtain (+)- or (-)-ketorolac.

[0095] The present invention uses the method for splitting cinchonidine to obtain a levoketorolac sample. The preparation process is described as follows:

[0096] 11.7 g of L-cinchonidine was dissolved in 200 ml of hot anhydrous ethanol and added to a solution of 10.2 g of racemic ketorolac in 50 ml of ethyl acetate. The mixture was heated to reflux temperature for 0.5 h, the solvent was removed under reduced pressure, and the residue was recrystallized from 200 ml of ethyl acetate to obtain about 3.7 g of left ketorolac.

[0097] 1) The specific rotation is -176° to -177° (c=0.1, ethanol).

[0098] 2) The H-NMR spectrum data are as follows, see Appendix Figure 1 .

[0099]

[0100]

[0101] 3) High-resolution mass spectrometry data are as follows, see Appendix Figure 2 .

[0102]

[0103] In positive ion mode ([C 15 H 13 NO3]+H) + The m / z of the sample is 256.09692, indicating that the mass-to-charge ratio of the sample is 255.089808. The calculated molecular composition is C 15 H 13 NO3. Conforms to the target molecular structure.

[0104] Since the water solubility of ketoconazole itself is poor, the aqueous solution is easily degraded and discolored under high temperature or light, resulting in the increase of related substances and the increase of isomeric impurity dexketorolac. Therefore, we investigated the preparation of ketoconazole into common salt forms, such as ketoconazole sodium salt and ketoconazole arginine salt. The method for preparing conventional salt forms is generally described as dissolving ketoconazole and an equimolar amount of a base in anhydrous ethanol, stirring at room temperature for 0.5 to 2 hours, then removing the solvent under reduced pressure, adding ethyl acetate and / or n-hexane, and the resulting solid precipitate, suction filtering, and drying under reduced pressure to obtain a salt-type finished product.

[0105] Test Example 2 Solubility Test of Levoketorolac in Phosphate Buffers at Different pH

[0106] After levoketorolac is further prepared into levoketorolac tromethamine salt and levoketorolac sodium salt, the stability of the raw material in the solid state is improved. Under high temperature, high humidity and strong light irradiation, the stability is significantly improved, and the appearance is always white or off-white, without color deepening. However, in aqueous solution, high temperature conditions will still aggravate its degradation and racemization, that is, the content of dexketorolac will increase significantly.

[0107] Levoketorolac has poor solubility in aqueous solution. In the process of screening pH regulators, we were pleasantly surprised to find that adding phosphates, i.e., disodium hydrogen phosphate and / or sodium dihydrogen phosphate, to the aqueous solution of levoketorolac not only helps to improve the solubility of the main drug ketorolac in water, but also can greatly improve the optical stability of levoketorolac in the preparation and slow down its racemization rate under accelerated stability test conditions.

[0108] With reference to the Chinese Pharmacopoeia 2020, phosphate buffer with a pH range of 6.5-7.8 was prepared, and an appropriate amount of levoketorolac (free acid) was added to make a mixture containing about 20 mg / mL. Each solution was placed in a 25°C air bath shaker and shaken for 24 hours. During this period, the dissolution of levoketorolac in each mixture was observed, and the solubility of the compound under each pH condition at 25°C and 1 day was detected, as shown in Table 1. The remaining samples were kept at 25°C and 40°C, and samples were taken at 2 days and 30 days to detect the formation of isomers, as shown in Table 2.

[0109] Table 1 Solubility of levoketorolac in phosphate buffers at different pH values

[0110]

[0111]

[0112] Table 2 Optical stability of levoketorolac in phosphate buffers at different pH values

[0113]

[0114] The above test results show that: 1) Levoketorolac is pH-dependently soluble, and its solubility increases with the increase of acidity. In a phosphate buffer solution with a pH of 7.8, the solubility jumps. 2) In the solution state of the sample, the optical purity of levoketorolac is greater than or equal to 95% when placed at 25°C for 1 month, but the generation of the isomer right ketorolac increases significantly when placed at 40°C for 1 month, indicating that the degradation and racemization of levoketorolac in a phosphate buffer solution under high temperature conditions will still be aggravated, and the optical stability needs to be improved through technical means.

[0115] In summary, levoketorolac or its pharmaceutically acceptable salt (including levoketorolac tromethamine salt, levoketorolac sodium salt) is likely to be unsuitable for preparation into conventional injection aqueous solution to maintain its optical purity, and further research and development of its suitable dosage form is needed to solve the above technical problems. Compared with injection water injection, freeze-dried powder injection is expected to maintain the optical purity of the drug, because it is not easily oxidized when prepared under vacuum, and the water content is very low, and the probability of degradation caused by water catalysis is low; and the special production process of freeze-dried powder injection makes the drug evenly dispersed in the freeze-drying protective agent, with a stable preparation environment. In summary, levoketorolac, or its pharmaceutically acceptable salt (including levoketorolac tromethamine salt, levoketorolac sodium salt) is suitable for development into freeze-dried powder injection, to solve the problem that the active ingredient levoketorolac injection aqueous solution is difficult to maintain its optical purity and physicochemical stability.

[0116] Test Example 3 Screening and Investigation of Excipients and pH Values ​​of Lyophilized Stock Solutions in Preparations

[0117] Preparation method: dissolve the excipient and pH regulator sodium dihydrogen phosphate dodecahydrate in 70-80% injection water to obtain a clear solution, then add levoketorolac and stir to dissolve it, adjust the pH with disodium hydrogen phosphate solution; make up to the total volume with injection water; after sterile filtration, freeze-drying process, the levoketorolac freeze-dried powder injection product is obtained.

[0118] The freeze-dried powder injections were placed at 25°C and 40°C for 20 days to investigate the changes in the content of dexketorolac in the freeze-dried powder injections under different excipients and different pH values ​​of the freeze-dried stock solution. The results are shown in Table 4.

[0119] Table 3 Effect of different excipients and different lyophilized stock solution pH values

[0120]

[0121]

[0122] Table 4 Properties of finished products obtained with different excipients

[0123]

[0124]

[0125] The above test results show that: from the perspective of the properties of the finished freeze-dried preparation after retaining samples at different temperatures, the freeze-dried samples with mannitol, maltodextrin and povidone K30 as excipients meet the requirements. From the analysis of the isomer detection results under different retention conditions, the freeze-dried samples with sucrose, maltose, maltodextrin and mannitol as excipients meet the requirements. In summary, the preferred excipients are maltodextrin and mannitol.

[0126] Experimental Example 4: Optical stability of lyophilized powder injection after dilution with saline

[0127] Table 5 Investigation of dexketorolac after dilution with saline

[0128]

[0129] The above test results show that: the isomers of each lyophilized preparation of levoketorolac have no obvious growth when the sample is kept at 25℃ for 24 hours.

[0130] When the sample was kept at 40°C for 24 hours, the isomers increased slightly, but were still within the controllable quality range.

[0131] Experimental Example 5: Stability of lyophilized powder injections of levoketorolac free acid and different salt forms

[0132] Preparation method: Similar to the preparation method of Test Example 3. Wherein, the pH regulator is disodium hydrogen phosphate or / and sodium dihydrogen phosphate, and the amount added varies with the content of the main drug left ketorolac or its pharmaceutically acceptable salt, and the concentration is 3 to 7.5 mg / mL, more preferably 5 g / mL. Placed under the conditions of accelerated test (temperature 40±2°C, relative humidity 75±5°C) for 6 months, the changes in various indicators such as the content, right ketorolac content, appearance, properties, and re-dissolution of the sample are investigated, and the results are as follows.

[0133] Table 6 Optical stability study of freeze-dried powder injections made from different APIs

[0134]

[0135]

[0136] The above test results show that: compared with the formulation 1 without adding the pH adjuster, the formulations 2 to 6 reduced the racemization of levoketorolac after adding disodium hydrogen phosphate and / or sodium dihydrogen phosphate.

[0137] Test Example 6 Stability Study of Mannitol and Samples Obtained under Different pH Conditions

[0138] Preparation method: Similar to the preparation method of Test Example 3. The samples were placed at room temperature (25°C ± 2°C) and under accelerated test conditions (temperature 40±2°C, relative humidity 75±5°C) for 15 days to examine the changes in the dexketorolac content, properties, re-dissolution rate and other indicators of the samples. The results are shown in Table 7.

[0139] Table 7 Properties of samples prepared under different pH conditions

[0140]

[0141]

[0142] The above test results show that: in the pH range of 6.0 to 7.5, acidic conditions are not conducive to the dissolution of the active ingredient ketoconazole, and the product molding and re-dissolution effects are not good. With the increase of pH, the rate of conformational flipping of ketoconazole to generate dexketorolac is very low, indicating that the optical stability of the ketoconazole freeze-dried preparation is better; when the pH is greater than 7.5, the rate of conformational flipping of ketoconazole to generate dexketorolac increases, the dexketorolac content in the freeze-dried preparation increases, the optical stability of the re-dissolved solution decreases, and when the pH is 7.8, the re-dissolution speed of the freeze-dried preparation is slow, and it needs to be dissolved by vortexing, which is not convenient for clinical use.

[0143] Experimental Example 7 Exploration of freeze-drying process

[0144] We investigated the changes in the appearance, properties, re-dissolution, water content and other indicators of the samples at different temperatures and times in each stage during the freezing control (i.e. pre-freezing) and sublimation drying stages. The results are shown in Table 8.

[0145] Table 8 Exploration of freeze-drying parameters

[0146]

[0147] The above test results show that the sample prepared according to freeze-drying process 1 has poor properties and high water content, while the samples prepared according to freeze-drying processes 2 to 5 have good properties and low water content. Therefore, the optimal freeze-drying process is determined as follows: after half-pressing and plugging, pre-freeze at -5℃~-10℃ for 2h, cool to -40℃ and keep warm for 3h, heat to -20℃~0℃ and sublimate and dry for 8~12h, then heat to 10~20℃, decompose and dry for 6h~12h, then press the plug and take out of the cabinet, and freeze-drying is completed.

[0148] Test Example 8 Effect of Stabilizer

[0149]

[0150] Weigh the prescribed amount of water for injection, stir at room temperature, add the prescribed amount of meglumine and mannitol, add the prescribed amount of levoketorolac after complete dissolution, measure the acidity of the solution, and adjust the pH of the solution to 6.9-7.1 with disodium hydrogen phosphate or phosphoric acid. Sterile filter the solution through 0.45μm, 0.22μm, and 0.22μm pore size polyethersulfone filter elements in turn, and test the content of the intermediate solution. Dispense the solution into 5mL neutral borosilicate glass tube injection bottles, the amount is determined according to the content of the intermediate, and the specification is 10mg of levoketorolac per bottle.

[0151] The freeze-drying procedure is as follows:

[0152] a. Pre-freezing: cool down to -5℃ within 20 minutes and keep warm for 1 hour; cool down to -10℃ within 20 minutes and keep warm for 1 hour; cool down to -30℃ within 20 minutes and keep warm for 6 hours, and the pre-freezing is over.

[0153] b. Sublimation drying: Adjust the vacuum degree in the freeze dryer to below 20 Pa for vacuum drying. Raise the temperature to -20°C within 20 minutes and keep it warm for 9 hours; raise the temperature to -10°C within 20 minutes and keep it warm for 8 hours; raise the temperature to 0°C within 20 minutes and keep it warm for 8 hours, and the sublimation drying is completed.

[0154] c. Desorption and drying: Keep the vacuum degree in the freeze dryer below 20 Pa, raise the temperature to 10°C within 20 minutes and keep it warm for 6 hours; adjust the vacuum degree in the freeze dryer to below 10 Pa, raise the temperature to 20°C within 20 minutes and keep it warm for 6 hours; keep the vacuum degree in the freeze dryer below 10 Pa, raise the temperature to 30°C within 20 minutes and keep it warm for 3 hours, and the desorption and drying is completed.

[0155] d. Press the stopper and take the sample out of the cabinet, and freeze-drying is completed.

[0156] 1. Investigation from the perspective of visible foreign matter and insoluble particles in the preparation after reconstitution

[0157] Take a number of samples from each example, place them in a constant temperature and humidity chamber at 5°C, 25°C, and 40°C, respectively, and keep them for 6 months. Then take out 2 bottles of samples from each example under each retention condition. Add 2 ml of physiological saline to dissolve them at room temperature, and record the time required for the block in the bottle to completely dissolve; the reconstituted solution is inspected by the visible foreign matter lamp inspection method in accordance with Item 0904 of the General Rules of the 2020 Edition of the Chinese Pharmacopoeia. If there is no foreign matter visible to the naked eye, observe the insoluble particles under a microscope in accordance with Item 0903 of the General Rules of the 2020 Edition of the Chinese Pharmacopoeia, and record them as follows:

[0158]

[0159] The above test results show that adding an appropriate amount of meglumine (≥0.5%) to the prescription is beneficial to the re-dissolution of the preparation and is beneficial to improving the stability and safety of the preparation in clinical use.

[0160] 2. Investigation of isomer changes in long-term samples

[0161] Several samples of each embodiment were taken and placed in a constant temperature and humidity chamber at 5°C, 25°C, and 40°C, respectively. After 1 month, 3 months, and 6 months, one bottle of each example sample was taken out from each retention condition for isomer detection, and the levoketorolac content was recorded as follows.

[0162]

[0163] The above test results show that: in each embodiment, under the sample retention condition, the racemization of levoketorolac increases with the increase of the dosage of meglumine. From the perspective of optical stability of the raw material compound, the preferred dosage of meglumine should be ≤1%.

[0164] The following Examples 1 to 12 further describe the present invention, and all of them can achieve the effects described in the above test examples, but the examples are only used to illustrate the present invention rather than to limit the present invention.

[0165] Example 1 Preparation of lyophilized powder injection of levoketorolac sodium salt

[0166] prescription:

[0167] Levoketorolac sodium salt: 1.1 g;

[0168] Mannitol: 11g;

[0169] Anhydrous disodium hydrogen phosphate: 1.44g;

[0170] 5% sodium dihydrogen phosphate solution: appropriate amount, adjusted to pH 6.8;

[0171] Water for injection: make up to a total volume of 200 g.

[0172] Preparation method:

[0173] Step 1: According to the above prescription, dissolve mannitol and anhydrous disodium hydrogen phosphate with 70-80% water for injection to obtain a clear solution, then add sodium levoketorolac and stir to dissolve it, adjust the pH to 6.8 with 5% sodium dihydrogen phosphate solution; and make up to the total volume with water for injection;

[0174] Step 2): The drug solution is sterile filtered through 0.45 μm, 0.22 μm, and 0.22 μm pore size polyethersulfone filter elements in sequence, and the intermediate solution is quality controlled for the content; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and plugging, it is pre-frozen at -5℃~-10℃ for 2 hours, cooled to -40℃ and kept warm for 3 hours, heated to -20℃~0℃ and sublimated and dried for 8~12 hours, then heated to 10~20℃, analyzed and dried for 6h~12h, then plugged, taken out of the cabinet, and finally capped to obtain the lyophilized powder injection product of levoketorolac sodium salt. The relevant test data are as follows.

[0175]

[0176] Example 2 Preparation of lyophilized powder injection of levoketorolac tromethamine salt

[0177] prescription:

[0178] Levoketorolac tromethamine salt: 1.5 g;

[0179] Mannitol: 10g;

[0180] Sodium dihydrogen phosphate dodecahydrate: 1.44 g;

[0181] 0.5 mol / L sodium dihydrogen phosphate solution: appropriate amount, adjust to pH 6.5;

[0182] Water for injection: make up to a total volume of 200 g.

[0183] Preparation method:

[0184] Step 1: According to the above prescription, dissolve mannitol and sodium dihydrogen phosphate dodecahydrate with 70-80% water for injection to obtain a clear solution, then add levoketorolac tromethamine salt and stir to dissolve it, adjust the pH to 6.5 with 0.5 mol / L sodium dihydrogen phosphate solution; and make up to the total volume with water for injection;

[0185] Step 2): The drug solution is sequentially sterilized through 0.45 μm, 0.22 μm, and 0.22 μm pore size polyethersulfone material filter elements, and the intermediate solution is quality controlled for the content; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and plugging, it is pre-frozen at -5°C to -10°C for 2 hours, cooled to -40°C and kept warm for 3 hours, heated to -20°C to 0°C and sublimated and dried for 8 to 12 hours, then heated to 10 to 20°C, analyzed and dried for 6 hours to 12 hours, then plugged, taken out of the cabinet, and finally capped to obtain the lyophilized powder injection product of levoketorolac tromethamine salt. The relevant test data are as follows.

[0186]

[0187] Example 3 Preparation of lyophilized powder injection of levoketorolac arginine salt

[0188] prescription:

[0189] Levoketorolac arginine salt: 1.7 g;

[0190] Mannitol: 14g;

[0191] Sodium citrate: 1.5g;

[0192] 0.5mol / L citric acid solution: appropriate amount, adjusted to pH 7.0;

[0193] Water for injection: make up to a total volume of 200 g.

[0194] Preparation method:

[0195] Step 1: According to the above prescription, dissolve mannitol and sodium citrate with 70-80% water for injection to obtain a clear solution, then add levoketorolac arginine salt and stir to dissolve it, adjust the pH to 7.0 with 0.5 mol / L citric acid solution; and make up to the total volume with water for injection;

[0196] Step 2): The drug solution is sterile filtered through 0.45 μm, 0.22 μm, and 0.22 μm pore size polyethersulfone filter elements in sequence, and the intermediate solution is quality controlled for the content; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and plugging, it is pre-frozen at -5°C to -10°C for 2 hours, cooled to -40°C and kept warm for 3 hours, heated to -20°C to 0°C and sublimated and dried for 8 to 12 hours, then heated to 10 to 20°C, analyzed and dried for 6 hours to 12 hours, then plugged, taken out of the cabinet, and finally capped to obtain the lyophilized powder injection product of levoketorolac arginine salt. The relevant test data are as follows.

[0197]

[0198] Example 4 Preparation of levoketorolac lyophilized powder injection

[0199] prescription:

[0200] Levoketorolac: 1.0 g;

[0201] Mannitol: 10g;

[0202] Disodium edetate: 0.1 g;

[0203] Sodium dihydrogen phosphate dodecahydrate: 3.60 g;

[0204] 0.5 mol / L disodium hydrogen phosphate solution: appropriate amount, adjust to pH 7.2;

[0205] Water for injection: make up to a total volume of 200 g.

[0206] Preparation method:

[0207] Step 1: According to the above prescription, dissolve mannitol, sodium dihydrogen phosphate dodecahydrate, and edetate disodium with 70-80% water for injection to obtain a clear solution, then add levoketorolac and stir to dissolve it, adjust the pH to 7.2 with 0.5 mol / L disodium hydrogen phosphate solution; and make up to the total volume with water for injection;

[0208] Step 2): The drug solution is sterile filtered through 0.45μm, 0.22μm, and 0.22μm pore size polyethersulfone filter elements in sequence, and the intermediate solution is quality controlled for the content; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and plugging, it is pre-frozen at -5℃~-10℃ for 2h, cooled to -40℃ and kept warm for 3h, heated to -20℃~0℃ and sublimated and dried for 8~12h, then heated to 10~20℃, analyzed and dried for 6h~12h, then plugged, taken out of the cabinet, and finally capped to obtain the finished freeze-dried powder injection of levoketorolac. The relevant test data are as follows.

[0209] Time Characteristics Dexketorolac (%) Inspection of visible foreign matter and insoluble particles in the reconstituted solution Day 0 White block 0.61 Meet the requirements 5℃ January White block 0.62 Meet the requirements 5℃ February White block 0.65 Meet the requirements 5℃ March White block 0.64 Does not meet the requirements, there are a few visible particles 5℃June White block 0.64 Does not meet the requirements, there are a few visible particles 25℃ January White block 0.67 Meet the requirements 25℃February White block 0.70 Meet the requirements 25℃March White block 0.79 Does not meet the requirements, there are a few visible particles 25℃June White block 0.86 Does not meet the requirements, there are a few visible particles 40℃ January White block 1.03 Meet the requirements 40℃ February White block 1.20 Meet the requirements 40℃ March White block 1.40 Meet the requirements 40℃June White block 1.53 Does not meet the requirements, there are a few visible particles

[0210] Example 5 Preparation of levoketorolac lyophilized powder injection

[0211] prescription:

[0212] Levoketorolac: 1.0 g;

[0213] Mannitol: 10g;

[0214] Meglumine: 2.0 g;

[0215] Sodium dihydrogen phosphate dodecahydrate: 3.64 g;

[0216] 0.5 mol / L disodium hydrogen phosphate solution: appropriate amount, adjust to pH 7.0;

[0217] Water for injection: make up to a total volume of 200 g.

[0218] Preparation method:

[0219] Step 1: According to the above prescription, dissolve mannitol, sodium dihydrogen phosphate dodecahydrate, and meglumine with 70-80% water for injection to obtain a clear solution, then add levoketorolac and stir to dissolve it, adjust the pH to 7.0 with 0.5 mol / L disodium hydrogen phosphate solution; and make up to the total volume with water for injection;

[0220] Step 2): The drug solution is sterile filtered through 0.45μm, 0.22μm, and 0.22μm pore size polyethersulfone filter elements in sequence, and the intermediate solution is quality controlled for the content; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and plugging, it is pre-frozen at -5℃~-10℃ for 2h, cooled to -40℃ and kept warm for 3h, heated to -20℃~0℃ and sublimated and dried for 8~12h, then heated to 10~20℃, analyzed and dried for 6h~12h, then plugged, taken out of the cabinet, and finally capped to obtain the finished freeze-dried powder injection of levoketorolac. The relevant test data are as follows.

[0221] Time Characteristics Dexketorolac (%) Inspection of visible foreign matter and insoluble particles in the reconstituted solution Day 0 White block 0.42 Meet the requirements 5℃, January White block 0.42 Meet the requirements 5℃, February White block 0.42 Meet the requirements 5℃, March White block 0.43 Meet the requirements 5℃, June White block 0.43 Meet the requirements 25℃, January White block 0.41 Meet the requirements 25℃, February White block 0.46 Meet the requirements 25℃, March White block 0.48 Meet the requirements 25℃, June White block 0.58 Meet the requirements 40℃, January White block 0.73 Meet the requirements 40℃, February White block 0.91 Meet the requirements 40℃, March White block 1.00 Meet the requirements 40℃, June White block 1.32 Meet the requirements

[0222] Example 6 Preparation of lyophilized powder injection of levoketorolac tromethamine salt

[0223] prescription:

[0224] Levoketorolac tromethamine salt: 3.0 g;

[0225] Mannitol: 15g;

[0226] Edetate calcium sodium: 0.2g;

[0227] Sodium acetate: 3.64 g;

[0228] 0.5mol / L acetic acid solution: appropriate amount, adjust to pH 6.9;

[0229] Water for injection: make up to a total volume of 200 g.

[0230] Preparation method:

[0231] Step 1: According to the above prescription, dissolve mannitol, sodium dihydrogen phosphate dodecahydrate, and meglumine with 70-80% water for injection to obtain a clear solution, then add levoketorolac and stir to dissolve it, adjust the pH to 7.0 with 0.5 mol / L disodium hydrogen phosphate solution; and make up to the total volume with water for injection;

[0232] Step 2): The drug solution is sterile filtered through 0.45μm, 0.22μm, and 0.22μm pore size polyethersulfone filter elements in sequence, and the intermediate solution is quality controlled for the content; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and plugging, it is pre-frozen at -5℃~-10℃ for 2h, cooled to -40℃ and kept warm for 3h, heated to -20℃~0℃ and sublimated and dried for 8~12h, then heated to 10~20℃, analyzed and dried for 6h~12h, then plugged, taken out of the cabinet, and finally capped to obtain the finished freeze-dried powder injection of levoketorolac. The relevant test data are as follows.

[0233]

[0234]

[0235] Example 7 Preparation of lyophilized powder injection of levoketorolac arginine salt

[0236] prescription:

[0237] Levoketorolac arginine salt: 2.0 g;

[0238] Maltodextrin: 13g;

[0239] Sodium bisulfite: 0.2g;

[0240] Sodium phosphate: 3.1 g;

[0241] 0.5 mol / L phosphoric acid solution: appropriate amount, adjust to pH 7.1;

[0242] Water for injection: make up to a total volume of 200 g.

[0243] Preparation method:

[0244] Step 1: According to the above prescription, dissolve maltodextrin, sodium phosphate and sodium bisulfite with 70-80% water for injection to obtain a clear solution, then add levoketorolac arginine salt and stir to dissolve it, adjust the pH to 7.0 with 0.5 mol / L phosphoric acid solution; make up to the total volume with water for injection;

[0245] Step 2): The drug solution is sterile filtered through 0.45μm, 0.22μm, and 0.22μm pore size polyethersulfone filter elements in sequence, and the intermediate solution is quality controlled for the content; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and plugging, it is pre-frozen at -5℃~-10℃ for 2h, cooled to -40℃ and kept warm for 3h, heated to -20℃~0℃ and sublimated and dried for 8~12h, then heated to 10~20℃, analyzed and dried for 6h~12h, then plugged, taken out of the cabinet, and finally capped to obtain the finished freeze-dried powder injection of levoketorolac arginine. The relevant test data are as follows.

[0246]

[0247]

[0248] Example 8 Preparation of levoketorolac lyophilized powder injection

[0249] prescription:

[0250] Levoketorolac: 1.0 g;

[0251] Mannitol: 10g;

[0252] Meglumine: 1.5 g;

[0253] Vitamin C: 0.5g;

[0254] Sodium dihydrogen phosphate dodecahydrate: 3.64 g;

[0255] 0.5 mol / L disodium hydrogen phosphate solution: appropriate amount, adjust to pH 7.0;

[0256] Water for injection: make up to a total volume of 200 g.

[0257] Preparation method:

[0258] Step 1: According to the above prescription, dissolve mannitol, sodium dihydrogen phosphate dodecahydrate, meglumine, and vitamin C with 70-80% water for injection to obtain a clear solution, then add levoketorolac and stir to dissolve it, adjust the pH to 7.0 with 0.5 mol / L disodium hydrogen phosphate solution; and make up to the total volume with water for injection;

[0259] Step 2): The drug solution is sterile filtered through 0.45μm, 0.22μm, and 0.22μm pore size polyethersulfone filter elements in sequence, and the intermediate solution is quality controlled for the content; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and plugging, it is pre-frozen at -5℃~-10℃ for 2h, cooled to -40℃ and kept warm for 3h, heated to -20℃~0℃ and sublimated and dried for 8~12h, then heated to 10~20℃, analyzed and dried for 6h~12h, then plugged, taken out of the cabinet, and finally capped to obtain the finished freeze-dried powder injection of levoketorolac. The relevant test data are as follows.

[0260]

[0261]

[0262] Example 9 Preparation of lyophilized powder injection of levoketorolac tromethamine salt

[0263] prescription:

[0264] Levoketorolac tromethamine salt: 1.8 g;

[0265] Mannitol: 12g;

[0266] Arginine: 0.9 g;

[0267] L-cysteine: 0.2 g;

[0268] Citric acid: 0.8 g;

[0269] 0.5 mol / L sodium citrate solution: appropriate amount, adjust to pH 7.2;

[0270] Water for injection: make up to a total volume of 200 g.

[0271] Preparation method:

[0272] Step 1: According to the above prescription, dissolve mannitol, arginine, L-cysteine ​​and citric acid with 70-80% water for injection to obtain a clear solution, then add levoketorolac tromethamine salt and stir to dissolve it, adjust the pH to 7.2 with 0.5 mol / L sodium citrate solution; and make up to the total volume with water for injection;

[0273] Step 2): The drug solution is sequentially sterilized through 0.45 μm, 0.22 μm, and 0.22 μm pore size polyethersulfone material filter elements, and the intermediate solution is quality controlled for the content; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and plugging, it is pre-frozen at -5°C to -10°C for 2 hours, cooled to -40°C and kept warm for 3 hours, heated to -20°C to 0°C and sublimated and dried for 8 to 12 hours, then heated to 10 to 20°C, analyzed and dried for 6 hours to 12 hours, then plugged, taken out of the cabinet, and finally capped to obtain the lyophilized powder injection product of levoketorolac tromethamine salt. The relevant test data are as follows.

[0274]

[0275] Example 10 Preparation of levoketorolac lyophilized powder injection

[0276] prescription:

[0277] Levoketorolac: 2.0 g;

[0278] Mannitol: 20g;

[0279] Meglumine: 2.0 g;

[0280] Sodium dihydrogen phosphate dodecahydrate: 7.22 g;

[0281] 0.5 mol / L disodium hydrogen phosphate solution: appropriate amount, adjust to pH 6.9-7.0;

[0282] Water for injection: make up to a total volume of 400 g.

[0283] Preparation method:

[0284] Step 1: According to the above prescription, dissolve mannitol, sodium dihydrogen phosphate dodecahydrate, and meglumine with 70-80% water for injection to obtain a clear solution, then add levoketorolac and stir to dissolve it, adjust the pH to 7.0 with 0.5 mol / L disodium hydrogen phosphate solution; and make up to the total volume with water for injection;

[0285] Step 2): the drug solution is sequentially sterilized through 0.45 μm, 0.22 μm, and 0.22 μm pore size polyethersulfone filter elements, and the content of the intermediate solution is quality controlled; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and stoppering, it is pre-frozen at -5°C to -10°C for 2 hours, cooled to -40°C and kept warm for 3 hours, then heated to -20°C to 0°C for sublimation drying for 8 to 12 hours, then heated to 10 to 20°C, analyzed and dried for 6 hours to 12 hours, then stoppered, taken out of the cabinet, and finally capped to obtain the finished freeze-dried powder injection of levoketorolac.

[0286] Example 11 Preparation of levoketorolac lyophilized powder injection

[0287] prescription:

[0288] Levoketorolac: 2.0 g;

[0289] Mannitol: 20g;

[0290] Arginine: 2.0 g;

[0291] Sodium dihydrogen phosphate dodecahydrate: 7.23 g;

[0292] 0.5 mol / L disodium hydrogen phosphate solution: appropriate amount, adjust to pH 7.0-7.1;

[0293] Water for injection: make up to a total volume of 400 g.

[0294] Preparation method:

[0295] Step 1: According to the above prescription, dissolve mannitol, sodium dihydrogen phosphate dodecahydrate, and arginine with 70-80% water for injection to obtain a clear solution, then add levoketorolac and stir to dissolve it, adjust the pH to 7.0 with 0.5 mol / L disodium hydrogen phosphate solution; and make up to the total volume with water for injection;

[0296] Step 2): the drug solution is sequentially sterilized through 0.45 μm, 0.22 μm, and 0.22 μm pore size polyethersulfone filter elements, and the content of the intermediate solution is quality controlled; the drug solution is divided into neutral borosilicate glass tube injection bottles; after half-pressing and stoppering, it is pre-frozen at -5°C to -10°C for 2 hours, cooled to -40°C and kept warm for 3 hours, then heated to -20°C to 0°C for sublimation drying for 8 to 12 hours, then heated to 10 to 20°C, analyzed and dried for 6 hours to 12 hours, then stoppered, taken out of the cabinet, and finally capped to obtain the finished freeze-dried powder injection of levoketorolac.

[0297] Example 12 Pharmacokinetic study of single-dose administration in beagle dogs and cynomolgus monkeys

[0298] The lyophilized powder injection of levoketorolac of the present invention was tested for drug metabolism in beagle dogs and cynomolgus monkeys using representative batches. The administration method was single intravenous administration, and the concentrations of levoketorolac and dexketorolac in plasma samples were determined by liquid chromatography-mass spectrometry (LC-MS / MS), and blood drug concentration-time curves were drawn to obtain the main pharmacokinetic parameters and investigate the chiral conversion of the two in animals. The data are summarized as follows.

[0299] Pharmacokinetic parameters of levoketorolac in male and female beagle dogs after single intravenous administration of different doses (mean ± SD)

[0300]

[0301] Chiral conversion rate (%) = (AUC 0-t ) R / [(AUC 0-t ) S +(AUC 0-t ) R ]×100

[0302] NA: Not available.

[0303] Pharmacokinetic parameters of levoketorolac tromethamine in male and female cynomolgus monkeys after single intravenous administration of different doses (mean ± SD)

[0304]

[0305] Chiral conversion rate (%) = (AUC 0-t ) R / [(AUC 0-t ) S +(AUC 0-t ) R ]×100

[0306] As can be seen from the above, in dogs and monkeys, the conversion rate of levoketorolac to dextroketorolac is low, which is close to the 6.5% conversion rate of human body reported in the literature (J ClnPharmacol 1996; 36: 521-539). Under high-dose conditions, the conversion rate of levoketorolac to racemization does not increase significantly, which shows that the levoketorolac lyophilized powder injection of the present invention can still maintain a high proportion of levoketorolac after intravenous injection into the animal body, which lays a good foundation for efficiently exerting the analgesic effect.

Claims

1. A pharmaceutical composition of levoketorolac, characterized in that: The dosage form of the pharmaceutical composition is a lyophilized powder injection, and the optical purity of the active ingredient of the lyophilized powder injection is greater than or equal to 95% after being placed under long-term stability test conditions for 6 months; the optical purity of the active ingredient of the lyophilized powder injection is greater than or equal to 90% after being placed under accelerated stability test conditions for 6 months; and the moisture content of the lyophilized powder injection is less than or equal to 5%; The freeze-dried powder injection is prepared by freeze-drying a freeze-dried stock solution, wherein the freeze-dried stock solution includes a raw material drug, an excipient, a stabilizer and a pH regulator; The API is selected from any one of levoketorolac, levoketorolac tromethamine salt or levoketorolac arginine salt or a combination of at least two thereof; the excipient is selected from mannitol or maltodextrin; the stabilizer is selected from arginine or meglumine; and the pH adjuster includes a buffer and a constant volume pH adjuster; The buffer is anhydrous or crystalline water-containing phosphate and its solution, wherein the anhydrous or crystalline water-containing phosphate is selected from one or a combination of at least two of sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, tripotassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, ammonium hydrogen phosphate, ammonium dihydrogen phosphate, ammonium phosphate, calcium dihydrogen phosphate, calcium hydrogen phosphate or zinc phosphate; and the constant volume pH regulator makes the pH of the freeze-dried stock solution between 6.5 and 7.

5.

2. The pharmaceutical composition according to claim 1, characterized in that The anhydrous or crystal water-containing phosphate is selected from sodium dihydrogen phosphate, disodium hydrogen phosphate, or a combination of the two; The constant volume pH regulator is selected from any one of sodium hydroxide, potassium hydroxide, tromethamine, triethanolamine, diethanolamine, ethanolamine, sodium citrate, potassium citrate, sodium carbonate, sodium bicarbonate, anhydrous or crystalline hydrate of disodium hydrogen phosphate, anhydrous or crystalline hydrate of sodium dihydrogen phosphate, anhydrous or crystalline hydrate of dipotassium hydrogen phosphate, anhydrous or crystalline hydrate of potassium dihydrogen phosphate, sodium phosphate, phosphoric acid, hydrochloric acid, tartaric acid or lactic acid, or a combination of at least two thereof.

3. The pharmaceutical composition according to claim 1, characterized in that The pH value of the freeze-dried stock solution is 6.8-7.

2.

4. The pharmaceutical composition according to claim 1, characterized in that In the freeze-dried stock solution, levoketorolac C 15 H 13 The drug concentration measured by NO3 is 2-30 mg / ml.

5. The pharmaceutical composition according to claim 1, characterized in that The constant volume pH value regulator is selected from disodium hydrogen phosphate anhydrous or crystalline water, sodium dihydrogen phosphate anhydrous or crystalline water, phosphoric acid or sodium hydroxide; The excipient is selected from mannitol; and, In the freeze-dried stock solution, the drug concentration calculated as levoketorolac is 5-7.5 mg / ml; the pH value of the freeze-dried stock solution is 6.8-7.

2.

6. The pharmaceutical composition according to claim 1, characterized in that In the freeze-dried powder injection, the molar concentration of phosphate used as a pH adjuster is 0.01-0.1 mmol / ml; and the molar ratio of levoketorolac to phosphate in the freeze-dried stock solution is 1:1-1:3; The mass percentage of the excipient mannitol in the freeze-dried stock solution is 3% to 7%.

7. The pharmaceutical composition according to claim 1, characterized in that The freeze-dried stock solution also contains one or more of a metal ion chelator and an antioxidant; wherein the metal ion chelator is selected from one or more of edetate disodium, edetate calcium sodium, sodium citrate, and citric acid; and the antioxidant is selected from one or more of sodium thiosulfate, sodium sulfite, sodium pyrosulfite, sodium bisulfite, vitamin C, and L-cysteine.

8. The pharmaceutical composition according to claim 7, characterized in that The metal ion chelating agent is selected from disodium edetate or sodium calcium edetate, and its weight percentage in the freeze-dried stock solution is 0.05% to 1%; the antioxidant is selected from sodium bisulfite or vitamin C, and its weight percentage in the freeze-dried stock solution is 0.02% to 2%. The mass percentage of the stabilizer in the freeze-dried stock solution is 0.1% to 5%.

9. The pharmaceutical composition according to claim 7, characterized in that The weight percentage of each component in the freeze-dried stock solution during the preparation of the freeze-dried powder injection is as follows: Levoketorolac: 0.5% to 0.7%; Disodium hydrogen phosphate dodecahydrate: 1.8% to 2.0%; Mannitol: 6% to 9%; Disodium edetate: 0.05% to 0.1%; Add water for injection to: 100%; pH value is 6.8-7.2; Furthermore, the above-mentioned lyophilized stock solution is aseptically filtered, packaged, and freeze-dried to obtain the lyophilized powder injection.

10. The pharmaceutical composition according to claim 7, characterized in that The weight percentage of each component in the freeze-dried stock solution during the preparation of the freeze-dried powder injection is as follows: Levoketorolac: 0.5% to 1%; Disodium hydrogen phosphate dodecahydrate: 1.8% to 2.5%; Mannitol: 5% to 15%; Meglumine: 1% to 2%; Add water for injection to: 100%; pH value is 6.8-7.2; Furthermore, the lyophilized stock solution is aseptically filtered, packaged, and freeze-dried to obtain the lyophilized powder injection.

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