CN115887360A - Celecoxib propionyl sodium injection and preparation method thereof - Google Patents

Abstract

The invention relates to a celecoxib propionyl sodium injection and a preparation method thereof. The celecoxib propionyl sodium injection comprises celecoxib propionyl sodium and optional injection auxiliary materials; the celecoxib propionyl sodium has the following structural formula:

Description

Celecoxib propionyl sodium injection and preparation method thereof

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a celecoxib propionyl sodium injection and a preparation method thereof.

Background

Since celecoxib has low solubility and is difficult to meet the requirements of injection, the celecoxib needs to be solubilized, and thus various solubilizers or organic solvents are required to be used in the conventional celecoxib compositions or preparations. For example, in patent application CN103211825A, cyclodextrin is used to solubilize celecoxib, but the pH of the composition is above 9, which causes problems such as pain when administered in large doses; in CN108472253A, celecoxib is prepared into a nano emulsion, and various oil phases are adopted for solubilization, so that the solubilization capacity is limited, and stability problems are easy to generate.

The invention is therefore proposed.

Disclosure of Invention

The first purpose of the invention is to provide a celecoxib propionyl sodium injection, which takes modified celecoxib-celecoxib propionyl sodium as a prodrug, can solve the problems of low solubility, hemolysis, irritation and the like of celecoxib, and can simultaneously meet the requirements of solubility, medication safety and the like even if no solubilizer is added; on the basis, auxiliary materials such as sulfobutyl-beta-cyclodextrin or salts thereof and the like are added to further improve hemolysis and improve the medication safety.

The second purpose of the invention is to provide a preparation method of celecoxib propionyl sodium.

The third purpose of the invention is to provide a preparation method of the celecoxib propionyl sodium injection, which solves the problem that the injection is difficult to store and transport by using a freeze-drying process and has good stability.

In order to achieve the above object, the present invention provides the following technical solutions.

One aspect of the invention provides a celecoxib propionyl sodium injection, which comprises celecoxib propionyl sodium and optional injection auxiliary materials;

the celecoxib propionyl sodium has a structural formula shown in a formula III:

the research of the invention finds that the solubility of the celecoxib propionyl-sodium is obviously improved (the solubility can reach 240mg/ml (equivalent to 200 mg/ml) of celecoxib), the hemolytic property is obviously improved (hemolysis does not occur even if the hemolysis is improved by 2.8mg/ml (calculated by the celecoxib), and the celecoxib propionyl-sodium can be metabolized into celecoxib at the concentration of the celecoxib, so that the clinical requirement can be met, and the drug effect is not influenced.

The injection auxiliary material can be at least one of an isotonic regulator, a pH regulator, an inclusion compound material, a buffering agent, an antioxidant, a bacteriostatic agent, an additive for reducing pain and irritation, water and the like.

The isotonic adjusting agent may be at least one of sodium chloride, glucose, and the like.

The pH regulator may be at least one of lactic acid, acetic acid, tartaric acid, hydrochloric acid, buffer salt, etc.

The clathrate material may be a cyclodextrin class of material.

The buffer may be at least one of disodium hydrogen phosphate, citric acid, etc.

The antioxidant may be at least one of sodium sulfite, sodium metabisulfite, vitamin C, etc.

The bacteriostatic agent may be at least one of benzyl alcohol, chlorobutanol, methyl hydroxybenzoate, ethylparaben, and butyl hydroxybenzoate.

The additive for reducing pain and irritation can be at least one of procaine hydrochloride, lidocaine, etc.

In some embodiments, the celecoxib propionyl sodium injection comprises at least one of celecoxib propionyl sodium, a clathrate material, a pH adjusting agent, an isotonic adjusting agent, and water for injection.

For example, the celecoxib propionyl sodium injection comprises celecoxib propionyl sodium and a clathrate material.

Or the celecoxib propionyl sodium injection comprises celecoxib propionyl sodium, an inclusion compound material and an isoosmotic adjusting agent.

Or the celecoxib propionyl sodium injection comprises celecoxib propionyl sodium, an inclusion compound material, a pH regulator and an isoosmotic adjusting agent.

Alternatively, the celecoxib propionyl sodium injection comprises celecoxib propionyl sodium, a pH regulator and an isoosmotic adjusting agent.

Or the celecoxib propionyl sodium injection comprises celecoxib propionyl sodium, an inclusion compound material, a pH regulator, an isotonic regulator and water for injection.

Or the celecoxib propionyl sodium injection comprises celecoxib propionyl sodium, an inclusion compound material, buffer salt, a pH regulator and water for injection.

In some embodiments, the isotonicity adjusting agent is preferably sodium chloride.

In some embodiments, the pH adjusting agent is preferably hydrochloric acid.

In some embodiments, the buffer salt is preferably disodium hydrogen phosphate and/or citric acid.

In some embodiments, the inclusion compound material is preferably sulfobutyl-beta-cyclodextrin or a salt thereof, and the invention finds that the sulfobutyl-beta-cyclodextrin or the salt thereof can achieve a surprisingly good effect after being combined with celecoxib propionyl sodium in research, so that the hemolysis and the injection irritation are greatly improved.

In some embodiments, the celecoxib propionyl sodium injection comprises celecoxib propionyl sodium, and sulfobutyl-beta-cyclodextrin and/or sulfobutyl-beta-cyclodextrin sodium.

Wherein the mass ratio of the total mass of sulfobutyl- β -cyclodextrin and sodium sulfobutyl- β -cyclodextrin to celecoxib propionyl sodium is preferably 3 to 480, such as 3.

In some embodiments, the mass ratio of sulfobutyl- β -cyclodextrin sodium to celecoxib propionyl sodium is preferably from 3 to 480, such as 3.

In some embodiments, the celecoxib propionyl sodium injection comprises sodium chloride, and the mass ratio of the sodium chloride to the celecoxib propionyl sodium is 0-9: 0.6 to 240, such as 0;8, 24, 2.25.

In the invention, the injection can exist in the form of a composition which is prepared as it is; or as a mixed injection solution; or mixing the composition with water, and lyophilizing to obtain lyophilized powder. For the injection in any form, the solution with proper osmotic pressure, pH value and other performance is prepared, and the celecoxib propionyl sodium is injected into human body without hemolysis, irritation and other side effects. In some embodiments, the celecoxib propionyl sodium injection is a solution type small water injection, and can be directly injected into muscle, skin, subcutaneous and other parts; in some embodiments, the celecoxib propionyl sodium injection is a freeze-dried powder injection, and is re-dissolved into a solution before use; in some embodiments, the celecoxib propionyl sodium injection is an infusion solution; in some embodiments, the celecoxib propionyl sodium injection is: independently packaging celecoxib propionyl sodium raw material medicine freeze-dried powder, namely A, independently packaging other auxiliary material solutions, namely B, and completely dissolving A in B before use.

In some embodiments, the injection is a solution containing water for injection or a lyophilized powder of the solution, and the pH of the solution is preferably 6.0 to 10.0, such as 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, etc., more preferably 6.0 to 9.0, more preferably 6.0 to 8.0, more preferably 7.0 to 8.0.

In some embodiments, the injection is in the form of a solution having a concentration of the active ingredient celecoxib propionyl sodium of 0.6 to 240mg/ml, such as 0.6mg/ml, 1mg/ml, 5mg/ml, 10mg/ml, 15mg/ml, 20mg/ml, 30mg/ml, 50mg/ml, 100mg/ml, 120mg/ml, 150mg/ml, 200mg/ml, 220mg/ml, 240mg/ml, and the like, preferably 0.6 to 24mg/ml,120 to 240mg/ml.

For injections of high concentration, the injection may be diluted appropriately at the time of use.

In another aspect of the invention, a method for preparing an injection is provided.

As mentioned above, the corresponding preparation method is selected according to different existing forms of the injection, and mainly comprises the following steps:

combining all the raw materials to form the injection; or optionally combining the raw materials and then adding water for injection to obtain an injection solution; optionally, freeze-drying the injection solution to obtain freeze-dried powder; or dissolving the celecoxib propionyl sodium raw material medicine, adjusting the pH value, freeze-drying, filling the rest auxiliary material solutions, sterilizing at the terminal, and directly dissolving the raw material medicine completely by adopting the auxiliary material solutions before use.

For the lyophilization process, preferred conditions are:

pre-freezing at-40 deg.C or below for more than 150 min; sublimation temperature of-15 deg.C or below for 900min or above, and vacuum degree of 0.3mbar or below; the secondary sublimation temperature is 30 ℃ or above, the retention time is 600min or above, and the vacuum pumping is carried out at the limit.

In another aspect of the invention, a method for preparing celecoxib propionyl sodium is provided:

wherein, the acid is preferably sulfuric acid solution, and the heating temperature is preferably 70-80 ℃;

the molar ratio of compound I to propionic anhydride is preferably 1.5 to 2.5, e.g. 1; the dosage ratio of the compound II to EtOH and NaOH is preferably 1mol: 1.05 to 1.2mol.

In summary, compared with the prior art, the invention achieves the following technical effects:

(1) The celecoxib is modified, propionyl groups are connected to amino groups, sodium salt is prepared, the solubility is greatly improved, even if other solubilizers are not added, the pH and osmotic pressure ranges of the prepared celecoxib injection are within physiologically acceptable ranges, the hemolytic capability is weaker than that of a celecoxib prototype, and the safety is higher.

(2) The sulfobutyl-beta-cyclodextrin or the sodium salt thereof is added into the celecoxib propionyl sodium injection, so that hemolysis and irritation can be further improved.

Description of the pharmaceutical practice of the invention

In some embodiments, the compound of the present invention or an injection comprising the compound of the present invention may be administered once or several times at different time intervals within a specified period of time according to a dosing schedule. For example, once, twice, three times or four times daily. In one embodiment, the administration is once daily. In yet another embodiment, the administration is twice daily. The administration may be carried out until the desired therapeutic effect is achieved or the desired therapeutic effect is maintained indefinitely. The appropriate dosing regimen for a compound of the invention or an injection comprising a compound of the invention depends on the pharmacokinetic properties of the compound, such as absorption, distribution and half-life, which can be determined by the skilled person. In addition, the appropriate dosage regimen of a compound of the invention or an injection comprising a compound of the invention, including the duration of time for which the regimen is carried out, will depend upon the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient being treated, the nature of concurrent therapy, the desired therapeutic effect, and other factors within the knowledge and experience of the skilled artisan. Such a skilled artisan will also appreciate that appropriate dosage regimens may be required to be adjusted for the individual patient's response to the dosage regimen, or as the individual patient needs to change over time.

The term "patient" as used herein is a mammal, including humans (adults and children) or other animals. In some embodiments, "patient" refers to a human.

The injectable formulations of the present invention may be administered simultaneously, or before or after, one or more other therapeutic agents. The injection of the present invention may be administered separately from the other therapeutic agents by the same or different routes of administration, or in the form of the same pharmaceutical composition.

In the production method of the present invention, "solution" means an aqueous solution unless otherwise specified.

The API in the invention refers to celecoxib propionyl sodium.

In the present invention, the concentration "mg/mL" means mg/mL, as weight/volume; d means days, e.g. 10d means 10 days; m refers to the number of months, e.g., 3M for 3 months; kg means kg, μ g means μ g, min means min, g means g, qs means adding, mbar means mbar, deg.c means celsius, mosm/kg means milliosmol/kg.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were carried out according to conventional conditions or conditions recommended by the manufacturer. The raw drugs, reagents or instruments used are conventional products which are commercially available or can be prepared according to the prior art, and manufacturers are not indicated.

The following examples measure celecoxib propionyl sodium using the HPLC method as follows.

Chromatographic conditions are as follows:

high performance liquid chromatography (Agilent HPLC-DAD);

a chromatographic column: agilent Zorbax SB C18,4.6 x 100mm,3.5 μm;

a detector: DAD detector, 220nm;

flow rate: 1.0ml/min;

a mobile phase A:0.1% phosphoric acid, mobile phase B: acetonitrile;

diluting liquid: acetonitrile-water (1: 25 ℃, sample pan temperature: the temperature was not controlled.

Gradient elution conditions are shown in Table 1 below, run time 23min, and sample size 2. Mu.l.

TABLE 1

Example 1

Preparation of celecoxib propionyl sodium

The synthetic route is as follows:

the first step is as follows: taking 1.0eq (eq represents molar equivalent), 2.0eq of propionic anhydride and 0.06eq of sulfuric acid of celecoxib to react at 75 ℃ to obtain celecoxib propionamide, and slowly cooling to room temperature of 25 +/-5 ℃ after the reaction is finished. Adding proper amount of tap water, stirring for 15min, standing for 15min, separating, removing water layer, and retaining toluene phase. And (3) carrying out reduced pressure distillation to remove the toluene, and controlling the temperature to be between 60 and 80 ℃ until no obvious distillate exists. The purity is more than 99.7 percent, and the yield is about 100 percent because of direct next step.

The second step: taking 1.0eq of celecoxib propionamide, 6-8 ml/eq of ethanol (taking the celecoxib propionamide as a molar reference) and 1.05-1.2 eq of sodium hydroxide, reacting at normal temperature, and slowly cooling to room temperature of 25 +/-5 ℃ after the reaction is finished. Centrifuging, adding appropriate amount of ethanol, leaching, and vacuum drying. The purity is more than 99.9 percent, and the yield is 93-97 percent.

Example 2

Determination of solubility of celecoxib propionyl sodium

Preliminary determination of the solubility of the compounds: respectively weighing 10ml of water for injection into a container, adding a stirrer, stirring, weighing a proper amount of the compound to be dissolved into the container for a few times, stirring for 10min, observing whether the compound is dissolved or not under a clarity detector until the compound cannot be dissolved, and calculating the initial solubility condition of the compound, wherein the results are shown in the following table 2.

TABLE 2

And (4) conclusion: the solubility of the celecoxib prototype is less than 5 mug/ml, which is consistent with the literature report, and the solubility is obviously increased after the modification, which can reach 240mg/ml (equivalent to 200mg/ml celecoxib), and completely meets the dosage requirement of the injection.

Example 3

Testing the stability of celecoxib propionyl sodium injection

The liquid preparation process comprises the following steps: weighing purified water with the total amount of about 70 percent, adding celecoxib propionyl sodium with the amount of the prescription shown in the table 3, stirring until the purified water is dissolved, adding sodium chloride with the amount of the prescription, adjusting the pH value to a proper value by adopting hydrochloric acid, fixing the volume, filtering, filling, and standing for high-temperature stability, wherein the data are shown in the following table 4 (the prescription 8-11 has no stability).

TABLE 3

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TABLE 4

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Remarking: the osmotic pressure of the formula 7 is 296mosm/kg, and the formula is an isotonic solution; RRT in the related substance item represents relative retention time.

And (4) conclusion: after all the prescriptions are placed at high temperature and stable, the content and the pH have no obvious change, and no precipitation phenomenon exists, only celecoxib in related substances has a certain increase, the celecoxib belongs to an active substance, and the limit can be set to be wider; the concentration of the celecoxib propionyl sodium can be 24-240 mg/ml (equivalent to the celecoxib concentration of 20-200 mg/ml), and stable samples can be obtained. Although the formulas 8-11 are not stable in standing, the appearance of the sample is not changed and no precipitation is generated after the sample is placed for 1 month at normal temperature.

Example 4

Effect of Sterilization on celecoxib propionyl sodium injections

The liquid preparation process comprises the following steps: weighing purified water with the total amount of about 70 percent, adding celecoxib propionyl sodium with the amount of the prescription shown in the table 5, stirring until the purified water is dissolved, adding auxiliary materials with the amount of the prescription, adjusting the pH value to a proper value by adopting hydrochloric acid, fixing the volume, filtering, filling, performing damp-heat sterilization on each 2ml, wherein the stability data of the sterilized samples are shown in the table 6 below.

TABLE 5

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TABLE 6

From the prescription and the sterilization conditions, the content and the pH of the sample do not change obviously before and after the sterilization of the prescription 1, the celecoxib is slightly increased, but the celecoxib is acceptable, the stability trend of the sample after the sterilization is equivalent to that before the sterilization, and the sample can bear the sterilization conditions of 121 ℃,15min and below, and 115 ℃ and 30min. As can be seen from formulas 1 and 2, the samples were essentially free of oxidizing impurities and no antioxidant was required.

And (4) conclusion: the celecoxib has certain growth after the sample is subjected to high-temperature sterilization, but does not precipitate, and is within an acceptable range.

Example 5

Determination of stability of celecoxib propionyl sodium injection with different pH values

The liquid preparation process comprises the following steps: weighing purified water with the total amount of about 70 percent, adding celecoxib propionyl sodium with the amount shown in the formula of the table 7, stirring until the celecoxib propionyl sodium is dissolved, adjusting the pH value to a proper value by adopting hydrochloric acid, fixing the volume, filtering, filling, wherein each bottle is 2ml, and the stability data is shown in the following table 8.

TABLE 7

TABLE 8

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And (4) conclusion: according to the stability data of different prescription samples, the pH value of the sample has little influence on impurity level, is acceptable, has small reduction in content, is still in an acceptable range, and has certain fluctuation in pH value in the stability process when the pH value is higher, so the pH value is preferably 9.0 or less.

Example 6

Celecoxib propionyl sodium freeze-dried powder

The liquid preparation process comprises the following steps: weighing purified water with the total amount of about 70 percent, adding celecoxib propionyl sodium with the amount of the prescription in the table 9, stirring until the mixture is dissolved, adjusting the pH value to a proper value by adopting hydrochloric acid, fixing the volume, filtering, filling 2ml of each bottle, and freeze-drying, wherein the freeze-drying process corresponding to the corresponding prescription is shown in the table 10.

TABLE 9

Watch 10

Lyophilized powder stability is shown in table 11 below.

TABLE 11

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And (4) conclusion: according to the prescription, the celecoxib propionyl sodium of 120-240 mg/ml can be lyophilized, the stability after lyophilization is better, the content and the pH are more stable, and the celecoxib in related substances is slowly increased, so that the celecoxib propionyl sodium is more favorable for storage.

By combining the above examples, the celecoxib propionyl-sodium composition is relatively stable, only celecoxib grows in the process of placement, and celecoxib belongs to an active substance, and the drug effect is not affected under the condition of no precipitation, so that the celecoxib propionyl-sodium composition can be placed in a wider range (only without precipitation); compared with the injection, the stability of the freeze-dried powder is better, the celecoxib is increased more slowly, and the precipitation risk is better, so that the freeze-dried powder is more preferably selected compared with the injection.

Example 7

Hemolysis experimental results of samples with different celecoxib propionyl sodium concentrations

When the injection is used for administration, the medicine enters blood rapidly, so that the blood concentration is high, the safety risk is high, and the safety of the injection needs to be strictly evaluated. Hemolysis refers to the rupture of erythrocytes, the escape of hemoglobin, and the hemolysis caused by any substance affecting erythrocyte membranes and rupturing erythrocytes, which causes a series of adverse reactions and seriously endangers life, so the hemolysis investigation must be carried out during preclinical research of injections.

Sample preparation:

preparation of a celecoxib prototype sample: dissolving and diluting with PEG400+ physiological saline to obtain final concentration of 0.25mg/ml and 0.1mg/ml, preparing solvent control, and filtering.

Preparation of celecoxib propionyl sodium sample: weighing 70g of water for injection into a container, adding 1.48g of celecoxib propionyl sodium, stirring until the celecoxib propionyl sodium is completely dissolved, adding 0.86g of sodium chloride, adjusting the pH to 7.6 by using hydrochloric acid, fixing the volume to 100ml, enabling the final concentration to be 14.8mg/ml, diluting 9.8,6.2,3.9 and 2.0mg/ml by using physiological saline, and respectively filtering for later use.

Hemolysis experiment: preparing 2% rabbit erythrocyte suspension, adding 2.5ml into a test tube, adding (2.5-X) ml of normal saline into the test tube, adding corresponding sample amount Xml into the test tube, uniformly mixing, placing in a thermostat, standing at the temperature of 37 +/-0.5 ℃, and observing the result after 3 h. The results are given in Table 12 below.

TABLE 12

Remarks 1: the celecoxib group solvent adopts PEG400+ water, and the solvent control group has no hemolysis;

remarks 2: the celecoxib propionyl sodium group sample adopts water as a solvent, sodium chloride adjusts osmotic pressure, pH is controlled to be 6-8, and the osmotic pressure is 280-350 mosm/kg;

as a result: the celecoxib prototype can be slightly hemolyzed at the concentration of 0.25mg/ml, the hemolytic capability of the celecoxib prototype on erythrocytes is weakened after the celecoxib prototype is modified into celecoxib propionyl sodium, the celecoxib propionyl sodium at 3.4mg/ml (equivalent to 2.8 mg/ml) can not be hemolyzed, and the celecoxib at 3.9mg/ml (equivalent to 3.2 mg/ml) can be slightly hemolyzed.

And (4) conclusion: the hemolysis condition of the sample can be improved after the reconstitution by integrating the hemolysis experimental result, and the infusion is carried out at the concentration of 3.4mg/ml (namely equivalent to 2.8mg/ml celecoxib) when the medicine is administrated, so that the hemolysis risk is avoided, and the medicine safety is improved.

Example 8

The metabolism of celecoxib propionyl sodium in vivo and in vitro

Liver microsome stability experiment: mu.L of liver microsomes (20 mg/ml) was added to 456.2. Mu.L of buffer (100 mM potassium phosphate buffer, pH 7.4. + -. 0.1) and incubated at 37 ℃ for 10min to obtain a liver microsome solution. Adding 25 μ L of sample solution, mixing, transferring 30 μ L of sample to each well of 96-well plate, wherein the sample concentration in each well is 1 μ M, incubating for a corresponding time, terminating the reaction (0, 20, 60min), measuring the amount of the sample remained in the system after treatment, and calculating the related parameters (no NADPH coenzyme added in the system), the results are shown in Table 13.

Watch 13

Remarking: t is a unit of _1/2 (min) is the metabolic half-life of the test sample in the system, T _1/2 Shorter refers to faster metabolism; ER (ethylene-propylene copolymer)>0.7 is rapid metabolism, 0.3<ER<0.7 is medium metabolic rate, ER<0.3 is slow metabolism; remainingg represents the amount of test article remaining in the system after 60min incubation.

And (4) conclusion: from the liver microsome metabolism results, the celecoxib propionyl sodium can be metabolized into a celecoxib prototype in different liver microsome systems, the metabolism rate is high, and the prodrug requirement is met.

Metabolism of celecoxib propionyl sodium in SD rats: the method comprises the steps of taking a celecoxib propionyl sodium solution, carrying out tail vein injection administration, collecting blood at different time points to measure blood concentration (simultaneously detecting celecoxib propionyl sodium and a celecoxib prototype), and calculating relevant pharmacokinetic parameters, wherein the result is shown in the following table 14.

TABLE 14

Remarking: AUC is the area under the time curve, C _max At maximum blood concentration, T _1/2 For metabolic half-life, T _max Time at maximum blood concentration;

and (4) conclusion: from the in vivo metabolism results, the celecoxib propionyl sodium can be quickly converted into celecoxib in vivo after being administered, and the exposure of the celecoxib is far higher than that of the celecoxib propionyl sodium.

From the results, the celecoxib propionyl sodium can be prepared into concentrated solution or freeze-dried powder or infusion solution, preferably freeze-dried powder, and diluted to corresponding concentration (< 2.8mg/ml in terms of celecoxib) for instillation before use, so that the celecoxib propionyl sodium is converted into celecoxib in vivo, the anti-inflammatory and analgesic effects are achieved, and hemolysis is avoided.

Example 9

Hemolysis of celecoxib propionyl sodium injection containing sulfobutyl-beta-cyclodextrin sodium

Preparation of prescription solution: weighing the total amount of about 60 percent of water for injection, adding the celecoxib propionyl sodium and the sulfobutyl-beta-cyclodextrin sodium in the amount of the prescription shown in the table 15, stirring until the celecoxib propionyl sodium and the sulfobutyl-beta-cyclodextrin sodium are completely dissolved, adjusting the pH to 6.0-8.0 by hydrochloric acid or sodium hydroxide, fixing the volume, filtering and filling for later use. The mixture was diluted with water for injection to the concentration shown in Table 16 by concentration gradient

Watch 15

Remarks 1: the actual dosage of the celecoxib propionyl-sodium is the dosage after the celecoxib propionyl-sodium is dried or purified;

remarks 2: the concentration refers to the celecoxib propionyl sodium concentration.

The procedure of the hemolysis experiment in example 7 was followed, and the results are shown in Table 16 below.

TABLE 16

Remarking: formula 1 was without sulfobutyl- β -cyclodextrin sodium, formula API was celecoxib propionyl sodium, "/" indicating that the experiment was not performed.

And (4) conclusion: compared with the formulas 2,3 and 4, the formula 1 can improve the hemolytic ability of the celecoxib propionyl sodium after the sulfobutyl-beta-cyclodextrin sodium is added, when the dosage of the sulfobutyl-beta-cyclodextrin sodium is 5 times or 10 times of that of the API, the hemolytic ability is improved to a certain extent, slight hemolysis is generated from 3.2mg/ml to 5.0mg/ml, hemolysis is not generated, when the dosage of the sulfobutyl-beta-cyclodextrin sodium is increased to 20 times of the API, the hemolytic ability is obviously reduced, hemolysis is not generated under the condition of 20mg/ml, and the safety is greatly improved. After the sulfobutyl-beta-cyclodextrin is added, the safety of injection administration can be improved.

Example 10

Test of hemolysis of celecoxib propionyl sodium injection containing sulfobutyl-beta-cyclodextrin sodium

Preparation of prescription solution: weighing the total amount of about 60 percent of water for injection, adding the celecoxib propionyl sodium and the sulfobutyl-beta-cyclodextrin sodium in the amount shown in the formula 17, stirring until the celecoxib propionyl sodium and the sulfobutyl-beta-cyclodextrin sodium are completely dissolved, adjusting the pH to 7.6 by hydrochloric acid or sodium hydroxide, fixing the volume, filtering, and filling for later use. The solution was diluted with water for injection to the concentration shown in Table 18.

TABLE 17

Hemolysis experiment: preparing 2% rabbit erythrocyte suspension, adding 2.5ml into a test tube, adding 2ml of physiological saline into the test tube, adding 0.5ml of corresponding sample into the test tube, uniformly mixing, placing in a thermostat, standing at the temperature of 37 +/-0.5 ℃, and observing the result after 3 h. The results are given in Table 18 below.

Watch 18

And (4) conclusion: formulation 1 does not cause hemolysis at concentrations of 8.0mg/ml and below, and causes slight hemolysis at 10.0 mg/ml; the other prescriptions can not generate hemolysis when the concentration is less than 20mg/ml, namely when the dosage of the sulfobutyl-beta-cyclodextrin sodium is 16 times or more than API, the administration concentration of the celecoxib propionyl sodium can reach 24mg/ml (namely equivalent to the celecoxib concentration of 20 mg/ml) and can not generate hemolysis, and the safety is better. From the results of examples 7, 9 and 10, it was found that when sulfobutyl- β -cyclodextrin sodium was not added to the formulation, hemolysis did not occur when celecoxib propionyl-sodium was administered at a concentration of 3.2mg/ml (equivalent to 2.8mg/ml celecoxib); when the dosage of the sulfobutyl-beta-cyclodextrin in the prescription is 5-15 times (not including 15 times) of the dosage of API, the celecoxib propionyl-sodium administration concentration is 6mg/ml (equivalent to 5mg/ml celecoxib) without hemolysis; when the dosage of the sulfobutyl-beta-cyclodextrin in the prescription is 15 times of that of API, the celecoxib propionyl sodium administration concentration is 9.6mg/ml (equivalent to 8mg/ml celecoxib) without hemolysis; when the dose of sulfobutyl-beta-cyclodextrin sodium in the prescription is 16-20 times of that of API, the celecoxib propionyl sodium dose concentration is 24mg/ml (equivalent to 20mg/ml celecoxib) without hemolysis.

EXAMPLE 11 stability of samples with varying amounts of sodium sulfobutyl-beta-cyclodextrin

The liquid preparation process comprises the following steps: weighing the total amount of 60% of water for injection, adding the API and the auxiliary materials in the amount prescribed in the table 19, stirring until the materials are completely dissolved, adjusting the pH to 6.0-8.0 by hydrochloric acid or sodium hydroxide, fixing the volume, filtering, filling, taking 2ml of each sample, and sterilizing a part of the samples at high temperature under the sterilization condition of 121 ℃ for 12-15min. All samples were left to stabilize and the results are shown in table 20.

Watch 19

Remarks 1: the dose of the celecoxib propionyl-sodium is fed after being dried or purified.

Watch 20

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From the prescription, different dosages of sulfobutyl-beta-cyclodextrin sodium have no influence on the pH value in the product stability process, but have certain influence on related substances and content, the larger the dosage of the sulfobutyl-beta-cyclodextrin sodium is, the faster the celecoxib in the related substances is increased, the faster the content is reduced, but as the celecoxib belongs to active substances, the limit can be relaxed as long as the celecoxib is controllable, the content and the related substances can be accepted when the dosage of the sulfobutyl-beta-cyclodextrin sodium is 10-20 times of API, and from the rule, the smaller the dosage of the sulfobutyl-beta-cyclodextrin sodium is, the slower the celecoxib is increased, so that the quality can be presumed to be accepted when the dosage is 5 times; after the product is sterilized, the content and the pH value are slightly reduced, but in an acceptable range, celecoxib in related substances is increased to a certain extent, but the increase of the celecoxib in the stability process is not influenced by the sterilization. Even if the product is sterilized and placed at high temperature for 10d,40 ℃ for 1 month and at room temperature for 12 months, the content of the celecoxib does not exceed 10 percent, the content is still more than 90 percent, the celecoxib is an active substance, and the precipitation phenomenon does not occur, so that the product quality is considered to be still acceptable.

And (4) conclusion: when the dosage of the sulfobutyl-beta-cyclodextrin is 5-20 times of the dosage of API, after the sample is placed under the conditions of high temperature, acceleration and room temperature without sterilization and after sterilization, although the content of the celecoxib in the product is increased to a certain extent, the celecoxib belongs to an active substance and does not precipitate, and the product quality is acceptable.

EXAMPLE 12 stability Studies of samples at different concentrations

The liquid preparation process comprises the following steps: weighing the total amount of about 60% of water for injection, adding the API and the auxiliary materials in the amount prescribed in the table 21, stirring until the materials are completely dissolved, adjusting the pH value to 6.0-8.0 by hydrochloric acid or sodium hydroxide, fixing the volume, filtering, filling, wherein each 2ml of the solution is placed stably, and the results are shown in the table 22.

TABLE 21

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Remarking: the dose of the celecoxib propionyl-sodium is fed after the celecoxib propionyl-sodium is dried or purified.

TABLE 22

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From the above prescription results, when the dosage of the fixed sulfobutyl-beta-cyclodextrin is 20 times of that of the API, the concentration of the API in the prescription has a certain influence on the increase of the celecoxib in the sample stability process, the higher the concentration is, the faster the celecoxib increases, but after the sample is accelerated for 3 months at high temperature for 10 days and at room temperature for 6 months, the content of the celecoxib in the sample still does not exceed 10%, and the content of the celecoxib is not lower than 90%, which are all within an acceptable range.

And (4) conclusion: when the concentration of the celecoxib propionyl sodium is 2.4-18 mg/ml, the celecoxib propionyl sodium is placed at high temperature for 10 days, the placing is accelerated for 3 months, and the placing is carried out at room temperature for 6 months, so that the sample is still acceptable.

Example 13 stability Studies of samples at different pH

The liquid preparation process comprises the following steps: weighing the total amount of about 60% of water for injection, adding the API and the auxiliary materials in the amount prescribed in Table 23, stirring until the materials are completely dissolved, adjusting the pH value to a proper value by hydrochloric acid or sodium hydroxide, fixing the volume, filtering, filling, wherein each 2ml of the solution is placed stably, and the result is shown in Table 24.

TABLE 23

Watch 24

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From the above formula results, it can be seen that the pH difference during the liquid preparation does not affect the increase of the content and related substances during the stability process, but the pH difference affects the physical stability of the sample, when the pH is lower than 5.5, the sample is easy to precipitate, and when the pH of the liquid preparation is lower than 7 or higher than 8, the pH fluctuates to some extent during the stability process, and finally the pH tends to be 7.5. For injection, the injection pain is weak when the pH is 4-9, if the preparation can not meet the requirement, the injection pain can be widened to 3-11, but pain or local inflammation is easily caused during injection, according to the result, the pH of the celecoxib propionyl sodium can be accepted when the pH is 6-9, and the prescription has certain fluctuation in the pH during the stability process, but the pH is in an acceptable range.

And (4) conclusion: the pH value of the prescription of the celecoxib propionyl sodium injection is acceptable when the pH value is 6-9, the sample is placed at high temperature for 10 days, the placing is accelerated for 3 months, and the placing is carried out at room temperature for 3 months to 6 months, so that the requirement is still met. However, at pH7 to 8, the pH fluctuation during the stabilization process is smaller and more stable.

Example 14 Freeze-dried powder stability Studies

The liquid preparation process comprises the following steps: weighing the total amount of about 60% of water for injection, adding the API and the auxiliary materials in the amount prescribed in Table 25, stirring until the materials are completely dissolved, adjusting the pH value to 7-8 with hydrochloric acid or sodium hydroxide, fixing the volume, filtering, filling, performing freeze-drying for 2ml each, wherein the freeze-drying procedure is shown in Table 26, and the materials are subjected to plug-pressing and discharging after the freeze-drying is completed, capping, standing stability and stability conditions are shown in Table 27.

TABLE 25

Remarking: the two formulas are different from each other in sulfobutyl-beta-cyclodextrin manufacturers, hydrochloric acid and sodium hydroxide are not added into the formula 1, and hydrochloric acid is added into the formula 2 to adjust the pH value to 7.4.

Watch 26

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The data show that the celecoxib propionyl sodium injection has good stability after being freeze-dried, the content and the pH value are relatively stable after being placed at high temperature for 10 days, being accelerated to be placed for 6 months and being placed at room temperature for 12 months, and the celecoxib in related substances is increased to a certain extent, is not more than 0.5 percent and can completely meet the administration requirement of the injection.

And (4) conclusion: the celecoxib propionyl-sodium sample has better stability after being freeze-dried, and the key quality is not obviously changed after the celecoxib propionyl-sodium sample is placed for 10 days at high temperature, is placed for 6 months at an accelerated speed and is placed for 12 months at room temperature, and is all within an acceptable range.

Example 15 stability post terminal Sterilization of API lyophilized powder and specialty solvents

The special solvent liquid preparation process comprises the following steps: weighing 80% of water for injection, adding adjuvants in the amount specified in Table 28, stirring to dissolve completely, adjusting pH to about 4.5 with hydrochloric acid or sodium hydroxide, diluting to desired volume, filtering, bottling, and sterilizing at 121 deg.C for 15min.

Preparing the API freeze-dried powder: weighing 180g of water for injection, adding the API in the formula shown in Table 28, stirring until the API is completely dissolved, fixing the volume, filtering, filling 2ml of the solution per bottle, freeze-drying, wherein the freeze-drying procedure is shown in Table 29, and after the freeze-drying is finished, plugging and discharging, capping, and placing stability are shown in tables 30 and 31.

Watch 28

Remarking: formula 1 is a special solvent containing only sulfobutyl-beta-cyclodextrin, and formula 2 is an API solution (prepared as a lyophilized powder).

Watch 29

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As can be seen from the data, the special solvent for the formula 1 has stable property after being subjected to moist heat sterilization and being placed at high temperature for 10 days and accelerated for 1 month; the celecoxib propionyl sodium API in the formula 2 has good stability after freeze-drying, and after the celecoxib propionyl sodium API is placed for 10 days at high temperature and is placed for 1 month at an accelerated speed, the content, the pH value and related substances are relatively stable, and the administration requirement of the injection can be completely met.

And (4) conclusion: the celecoxib propionyl sodium API can be redissolved by a special solvent for damp-heat sterilization after being freeze-dried, and is good in stability.

Example 16 Low temperature stability Studies of Small squirt samples with different Cyclodextrin dosages

The liquid preparation process comprises the following steps: weighing about 70% of total amount of water for injection, adding API and adjuvants in the amount prescribed in Table 32, stirring to dissolve completely, adjusting pH to 7.0 with hydrochloric acid or sodium hydroxide, diluting to constant volume, filtering, bottling, sterilizing 2ml per bottle, and sterilizing a part of sample at 115-121 deg.C for 8-30min. All samples were left for high temperature stability and the results are shown in table 33.

Watch 32

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According to the formula, small water injection samples with different dosages of sulfobutyl-beta-cyclodextrin sodium have good stability at low temperature (5 ℃) and room temperature (25 ℃); after the product is sterilized, the content of celecoxib is reduced in a small degree, but in an acceptable range, certain increase of celecoxib in related substances is achieved, but the increase of celecoxib in the stability process is not influenced by sterilization.

And (4) conclusion: the sterilized sample is placed at low temperature and room temperature and has good stability.

Example 17 preparation of samples containing buffer salts

Preparation of prescription solution: weighing the total amount of 60% of water for injection, adding the API and the auxiliary materials in the formula amount shown in Table 34, stirring until the materials are completely dissolved, adding the buffer salt in the formula amount, adjusting the pH to 7-8 by using hydrochloric acid or sodium hydroxide, fixing the volume, filtering, filling, wherein each 2ml of the solution is placed stably, and the stability result is shown in Table 35.

Watch 34

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It can be seen from the above formula that after a certain amount of buffer salt is added, the content of the sample is not affected, the pH change range in the high-temperature process can be relatively stabilized after the buffer salt is added, but the influence is not great, and the increase of celecoxib in related substances is not affected basically by adding the buffer salt.

And (4) conclusion: after the buffer salt is added into the prescription, the fluctuation of pH in the stability process can be reduced, and the change of content and related substances is not influenced. The sample is placed at high temperature for 10 days, the placing is accelerated for 3 months, and the sample still meets the requirements after being placed at room temperature for 12 months; when the pH value of the preparation solution is between 7 and 8, the pH change in the stability process can be accepted when no buffer salt is added.

Example 18

Irritation test of celecoxib propionyl sodium with different prescriptions

Preparation of prescription solution: weighing the total amount of 60% of water for injection, adding the API and the auxiliary materials in the amount prescribed in the table 36, stirring until the materials are completely dissolved, adjusting the pH value to 6.0-8.0 by hydrochloric acid or sodium hydroxide, fixing the volume, filtering to obtain a prescribed solution of 24mg/ml (20 mg/ml calculated by celecoxib), and filling for later use.

Watch 36

The stimulation test was performed using SD rats (300 to 350 g) in which 3 animals per group were administered in the tail vein for 7 days, and the response of the animals after administration was observed, and the results are shown in Table 37 below.

Watch 37

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From the above results, after adding sodium sulfobutyl-beta-cyclodextrin, the tolerance of injection administration of rats is improved, the stress response of animals in high-dose groups is obviously slowed down, and the hemolysis is also greatly improved.

In conclusion, the celecoxib propionyl sodium can be prepared into concentrated solution or freeze-dried powder or infusion solution, preferably freeze-dried powder, and is diluted to corresponding concentration for instillation before use, the prescription without sulfobutyl-beta-cyclodextrin needs to be instilled at the concentration lower than 3.2mg/ml, and the prescription containing sulfobutyl-beta-cyclodextrin can be instilled at the concentration lower than 24 mg/ml; after administration, the celecoxib propionyl sodium is converted into celecoxib in vivo, so that the effects of resisting inflammation and easing pain are achieved, and hemolysis is avoided.

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.

Claims (12)

1. The celecoxib propionyl sodium injection is characterized by comprising celecoxib propionyl sodium and optional injection auxiliary materials;

the celecoxib propionyl sodium has a structural formula shown in a formula III:

2. the celecoxib propionyl sodium injection of claim 1, wherein the injection excipients comprise at least one of isotonic adjusting agent, buffer, pH adjusting agent, clathrate material, and water.

3. The celecoxib propionyl sodium injection of claim 2,

the isotonic regulator is preferably sodium chloride;

the buffering agent is preferably disodium hydrogen phosphate and citric acid;

the pH regulator is preferably hydrochloric acid;

the inclusion compound material is preferably sulfobutyl-beta-cyclodextrin or a salt thereof.

4. The celecoxib propionyl sodium injection of any one of claims 1-3, comprising celecoxib propionyl sodium, and sulfobutyl- β -cyclodextrin and/or sulfobutyl- β -cyclodextrin sodium.

5. The celecoxib propionyl sodium injection according to claim 4, wherein the mass ratio of the total mass of sulfobutyl-beta-cyclodextrin to sulfobutyl-beta-cyclodextrin sodium to the mass of celecoxib propionyl sodium is 3 to 480, 0.6 to 24, preferably 5 to 20; or the mass ratio of the sulfobutyl-beta-cyclodextrin sodium to the celecoxib propionyl sodium is 3-480, preferably 5-20.

6. The celecoxib propionyl sodium injection according to any one of claims 1 to 3, further comprising sodium chloride, wherein the mass ratio of the sodium chloride to the celecoxib propionyl sodium is 0-9: 0.6 to 240, preferably 1.5 to 32.

7. The celecoxib propionyl sodium injection according to any one of claims 1-3, comprising a buffering agent, preferably disodium hydrogen phosphate and/or citric acid.

8. The celecoxib propionyl sodium injection according to any one of claims 1 to 3, wherein the injection is a solution containing water for injection or a lyophilized powder thereof, and the pH value of the solution or the solution after reconstitution of the lyophilized powder is preferably 6.0 to 9.0, more preferably 6.0 to 8.0.

9. The celecoxib propionyl sodium injection of claim 8, wherein the concentration of celecoxib propionyl sodium in the solution is 0.6-240 mg/ml.

10. The method of preparing a celecoxib propionyl sodium injection of any one of claims 1-9, comprising:

combining all the raw materials to form the injection; or optionally combining the raw materials and then adding water for injection to obtain an injection solution; optionally lyophilizing the injection solution to obtain lyophilized powder; or dissolving the celecoxib propionyl sodium raw material medicine, adjusting the pH value, freeze-drying, filling the rest auxiliary material solutions, sterilizing at the terminal, and directly dissolving the raw material medicine completely by adopting the auxiliary material solutions before use.

11. The method of claim 10, wherein the lyophilization process is:

pre-freezing at-40 deg.C or below for over 150 min; sublimation temperature of-15 deg.C or below for 900min or above, and vacuum degree of 0.3mbar or below; the secondary sublimation temperature is 30 ℃ or above, the retention time is 600min or above, and the vacuum pumping is limited.

12. The process according to claim 10 or 11, wherein the celecoxib propionyl sodium is prepared by the following route:

wherein, the acid is preferably sulfuric acid solution, and the heating temperature is preferably 70-80 ℃;

the mol ratio of the compound I to the propionic anhydride is preferably 1.5-2.5, the dosage ratio of the compound II to EtOH and NaOH is preferably 1mol: 1.05 to 1.2mol.