More stable dexibuprofen injection

Abstract

The dexibuprofen injection composition provided by the invention is more stable, and the inventor establishes a specific molar ratio of arginine to dexibuprofen to control the pH value of the injection within a specific range, so that the problem of clarity of the dexibuprofen injection is solved, the yield is greatly improved, and the requirements of industrial mass production are met.

Description

[0001] Technical Field The present invention relates to a pharmaceutical composition of dexibuprofen and arginine for injection. Background Art

[0002] Dexibuprofen is an aryl alkanoic acid compound and belongs to non-steroidal antipyretic analgesics (NSAIDS). However, due to its physical property of being almost insoluble in water, currently, clinically, there are only common oral preparations such as dexibuprofen tablets, capsules, dispersible tablets, and oral suspensions. Since dexibuprofen has low solubility and is absorbed slowly, its onset is relatively slow, and its bioavailability is also low. Moreover, it is inconvenient to use for the elderly and patients who cannot swallow solid preparations. Although it has the incomparable superiority of oral preparations, its extremely low solubility limits the development of injection preparations.

[0003] CN201410227075.3 discloses a method for preparing a dextrorotatory ibuprofen injection, which is composed of a main drug dextrorotatory ibuprofen, a cosolvent L-arginine and an antioxidant sodium bisulfite, and the pH of the injection is 7.0-8.0. The concentration of dextrorotatory ibuprofen is 10-100 mg / ml. The patent uses two cosolvents and introduces more excipients, which leaves safety risks for human medication.

[0004] CN201410309140.7 discloses a dextrorotatory ibuprofen injection and a preparation method thereof, wherein poloxamer-188 alone can significantly improve the solubility of dextrorotatory ibuprofen having an aryl alkanoic acid structure, and a pH regulator is used to adjust the pH of the injection to 7.5 to 8.5. Also, more excipients are introduced, increasing the potential risk of interactions between electrolytes and drugs.

[0005] CN201610161546.4 discloses a pharmaceutical composition containing ibuprofen and a preparation method thereof. The composition comprises ibuprofen, arginine, and one or more of chlorpromazine hydrochloride, L-malic acid, and povidone K30; wherein the molar ratio of arginine to ibuprofen is (1.01-1.05):1; and the pH is 7.2-8.2.

[0006] The above inventions still cannot meet the requirements of large-scale production for clarity.

[0007] We solve the problem of dexibuprofen dissolution by adding fewer types and lower amounts of excipients based on clinical safety. Therefore, we only use arginine as a dissolution aid and do not need to introduce a pH adjuster. We were surprised to find that there is a delicate balance between the molar ratio of arginine to dexibuprofen and the pH and clarity of the injection solution. Through precise process control, the yield rate is greatly improved, especially for the clarity of the preparation solution with a higher concentration (≥100mg / m1), which meets the needs of large-scale industrial production and avoids the losses caused by unstable production. Summary of the invention

[0008] Through extensive research in formulation studies, we determined that the addition of arginine salts can improve the solubility of dexibuprofen in water and produce 100-200 mg / ml dexibuprofen injection. Its mechanism of action is to increase the pH value of the solution, allowing the dexibuprofen of the aromatic alkanoic acid class to exist in ionic form and increase solubility.

[0009] At the same time, considering the human body's tolerance and the better solubility of dextrorotatory ibuprofen under alkaline conditions, the pH value of the preparations was controlled at 7.0-9.0 when studying the preparations related to dextrorotatory ibuprofen injection, which is an acceptable range for pharmaceutics. However, we found that even if the personnel, production equipment, raw material batches, manufacturing methods, and production environment were fully managed for quality, the stability of the solution clarity of the preparations obtained in different batches within this range was still significantly different, especially after terminal sterilization, the most obvious was the significant increase in visible foreign matter in the preparations, and even the appearance of suspended particles and opalescence. The unqualified rate of the finished product for visible foreign matter alone was as high as 20%, resulting in extremely unstable production quality, and it would increase based on the change of time, especially the phenomenon of unqualified clarity increased during the placement process, which did not meet the requirements of drug registration, could not be approved, and the company could not put the product on the market, and could not industrialize the production. The unstable problem of clarity that was sometimes good and sometimes bad has always troubled us.

[0010] To better identify instabilities and possible causes of increased visible foreign matter, we use automated particle counting or image analysis on samples during development and stability studies to fully characterize the inherent particles associated with the formulation to determine normal characteristics and possible time-based changes that may occur.

[0011] At the same time, considering that endogenous foreign matter may come from product components, containers and seals (such as glass bottles, rubber stoppers), and process equipment that contacts the product (such as pipes, filters, gaskets), etc. Therefore, the compatibility study of packaging materials also focuses on the visible particles; the components of auxiliary accessories / materials such as silicone oil used for lubrication or fluid transmission pipelines and various polymer accessories and seals used in processing equipment must be compatible with the formula to minimize leachate, and the amount used during processing must not exceed the minimum, etc., to eliminate the influence of other factors on clarity.

[0012] But the specific reason was not found. The clarity quality of different batches of products is still unstable. After a long period of analysis and a large number of experiments, in the validation test of the analytical methodology of membrane adsorption, we filtered the preparation solutions of different batches with a 0.1μm microporous filter membrane, eluted the insoluble particles on the filter membrane, and analyzed and tested them. Surprisingly, we found that the particles in some solutions were dexibuprofen, while some were arginine, and there were no arginine dexibuprofen particles.

[0013] In order to find out the cause of the precipitation of substances more clearly, the pH value of these batches of preparations was further monitored. The results showed that when the pH value was lower than 7.5, there was undissolved or precipitated dexibuprofen in the solution, and when the pH value exceeded 7.75, the particles in the solution were arginine. The further the preparation solution deviated from this pH range, the worse the clarity of the solution became, and it even led to an increase in visible foreign matter, which showed a certain pattern.

[0014] In order to further confirm the law we found, the applicant selected pH endpoint values ​​(7.50-7.75) and intermediate values ​​to carry out production verification. Finally, we found that: arginine cosolvent can significantly improve the solubility of dextrorotatory ibuprofen with aryl alkanoic acid structure, but the molar ratio of arginine to dextrorotatory ibuprofen and the pH and clarity of the injection solution have a delicate balance. Different pH has different requirements for different dextrorotatory ibuprofen and arginine molar ratios. When the pH value of dextrorotatory ibuprofen injection is controlled in the specific range of 7.50-7.75, the specific dextrorotatory ibuprofen and arginine molar ratio can ensure that the clarity and visible foreign matter meet the standards, the preparation solution is clear and transparent, without opalescence, the clarity quality is the most stable, and the defective product rate is reduced from 20% to below 3%, and can even be reduced to below 1%, ensuring the stability of quality, meeting the requirements of regulations and having the feasibility of large-scale production. The pH value can be controlled by controlling the ratio of arginine to dextrorotatory ibuprofen, that is, the molar ratio of arginine to dextrorotatory ibuprofen in the composition is about 0.945:1 to 0.980:1.

[0015] Based on this, the applicant has completed the present invention:

[0016] In a first aspect, the present invention provides a dexibuprofen injection, which contains dexibuprofen and arginine, wherein the molar ratio of dexibuprofen to arginine is about 0.945:1 to 0.980:1.

[0017] Furthermore, the pH of the injection is between 7.50 and 7.80; preferably, the pH is between 7.60 and 7.70.

[0018] Furthermore, the molar ratio of dexibuprofen to arginine is about 0.960:1 to 0.970:1.

[0019] In a second aspect, the present invention provides a method for preparing ibuprofen injection;

[0020] In a third aspect, the present invention provides a use of a specific ratio of dexibuprofen and arginine in the preparation of dexibuprofen injection, wherein the molar ratio of dexibuprofen to arginine is about 0.945:1 to 0.980:1.

[0021] Furthermore, the pH of the injection is between 7.50 and 7.80; preferably, the pH is between 7.60 and 7.70.

[0022] Furthermore, the molar ratio of dexibuprofen to arginine is about 0.960:1 to 0.970:1.

[0023] The following examples provide specific embodiments of the above findings, but they do not represent the entire scope of the present invention. The ibuprofen and arginine used in the examples are both pharmaceutically acceptable materials. DETAILED DESCRIPTION

[0024] Example 1

[0025] 1000ml product prescription composition concentration: 100mg / ml

[0026]

[0027] The process is described as follows:

[0028] 1) Weigh arginine according to the prescribed amount, add it to 4 / 5 of the prescribed amount of water for injection, stir and dissolve it.

[0029] 2) Weigh dexibuprofen according to the prescribed amount, add it to the above solution, and stir it at 50℃±5℃ to dissolve it.

[0030] 3) Add water for injection to the prescribed volume, stir and mix to obtain a 100 mg / ml solution;

[0031] 4) filtering the above solution through a 0.45 μm filter;

[0032] 5) Take samples and conduct intermediate detection; (pH value should be 7.50-7.75.

[0033] 6) Sterile filtration using a 0.2 μm cartridge filter;

[0034] 7) Filling (nitrogen protection may be used), capping, and sterilization to obtain a sterile preparation.

[0035] Example 2

[0036] 1000ml product prescription composition concentration: 100mg / ml

[0037]

[0038] The process description is as follows: Same as above

[0039] Example 3

[0040] 1000ml product prescription composition concentration: 100mg / ml

[0041]

[0042] The process description is as follows: Same as above

[0043] Example 4

[0044] 1000ml product prescription composition concentration: 100mg / ml

[0045]

[0046] The process description is as follows: Same as above

[0047] Example 5

[0048] 1000ml product prescription composition concentration: 100mg / ml

[0049]

[0050] The process description is as follows: Same as above

[0051] Example 6

[0052] 1000ml product prescription composition concentration: 100mg / ml

[0053]

[0054]

[0055] The process description is as follows: Same as above

[0056] Example 7

[0057] 1000ml product prescription composition concentration: 150mg / ml

[0058]

[0059] The process description is as follows: Same as above

[0060] Example 8

[0061] 1000ml product prescription composition concentration: 200mg / ml

[0062]

[0063] The process description is as follows: Same as above

[0064] Comparative Example 1:

[0065] 1000ml product prescription composition

[0066]

[0067] The process is described as follows:

[0068] 1) Weigh arginine according to the prescribed amount, add it to 4 / 5 of the prescribed amount of water for injection, stir and dissolve it.

[0069] 2) Weigh dexibuprofen according to the prescribed amount, add it to the above solution, and stir it at 50℃±5℃ to dissolve it.

[0070] 3) Add water for injection to the prescribed volume, stir and mix to obtain a 100 mg / ml solution;

[0071] 4) filtering the above solution through a 0.45 μm filter;

[0072] 5) Sampling and testing of intermediates;

[0073] 6) Sterile filtration using a 0.2 μm cartridge filter;

[0074] 7) Filling (nitrogen protection may be used), capping, and sterilization to obtain a sterile preparation.

[0075] Comparative Example 2:

[0076] 1000ml product prescription composition

[0077]

[0078]

[0079] The process description is as follows: Same as above

[0080] Comparative Example 3:

[0081] 1000ml product prescription composition

[0082]

[0083] The process description is as follows: Same as above

[0084] Technical effect comparison

[0085] Visible foreign matter inspection:

[0086] Use the light inspection method, that is, place the test sample under a light intensity of 1000-1500lx for inspection

[0087] Result determination: No obviously visible foreign matter such as metal shavings, glass shavings, fibers longer than 2mm, lumps with a maximum particle size exceeding 2mm, smoke-like particle deposits visible to the naked eye when gently rotated after standing for a certain period of time, countless particle groups, or precipitates that cannot be shaken off shall be detected in the test sample.

[0088]

[0089]

[0090] From the above, we can see that precise control of pH value can not only greatly improve the yield rate of production and manufacturing and reduce the rate of defective products, but also effectively improve the stability of product quality, avoid huge economic losses that may be caused by corporate production, and provide great safety guarantees for clinical applications.

Claims

1. A more stable dexibuprofen injection, characterized in that The molar ratio of dexibuprofen to arginine in the injection is 0.945:1-0.980:

1.

2. A more stable dexibuprofen injection as claimed in claim 1, characterized in that The injection has a pH value between 7.45 and 7.

80.

3. A more stable dexibuprofen injection as claimed in claim 1, 2, characterized in that The molar ratio of dexibuprofen to arginine in the injection is 0.960:1-0.970:

1.

4. A more stable dexibuprofen injection as claimed in claim 1, 2, characterized in that The pH value of the injection is between 7.60 and 7.

70.

5. Use of a specific ratio of dexibuprofen and arginine in the preparation of dexibuprofen injection, wherein the molar ratio of dexibuprofen to arginine in the injection is 0.945:1 to 0.980:

1.

6. The use according to claim 5, wherein the molar ratio of dexibuprofen to arginine in the injection is 0.960:1 to 0.970:

1.

7. The use according to claim 5 or 6, wherein the pH of the injection is between 7.45 and 7.

80.

8. The use according to any one of claims 5 to 7, wherein the injection has a pH value between 7.60 and 7.70.

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