Fleroxacin medicinal composition for injection and preparation method thereof

Abstract

The invention provides a fleroxacin pharmaceutical composition for injection and a preparation method thereof, the pharmaceutical composition is composed of fleroxacin, a stabilizer, an excipient, water, a pH regulator and a solvent, and the ratio of fleroxacin to the stabilizer is 10: 0.1-10: 1.5. According to the fleroxacin pharmaceutical composition for injection and the preparation method of the fleroxacin pharmaceutical composition, the production process is simple, the product stability is good, and light impurities generated by illumination can be greatly reduced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a pharmaceutical composition for injection of fleroxacin and its preparation method. Background Technology

[0002] Fleroxacin is a quinolone antibacterial drug. Its mechanism of action is to inhibit bacterial DNA gyrase to achieve a bactericidal effect. It has the characteristics of broad antibacterial spectrum, strong antibacterial activity, high bioavailability, strong tissue penetration, long elimination half-life (10-20 h), and can be administered once daily. The main ingredient of this product is fleroxacin. Its chemical name is 6,8-difluoro-1-(2-fluoroethyl)1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.

[0003] Fluroxacin has strong antibacterial activity against Gram-negative bacteria, including Escherichia coli, Klebsiella pneumoniae, Proteus spp., Salmonella typhi, Salmonella paratyphi, Shigella spp., Enterobacter cloacae, Enterobacter aerogenes, Citrobacter spp., Serratia marcescens, Pseudomonas aeruginosa, Neisseria meningitidis, Haemophilus influenzae, Moraxella catarrhalis, Colletotrichum pneumophila, and Neisseria gonorrhoeae. It also has moderate antibacterial activity against Gram-positive cocci such as Staphylococcus spp. and hemolytic streptococci.

[0004] This product does not exhibit cross-resistance with other antibiotics. Clinically, it is mainly used for infections of the respiratory tract, urinary tract, and biliary tract caused by susceptible bacteria and chlamydia, such as gonococcal urethritis and bacterial enteritis. Dosage: Adults, 200mg-300mg / day, divided into oral doses of fleroxacin. Side effects are relatively mild, generally gastrointestinal reactions such as nausea, diarrhea, and loss of appetite; a few may experience insomnia, rash, and itching.

[0005] Fleroxacin is a quinolone antibiotic. Because it incorporates a fluorine substituent at the 8-position of the quinoline ring, it improves oral absorption, broadens its antibacterial spectrum, and enhances its in vivo activity. However, the introduction of fluorine also significantly increases its photosensitivity, resulting in greater phototoxicity than other classes. This also leads to poor stability during production, storage, transportation, and use, especially in liquid formulations of fleroxacin, such as fleroxacin injection, which are highly susceptible to photosensitive impurities. These impurities pose a significant health risk and greatly affect the drug's application.

[0006] Fleroxacin is thermally stable in solution and undergoes minimal degradation in the absence of light. Therefore, the reaction that occurs in a fleroxacin solution under light is photoinduced. Thus, the production, use, and in vivo processes of fleroxacin involve light and can generate photodegradation impurities, which are the main impurities in this drug. Therefore, addressing the issue of photodegradation impurities can significantly improve the drug's application.

[0007] Furthermore, fleroxacin injections are unstable in aqueous solutions under light, leading to a decline in quality. This is especially true for liquid injectable formulations, which require high temperatures and light exposure during preparation. Research data shows the changes in impurities during the preparation of formulations using existing technologies; see Table 1 for details.

[0008] Table 1: Therefore, there is an urgent need to provide a new injectable fleroxacin pharmaceutical composition and its preparation method to solve the above problems. Summary of the Invention

[0009] To address the aforementioned problems, this invention provides a pharmaceutical composition for injectable fleroxacin and its preparation method. This pharmaceutical composition has a simple production process, good product stability, and can significantly reduce light impurities caused by light exposure.

[0010] On one hand, the present invention discloses a pharmaceutical composition for injectable fleroxacin, wherein the pharmaceutical composition comprises fleroxacin, stabilizer, excipient, water, pH adjuster and solvent, and the ratio of fleroxacin to stabilizer is 10:0.1-10:1.5.

[0011] Preferably, the stabilizer is one or more of benzoin, melatonin, and chlorophyll.

[0012] Preferably, the excipient is one or more of mannitol, lactose, glucose, sorbitol and sodium chloride.

[0013] Preferably, the pH adjuster is one or more of hydrochloric acid, lactic acid, sodium hydroxide, phosphoric acid, and phosphate buffer.

[0014] Preferably, the solvent includes one or more of ethanol, isopropanol, glycerol, polyethylene glycol, and water.

[0015] On the other hand, the present invention also discloses a method for preparing the above-mentioned pharmaceutical composition, the method comprising the following steps: S1, Solution preparation and filtration Weigh an appropriate amount of water and the prescribed amount of isopropanol into a mixing tank, control the temperature at about 20℃, add the stabilizer and fleroxacin in sequence, stir for 10-30 min, then add the excipient and stir for 10-20 min, add the pH adjuster and stir until the pH value is 4.0-6.5, then add water for injection to the prescribed amount, make up the volume, stir for 10-20 min, and filter with 0.45μm and 0.22μm polyethersulfone filter cartridges in sequence. S2, Filling The drug solution was filled into cleaned and sterilized neutral borosilicate glass vials for injection, and then partially sealed with cleaned and sterilized chlorinated butyl rubber stoppers. S3, freeze-dried The product is transferred to a freeze-drying chamber and freeze-dried using a freeze-drying process. S4, Roller Cap Remove the capped products from the box and place them under protection in a clean area. Remove defective products such as those with missing caps, misaligned caps, or broken bottles. For qualified products, roll aluminum caps and check the integrity of the seal.

[0016] Preferably, in step S3, the freeze-drying process is as follows: Compared with the prior art, the beneficial effects of the present invention are: The pharmaceutical composition prepared by this invention has a simple preparation process, good process reproducibility, is suitable for large-scale production by enterprises, and has good market development prospects.

[0017] The pharmaceutical composition prepared by this invention can reduce photodegradation impurities, reduce the toxicity of impurities in vivo, and increase the stability of the formulation. Detailed Implementation

[0018] The technical solution of the present invention will be clearly and completely described below with reference to the embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0019] Example 1 The pharmaceutical composition provided in this embodiment is formulated based on 1000 dosage units as follows: Preparation method of pharmaceutical composition: S1. Dissolve melatonin, chlorophyll, fleroxacin, mannitol, isopropanol, and ethanol in water for injection.

[0020] S2. Adjust the pH to 4.3 using lactic acid, a pH adjuster. S3. Filter the above liquid through a microporous membrane (0.45μm→0.22μm), fill it into vials, and stopper them halfway. S4. The freeze-drying curves are shown in the table below. S5. Capping: Remove the capped products from the box and place them in a clean area for protection. Remove defective products such as those with missing caps, misaligned caps, or broken bottles. Crush aluminum caps onto qualified products and check the integrity of the seal.

[0021] Example 2 The pharmaceutical composition provided in this embodiment is formulated based on 1000 dosage units as follows: Preparation method of pharmaceutical composition: S1. Dissolve melatonin, fleroxacin, mannitol, isopropanol, and ethanol in water for injection.

[0022] S2. Adjust the pH to 4.3 using lactic acid, a pH adjuster. S3. Filter the above liquid through a microporous membrane (0.45μm→0.22μm), fill it into vials, and stopper them halfway. S4. The freeze-drying curves are shown in the table below. S5. Capping: Remove the capped products from the box and place them in a clean area for protection. Remove defective products such as those with missing caps, misaligned caps, or broken bottles. Crush aluminum caps onto qualified products and check the integrity of the seal.

[0023] Example 3 The pharmaceutical composition provided in this embodiment is formulated based on 1000 dosage units as follows: Preparation method of pharmaceutical composition: S1. Dissolve benzoin, chlorophyll, fleroxacin, mannitol, isopropanol, and ethanol in water for injection.

[0024] S2. Adjust the pH to 4.3 using lactic acid, a pH adjuster. S3. Filter the above liquid through a microporous membrane (0.45μm→0.22μm), fill it into vials, and stopper them halfway. S4. The freeze-drying curves are shown in the table below. S5. Capping: Remove the capped products from the box and place them in a clean area for protection. Remove defective products such as those with missing caps, misaligned caps, or broken bottles. Crush aluminum caps onto qualified products and check the integrity of the seal.

[0025] Table 2 compares the stability data of the pharmaceutical compositions prepared in Example 1. Among them, the prior art preparation is fleroxacin injection from Zhejiang Procon Natural Pharmaceutical Co., Ltd.

[0026] Table 2: The pharmaceutical composition prepared according to the embodiments of the present invention can reduce photodegradable impurities, reduce the toxicity of impurities in vivo, and increase the stability of the formulation.

[0027] In addition, the pharmaceutical composition prepared by this invention has a simple preparation process, good process reproducibility, is suitable for large-scale production by enterprises, and has good market development prospects.

[0028] The detailed descriptions listed above are merely specific descriptions of feasible embodiments of the present invention, and are not intended to limit the scope of protection of the present invention. All equivalent embodiments or modifications made without departing from the spirit of the present invention should be included within the scope of protection of the present invention.

[0029] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or essential characteristics. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

[0030] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style of the specification is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A pharmaceutical composition of fluroxquinolone for injection, characterized by, The pharmaceutical composition is composed of fleroxacin, stabilizer, excipient, water, pH regulator and solvent, the ratio of fleroxacin and stabilizer is 10:0.1-10:1.

5.

2. The pharmaceutical composition of claim 1, wherein The stabilizer is one or more of benzoin, melatonin and chlorophyll.

3. The pharmaceutical composition of claim 2, wherein The excipient is one or more of mannitol, lactose, glucose, sorbitol and sodium chloride.

4. The pharmaceutical composition of claim 3, wherein The pH regulator is one or more of hydrochloric acid, lactic acid, sodium hydroxide, phosphoric acid and phosphate buffer.

5. The pharmaceutical composition of claim 4, wherein The solvent includes one or more of ethanol, isopropyl alcohol, glycerol, polyethylene glycol and water.

6. Process for the preparation of a pharmaceutical composition according to any one of claims 1-5, characterized in that, The method comprises the following steps: S1, liquid preparation, filtration An appropriate amount of water and the prescription amount of isopropyl alcohol are weighed in a liquid preparation tank, the temperature is controlled at about 20℃, the stabilizer and fleroxacin are added in turn, stirred for 10-30min, then the excipient is added and stirred for 10-20min, the pH regulator is stirred until the pH is 4.0-6.5, then water for injection is added to the prescription amount, constant volume, then stirred for 10-20min, filtered with 0.45μm and 0.22μm polyether sulfone filter core in turn; S2, filling The liquid medicine is filled into a clean and sterilized neutral borosilicate glass tube injection vial, and a clean and sterilized chlorobutyl rubber plug is half-filled; S3, freeze-drying The product is transferred to a freeze-drying box, and freeze-drying is carried out by using a freeze-drying process; S4, cap rolling The product with the plug is taken out of the box and placed under protection in a clean area, and unqualified products such as missing plug, cap displacement and bottle breakage are removed, and qualified products are capped with aluminum cap, and the sealing integrity is checked.

7. The production method according to claim 6, wherein In step S3, the freeze-drying process is: 。

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