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CN-121987566-A - Ciprofloxacin hydrochloride liquid medicinal preparation with low disubstituted impurities and preparation method thereof

CN121987566ACN 121987566 ACN121987566 ACN 121987566ACN-121987566-A

Abstract

The invention discloses a ciprofloxacin hydrochloride liquid pharmaceutical preparation with low disubstituted impurities and a preparation method thereof, belonging to the field of pharmacy. Aiming at the problem that the light stability and the wet heat stability of the existing ciprofloxacin hydrochloride solution preparation are difficult to improve synchronously, the preparation provided by the invention consists of ciprofloxacin hydrochloride, tryptophan, weak acid buffer pair salt, a solvent and pharmaceutically acceptable auxiliary materials, and the pH value of the preparation is 5.5-7.0. The tryptophan is added and the pH value is regulated and controlled in a synergistic way, so that the light stability and the damp-heat stability of the preparation are obviously improved, the preparation process is simple and controllable, and the preparation process can be adapted to various liquid dosage forms such as injection, eye drops, oral solution and the like, and has good industrial conversion prospect.

Inventors

  • CHEN RUQIANG
  • ZHOU WENXIANG
  • TAO KAIYUE
  • Yang huafang
  • PU JIN
  • CHEN ZHONGPING
  • HUANG ZHENGFU

Assignees

  • 浙江朗华制药有限公司

Dates

Publication Date
20260508
Application Date
20260401

Claims (10)

  1. 1. The ciprofloxacin hydrochloride liquid medicine preparation is characterized by comprising ciprofloxacin hydrochloride, a light stabilizer, weak acid buffer pair salt, a solvent and pharmaceutically acceptable auxiliary materials; The light stabilizer is tryptophan; the pharmaceutically acceptable auxiliary materials are at least one of pH regulator and flavoring agent.
  2. 2. The liquid pharmaceutical formulation of ciprofloxacin hydrochloride according to claim 1, wherein the pH of the liquid formulation of ciprofloxacin hydrochloride is 5.5-7.0.
  3. 3. The liquid pharmaceutical formulation of ciprofloxacin hydrochloride according to claim 1, wherein the weight ratio of ciprofloxacin hydrochloride to tryptophan in the liquid formulation is 1:0.1-0.5.
  4. 4. The ciprofloxacin hydrochloride liquid pharmaceutical preparation according to claim 1, wherein the weak acid buffer pair salt is at least one of sodium dihydrogen phosphate and disodium hydrogen phosphate, acetic acid and sodium acetate, citric acid and sodium citrate, tartaric acid and sodium tartrate, succinic acid and sodium succinate, lactic acid and sodium lactate, and the solvent is at least one of purified water, water for injection and aqueous ethanol solution.
  5. 5. The ciprofloxacin hydrochloride liquid medicine preparation according to claim 1, wherein the pH regulator is at least one of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, succinic acid, tartaric acid, sodium hydroxide and sodium bicarbonate, and the flavoring agent is at least one of sucrose, mannitol, sorbitol, sucralose, aspartame, saccharin sodium and essence.
  6. 6. The liquid pharmaceutical formulation of ciprofloxacin hydrochloride according to any one of claims 1 to 5, wherein the ciprofloxacin hydrochloride contains a disubstituted impurity of not more than 0.03%, wherein the impurity is a 7, 8-disubstituted quinolone structure having the chemical structural formula: 。
  7. 7. the liquid pharmaceutical preparation of ciprofloxacin hydrochloride according to claim 6, wherein the preparation method of the disubstituted impurity in ciprofloxacin hydrochloride is as follows: piperazine, 1-cyclopropyl-6-fluoro-7-chloro-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid with the weight ratio of 4:1 are reacted for 48 hours at 90 ℃, cooled, washed by saline-alkali aqueous solution, added with hydrochloric acid aqueous solution, heated to reflux, cooled to 50 ℃, filtered to obtain crude products, separated by preparative chromatography, chromatographic peak fractions corresponding to target impurities are collected, concentrated and dried to obtain the disubstituted impurities.
  8. 8. The method of preparing a liquid pharmaceutical formulation of ciprofloxacin hydrochloride according to claim 1, wherein the liquid pharmaceutical formulation is an injection or eye drop, comprising the steps of: s1, preparing a concentrated solution: Adding a solvent accounting for 10% of the total solvent in a preparation container, adding ciprofloxacin hydrochloride and tryptophan, and stirring for reaction to obtain a concentrated solution of the medicinal active ingredient; s2, solvent dilution: Adding solvent into a liquid preparation tank, controlling the temperature to 15-85 ℃, adding weak acid buffer to stir the salt until the salt is completely dissolved, then adding the concentrated solution of the medicinal active ingredient prepared in the step S1, stirring uniformly, adjusting the pH value of the liquid medicine to 5.5-7.0 by using a pH regulator, then supplementing the solvent to the full amount, and stirring uniformly; s3, fine filtration and sterilization: the obtained liquid medicine was filtered by using two-stage filter elements with pore diameters of 0.45 μm and 0.22 μm, and the obtained filtrate was sub-packaged, and subjected to wet heat autoclaving at 121℃for 15 minutes.
  9. 9. The method of preparing a liquid pharmaceutical formulation of ciprofloxacin hydrochloride according to claim 1, wherein the liquid pharmaceutical formulation is an oral solution, comprising the steps of: s1, preparing a concentrated solution: Adding a solvent accounting for 10% of the total solvent in a preparation container, adding ciprofloxacin hydrochloride and tryptophan, and stirring for reaction to obtain a concentrated solution of the medicinal active ingredient; s2, solvent dilution: adding solvent into a liquid preparation tank, controlling the temperature to 15-85 ℃, adding weak acid buffer to completely dissolve salt and flavoring agent, adding the concentrated solution of the medicinal active ingredient prepared in the step S1, uniformly stirring, adjusting the pH value of the liquid medicine to 5.5-7.0 by using a pH regulator, then supplementing the solvent to full quantity, and uniformly stirring; s3, fine filtration and sterilization: Filtering the obtained medicinal liquid with filter element with aperture of 0.45 μm, packaging, and sterilizing with steam at 100deg.C for 30 min.
  10. 10. The method for preparing the ciprofloxacin hydrochloride liquid medicine preparation according to claim 8 or 9, wherein the temperature is controlled to be 15-30 ℃ in the preparation of the concentrated solution, and the reaction time is 30-120min.

Description

Ciprofloxacin hydrochloride liquid medicinal preparation with low disubstituted impurities and preparation method thereof Technical Field The invention belongs to the field of pharmacy, and in particular relates to a ciprofloxacin hydrochloride liquid medicine preparation with low disubstituted impurities and a preparation method thereof. Background Ciprofloxacin (Ciprofloxacin) belongs to a high-efficiency broad-spectrum antibiotic, has the chemical name of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7- (1-piperazinyl) -3-quinolinecarboxylic acid, and belongs to third-generation quinolone antibacterial drugs. Due to the special structure, ciprofloxacin has various stability problems such as photodegradation, pH sensitivity, metal chelation, thermal degradation, strong hygroscopicity and the like, so that the development difficulty of the preparation is high, and the development of the liquid medicine preparation is particularly restricted. Currently, most of clinically used ciprofloxacin hydrochloride is solid preparations such as oral preparation tablets and capsules. The specifications of ciprofloxacin hydrochloride tablets and capsules on the market indicate that "crystallization urine can occur when the pH value of urine is above 7 in large dosage application, in order to avoid crystallization urine, more water is needed, and the urine output of 24 hours is kept above 1200mL, so that the simultaneous use of an alkalizing agent should be avoided. The daily intake of water must be sufficient to maintain a daily urine volume above 1200-1500 mL. Because ciprofloxacin hydrochloride is easy to separate out under alkaline conditions and the ciprofloxacin hydrochloride is absorbed in gastrointestinal tracts, partial ciprofloxacin hydrochloride is separated out and crystallized in a slightly alkaline small intestine environment, cannot be absorbed by human bodies, influences the drug effect and is easy to form stones of urinary systems. In addition, the gastrointestinal tract pH of different patients is greatly different, so that the problem of in-vivo absorption difference is easily caused when the medicine is taken for different gastrointestinal tract alkaline patients, and the medicine effect exerted by patients with the same illness state after taking the medicine is inconsistent. Patent CN 103536542A provides ciprofloxacin hydrochloride composition freeze-dried powder injection for injection, which comprises 2-7 parts by weight of ciprofloxacin hydrochloride, 1.5-3.5 parts by weight of chitosan nanoparticle and 89.5-95.5 parts by weight of water for injection. The preparation is prepared by freeze drying. The patent CN 113061110A provides ciprofloxacin hydrochloride freeze-dried powder for injection and a preparation method thereof, wherein the ciprofloxacin hydrochloride freeze-dried powder for injection is prepared by heating and dissolving purified ciprofloxacin hydrochloride and mannitol (the mass ratio is 1:0.4-0.6) in water for injection, adding medicinal active carbon, stirring and filtering, adding water for injection into filtrate, adjusting pH to 3.0-4.5, filtering again to obtain a semi-finished product, detecting the semi-finished product to be qualified, and freeze-drying. The prior art described above takes the form of a freeze-dried injection for storage in solid form during production, protected from light and in storage and transportation. The freeze-drying equipment related to the process is high in manufacturing cost, the production period of the product is long, the sterile guarantee level of filtration sterilization is far lower than that of terminal overkill, potential safety hazards are brought to clinical patients, and the freeze-drying preparation is required to be operated in a light-proof environment when the medicine is dissolved in clinical application, a light-proof infusion bag or a light-proof cover is used for wrapping an infusion device, the infusion time is not too long (usually not more than 1 hour), and the medicine is prevented from being degraded due to long-time exposure to light. The clinical care is complicated, and the use convenience of the medicine is reduced. The development of the ciprofloxacin hydrochloride solution pharmaceutical preparation with good stability and high sterility assurance level, which is convenient for doctors and patients to use, is necessary for clinical application. The patent CN 116585263B provides a veterinary ciprofloxacin lactate injection and a preparation method thereof, wherein water for injection is used as a solvent, the veterinary ciprofloxacin lactate injection comprises the following components of 2.5-12.7 g/100mL of ciprofloxacin lactate, 10-30 mL/100mL of propylene glycol, 10-30 mL/100mL of glycerin, 0.5-2 mL/100mL of lactic acid, 2-20 g/100mL of beta-cyclodextrin derivative, 5-20 mL/100mL of glycerol formal, 0.5-2 mL/100mL of benzyl alcohol, 0.5-1.5 g/100mL of sodium chloride and 0.005-0.5 g/100mL of antioxidant, and the sub