CN106821972A - Moxifloxacin hydrochloride injection pharmaceutical composition and its preparation and quality control method - Google Patents

Moxifloxacin hydrochloride injection pharmaceutical composition and its preparation and quality control method Download PDF

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CN106821972A
CN106821972A CN201710154924.0A CN201710154924A CN106821972A CN 106821972 A CN106821972 A CN 106821972A CN 201710154924 A CN201710154924 A CN 201710154924A CN 106821972 A CN106821972 A CN 106821972A
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acid
moxifloxacin hydrochloride
moxifloxacin
injection
pharmaceutical composition
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CN106821972B (en
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赵东明
方专
陈娟
吴国庆
张莲莲
余茹
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CHENGDU TIANTAISHAN PHARMACEUTICAL CO LTD
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CHENGDU TIANTAISHAN PHARMACEUTICAL Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography

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Abstract

The present invention relates to Moxifloxacin hydrochloride injection pharmaceutical composition and its preparation and quality control method.Specifically, the present invention relates to a kind of Moxifloxacin hydrochloride injection pharmaceutical composition, wherein comprising moxifloxacin hydrochloride, L-aminobutanedioic acid, mosatil, optional acid-base modifier and water for injection.The invention further relates to the preparation method of the Moxifloxacin hydrochloride injection pharmaceutical composition, and to method that the RR isomers in Moxifloxacin hydrochloride injection pharmaceutical composition carries out assay.The present composition, its preparation method and method of quality control have excellent technique effect as used in the description.

Description

Moxifloxacin hydrochloride injection pharmaceutical composition and its preparation and quality control method
Technical field
The present invention relates to containing moxifloxacin hydrochloride for preparation of injection and preparation method thereof of main pharmacodynamics composition and Purposes, further relates to the method for quality control of this Moxifloxacin hydrochloride injection pharmaceutical composition.
Technical background
FQNS is nearly two to develop very fast a kind of fully synthetic antibacterials, Main Function during the last ten years It is strong with has a broad antifungal spectrum, antibacterial action in the helicase and topoisomerase of DNA of bacteria, the features such as safe, clinically Be widely used in respiratory tract, the urinary tract, skin soft tissue that treatment causes by gram-positive bacteria, negative bacterium, anaerobic bacteria etc., The various infection such as ear-nose-throat department, gynaecology and tuberculosis.Chemical constitution, antibacterial action and physiological disposition according to QNS Can be divided into for one, two, three, four generations, wherein third generation medicine such as Ciprofloxacin, levofloxacin magnitude is due to excellent anti-sense Dye is acted on and security, has ranked among the row of world's well selling medicine.But with QNS using scope expansion and The increase of consumption, while various infectious diseases are resisted, resistance phenomenon is on the rise, mainly by Staphylococcus aureus The resistance that bacterium, gram-positive bacteria and green pus bacterium etc. cause, and with NSAIDs share induction spasm, photosensitive toxicity, The adverse reactions such as joint toxicity, it is therefore desirable to develop new QNS to overcome these problems.
Moxifloxacin hydrochloride is the new broad-spectrum high efficacy forth generation fluoroquinolone antibacterial agents of German Bayer companies research and development, Listed in Germany at first in June, 1996, trade name：Avelox, December in the same year obtains U.S. FDA approval listing.This product tablet in In Discussion on Chinese Listed, moxifloxacin hydrochloride injection is in Discussion on Chinese Listed, trade name within 2005 within 2002：Visit multiple pleasure.From change Learn from the point of view of structure, the bit substituent of MOXIFLOXACIN 7 group is diazabicyclo, can reduce the resistance caused by the outer row of microorganism active (is The main mechanism of QNS crossing drug resistant), it is ensured that the low advantage of its drug resistance, methoxy group is introduced at 8, make this Product are enhanced to gram-positive bacteria, non-while QNS original to Gram-negative bacteria antibacterial activity is retained Typical pathogen and the antibacterial action of anaerobic bacteria.MOXIFLOXACIN is weaker than lavo-ofloxacin except the antibacterial activity to pseudomonas aeruginosa Outside, to atypical bacteria opportunistic pathogen such as streptococcus pneumonia, Chlamydia, Legionella, there are brood cell and asporous anaerobic bacteria etc. to be all better than Lavo-ofloxacin.Additionally, MOXIFLOXACIN is resistance to beta-lactam, macrolides, aminoglycoside and TCs The bacterium of medicine is also effective, and with these antibacterials without cross resistance.MOXIFLOXACIN is not liver cell pigment P-450 isodynamic enzymes Inhibitor, therefore in the absence of interaction between many other medicines.
Moxifloxacin hydrochloride is clinically applied to treat the upper respiratory tract and ALRI, such as acute sinusitis, chronic branch Tracheitis urgency hair tonic work, community acquired pneumonia, and Skin and soft tissue infection etc..In treatment community acquired pneumonia side Face, the monitoring result after being listed to this product according to Koch H etc., 1467 are diagnosed as the oral Moses of Patients with Simple Community Acquired Pneumonia Husky star 0.4g, one time a day, and the symptom of 90%~99% patient is improved or cured, and 54.2% patient takes MOXIFLOXACIN, Symptom improves after 3 days, and average cure time is 8.0 ± 2.7, and adverse reaction rate is 0.7%, and predominantly intestines and stomach are anti- Should, this product can be used as the choice drug of Treatment of Community-acquired Pneumonia.
MOXIFLOXACIN as super wide spectrum Development of Fluoroquinolone Antibacterials, because two target position that this product acts on bacterium are opened up Allomerase II and IV are flutterred, so this product is not only effective to sensitive bacterium, and also has high activity to antibody-resistant bacterium.It is clinical On excellent therapeutic effect is shown to multi-infection.The maximum feature of this product is to the common bacterium for causing respiratory tract infection There is the high activity to include including streptococcus pneumonia, Bacillus influenzae, catarrh Mo Lahan Salmonellas and mycoplasma pneumoniae, CPN To the bacterial strain of beta-lactam class antibiotic, macrolides and the equal resistance of existing flouroquinolone drugs.This product is to breathing simultaneously The permeability of system tissue and body fluid is good, and tolerance and security are good.The penetration power of MOXIFLOXACIN is strong, in lung tissue Higher concentration can be kept, to AECB and the special effect of chronic obstructive pulmonary disease bacterium infection.Closely Several years, due to many reasons such as air pollutions, China's infection in respiratory system incidence of disease straight line was reached the standard grade, and this product has aobvious in this field The advantage of work.Demand rises steadily.From the Bayer companies on the 1st of September in 1999 first since Germany's listing this product, in succession In the U.S., Europe alliance, Latin America and Asia dozens of, country lists, trade name Avelox, Actira, Octegra, Proflox.World wide at least has 600 multi-party patients and applied this product.This product has been increasingly becoming treatment respiratory tract infection Important drugs.Chinese patent 00811427.7 relate to a kind of Moxilfloxacin formulation containing common salt.Chinese patent 00811427.7 Describe moxifloxacin hydrochloride causes the stability of this kind of preparation very poor with the water formulation of glucose due to iron ion.
CN1368891A (00811427.7) is related to the waterborne compositions containing moxifloxacin hydrochloride and sodium chloride, conduct The composite preparation and the composition of medicine are used in the medicine treated or prevent human or animal's bacterium infection in production Application, 0.04%-0.4% (w/v) (amount based on MOXIFLOXACIN) moxifloxacin hydrochloride and 0.4%- are contained in composition The water formulation of 0.9% (w/v) sodium chloride.
CN103830164A (201210472535.X) discloses the hydrochloric acid containing solubilizer and complexing of metal ion agent not The preparation method of Xisha star parenteral solution and the parenteral solution, the Moxifloxacin hydrochloride injection, based on the volume of the parenteral solution, The solubilizer and the complexing of metal ion of 0.001~0.1W/V of moxifloxacin hydrochloride, 0.005~0.6W/V comprising 1~2W/V Agent.
CN103520093A (201310477145.6) discloses a kind of Moxifloxacin hydrochloride injection and preparation method thereof, The parenteral solution is with glucose as isotonic regulator, wherein contain ammonium acetate and acetic acid in described parenteral solution, acetic acid regulation injection The pH of liquid is 3.0-4.0.The present invention is prepared for a kind of moxifloxacin hydrochloride glucose injection of stabilization, it is easy to industrial metaplasia Produce, selected to a kind of new medication should not be provided using the patient of sodium chloride injection.
CN101972257A (201010280041.2) is related to a kind of pharmaceutical composition containing MOXIFLOXACIN, and its feature exists It is made up of MOXIFLOXACIN or its salt and balanced electrolyte solution in it, balanced electrolyte solution is selected from sodium lactate ringer's injection or acetic acid Sodium ringer's injection.Pharmaceutical composition of the present invention, MOXIFLOXACIN or its salt dissolubility are good, less to cause metabolic acidosis, While carrying out antibacterial therapy, body fluid, electrolyte and acid-base balance can also be adjusted.Pharmaceutical composition of the present invention is stable in properties.
CN102631316A (201210127205.7) is related to a kind of moxifloxacin injection preparation, its include MOXIFLOXACIN or its The PH conditioning agents of salt or their hydrate and regulation solution pH value.Moxifloxacin injection preparation steady quality of the invention, peace It is complete reliable.
CN104771359A (201510155726.7) discloses a kind of Moxifloxacin hydrochloride injection of stabilization, by hydrochloric acid not Xisha star, pH adjusting agent, stabilizer and water for injection composition, it is characterised in that stabilizer is polyethylene glycol.The Moses of invention Sha Xing stabilizations, it is easy to store, solve the problems, such as to be susceptible to crystallization and solution colour intensification in MOXIFLOXACIN storing process.
CN102688183A (201110067458.5) is related to a kind of moxifloxacin hydrochloride injection of stabilization.The injection Specifically contain moxifloxacin hydrochloride and xylitol.The injection can be parenteral solution, transfusion and freeze drying powder injection.The present invention improves Prepared by moxifloxacin hydrochloride glucose present in existing product or technology or moxifloxacin hydrochloride injection, storage Material relevant with moxifloxacin hydrochloride during use, solution colour, insoluble microparticle equistability.Preparation process pair of the invention The requirement of equipment is not harsh, it is easy to industrialized production.
CN103919779A (201410132555.1) discloses a kind of pharmaceutical composition containing MOXIFLOXACIN, and its feature exists It is made up of MOXIFLOXACIN or its salt and sodium lactate ringer's injection in said composition, is specifically comprised：Per the 100ml drug regimens In thing containing 0.1~0.4 gram of MOXIFLOXACIN or its salt based on MOXIFLOXACIN, 0.54~0.66 gram of sodium chloride, sodium lactate 0.28~ 0.34 gram, 0.027~0.033 gram of potassium chloride, calcium chloride CaCl2.2H200.018~0.022 gram；Described pharmaceutical composition according to It is prepared by following method：Recipe quantity calcium chloride, plus appropriate water for injection dissolving are weighed, and adds proper amount of active carbon, dispensed, after sealing Damp and hot 115 degree sterilize 30 minutes, obtain calcium chloride concentrated solution；By in recipe quantity sodium chloride, sodium lactate addition dense preparing tank, add suitable Amount water for injection, heating stirring dissolving adds proper amount of active carbon, and stirring is boiled insulation 30 minutes, filtered to dilute through titanium rod and matched somebody with somebody Tank, adds recipe quantity moxifloxacin hydrochloride, potassium chloride, calcium chloride concentrated solution, injects water to full amount, and adjust pH4.5~ 7.0, to be filtered through 0.2um filters, packing, damp and hot 115 degree sterilize 30 minutes after sealing.
CN102000024A (201010548680.2) discloses a kind of moxifloxacin hydrochloride injection, containing being based on MOXIFLOXACIN amount is the moxifloxacin hydrochloride of 0.03%~1% weight/volume；The pH regulations of 0.0001%~3% weight/volume Agent (organic acid, organic base, inorganic acid, inorganic base)；The complexing of metal ion agent of 0.0001%~0.1% weight/volume；0.65 ~0.95% sodium chloride.
CN101732246A (200910255714.6) discloses a kind of moxifloxacin aqueous solution type injection, and it contains not Xisha star or its pharmaceutically acceptable salt, the sodium salt of the sodium salt of weak acid or phosphoric acid, water for injection；Wherein MOXIFLOXACIN contains It is 0.8%~4% (g/ml) to measure, and the molar concentration of the sodium salt of weak acid or the sodium salt of phosphoric acid is 0.0002~1mol/L.The present invention Moxifloxacin aqueous solution type injection product dissolubility it is strong, with the acceptable pH value of human body, product quality is more easy to control, storage Stabilization in the phase is deposited, has good compatibility, low production cost, small volume, transport and storage side with clinical conventional isotonic solution Just.
CN103356479A (201310322660.7) is related to Moxifloxacin hydrochloride injection aqua, it is characterised in that be Adjusted as pH adjusting agent with sodium carbonate liquor and formed, and the pH value of preparation is 7.1~8.0.In the preparation method of said preparation, It is preferred that with the water dissolves moxifloxacin hydrochloride of total water consumption 50~80%, with 15~35% water in the form of sodium carbonate liquor Introduce.More preferably after pH value is regulated, stand at room temperature or weak stirring a period of time, make pH value constant.It is of the invention Preparation can obtain valid density higher and preferably storage stability.
CN102895178A (201110214515.8) discloses a kind of lomefloxacin hydrochloride for injection concentrated solution type injection Agent, it is characterised in that the amino acid or its medicine of the not sulfur-bearing containing MOXIFLOXACIN 1%~4% (g/ml) and 0.005~1mol/L Acceptable salt on；Or containing MOXIFLOXACIN 1%~4% (g/ml), the amino acid of the not sulfur-bearing of 0.005~1mol/L and its Pharmaceutically acceptable salt；Wherein described MOXIFLOXACIN is preferably 1.8%~4% (g/ml).
In addition, used as a kind of clinically important product, the quality control of MOXIFLOXACIN is also that people pay special attention to.Example Such as, CN103869033A (201210544571.2) is related to the side of a kind of liquid chromatography for separating and determining MOXIFLOXACIN and its impurity Method, it is characterised in that：Chromatographic column with phenyl bonded silica as filler, with methyl alcohol-cushioning liquid as mobile phase, is washed using gradient De-, wherein methyl alcohol cushioning liquid initial volume ratio is 30：70~10：90, cushioning liquid contains tetrabutyl quaternary ammonium salt, tetrabutyl phosphorus Hydrochlorate or tetrabutyl sulfate and phosphate, the combination of phosphoric acid.
CN103543230A (201210236984.4) discloses the separation of a kind of moxifloxacin hydrochloride and its enantiomter Assay method, it is characterised in that including：1) control substance of plant drug is selected：Moxifloxacin hydrochloride raceme, moxifloxacin hydrochloride；2) sample It is prepared by product：Moxifloxacin hydrochloride raceme, plus mobile phase dissolved dilution are taken, the hydrochloric acid Moses of 1 μ g/ml~20 μ g/ml is configured to Husky star racemization liquid solution；Moxifloxacin hydrochloride, plus mobile phase dissolved dilution are taken, the hydrochloric acid of 0.4mg/ml~1mg/ml is configured to not Xisha star solution；3) chromatographic condition：High performance liquid chromatograph, chromatographic column used is reverse-phase chromatographic column, with copper sulphate and chiral examination The mixed aqueous solution of agent is water phase, and the mixed liquor of water phase-organic phase is mobile phase, and column temperature is：20 DEG C~45 DEG C；Flow velocity is： 0.6ml/min~1.4ml/min；Detection wavelength is：270~310nm；4) determine：Precision measures the moxifloxacin hydrochloride respectively Star racemization liquid solution and each 2 μ l~50 μ l of the moxifloxacin hydrochloride solution, inject liquid chromatograph, record chromatogram, but This method is it is not clear whether suitable for the formula of test parenteral solution of the present invention.
CN102584819A (201210020365.1) is related to the 8- BAY 128039 first that N- shown in a kind of Formulas I methylates Acid compounds, acid-addition salts or alkali metal salt, and preparation method thereof and moxifloxacin hydrochloride quality testing with analysis in Application.Using the compound or its salt as impurity reference substance, detected with external standard method and analyze moxifloxacin hydrochloride, can be right Such impurity that may contain in the moxifloxacin hydrochloride raw material and preparation of industrialized production carries out quantitative control, is conducive to improving The quality of moxifloxacin hydrochloride, improves the security of clinical application.
CN103185757A (201110445346.9) there is provided a kind of MOXIFLOXACIN (R, R)-isomers detection method, The detection method is detected that its condition is as follows using high performance liquid chromatograph：Chromatographic column is octadecylsilane chemically bonded silica Chromatographic column, mobile phase is the solvent containing L-Leu and metal ion, wherein the metal ion is Cu2+, Zn2+ or it is mixed Ion is closed, the solvent includes water and organic solvent, and the volume ratio of water and organic solvent is 77~82: 23~18.The present invention is carried The detection method of confession have sensitivity higher and specificity, it is simple to operation, can fast and accurately detect MOXIFLOXACIN (R, R)-isomers, can be used for the quality control of MOXIFLOXACIN, and for base has been established in the research and development and quality testing of such compound Plinth, with realistic meaning.
It has been found by the present inventors that above-mentioned CN102895178A is had using the parenteral solution that the formula comprising amino acid is made Excellent chemical stability.However, the present inventors have additionally discovered that, above-mentioned CN102895178A for example includes door winter ammonia comprising amino acid Ring of the parenteral solution of acid in somewhat low temperature (this environment is likely to encounter, such as frequently encountered in some intermediate links) Micro- there can be opalescence to occur after being preserved under border, although whether unclear this can generation on the security of product influences, this Art personnel are still to need to avoid known as street drug.The present inventor pass through further investigation revealed that, this Planting opalescence can be avoided by parenteral solution process for preparation with charcoal absorption；Unfortunately, because using The new problem that charcoal absorption is drawn is when using charcoal absorption, to show the situation to the notable absorption of active component, The notable loss of active component in finished product is caused, this is accomplished by overcoming by increasing inventory.Therefore, those skilled in the art Still expect to solve above-mentioned various technical problems and/or contradiction.
The content of the invention
Present invention aim at a kind of Moxifloxacin hydrochloride injection is provided and can overcome above-mentioned various technical problems with/ Or avoid various contradictions.It has been had now surprisingly been found that, using the inventive method and the hydrochloric acid of the present invention for preparing of formula not Xisha star parenteral solution, what can be satisfied with realizes above-mentioned purpose.
Therefore, first aspect present invention provides a kind of Moxifloxacin hydrochloride injection pharmaceutical composition, wherein comprising salt Sour MOXIFLOXACIN, L-aminobutanedioic acid, mosatil, optional acid-base modifier and water for injection.
The Moxifloxacin hydrochloride injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is per 20ml In include：Moxifloxacin hydrochloride 350~450mg in terms of MOXIFLOXACIN, 80~120mg of L-aminobutanedioic acid, mosatil 8~ 12mg。
The Moxifloxacin hydrochloride injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is per 20ml In include：Moxifloxacin hydrochloride 380~420mg in terms of MOXIFLOXACIN, 90~115mg of L-aminobutanedioic acid, mosatil 9~ 11mg。
The Moxifloxacin hydrochloride injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is per 20ml In include：Moxifloxacin hydrochloride 400mg in terms of MOXIFLOXACIN, 90~115mg of L-aminobutanedioic acid, 9~11mg of mosatil.
The Moxifloxacin hydrochloride injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, its pH value is 4~5, such as its pH value is 4.2~4.8.
The Moxifloxacin hydrochloride injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein described Acid-base modifier can be any acid-base modifier in parenteral solution pH regulations commonly used in the art, such as hydrochloric acid, phosphoric acid, sulfuric acid etc. Alkali and their aqueous solution such as acid and NaOH, sodium acid carbonate, sodium carbonate.In the present invention, the acid-base modifier It is selected from following acid-base modifier：Hydrochloric acid, NaOH and their aqueous solution.
The Moxifloxacin hydrochloride injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein described The consumption of acid-base modifier is so that the Moxifloxacin hydrochloride injection pharmaceutical composition, and its pH value is 4~5, such as its pH Be worth is 4.2~4.8.
The Moxifloxacin hydrochloride injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is being prepared The technique for having used charcoal absorption to process during liquid.Charcoal absorption handling process is in parenteral solution process for preparation A kind of common process, generally determines the need for this operating procedure depending on specific kind.This charcoal absorption handling process is usual For include to needle-use activated carbon is added in the liquid prepared, then stirring a period of time, last filtering decarbonization.
The Moxifloxacin hydrochloride injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is according to bag Include what the steps was prepared：
A () makes L-aminobutanedioic acid and according to ground with liquid total amount 60~80% water for injection (such as water temperature is 50~90 DEG C) Sour calcium sodium dissolving, it is 4.3~4.7 to adjust gained liquid pH value with acid-base modifier, (for example treats fluid temperature in 40~70 DEG C of models When enclosing) moxifloxacin hydrochloride is added to, it is stirred to dissolve；
(b) (such as when fluid temperature is in 40~70 DEG C of scopes) to gained liquid in add activated carbon (with liquor capacity 0.05~0.15%w/v of meter), stirring and adsorbing 20~60 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, at the same verified with acid-base modifier and adjust gained liquid pH value be 4.3~ 4.7；
D be filled to gained medical filtration in vial by (), sealing, and sterilizing is obtained final product.
Further, second aspect present invention is provided and prepares Moxifloxacin hydrochloride injection pharmaceutical composition such as this hair The method of the Moxifloxacin hydrochloride injection pharmaceutical composition described in bright first aspect any embodiment, the moxifloxacin hydrochloride In star injection pharmaceutical composition comprising moxifloxacin hydrochloride, L-aminobutanedioic acid, mosatil, optional acid-base modifier and Water for injection；The method includes the technique preparating liquid processed using charcoal absorption.
The method of any embodiment according to a second aspect of the present invention, the method comprises the following steps：
A () makes L-aminobutanedioic acid and according to ground with liquid total amount 60~80% water for injection (such as water temperature is 50~90 DEG C) Sour calcium sodium dissolving, it is 4.3~4.7 to adjust gained liquid pH value with acid-base modifier, (for example treats fluid temperature in 40~70 DEG C of models When enclosing) moxifloxacin hydrochloride is added to, it is stirred to dissolve；
(b) (such as when fluid temperature is in 40~70 DEG C of scopes) to gained liquid in add activated carbon (with liquor capacity 0.05~0.15%w/v of meter), stirring and adsorbing 20~60 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, at the same verified with acid-base modifier and adjust gained liquid pH value be 4.3~ 4.7；
D be filled to gained medical filtration in vial by (), sealing, and sterilizing is obtained final product.
The method of any embodiment according to a second aspect of the present invention, wherein the Moxifloxacin hydrochloride injection medicine group Included in the every 20ml of compound：Moxifloxacin hydrochloride 350~450mg in terms of MOXIFLOXACIN, 80~120mg of L-aminobutanedioic acid, edetic acid(EDTA) 8~12mg of calcium sodium.
The method of any embodiment according to a second aspect of the present invention, wherein the Moxifloxacin hydrochloride injection medicine group Included in the every 20ml of compound：Moxifloxacin hydrochloride 380~420mg in terms of MOXIFLOXACIN, 90~115mg of L-aminobutanedioic acid, edetic acid(EDTA) 9~11mg of calcium sodium.
The method of any embodiment according to a second aspect of the present invention, wherein the Moxifloxacin hydrochloride injection medicine group Included in the every 20ml of compound：Moxifloxacin hydrochloride 400mg in terms of MOXIFLOXACIN, 90~115mg of L-aminobutanedioic acid, mosatil 9 ~11mg.
The method of any embodiment according to a second aspect of the present invention, wherein the Moxifloxacin hydrochloride injection medicine group The pH value of compound is 4~5, and such as its pH value is 4.2~4.8.
The method of any embodiment according to a second aspect of the present invention, wherein the acid-base modifier can be any ability Domain be usually used in parenteral solution pH regulation acid-base modifier, for example hydrochloric acid, phosphoric acid, sulfuric acid etc. acid and NaOH, sodium acid carbonate, The alkali such as sodium carbonate and their aqueous solution.In the present invention, the acid-base modifier is selected from following acid-base modifier：Salt Acid, NaOH and their aqueous solution.
The method of any embodiment according to a second aspect of the present invention, wherein the consumption of the acid-base modifier is so that institute Moxifloxacin hydrochloride injection pharmaceutical composition is stated, its pH value is 4~5, such as its pH value is 4.2~4.8.
The moxifloxacin hydrochloride of Clinical practice is SS configurations, and its bulk drug and preparation such as parenteral solution generally need to monitor it The content of middle RR- isomers, has had now surprisingly been found that, the present invention with the addition of L-aminobutanedioic acid and mosatil injection simultaneously Liquid its carrying out needing the special chromatographic condition could to realize excellent chromatography when content of isomer is determined.
Therefore, third aspect present invention is provided to the Moxifloxacin hydrochloride injection pharmaceutical composition such as present invention first RR isomers (i.e. R, R hydrochloric acid Moses in Moxifloxacin hydrochloride injection pharmaceutical composition described in aspect any embodiment The method for Sha Xing) carrying out assay, includes moxifloxacin hydrochloride, door in the Moxifloxacin hydrochloride injection pharmaceutical composition Winter propylhomoserin, mosatil, optional acid-base modifier and water for injection；The method includes following operation：
(1) parenteral solution 0.5ml is taken, in putting 100ml measuring bottles, plus mobile phase is diluted to scale, shakes up, molten as test sample Liquid；It is another to take moxifloxacin hydrochloride raceme reference substance about 10mg, it is accurately weighed, in putting 100ml measuring bottles, plus mobile phase dissolved dilution To scale, solution of every 1ml containing about 0.1mg is made, as system suitability experimental solutions；
(2) chromatographic condition and system suitability：With the chromatographic column that octadecylsilane chemically bonded silica is filler；With Methyl alcohol-buffer solution (takes D-phenylalanine 1.32g and copper sulphate 1.0g, after the 1000ml that adds water dissolvings, pH value is adjusted with alkaline matter To 3.3~3.7) (25：75) it is mobile phase；Flow velocity 1.0ml/min；40 DEG C of column temperature；Detection wavelength 293nm；Take system suitability The μ l of testing liquid 20 inject liquid chromatograph, record chromatogram, moxifloxacin hydrochloride and RR- isomers appearance successively, two peaks it Between separating degree should be greater than 2.0, theoretical cam curve should be no less than 2000 based on MOXIFLOXACIN peak；
(3) precision measures the μ l of need testing solution 20 injection liquid chromatographs, records chromatogram, reads the need testing solution color The peak area of SS isomers (the active ingredient hydrochloric acid MOXIFLOXACIN i.e. in parenteral solution) and RR isomers, is calculated as follows in spectrogram The content of the RR- isomers in parenteral solution：
RR content of isomer=[RR isomers peak areas ÷ (SS isomers peak area+RR isomers peak area)] × 100%.
Percentage composition of the RR isomers relative to whole configuration materials in parenteral solution can be calculated by above-mentioned formula. Generally, it is desirable to which the content of the RR isomers in Moxifloxacin hydrochloride injection pharmaceutical composition is less than 0.10%.
The method of any embodiment, selects for preparing alkaline matter during mobile phase according to a third aspect of the present invention From NaOH, sodium acid carbonate, triethylamine.It has been had now surprisingly been found that, as the pH that buffer solution is adjusted using triethylamine, can be with Overcome is probably due to the defect on the influence of RR isomery body measurements precision that mosatil causes.
The method of any embodiment, the Moxifloxacin hydrochloride injection pharmaceutical composition according to a third aspect of the present invention Included in per 20ml：Moxifloxacin hydrochloride 350~450mg in terms of MOXIFLOXACIN, 80~120mg of L-aminobutanedioic acid, mosatil 8 ~12mg.
The method of any embodiment, the Moxifloxacin hydrochloride injection pharmaceutical composition according to a third aspect of the present invention Included in per 20ml：Moxifloxacin hydrochloride 380~420mg in terms of MOXIFLOXACIN, 90~115mg of L-aminobutanedioic acid, mosatil 9 ~11mg.
The method of any embodiment, the Moxifloxacin hydrochloride injection pharmaceutical composition according to a third aspect of the present invention Included in per 20ml：Moxifloxacin hydrochloride 400mg in terms of MOXIFLOXACIN, 90~115mg of L-aminobutanedioic acid, mosatil 9~ 11mg。
The method of any embodiment, the Moxifloxacin hydrochloride injection pharmaceutical composition according to a third aspect of the present invention PH value is 4~5, and such as its pH value is 4.2~4.8.
The method of any embodiment according to a third aspect of the present invention, wherein the acid-base modifier can be any ability Domain be usually used in parenteral solution pH regulation acid-base modifier, for example hydrochloric acid, phosphoric acid, sulfuric acid etc. acid and NaOH, sodium acid carbonate, The alkali such as sodium carbonate and their aqueous solution.In the present invention, the acid-base modifier is selected from following acid-base modifier：Salt Acid, NaOH and their aqueous solution.
The method of any embodiment according to a third aspect of the present invention, wherein the consumption of the acid-base modifier is so that institute Moxifloxacin hydrochloride injection pharmaceutical composition is stated, its pH value is 4~5, such as its pH value is 4.2~4.8.
The method of any embodiment, the Moxifloxacin hydrochloride injection pharmaceutical composition according to a third aspect of the present invention The technique for having used charcoal absorption to process during preparating liquid.
The method of any embodiment, the Moxifloxacin hydrochloride injection pharmaceutical composition according to a third aspect of the present invention Shining includes that the steps is prepared：
A () makes L-aminobutanedioic acid and according to ground with liquid total amount 60~80% water for injection (such as water temperature is 50~90 DEG C) Sour calcium sodium dissolving, it is 4.3~4.7 to adjust gained liquid pH value with acid-base modifier, (for example treats fluid temperature in 40~70 DEG C of models When enclosing) moxifloxacin hydrochloride is added to, it is stirred to dissolve；
(b) (such as when fluid temperature is in 40~70 DEG C of scopes) to gained liquid in add activated carbon (with liquor capacity 0.05~0.15%w/v of meter), stirring and adsorbing 20~60 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, at the same verified with acid-base modifier and adjust gained liquid pH value be 4.3~ 4.7；
D be filled to gained medical filtration in vial by (), sealing, and sterilizing is obtained final product.
Any technical characteristic that any embodiment of either side of the present invention or the either side has is equally applicable Any embodiment of other any embodiments or other either sides, as long as they will not be conflicting, certainly mutual Between where applicable, if necessary can individual features be made with appropriate modification.Make into one with feature to various aspects of the present invention below The description of step.
All documents recited in the present invention, their full content is incorporated herein by reference, and if these are literary Offer expressed implication with it is of the invention inconsistent when, be defined by statement of the invention.Additionally, the various terms that use of the present invention and Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explains, the term and phrase for referring to if any inconsistent with common art-recognized meanings, with institute's table of the present invention The implication stated is defined.
Moxifloxacin hydrochloride is in a kind of wide spectrum of U.S.'s listing and the 8- methoxy fluoroquinolone classes with antibacterial activity Antimicrobial, is applied to the antibiotics of the adult of the upper respiratory tract and ALRI.The English of moxifloxacin hydrochloride Entitled MoxifloxacinHydrochloride, molecular formula is C21H24FN3O4HCl, and molecular weight is 437.89, and No. CAS is 186826-86-8, Chinese chemical name is that 1- cyclopropyl -7- (ring [4.3.0] nonane -8- of S, S-2,8- diazonium-two bases) -6- is fluoro- 8- methoxy-Isosorbide-5-Nitrae-dihydro -4- oxygen -3- quinoline carboxylic acid hydrochlorides, English language Chemical entitled 1-Cyclopropyl-6-fluoro-1,4- dihydro-8-methoxy-7-[(4aS,7aS)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4- Oxo-3-quinolinecarboxylic acid, monohydrochloride, its chemical structural formula are as follows：
The RR enantiomters of moxifloxacin hydrochloride be 1- cyclopropyl -7- (R, R-2,8- diazonium-two ring [4.3.0] nonane - 8- yls) the fluoro- 8- methoxies -1,4- dihydros -4- oxygen -3- quinoline carboxylic acid hydrochlorides of -6-.
The characteristics of Moxifloxacin hydrochloride injection that inventive formulation and method are prepared is presented excellent, and the present invention Method for analyzing the isomers in parenteral solution also has excellent Methodological characteristics.
Specific embodiment
The present invention can be conducted further description by the following examples, however, the scope of the present invention is not limited In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention Various change and modification are carried out to the present invention.The present invention to used in experiment to material and test method carry out generality And/or specific description.Although for realize many materials that the object of the invention used and operating method be it is known in the art that But the present invention is still described in detail as far as possible herein.Following examples further illustrate the present invention, rather than limiting this hair It is bright.
In the present invention hereinafter, if not otherwise indicated, illustrated with the amount of every 20ml during the bright injection formula of liquid of example, but It is each inventory at least 10L when actual production is operated.Hereinafter, unless otherwise noted, acid-base modifier used is 1M sodium hydroxide solutions.
Test example 1：The Related substances separation method of principal component in parenteral solution
Lucifuge is operated.
Chromatographic condition and system suitability：It is filler, 45 DEG C of column temperature with phenyl silane bonded silica gel；Check wavelength 293nm；Flow velocity 1.3ml/min, with buffer solution (TMAH containing 0.5g, 1.0g potassium dihydrogen phosphates and 2.0ml in 1L water Phosphoric acid), it is mobile phase A, methyl alcohol is Mobile phase B, and according to the form below carries out gradient elution.Take the μ l of contrast solution 20 injection liquid chromatograies Instrument, adjusts detection sensitivity, makes the 20% of the peak height about full scale of principal component chromatographic peak；Measure system suitability solution 20 μ l inject liquid chromatograph, record chromatogram, peak sequence be MOXIFLOXACIN, moxifloxacin hydrochloride impurity A (RRT about 1.1), B (RRT about 1.2), C (RRT about 1.30), D (RRT about 1.4), E (RRT about 1.6), impurity A should be big with the separating degree of MOXIFLOXACIN In 2.0.
Time (minute) Mobile phase A (%) Mobile phase B (%)
0 75 25
25 75 25
35 47 53
50 47 53
60 78 22
85 78 22
Precision measures this product 5ml, in putting 100ml brown measuring bottles, plus dilution (weigh 0.50g TMAHs and 1.0g potassium dihydrogen phosphates, are dissolved in 500ml water, add 2ml phosphoric acid and 0.050g anhydrous sodium sulfites, are diluted with water to Scale 1000ml) is diluted to, is shaken up, the solution containing about moxifloxacin hydrochloride 1.0mg is made in every 1ml, as need testing solution； Precision measures need testing solution 5ml, puts in 100ml measuring bottles, with diluted to scale, shakes up, then precision measures 2ml, puts In 100ml measuring bottles, with diluted to scale, shake up, the solution containing about 1.0 μ g is made in every 1ml, as contrast solution. Quinoline carboxylic acid's reference substance 5mg is taken, it is accurately weighed, put in 100ml measuring bottles, with methyl alcohol dissolved dilution to scale, mix, then accurate amount 5ml is taken, is put in 25ml measuring bottles plus methanol dilution is to scale, mixed, be made in every 1ml the solution containing about 10ug, it is fixed as impurity Position solution.Another to take MOXIFLOXACIN peak discriminating reference substance (hydrochloric moxifloxacin impurity A, B, C, D, E) about 10mg, precision claims Fixed, in putting 10ml measuring bottles, plus dilution dissolved dilution is to scale, solution of every 1ml containing about 1mg is made, as system suitability Testing liquid.
Precision measures impurity positioning solution, contrast solution and each 20ul of need testing solution, is injected separately into liquid chromatograph, remembers Record chromatogram.If any impurity peaks in the chromatogram of need testing solution, if any impurity peaks in the chromatogram of need testing solution, quinoline carboxylic Acid, moxifloxacin hydrochloride impurity B, E are by the calculated by peak area (being multiplied by correction factor 4.2,1.4,3.5 respectively) after correction；Generally For, it is desirable in Moxifloxacin hydrochloride injection, impurity A, B, C, D, E and other single impurity peak areas cannot be greater than control Solution main peak area (0.08%)；1.4 times (0.14%) each impurity peak area and that cannot be greater than contrast solution main peak area.
Analysis：The impurity content in need testing solution chromatogram is calculated by Self-control method.
Wherein：
SQuinoline carboxylic acid：It is the peak area of quinoline carboxylic acid in need testing solution；
SMiscellaneous A：It is the peak area of moxifloxacin hydrochloride impurity A in need testing solution；
SMiscellaneous B：It is the peak area of moxifloxacin hydrochloride impurity B in need testing solution；
SMiscellaneous C：It is the peak area of moxifloxacin hydrochloride impurity C in need testing solution；
SMiscellaneous D：It is the peak area of moxifloxacin hydrochloride impurity D in need testing solution；
SMiscellaneous E：It is the peak area of moxifloxacin hydrochloride impurity E in need testing solution；
SFor list：It is the peak area of other single maximum contaminants in need testing solution；
SFor with：It is the sum of each impurity peak area in need testing solution；
SIt is right：It is the main peak area of contrast solution.
Above-mentioned impurity A, B, C, D, E are respectively：
Wherein, impurity A is R=R '=F,
Impurity B is R=R '=OCH3,
Impurity C be R=F, R '=OC2H5,
Impurity D be R=OCH3, R '=F,
Impurity E is R=F, R '=OH.
Test example 2：The content assaying method of principal component in parenteral solution
Chromatographic condition and system suitability：It is filler with phenyl silane bonded silica gel；With methyl alcohol-buffer solution (1L 0.5g containing TMAH in water, potassium dihydrogen phosphate 1.0g and phosphoric acid 2.0ml) (22：78) it is mobile phase；45 DEG C of column temperature； Detection wavelength 293nm；Flow velocity 1.3ml/min, theoretical cam curve is calculated by MOXIFLOXACIN peak and is not less than 3000, and tailing factor must not More than 1.5.
Determination method：This product 5ml is taken, in putting 100ml brown measuring bottles, plus dilution (takes TMAH 0.5g and phosphorus Acid dihydride potassium 1.0g, is dissolved in 500ml water, and phosphorate sour 2.0ml and anhydrous sodium sulfite 0.05g, is diluted with water to 1000ml) Scale is diluted to, is shaken up, precision measures 5ml, in putting 50ml brown measuring bottles, plus diluted is to scale, shakes up, and is made 1ml In solution containing about 0.1mg need testing solution (2) is obtained as need testing solution (1), with legal system, precision measures 20ul injection liquid phases Chromatograph, records chromatogram；It is another to take moxifloxacin hydrochloride reference substance about 10mg, it is accurately weighed, it is in putting 100ml volumetric flasks plus dilute Release liquid to dissolve and be diluted to scale, shake up, reference substance solution (2) is obtained as reference substance solution (1), with legal system, be measured in the same method.
Analysis：By external standard method with calculated by peak area moxifloxacin hydrochloride with MOXIFLOXACIN (C21H24FN3O4) meter content.
In formula：
SFor：It is the main peak area of need testing solution；
nFor：It is the extension rate of need testing solution；
VFor：It is test sample sampling amount；
mIt is right：It is reference substance sample weighting amount；
CIt is right：It is the content of reference substance；
SIt is right：It is the main peak area of reference substance solution；
nIt is right：It is the extension rate of reference substance solution；
KIt is right：It is the average milligram peak area of reference substance,
KIt is right=SIt is right/(mIt is right×CIt is right)。
Typically, it is desirable to which hydrochloric MOXIFLOXACIN is with MOXIFLOXACIN (C in Moxifloxacin hydrochloride injection21H24FN3O4) Meter should be the 97.0%~105.0% of labelled amount.
Test example 3：The content assaying method of RR isomers (i.e. R, R moxifloxacin hydrochloride) in parenteral solution
(1) parenteral solution 0.5ml is taken, in putting 100ml measuring bottles, plus mobile phase is diluted to scale, shakes up, molten as test sample Liquid；It is another to take moxifloxacin hydrochloride raceme reference substance about 10mg, it is accurately weighed, in putting 100ml measuring bottles, plus mobile phase dissolved dilution To scale, solution of every 1ml containing about 0.1mg is made, as system suitability experimental solutions；
(2) chromatographic condition and system suitability：With the chromatographic column that octadecylsilane chemically bonded silica is filler；With Methyl alcohol-buffer solution (takes D-phenylalanine 1.32g and copper sulphate 1.0g, after the 1000ml that adds water dissolvings, (is specifically made with alkaline matter It is triethylamine) adjust pH value to 3.3~3.7) (25：75) it is mobile phase；Flow velocity 1.0ml/min；40 DEG C of column temperature；Detection ripple 293nm long；The μ l of system suitability solution 20 injection liquid chromatographs are taken, chromatogram is recorded, moxifloxacin hydrochloride and RR- are different Structure body appearance successively, separating degree should be greater than 2.0 between two peaks, and theoretical cam curve should be no less than 2000 based on MOXIFLOXACIN peak；
(3) precision measures the μ l of need testing solution 20 injection liquid chromatographs, records chromatogram, reads the need testing solution color The peak area of SS isomers (the active ingredient hydrochloric acid MOXIFLOXACIN i.e. in parenteral solution) and RR isomers, is calculated as follows in spectrogram The content of the RR- isomers in parenteral solution：
RR content of isomer=[RR isomers peak areas ÷ (SS isomers peak area+RR isomers peak area)] × 100%.
Percentage composition of the RR isomers relative to whole configuration materials in parenteral solution can be calculated by above-mentioned formula. Generally, it is desirable to which the content of the RR isomers in Moxifloxacin hydrochloride injection pharmaceutical composition is less than 0.10%.
Check experiment example 1：The method for determining the enantiomter in Moxifloxacin hydrochloride injection
Carried out with reference to the method for the embodiment 1 of the B of CN 103543230.
Check experiment example 2：The method for determining the enantiomter in Moxifloxacin hydrochloride injection
With reference to the method for the embodiment 1 of the B of CN 103543230 but different is only to use octadecylsilane bonded silica instead Glue is carried out for the chromatographic column of filler.
Check experiment example 3：The method for determining the enantiomter in Moxifloxacin hydrochloride injection
The method of test example 3 of the present invention with reference to more than, different is only that the alkaline matter used when mobile phase is prepared changes Use NaOH.
Test example 4：The study on the stability of parenteral solution：
The parenteral solution obtained by example 1 below -6, embodiment 11-13 is placed in 45 DEG C of high temperature and place April (in the present invention In can be described as the disposal of 45 DEG C of April), according to any of the above test example, the active component Moses in 0 month and June determine parenteral solution The content of Sha Xing, relevant content of material, enantiomter content.For each index, be calculated as follows its through this 45 DEG C of April at The percent change for postponing：
Certain index percent change=[(| 0 month desired value-June desired value |) 0 month desired value of ÷] × 100%
Above-mentioned percent change is positive number after being taken absolute value through 0 month value and June value difference value, represents the change feelings of the index Condition, it is more big, shows that the change of the parenteral solution index is bigger, such as the content of active component MOXIFLOXACIN, the change hundred Fraction is bigger to represent that active component content reduction is more.Result shows that embodiment 1-6, embodiment 11-13 gained are all injected Liquid, whether adds EDTA, is whether adsorbed with charcoal in process, shows that three Parameters variation percentages are in small change The result of change, such as MOXIFLOXACIN changes of contents percentage are in the range of 1.6~3.1% and each sample is each other without substantially Difference, relevant Substances variation percentage in the range of 1.13~1.74% and each sample no significant difference each other, Enantiomter changes of contents percentage is in the range of 0.86~1.44% and each sample no significant difference each other.
In addition, the parenteral solution obtained by embodiment 1-6, embodiment 11-13 is placed under 8~10 DEG C of cryogenic conditions placing 1 The moon (can be described as 10 DEG C of January disposal) in the present invention, living in 0 month and January determine parenteral solution according to any of the above test example Property composition MOXIFLOXACIN content, relevant content of material, enantiomter content.Disposed through this 10 DEG C of January for each index Percent change afterwards also refers to the calculating formula treatment of above-mentioned 45 DEG C of April disposal, as a result shows as high-temperature treatment, Moses The content of Sha Xing, relevant content of material, three indexs of enantiomter content do not show bright between different injection fluid samples Significant difference is different, and three changes of contents percentages are respectively in 0.12~0.16%, 0.07~0.11% and 0.02~0.03% scope It is interior.
Visual inspection：The parenteral solution of the whole batches of embodiment 1-6, embodiment 11-13 gained, observes after the completion of preparation, Clear solution is, and does not observe there is opalescence phenomenon.The parenteral solution of the whole batches of embodiment 1-6, embodiment 11-13 gained Observation is postponed at 45 DEG C of April are experienced, clear solution is, and do not observe there is opalescence phenomenon.Embodiment 1-6, embodiment 11 whole batches of gained postpone observation through carbon treatment process gained parenteral solution at 10 DEG C of January are experienced, and are clear solution, and Do not observe there is opalescence phenomenon.Embodiment 12, the whole batches of the gained of embodiment 13 without carbon treatment process gained parenteral solution Observation is postponed at 10 DEG C of January are experienced, opalescence after observing has opalescence phenomenon, and these samples place January through room temperature again Will not disappear, this is can not to make us receiving completely, therefore in circulation, storage, transportation in medicine particularly parenteral solution Being entirely possible to can be at a temperature of 10 DEG C or so and this open-assembly time is entirely possible more than 1 month.Tied more than Really visible, the parenteral solution processed without charcoal absorption occurs unacceptable opalescence phenomenon after low temperature environment is experienced, and This opalescence can be overcome to be formed after being processed with activated carbon.
Test example 5：Injection Process Performance：
In the technique that embodiment 1-6, embodiment 11 prepare parenteral solution, charcoal absorption treatment is used, in charcoal filtering It is front and rear, the concentration of the active component in liquid is determined, with concentration in liquid after filter divided by concentration in liquid before filter multiplied by with 100% Gained percentage, as the remaining percentage of active component in liquid after filtering, as a result shows 6 injections prepared by embodiment 11 Remaining percentage is in the range of 91~92% during liquid, and remaining percentage is 99 during 6 parenteral solutions of embodiment 1-6 preparations In the range of~100%, show that charcoal absorption has the notable loss of active component, and mosatil is with the addition of in working as liquid Afterwards, this loss can be avoided completely, and this is completely unexpected, has any this technology to teach because prior art has not been shown in Lead, for example, can overcome teaching of the activated carbon to Drug absorbability on mosatil.In addition, the present inventor is in reference The formula and preparation method of CN102631316B embodiments 1 also find when preparing Moxifloxacin hydrochloride injection, in titanium filter decarburization In front and rear liquid, the remaining percentage of active component is 90.8%, shows to equally exist adsorption loss, and this loss is generally needed Increase is fed intake in bulk drug to liquidate.
Test example 6：RR isomers is detected
Using above-mentioned test example 3 of the invention, check experiment example 1, check experiment example 2, the method for check experiment example 3, determine The content of RR isomers in obtained various parenteral solutions of the invention.
Result shows, the method for test example 3 gained chromatogram and check experiment example 1, check experiment example 2, the side of check experiment example 3 Method gained chromatogram is substantially the same, and Fig. 1 and Fig. 2 with CN103543230B is essentially identical, and particularly for example SS is different Structure body and RR isomers are in the aspect such as separating degree, number of theoretical plate test example 3, check experiment example 1, check experiment example 2, check experiment The method of example 3 is essentially identical with Fig. 1 and Fig. 2 of CN103543230B (such as between moxifloxacin hydrochloride and the peak of RR- isomers two Separating degree is all higher than 3.0, and 3000) theoretical cam curve is all higher than based on MOXIFLOXACIN peak.
In parenteral solution, because RR content of isomer is very low, such as shown in the peak 2 in Fig. 2 of CN103543230B, this Sample, the deviation for easily causing chromatographic peak record is big, thereby results in the fluctuation of small peak peak area when different sample introductions are tested, this Plant fluctuation to be easily reflected in the precision of peak area, can be represented with the relative standard deviation RSD of the RR isomers peak areas, I.e. for same injection liquid samples, tested 6 times using a certain method of testing, calculate the peak area of RR isomers in this 6 times tests, Calculate its relative standard deviation RSD again, typically RSD is preferred less than 0.5%, and when more than 1% be it is unfavorable even It is unacceptable, especially for the inexplicit impurity of this BA, accurate measure is necessary.
For embodiment 11, the parenteral solution for being not added with mosatil of the whole batches of the gained of embodiment 13, make respectively When determining the isomers in parenteral solution with test example 3, check experiment example 1, check experiment example 2,3 four kinds of methods of check experiment example, The RSD of SS isomers is in the range of 0.1~0.2%, the RSD of RR isomers in the range of 0.2~0.3%, show various Method is for two kinds of test precision indifferences of isomers and non-excellent；
For embodiment 1-6, the parenteral solution that with the addition of mosatil of the whole batches of the gained of embodiment 12, examination is being used During the isomers tested during the method for example 3 determines parenteral solution, the RSD of SS isomers is in the range of 0.1~0.2%, RR isomers RSD shows this method for two kinds of test precision indifferences of isomers and non-in the range of 0.1~0.3% It is excellent；
For embodiment 1-6, the parenteral solution that with the addition of mosatil of the whole batches of the gained of embodiment 12, make respectively When determining the isomers in parenteral solution with check experiment example 1, check experiment example 2,3 three kinds of methods of check experiment example, SS isomers RSD in the range of 0.1~0.3%, the RSD of RR isomers in the range of 1.6~2.1%, show this method for The test precision indifference of SS isomers and non-excellent, but obviously can not be connect for the precision that RR isomers is tested Receive.Said circumstances shows, it may be possible to which, due to the presence of mosatil in formula, different isomers method of testings is different for RR Structure body response precision is different, when using the alkaline matter that NaOH is regulation mobile phase, there is potential methodology and lacks Fall into, and when using the method for test example of the present invention 3 instead, this defect is overcome.
Embodiment 1：Prepare Moxifloxacin hydrochloride injection
Prescription：
Moxifloxacin hydrochloride (in terms of MOXIFLOXACIN) 400mg,
L-aminobutanedioic acid 100mg,
Mosatil 10mg,
Acid-base modifier adjusts parenteral solution pH in right amount,
Appropriate water for injection, to 20ml.
Preparation method：
A () dissolves L-aminobutanedioic acid and mosatil with liquid total amount 70% water for injection (70 DEG C of water temperature), use Acid-base modifier regulation gained liquid pH value is 4.5, and moxifloxacin hydrochloride is added to when fluid temperature is at 60 DEG C, is stirred Make dissolving；
(b) when fluid temperature is at 40~70 DEG C to gained liquid in add the activated carbon (0.1%w/ in terms of liquor capacity V), stirring and adsorbing 30 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, while it is 4.5 to be verified with acid-base modifier and adjust gained liquid pH value；
D be filled to gained medical filtration in vial (20ml/ bottles) by (), sealing, and sterilizing is obtained final product.
Embodiment 2：Prepare Moxifloxacin hydrochloride injection
Prescription：
Moxifloxacin hydrochloride (in terms of MOXIFLOXACIN) 350mg,
L-aminobutanedioic acid 80mg,
Mosatil 12mg,
Acid-base modifier adjusts parenteral solution pH in right amount,
Appropriate water for injection, to 20ml.
Preparation method：
A () dissolves L-aminobutanedioic acid and mosatil with liquid total amount 60% water for injection (75 DEG C of water temperature), use Acid-base modifier regulation gained liquid pH value is 4.3, and moxifloxacin hydrochloride is added to when fluid temperature is at 70 DEG C, is stirred Make dissolving；
(b) when fluid temperature is at 40~70 DEG C to gained liquid in add the activated carbon (0.125%w/ in terms of liquor capacity V), stirring and adsorbing 40 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, while it is 4.3 to be verified with acid-base modifier and adjust gained liquid pH value；
D be filled to gained medical filtration in vial (20ml/ bottles) by (), sealing, and sterilizing is obtained final product.
Embodiment 3：Prepare Moxifloxacin hydrochloride injection
Prescription：
Moxifloxacin hydrochloride (in terms of MOXIFLOXACIN) 450mg,
L-aminobutanedioic acid 120mg,
Mosatil 8mg,
Acid-base modifier adjusts parenteral solution pH in right amount,
Appropriate water for injection, to 20ml.
Preparation method：
A () dissolves L-aminobutanedioic acid and mosatil with liquid total amount 80% water for injection (60 DEG C of water temperature), use Acid-base modifier regulation gained liquid pH value is 4.7, and moxifloxacin hydrochloride is added to when fluid temperature is at 40 DEG C, is stirred Make dissolving；
(b) when fluid temperature is at 40~70 DEG C to gained liquid in add the activated carbon (0.075%w/ in terms of liquor capacity V), stirring and adsorbing 20 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, while it is 4.7 to be verified with acid-base modifier and adjust gained liquid pH value；
D be filled to gained medical filtration in vial (20ml/ bottles) by (), sealing, and sterilizing is obtained final product.
Embodiment 4：Prepare Moxifloxacin hydrochloride injection
Prescription：
Moxifloxacin hydrochloride (in terms of MOXIFLOXACIN) 380mg,
L-aminobutanedioic acid 115mg,
Mosatil 9mg,
Acid-base modifier adjusts parenteral solution pH in right amount,
Appropriate water for injection, to 20ml.
Preparation method：
A () dissolves L-aminobutanedioic acid and mosatil with liquid total amount 75% water for injection (90 DEG C of water temperature), use Acid-base modifier regulation gained liquid pH value is 4.4, and moxifloxacin hydrochloride is added to when fluid temperature is at 55 DEG C, is stirred Make dissolving；
(b) when fluid temperature is at 40~70 DEG C to gained liquid in add the activated carbon (0.15%w/ in terms of liquor capacity V), stirring and adsorbing 60 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, while it is 4.4 to be verified with acid-base modifier and adjust gained liquid pH value；
D be filled to gained medical filtration in vial (20ml/ bottles) by (), sealing, and sterilizing is obtained final product.
Embodiment 5：Prepare Moxifloxacin hydrochloride injection
Prescription：
Moxifloxacin hydrochloride (in terms of MOXIFLOXACIN) 420mg,
L-aminobutanedioic acid 90mg,
Mosatil 11mg,
Acid-base modifier adjusts parenteral solution pH in right amount,
Appropriate water for injection, to 20ml.
Preparation method：
A () dissolves L-aminobutanedioic acid and mosatil with liquid total amount 70% water for injection (50 DEG C of water temperature), use Acid-base modifier regulation gained liquid pH value is 4.6, and moxifloxacin hydrochloride is added to when fluid temperature is at 50 DEG C, is stirred Make dissolving；
(b) when fluid temperature is at 40~70 DEG C to gained liquid in add the activated carbon (0.05%w/ in terms of liquor capacity V), stirring and adsorbing 30 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, while it is 4.6 to be verified with acid-base modifier and adjust gained liquid pH value；
D be filled to gained medical filtration in vial (20ml/ bottles) by (), sealing, and sterilizing is obtained final product.
Embodiment 6：Prepare Moxifloxacin hydrochloride injection
Prescription：
Moxifloxacin hydrochloride (in terms of MOXIFLOXACIN) 400mg,
L-aminobutanedioic acid 105mg,
Mosatil 10mg,
Acid-base modifier adjusts parenteral solution pH in right amount,
Appropriate water for injection, to 20ml.
Preparation method：
A () dissolves L-aminobutanedioic acid and mosatil with liquid total amount 65% water for injection (70 DEG C of water temperature), use Acid-base modifier regulation gained liquid pH value is 4.5, and moxifloxacin hydrochloride is added to when fluid temperature is at 65 DEG C, is stirred Make dissolving；
(b) when fluid temperature is at 40~70 DEG C to gained liquid in add the activated carbon (0.1%w/ in terms of liquor capacity V), stirring and adsorbing 45 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, while it is 4.5 to be verified with acid-base modifier and adjust gained liquid pH value；
D be filled to gained medical filtration in vial (20ml/ bottles) by (), sealing, and sterilizing is obtained final product.
Embodiment 11：Prepare Moxifloxacin hydrochloride injection
Prescription and technique respectively refer to embodiment 1- embodiments 6, and different is only, without mosatil, to obtain 6 Injection liquid samples.
Embodiment 12：Prepare Moxifloxacin hydrochloride injection
Prescription and technique respectively refer to embodiment 1- embodiments 6, and different is only the work for not carrying out step (b) in the preparation Property charcoal adsorption treatment.
Embodiment 13：Prepare Moxifloxacin hydrochloride injection (#178-Ex2)
Prescription：Moxifloxacin hydrochloride 21.82g (equivalent to MOXIFLOXACIN 20g), L-aminobutanedioic acid 6.66g, NaOH are fitted Amount, water for injection add to 1000ml.
Preparation method：700ml waters for injection are taken, recipe quantity L-aminobutanedioic acid and the dissolving of moxifloxacin hydrochloride heating stirring is added, plus Sodium hydroxide solution injects water to 1000ml to pH value 4.40.0.22um filtering with microporous membrane, props up filling with 20ml/, 121 DEG C of pressure sterilizing 15min.
Embodiment described above is only the preferred embodiment lifted to absolutely prove the present invention, protection model of the invention Enclose not limited to this.Equivalent substitute or conversion that those skilled in the art are made on the basis of the present invention, in the present invention Protection domain within.Protection scope of the present invention is defined by claims.

Claims (10)

1. the method that the RR isomers in pair Moxifloxacin hydrochloride injection pharmaceutical composition carries out assay, the hydrochloric acid is not Moxifloxacin hydrochloride, L-aminobutanedioic acid, mosatil, optional acid-base accommodation are included in the star injection pharmaceutical composition of Xisha Agent and water for injection；The method includes following operation：
(1) parenteral solution 0.5ml is taken, in putting 100ml measuring bottles, plus mobile phase is diluted to scale, shakes up, as need testing solution；Separately Moxifloxacin hydrochloride raceme reference substance about 10mg is taken, accurately weighed, in putting 100ml measuring bottles, plus mobile phase dissolved dilution is to carving Degree, is made solution of every 1ml containing about 0.1mg, as system suitability experimental solutions；
(2) chromatographic condition and system suitability：With the chromatographic column that octadecylsilane chemically bonded silica is filler；With first Alcohol-buffer solution (take D-phenylalanine 1.32g and copper sulphate 1.0g, after the 1000ml that adds water dissolvings, with alkaline matter adjust pH value to 3.3~3.7) (25：75) it is mobile phase；Flow velocity 1.0ml/min；40 DEG C of column temperature；Detection wavelength 293nm；Take system suitability examination The μ l of solution 20 injection liquid chromatographs are tested, chromatogram is recorded, moxifloxacin hydrochloride and RR- isomers appearance successively, between two peaks Separating degree should be greater than 2.0, and theoretical cam curve should be no less than 2000 based on MOXIFLOXACIN peak；
(3) precision measures the μ l of need testing solution 20 injection liquid chromatographs, records chromatogram, reads the need testing solution chromatogram Middle SS isomers (the active ingredient hydrochloric acid MOXIFLOXACIN i.e. in parenteral solution) and the peak area of RR isomers, are calculated as follows injection The content of the RR- isomers in liquid：
RR content of isomer=[RR isomers peak areas ÷ (SS isomers peak area+RR isomers peak area)] × 100%.
2. method according to claim 1, it is characterised in that：
Included in the every 20ml of the Moxifloxacin hydrochloride injection pharmaceutical composition：Moxifloxacin hydrochloride in terms of MOXIFLOXACIN 350 ~450mg, 80~120mg of L-aminobutanedioic acid, 8~12mg of mosatil；
Included in the every 20ml of the Moxifloxacin hydrochloride injection pharmaceutical composition：Moxifloxacin hydrochloride in terms of MOXIFLOXACIN 380 ~420mg, 90~115mg of L-aminobutanedioic acid, 9~11mg of mosatil；
Included in the every 20ml of the Moxifloxacin hydrochloride injection pharmaceutical composition：Moxifloxacin hydrochloride is in terms of MOXIFLOXACIN 400mg, 90~115mg of L-aminobutanedioic acid, 9~11mg of mosatil；
The Moxifloxacin hydrochloride injection pharmaceutical composition pH value is 4~5, and such as its pH value is 4.2~4.8；
The acid-base modifier is selected from following acid-base modifier：Hydrochloric acid, NaOH and their aqueous solution；And/or
The consumption of the acid-base modifier is so that the Moxifloxacin hydrochloride injection pharmaceutical composition, and its pH value is 4~5, Such as its pH value is 4.2~4.8.
3. method according to claim 1, it is characterised in that：
The Moxifloxacin hydrochloride injection pharmaceutical composition has used what charcoal absorption was processed during preparating liquid Technique；And/or
The Moxifloxacin hydrochloride injection pharmaceutical composition is prepared according to including the steps：
A () makes L-aminobutanedioic acid and Ca-EDTA with liquid total amount 60~80% water for injection (such as water temperature is 50~90 DEG C) Sodium dissolves, and it is 4.3~4.7 to adjust gained liquid pH value with acid-base modifier, (for example treats fluid temperature in 40~70 DEG C of scopes When) moxifloxacin hydrochloride is added to, it is stirred to dissolve；
(b) (such as when fluid temperature is in 40~70 DEG C of scopes) to gained liquid in add activated carbon (in terms of liquor capacity 0.05~0.15%w/v), stirring and adsorbing 20~60 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, while it is 4.3~4.7 to be verified with acid-base modifier and adjust gained liquid pH value；
D be filled to gained medical filtration in vial by (), sealing, and sterilizing is obtained final product.
4. a kind of Moxifloxacin hydrochloride injection pharmaceutical composition, wherein comprising moxifloxacin hydrochloride, L-aminobutanedioic acid, Ca-EDTA Sodium, optional acid-base modifier and water for injection.
5. Moxifloxacin hydrochloride injection pharmaceutical composition according to claim 4, it is characterised in that：
Included in its every 20ml：Moxifloxacin hydrochloride 350~450mg in terms of MOXIFLOXACIN, 80~120mg of L-aminobutanedioic acid, according to ground 8~12mg of sour calcium sodium；
Included in its every 20ml：Moxifloxacin hydrochloride 380~420mg in terms of MOXIFLOXACIN, 90~115mg of L-aminobutanedioic acid, according to ground 9~11mg of sour calcium sodium；And/or
Included in its every 20ml：Moxifloxacin hydrochloride 400mg in terms of MOXIFLOXACIN, 90~115mg of L-aminobutanedioic acid, mosatil 9~11mg.
6. Moxifloxacin hydrochloride injection pharmaceutical composition according to claim 4, it is characterised in that：
Its pH value is 4~5, and such as its pH value is 4.2~4.8；
The acid-base modifier is selected from following acid-base modifier：Hydrochloric acid, NaOH and their aqueous solution；And/or
The consumption of the acid-base modifier is so that the Moxifloxacin hydrochloride injection pharmaceutical composition, and its pH value is 4~5, Such as its pH value is 4.2~4.8.
7. Moxifloxacin hydrochloride injection pharmaceutical composition according to claim 4, it is characterised in that：
It has used the technique that charcoal absorption is processed during preparating liquid；And/or
It is prepared according to including the steps：
A () makes L-aminobutanedioic acid and Ca-EDTA with liquid total amount 60~80% water for injection (such as water temperature is 50~90 DEG C) Sodium dissolves, and it is 4.3~4.7 to adjust gained liquid pH value with acid-base modifier, (for example treats fluid temperature in 40~70 DEG C of scopes When) moxifloxacin hydrochloride is added to, it is stirred to dissolve；
(b) (such as when fluid temperature is in 40~70 DEG C of scopes) to gained liquid in add activated carbon (in terms of liquor capacity 0.05~0.15%w/v), stirring and adsorbing 20~60 minutes, decarbonization filtering；
C () is mended and is added to the full amount of water for injection, while it is 4.3~4.7 to be verified with acid-base modifier and adjust gained liquid pH value；
D be filled to gained medical filtration in vial by (), sealing, and sterilizing is obtained final product.
8. the method for preparing Moxifloxacin hydrochloride injection pharmaceutical composition described in claim any one of 4-7, the method includes Following steps：
A () dissolves L-aminobutanedioic acid and mosatil with liquid total amount 60~80% water for injection, use acid-base modifier Regulation gained liquid pH value is 4.3~4.7, is added to moxifloxacin hydrochloride, is stirred to dissolve；
B () is to adding activated carbon, stirring and adsorbing 20~60 minutes, decarbonization filtering in gained liquid；
C () is mended and is added to the full amount of water for injection, while it is 4.3~4.7 to be verified with acid-base modifier and adjust gained liquid pH value；
D be filled to gained medical filtration in vial by (), sealing, and sterilizing is obtained final product.
9. method according to claim 7, the water temperature of water for injection is 50~90 DEG C wherein in step (a)；Medicine is treated in step (a) Liquid temperature degree adds moxifloxacin hydrochloride in 40~70 DEG C of scopes；And/or, treat fluid temperature in 40~70 DEG C of models in step (b) To adding activated carbon in gained liquid when enclosing.
10. method according to claim 7, wherein in step (b) addition of activated carbon be calculated as 0.05 with liquor capacity~ 0.15%w/v.
CN201710154924.0A 2017-03-15 2017-03-15 Moxifloxacin hydrochloride injection pharmaceutical composition and its preparation and quality control method Active CN106821972B (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111024831A (en) * 2018-10-09 2020-04-17 江苏正大丰海制药有限公司 Method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101836950A (en) * 2010-03-12 2010-09-22 陕西合成药业有限公司 Moxifloxacin hydrochloride glucose injection and preparation method and use thereof
CN102895178A (en) * 2011-07-29 2013-01-30 成都国为医药科技有限公司 Strong solution-type moxifloxacin hydrochloride injection and preparation method thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101836950A (en) * 2010-03-12 2010-09-22 陕西合成药业有限公司 Moxifloxacin hydrochloride glucose injection and preparation method and use thereof
CN102895178A (en) * 2011-07-29 2013-01-30 成都国为医药科技有限公司 Strong solution-type moxifloxacin hydrochloride injection and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
陈夷花等: "盐酸莫西沙星对映异构体含量的HPLC法测定", 《中国医药工业杂志》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111024831A (en) * 2018-10-09 2020-04-17 江苏正大丰海制药有限公司 Method for separating moxifloxacin hydrochloride and impurities thereof by high performance liquid chromatography

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Address after: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province

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Address before: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province

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