CN106821972B - 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 PDFInfo
- Publication number
- CN106821972B CN106821972B CN201710154924.0A CN201710154924A CN106821972B CN 106821972 B CN106821972 B CN 106821972B CN 201710154924 A CN201710154924 A CN 201710154924A CN 106821972 B CN106821972 B CN 106821972B
- Authority
- CN
- China
- Prior art keywords
- moxifloxacin
- acid
- moxifloxacin hydrochloride
- solution
- injection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Analytical Chemistry (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
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 including 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 the method that assay is carried out to the RR isomers in Moxifloxacin hydrochloride injection pharmaceutical composition.The present composition, its preparation method and method of quality control have excellent technique effect as used in the description.
Description
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 relate to the method for quality control of this Moxifloxacin hydrochloride injection pharmaceutical composition.
Technical background
FQNS is nearly two to develop a kind of very fast fully synthetic antibacterials, main function during the last ten years
In the helicase and topoisomerase of DNA of bacteria, there is the features such as has a broad antifungal spectrum, antibacterial action are strong, safe, clinically
Be widely used in treat the respiratory tract as caused by gram-positive bacteria, negative bacterium, anaerobic bacteria etc., the urinary tract, skin soft tissue,
The various infection such as ear-nose-throat department, gynaecology and tuberculosis.According to the chemical constitution of QNS, antibacterial action and physiological disposition
It 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 acts on and security, has ranked among the row of world's well selling medicine.But with QNS use range expansion and
The increase of dosage, while various infectious diseases are resisted, resistance phenomenon is on the rise, mainly by Staphylococcus aureus
Resistance caused by bacterium, gram-positive bacteria and green pus bacterium etc., and with NSAIDs share induce 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 at first in Germany in June, 1996, trade name：Avelox, obtain U.S. FDA approval listing December in the same year.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
From the point of view of learning structure, the bit substituent of MOXIFLOXACIN 7 group is diazabicyclo, and can reduce resistance of the microorganism actively caused by outer row (is
The main mechanism of QNS crossing drug resistant), the low advantage of its drug resistance is ensure that, methoxy group is introduced at 8, makes this
Product are enhanced to gram-positive bacteria, non-while QNS original to Gram-negative bacteria antibacterial activity is retained
The antibacterial action of typical pathogen and anaerobic bacteria.MOXIFLOXACIN removes is weaker than lavo-ofloxacin to the antibacterial activity of 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.In addition, MOXIFLOXACIN is resistance to beta-lactam, macrolides, aminoglycoside and tetracycline antibiotics
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 interaction is not present between many other medicines.
Moxifloxacin hydrochloride is clinically applied to the treatment 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 according to Koch H etc. to this product, 1467 are diagnosed as the oral Moses of Patients with Simple Community Acquired Pneumonia
Husky star 0.4g, one time a day, 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 0.7%, predominantly intestines and stomach are anti-
Should, this product can be as the choice drug of Treatment of Community-acquired Pneumonia.
MOXIFLOXACIN is used as super wide spectrum Development of Fluoroquinolone Antibacterials, and two target position that bacterium is acted on due to this product are opened up
Allomerase II and IV are flutterred, so this product is not only effective to the bacterium of sensitivity, 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 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, it is unique the effect of to AECB and 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 lists this product, in succession
Listed in the U.S., Europe alliance, Latin America and Asia dozens of country, 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 the water formulation of moxifloxacin hydrochloride and glucose causes the stability of such a preparation very poor 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 being produced for treating or preventing in the medicine of human or animal's bacterium infection
Application, contain 0.04%-0.4% (w/v) (amount based on MOXIFLOXACIN) moxifloxacin hydrochlorides and 0.4%- 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 of moxifloxacin hydrochloride, 0.005~0.6W/V and 0.001~0.1W/V complexing of metal ion comprising 1~2W/V
Agent.
CN103520093A (201310477145.6) discloses a kind of Moxifloxacin hydrochloride injection and preparation method thereof,
The parenteral solution is using 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, is easy to industrial metaplasia
Production, a kind of new medication selection is provided to the patient of sodium chloride injection should not be used.
CN101972257A (201010280041.2) is related to a kind of pharmaceutical composition containing MOXIFLOXACIN, and its feature exists
It is made up of in it MOXIFLOXACIN or its salt and balanced electrolyte solution, 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 property of the present invention is stable.
CN102631316A (201210127205.7) is related to a kind of moxifloxacin injection preparation, its include MOXIFLOXACIN or its
Salt or their hydrate and the PH conditioning agents for adjusting solution pH value.The moxifloxacin injection preparation steady quality of the present 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 is stable, easily stored, solves the problems, such as that crystallization easily occurs in MOXIFLOXACIN storing process and solution colour is deepened.
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.The preparation process pair of the present invention
The requirement of equipment is not harsh, 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, specifically comprises MOXIFLOXACIN or its salt and sodium lactate ringer's injection in said composition：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 is weighed, adds appropriate water for injection to dissolve, and adds proper amount of active carbon, is dispensed, after sealing
Damp and hot 115 degree sterilize 30 minutes, obtain calcium chloride concentrated solution；Recipe quantity sodium chloride, sodium lactate are added in dense preparing tank, added suitable
Water for injection is measured, heating stirring dissolving, proper amount of active carbon is added, stirring, boils insulation 30 minutes, filter to dilute and match somebody with somebody through stud
Tank, add recipe quantity moxifloxacin hydrochloride, potassium chloride, calcium chloride concentrated solution, inject water to full amount, and adjust pH4.5~
7.0, 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 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
Measure as 0.8%~4% (g/ml), 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, there is the acceptable pH value of human body, product quality is more easy to control, storage
Stabilization in the phase is deposited, conventional isotonic solution has good compatibility with clinic, and production cost is low, small volume, transport and storage side
Just.
CN103356479A (201310322660.7) is related to Moxifloxacin hydrochloride injection aqua, it is characterised in that is
Formed by the use of sodium carbonate liquor as pH adjusting agent regulation, and the pH value of preparation is 7.1~8.0.In the preparation method of said preparation,
It is preferred that moxifloxacin hydrochloride is dissolved with the water 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, at room temperature standing or weak stirring a period of time, make pH value constant.The present invention's
Preparation can obtain higher valid density and preferable 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), 0.005~1mol/L not sulfur-bearing amino acid and its
Pharmaceutically acceptable salt；Wherein described MOXIFLOXACIN is preferably 1.8%~4% (g/ml).
In addition, 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 a kind of side of liquid chromatography for separating and determining MOXIFLOXACIN and its impurity
Method, it is characterised in that：Chromatographic column using phenyl bonded silica as filler, using methanol-cushioning liquid as mobile phase, is washed using gradient
De-, wherein methanol cushioning liquid initial volume ratio is 30：70~10：90, cushioning liquid contains tetrabutyl quaternary ammonium salt, tetrabutyl phosphorus
The combination of hydrochlorate or tetrabutyl sulfate and phosphate, 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 is taken, adds mobile phase dissolved dilution, is configured to the μ g/ml of 1 μ g/ml~20 hydrochloric acid Moses
Husky star racemization liquid solution；Moxifloxacin hydrochloride is taken, adds mobile phase dissolved dilution, is configured to 0.4mg/ml~1mg/ml hydrochloric acid not
Xisha star solution；3) chromatographic condition：High performance liquid chromatograph, chromatographic column used are reverse-phase chromatographic column, with copper sulphate and chiral examination
The mixed aqueous solution of agent is aqueous phase, and the mixed liquor of aqueous 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
The μ l of star racemization liquid solution and each 2 μ l of the moxifloxacin hydrochloride solution~50, inject liquid chromatograph, record chromatogram, still
This method is it is not clear whether formula suitable for testing 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., can be right with external standard method detection with analyzing moxifloxacin hydrochloride using the compound or its salt as impurity reference substance
Such impurity that may contain in the moxifloxacin hydrochloride raw material and preparation of industrialized production carries out quantitative control, is advantageous to improve
The quality of moxifloxacin hydrochloride, improve the security of clinical application.
CN103185757A (201110445346.9) provides a kind of detection method of MOXIFLOXACIN (R, R)-isomers,
The detection method is detected using high performance liquid chromatograph, and its condition is as follows：Chromatographic column is octadecylsilane chemically bonded silica
Chromatographic column, mobile phase are the solvent containing L-Leu and metal ion, wherein the metal ion is Cu2+, Zn2+ or it is mixed
Ion is closed, the solvent include water and organic solvent, and the volume ratio of water and organic solvent is 77~82: 23~18.The present invention carries
The detection method of confession has higher sensitivity and specificity, simple to operation, can fast and accurately detect MOXIFLOXACIN (R,
R)-isomers, base has been established available for the quality control of MOXIFLOXACIN, and for the research and development and quality testing of such compound
Plinth, there is realistic meaning.
Have it has been found by the present inventors that above-mentioned CN102895178A uses comprising parenteral solution made of the formula of amino acid
Excellent chemical stability.However, the present inventors have additionally discovered that, above-mentioned CN102895178A includes amino acid for example comprising door winter ammonia
Ring of the parenteral solution of acid in somewhat low temperature (this environment is likely to encounter, such as is being frequently encountered in some intermediate links)
Under border store after can it is micro- have opalescence appearance, although it is unclear it is this whether the security of product can be had an impact, this
Art personnel are still to need to avoid known as street drug.The present inventor further investigation revealed that, this
Kind opalescence in parenteral solution process for preparation with charcoal absorption by that can be avoided；Unfortunately, because using
Charcoal absorption draw it is new the problem of be using charcoal absorption when, show the situation to the notable absorption of active component,
The notable loss of active component in finished product is caused, this just needs to overcome by increasing inventory.Therefore, those skilled in the art
Still expect solve above-mentioned various technical problems and/or contradiction.
The content of the invention
Present invention aims 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 be formulated the hydrochloric acid of the present invention being prepared 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 including 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, its pH value are according to a first aspect of the present invention
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 commonly used in the art in parenteral solution pH regulations, such as hydrochloric acid, phosphoric acid, sulfuric acid etc.
Alkali and their aqueous solution such as acid and sodium hydroxide, sodium acid carbonate, sodium carbonate.In the present invention, the acid-base modifier
It is to be selected from following acid-base modifier：Hydrochloric acid, sodium hydroxide 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 dosage of acid-base modifier is so that the Moxifloxacin hydrochloride injection pharmaceutical composition, and its pH value is 4~5, such as its pH
It is worth for 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 handle during decoction.Charcoal absorption handling process is in parenteral solution process for preparation
A kind of common process, generally determine the need for this operating procedure depending on specific kind.This charcoal absorption handling process is usual
For include needle-use activated carbon is added into the decoction 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) L-aminobutanedioic acid is made and according to ground with 60~80% water for injection (such as water temperature is 50~90 DEG C) with liquid total amount
Sour calcium sodium dissolving, it is 4.3~4.7 to adjust gained decoction pH value with acid-base modifier, (such as treat fluid temperature in 40~70 DEG C of models
When enclosing) moxifloxacin hydrochloride is added thereto, it is stirred to dissolve；
(b) (such as when fluid temperature is in 40~70 DEG C of scopes) adds activated carbon into gained decoction (with liquor capacity
Count 0.05~0.15%w/v), stirring and adsorbing 20~60 minutes, decarbonization filtering；
(c) mend and add to the full amount of water for injection, at the same verify with acid-base modifier and adjust gained decoction pH value for 4.3~
4.7；
(d) by gained medical filtration, it is filled in vial, seals, sterilizing, produces.
Further, second aspect of the present invention, which provides, prepares Moxifloxacin hydrochloride injection pharmaceutical composition such as this hair
The method of 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 technique preparating liquid that this method is handled including the use of charcoal absorption.
The method of any embodiment, this method comprise the following steps according to a second aspect of the present invention：
(a) L-aminobutanedioic acid is made and according to ground with 60~80% water for injection (such as water temperature is 50~90 DEG C) with liquid total amount
Sour calcium sodium dissolving, it is 4.3~4.7 to adjust gained decoction pH value with acid-base modifier, (such as treat fluid temperature in 40~70 DEG C of models
When enclosing) moxifloxacin hydrochloride is added thereto, it is stirred to dissolve；
(b) (such as when fluid temperature is in 40~70 DEG C of scopes) adds activated carbon into gained decoction (with liquor capacity
Count 0.05~0.15%w/v), stirring and adsorbing 20~60 minutes, decarbonization filtering；
(c) mend and add to the full amount of water for injection, at the same verify with acid-base modifier and adjust gained decoction pH value for 4.3~
4.7；
(d) by gained medical filtration, it is filled in vial, seals, sterilizing, produces.
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, 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, such as hydrochloric acid, phosphoric acid, sulfuric acid etc. acid and sodium hydroxide, sodium acid carbonate,
The alkali such as sodium carbonate and their aqueous solution.In the present invention, the acid-base modifier is to be selected from following acid-base modifier：Salt
Acid, sodium hydroxide and their aqueous solution.
The method of any embodiment according to a second aspect of the present invention, wherein the dosage 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 usually require 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 need special chromatographic condition to realize excellent chromatography when carrying out content of isomer measure.
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, moxifloxacin hydrochloride, door are included in the Moxifloxacin hydrochloride injection pharmaceutical composition
Winter propylhomoserin, mosatil, optional acid-base modifier and water for injection；This method includes following operation：
(1) parenteral solution 0.5ml is taken, puts in 100ml measuring bottles, adds mobile phase to be diluted to scale, shake up, it is molten as test sample
Liquid；It is another to take moxifloxacin hydrochloride raceme reference substance about 10mg, it is accurately weighed, put in 100ml measuring bottles, add 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
Methanol-buffer solution (takes D-phenylalanine 1.32g and copper sulphate 1.0g, after adding water 1000ml to dissolve, 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 in spectrogram, is calculated as follows
The content of RR- isomers in parenteral solution：
RR content of isomer=[RR isomers peak areas ÷ (SS isomers peak area+RR isomers peak area)] ×
100%.
RR isomers can be calculated in parenteral solution relative to the percentage composition of whole configuration materials 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 according to a third aspect of the present invention, alkaline matter choosing during for preparing mobile phase
From sodium hydroxide, sodium acid carbonate, triethylamine.It has been had now surprisingly been found that, can be with as the pH using triethylamine regulation buffer solution
Overcome is probably due to influenceed caused by mosatil on RR isomery body measurements precision the defects of.
The method of any embodiment according to a third aspect of the present invention, the Moxifloxacin hydrochloride injection pharmaceutical composition
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 according to a third aspect of the present invention, the Moxifloxacin hydrochloride injection pharmaceutical composition
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 according to a third aspect of the present invention, the Moxifloxacin hydrochloride injection pharmaceutical composition
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 according to a third aspect of the present invention, the Moxifloxacin hydrochloride injection pharmaceutical composition
PH value is 4~5, 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, such as hydrochloric acid, phosphoric acid, sulfuric acid etc. acid and sodium hydroxide, sodium acid carbonate,
The alkali such as sodium carbonate and their aqueous solution.In the present invention, the acid-base modifier is to be selected from following acid-base modifier：Salt
Acid, sodium hydroxide and their aqueous solution.
The method of any embodiment according to a third aspect of the present invention, wherein the dosage 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 according to a third aspect of the present invention, the Moxifloxacin hydrochloride injection pharmaceutical composition
The technique for having used charcoal absorption to handle during preparating liquid.
The method of any embodiment according to a third aspect of the present invention, the Moxifloxacin hydrochloride injection pharmaceutical composition
It is prepared according to the steps is included：
(a) L-aminobutanedioic acid is made and according to ground with 60~80% water for injection (such as water temperature is 50~90 DEG C) with liquid total amount
Sour calcium sodium dissolving, it is 4.3~4.7 to adjust gained decoction pH value with acid-base modifier, (such as treat fluid temperature in 40~70 DEG C of models
When enclosing) moxifloxacin hydrochloride is added thereto, it is stirred to dissolve；
(b) (such as when fluid temperature is in 40~70 DEG C of scopes) adds activated carbon into gained decoction (with liquor capacity
Count 0.05~0.15%w/v), stirring and adsorbing 20~60 minutes, decarbonization filtering；
(c) mend and add to the full amount of water for injection, at the same verify with acid-base modifier and adjust gained decoction pH value for 4.3~
4.7；
(d) by gained medical filtration, it is filled in vial, seals, sterilizing, produces.
Any technical characteristic possessed by any embodiment of either side or the either side of the present invention 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 to various aspects of the present invention with feature into one below
The description of step.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary
When offering expressed implication and the inconsistent present invention, it is defined by the statement of the present invention.In addition, 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 referred to is 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, the antibiotics applied to the adult for having the upper respiratory tract and ALRI.The English of moxifloxacin hydrochloride
Entitled MoxifloxacinHydrochloride, molecular formula C21H24FN3O4HCl, molecular weight 437.89, No. CAS is
186826-86-8, Chinese chemical name are that 1- cyclopropyl -7- (ring of S, S-2,8- diazonium-two [4.3.0] nonane -8- 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- (ring of R, R-2,8- diazonium-two [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 excellent, and the present invention is presented in the Moxifloxacin hydrochloride injection that inventive formulation and method are prepared
Method for analyzing the isomers in parenteral solution also has excellent Methodological characteristics.
Embodiment
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited
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 carries out general to the material and test method that are arrived used in experiment
And/or specific description.Although for realize many materials used in the object of the invention 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 limit this hair
It is bright.
The present invention hereinafter, example it is bright injection formula of liquid when, if not otherwise indicated, illustrated with every 20ml amount, but
It is each inventory at least 10L when actual production operates.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 operates.
Chromatographic condition and system suitability：It is filler with phenyl silane bonded silica gel, 45 DEG C of column temperature；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, methanol is Mobile phase B, and according to the form below carries out gradient elution.The μ l of contrast solution 20 are taken to inject liquid chromatogram
Instrument, detection sensitivity is adjusted, the peak height for making principal component chromatographic peak is about the 20% of full scale；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), the separating degree of impurity A and MOXIFLOXACIN should be big
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, puts in 100ml brown measuring bottles, add dilution (weigh 0.50g TMAHs and
1.0g potassium dihydrogen phosphates, it is dissolved in 500ml water, adds 2ml phosphoric acid and 0.050g anhydrous sodium sulfites, be diluted with water to
Scale 1000ml) is diluted to, is shaken up, is made containing about moxifloxacin hydrochloride 1.0mg solution 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, be made containing about 1.0 μ g solution 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 methanol dissolved dilution to scale, mix, then accurate amount
5ml is taken, puts in 25ml measuring bottles plus methanol dilution is to scale, mix, the solution containing about 10ug in every 1ml is made, determines as impurity
Position solution.Another to take MOXIFLOXACIN peak discriminating reference substance (hydrochloric moxifloxacin impurity A, B, C, D, E) about 10mg, precision claims
It is fixed, put in 10ml measuring bottles, add dilution dissolved dilution solution of every 1ml containing about 1mg to be made, as system suitability to scale
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, quinoline carboxylic in the chromatogram of need testing solution
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 compareing
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：For the peak area of quinoline carboxylic acid in need testing solution；
SMiscellaneous A：For the peak area of moxifloxacin hydrochloride impurity A in need testing solution；
SMiscellaneous B：For the peak area of moxifloxacin hydrochloride impurity B in need testing solution；
SMiscellaneous C：For the peak area of moxifloxacin hydrochloride impurity C in need testing solution；
SMiscellaneous D：For the peak area of moxifloxacin hydrochloride impurity D in need testing solution；
SMiscellaneous E：For the peak area of moxifloxacin hydrochloride impurity E in need testing solution；
SFor list：For the peak area of the single maximum contaminant of other in need testing solution；
SFor with：For the sum of each impurity peak area in need testing solution；
SIt is right：For 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 is R=F, R '=OC2H5,
Impurity D is 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 methanol-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 is not less than 3000, and tailing factor must not
More than 1.5.
Determination method：This product 5ml is taken, is put in 100ml brown measuring bottles, adds dilution (to take 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, puts in 50ml brown measuring bottles, adds diluted to shake up to scale, 1ml is made
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, record chromatogram；It is another to take moxifloxacin hydrochloride reference substance about 10mg, it is accurately weighed, put in 100ml volumetric flasks, add 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, is 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：For the main peak area of need testing solution；
nFor：For the extension rate of need testing solution；
VFor：For test sample sampling amount；
mIt is right：For reference substance sample weighting amount；
CIt is right：For the content of reference substance；
SIt is right：For the main peak area of reference substance solution；
nIt is right：For the extension rate of reference substance solution；
KIt is right：For 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, puts in 100ml measuring bottles, adds mobile phase to be diluted to scale, shake up, it is molten as test sample
Liquid；It is another to take moxifloxacin hydrochloride raceme reference substance about 10mg, it is accurately weighed, put in 100ml measuring bottles, add 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
Methanol-buffer solution (takes D-phenylalanine 1.32g and copper sulphate 1.0g, after adding water 1000ml to dissolve, (specifically made with alkaline matter
It is triethylamine) pH value is adjusted to 3.3~3.7) (25：75) it is mobile phase；Flow velocity 1.0ml/min；40 DEG C of column temperature；Detect ripple
Long 293nm；Take the μ l of system suitability solution 20 to inject liquid chromatograph, record chromatogram, 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 in spectrogram, is calculated as follows
The content of RR- isomers in parenteral solution：
RR content of isomer=[RR isomers peak areas ÷ (SS isomers peak area+RR isomers peak area)] ×
100%.
RR isomers can be calculated in parenteral solution relative to the percentage composition of whole configuration materials 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 B of CN 103543230 embodiment 1.
Check experiment example 2：The method for determining the enantiomter in Moxifloxacin hydrochloride injection
With reference to the method for the B of CN 103543230 embodiment 1, 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 preparing mobile phase changes
Use sodium hydroxide.
Test example 4：The study on the stability of parenteral solution：
Example 1 below -6, the parenteral solution obtained by embodiment 11-13 is placed in 45 DEG C of high temperature and place April (in the present invention
In can be described as disposal in 45 DEG C of April), according to any of the above test example, respectively at active component Moses in 0 month and June measure parenteral solution
Sha Xing content, 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 postponed：
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 0 month value takes absolute value with value difference value in June, 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 for active component MOXIFLOXACIN, the change hundred
Fraction is bigger to represent that active component content reduction is more.As a result show, all injections obtained by embodiment 1-6, embodiment 11-13
Liquid, whether add EDTA, whether adsorbed in process with charcoal, show that three Parameters variation percentages are in small change
The result of change, such as MOXIFLOXACIN changes of contents percentage is in the range of 1.6~3.1% and each sample is between each other without obvious
Difference, relevant Substances variation percentage in the range of 1.13~1.74% and the mutual no significant difference of each sample,
Enantiomter changes of contents percentage is in the range of 0.86~1.44% and the mutual no significant difference of each sample.
1 is placed in addition, the parenteral solution obtained by embodiment 1-6, embodiment 11-13 is placed under 8~10 DEG C of cryogenic conditions
The moon (can be described as 10 DEG C of disposal in January) in the present invention, according to any of the above test example, be determined respectively at 0 month and January living in parenteral solution
Property composition MOXIFLOXACIN content, relevant content of material, enantiomter content.For each index through this 10 DEG C of disposal in January
Percent change afterwards also refers to the calculating formula processing of above-mentioned disposal in 45 DEG C of April, and as a result display is as high-temperature treatment, Moses
Three Sha Xing content, relevant content of material, enantiomter content indexs 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 whole batches, is observed after the completion of preparation obtained by embodiment 1-6, embodiment 11-13,
It is clear solution, and does not observe there is opalescence phenomenon.The parenteral solution of whole batches obtained by embodiment 1-6, embodiment 11-13
Observed after 45 DEG C of disposal in April of experience, be clear solution, and do not observe there is opalescence phenomenon.Embodiment 1-6, embodiment
Being observed through parenteral solution obtained by carbon treatment process after 10 DEG C of disposal in January of experience for the 11 whole batches of gained, is clear solution, and
Do not observe there is opalescence phenomenon.Embodiment 12, the whole batches of the gained of embodiment 13 without parenteral solution obtained by carbon treatment process
Observed after experience disposal in 10 DEG C of January, observing has opalescence phenomenon, and these samples opalescence after room temperature places January again
It will not disappear, this is can not to make us receiving completely, therefore in the circulation, storage, transportation of medicine particularly parenteral solution
It is entirely possible at a temperature of being exposed to 10 DEG C or so and this open-assembly time is entirely possible more than 1 month.Tied more than
Fruit is visible, and unacceptable opalescence phenomenon occurs in the parenteral solution handled without charcoal absorption after low temperature environment is undergone, and
After being handled with activated carbon this opalescence can be overcome to be formed.
Test example 5：Injection Process Performance：
In embodiment 1-6, embodiment 11 prepare the technique of parenteral solution, charcoal absorption processing has been used, has been filtered in charcoal
It is front and rear, the concentration of the active component in decoction is determined, with concentration in decoction before concentration in decoction after filter divided by filter multiplied by with 100%
Gained percentage, as the remaining percentage of active component in decoction after filtering, as a result show 6 injections prepared by embodiment 11
Remnants percentages are in the range of 91~92% during liquid, and remnants percentages are 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 work as in decoction and with the addition of mosatil
Afterwards, this loss can be avoided completely, and this is completely unexpected, because prior art, which be not shown in, any this technology religion
Lead, such as 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 are also found when preparing Moxifloxacin hydrochloride injection, in titanium filter decarburization
In front and rear decoction, the remaining percentage of active component is 90.8%, shows to equally exist adsorption loss, this loss generally needs
Increase is fed intake in bulk drug to liquidate.
Test example 6：RR isomers detects
Use the above-mentioned test example 3 of the present invention, check experiment example 1, check experiment example 2, the method for check experiment example 3, measure
The content of RR isomers in various parenteral solutions produced by the present invention.
As a result show, chromatogram obtained by the method for test example 3 and check experiment example 1, check experiment example 2, the side of check experiment example 3
Chromatogram obtained by method is substantially the same and essentially identical with CN103543230B Fig. 1 and Fig. 2, and particularly for example SS is different
Structure body and RR isomers are in separating degree, number of theoretical plate etc. test example 3, check experiment example 1, check experiment example 2, check experiment
The method of example 3 is essentially identical with CN103543230B Fig. 1 and Fig. 2 (such as between moxifloxacin hydrochloride and the peak of RR- isomers two
Separating degree is all higher than 3.0,3000) 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 peak 2 in CN103543230B Fig. 2, this
Sample, easily cause the chromatographic peak record deviation it is big, thereby result in the fluctuation of small peak peak area when different sample introductions are tested, this
Kind fluctuation is 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 less than 0.5% being preferable, and when be more than 1% be it is unfavorable even
It is unacceptable, especially for the inexplicit impurity of this biological activity, accurate measure is necessary.
For the parenteral solution for being not added with mosatil of embodiment 11, the whole batches of the gained of embodiment 13, make respectively
When determining the isomers in parenteral solutions with 3 four kinds of test example 3, check experiment example 1, check experiment example 2, check experiment example methods,
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 the test precision indifference of two kinds 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
When testing the isomers in the method for example 3 measure parenteral solution, the RSD of SS isomers is in the range of 0.1~0.2%, RR isomers
RSD shows this method for the test precision indifference of two kinds 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 solutions with 3 three kinds of check experiment example 1, check experiment example 2, check experiment example methods, 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 of RR isomers test
By.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 sodium hydroxide to adjust the alkaline matter of mobile phase, potential methodology be present and lacks
When falling into, and using the method for test example 3 of the present invention 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) L-aminobutanedioic acid and mosatil are dissolved with 70% water for injection (70 DEG C of water temperature) with liquid total amount, used
Acid-base modifier regulation gained decoction pH value is 4.5, adds moxifloxacin hydrochloride thereto when fluid temperature is at 60 DEG C, stirs
Make dissolving；
(b) activated carbon (0.1%w/ in terms of liquor capacity is added into gained decoction when fluid temperature is at 40~70 DEG C
V), stirring and adsorbing 30 minutes, decarbonization filtering；
(c) mend and add to the full amount of water for injection, while it is 4.5 to be verified with acid-base modifier and adjust gained decoction pH value；
(d) by gained medical filtration, it is filled in vial (20ml/ bottles), seals, sterilizing, produces.
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) L-aminobutanedioic acid and mosatil are dissolved with 60% water for injection (75 DEG C of water temperature) with liquid total amount, used
Acid-base modifier regulation gained decoction pH value is 4.3, adds moxifloxacin hydrochloride thereto when fluid temperature is at 70 DEG C, stirs
Make dissolving；
(b) activated carbon (0.125%w/ in terms of liquor capacity is added into gained decoction when fluid temperature is at 40~70 DEG C
V), stirring and adsorbing 40 minutes, decarbonization filtering；
(c) mend and add to the full amount of water for injection, while it is 4.3 to be verified with acid-base modifier and adjust gained decoction pH value；
(d) by gained medical filtration, it is filled in vial (20ml/ bottles), seals, sterilizing, produces.
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) L-aminobutanedioic acid and mosatil are dissolved with 80% water for injection (60 DEG C of water temperature) with liquid total amount, used
Acid-base modifier regulation gained decoction pH value is 4.7, adds moxifloxacin hydrochloride thereto when fluid temperature is at 40 DEG C, stirs
Make dissolving；
(b) activated carbon (0.075%w/ in terms of liquor capacity is added into gained decoction when fluid temperature is at 40~70 DEG C
V), stirring and adsorbing 20 minutes, decarbonization filtering；
(c) mend and add to the full amount of water for injection, while it is 4.7 to be verified with acid-base modifier and adjust gained decoction pH value；
(d) by gained medical filtration, it is filled in vial (20ml/ bottles), seals, sterilizing, produces.
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) L-aminobutanedioic acid and mosatil are dissolved with 75% water for injection (90 DEG C of water temperature) with liquid total amount, used
Acid-base modifier regulation gained decoction pH value is 4.4, adds moxifloxacin hydrochloride thereto when fluid temperature is at 55 DEG C, stirs
Make dissolving；
(b) activated carbon (0.15%w/ in terms of liquor capacity is added into gained decoction when fluid temperature is at 40~70 DEG C
V), stirring and adsorbing 60 minutes, decarbonization filtering；
(c) mend and add to the full amount of water for injection, while it is 4.4 to be verified with acid-base modifier and adjust gained decoction pH value；
(d) by gained medical filtration, it is filled in vial (20ml/ bottles), seals, sterilizing, produces.
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) L-aminobutanedioic acid and mosatil are dissolved with 70% water for injection (50 DEG C of water temperature) with liquid total amount, used
Acid-base modifier regulation gained decoction pH value is 4.6, adds moxifloxacin hydrochloride thereto when fluid temperature is at 50 DEG C, stirs
Make dissolving；
(b) activated carbon (0.05%w/ in terms of liquor capacity is added into gained decoction when fluid temperature is at 40~70 DEG C
V), stirring and adsorbing 30 minutes, decarbonization filtering；
(c) mend and add to the full amount of water for injection, while it is 4.6 to be verified with acid-base modifier and adjust gained decoction pH value；
(d) by gained medical filtration, it is filled in vial (20ml/ bottles), seals, sterilizing, produces.
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) L-aminobutanedioic acid and mosatil are dissolved with 65% water for injection (70 DEG C of water temperature) with liquid total amount, used
Acid-base modifier regulation gained decoction pH value is 4.5, adds moxifloxacin hydrochloride thereto when fluid temperature is at 65 DEG C, stirs
Make dissolving；
(b) activated carbon (0.1%w/ in terms of liquor capacity is added into gained decoction when fluid temperature is at 40~70 DEG C
V), stirring and adsorbing 45 minutes, decarbonization filtering；
(c) mend and add to the full amount of water for injection, while it is 4.5 to be verified with acid-base modifier and adjust gained decoction pH value；
(d) by gained medical filtration, it is filled in vial (20ml/ bottles), seals, sterilizing, produces.
Embodiment 11：Prepare Moxifloxacin hydrochloride injection
Prescription and technique respectively refer to embodiment 1- embodiments 6, and different is only not add mosatil, obtains 6
Injection liquid samples.
Embodiment 12：Prepare Moxifloxacin hydrochloride injection
Prescription and technique respectively refer to embodiment 1- embodiments 6, and different is only in the preparation without the work of step (b)
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, sodium hydroxide 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, adds
Sodium hydroxide solution injects water to 1000ml to pH value 4.40.0.22um filtering with microporous membrane, it is filling with 20ml/ branch,
121 DEG C of pressure sterilizing 15min.
Embodiment described above is only to absolutely prove preferred embodiment that is of the invention and being lifted, protection model of the invention
Enclose not limited to this.The 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 (5)
1. the method that the RR isomers in pair Moxifloxacin hydrochloride injection pharmaceutical composition carries out assay, the hydrochloric acid is not
Xisha star injection pharmaceutical composition is by moxifloxacin hydrochloride, L-aminobutanedioic acid, mosatil, optional acid-base modifier and note
Penetrate and formed with water, included in the every 20ml of the Moxifloxacin hydrochloride injection pharmaceutical composition：Moxifloxacin hydrochloride is with MOXIFLOXACIN
350 ~ 450mg, 80 ~ 120mg of L-aminobutanedioic acid, 8 ~ 12mg of mosatil are counted, its pH value is 4.2 ~ 4.8, the acid-base modifier
It is selected from：Hydrochloric acid, sodium hydroxide and their aqueous solution；The Moxifloxacin hydrochloride injection pharmaceutical composition is in preparating liquid
During used charcoal absorption handle technique；This method includes following operation：
(1) parenteral solution 0.5ml is taken, puts in 100ml measuring bottles, adds mobile phase to be diluted to scale, shake up, as need testing solution；Separately
Moxifloxacin hydrochloride raceme reference substance 10mg is taken, it is accurately weighed, put in 100ml measuring bottles, add flowing phased soln and be diluted to quarter
Degree, is made solution of every 1ml containing 0.1mg, as system suitability solution；
(2) chromatographic condition and system suitability：With the chromatographic column that octadecylsilane chemically bonded silica is filler；With volume
Than 25：75 methanol-buffer solution is mobile phase, and the compound method of the buffer solution is：Take D-phenylalanine 1.32g and copper sulphate
1.0g, after adding water 1000ml to dissolve, pH value is adjusted to 3.3 ~ 3.7 with alkaline matter triethylamine；Flow velocity 1.0ml/min；Column temperature 40
℃；Detection wavelength 293nm；Take the μ l of system suitability solution 20 to inject liquid chromatograph, record chromatogram, moxifloxacin hydrochloride
Star and RR- isomers appearance successively, separating degree should be greater than 2.0 between two peaks, and theoretical cam curve should be many based on MOXIFLOXACIN peak
In 2000；
(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 is the peak area of the active ingredient hydrochloric acid MOXIFLOXACIN and RR isomers in parenteral solution, and parenteral solution is calculated with following formula
In RR- isomers content：
RR content of isomer=[RR isomers peak areas ÷ (SS isomers peak area+RR isomers peak area)] × 100%.
2. method according to claim 1, the Moxifloxacin hydrochloride injection pharmaceutical composition per 20ml in include：Hydrochloric acid is not
Xisha star 380 ~ 420mg in terms of MOXIFLOXACIN, 90 ~ 115mg of L-aminobutanedioic acid, 9 ~ 11mg of mosatil.
3. method according to claim 1, the Moxifloxacin hydrochloride injection pharmaceutical composition per 20ml in include：Hydrochloric acid is not
Xisha star 400mg in terms of MOXIFLOXACIN, 90 ~ 115mg of L-aminobutanedioic acid, 9 ~ 11mg of mosatil.
4. method according to claim 1, the dosage of the acid-base modifier is so that the Moxifloxacin hydrochloride injection medicine
The pH value of compositions is 4.2 ~ 4.8.
5. method according to claim 1, the Moxifloxacin hydrochloride injection pharmaceutical composition is according to comprising the following steps
What method was prepared：
(a) dissolve L-aminobutanedioic acid and mosatil with the water for injection that 60 ~ 80% water temperature with liquid total amount is 50 ~ 90 °C,
It is 4.3 ~ 4.7 to adjust gained decoction pH value with acid-base modifier, and hydrochloric acid is added thereto when fluid temperature is in 40 ~ 70 °C of scopes
MOXIFLOXACIN, it is stirred to dissolve；
(b) activated carbon is added into gained decoction when fluid temperature is in 40 ~ 70 °C of scopes, activated carbon dosage is in terms of liquor capacity
0.05 ~ 0.15%w/v, stirring and adsorbing 20 ~ 60 minutes, decarbonization filtering；
(c) mend and add 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 decoction pH value；
(d) by gained medical filtration, it is filled in vial, seals, sterilizing, produces.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710154924.0A CN106821972B (en) | 2017-03-15 | 2017-03-15 | Moxifloxacin hydrochloride injection pharmaceutical composition and its preparation and quality control method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710154924.0A CN106821972B (en) | 2017-03-15 | 2017-03-15 | Moxifloxacin hydrochloride injection pharmaceutical composition and its preparation and quality control method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106821972A CN106821972A (en) | 2017-06-13 |
| CN106821972B true CN106821972B (en) | 2018-03-23 |
Family
ID=59144001
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710154924.0A Active CN106821972B (en) | 2017-03-15 | 2017-03-15 | Moxifloxacin hydrochloride injection pharmaceutical composition and its preparation and quality control method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106821972B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111024831B (en) * | 2018-10-09 | 2023-05-02 | 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)
| 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 |
-
2017
- 2017-03-15 CN CN201710154924.0A patent/CN106821972B/en active Active
Patent Citations (2)
| 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)
| Title |
|---|
| 盐酸莫西沙星对映异构体含量的HPLC法测定;陈夷花等;《中国医药工业杂志》;20130110;第44卷(第1期);第65页左栏"2 方法与结果"项下 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106821972A (en) | 2017-06-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US9629828B2 (en) | Methods of treating traveler's diarrhea and hepatic encephalopathy | |
| US9855254B2 (en) | Methods of treating hepatic encephalopathy | |
| CN110279698A (en) | Cephalo spy coughs up a ceremonial jade-ladle, used in libation antibiotic composition | |
| EP3964066A1 (en) | Methods of treating hepatic encephalopathy | |
| Di Stefano et al. | Systemic absorption of rifamycin SV MMX administered as modified-release tablets in healthy volunteers | |
| CN101836950A (en) | Moxifloxacin hydrochloride glucose injection and preparation method and use thereof | |
| CN106821972B (en) | Moxifloxacin hydrochloride injection pharmaceutical composition and its preparation and quality control method | |
| CN102000024A (en) | Moxifloxacin hydrochloride injection, preparation method and application thereof | |
| CN104095809B (en) | Clindamycin phosphate injection pharmaceutical composition and preparation method | |
| CN104546699B (en) | Sisomicin sulfate injection pharmaceutical composition and preparation method | |
| CN103159787A (en) | Preparation method for high-purity sterilized cefotiam hydrochloride and pharmaceutical composition containing cefotiam hydrochloride | |
| CN105147599B (en) | Netilmicin sulfate injection and preparation method | |
| CN101642429A (en) | Method for preparing stable rifamycin sodium injection and rifamycin sodium and sodium chloride (glucose) injection | |
| CN104721154B (en) | Injection norfloxacin glutamate freeze-drying powder-injection pharmaceutical composition | |
| CN104666253B (en) | Clindamycin phosphate powder for injection pharmaceutical composition and preparation method | |
| CN105193712B (en) | Ambroxol hydrochloride injection and preparation method | |
| CN105213301B (en) | Netilmicin sulfate injection and its quality control method | |
| CN101884613A (en) | Moxifloxacinhydrochloride sodium chloride injection, preparation method thereof and use thereof | |
| CN112379021A (en) | Impurity and quality detection method of clindamycin hydrochloride capsule | |
| CN103232476B (en) | A kind of antimicrobial compounds | |
| CN103655460B (en) | Injection medicinal composition containing aztreonam, as well as preparation method and application thereof | |
| CN110003240A (en) | A kind of Cefminox sodium raw materials and preparation method thereof and preparation | |
| US20230091701A1 (en) | Methods of treating hepatic encephalopathy | |
| CN106109485A (en) | Water-soluble vitamin composition for injection and quality control method | |
| Kavi et al. | Tissue penetration and pharmacokinetics of lomefloxacin following multiple doses |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee after: Chengdu Tiantaishan Pharmaceutical Co.,Ltd. Address before: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee before: CHENGDU TIANTAISHAN PHARMACEUTICAL Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |