CN106937944A - A kind of injection metronidazole freeze-dried powder and preparation method thereof - Google Patents

Abstract

The present invention relates to a kind of injection metronidazole freeze-dried powder and preparation method thereof, metronidazole, glutamic acid, sorbierite and polyvinylpyrrolidone are included.It can effectively reduce nitrite and iron ion in Metronidazule injection, avoid transfusion pain, phlebitis problem, and the impurity such as nitrite and cause the side reaction problems such as dizzy, uncomfortable in chest, diarrhoea, the freeze-dried powder of the present invention has that the redissolution time is short, particulate matter is few simultaneously, and it is easy to compounding, and improve the advantage of stability.

Description

A kind of injection metronidazole freeze-dried powder and preparation method thereof

Technical field

The present invention relates to pharmaceutical technology field, and in particular to a kind of injection metronidazole freeze-dried powder and its preparation side Method.

Background technology

Metronidazole is that nitro miaow files derivative, and the effect of tool wide spectrum anaerobe resistant and antiprotozoan, clinic is mainly used in prevention Infected with caused by treatment anaerobic bacteria, such as respiratory tract, alimentary canal, abdominal cavity and the infection of basin purulence, the infection at the position such as skin soft tissue And endocarditis, septicemia and meningitis etc. caused by bacteroides fragilis, oral cavity anaerobium infection is also widely used in addition. Current pharmacopeia has included Metronidazole Tablet, metronidazole vagina effervescent tablet, metronidazole suppository, Metronidazole Capsule, Metrogel, first nitre The kinds such as azoles parenteral solution, Metronidazole and Glucose Injection, metronidazole injection.The secondary work of poison when the consumption of metronidazole is big With very by force, the metronidazole of normal therapeutic dose can produce digestive tract reaction, most commonly seen including Nausea and vomiting, poor appetite, abdomen Portion's angina and higher neurotoxicity.

But current Metronidazule injection still suffers from more problem, there is document report total in National Drug Administration In 37th phase drug quality publication subordinate list 2, the Metronidazule injection disqualified upon inspection of 3 medical institutions and 5 pharmaceutical factory's production Project is clarity.When preparing injection, the metal chelant that can be added by the property of medicine in suitable additives, additives Agent using it is more be that iron ion reaches 0.6ug/ml in natrium adetate salt, Metronidazule injection when, start after sterilizing Existing off-white color is muddy, and turbidity is raised and increased with iron concentration.It can be seen that iron ion can significantly affect Metronidazule injection Stability, but the metal complexation of natrium adetate salt can be combined with internal calcium, cause the loss of calcium.Document report first Contain micro catabolite nitrite in nitre parenteral solution, regulation Metronidazule injection nitrite highest limitation is 20ug/ml, with the extension of period of storage, nitrous acid catabolite will increase therewith.Other pH and sterilization time are to nitrous acid The concentration of radical ion has a certain impact, and the concentration of nitrite ion increases with the increase of sterilization time, in bulk drug simultaneously Without nitrite ion, the Metronidazule injection after sterilizing can produce certain nitrite ion.If period of storage is oversize, Have more nitrite ion catabolites to produce, some possible nitrite ion is aoxidized by the oxygen in air and converted For nitrate anion.And the presence of the impurity such as these iron ions, the transfusion pain further resulted in, phlebitis problem, nitrite etc. Impurity easily causes the side reaction problems such as dizzy, uncomfortable in chest, diarrhoea.In view of the problem of Metronidazule injection has above-mentioned, also there is production Examination is tasted powder pin is made to solve the problem of metronidazole is unstable in the aqueous solution by metronidazole.

Have document report, because metronidazole solubility is very low, the parenteral solution sold of the country be generally 0.5% sodium chloride it is molten Liquid, transport and storage have inconvenience, and combination drug is also restrained.And injection Dinatrii Metronidazoli Phosphas small volume, weight Gently, it is easy to transport and storage, direct drip-feed after can before use being dissolved with sodium chloride injection or 5% glucose injection. Existing more than ten pharmaceutical factories domestic at present are in production and sales injection Dinatrii Metronidazoli Phosphas.Although actual clinical is in use, injection The dissolving operation of aseptic powdery is loaded down with trivial details compared with infusion solution, and adds the microbiological contamination chance of sterile product and the risk of drug safety.Separately Outside, because injection sterile powder need to be dissolved with solvent, and the consumption of disposable syringe etc. is added, it is contemplated that first nitre The problem of azoles parenteral solution is present, also there is a freeze-dried powder product at present, and to the injection of the injection Dinatrii Metronidazoli Phosphas without Bacterium powder end and Metronidazule injection compare, and find after injection compounding, with aseptic powdery after compounding, small particle particulate largely increases Plus, its reason is probably that injection sterile powder dissolves operation uncomfortable in the incomplete, influence of transfusion pH value, compound process etc.. Experiment is it has also been found that after aseptic powdery product compounding, 2.5 μm of particulates account for 99% or so, and more than 10 μm only account for about 1%.《Middle traditional Chinese medicines Allusion quotation》Not yet less than 10 μm of particulate is defined, and less than 10 μm particulates still have harm to body, therefore on the one hand will be to small The particulate of particle diameter has been controlled.And after metronidazole infusion solution compounding, its particulate matter is less than aseptic powder injection preparation.

In addition the lyophilized formulations of metronidazole also have pertinent literature report, including lyophilized tablet, lyophilized facial mask and freeze-dried powder Pin etc., freezes disintegrated tablet and preparation method thereof as CN102784120A discloses metronidazole composition vagina, utilizes cyclodextrin bag Conjunction technology, the water solubility for increasing metronidazole, the stability for improving metronidazole, reduction vaginal irritation.The main ingredient of said composition is first Nitre azoles, also includes skeleton agent (mannitol), forming agent (gelatin), solubilizer (medium substitution value hydroxypropyl-beta-schardinger dextrin).a) Medium substitution value hydroxypropyl-beta-schardinger dextrin of group component is dissolved in the 70%-80% of component water total amount purified water, stirred Mix and 55 DEG C be heated under state, be slowly added to the metronidazole of group component, continue to stir 10 hours, treat medium substitution value hydroxypropyl- After beta-schardinger dextrin includes metronidazole, the mannitol of group component is added；B) gelatin of group component is dissolved in component water consumption In 20%-30% purified water, it is heated to being completely dissolved；C) two kinds of solution ＆ stirs that merging above-mentioned steps a, step b are obtained Uniformly；D) pH value is adjusted to 5.5-6.5 with sodium acid carbonate；Then tablet is made in freeze-drying.Also CN104586749A is disclosed A kind of metronidazole composition freeze-drying piece and preparation method thereof, comprising metronidazole, starch, sucrose and purified water, with starch and sugarcane Sugar is cooked auxiliary material, and heating PROCESS FOR TREATMENT is carried out to common corn starch, can improve starch bonding in tablets, calving disaggregation, The mouldability of tablet is improved, metronidazole composition freeze-drying piece only needs two kinds of auxiliary materials of starch and sucrose.Metronidazole composition freeze-drying piece Using two two liters of lyophilized techniques of drop, cooling twice, twice heating can make sheetmolding more preferable, it is possible to increase tablet it is molten Out-degree and bioavilability.

Such as transdermal lyophilized formulations：A kind of sustained-release transdermal medicament delivery systems for being used to treat ulcer or the surface of a wound of CN101919799A, Contain 0.1-5000 milligrams of active medicine in per unit dose preparation, the high molecular polymer 5-5000 with adhesion is in the least Gram, wherein the polymer is the one or more in the following group：PVP, hydroxyethyl cellulose, hydroxypropyl methyl are fine Tie up element, carbopol, sodium alginate, hydroxypropyl cellulose, POLYOX, sodium carboxymethylcellulose；The delivery system is by following What method was made：Solution is made in high molecular polymer and active component, is then freeze-dried.

Freeze-dried powder：Such as CN103110625 A, CN103110642, which discloses the pharmaceutical composition, includes first Nitre azoles lipid microsphere, the pharmaceutical composition is prepared into powder ampoule agent for injection, and wherein metronidazole lipid microsphere is made up of following components： Metronidazole, long-chain fat acid glyceride, medium-chain fatty glyceride, Fabaceous Lecithin, the husky nurse of pool network, oleic acid, oil for injection, and by fat Matter is microballoon lyophilized to be made freeze-dried powder.Other CN1082893 A disclose injection of disodium methyl nitrozole phosphate powder, are not added with auxiliary material, Powder pin is made.Metronidazole present is higher than existing parenteral solution concentration after product dissolving, and such as bottled amount is 0.915g powder-injection, 3~5ml of water for injection dissolvings can be used, then metronidazole present is up to 10~17%.And the Metronidazule injection concentration of domestic production Only 0.5%, Dinatrii Metronidazoli Phosphas parenteral solution its metronidazole present of prior art 5% is about 2.7%.Due to metronidazole dissolving Degree is small, and existing metronidazole injection agent concentration is only 0.5%, and clinical anti anaerobic bacteria infection common dose is in more than 1g, if as putting Its dosage for the treatment of sensitizer is up to more than 10g, therefore injection volume is larger.Also CN1830439 A disclose metronidazole freeze-dried powder Preparation method：A fresh water for injection) is taken, the metronidazole dissolving that lucifuge is added in prescription is closed, refrigerates, ultrafiltration obtains ultrafiltrate I；B fresh water for injection) is taken, the natrium adetate dissolving added in prescription, refrigeration, ultrafiltration obtains ultrafiltrate II；C) will be above-mentioned super Filtrate I, II be well mixed, constant volume, adjust pH value, intermediate products after the assay was approved, by decoction after end-filtration, under the conditions of lucifuge It is filling after freeze-drying, to roll lid pack in cillin bottle, produce metronidazole freeze dried powder injection finished product.Sunk, refrigerated, surpassed using water Technical finesse filtered, and take the safeguard measures such as lucifuge, it is to avoid the degraded of metronidazole, it is ensured that invalid element is completely removed, The relevant material in preparation is reduced, makes that the preparation quality being made is loose, solubility is good, stability increase, excitant reduce, clear Lightness improves, and curative effect is stable.

It can be seen that at present main metronidazole freeze-dried powder include Dinatrii Metronidazoli Phosphas powder pin (auxiliary material is few) and comprising Two kinds of metronidazole and natrium adetate, although current metronidazole freeze-dried powder reduces nitrite to a certain extent And the adverse effect of iron ion, but powder pin also bring particulate matter increase, the redissolution time it is longer and be difficult compounding or New a series of problems of unstable grade after person's compounding.

The content of the invention

The purpose of the present invention be the defect for overcoming prior art there is provided a kind of injection metronidazole freeze-dried powder, The nitrite and iron ion in Metronidazule injection can effectively be reduced, it is to avoid transfusion pain, phlebitis problem, Yi Jiya The impurity such as nitrate and cause it is dizzy, uncomfortable in chest, diarrhoea etc. side reaction problem, while the present invention freeze-dried powder there is the redissolution time Short, particulate matter is few, and is easy to compounding, and improves the advantage of stability.

The present invention solve the technical problem technical scheme be：

The present invention provides a kind of metronidazole freeze-dried powder, and the freeze-dried powder includes metronidazole, glutamic acid, mountain Pears alcohol and polyvinylpyrrolidone.

The freeze-dried powder is made up of metronidazole, glutamic acid, sorbierite and polyvinylpyrrolidone.

The weight of the freeze-dried powder each component is：1-8 parts of metronidazole, 1-10 parts of glutamic acid, sorbierite 5-25 parts and 0.1-2 parts of compositions of polyvinylpyrrolidone.

The weight of the freeze-dried powder each component is：2-7 parts of metronidazole, 3-10 parts of glutamic acid, sorbierite 10-20 parts and 0.5-2 parts of compositions of polyvinylpyrrolidone.

The weight of the freeze-dried powder each component is：5-6 parts of metronidazole, 5-8 parts of glutamic acid, sorbierite 12-27 parts and 0.5-1.5 parts of compositions of polyvinylpyrrolidone.

The freeze-dried powder is chilled by metronidazole, glutamic acid, sorbierite, polyvinylpyrrolidone and water for injection Drying is prepared from.

Freeze-dried powder sodium chloride injection redissolved the time less than 50 seconds, preferably 30-50 seconds, more preferably 40- 48 seconds.

After the freeze-dried powder sodium chloride injection redissolves, the particulate matter 0- more than 10 μm and less than 25 μm 5/ml, the particulate matter 10-50/ml more than 5 μm and less than 10 μm, preferably 12-30/ml.

The freeze-dried powder places 6 months total impurities contents less than 0.3% under the conditions of 40 DEG C, humidity 75%, excellent Select 0.2-0.3%.

The preparation of the present invention may include following auxiliary material.These include, but are not limited to cyclodextrin, Tego-stearate, Tristerin, glycerine mono bis caprylate/decylate, behenic acids glyceride, glyceryl monooleate, glycerin monostearate, Glyceryl palmitostearate, lecithin, PLURONICS F87, polyethylene glycol, polyglyceryl oleate, polyoxyethylene (40) stearic acid Ester, polysorbate 20, polyoxyethylene sorbitan fatty acid ester, Myrj 45, lauric acid propylene glycol ester, 12 Sodium alkyl sulfate, sodium stearyl fumarate, Isosorbide Dinitrate (fatty acid esters of sorbitan), sucrose octaacetate, tristearin Sour and other pharmaceutically acceptable auxiliary materials for being used for solubilising or emulsifying water-insoluble drug.

In addition to the aforementioned ingredients, it may also be necessary in right amount add dissolution aids (such as polyoxyethylene hardened castor oil 60), Additive buffer (such as phosphate), isotonic agent (such as sodium chloride), soothing agent (such as benzylalcohol).

The present invention furthermore provides a kind of preparation method of metronidazole freeze-dried powder, and the freeze-dried powder is included such as Lower step：

A, the water for injection for taking recipe quantity 85%, injection is slowly added into by the metronidazole of recipe quantity, polyvinylpyrrolidone With in water, the stirring and dissolving at a temperature of 40-50 DEG C then proceedes to add sorbierite and glutamic acid stirring and dissolving, then residue Water for injection supply, intermediate decoction is made, then membrane filtration,

B, pre-freeze stage：- 40--45 DEG C are incubated 3-5 hours, vacuumize；

C, once distil：Temperature rise to -30 DEG C keep 3-5 hour, then temperature rise to -18--25 DEG C holding 3-5 hours, Then temperature rises to 0 DEG C and kept for 4-7 hours；

D, redrying：Temperature rises to 25-30 DEG C of holding and produced for 5-9 hours

Beneficial effects of the present invention：

1st, freeze-dried powder of the invention solves Metronidazule injection and there is catabolite nitrite, and iron from The problem of son influence metronidazole stability；

Transfusion pain that 2nd, freeze-dried powder of the invention solves the impurity such as Metronidazule injection iron ion and caused, Phlebitis problem, it is to avoid the impurity such as nitrous acid inflammation in liquid drugs injection metronidazole and cause the side reactions such as dizzy, uncomfortable in chest, diarrhoea to ask Topic.

3rd, freeze-dried powder of the invention shortens the redissolution time, reduces particulate matter, it is easy to clinic compounding, and tool There are higher long-time stability, beneficial to clinical practice application.

Embodiment

With reference to specific embodiment, the present invention is expanded on further.It should be understood that these embodiments are merely to illustrate the present invention Rather than limitation the scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to conventional strip Part or according to the condition proposed by manufacturer.

Unless otherwise defined, all specialties used in text known to scientific words and one skilled in the art with anticipating Justice is identical.In addition, any method similar or impartial to described content and material all can be applied in the inventive method.Wen Zhong Described preferable implementation only presents a demonstration with material to be used.

Embodiment 1：The screening and optimization of injection prescription of freeze-drying powder

Metronidazole decoction is prepared respectively by the prescription of table 1, then obtained by freeze drying freeze-dried powder.Wherein it is freeze-dried Process is as follows：The pre-freeze stage：- 40 DEG C are incubated 3 hours, vacuumize；Once distil：Temperature rise to -30 DEG C keep 4 hours, then Temperature rise to -20 DEG C keep 4 hours, then temperature rise to 0 DEG C keep 6 hours；Redrying：It is small that temperature rises to 30 DEG C of holdings 6 When.Then clarity respectively after the outward appearance of detection freeze-dried powder, redissolution time, redissolution, particulate matter inspection.

Appearance character and clarity：Visually inspect appearance character.Powder needle injection is first molten with 100mL sodium chloride injections Reexamined after solution, reference《Chinese Pharmacopoeia》Version two in 2015, randomly selects 20 parts of test samples and carries out lamp inspection, visually inspect clear and bright Degree.

Particulate matter：Every batch of product samples 3, presses《Chinese Pharmacopoeia》Checked using light blockage method.Powder pin is injected Agent is first dissolved with 100mL sodium chloride injections, is needed first to check the particulate matter number of sodium chloride injection by the same method, is recorded number According to, then the particle number after dissolving is subtracted to the particle number of the particle number, as sample of sodium chloride solution.For there is muddy sample Product, do not continue to determine its particulate matter.

The different injection prescription of freeze-drying powder compatibilities of table 1

The quality evaluation result of table 2

Due to adding other auxiliary materials in the above-mentioned prescription for preparing powder pin, and when sodium chloride and other auxiliary materials compounding, one There may be muddy situation under fixed condition, and table 1, the result of table 2 show metronidazole and glutamic acid, sorbierite, polyethylene The freeze-dried powder that pyrrolidones is prepared, compared to other prescriptions, the prescription outward appearance loose full, the redissolution time is short and insoluble micro- Grain is substantially reduced.

Embodiment 2

Prescription：

Preparation method：The water for injection of recipe quantity 85% is taken, the metronidazole of recipe quantity, polyvinylpyrrolidone are slowly added Enter in water for injection, the stirring and dissolving at a temperature of 40-50 DEG C, then proceed to add sorbierite and glutamic acid stirring and dissolving, then Remaining water for injection is supplied, intermediate decoction is made, freeze-dried powder is made after being then freeze-dried after membrane filtration, wherein Freezing dry process is as follows：The pre-freeze stage：- 40 DEG C are incubated 3 hours, vacuumize；Once distil：It is small that temperature rises to -30 DEG C of holdings 4 When, then temperature rise to -20 DEG C keep 4 hours, then temperature rise to 0 DEG C keep 6 hours；Redrying：Temperature rises to 30 DEG C Kept for 6 hours.

Embodiment 3

Prescription：

Preparation method：The water for injection of recipe quantity 85% is taken, the metronidazole of recipe quantity, polyvinylpyrrolidone are slowly added Enter in water for injection, the stirring and dissolving at 50 DEG C, then proceed to add sorbierite and glutamic acid stirring and dissolving, then remaining Water for injection is supplied, and intermediate decoction is made, and freeze-dried powder is made after being then freeze-dried after membrane filtration, wherein being freeze-dried Process is as follows：The pre-freeze stage：- 45 DEG C are incubated 4 hours, vacuumize；Once distil：Temperature rise to -30 DEG C keep 4 hours, then Temperature rise to -15 DEG C keep 5 hours, then temperature rise to 0 DEG C keep 5 hours；Redrying：It is small that temperature rises to 28 DEG C of holdings 7 When.

Embodiment 4

Prescription：

Preparation method：The water for injection of recipe quantity 85% is taken, the metronidazole of recipe quantity, polyvinylpyrrolidone are slowly added Enter in water for injection, the stirring and dissolving at a temperature of 40-50 DEG C, then proceed to add sorbierite and glutamic acid stirring and dissolving, then Remaining water for injection is supplied, intermediate decoction is made, freeze-dried powder is made after being then freeze-dried after membrane filtration, wherein Freezing dry process is as follows：The pre-freeze stage：- 40 DEG C are incubated 3 hours, vacuumize；Once distil：It is small that temperature rises to -30 DEG C of holdings 3 When, then temperature rise to -25 DEG C keep 4 hours, then temperature rise to 0 DEG C keep 5 hours；Redrying：Temperature rises to 28 DEG C Kept for 6 hours.

Embodiment 5

Prescription：

Preparation method：The water for injection of recipe quantity 85% is taken, the metronidazole of recipe quantity, polyvinylpyrrolidone are slowly added Enter in water for injection, the stirring and dissolving at a temperature of 40-50 DEG C, then proceed to add sorbierite and glutamic acid stirring and dissolving, then Remaining water for injection is supplied, intermediate decoction is made, freeze-dried powder is made after being then freeze-dried after membrane filtration, wherein Freezing dry process is as follows：The pre-freeze stage：- 45 DEG C are incubated 2 hours, vacuumize；Once distil：It is small that temperature rises to -30 DEG C of holdings 3 When, then temperature rise to -15 DEG C keep 4 hours, then temperature rise to 0 DEG C keep 5 hours；Redrying：Temperature rises to 25 DEG C Kept for 7 hours.

Embodiment 6

Prescription：

Preparation method：The water for injection of recipe quantity 85% is taken, the metronidazole of recipe quantity, polyvinylpyrrolidone are slowly added Enter in water for injection, the stirring and dissolving at a temperature of 40-50 DEG C, then proceed to add sorbierite and glutamic acid stirring and dissolving, then Remaining water for injection is supplied, intermediate decoction is made, freeze-dried powder is made after being then freeze-dried after membrane filtration, wherein Freezing dry process is as follows：The pre-freeze stage：- 40 DEG C are incubated 3 hours, vacuumize；Once distil：It is small that temperature rises to -30 DEG C of holdings 3 When, then temperature rise to -18 DEG C keep 5 hours, then temperature rise to 0 DEG C keep 5 hours；Redrying：Temperature rises to 25 DEG C Kept for 7 hours.

Embodiment 7

Prescription：

Preparation method：The water for injection of recipe quantity 85% is taken, the metronidazole of recipe quantity, polyvinylpyrrolidone are slowly added Enter in water for injection, the stirring and dissolving at a temperature of 40-50 DEG C, then proceed to add sorbierite and glutamic acid stirring and dissolving, then Remaining water for injection is supplied, intermediate decoction is made, freeze-dried powder is made after being then freeze-dried after membrane filtration, wherein Freezing dry process is as follows：The pre-freeze stage：- 40 DEG C are incubated 3 hours, vacuumize；Once distil：It is small that temperature rises to -30 DEG C of holdings 3 When, then temperature rise to -18 DEG C keep 5 hours, then temperature rise to 0 DEG C keep 5 hours；Redrying：Temperature rises to 25 DEG C Kept for 7 hours.

Embodiment 8

Prescription：

Preparation method：The water for injection of recipe quantity 85% is taken, the metronidazole of recipe quantity, polyvinylpyrrolidone are slowly added Enter in water for injection, the stirring and dissolving at a temperature of 40-50 DEG C, then proceed to add sorbierite and glutamic acid stirring and dissolving, then Remaining water for injection is supplied, intermediate decoction is made, freeze-dried powder is made after being then freeze-dried after membrane filtration, wherein Freezing dry process is as follows：The pre-freeze stage：- 40 DEG C are incubated 3 hours, vacuumize；Once distil：It is small that temperature rises to -30 DEG C of holdings 3 When, then temperature rise to -18 DEG C keep 5 hours, then temperature rise to 0 DEG C keep 5 hours；Redrying：Temperature rises to 25 DEG C Kept for 7 hours.

Embodiment 9

Prescription：

Preparation method：The water for injection of recipe quantity 85% is taken, the metronidazole of recipe quantity, polyvinylpyrrolidone are slowly added Enter in water for injection, the stirring and dissolving at a temperature of 40-50 DEG C, then proceed to addition sorbierite, sodium chloride and glutamic acid stirring molten Solution, then supplies remaining water for injection, and intermediate decoction is made, and freeze-dried powder is made after being then freeze-dried after membrane filtration Pin, wherein freezing dry process are as follows：The pre-freeze stage：- 40 DEG C are incubated 3 hours, vacuumize；Once distil：Temperature rises to -30 DEG C Keep 3 hours, then temperature rise to -25 DEG C keep 4 hours, then temperature rise to 0 DEG C keep 5 hours；Redrying：Temperature liter Kept for 6 hours to 28 DEG C.

Embodiment 10

Prescription：

Preparation method：The water for injection of recipe quantity 85% is taken, the metronidazole of recipe quantity, polyvinylpyrrolidone are slowly added Enter in water for injection, the stirring and dissolving at a temperature of 40-50 DEG C, then proceed to addition sorbierite, citric acid and glutamic acid stirring molten Solution, then supplies remaining water for injection, and intermediate decoction is made, and freeze-dried powder is made after being then freeze-dried after membrane filtration Pin, wherein freezing dry process are as follows：The pre-freeze stage：- 40 DEG C are incubated 4 hours, vacuumize；Once distil：Temperature rises to -30 DEG C Keep 3 hours, then temperature rise to -20 DEG C keep 4 hours, then temperature rise to 0 DEG C keep 5 hours；Redrying：Temperature liter Kept for 7 hours to 28 DEG C.

Embodiment 11

Prescription：

Preparation method：The water for injection of recipe quantity 85% is taken, the metronidazole of recipe quantity, polyvinylpyrrolidone are slowly added Enter in water for injection, the stirring and dissolving at a temperature of 40-50 DEG C, then proceed to addition sorbierite, sodium phosphate and glutamic acid stirring molten Solution, then supplies remaining water for injection, and intermediate decoction is made, and freeze-dried powder is made after being then freeze-dried after membrane filtration Pin, wherein freezing dry process are as follows：The pre-freeze stage：- 40 DEG C are incubated 4 hours, vacuumize；Once distil：Temperature rises to -30 DEG C Keep 3 hours, then temperature rise to -20 DEG C keep 4 hours, then temperature rise to 0 DEG C keep 4 hours；Redrying：Temperature liter Kept for 7 hours to 30 DEG C.

Experimental example 1

Powder injection formulation compatibility stability is investigated

Sample obtained by prescription 3 in embodiment 1, prescription 6, prescription 11 and embodiment 2-4 is noted with 0.9% sodium chloride Penetrate under liquid hybrid combination, room temperature condition and place 24 hours, investigate its stability of solution, and determine its relevant material impurities respectively and contain Amount, the results are shown in Table 3.

About the assay method of material：

Lucifuge is operated.Take this product appropriate, the solution being made in every 1ml containing about metronidazole 0.2mg is diluted with water, as trying Product solution；2- 5-nitro imidazoles (impurity I) reference substance about 20mg separately is taken, is put in 100ml measuring bottles, plus methanol dissolves and dilute Release to scale, shake up, be used as reference substance solution；Precision measures need testing solution 2ml and reference substance solution 1ml respectively, puts same In 100ml measuring bottles, scale is diluted to mobile phase, is shaken up, precision measures 5ml, is put in 50ml measuring bottles, quarter is diluted to mobile phase Degree, shakes up, is used as contrast solution.According to high performance liquid chromatography (general rule 0512) experiment, it is with octadecylsilane chemically bonded silica Filler；With methanol-water (20: 80) for mobile phase；Detection wavelength is 315nm.The μ l of contrast solution 20 are taken to inject liquid chromatograph, Chromatogram is recorded, number of theoretical plate is calculated by metronidazole peak is not less than 2000, and the separating degree at metronidazole peak and impurity I peaks should be greater than 2.0.Precision measures need testing solution and each 20 μ l of contrast solution, is injected separately into liquid chromatograph, record chromatogram to principal component 2 times of peak retention time.If any the chromatogram consistent with impurity I peaks retention time in contrast solution in the chromatogram of need testing solution Peak.

Impurity 1

2- 5-nitro imidazoles

The compatibility stability result of table 3

The result of table 3 shows, when being compounded with sodium chloride injection, can be substantially reduced using the injection prescription of freeze-drying powder of the present invention The impurity such as relevant material, are conducive to improving the security of clinical practice, reduce the generation of adverse reaction.Thus, jelly of the invention Dry powder pin disclosure satisfy that the clinical demand of metronidazole injection.

Experimental example 1

Long-time stability are investigated

Sample obtained by prescription 3 in embodiment 1, prescription 6, prescription 11 and embodiment 2-4 is placed on 40 degree, humidity Placed 6 months under the conditions of 75%, investigate its long-time stability, and investigate its outward appearance, redissolution time and total impurities content respectively, It the results are shown in Table 4.Wherein outward appearance, redissolution time and total impurities content are with reference to above-mentioned detection method.

The long-time stability result of table 4

Result above shows that the various aspects of performance of freeze-dried powder product of the invention is stable, and better than other prescriptions.This hair Bright above-mentioned experimental example is only the example of part Experiment, and the above results explanation, freeze-drying prods of the invention are reducing the same of side effect When, it can also reduce the redissolution time, reduce particulate matter, and it is easy to compounding, and with long-term stability.

Presently preferred embodiments of the present invention is the foregoing is only, the substantial technological content model of the present invention is not limited to Enclose, substantial technological content of the invention is broadly to be defined in the right of application, any technology that other people complete Entity or method, if identical with defined in the right of application, also or a kind of equivalent change, will It is considered as being covered by among the right.

Bibliography：

1st, " quality evaluation of commercially available 3 producer metronidazole injection ", all beautiful duckweed, China Dispensary, 2010.

2nd, " research of first nitre parenteral solution stability ", Feng Shijia, Journal of Chinese Hospital Pharmacy, 1993.

3rd, the influence of Zhan Xueyi, pH value and sterilization time to first nitre catabolite, Journal of Chinese Hospital Pharmacy, 1990 Year.

4、CN102784120A

5、CN104586749 A

6、CN101919799A

7、CN103110625 A、CN103110642A

8、CN1082893 A

9、CN1830439 A

Claims (10)

1. a kind of metronidazole freeze-dried powder, it is characterised in that the freeze-dried powder includes metronidazole, glutamic acid, mountain Pears alcohol and polyvinylpyrrolidone.

2. metronidazole freeze-dried powder as claimed in claim 1, it is characterised in that the freeze-dried powder is by first nitre Azoles, glutamic acid, sorbierite and polyvinylpyrrolidone composition.

3. metronidazole freeze-dried powder as claimed in claim 2, it is characterised in that the weight of each component is：First 1-8 parts of nitre azoles, 1-10 parts of glutamic acid, 0.1-2 parts of compositions of 5-25 parts of sorbierite and polyvinylpyrrolidone.

4. metronidazole freeze-dried powder as claimed in claim 2, it is characterised in that the weight of each component is：First 2-7 parts of nitre azoles, 3-10 parts of glutamic acid, 0.5-2 parts of compositions of 10-20 parts of sorbierite and polyvinylpyrrolidone.

5. metronidazole freeze-dried powder as claimed in claim 2, it is characterised in that the weight of each component is：First 5-6 parts of nitre azoles, 5-8 parts of glutamic acid, 0.5-1.5 parts of compositions of 12-27 parts of sorbierite and polyvinylpyrrolidone.

6. a kind of metronidazole freeze-dried powder, it is characterised in that the freeze-dried powder is by metronidazole, glutamic acid, sorb Alcohol, polyvinylpyrrolidone and water for injection is freeze-dried is prepared from.

7. metronidazole freeze-dried powder as claimed in any one of claims 1 to 6, it is characterised in that the freeze-dried powder is used Sodium chloride injection redissolves the time less than 50 seconds, preferably 30-50 seconds, more preferably 40-48 seconds.

8. metronidazole freeze-dried powder as claimed in any one of claims 1 to 6, it is characterised in that the freeze-dried powder is used After sodium chloride injection redissolves, the 0-5/ml of particulate matter more than 10 μm and less than 25 μm, more than 5 μm and less than 10 μm Particulate matter 10-50/ml, preferably 12-30/ml.

9. metronidazole freeze-dried powder as claimed in any one of claims 1 to 6, it is characterised in that the freeze-dried powder exists 40 DEG C, 6 months total impurities contents are placed under the conditions of humidity 75% and are less than 0.3%, preferably 0.2-0.3%.

10. the preparation method of the metronidazole freeze-dried powder according to claim 1-9 any one, it is characterised in that The freeze-dried powder comprises the following steps：

A, the water for injection for taking recipe quantity 85%, water for injection is slowly added into by the metronidazole of recipe quantity, polyvinylpyrrolidone In, the stirring and dissolving at a temperature of 40-50 DEG C then proceedes to add sorbierite and glutamic acid stirring and dissolving, then remaining note Penetrate and supplied with water, intermediate decoction is made, then membrane filtration,

B, pre-freeze stage：- 40--45 DEG C are incubated 3-5 hours, vacuumize；

C, once distil：Temperature rise to -30 DEG C keep 3-5 hour, then temperature rise to -18--25 DEG C holding 3-5 hours, then Temperature rises to 0 DEG C and kept for 4-7 hours；

D, redrying：Temperature rises to 25-30 DEG C of holding and produced for 5-9 hours.