CN104352454A

CN104352454A - Sodium fusidate powder-injection pharmaceutical composition for injection and preparation method

Info

Publication number: CN104352454A
Application number: CN201410649859.5A
Authority: CN
Inventors: 王敬; 江威; 方专; 吴国庆; 左伟; 赵东明
Original assignee: CHENGDU TIANTAISHAN PHARMACEUTICAL Co Ltd
Current assignee: CHENGDU TIANTAISHAN PHARMACEUTICAL CO LTD
Priority date: 2014-11-15
Filing date: 2014-11-15
Publication date: 2015-02-18
Anticipated expiration: 2034-11-15
Also published as: CN104352454B

Abstract

The invention relates to a sodium fusidate powder-injection pharmaceutical composition for injection and a preparation method. Specifically, the invention belongs to the technical field of medicines, relates to a medicine which can be used for treating various infections such as osteomyelitis, sepsis, endocarditis, repeatedly infected cystic fibrosis, pneumonia, skin and soft tissue infections, surgical and traumatic infections and the like caused by various sensitive bacteria, especially staphylococcus, and particularly relates to a pharmaceutical composition such as a freeze-dried powder injection prepared by taking sodium fusidate as an active component. The invention also relates to a preparation method of the pharmaceutical composition. In an implementation scheme, the invention relates to a sodium fusidate powder-injection pharmaceutical composition for injection, which comprises sodium fusidate, a neutral amino acid and an alkaline amino acid. The pharmaceutical composition has excellent pharmaceutical properties.

Description

Sodium fusidafe as injection injectable powder pharmaceutical composition and method for making

Technical field

The invention belongs to medical art, relate to one and can be used for treatment by various sensitive bacterial, especially the various infection that cause of staphylococcus, as osteomyelitis, septicemia, endocarditis, the cystic fibrosis of repeated infection, pneumonia, skin and soft tissue infection, the medicine of surgery and traumatic infection etc., particularly relates to a kind of pharmaceutical composition such as lyophilization injectable powder taking sodium fusidate as active component and make.The invention still further relates to the preparation method of this pharmaceutical composition.

Background technology

Sodium fusidate (Sodium Fusidate), wherein science of culture name is called: 16 α-acetoxy-3 β, 11 beta-dihydroxy-4 β, 8 β, nor--5 β of 14 α-trimethyl-18-, 10 α-gallbladder steroid-(17Z)-17 (20), 24-diene-21-acid sodium, English language Chemical name is called: Sodium ent-(17Z)-16 α-(acetyloxy)-3 β, 11 β-dihydroxy-4 β, 8, 14-trimethyl-18-nor-5 β, 10 α-cholesta-17 (20), 24-dien-21-oate, molecular formula: C31H47NaO6, molecular weight: 538.70, its structural formula is as follows:

Fusidic acid is colorless needle crystals, is dissolved in the organic solvents such as ethanol, acetone, chloroform and pyridine, water insoluble.Sodium fusidate is white crystalline powder, soluble in water, intravenous injection good absorbing, has extremely strong penetrance to tissue and body fluid.Sodium fusidate produces bactericidal action by the protein synthesis of anti-bacteria, has powerful antibacterial action to a series of gram-positive bacterium.Staphylococcus, comprises the bacterial strain to penicillin, methicillin and other antibiotics drug resistance, all extremely sensitive to this product.Without cross resistance between other antibacterials of sodium fusidate and Clinical practice, but it places instability in an acidic solution, point out in the sodium fusidafe as injection description of Clinical practice, if glucose injection agent peracid, solution can in emulsus and when pH value lower than 7.4 time, this product can precipitate.Wang Yaqun, HPLC method measures the content of sodium fusidafe as injection, " Chinese Medicine guide ", 18 phases in 2008, the 55th page.

Fusidic acid (Fusidic Acid, also known as fuscomycin), belongs to shuttle chain and embraces acids antibiotic.Extracted from fat ball fungus (Fusidium coccineum fungus) first in 1962 by Leo drugmaker of Denmark.Antibacterial Mechanism is by suppressing ribosomal transposition to disturb elongation factor G, thus hinders the synthesis of bacterioprotein.The mechanism of action of this uniqueness avoids the cross resistance with other antibacterials.Although be widely used more than 30 year abroad (domestic clinical practice is less), but still stronger antibacterial activity and very low resistant rate are kept to most aureus strains, more and more receive the concern of people, under the special present situation day by day difficult at current anti-Staphylococcus aureus drug-fast bacteria infection, fusidic acid has higher clinical value.

Because fusidic acid is water insoluble, its soluble-salt commonly used by clinical injection preparation, the sodium salt of preferred fusidic acid.Sodium fusidate is white or off-white color crystalline powder, slightly draws moist, soluble in water and ethanol.0.125g is dissolved in 10ml water, pH7.5 ~ 9.5.Sodium fusidate places instability in the solution, and pH lower than 7.3 time, then during compatibility occur precipitation.Therefore commercialized product (trade name Li Siding) adopts aseptic subpackaged sodium fusidate, and subsidiary pH is the dedicated buffering salt solvent of 7.4 ~ 7.6, solves product clinical compatibility stability problem.

Prior art discloses many documents prepared about fusidic acid sodium raw materials.Such as, CN103012536A (201210592628.6, North China pharmacy) disclose a kind of method for crystallising of sodium fusidate, comprise the following steps: a, preparation fusidic acid sodium solution: sodium fusidate being added to volume by volume concentration is in the aqueous acetone solution of 50-90%, stirs, dissolves; B, crystallization, growing the grain: fusidic acid sodium solution is heated to 30-60 DEG C, insulation, add acetone stirring is dirty, stream rate of acceleration is 20-24mL/h, when after crystallization, stream rate of acceleration is reduced to 6-18mL/h, when the stream dosage of acetone is the 10-15 times of sodium fusidate liquor capacity, stream is stopped to add, growing the grain 16-20h, filter, solid-liquid separation; C, carry out dried by after the drip washing of gained solid acetone, obtain Sodium fusidate crystal.It is believed that the described method of this invention is simple to operate, with low cost, the Sodium fusidate crystal prepared by the method, stable crystal form, good fluidity.

In addition, CN103214540A (201310159052.9, North China pharmacy) discloses Sodium fusidate crystal and preparation method thereof.The X-ray powder diffraction spectral signature peak of the Sodium fusidate crystal that this invention newly provides represents with 2 θ ± 0.2 ° and is positioned at 6.960,7.117,8.180,8.355,11.895,14.460,15.176,16.389,16.574,24.837,28.967 and 36.344 places.Its preparation method comprises the steps: 1) fusidic acid is dissolved in low-alcohol solution, obtain fusidic acid sodium solution; 2) add ethyl acetate solution to stream in fusidic acid sodium solution, make sodium fusidate crystallization, collect solid phase; 3) solid phase is carried out drying, obtain Sodium fusidate crystal.It is believed that Sodium fusidate crystal that this invention provides has that outward appearance is glittering and translucent, uniform particles, stable crystal form, is conducive to the advantage such as subpackage and preservation.It is believed that method that this invention provides has prepared Sodium fusidate crystal good stability, and technique is simple, environmental friendliness, solvent for use can repeat advantages such as recycling, production cost is low.

Prior art discloses many documents prepared about fusidic acid preparation of sodium.Such as, CN103040747A (201210551292.9, BEST) disclose a kind of sodium fusidate lipidosome injection and method for making thereof, this lipidosome injection is made up of sodium fusidate, soybean lecithin, cholesterol succinate, PLURONICS F87, polyvidone and mannitol.It is believed that the lipidosome injection of this invention have liposomal particle size little and be evenly distributed, good preparation stability, good envelop rate and lower percolation ratio; Decrease impurity and toxic and side effects, improve quality and the curative effect of product.

Prior art discloses many documents relevant with its injectable powder about sodium fusidate.Such as, CN103405392A (201310383401.5, Luo Xin) discloses special injection of a kind of sodium fusidate freezing-dried powder injection and preparation method thereof.It is believed that the special injection of the described sodium fusidate freezing-dried powder injection of this invention is made up of nitrilotriacetic acid, methionine, sodium potassium tartrate tetrahydrate, sodium pyrosulfite, sodium hydrogen phosphate and water for injection.It is believed that the preferred nitrilotriacetic acid of this invention, methionine, sodium potassium tartrate tetrahydrate, sodium pyrosulfite, the sodium hydrogen phosphate component as the special injection of sodium fusidate freezing-dried powder injection, mutual synergism improves the stability of the sodium fusidate freezing-dried powder injection after dissolving, the content of maintenance sodium fusidate and product characteristics, in normal requirement, are specifically conducive to the safe handling of clinical medicine.

Prior art discloses many documents relevant about fusidic acid sodium injection.Such as, CN103169673A (201310125429.9, Luo Xin) discloses a kind of sodium fusidate freezing-dried powder injection and preparation method thereof.It is believed that the described sodium fusidate freezing-dried powder injection of this invention is made up of sodium fusidate, dimercaptopropanol, BAL, arabo-ascorbic acid, cysteine hydrochloride, phenylalanine, arginine and water for injection lyophilizing.It is believed that the preferred arginine of this invention, dimercaptopropanol, BAL, arabo-ascorbic acid, cysteine hydrochloride, the phenylalanine adjuvant as sodium fusidate freezing-dried powder injection, mutual synergism improves the stability of sodium fusidate freezing-dried powder injection, reduce the content of related substance and maintain product characteristics in normal requirement, being conducive to safe handling and the long term storage of clinical medicine.

CN101143133A (200710050222.4, Han Lang) discloses a kind of sodium fusidate freezing-dried powder injection.It comprises following component and content (weight portion): sodium fusidate 450 ~ 550, glycine 30 ~ 500, arginine 40 ~ 600.Above-mentioned lyophilized injectable powder also can comprise excipient further as at least one in lactose, mannitol, sorbitol.Consumption is 1 ~ 10% of described lyophilized injectable powder percentage by weight.It is believed that this sodium fusidate freezing-dried powder injection is owing to adding a certain amount of stabilizing agent, its long-term stability is good, improves safety during patient's medication, reduces drug risk.

CN102743342A (201210103795.X, Olympic Competition health) discloses a kind of injection Fusidate sodium composition.It comprises following component and content (weight portion): sodium fusidate: arginine: citric acid 500:(100 ~ 400): (5 ~ 100).It is believed that this sodium fusidate freezing-dried powder injection has long-time stability good, stay-in-grade feature during medication, improves safety during patient's medication, reduces drug risk.

CN101264089A (200810045003.1, sunlight profit standing grain) disclose a kind of Fusidate sodium composition and lyophilized formulations preparation method thereof, in this Fusidate sodium composition, the weight ratio of sodium fusidate, excipient, stabilizing agent/pH adjusting agent is 25 ~ 100:2 ~ 100:1 ~ 50.Wherein excipient is preferably glucose and/or mannitol, and stabilizing agent/pH adjusting agent is preferably one in arginine, disodiumedetate and calcio-disodium edetate or its mixture.Its preparation method is solvent with water for injection, and sodium fusidate, excipient, stabilizing agent/pH adjusting agent are made clear transparent solutions, filters subpackage, made the lyophilized formulations meeting injection requirement by drying bu sublimation.The pH value of said preparation is 7.5 ~ 9.0.Containing sodium fusidate 125 ~ 500MG in the preparation of per unit dosage.It is believed that the Fusidate sodium composition freeze-dried powder described in this invention, good stability, easy to use, improve the toleration of patient's medication and the simplicity of medical care precess, there is very strong practicality.It is believed that the preparation method of this invention, there is technique simple, the advantage of manufactured goods good stability.

CN1817340A (200610042212.1, hundred promises) discloses a kind of lyophilized formulations and preparation method thereof containing sodium fusidate being used for the treatment of various severe staphylococcal infections.The composition of sodium fusidafe as injection of this invention, is characterized in that adopting freeze-dry process to make lyophilized formulations, comprises following component: the weight ratio of sodium fusidate, sodium hydrogen phosphate, citric acid is 500:78 ~ 113:4 ~ 5.7.It is believed that the composition of sodium fusidafe as injection of this invention, be solvent with water for injection, stablize, easy to use, improve toleration during patient's medication, reduce production cost.It is believed that this invention preparation method has technique simple, the advantage of manufactured goods good stability.

In addition, during known Clinical practice, when medicine mixes with sodium fusidate or meets, there will be muddiness or precipitation.Reason may be: 1) acid stronger medicine, as vitamin C, ligustrazine phosphate etc. can because reducing the pH of solvent, fusidic acid is isolated from sodium fusidate middle reaches, form muddy or precipitation, therefore selective solvent should be noted, if States Pharmacopoeia specifications glucose injection pH scope is that 3.5 ~ 6.5 sodium fusidate probably separate out precipitation within the scope of this pH.2) the less double salt of dissolubility may be combined into fusidic acid, easily form muddy or precipitation.3) containing multivalent ion as the medicines such as Ca2+ and Mg2+ and sodium fusidate compatibility, by fusidic acid chelating salify, its solubility behavior may be changed and forms muddiness or precipitation.Therefore sodium fusidate has alkalescence, sequestration properties, avoids clinically and uses with faintly acid, polyvalent metal ion compound compatibility.

Have been found that the sodium fusidate that existing method prepares is unsafty in some drugs properties, such as their chemical stability.Therefore, those skilled in the art still expect to have the demand of the fusidic acid preparation of sodium preparing tool new feature, expect that this preparation presents excellent pharmaceutical properties in one or more.

Summary of the invention

Of the present invention being provides a kind of new sodium fusidate formulation example as its injectable powder, expects that it such as has excellent pharmaceutical properties, such as but not limited to having excellent chemical stability.The present inventor have been surprisingly found that, adopts technical scheme of the present invention easily can realize above-mentioned purpose.The present invention is based on this find and be accomplished.

For this reason, the pharmaceutical composition providing a kind of sodium fusidafe as injection injectable powder of first aspect present invention, it comprises sodium fusidate, neutral amino acid and basic amino acid.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said neutral amino acid is selected from: glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, methionine and hydroxyproline and combination thereof.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein in the sodium fusidate of every 0.5 weight portion, the amount of the neutral amino acid comprised is 0.05 ~ 0.5 weight portion, such as 0.05 ~ 0.3 weight portion, 0.05 ~ 0.25 weight portion.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said basic amino acid is selected from: arginine, lysine, histidine and combination thereof.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein in the sodium fusidate of every 0.5 weight portion, the amount of the basic amino acid comprised is 0.05 ~ 0.5 weight portion, such as 0.075 ~ 0.3 weight portion, 0.1 ~ 0.25 weight portion.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, when it makes the solution containing sodium fusidate 0.05 ~ 0.15g in every 1ml solution with water dissolution, the pH value of this solution is 7.5 to 9.0, and the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the kind of wherein said acid-base modifier is not particularly limited, as long as the pH value of described lyophilized injectable powder (and/or will preparing intermedium in this lyophilized injectable powder process of preparation) can be adjusted to the scope of expectation by it.In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the consumption of wherein said acid-base modifier is, described pharmaceutical composition water for injection is made to redissolve to substantially identical with solution before lyophilization volume, gained solution measures according to the method under Chinese Pharmacopoeia version in 2010 two annex VI H items, the pH value of this solution is 7.5 to 9.0, the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the consumption of wherein said acid-base modifier is, when making described pharmaceutical composition water for injection dissolve the solution made containing sodium fusidate 0.05 ~ 0.15g in every 1ml solution, measure according to the method under Chinese Pharmacopoeia version in 2010 two annex VI H items, the pH value of this solution is 7.5 to 9.0, the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, its solid content before lyophilization in solution is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein the weight sum of sodium fusidate, neutral amino acid and basic amino acid accounts for 5 ~ 30% (w/v) of liquor capacity before lyophilization, such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it redissolves to substantially identical with solution before lyophilization volume with water for injection, solid content in gained solution is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it redissolves to substantially identical with solution before lyophilization volume with water for injection, wherein the weight sum of sodium fusidate, neutral amino acid and basic amino acid accounts for 5 ~ 30% (w/v) of redissolution liquor capacity, such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein moisture is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.

The pharmaceutical composition of arbitrary embodiment, wherein also optionally comprises freeze-dried excipient according to a first aspect of the present invention, such as, be selected from mannitol, lactose, sorbitol, sucrose etc.Their amount can be determined according to universal experience by those skilled in the art.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein also comprises trehalose (Trehalose).

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein in the sodium fusidate of every 0.5 weight portion, the amount of the trehalose comprised is 0.05 ~ 0.2 weight portion, such as 0.05 ~ 0.15 weight portion, 0.05 ~ 0.1 weight portion.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is prepare by comprising following step substantially:

A () gets the active component of recipe quantity and neutral amino acid and basic amino acid, add appropriate water for injection, make dissolving, optionally add trehalose and make dissolving, then add active carbon, stir, filtering decarbonization;

B () is mended and is injected water to its recipe quantity, stir, measure solution ph and optional mensuration active component content, use acid-base modifier (such as acid solution or aqueous slkali) to be adjusted to pH value 7.5 to 9.0 if desired, such as pH value 8.0 to 9.0, such as pH value 8.0 to 8.5;

C (), by medicinal liquid aseptic filtration, fill is in cillin bottle, and lyophilization removing moisture, tamponade, to obtain final product.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the wherein filtered filtrate of step (c) gained, wherein solid content is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein the described appropriate water for injection of step (a) is about 70 ~ 90% of water for injection recipe quantity.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein the described benefit of step (b) injects water to its recipe quantity and refers to add water to and make the concentration of active component in solution reach 0.05 ~ 0.15g/ml, and such as concentration reaches 0.0625 ~ 0.125g/ml.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein the described activated carbon dosage of step (a) is 0.05% ~ 1% of solution weight, preferably 0.05% ~ 0.5%.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein acid solution described in step (b) and aqueous slkali use the aqueous solution being selected from following pH adjusting agent and being mixed with: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.The concentration of these aqueous solutions well known to a person skilled in the art, such as 1 ~ 10%, such as 2% ~ 5%.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein in step (c) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.

Further, second aspect present invention provides the method for the pharmaceutical composition (described in the arbitrary embodiment of such as first aspect present invention pharmaceutical composition) preparing sodium fusidafe as injection injectable powder, and described pharmaceutical composition comprises sodium fusidate, neutral amino acid and basic amino acid; The method comprises the following steps:

A () gets the active component of recipe quantity and neutral amino acid and basic amino acid, add appropriate water for injection, make dissolving (optionally add other adjuvant such as trehalose and make dissolving), then add active carbon, stir, filtering decarbonization;

The method of arbitrary embodiment according to a second aspect of the present invention, the wherein filtered filtrate of step (c) gained, wherein solid content is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

The method of arbitrary embodiment according to a second aspect of the present invention, wherein the described appropriate water for injection of step (a) is about 70 ~ 90% of water for injection recipe quantity.

The method of arbitrary embodiment according to a second aspect of the present invention, wherein the described benefit of step (b) injects water to its recipe quantity and refers to add water to and make the concentration of active component in solution reach 0.05 ~ 0.15g/ml, and such as concentration reaches 0.0625 ~ 0.125g/ml.

The method of arbitrary embodiment according to a second aspect of the present invention, wherein the described activated carbon dosage of step (a) is 0.05% ~ 1% of solution weight, preferably 0.05% ~ 0.5%.

The method of arbitrary embodiment according to a second aspect of the present invention, wherein acid solution described in step (b) and aqueous slkali use the aqueous solution being selected from following pH adjusting agent and being mixed with: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.The concentration of these aqueous solutions well known to a person skilled in the art, such as 1 ~ 10%, such as 2% ~ 5%.

The method of arbitrary embodiment according to a second aspect of the present invention, wherein in step (c) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.

The method of arbitrary embodiment according to a second aspect of the present invention, wherein said neutral amino acid is selected from: glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, methionine and hydroxyproline and combination thereof.

The method of arbitrary embodiment according to a second aspect of the present invention, in the sodium fusidate of every 0.5 weight portion in wherein said pharmaceutical composition, the amount of the neutral amino acid comprised is 0.05 ~ 0.5 weight portion, such as 0.05 ~ 0.3 weight portion, 0.05 ~ 0.25 weight portion.

The method of arbitrary embodiment according to a second aspect of the present invention, wherein said basic amino acid is selected from: arginine, lysine, histidine and combination thereof.

The method of arbitrary embodiment according to a second aspect of the present invention, in the sodium fusidate of every 0.5 weight portion in wherein said pharmaceutical composition, the amount of the basic amino acid comprised is 0.05 ~ 0.5 weight portion, such as 0.075 ~ 0.3 weight portion, 0.1 ~ 0.25 weight portion.

The method of arbitrary embodiment according to a second aspect of the present invention, when wherein said pharmaceutical composition water dissolution makes the solution containing sodium fusidate 0.05 ~ 0.15g in every 1ml solution, the pH value of this solution is 7.5 to 9.0, the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5.

The method of arbitrary embodiment according to a second aspect of the present invention, the kind of wherein said acid-base modifier is not particularly limited, as long as the pH value of described lyophilized injectable powder (and/or will preparing intermedium in this lyophilized injectable powder process of preparation) can be adjusted to the scope of expectation by it.In one embodiment, described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.

The method of arbitrary embodiment according to a second aspect of the present invention, the consumption of wherein said acid-base modifier is, described pharmaceutical composition water for injection is made to redissolve to substantially identical with solution before lyophilization volume, gained solution measures according to the method under Chinese Pharmacopoeia version in 2010 two annex VI H items, the pH value of this solution is 7.5 to 9.0, the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5.

The method of arbitrary embodiment according to a second aspect of the present invention, the consumption of wherein said acid-base modifier is, when making described pharmaceutical composition water for injection dissolve the solution made containing sodium fusidate 0.05 ~ 0.15g in every 1ml solution, measure according to the method under Chinese Pharmacopoeia version in 2010 two annex VI H items, the pH value of this solution is 7.5 to 9.0, the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5.

The method of arbitrary embodiment according to a second aspect of the present invention, the solid content of wherein said pharmaceutical composition before lyophilization in solution is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

The method of arbitrary embodiment according to a second aspect of the present invention, in wherein said pharmaceutical composition, the weight sum of sodium fusidate, neutral amino acid and basic amino acid accounts for 5 ~ 30% (w/v) of liquor capacity before lyophilization, such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition water for injection redissolves to substantially identical with solution before lyophilization volume, solid content in gained solution is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

The method of arbitrary embodiment according to a second aspect of the present invention, wherein said pharmaceutical composition water for injection redissolves to substantially identical with solution before lyophilization volume, wherein the weight sum of sodium fusidate, neutral amino acid and basic amino acid accounts for 5 ~ 30% (w/v) of redissolution liquor capacity, such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

The method of arbitrary embodiment according to a second aspect of the present invention, in wherein said pharmaceutical composition, moisture is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.

The method of arbitrary embodiment according to a second aspect of the present invention, also comprises trehalose (Trehalose) in wherein said pharmaceutical composition.

The method of arbitrary embodiment according to a second aspect of the present invention, in the sodium fusidate of every 0.5 weight portion in wherein said pharmaceutical composition, the amount of the trehalose comprised is 0.05 ~ 0.2 weight portion, such as 0.05 ~ 0.15 weight portion, 0.05 ~ 0.1 weight portion.

Arbitrary technical characteristic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can not be conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.

All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if the implication expressed by these documents and the present invention inconsistent time, be as the criterion with statement of the present invention.In addition, the various term that the present invention uses and phrase have and well known to a person skilled in the art general sense, nonetheless, the present invention still wishes to be described in more detail at this these terms and phrase and to explain, the term mentioned and phrase, if any inconsistent with common art-recognized meanings, are as the criterion with the implication that the present invention states.

Be further described to various aspects of the present invention below.

In the method for the invention step, although its concrete steps described in some details or the language step described in preparation example that describes up and down literary composition detailed description of the invention part distinguish to some extent, but those skilled in the art can summarize above the method for the invention step completely according to the open in detail of the present invention's full text.

In the present invention, if not otherwise indicated, when measuring the amount of the related substance in various material, be all carry out according to the present invention's [HPLC method].In the present invention, if not otherwise indicated, in the material measuring various compositions during the content of active component, be all carry out according to the present invention's [HPLC method].

The preparation process of lyophilization injectable powder well known to a person skilled in the art pharmaceutical technology, such as following kind of the schematic freeze-drying curve of two shown in freeze-drying curve A and freeze-drying curve B:

Hereafter preparing in the instantiation in lyophilization injectable powder, if not otherwise specified, freeze-drying curve used is freeze-drying curve A.

Moisture in lyophilization injectable powder is general below 8%, preferably lower than 5%, more preferably less than 4%.Moisture Control is by suitably adjusting lyophilization program to control.Moisture in this lyophilization injectable powder can measure according to many known methods, such as dry weight-loss method.

When preparing lyophilized injectable powder of the present invention, in the medicinal liquid prepared, solid content is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).Obtain because lyophilized injectable powder normally carries out lyophilization in tubulose cillin bottle, those skilled in the art understand this product at acquisition finished product even before for doctor, usually a round pie is all presented, although in the volume theory of this cake, lecture is fewer than the volume of original aqueous solution (slightly reducing), but this reducing can not narrow down to former aqueous solution volume 50% usually usually, usual meeting is between the 80-120% of former aqueous solution volume, between the 90-100% being more typically in former aqueous solution volume, and can be observed in finished product cillin bottle former aqueous solution liquid level vestige (main body cake because of lyophilizing reduce after remain in liquid level vestige bottle wall, even if the dried frozen aquatic products in cillin bottle is Powdered because of reasons such as a variety of causes such as collide, usually original liquid level vestige can still be retained), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, but still roughly can estimate it when preparing according to this injectable powder, medicine liquid volume at least before lyophilization starts, the weight of the dry end-product in the volume estimated according to this and cillin bottle, also can calculate when preparing lyophilized injectable powder of the present invention, the content of the solid content in the medicinal liquid prepared.Therefore, lyophilized injectable powder according to a first aspect of the present invention, its solid content of medicinal liquid when preparing is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v).

Term " solid content " refers to solid matter (such as reactive compound of the present invention and whole excipient used, weight/gram) join in solvent (such as water for injection), a solution is obtained after dissolving, the weight of described solid matter such as, divided by the percent (weight/volume percent, g/100ml) of whole liquor capacity.Such as in the present invention, add appropriate aqueous solution for injection with 0.5g reactive compound and other solid content amounting to about 0.3g, be mixed with the solution that final volume is 4ml, its solid content is 20%.

In the present invention, symbol %, according to the linguistic context that it uses, can have the implication of those skilled in the art's easy understand.Such as when mentioning solid content, this symbol represents the percent (w/v, such as g/100ml) of weight/volume; Again such as when mentioning " water content " in lyophilization injectable powder, such as water content is below 8%, and now this symbol % represents the percent (w/w, g/100g) of w/w.Generally speaking, solid dispersal in a liquid time, % represents weight/volume percent; Solid dispersal in solids or liquid dispersion in solids (such as the water content of powder pin) time, % represents w/w percent.In other cases, unless otherwise noted, symbol % represents w/w percent.

When preparing medicinal liquid of the present invention, as well known to those skilled in the art, the microporous filter membrane of example 0.45um according to appointment can carry out coarse filtration filtration, by before in liquid medicine filling to cillin bottle, the microporous filter membrane of example 0.22um according to appointment can carry out fine straining and filter with degerming, can filter repeatedly if desired.

According to injectable powder of the present invention, it redissolves with water for injection, and typically the redissolution time is in 30 seconds, preferably in 20 seconds, more preferably in 15 seconds.

According to lyophilized injectable powder of the present invention, it is made in every 1ml containing the solution of reactive compound 0.05 ~ 0.15g and according to the method mensuration under Chinese Pharmacopoeia version in 2010 two annex VI H items with water, the pH value of this solution is 7.5 to 9.0, the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5.

Lyophilized injectable powder provided by the invention can be preserved at least 24 months in cool dark place, can meet the Storage Requirement of general lyophilization injectable powder.

Have been found that lyophilization injectable powder of the present invention has good pharmaceutical properties and such as has excellent chemical stability.

Sodium fusidafe as injection lyophilization injectable powder provided by the invention, its active component is sodium fusidate.Injection lyophilization injectable powder of the present invention can use classical sterile buffer to dissolve, and then with 5% glucose injection or 0.9% chloride injection solution dilution, for clinical infusion administration.In the present invention, if not otherwise specified, the sterile buffer used is composed as follows: disodiumedetate 5mg, disodium phosphate dihydrate 196mg, citric acid 10mg, water adds to 10ml.In the present invention, if not otherwise specified, carry out as follows in its Clinical practice or test: make the injection powder pin containing active component 0.5g be dissolved in the aseptic buffer solution appended by 10 milliliters, be then diluted to the venoclysis of 250-500 milliliter with sodium chloride injection or 5% glucose injection.

Lyophilization injectable powder of the present invention can be used for by various sensitive bacterial clinically, especially the various infection that cause of staphylococcus, as osteomyelitis, septicemia, endocarditis, the cystic fibrosis of repeated infection, pneumonia, skin and soft tissue infection, surgery and traumatic infection etc.

Typical usage and dosage: intravenous injection is applicable to unsuitable oral administration or the bad patient of gastrointestinal absorption.Adult: 0.5 gram (1 bottle), every day 3 times.Child and baby: 20 mgs/kg of body weight/day, point 3 administrations.

Typical usage and dosage: get 1 bottle, this product injection powder pin (0.5 gram) and be dissolved in the aseptic buffer solution appended by 10 milliliters, be then diluted to the venoclysis of 250-500 milliliter with sodium chloride injection or 5% glucose injection.The Infusion Time of every bottle should not be less than 2-4 hour.It is good that this product should input blood flow, the vein that diameter is larger, or Central catheterization input, to reduce the danger that venospasm and thrombophlebitis occur.Should be finished in 24 hours after venoclysis liquid prepares.This product solution of not diluted must not directly intravenous injection.For avoiding local tissue damage, this product also must not intramuscular injection or subcutaneous injection.According to the feature of this product metabolism and excretion, renal insufficiency and hemodialysis patient use this product without the need to adjusting dosage, and the dialysis amount of cancellation of this product is not high yet.

Due to metabolism and the drainage properties of this product, when long-term, high-dose medication or this product combine the similar medicine of other discharge approach (as lincomycin or rifampicin), liver function should be made regular check on to the patient of hepatic insufficiency and biliary tract exception.When testing in vitro, this product can replace bilirubin on albumin binding site.The clinical meaning of this metalepsis it be unclear that, and neonate does not also find bilirubin encephalopathy after using this product.But premature infant, jaundice, acidosis and seriously sick and weak neonate use during this product need notice this factor.This product intravenous injection can not mix with kanamycin, gentamycin, vancomycin, cefaloridine or carbenicillin, and this product also with whole blood, Freamine Ⅲ or can not mix containing calcium solution.When solution pH lower than 7.4 time, this product can precipitate.

Sodium fusidafe as injection lyophilization injectable powder provided by the invention produces bactericidal action by the protein synthesis of anti-bacteria.This product has powerful antibacterial action to a series of gram-positive bacterium.Staphylococcus, comprises the bacterial strain to penicillin, methicillin and other antibiotics drug resistance, all extremely sensitive to this product.Without cross resistance between other antibacterials of fusidic acid and Clinical practice.

Sodium fusidafe as injection lyophilization injectable powder provided by the invention has fabulous tissue penetration capacity, widely distributed in body.Clinically significantly, this product not only has high concentration, even if having high concentration too in the tissue that vascularity is less in the abundant tissue of blood supply.Known to pus, sputum, soft tissue, heart, osseous tissue, synovial fluid, sequestrum, burn crust, brain abscess and ophthalmic, the concentration of this product all exceedes it to staphylococcic minimal inhibitory concentration (0.03-0.16 mcg/ml).

Sodium fusidafe as injection lyophilization injectable powder provided by the invention, at liver metabolism, is discharged, hardly through renal excretion primarily of bile.This product toxicity is extremely low, and without cross anaphylaxis between other antibacterials of Clinical practice, and therefore this product can be used for treating the patient avoided other antibiotics, as to penicillin or other antibiotics allergy sufferers.To when needing long-time medication because of serious or deep infection, suggestion sodium fusidate and other staphylococcus drug combination are to reduce the generation of drug resistance.Sodium fusidate also can obtain with the penicillins of penicillin resistant enzyme, cephalosporins, erythromycin, aminoglycoside, lincomycin, rifampicin or vancomycin conbined usage and be added or synergistic effect.

Detailed description of the invention

Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and operational approach is well known in the art, the present invention still describes in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.

The hereafter object of preparation process in order to illustrate, and based on each citing comparability and make some specific description, those skilled in the art therefrom can summarize the method obtaining the present invention and prepare lyophilized injectable powder completely according to existing knowledge.Dosing is prepared in various compositions below, and if not otherwise indicated, the total dosing amount often criticized is 5000ml; But when listing formula and preparation process, for injectable powder, illustrate formula and method for making with the composition of other material of every 500mg part active component and corresponding weight portion.No matter be liquid drugs injection or powder pin, when subpackage, every bottle is 500mg containing active component.When dosing, when using acid-base modifier (i.e. pH adjusting agent), for 2M hydrochloric acid solution or 2M sodium hydroxide solution, on the basis employing described auxiliary agent, the amount of this acid-base modifier is that the pH value of medicinal liquid before making lyophilization is in 8.0 ~ 8.5 scopes.

In following test, if not otherwise indicated, when using activated carbon adsorption, consumption is produces upper conventional amount, i.e. 0.1% (namely adding active carbon 0.1g in every 100ml medicinal liquid).In following test, when preparing lyophilized injectable powder, the active component of use is with a collection of crude drug (it checks according to the present invention's [HPLC method], impurity G content 0.17%), except as otherwise noted.

[HPLC method]:

Solvent mixture: methanol-5g/L phosphoric acid solution-acetonitrile (10:40:50V/V/V);

Test solution: the sample to be tested (raw material or injectable powder) being equivalent to active component 25mg is dissolved in solvent mixture, then is diluted to 10.0mL with this solvent mixture;

Reference solution (a): 2mg peak identification fusidic acid (wherein containing impurity G) is dissolved in this solvent mixture, then is diluted to 1.0mL with this solvent mixture;

Reference solution (b): get test solution 1.0mL solvent mixture and be diluted to 100.0mL, to obtain final product;

Reference solution (c): get reference solution (b) 1.0mL solvent mixture and be diluted to 10.0mL, to obtain final product;

Chromatographic column: column length 0.15m, immobile phase is the octadecylsilane base bonded silica gel (3.5 μm) of end-blocking, and column temperature is 30 DEG C;

Mobile phase: mobile phase A is methanol-acetonitrile-5g/L phosphoric acid solution (20:40:40V/V/V), Mobile phase B is 5g/L phosphoric acid solution-methanol-acetonitrile (10:20:70V/V/V), according to carrying out eluting with Gradient:

Time (min)	Mobile phase A (%, V/V)	Mobile phase B (%, V/V)
			0-3	100	0
3-28	100—>0	0—>100
			28-33	0	100

Flow velocity: 1.0mL/min;

Detector: UV-detector, determined wavelength 235nm;

Sample size: 20 μ L;

Impurity is differentiated: use peak identification fusidic acid gained chromatogram and reference solution (a) gained chromatogram to differentiate fusidic acid and impurity G, wherein fusidic acid retention time is about 18min, take fusidic acid as benchmark, the relative retention time of impurity G is about 0.82.

With regard to this area, for a kind of acceptable sodium fusidate as crude drug, wherein impurity G should lower than 0.7% relative to the amount of active component.

Wherein impurity G is the material with following chemical constitution:

Its chemistry is by name: ent-(17Z)-16 α-(acetyloxy)-11 β-hydroxy-4 β, 8,14-trimethyl-3-oxo-18-nor-5 β, 10 α-cholesta-17 (20), 24-dien-21-oic acid (3-didehydrofusidic acid).

embodiment 1: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.2g,

Arginine 0.2g,

Water for injection, in right amount, adds to 8ml.

Method for making:

A () gets the active component of recipe quantity and neutral amino acid and basic amino acid, add appropriate water for injection, make dissolving, then add active carbon, stir, filtering decarbonization;

B () is mended and is injected water to its recipe quantity, stir, and measures solution ph and optional mensuration active component content, is adjusted to pH value 8.0 to 8.5 if desired with acid-base modifier;

Wherein mentioned in prescription water for injection is being removed after lyophilization, lower same.

embodiment 2: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.08g,

Arginine 0.165g,

Water for injection, in right amount, adds to 4ml.

Method for making:

C (), by medicinal liquid aseptic filtration, fill is in cillin bottle, and lyophilization (freeze-drying curve B) removes moisture, tamponade, to obtain final product.

embodiment 3: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.2g,

Arginine 0.2g,

Mannitol 0.25g,

Water for injection, in right amount, adds to 10ml.

Method for making:

A () gets active component and mannitol, neutral amino acid and the basic amino acid of recipe quantity, add appropriate water for injection, make dissolving, then add active carbon, stirs, filtering decarbonization;

embodiment 4: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.08g,

Arginine 0.165g,

Lactose 0.1g,

Water for injection, in right amount, adds to 4ml.

Method for making:

A () gets active component and lactose, neutral amino acid and the basic amino acid of recipe quantity, add appropriate water for injection, make dissolving, then add active carbon, stirs, filtering decarbonization;

embodiment 5: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.12g,

Arginine 0.1g,

Water for injection, in right amount, adds to 6ml.

Method for making:

embodiment 6: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.05g,

Arginine 0.25g,

Water for injection, in right amount, adds to 3.2ml.

Method for making:

embodiment 7: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.25g,

Arginine 0.1g,

Water for injection, in right amount, adds to 8.5ml.

Method for making:

embodiment 8: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Sodium hydrogen phosphate 98mg,

Citric acid 5mg,

Disodiumedetate 2.5mg,

Mannitol 120mg,

Water for injection 6ml.

Method for making:

Get 4/5 recipe quantity water for injection, add recipe quantity disodiumedetate, stirring and dissolving, add the mannitol of recipe quantity, sodium hydrogen phosphate and citric acid stirring and dissolving complete, cool to room temperature, add the sodium fusidate of recipe quantity, stirring and dissolving, adds to the full amount of water for injection.Add injection special-purpose activated charcoal in medicinal liquid, stir 30min, decarbonization filtering.0.22um microporous filter membrane fine straining is degerming, and liquid drug is partly jumped a queue, lyophilization, and tamponade Zha Gai, to obtain final product.

embodiment 9: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 120mg,

Arginine 180mg,

Water for injection 6ml.

Method for making:

Get 4/5 recipe quantity water for injection, let cool to 30 DEG C, add glycine and the arginine of recipe quantity, stirring and dissolving, the pH of adjustment solution is 8.0 ~ 9.0, adds the active component of recipe quantity, stirring and dissolving, adds to the full amount of water for injection.Add injection special-purpose activated charcoal in medicinal liquid, stir 15min, decarbonization filtering.0.22um ~ 0.45um microporous filter membrane fine straining is degerming, and liquid drug is partly jumped a queue, lyophilization, and tamponade Zha Gai, to obtain final product.

embodiment 10: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 70mg,

Arginine 85mg,

Mannitol 20mg,

Water for injection 6ml.

Method for making:

Get 4/5 recipe quantity water for injection, let cool to 30 DEG C, add the glycine of recipe quantity, arginine and mannitol, stirring and dissolving, the pH of adjustment solution is 8.0 ~ 9.0, adds the active component of recipe quantity, stirring and dissolving, adds to the full amount of water for injection.Add injection special-purpose activated charcoal in medicinal liquid, stir 15min, decarbonization filtering.0.22um ~ 0.45um microporous filter membrane fine straining is degerming, and liquid drug is partly jumped a queue, lyophilization, and tamponade Zha Gai, to obtain final product.

embodiment 11: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 500mg,

Mannitol 80mg,

Arginase 12 0mg,

Water for injection 8ml.

Method for making:

Take mannitol and the arginine of recipe quantity, add water for injection 8ml, stirring makes it to dissolve, solution temperature is down to less than 60 DEG C, then adds the sodium fusidate of recipe quantity, constantly stirs and makes it to dissolve completely, add 0.5% (W/V) injection active carbon of preparation total amount, stir and leave standstill 25 minutes, filter decarburization, for subsequent use after injecting water to 8ml.By clear and bright to filtrate for above-mentioned solution 0.22um microporous filter membrane fine straining, after the inspection of semifinished product is qualified, subpackage, embedding is in 20ml cillin bottle, its drug content is made to be 500mg, through freezing 3 hours of low temperature (-40 DEG C), primary drying temperature-25 DEG C 4 hours, 0 DEG C 7 hours, 18 DEG C 7 hours, below vacuum control scope 30Pa; Redrying temperature 28 DEG C 10 hours, after terminating, rolls lid, obtains finished product.

embodiment 12: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 500mg,

Mannitol 80mg,

Arginine 400mg,

Disodiumedetate 4mg.

Method for making:

Take mannitol and the arginine of recipe quantity, add water for injection 8ml, stirring makes it to dissolve, solution temperature is down to less than 60 DEG C, then adds the sodium fusidate of recipe quantity, constantly stirs and makes it to dissolve completely, add 0.5% (W/V) injection active carbon of preparation total amount, stir and leave standstill 25 minutes, filter decarburization, for subsequent use after injecting water to 9ml.By clear and bright to filtrate for above-mentioned solution 0.22um microporous filter membrane fine straining, after the inspection of semifinished product is qualified, subpackage, embedding is in 20ml cillin bottle, its drug content is made to be 500mg, through freezing 3 hours of low temperature (-40 DEG C), primary drying temperature-25 DEG C 4 hours, 0 DEG C 7 hours, 18 DEG C 7 hours, below vacuum control scope 30Pa; Redrying temperature 28 DEG C 10 hours, after terminating, rolls lid, obtains finished product.

embodiment 13: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 500mg,

Arginase 12 50mg,

Citric acid 50mg,

Water for injection, adds to 5ml.

Method for making:

Take arginine and the citric acid of recipe quantity, add water for injection 5ml, stirring makes it to dissolve, solution temperature is down to less than 25 DEG C, then adds the sodium fusidate of recipe quantity, constantly stirs and makes it to dissolve completely, add 0.1% (W/V) injection active carbon of preparation total amount, stir and leave standstill 20 minutes, filter decarburization, for subsequent use after adding to the full amount of water for injection.Above-mentioned solution is clear and bright to filtrate with 0.22 μm of microporous filter membrane fine straining, after the inspection of semifinished product is qualified, subpackage, embedding is in 25ml cillin bottle, its drug content is made to be 500mg, through low temperature (-40 DEG C) freezing 3 hours, one time sublimation temperature-10 DEG C 6 hours, 0 DEG C 6 hours, redrying temperature 30 DEG C 6 hours, after terminating, roll lid, obtain finished product.

embodiment 14: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 500mg,

Arginase 12 40mg,

Citric acid 100mg,

Mannitol 500mg,

Water for injection, adds to 10ml.

Method for making:

Take arginine and the citric acid of recipe quantity, add water for injection 10ml, stirring makes it to dissolve, solution temperature is down to less than 25 DEG C, then adds the sodium fusidate of recipe quantity, constantly stirs and makes it to dissolve completely, add 0.1% (W/V) injection active carbon of preparation total amount, stir and leave standstill 20 minutes, filter decarburization, for subsequent use after adding to the full amount of water for injection.Above-mentioned solution is clear and bright to filtrate with 0.22 μm of microporous filter membrane fine straining, after the inspection of semifinished product is qualified, subpackage, embedding is in 30ml cillin bottle, make its drug content be 500mg, by fusidic acid sodium solution pre-freeze to less than-30 DEG C, maintain 2-8 hour, the indoor temperature of condensation is simultaneously down to-35 DEG C ~-50 DEG C, start vacuum pump, under vacuum, rising products temperature reaches-20 DEG C ~-8 DEG C and distils, until exist without ice crystal, heat up dry removing residual moisture again, makes lyophilizing moisture content of finished products lower than 3%, after terminating, roll lid, obtain finished product.

embodiment 15: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 500mg,

Dimercaptopropanol, BAL 20mg,

Arabo-ascorbic acid 10mg,

Cysteine hydrochloride 15mg,

Phenylalanine 10mg,

Arginine 100mg,

Water for injection, adds to 5ml.

Method for making:

Take dimercaptopropanol, BAL, arabo-ascorbic acid, cysteine hydrochloride, phenylalanine, by 80% stirring and dissolving of less than 35 DEG C water for injection total amounts, be cooled to room temperature again and sodium fusidate is added dissolving at stirring, then adding arginine adjust ph is 8.6, then remaining water for injection is added, then add active carbon to stir, after filtering decarbonization, filtrate is put into freeze drying box, be chilled to less than-35 DEG C, be incubated more than 1.5 hours, open vacuum pump, 0 DEG C sublimes up into ice heading line off, then 30 DEG C are warming up to, be incubated and be drying to obtain sodium fusidate freezing-dried powder injection in 12 hours, product is white crystalline powder.

embodiment 16: sodium fusidate freezing-dried powder injection pharmaceutical composition is provided

Commercially available product, commercially available approval number H20090197, every bottle containing active component 500mg.

embodiment 21: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.2g,

Arginine 0.2g,

Trehalose 0.075g,

Water for injection, in right amount, adds to 8ml.

Method for making:

A () gets active component and trehalose, neutral amino acid and the basic amino acid of recipe quantity, add appropriate water for injection, make dissolving, then add active carbon, stirs, filtering decarbonization;

embodiment 22: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.08g,

Arginine 0.165g,

Trehalose 0.05g,

Water for injection, in right amount, adds to 4ml.

Method for making:

embodiment 23: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.2g,

Arginine 0.2g,

Mannitol 0.25g,

Trehalose 0.1g,

Water for injection, in right amount, adds to 10ml.

Method for making:

A () gets active component and mannitol, trehalose, neutral amino acid and the basic amino acid of recipe quantity, add appropriate water for injection, make dissolving, then add active carbon, stirs, filtering decarbonization;

embodiment 24: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.08g,

Arginine 0.165g,

Lactose 0.1g,

Trehalose 0.06g,

Water for injection, in right amount, adds to 4ml.

Method for making:

A () gets active component and trehalose, lactose, neutral amino acid and the basic amino acid of recipe quantity, add appropriate water for injection, make dissolving, then add active carbon, stirs, filtering decarbonization;

embodiment 25: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.12g,

Arginine 0.1g,

Trehalose 0.08g,

Water for injection, in right amount, adds to 6ml.

Method for making:

embodiment 26: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.05g,

Arginine 0.25g,

Trehalose 0.07g,

Water for injection, in right amount, adds to 3.2ml.

Method for making:

embodiment 27: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.25g,

Arginine 0.1g,

Trehalose 0.75g,

Water for injection, in right amount, adds to 8.5ml.

Method for making:

embodiment 28: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Sodium hydrogen phosphate 98mg,

Citric acid 5mg,

Disodiumedetate 2.5mg,

Mannitol 120mg,

Trehalose 0.07g,

Water for injection 6ml.

Method for making:

Get 4/5 recipe quantity water for injection, add recipe quantity disodiumedetate, stirring and dissolving, add the trehalose of recipe quantity, mannitol, sodium hydrogen phosphate and citric acid stirring and dissolving complete, cool to room temperature, add the sodium fusidate of recipe quantity, stirring and dissolving, adds to the full amount of water for injection.Add injection special-purpose activated charcoal in medicinal liquid, stir 30min, decarbonization filtering.0.22um microporous filter membrane fine straining is degerming, and liquid drug is partly jumped a queue, lyophilization, and tamponade Zha Gai, to obtain final product.

embodiment 29: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 120mg,

Arginine 180mg,

Trehalose 0.08g,

Water for injection 6ml.

Method for making:

Get 4/5 recipe quantity water for injection, let cool to 30 DEG C, add the trehalose of recipe quantity, glycine and arginine, stirring and dissolving, the pH of adjustment solution is 8.0 ~ 9.0, adds the active component of recipe quantity, stirring and dissolving, adds to the full amount of water for injection.Add injection special-purpose activated charcoal in medicinal liquid, stir 15min, decarbonization filtering.0.22um ~ 0.45um microporous filter membrane fine straining is degerming, and liquid drug is partly jumped a queue, lyophilization, and tamponade Zha Gai, to obtain final product.

embodiment 30: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 70mg,

Arginine 85mg,

Mannitol 20mg,

Trehalose 0.08g,

Water for injection 6ml.

Method for making:

Get 4/5 recipe quantity water for injection, let cool to 30 DEG C, add the trehalose of recipe quantity, glycine, arginine and mannitol, stirring and dissolving, the pH of adjustment solution is 8.0 ~ 9.0, adds the active component of recipe quantity, stirring and dissolving, adds to the full amount of water for injection.Add injection special-purpose activated charcoal in medicinal liquid, stir 15min, decarbonization filtering.0.22um ~ 0.45um microporous filter membrane fine straining is degerming, and liquid drug is partly jumped a queue, lyophilization, and tamponade Zha Gai, to obtain final product.

embodiment 31: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 500mg,

Mannitol 80mg,

Arginase 12 0mg,

Trehalose 0.09g,

Water for injection 8ml.

Method for making:

Take the trehalose of recipe quantity, mannitol and arginine, add water for injection 8ml, stirring makes it to dissolve, solution temperature is down to less than 60 DEG C, then adds the sodium fusidate of recipe quantity, constantly stirs and makes it to dissolve completely, add 0.5% (W/V) injection active carbon of preparation total amount, stir and leave standstill 25 minutes, filter decarburization, for subsequent use after injecting water to 8ml.By clear and bright to filtrate for above-mentioned solution 0.22um microporous filter membrane fine straining, after the inspection of semifinished product is qualified, subpackage, embedding is in 20ml cillin bottle, its drug content is made to be 500mg, through freezing 3 hours of low temperature (-40 DEG C), primary drying temperature-25 DEG C 4 hours, 0 DEG C 7 hours, 18 DEG C 7 hours, below vacuum control scope 30Pa; Redrying temperature 28 DEG C 10 hours, after terminating, rolls lid, obtains finished product.

embodiment 32: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 500mg,

Mannitol 80mg,

Arginine 400mg,

Trehalose 60mg,

Disodiumedetate 4mg.

Method for making:

Take the trehalose of recipe quantity, mannitol and arginine, add water for injection 8ml, stirring makes it to dissolve, solution temperature is down to less than 60 DEG C, then adds the sodium fusidate of recipe quantity, constantly stirs and makes it to dissolve completely, add 0.5% (W/V) injection active carbon of preparation total amount, stir and leave standstill 25 minutes, filter decarburization, for subsequent use after injecting water to 9ml.By clear and bright to filtrate for above-mentioned solution 0.22um microporous filter membrane fine straining, after the inspection of semifinished product is qualified, subpackage, embedding is in 20ml cillin bottle, its drug content is made to be 500mg, through freezing 3 hours of low temperature (-40 DEG C), primary drying temperature-25 DEG C 4 hours, 0 DEG C 7 hours, 18 DEG C 7 hours, below vacuum control scope 30Pa; Redrying temperature 28 DEG C 10 hours, after terminating, rolls lid, obtains finished product.

embodiment 33: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 500mg,

Arginase 12 50mg,

Citric acid 50mg,

Trehalose 100mg,

Water for injection, adds to 5ml.

Method for making:

Take the trehalose of recipe quantity, arginine and citric acid, add water for injection 5ml, stirring makes it to dissolve, solution temperature is down to less than 25 DEG C, then adds the sodium fusidate of recipe quantity, constantly stirs and makes it to dissolve completely, add 0.1% (W/V) injection active carbon of preparation total amount, stir and leave standstill 20 minutes, filter decarburization, for subsequent use after adding to the full amount of water for injection.Above-mentioned solution is clear and bright to filtrate with 0.22 μm of microporous filter membrane fine straining, after the inspection of semifinished product is qualified, subpackage, embedding is in 25ml cillin bottle, its drug content is made to be 500mg, through low temperature (-40 DEG C) freezing 3 hours, one time sublimation temperature-10 DEG C 6 hours, 0 DEG C 6 hours, redrying temperature 30 DEG C 6 hours, after terminating, roll lid, obtain finished product.

embodiment 34: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 500mg,

Arginase 12 40mg,

Citric acid 100mg,

Mannitol 500mg,

Trehalose 80mg,

Water for injection, adds to 10ml.

Method for making:

Take the trehalose of recipe quantity, arginine and citric acid, add water for injection 10ml, stirring makes it to dissolve, solution temperature is down to less than 25 DEG C, then adds the sodium fusidate of recipe quantity, constantly stirs and makes it to dissolve completely, add 0.1% (W/V) injection active carbon of preparation total amount, stir and leave standstill 20 minutes, filter decarburization, for subsequent use after adding to the full amount of water for injection.Above-mentioned solution is clear and bright to filtrate with 0.22 μm of microporous filter membrane fine straining, after the inspection of semifinished product is qualified, subpackage, embedding is in 30ml cillin bottle, make its drug content be 500mg, by fusidic acid sodium solution pre-freeze to less than-30 DEG C, maintain 2-8 hour, the indoor temperature of condensation is simultaneously down to-35 DEG C ~-50 DEG C, start vacuum pump, under vacuum, rising products temperature reaches-20 DEG C ~-8 DEG C and distils, until exist without ice crystal, heat up dry removing residual moisture again, makes lyophilizing moisture content of finished products lower than 3%, after terminating, roll lid, obtain finished product.

embodiment 35: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 500mg,

Dimercaptopropanol, BAL 20mg,

Arabo-ascorbic acid 10mg,

Cysteine hydrochloride 15mg,

Phenylalanine 10mg,

Arginine 100mg,

Trehalose 75mg,

Water for injection, adds to 5ml.

Method for making:

Take dimercaptopropanol, BAL, arabo-ascorbic acid, cysteine hydrochloride, phenylalanine, trehalose, by 80% stirring and dissolving of less than 35 DEG C water for injection total amounts, be cooled to room temperature again and sodium fusidate is added dissolving at stirring, then adding arginine adjust ph is 8.6, then remaining water for injection is added, then add active carbon to stir, after filtering decarbonization, filtrate is put into freeze drying box, be chilled to less than-35 DEG C, be incubated more than 1.5 hours, open vacuum pump, 0 DEG C sublimes up into ice heading line off, then 30 DEG C are warming up to, be incubated and be drying to obtain sodium fusidate freezing-dried powder injection in 12 hours, product is white crystalline powder.

embodiment 36: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.2g,

Mannitol 0.2g,

Trehalose 0.075g,

Water for injection, in right amount, adds to 8ml.

Method for making:

embodiment 37: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.245g,

Trehalose 0.05g,

Water for injection, in right amount, adds to 4ml.

Method for making:

embodiment 38: prepare sodium fusidate freezing-dried powder injection pharmaceutical composition

Formula:

Sodium fusidate 0.5g,

Glycine 0.4g,

Mannitol 0.25g,

Trehalose 0.1g,

Water for injection, in right amount, adds to 10ml.

Method for making:

test example 1: the stability measuring each injectable powder

1, in this test example, the lyophilization injectable powder of each embodiment gained is measured after 42 DEG C of temperature places place 5 months, wherein the content [42 DEG C of active component, May, can be described as high temperature average content, mg/ bottle, measure the meansigma methods of 10 bottles] content [20 DEG C of active component when processing the corresponding time relative to this sample at 20 DEG C, May, can be described as room temperature average content, mg/ bottle, measure the meansigma methods of 10 bottles] percent, i.e. remaining percent (%), namely

Wherein, high temperature average content (mg/ bottle) and room temperature average content (mg/ bottle) measure and the content (averages of 10 bottles) of active component in every bottle that calculates through HPLC method after sample dissolution.

Result shows, and the remaining percent (%) of embodiment 1-16, embodiment 21-38 whole injectable powder sample is all between 96.1% ~ 100.3%, and the remaining percent (%) of such as Ex1 is 97.2%.This result shows, various sample does not have notable difference from the angle of active component content change.

2, in addition, for the above injectable powder placing whole embodiments of 5 months through 42 DEG C of temperature places, measure their impurity G content 0 month time, also measure their impurity G content when May; In addition, for each sample, calculate its impurity G before and after this high-temperature treatment of experience and increase percent, impurity G content gained difference when wherein parameter " impurity G increases percent " refers to and deducts 0 month for its impurity G content when May of a certain powder pin sample, again divided by impurity G content when 0 month, be multiplied by 100% again, the percent of gained.

Result shows: the impurity G content that whole sample (was equivalent to the injectable powder of original state) 0 month time is all in 0.21% ~ 0.38% scope, show whole sample after preparation processing process, impurity G content has no significant change, i.e. the no significant difference in the quality characterized with impurity G of different formulations gained injectable powder; The impurity G of the whole injectable powder sample of embodiment 1-16, embodiment 28, embodiment 31-38 increases percent in 226% ~ 362% scope; The maximum single contaminant of embodiment 21-27, embodiment 29-30 whole injectable powder sample increases percent in 42% ~ 63% scope;

Above result display, although its initial quality of injectable powder that different formulations obtains is substantially suitable, but they stability features particularly with impurity G characterize stability in present complete beat all effect, because illustrated prescription difference it will be appreciated by those skilled in the art that for obtaining the injectable powder with different initial quality, but the stability difference presented but is can explain clearly without any theory.Particularly only in the simultaneous situation of both glycine and arginine, effectively could control impurity G (being a kind of impurity that a kind of this area needs are extremely paid close attention to this medicine) growth in long-term preservation process after adding trehalose.Cannot with existing any theoretical explanation, the chemical stability relatedness between the character of above-mentioned adjuvant well known by persons skilled in the art and the impurity with impurity G chemical constitution, in fact there is not the instruction of this relatedness any in prior art.

industrial applicability

Sodium fusidafe as injection injectable powder pharmaceutical composition of the present invention has excellent pharmaceutical properties, can be used for treatment clinically by various sensitive bacterial, especially the various infection that cause of staphylococcus, as osteomyelitis, septicemia, endocarditis, the cystic fibrosis of repeated infection, pneumonia, skin and soft tissue infection, surgery and traumatic infection etc.

Claims

1. the pharmaceutical composition of sodium fusidafe as injection injectable powder, it comprises sodium fusidate, neutral amino acid and basic amino acid.

2. pharmaceutical composition according to claim 1, is characterized in that following any one or multinomial:

Described neutral amino acid is selected from: glycine, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine, tyrosine, tryptophan, proline, methionine and hydroxyproline and combination thereof;

In the sodium fusidate of every 0.5 weight portion, the amount of the neutral amino acid comprised is 0.05 ~ 0.5 weight portion, such as 0.05 ~ 0.3 weight portion, 0.05 ~ 0.25 weight portion;

Described basic amino acid is selected from: arginine, lysine, histidine and combination thereof; And/or

In the sodium fusidate of every 0.5 weight portion, the amount of the basic amino acid comprised is 0.05 ~ 0.5 weight portion, such as 0.075 ~ 0.3 weight portion, 0.1 ~ 0.25 weight portion.

3. pharmaceutical composition according to claim 1, is characterized in that following any one or multinomial:

When it makes the solution containing sodium fusidate 0.05 ~ 0.15g in every 1ml solution with water dissolution, the pH value of this solution is 7.5 to 9.0, and the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5;

Described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination;

The consumption of described acid-base modifier is, described pharmaceutical composition water for injection is made to redissolve to substantially identical with solution before lyophilization volume, gained solution measures according to the method under Chinese Pharmacopoeia version in 2010 two annex VI H items, the pH value of this solution is 7.5 to 9.0, the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5;

The consumption of described acid-base modifier is, when making described pharmaceutical composition water for injection dissolve the solution made containing sodium fusidate 0.05 ~ 0.15g in every 1ml solution, measure according to the method under Chinese Pharmacopoeia version in 2010 two annex VI H items, the pH value of this solution is 7.5 to 9.0, the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5.

4. pharmaceutical composition according to claim 1, is characterized in that following any one or multinomial:

Its solid content before lyophilization in solution is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v);

Wherein the weight sum of sodium fusidate, neutral amino acid and basic amino acid accounts for 5 ~ 30% (w/v) of liquor capacity before lyophilization, such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v);

It redissolves to substantially identical with solution before lyophilization volume with water for injection, and the solid content in gained solution is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v);

It redissolves to substantially identical with solution before lyophilization volume with water for injection, wherein the weight sum of sodium fusidate, neutral amino acid and basic amino acid accounts for 5 ~ 30% (w/v) of redissolution liquor capacity, such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v); And/or

Wherein moisture is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.

5. pharmaceutical composition according to claim 1, is characterized in that following any one or multinomial:

Wherein also optionally comprise freeze-dried excipient, such as, be selected from mannitol, lactose, sorbitol, sucrose etc.; Or wherein also comprise trehalose;

In the sodium fusidate of every 0.5 weight portion, the amount of the trehalose comprised is 0.05 ~ 0.2 weight portion, such as 0.05 ~ 0.15 weight portion, 0.05 ~ 0.1 weight portion.

6. pharmaceutical composition according to claim 1, it is prepare by comprising following step substantially:

7. pharmaceutical composition according to claim 6, is characterized in that following any one or multinomial:

The filtered filtrate of step (c) gained, wherein solid content is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v);

The described appropriate water for injection of step (a) is about 70 ~ 90% of water for injection recipe quantity;

The described benefit of step (b) injects water to its recipe quantity and refers to add water to and make the concentration of active component in solution reach 0.05 ~ 0.15g/ml, and such as concentration reaches 0.0625 ~ 0.125g/ml;

The described activated carbon dosage of step (a) is 0.05% ~ 1% of solution weight, preferably 0.05% ~ 0.5%;

Acid solution described in step (b) and aqueous slkali use the aqueous solution being selected from following pH adjusting agent and being mixed with: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination;

In step (c) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.

8. prepare the method for the pharmaceutical composition of sodium fusidafe as injection injectable powder, described pharmaceutical composition comprises sodium fusidate, neutral amino acid and basic amino acid; The method comprises the following steps:

9. method according to claim 8, is characterized in that following any one or multinomial:

Acid solution described in step (b) and aqueous slkali use the aqueous solution being selected from following pH adjusting agent and being mixed with: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination; And/or

10. method according to claim 8, is characterized in that following any one or multinomial:

In the sodium fusidate of every 0.5 weight portion in described pharmaceutical composition, the amount of the neutral amino acid comprised is 0.05 ~ 0.5 weight portion, such as 0.05 ~ 0.3 weight portion, 0.05 ~ 0.25 weight portion;

Described basic amino acid is selected from: arginine, lysine, histidine and combination thereof;

In the sodium fusidate of every 0.5 weight portion in described pharmaceutical composition, the amount of the basic amino acid comprised is 0.05 ~ 0.5 weight portion, such as 0.075 ~ 0.3 weight portion, 0.1 ~ 0.25 weight portion;

When described pharmaceutical composition water dissolution makes the solution containing sodium fusidate 0.05 ~ 0.15g in every 1ml solution, the pH value of this solution is 7.5 to 9.0, and the pH value of such as this solution is 8.0 to 9.0, and the pH value of such as this solution is 8.0 to 8.5;

The solid content of described pharmaceutical composition before lyophilization in solution is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v);

In described pharmaceutical composition, the weight sum of sodium fusidate, neutral amino acid and basic amino acid accounts for 5 ~ 30% (w/v) of liquor capacity before lyophilization, such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v);

Described pharmaceutical composition water for injection redissolves to substantially identical with solution before lyophilization volume, solid content in gained solution is 5 ~ 30% (w/v), such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v);

Described pharmaceutical composition water for injection redissolves to substantially identical with solution before lyophilization volume, wherein the weight sum of sodium fusidate, neutral amino acid and basic amino acid accounts for 5 ~ 30% (w/v) of redissolution liquor capacity, such as 7.5 ~ 25% (w/v), such as 10 ~ 25% (w/v);

In described pharmaceutical composition, moisture is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%;

Also trehalose is comprised in described pharmaceutical composition; And/or

In the sodium fusidate of every 0.5 weight portion in described pharmaceutical composition, the amount of the trehalose comprised is 0.05 ~ 0.2 weight portion, such as 0.05 ~ 0.15 weight portion, 0.05 ~ 0.1 weight portion.