CN104352454B - Sodium fusidafe as injection powder-injection pharmaceutical composition and preparation method - Google Patents
Sodium fusidafe as injection powder-injection pharmaceutical composition and preparation method Download PDFInfo
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- CN104352454B CN104352454B CN201410649859.5A CN201410649859A CN104352454B CN 104352454 B CN104352454 B CN 104352454B CN 201410649859 A CN201410649859 A CN 201410649859A CN 104352454 B CN104352454 B CN 104352454B
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- injection
- solution
- pharmaceutical composition
- water
- acid
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to sodium fusidafe as injection powder-injection pharmaceutical composition and preparation method.Specifically, the invention belongs to pharmaceutical technology field, it is related to one kind to can be used to treat by various sensitive bacterials, the various infection that especially staphylococcus causes, such as osteomyelitis, septicemia, endocarditis, the medicine of the cystic fibrosis of repeated infection, pneumonia, skin and soft tissue infection, surgery and traumatic infection etc., the more particularly to a kind of pharmaceutical composition being made as active component with sodium fusidate such as freeze-drying powder-injection.The invention further relates to the preparation method of the pharmaceutical composition.In one embodiment, the present invention relates to the pharmaceutical composition of sodium fusidafe as injection powder-injection, it includes sodium fusidate, neutral amino acid and basic amino acid.The pharmaceutical composition has excellent pharmaceutical properties.
Description
Technical field
The invention belongs to pharmaceutical technology field, it is related to one kind to can be used to treat by various sensitive bacterials, especially grape ball
Microbial various infection, such as osteomyelitis, septicemia, endocarditis, the cystic fibrosis of repeated infection, pneumonia, skin and soft
The medicine of tissue infection, surgery and traumatic infection etc., it is more particularly to a kind of to be made by active component of sodium fusidate
Pharmaceutical composition such as freeze-drying powder-injection.The invention further relates to the preparation method of the pharmaceutical composition.
Background technology
Sodium fusidate (Sodium Fusidate), wherein science of culture is entitled：16 α-acetoxy-3 β, 11 β-dihydroxy
Base -4 β, 8 β, 14 α-trimethyl -18- go first -5 β, 10 α-cholesteric-(17Z) -17 (20), 24- diene -21- acid sodium, English language Chemical
It is entitled：Sodium ent-(17Z)-16α-(acetyloxy)-3β,11β-dihydroxy-4β,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.Husband
The western sour sodium in ground is white crystalline powder, soluble in water, is injected intravenously good absorbing, has extremely strong penetrability to tissue and body fluid.
Sodium fusidate is to produce bactericidal action by suppressing the protein synthesis of bacterium, is had by force to a series of gram-positive bacteriums
Big antibacterial action.Staphylococcus, including to the bacterial strain of penicillin, methicillin and other antibiotic resistances, it is high to this product
Degree is sensitive.Without cross resistance between other antibacterials of sodium fusidate and Clinical practice, but it puts in an acidic solution
Put unstable, pointed out in the sodium fusidafe as injection specification of Clinical practice, if glucose injection agent peracid, solution can be in breast
Shape and when pH value be less than 7.4 when, this product can be precipitated.Wang Yaqun, HPLC method determine the content of sodium fusidafe as injection,《China
Medical guide》, 18 phases in 2008, page 55.
Fusidic Acid (Fusidic Acid, also known as fuscomycin), category shuttle chain embraces acids antibiotic.It is public by Denmark's Leo pharmacy
Take charge of and extracted from fat ball fungi (Fusidium coccineum fungus) first in 1962.Antibacterial Mechanism is to pass through
Suppress ribosomal transposition to disturb elongation factor G, so as to hinder the synthesis of bacterioprotein.This unique mechanism of action is avoided
Cross resistance with other antibacterials.Although being widely used more than 30 years (domestic clinical practice is less) abroad,
But still most aureus strains are kept with stronger antibacterial activity and very low resistant rate, increasingly by people's
Concern, especially under the increasingly difficult present situation of current anti-Staphylococcus aureus drug-fast bacteria infection, Fusidic Acid has higher
Clinical value.
Because Fusidic Acid is water insoluble, clinical injection preparation often uses its soluble-salt, the preferably sodium salt of Fusidic Acid.Husband
The western sour sodium in ground is white or off-white color crystalline powder, slightly draws moist, soluble in water and ethanol.0.125g is dissolved in 10ml water
In, pH7.5~9.5.Sodium fusidate places unstable in the solution, and pH be less than 7.3 when, then during compatibility occur precipitation.Cause
This commercialized product (trade name Li Siding) uses aseptic subpackaged sodium fusidate, and subsidiary pH is 7.4~7.6 dedicated buffering salt
Solvent solves product clinical compatibility stability problem.
Prior art discloses many documents prepared about Fusidic Acid sodium raw materials.For example, CN103012536A
(201210592628.6, North China pharmacy) disclose a kind of method for crystallising of sodium fusidate, comprise the following steps：A, preparation husband
Western ground acid sodium solution：Sodium fusidate is added in the aqueous acetone solution that volume by volume concentration is 50-90%, stirring, dissolving；B, knot
Brilliant, growing the grain：Fusidic Acid sodium solution is heated to 30-60 DEG C, insulation flows down plus acetone in stirring, stream rate of acceleration is 20-
24mL/h, after crystallization is separated out, 6-18mL/h is reduced to by stream rate of acceleration, when the stream dosage of acetone is sodium fusidate liquor capacity
10-15 times when, stop stream plus, growing the grain 16-20h, filtering, separation of solid and liquid；C, by gained solid with being done after acetone drip washing
Dry treatment, obtains Sodium fusidate crystal.It is believed that the invention methods described is simple to operate, with low cost, prepared by the method
Sodium fusidate crystal, stable crystal form, good fluidity.
Additionally, CN103214540A (201310159052.9, North China pharmacy) discloses Sodium fusidate crystal and its system
Preparation Method.The X-ray powder diffraction spectral signature peak of the Sodium fusidate crystal that the invention is newly provided represents position with 2 θ ± 0.2 °
In 6.960,7.117,8.180,8.355,11.895,14.460,15.176,16.389,16.574,24.837,28.967 Hes
At 36.344.Its preparation method comprises the steps：1) Fusidic Acid is dissolved in low-alcohol solution, obtains sodium fusidate molten
Liquid；2) to stream plus ethyl acetate solution in Fusidic Acid sodium solution, sodium fusidate is crystallized, collects solid phase；3) solid phase is entered
Row drying, obtains Sodium fusidate crystal.It is believed that the Sodium fusidate crystal that the invention is provided have outward appearance it is glittering and translucent,
Grain is uniform, stable crystal form, is conducive to the advantages of dispensing and preserve.It is believed that the method that the invention is provided has prepared Fu Xi
The sour sodium crystal good stability in ground, and process is simple, environment-friendly, solvent for use it is repeatable recycle, production cost it is low
Advantage.
Prior art discloses many documents prepared about Fusidic Acid preparation of sodium.For example, CN103040747A
(201210551292.9, BEST) disclose a kind of sodium fusidate lipidosome injection and its preparation method, the liposome injection
Agent is made up of sodium fusidate, soybean lecithin, cholesterol succinate, PLURONICS F87, PVP and mannitol.It is believed that
The lipidosome injection of the invention has liposomal particle size small and is evenly distributed, good preparation stability, good envelop rate
With relatively low percolation ratio；Impurity and toxic and side effect are reduced, the quality and curative effect of product is improve.
Prior art discloses many documents relevant with its powder-injection about sodium fusidate.For example,
CN103405392A (201310383401.5, Luo Xin) disclose a kind of special injection of sodium fusidate freezing-dried powder injection and its
Preparation method.It is believed that the special injection of the invention sodium fusidate freezing-dried powder injection is by nitrilotriacetic acid, methionine, tartaric acid
Potassium sodium, sodium pyrosulfite, disodium hydrogen phosphate and water for injection composition.It is believed that the preferred nitrilotriacetic acid of the invention, methionine, tartaric acid
Potassium sodium, sodium pyrosulfite, disodium hydrogen phosphate are mutually cooperateed with and made as the component of the special injection of sodium fusidate freezing-dried powder injection
With the stability for improving the sodium fusidate freezing-dried powder injection after dissolving, the content and product characteristics of sodium fusidate are maintained
In normal requirement, the safe handling of clinical medicine is particularly advantageous.
Prior art discloses many documents relevant about Fusidic Acid sodium injection.For example, CN103169673A
(201310125429.9, Luo Xin) disclose a kind of sodium fusidate freezing-dried powder injection and preparation method thereof.It is believed that the invention institute
Sodium fusidate freezing-dried powder injection is stated by sodium fusidate, dimercaprol dimercaptopropanol, arabo-ascorbic acid, cysteine hydrochloride, phenylpropyl alcohol ammonia
Acid, arginine and water for injection are lyophilized to be made.It is believed that the preferred arginine of the invention, dimercaprol dimercaptopropanol, arabo-ascorbic acid, hydrochloric acid half
Cystine, phenylalanine as sodium fusidate freezing-dried powder injection auxiliary material, mutually synergy improve sodium fusidate freeze
The stability of powder-injection, reduces the content about material and maintains product characteristics in normal requirement, is conducive to clinical medicine
Safe handling and long term storage.
CN101143133A (200710050222.4, Han Lang) discloses a kind of sodium fusidate freezing-dried powder injection.It is wrapped
Containing following component and content (weight portion):Sodium fusidate 450~550, glycine 30~500, arginine 40~600.It is above-mentioned
Freeze drying powder injection also can further include at least one in excipient such as lactose, mannitol, sorbierite.Consumption is described lyophilized
The 1~10% of powder-injection percentage by weight.It is believed that the sodium fusidate freezing-dried powder injection is due to adding a certain amount of stabilizer,
It is steady in a long-term good, improves security during patient's medication, reduces drug risk.
CN102743342A (201210103795.X, Olympic Competition health) discloses a kind of injection sodium fusidate combination
Thing.It includes following component and content (weight portion):Sodium fusidate：Arginine：Citric acid 500：(100~400)：(5~
100).It is believed that the sodium fusidate freezing-dried powder injection has long-time stability good, during medication the characteristics of steady quality, disease is improve
Security during people's medication, reduces drug risk.
CN101264089A (200810045003.1, sunlight profit standing grain) discloses a kind of Fusidate sodium composition and its jelly
Dry preparation preparation method, the weight ratio of sodium fusidate, excipient, stabilizer/pH adjusting agent in the Fusidate sodium composition
It is 25~100：2~100：1~50.Wherein excipient is preferably glucose and/or mannitol, and stabilizer/pH adjusting agent is preferred
It is the one kind in arginine, disodium ethylene diamine tetraacetate and calcio-disodium edetate or its mixture.Its preparation method is to use
Water for injection is solvent, and sodium fusidate, excipient, stabilizer/pH adjusting agent are made into clear transparent solutions, and filtration is dispensed,
The lyophilized formulations for meeting injection requirement are made up of drying bu sublimation.The pH value of said preparation is 7.5~9.0.Per unit agent
Contain 125~500MG of sodium fusidate in the preparation of amount.It is believed that the Fusidate sodium composition freeze-dried powder system described in the invention
Agent, good stability is easy to use, the tolerance of patient's medication and the simplicity of medical care precess is improve, with very strong reality
The property used.It is believed that the preparation method of the invention, with process is simple, the advantage of manufactured goods good stability.
CN1817340A (200610042212.1, hundred promises) discloses a kind of for treating various severe staphylococcal infections
Lyophilized formulations containing sodium fusidate and preparation method thereof.The composition of sodium fusidafe as injection of the invention, it is characterized in that
Lyophilized formulations are made using lyophilized technique, comprising following components：Sodium fusidate, disodium hydrogen phosphate, the weight ratio of citric acid are
500：78~113：4~5.7.It is believed that the composition of sodium fusidafe as injection of the invention, with water for injection as solvent, stablizes
It is good, it is easy to use, tolerance during patient's medication is improve, reduce production cost.It is believed that the invention preparation method has work
Skill is simple, the advantage of manufactured goods good stability.
Additionally, it is known that during Clinical practice, medicine occurs muddy or precipitation when mixing or meet with sodium fusidate.Reason
It is probably：1) acid stronger medicine, such as vitamin C, ligustrazine phosphat can make Fusidic Acid from husband because of the pH of reduction solvent
The western sour sodium middle reaches in ground isolate, and form muddy or precipitation, therefore selection solvent it may be noted that such as States Pharmacopoeia specifications glucose injection pH models
Enclose for 3.5~6.5 sodium fusidates are likely to separate out precipitation in the range of this pH.2) dissolving may be combined into Fusidic Acid
The smaller double salt of degree, easily forms muddy or precipitation.3) match somebody with somebody with sodium fusidate containing medicines such as multivalent ion such as Ca2+ and Mg2+
5, salt may be chelated into by Fusidic Acid, change its solubility behavior and form muddy or precipitation.Therefore sodium fusidate has weak
Alkalescence, chelant physical property matter, clinically avoid and are used with faintly acid, polyvalent metal ion compound compatibility.
It has been found that the sodium fusidate that existing method is prepared is that can not make us full in some drugses properties
Meaning, such as their chemical stability.Therefore, those skilled in the art still expect there is the Fusidic Acid for preparing tool new feature
The demand of preparation of sodium, expects that this preparation is presented excellent pharmaceutical properties in terms of one or more.
The content of the invention
Of the invention is to provide a kind of new sodium fusidate preparation such as its powder-injection, expects that it for example has excellent
Pharmaceutical properties, such as but not limited to excellent chemical stability.Present inventors have surprisingly discovered that, using the present invention
Technical scheme can easily realize above-mentioned purpose.The present invention is accomplished based on this discovery.
Therefore, first aspect present invention there is provided a kind of pharmaceutical composition of sodium fusidafe as injection powder-injection, its
Including sodium fusidate, neutral amino acid and basic amino acid.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the neutral amino acid is selected from：It is sweet
Propylhomoserin, alanine, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, benzene
Alanine, tyrosine, tryptophan, proline, methionine and hydroxyproline and combinations thereof.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein with the husband west ground of every 0.5 weight portion
Sour sodium meter, comprising neutral amino acid amount be 0.05~0.5 weight portion, such as 0.05~0.3 weight portion, 0.05~0.25 weight
Amount part.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the basic amino acid is selected from：Essence
Propylhomoserin, lysine, histidine and combinations thereof.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein with the husband west ground of every 0.5 weight portion
Sour sodium meter, comprising basic amino acid amount be 0.05~0.5 weight portion, such as 0.075~0.3 weight portion, 0.1~0.25 weight
Amount part.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is made in every 1ml solution with water dissolves
During solution containing 0.05~0.15g of sodium fusidate, the pH value of the solution is 7.5 to 9.0, and the pH value of such as solution is 8.0
To 9.0, the pH value of such as solution is 8.0 to 8.5.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the species of the acid-base modifier is not
Be particularly limited, if its can by the freeze drying powder injection (and/or prepare the freeze drying powder injection during will prepare in the middle of
Thing) pH value adjust to desired scope.In one embodiment, the acid-base modifier is selected from NaOH, hydrogen
Potassium oxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its group
Close.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the consumption of the acid-base modifier
Be so that described pharmaceutical composition water for injection redissolve to substantially with freeze-drying before solution identical volume, gained is molten
Liquid is determined according to the method under Chinese Pharmacopoeia annex VI H of version two in 2010, and the pH value of the solution is 7.5 to 9.0, for example
The pH value of the solution is 8.0 to 9.0, and the pH value of such as solution is 8.0 to 8.5.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the consumption of the acid-base modifier
It is so that the dissolving of described pharmaceutical composition water for injection contains the molten of 0.05~0.15g of sodium fusidate in being made every 1ml solution
During liquid, determined according to the method under Chinese Pharmacopoeia annex VI H of version two in 2010, the pH value of the solution is 7.5 to 9.0, example
Such as the pH value of the solution is 8.0 to 9.0, and the pH value of such as solution is 8.0 to 8.5.
The pharmaceutical composition of any embodiment, its solid in solution before freeze-drying according to a first aspect of the present invention
Thing content is 5~30% (w/v), such as 7.5~25% (w/v), such as 10~25% (w/v).
The pharmaceutical composition of any embodiment, wherein sodium fusidate, neutral amino acid according to a first aspect of the present invention
With 5~30% (w/v) that the weight sum of basic amino acid accounts for liquor capacity before freeze-drying, such as 7.5~25% (w/v),
Such as 10~25% (w/v).
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, its with water for injection redissolve to substantially with
Solution identical volume before freeze-drying, the solid content in resulting solution is 5~30% (w/v), such as 7.5~25%
(w/v), such as 10~25% (w/v).
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, its with water for injection redissolve to substantially with
The weight sum of solution identical volume before freeze-drying, wherein sodium fusidate, neutral amino acid and basic amino acid accounts for multiple
5~30% (w/v) of molten liquor capacity, such as 7.5~25% (w/v), such as 10~25% (w/v).
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein moisture are less than 10%, preferably
Less than 8%, preferably shorter than 5%, more preferably less than 3%.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein also optionally including lyophilized figuration
Agent, is selected from mannitol, lactose, sorbierite, sucrose etc..Their amount can be by those skilled in the art according to general
Empirically determined.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein also including trehalose
(Trehalose)。
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein with the husband west ground of every 0.5 weight portion
Sour sodium meter, comprising trehalose amount be 0.05~0.2 weight portion, such as 0.05~0.15 weight portion, 0.05~0.1 weight
Part.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is substantially by including the steps
Prepare：
A () takes the active component and neutral amino acid and basic amino acid of recipe quantity, add appropriate water for injection, makes molten
Solution, being optionally added into trehalose makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 9.0, such as pH value 8.0 to 9.0 with acid-base modifier (such as acid solution or aqueous slkali) if necessary,
Such as pH value 8.0 to 8.5；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
The filtered filter of the pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein step (c) gained
Liquid, wherein solid content are 5~30% (w/v), such as 7.5~25% (w/v), such as 10~25% (w/v).
The pharmaceutical composition of any embodiment, wherein step (a) the appropriate injection according to a first aspect of the present invention
Water is about the 70~90% of water for injection recipe quantity.
The pharmaceutical composition of any embodiment, wherein adds injection described in step (b) according to a first aspect of the present invention
Water to its recipe quantity refer to add water to cause solution in active component concentration up to 0.05~0.15g/ml, such as concentration reaches
0.0625~0.125g/ml.
The pharmaceutical composition of any embodiment, wherein step (a) activated carbon dosage according to a first aspect of the present invention
It is the 0.05%~1% of solution weight, preferably 0.05%~0.5%.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein described in step (b) acid solution and
Aqueous slkali is to use the aqueous solution being configured to selected from following pH adjusting agent：NaOH, potassium hydroxide, sodium dihydrogen phosphate, phosphorus
Sour disodium hydrogen, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.The concentration of these aqueous solution
It is well known to a person skilled in the art such as 1~10%, such as 2%~5%.
The pharmaceutical composition of any embodiment, wherein removes institute after moisture according to a first aspect of the present invention in step (c)
Moisture is less than 10%, preferably shorter than 8%, preferably shorter than 5%, more preferably less than 3% in obtaining freeze-drying material.
Further, second aspect present invention provides the pharmaceutical composition for preparing sodium fusidafe as injection powder-injection
The method of (such as first aspect present invention any embodiment described pharmaceutical composition), described pharmaceutical composition includes husband west ground
Sour sodium, neutral amino acid and basic amino acid；The method is comprised the following steps：
A () takes the active component and neutral amino acid and basic amino acid of recipe quantity, add appropriate water for injection, makes molten
Solution (being optionally added into other auxiliary materials such as trehalose makes dissolving), adds activated carbon, stirs, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 7.5 to 9.0, such as pH value 8.0 to 9.0 with acid-base modifier (such as acid solution or aqueous slkali) if necessary,
Such as pH value 8.0 to 8.5；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
The filtered filtrate of the method for any embodiment according to a second aspect of the present invention, wherein 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 any embodiment according to a second aspect of the present invention, wherein step (a) the appropriate water for injection are notes
Penetrate about 70~90% with water recipe quantity.
The method of any embodiment according to a second aspect of the present invention, wherein step (b) benefit injects water to it
Recipe quantity refers to add water to cause the concentration of active component in solution up to 0.05~0.15g/ml, such as concentration up to 0.0625~
0.125g/ml。
The method of any embodiment according to a second aspect of the present invention, wherein step (a) activated carbon dosage is solution
The 0.05%~1% of weight, preferably 0.05%~0.5%.
The method of any embodiment, acid solution and aqueous slkali wherein described in step (b) according to a second aspect of the present invention
It is to use the aqueous solution being configured to selected from following pH adjusting agent：NaOH, potassium hydroxide, sodium dihydrogen phosphate, phosphoric acid hydrogen two
Sodium, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.The concentration of these aqueous solution is ability
Known to field technique personnel, such as 1~10%, such as 2%~5%.
The method of any embodiment, wherein removes gained freezing after moisture according to a second aspect of the present invention in step (c)
Moisture is less than 10%, preferably shorter than 8%, preferably shorter than 5%, more preferably less than 3% in dried material.
The method of any embodiment according to a second aspect of the present invention, wherein the neutral amino acid is selected from：Glycine, third
Propylhomoserin, leucine, isoleucine, valine, cystine, cysteine, methionine, threonine, serine, phenylalanine,
Tyrosine, tryptophan, proline, methionine and hydroxyproline and combinations thereof.
The method of any embodiment according to a second aspect of the present invention, with every 0.5 weight wherein in described pharmaceutical composition
Part sodium fusidate meter, comprising neutral amino acid amount be 0.05~0.5 weight portion, such as 0.05~0.3 weight portion,
0.05~0.25 weight portion.
The method of any embodiment according to a second aspect of the present invention, wherein the basic amino acid is selected from：Arginine, rely
Propylhomoserin, histidine and combinations thereof.
The method of any embodiment according to a second aspect of the present invention, with every 0.5 weight wherein in described pharmaceutical composition
Part sodium fusidate meter, comprising basic amino acid amount be 0.05~0.5 weight portion, such as 0.075~0.3 weight portion,
0.1~0.25 weight portion.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition is made often with water dissolves
When containing the solution of 0.05~0.15g of sodium fusidate in 1ml solution, the pH value of the solution is 7.5 to 9.0, such as solution
PH value is 8.0 to 9.0, and the pH value of such as solution is 8.0 to 8.5.
The method of any embodiment according to a second aspect of the present invention, wherein the species of the acid-base modifier is by special
Limitation, as long as it can be by the freeze drying powder injection (and/or will prepare intermediate during the freeze drying powder injection is prepared)
PH value is adjusted to desired scope.In one embodiment, the acid-base modifier is selected from NaOH, hydroxide
Potassium, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.
The method of any embodiment according to a second aspect of the present invention, wherein the consumption of the acid-base modifier is so that
Described pharmaceutical composition with water for injection redissolve to substantially with freeze-drying before solution identical volume, resulting solution is according in
Method under state's pharmacopeia annex VI H of version two in 2010 is determined, and the pH value of the solution is 7.5 to 9.0, such as solution
PH value is 8.0 to 9.0, and the pH value of such as solution is 8.0 to 8.5.
The method of any embodiment according to a second aspect of the present invention, wherein the consumption of the acid-base modifier is so that
When the dissolving of described pharmaceutical composition water for injection is made in every 1ml solution the solution containing 0.05~0.15g of sodium fusidate, root
Determined according to the method under Chinese Pharmacopoeia annex VI H of version two in 2010, the pH value of the solution is 7.5 to 9.0, and for example this is molten
The pH value of liquid is 8.0 to 9.0, and the pH value of such as solution is 8.0 to 8.5.
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition is molten before freeze-drying
Solid content in liquid is 5~30% (w/v), such as 7.5~25% (w/v), such as 10~25% (w/v).
The method of any embodiment according to a second aspect of the present invention, sodium fusidate wherein in described pharmaceutical composition,
The weight sum of neutral amino acid and basic amino acid accounts for 5~30% (w/v) of liquor capacity before freeze-drying, such as 7.5~
25% (w/v), such as 10~25% (w/v).
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition water for injection redissolves
To substantially with freeze-drying before solution identical volume, solid content in resulting solution is 5~30% (w/v), for example
7.5~25% (w/v), such as 10~25% (w/v).
The method of any embodiment according to a second aspect of the present invention, wherein described pharmaceutical composition water for injection redissolves
To substantially with freeze-drying before solution identical volume, the wherein weight of sodium fusidate, neutral amino acid and basic amino acid
Amount sum accounts for 5~30% (w/v), such as 7.5~25% (w/v), such as 10~25% (w/v) for redissolving liquor capacity.
The method of any embodiment according to a second aspect of the present invention, wherein moisture is less than in described pharmaceutical composition
10%, preferably shorter than 8%, preferably shorter than 5%, more preferably less than 3%.
The method of any embodiment, also includes trehalose according to a second aspect of the present invention wherein in described pharmaceutical composition
(Trehalose)。
The method of any embodiment according to a second aspect of the present invention, with every 0.5 weight wherein in described pharmaceutical composition
Part sodium fusidate meter, comprising trehalose amount be 0.05~0.2 weight portion, such as 0.05~0.15 weight portion, 0.05
~0.1 weight portion.
Any technical characteristic that any embodiment of either side of the present invention or the either side has is equally applicable
Any embodiment of other any embodiments or other either sides, as long as they will not be conflicting, certainly mutual
Between where applicable, if necessary can individual features be made with appropriate modification.Make into one with feature to various aspects of the present invention below
The description of step.
All documents recited in the present invention, their full content is incorporated herein by reference, and if these are literary
Offer expressed implication with it is of the invention inconsistent when, be defined by statement of the invention.Additionally, the various terms that use of the present invention and
Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and
Phrase is described in more detail and explains, the term and phrase for referring to if any inconsistent with common art-recognized meanings, with institute's table of the present invention
The implication stated is defined.
It is further described to various aspects of the present invention below.
In the method for the invention step, although its description specific steps in some details or language description on
The step of described in the preparation example of following detailed description part, is otherwise varied, however, those skilled in the art are according to this
The detailed disclosure of invention full text can summarize above the method for the invention step completely.
In the present invention, if not otherwise indicated, it is according to the present invention during amount of the relevant material in the various materials of measure
【HPLC methods】Carry out.In the present invention, if not otherwise indicated, in the material for determining various compositions active component content
When, it is according to the present invention【HPLC methods】Carry out.
The preparation process of freeze-drying powder-injection is well known to a person skilled in the art pharmaceutical technology, such as following lyophilized song
Two kinds of schematical freeze-drying curves shown in line A and freeze-drying curve B：
In preparing the instantiation in freeze-drying powder-injection below, if not otherwise specified, lyophilized song used
Line is freeze-drying curve A.
Moisture in freeze-drying powder-injection is general below 8%, preferably shorter than 5%, more preferably less than 4%.
Moisture control can be controlled by appropriate adjustment freeze-drying program.Moisture in the freeze-drying powder-injection can be according to perhaps
Many known methods are determined, such as dry weight-loss method.
When freeze drying powder injection of the present invention is prepared, in the liquid prepared, solid content is 5~30% (w/v), for example
7.5~25% (w/v), such as 10~25% (w/v).Because freeze drying powder injection is typically to carry out freezing in tubulose cillin bottle to do
It is dry to obtain, skilled artisan understands that this product is obtaining finished product even before for doctor's use, typically each it is presented one
Individual round pie, although lecture is fewer than the volume of original aqueous solution in the volume theory of the cake (slightly reduce), but generally this
Plant to reduce and will not generally narrow down to raw water liquor capacity 50%, it will usually be more logical between the 80-120% of raw water liquor capacity
Often between the 90-100% of raw water liquor capacity, and it is (main that raw water liquid level of solution vestige can be observed from finished product cillin bottle
Body pie because freeze reduce after remain in liquid level vestige in bottle wall, even if the dried frozen aquatic products in cillin bottle because of a variety of causes for example
Collision etc. reason and be in powdered, still can generally retain original liquid level vestige), vestige can also estimate the freezing accordingly
Aqueous solution volume of the dry compositions before freeze-drying.Therefore, although the present invention is to provide a kind of substantially anhydrous cold
Dry powder-injection is freezed, but it still can be substantially estimated according to the powder-injection when preparing, at least started in freeze-drying
Medicine liquid volume before, the weight for drying end-product in the volume estimated according to this and cillin bottle, can also calculate
When preparing freeze drying powder injection of the present invention, the content of the solid content in the liquid prepared.Therefore, according to a first aspect of the present invention
Freeze drying powder injection, its prepare when liquid solid content be 5~30% (w/v), such as 7.5~25% (w/v), for example
10~25% (w/v).
Term " solid content " refer to solid matter (such as reactive compound of the present invention and whole excipient used,
Weight/gram) be added in solvent (such as water for injection), obtain a solution after dissolving, the weight of the solid matter divided by
The percentage (weight/volume percentage, such as g/100ml) of whole liquor capacity.For example in the present invention, with 0.5g active ingredients
Other solid contents of thing and a total of about 0.3g add appropriate aqueous solution for injection, are configured to the solution that final volume is 4ml, its solid content
Content is 20%.
In the present invention, symbol %, according to the linguistic context that it is used, can have skilled addressee readily understands that
Implication.For example when solid content is referred to, the symbol represents the percentage (w/v, such as g/100ml) of weight/volume；And example
Such as in " water content " in referring to freeze-drying powder-injection, below 8%, now symbol % represents weight to such as water content
The percentage (w/w, g/100g) of amount/weight.In general, when solid disperses in a liquid, % represents weight/volume percentage
Number；In solid dispersion in solids or during liquid dispersion (such as the water content of powder pin) in solids, % represents w/w
Percentage.In other cases, unless otherwise noted, symbol % represents w/w percentage.
It is as well known to those skilled in the art when liquid of the invention is prepared, the e.g., from about miillpore filter of 0.45um can be used
Coarse filtration filtering is carried out, before liquid is filled in cillin bottle, it is possible to use e.g., from about the miillpore filter of 0.22um carries out essence
Filtration filter is with degerming, it may be necessary to which filtering is multiple.
Powder-injection of the invention, it is redissolved with water for injection, typically redissolves the time in 30 seconds, preferably 20
In second, more preferably in 15 seconds.
Freeze drying powder injection of the invention, it is made in every 1ml the solution containing 0.05~0.15g of reactive compound of water
And determined according to the method under Chinese Pharmacopoeia annex VI H of version two in 2010, the pH value of the solution is 7.5 to 9.0, for example
The pH value of the solution is 8.0 to 9.0, and the pH value of such as solution is 8.0 to 8.5.
The freeze drying powder injection that the present invention is provided can be preserved at least 24 months in cool dark place, can be met general freezing and be done
The Storage Requirement of dry powder-injection.
It has been found that freeze-drying powder-injection of the present invention has good pharmaceutical properties for example with excellent chemically stable
Property.
The sodium fusidafe as injection freeze-drying powder-injection that the present invention is provided, its active component is sodium fusidate.This
Invention injection freeze-drying powder-injection can be dissolved using classical sterile buffer, then again with 5% glucose injection
Or 0.9% chloride injection solution dilution, for clinical infusion be administered.In the present invention, if not otherwise specified, use
The sterile buffer composition for arriving is as follows：Disodium ethylene diamine tetraacetate 5mg, disodium phosphate dihydrate 196mg, citric acid
10mg, water adds to 10ml.In the present invention, if not otherwise specified, carried out as follows in its Clinical practice or experiment：
The injection powder pin containing active component 0.5g is dissolved in the aseptic buffer solution appended by 10 milliliters, then use sodium chloride injection
Or 5% glucose injection be diluted to 250-500 milliliters of venoclysis.
Freeze-drying powder-injection of the present invention clinically can be used to be caused by various sensitive bacterials, especially staphylococcus
Various infection, such 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：The patient that intravenous injection is applied to should not be administered orally or gastrointestinal absorption is bad.Into
People：0.5 gram (1 bottle), three times a day.Children and baby：20 mg kg of body weight/day, point 3 administrations.
Typical usage and dosage：Take this product injection powder pin 1 bottle (0.5 gram) and be dissolved in the aseptic buffer solution appended by 10 milliliters
In, then it is diluted to 250-500 milliliters of venoclysis with sodium chloride injection or 5% glucose injection.During every bottle of infusion
Between should not be less than 2-4 hours.This product should be input into blood flow well, the vein being relatively large in diameter, or Central catheterization input, to reduce
There is the danger of venospasm and thrombophlebitis.Venoclysis liquid should be finished after preparing in 24 hours.Not diluted
This product solution must not directly be injected intravenously.To avoid local tissue damage, this product also must not intramuscular injection or hypodermic injection.According to
The characteristics of this product is metabolized and drains, renal insufficiency and hemodialysis patient need not adjust dosage using this product, and this product is saturating
Analysis elimination amount is not also high.
Metabolism and drainage properties due to this product, when long-term, high-dose medication or this product, to combine other discharge approach similar
During medicine (such as lincomycin or rifampin), liver function should be inspected periodically to dyshepatia and the abnormal patient of biliary tract.In body
During outer experiment, this product can replace bilirubin on albumin binding site.The clinical meaning of this metalepsis is unclear, newly
Raw youngster after this product using also not having found nuclear icterus.But when premature, jaundice, acid poisoning and serious sick and weak neonate use this product
This factor need to be noticed.This product intravenous injection can not be with kanamycins, gentamicin, vancomycin, cefaloridine or hydroxyl benzyl
Penicillin mixes, and this product can not also mix with whole blood, Freamine Ⅲ or containing calcium solution.When the pH of solution is less than 7.4, this product
Can precipitate.
The present invention provide sodium fusidafe as injection freeze-drying powder-injection by suppress bacterium protein synthesize and
Produce bactericidal action.This product has powerful antibacterial action to a series of gram-positive bacteriums.Staphylococcus, including to mould
The bacterial strain of element, methicillin and other antibiotic resistances, it is extremely sensitive to this product.Other of Fusidic Acid and Clinical practice resist
Without cross resistance between bacterium medicine.
The sodium fusidafe as injection freeze-drying powder-injection that the present invention is provided has fabulous tissue penetration capacity, in body
It is interior widely distributed.Clinically particular, it is important that this product not only has high concentration in the tissue that blood supply is enriched, even if in blood
Pipe similarly has high concentration in being distributed less tissue.It is known in fester, it is sputum, soft tissue, heart, bone tissue, synovia, dead
Osteocomma, burn scab, brain abscess and intraocular, the concentration of this product exceed it to staphylococcic minimal inhibitory concentration (0.03-0.16
Mcg/ml).
The sodium fusidafe as injection freeze-drying powder-injection that the present invention is provided mainly is discharged in liver metabolism by bile,
Almost without RE.This product toxicity is extremely low, without cross anaphylaxis and other antibacterials of Clinical practice between, therefore this
Product can be used to treat the patient to the taboo of other antibiotic, such as to penicillin or other antibiotic allergy sufferers.To because serious or deep
Portion infect and when needing long-time medication, it is proposed that sodium fusidate and other antistaphylohemolysin drug combinations are reducing the product of drug resistance
It is raw.Sodium fusidate can with the PCs of penicillin resistant enzyme, cephalosporins, erythromycin, aminoglycoside, lincomycin,
The effect that rifampin or vancomycin are used in combination and can be added or acted synergistically.
Specific embodiment
The present invention can be conducted further description by the following examples, however, the scope of the present invention is not limited
In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention
Various change and modification are carried out to the present invention.The present invention to used in experiment to material and test method carry out generality
And/or specific description.Although for realize many materials that the object of the invention used and operating method be it is known in the art that
But the present invention is still described in detail as far as possible herein.Following examples further illustrate the present invention, rather than limiting this hair
It is bright.
Hereafter preparation process in order to citing purpose, and the comparability based on each citing and make some specific description,
Those skilled in the art can therefrom summarize the method that the present invention prepares freeze drying powder injection that obtains according to existing knowledge completely.Under
Face prepares in various compositions with liquid, and if not otherwise indicated, every batch is always 5000ml with liquid measure；But list formula and prepare
During process, for powder-injection, with the composition of every 500mg parts of active component and other materials of corresponding weight portion illustrate formula and
Preparation method.Either liquid drugs injection or powder pin, in packing, every bottle is 500mg containing active component.When with liquid, when using acid
It is 2M hydrochloric acid solutions or 2M sodium hydroxide solutions during alkali conditioning agent (i.e. pH adjusting agent), is using the basis of the auxiliary agent
On, the amount of the acid-base modifier is the pH value for making the liquid before freeze-drying in the range of 8.0~8.5.
In tests below, if not otherwise indicated, during using charcoal absorption, consumption is the amount commonly used in production, i.e.,
0.1% (adding activated carbon 0.1g in i.e. per 100ml liquids).In tests below, when preparing freeze drying powder injection, the activity for using
Composition is that (it is according to the present invention with a collection of bulk drug【HPLC methods】Checked, impurity G contents 0.17%), unless otherwise indicated.
【HPLC methods】：
Solvent mixture：Methyl alcohol -5g/L phosphoric acid solutions-acetonitrile (10:40:50V/V/V)；
Test solution：Will be equivalent to active component 25mg sample to be tested (raw material or powder-injection) be dissolved in solvent mix
In compound, then 10.0mL is diluted to the solvent mixture；
Reference solution (a)：2mg peaks discriminating Fusidic Acid (wherein containing impurity G) is dissolved in the solvent mixture,
Again 1.0mL is diluted to the solvent mixture；
Reference solution (b)：Take test solution 1.0mL solvent mixtures and be diluted to 100.0mL, obtain final product；
Reference solution (c)：Take reference solution (b) 1.0mL solvent mixtures and be diluted to 10.0mL, obtain final product；
Chromatographic column：Column length 0.15m,Fixing phase is the octadecylsilane base bonded silica gel (3.5 μm) of end-blocking,
Column temperature is 30 DEG C；
Mobile phase：Mobile phase A is methanol-acetonitrile -5g/L phosphoric acid solutions (20:40:40V/V/V), Mobile phase B is 5g/L phosphorus
Acid solution-methanol-acetonitrile (10:20:70V/V/V), eluted according to 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, Detection wavelength 235nm；
Sample size：20μL；
Impurity differentiates：Reflected with Fusidic Acid gained chromatogram and reference solution (a) gained chromatogram using peak discriminating
Other Fusidic Acid and impurity G, wherein Fusidic Acid retention time about 18min, are calculated, the phase of impurity G on the basis of Fusidic Acid
0.82 is about to retention time.
For this area, for a kind of acceptable sodium fusidate as bulk drug, wherein impurity G is relative to work
Property composition amount should be less than 0.7%.
Wherein impurity G is the material with following chemical constitution：
Its chemistry is entitled：ent-(17Z)-16α-(acetyloxy)-11β-hydroxy-4β,8,14-trimethyl-3-
oxo-18-nor-5β,10α-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.
Preparation method：
A () takes the active component and neutral amino acid and basic amino acid of recipe quantity, add appropriate water for injection, makes molten
Solution, adds activated carbon, stirs, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
Water for injection wherein mentioned in prescription is removed after freeze-dried, similarly hereinafter.
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.
Preparation method：
A () takes the active component and neutral amino acid and basic amino acid of recipe quantity, add appropriate water for injection, makes molten
Solution, adds activated carbon, stirs, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying (freeze-drying curve B) removing moisture, tamponade, i.e.,
.
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.
Preparation method：
A () takes active component and mannitol, the neutral amino acid and basic amino acid of recipe quantity, add appropriate injection
Water, makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
Water for injection wherein mentioned in prescription is removed after freeze-dried, similarly hereinafter.
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.
Preparation method：
A () takes active component and lactose, the neutral amino acid and basic amino acid of recipe quantity, add appropriate injection
Water, makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
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.
Preparation method：
A () takes the active component and neutral amino acid and basic amino acid of recipe quantity, add appropriate water for injection, makes molten
Solution, adds activated carbon, stirs, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
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.
Preparation method：
A () takes the active component and neutral amino acid and basic amino acid of recipe quantity, add appropriate water for injection, makes molten
Solution, adds activated carbon, stirs, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
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.
Preparation method：
A () takes the active component and neutral amino acid and basic amino acid of recipe quantity, add appropriate water for injection, makes molten
Solution, adds activated carbon, stirs, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
Embodiment 8：Prepare sodium fusidate freezing-dried powder injection pharmaceutical composition
Formula：
Sodium fusidate 0.5g,
Disodium hydrogen phosphate 98mg,
Citric acid 5mg,
Disodium ethylene diamine tetraacetate 2.5mg,
Mannitol 120mg,
Water for injection 6ml.
Preparation method：
4/5 recipe quantity water for injection is taken, recipe quantity disodium ethylene diamine tetraacetate is added, stirring and dissolving adds recipe quantity
Mannitol, disodium hydrogen phosphate and citric acid stirring and dissolving completely, cool the sodium fusidate that recipe quantity is added to room temperature, stirring
Dissolving, adds to the full amount of water for injection.Add in injection special-purpose activated charcoal to liquid, stir 30min, decarbonization filtering.0.22um is micro-
Hole filter membrane refined filtration is degerming, and liquid drug is partly jumped a queue, freeze-drying, and tamponade Zha Gai is obtained 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.
Preparation method：
4/5 recipe quantity water for injection is taken, is let cool to 30 DEG C, add the glycine and arginine of recipe quantity, stirring and dissolving is adjusted
The pH of whole solution is 8.0~9.0, adds the active component of recipe quantity, and stirring and dissolving adds to the full amount of water for injection.Add injection
In special-purpose activated charcoal to liquid, 15min, decarbonization filtering are stirred.0.22um~0.45um miillpore filter refined filtrations are degerming, filling medicine
Liquid, partly jumps a queue, freeze-drying, tamponade Zha Gai, obtains 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.
Preparation method：
4/5 recipe quantity water for injection is taken, is let cool to 30 DEG C, add glycine, arginine and the mannitol of recipe quantity, stirring
Dissolving, the pH for adjusting solution is 8.0~9.0, adds the active component of recipe quantity, and stirring and dissolving adds to the full amount of water for injection.Plus
Enter in injection special-purpose activated charcoal to liquid, stir 15min, decarbonization filtering.0.22um~0.45um miillpore filter refined filtrations are degerming, fill
Powder charge liquid, partly jumps a queue, freeze-drying, tamponade Zha Gai, obtains 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.
Preparation method：
The mannitol and arginine of recipe quantity are weighed, water for injection 8ml is added, stirring is allowed to dissolve, and solution temperature is down to
Less than 60 DEG C, the sodium fusidate of recipe quantity is added, be stirred continuously and be allowed to be completely dissolved, add the 0.5% (W/ for preparing total amount
V) injection activated carbon, stirring stands 25 minutes, filters decarburization, injects water to standby after 8ml.Above-mentioned solution is used
0.22um miillpore filters refined filtration is clear and bright to filtrate, and after the inspection of semifinished product is qualified, packing, embedding leads it in 20ml cillin bottles
Medicine content is 500mg, through (- 40 DEG C) of low temperature freeze 3 hours, primary drying temperature -25 DEG C 4 hours, 0 DEG C 7 hours, 18 DEG C 7 small
When, 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,
Disodium ethylene diamine tetraacetate 4mg.
Preparation method：
The mannitol and arginine of recipe quantity are weighed, water for injection 8ml is added, stirring is allowed to dissolve, and solution temperature is down to
Less than 60 DEG C, the sodium fusidate of recipe quantity is added, be stirred continuously and be allowed to be completely dissolved, add the 0.5% (W/ for preparing total amount
V) injection activated carbon, stirring stands 25 minutes, filters decarburization, injects water to standby after 9ml.Above-mentioned solution is used
0.22um miillpore filters refined filtration is clear and bright to filtrate, and after the inspection of semifinished product is qualified, packing, embedding leads it in 20ml cillin bottles
Medicine content is 500mg, through (- 40 DEG C) of low temperature freeze 3 hours, primary drying temperature -25 DEG C 4 hours, 0 DEG C 7 hours, 18 DEG C 7 small
When, 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.
Preparation method：
The arginine and citric acid of recipe quantity are weighed, water for injection 5ml is added, stirring is allowed to dissolve, and solution temperature is down to
Less than 25 DEG C, the sodium fusidate of recipe quantity is added, be stirred continuously and be allowed to be completely dissolved, add the 0.1% (W/ for preparing total amount
V) injection activated carbon, stirring stands 20 minutes, filters decarburization, standby after adding to the full amount of water for injection.Above-mentioned solution is used
0.22 μm of miillpore filter refined filtration is clear and bright to filtrate, and after the inspection of semifinished product is qualified, packing, embedding leads it in 25ml cillin bottles
Medicine content is 500mg, through (- 40 DEG C) of low temperature freeze 3 hours, sublimation temperature -10 DEG C 6 hours, 0 DEG C 6 hours, redrying
Temperature 30 DEG C 6 hours, after terminating, rolls lid, obtains 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.
Preparation method：
The arginine and citric acid of recipe quantity are weighed, water for injection 10ml is added, stirring is allowed to dissolve, and solution temperature is down to
Less than 25 DEG C, the sodium fusidate of recipe quantity is added, be stirred continuously and be allowed to be completely dissolved, add the 0.1% (W/ for preparing total amount
V) injection activated carbon, stirring stands 20 minutes, filters decarburization, standby after adding to the full amount of water for injection.Above-mentioned solution is used
0.22 μm of miillpore filter refined filtration is clear and bright to filtrate, and after the inspection of semifinished product is qualified, packing, embedding leads it in 30ml cillin bottles
Medicine content is 500mg, by Fusidic Acid sodium solution pre-freeze to less than -30 DEG C, is maintained 2-8 hours, while condensing indoor temperature drop
To -35 DEG C~-50 DEG C, start vavuum pump, under vacuum, raise products temperature and distilled up to -20 DEG C~-8 DEG C, until
Exist without ice crystal, then the dry removing residual moisture that heats up, make lyophilized moisture content of finished products less than 3%, after terminating, lid is rolled, obtain finished product.
Embodiment 15：Prepare sodium fusidate freezing-dried powder injection pharmaceutical composition
Formula：
Sodium fusidate 500mg,
Dimercaprol dimercaptopropanol 20mg,
Arabo-ascorbic acid 10mg,
Cysteine hydrochloride 15mg,
Phenylalanine 10mg,
Arginine 100mg,
Water for injection, adds to 5ml.
Preparation method：
Dimercaprol dimercaptopropanol, arabo-ascorbic acid, cysteine hydrochloride, phenylalanine are weighed, it is total with less than 35 DEG C waters for injection
80% stirring and dissolving of amount, then room temperature is cooled to by sodium fusidate in stirring addition dissolving, it is subsequently adding arginine tune
Section pH value is 8.6, then adds remaining water for injection, is subsequently added into activated carbon stirring, is put into filtrate after filtering decarbonization cold
Freeze in drying box, be chilled to less than -35 DEG C, be incubated more than 1.5 hours, open vavuum pump, 0 DEG C sublimes up into ice heading line off, then
30 DEG C are warming up to, insulation is drying to obtain sodium fusidate freezing-dried powder injection for 12 hours, and 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 of 500mg containing active component.
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.
Preparation method：
A () takes active component and trehalose, the neutral amino acid and basic amino acid of recipe quantity, add appropriate injection
Water, makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
Water for injection wherein mentioned in prescription is removed after freeze-dried, similarly hereinafter.
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.
Preparation method：
A () takes active component and trehalose, the neutral amino acid and basic amino acid of recipe quantity, add appropriate injection
Water, makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying (freeze-drying curve B) removing moisture, tamponade, i.e.,
.
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.
Preparation method：
A () takes active component and mannitol, trehalose, neutral amino acid and the basic amino acid of recipe quantity, add suitable
Amount water for injection, makes dissolving, adds activated carbon, stirs, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
Water for injection wherein mentioned in prescription is removed after freeze-dried, similarly hereinafter.
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.
Preparation method：
A () takes active component and trehalose, lactose, neutral amino acid and the basic amino acid of recipe quantity, add appropriate
Water for injection, makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
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.
Preparation method：
A () takes active component and trehalose, the neutral amino acid and basic amino acid of recipe quantity, add appropriate injection
Water, makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
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.
Preparation method：
A () takes active component and trehalose, the neutral amino acid and basic amino acid of recipe quantity, add appropriate injection
Water, makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
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.
Preparation method：
A () takes active component and trehalose, the neutral amino acid and basic amino acid of recipe quantity, add appropriate injection
Water, makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
Embodiment 28：Prepare sodium fusidate freezing-dried powder injection pharmaceutical composition
Formula：
Sodium fusidate 0.5g,
Disodium hydrogen phosphate 98mg,
Citric acid 5mg,
Disodium ethylene diamine tetraacetate 2.5mg,
Mannitol 120mg,
Trehalose 0.07g,
Water for injection 6ml.
Preparation method：
4/5 recipe quantity water for injection is taken, recipe quantity disodium ethylene diamine tetraacetate is added, stirring and dissolving adds recipe quantity
Trehalose, mannitol, disodium hydrogen phosphate and citric acid stirring and dissolving completely, cool the Fusidic Acid that recipe quantity is added to room temperature
Sodium, stirring and dissolving adds to the full amount of water for injection.Add in injection special-purpose activated charcoal to liquid, stir 30min, decarbonization filtering.
0.22um miillpore filter refined filtrations are degerming, and liquid drug is partly jumped a queue, freeze-drying, and tamponade Zha Gai is obtained 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.
Preparation method：
4/5 recipe quantity water for injection is taken, is let cool to 30 DEG C, add trehalose, glycine and the arginine of recipe quantity, stirring
Dissolving, the pH for adjusting solution is 8.0~9.0, adds the active component of recipe quantity, and stirring and dissolving adds to the full amount of water for injection.Plus
Enter in injection special-purpose activated charcoal to liquid, stir 15min, decarbonization filtering.0.22um~0.45um miillpore filter refined filtrations are degerming, fill
Powder charge liquid, partly jumps a queue, freeze-drying, tamponade Zha Gai, obtains 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.
Preparation method：
4/5 recipe quantity water for injection is taken, is let cool to 30 DEG C, add trehalose, glycine, arginine and the sweet dew of recipe quantity
Alcohol, stirring and dissolving, the pH for adjusting solution is 8.0~9.0, adds the active component of recipe quantity, and stirring and dissolving is injected water to
Full dose.Add in injection special-purpose activated charcoal to liquid, stir 15min, decarbonization filtering.0.22um~0.45um miillpore filter refined filtrations
Degerming, liquid drug is partly jumped a queue, freeze-drying, and tamponade Zha Gai is obtained 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.
Preparation method：
Trehalose, mannitol and the arginine of recipe quantity are weighed, water for injection 8ml is added, stirring is allowed to dissolve, solution temperature
Degree is down to less than 60 DEG C, adds the sodium fusidate of recipe quantity, is stirred continuously and is allowed to be completely dissolved, and adds and prepares total amount
0.5% (W/V) injection activated carbon, stirring stands 25 minutes, filters decarburization, injects water to standby after 8ml.Will be above-mentioned molten
Liquid is clear and bright to filtrate with 0.22um miillpore filters refined filtration, and after the inspection of semifinished product is qualified, packing, embedding makes in 20ml cillin bottles
Its drug content is 500mg, through (- 40 DEG C) of low temperature freeze 3 hours, 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,
Disodium ethylene diamine tetraacetate 4mg.
Preparation method：
Trehalose, mannitol and the arginine of recipe quantity are weighed, water for injection 8ml is added, stirring is allowed to dissolve, solution temperature
Degree is down to less than 60 DEG C, adds the sodium fusidate of recipe quantity, is stirred continuously and is allowed to be completely dissolved, and adds and prepares total amount
0.5% (W/V) injection activated carbon, stirring stands 25 minutes, filters decarburization, injects water to standby after 9ml.Will be above-mentioned molten
Liquid is clear and bright to filtrate with 0.22um miillpore filters refined filtration, and after the inspection of semifinished product is qualified, packing, embedding makes in 20ml cillin bottles
Its drug content is 500mg, through (- 40 DEG C) of low temperature freeze 3 hours, 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.
Preparation method：
Trehalose, arginine and the citric acid of recipe quantity are weighed, water for injection 5ml is added, stirring is allowed to dissolve, solution temperature
Degree is down to less than 25 DEG C, adds the sodium fusidate of recipe quantity, is stirred continuously and is allowed to be completely dissolved, and adds and prepares total amount
0.1% (W/V) injection activated carbon, stirring stands 20 minutes, filters decarburization, standby after adding to the full amount of water for injection.Will be above-mentioned
Solution is clear and bright to filtrate with 0.22 μm of miillpore filter refined filtration, after the inspection of semifinished product is qualified, packing, embedding in 25ml cillin bottles,
Make its drug content for 500mg, through (- 40 DEG C) of low temperature freeze 3 hours, sublimation temperature -10 DEG C 6 hours, 0 DEG C 6 hours, two
Secondary drying temperature 30 DEG C 6 hours, after terminating, rolls lid, obtains 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.
Preparation method：
Trehalose, arginine and the citric acid of recipe quantity are weighed, water for injection 10ml is added, stirring is allowed to dissolve, solution
Temperature is down to less than 25 DEG C, adds the sodium fusidate of recipe quantity, is stirred continuously and is allowed to be completely dissolved, and adds and prepares total amount
0.1% (W/V) injection activated carbon, stirring stands 20 minutes, filters decarburization, standby after adding to the full amount of water for injection.Will be above-mentioned
Solution is clear and bright to filtrate with 0.22 μm of miillpore filter refined filtration, after the inspection of semifinished product is qualified, packing, embedding in 30ml cillin bottles,
Make its drug content for 500mg, by Fusidic Acid sodium solution pre-freeze to less than -30 DEG C, maintain 2-8 hours, while in condensation chamber
Temperature is down to -35 DEG C~-50 DEG C, starts vavuum pump, under vacuum, raises products temperature and is risen up to -20 DEG C~-8 DEG C
China, exists until without ice crystal, then the dry removing residual moisture that heats up, and makes lyophilized moisture content of finished products less than 3%, after terminating, rolls lid, obtains
Finished product.
Embodiment 35：Prepare sodium fusidate freezing-dried powder injection pharmaceutical composition
Formula：
Sodium fusidate 500mg,
Dimercaprol dimercaptopropanol 20mg,
Arabo-ascorbic acid 10mg,
Cysteine hydrochloride 15mg,
Phenylalanine 10mg,
Arginine 100mg,
Trehalose 75mg,
Water for injection, adds to 5ml.
Preparation method：
Dimercaprol dimercaptopropanol, arabo-ascorbic acid, cysteine hydrochloride, phenylalanine, trehalose are weighed, is injected with less than 35 DEG C
80% stirring and dissolving of water total amount, then room temperature is cooled to by sodium fusidate in stirring addition dissolving, it is subsequently adding essence
Ammonia acid for adjusting pH value is 8.6, then adds remaining water for injection, activated carbon stirring is subsequently added into, by filtrate after filtering decarbonization
It is put into freeze drying box, is chilled to less than -35 DEG C, be incubated more than 1.5 hours, open vavuum pump, 0 DEG C sublimes up into ice line and disappears
Lose, then heat to 30 DEG C, insulation is drying to obtain sodium fusidate freezing-dried powder injection for 12 hours, and product is white crystalline powder
End.
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.
Preparation method：
A () takes active component and trehalose, the neutral amino acid and basic amino acid of recipe quantity, add appropriate injection
Water, makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
Water for injection wherein mentioned in prescription is removed after freeze-dried, similarly hereinafter.
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.
Preparation method：
A () takes active component and trehalose, the neutral amino acid and basic amino acid of recipe quantity, add appropriate injection
Water, makes dissolving, adds activated carbon, stirring, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying (freeze-drying curve B) removing moisture, tamponade, i.e.,
.
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.
Preparation method：
A () takes active component and mannitol, trehalose, neutral amino acid and the basic amino acid of recipe quantity, add suitable
Amount water for injection, makes dissolving, adds activated carbon, stirs, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component contains
Amount, is adjusted to pH value 8.0 to 8.5 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
Water for injection wherein mentioned in prescription is removed after freeze-dried, similarly hereinafter.
Test example 1：Determine the stability of each powder-injection
1st, in this test example, after the freeze-drying powder-injection obtained by each embodiment of measure is placed 5 months at 42 DEG C of temperature,
Wherein the content [42 DEG C, in May, can be described as high temperature average content, mg/ bottles, determine 10 bottles of average value] of active component relative to
When the sample processes the corresponding time at 20 DEG C active component content [20 DEG C, in May, can be described as normal temperature average content, mg/ bottles,
Determine 10 bottles of average value] percentage, i.e., remaining percentage (%), i.e.,
Wherein, high temperature average content (mg/ bottles) and normal temperature average content (mg/ bottles) are determined through HPLC methods after sample dissolves
And in every bottle for calculating active component content (10 bottles of averages).
Result shows that the remaining percentage (%) of embodiment 1-16, embodiment 21-38 whole powder-injection sample exists
Between 96.1%~100.3%, the remaining percentage (%) of such as Ex1 is 97.2%.This result shows, various samples are from work
Property component content change from the point of view of be no notable difference.
2nd, in addition, through placing the powder-injection of the whole embodiments of 5 months at 42 DEG C of temperature for more than, determining them 0
Impurity G contents during the moon, also determine their impurity G contents in May；In addition, for each sample, calculating it and experiencing this
Impurity G increases percentage before and after high-temperature treatment, wherein parameter " impurity G increase percentage " refer to for a certain powder pin sample its
Impurity G contents gained difference when impurity G contents subtract 0 month during May, then divided by impurity G contents at 0 month, multiplied by with 100%, institute
The percentage for obtaining.
Result shows：Impurity G content of whole samples at 0 month (equivalent to the powder-injection of original state) is 0.21%
In the range of~0.38%, after being processed through preparation processing, impurity G contents are had no significant change the whole samples of display, i.e., difference is matched somebody with somebody
The no significant difference in terms of the quality characterized with impurity G of side's gained powder-injection；Embodiment 1-16, embodiment 28, embodiment 31-
The impurity G of 38 whole powder-injection samples increases percentage in the range of 226%~362%；Embodiment 21-27, embodiment 29-30
The maximum single contaminant of whole powder-injection samples increases percentage in the range of 42%~63%；
Result above shows that, although its initial quality of powder-injection obtained in different formulations is substantially suitable, they are steady
Qualitative features are particularly the stability aspect characterized with impurity G and completely unexpected effect are presented, because place shown in the present invention
Variance it is different for obtain the powder-injection with different initial qualities be it will be appreciated by those skilled in the art that, but show
Stability difference can be explained clearly without any theory.Particularly only in both glycine and arginine simultaneously
In the presence of, it (is that a kind of this area needs extremely to close the medicine that impurity G can be just efficiently controlled after trehalose is added
A kind of impurity of note) growth during long-term preservation.Existing any theoretical explanation, people in the art cannot be used
Chemical stability relevance between the property and the impurity with impurity G chemical constitutions of the known above-mentioned auxiliary material of member, in fact
Teaching of the prior art in the absence of any this relevance.
Industrial applicability
Sodium fusidafe as injection powder-injection pharmaceutical composition of the invention has excellent pharmaceutical properties, clinically may be used
For treating the various infection caused by various sensitive bacterials, especially staphylococcus, such as osteomyelitis, septicemia, endocarditis,
The cystic fibrosis of repeated infection, pneumonia, skin and soft tissue infection, surgery and traumatic infection etc..
Claims (15)
1. the pharmaceutical composition of sodium fusidafe as injection powder-injection, it includes the weight portion of sodium fusidate 0.5, neutral amino acid
The weight portion of glycine 0.05 ~ 0.25, the weight portion of basic amino acids arginine 0.1 ~ 0.25, the weight portion of trehalose 0.05 ~ 0.1, with
And it is optional selected from following freeze-dried excipient：Mannitol, lactose；Its solid content in solution before freeze-drying is 10
~25%(w/v)。
2. pharmaceutical composition according to claim 1, it is made in every 1ml solution containing sodium fusidate 0.05 of water dissolves ~
During the solution of 0.15g, the pH value of the solution is 7.5 to 9.0.
3. pharmaceutical composition according to claim 1, it is made in every 1ml solution containing sodium fusidate 0.05 of water dissolves ~
During the solution of 0.15g, the pH value of the solution is 8.0 to 9.0.
4. pharmaceutical composition according to claim 1, it is made in every 1ml solution containing sodium fusidate 0.05 of water dissolves ~
During the solution of 0.15g, the pH value of the solution is 8.0 to 8.5.
5. pharmaceutical composition according to claim 1, wherein also include acid-base modifier, its be selected from NaOH, potassium hydroxide,
Sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.
6. pharmaceutical composition according to claim 5, the consumption of the acid-base modifier is so that described pharmaceutical composition is noted
Penetrate with water redissolve arrive with freeze-drying before solution identical volume, resulting solution is according to two annex VI of Chinese Pharmacopoeia version in 2010
Method under H is determined, and the pH value of the solution is 7.5 to 9.0.
7. pharmaceutical composition according to claim 5, the consumption of the acid-base modifier is so that described pharmaceutical composition is noted
Penetrate with water redissolve arrive with freeze-drying before solution identical volume, resulting solution is according to two annex VI of Chinese Pharmacopoeia version in 2010
Method under H is determined, and the pH value of the solution is 8.0 to 9.0.
8. pharmaceutical composition according to claim 5, the consumption of the acid-base modifier is so that described pharmaceutical composition is noted
Penetrate with water redissolve arrive with freeze-drying before solution identical volume, resulting solution is according to two annex VI of Chinese Pharmacopoeia version in 2010
Method under H is determined, and the pH value of the solution is 8.0 to 8.5.
9. pharmaceutical composition according to claim 5, the consumption of the acid-base modifier is so that described pharmaceutical composition is noted
Penetrate be made of water dissolves in every 1ml solution containing 0.05 ~ 0.15g of sodium fusidate solution when, according to Chinese Pharmacopoeia version in 2010
Method under two annex VI H is determined, and the pH value of the solution is 7.5 to 9.0.
10. pharmaceutical composition according to claim 5, the consumption of the acid-base modifier is so that described pharmaceutical composition is used
When water for injection dissolving is made in every 1ml solution the solution containing 0.05 ~ 0.15g of sodium fusidate, according to Chinese Pharmacopoeia 2010
Method under two annex VI H of version is determined, and the pH value of the solution is 8.0 to 9.0.
11. pharmaceutical compositions according to claim 5, the consumption of the acid-base modifier is so that described pharmaceutical composition is used
When water for injection dissolving is made in every 1ml solution the solution containing 0.05 ~ 0.15g of sodium fusidate, according to Chinese Pharmacopoeia 2010
Method under two annex VI H of version is determined, and the pH value of the solution is 8.0 to 8.5.
12. pharmaceutical compositions according to claim 1, it is redissolved with water for injection and arrived and solution identical body before freeze-drying
Product, the solid content in resulting solution is 10 ~ 25% (w/v).
13. pharmaceutical compositions according to claim 1, wherein moisture are less than 5%.
14. pharmaceutical compositions according to claim 1, wherein moisture are less than 3%.
15. methods for preparing the pharmaceutical composition of sodium fusidafe as injection powder-injection described in claim any one of 1-14, should
Method is comprised the following steps：
A () takes the active component and neutral amino acid and basic amino acid of recipe quantity, add appropriate water for injection, makes dissolving；
Adding trehalose makes dissolving, adds activated carbon, stirs, filtering decarbonization；
B () mends and injects water to its recipe quantity, stir, and determines solution ph and optional measure active component content,
Adjusted to pH value 7.5 to 9.0 with acid-base modifier if necessary；
C () is filling in cillin bottle by liquid aseptic filtration, freeze-drying removes moisture, and tamponade is obtained final product.
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| CN115463136B (en) * | 2021-12-16 | 2024-02-23 | 南京市儿童医院 | Application of fusidic acid or pharmaceutically acceptable salt thereof in preparation of medicines for preventing and treating chronic kidney disease renal interstitial fibrosis |
| CN114432250B (en) * | 2022-02-22 | 2022-10-04 | 深圳市泰力生物医药有限公司 | Method for stabilizing amorphous fusidic acid |
| TW202345825A (en) * | 2022-03-30 | 2023-12-01 | 大陸商四川海思科製藥有限公司 | Pharmaceutical composition for injection comprising cyclic lactam compound and method for preparing same |
| CN115267004A (en) * | 2022-08-09 | 2022-11-01 | 宣城菁科生物科技有限公司 | Method for detecting content of related substances in fusidic acid |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101143133A (en) * | 2007-10-12 | 2008-03-19 | 成都翰朗生物科技有限公司 | Sodium fusidate freezing-dried powder injection |
| CN102743342A (en) * | 2012-04-11 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Sodium fusidate lyophilized composition for injection |
| CN103169673A (en) * | 2013-04-11 | 2013-06-26 | 山东罗欣药业股份有限公司 | Sodium fusidate freeze-dried powder injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101143133A (en) * | 2007-10-12 | 2008-03-19 | 成都翰朗生物科技有限公司 | Sodium fusidate freezing-dried powder injection |
| CN102743342A (en) * | 2012-04-11 | 2012-10-24 | 江苏奥赛康药业股份有限公司 | Sodium fusidate lyophilized composition for injection |
| CN103169673A (en) * | 2013-04-11 | 2013-06-26 | 山东罗欣药业股份有限公司 | Sodium fusidate freeze-dried powder injection and preparation method thereof |
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Address after: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee after: Chengdu Tiantaishan Pharmaceutical Co.,Ltd. Address before: 611531 Tiantaishan Pharmaceutical Co., Ltd., 88 Tianxing Avenue, Qionglai City, Chengdu City, Sichuan Province Patentee before: CHENGDU TIANTAISHAN PHARMACEUTICAL Co.,Ltd. |
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Granted publication date: 20170616 |