CN105769756A - Sitafloxacin fumarate injection and preparation method thereof - Google Patents
Sitafloxacin fumarate injection and preparation method thereof Download PDFInfo
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- CN105769756A CN105769756A CN201410819608.7A CN201410819608A CN105769756A CN 105769756 A CN105769756 A CN 105769756A CN 201410819608 A CN201410819608 A CN 201410819608A CN 105769756 A CN105769756 A CN 105769756A
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Abstract
The invention discloses a sitafloxacin fumarate injection. Additive composition of the injection is simple. But stability is obviously raised under high temperature sterilization and high-light exposure, and the preparation can be effectively avoided from being precipitated out under a low-temperature condition during the storage process. The injection is composed of the following ingredients: sitafloxacin fumarate and methionine are used as main drugs; a cosolvent is one ingredient selected from aspartic acid, citric acid and lactic acid; a pH regulator is one ingredient selected from histidine, sodium citrate or disodium hydrogen phosphate; D-sorbitol is used as an antifreezing agent capable of greatly preventing low-temperature crystallization; and water for injection is also included. The injection can be applied in the form of a small-volume injection, a large-volume infusion or freeze-dried powder injection. During the preparation process of the injection, a specific addition order is applied such that dosage of the cosolvent for dissolving the main drug sitafloxacin fumarate is minimized as much as possible; and with addition of methionine and sorbitol, stability of the injection during high temperature sterilization, high-light exposure and low-temperature storage is raised. The preparation technology of the injection can completely meet industrial production and quality requirements.
Description
Technical field
The invention belongs to technical field of pharmaceuticals, relate to new fluoroquinolones antibiotic preparation, specifically a kind of fumaric acid Sitafloxacin hydrate injection and preparation method thereof.
Background technology
Sitafloxacin (sitafloxacin) is the first pharmacy Sankyo Co., Ltd (Daiichi
Sankyo) the broad spectrum quinolone class antimicrobial drug developed, this medicine is respectively provided with stronger antibacterial activity to gram positive bacteria, gram negative bacteria, the common resistance to fluoroquinolones bacterium of various clinical, mycoplasma and chlamydia etc..
The chemical name of sitafloxacin is 7-[4 (S)-amino-6-azaspiros [2,4] heptane-6-base] the chloro-6-of-8-fluoro-1-[(1R, 2S)-2-fluorine cyclopropyl]-4-oxo-Isosorbide-5-Nitrae-dihydroquinoline-3-carboxylic acid, there is the chemical constitution shown in following formula.Owing to there being cis (1R, 5R)-2-fluorine cyclopropylamine group in the chemical constitution of this compound, there is good pharmaco-kinetic properties, and untoward reaction is few
。
Research about the antibacterial activity in vitro of sitafloxacin shows, this product has broad-spectrum antibacterial action, not only gram negative bacteria there is antibacterial activity, and to gram positive bacteria (methicillin-resistant staphylococcus aureus, Methicillin-resistant Staphylococcus epidermidis), anaerobe (including bacteroides fragilis) and mycoplasma, chlamydia etc. have stronger antibacterial activity, and many clinical common bacterial strains of resistance to fluoroquinolones are also had good bactericidal action.This product tissue distribution is extensive, and the drug level in Various Tissues outside central nervous system is above serum drug level, therefore, is the single or important drugs of mixed cell infection such as treatment respiratory tract, urogenital tract, abdominal cavity and skin soft tissue.
In sitafloxacin water, dissolubility is low, needs to increase dissolubility by the way of hydrotropy；Sitafloxacin aqueous solution is the most unstable, and more unstable to the environment of illumination and heat, aqueous solution elapses in time and can produce certain degradation impurity, affects the toxicological profile of preparation.Present inventor's early stage is screened by salt form widely, it is thus achieved that the fumaric acid salt form that water solublity improves, and by 0.1mg/mL, sitafloxacin dissolubility in water is brought up to 1.6mg/mL.But this concentration still seems on the low side, can not preferably meet the quantity requirement of injection, particularly when preparing small-volume injection concentrated solution or lyophilizing minute hand, how to obtain a kind of concentration high, the Sitafloxacin hydrate injection of good stability becomes the pressing issues needing solution badly.
Patent CN01811696 reports the method for the sitafloxacin solution of a kind of resistance to illumination, and it is to be dissolved in acidic aqueous solution by sitafloxacin, addition about 0.5～the sodium chloride of 1% (w/w), avoids the generation of photolytic product to a certain extent.But, in order to meet the prescription of injection, terminal sterilization is necessary step, and this description necessary high temperature sterilize condition one word does not carries.This sitafloxacin sodium chloride injection, according to this literature method, is found after high temperature sterilize by present inventor, and color transition is buff, has related substance total amount to be significantly increased, and pH value declines.In addition, solubilized sitafloxacin is carried out so that the pH value of this injection must be maintained at degree (about 3.7～4.2) on the low side, and the pH value range being applicable to human vein injection is 4-9 owing to employing a large amount of hydrochloric acid, the most easily cause pain stimulation during injection, reduce the compliance of patient.
Patent CN201210060891 description part discloses several injection embodiment (see description embodiment 19～22) including principal agent fumaric acid sitafloxacin and different additives.We test according to this patent technique and formula, investigate its stability of solution further.Embodiment 19 and 20 is to be dissolved in fumaric acid sitafloxacin in the middle of water for injection and sodium-chloride water solution respectively being configured to simple injection.We have found that the two prescription injection increased and the phenomenon of progressively crystallize along with the storage time, solution is the most saturated；And work as through high temperature sterilize, or under the conditions of strong illumination, having related substance to increase a lot, appearance color turns deep, and particulate matter increases, and brings clinical safety hidden danger.The injection of embodiment 21 and 22 is owing to the addition of antioxidant sodium sulfite and cysteine, although the related substance increasing degree that has after high temperature sterilize diminishes, but still can not maintain the stability under illumination condition, Photodegradation Products increases, the most miscellaneous increase, color is the most filbert, it is seen that the light durability of embodiment 21 and 22 the two injection is poor.It addition, above four injections exist the problem of easy crystallize under low temperature is placed, it is unfavorable for storage and the transport of medicine.
Patent CN200910063772.9, in order to solve the problem of sitafloxacin water solublity and stability, adds substantial amounts of antioxidant, metal chelating agent, cosolvent, osmotic pressure regulator, surfactant in prescription.If being 0.1mg/mL according to sitafloxacin dissolubility in water, if required up the concentration of " every milliliter contain sitafloxacin 1～50mg " as described in that patent, the cosolvent added and the consumption of surfactant is big well imagines.And adjuvant used is the most, the potential hazard brought to human body is the biggest.Such as, metal ion chelation agent disodiumedetate has the risk causing human body blood calcium to reduce, surfactant Cremophor, sucrose laurate, and carbomer easily causes a series of clinical safety problems such as haemolysis.
Summary of the invention
Understanding according to above-mentioned, there is a series of unstable factor in aqueous in fumaric acid sitafloxacin, is particularly easily generated oxidation and illumination degrading impurity under high temperature and illumination condition, often occurs that medicinal liquid color becomes deep yellow, the problem that pH value instability and content decline.In view of the deficiencies in the prior art, it is an object of the invention to by the prescription of sitafloxacin injection and technique are carried out a large amount of screening test research, there is provided a kind of stability strong, it is possible to tolerance high temperature sterilize, Sitafloxacin hydrate injection of the condition such as strong illumination and low temperature storage and preparation method thereof.The first disclosed injection scheme of the present invention is as follows:
A kind of fumaric acid Sitafloxacin hydrate injection, it is characterised in that include principal agent fumaric acid sitafloxacin, methionine, and pharmaceutically acceptable cosolvent and pH adjusting agent.
Further, " fumaric acid sitafloxacin " refers to fumaric acid sitafloxacin anhydride or fumaric acid sitafloxacin monohydrate；Cosolvent is selected from Aspartic Acid, the one in citric acid and lactic acid；PH adjusting agent is selected from histidine, the one in sodium citrate or disodium hydrogen phosphate；Methionine is as solution stabilizer and the auxiliary reagent of hydrotropy, and its consumption is 0.5～1 times (w/w).
Further, antifreeze D-glucitol is also included.
Further, its application form is small-volume injection, large capacity transfusion injection, and freeze-dried powder.
As small-volume injection, its prescription can be optimized for further: it comprises the component of following w/v (g/mL):
Fumaric acid sitafloxacin 0.25-0.5%(is in terms of sitafloxacin)
Aspartic Acid 1～1.5%
Histidine is appropriate, regulates pH 5.5～6.5
Methionine 0.5～0.8%
Sorbitol 0.1%
Water for injection surplus.
As small-volume injection, its prescription can be optimized for further: it comprises the component of following w/v (g/mL):
Fumaric acid sitafloxacin 0.25～0.5%(is in terms of sitafloxacin)
Citric acid 0.6～1%
Sodium citrate is appropriate, regulates pH
5.5～6.5
Methionine 0.3～.5%
Sorbitol 0.1%
Water for injection surplus.
As small-volume injection, its prescription can be optimized for further:, it comprises the component of following w/v (g/mL):
Fumaric acid sitafloxacin 0.25～0.5%(is in terms of sitafloxacin)
Lactic acid 0.8～1.5%
Disodium hydrogen phosphate is appropriate, regulates pH 5.5～6.5
Methionine 0.4～0.8%
Sorbitol 0.1%
Water for injection surplus.
Another application form as invention formulation is large capacity transfusion, it is that the small-volume injection as according to any one of claim 5～7 uses water for injection dilution, and add 0.9% sodium chloride or 5% glucose sugar prepares as isoosmotic adjusting agent, the drug level in infusion solutions is 0.02～0.1%(in terms of sitafloxacin).
Another application form as invention formulation is large capacity transfusion, it is addition lyophilizing proppant in the small-volume injection as according to any one of claim 5～7, freeze-dried and prepared, wherein, lyophilizing proppant is selected from mannitol, the one in lactose or dextran.
A kind of method that it is a further object of the invention to provide small-volume injection prepared as according to any one of claim 5～7, it can comprise following operating procedure:
(1) weigh cosolvent by proportioning and methionine is dissolved in water for injection, both gross weights of preparation account for 20～30%(w/w) concentrated solution, it is incubated 45 DEG C～55 DEG C, after stirring and dissolving, adding fumaric acid sitafloxacin, stirring makes the most molten, adds the dilution of recipe quantity 70% water for injection, add sorbitol stirring and dissolving, be cooled to room temperature；
(2) pH adjusting agent being dissolved in appropriate water for injection, be slowly dropped in above-mentioned solution, regulation pH is 5.5～6.5, mends water for injection to full dose；
(3) add 0.05% (g/ml) needle-use activated carbon, stir 15～20min, successively through 0.45 μm and 0.22 μm filter membrane fine straining after de-charcoal；Sampling and measuring intermediates content, qualified rear fill is in ampoule, and nitrogen filled protection, sealing by fusing；
(4) 121 DEG C of sterilizing 15min of flowing steam hot pressing, leak detection, lamp inspection, packaging.
In addition, other two kinds of application forms for invention formulation: large capacity transfusion and the preparation method of freeze-dried powder, can be according to the preparation method of above-mentioned small-volume injection, the technological procedure preparing large capacity transfusion and freeze-dried powder the most well known to those skilled in the art, and improve relatively simplely and obtain.
Present invention offers the most useful technique effect:
(1) drug solubility is promoted: although the water solubility of fumaric acid sitafloxacin increases than sitafloxacin, but still can not meet clinical demand, prior art with the addition of the surfactants such as substantial amounts of solubilizing agent mostly, though Expected Results can be temporarily reached, but when intravenous injection, occur the probability of the clinical risks such as haemolysis to also increase.(cosolvent is selected for Aspartic Acid by the combination of cosolvent and methionine for the present invention, citric acid and lactic acid) to be made into concentrated solution permissible to dissolve fumaric acid sitafloxacin, make cosolvent consumption minimum, when particularly using citric acid as cosolvent, it is combined with the methionine of auxiliary hydrotropy function, best results.It addition, use sodium citrate as pH adjusting agent with citric acid pairing, form reliable hydrotropy buffer system, maintain the stability of injection pH value.
(2) pH value preferred range: sitafloxacin injection pH of the prior art is mostly slant acidity, about pH value about 4 can cause stimulation pain and the necrosis of local organization, even produce the risk of acid alkali poisoning during injection.Even if having indivedual document report pH value is 5-6 sitafloxacin injection, also need to improve because of existence and stability problem.Injection pH value of the present invention is 5.5-6.5, it is to avoid injection zest problem, has played methionine stabilizer function, and the buffer system of such as citric acid or sodium citrate, it is possible to the pH scope of the most stabilized above-mentioned injection simultaneously.
(3) methionine is one of essential amino acid, present inventor has been surprisingly found that, the addition of methionine can reduce and causes sitafloxacin to degrade because of strong illumination, finished product color and luster takes on a new look significantly, its hydrotropy ability can be increased considerably after combination cosolvent citric acid, the free radical generation under illumination may can be suppressed with methionine relevant.It addition, injection carries out the heat stability under the conditions of high temperature sterilize (121 DEG C, 15min), with sterilizing after injection storage time stable content better.More than improving and avoid adding conventional antioxidant sodium sulfite, metal chelating agent disodiumedetate, supplementary product kind is few, improves injection safety.
(4) for the sitafloxacin problem that dissolubility is the highest in the solution containing sodium chloride, under low-temp storage, particularly easily separate out the phenomenon that medicine is brilliant, present inventor works out, add the D-glucitol with freeze proof effect, consumption is about 0.1%, can be effectively prevented its crystallize under 4 DEG C of storage conditions, improves the stability that low temperature is placed, it is convenient to storage, transport and clinical practice.
(5) the sitafloxacin injection of prior art report contains sodium chloride more, but this exactly also limit at edema disease, dosage form renal failure, hypertension, the anti-infective therapy of the patients such as hypokalemia.And the concentrated solution type injection used as vein, due to before using can selective chlorination sodium neatly, glucose, mannose, reducing sugar, the diluent dilution such as ringer's solution uses.In order to make patient's subject range wider, toleration is more preferable, and fumaric acid sitafloxacin small-volume injection (concentrated solution) injection that the present invention provides is the most necessary.
Detailed description of the invention
Every 50mg/20mL of embodiment 1,1000
Fumaric acid sitafloxacin 0.25%(is in terms of sitafloxacin)
Aspartic Acid 1%
Histidine is appropriate, regulates pH 5.5～6.5
Methionine 0.5%
Sorbitol 0.1%
Water for injection surplus.
Preparation method:
(1) weigh Aspartic Acid by proportioning and methionine is dissolved in water for injection, both gross weights of preparation account for 20～30%(w/w) concentrated solution, it is incubated 45 DEG C～55 DEG C, after stirring and dissolving, adding fumaric acid sitafloxacin, stirring makes the most molten, adds the dilution of recipe quantity 70% water for injection, add sorbitol stirring and dissolving, be cooled to room temperature；
(2) being dissolved in appropriate water for injection by histidine, be slowly dropped in above-mentioned solution, regulation pH is 5.5～6.5, mends water for injection to full dose；
(3) add 0.05% (g/ml) needle-use activated carbon, stir 15～20min, successively through 0.45 μm and 0.22 μm filter membrane fine straining after de-charcoal；Sampling and measuring intermediates content, qualified rear fill is in ampoule, and nitrogen filled protection, sealing by fusing；
(4) 121 DEG C of sterilizing 15min of flowing steam hot pressing, leak detection, lamp inspection, packaging.
Every 100mg/20mL of embodiment 2,1000
Fumaric acid sitafloxacin 0.5%(is in terms of sitafloxacin)
Aspartic Acid 1.5%
Histidine is appropriate, regulates pH 5.5～6.5
Methionine 0.8%
Sorbitol 0.1%
Water for injection surplus.
Preparation method:
(1) weigh Aspartic Acid by proportioning and methionine is dissolved in water for injection, both gross weights of preparation account for 20～30%(w/w) concentrated solution, it is incubated 45 DEG C～55 DEG C, after stirring and dissolving, adding fumaric acid sitafloxacin, stirring makes the most molten, adds the dilution of recipe quantity 70% water for injection, add sorbitol stirring and dissolving, be cooled to room temperature；
(2) being dissolved in appropriate water for injection by histidine, be slowly dropped in above-mentioned solution, regulation pH is 5.5～6.5, mends water for injection to full dose；
(3) add 0.05% (g/ml) needle-use activated carbon, stir 15～20min, successively through 0.45 μm and 0.22 μm filter membrane fine straining after de-charcoal；Sampling and measuring intermediates content, qualified rear fill is in ampoule, and nitrogen filled protection, sealing by fusing；
(4) 121 DEG C of sterilizing 15min of flowing steam hot pressing, leak detection, lamp inspection, packaging.
Every 50mg/20mL of embodiment 3,1000
Fumaric acid sitafloxacin 0.25%(is in terms of sitafloxacin)
Citric acid 0.6%
Sodium citrate is appropriate, regulates pH 5.5～6.5
Methionine 0.3%
Sorbitol 0.1%
Water for injection surplus.
Preparation method:
(1) weigh citric acid by proportioning and methionine is dissolved in water for injection, both gross weights of preparation account for 20～30%(w/w) concentrated solution, it is incubated 45 DEG C～55 DEG C, after stirring and dissolving, adding fumaric acid sitafloxacin, stirring makes the most molten, adds the dilution of recipe quantity 70% water for injection, add sorbitol stirring and dissolving, be cooled to room temperature；
(2) being dissolved in appropriate water for injection by sodium citrate, be slowly dropped in above-mentioned solution, regulation pH is 5.5～6.5, mends water for injection to full dose；
(3) add 0.05% (g/ml) needle-use activated carbon, stir 15～20min, successively through 0.45 μm and 0.22 μm filter membrane fine straining after de-charcoal；Sampling and measuring intermediates content, qualified rear fill is in ampoule, and nitrogen filled protection, sealing by fusing；
(4) 121 DEG C of sterilizing 15min of flowing steam hot pressing, leak detection, lamp inspection, packaging.
Every 100mg/20mL of embodiment 4,1000
Fumaric acid sitafloxacin 0.5%(is in terms of sitafloxacin)
Citric acid 1%
Sodium citrate is appropriate, regulates pH 5.5～6.5
Methionine 0.5%
Sorbitol 0.1%
Water for injection surplus.
Preparation method:
(1) weigh citric acid by proportioning and methionine is dissolved in water for injection, both gross weights of preparation account for 20～30%(w/w) concentrated solution, it is incubated 45 DEG C～55 DEG C, after stirring and dissolving, adding fumaric acid sitafloxacin, stirring makes the most molten, adds the dilution of recipe quantity 70% water for injection, add sorbitol stirring and dissolving, be cooled to room temperature；
(2) being dissolved in appropriate water for injection by sodium citrate, be slowly dropped in above-mentioned solution, regulation pH is 5.5～6.5, mends water for injection to full dose；
(3) add 0.05% (g/ml) needle-use activated carbon, stir 15～20min, successively through 0.45 μm and 0.22 μm filter membrane fine straining after de-charcoal；Sampling and measuring intermediates content, qualified rear fill is in ampoule, and nitrogen filled protection, sealing by fusing；
(4) 121 DEG C of sterilizing 15min of flowing steam hot pressing, leak detection, lamp inspection, packaging.
Every 50mg/20mL of embodiment 5,1000
Fumaric acid sitafloxacin 0.25%(is in terms of sitafloxacin)
Lactic acid 0.8%
Disodium hydrogen phosphate is appropriate, regulates pH 5.5～6.5
Methionine 0.4%
Sorbitol 0.1%
Water for injection surplus.
Preparation method:
(1) weigh lactic acid by proportioning and methionine is dissolved in water for injection, both gross weights of preparation account for 20～30%(w/w) concentrated solution, it is incubated 45 DEG C～55 DEG C, after stirring and dissolving, adding fumaric acid sitafloxacin, stirring makes the most molten, adds the dilution of recipe quantity 70% water for injection, add sorbitol stirring and dissolving, be cooled to room temperature；
(2) being dissolved in appropriate water for injection by disodium hydrogen phosphate, be slowly dropped in above-mentioned solution, regulation pH is 5.5～6.5, mends water for injection to full dose；
(3) add 0.05% (g/ml) needle-use activated carbon, stir 15～20min, successively through 0.45 μm and 0.22 μm filter membrane fine straining after de-charcoal；Sampling and measuring intermediates content, qualified rear fill is in ampoule, and nitrogen filled protection, sealing by fusing；
(4) 121 DEG C of sterilizing 15min of flowing steam hot pressing, leak detection, lamp inspection, packaging.
Every 100mg/20mL of embodiment 6,1000
Fumaric acid sitafloxacin 0.5%(is in terms of sitafloxacin)
Lactic acid 1.5%
Disodium hydrogen phosphate is appropriate, regulates pH 5.5～6.5
Methionine 0.8%
Sorbitol 0.1%
Water for injection surplus.
Preparation method:
(1) weigh lactic acid by proportioning and methionine is dissolved in water for injection, both gross weights of preparation account for 20～30%(w/w) concentrated solution, it is incubated 45 DEG C～55 DEG C, after stirring and dissolving, adding fumaric acid sitafloxacin, stirring makes the most molten, adds the dilution of recipe quantity 70% water for injection, add sorbitol stirring and dissolving, be cooled to room temperature；
(2) being dissolved in appropriate water for injection by disodium hydrogen phosphate, be slowly dropped in above-mentioned solution, regulation pH is 5.5～6.5, mends water for injection to full dose；
(3) add 0.05% (g/ml) needle-use activated carbon, stir 15～20min, successively through 0.45 μm and 0.22 μm filter membrane fine straining after de-charcoal；Sampling and measuring intermediates content, qualified rear fill is in ampoule, and nitrogen filled protection, sealing by fusing；
(4) 121 DEG C of sterilizing 15min of flowing steam hot pressing, leak detection, lamp inspection, packaging.
Comparative example 1 CN201210060891.0 description embodiment 19
Fumaric acid sitafloxacin 25g(is in terms of sitafloxacin)
Water for injection 5L
Prepare 1000 altogether
Preparation method: mixed homogeneously with water for injection by the fumaric acid sitafloxacin of above-mentioned recipe quantity, obtain clear solution, filters, sterile filling, to obtain final product.
Comparative example 2 CN201210060891.0 description embodiment 20
Fumaric acid sitafloxacin 25g(is in terms of sitafloxacin)
Sodium chloride 50g
Water for injection 5L
Prepare 1000 altogether
Preparation method: by the mix homogeneously of above-mentioned recipe quantity, obtains clear solution, filters, sterile filling, to obtain final product.
Comparative example 3 CN201210060891.0 description embodiment 21
Fumaric acid sitafloxacin 50g(is in terms of sitafloxacin)
Sodium sulfite 30g
Sodium hydroxide q. s
Water for injection 5L
Prepare 1000 altogether, pH5～6
Preparation method: fumaric acid sitafloxacin and other adjuvants of recipe quantity are dissolved in 70% water for injection, pH value of solution 5～6 is regulated with 0.5mol/L sodium hydroxide solution, water for injection constant volume, add 0.1%(g/mL) activated carbon adsorption 20min, filters carbon removal, 0.22 μm filter membrane fine straining, the qualified rear fill of intermediate detection level, sterilizing 15min at a temperature of 121 DEG C, lamp inspection is qualified, subpackage finished product.
Comparative example 4
CN201210060891.0 description embodiment 22
Fumaric acid sitafloxacin 50g(is in terms of sitafloxacin)
L-cysteine hydrochloride 50g
Sodium sulfite 50g
Sodium chloride 40g
Phosphate buffer is appropriate
Water for injection 2L
Prepare 1000 altogether, pH5-6
Preparation method: fumaric acid sitafloxacin and other adjuvants of recipe quantity are dissolved in 70% water for injection, pH value of solution 5～6 is regulated with 0.5mol/L sodium hydroxide solution, water for injection constant volume, add 0.1%(g/mL) activated carbon adsorption 20min, filters carbon removal, 0.22 μm filter membrane fine straining, the qualified rear fill of intermediate detection level, sterilizing 15min at a temperature of 121 DEG C, lamp inspection is qualified, subpackage finished product.
Test example 1 high temperature sterilize is tested
Sterilising conditions: 121 DEG C of sterilizing 15min of flowing steam hot pressing, impurity content unit %, result is as follows:
Test example 2 strong illumination is tested
Under medicine exposure experiments to light instrument, intensity 5000Lx, temperature 25 ± 2 DEG C, to place 10 days, impurity content unit %, result is as follows:
Test example 3 low-temp storage is tested
Being preserved 10 days at low temperature 4 DEG C by each sample, result is as follows:
The comparison of the different preparating liquid method consumption of test example 4
To those skilled in the art, when carrying out liquid preparation and producing, the conventional method of compounding pharmaceutical solution has the most several: adjuvant is first dissolved in solvent by (1), adds medicine dissolution；(2) first by medicine dissolution in solvent, add adjuvant；(3) medicine is dissolved in solvent together with adjuvant.
In the research to fumaric acid sitafloxacin drug solution preparation method, it has been surprisingly found that, first being dissolved in the concentrated solution of cosolvent and methionine by fumaric acid sitafloxacin, then mix with the solution containing other adjuvants, the solution obtained remains stable dissolved state and clarity.Use the method preparating liquid, compared to first adjuvant being dissolved in solvent, add drug solvent or medicine is dissolved in together with adjuvant the method in solvent, it is possible to fumaric acid sitafloxacin dissolves rapidly, and the consumption of cosolvent is well below above two compound method.
A) the dissolving part operation of embodiment 1 is: weigh cosolvent by proportioning and methionine is dissolved in water for injection, both gross weights of preparation account for 20～30%(w/w) concentrated solution, it is incubated 45 DEG C～55 DEG C, after stirring and dissolving, adding fumaric acid sitafloxacin, stirring makes the most molten, adds the dilution of recipe quantity 70% water for injection, add sorbitol stirring and dissolving, be cooled to room temperature.
B) citric acid considerable amount of with embodiment 1 is weighed, methionine, sorbitol, adds commensurability water for injection, with stirring and dissolving under 45～55 DEG C of water-baths, it is cooled to room temperature, adding fumaric acid sitafloxacin, stirring 60 minutes, if there being undissolved medicine seen from naked eyes, it is slowly added to extra citric acid saturated solution the most while stirring, until solution clarification.
C) citric acid considerable amount of with embodiment 1, methionine, sorbitol are weighed, fumaric acid sitafloxacin, adds commensurability water for injection, stirs 60 minutes, if there being undissolved medicine seen from naked eyes, it is slowly added to extra citric acid saturated solution the most while stirring, until solution clarification.
Result shows: the amount of test citric acid used by A is minimum, use at citric acid and methionine 20-30%(w/w) concentrated solution adds fumaric acid sitafloxacin, the mode progressively dissolved so that the amount of cosolvent used is minimum, and does not separates out after injecting dilute with water.But, although test B and C can finally dissolve the sitafloxacin of same amount, but the consumption of citric acid is significantly increased, with test A ratio, it is respectively increased 2.2 times and 3.1 times, and the time used by stirring and dissolving is also greatly prolonged, the energy consumption produced greatly in view of industry, the application of latter two dissolution mechanism is not considered.
Test example 5 hemolytic test, sensitivity test and vascular stimulation tests
The present invention has carried out 0.25% simultaneously, and the sitafloxacin injection of 0.5% is to blood vessel irritation and hemolytic experimentation, and analysis result is as follows:
Hemolytic test: by 0.25%, 0.5% sitafloxacin intravenous fluid 0.5mL joins in 2% rabbit erythrocyte suspension, and haemolysis occur in Continuous Observation 6h, each Guan Junwei.
Sensitivity test: by 0.25%, the auricular vein of 0.5% sitafloxacin injection in Guinea-pigs carries out the test of sensitivity response, after twice excites administration, all do not observe and search, rolling up, perpendicular hair, dyspnea, the sensitization phenomenons such as death, show 0.25%, and 0.5% sitafloxacin injection is to animal subject thing sensitization.
Vascular stimulation tests: test use 0.25% for rabbit auricular vein, 0.5% sitafloxacin injection, its histopathology result shows: ear's normal configuration exists, Mild edema, ear vein tube wall is intact, has no downright bad, blood engorgement in tube chamber, having no thrombosis, the intact nothing of vascular endothelial cell comes off.Similar compared to the ear vein pathomorphology change of solvent group, have no that notable blood vessel irritation reacts.
The foregoing is only presently preferred embodiments of the present invention, it is not limited to the substantial technological content of the present invention, the substantial technological content of the present invention is that the right being broadly defined in application collects, any technology entities that other people complete or method, if with application right defined in identical, also or the change of a kind of equivalence, all it is covered by being considered among present claims scope.
Claims (10)
1. a fumaric acid Sitafloxacin hydrate injection, it is characterised in that include principal agent fumaric acid sitafloxacin, methionine, and pharmaceutically acceptable cosolvent and pH adjusting agent.
Injection the most according to claim 1, it is characterised in that " fumaric acid sitafloxacin " refers to fumaric acid sitafloxacin anhydride or fumaric acid sitafloxacin monohydrate；Cosolvent is selected from Aspartic Acid, the one in citric acid and lactic acid；PH adjusting agent is selected from histidine, the one in sodium citrate or disodium hydrogen phosphate；Methionine is as solution stabilizer and the auxiliary reagent of hydrotropy, and its consumption is 0.5～1 times (w/w).
Injection the most according to claim 1, it is characterised in that also include antifreeze D-glucitol.
Injection the most according to claim 1, it is characterised in that its application form is small-volume injection, large capacity transfusion injection and freeze-dried powder.
Small-volume injection the most according to claim 4, it is characterised in that it comprises the component of following w/v (g/mL):
Fumaric acid sitafloxacin
0.25～0.5%(in terms of sitafloxacin)
Aspartic Acid
1～1.5%
Histidine
In right amount, regulation pH 5.5～6.5
Methionine
0.5～0.8%
Sorbitol
0.1%
Water for injection
Surplus.
Small-volume injection the most according to claim 4, it is characterised in that it comprises the component of following w/v (g/mL):
Fumaric acid sitafloxacin
0.25～0.5%(in terms of sitafloxacin)
Citric acid
0.6～1%
Sodium citrate
In right amount, regulation pH 5.5～6.5
Methionine
0.3～0.5%
Sorbitol
0.1%
Water for injection surplus.
Small-volume injection the most according to claim 4, it is characterised in that it comprises the component of following w/v (g/mL):
Fumaric acid sitafloxacin
0.25～0.5%(in terms of sitafloxacin)
Lactic acid
0.8～1.5%
Disodium hydrogen phosphate
In right amount, regulation pH 5.5～6.5
Methionine
0.4～0.8%
Sorbitol
0.1%
Water for injection
Surplus.
Large capacity transfusion the most according to claim 4, it is characterized in that, it is that the small-volume injection as according to any one of claim 5～7 is used water for injection dilution, and add 0.9% sodium chloride or 5% glucose sugar prepares as isoosmotic adjusting agent, the drug level in infusion solutions is 0.02～0.1%(in terms of sitafloxacin).
Freeze-dried powder the most according to claim 4, it is characterised in that be addition lyophilizing proppant in the small-volume injection as according to any one of claim 5～7, freeze-dried and prepared, wherein, lyophilizing proppant is selected from mannitol, the one in lactose or dextran.
10. the method for the small-volume injection prepared as according to any one of claim 5～7, it is characterised in that comprise the steps of:
(1) weigh cosolvent by proportioning and methionine is dissolved in water for injection, both gross weights of preparation account for 20～30%(w/w) concentrated solution, it is incubated 45 DEG C～55 DEG C, after stirring and dissolving, adding fumaric acid sitafloxacin, stirring makes the most molten, adds the dilution of recipe quantity 70% water for injection, add sorbitol stirring and dissolving, be cooled to room temperature；
(2) pH adjusting agent being dissolved in appropriate water for injection, be slowly dropped in above-mentioned solution, regulation pH is 5.5～6.5, mends water for injection to full dose；
(3) add 0.05% (g/ml) needle-use activated carbon, stir 15～20min, successively through 0.45 μm and 0.22 μm filter membrane fine straining after de-charcoal；Sampling and measuring intermediates content, qualified rear fill is in ampoule, and nitrogen filled protection, sealing by fusing；
(4) 121 DEG C of sterilizing 15min of flowing steam hot pressing, leak detection, lamp inspection, packaging.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019112701A1 (en) * | 2017-12-07 | 2019-06-13 | Massachusetts Institute Of Technology | Sensitization of bacterial cells to quinolone antibiotics |
| CN110790744A (en) * | 2018-08-03 | 2020-02-14 | 南京优科生物医药研究有限公司 | Pyridonecarboxylic acid derivatives, process for preparing same and compositions containing same |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101352439A (en) * | 2007-07-24 | 2009-01-28 | 张嵩 | Composition injection containing tetrandrine and preparation method thereof |
| CN103087042A (en) * | 2012-03-09 | 2013-05-08 | 南京优科生物医药有限公司 | Salts of sitafloxacin and pharmaceutical purposes thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101352439A (en) * | 2007-07-24 | 2009-01-28 | 张嵩 | Composition injection containing tetrandrine and preparation method thereof |
| CN103087042A (en) * | 2012-03-09 | 2013-05-08 | 南京优科生物医药有限公司 | Salts of sitafloxacin and pharmaceutical purposes thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019112701A1 (en) * | 2017-12-07 | 2019-06-13 | Massachusetts Institute Of Technology | Sensitization of bacterial cells to quinolone antibiotics |
| US20190201532A1 (en) * | 2017-12-07 | 2019-07-04 | Massachusetts Institute Of Technology | Sensitization of bacterial cells to quinolone antibiotics |
| US10842874B2 (en) | 2017-12-07 | 2020-11-24 | Massachusetts Institute Of Technology | Sensitization of bacterial cells to quinolone antibiotics |
| CN110790744A (en) * | 2018-08-03 | 2020-02-14 | 南京优科生物医药研究有限公司 | Pyridonecarboxylic acid derivatives, process for preparing same and compositions containing same |
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| CN105769756B (en) | 2019-03-12 |
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