CN103656616B - Batifeiban injection and preparation thereof - Google Patents

Abstract

The present invention relates to the injection of Batifeiban and pharmaceutically-acceptable salts thereof, and prepare and pharmaceutical applications.Result shows, and this injection has good stability and safety in production and Clinical practice.

Description

Batifeiban injection and preparation thereof

Technical field

The present invention relates to the injection field for the treatment of thrombotic disease, the injection field of the Batifeiban particularly containing treatment thrombotic disease effective ingredient.

Background technology

Coronary heart disease refers to because of coronary artery being obstructed and the blood supply insufficiency caused and myocardial ischemic heart disease in various degree.Coronary heart disease is western countries always, especially the No.1 fatal disease of the U.S..In the U.S., nearly 1,550,000 people's morbidities every year.But cardiovascular morbidity and the mortality rate of developing country rise year by year.Percutaneous coronary intervention (pci) (PercutaneousCornonaryIntervention, PCI) is main effectively one for the treatment of means that arteria coronaria blocks.But in PCI art or postoperative at PCI, the acute coronary thrombosis caused by platelet aggregation, to block be main again, normally fatal adverse events.

The Drug therapy of patients with coronary heart disease, it is the most frequently used that aspirin adds clopidogrel, but aspirin adds clopidogrel can only suppress part platelet aggregation, GPIIb/IIIa antagonist action be the last passage of platelet activation, can more effectively reduce in PCI art or postoperative thrombotic ischemic complications.While PCI operation, medicine is prevented in application antiplatelet glycoprotein receptor GPIIb/IIIa (α IIb β 3), can effectively reduce the probability of blocking generation again.

Abciximab (Reopro), tirofiban (Tirofiban, trade name Aggrastatt), eptifibatide (Eptifibatide, trade name Integrilin) common feature be block GPIIb/IIIa be combined with part Fibrinogen, and reach anticoagulant, be widely used in coronary heart disease, comprise unstable angina pectoris, acute coronary syndrome and PCI.Although these three kinds of medicines have the function suppressing GPIIb/IIIa and its ligand binding jointly, but biochemical characteristic, clinical practice are variant: abciximab goes through to be applied to PCI, tirofiban is used for unstable angina pectoris, and eptifibatide can be used for PCI and unstable angina pectoris.Clinical research shows the probability that platelet glycoprotein receptor antagonist effectively can reduce the complication after intracavity coronary artery procedure and myocardial infarction death and occurs.

Tirofiban and eptifibatide can special suppression GPIIb/IIIa and its ligand bindings, and abciximab can not only suppress GPIIb/IIIa, the information transmission of suppression blood vessel endothelium and smooth muscle cell integrin receptor α v β 3 simultaneously.Block relevant receptor because abciximab can act on two simultaneously to arteria coronaria, on clinical effectiveness, demonstrate superiority.But abciximab is human mouse chimeric antibody, although its immunogenicity reduces a lot, but after all and inhuman source or humanized antibody, in clinical practice, find that abciximab still causes the immunoreation of anti-mouse antibody many patients, cause thrombocytopenia (Thrombocytopenia).Abciximab long half time, even if hemorrhage reaction drug withdrawal immediately, can not stop its untoward reaction after occurring immediately.To transfuse blood salvage pathway unique often.And small-molecule peptide, generally there is no antigenicity, can reuse; And the general half-life is short, if any hemorrhage reaction, just can stop hemorrhage after drug withdrawal.Therefore, be necessary the medicine of the anti-GPIIb/IIIa researching and developing a new generation, it is made to possess following characteristics: very high affinity can be had to GPIIb/IIIa (integrin IIb3), stop platelet aggregation, the integrin v3 (its subunit the same) close with GPIIb/IIIa can be suppressed again, to suppress the growth of vascular smooth muscle, arteries is suppressed to block further again; This inhibitor should not have antigenicity, can reuse; And the half-life is short, once drug withdrawal, can the advantage such as Bleeding control reaction.

Batifeiban belongs to the antiplatelet glycoprotein receptor repressor of a new generation, more existing (go on the market abroad, or bibliographical information) other antiplatelet acceptor compound, there is a lot of significantly advantage and characteristic.Batifeiban peptide is not only strong to the affinity of platelet glycoprotein receptor GPIIb/IIIa target spot, can anticoagulant, also suppresses vascular smooth muscle to grow by suppressing glass-based albumen Vitronectin receptor.

Injection is the direct intravasation of intravenous fluid especially, without absorption process, bioavailability is high, onset is rapid, and (main adverse reaction of Batifeiban is symptom, sign and laboratory abnormalities caused by platelet aggregation reduces: bleeding episode as various in prolonged bleeding time, hematuria etc. can to stop administration at any time according to the state of an illness, need to stop administration immediately after there is untoward reaction, otherwise more serious untoward reaction can be caused), be widely used clinical.At present, although Batifeiban possesses some special knowledge as active constituents of medicine, but because of the restriction of Batifeiban dissolubility: can only be soluble in 0.1mol/L hydrochloric acid solution, slightly soluble in methanol, ethanol, ethyl acetate and 50% acetonitrile, almost insoluble in water, acetone, ether and 0.1mol/L sodium hydroxide solution, be difficult to by injection routine prescription the preparation being prepared into applicable medicinal requirements.

Sodium citrate is anticoagulant, main use is (blood for blood transfusion) anticoagulation in vitro, its pharmacological action principle is: calcium is required material in coagulation process, thrombokinase (thromboplastin) can be promoted, thrombin and fibrinous formation, and activate intra platelet free calcium thrombin reaction etc.In citric acid radical ion and blood calcium ion generate be difficult to resolve from soluble complexes calcium citrate, this complex is soluble in water but not easily dissociate, and calcium ion in blood is reduced, and coagulation process is suppressed, thus stops blood coagulation.Sodium citrate is prepared into blood transfusion sodium citrate injection, i.e. 2.35%-2.65% sodium citrate (C ₆h ₅na ₃o ₇.2H ₂o) sterile water solution made, the present invention is active component with Batifeiban and is aided with the injection of citric acid, above-mentioned deliquescent problem can not only be solved well, and citric acid itself has certain biological activity, play collaborative anticoagulation, clinically to show: with the injection of embodiment 1 formula preparation and placebo (namely only containing the citric acid with the concentration) ratio not containing Batifeiban, after medication, placebo group 4h, 1 day platelet aggregation inhibition rate median are respectively 13.33% and 15.64%.

The injection made by this patent has good stability, can reach 2 years in Leng Chu (2 ~ 10 DEG C) preservation effect duration, also the short time can preserve the several months at room temperature (10-30 DEG C).

Summary of the invention

Treatment thrombotic disease injection mentioned by the present invention contains Batifeiban and pharmaceutically acceptable salt thereof.Injection can be injection, injectable sterile powder, concentrated solution for injection form.Injection is applicable to intramuscular injection, intravenous injection, intravenous drip.Other component in this injection can optionally comprise; such as, at least one water for injection, nonaqueous solvent, pharmaceutical addition agent from osmotic pressure regulator, pH adjusting agent, solubilizing agent, cosolvent, antioxidant, antibacterial, emulsifying agent, suspending agent, protective agent and other component.

Liquid vehicle can be any pharmaceutically acceptable liquid or solid carrier, comprises water, moisture organic solvent and non-aqueous solvent.Medicinal fluid can direct injection or dilution after injection, acceptable solid carrier need with injection solvent dissolve after injection.

Injection can comprise active component Batifeiban and the pharmaceutically acceptable salt thereof of any amount suitably.In some embodiments, Batifeiban pharmaceutically acceptable salt is in Batifeiban, and injectable sterile powder calculates after adding solution, and Batifeiban concentration is 0.1mg/ml to 40mg/ml.

Osmotic pressure regulator is optionally added in injection, and keep injection osmotic pressure in use with osmotic pressure, injection in use osmotic pressure is equal with blood plasma, or equal with erythrocyte tension force.In some embodiments, add the osmotic pressure that osmotic pressure regulator helps to keep injection, glucose is suitable for keeping the pharmaceutically useful example of osmotic pressure to have citric acid/citrate, acetic acid/acetate, sodium chloride, in some embodiments, osmotic pressure molar density is that 285-310mOsmol/kg keeps isotonic, amount can be about 0mg/ml to 20mg/ml, about 5mg/ml to 20mg/ml, about 50mg/ml to 200mg/ml.

PH adjusting agent is optionally added in injection, for the dissolubility that such as strengthens forms of pharmacologically active agents or the forms of pharmacologically active agents stability keeping in scope needed for pH.In some embodiments, pH can be about 5 to 8, pH and can be about 5.0 to 5.5, pH and can be about 5.2 to 5.4.In some embodiments, pH about 5.25, or pH about 5.35.Be suitable for keeping the example of pharmaceutically acceptable buffer agent of acid pH comprise hydrochloric acid, citric acid/sodium citrate, tartaric acid/, sodium hydrogen phosphate/sodium dihydrogen phosphate etc., the available any suitable alkali of these acid, if sodium citrate, sodium hydroxide, sodium tartrate, sodium hydrogen phosphate neutralization are to reach required pH.PH adjusting agent can be obtained according to method known to those skilled in the art and preferably use consumption and form.

Suitable cosolvent is well known in the art and comprises such as Tween-40, Tween-60, tween 80, pluronic gram F-68, lecithin, fabaceous lecithin, hexadecanol, octadecanol, PLURONICS F87, polyoxyethylene castor oil, NaTDC etc., nothing or one or more mixture.The amount that cosolvent can exist is such as about 0% to 0.2%, about 0% to 5%, about 1% to 65%.

Suitable antioxidant and antioxidant synergist are well known in the art and comprise sodium sulfite, sodium sulfite, pyrosulfurous acid hydrogen sodium, sodium thiosulfate, thiourea, dibenzylatiooluene, Butylated hydroxyanisole, disodiumedetate and salt thereof etc., nothing or one or more mixture.The amount that antioxidant and antioxidant synergist can exist is such as about 0.001% to 0.02%, about 0.05% to 0.5%, about 0.01% to 0.1%.

Suitable antibacterial is well known in the art and comprises phenol, cresol, chlorocresol, chlorobutanol, benzyl alcohol, thimerosal etc., nothing or one or more mixture.Can obtain antioxidant according to method known to those skilled in the art and preferably use consumption and form, the amount that antibacterial can exist is such as about 0% to 0.01%, about 0% to 0.5%, about 0.5% to 2%, about 1% to 2%.

Suitable noble gas has protective effect to injection; can fill when injection fill or not blanketing gas; suitable blanketing gas is well known in the art and comprises is the gas such as carbon dioxide, nitrogen, the Purge gas after, oil removing degerming through cleaning, dedusting.

Suitable solvent be well known in the art and comprise water for injection, containing the organic solvent of water for injection and non-aqueous solvent, containing or be not well known in the art containing the organic solvent of water for injection and comprise water for injection, ethanol, propylene glycol, glycerol, Polyethylene Glycol wherein one or more mixture.

Suitable solvent is well known in the art and comprises oil for injection, is well known in the art soybean oil, Oleum Sesami, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen wherein one or more mixture containing oil for injection.

The invention provides a kind of method preparing injection, adopt injection preparation method well known by persons skilled in the art, comprising following steps: described medicine and additives are pressed recipe quantity, successively or add in no particular order in water for injection to stir and make it dissolve, add pH adjusting agent as required, be adjusted to the most stable pH, inject and use water standardize solution, aseptic filtration, be sub-packed in aseptic apyrogeneity container by regulation loading amount asepsis, sealing by fusing or sternly seal, adopts decompression method or other suitable method to carry out container leak detection.Injection is preserved at Leng Chu (2 ~ 10 DEG C), and the short time preserves at room temperature (10-30 DEG C).

Or the injection above-mentioned asepsis is sub-packed in clean container, lyophilizing, sealing by fusing or tight envelope make freeze dried injection, adopt decompression method or other suitable method to carry out container leak detection.

Or by Batifeiban or its pharmaceutically-acceptable salts, direct packaging is in aseptic pyrogen-free clean medicament packaging container, and sealing by fusing or sternly seal, adopts decompression method or other suitable method to carry out container leak detection.

Or by Batifeiban or Batifeiban or its pharmaceutically-acceptable salts and injection pharmaceutic adjuvant one or more, aseptic mixing in apyrogeneity clean container, be divided in aseptic pyrogen-free medicament packaging container by regulation loading amount asepsis, sealing by fusing or sternly seal, adopts decompression method or other suitable method to carry out container leak detection.

The purposes of Batifeiban injection treatment thrombotic disease of the present invention, indication comprises patients with coronary artery disease, may take or inject other antithrombotic therapy agent before these patients.These patients are accepting the patients with coronary artery disease of PCI treatment, artery bypass grafting in treatment of patients or other interventional therapy methods.

The injection made by this patent has good stability and safety in production and Clinical practice.Have dosage few, avoid the stimulation to gastrointestinal, avoid first pass effect, bioavailability high, be applicable to the treatment of thrombotic disease, especially myocardial infarction and acute coronary syndrome need the patient of undergoing percutaneous coronary interventional therapy (PCI).

Detailed description of the invention

For making the present invention easier to understand, below in conjunction with specific embodiment, the expert of same domain should be able to expand and extend its application conditions and set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.

Embodiment 1

Prescription

Specification: 10ml: 20mg

Prescription:

Get citric acid 52.5g, after dissolving with 200ml water for injection, add 20g Batifeiban, stir and make it dissolve, then use 1mol/L sodium hydroxide solution adjust pH to 5.25; 10000ml is diluted to, coarse filtration with water for injection; Filter with 0.22 μm of sterilised membrane filter, ultrafiltration, inspection, every bottle of subpackage 10.5ml, tamponade, adds plastic-aluminum combined lid Zha Gai, outer package, and inspection, obtains product.

Embodiment 2:

Prescription

Specification: 100ml: 75mg

Prescription:

Get citric acid 525g, after dissolving with 2000ml water for injection, add 75g Batifeiban, stir and make it dissolve, then use 1mol/L sodium hydroxide solution adjust pH to 5.35; Then 100000ml is diluted to water for injection, coarse filtration; Filter with 0.22 μm of sterilised membrane filter, inspection, every bottle of subpackage 100ml, tamponade, adds plastic-aluminum combined lid, Zha Gai, outer package, and inspection, obtains product.

Embodiment 3

Prescription:

Get citric acid 52.5g, after dissolving with 200ml water for injection, add 20g Batifeiban, stir and make it dissolve, then use 1mol/L sodium hydroxide solution adjust pH to 5.25, add mannitol 500g, be diluted to 10000ml with water for injection, coarse filtration; Filter with 0.22 μm or following aperture sterile filters, inspection, every bottle of subpackage 10.1-10.5ml, partly jumps a queue, puts into freeze drying box, notices that medicine bottle will be evenly distributed on flaggy.

Pre-freeze: set flaggy temperature as-45 DEG C, controls medicine temperature below-40 DEG C, keeps 4 ~ 6 hours.

Primary drying: condenser temperature is down to after below-40 DEG C and is started evacuation; As vacuum≤10Pa, setting plate temperature-20 DEG C, opens vacuum and reports to the police and electrical heating, keep 8 ~ 10 hours; Improve plate temperature depending on medicine temperature, the temperature difference of holding plate Wen Yupin temperature is advisable at 10 DEG C ~ 20 DEG C in good time, keep medicine temperature≤-10 DEG C.

Redrying: improve plate temperature and retain 2 ~ 3 hours after 5 ~ 10 DEG C, setting plate temperature is 36 DEG C, makes medicine temperature rise to rapidly 28 ~ 33 DEG C, keeps more than 4 hours.

By plate temperature drop to 15 ~ 20 DEG C, open tamponade device and carry out tamponade, add plastic-aluminum combined lid Zha Gai, outer package, inspection, obtains product.

Embodiment 4:

Prescription

Specification: 10ml: 20mg

Prescription:

1/2 cumulative volume water for injection dissolves sodium chloride, adds in sodium chloride solution, inject water to 90% volume after appropriate 0.01mol/L dissolving with hydrochloric acid Batifeiban, 1mol/L sodium hydroxide solution adjust pH to 5.25, supplies water for injection to prescribed volume, coarse filtration, filter with 0.22 μm and following aperture sterile filters, inspection, every bottle of subpackage 10.5ml, tamponade, add plastic-aluminum combined lid Zha Gai, outer package, inspection, obtains product.

Embodiment 5

Stability experiment

According to the stability test requirement of pharmacopeia to medicine preparation, to the research having carried out influence factor's test, accelerated test and long term test by test product (sample by prepared by embodiment 1), long-term test results sees the following form.

Table 1 long-term test results (6 DEG C)

Below the sample that keeps sample for a long time samples respectively when keeping sample 12 months and 24 months and carries out bacterial endotoxin and sterility test, and check result shows sample bacterium endotoxin and asepticly all to conform with the regulations.

Result shows: this product is under listing terms of packing, and after keeping sample 24 months for a long time, sample appearance color and luster, clarity, pH value, aseptic, bacterial endotoxin, related substance and content still conform with the regulations.

Embodiment 6

Compatibility stability

This product clinically can intravenous drip, main dilute with 10% glucose injection 250ml or 0.9%NaCl injection 250ml after slowly instil, therefore investigation and 10% glucose injection and 0.9%NaCl injection compatibility stability.

10% glucose injection compatibility stability

Get this product 10ml (sample by prepared by embodiment 1), be added in 10% glucose injection of 250ml, shake up, respectively 0,2,4,6,8,24 littlely measure its pH value and content (with 0 hour for 100%) constantly, observe cosmetic variation simultaneously.

The compatibility stability result of table 210% glucose

All unchanged in the outward appearance of each time point, solution clarity is all qualified.

0.9%NaCl injection compatibility stability

Get this product 10ml (sample by prepared by embodiment 1), be added in the 0.9%NaCl injection of 250ml, shake up, respectively 0,2,4,6,8,24 littlely measure its pH value and content (with 0 hour for 100%) constantly, observe cosmetic variation simultaneously.

The compatibility stability result of table 30.9%NaCl injection

All unchanged in the outward appearance of each time point, solution clarity is all qualified, and all indexs all conform with the regulations.

Show this product and 10% glucose injection and the stability test of 0.9%NaCl injection compatibility, this product and the compatibility of the two are stablized, and meet clinical requirement.

Embodiment 7 Batifeiban is on the impact of patients with coronary artery disease platelet aggregation

Patient experimenter that all screenings are qualified, the person that meets inclusion criteria, in 1: 1: 1 ratio, after radiography terminates to determine row PCI, randomized, double-blind enters test group (Batifeiban injection high dose is injected, low dosage inject) and matched group (the same concentrations citric acid injection without Batifeiban), use micro pump to carry out intravenous drip, continue medication 24h.And after 4h before administration, after administration and administration, 24h detects platelet aggregation rate, observes PCI postoperative to the bleeding of 30 days, slow blood flow event, MACE event and safety.Concrete administration is as follows: high dose injects group: after radiography terminates to determine row PCI, first intravenous injection Batifeiban injection 220ug/kg (0.11ml/kg), then Intravenous Infusion Batifeiban injection 2.5ug/kg/min, continues 24h (0.075ml/kg/h24h); Low dosage injects group: after radiography terminates to determine row PCI, first intravenous injection Batifeiban injection 180ug/kg (0.09ml/kg), then Intravenous Infusion Batifeiban injection 2.5ug/kg/min, continues 24h (0.075ml/kg/h24h); Matched group (placebo): after radiography terminates to determine row PCI, first intravenous injection placebo 0ug/kg (0.11ml/kg), then Intravenous Infusion placebo 0ug/kg/min, continues 24h (0.075ml/kg/h24h).

Clinical study results shows: three groups of platelet aggregation rates are at the preoperative there was no significant difference of PCI, placebo group, low dosage injects group and high dose is injected the postoperative 4h platelet aggregation inhibition rate median of group three groups and is respectively 13.33%, 91.07%, 89.19%, comparing difference between group has statistical significance (P < 0.001); Within postoperative 1 day, platelet aggregation inhibition rate median is respectively 15.64%, 90.99%, 87.24%, and comparing difference between group has statistical significance (P < 0.001).

Claims (42)

1. treat a thrombotic disease injection, this injection contains active constituents of medicine Batifeiban or its pharmaceutically-acceptable salts, and citric acid/citrate; The concentration of its Batifeiban contained or its pharmaceutically-acceptable salts is, the salt of Batifeiban is converted to Batifeiban, and injectable sterile powder calculates by after final solubilizer, and Batifeiban concentration is 0.1 mg/ml to 40 mg/ml.

2. the injection of claim 1, it is characterized in that, the pharmaceutically-acceptable salts of Batifeiban is inorganic acid salt, and wherein mineral acid is: Hypoiodous acid (HIO), hypochlorous acid, Hydrogen oxybromide (HOBr), iodic acid, perchloric acid, peroxy-disulfuric acid, excessively two carbonic acid, percarbonic acid, pyrophosphoric acid, pyrosulfuric acid, pyrosulfurous acid, tetrathionic acid, phosphoric acid, thiosulfuric acid, sulphuric acid, chloric acid, Metaphosphoric acid, hydroiodic acid, hydronitric acid, Fluohydric acid., hydrosulphuric acid, hydrochloric acid, hydrobromic acid, tetraboric acid, carbonic acid, nitric acid, bromic acid, sulfurous acid, phosphorous acid, chlorous acid, hydrochloric acid, nitrous acid or orthocarbonic acid.

3. the injection of claim 2, is characterized in that, mineral acid is sulphuric acid, hydrochloric acid, nitric acid, phosphoric acid.

4. the injection of claim 1, it is characterized in that, the pharmaceutically-acceptable salts of Batifeiban is acylate, and wherein organic acid is: tartaric acid, oxalic acid, malic acid, citric acid, ascorbic acid, benzoic acid, salicylic acid, caffeic acid, lactic acid, sorbic acid, Fumaric acid, formic acid, acetic acid, benzoic acid, ethanedioic acid, succinic acid, acetone acid, α-one succinic acid, benzenesulfonic acid, trifluoroacetic acid, maleic acid, tetrasulfonic acid, methanesulfonic acid, fumaric acid or aminoacid.

5. the injection of claim 4, is characterized in that, organic acid is citric acid, malic acid, lactic acid, acetic acid, ethanedioic acid or aminoacid.

6. the injection of claim 1, is characterized in that, injection is injection, injectable sterile powder or concentrated solution for injection, and it is for intramuscular injection, intravenous injection or intravenous drip.

7. the injection of claim 6, is characterized in that, injection is solution-type, emulsion type or suspension type injection.

8. the injection of claim 6, is characterized in that, injectable sterile powder, takes solvent crystallization, spray drying method or freezing or cold drying to obtain with maybe adding adjuvant.

9. the injection of claim 6, is characterized in that, concentrated solution for injection, instils for diluting posterior vein before use.

10. the injection of claim 7, is characterized in that, solvent is aqueous solvent and nonaqueous solvent or moisture organic solvent.

The injection of 11. claim 10, is characterized in that, aqueous solvent is water for injection.

The injection of 12. claim 10, is characterized in that, non-aqueous solvent is one or more the mixture be selected from ethanol, propylene glycol, Polyethylene Glycol, glycerol, or with the mixture of water.

The injection of 13. claim 10, is characterized in that, organic solvent is oil for injection, and wherein containing oil for injection is one or more the mixture be selected from soybean oil, Oleum Sesami, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen.

The injection of 14. claim 9, is characterized in that, it is also containing the one or more kinds of additives be selected from osmotic pressure regulator, pH adjusting agent, solubilizing agent, cosolvent, antioxidant, antibacterial, emulsifying agent, suspending agent, protective agent.

The injection of 15. claim 14, it is characterized in that, osmotic pressure is adjusted to osmotic pressure molar density 100-500mOsmol/kg, and wherein osmotic pressure regulator is selected from one or more the mixture in citric acid/citrate, acetate, mannitol, lactose, sorbitol, glucose, sodium chloride.

The injection of 16. claim 14, is characterized in that, osmotic pressure regulator is the citrate of 2.00-10.00 mg/ml.

The injection of 17. claim 14, is characterized in that, osmotic pressure regulator is the acetate of 2.00-20.00 mg/ml.

The injection of 18. claim 17, is characterized in that, osmotic pressure regulator is the acetate of 5.00-15.00 mg/ml.

The injection of 19. claim 14, is characterized in that, osmotic pressure regulator is 0.5%-1.5% sodium chloride.

The injection of 20. claim 14, is characterized in that, osmotic pressure regulator is the glucose of 1%-15%.

The injection of 21. claim 15, is characterized in that, osmotic pressure is adjusted to osmotic pressure molar density 285-310mOsmol/kg.

The injection of 22. claim 14, is characterized in that, pH adjusting agent is for being selected from hydrochloric acid, citric acid/sodium citrate, sodium hydroxide, tartaric acid/sodium tartrate, one or more the mixture in sodium hydrogen phosphate/sodium dihydrogen phosphate, wherein adds described pH adjusting agent to pH3-10.

The injection of 23. claim 22, is characterized in that, adds described pH adjusting agent to pH5-8.

The injection of 24. claim 14, it is characterized in that, cosolvent is be selected from one or more the mixture in Tween-40, Tween-60, tween 80, pluronic gram F-68, lecithin, fabaceous lecithin, hexadecanol, octadecanol, PLURONICS F87, polyoxyethylene castor oil, NaTDC.

The injection of 25. claim 14, is characterized in that, the concentration of cosolvent is 0.001%-80%.

The injection of 26. claim 14, it is characterized in that, antioxidant is be selected from one or more the mixture in sodium sulfite, sodium sulfite, pyrosulfurous acid hydrogen sodium, sodium thiosulfate, thiourea, dibenzylatiooluene, Butylated hydroxyanisole, disodiumedetate and salt thereof.

The injection of 27. claim 14, is characterized in that, the concentration of antioxidant is 0.001%-80%.

The injection of 28. claim 14, is characterized in that, antibacterial is one or more the mixture be selected from phenol, cresol, chlorocresol, chlorobutanol, benzyl alcohol, thimerosal.

The injection of 29. claim 14, is characterized in that, the concentration of antibacterial is 0.001%-5%.

The injection of 30. claim 14, is characterized in that, protective agent is carbon dioxide and/or nitrogen.

The injection of 31. claim 8, is characterized in that, injectable sterile powder, and contain pharmaceutically acceptable powder pin filler, it is the one or more kinds of mixture be selected from glucose, lactose, sucrose, mannitol, maltose.

The injection of 32. claim 31, is characterized in that, the concentration of powder pin filler is 0.001%-30%.

The injection of 33. claim 1, it exists with the dosage form of unit dose, makes the injection packaged form of vial, glass tube vial, Carlsberg's flask, plastic bottle, infusion bottle, plastic bag or pre-encapsulated injector.

The injection of 34. claim 1, it exists with the dosage form of unit dose, makes the injection packaged form of glass ampule or cillin bottle.

The injection of 35. claim 33 or 34, in injection packaging, wherein often to prop up or in every bottle of injection, the specification of injection is between 0.5-500ml.

The injection of 36. claim 35, wherein often props up or in every bottle of injection, the specification of injection is 5ml, 10ml, 30ml, 20ml, 50ml, 60ml, 100ml, 150ml, 200ml, 250ml, 300ml or 500ml.

The injection of 37. claim 35, wherein often props up or in every bottle of injection, the specification of injection is 5ml, 10ml, 20ml, 50ml, 100ml or 250ml.

The injection of 38. claim 35, is characterized in that often propping up or in every bottle of injection, the specification of injection is 10ml or 100ml.

The preparation method of the injection any one of 39. claim 10-15, is characterized in that, through following steps:

(1) by the solvent any one of Batifeiban or its pharmaceutically-acceptable salts and citric acid/citrate, claim 10-15 and additives successively or adding in preparing tank in no particular order, stir and make it dissolve or mix homogeneously;

(2) add the pH adjusting agent in claim 14, be adjusted to pH5.0-5.5;

(3) solubilizer standardize solution, aseptic filtration, is dispensed in clean packaging by regulation loading amount asepsis, sealing by fusing or sternly seal, and adopts decompression method or other suitable method to hunt leak;

(4) preserve for a long time or short time preservation at 10-30 DEG C at 2 ~ 10 DEG C.

The preparation method of the injection of 40. claim 39, wherein in step (2), adds pH adjusting agent and is adjusted to pH5.2-5.4.

The preparation method of the injection of 41. claim 1, it is characterized in that, by Batifeiban or its pharmaceutically-acceptable salts and citric acid/citrate, be dispensed in clean packaging by regulation loading amount asepsis, sealing by fusing or sternly seal, adopts decompression method or other suitable method to carry out container leak detection.

The preparation method of the injection of 42. claim 1, it is characterized in that, by Batifeiban or its pharmaceutically-acceptable salts, citric acid/citrate and one or more injection additives, aseptic mixing in clean container, be dispensed in clean packaging by regulation loading amount asepsis, sealing by fusing or sternly seal, adopts decompression method or other suitable method to carry out container leak detection.