CN107019675A - Adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition and quality control method and preparation method - Google Patents
Adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition and quality control method and preparation method Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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Abstract
The present invention relates to adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition and quality control method and preparation method.Specifically, included in the adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition provided in one embodiment of the invention：Adenosine cyclophosphate, mannitol and acid-base modifier.In said composition, the amount of mannitol is counted as 10~50 parts by weight using every 10 parts by weight of adenosine cyclophosphate, acid-base modifier be selected from sodium hydroxide, 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, its consumption be so that the pharmaceutical composition be dissolved in water and dilute the solution of the 10mg containing adenosine cyclophosphate in every 1ml is made when the solution pH value be 5.5~7.0.The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition and other each side of the present invention have good nature as used in the description.
Description
Technical field
The invention belongs to pharmaceutical preparations technology field, be related to it is a kind of can be used for heart failure, myocarditis, sick sinus syndrome,
Coronary heart disease and cardiomyopathy, it may also be used for the medicine of the auxiliary treatment of arrhythmia cordis, more particularly to a kind of adenosine cyclophosphate for injection
Freeze drying powder injection pharmaceutical composition, and its quality control method and their preparation method, the adenosine cyclophosphate for injection freeze-dried powder
Agent pharmaceutical compositions pharmaceutical compositions have good pharmaceutical properties.
Background technology
Adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition of the present invention is a kind of effectively available for mental and physical efforts
Exhaustion, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy, it may also be used for the medicine of the auxiliary treatment of arrhythmia cordis.It is believed that this
The meglumine cyclic adenosine for injecta powder-injection of invention is generally used for following disease：Angiocardiopathy (coronary heart disease, rheumatic heart disease, the heart
Myositis, arrhythmia cordis etc.)；Cranial vascular disease (cerebral ischemia, cerebral thrombus and its sequelae)；Cerebrovas-cularaccident；Tumour patient；Operation
Patient's (routine administration etc. before various bone surgeries, operations on cranium and brain, organ transplant, anesthesia)；Diabetes, nephrosis etc. are various chronic to disappear
Consumption disease；Various hepatitis；Asthma, psoriasis, senile chronic bronchitis.
The chemical entitled 6- amino -9- β-D-RIBOSE bases-of adenosine cyclophosphate (Adenosine Cyclophosphate)
9H- purine -4 ', 5 '-cycli phosphate hydrogen ester, molecular formula is C10H12N5O6P, and molecular weight is 329.21, and its chemical structural formula is：
Because adenosine cyclophosphate is slightly soluble in water, increase meglumine (Meglumine, 1- deoxidation -1- (first ammonia in adenosine cyclophosphate
Base)-D-glucitol, molecular formula C7H17NO5, molecular weight 195.22) its dissolubility can be increased, while meglumine is to di(2-ethylhexyl)phosphate
Esterase has certain inhibitory action, is allowed to the decomposition reduction to adenosine cyclophosphate, therefore the positive inotropic of meglumine adenosine cycle phosphate is made
It is stronger with more considerable amount of adenosine cyclophosphate, thus it is clinical adenosine cyclophosphate and meglumine are often combined into meglumine adenosine cycle phosphate used,
Pharmacological action meglumine adenosine cycle phosphate is non-digitalis cardiotonic, with positive inotropic action, can strengthen myocardial contractive power, is improved
Myocardium blood-pumping function, has expansion blood vessel function, it is possible to decrease myocardial oxygen consumption；Improve metabolism of myocardium, protection ischemic, anoxic
Cardiac muscle；Sinoatrial node P cell functions can be improved.The existing adenosine cyclophosphate for injection freeze drying powder injection of prior art has particulate matter not
It is stable, the shortcomings of light is degradable is met, the stability heart is poor.
Adenosine cyclophosphate is a kind of nucleotide drug, is non-digitalis cardiotonic drug.Adenosine cyclophosphate (cAMP) is intracellular
The important substance of Auto-regulator metabolism and biological function is participated in, is life-information transmission " second messenger ".It is used as a heart
Blood vessel drug eluting, adenosine cyclophosphate has the advantages that penetrability is good, pharmacological action is gentle, stability is high, toxic side effect is small.Ring in vivo
Phosphorus adenosine can promote the survival of cardiac muscle cell, enhancing cardiac muscle cell antibody Monoclonal, anti-ischemic and hypoxia ability；Promote calcium ion to
Flowed in cardiac muscle cell, strengthen phosphorylation, promote E-C coupling, improve mycardial contractility power, increase heart output
Amount；Peripheral vascular is also expanded simultaneously, cardiac ejection impedance is reduced, mitigates load before and after heart, increases heart discharge, improves heart work(
Energy.So as to play cardiac nutrition, positive inotropic, vasodilator, anti-platelet aggregation and antiarrhythmic effect to heart.
Clinically it is mainly used in treatment cardiac insufficiency, angina pectoris and myocardial infarction.Especially ocean is poisoned to yellow class cardiotonic drug or not
Sensitive patient.
Adenosine cyclophosphate into cell is degraded into 5- adenosines -5 '-phosphoric acid after biological effect is played by phosphodiesterase
(5-AMP) loses activity, and then is broken down into adenosine and phosphoric acid.Adenosine cyclophosphate is used clinically for cardiac insufficiency, angina pectoris
And myocardial infarction；To the poisoning of digitalis cardiotonic drug or insensitive patient；Treat the ancillary drug of arrhythmia cordis.
Because the dissolubility of adenosine cyclophosphate is not enough, people are made into meglumine with mole ratio 1:1 mode is mixed
Injection is made to increase the solubility of adenosine cyclophosphate.Although preparing meglumine adenosine cycle phosphate preparation such as its powder-injection or liquid drugs injection
When be with mole ratio 1 with two kinds of materials of adenosine cyclophosphate and meglumine:1 ratio directly feeds intake what is prepared, but people
Occasionally have and be referred to as a kind of saying of double salt, it is said that for example form the compound of following structure：
There are many relevant adenosine cyclophosphate technology such as its preparation technique such as its powder-injection or liquid drugs injection in the prior art
Technology is reported.
Meglumine adenosine cyclophosphate composite medicament or ring phosphorus that CN101780099A (201010108233.5, Deng Xuefeng) is related to
Adenosine composition of medicine, is made up of the effective component of following parts by weight:Meglumine adenosine cycle phosphate or adenosine cyclophosphate 20-60, rely ammonia
Sour aspirin 100-200, reduced glutathione is with vitamin C weight than 1: 10-15 mixture 200-300.The system of having invented
Preparation Method.The meglumine adenosine cyclophosphate composite medicament or adenosine cyclophosphate composition of medicine of the present invention, eliminates prior art preparation
Heating, fash, the adverse reaction of pain of meglumine adenosine cycle phosphate or adenosine cyclophosphate.
CN103613626A (201310619163.3, Merrill Lynch) is related to a kind of adenosine cyclophosphate compound and its adenosine cyclophosphate Portugal
Drug amine composition.Adenosine cyclophosphate compound of the present invention is crystal, is determined using X-ray powder diffraction, characteristic peak in its collection of illustrative plates
2 θ ± 0.2 ° be 5.8 °, 6.9 °, 7.6 °, 11.3 °, 16.5 °, 19.2 °, 21.7 °, 22.6 °, 24.0 °, 25.9 °, 30.1 °,
31.2 °, 33.4 ° of displays.The present invention is also provided with imitating the parenteral solution and ring that composition is adenosine cyclophosphate compound of the present invention
Phosphorus adenosine Portugal amine composition parenteral solution and its meglumine adenosine cycle phosphate dextrose composition parenteral solution.Cyclic AMP injecta of the present invention
Stability is significantly increased compared with prior art, and L MALIC ACID, sodium tartrate are added in prescription can further improve stability.
CN102988305A (201210303740.3, Yao Yun) is related to a kind of medicine containing meglumine cyclic adenosine monophosphate compound
Composition, more particularly to a kind of freeze-dried powder of meglumine adenosine cycle phosphate and preparation method thereof, every 1000 injections, by with
The component of lower proportioning is made：Meglumine adenosine cycle phosphate 20g；Mannitol 100-200g；EDTA calcium 1-3g；Vitamin C 1-2g, mol ratio
For 1：4 DisodiumHydrogen Citrate and trisodium citrate buffer solution 2000ml.
CN1579413A (200410013546.7, Jiang Weishi) discloses meglumine cyclic adenosine for injecta and its prepares work
Skill.In meglumine adenosine cycle phosphate solution, with the extension of holding time, adenosine cyclophosphate can be separated out gradually, decoction generation is gone bad,
Muddiness, serious adverse reaction can occur to patient's application, so as to influence the curative effect of medicine and the security of medication.Injection ring
Phosphorus adenosine Portugal amine, its composition includes:Freeze drying powder injection is made with meglumine and excipient in adenosine cyclophosphate, described adenosine cyclophosphate,
Its parts by weight is adenosine cyclophosphate 1.7~63, meglumine 1.0~37, excipient 0.675~90, described adenosine cyclophosphate and institute
The ratio of weight and number for the meglumine stated is 1.7: 1, and pH value is 3.5-9.0, and character is that white or off-white color freeze block or powder
End, just shows reddish brown precipitation with the reaction of ferric trichloride test solution, brown-red solution is dissolved into immediately.This product is used to treat heart failure
Exhaust, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy, it can also be used to the auxiliary treatment of arrhythmia cordis.
CN1459288A (03124559.5, Zhao Chen) is related to a kind of meglumine adenosine cycle phosphate great transfusion preparation and preparation method thereof
And adenosine cyclophosphate Portugal amine content assay method in the great transfusion preparation.The isotonic great transfusion preparation of meglumine adenosine cycle phosphate, it is matched somebody with somebody
Side is meglumine adenosine cycle phosphate containing main ingredient 54-66mg, isotonic medium glucose 4.5-5.5g or sodium chloride 0.85- in 100ml preparations
0.95g.Present invention determine that the stable key condition pH value range of meglumine adenosine cycle phosphate great transfusion preparation and its great transfusion preparation
Preparation method simultaneously solves meglumine adenosine cycle phosphate content assaying method, is conducive to producing meglumine adenosine cycle phosphate great transfusion preparation
The control of quality, so as to formulate suitable production method, enables meglumine adenosine cycle phosphate great transfusion preparation industrial mass to give birth to
Production is possibly realized.Using this preparation, it can avoid extracting the intermediate link of decoction injection glucose or the big transfusion of sodium chloride from small pin,
Prevent the cross-infection and pollution during medication, it is safer, conveniently using medicine.The present invention can be made into plurality of specifications, supply
Medical personnel take the circumstances into consideration to select.
CN101721357A (200810230677.9, Central China) discloses one kind of meglumine adenosine cycle phosphate high-capacity injection
Filter method.The present invention is preprocessed first by the preparation liquid of meglumine adenosine cycle phosphate high-capacity parenteral solution, then again through ultrafiltration skill
Art processing, it is ensured that macromolecular invalid components are completely removed, high, the relevant material of the injection clarity being made is small, pyrogen is closed
Lattice, stability are good.
CN1923180A (200610116409.5, ten thousand nations) and a kind of preparation technology of meglumine cyclic adenosine for injecta, category
Chemical pharmacy.A kind of preparation technology of meglumine cyclic adenosine for injecta:Take 6% meglumine adenosine cycle phosphate solution and add in its solution
Enter excipient aseptic powder, stirring and dissolving adds water for injection dilution, adjusts pH value in the range of 5.5~7.0, cooling, when product temperature reaches
To after -35 DEG C to 1-2 hours, condensation, when condenser temperature is down to -45 DEG C, is evacuated to pressure for -1.5 × 10-2KPA,
Heated up with 3 DEG C/h of speed, when product temperature reaches room temperature or more than 30 DEG C, be incubated 2 hours, whole freeze-drying process is needed 24-26 hours.
The meglumine cyclic adenosine for injecta of the present invention, is the aseptic freeze-dried powder-injection being made of Modern preparations technology, can normal temperature transport,
Preserve, improve the stability and security of the product.The preparation technology of this product is simple, scientific and reasonable, easily operation.
CN101455631A (200910060427.X, De Kang) be related to a kind of adenosine cyclophosphate for injection freeze drying powder injection and its
Preparation technology, it is that citric acid is put into magnetic agitation tank, plus the water for injection of amount of preparation 50% is stirred to dissolve, then by ring phosphorus
Adenosine, meglumine are added in above-mentioned solution, are stirred to dissolve, and add 0.02% needle-use activated carbon by volume, are stirred 30 minutes,
Coarse filtration carbon removal, is made meglumine adenosine cycle phosphate solution for standby, and benefit adds to the full amount of water for injection, and PH is adjusted with 10% sodium hydroxide solution
Colourless clear and bright parenteral solution is made to 6.0-6.5 in value.The present invention not only has the advantages that effect is direct, quick, and this product is not
Good reaction is few, can normal temperature transport, preserve, thus improve the stability and security of the product.
CN102283804A (201010214356.7, Fang Ming) be related to a kind of adenosine cyclophosphate for injection freeze drying powder injection and its
Preparation method.Its preparation technology is to take appropriate water for injection, adds sodium chloride, adenosine cyclophosphate, meglumine, and stirring makes completely molten
Solution, 0.05~0.2% (W/V) needle-use activated carbon is added by volume, is stirred 15~30 minutes, is filtered carbon removal, is added water for injection
To nearly full dose, between phosphate buffer tune pH value to 6.0~6.5, benefit adds to the full amount of water for injection, and detection semi-finished product are qualified
Afterwards, filter, embedding (overall process inflated with nitrogen), sterilizing, lamp inspection, packaging are produced.It the advantage is that:Suitable solvent is selected and attached
Plus agent, the dissolubility and stability of meglumine adenosine cycle phosphate are improved, using the preparation method of final sterilization, medicine is effectively guaranteed
The sterility assurance level of product.Simple with prescription, technique, production cost is low, the features such as medicine stability, high safety.
CN102600070A (201110435919.X, De Kang) is related to a kind of preparation method of chemicals, specifically
It is a kind of meglumine adenosine cyclophosphate composition injection and its preparation.Its parts by weight is：5-15 parts of adenosine cyclophosphate, meglumine 3-10
Part, 2.0-2.2 parts of citric acid, 0.6-0.8 parts of sodium hydroxide, 2-4 parts of sodium chloride, 2-5 parts of water for injection；Preparation process is as follows：
Citric acid is taken, filling is penetrated after dissolving of blunging, adjust pH value to 5.9~6.5 formation cushioning liquid with sodium hydroxide, add
Sodium chloride and cosolvent stirring and dissolving, add water for injection, and adenosine cyclophosphate, meglumine are added while stirring, until completely dissolved,
Activated carbon stirring is added, colourless clear liquid is made through filtering, backflow.Clarity of injection of the present invention is good, and stability is good, uses
Medicine safety.
CN102796156A (201210314213.2, Ning Hui) is related to a kind of Adenosine cyclophosphate double-molecule meglumine compound and its system
Compound that Preparation Method is formed there is provided the meglumine by 1 molecule adenosine cyclophosphate and 2 molecules, its preparation method, and comprising it
Pharmaceutical composition.The compound water soluble, stability are superior to existing compound.
CN102258531A (201110102704.6, Ning Hui) provides a kind of medicine containing adenosine cyclophosphate and meglumine
Composition and preparation method thereof, it is comprising the adenosine cyclophosphate as active component, the meglumine as stabilizer and is used as skeleton
Mannitol, with it is certain proportioning exist.The present composition minimizes the degraded of adenosine cyclophosphate, so as to protect drug substance stable
Property, validity and security.
CN101455631A (200910060427.X, De Kang) be related to a kind of adenosine cyclophosphate for injection freeze drying powder injection and its
Preparation technology, it is that citric acid is put into magnetic agitation tank, plus the water for injection of amount of preparation 50% is stirred to dissolve, then by ring phosphorus
Adenosine, meglumine are added in above-mentioned solution, are stirred to dissolve, and add 0.02% needle-use activated carbon by volume, are stirred 30 minutes,
Coarse filtration carbon removal, is made meglumine adenosine cycle phosphate solution for standby, and benefit adds to the full amount of water for injection, and PH is adjusted with 10% sodium hydroxide solution
Colourless clear and bright parenteral solution is made to 6.0-6.5 in value.The present invention not only has the advantages that effect is direct, quick, and this product is not
Good reaction is few, can normal temperature transport, preserve, thus improve the stability and security of the product.
However, existing adenosine cyclophosphate preparation such as its freeze-drying pulvis still has technical problem to be overcome.
Therefore, those skilled in the art still expect have new method to freeze to prepare the adenosine cyclophosphate for injection with Good Pharmacy performance
Dry powder injection drug composition.
The content of the invention
Present invention aims at provide a kind of adenosine cyclophosphate for injection freeze drying powder injection medicine with Good Pharmacy performance
Composition.The present inventor is it has been unexpectedly discovered that the adenosine cyclophosphate for injection freeze-dried powder with present composition feature
Injection drug composition can valuably realize above-mentioned purpose.Therefore the present invention is accomplished.
Therefore, first aspect present invention provides a kind of adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition, wherein
Comprising：Adenosine cyclophosphate, mannitol and acid-base modifier.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, wherein the material included is every with adenosine cyclophosphate
10 parts by weight meters, the amount of mannitol is 10~50 parts by weight；The amount of such as mannitol is 10~25 parts by weight.
The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, its
Described in acid-base modifier be selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, phosphoric acid
Hydrogen dipotassium, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.
The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, its
Described in acid-base modifier be phosphoric acid and/or disodium hydrogen phosphate.
The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, its
Described in acid-base modifier be phosphoric acid and/or disodium hydrogen phosphate, its consumption is so that the pharmaceutical composition is being dissolved in water simultaneously
Dilution is when being made the solution of the 10mg containing adenosine cyclophosphate in every 1ml, and the pH value of the solution is 5.5~7.0, and such as pH value is 6.0~
6.5。
The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, its
In also include sodium chloride.
The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, its
In also include sodium chloride, in terms of every 10 parts by weight of adenosine cyclophosphate, the amount of sodium chloride is 0.5~3mg, such as 1~2mg.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is freeze-drying powder-injection.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, its solution before freeze-drying is except bag
Include outside adenosine cyclophosphate, mannitol and optional sodium chloride and optional acid-base modifier, in addition to water for injection.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, its solution before freeze-drying is except bag
Include outside adenosine cyclophosphate, mannitol and optional sodium chloride and optional acid-base modifier, in addition to water for injection, the solution
Solid content be 1~20% (w/v), preferably 2~15% (w/v), even more preferably 2~10%.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, its with water for injection redissolve to substantially with
Solid content before freeze-drying in solution identical volume, resulting solution is 1~20% (w/v), preferably 2~15% (w/
V), even more preferably 2~10%.
The pharmaceutical composition of any embodiment according to a first aspect of the present invention, it is freeze-drying powder-injection, its every bottle
The adenosine cyclophosphate weight included is 10~100mg, and such as every bottle adenosine cyclophosphate weight included is 10~75mg, for example often
The adenosine cyclophosphate weight that bottle includes is 10~50mg.
It is well known that the freeze-drying powder-injection obtained through cryogenic freezing-vacuum drying (is often referred to simply as freeze-dried powder
Agent or freeze-dried powder), it is that each material solvent is dissolved into (being dissolved with water) first, is configured to a solution, so
After the solution is carried out cryogenic freezing, then a kind of substantially anhydrous (the typically water vacuumized, distilled, dried and obtain
Content is less than 8%, is especially generally lower than 5%, is especially generally lower than powdered thing or block 3%).Therefore, this is consolidated
The acid-base value of body lyophilized products generally adjusts the pH value of solution to control by process for preparation；Or can by prescription adjust so that
The solid lyophilized products of acquisition control the pH value of the dissolving/dilution to control (referred to herein as to control under defined dissolving/dilute strength
The acid-base value of solid lyophilized products processed)；Latter means are generally more generally used, such as contained many freeze drying powder injections in pharmacopeia
The acid-base value of product is controlled in this way, and this mode controls the acid-base value of product generally can not concrete regulation soda acid tune
The recipe quantity of agent is saved, and only provides the acid-base value of finished product.The present invention is equally applicable to, according to first party of the present invention
Pharmaceutical composition described in any embodiment of face, wherein the amount of the optional acid-base modifier is to make the freeze-dried powder
The pH value of the solution is in the range of 5.5~7.0 when agent is dissolved into the solution of the concentration of 10mg/ml containing active component with water for injection
Amount, the amount of the pH value of such as solution in the range of 6.0~6.5.
The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, its
Described in sodium chloride be configured in advance together with adenosine cyclophosphate solution and pH value be less than 4.5 (such as pH value 3.5~4.0)
Under the conditions of handled with charcoal absorption.It has been had now surprisingly been found that, adenosine cyclophosphate has been entered in advance when using appropriate sodium chloride
After row particular procedure, obtained adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition has excellent property such as chemistry steady
It is qualitative.
The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition of any embodiment according to a first aspect of the present invention, its
It is to be prepared according to the method comprised the following steps：
(1) adenosine cyclophosphate and sodium chloride is made to add in the room temperature water for injection of amount of preparation 60%, stirring and dissolving is adjusted with soda acid
Agent regulating liquid medicine pH value is saved to 3.5~4.0, needle-use activated carbon, stirring and adsorbing 20 are added by 0.05~0.15w/v% of medicine liquid volume
Minute, filtering decarbonization is standby；
(2) mannitol is added in the room temperature water for injection of amount of preparation 20%, stirring and dissolving, by medicine liquid volume 0.05~
0.15w/v% addition needle-use activated carbons, stirring and adsorbing 20 minutes, filtering decarbonization is standby；
(3) decoction mixing obtained by step (1) and step (2) is made, with acid-base modifier regulating liquid medicine pH value to 6.0~6.5,
After the titanium rod filter for being 1um with aperture is filtered, room temperature water for injection is added to amount of preparation, the pH value for determining solution simultaneously uses soda acid
Conditioning agent regulating liquid medicine pH value is to 6.0~6.5；
(4) it is that 0.22um miillpore filters filter core circulates aseptic filtration to solution to filtrate through visible foreign matters inspection conjunction with aperture
After lattice, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
The pharmaceutical composition of any embodiment, wherein adds room temperature note according to a first aspect of the present invention described in step (3)
Penetrate with water to amount of preparation, refer to that the solid content in gained decoction is 1~20% (w/v), preferably 2~15% (w/v), then more
It is preferred that 2~10%.
Further, second aspect of the present invention provides and prepares adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition
Included in method, the adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition：Adenosine cyclophosphate, mannitol, sodium chloride and acid
Alkali conditioning agent, this method comprises the following steps：
(1) adenosine cyclophosphate and sodium chloride is made to add in the room temperature water for injection of amount of preparation 60%, stirring and dissolving is adjusted with soda acid
Agent regulating liquid medicine pH value is saved to 3.5~4.0, needle-use activated carbon, stirring and adsorbing 20 are added by 0.05~0.15w/v% of medicine liquid volume
Minute, filtering decarbonization is standby；
(2) mannitol is added in the room temperature water for injection of amount of preparation 20%, stirring and dissolving, by medicine liquid volume 0.05~
0.15w/v% addition needle-use activated carbons, stirring and adsorbing 20 minutes, filtering decarbonization is standby；
(3) decoction mixing obtained by step (1) and step (2) is made, with acid-base modifier regulating liquid medicine pH value to 6.0~6.5,
After the titanium rod filter for being 1um with aperture is filtered, room temperature water for injection is added to amount of preparation, the pH value for determining solution simultaneously uses soda acid
Conditioning agent regulating liquid medicine pH value is to 6.0~6.5；
(4) it is that 0.22um miillpore filters filter core circulates aseptic filtration to solution to filtrate through visible foreign matters inspection conjunction with aperture
After lattice, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
The method of any embodiment, the adenosine cyclophosphate for injection freeze-dried powder obtained by it according to a second aspect of the present invention
Agent pharmaceutical composition is the pharmaceutical composition of freeze-drying powder-injection form.
The method of any embodiment, the adenosine cyclophosphate for injection freeze-dried powder obtained by it according to a second aspect of the present invention
The material included in agent pharmaceutical composition is in terms of every 10 parts by weight of adenosine cyclophosphate, and the amount of mannitol is 10~50 parts by weight；For example
The amount of mannitol is 10~25 parts by weight.
The method of any embodiment according to a second aspect of the present invention, wherein described acid-base modifier is selected from hydroxide
Sodium, 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.
The method of any embodiment according to a second aspect of the present invention, wherein described acid-base modifier be phosphoric acid and/or
Disodium hydrogen phosphate.
The method of any embodiment according to a second aspect of the present invention, wherein described acid-base modifier be phosphoric acid and/or
Disodium hydrogen phosphate, its consumption is so that 10mg containing adenosine cyclophosphate in every 1ml is made being dissolved in water and dilute in the pharmaceutical composition
Solution when, the pH value of the solution is 5.5~7.0, and such as pH value is 6.0~6.5.
The method of any embodiment, the adenosine cyclophosphate for injection freeze-dried powder obtained by it according to a second aspect of the present invention
Agent pharmaceutical composition, in terms of every 10 parts by weight of adenosine cyclophosphate, the amount of sodium chloride is 0.5~3mg, such as 1~2mg.
The method of any embodiment, the adenosine cyclophosphate for injection freeze-dried powder obtained by it according to a second aspect of the present invention
Agent pharmaceutical composition is freeze-drying powder-injection.
The method of any embodiment, the adenosine cyclophosphate for injection freeze-dried powder obtained by it according to a second aspect of the present invention
Solution of the agent pharmaceutical composition before freeze-drying remove include adenosine cyclophosphate, mannitol and optional sodium chloride and optionally
Outside acid-base modifier, in addition to water for injection.
The method of any embodiment, the adenosine cyclophosphate for injection freeze-dried powder obtained by it according to a second aspect of the present invention
Solution of the agent pharmaceutical composition before freeze-drying remove include adenosine cyclophosphate, mannitol and optional sodium chloride and optionally
Outside acid-base modifier, in addition to water for injection, the solid content of the solution is 1~20% (w/v), preferably 2~15% (w/
V), even more preferably 2~10%.
The method of any embodiment, the adenosine cyclophosphate for injection freeze-dried powder obtained by it according to a second aspect of the present invention
Agent pharmaceutical composition water for injection is redissolved to the solid substantially with being freeze-dried in preceding solution identical volume, resulting solution
Thing content is 1~20% (w/v), preferably 2~15% (w/v), even more preferably 2~10%.
The method of any embodiment, the adenosine cyclophosphate for injection freeze-dried powder obtained by it according to a second aspect of the present invention
Agent pharmaceutical composition is freeze-drying powder-injection, during its every bottle adenosine cyclophosphate weight included is 10~100mg, such as every bottle
Including adenosine cyclophosphate weight be 10~75mg, such as every bottle adenosine cyclophosphate weight that includes is 10~50mg.
The method of any embodiment, wherein adds room temperature water for injection described in step (3) according to a second aspect of the present invention
To amount of preparation, refer to that the solid content in gained decoction is 1~20% (w/v), preferably 2~15% (w/v), even more preferably 2
~10%.
Further, third aspect present invention is provided is carried out to adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition
Included in the method for quality control, the adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition：Adenosine cyclophosphate, mannitol,
And acid-base modifier, the method for quality control is including the use of the adenosine cyclophosphate content in high effective liquid chromatography for measuring injection
And/or relevant amount of substance.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Pharmaceutical composition is the pharmaceutical composition of freeze-drying powder-injection form.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
The material included in pharmaceutical composition is in terms of every 10 parts by weight of adenosine cyclophosphate, and the amount of mannitol is 10~50 parts by weight；For example it is sweet
The amount for revealing alcohol is 10~25 parts by weight.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Acid-base modifier described in pharmaceutical composition is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, phosphoric acid
Potassium dihydrogen, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Acid-base modifier described in pharmaceutical composition is phosphoric acid and/or disodium hydrogen phosphate.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Acid-base modifier described in pharmaceutical composition is phosphoric acid and/or disodium hydrogen phosphate, and its consumption is so that the pharmaceutical composition exists
It is dissolved in water and dilutes when the solution of the 10mg containing adenosine cyclophosphate in every 1ml is made, the pH value of the solution is 5.5~7.0, such as pH
It is worth for 6.0~6.5.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Also include sodium chloride in pharmaceutical composition.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Also include sodium chloride in pharmaceutical composition, in terms of every 10 parts by weight of adenosine cyclophosphate, the amount of sodium chloride is 0.5~3mg, such as 1~
2mg。
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Pharmaceutical composition is freeze-drying powder-injection.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Solution of the pharmaceutical composition before freeze-drying, which is removed, includes adenosine cyclophosphate, mannitol and optional sodium chloride and optional acid
Outside alkali conditioning agent, in addition to water for injection.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Solution of the pharmaceutical composition before freeze-drying, which is removed, includes adenosine cyclophosphate, mannitol and optional sodium chloride and optional acid
Outside alkali conditioning agent, in addition to water for injection, the solid content of the solution is 1~20% (w/v), preferably 2~15% (w/
V), even more preferably 2~10%.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Pharmaceutical composition water for injection is redissolved to the solid content substantially with being freeze-dried in preceding solution identical volume, resulting solution
Content is 1~20% (w/v), preferably 2~15% (w/v), even more preferably 2~10%.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Pharmaceutical composition is freeze-drying powder-injection, and its every bottle adenosine cyclophosphate weight included is bag in 10~100mg, such as every bottle
The adenosine cyclophosphate weight included is 10~75mg, and such as every bottle adenosine cyclophosphate weight included is 10~50mg.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Sodium chloride described in pharmaceutical composition is to be configured to solution together with adenosine cyclophosphate in advance and be less than 4.5 (such as pH value in pH value
3.5~4.0) under conditions of handled with charcoal absorption.It has been had now surprisingly been found that, when right in advance using appropriate sodium chloride
Adenosine cyclophosphate is carried out after particular procedure, and obtained adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition has excellent property
Such as chemical stability.
The method of any embodiment according to a third aspect of the present invention, wherein the adenosine cyclophosphate for injection freeze drying powder injection
Pharmaceutical composition is prepared according to the method comprised the following steps：
(1) adenosine cyclophosphate and sodium chloride is made to add in the room temperature water for injection of amount of preparation 60%, stirring and dissolving is adjusted with soda acid
Agent regulating liquid medicine pH value is saved to 3.5~4.0, needle-use activated carbon, stirring and adsorbing 20 are added by 0.05~0.15w/v% of medicine liquid volume
Minute, filtering decarbonization is standby；
(2) mannitol is added in the room temperature water for injection of amount of preparation 20%, stirring and dissolving, by medicine liquid volume 0.05~
0.15w/v% addition needle-use activated carbons, stirring and adsorbing 20 minutes, filtering decarbonization is standby；
(3) decoction mixing obtained by step (1) and step (2) is made, with acid-base modifier regulating liquid medicine pH value to 6.0~6.5,
After the titanium rod filter for being 1um with aperture is filtered, room temperature water for injection is added to amount of preparation, the pH value for determining solution simultaneously uses soda acid
Conditioning agent regulating liquid medicine pH value is to 6.0~6.5；
(4) it is that 0.22 μm of miillpore filter filter core circulates aseptic filtration to solution to filtrate through visible foreign matters inspection conjunction with aperture
After lattice, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
The method of any embodiment, wherein adds room temperature water for injection described in step (3) according to a third aspect of the present invention
To amount of preparation, refer to that the solid content in gained decoction is 1~20% (w/v), preferably 2~15% (w/v), even more preferably 2
~10%.
The method of any embodiment according to a third aspect of the present invention, wherein the high performance liquid chromatography is to adenosine cyclophosphate
The step of carrying out assay and relevant substance-measuring includes following operation：
(1) Chinese Pharmacopoeia version in 2015 four the 59th specification in Section of 0512 contained high performance liquid chromatography carry out
Determine；
(2) chromatographic condition and system suitability：With the chromatographic column (example that octadecylsilane chemically bonded silica is filler
Such as, the specification of chromatographic column is 250mm × 4.6mm, 5 μm), with 0.01 phosphoric acid solution-acetonitrile with volume ratio 95：5 mixed liquor is
Mobile phase, flow velocity 1ml/min, 30 DEG C of column temperature, Detection wavelength is 259nm；System suitability solution is taken to determine, number of theoretical plate
5000 should be not less than based on adenosine cyclophosphate peak, the separating degree between adenosine cyclophosphate and adenosine should be greater than 2；
(3) prepared by solution：
Take adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition appropriate, plus flowing phase dilution, it is made in every 1ml solution
Solution containing adenosine cyclophosphate 1mg, filtering, as Related substances separation with need testing solution (that is, 1000 μ g/ml)；
Precision measures Related substances separation and is placed in need testing solution 1ml in 100ml measuring bottles, with flowing phase dilution scale,
Shake up, the solution that concentration containing adenosine cyclophosphate is 10 μ g/ml is made, Related substances separation contrast solution (that is, 10 μ g/ are used as
ml)；
Precision measures Related substances separation and is placed in need testing solution 1ml in 20ml measuring bottles, with flowing phase dilution scale, shakes
It is even, the solution that concentration containing adenosine cyclophosphate is 50 μ g/ml is made, as assay with need testing solution (that is, 50 μ g/ml)；
Precision weighs that adenosine cyclophosphate reference substance is appropriate, with flowing phased soln and the solution that concentration is 50 μ g/ml is made, as
Adenosine cyclophosphate assay is with reference substance solution (that is, 50 μ g/ml)；
It is each appropriate that precision weighs adenosine cyclophosphate reference substance, adenosine reference substance, plus flowing phased soln and dilutes, and every 1ml is made
Mixed solution containing the μ g of adenosine cyclophosphate 1000, the μ g of adenosine 10 in solution, is used as system suitability solution (that is, 1000 μ g/
ml+10μg/ml)；
(4) determine：
Precision measures the μ l of system suitability solution 20, injects liquid chromatograph, records chromatogram, calculates theoretical plate number
The separating degree between separating degree peak between adenosine cyclophosphate and adenosine, and when determining the reservation of adenosine cyclophosphate and both adenosines
Between；
Precision measures Related substances separation need testing solution and each 20 μ l of Related substances separation contrast solution respectively, point
Do not inject liquid chromatograph, 3 times of record chromatogram to adenosine cyclophosphate retention time, read in need testing solution chromatogram it is main into
The peak area of peak peak area and each impurity, when detecting the presence of acrobatics, with Related substances separation with contrast solution chromatogram
Main composition peak area is 1.0%, calculates each impurities phase in need testing solution chromatogram and, for the percentage composition of adenosine cyclophosphate, produces
The content of single contaminant into test sample is (if i.e., for example, contrast solution main peak area is 100, need testing solution chromatogram
In certain impurity peak area be 115, then the impurities phase for adenosine cyclophosphate percentage composition, referred to as the impurity content be
1.15%；The peak area of certain impurity is 87 in need testing solution chromatogram, then 0.87%) impurity content is；
Precision measures assay need testing solution and each 20 μ l of assay reference substance solution respectively, is injected separately into
Liquid chromatograph, record chromatogram obtains two chromatograms, two chromatograms is read respectively to 2 times of adenosine cyclophosphate retention time
It is middle main into peak peak area, by external standard method with the content of adenosine cyclophosphate in calculated by peak area test sample.
Document (the He Xiaoyan, etc. HPLC methods measure adenosine cyclophosphate for injection freeze drying powder injection of the above method and He Xiaoyan etc.
The content of middle adenosine cyclophosphate, Chinese pharmacists, 2011,14 (5):682) it is a kind of disclosed in determine active component in adenosine cyclophosphate preparation
The method of content is essentially identical, and the present invention through determining in aforementioned manners, adenosine cyclophosphate number of theoretical plate 75000, adenosine cyclophosphate and gland
The separating degree of glycosides about 2.73, adenosine cyclophosphate tailing factor 1.008, adenosine cyclophosphate retention time about 6.69, adenosine is relative to ring phosphorus
The relative retention time RRT=0.88 of adenosine, it is basically identical what these results know gorgeous result by references with.However, in adenosine cyclophosphate
In preparation, determined using the above method, there is an obvious unknown impuritie at relative retention time about RRT=1.08, this
Separating degree between impurity and adenosine cyclophosphate peak is about 1.34, and separating degree is unsatisfied with, and has influence on adenosine cyclophosphate and the unknown impuritie
The calculating of peak area.Therefore, above-mentioned HPLC methods are still Shortcomings.
The method of any embodiment according to a third aspect of the present invention, wherein in the mobile phase of the high performance liquid chromatography
Also add 0.2~0.5w/v% formic acid.In one embodiment, 0.3w/v% formic acid is also added in the mobile phase.
It has been found that when adding 0.3w/v% formic acid in mobile phase, relative to the situation for being not added with formic acid, number of theoretical plate, ring
The separating degree of phosphorus adenosine and adenosine, adenosine cyclophosphate tailing factor, adenosine cyclophosphate retention time, adenosine RRT these parameters are substantially
Do not change, but be extended down to after unknown impuritie retention time RRT be about 1.17 (it can be described as impurity RRT1.17 in the present invention) and
Separating degree between adenosine cyclophosphate reaches 2.42, fully meets the requirement for determining principal component and the unknown impuritie.In addition,
It was found that, when formic acid is replaced with into this similar organic acid of acetic acid, do not reach above-mentioned separating effect, i.e. unknown impuritie completely but
RRT is about 1.08 and the separating degree between adenosine cyclophosphate is 1.39, and remaining parameter is essentially identical.
Further, it has been found that in the preparation that above-mentioned impurity RRT1.17 is made in bulk drug and initially in adenosine cyclophosphate preparation
It is substantially not present (or content is extremely low), but be gradually increased during long-term storage.This hair is being prepared it has been found that working as
A small amount of sodium chloride is added into preparation and make the sodium chloride handle to make with special mode of operation during bright adenosine cyclophosphate preparation
During standby said preparation, gained preparation impurity RRT1.17 during long-term storage gathers way extremely low, and this is that prior art is basic
Can not be expected.
In the step of above-mentioned preparation method of the invention, although specific steps that it is described are in some details or language
The step of described in preparation example in description with following detailed description part, is otherwise varied, however, people in the art
Member can summarize approach described above step completely according to the detailed disclosure of full text of the present invention.
Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not
Contradiction occurs.In addition, in any embodiment of either side of the present invention, any technical characteristic goes for other realities
The technical characteristic in scheme is applied, as long as they are not in contradiction.The invention will be further described below.
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 the statement of the present invention.In addition, 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 explained that the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention
The implication stated is defined.
Adenosine cyclophosphate is non-digitalis cardiotonic, with positive correction myodyamia effect, can strengthen myocardial contractive power, improve the heart
Flesh blood-pumping function, has expansion blood vessel function, it is possible to decrease myocardial oxygen consumption；Improve metabolism of myocardium, protection ischemic, the heart of anoxic
Flesh；Sinoatrial node P cell functions can be improved.Adenosine cyclophosphate enters human body, and half-life period in blood is 60~150min, due to
It has preferable hydrophily, especially fat-soluble relatively strong, is easier to enter through fat-soluble cell membrane and is played a role in cardiac muscle cell,
5-AMP is decomposed to form through di-phosphate ester undergraduate course, then adenosine and phosphoric acid are degraded to through 5-AMP undergraduate courses, adenosine cyclophosphate is 10 after medication
Start effect after~20min, effective rush hour, drug effect extinction time was at 6~8 hours at 1~2 hour.
The Main Ingredients and Appearance of adenosine cyclophosphate preparation of the present invention is adenosine cyclophosphate, is non-digitalis cardiotonic, with positivity flesh
Power is acted on, and strengthens myocardial contractive power, improves myocardium blood-pumping function, has expansion blood vessel function, it is possible to decrease myocardial oxygen consumption, improves the heart
Muscle Cells Metabolism, protection ischemic, the cardiac muscle cell of anoxic, can improve the p cell functions of sinoatrial node, clinically have been used for treating the heart
Force failure, coronary heart disease, cerebral infarction and Other diseases.
Adenosine cyclophosphate preparation of the present invention can be used for treatment angiocardiopathy.
To the therapeutic action aspect of congestive heart failure.Congestive heart failure is common in coronary heart disease, dilated cardiomyopathy
Disease, rheumatic heart disease etc., 48 cases of congestive heart failure is treated using adenosine cyclophosphate ejection preparation.Male in treatment group 48
28, women 20, heart function II-III grade 30, IV grade 18, control group 40, male 24, women 16, heart function
II-III grade 28, IV grade 16.Sex, Age and cardiac functional grading compare for without significant (p>0.05).Treatment group uses
90 milligrams of adenosine cyclophosphate ejection preparation is added in 250 milliliters of 3% glucose or 0.9% physiological saline, and vein is instilled, two Zhou Weiyi
The course for the treatment of, uses two courses for the treatment of.Control group is given only cardiac stimulant diuresis and the treatment of renin angiotensin converting enzyme inhibitor.Treatment group：
Effective 17 (35.4%), effective 26 (54.18%), invalid 5 (10.42), control group：Effective 6 (15%), effective 23
Example (57.5%), invalid 11 (27.5), treatment group's total effective rate 89.58%, control group 72.5%, treatment group's total effective rate is bright
It is aobvious to be higher than control group.
As a result show that treatment group is substantially better than control group, adenosine cyclophosphate ejection preparation can significantly improve the courageous and upright heart failure of punching
The myocardial systolic property of patient is exhausted, exercise tolerance, quality of making the life better is improved.
84 congestive heart failures are treated with adenosine cyclophosphate ejection preparation, two groups are used cardiac stimulant, and diuresis is expanded blood vessel and controlled
Treat, treatment group, which adds, uses 60 milligrams to 180 milligrams of adenosine cyclophosphate ejection preparation, adds 250 milligrams of 5% glucose or physiological saline
In, vein is instilled, once a day, 15 days as one therapeutic course.Treatment group is effective 31 (73.8%), effective 10, and (23.8) are invalid
1 (2.4%) is effective 19 (45.2%), invalid 6 (14.3%), total effective rate 36 (85.7%).Compared with control group
(p<0.01)。
As a result the remission of adenosine cyclophosphate ejection preparation treatment group is shown, heart failure improves degree and is considerably better than control
Group.Think adenosine cyclophosphate ejection preparation can by expand peripheral vascular, reduce heart before and after load, heart failure can be obviously improved
The symptom and sign of patient, with significant curative effect.
Treat heart failure in patients with coronary artery disease 39 with adenosine cyclophosphate ejection preparation, treatment group and control group using cardiac stimulant,
Blood vessel is expanded in diuresis.Treatment group, which adds, uses 90 milligrams of adenosine cyclophosphate ejection preparation to add 250 milligrams of 5% glucose or physiological saline,
Drip off within 90 minutes or so, be within 14 days a course for the treatment of once a day.Treatment group's total effective rate 92.3%, (p of control group 69.2%<
0.05).Symptom is obviously improved after treatment group's medication, and left chamber function is remarkably reinforced, often the amount of fighting, minute output, left ventricular ejection point
Significant difference (p after number medication<0.05) adverse reaction, is had no.
To the therapeutic action aspect of coronary heart disease.By coronary heart disease, 58 are divided into two groups, and treatment group 30 uses adenosine cyclophosphate 90
Milligram adds in 5% glucose or physiological saline 25 milligrams, and vein is instilled, once a day, is within 15 days a course for the treatment of.Control group 28
Example is added in 250 milligrams of 5% glucose or physiological saline for 15 milligrams with compound Danshen Root ejection preparation, and vein is instilled, once a day,
It is within 15 days a course for the treatment of.Two groups of clinical treatments compare, and adenosine cyclophosphate ejection preparation is improving electrocardiogram, uncomfortable in chest, angina pectoris, the heart
Throb with fear, the symptom obvious effective rate such as shortness of breath substantially, for compound Danshen Root ejection preparation group, the total effective rate for improving heart function is also obviously served in
Control group.
As a result confirm that adenosine cyclophosphate ejection preparation has positive inotropic action, can strengthen myocardial contractive power, improve myocardium pump
Blood function, expansion blood vessel, reduction myocardial oxygen consumption improve metabolism of myocardium, protection ischemic, the cardiac muscle of anoxic alleviate coronary heart disease
Face not symptom be better than compound Danshen Root ejection preparation.
To the therapeutic action aspect of pulmonary heart disease.Pulmonary heart disease 45, male 39, female are treated using adenosine cyclophosphate ejection preparation
Property 6,65-70 years old ages, medical history 5-25 years.90 milligrams of adenosine cyclophosphate ejection preparation adds 5% glucose or physiological saline
In 250 milligrams, vein is instilled, once a day, and 10-15 are a course for the treatment of, and blood vessel medicines are expanded and strong with other simultaneously during medication
Heart agent diuretics.Clinical observation shows, pulmonary heart disease give with uncomfortable in chest, palpitaition after the treatment of adenosine cyclophosphate ejection preparation, shortness of breath liver function,
Renal function, PFT, electrocardiogram obvious effective rate is more than 83%, total effective rate more than 95%.It is treatment pulmonary heart disease to think the medicine, special
Be not the first-line drug with heart failure, expansible blood vessel reduces pulmonary arterial pressure, enhancing myocardial contractive power improve the heart, liver, lung,
Renal function, improves life quality, extends life cycle.It is positive inotropic medicament safely, effectively, with applications well prospect.
To the therapeutic action aspect of dilated cardiomyopathy.Dilated cardiomyopathy 44 is treated using adenosine cyclophosphate ejection preparation
Example, treatment group using adenosine cyclophosphate ejection preparation vein instill, plus use cardiac stimulant, diuresis, Vasodilator therapy, control group be use by force
The general treatments such as the heart, diuresis, expansion blood vessel.Left room systolic and diastolic function is surveyed using colored cardiograph before treatment, is as a result shown, treatment group is left
Room diastole early stage peak velocity rises, and left room late diastolic peak velocity declines, and cardiac diastolic function substantially changes,
Stroke output, LVEF, cardiac index has improvement, incidence of arrhythmia reduction.
To the therapeutic action aspect of high blood pressure.Use adenosine cyclophosphate ejection preparation Hypertension 48, treatment group
With adenosine cyclophosphate ejection preparation, 90 milligrams are added in 250 milligrams of 5% glucose or physiological saline, and vein is instilled, once a day, even
Continue with 15 days.Control group 42, only oral 30 milligrams of nifedipine (Bayer public affairs can be produced) once a day, shares 15.Treatment group
Close control group and use other antihypertensive drugs and lipid-lowering medicine, as a result control group decompression effective percentage 91.67%.Systolic pressure diastolic pressure is equal
It is decreased significantly, the symptom such as giddy, dim eyesight, headache is notable, hence it is evident that better than control group, it is believed that adenosine cyclophosphate ejection preparation is a kind of
Treatment is notable, the good antihypertensive drugs of security.
Adenosine cyclophosphate preparation can be used for treatment cerebral infarction.Cerebral Infarction 32 Cases are treated using adenosine cyclophosphate ejection preparation.Treatment
Group 32, using adenosine cyclophosphate ejection preparation, 90 milligrams are added in 250 milligrams of 5% glucose or physiological saline, and vein is instilled, often
Day, once continuous was a course for the treatment of with 20 days.Control group 32,5% glucose or physiology salt are added using the phosphorus cholate 0.5 of born of the same parents two
In 250 milligrams of water, vein is instilled, once a day, and continuous was a course for the treatment of with 20 days.As a result treatment group's total effective rate 93.8%,
Control group 81.3%, two groups of treatments have notable difference.Think that adenosine cyclophosphate ejection preparation can promote in intracerebral intracellular mitochondrial
Energetic supersession, increases cerebral blood flow (CBF), improves brain partial pressure of oxygen, mitigates encephaledema, reduces Brain stem injury, promotes brain function to recover.
Cerebral infarction short treating period is treated, nervous lesion is light, achieves good efficacy.
Adenosine cyclophosphate preparation can be used for treatment chronic renal failure.Chronic renal work(is treated using adenosine cyclophosphate ejection preparation
Energy exhaustion, treatment group 20 adds on basis of conventional therapy and uses adenosine cyclophosphate 90 milligrams of ejection preparation, 250 milligrams of physiological saline
In, vein is instilled, once a day, and continuous was a course for the treatment of, general 1-2 course for the treatment of with 15 days.Control group 20, is given only routine
Treatment.As a result effective 4 for the treatment of group, (20%), effective 8 (40%), stablize 3, (15%), invalid 3 (25%).Control
Group effective 3 (15%), effective 5 (25%) stablize 6, (30%), invalid 6 (30%).By observing to renal function not
The treatment of full decompensation has good therapeutic effect, and the patients with renal failure treatment that 707umol/l is more than to creatinine is poor.Chronic kidney
Exhaustion is lost is coordinating adenosine cyclophosphate ejection preparation to treat simultaneously for phase patient using traditional dialysis treatment, can obtain delaying chronic
The effect of renal failure development.
According to the present invention, term " excipient " is also referred to as auxiliary material, filler etc..It is used herein " pharmaceutically acceptable
Excipient " refers to the excipient available for compounding pharmaceutical, and it there is no harmful effect to organism, and is typically to give birth to
Object is tolerable.
The preparation process of freeze-drying powder-injection is that 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：
Prepare below in the instantiation in freeze-drying powder-injection, 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 3%.
Moisture control can be controlled by suitably adjusting 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.
In the present invention, for the pH value of regulating liquid medicine when necessary, appropriate pH regulations can be added into composition
Agent.Although available strong acid or the strong base solution such as sodium hydrate aqueous solution and aqueous hydrochloric acid solution for not having buffer capacity of the present inventor
It is adjusted, if however, it will be appreciated by those skilled in the art that body can be met with this pH adjusting agent processing for not having buffer capacity
The pH requirements of system, then the pH adjusting agent with buffer capacity will be better able to realize the object of the invention, therefore these buffers are not
But pH value can be adjusted, and can stable pH value.Therefore the listed any pH adjusting agent of the present invention or its combination are included in this hair
In bright spirit and scope.
When preparing freeze drying powder injection of the present invention, in the decoction prepared, solid content be for 1~20% (w/v), it is excellent
2~15% (w/v) are selected, even more preferably 2~10%.Because freeze drying powder injection is typically to be freeze-dried in tubulose cillin bottle
Obtain, skilled artisan understands that this product is obtaining finished product even before for doctor's use, be typically each presented one
Round pie, although lecture is fewer than the volume of original aqueous solution in the volume theory of the cake (slightly reducing), however it is generally this
Diminution will not generally narrow down to raw water liquor capacity 50%, it will usually between the 80-120% of raw water liquor capacity, more generally
Between the 90-100% of raw water liquor capacity, and raw water liquid level of solution vestige (main body can be observed out of finished product cillin bottle
Pie after lyophilized reduce because remaining in the liquid level vestige in bottle wall, even if the dried frozen aquatic products in cillin bottle is for example touched because of a variety of causes
The reason such as hit and in powdered, still can generally retain original liquid level vestige), vestige can also estimate the freezing and do accordingly
Aqueous solution volume of the dry composition before freeze-drying.Therefore, although the present invention is to provide a kind of substantially anhydrous freezing
Powder-injection is dried, but it still can be substantially estimated according to the powder-injection when preparing, at least in freeze-drying beginning
The weight of drying end-product in preceding medicine liquid volume, the volume estimated according to this and cillin bottle, can also be calculated in system
During standby freeze drying powder injection of the present invention, the content of the solid content in the decoction prepared.Therefore, jelly according to a first aspect of the present invention
Dry powder injection, its prepare when decoction solid content be 1~20% (w/v), preferably 2~15% (w/v), even more preferably
2~10%.
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, activated with 100mg
Compound and a total of about 20mg other solid contents add appropriate aqueous solution for injection, are configured to the solution that final volume is 2ml, its solid
Thing content is 6%.
In the present invention, symbol %, according to its used linguistic context, can have skilled addressee readily understands that
Implication.For example when referring to solid content, 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, such as water content is below 8%, and now symbol % represents weight
The percentage (w/w, g/100g) of amount/weight.In general, when solid disperses in a liquid, % represents weight/volume percentage
Number；Scattered in solids or during liquid dispersion (such as the water content of powder pin) in solids in solid, % 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 preparing the decoction of the present invention, e.g., from about 0.45um miillpore filter can be used
Coarse filtration filtering is carried out, before decoction is filled in cillin bottle, e.g., from about 0.22um miillpore filter can be used to carry out essence
Filtration filter is with degerming, it may be necessary to which filtering is multiple.
The adenosine cyclophosphate preparation that the present invention is provided can be preserved at least 24 months below 25 DEG C at drying, can meet one
As ejection preparation Storage Requirement.
According to the pharmaceutical composition of the present invention, it is freeze-drying powder-injection.In one embodiment, the freeze-drying
Powder-injection is single-dose preparations (the bottled powder-injection in such as XiLin), and (it is at this for the amount of reactive compound in per unit dosage
In invention if not otherwise indicated, in terms of adenosine cyclophosphate) can such as, but not limited to about 10mg, about 20mg, about 30mg, about
50mg。
According to the pharmaceutical composition of the present invention, it is redissolved with water for injection, typically redissolves the time in 30 seconds, preferably
In 20 seconds, more preferably in 15 seconds.
According to the freeze drying powder injection of the present invention, the solution of the 10mg containing adenosine cyclophosphate is made in every 1ml and in it of water
Method under state's pharmacopeia annex VI H of version two in 2010 is determined, and the pH value of the solution is 5.5~7.0, and such as pH value is 6.0
~6.5.
Obtained freeze-drying powder-injection of the present invention particularly freeze-drying powder-injection is usually white or the lyophilized bulk of off-white color
Thing or its fragment or its powder, odorless, bitter are soluble in water.
Embodiment
The present invention can be further described 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 carries out general to the material and test method that are arrived used in experiment
And/or specific description.Although for realize many materials used in the object of the invention 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 limit this hair
It is bright.In following example, the pH adjusting agent (in the present invention that is, acid-base modifier) used unless otherwise noted, is
1mo1/L disodium phosphate solns or 0.1mol/L phosphorus acid-conditioning solutions, its consumption be make the preparation of preparation adjust to setting or
Scope.
Hereafter preparation process is for the purpose of citing, and the comparability based on each citing and make some specific description,
Those skilled in the art can therefrom summarize the method for obtaining preparation of preparation of the present invention according to existing knowledge completely.Match somebody with somebody liquid below
Prepare in various compositions, if not otherwise indicated, every batch is always 10000ml with liquid measure, but when listing formula, with relative
Illustrated in amounts of every 1ml with liquid measure (wherein adenosine cyclophosphate concentration about 10mg/ml), and with every bottle of 20mg containing adenosine cyclophosphate amount
It is dispensed into vial；20mg containing adenosine cyclophosphate in every bottle obtained of preparation.
First, composition quality control method
Using high performance liquid chromatography, assay is carried out to adenosine cyclophosphate preparation obtained by the present invention and relevant material is surveyed
Fixed, step includes following operation：
(1) Chinese Pharmacopoeia version in 2015 four the 59th specification in Section of 0512 contained high performance liquid chromatography carry out
Determine；
(2) chromatographic condition and system suitability：With chromatographic column (this that octadecylsilane chemically bonded silica is filler
In example, the specification of chromatographic column is 250mm × 4.6mm, 5 μm), with 0.01 phosphoric acid solution-acetonitrile with volume ratio 95：5 mixing
Liquid and in the mixed liquor supplement addition 0.3w/v% formic acid be mobile phase, flow velocity 1ml/min, 30 DEG C of column temperature, detect ripple
A length of 259nm；System suitability solution is taken to determine, number of theoretical plate should be not less than 5000, ring phosphorus gland based on adenosine cyclophosphate peak
Separating degree between glycosides and adenosine should be greater than 2；
(3) prepared by solution：
Take adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition appropriate, plus flow phased soln and dilute, every 1ml is made
Solution containing adenosine cyclophosphate 1mg in solution, filtering, as Related substances separation with need testing solution (that is, 1000 μ g/ml)；
Precision measures Related substances separation and is placed in need testing solution 1ml in 100ml measuring bottles, with flowing phase dilution scale,
Shake up, the solution that concentration containing adenosine cyclophosphate is 10 μ g/ml is made, Related substances separation contrast solution (that is, 10 μ g/ are used as
ml)；
Precision measures Related substances separation and is placed in need testing solution 1ml in 20ml measuring bottles, with flowing phase dilution scale, shakes
It is even, the solution that concentration containing adenosine cyclophosphate is 50 μ g/ml is made, as assay with need testing solution (that is, 50 μ g/ml)；
Precision weighs that adenosine cyclophosphate reference substance is appropriate, with flowing phased soln and the solution that concentration is 50 μ g/ml is made, as
Adenosine cyclophosphate assay is with reference substance solution (that is, 50 μ g/ml)；
It is each appropriate that precision weighs adenosine cyclophosphate reference substance, adenosine reference substance, plus flowing phased soln and dilutes, and every 1ml is made
Mixed solution containing the μ g of adenosine cyclophosphate 1000, the μ g of adenosine 10 in solution, is used as system suitability solution (that is, 1000 μ g/
ml+10μg/ml)；
(4) determine：
Precision measures the μ l of system suitability solution 20, injects liquid chromatograph, records chromatogram, calculates theoretical plate number
The separating degree between separating degree peak between adenosine cyclophosphate and adenosine, and when determining the reservation of adenosine cyclophosphate and both adenosines
Between；
Precision measures Related substances separation need testing solution and each 20 μ l of Related substances separation contrast solution respectively, point
Do not inject liquid chromatograph, 3 times of record chromatogram to adenosine cyclophosphate retention time, read in need testing solution chromatogram it is main into
The peak area of peak peak area and each impurity, when detecting the presence of acrobatics, with Related substances separation with contrast solution chromatogram
Main composition peak area is 1.0%, calculates each impurities phase in need testing solution chromatogram and, for the percentage composition of adenosine cyclophosphate, produces
The content of single contaminant into test sample is (if i.e., for example, contrast solution main peak area is 100, need testing solution chromatogram
In certain impurity peak area be 115, then the impurities phase for adenosine cyclophosphate percentage composition, referred to as the impurity content be
1.15%；The peak area of certain impurity is 87 in need testing solution chromatogram, then 0.87%) impurity content is；
Precision measures assay need testing solution and each 20 μ l of assay reference substance solution respectively, is injected separately into
Liquid chromatograph, record chromatogram obtains two chromatograms, two chromatograms is read respectively to 2 times of adenosine cyclophosphate retention time
It is middle main into peak peak area, by external standard method with the content of adenosine cyclophosphate in calculated by peak area test sample.
Using the above method, whole preparations obtained by hereafter preparation example 1-7 are determined, as a result：Adenosine cyclophosphate number of theoretical plate is about
75000, the separating degree about 2.73 of adenosine cyclophosphate and adenosine, adenosine cyclophosphate tailing factor about 1.008, adenosine cyclophosphate retention time is about
6.69, relative retention time about RRT=0.88 of the adenosine relative to adenosine cyclophosphate.In addition, if by above-mentioned HPLC methods mobile phase
In formic acid remove or use instead the acetic acid of same concentration, these above-mentioned location parameters are basically unchanged.
Make preparation example 1 gained preparation is placed January at 35 DEG C, determined, as a result shown, its theoretical plate using above-mentioned HPLC methods
Number, the separating degree of adenosine cyclophosphate and adenosine, adenosine cyclophosphate tailing factor, adenosine cyclophosphate retention time, adenosine RRT these parameter bases
Do not change in sheet, but occur an obvious impurity peaks (impurity RRT1.17), impurity RRT1.17 and ring phosphorus at RRT1.17
Separating degree between adenosine reaches 2.42, fully meets the requirement for determining principal component and the unknown impuritie.Will be above-mentioned in addition, working as
When formic acid in HPLC method mobile phases removes or uses the acetic acid of same concentration instead, the system after preparation example 1 places January through 35 DEG C is determined
During agent, although its number of theoretical plate, the separating degree of adenosine cyclophosphate and adenosine, adenosine cyclophosphate tailing factor, adenosine cyclophosphate retention time,
These parameters of adenosine RRT do not change substantially, but RRT1.17 impurity does not occur and occurs a peak at about RRT=1.08
Area substantially with RRT1.17 impurity identical impurity peaks, the two may for same impurity and because flow phase change cause protect
The change of time is stayed, is computed, the separating degree between this RRT1.08 impurity and adenosine cyclophosphate peak is about 1.34, it is impossible to meets and surveys
Provisioning request.The above results show, effectively to determine impurity RRT1.17, added in mobile phase a small amount of formic acid be it is necessary, it is complete
It is complete it was unexpectedly determined that when being not added with formic acid or the addition material acetic acid similar with formic acid, can not but make principal component and the impurity
RRT1.17 is efficiently separated.
For whole powder-injection obtained by this paper preparation examples 1-7, their content is determined, their adenosine cyclophosphate is as a result shown
Content is in the range of the 99~101% of theoretical inventory.
For whole powder-injection obtained by this paper preparation examples 1-7, their relevant material is determined, is particularly paid close attention to wherein
RRT1.17 impurity levels, as a result show that each single impurity of these preparations is respectively less than 0.1%, each impurity summation is respectively less than 0.25%, this
The RRT1.17 impurity of a little preparations is respectively less than 0.02%, and these results show that whole powder-injection are initial obtained by this paper preparation examples 1-7
Good property is respectively provided with state.
For whole injections obtained by this paper preparation examples 1-7, make them through 35 DEG C of placement Mays, determine their content and
Relevant material, as a result shows：These preparations in terms of content when it was at 0 month compared with change it is basically identical, residual volume (i.e. May
Contain divided by 0 month content be multiplied by with 100% gained percentage) in the range of 95~98%；In relevant substance-measuring, except
It is basically identical in terms of other impurity changes between each preparation outside RRT1.17 impurity, and during May each preparation it is each single miscellaneous
Matter is respectively less than 0.1%, and each impurity summation is respectively less than 0.25%；In relevant substance-measuring, the change of RRT1.17 impurity preparation it
Between exist significantly different, be specifically that the RRT1.17 impurity of each injections of preparation example 1-4 is when preparation 0 month compared to increase multiple
(i.e. impurity content in May subtract 0 month impurity content again divided by the numerical value obtained by 0 month impurity content) be 0.18~0.23 times, and make
The RRT1.17 impurity of standby each injections of example 5-7 is 3.24~4.46 times compared to increase multiple when preparation 0 month.This result table
Bright, difference is presented in preparation obtained by different prescription different process in terms of stability, the stabilization particularly characterized with RRT1.17 impurity
Sex differernce.
In addition, for whole injections made from hereafter preparation example 1-4, according to it《Chinese Pharmacopoeia》Version two 588 in 2015
The standard of " adenosine cyclophosphate for injection " that page is recorded, at 0 month and after room temperature places 2 years, is determined, all system according to above-mentioned standard
Agent meets the quality standard of above-mentioned pharmacopeia two time points.
First, composition preparation example part
Preparation example 1, preparation include the injection of adenosine cyclophosphate
Prescription：Adenosine cyclophosphate 10mg, mannitol 15mg, sodium chloride 1.5mg, appropriate acid-base modifier, appropriate water for injection
Add to 1ml.
Preparation method：
(1) adenosine cyclophosphate and sodium chloride is made to add in the room temperature water for injection of amount of preparation 60%, stirring and dissolving is adjusted with soda acid
Agent regulating liquid medicine pH value is saved to 3.5~4.0, needle-use activated carbon, stirring and adsorbing 20 minutes, mistake are added by medicine liquid volume 0.1w/v%
The de- charcoal of filter, it is standby；
(2) mannitol is made to add in the room temperature water for injection of amount of preparation 20%, stirring and dissolving, by medicine liquid volume 0.05w/
V% addition needle-use activated carbons, stirring and adsorbing 20 minutes, filtering decarbonization is standby；
(3) decoction mixing obtained by step (1) and step (2) is made, with acid-base modifier regulating liquid medicine pH value to 6.0~6.5,
After the titanium rod filter for being 1um with aperture is filtered, room temperature water for injection is added to amount of preparation, the pH value for determining solution simultaneously uses soda acid
Conditioning agent regulating liquid medicine pH value is to 6.0~6.5；
(4) it is that 0.22um miillpore filters filter core circulates aseptic filtration to solution to filtrate through visible foreign matters inspection conjunction with aperture
After lattice, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
Preparation example 2, preparation include the injection of adenosine cyclophosphate
Prescription：Adenosine cyclophosphate 9mg, mannitol 10mg, sodium chloride 2mg, appropriate acid-base modifier, water for injection are added in right amount
1ml。
Preparation method：
(1) adenosine cyclophosphate and sodium chloride is made to add in the room temperature water for injection of amount of preparation 60%, stirring and dissolving is adjusted with soda acid
Agent regulating liquid medicine pH value is saved to 3.5~4.0, needle-use activated carbon is added by medicine liquid volume 0.05w/v%, stirring and adsorbing 20 minutes,
Filtering decarbonization, it is standby；
(2) mannitol is made to add in the room temperature water for injection of amount of preparation 20%, stirring and dissolving, by medicine liquid volume 0.15w/
V% addition needle-use activated carbons, stirring and adsorbing 20 minutes, filtering decarbonization is standby；
(3) decoction mixing obtained by step (1) and step (2) is made, with acid-base modifier regulating liquid medicine pH value to 6.0~6.5,
After the titanium rod filter for being 1um with aperture is filtered, room temperature water for injection is added to amount of preparation, the pH value for determining solution simultaneously uses soda acid
Conditioning agent regulating liquid medicine pH value is to 6.0~6.5；
(4) it is that 0.22um miillpore filters filter core circulates aseptic filtration to solution to filtrate through visible foreign matters inspection conjunction with aperture
After lattice, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
Preparation example 3, preparation include the injection of adenosine cyclophosphate
Prescription：Adenosine cyclophosphate 11mg, mannitol 25mg, sodium chloride 1mg, appropriate acid-base modifier, water for injection add in right amount
To 1ml.
Preparation method：
(1) adenosine cyclophosphate and sodium chloride is made to add in the room temperature water for injection of amount of preparation 60%, stirring and dissolving is adjusted with soda acid
Agent regulating liquid medicine pH value is saved to 3.5~4.0, needle-use activated carbon is added by medicine liquid volume 0.15w/v%, stirring and adsorbing 20 minutes,
Filtering decarbonization, it is standby；
(2) mannitol is made to add in the room temperature water for injection of amount of preparation 20%, stirring and dissolving, by medicine liquid volume 0.05w/
V% addition needle-use activated carbons, stirring and adsorbing 20 minutes, filtering decarbonization is standby；
(3) decoction mixing obtained by step (1) and step (2) is made, with acid-base modifier regulating liquid medicine pH value to 6.0~6.5,
After the titanium rod filter for being 1um with aperture is filtered, room temperature water for injection is added to amount of preparation, the pH value for determining solution simultaneously uses soda acid
Conditioning agent regulating liquid medicine pH value is to 6.0~6.5；
(4) it is that 0.22um miillpore filters filter core circulates aseptic filtration to solution to filtrate through visible foreign matters inspection conjunction with aperture
After lattice, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
Preparation example 4, preparation include the injection of adenosine cyclophosphate
Prescription：Adenosine cyclophosphate 10mg, mannitol 20mg, sodium chloride 1.5mg, appropriate acid-base modifier, appropriate water for injection
Add to 1ml.
Preparation method：
(1) adenosine cyclophosphate and sodium chloride is made to add in the room temperature water for injection of amount of preparation 60%, stirring and dissolving is adjusted with soda acid
Agent regulating liquid medicine pH value is saved to 3.5~4.0, needle-use activated carbon is added by medicine liquid volume 0.15w/v%, stirring and adsorbing 20 minutes,
Filtering decarbonization, it is standby；
(2) mannitol is made to add in the room temperature water for injection of amount of preparation 20%, stirring and dissolving, by medicine liquid volume 0.1w/v%
Addition needle-use activated carbon, stirring and adsorbing 20 minutes, filtering decarbonization is standby；
(3) decoction mixing obtained by step (1) and step (2) is made, with acid-base modifier regulating liquid medicine pH value to 6.0~6.5,
After the titanium rod filter for being 1um with aperture is filtered, room temperature water for injection is added to amount of preparation, the pH value for determining solution simultaneously uses soda acid
Conditioning agent regulating liquid medicine pH value is to 6.0~6.5；
(4) it is that 0.22um miillpore filters filter core circulates aseptic filtration to solution to filtrate through visible foreign matters inspection conjunction with aperture
After lattice, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
Carried out when this preparation example 4 is freezed using freeze-drying curve B.
Preparation example 5, prepare adenosine cyclophosphate preparation
Preparation example 1-4 formula and preparation method is respectively referred to, different is only, without sodium chloride, four batches of preparations to be made.
Preparation example 6, prepare adenosine cyclophosphate preparation
Preparation example 1-4 formula is respectively referred to, but is not that sodium chloride is individually handled in advance with adenosine cyclophosphate in the preparation
But handled together with mannitol, four batches of preparations are made.Specific preparation method is as follows：
(1) adenosine cyclophosphate, mannitol and sodium chloride is made to add in the room temperature water for injection of amount of preparation 80%, stirring and dissolving,
With acid-base modifier regulating liquid medicine pH value to setting, (regulating liquid medicine pH value is to 3.5~4.0 during with reference to preparation example 1-2, with reference to system
During standby example 3-4 regulating liquid medicine pH value to 6.0~6.5), add needle-use activated carbon, stirring and adsorbing 20 by medicine liquid volume 0.1w/v%
Minute, filtering decarbonization is standby；
(2) it is 1um's with aperture to 6.0~6.5 to make decoction acid-base modifier regulating liquid medicine pH value obtained by step (1)
After the filtering of titanium rod filter, room temperature water for injection is added to amount of preparation, the pH value of solution is determined and uses acid-base modifier regulating
Liquid pH value is to 6.0~6.5；
(3) it is that 0.22um miillpore filters filter core circulates aseptic filtration to solution to filtrate through visible foreign matters inspection conjunction with aperture
After lattice, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
Preparation example 7, prepare adenosine cyclophosphate preparation
Preparation example 1-4 formula is respectively referred to, but in the preparation, without sodium chloride, and adenosine cyclophosphate and sweet dew
Alcohol is handled together, and four batches of preparations are made.Specific preparation method is as follows：
(1) adenosine cyclophosphate, mannitol is made to add in the room temperature water for injection of amount of preparation 80%, stirring and dissolving is adjusted with soda acid
Saving agent regulating liquid medicine pH value, (regulating liquid medicine pH value is to 3.5~4.0 during with reference to preparation example 1-2, with reference to preparation example 3-4 to setting
When regulating liquid medicine pH value to 6.0~6.5), add needle-use activated carbon, stirring and adsorbing 20 minutes, mistake by medicine liquid volume 0.1w/v%
The de- charcoal of filter, it is standby；
(2) it is 1um's with aperture to 6.0~6.5 to make decoction acid-base modifier regulating liquid medicine pH value obtained by step (1)
After the filtering of titanium rod filter, room temperature water for injection is added to amount of preparation, the pH value of solution is determined and uses acid-base modifier regulating
Liquid pH value is to 6.0~6.5；
(3) it is that 0.22um miillpore filters filter core circulates aseptic filtration to solution to filtrate through visible foreign matters inspection conjunction with aperture
After lattice, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
Each powder-injection, is freeze-dried and removes after moisture above, and moisture is less than 3% in dried frozen aquatic products.
Claims (10)
1. pair adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition carries out the method for quality control, the injection ring phosphorus gland
Included in glycoside freeze dried powder injection agent pharmaceutical composition：Adenosine cyclophosphate, mannitol and acid-base modifier, the method for quality control include
Use the adenosine cyclophosphate content and/or relevant amount of substance in high effective liquid chromatography for measuring injection.
2. method according to claim 1, wherein：
The material included in the adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition in terms of every 10 parts by weight of adenosine cyclophosphate,
The amount of mannitol is 10~50 parts by weight；The amount of such as mannitol is 10~25 parts by weight；
Acid-base modifier described in the adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition is selected from sodium hydroxide, hydrogen-oxygen
Change potassium, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its group
Close；
Acid-base modifier described in the adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition is phosphoric acid and/or phosphoric acid hydrogen
Disodium；
Acid-base modifier described in the adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition is phosphoric acid and/or phosphoric acid hydrogen
Disodium, its consumption is so that the solution of the 10mg containing adenosine cyclophosphate in every 1ml is made being dissolved in water and dilute in the pharmaceutical composition
When, the pH value of the solution is 5.5~7.0, and such as pH value is 6.0~6.5；
Also include sodium chloride in the adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition；
Solution of the adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition before freeze-drying except include adenosine cyclophosphate,
Outside mannitol and optional sodium chloride and optional acid-base modifier, in addition to water for injection, the solid content of the solution contains
Measure as 1~20% (w/v), preferably 2~15% (w/v), even more preferably 2~10%；And/or
The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition with water for injection redissolve to substantially with before freeze-drying
Solid content in solution identical volume, resulting solution is 1~20% (w/v), preferably 2~15% (w/v), even more preferably
2~10%.
3. method according to claim 1, wherein：
The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition is freeze-drying powder-injection, its every bottle ring phosphorus that includes
Adenosine weight is 10~100mg, and such as every bottle adenosine cyclophosphate weight that includes is 10~75mg, such as every bottle ring that includes
Phosphorus adenosine weight is 10~50mg；
Sodium chloride is to match somebody with somebody in advance together with adenosine cyclophosphate described in the adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition
Solution is made and is handled under conditions of pH value is less than 4.5 (such as pH value 3.5~4.0) with charcoal absorption；
The adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition is prepared according to the method comprised the following steps：
(1) adenosine cyclophosphate and sodium chloride is made to add in the room temperature water for injection of amount of preparation 60%, stirring and dissolving uses acid-base modifier
Regulating liquid medicine pH value adds needle-use activated carbon, 20 points of stirring and adsorbing to 3.5~4.0 by 0.05~0.15w/v% of medicine liquid volume
Clock, filtering decarbonization is standby；
(2) mannitol is made to add in the room temperature water for injection of amount of preparation 20%, stirring and dissolving, by 0.05~0.15w/ of medicine liquid volume
V% addition needle-use activated carbons, stirring and adsorbing 20 minutes, filtering decarbonization is standby；
(3) make decoction mixing obtained by step (1) and step (2), with acid-base modifier regulating liquid medicine pH value to 6.0~6.5, use hole
After 1um titanium rod filter filtering is in footpath, room temperature water for injection is added to amount of preparation (such as solid content in gained decoction
For 1~20% (w/v), preferably 2~15% (w/v), even more preferably 2~10%), the pH value for determining solution simultaneously uses acid-base modifier
Regulating liquid medicine pH value is to 6.0~6.5；
(4) it is that 0.22 μm of miillpore filter filter core circulates aseptic filtration to solution to filtrate through visible foreign matters passed examination with aperture
Afterwards, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
4. method according to claim 1, the high performance liquid chromatography carries out assay and relevant material to adenosine cyclophosphate
The step of measure, includes following operation：
(1) Chinese Pharmacopoeia version in 2015 four the 59th specification in Section of 0512 contained high performance liquid chromatography surveyed
It is fixed；
(2) chromatographic condition and system suitability：With chromatographic column that octadecylsilane chemically bonded silica is filler (for example,
The specification of chromatographic column is 250mm × 4.6mm, 5 μm), with 0.01 phosphoric acid solution-acetonitrile with volume ratio 95：5 mixed liquor is flowing
Phase (formic acid that 0.2~0.5w/v% such as 0.3w/v% are also optionally added in the mobile phase), flow velocity 1ml/min, 30 DEG C of column temperature,
Detection wavelength is 259nm；System suitability solution is taken to determine, number of theoretical plate should be not less than 5000 based on adenosine cyclophosphate peak,
Separating degree between adenosine cyclophosphate and adenosine should be greater than 2；
(3) prepared by solution：
Take adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition appropriate, plus flowing phase dilution, it is made in every 1ml solution and contains
Adenosine cyclophosphate 1mg solution, filtering, as Related substances separation with need testing solution (that is, 1000 μ g/ml)；
Precision measures Related substances separation and is placed in need testing solution 1ml in 100ml measuring bottles, with flowing phase dilution scale, shakes up,
The solution that concentration containing adenosine cyclophosphate is 10 μ g/ml is made, as Related substances separation with contrast solution (that is, 10 μ g/ml)；
Precision measures Related substances separation and is placed in need testing solution 1ml in 20ml measuring bottles, with flowing phase dilution scale, shakes up,
The solution that concentration containing adenosine cyclophosphate is 50 μ g/ml is made, as assay with need testing solution (that is, 50 μ g/ml)；
Precision weighs adenosine cyclophosphate reference substance in right amount, with flowing phased soln and the solution that concentration is 50 μ g/ml being made, is used as ring phosphorus
Determination of Adenosine is with reference substance solution (that is, 50 μ g/ml)；
It is each appropriate that precision weighs adenosine cyclophosphate reference substance, adenosine reference substance, plus flowing phased soln and dilutes, and every 1ml solution is made
In the mixed solution containing the μ g of adenosine cyclophosphate 1000, the μ g of adenosine 10, be used as system suitability solution (that is, 1000 μ g/ml+
10μg/ml)；
(4) determine：
Precision measures the μ l of system suitability solution 20, injects liquid chromatograph, records chromatogram, calculates theoretical plate number and ring
The separating degree between separating degree peak between phosphorus adenosine and adenosine, and determine the retention time of adenosine cyclophosphate and both adenosines；
Precision measures Related substances separation need testing solution and each 20 μ l of Related substances separation contrast solution respectively, notes respectively
Enter liquid chromatograph, 3 times of record chromatogram to adenosine cyclophosphate retention time, read main into peak peak in need testing solution chromatogram
The peak area of area and each impurity, when detecting the presence of acrobatics, with Related substances separation with contrast solution chromatogram it is main into
Part peak area is 1.0%, calculates each impurities phase in need testing solution chromatogram and for the percentage composition of adenosine cyclophosphate, that is, is supplied
The content of single contaminant in test product；
Precision measures assay need testing solution and each 20 μ l of assay reference substance solution respectively, is injected separately into liquid phase
Chromatograph, record chromatogram obtains two chromatograms to 2 times of adenosine cyclophosphate retention time, reads respectively main in two chromatograms
Into peak peak area, by external standard method with the content of adenosine cyclophosphate in calculated by peak area test sample.
5. a kind of adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition, it is included：Adenosine cyclophosphate, mannitol and soda acid are adjusted
Save agent.
6. pharmaceutical composition according to claim 5, wherein：
Its material included is in terms of every 10 parts by weight of adenosine cyclophosphate, and the amount of mannitol is 10~50 parts by weight；Such as mannitol
Measure as 10~25 parts by weight；
Described acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, phosphorus
Sour hydrogen dipotassium, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or its combination；
Described acid-base modifier is phosphoric acid and/or disodium hydrogen phosphate, and its consumption is so that the pharmaceutical composition is being dissolved in water
And dilute when the solution of the 10mg containing adenosine cyclophosphate in every 1ml is made, the pH value of the solution is 5.5~7.0, and such as pH value is 6.0
~6.5；And/or
Wherein also include sodium chloride, in terms of every 10 parts by weight of adenosine cyclophosphate, in an amount of from 0.5~3mg, such as 1~2mg.
7. pharmaceutical composition according to claim 5, wherein：
Its solution before freeze-drying, which is removed, includes adenosine cyclophosphate, mannitol and optional sodium chloride and optional soda acid tune
Save outside agent, in addition to water for injection；
Its solution before freeze-drying, which is removed, includes adenosine cyclophosphate, mannitol and optional sodium chloride and optional soda acid tune
Save outside agent, in addition to water for injection, the solid content of the solution is 1~20% (w/v), preferably 2~15% (w/v), then
More preferably 2~10%；
It is redissolved to the solid content substantially with being freeze-dried in preceding solution identical volume, resulting solution with water for injection
For 1~20% (w/v), preferably 2~15% (w/v), even more preferably 2~10%；
It is freeze-drying powder-injection, its every bottle adenosine cyclophosphate weight included is 10~100mg, and such as every bottle includes
Adenosine cyclophosphate weight is 10~75mg, and such as every bottle adenosine cyclophosphate weight included is 10~50mg；
The sodium chloride is to be configured to solution together with adenosine cyclophosphate in advance and be less than 4.5 (such as pH value 3.5~4.0) in pH value
Under conditions of handled with charcoal absorption；
It is prepared according to the method comprised the following steps：
(1) adenosine cyclophosphate and sodium chloride is made to add in the room temperature water for injection of amount of preparation 60%, stirring and dissolving uses acid-base modifier
Regulating liquid medicine pH value adds needle-use activated carbon, 20 points of stirring and adsorbing to 3.5~4.0 by 0.05~0.15w/v% of medicine liquid volume
Clock, filtering decarbonization is standby；
(2) mannitol is made to add in the room temperature water for injection of amount of preparation 20%, stirring and dissolving, by 0.05~0.15w/ of medicine liquid volume
V% addition needle-use activated carbons, stirring and adsorbing 20 minutes, filtering decarbonization is standby；
(3) make decoction mixing obtained by step (1) and step (2), with acid-base modifier regulating liquid medicine pH value to 6.0~6.5, use hole
After 1um titanium rod filter filtering is in footpath, room temperature water for injection is added to amount of preparation, the pH value of solution is determined and uses acid-base accommodation
Agent regulating liquid medicine pH value is to 6.0~6.5；
(4) it is that 0.22um miillpore filters filter core circulates aseptic filtration to solution to filtrate through visible foreign matters passed examination with aperture
Afterwards, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
8. pharmaceutical composition according to claim 7, wherein step (3) are described to add room temperature water for injection to amount of preparation, refer to
Solid content in gained decoction is 1~20% (w/v), preferably 2~15% (w/v), even more preferably 2~10%.
9. prepare the method for any one of the claim 5-8 adenosine cyclophosphate for injection freeze drying powder injection pharmaceutical composition, the party
Method comprises the following steps：
(1) adenosine cyclophosphate and sodium chloride is made to add in the room temperature water for injection of amount of preparation 60%, stirring and dissolving uses acid-base modifier
Regulating liquid medicine pH value adds needle-use activated carbon, 20 points of stirring and adsorbing to 3.5~4.0 by 0.05~0.15w/v% of medicine liquid volume
Clock, filtering decarbonization is standby；
(2) mannitol is made to add in the room temperature water for injection of amount of preparation 20%, stirring and dissolving, by 0.05~0.15w/ of medicine liquid volume
V% addition needle-use activated carbons, stirring and adsorbing 20 minutes, filtering decarbonization is standby；
(3) make decoction mixing obtained by step (1) and step (2), with acid-base modifier regulating liquid medicine pH value to 6.0~6.5, use hole
After 1um titanium rod filter filtering is in footpath, room temperature water for injection is added to amount of preparation, the pH value of solution is determined and uses acid-base accommodation
Agent regulating liquid medicine pH value is to 6.0~6.5；
(4) it is that 0.22um miillpore filters filter core circulates aseptic filtration to solution to filtrate through visible foreign matters passed examination with aperture
Afterwards, then decoction is aseptic subpackaged into cillin bottle, freeze-drying removes moisture, and tamponade is produced.
10. method according to claim 9, wherein step (3) are described to add room temperature water for injection to amount of preparation, refer to gained medicine
Solid content in liquid is 1~20% (w/v), preferably 2~15% (w/v), even more preferably 2~10%.
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