CN104706655A

CN104706655A - Meglumine adenosine cyclophosphate powder injection medicine composition for injection and preparation method thereof

Info

Publication number: CN104706655A
Application number: CN201510149233.2A
Authority: CN
Inventors: 赵丽颖; 郭明娟; 林丽娟; 夏云; 李敏
Original assignee: Shandong Pku High-Tech Huatai Pharmaceutical Co Ltd
Current assignee: Shandong Pku High-Tech Huatai Pharmaceutical Co Ltd
Priority date: 2015-03-31
Filing date: 2015-03-31
Publication date: 2015-06-17
Anticipated expiration: 2035-03-31
Also published as: CN104706655B

Abstract

The invention relates to a meglumine adenosine cyclophosphate powder injection medicine composition for injection and a preparation method thereof. Specifically, the invention relates to a medicine composition on one hand and the medicine composition comprises adenosine cyclophosphate, meglumine, mannitol and an optional acid-alkali regulator, wherein based on every 10 parts of adenosine cyclophosphate by weight, the medicine composition comprises the following materials in parts by weight: 5.5-6.5 parts of meglumine, 9-15 parts of mannitol and a proper use amount of the acid-alkali regulator; and the use amount of the acid-alkali regulator ensures that when the medicine composition is dissolved and diluted in water to prepare a solution every 1ml of which contains 10mg of adenosine cyclophosphate, the pH value of the solution is 5.5-7.0. The powder injection composition disclosed by the invention can be used for treating cardiac failure, myocarditis, sick sinus syndromes, coronary heart diseases and cardiomyopathy and can also be applied to adjuvant therapy of cardiac arrhythmia; and the meglumine adenosine cyclophosphate powder injection medicine composition for injection disclosed by the invention has good pharmaceutical properties.

Description

Meglumine cyclic adenosine for injecta injectable powder pharmaceutical composition and method for making

Technical field

The invention belongs to pharmaceutical preparations technology field, relate to one and can be used for heart failure, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy, also can be used for the medicine of ARR auxiliary treatment, particularly relate to a kind of meglumine cyclic adenosine for injecta injectable powder pharmaceutical composition, and their preparation method, this meglumine cyclic adenosine for injecta injectable powder pharmaceutical composition has good pharmaceutical properties.

Background technology

The meglumine cyclic adenosine for injecta injectable powder that the present invention relates to is that one effectively can be used for heart failure, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy, also can be used for the medicine of ARR auxiliary treatment.It is believed that meglumine cyclic adenosine for injecta injectable powder of the present invention can be used for following disease usually: cardiovascular disease (coronary heart disease, rheumatic heart disease, myocarditis, arrhythmia etc.); Cerebrovascular disease (cerebral ischemia, cerebral thrombosis and sequela thereof); Cerebrovas-cularaccident; Tumour patient; Surgical patient (before various bone surgery, craniocerebral operations, organ transplantation, anesthesia routine administration etc.); The various Chronic consumptions such as diabetes, nephropathy; Various hepatitis; Asthma, psoriasis, senile chronic bronchitis.

The chemistry of adenosine cyclophosphate (Adenosine Cyclophosphate) is called 6-amino-9-β-D-RIBOSE base-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, meglumine (Meglumine is increased in adenosine cyclophosphate, 1-deoxidation-1-(methylamino)-D-glucitol, molecular formula C7H17NO5, molecular weight 195.22) its dissolubility can be increased, meglumine has certain inhibitory action to phosphodiesterase simultaneously, make it to reduce the decomposition of adenosine cyclophosphate, therefore the positive inotropic action of meglumine adenosine cycle phosphate is stronger compared with the adenosine cyclophosphate of a great deal of, therefore clinically often adenosine cyclophosphate and meglumine are combined into meglumine adenosine cycle phosphate and use, pharmacological action meglumine adenosine cycle phosphate is non-digitalis cardiac tonic, there is positive inotropic action, myocardial contraction can be strengthened, improve myocardium blood-pumping function, there is blood vessel dilating effect, myocardial oxygen consumption can be reduced, improve metabolism of myocardium, the cardiac muscle of protection ischemia, anoxia, sinuatrial node P cell function can be improved.Prior art has meglumine cyclic adenosine injection has particulate matter unstable, and meet light and the shortcoming such as easily to degrade, the stability heart is poor.

Adenosine cyclophosphate is a kind of nucleotide drug, is non-digitalis cardiac tonic.Adenosine cyclophosphate (cAMP) is the important substance participating in Auto-regulator metabolism and biological function in cell, is that life-information transmits " second message,second messenger ".As a cardiovascular drugs, adenosine cyclophosphate has the advantage that penetrance is good, pharmacological action is gentle, stability is high, toxic and side effects is little.Adenosine cyclophosphate can promote the survival of myocardial cell in vivo, strengthens myocardial cell antibody Monoclonal, ischemia resisting and hypoxia ability; Promote flowing in calcium ion cells into cardiomyocytes, strengthen phosphorylation, promote E-C coupling, improve mycardial contractility power, increase cardiac output; Also expand peripheral blood vessel simultaneously, reduce cardiac ejection impedance, alleviate load before and after heart, increase heart output, improve cardiac function.Thus cardiac nutrition, positive inotropic, vasodilator, anti-platelet aggregation and antiarrhythmic effect are played to heart.Be mainly used in treatment cardiac insufficiency, angina pectoris and myocardial infarction clinically.Especially to ocean to yellow class cardiac tonic poisoning or insensitive patient.

The adenosine cyclophosphate entering cell is degraded into 5-adenosine-5 '-phosphoric acid (5-AMP) by phosphodiesterase and loses activity after performance biological effect, and then is broken down into adenosine and phosphoric acid.Adenosine cyclophosphate is clinically for cardiac insufficiency, angina pectoris and myocardial infarction; Poisoning or insensitive patient to digitalis cardiac tonic; Treat ARR ancillary drug.

Because the dissolubility of adenosine cyclophosphate is not enough, people are made into and are mixed and made into injection to increase the dissolubility of adenosine cyclophosphate with meglumine in the mode of mole ratio 1:1.Although prepare meglumine adenosine cycle phosphate formulation example as being directly to feed intake with the ratio of mole ratio 1:1 with adenosine cyclophosphate and meglumine two kinds of materials to prepare when its injectable powder or aqueous injection, such as, but people are even the saying being referred to as a kind of double salt, allegedly forms the compound of following structure:

Many technology about meglumine adenosine cycle phosphate technology such as its preparation technique such as its injectable powder or aqueous injection are had to report in prior art.

CN101780099A (201010108233.5, meglumine adenosine cyclophosphate composite medicament Deng Xuefeng) related to or adenosine cyclophosphate composition of medicine, be made up of the active ingredient of following parts by weight: meglumine adenosine cycle phosphate or adenosine cyclophosphate 20-60, Aspisol 100-200, reduced glutathion and vitamin C weight ratio 1: 10-15 mixture 200-300.Invent preparation method.Meglumine adenosine cyclophosphate composite medicament of the present invention or adenosine cyclophosphate composition of medicine, eliminate the untoward reaction of the heating of meglumine adenosine cycle phosphate prepared by prior art or adenosine cyclophosphate, erythra, pain.

CN103613626A (201310619163.3, Merrill Lynch) relates to a kind of adenosine cyclophosphate compound and meglumine adenosine cyclophosphate medicine composition thereof.Adenosine cyclophosphate compound of the present invention is crystal, adopt X-ray powder diffraction to measure, in its collection of illustrative plates, characteristic peak ° is 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 ° displays in 2 θ ± 0.2.The present invention also provides effective ingredient to be the injection of adenosine cyclophosphate compound of the present invention and meglumine adenosine cyclophosphate composition injection and meglumine adenosine cycle phosphate dextrose composition injection thereof.Cyclic AMP injecta of the present invention compared to existing technology stability is significantly increased, and adds L MALIC ACID, sodium tartrate can improve stability further in prescription.

CN102988305A (201210303740.3, Yao Yun) relate to a kind of pharmaceutical composition containing meglumine cyclic adenosine monophosphate compound, in particular to a kind of freeze-dried powder and preparation method thereof of meglumine adenosine cycle phosphate, every 1000 injections, are made up of the component of following proportioning: meglumine adenosine cycle phosphate 20g; Mannitol 100-200g; EDTA calcium 1-3g; Vitamin C 1-2g, mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 2000ml of 1:4.

CN1579413A (200410013546.7, Jiang Weishi) discloses meglumine cyclic adenosine for injecta and preparation technology thereof.In meglumine adenosine cycle phosphate solution, along with the prolongation of holding time, adenosine cyclophosphate can be separated out gradually, medicinal liquid is occurred rotten, muddy, applies and serious untoward reaction can occur, thus affect the curative effect of medicine and the safety of medication to patient.Meglumine cyclic adenosine for injecta, its composition comprises: adenosine cyclophosphate, lyophilized injectable powder made by described adenosine cyclophosphate and meglumine and excipient, its parts by weight are adenosine cyclophosphate 1.7 ~ 63, meglumine 1.0 ~ 37, excipient 0.675 ~ 90, the ratio of weight and number of described adenosine cyclophosphate and described meglumine is 1.7: 1, and pH value is 3.5-9.0, and character is white or off-white color lyophilizing block or powder, react just aobvious reddish brown precipitation with ferric chloride test solution, be dissolved into brown-red solution immediately.This product is used for the treatment of heart failure, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy, also can be used for ARR auxiliary treatment.

CN1459288A (03124559.5, Zhao Chen) relates to adenosine cyclophosphate Portugal amine content assay method in a kind of meglumine adenosine cycle phosphate great transfusion preparation and preparation method thereof and this great transfusion preparation.The isotonic great transfusion preparation of meglumine adenosine cycle phosphate, its formula is containing principal agent meglumine adenosine cycle phosphate 54-66mg, isotonic medium glucose 4.5-5.5g or sodium chloride 0.85-0.95g in 100ml preparation.The present invention determines the stable key condition pH value range of meglumine adenosine cycle phosphate great transfusion preparation and great transfusion preparation preparation method thereof and solves meglumine adenosine cycle phosphate content assaying method, be conducive to the control to the meglumine adenosine cycle phosphate great transfusion preparation quality of production, thus formulate suitable production method, making meglumine adenosine cycle phosphate great transfusion preparation be able to industrialized mass becomes possibility.Use this preparation, can avoid extracting from little pin the intermediate link that medicinal liquid injects glucose or sodium chloride infusion solutions, stop the cross infection in medication process and pollution, make medication safer, convenient.The present invention can be made into plurality of specifications, takes the circumstances into consideration to select for medical personnel.

CN101721357A (200810230677.9, Central China) discloses a kind of filter method of meglumine adenosine cycle phosphate high-capacity injection.The preparation liquid of meglumine adenosine cycle phosphate high-capacity injection first through pretreatment, and then through hyperfiltration technique process, be ensure that macromole invalid components is completely removed by the present invention, and the injection clarity made is high, related substance is little, pyrogen is qualified, good stability.

The preparation technology of CN1923180A (200610116409.5, ten thousand nations) and a kind of meglumine cyclic adenosine for injecta, belongs to chemical pharmacy.The preparation technology of meglumine cyclic adenosine for injecta: get 6% meglumine adenosine cycle phosphate solution and add an excipient aseptic powder in its solution, stirring and dissolving, adds water for injection dilution, adjust pH value in 5.5 ~ 7.0 scopes, cooling, after product temperature reaches-35 DEG C to 1-2 hour, condensation, when condenser temperature is down to-45 DEG C, being evacuated to pressure is-1.5 × 10-2KPA, heats up, when product temperature reaches room temperature or more than 30 DEG C with 3 DEG C/h of speed, be incubated 2 hours, whole freeze-drying process needs 24-26 hour.Meglumine cyclic adenosine for injecta of the present invention is the aseptic freeze-dried injectable powder adopting Modern preparations technology to make, and can transport, preserves by room temperature, improve stability and the safety of this product.The preparation technology of this product is simple, scientific and reasonable, easily operates.

CN101455631A (200910060427.X, De Kang) relate to a kind of meglumine cyclic adenosine injection and preparation technology thereof, it is that citric acid is put into magnetic agitation tank, add amount of preparation 50% water for injection to be stirred to dissolve, again adenosine cyclophosphate, meglumine are added in above-mentioned solution, be stirred to dissolve, and by volume add 0.02% needle-use activated carbon, stir 30 minutes, coarse filtration carbon removal, obtained meglumine adenosine cycle phosphate solution for standby, benefit adds to the full amount of water for injection, regulate pH value to 6.0-6.5 with 10% sodium hydroxide solution, make colourless clear and bright injection.The present invention not only has the effect advantage such as direct, quick, and this product untoward reaction is few, can room temperature transport, preserve, thus improve stability and the safety of this product.

CN102283804A (201010214356.7, Fang Ming) relates to a kind of meglumine cyclic adenosine injection and preparation method thereof.Its preparation technology gets appropriate water for injection, adds sodium chloride, adenosine cyclophosphate, meglumine, stirs and makes to dissolve completely, by volume add 0.05 ~ 0.2% (W/V) needle-use activated carbon, stir 15 ~ 30 minutes, filter carbon removal, benefit injects water to nearly full dose, between phosphate buffer adjust pH to 6.0 ~ 6.5, benefit adds to the full amount of water for injection, after detection semi-finished product are qualified, filter, embedding (overall process inflated with nitrogen), sterilizing, lamp inspection, packs and get final product.Its advantage is: selected suitable solvent and additives, improved dissolubility and the stability of meglumine adenosine cycle phosphate, adopt terminally sterilised preparation method, effectively ensure that the sterility assurance level of medicine.Have prescription, technique is simple, production cost is low, the feature such as medicine stability, high safety.

CN102600070A (201110435919.X, De Kang) relates to a kind of preparation method of chemical drugs, specifically a kind of meglumine adenosine cyclophosphate composition injection and preparation thereof.Its parts by weight are: adenosine cyclophosphate 5-15 part, meglumine 3-10 part, citric acid 2.0-2.2 part, sodium hydroxide 0.6-0.8 part, sodium chloride 2-4 part, water for injection 2-5 part; Preparation process is as follows: get citric acid, after injecting dissolving of blunging, buffer solution is formed with sodium hydroxide adjust ph to 5.9 ~ 6.5, add sodium chloride and cosolvent stirring and dissolving again, add water for injection, add adenosine cyclophosphate, meglumine while stirring, until completely dissolved, add active carbon to stir, after filtration, reflux and make colourless clear liquid.Clarity of injection of the present invention is good, good stability, drug safety.

CN102796156A (201210314213.2, Ning Hui) relate to a kind of adenosine cyclophosphate two meglumine compound and preparation method thereof, the compound, its preparation method that are formed by the meglumine of 1 molecule adenosine cyclophosphate and 2 molecules are provided, and comprise its pharmaceutical composition.Described compound water soluble, stability are all better than existing compound.

CN102258531A (201110102704.6, Ning Hui) provide a kind of pharmaceutical composition containing adenosine cyclophosphate and meglumine and preparation method thereof, it comprises the adenosine cyclophosphate as active component, the meglumine as stabilizing agent and the mannitol as skeleton, exists with certain proportioning.The present composition makes the minimum degradation of adenosine cyclophosphate, thus protects medicine stability, effectiveness and safety.

But existing meglumine adenosine cycle phosphate preparation particularly its lyophilized injectable powder still has technical problem to be overcome.Therefore, those skilled in the art still expect there is new method to prepare the meglumine cyclic adenosine for injecta lyophilized injectable powder with Good Pharmacy performance.

Summary of the invention

The object of the invention is to provide a kind of meglumine cyclic adenosine for injecta lyophilized injectable powder with Good Pharmacy performance.The present inventor has been surprisingly found that, the meglumine cyclic adenosine for injecta lyophilized injectable powder with present composition feature can realize above-mentioned purpose valuably.Therefore the present invention is accomplished.

For this reason, first aspect present invention provides a kind of pharmaceutical composition, wherein comprises: adenosine cyclophosphate, meglumine, mannitol and optional acid-base modifier.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the material wherein comprised is with every 10 parts by weight of adenosine cyclophosphate, and the amount of meglumine is 5.5 ~ 6.5 weight portions; The amount of such as meglumine is 5.75 ~ 6.25 weight portions.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the material wherein comprised is with every 10 parts by weight of adenosine cyclophosphate, and the amount of mannitol is 9 ~ 15 weight portions; The amount of such as mannitol is 10 ~ 14 weight portions.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein said acid-base modifier is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein the consumption of acid-base modifier is, make this pharmaceutical composition when being dissolved in water and dilute the solution made containing adenosine cyclophosphate 10mg in every 1ml, the pH value of this solution is 5.5 ~ 7.0, and such as pH value is 6.0 ~ 6.5.

The pharmaceutical composition of arbitrary embodiment, wherein also optionally comprises saccharide according to a first aspect of the present invention.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, described saccharide is selected from sucrose, lactose, glucose, fructose, maltose etc.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the material wherein comprised is with every 10 parts by weight of adenosine cyclophosphate, and the amount of saccharide is 0.5 ~ 5 weight portion; The amount of such as saccharide is 0.5 ~ 2 weight portion.Have been surprisingly found that, use appropriate certain sugars can overcome certain undesirable property of the present composition.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein comprises: adenosine cyclophosphate 10 weight portion, meglumine 5.5 ~ 6.5 weight portion, mannitol 9 ~ 15 weight portion, saccharide 0.5 ~ 5 weight portion, and optional acid-base modifier.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein comprises: adenosine cyclophosphate 10 weight portion, meglumine 5.75 ~ 6.25 weight portion, mannitol 10 ~ 14 weight portion, saccharide 0.5 ~ 2 weight portion, and optional acid-base modifier.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is dissolved in water and dilutes the solution made containing adenosine cyclophosphate 10mg in every 1ml, and the pH value of this solution is 5.5 ~ 7.0, and such as pH value is 6.0 ~ 6.5.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is lyophilization injectable powder.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, its solution before lyophilization, except comprising adenosine cyclophosphate, meglumine, mannitol and optional saccharide and optional acid-base modifier, also comprises water for injection.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, its solution before lyophilization is except comprising adenosine cyclophosphate, meglumine, mannitol and optional saccharide and optional acid-base modifier, also comprise water for injection, the solid content of described solution is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it redissolves to substantially identical with solution before lyophilization volume with water for injection, solid content in gained solution is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, wherein comprise: adenosine cyclophosphate 10 weight portion, meglumine 5.5 ~ 6.5 weight portion (such as 5.75 ~ 6.25 weight portions), mannitol 9 ~ 15 weight portion (such as 10 ~ 14 weight portions), saccharide 0.5 ~ 5 weight portion (such as 0.5 ~ 2 weight portion), and optional acid-base modifier.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is lyophilization injectable powder, its the every bottle adenosine cyclophosphate weight comprised is 10 ~ 100mg, and the such as every bottle adenosine cyclophosphate weight comprised is 10 ~ 75mg, and the such as every bottle adenosine cyclophosphate weight comprised is 15 ~ 50mg.

As everyone knows, the lyophilization injectable powder (usually referred to as lyophilized injectable powder or freeze-dried powder) obtained through freezing-vacuum drying, it is first by each material dissolution with solvents (being typically with water dissolution), be mixed with a solution, then this solution is made to carry out freezing, carry out evacuation, distillation again, substantially anhydrous (typically water content is lower than 8% for drying and the one that obtains, particularly be usually less than 5%, be particularly usually less than 3%) Powdered thing or block.Therefore, the acid-base value of this solid lyophilized products regulates the pH value of solution to control by process for preparation usually; Or the pH value that the solid lyophilized products of acquisition can be made under the dissolve/dilute degree of regulation to control this dissolve/dilute liquid by prescription adjustment controls (this is called the acid-base value controlling solid lyophilized products); A rear mode more generally uses usually, such as, in pharmacopeia contained many lyophilized injectable powders control the acid-base value of goods all in this way, and the acid-base value that this mode controls product usually can not the recipe quantity of concrete regulation acid-base modifier, and only specify the acid-base value of finished product.Be equally applicable to of the present inventionly be, pharmaceutical composition according to a first aspect of the present invention described in arbitrary embodiment, the amount of wherein said optional acid-base modifier is, the amount of pH value in 5.5 ~ 7.0 scopes of this solution during the solution making described lyophilized injectable powder water for injection be dissolved into containing active component 10mg/ml concentration, the amount of pH value in 6.0 ~ 6.5 scopes of such as this solution.

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

A () takes the adenosine cyclophosphate of recipe quantity, meglumine and mannitol and optional saccharide, add appropriate water for injection, make dissolving, then add active carbon, stirs, filtering decarbonization;

B () is mended and is injected water to its recipe quantity, stir, and measures solution ph and optional mensuration active component content, if desired by the scope that acid-base modifier regulates this solution to conform with the regulations to pH;

C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;

D () lyophilization removing moisture, tamponade, to obtain final product.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the scope that wherein the described pH of step (b) conforms with the regulations refers to: when this solution water for injection is diluted to the concentration containing adenosine cyclophosphate 10mg/ml, the pH value of gained dilute solution is in 5.5 ~ 7.0 scopes, the pH value of such as this dilute solution is in 6.0 ~ 6.5 scopes, and the pH value of such as this dilute solution is 6.2.Although the adenosine cyclophosphate concentration (about 12mg/ml) of step (b) gained solution measures the normal concentration (being about 1.2 times) of pH value higher than finished product, but step (b) solution dilution 1.2 times easily can be measured the pH value of gained diluent by those skilled in the art, needs according to this pH value determining step (b) gained solution the amplitude regulating Acidity of Aikalinity.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, the wherein filtered filtrate of step (c) gained, wherein solid content is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, particle number containing >=10 μm in each test sample container is less than 6000, such as be less than 3000, such as be less than 1500, such as be less than 1000, such as be less than 500, such as, be less than 250.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, particle number containing >=25 μm in each test sample container is less than 600, such as be less than 300, such as be less than 150, such as be less than 100, such as be less than 50, such as, be less than 25.

The pharmaceutical composition of arbitrary embodiment according to a first aspect of the present invention, it is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, be less than 6000 containing the particle number of >=10 μm in each test sample container and (be such as less than 3000, such as be less than 1500, such as be less than 1000, such as be less than 500, such as be less than 250), and the particle number of >=25 μm is less than 600 and (is such as less than 300, such as be less than 150, such as be less than 100, such as be less than 50, such as be less than 25).

Further, second aspect present invention provides the method for the pharmaceutical composition described in the arbitrary embodiment of preparation first aspect present invention, and it consists essentially of following steps:

C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;

D () lyophilization removing moisture, tamponade, to obtain final product.

The method of arbitrary embodiment according to a second aspect of the present invention, the scope that wherein the described pH of step (b) conforms with the regulations refers to: when this solution water for injection is diluted to the concentration containing adenosine cyclophosphate 10mg/ml, the pH value of gained dilute solution is in 5.5 ~ 7.0 scopes, the pH value of such as this dilute solution is in 6.0 ~ 6.5 scopes, and the pH value of such as this dilute solution is 6.2.

Method according to a second aspect of the present invention described in arbitrary embodiment, the wherein filtered filtrate of step (c) gained, wherein solid content is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%.

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

Method according to a second aspect of the present invention described in arbitrary embodiment, the water for injection of described " recipe quantity " wherein in step (b) in " benefit injects water to its recipe quantity " is 20-200 times of adenosine cyclophosphate weight, such as 50-150 doubly, such as 60-100 doubly, such as about 80 times.The amount of this water for injection easily controls by solid content described in step (c).

Method according to a second aspect of the present invention described in arbitrary embodiment, wherein the described activated carbon dosage of step (a) is 0.02% ~ 0.5% (w/v) of solution weight, preferably 0.05% ~ 0.2%.

Method according to a second aspect of the present invention described in arbitrary embodiment, wherein acid-base modifier described in step (b) is the aqueous solution being selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.The concentration of these aqueous solutions well known to a person skilled in the art, such as 1 ~ 10%, such as 2% ~ 5%.In one embodiment, described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

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

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

Arbitrary embodiment of either side of the present invention, can combine with other embodiment, as long as they there will not be contradiction.In addition, in arbitrary embodiment of either side of the present invention, arbitrary technical characteristic goes for this technical characteristic in other embodiment, as long as they there will not be contradiction.The invention will be further described below.

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

Meglumine adenosine cycle phosphate is non-digitalis cardiac tonic, has and just corrects myodyamia effect, can strengthen myocardial contraction, improves myocardium blood-pumping function, has blood vessel dilating effect, can reduce myocardial oxygen consumption; Improve metabolism of myocardium, the cardiac muscle of protection ischemia, anoxia; Sinuatrial node P cell function can be improved.Meglumine adenosine cycle phosphate enters human body, half-life is in blood 60 ~ 150min, because it has good hydrophilic, especially fat-soluble comparatively strong, easier entering in myocardial cell through fat-soluble cell membrane plays a role, and is decomposed to form 5-AMP through di-phosphate ester undergraduate course, adenosine and phosphoric acid is degraded to again through 5-AMP undergraduate course, meglumine adenosine cycle phosphate starts effect after medication after 10 ~ 20min, effective rush hour, the drug action subsides time was at 6 ~ 8 hours at 1 ~ 2 hour.

The Main Ingredients and Appearance of meglumine adenosine cycle phosphate preparation is meglumine adenosine cycle phosphate; be adenosine cyclophosphate and meglumine in molar ratio about 1:1 ratio prepare; it is non-digitalis cardiac tonic; there is positive inotropic action; strengthen myocardial contraction; improve myocardium blood-pumping function; there is blood vessel dilating effect; myocardial oxygen consumption can be reduced; improve metabolism of myocardium; the myocardial cell of protection ischemia, anoxia, can improve the p cell function of sinuatrial node, be used for the treatment of heart failure, coronary heart disease, cerebral infarction and Other diseases clinically.。

Meglumine adenosine cycle phosphate preparation can be used for Cardiovarscular.

To the therapeutical effect aspect of congestive heart failure.Congestive heart failure is common in coronary heart disease, dilated cardiomyopathy, rheumatic heart disease etc., application meglumine adenosine cycle phosphate ejection preparation treatment 48 cases of congestive heart failure.Male 28 example in treatment group 48 example, women 20 example, cardiac function II-III grade of 30 example, IV grade of 18 example, matched group 40 example, male 24 example, women 16 example, cardiac function II-III grade of 28 example, IV grade of 16 example.Sex, Age and cardiac functional grading compare for without significant (p>0.05).Treatment group meglumine adenosine cycle phosphate ejection preparation 90 milligrams adds in 3% glucose or 0.9% normal saline 250 milliliters, and vein instills, and within two weeks, is a course for the treatment of, uses two courses for the treatment of.Matched group only gives heart tonifying diuresis and the treatment of renin angiotensin converting enzyme inhibitor.Treatment group: effective 17 examples (35.4%), effective 26 examples (54.18%), invalid 5 examples (10.42), matched group: effective 6 examples (15%), effective 23 examples (57.5%), invalid 11 examples (27.5), treatment group total effective rate 89.58%, matched group 72.5%, treatment group total effective rate is apparently higher than matched group.

Result display treatment group is obviously better than matched group, meglumine adenosine cycle phosphate ejection preparation, can significantly improve the myocardial systolic property rushing courageous and upright heart failure patient, improves exercise tolerance, quality of making the life better.

Meglumine adenosine cycle phosphate ejection preparation is used to treat 84 routine congestive heart failures, all use heart tonifying for two groups, diuresis, Vasodilator therapy, treatment group adds with meglumine adenosine cycle phosphate ejection preparation 60 milligrams to 180 milligrams, adds in 5% glucose or normal saline 250 milligrams, and vein instills, once a day, within 15 days, be a course for the treatment of.Effective 31 examples (73.8%) for the treatment of group, effective 10 examples, (23.8), effective 19 examples (45.2%) of invalid 1 example (2.4%), invalid 6 examples (14.3%), total effective rate 36 example (85.7%).Compare with matched group (p<0.01).

The remission of result display meglumine adenosine cycle phosphate ejection preparation treatment group, heart failure improves degree and is significantly better than matched group.Think that meglumine adenosine cycle phosphate ejection preparation is by load before and after expansion peripheral blood vessel, minimizing heart, obviously can improve the symptom and sign of heart failure patient, have significant curative effect.

Use meglumine adenosine cycle phosphate ejection preparation treatment heart failure in patients with coronary artery disease 39 example, treatment group and matched group all use heart tonifying, blood vessel is expanded in diuresis.Treatment group adds and adds 5% glucose or normal saline 250 milligrams with meglumine adenosine cycle phosphate ejection preparation 90 milligrams, drips off at about 90 minutes, once a day, within 14 days, is a course for the treatment of.Treatment group total effective rate 92.3%, matched group 69.2% (p<0.05).After treatment group medication, symptom is obviously improved, and left chamber function obviously strengthens, often the amount of fighting, minute output, and after Left Ventricular Ejection Fraction medication, significant difference (p<0.05), has no untoward reaction.

To the therapeutical effect aspect of coronary heart disease.Coronary heart disease 58 example is divided into two groups, treatment group 30 example, use meglumine adenosine cycle phosphate 90 milligrams to add in 5% glucose or normal saline 25 milligrams, vein instills, and once a day, within 15 days, is a course for the treatment of.Matched group 28 example compound Salviae Miltiorrhizae ejection preparation 15 milligrams adds in 5% glucose or normal saline 250 milligrams, and vein instills, and once a day, within 15 days, is a course for the treatment of.Two groups of clinical treatments compare, and meglumine adenosine cycle phosphate ejection preparation is to improve the symptom obvious effective rates such as electrocardiogram, uncomfortable in chest, angina pectoris, cardiopalmus, tachypnea obvious, and for compound Salviae Miltiorrhizae ejection preparation group, the total effective rate improving cardiac function is also obvious for matched group.

Result confirms that meglumine adenosine cycle phosphate ejection preparation has positive inotropic action; myocardial contraction can be strengthened; improve myocardium blood-pumping function; blood vessel dilating, reduction myocardial oxygen consumption; improve metabolism of myocardium; the cardiac muscle of protection ischemia, anoxia, the not symptom of facing alleviating coronary heart disease is better than compound Salviae Miltiorrhizae ejection preparation.

To the therapeutical effect aspect of pulmonary heart disease.Use meglumine adenosine cycle phosphate ejection preparation treatment pulmonary heart disease 45 example, male 39 example, women 6 example, 65-70 years old ages, medical history 5-25 years.Meglumine adenosine cycle phosphate ejection preparation 90 milligrams adds in 5% glucose or normal saline 250 milligrams, and vein instills, and once a day, within 10-15th, is a course for the treatment of, expands blood vessel medicine and cardiac tonic diuretic during medication with other simultaneously.Clinical observation shows, and pulmonary heart disease is given with uncomfortable in chest, cardiopalmus, tachypnea liver function, renal function, pulmonary function after the treatment of meglumine adenosine cycle phosphate ejection preparation, electrocardiogram obvious effective rate more than 83%, total effective rate more than 95%.Think that this medicine is treatment pulmonary heart disease, particularly accompany the first-line drug of heart failure, expansible blood vessel, reduce pulmonary artery pressure, strengthen myocardial contraction and improve the heart, liver, lung, renal function, improve life quality, extend life cycle.It is the positive inotropic medicament safe, effective, there is applications well prospect.

To the therapeutical effect aspect of dilated cardiomyopathy.Use meglumine adenosine cycle phosphate ejection preparation treatment dilated cardiomyopathy 44 example, treatment group uses the instillation of meglumine adenosine cycle phosphate ejection preparation vein, adds with heart tonifying, diuresis, Vasodilator therapy, and matched group is with general treatments such as heart tonifying, diuresis, expansion blood vessels.Colored cardiograph is used to survey left room systolic and diastolic function before treatment, result shows, treatment group Left ventricular early diastolic blood flow peak velocity rises, left room late diastolic peak velocity declines, cardiac diastolic function obviously changes, stroke volume, ejection fraction, cardiac index is all improved, and incidence of arrhythmia reduces.

To the therapeutical effect aspect of hypertension.Use meglumine adenosine cycle phosphate ejection preparation Hypertension 48 example, treatment group meglumine adenosine cycle phosphate ejection preparation 90 milligrams adds in 5% glucose or normal saline 250 milligrams, and vein instills, once a day, continuously with 15 days.Matched group 42 example, only oral nifedipine (Bayer public affairs can be produced) 30 milligrams, once a day, shares 15.Therapeutic combination matched group all uses other antihypertensive drugs and lipid lowerers, result matched group blood pressure lowering effective percentage 91.67%.Systolic pressure diastolic pressure is all decreased significantly, and the symptoms such as giddy, dim eyesight, headache are remarkable, are obviously better than matched group, think that meglumine adenosine cycle phosphate ejection preparation is that one is treated significantly, the antihypertensive drugs that safety is good.

Meglumine adenosine cycle phosphate preparation can be used for treating cerebral infarction.Use meglumine adenosine cycle phosphate ejection preparation treatment Cerebral Infarction 32 Cases.Treatment group 32 example, use meglumine adenosine cycle phosphate ejection preparation 90 milligrams to add in 5% glucose or normal saline 250 milligrams, vein instills, and once a day, continuous was a course for the treatment of with 20 days.Matched group 32 example, use born of the same parents two phosphorus cholate 0.5 to add in 5% glucose or normal saline 250 milligrams, vein instills, and once a day, continuous was a course for the treatment of with 20 days.Result treatment group total effective rate 93.8%, matched group 81.3%, two groups of treatments have notable difference.Think that meglumine adenosine cycle phosphate ejection preparation can promote the metabolism of brain inner cell mitochondrial self-energy, increase cerebral blood flow, improve brain partial pressure of oxygen, alleviate cerebral edema, reduce Brain stem injury, promote that brain function recovers.Treatment cerebral infarction short treating period, nervous lesion is light, achieves good efficacy.

Meglumine adenosine cycle phosphate preparation can be used for treating chronic renal failure.Use meglumine adenosine cycle phosphate ejection preparation treatment chronic renal failure, treatment group 20 example, basis of conventional therapy adds with in meglumine adenosine cycle phosphate ejection preparation 90 milligrams of normal saline 250 milligrams, vein instills, once a day, continuous was a course for the treatment of with 15 days, general 1-2 courses for the treatment of.Matched group 20 example, only gives conventional therapy.Effective 4 examples of result treatment group, (20%), effective 8 examples (40%), stablize 3 examples, (15%), invalid 3 examples (25%).Effective 3 examples (15%) of matched group, effective 5 examples (25%), stablize 6 examples, (30%), invalid 6 examples (30%).Lose compensatory treatment by observation to renal insufficiency and have good therapeutic effect, patients with renal failure treatment creatinine being greater than to 707umol/l is poor.Chronic renal failure is lost coordinate meglumine adenosine cycle phosphate ejection preparation to treat for phase patient at the traditional dialysis treatment of employing simultaneously, can obtain the effect of postponing chronic kidney function failure development.

According to the present invention, term " excipient " also can be described as adjuvant, filler etc." the acceptable excipient of pharmacy " used herein refers to the excipient that can be used for compounding pharmaceutical, it there is no harmful effect to organism, and normally organism can tolerate.

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

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

Moisture in lyophilization injectable powder is general below 8%, preferably lower than 5%, more preferably less than 3%.Moisture Control is by suitably adjusting lyophilization program to control.Moisture in this lyophilization injectable powder can measure according to many known methods, such as dry weight-loss method.

In the present invention, in order to regulate the pH value of medicinal liquid where necessary, suitable pH adjusting agent can be added in compositions.Although the present inventor only regulates with not having the strong acid of buffer capacity or strong base solution such as a sodium hydrate aqueous solution and aqueous hydrochloric acid solution, but, those skilled in the art understand, if the pH requirement of system can be met with this pH adjusting agent process of not having buffer capacity, the pH adjusting agent then with buffer capacity will can realize the object of the invention more, therefore these buffer agents not only can adjust ph, and can stablize pH value.Therefore arbitrary pH adjusting agent listed by the present invention or its combination include in spirit and scope of the invention.

When preparing lyophilized injectable powder of the present invention, in the medicinal liquid prepared, solid content is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%.Obtain because lyophilized injectable powder normally carries out lyophilization in tubulose cillin bottle, those skilled in the art understand this product at acquisition finished product even before for doctor, usually a round pie is all presented, although in the volume theory of this cake, lecture is fewer than the volume of original aqueous solution (slightly reducing), but this reducing can not narrow down to former aqueous solution volume 50% usually usually, usual meeting is between the 80-120% of former aqueous solution volume, between the 90-100% being more typically in former aqueous solution volume, and can be observed in finished product cillin bottle former aqueous solution liquid level vestige (main body cake because of lyophilizing reduce after remain in liquid level vestige bottle wall, even if the dried frozen aquatic products in cillin bottle is Powdered because of reasons such as a variety of causes such as collide, usually original liquid level vestige can still be retained), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, but still roughly can estimate it when preparing according to this injectable powder, medicine liquid volume at least before lyophilization starts, the weight of the dry end-product in the volume estimated according to this and cillin bottle, also can calculate when preparing lyophilized injectable powder of the present invention, the content of the solid content in the medicinal liquid prepared.Therefore, lyophilized injectable powder according to a first aspect of the present invention, its solid content of medicinal liquid when preparing is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%.

Term " solid content " refers to solid matter (such as reactive compound of the present invention and whole excipient used, weight/gram) join in solvent (such as water for injection), a solution is obtained after dissolving, the weight of described solid matter such as, divided by the percent (weight/volume percent, g/100ml) of whole liquor capacity.Such as in the present invention, add appropriate aqueous solution for injection with 100mg reactive compound and other solid content amounting to about 20mg, be mixed with the solution that final volume is 2ml, its solid content is 6%.

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

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

According to pharmaceutical composition of the present invention, it is lyophilization injectable powder.In one embodiment, this lyophilization injectable powder is single-dose preparations (injectable powder that such as XiLin is bottled), in per unit dosage, the amount (its in the present invention if not otherwise indicated, all in adenosine cyclophosphate) of reactive compound can such as but not limited to about 15mg, about 19mg, about 38mg, about 50mg.

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

According to lyophilized injectable powder of the present invention, its with water make in every 1ml containing adenosine cyclophosphate 10mg solution and according under Chinese Pharmacopoeia version in 2010 two annex VI H items method measure, the pH value of this solution is 5.5 ~ 7.0, and such as pH value is 6.0 ~ 6.5.

Lyophilized injectable powder provided by the invention can be preserved at least 24 months at dry place below 25 DEG C, can meet the Storage Requirement of general lyophilization injectable powder.

Obtained freeze-drying injectable powder of the present invention particularly lyophilization injectable powder is generally white or the lyophilizing block of off-white color or its fragment or its powder, odorless, bitter in the mouth, soluble in water.

Detailed description of the invention

Can be conducted further description the present invention by the following examples, but scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite not deviating from the spirit and scope of the present invention, can carry out various change and modification to the present invention.The present invention carries out generality and/or concrete description to the material used in test and test method.Although for realizing many materials that the object of the invention uses and operational approach is well known in the art, the present invention still describes in detail as far as possible at this.Following examples further illustrate the present invention, instead of restriction the present invention.In example below, the pH adjusting agent (in the present invention that is acid-base modifier) used, unless otherwise noted, 1M sodium hydroxide solution or 1M hydrochloric acid solution, its consumption is when making to prepare injectable powder, make the pH value of the solution prepared before lyophilization be adjusted to a certain setting or scope, this setting or scope are value or the scopes that lyophilization gained dry powder water for injection is diluted to the pH value that the solution containing adenosine cyclophosphate 10mg/ml measures.The hereafter object of preparation process in order to illustrate, and based on each citing comparability and make some specific description, those skilled in the art therefrom can summarize the method obtaining the present invention and prepare lyophilized injectable powder completely according to existing knowledge.Dosing is prepared in various compositions below, and if not otherwise indicated, the total dosing amount often criticized is 10000ml, but when listing formula, all to illustrate relative to the amount of adenosine cyclophosphate 10mg, and be dispensed in 5ml cillin bottle with every bottle of amount containing adenosine cyclophosphate 18.8mg, carry out lyophilization; Containing adenosine cyclophosphate 18.8mg in the lyophilized injectable powder every bottle obtained.

The method of quality control of injectable powder and standard issue concrete grammar in standard YBH02762005 according to office of State Food and Drug Administration and standard is carried out.The clarity of the character of such as gained injectable powder of the present invention, discriminating, acidity, solution and color, related substance, moisture, aseptic, the project such as pyrogen, assay (being the amount of meglumine adenosine cycle phosphate but not the amount of adenosine cyclophosphate of mensuration).

Some mensuration project in these projects can also measure with reference to relevant official method, and the method for the particulate matter inspection of such as injectable powder is carried out according to " first method (light blockage method) " in Chinese Pharmacopoeia 2010 editions two annex IX C particulate matter inspection techniques.

Extraly, injectable powder prepared by the present invention, can use HPLC to measure the amount of their adenosine cyclophosphate, particularly investigates their amounts of remaining adenosine cyclophosphate in vial when experiencing simulation clinical redissolution.HPLC method is used to measure the method for the amount of adenosine cyclophosphate with reference to literature method (He Xiaoyan such as He Xiaoyan, Deng, HPLC method measures the content of adenosine cyclophosphate in meglumine cyclic adenosine injection, Chinese pharmacists, 2011,14 (5): 682), the content assaying method of this adenosine cyclophosphate can be described as what dawn of gorgeous method in the present invention.

Clinically, the usage and dosage of meglumine cyclic adenosine for injecta lyophilized injectable powder is: 1) intravenous drip: 5% glucose injection adding 200 ~ 500ml dissolves posterior vein and instils, once-a-day, and a 60 ~ 180mg; 2) intravenous injection: 25% or 10% glucose injection adding 20 ~ 40ml dissolves rear slowly intravenous injection, once-a-day, a 90mg.But in production, typically comprise the injectable powder that adenosine cyclophosphate is about the specification of 18.8mg in every bottle, it uses the cillin bottle sealed packet of 5ml to dress up single-dose preparations usually.When in use, get about 3ml water for injection or glucose injection injects this cillin bottle, then jolting makes lyophilized powder dissolve, then is extracted out by the medicinal liquid after dissolving.But; have been found that; for this preparation when redissolving; usually can produce foam, after being extracted out by the medicinal liquid after redissolution, then add water for injection quantitatively in empty cillin bottle; measure adenosine cyclophosphate content remaining in this solution; result have been surprisingly found that completely, and the adenosine cyclophosphate amount that the injectable powder of different prescription is remaining in cillin bottle presents diverse degree, and the adenosine cyclophosphate amount that the present invention adds remnants in the formula of certain sugars is extremely low.

one, compositions preparation example part

Preparing in example of each injectable powder below

preparation example 1, preparation comprise the injectable powder of meglumine cyclic adenylate

Formula:

adenosine cyclophosphate	10mg,
		meglumine	6mg,
mannitol	12mg,
		maltose	1mg,
pH adjusting agent	to pH6.2,
		water for injection	in right amount, 0.8ml is added to.

Preparation method:

(1) principal agent and the adjuvant (except pH adjusting agent) of recipe quantity is taken, be placed in stainless steel cask, add the water for injection of recipe quantity about 80%, be stirred to dissolve, the active carbon of 0.1% (w/v) is added again by liquor capacity, stir 30 minutes, filtering decarbonization, mend and inject water to close to prescription full dose.

(2) filtrate sampling, measure pH value, setting is adjusted to (namely if desired by pH adjusting agent, get filtrate to inject in right amount and be diluted with water to containing active component 10mg/ml, the pH value measuring this diluent should reach 6.2, otherwise suitably regulates with pH adjusting agent and acid-base modifier again), then benefit injects water to prescription full dose, measure pH value, pH adjusting agent described above is adjusted to the pH6.2 of regulation again if desired; Measure the content of active component in medicinal liquid.

(3) 0.45um filtering with microporous membrane first used by medicinal liquid, then uses 0.22um filtering with microporous membrane 2 times.

(4) so that in the medicinal liquid of every bottle of fill, containing the amount fill of adenosine cyclophosphate 18.8mg, in 5ml cillin bottle, (in following example, when quoting this preparation example method, if not otherwise indicated, liquid drug amount is the medicine liquid volume comprising 18.8mg adenosine cyclophosphate; If liquid drug volume obviously increases or obviously reduces in other example, the volume of cillin bottle rule of thumb suitably can be adjusted), false add plug.

(5) lyophilization is carried out, to moisture lower than 3% according to freeze-drying curve A described herein; After lyophilizing terminates, carry out hydraulic pressure and jump a queue; Prick aluminium lid, to obtain final product.The sample of preparation example 1 can referred to as Ex1 in the present invention; The sample of other preparation example also can similarly represent.

Supplement preparation example 1: with reference to the method for above preparation example 1, adjust unlike by the amount of mannitol wherein, be respectively 0mg, 4mg, 9mg, 15mg, 25mg or 50mg, the injectable powder numbering obtained is respectively Ex111, Ex112, Ex113, Ex114, Ex115, Ex116 six powder pins.Supplement preparation example 2: with reference to the method for above preparation example 1, adjust unlike by the amount of maltose wherein, be respectively 0mg, 0.2mg, 0.5mg, 2mg, 5mg, 10mg or 20mg, the injectable powder numbering obtained is respectively Ex121, Ex122, Ex123, Ex124, Ex125, Ex126, Ex127.Supplement preparation example 3: with reference to the method for above preparation example 1, amount unlike maltose is 0.5mg, the amount of mannitol is 0mg, 4mg, 9mg, 15mg, 25mg or 50mg, and the injectable powder numbering obtained is respectively Ex131, Ex132, Ex133, Ex134, Ex135, Ex136.Supplement preparation example 4: with reference to the method for above preparation example 1, amount unlike maltose is 5mg, the amount of mannitol is 0mg, 4mg, 9mg, 15mg, 25mg or 50mg, and the injectable powder numbering obtained is respectively Ex141, Ex142, Ex143, Ex144, Ex145, Ex146.Supplement preparation example 5: with reference to the method for above preparation example 1, amount unlike mannitol is 9mg, the amount of maltose is 0mg, 0.2mg, 0.5mg, 2mg, 5mg, 10mg or 20mg, and the injectable powder numbering obtained is respectively Ex151, Ex152, Ex153, Ex154, Ex155, Ex156, Ex157.Supplement preparation example 6: with reference to the method for above preparation example 1, amount unlike mannitol is 15mg, the amount of maltose is 0mg, 0.2mg, 0.5mg, 2mg, 5mg, 10mg or 20mg, and the injectable powder numbering obtained is respectively Ex161, Ex162, Ex163, Ex164, Ex165, Ex166, Ex167.Supplement preparation example 7: with reference to the method for above preparation example 1, replace with the sucrose of equivalent, glucose, lactose or fructose unlike maltose, the injectable powder obtained numbering is respectively Ex171, Ex172, Ex173, Ex174; With reference to the method for above preparation example 1, replace with the sorbitol of equivalent, dextran, sodium chloride or lactose unlike mannitol, the injectable powder obtained numbering is respectively Ex175, Ex176, Ex177, Ex178.Supplement preparation example 8: with reference to the method for above preparation example 1, unlike not adding meglumine, obtained not containing the adenosine cyclophosphate freeze-dry powder pin Ex181 of meglumine; With reference to the method for above preparation example 1, unlike not adding meglumine and not adding maltose, obtained not containing meglumine and not containing the adenosine cyclophosphate freeze-dry powder pin Ex182 of maltose.Supplement preparation example 9: according to formula and the method for making of CN1579413A description embodiment 1, wherein excipient uses mannitol, obtains powder pin and is designated as Ex191; According to formula and the method for making of CN102258531B description embodiment 4, obtain powder pin and be designated as Ex192; According to formula and the method for making of CN 102988305B description embodiment 1, obtain powder pin and be designated as Ex193; Three batches of commercially available meglumine cyclic adenosine for injecta injectable powder (H2004**39, H2005**64, H2005**21) are buied from market, every bottle indicates containing adenosine cyclophosphate 18.8mg (being equivalent to meglumine adenosine cycle phosphate 30mg), and three batches of commercially available powder pins are designated as Ex194, Ex195, Ex196 respectively.

preparation example 2, preparation comprise the injectable powder of meglumine cyclic adenylate

Formula:

Adenosine cyclophosphate	10mg，
		Meglumine	6.5mg，

mannitol	9mg,
		maltose	5mg,
pH adjusting agent	to pH6.5,
		water for injection	in right amount, 0.3ml is added to.

Preparation method: prepared by the method with reference to above preparation example 1, but carry out lyophilization according to freeze-drying curve B described herein, and gained injectable powder is designated as Ex2.

preparation example 3, preparation comprise the injectable powder of meglumine cyclic adenylate

Formula:

adenosine cyclophosphate	10mg,
		meglumine	5.5mg,
mannitol	15mg,
		maltose	0.5mg,
pH adjusting agent	to pH6.0,
		water for injection	in right amount, 1.5ml is added to.

Preparation method: prepared by the method with reference to above preparation example 1, gained injectable powder is designated as Ex3.

preparation example 4, preparation comprise the injectable powder of meglumine cyclic adenylate

Formula:

adenosine cyclophosphate	10mg,
		meglumine	5.75mg,
mannitol	14mg,
		maltose	2mg,
pH adjusting agent	to pH6.4,
		water for injection	in right amount, 1ml is added to.

Preparation method: prepared by the method with reference to above preparation example 1, gained injectable powder is designated as Ex4.

preparation example 5, preparation comprise the injectable powder of meglumine cyclic adenylate

Formula:

Adenosine cyclophosphate	10mg，
		Meglumine	6.25mg，
Mannitol	10mg，

maltose	0.5mg,
		pH adjusting agent	to pH6.2,
water for injection	in right amount, 1ml is added to.

Preparation method: prepared by the method with reference to above preparation example 1, gained injectable powder is designated as Ex5.

test example part

test example 1: injectable powder character is investigated

The sample that each preparation example and supplementary preparation example obtain above is investigated.

For often criticizing powder pin sample, get 10 bottles, every bottle uses water for injection 5ml dissolve and be transferred to 100ml completely, be diluted to scale with water for injection, shake up, measure this solution medium ring phosphorus adenosine content, the average content (mg can be expressed as M1) of adenosine cyclophosphate in calculating every bottle; Then, for often criticizing powder pin sample, get 10 bottles, to keeping 5% glucose injection injecting 3ml in every bottle of rubber stopper seal with syringe, shake up and powder pin is dissolved, with this syringe, medicinal liquid is extracted out (now completely again, the foam that the product of different batches has in various degree in bottle is remaining), then, in each empty cillin bottle, quantitatively water for injection 1ml is added, to clean cillin bottle, merge the washing liquid of 10 cillin bottles, measure this solution medium ring phosphorus adenosine content, the average content (mg can be expressed as M2) of adenosine cyclophosphate in calculating every bottle; The remaining rate (%) of adenosine cyclophosphate in calculating every bottle with following formula:

Remaining rate (%)=(M2 ÷ M1) × 100% of adenosine cyclophosphate

Result: five injectable powder that whole preparation example 1 to preparation examples 5 is obtained and Ex113, Ex114, Ex123, Ex124, Ex125, Ex133, Ex134, Ex143, Ex144, Ex153, Ex154, Ex155, Ex163, Ex164, Ex165, it is remaining that these injectable powder have no obvious foam in cillin bottle, and the remaining rate of their adenosine cyclophosphate is all lower than 1%, all in 0.16 ~ 0.41% scope; In addition, Ex115, Ex116, Ex126, Ex127, Ex135, Ex136, Ex145, Ex146, Ex156, Ex157, Ex166, Ex167, supplementary preparation example 8 gained 2 powder pin samples, it is remaining that these injectable powder also have no obvious foam in cillin bottle, and the remaining rate of their adenosine cyclophosphate is all lower than 1%, all in 0.14 ~ 0.45% scope; But, 6 powder pin samples described in Ex111, Ex112, Ex121, Ex122, Ex131, Ex132, Ex141, Ex142, Ex151, Ex152, Ex161, Ex162, supplementary preparation example 7 gained 8 powder pin samples, supplementary preparation example 9, these injectable powder visible significantly foam in cillin bottle is remaining, and the remaining rate of their adenosine cyclophosphate is all lower than 4%, all in 4.36 ~ 8.41% scopes, showing these samples may because the considerable adenosine cyclophosphate that foam causes remains in cillin bottle.Above result is the result that use 5% glucose injection is observed as redissolution solution, applicant is in the test supplemented, find when use instead water for injection as redissolve solution time, can observe equally with above-mentioned use 5% glucose injection as redissolving the identical result of solution.

test example 2: injectable powder character is investigated

The aliquot that each preparation example and supplementary preparation example obtain above is investigated.For often criticizing powder pin sample, getting 10 bottles, in every bottle, injecting water for injection 3ml, leave standstill, observe the consoluet time, and calculate the time of often criticizing injectable powder and redissolving with this understanding.Result: five injectable powder that whole preparation example 1 to preparation examples 5 is obtained and Ex113, Ex114, Ex123, Ex124, Ex125, Ex133, Ex134, Ex143, Ex144, Ex153, Ex154, Ex155, Ex163, Ex164, Ex165, the redissolution time of these injectable powder is all less than 27 seconds, all between 14 seconds to 26 seconds; But, Ex115, Ex116, Ex126, Ex127, Ex135, Ex136, Ex145, Ex146, Ex156, Ex157, Ex166, Ex167 these use mannitol or the excessive injectable powder of maltose, their redissolution time is all greater than 120 seconds, all between 124 ~ 217 seconds.In addition, when use instead 5% glucose injection for redissolve solution time, also to observe in the time with above-mentioned use water for injection as redissolving the identical result of solution redissolving.

test example 3: medicine character is investigated

Issue the concrete grammar in standard YBH02762005 according to office of State Food and Drug Administration, these have the sample of present composition feature to measure Ex1, Ex2, Ex3, Ex4, Ex5, Ex113, Ex114, Ex123, Ex124, Ex125, Ex133, Ex134, Ex143, Ex144, Ex153, Ex154, Ex155, Ex163, Ex164, Ex165: the projects such as the clarity of acidity, solution and color, related substance, moisture, visible foreign matters, particulate matter, assay.According to above-mentioned standard, assay method and the standard of these projects provide as follows:

Acidity: get test sample, be dissolved in water and dilute the solution made containing meglumine adenosine cycle phosphate 15mg in every 1ml, measure (annex VI H), pH value should be 5.5 ~ 7.0 in accordance with the law;

The clarity of solution and color: get test sample, be dissolved in water and dilute the solution made containing meglumine adenosine cycle phosphate 15mg in every 1ml, solution answers clear, colorless; As colour developing, compare with yellow No. 1 standard color solution (Chinese Pharmacopoeia version in 2010 two annex Ⅸ A first methods), must not be darker;

Related substance: get test sample, add water the solution made containing meglumine adenosine cycle phosphate 15mg in every 1ml, as need testing solution, according to the chromatographic condition under assay item and method test, draw need testing solution 10 μ l, point is in chromatography filter paper, after expansion, dry, inspect under putting ultra-violet lamp (254nm), at below and the initial point place of Rf value 0.4 ~ 0.5 principal spot, as also shown comparatively small impurities speckle, impurity speckle is cut, be cut into strip, put into test tube, precision adds 0.01mol/L hydrochloric acid solution 5ml, jolting, place after 1 hour, incline and get supernatant, according to spectrophotography (Chinese Pharmacopoeia version in 2010 two annex IV A), measure at 257nm wavelength place, using 0.01mol/L hydrochloric acid solution as blank, absorbance must not be greater than 0.02,

Moisture: get test sample, measure according to aquametry (Chinese Pharmacopoeia version in 2010 two annex VIII M first method A), moisture content should cross 4.5%;

Visible foreign matters: get test sample, checks (Chinese Pharmacopoeia version in 2010 two annex Ⅸ H) in accordance with the law, should conform with the regulations;

Particulate matter: get test sample, checks (Chinese Pharmacopoeia version in 2010 two annex Ⅸ C) in accordance with the law, should conform with the regulations;

Assay: get the content mixing under content uniformity item, precision takes in right amount, add water the solution made containing meglumine adenosine cycle phosphate 15mg in every 1ml, as need testing solution, separately get adenosine cyclophosphate reference substance appropriate, the water adding 60 DEG C makes the solution about containing 10mg in every 1ml, product solution in contrast, test according to paper chromatography (Chinese Pharmacopoeia version in 2010 two annex V A), the each 10 μ l of the above-mentioned two kinds of solution of accurate absorption, point is in the chromatography filter paper being about 30cm, with isopropyl alcohol-liquor ammoniae fortis-water (9:1:2) for developing solvent, launch after about 15 hours, dry, inspect under putting ultra-violet lamp (254nm), mark test sample purple dot existing together mutually with reference substance speckle displacement, this speckle is cut, and be cut into fine strip shape, put into test tube, precision adds 0.01mol/L hydrochloric acid solution 10ml, jolting, place after 1 hour, get supernatant, according to spectrophotography (Chinese Pharmacopoeia version in 2010 two annex IV A), absorbance is measured at the wavelength place of 257nm, replace need testing solution with water simultaneously, operate with method, as blank correction.By adenosine cyclophosphate ( ) be 447 divided by 0.6278, be the amount molecular weight ratio of adenosine cyclophosphate and meglumine adenosine cycle phosphate (0.6278 be) of meglumine adenosine cycle phosphate.

Result: these of above-mentioned detection sample detect/mensuration project all in the scope that above-mentioned standard specifies, the acidity of such as Ex1 is 6.23, the clarity of solution and coloration compliance, moisture 2.18%, content are theoretical labelled amount 99.52%.

In addition, the above-mentioned sample that these have present composition feature is experienced 42 DEG C of process in 5 months, then according to the above-mentioned test item of above-mentioned standard and method, measure these projects through the injectable powder of high-temperature treatment (simulation keeps sample for a long time); Result shows, these projects still all in the scope that above-mentioned standard specifies, such as Ex1 the acidity after 42 DEG C of process in 5 months be 6.25, the clarity of solution and coloration compliance, moisture 2.12%, content is theoretical labelled amount 99.21%.

safety testing example: safety testing investigation is carried out to present composition powder pin

Gained sample Ex1, Ex2, Ex3 of the present invention and control sample (commercially available product, meglumine cyclic adenosine for injecta, H20050249, high-tech China of Beijing University is safe to produce), according to existing drug registration laws and regulations requirement, carry out vascular stimulation test, hemolytic experiment, anaphylaxis experiment, result shows the regulation that these samples all meet vascular stimulation test, hemolytic experiment, anaphylaxis experiment.Show these injectable powder compositionss and there is good safety.

Claims

1. a pharmaceutical composition, wherein comprises: adenosine cyclophosphate, meglumine, mannitol and optional acid-base modifier.

2. pharmaceutical composition according to claim 1, is characterized in that:

The material wherein comprised is with every 10 parts by weight of adenosine cyclophosphate, and the amount of meglumine is 5.5 ~ 6.5 weight portions; The amount of such as meglumine is 5.75 ~ 6.25 weight portions;

The material wherein comprised is with every 10 parts by weight of adenosine cyclophosphate, and the amount of mannitol is 9 ~ 15 weight portions; The amount of such as mannitol is 10 ~ 14 weight portions;

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

Described acid-base modifier is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution; And/or

Wherein the consumption of acid-base modifier is, make this pharmaceutical composition when being dissolved in water and dilute the solution made containing adenosine cyclophosphate 10mg in every 1ml, the pH value of this solution is 5.5 ~ 7.0, and such as pH value is 6.0 ~ 6.5.

3. pharmaceutical composition according to claim 1, is characterized in that:

Wherein also optionally comprise saccharide;

Described saccharide is selected from sucrose, lactose, glucose, fructose, maltose etc.;

The material wherein comprised is with every 10 parts by weight of adenosine cyclophosphate, and the amount of saccharide is 0.5 ~ 5 weight portion; The amount of such as saccharide is 0.5 ~ 2 weight portion;

Wherein comprise: adenosine cyclophosphate 10 weight portion, meglumine 5.5 ~ 6.5 weight portion, mannitol 9 ~ 15 weight portion, saccharide 0.5 ~ 5 weight portion, and optional acid-base modifier;

Wherein comprise: adenosine cyclophosphate 10 weight portion, meglumine 5.75 ~ 6.25 weight portion, mannitol 10 ~ 14 weight portion, saccharide 0.5 ~ 2 weight portion, and optional acid-base modifier; And/or

It is dissolved in water and dilutes the solution made containing adenosine cyclophosphate 10mg in every 1ml, and the pH value of this solution is 5.5 ~ 7.0, and such as pH value is 6.0 ~ 6.5.

4. pharmaceutical composition according to claim 1, is characterized in that:

It is lyophilization injectable powder;

Its solution before lyophilization, except comprising adenosine cyclophosphate, meglumine, mannitol and optional saccharide and optional acid-base modifier, also comprises water for injection;

Its solution before lyophilization is except comprising adenosine cyclophosphate, meglumine, mannitol and optional saccharide and optional acid-base modifier, also comprise water for injection, the solid content of described solution is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%;

It redissolves to substantially identical with solution before lyophilization volume with water for injection, and the solid content in gained solution is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%;

Wherein comprise: adenosine cyclophosphate 10 weight portion, meglumine 5.5 ~ 6.5 weight portion (such as 5.75 ~ 6.25 weight portions), mannitol 9 ~ 15 weight portion (such as 10 ~ 14 weight portions), saccharide 0.5 ~ 5 weight portion (such as 0.5 ~ 2 weight portion), and optional acid-base modifier; And/or

It is lyophilization injectable powder, and its every bottle adenosine cyclophosphate weight comprised is 10 ~ 100mg, and the such as every bottle adenosine cyclophosphate weight comprised is 10 ~ 75mg, and the such as every bottle adenosine cyclophosphate weight comprised is 15 ~ 50mg.

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

C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;

D () lyophilization removing moisture, tamponade, to obtain final product.

6. pharmaceutical composition according to claim 5, is characterized in that:

The scope that wherein the described pH of step (b) conforms with the regulations refers to: when this solution water for injection is diluted to the concentration containing adenosine cyclophosphate 10mg/ml, the pH value of gained dilute solution is in 5.5 ~ 7.0 scopes, and the pH value of such as this dilute solution is in 6.0 ~ 6.5 scopes; And/or

The wherein filtered filtrate of step (c) gained, wherein solid content is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%.

7., according to the pharmaceutical composition of any one of claim 1-6, it is characterized in that:

It is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, particle number containing >=10 μm in each test sample container is less than 6000, such as be less than 3000, such as be less than 1500, such as be less than 1000, such as, be less than 500, such as, be less than 250;

It is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, particle number containing >=25 μm in each test sample container is less than 600, such as be less than 300, such as be less than 150, such as be less than 100, such as, be less than 50, such as, be less than 25;

It is lyophilization injectable powder, it checks according to " first method (light blockage method) " in Pharmacopoeia of People's Republic of China version in 2010 two (in the present invention can referred to as " Chinese Pharmacopoeia 2010 editions two " or similar address) annex IX C particulate matter inspection technique, be less than 6000 containing the particle number of >=10 μm in each test sample container and (be such as less than 3000, such as be less than 1500, such as be less than 1000, such as be less than 500, such as be less than 250), and the particle number of >=25 μm is less than 600 and (is such as less than 300, such as be less than 150, such as be less than 100, such as be less than 50, such as be less than 25).

8. prepare the method for the pharmaceutical composition of any one of claim 1-7, it consists essentially of following steps:

C (), by medicinal liquid aseptic filtration, fill is in cillin bottle;

D () lyophilization removing moisture, tamponade, to obtain final product.

9. method according to claim 8, is characterized in that:

The scope that wherein the described pH of step (b) conforms with the regulations refers to: when this solution water for injection is diluted to the concentration containing adenosine cyclophosphate 10mg/ml, the pH value of gained dilute solution is in 5.5 ~ 7.0 scopes, the pH value of such as this dilute solution is in 6.0 ~ 6.5 scopes, and the pH value of such as this dilute solution is 6.2;

The wherein filtered filtrate of step (c) gained, wherein solid content is 1 ~ 20% (w/v), preferably 2 ~ 15% (w/v), more more preferably 2 ~ 10%;

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

The water for injection of described " recipe quantity " wherein in step (b) in " benefit injects water to its recipe quantity " is 20-200 times of adenosine cyclophosphate weight, and such as 50-150 doubly, and such as 60-100 doubly;

Wherein the described activated carbon dosage of step (a) is 0.02% ~ 0.5% (w/v) of solution weight, preferably 0.05% ~ 0.2%;

Wherein acid-base modifier described in step (b) is the aqueous solution being selected from following acid-base modifier: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid or its combination.

10. method according to claim 8, wherein in step (d) after removing moisture in gained lyophilization material moisture lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.