CN104706655A - Pharmaceutical composition and preparation method of meglumine cyclic adenosine monophosphate injection powder injection - Google Patents

Abstract

The invention relates to a meglumine adenosine cyclophosphate powder injection pharmaceutical composition for injection and a preparation method thereof. In particular, one aspect of the present invention relates to a pharmaceutical composition comprising: adenosine cyclophosphate, meglumine, mannitol and an optional acid-base regulator; the drug composition comprises the following materials, by weight, every 10 parts of adenosine cyclophosphate, 5.5-6.5 parts of meglumine, 9-15 parts of mannitol, and the dosage of the acid-base regulator is such that when the drug composition is dissolved in water and diluted to prepare a solution containing 10mg of adenosine cyclophosphate in every 1ml, the pH value of the solution is 5.5-7.0. The powder injection composition can be used for treating heart failure, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy, and can also be used for the auxiliary treatment of arrhythmia. The meglumine adenosine cyclophosphate powder injection medicine composition for injection has good pharmaceutical properties.

Description

Pharmaceutical composition and preparation method of meglumine cyclic adenosine monophosphate injection powder injection

technical field

The invention belongs to the technical field of pharmaceutical preparations, and relates to a drug that can be used for heart failure, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy, and can also be used for adjuvant treatment of arrhythmia, in particular to a cyclophosphine for injection Meglumine glucosamine powder injection pharmaceutical composition, and their preparation method, the injection of meglumine cyclic adenosine meglumine powder injection pharmaceutical composition has good pharmaceutical properties.

Background technique

The meglumine cyclic adenosine monophosphate powder for injection involved in the present invention is an effective drug that can be used for heart failure, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy, and can also be used for adjuvant treatment of arrhythmia. It is believed that the meglumine cyclic adenosine monophosphate injection powder for injection of the present invention can usually be used for the following diseases: cardiovascular disease (coronary heart disease, rheumatic heart disease, myocarditis, arrhythmia, etc.); sequelae); cerebrovascular accident; tumor patients; surgical patients (various orthopedic surgery, brain surgery, organ transplantation, routine medication before anesthesia, etc.); diabetes, kidney disease and other chronic wasting diseases; various hepatitis; asthma, silver Psoriasis, chronic bronchitis in the elderly.

The chemical name of cyclic adenosine monophosphate (Adenosine Cyclophosphate) is 6-amino-9-β-D-ribofuranosyl-9H-purine-4',5'-cyclic hydrogen phosphate, the molecular formula is C10H12N5O6P, and the molecular weight is 329.21. The chemical structural formula is:

Since cyclic adenosine monophosphate is slightly soluble in water, increasing meglumine (1-deoxy-1-(methylamino)-D-sorbitol, molecular formula C7H17NO5, molecular weight 195.22) in cyclic adenosine monophosphate can increase its solubility At the same time, meglumine has a certain inhibitory effect on phosphodiesterase, which reduces its decomposition effect on cyclic adenosine monophosphate, so the positive inotropic effect of cyclic adenosine monophosphate meglumine is stronger than that of an equivalent amount of cyclic adenosine monophosphate. Strong, so the combination of cyclic adenosine monophosphate and meglumine is often used clinically to form cyclic adenosine monophosphate meglumine. It can improve myocardial pumping function, expand blood vessels, reduce myocardial oxygen consumption, improve myocardial cell metabolism, protect ischemic and hypoxic myocardium, and improve sinoatrial node P cell function. Prior Art The existing meglumine cyclic adenosine monophosphate injection has the disadvantages of unstable insoluble particles and easy degradation when exposed to light, and its stability is relatively poor.

Cyclic adenosine monophosphate is a nucleotide drug, which is a non-digital cardiotonic drug. Cyclic adenosine monophosphate (cAMP) is an important substance involved in the regulation of substance metabolism and biological functions in cells, and is the "second messenger" for the transmission of life information. As a cardiovascular drug, cyclic adenosine monophosphate has the advantages of good penetration, mild pharmacological effects, high stability, and less toxic and side effects. In vivo, cyclic adenosine monophosphate can promote the survival of cardiomyocytes, enhance the ability of cardiomyocytes to resist injury, anti-ischemia and hypoxia; promote the flow of calcium ions into cardiomyocytes, enhance phosphorylation, promote excitation-contraction coupling, and improve myocardial Cell contractility, increase cardiac output; at the same time, it also expands peripheral blood vessels, reduces cardiac ejection resistance, reduces cardiac preload and postload, increases cardiac output, and improves cardiac function. Thereby, it plays the role of nourishing myocardium, positive muscle strength, relaxing blood vessels, anti-platelet aggregation and anti-arrhythmia to the heart. It is mainly used clinically to treat cardiac insufficiency, angina pectoris and myocardial infarction. Especially for patients who are poisoned or insensitive to xanthophylls.

The cyclic adenosine monophosphate that enters the cell is degraded by phosphodiesterase into 5-adenosine-5′-phosphate (5-AMP) after exerting its biological effect, which loses its activity, and then is decomposed into adenosine and phosphoric acid. Cyclic adenosine monophosphate is clinically used for cardiac insufficiency, angina pectoris and myocardial infarction; patients who are poisoned or insensitive to digitalis cardiac drugs; adjuvant drugs for the treatment of arrhythmia.

Due to the lack of solubility of cyclic adenosine monophosphate, people make injections by mixing it with meglumine at a molar ratio of 1:1 to increase the solubility of cyclic adenosine monophosphate. Although the preparation of meglumine cyclic adenosine monophosphate preparations, such as its powder injection or water injection, is prepared by directly feeding two materials, adenosine cyclic monophosphate and meglumine, in a molar ratio of 1:1, people occasionally use It is a term for a double salt, for example it is said to form compounds of the following structure:

In the prior art, there are many technical reports on meglumine cyclic adenosine monophosphate technology, such as its preparation technology, such as its powder injection or water injection.

CN101780099A (201010108233.5, Deng Xuefeng) relates to adenosine cyclic monophosphate meglumine combination medicine or cyclic adenosine monophosphate combination medicine, which is made of the following medicinal ingredients in parts by weight: adenosine cyclic monophosphate meglumine or cyclic adenosine monophosphate 20-60, lysine aspirin 100-200, reduced glutathione and vitamin C weight ratio 1: 10-15 mixture 200-300. The method of preparation was invented. The combination drug of adenosine cyclic monophosphate meglumine or cyclic adenosine monophosphate combination drug of the present invention eliminates the adverse reactions of fever, rash and pain of the cyclic adenosine monophosphate meglumine or cyclic adenosine monophosphate prepared in the prior art.

CN103613626A (201310619163.3, Merrill Lynch) relates to a cyclic adenosine monophosphate compound and a cyclic adenosine monophosphate meglumine pharmaceutical composition. The cyclic adenosine monophosphate compound of the present invention is a crystal, which is determined by X-ray powder diffraction. The characteristic peaks in the spectrum are 5.8°, 6.9°, 7.6°, 11.3°, 16.5°, 19.2°, 21.7°, 2θ±0.2°, 22.6°, 24.0°, 25.9°, 30.1°, 31.2°, 33.4° display. The present invention also provides the injection of the cyclic adenosine monophosphate compound, the composition injection of adenosine cyclic monophosphate meglumine and the injection of the cyclic adenosine monophosphate meglumine glucose composition as the active ingredient. Compared with the prior art, the stability of the cyclic adenosine monophosphate injection of the present invention is significantly improved, and the addition of L-malic acid and sodium tartrate in the prescription can further improve the stability.

CN102988305A (201210303740.3, Yao Yun) relates to a pharmaceutical composition containing meglumine cyclic adenosine monophosphate compound, in particular to a freeze-dried powder injection of meglumine cyclic adenosine monophosphate and its preparation method. Made with the following ingredients: 20g of meglumine cyclophosphate; 100-200g of mannitol; 1-3g of calcium EDTA; 1-2g of vitamin C, disodium hydrogen citrate and trisodium citrate at a molar ratio of 1:4 Sodium buffer 2000ml.

CN1579413A (200410013546.7, Jiang Weishi) discloses adenosine cyclophosphate meglumine for injection and its preparation process. In the meglumine cyclic adenosine monophosphate solution, as the storage time prolongs, the cyclic adenosine monophosphate will gradually precipitate, causing the liquid to deteriorate and become turbid, and serious adverse reactions will occur when it is applied to patients, thus affecting the efficacy and medication of the drug. security. Cyclic adenosine monophosphate meglumine for injection, its composition comprises: cyclic adenosine monophosphate, described cyclic adenosine monophosphate and meglumine and excipient are made into freeze-dried powder injection, and its parts by weight are cyclic adenosine monophosphate 1.7 ～63, meglumine 1.0～37, excipient 0.675～90, the weight ratio of the described cyclic adenosine monophosphate and the described meglumine is 1.7:1, the pH value is 3.5-9.0, and the properties are White or off-white freeze-dried block or powder, when reacting with ferric chloride test solution, a brown-red precipitate initially appears, and then dissolves into a brown-red solution. This product is used for the treatment of heart failure, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy, and can also be used for adjuvant treatment of arrhythmia.

CN1459288A (03124559.5, Zhao Chen) relates to a large infusion preparation of meglumine cyclic adenosine monophosphate, a preparation method thereof and a method for determining the content of meglumine cyclic adenosine monophosphate in the large infusion preparation. The isotonic large infusion preparation of meglumine cyclic adenosine monophosphate has a formula of 54-66 mg of the main drug meglumine cyclic adenosine monophosphate, and 4.5-5.5 g of glucose or 0.85-0.95 g of sodium chloride in the isotonic medium. The present invention determines the pH value range of the key condition for the stability of the large infusion preparation of adenosine monophosphate meglumine and the preparation method of the large infusion preparation, and solves the content determination method of adenosine cyclophosphate meglumine, which is beneficial to the control of adenosine monophosphate meglumine The production quality control of large infusion preparations, so as to formulate suitable production methods, make it possible to industrialize mass production of adenosine cyclophosphate meglumine large infusion preparations. The use of the preparation can avoid the intermediate link of extracting the medicinal liquid from a small needle and injecting it into the glucose or sodium chloride large infusion, thereby eliminating the cross-infection and pollution during the medication process, and making the medication safer and more convenient. The present invention can be made into various specifications for selection by medical personnel as appropriate.

CN101721357A (200810230677.9, Huazhong) discloses a method for filtering adenosine cyclic monophosphate meglumine large volume injection. In the present invention, the preparation liquid of meglumine cyclic adenosine monophosphate large-capacity injection is firstly pretreated, and then processed by ultrafiltration technology to ensure that the macromolecular ineffective components are completely removed, and the prepared injection has high clarity and small related substances. , Pyrogen qualified, good stability.

CN1923180A (200610116409.5, Wanbang) and a preparation process of meglumine cyclic adenosine monophosphate for injection belong to chemical pharmacy. A kind of preparation technology of meglumine cyclic adenosine monophosphate: get 6% meglumine cyclic adenosine monophosphate solution and add excipient sterile powder in its solution, stir and dissolve, add water for injection to dilute, adjust pH value at 5.5 ～7.0 range, cooling, when the product temperature reaches -35°C to 1-2 hours, condense, when the temperature of the condenser drops to -45°C, vacuumize to the pressure of -1.5×10-2KPA, at 3°C/ The temperature rises at an hourly speed. When the temperature of the product reaches room temperature or above 30°C, keep it warm for 2 hours. The entire freeze-drying process takes 24-26 hours. The meglumine cyclic adenosine monophosphate of the present invention is a sterile freeze-dried powder injection prepared by modern preparation technology, which can be transported and stored at normal temperature, and the stability and safety of the product are improved. The preparation process of the product is simple, scientific and reasonable, and easy to operate.

CN101455631A (200910060427.X, Dekang) relates to a kind of adenosine cyclic monophosphate meglumine injection and its preparation process, it is to put citric acid into a magnetic stirring tank, add 50% of the preparation amount of water for injection to stir to dissolve, and then Add cyclic adenosine monophosphate and meglumine to the above solution, stir to dissolve, and add 0.02% activated carbon for needles according to the volume, stir for 30 minutes, coarsely filter out the carbon, and prepare the cyclic adenosine monophosphate meglumine solution for later use, add Add water for injection to the full amount, adjust the pH value to 6.0-6.5 with 10% sodium hydroxide solution, and prepare a colorless clear injection. The invention not only has the advantages of direct and rapid action, but also has less adverse reactions and can be transported and stored at normal temperature, thus improving the stability and safety of the product.

CN102283804A (201010214356.7, Fang Ming) relates to an injection of meglumine cyclic adenosine monophosphate and a preparation method thereof. Its preparation process is to take an appropriate amount of water for injection, add sodium chloride, cyclic adenosine monophosphate, and meglumine, stir to dissolve completely, add 0.05-0.2% (W/V) activated carbon for needles by volume, and stir for 15-30 minutes. Filter to remove carbon, add water for injection to nearly full amount, use phosphate buffer to adjust the pH value to between 6.0 and 6.5, add water for injection to full amount, and check that the semi-finished product is qualified, filter, pot and seal (full nitrogen gas in the whole process), and extinguish Bacteria, light inspection, packaging. The method has the advantages of selecting suitable solvents and additives, improving the solubility and stability of meglumine cyclic adenosine monophosphate, and adopting a terminal sterilization preparation method to effectively ensure the sterility assurance level of the drug. The invention has the characteristics of formula composition, simple process, low production cost, strong drug stability and safety, and the like.

CN102600070A (201110435919.X, Dekang) relates to a method for preparing chemicals, in particular to an injection of meglumine cyclic adenosine monophosphate composition and its preparation. Its parts by weight are: 5-15 parts of cyclic adenosine monophosphate, 3-10 parts of meglumine, 2.0-2.2 parts of citric acid, 0.6-0.8 parts of sodium hydroxide, 2-4 parts of sodium chloride, 2 parts of water for injection -5 parts; the preparation steps are as follows: take citric acid, add water for injection and stir to dissolve, adjust the pH value to 5.9-6.5 with sodium hydroxide to form a buffer solution, then add sodium chloride and co-solvent and stir to dissolve, add water for injection, While stirring, add cyclic adenosine monophosphate and meglumine, after being completely dissolved, add activated carbon and stir, filter and reflux to make a colorless clear liquid. The injection solution of the invention has good clarity, good stability and safe medication.

CN102796156A (201210314213.2, Ning Hui) relates to a cyclic adenosine monophosphate dimeglumine compound and a preparation method thereof, providing a compound formed from 1 molecule of cyclic adenosine monophosphate and 2 molecules of meglumine, a preparation method thereof, and a compound containing it pharmaceutical composition. The water solubility and stability of the compound are better than the existing compounds.

CN102258531A (201110102704.6, Ning Hui) provides a pharmaceutical composition containing cyclic adenosine monophosphate and meglumine and a preparation method thereof, which comprises cyclic adenosine monophosphate as an active ingredient, meglumine as a stabilizer and a skeleton The mannitol exists in a certain proportion. The composition of the present invention minimizes the degradation of cyclic adenosine monophosphate, thereby protecting drug stability, effectiveness and safety.

CN101455631A (200910060427.X, Dekang) relates to a kind of adenosine cyclic monophosphate meglumine injection and its preparation process, it is to put citric acid into a magnetic stirring tank, add 50% of the preparation amount of water for injection to stir to dissolve, and then Add cyclic adenosine monophosphate and meglumine to the above solution, stir to dissolve, and add 0.02% activated carbon for needles according to the volume, stir for 30 minutes, coarsely filter out the carbon, and prepare the cyclic adenosine monophosphate meglumine solution for later use, add Add water for injection to the full amount, adjust the pH value to 6.0-6.5 with 10% sodium hydroxide solution, and prepare a colorless clear injection. The invention not only has the advantages of direct and rapid action, but also has less adverse reactions and can be transported and stored at normal temperature, thus improving the stability and safety of the product.

However, the existing meglumine cyclophosphate preparations, especially its freeze-dried powder injection, still have technical problems to be overcome. Therefore, those skilled in the art still look forward to a new method to prepare the freeze-dried powder injection of meglumine cyclic adenosine monophosphate with good pharmaceutical properties.

Contents of the invention

The object of the present invention is to provide a freeze-dried powder injection of adenosine cyclophosphate meglumine for injection with good pharmaceutical properties. The present inventors have unexpectedly found that the lyophilized powder injection of meglumine cyclic adenosine monophosphate injection having the characteristics of the composition of the present invention can beneficially achieve the above-mentioned purpose. The present invention has thus been accomplished.

To this end, the first aspect of the present invention provides a pharmaceutical composition, which comprises: cyclic adenosine monophosphate, meglumine, mannitol and an optional acid-base regulator.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, the amount of meglumine is 5.5-6.5 parts by weight based on cyclic adenosine monophosphate per 10 parts by weight; for example, the amount of meglumine is 5.75 parts by weight. ~6.25 parts by weight.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, the amount of mannitol is 9-15 parts by weight for every 10 parts by weight of cyclic adenosine monophosphate; for example, the amount of mannitol is 10-14 parts by weight. parts by weight.

According to the pharmaceutical composition of any embodiment of the first aspect of the present invention, wherein said acid-base regulator is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, hydrogen phosphate Dipotassium, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof. In one embodiment, the acid-base regulator is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the dosage of the acid-base regulator is such that when the pharmaceutical composition is dissolved in water and diluted to make a solution containing 10 mg of cyclic adenosine monophosphate per 1 ml, the The pH value of the solution is 5.5-7.0, for example, the pH value is 6.0-6.5.

The pharmaceutical composition according to any embodiment of the first aspect of the present invention further optionally includes sugars.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, the sugar is selected from sucrose, lactose, glucose, fructose, maltose and the like.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, the material contained therein is based on 10 parts by weight of cyclic adenosine monophosphate, and the amount of sugar is 0.5-5 parts by weight; for example, the amount of sugar is 0.5-2 parts by weight. It has surprisingly been found that certain undesirable properties of the compositions of the present invention can be overcome by using appropriate amounts of specific carbohydrates.

The pharmaceutical composition according to any embodiment of the first aspect of the present invention, which comprises: 10 parts by weight of cyclic adenosine monophosphate, 5.5-6.5 parts by weight of meglumine, 9-15 parts by weight of mannitol, and 0.5-5 parts by weight of sugars , and an optional pH regulator.

The pharmaceutical composition according to any embodiment of the first aspect of the present invention, which comprises: 10 parts by weight of cyclic adenosine monophosphate, 5.75-6.25 parts by weight of meglumine, 10-14 parts by weight of mannitol, and 0.5-2 parts by weight of sugars , and an optional pH regulator.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, it is dissolved in water and diluted to make a solution containing 10 mg of cyclic adenosine monophosphate per 1 ml. The pH value of the solution is 5.5-7.0, for example, the pH value is 6.0- 6.5.

The pharmaceutical composition according to any embodiment of the first aspect of the present invention is a freeze-dried powder injection.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, its solution before freeze-drying includes cyclic adenosine monophosphate, meglumine, mannitol, and optional sugars and optional acid-base regulators , including water for injections.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, its solution before freeze-drying includes cyclic adenosine monophosphate, meglumine, mannitol, and optional sugars and optional acid-base regulators , also includes water for injection, the solid content of the solution is 1-20% (w/v), preferably 2-15% (w/v), more preferably 2-10%.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, it is reconstituted with water for injection to substantially the same volume as the solution before freeze-drying, and the solid content in the obtained solution is 1-20% (w/v) , preferably 2 to 15% (w/v), still more preferably 2 to 10%.

According to the pharmaceutical composition of any embodiment of the first aspect of the present invention, wherein said acid-base regulator is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, hydrogen phosphate Dipotassium, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof. In one embodiment, the acid-base regulator is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

The pharmaceutical composition according to any embodiment of the first aspect of the present invention, which comprises: 10 parts by weight of cyclic adenosine monophosphate, 5.5-6.5 parts by weight of meglumine (for example, 5.75-6.25 parts by weight), 9-15 parts by weight of mannitol (eg 10-14 parts by weight), 0.5-5 parts by weight of sugar (eg 0.5-2 parts by weight), and an optional acid-base regulator.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the dosage of the acid-base regulator is such that when the pharmaceutical composition is dissolved in water and diluted to make a solution containing 10 mg of cyclic adenosine monophosphate per 1 ml, the The pH value of the solution is 5.5-7.0, for example, the pH value is 6.0-6.5.

The pharmaceutical composition according to any embodiment of the first aspect of the present invention is a freeze-dried powder injection.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, its solution before freeze-drying includes cyclic adenosine monophosphate, meglumine, mannitol, and optional sugars and optional acid-base regulators , including water for injections.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, its solution before freeze-drying includes cyclic adenosine monophosphate, meglumine, mannitol, and optional sugars and optional acid-base regulators , also includes water for injection, the solid content of the solution is 1-20% (w/v), preferably 2-15% (w/v), more preferably 2-10%.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, it is reconstituted with water for injection to substantially the same volume as the solution before freeze-drying, and the solid content in the obtained solution is 1-20% (w/v) , preferably 2 to 15% (w/v), still more preferably 2 to 10%.

According to the pharmaceutical composition of any embodiment of the first aspect of the present invention, wherein said acid-base regulator is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, hydrogen phosphate Dipotassium, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof. In one embodiment, the acid-base regulator is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

The pharmaceutical composition according to any embodiment of the first aspect of the present invention, which comprises: 10 parts by weight of cyclic adenosine monophosphate, 5.5-6.5 parts by weight of meglumine (for example, 5.75-6.25 parts by weight), 9-15 parts by weight of mannitol (eg 10-14 parts by weight), 0.5-5 parts by weight of sugar (eg 0.5-2 parts by weight), and an optional acid-base regulator.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, it is a freeze-dried powder injection, and the weight of cyclic adenosine monophosphate included in each bottle is 10-100 mg, for example, the weight of cyclic adenosine monophosphate included in each bottle is 10-75 mg, for example, the weight of cyclic adenosine monophosphate included in each bottle is 15-50 mg.

As we all know, the freeze-dried powder injection obtained by low-temperature freeze-vacuum drying (usually referred to as freeze-dried powder injection or freeze-dried powder injection) is firstly dissolved in a solvent (usually dissolved in water), and prepared into a solution, and then the solution is subjected to low-temperature freezing, and then vacuumized, sublimated, and dried to obtain a substantially anhydrous (generally speaking, the water content is lower than 8%, especially usually lower than 5%, especially usually lower than 3%) powder or block. Therefore, the pH of the lyophilized solid is usually controlled by adjusting the pH of the solution during the preparation process; or it can be adjusted through the prescription so that the lyophilized solid obtained controls the pH of the dissolved/diluted solution at a prescribed degree of dissolution/dilution value to control (this is called controlling the pH of the solid lyophilized product); the latter method is usually more commonly used, for example, many freeze-dried powder injections listed in the Pharmacopoeia control the pH of the product in this way, and this method controls the pH of the product. The pH of the product usually does not specify the prescription amount of the acid-base regulator, but only the pH of the final product. Also applicable to the present invention is the pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the amount of the optional acid-base regulator is such that the lyophilized powder injection is dissolved in water for injection When forming a solution containing the active ingredient at a concentration of 10 mg/ml, the pH of the solution is in the range of 5.5 to 7.0, for example, the pH of the solution is in the range of 6.0 to 6.5.

The pharmaceutical composition according to any embodiment of the first aspect of the present invention is basically prepared by the following steps:

(a) Take by weighing adenosine cyclic monophosphate, meglumine and mannitol, and optional sugars of the prescribed amount, add an appropriate amount of water for injection to dissolve, then add activated carbon, stir, and decarbonize by filtration;

(b) Add water for injection to its prescription amount, stir evenly, measure the pH value of the solution and optionally measure the content of active ingredients, and adjust the solution to the specified pH range with an acid-base regulator if necessary;

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the pH in step (b) conforms to the specified range means: when the solution is diluted with water for injection to a concentration containing 10 mg/ml of cyclic adenosine monophosphate , the pH value of the obtained diluted solution is in the range of 5.5-7.0, for example, the pH value of the diluted solution is in the range of 6.0-6.5, for example, the pH value of the diluted solution is 6.2. Although the cyclic adenosine monophosphate concentration (about 12 mg/ml) of the solution obtained in step (b) is higher than the specified concentration (about 1.2 times) of the final product measured pH value, those skilled in the art can easily make the step (b) solution Dilute 1.2 times and measure the pH value of the resulting diluted solution, and determine the range of acidity and alkalinity of the solution obtained in step (b) according to the pH value.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the filtered filtrate obtained in step (c) has a solid content of 1-20% (w/v), preferably 2-15% (w/v ), still more preferably 2 to 10%.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, it is a freeze-dried powder injection prepared according to the Pharmacopoeia of the People's Republic of China 2010 Edition II (in the present invention may be referred to as "Chinese Pharmacopoeia 2010 Edition II" or similar Appellation) "Method 1 (light-blocking method)" in Appendix IX C insoluble particle inspection method, the number of particles ≥ 10 μm in each container of the test product is less than 6000 particles, such as less than 3000 particles, such as less than 1500 particles, For example, less than 1000 grains, such as less than 500 grains, such as less than 250 grains.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, it is a freeze-dried powder injection prepared according to the Pharmacopoeia of the People's Republic of China 2010 Edition II (in the present invention may be referred to as "Chinese Pharmacopoeia 2010 Edition II" or similar Appellation) "Method 1 (light-resisting method)" in Appendix IX C insoluble particle inspection method, the number of particles ≥ 25 μm in each test sample container is less than 600 particles, such as less than 300 particles, such as less than 150 particles, For example, less than 100 grains, such as less than 50 grains, such as less than 25 grains.

According to the pharmaceutical composition according to any embodiment of the first aspect of the present invention, it is a freeze-dried powder injection prepared according to the Pharmacopoeia of the People's Republic of China 2010 Edition II (in the present invention may be referred to as "Chinese Pharmacopoeia 2010 Edition II" or similar Appellation) "Method 1 (light-resisting method)" in Appendix IX C insoluble particle inspection method, the number of particles ≥ 10 μm in each container of the test product is less than 6000 particles (for example, less than 3000 particles, such as less than 1500 particles, Such as less than 1000 grains, such as less than 500 grains, such as less than 250 grains), and the number of particles ≥ 25 μm is less than 600 grains (such as less than 300 grains, such as less than 150 grains, such as less than 100 grains, such as less than 50 grains, such as less than 25 grains ).

Further, the second aspect of the present invention provides a method for preparing the pharmaceutical composition according to any embodiment of the first aspect of the present invention, which basically includes the following steps:

(a) Take by weighing adenosine cyclic monophosphate, meglumine and mannitol, and optional sugars of the prescribed amount, add an appropriate amount of water for injection to dissolve, then add activated carbon, stir, and decarbonize by filtration;

(b) Add water for injection to its prescription amount, stir evenly, measure the pH value of the solution and optionally measure the content of active ingredients, and adjust the solution to the specified pH range with an acid-base regulator if necessary;

(c) sterilize and filter the medicinal liquid, and fill it in a vial;

(d) Freeze-drying to remove moisture, and stoppering, to obtain.

According to the method according to any embodiment of the second aspect of the present invention, wherein the pH in step (b) conforms to the specified range means: when the solution is diluted with water for injection to a concentration containing 10 mg/ml of cyclic adenosine monophosphate, the obtained The pH value of the diluted solution is in the range of 5.5-7.0, for example, the pH value of the diluted solution is in the range of 6.0-6.5, for example, the pH value of the diluted solution is 6.2.

According to the method described in any embodiment of the second aspect of the present invention, wherein the filtered filtrate obtained in step (c) has a solid content of 1 to 20% (w/v), preferably 2 to 15% (w/v ), still more preferably 2 to 10%.

The method according to any embodiment of the second aspect of the present invention, wherein the appropriate amount of water for injection in step (a) is about 70-90% of the prescribed amount of water for injection.

According to the method described in any embodiment of the second aspect of the present invention, wherein the water for injection of the "recipe amount" in "adding water for injection to its prescription amount" in step (b) is 20% of the weight of cyclic adenosine monophosphate -200 times, such as 50-150 times, such as 60-100 times, such as about 80 times. The amount of this water for injection can be easily controlled by the solid content in step (c).

The method according to any embodiment of the second aspect of the present invention, wherein the amount of activated carbon in step (a) is 0.02%-0.5% (w/v) of the solution weight, preferably 0.05%-0.2%.

According to the method described in any embodiment of the second aspect of the present invention, wherein the acid-base regulator described in step (b) is an aqueous solution of an acid-base regulator selected from the following: sodium hydroxide, potassium hydroxide, dihydrogen phosphate Sodium, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof. The concentration of these aqueous solutions is well known to those skilled in the art, such as 1-10%, such as 2%-5%. In one embodiment, the acid-base regulator is hydrochloric acid solution or sodium hydroxide solution, such as 1M hydrochloric acid solution or 1M sodium hydroxide solution.

According to the method described in any embodiment of the second aspect of the present invention, wherein the moisture content in the freeze-dried material obtained after removing moisture in step (d) is lower than 10%, preferably lower than 8%, preferably lower than 5%, more preferably less than 3%.

In the steps of the above-mentioned preparation method of the present invention, although the specific steps described in it are different from the steps described in the preparation examples of the specific embodiment section below in some details or language descriptions, those skilled in the art according to The detailed disclosure of the present invention in its entirety can fully summarize the method steps described above.

Any embodiment of any aspect of the present invention may be combined with other embodiments as long as they do not contradict each other. In addition, in any embodiment of any aspect of the present invention, any technical feature can be applied to the technical feature in other embodiments, as long as there is no contradiction between them. The present invention will be further described below.

All the documents cited in the present invention are incorporated herein by reference in their entirety, and if the meaning expressed in these documents is inconsistent with the present invention, the expression of the present invention shall prevail. In addition, various terms and phrases used in the present invention have common meanings known to those skilled in the art. Even so, the present invention still hopes to make a more detailed description and explanation of these terms and phrases here. The mentioned terms and phrases are as follows: If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail.

Meglumine cyclic adenosine monophosphate is a non-digital cardiotonic agent, which has the effect of correcting muscle strength, enhancing myocardial contractility, improving myocardial pumping function, expanding blood vessels, and reducing myocardial oxygen consumption; improving myocardial cell metabolism, protecting Ischemic and hypoxic myocardium; can improve sinoatrial node P cell function. When meglumine cyclic adenosine monophosphate enters the human body, its half-life in the blood is 60-150 minutes. Because of its good hydrophilicity, especially its strong fat solubility, it is easier to enter the myocardial cells through the fat-soluble cell membrane to play a role. Phosphodiester is decomposed to form 5-AMP, and then degraded into adenosine and phosphoric acid by 5-AMP. Cyclic adenosine meglumine begins to take effect 10 to 20 minutes after administration, and the peak time of effective effect is 1 to 2 hours. The effect disappears within 6-8 hours.

The main ingredient of meglumine cyclic adenosine monophosphate preparation is adenosine cyclic monophosphate meglumine, which is prepared from cyclic adenosine monophosphate and meglumine in a molar ratio of about 1:1. It is a non-digital cardiotonic agent with positive inotropic effects Function, enhance myocardial contractility, improve myocardial pumping function, have the effect of dilating blood vessels, reduce myocardial oxygen consumption, improve myocardial cell metabolism, protect ischemic and hypoxic myocardial cells, and improve the p-cell function of the sinoatrial node. It has been used clinically to treat heart failure, coronary heart disease, cerebral infarction and other diseases. .

Cyclic meglumine preparations can be used in the treatment of cardiovascular disease.

In terms of the therapeutic effect on congestive heart failure. Congestive heart failure is common in coronary heart disease, dilated cardiomyopathy, rheumatic heart disease, etc. 48 cases of congestive heart failure were treated with meglumine cyclic adenosine monophosphate injection. Among the 48 cases in the treatment group, there were 28 males, 20 females, 30 cases of cardiac function II-III, 18 cases of IV, 40 cases of control group, 24 males, 16 females, 28 cases of cardiac function II-III, IV Grade 16 cases. There was no significant difference in gender, age and cardiac function classification (p>0.05). The treatment group received 90 mg of meglumine cyclic adenosine monophosphate injection preparation added to 250 ml of 3% glucose or 0.9% normal saline, intravenously, two weeks as a course of treatment, and two courses of treatment were used. The control group was only given cardiotonic diuresis and renin-angiotensin-converting enzyme inhibitors. Treatment group: markedly effective 17 examples (35.4%), effective 26 examples (54.18%), invalid 5 examples (10.42), matched group: markedly effective 6 examples (15%), effective 23 examples (57.5%), invalid 11 examples (27.5%) ), the total effective rate of the treatment group was 89.58%, and that of the control group was 72.5%. The total effective rate of the treatment group was significantly higher than that of the control group.

The results showed that the treatment group was significantly better than the control group. The injection preparation of meglumine cyclic adenosine monophosphate can significantly improve the myocardial diastolic and systolic function in patients with congestive heart failure, improve exercise tolerance, and improve the quality of life.

84 cases of congestive heart failure were treated with cyclic adenosine meglumine injection preparations. Both groups were treated with cardiotonic, diuretic and vasodilator treatments. % glucose or normal saline 250 mg, intravenous drip, once a day, 15 days as a course of treatment. In the treatment group, 31 cases were markedly effective (73.8%), 10 cases were effective, (23.8%), 1 case was ineffective (2.4%), 19 cases (45.2%) were effective, 6 cases were ineffective (14.3%), and the total effective rate was 36 cases (85.7%) . Compared with the control group (p<0.01).

The results showed that the symptoms of the meglumine cyclic adenosine monophosphate injection treatment group were relieved, and the degree of improvement of heart failure was significantly better than that of the control group. It is believed that meglumine cyclic adenosine monophosphate injection can significantly improve the symptoms and signs of patients with heart failure by dilating peripheral blood vessels and reducing cardiac preload and postload, and has a significant curative effect.

Thirty-nine cases of heart failure due to coronary heart disease were treated with meglumine cyclic adenosine monophosphate injection. Both the treatment group and the control group were given cardiotonic and diuretic vasodilators. The treatment group additionally received 90 mg of meglumine cyclic adenosine monophosphate injection preparation, added 5% glucose or 250 mg of normal saline, dripped in about 90 minutes, once a day, and 14 days was a course of treatment. The total effective rate was 92.3% in the treatment group and 69.2% in the control group (p<0.05). The symptoms of the treatment group were significantly improved after medication, and the left ventricular function was significantly enhanced. The stroke volume, output volume per minute, and left ventricular ejection fraction were significantly different after medication (p<0.05), and no adverse reactions were seen.

Therapeutic effect on coronary heart disease. Divide 58 cases of coronary heart disease into two groups, 30 cases in the treatment group, use 90 mg of meglumine cyclophosphate plus 5% glucose or 25 mg of normal saline, intravenously, once a day, 15 days as a course of treatment. The 28 cases in the control group received 15 mg compound Danshen injection, added 5% glucose or 250 mg normal saline, intravenously, once a day, 15 days as a course of treatment. Comparing the clinical treatment of the two groups, the meglumine cyclic adenosine monophosphate injection preparation was significantly effective in improving electrocardiogram, chest tightness, angina pectoris, palpitations, shortness of breath and other symptoms, and the total effective rate of improving heart function was also significantly higher when used in the compound Danshen injection preparation group. in the control group.

The results confirmed that meglumine cyclic adenosine monophosphate injection has positive inotropic effect, can enhance myocardial contractility, improve myocardial pump function, dilate blood vessels, reduce myocardial oxygen consumption, improve myocardial cell metabolism, and protect ischemic and hypoxic myocardium , It is better than the compound Danshen injection preparation for relieving the temporary symptoms of coronary heart disease.

Therapeutic effect on pulmonary heart disease. 45 cases of cor pulmonale were treated with meglumine cyclophosphate injection preparation, 39 males and 6 females, aged 65-70 years, with a medical history of 5-25 years. Add 90 mg of meglumine cyclic adenosine monophosphate injection into 5% glucose or 250 mg of normal saline, intravenously, once a day, 10-15 days as a course of treatment, and use other vasodilators and cardiotonic diuretics at the same time. Clinical observations show that after cor pulmonale is treated with meglumine cyclic adenosine monophosphate injection preparations, chest tightness, palpitations, shortness of breath, liver function, kidney function, lung function, electrocardiogram marked rate are over 83%, and the total effective rate is over 95%. It is believed that this drug is the first-line drug for the treatment of pulmonary heart disease, especially with heart failure, which can dilate blood vessels, reduce pulmonary arterial pressure, enhance myocardial contractility, improve heart, liver, lung, and kidney functions, improve quality of life, and prolong survival. It is a positive inotropic drug that is safe, effective and has good application prospects.

in the treatment of dilated cardiomyopathy. 44 cases of dilated cardiomyopathy were treated with meglumine cyclic adenosine injection preparations. The treatment group was given intravenous infusion of meglumine cyclic adenosine monophosphate injection preparations, plus cardiotonic, diuretic, and vasodilator treatments. The control group was treated with cardiotonic, General treatment such as diuresis and vasodilator. Before treatment, the left ventricular diastolic and systolic function was measured with a color cardiograph. The results showed that the peak velocity of left ventricular diastolic blood flow increased in the treatment group, and the peak velocity of left ventricular diastolic blood flow decreased in the late diastolic period. The diastolic function of the heart changed significantly. The blood fraction and heart index were all improved, and the incidence of arrhythmia was reduced.

Therapeutic effect on hypertension. Use cyclic adenosine monophosphate meglumine injection preparations to treat 48 cases of hypertension. The treatment group used cyclic adenosine monophosphate meglumine injection preparations 90 mg added to 5% glucose or 250 mg normal saline, intravenously, once a day, continuously 15th. The 42 cases in the control group took 30 mg of Baixintong (manufactured by Bayer) orally, once a day for 15 days. The treatment combination and the control group all used other antihypertensive drugs and lipid-lowering drugs. As a result, the effective rate of antihypertensive in the control group was 91.67%. The systolic and diastolic blood pressures all decreased significantly, and symptoms such as dizziness, vertigo, and headache were obvious, which were significantly better than those in the control group. It is believed that the injection preparation of meglumine cyclic adenosine monophosphate is a kind of antihypertensive drug with significant treatment and good safety.

Cyclic adenosine meglumine preparations can be used to treat cerebral infarction. Thirty-two cases of cerebral infarction were treated with meglumine cyclic adenosine monophosphate injection preparation. The 32 patients in the treatment group received 90 mg of meglumine cyclic adenosine monophosphate injection, added to 5% glucose or 250 mg of normal saline, intravenously, once a day, and used continuously for 20 days as a course of treatment. For 32 cases in the control group, 0.5 citicole salt was added to 5% glucose or 250 mg normal saline, intravenously, once a day, and 20 consecutive days was a course of treatment. Results The total effective rate was 93.8% in the treatment group and 81.3% in the control group. There was a significant difference between the two groups. It is believed that meglumine cyclic adenosine monophosphate injection preparation can promote the energy metabolism in the mitochondria in the brain cells, increase the cerebral blood flow, increase the partial pressure of oxygen in the brain, reduce cerebral edema, reduce the scope of cerebral infarction, and promote the recovery of brain function. The course of treatment for cerebral infarction is short, the nerve damage is light, and good curative effect has been achieved.

Cyclic meglumine preparations can be used in the treatment of chronic renal failure. Use meglumine cyclic adenosine injection preparations to treat chronic renal failure, 20 cases in the treatment group, on the basis of conventional treatment, add meglumine cyclic adenosine injection preparations 90 mg in normal saline 250 mg, intravenously, once a day , Continuous use for 15 days is a course of treatment, generally 1-2 courses of treatment. 20 cases in the control group were given conventional treatment only. Results In the treatment group, 4 cases were markedly effective (20%), 8 cases were effective (40%), 3 cases were stable (15%), and 3 cases (25%) were ineffective. In the control group, 3 cases were markedly effective (15%), 5 cases were effective (25%), 6 cases were stable (30%), and 6 cases were ineffective (30%). According to the observation, it has a good curative effect on the treatment of decompensation of renal insufficiency, but it is poor in the treatment of renal failure patients with creatinine greater than 707umol/l. Patients in the degeneration stage of chronic renal failure can achieve the effect of delaying the development of chronic renal failure by using traditional dialysis treatment combined with meglumine cyclic adenosine monophosphate injection.

According to the present invention, the term "excipient" may also be referred to as excipient, filler or the like. As used herein, "pharmaceutically acceptable excipient" refers to an excipient that can be used in the formulation of a drug, which has substantially no adverse effects on the organism and is generally tolerated by the organism.

The preparation process of freeze-dried powder injection is a pharmaceutical process well known to those skilled in the art, such as two schematic freeze-drying curves shown in the following freeze-drying curve A and freeze-drying curve B:

In the following specific examples in the preparation of freeze-dried powder injections, if not otherwise specified, the freeze-drying curve used is freeze-drying curve A.

The moisture content in the freeze-dried powder injection is generally below 8%, preferably below 5%, more preferably below 3%. Moisture control can be controlled by adjusting the freeze-drying program appropriately. The moisture content in the freeze-dried powder injection can be determined according to many known methods, such as the loss on drying method.

In the present invention, an appropriate pH adjusting agent may be added to the composition in order to adjust the pH of the medicinal solution when necessary. Although the present inventors only adjust with strong acid or strong alkali solutions without buffering capacity such as aqueous sodium hydroxide solution and aqueous hydrochloric acid solution, those skilled in the art understand that if the pH regulator treatment without buffering capacity of this kind can meet the requirements of the system pH requirements, then the pH regulator with buffering capacity will be more able to achieve the purpose of the present invention, so these buffering agents can not only adjust the pH value, but also stabilize the pH value. Therefore, any pH regulator listed in the present invention or its combination is included in the spirit and scope of the present invention.

When preparing the freeze-dried powder injection of the present invention, in the prepared medicinal solution, the solid content is 1-20% (w/v), preferably 2-15% (w/v), more preferably 2-10% . Because the freeze-dried powder injection is usually obtained by freeze-drying in a tubular vial, those skilled in the art understand that this product usually presents a round cake before obtaining the finished product or even being used by a doctor, although the volume of the round cake is theoretical. Said above will be less than the volume of the original aqueous solution (slightly reduced), but usually this reduction is usually not reduced to 50% of the original aqueous solution volume, usually between 80-120% of the original aqueous solution volume, more usually in the original aqueous solution volume Between 90-100% of the final product, and traces of the liquid level of the original aqueous solution can be observed in the final product vial (the trace of the liquid level remaining on the bottle wall after the main body cake shrinks due to freeze-drying, even if the freeze-dried in the vial If the product is powdered due to various reasons such as collision, the original liquid surface traces can still be retained usually), based on this trace, the volume of the aqueous solution of the freeze-dried composition before freeze-drying can also be estimated. Therefore, although the present invention provides a substantially anhydrous freeze-dried powder injection, it is still possible to roughly estimate the volume of the liquid medicine at least before the start of freeze-drying at the time of preparation according to the powder injection, and according to the estimated The volume and the weight of the dried final product in the vial can also be calculated into the content of solids in the prepared medicinal liquid when preparing the freeze-dried powder injection of the present invention. Therefore, according to the freeze-dried powder injection of the first aspect of the present invention, the solid content of the liquid medicine during preparation is 1-20% (w/v), preferably 2-15% (w/v), and more preferably 2 to 10%.

The term "solid content" means that a solid substance (such as the active compound of the present invention and all excipients used, weight/gram) is added in a solvent (such as water for injection) to obtain a solution after dissolving, and the weight of the solid substance Divide by the percentage of the final solution volume (weight/volume percentage, eg g/100ml). For example, in the present invention, 100 mg of the active compound and a total of about 20 mg of other solids are added to an appropriate amount of aqueous solution for injection to prepare a solution with a final volume of 2 ml, and the solids content is 6%.

In the present invention, the symbol % may have a meaning easily understood by those skilled in the art according to the context in which it is used. For example, when referring to the solid content, the symbol represents the percentage of weight/volume (w/v, such as g/100ml); Below %, the symbol % at this time represents the percentage of weight/weight (w/w, g/100g). Generally speaking, when a solid is dispersed in a liquid, % means weight/volume percentage; when a solid is dispersed in a solid or a liquid is dispersed in a solid (such as the water content of a powder), % means a weight/weight percentage. In other cases, the symbols % represent weight/weight percentages, unless stated otherwise.

When preparing the medicinal solution of the present invention, it is well known to those skilled in the art that for example, a microporous filter membrane of about 0.45um can be used for coarse filtration; The microporous filter membrane is used for fine filtration to eliminate bacteria, and can be filtered multiple times if necessary.

According to the pharmaceutical composition of the present invention, it is freeze-dried powder injection. In one embodiment, the freeze-dried powder injection is a single-dose preparation (such as a vial-packed powder injection), and the amount of the active compound in each unit dose (it is expressed in terms of cyclic adenosine monophosphate if not otherwise specified in the present invention) ) can be, for example but not limited to, about 15 mg, about 19 mg, about 38 mg, about 50 mg.

According to the pharmaceutical composition of the present invention, it is reconstituted with water for injection, usually within 30 seconds, preferably within 20 seconds, more preferably within 15 seconds.

According to the freeze-dried powder injection of the present invention, it is made into a solution containing 10 mg of cyclic adenosine monophosphate per 1 ml of water and measured according to the method under the item of Appendix VI H of Part Two of the Chinese Pharmacopoeia 2010 Edition, the pH value of the solution is 5.5 to 7.0 , for example, the pH value is 6.0-6.5.

The freeze-dried powder injection provided by the invention can be stored in a dry place below 25°C for at least 24 months, which can meet the general storage requirements of the freeze-dried powder injection.

The freeze-dried powder injection obtained in the present invention, especially the freeze-dried powder injection, is usually a white or off-white freeze-dried block or fragment or powder thereof, odorless, bitter in taste, and easily soluble in water.

Detailed ways

The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made in the present invention without departing from the spirit and scope of the present invention. The present invention provides general and/or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of manipulation which are employed for the purposes of the invention are well known in the art, the invention has been described here in as much detail as possible. The following examples further illustrate the invention without limiting it. In the following examples, the pH regulator (i.e. acid-base regulator in the present invention) used, if not otherwise specified, is 1M sodium hydroxide solution or 1M hydrochloric acid solution, and its consumption is to make when preparing powder injection, make The pH value of the solution prepared before freeze-drying is adjusted to a certain specified value or range, and the specified value or range is the pH value measured by diluting the dry powder obtained by freeze-drying into a solution containing cyclic adenosine monophosphate 10mg/ml. value or range. The following preparation steps are for the purpose of illustration, and based on the comparability of each example, some specific descriptions are made. Those skilled in the art can fully obtain the method for preparing the freeze-dried powder injection of the present invention based on the existing knowledge. In the preparation of various compositions below, if not otherwise stated, the total liquid volume of each batch is 10000ml, but when listing the formula, it is stated in terms of the amount relative to cyclic adenosine monophosphate 10mg, and each bottle contains The amount of 18.8 mg of cyclic adenosine monophosphate was divided into 5 ml vials and freeze-dried; each bottle of the obtained freeze-dried powder injection contained 18.8 mg of cyclic adenosine monophosphate.

The quality control methods and standards of powder injections are carried out according to the specific methods and standards in the standard YBH02762005 issued by the State Food and Drug Administration. For example, the properties, identification, acidity, clarity and color of the solution, related substances, moisture, sterility, pyrogen, and content determination of the powder injection obtained in the present invention (measurement is the amount of adenosine cyclophosphate meglumine rather than adenosine cyclophosphate). The amount of glycosides) and other items.

Certain measurement items in these items can also be measured with reference to relevant pharmacopoeia methods, for example, the method for insoluble particle inspection of powder injection is according to the "first method (photoresistance method)" in Chinese Pharmacopoeia 2010 edition two appendix IX C insoluble particle inspection method "conduct.

Additionally, HPLC can be used to measure the amount of cyclic adenosine monophosphate in the powder injection prepared by the present invention, especially to investigate the amount of cyclic adenosine monophosphate remaining in the glass bottle when they undergo simulated clinical reconstitution. Use HPLC method to measure the amount of cyclic adenosine monophosphate with reference to literature methods such as He Xiaoyan (He Xiaoyan, etc., HPLC method measures the content of cyclic adenosine monophosphate meglumine injection, Chinese Pharmacist, 2011, 14 (5): 682), the content determination method of cyclic adenosine monophosphate can be called He Xiaoyan method in the present invention.

Clinically, the usage and dosage of cyclic adenosine meglumine lyophilized powder for injection are as follows: 1) Intravenous infusion: add 200-500ml of 5% glucose injection to dissolve and infuse intravenously, once a day, 60-60ml once a day. 180mg; 2) Intravenous injection: add 20-40ml of 25% or 10% glucose injection to dissolve and slowly inject intravenously, once a day, 90mg each time. However, in terms of production, generally speaking, for each bottle of powder injection containing about 18.8 mg of cyclic adenosine monophosphate, it is usually sealed and packaged into a single-dose preparation in a 5 ml vial. When in use, inject about 3ml of water for injection or glucose injection into the vial, then shake to dissolve the lyophilized powder, and then draw out the dissolved medicinal solution. However, it has been found that when reconstituted for this preparation, foams are usually produced. After the reconstituted medicinal solution is drawn out, water for injection is quantitatively added to the empty penicillin bottle, and the residual cyclophosphine in the solution is measured. As a result, it was completely unexpected to find that the amount of residual cyclic adenosine monophosphate in the vials of powder injections of different prescriptions showed completely different levels, and the amount of residual cyclic adenosine monophosphate in the formula added with specific sugars in the present invention was extremely low .

One, composition preparation example part

In the preparation examples of each powder injection below

Preparation Example 1, Preparation of Powder Injection Containing Adenosine Cyclic Meglumine

formula:

cyclic adenosine monophosphate 10mg, meglumine 6mg, Mannitol 12 mg, Maltose 1 mg, pH regulator to pH6.2, Water for Injection Appropriate amount, add to 0.8ml.

Preparation:

(1) Weigh the main drug and auxiliary materials (except the pH regulator) of the prescribed amount, place them in a stainless steel bucket, add about 80% of the prescribed amount of water for injection, stir to dissolve, and then add 0.1% (w/v) according to the volume of the solution ) of activated carbon, stirred for 30 minutes, decarbonized by filtration, and added water for injection to close to the full amount of the prescription.

(2) The filtrate is sampled, and the pH value is measured, and if necessary, adjust to a specified value with a pH regulator (that is, take an appropriate amount of the filtrate and dilute it with water for injection to contain an active ingredient of 10 mg/ml, and determine that the pH value of the diluted solution should reach 6.2, otherwise Then use a pH regulator (that is, an acid-base regulator to adjust appropriately), then add water for injection to the full amount of the prescription, measure the pH value, and adjust to the prescribed pH 6.2 with the pH regulator as described above if necessary; measure the activity in the liquid content of ingredients.

(3) The liquid medicine is first filtered with a 0.45um microporous membrane, and then filtered twice with a 0.22um microporous membrane.

(4) Fill in 5ml vials with the amount of cyclic adenosine monophosphate 18.8mg in the medicinal solution filled in each bottle (in the following examples, when citing the method of this preparation example, if not otherwise specified, the filling medicine The liquid volume is the volume of the liquid medicine containing 18.8 mg cyclic adenosine monophosphate; in other cases, if the volume of the filled medicine liquid increases or decreases significantly, the volume of the vial can be adjusted appropriately based on experience), and a rubber stopper is half added.

(5) Freeze-dry according to the freeze-drying curve A described herein until the water content is lower than 3%; after the freeze-drying is completed, perform hydraulic stoppering; tie an aluminum cover, and the product is ready. In the present invention, the sample of Preparation Example 1 can be referred to as Ex1 for short; the samples of other preparation examples can also be similarly represented.

Supplementary Preparation Example 1: Referring to the method of Preparation Example 1 above, the difference is that the amount of mannitol in it is adjusted to 0 mg, 4 mg, 9 mg, 15 mg, 25 mg, or 50 mg, respectively, and the obtained powder injection numbers are Ex111, Ex112, Ex113, Ex114, Ex115, Ex116 six powder needles. Supplementary Preparation Example 2: Referring to the method of Preparation Example 1 above, the difference is that the amount of maltose in it is adjusted to 0mg, 0.2mg, 0.5mg, 2mg, 5mg, 10mg, or 20mg, and the numbers of the obtained powder injections are respectively Ex121, Ex122, Ex123, Ex124, Ex125, Ex126, Ex127. Supplementary Preparation Example 3: Referring to the method of Preparation Example 1 above, the difference is that the amount of maltose is 0.5 mg, and the amount of mannitol is 0 mg, 4 mg, 9 mg, 15 mg, 25 mg, or 50 mg. The numbers of the obtained powder injections are Ex131, Ex132, Ex133, Ex134, Ex135, Ex136. Supplementary Preparation Example 4: Referring to the method of Preparation Example 1 above, the difference is that the amount of maltose is 5 mg, and the amount of mannitol is 0 mg, 4 mg, 9 mg, 15 mg, 25 mg, or 50 mg, and the numbers of the obtained powder injections are Ex141 and Ex142 respectively , Ex143, Ex144, Ex145, Ex146. Supplementary Preparation Example 5: Referring to the method of Preparation Example 1 above, the difference is that the amount of mannitol is 9 mg, and the amount of maltose is 0 mg, 0.2 mg, 0.5 mg, 2 mg, 5 mg, 10 mg, or 20 mg. The numbers of the obtained powder injections are respectively Ex151, Ex152, Ex153, Ex154, Ex155, Ex156, Ex157. Supplementary Preparation Example 6: Referring to the method of Preparation Example 1 above, the difference is that the amount of mannitol is 15 mg, and the amount of maltose is 0 mg, 0.2 mg, 0.5 mg, 2 mg, 5 mg, 10 mg, or 20 mg. The numbers of the obtained powder injections are respectively Ex161, Ex162, Ex163, Ex164, Ex165, Ex166, Ex167. Supplementary Preparation Example 7: Refer to the method of Preparation Example 1 above, except that maltose is replaced by an equivalent amount of sucrose, glucose, lactose, or fructose, and the numbers of the obtained powder injections are respectively Ex171, Ex172, Ex173, and Ex174; refer to the above Preparation Example 1, the difference is that mannitol is replaced by an equivalent amount of sorbitol, dextran, sodium chloride, or lactose, and the obtained powder injection numbers are respectively Ex175, Ex176, Ex177, and Ex178. Supplementary preparation example 8: refer to the method of the above preparation example 1, the difference is that no meglumine is added, and the cyclic adenosine monophosphate freeze-dried powder injection Ex181 without meglumine is obtained; referring to the method of the above preparation example 1, the different Without adding meglumine and maltose, the cyclic adenosine monophosphate freeze-dried powder injection Ex182 without meglumine and maltose was prepared. Supplementary preparation example 9: According to the formula and preparation method of Example 1 of the CN1579413A specification, wherein the excipient uses mannitol, the obtained powder injection is recorded as Ex191; according to the formula and preparation method of CN102258531B Example 4, the obtained powder injection is recorded as Ex192 According to the formula and the preparation method of CN 102988305B specification example 1, the powder injection obtained is recorded as Ex193; three batches of commercially available meglumine cyclophosphate injection powder injections (H2004**39, H2005**64, H2005**64, H2005**21), each bottle is marked to contain cyclic adenosine monophosphate 18.8mg (equivalent to cyclic adenosine monophosphate meglumine 30mg), and three batches of commercially available powder injections are respectively marked as Ex194, Ex195, and Ex196.

Preparation Example 2, Preparation of Powder Injection Containing Adenosine Cyclic Meglumine

formula:

cyclic adenosine monophosphate 10mg, meglumine 6.5 mg,

Mannitol 9 mg, Maltose 5 mg, pH regulator to pH6.5, Water for Injection Appropriate amount, add to 0.3ml.

Preparation method: refer to the preparation method of Preparation Example 1 above, but freeze-dry according to the freeze-drying curve B described herein, and the obtained powder injection is marked as Ex2.

Preparation Example 3, Preparation of Powder Injection Containing Adenosine Cyclic Meglumine

formula:

cyclic adenosine monophosphate 10mg, meglumine 5.5 mg, Mannitol 15 mg, Maltose 0.5 mg, pH regulator to pH6.0, Water for Injection Appropriate amount, add to 1.5ml.

Preparation method: refer to the preparation method of Preparation Example 1 above, and the obtained powder injection is marked as Ex3.

Preparation Example 4, Preparation of Powder Injection Containing Adenosine Cyclic Meglumine

formula:

cyclic adenosine monophosphate 10mg, meglumine 5.75 mg, Mannitol 14mg, Maltose 2 mg, pH regulator to pH6.4, Water for Injection Appropriate amount, add to 1ml.

Preparation method: refer to the preparation method of the above preparation example 1, and the obtained powder injection is marked as Ex4.

Preparation Example 5, Preparation of Powder Injection Containing Adenosine Cyclic Meglumine

formula:

cyclic adenosine monophosphate 10mg, meglumine 6.25 mg, Mannitol 10mg,

Maltose 0.5 mg, pH regulator to pH6.2, Water for Injection Appropriate amount, add to 1ml.

Preparation method: refer to the preparation method of the above preparation example 1, and the obtained powder injection is marked as Ex5.

Test case part

Test Example 1: Investigation of the Properties of Powder Injection

The samples prepared in the above preparation examples and supplementary preparation examples were investigated.

For each batch of powder injection samples, take 10 bottles, dissolve each bottle with 5ml of water for injection and transfer it completely to 100ml, dilute to the mark with water for injection, shake well, measure the content of cyclic adenosine monophosphate in the solution, and calculate the content of cyclic adenosine monophosphate in each bottle. The average content of glucoside (mg, can be expressed as M1); Then, for every batch of powder injection samples, get 10 bottles, inject 3ml of 5% glucose injection with a syringe into each bottle that keeps the rubber stopper sealed, shake up to make Dissolve the powder for injection, and then use the syringe to completely extract the medicinal solution (at this time, different batches of products will have foam residues in different degrees in the bottle), then, quantitatively add 1ml of water for injection in each empty vial, to Clean the vials, combine the washing liquid of 10 vials, measure the content of cyclic adenosine monophosphate in the solution, calculate the average content (mg, can be expressed as M2) of cyclic adenosine monophosphate in each bottle; the following formula calculates cyclic adenosine monophosphate in each bottle Residual rate (%):

Residual rate of cyclic adenosine monophosphate (%)=(M2÷M1)×100%

Result: All the five powder injections prepared in Preparation Example 1 to Preparation Example 5 and Ex113, Ex114, Ex123, Ex124, Ex125, Ex133, Ex134, Ex143, Ex144, Ex153, Ex154, Ex155, Ex163, Ex164, Ex165, these The powder injections have no obvious foam residues in the vials, and their cyclic adenosine monophosphate residual rates are all lower than 1%, all in the range of 0.16 to 0.41%; in addition, Ex115, Ex116, Ex126, Ex127, Ex135, Ex136 , Ex145, Ex146, Ex156, Ex157, Ex166, Ex167, 2 powder injection samples obtained in Supplementary Preparation Example 8, these powder injections have no obvious foam residue in the vials, and their residual rates of cyclic adenosine monophosphate are all less than 1%, all in the range of 0.14 to 0.45%; 6 powder injection samples as described in Supplementary Preparation Example 9, obvious foam residues can be seen in the vials of these powder injections, and their cyclic adenosine monophosphate residual rates are all lower than 4%, all in the range of 4.36-8.41% , it shows that these samples may have a considerable amount of cyclic adenosine monophosphate remaining in the vial due to foaming. The above results are the results observed using 5% glucose injection as the reconstitution solution. In the supplementary test, the applicant found that when water for injection was used as the reconstitution solution, the same observations as above using 5% glucose injection can be observed. Same result as reconstitution solution.

Test Example 2: Investigation of the Properties of Powder Injection

Some samples prepared in the above preparation examples and supplementary preparation examples were investigated. For each batch of powder injection samples, take 10 bottles, inject 3ml of water for injection into each bottle, let it stand, observe the time for complete dissolution, and calculate the time for reconstitution of each batch of powder injection under this condition. Result: All the five powder injections prepared in Preparation Example 1 to Preparation Example 5 and Ex113, Ex114, Ex123, Ex124, Ex125, Ex133, Ex134, Ex143, Ex144, Ex153, Ex154, Ex155, Ex163, Ex164, Ex165, these The reconstitution time of the powder injections was all less than 27 seconds, all between 14 seconds and 26 seconds; however, Ex115, Ex116, Ex126, Ex127, Ex135, Ex136, Ex145, Ex146, Ex156, Ex157, Ex166, Ex167 used mannitol Or the powder injections with excess maltose, their reconstitution time is greater than 120 seconds, and both are between 124 and 217 seconds. In addition, when 5% glucose injection was used as the reconstitution solution, the same result as the above-mentioned use of water for injection was also observed in terms of reconstitution time.

Test Example 3: Investigation of Drug Properties

According to the specific method in the standard YBH02762005 issued by the State Food and Drug Administration, Ex1, Ex2, Ex3, Ex4, Ex5, Ex113, Ex114, Ex123, Ex124, Ex125, Ex133, Ex134, Ex143, Ex144, Ex153, Ex154, Ex155 were determined , Ex163, Ex164, Ex165 these samples with the characteristics of the composition of the present invention: acidity, clarity and color of the solution, related substances, moisture, visible foreign matter, insoluble particles, content determination and other items. According to the above-mentioned standards, the measurement methods and standards of these items are stipulated as follows:

Acidity: Take the test sample, add water to dissolve and dilute to make a solution containing 15 mg of meglumine cyclic adenosine monophosphate in every 1 ml, measure according to the law (Appendix VI H), the pH value should be 5.5 to 7.0;

Clarity and color of the solution: Take the test product, dissolve it with water and dilute it to make a solution containing 15 mg of meglumine cyclic adenosine monophosphate per 1 ml. The solution should be clear and colorless; (Chinese Pharmacopoeia 2010 edition two appendix IXA first method) comparison, not deeper;

Related substances: get the test product, add water to make a solution containing 15 mg of meglumine cyclic adenosine monophosphate in every 1 ml, as the test solution; test according to the chromatographic conditions and methods under the content determination item, draw the test solution 10 μ l, Spot on chromatographic filter paper, unfold, dry, and inspect under ultraviolet light (254nm). If there are still small impurity spots under the main spot with a ratio shift value of 0.4~0.5 and at the origin, cut out the impurity spots , cut into strips, put into a test tube, accurately add 5ml of 0.01mol/L hydrochloric acid solution, shake, and after standing for 1 hour, pour the supernatant, according to spectrophotometry (Chinese Pharmacopoeia 2010 edition two appendix IV A) , measured at a wavelength of 257nm, using 0.01mol/L hydrochloric acid solution as a blank, the absorbance shall not be greater than 0.02;

Moisture: get test sample, measure according to moisture determination method (Chinese Pharmacopoeia 2010 edition two appendix VIII M the first method A), contain moisture and should not exceed 4.5%;

Visible foreign matter: take the test product and check according to the law (Appendix IX H of Part Two of the Chinese Pharmacopoeia 2010 Edition), and it should meet the regulations;

Insoluble particles: Take the test sample and check according to the law (Appendix IXC of Part Two of the Chinese Pharmacopoeia 2010 Edition), and it should meet the requirements;

Determination of content: Take the contents under the item of difference in loading volume and mix, accurately weigh an appropriate amount, add water to make a solution containing 15 mg of adenosine cyclic monophosphate meglumine per 1 ml, as the test solution; take another adenosine cyclic monophosphate control Appropriate amount of product, add water of 60 ℃ to make a solution containing about 10 mg in every 1 ml, as the reference solution; according to paper chromatography (Chinese Pharmacopoeia 2010 edition two appendix V A) test, accurately draw 10 μ l of each of the above two solutions, point Use isopropanol-concentrated ammonia solution-water (9:1:2) as the developing solvent on a chromatographic filter paper about 30 cm long. After developing for about 15 hours, dry it and examine it under a UV lamp (254nm). Draw the purple spot of the test product at the same position as the spot of the reference substance, cut off the spot, and cut it into thin strips, put it into a test tube, add 10ml of 0.01mol/L hydrochloric acid solution precisely, shake it, and let it stand for 1 hour. Take the supernatant, and measure the absorbance at a wavelength of 257nm according to the spectrophotometric method (Chinese Pharmacopoeia 2010 edition two appendix IV A), while replacing the test solution with water, operate in the same way as a blank correction. According to cyclic adenosine monophosphate ( ) is 447 divided by 0.6278, which is the amount of meglumine cyclic adenosine monophosphate (0.6278 is the molecular weight ratio of adenosine cyclic adenosine monophosphate and meglumine cyclic adenosine monophosphate).

Results: The test/determination items of the above test samples are all within the range specified in the above standards, for example, the acidity of Ex1 is 6.23, the clarity and color of the solution are qualified, the water content is 2.18%, and the content is 99.52% of the theoretical label.

In addition, the above-mentioned samples with the characteristics of the composition of the present invention were processed at 42°C for 5 months, and then measured according to the above-mentioned detection items and methods of the above-mentioned standards, and measured the various items of these powder injections treated at high temperature (simulating long-term sample retention) The results show that these items are still within the scope of the above-mentioned standards. For example, the acidity of Ex1 after 5 months of treatment at 42°C is 6.25, the clarity and color of the solution are qualified, the moisture is 2.12%, and the content is 99.21% of the theoretical label. %.

Safety test example: carry out safety test investigation to composition powder injection of the present invention

Gained sample Ex1, Ex2, Ex3 of the present invention and control sample (commercially available, adenosine cyclophosphate meglumine for injection, H20050249, produced by Peking University Hi-Tech Huatai), according to the requirements of the existing drug registration regulations, carry out vascular stimulation test, Hemolysis test, allergy test, the results show that these samples all meet the regulations of vascular irritation test, hemolysis test and allergy test. It is shown that these powder injection compositions have good safety.

Claims (10)

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:

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.

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:

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.

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%.