CN107019675B - Adenosine cyclophosphate freeze-dried powder injection medicine composition for injection and quality control method and preparation method thereof - Google Patents

Adenosine cyclophosphate freeze-dried powder injection medicine composition for injection and quality control method and preparation method thereof Download PDF

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CN107019675B
CN107019675B CN201710276917.8A CN201710276917A CN107019675B CN 107019675 B CN107019675 B CN 107019675B CN 201710276917 A CN201710276917 A CN 201710276917A CN 107019675 B CN107019675 B CN 107019675B
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injection
adenosine cyclophosphate
solution
adenosine
acid
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CN107019675A (en
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江威
左伟
肖流婷
王晓霞
朱玉婷
曾业浩
黄小石
方专
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CHENGDU TIANTAISHAN PHARMACEUTICAL CO LTD
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    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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Abstract

The invention relates to a freeze-dried adenosine cyclophosphate powder injection pharmaceutical composition for injection, a quality control method and a preparation method. Specifically, the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection provided by one embodiment of the invention comprises: adenosine cyclophosphate, mannitol and an acid-base regulator. In the composition, the mannitol accounts for 10-50 parts by weight of adenosine cyclophosphate per 10 parts by weight, the acid-base regulator is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid or a combination thereof, and the dosage of the acid-base regulator is such that the pH value of a solution containing 10mg of adenosine cyclophosphate per 1ml of the solution is 5.5-7.0 when the pharmaceutical composition is dissolved and diluted by adding water. The adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection and other aspects of the invention have good properties as described in the specification.

Description

Adenosine cyclophosphate freeze-dried powder injection medicine composition for injection and quality control method and preparation method thereof
Technical Field
The invention belongs to the technical field of medicinal preparations, relates to a medicament for heart failure, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy and auxiliary treatment of arrhythmia, and particularly relates to an adenosine cyclophosphate freeze-dried powder injection medicinal composition for injection, a quality control method and a preparation method thereof.
Background
The adenosine cyclophosphate freeze-dried powder injection medicine composition for injection is an effective medicine which can be used for heart failure, myocarditis, sick sinus syndrome, coronary heart disease and cardiomyopathy and can also be used for the adjuvant therapy of arrhythmia. The meglumine adenosine cyclophosphate powder injection for injection can be generally used for the following diseases: cardiovascular diseases (coronary heart disease, rheumatic heart disease, myocarditis, arrhythmia, etc.); cerebrovascular diseases (cerebral ischemia, cerebral thrombosis and sequelae thereof); cerebrovascular accident; a tumor patient; patients after operation (various orthopedic operations, craniocerebral operations, organ transplantation, general medication before anesthesia, etc.); various chronic consumptive diseases such as diabetes and nephropathy; various kinds of hepatitis; asthma, psoriasis, senile chronic bronchitis.
The chemical name of Adenosine Cyclophosphate (Adenosine Cyclophosphate) is 6-amino-9-beta-D-ribofuranosyl-9H-purine-4 ', 5' -cyclic hydrogen phosphate, the molecular formula is C10H12N5O6P, the molecular weight is 329.21, and the chemical structural formula is as follows:
Figure BDA0001278458990000011
because adenosine cyclophosphate is slightly soluble in water, the solubility of Meglumine (Meglumine, 1-deoxy-1- (methylamino) -D-sorbitol, the molecular formula of C7H17NO5 and the molecular weight of 195.22) is increased in adenosine cyclophosphate, and the Meglumine has a certain inhibition effect on phosphodiesterase so that the decomposition effect on the adenosine cyclophosphate is reduced, the positive inotropic effect of the Meglumine adenosine cyclophosphate is stronger than that of equivalent adenosine cyclophosphate, so that the adenosine cyclophosphate and the Meglumine are combined into the Meglumine cyclophosphate for use in clinic, and the Meglumine adenosine cyclophosphate with pharmacological effect is a non-digitalis cardiotonic agent, has the positive inotropic effect, can increase the myocardial contractility, improve the myocardial pumping function, has the effect of expanding blood vessels and can reduce the myocardial oxygen consumption; improving myocardial cell metabolism, and protecting ischemic and anoxic myocardium; can improve the function of P cells in the sinus node. The existing adenosine cyclophosphate freeze-dried powder injection for injection in the prior art has the defects of unstable insoluble particles, easy degradation when being exposed to light and the like, and has poor stability.
Adenosine cyclophosphate is a nucleotide medicine, and is a non-digitalis heart-strengthening medicine. Cyclic adenosine monophosphate (cAMP) is an important substance participating in regulation of metabolism and biological functions in cells, and is a "second messenger" for transmission of life information. As a cardiovascular drug, adenosine cyclophosphate has the advantages of good penetrability, mild pharmacological action, high stability and small toxic and side effects. Adenosine cyclophosphate can promote the survival of the myocardial cells in vivo and enhance the anti-injury, anti-ischemia and anti-hypoxia capability of the myocardial cells; promoting calcium ion flow into cardiac muscle cells, enhancing phosphorylation, promoting excitation-contraction coupling, improving cardiac muscle cell contractility, and increasing cardiac output; simultaneously, the composition also expands peripheral blood vessels, reduces the resistance of heart ejection, relieves the load of the heart, increases the cardiac output and improves the cardiac function. Thereby playing the roles of nourishing cardiac muscle, strengthening muscle, relaxing blood vessels, resisting platelet aggregation and resisting arrhythmia on the heart. Is mainly used for treating cardiac insufficiency, angina and myocardial infarction clinically. Especially for patients who are poisoned or insensitive to yellow cardiotonic drugs.
Cyclic adenosine monophosphate entering cells is degraded by phosphodiesterase into 5-adenosine-5' -phosphate (5-AMP) to lose activity after exerting a biological effect, and is further decomposed into adenosine and phosphate. Adenosine cyclophosphate is clinically used for cardiac insufficiency, angina and myocardial infarction; patients who are poisoned or insensitive to digitalis cardiotonic drugs; an adjuvant medicine for treating arrhythmia.
Because of the insufficient solubility of adenosine cyclophosphate, the adenosine cyclophosphate is prepared into an injection by mixing the adenosine cyclophosphate and meglumine in a molar ratio of 1:1 so as to increase the solubility of the adenosine cyclophosphate. Although meglumine adenosine cyclophosphate preparations such as powder injection or water injection are prepared by directly feeding adenosine cyclophosphate and meglumine in a molar ratio of 1:1, there is occasionally a statement that they are called double salts, for example, compounds of the following structure are said to be formed:
Figure BDA0001278458990000021
in the prior art, a plurality of technical reports about adenosine cyclophosphate technology, such as preparation technology of the adenosine cyclophosphate technology, such as powder injection or water injection of the adenosine cyclophosphate technology, exist.
CN101780099A (201010108233.5, Deng chemical peak) relates to a meglumine adenosine cyclophosphate composite drug or a meglumine adenosine cyclophosphate composite drug, which is prepared from the following medicinal components in parts by weight, namely 20-60 parts of meglumine adenosine cyclophosphate or adenosine cyclophosphate, 100 parts of lysine aspirin and 200 parts of reduced glutathione and 200 parts of a mixture of vitamin C in a weight ratio of 1: 10-15. The invention also discloses a preparation method. The meglumine adenosine cyclophosphate composite medicine or the adenosine cyclophosphate composite medicine eliminates adverse reactions of fever, rash and pain of the meglumine adenosine cyclophosphate or adenosine cyclophosphate prepared by the prior art.
CN103613626A (201310619163.3, Meline) relates to a adenosine cyclophosphate compound and a meglumine adenosine cyclophosphate medicine composition thereof. The adenosine cyclophosphate compound is a crystal, and the characteristic peaks in the map are shown at 5.8 degrees, 6.9 degrees, 7.6 degrees, 11.3 degrees, 16.5 degrees, 19.2 degrees, 21.7 degrees, 22.6 degrees, 24.0 degrees, 25.9 degrees, 30.1 degrees, 31.2 degrees and 33.4 degrees at 2 theta +/-0.2 degrees by adopting X-ray powder diffraction measurement. The invention also provides an injection containing the adenosine cyclophosphate compound as an active ingredient, a meglumine adenosine cyclophosphate composition injection and a meglumine adenosine cyclophosphate glucose composition injection. Compared with the prior art, the adenosine cyclophosphate injection has obviously improved stability, and the stability can be further improved by adding L-malic acid and sodium tartrate in the formula.
CN102988305A (201210303740.3, Yaotong) relates to a pharmaceutical composition containing meglumine adenosine cyclophosphate compound, in particular to a freeze-dried powder injection of meglumine adenosine cyclophosphate and a preparation method thereof, wherein each 1000 injections are prepared from the following components in proportion: meglumine adenosine cyclophosphate 20 g; 100-200g of mannitol; 1-3g of EDTA calcium; 1-2g of vitamin C, and the molar ratio is 1: 4 disodium hydrogen citrate and trisodium citrate buffer 2000 ml.
CN1579413A (200410013546.7, Jiangwang) discloses meglumine adenosine cyclophosphate for injection and a preparation process thereof. In the meglumine adenosine cyclophosphate solution, adenosine cyclophosphate is gradually separated out along with the prolonging of the preservation time, so that the medicine liquid is deteriorated and turbid, and serious adverse reaction can occur when the medicine liquid is applied to patients, thereby affecting the curative effect and the safety of the medicine. The meglumine adenosine cyclophosphate for injection comprises adenosine cyclophosphate, wherein the adenosine cyclophosphate, meglumine and an excipient are prepared into a freeze-dried powder injection, the parts by weight of the freeze-dried powder injection are 1.7-63 parts of adenosine cyclophosphate, 1.0-37 parts of meglumine and 0.675-90 parts of the excipient, the ratio of the adenosine cyclophosphate to the meglumine by weight is 1.7: 1, the pH value is 3.5-9.0, the freeze-dried block or powder is white or white-like, and the freeze-dried block or powder reacts with an iron trichloride test solution to form a brownish red precipitate, and then the brownish red precipitate is dissolved into a brownish red solution. The product can be used for treating heart failure, myocarditis, sick sinus syndrome, coronary heart disease, cardiomyopathy, and arrhythmia.
CN1459288A (03124559.5, Gem) relates to a large infusion preparation of adenosine cyclophosphate glucamine, a preparation method thereof and a method for measuring the content of adenosine cyclophosphate glucamine in the large infusion preparation. The recipe of the isotonic transfusion preparation of meglumine adenosine cyclophosphate is 100ml, which contains 54-66mg of meglumine adenosine cyclophosphate as main medicine, 4.5-5.5g of isotonic medium glucose or 0.85-0.95g of sodium chloride. The invention determines the pH value range of the key condition for stabilizing the large infusion preparation of the meglumine adenosine cyclophosphate and the preparation method of the large infusion preparation, solves the problem of measuring the content of the meglumine adenosine cyclophosphate, is beneficial to controlling the production quality of the large infusion preparation of the meglumine adenosine cyclophosphate, thereby establishing a proper production method and enabling the large infusion preparation of the meglumine adenosine cyclophosphate to be industrially produced in large scale. The preparation can avoid the intermediate link of extracting the liquid medicine from a small needle and injecting the liquid medicine into glucose or sodium chloride large transfusion, avoids cross infection and pollution in the medication process, and is safer and more convenient to use. The invention can be made into various specifications for medical staff to select as appropriate.
CN101721357A (200810230677.9, Huazhong) discloses a filtration method of meglumine adenosine cyclophosphate high-volume injection. The invention firstly pretreats the preparation liquid of meglumine adenosine cyclophosphate high-capacity injection, and then carries out ultrafiltration technology treatment, so that the macromolecule invalid components are completely removed, and the prepared injection has high clarity, small related substances, qualified pyrogen and good stability.
CN1923180A (200610116409.5, Wanbang) and a preparation process of meglumine adenosine cyclophosphate for injection, belonging to the field of chemical pharmacy. A process for preparing meglumine adenosine cyclophosphate for injection includes such steps as adding aseptic excipient powder to 6% meglumine adenosine cyclophosphate solution, stirring for dissolving, diluting with water for injection, regulating pH value to 5.5-7.0, cooling, condensing when the temp of product reaches-35 deg.C to 1-2 hr, cooling to-45 deg.C, vacuumizing to-1.5X 10-2KPA, heating at 3 deg.C/hr, and holding the temp for 2 hr when it reaches room temp or 30 deg.C or more, and freeze drying for 24-26 hr. The meglumine adenosine cyclophosphate for injection is a sterile freeze-dried powder injection prepared by adopting the modern preparation technology, can be transported and stored at normal temperature, and improves the stability and safety of the product. The preparation process of the product is simple, scientific and reasonable and is easy to operate.
CN101455631A (200910060427.X, Dekang) relates to adenosine cyclophosphate freeze-dried powder injection for injection and a preparation process thereof, citric acid is put into a magnetic stirring tank, injection water with the preparation amount of 50% is added and stirred to be dissolved, adenosine cyclophosphate and meglumine are added into the solution and stirred to be dissolved, 0.02% of needle activated carbon is added according to volume and stirred for 30 minutes, the carbon is removed by rough filtration to prepare a meglumine adenosine cyclophosphate solution for standby, the injection water is added to the full amount, the pH value is adjusted to 6.0-6.5 by 10% of sodium hydroxide solution, and the colorless clear injection is prepared. The invention not only has the advantages of direct and rapid action, but also has less adverse reaction and can be transported and stored at normal temperature, thereby improving the stability and safety of the product.
CN102283804A (201010214356.7, Fangming) relates to adenosine cyclophosphate freeze-dried powder injection for injection and a preparation method thereof. The preparation process comprises the steps of taking a proper amount of water for injection, adding sodium chloride, adenosine cyclophosphate and meglumine, stirring to completely dissolve, adding 0.05-0.2% (W/V) of activated carbon for injection according to volume, stirring for 15-30 minutes, filtering to remove carbon, adding the water for injection to nearly the full amount, adjusting the pH value to 6.0-6.5 by using a phosphate buffer solution, adding the water for injection to the full amount, filtering after a semi-finished product is detected to be qualified, filling and sealing (filling nitrogen in the whole process), sterilizing, performing lamp inspection and packaging to obtain the injection. The method has the advantages that the proper solvent and additive are selected, the solubility and the stability of the meglumine adenosine cyclophosphate are improved, and the sterility guarantee level of the medicine is effectively guaranteed by adopting a final sterilization preparation method. Has the characteristics of simple formula and process, low production cost, strong medicament stability and safety and the like.
CN102600070A (201110435919.X, Dekang) relates to a preparation method of a chemical, in particular to meglumine adenosine cyclophosphate composition injection and preparation thereof. The weight portions are as follows: 5-15 parts of adenosine cyclophosphate, 3-10 parts of meglumine, 2.0-2.2 parts of citric acid, 0.6-0.8 part of sodium hydroxide, 2-4 parts of sodium chloride and 2-5 parts of water for injection; the preparation steps are as follows: adding water for injection into citric acid, stirring and dissolving, then adjusting the pH value to 5.9-6.5 by using sodium hydroxide to form a buffer solution, then adding sodium chloride and a cosolvent, stirring and dissolving, adding water for injection, adding adenosine cyclophosphate and meglumine while stirring, adding activated carbon after complete dissolution, stirring, filtering, and refluxing to prepare colorless clear liquid. The injection has good clarity, good stability and safe medication.
CN102796156A (201210314213.2, Ninghui) relates to adenosine cyclophosphate meglumine compound and a preparation method thereof, and provides a compound formed by 1 molecule of adenosine cyclophosphate and 2 molecules of meglumine, a preparation method thereof and a pharmaceutical composition containing the compound. The water solubility and the stability of the compound are superior to those of the existing compound.
CN102258531A (201110102704.6, ninghui) provides a pharmaceutical composition containing adenosine cyclophosphate and meglumine and a preparation method thereof, which comprises adenosine cyclophosphate as an active ingredient, meglumine as a stabilizer and mannitol as a framework, wherein the components are present in a certain ratio. The composition of the present invention minimizes degradation of adenosine cyclophosphate, thereby protecting drug stability, effectiveness and safety.
CN101455631A (200910060427.X, Dekang) relates to adenosine cyclophosphate freeze-dried powder injection for injection and a preparation process thereof, citric acid is put into a magnetic stirring tank, injection water with the preparation amount of 50% is added and stirred to be dissolved, adenosine cyclophosphate and meglumine are added into the solution and stirred to be dissolved, 0.02% of needle activated carbon is added according to volume and stirred for 30 minutes, the carbon is removed by rough filtration to prepare a meglumine adenosine cyclophosphate solution for standby, the injection water is added to the full amount, the pH value is adjusted to 6.0-6.5 by 10% of sodium hydroxide solution, and the colorless clear injection is prepared. The invention not only has the advantages of direct and rapid action, but also has less adverse reaction and can be transported and stored at normal temperature, thereby improving the stability and safety of the product.
However, the existing adenosine cyclophosphate preparations such as freeze-dried powder thereof still have technical problems to be overcome. Therefore, the technicians in the field still expect to have a new method for preparing the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition with good pharmaceutical performance.
Disclosure of Invention
The invention aims to provide a adenosine cyclophosphate freeze-dried powder injection medicine composition with good pharmaceutical performance for injection. The present inventors have surprisingly found that the pharmaceutical composition of adenosine cyclophosphate lyophilized powder for injection having the characteristics of the composition of the present invention can advantageously achieve the above object. The present invention has been completed accordingly.
Therefore, the invention provides a adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection, which comprises the following components: adenosine cyclophosphate, mannitol and an acid-base regulator.
The pharmaceutical composition according to any one of the embodiments of the first aspect of the present invention, wherein the material is comprised in an amount of 10 to 50 parts by weight of mannitol per 10 parts by weight of adenosine cyclophosphate; for example, the amount of mannitol is 10 to 25 parts by weight.
The adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection according to any one of the embodiments of the first aspect of the invention, wherein the pH regulator is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or a combination thereof.
The adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection according to any one of the embodiments of the first aspect of the invention, wherein the pH regulator is phosphoric acid and/or disodium hydrogen phosphate.
According to the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection in any embodiment of the first aspect of the invention, the acid-base regulator is phosphoric acid and/or disodium hydrogen phosphate, and the dosage of the acid-base regulator is such that when the pharmaceutical composition is dissolved and diluted by adding water to prepare a solution containing 10mg of adenosine cyclophosphate in each 1ml, the pH value of the solution is 5.5-7.0, for example, the pH value is 6.0-6.5.
The adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection according to any one embodiment of the first aspect of the invention further comprises sodium chloride.
The adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection according to any one embodiment of the first aspect of the invention further comprises sodium chloride, and the amount of the sodium chloride is 0.5-3 mg, such as 1-2 mg, based on 10 parts by weight of adenosine cyclophosphate.
The pharmaceutical composition according to any one of the embodiments of the first aspect of the present invention is a freeze-dried powder injection.
The pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, the solution of which before freeze-drying comprises water for injection in addition to adenosine cyclophosphate, mannitol and optionally sodium chloride and optionally an acidifying or alkalizing agent.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the solution before freeze-drying comprises water for injection in addition to adenosine cyclophosphate, mannitol and optionally sodium chloride and optionally an acid-base regulator, and the solid content of the solution is 1-20% (w/v), preferably 2-15% (w/v), and more preferably 2-10%.
The pharmaceutical composition according to any one of the embodiments of the first aspect of the present invention, which is reconstituted with water for injection to substantially the same volume as the solution before lyophilization, has a solid content of 1 to 20% (w/v), preferably 2 to 15% (w/v), and more preferably 2 to 10%.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention is a freeze-dried powder injection comprising 10 to 100mg of adenosine cyclophosphate in each bottle, such as 10 to 75mg of adenosine cyclophosphate in each bottle, such as 10 to 50mg of adenosine cyclophosphate in each bottle.
As is well known, freeze-dried powder injection (usually, referred to as freeze-dried powder injection or freeze-dried powder injection) obtained by low-temperature freeze-vacuum drying is a substantially anhydrous powder or block obtained by dissolving each material in a solvent (usually, in water) to prepare a solution, then freezing the solution at a low temperature, and then performing vacuum-pumping, sublimation and drying (usually, the water content is less than 8%, particularly, usually, less than 5%, particularly, usually, less than 3%). Therefore, the pH of the solid lyophilizate is usually controlled by adjusting the pH of the solution during the formulation process; or can be controlled by adjusting the prescription so that the pH value of the obtained solid lyophilizate is controlled under the specified dissolving/diluting degree (the pH value of the solid lyophilizate is controlled); the latter method is generally more commonly used, for example, many lyophilized powder injections carried in pharmacopoeia control the pH value of the preparation in this way, and the pH value of the product can be controlled in this way, and the pH value of the final product can be only regulated without specifically specifying the prescription amount of the pH regulator. Also suitable for use in the present invention is the pharmaceutical composition according to any of the embodiments of the first aspect of the present invention, wherein the amount of the optional pH adjusting agent is an amount such that the pH of the solution when the lyophilized powder for injection is dissolved in water for injection to a solution containing 10mg/ml of the active ingredient 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 adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection according to any one of the embodiments of the first aspect of the invention, wherein the sodium chloride is prepared into a solution with adenosine cyclophosphate in advance and is adsorbed by activated carbon under the condition that the pH value is lower than 4.5 (for example, the pH value is 3.5-4.0). It has been unexpectedly found that when adenosine cyclophosphate is subjected to specific treatment in advance by using a proper amount of sodium chloride, the prepared freeze-dried adenosine cyclophosphate injection pharmaceutical composition for injection has excellent properties such as chemical stability.
The adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection according to any one embodiment of the first aspect of the invention is prepared by a method comprising the following steps:
(1) adding adenosine cyclophosphate and sodium chloride into room-temperature injection water with the preparation amount of 60%, stirring and dissolving, adjusting the pH value of the liquid medicine to 3.5-4.0 by using an acid-base regulator, adding active carbon for injection according to 0.05-0.15 w/v% of the volume of the liquid medicine, stirring and adsorbing for 20 minutes, and filtering and decarburizing for later use;
(2) adding mannitol into room-temperature injection water with the preparation amount of 20%, stirring for dissolving, adding active carbon for injection according to 0.05-0.15 w/v% of the volume of the liquid medicine, stirring for adsorbing for 20 minutes, filtering and removing carbon for later use;
(3) mixing the liquid medicines obtained in the step (1) and the step (2), adjusting the pH value of the liquid medicine to 6.0-6.5 by using an acid-base regulator, filtering by using a titanium rod filter with the aperture of 1um, supplementing water for injection at room temperature to a preparation amount, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0-6.5 by using the acid-base regulator;
(4) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22um until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
The pharmaceutical composition according to any embodiment of the first aspect of the present invention, wherein the addition of room temperature water for injection in step (3) to a formulation amount means that the solid content in the obtained liquid medicine is 1-20% (w/v), preferably 2-15% (w/v), and more preferably 2-10%.
Further, the second aspect of the present invention provides a method for preparing a freeze-dried adenosine cyclophosphate injection pharmaceutical composition, wherein the freeze-dried adenosine cyclophosphate injection pharmaceutical composition comprises: adenosine cyclophosphate, mannitol, sodium chloride and an acid-base regulator, wherein the method comprises the following steps:
(1) adding adenosine cyclophosphate and sodium chloride into room-temperature injection water with the preparation amount of 60%, stirring and dissolving, adjusting the pH value of the liquid medicine to 3.5-4.0 by using an acid-base regulator, adding active carbon for injection according to 0.05-0.15 w/v% of the volume of the liquid medicine, stirring and adsorbing for 20 minutes, and filtering and decarburizing for later use;
(2) adding mannitol into room-temperature injection water with the preparation amount of 20%, stirring for dissolving, adding active carbon for injection according to 0.05-0.15 w/v% of the volume of the liquid medicine, stirring for adsorbing for 20 minutes, filtering and removing carbon for later use;
(3) mixing the liquid medicines obtained in the step (1) and the step (2), adjusting the pH value of the liquid medicine to 6.0-6.5 by using an acid-base regulator, filtering by using a titanium rod filter with the aperture of 1um, supplementing water for injection at room temperature to a preparation amount, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0-6.5 by using the acid-base regulator;
(4) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22um until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
According to the method of any embodiment of the second aspect of the invention, the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection prepared by the method is in the form of freeze-dried powder injection.
According to the method of any embodiment of the second aspect of the invention, the prepared adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection contains 10-50 parts by weight of mannitol per 10 parts by weight of adenosine cyclophosphate; for example, the amount of mannitol is 10 to 25 parts by weight.
The method according to any embodiment of the second aspect of the present invention, wherein said ph adjusting agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or combinations thereof.
The method according to any one of the embodiments of the second aspect of the present invention, wherein said pH modifying agent is phosphoric acid and/or disodium hydrogen phosphate.
The method according to any of the embodiments of the second aspect of the present invention, wherein the pH adjusting agent is phosphoric acid and/or disodium hydrogen phosphate in an amount such that when the pharmaceutical composition is dissolved in water and diluted to a solution containing 10mg of adenosine cyclophosphate per 1ml, the pH of the solution is 5.5 to 7.0, for example, 6.0 to 6.5.
According to the method of any embodiment of the second aspect of the invention, the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition prepared by the method is 0.5-3 mg, such as 1-2 mg, of sodium chloride per 10 parts by weight of adenosine cyclophosphate.
According to the method of any embodiment of the second aspect of the invention, the prepared adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is freeze-dried powder injection.
According to the method of any embodiment of the second aspect of the invention, the prepared solution of the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection before freeze drying comprises water for injection in addition to adenosine cyclophosphate, mannitol, optional sodium chloride and optional acid-base regulator.
According to the method of any embodiment of the second aspect of the invention, the prepared solution of the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection before freeze drying comprises adenosine cyclophosphate, mannitol, optional sodium chloride and optional acid-base regulator, and also comprises water for injection, and the solid content of the solution is 1-20% (w/v), preferably 2-15% (w/v), and still more preferably 2-10%.
According to the method of any embodiment of the second aspect of the invention, the prepared adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is re-dissolved with water for injection to the volume which is basically the same as that of the solution before freeze-drying, and the solid content in the obtained solution is 1-20% (w/v), preferably 2-15% (w/v), and still more preferably 2-10%.
According to the method of any embodiment of the second aspect of the invention, the prepared adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is freeze-dried powder injection, wherein the weight of adenosine cyclophosphate contained in each bottle is 10-100 mg, for example, the weight of adenosine cyclophosphate contained in each bottle is 10-75 mg, for example, the weight of adenosine cyclophosphate contained in each bottle is 10-50 mg.
The method according to any embodiment of the second aspect of the present invention, wherein the adding of room temperature water for injection to a preparation amount in step (3) means that the solid content in the obtained liquid medicine is 1-20% (w/v), preferably 2-15% (w/v), and more preferably 2-10%.
Further, the third aspect of the present invention provides a method for quality control of a freeze-dried adenosine cyclophosphate injection pharmaceutical composition for injection, wherein the freeze-dried adenosine cyclophosphate injection pharmaceutical composition for injection comprises: adenosine cyclophosphate, mannitol and an acid-base regulator, wherein the quality control method comprises the step of measuring the adenosine cyclophosphate content and/or the related substance quantity in the injection by using high performance liquid chromatography.
The method according to any embodiment of the third aspect of the invention, wherein the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is a pharmaceutical composition in the form of freeze-dried powder injection.
The method according to any embodiment of the third aspect of the invention, wherein the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection contains 10-50 parts by weight of mannitol based on 10 parts by weight of adenosine cyclophosphate; for example, the amount of mannitol is 10 to 25 parts by weight.
The method according to any embodiment of the third aspect of the present invention, wherein the acid-base modifier in the adenosine cyclophosphate lyophilized powder injection pharmaceutical composition for injection is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or a combination thereof.
The method according to any embodiment of the third aspect of the invention, wherein the acid-base regulator in the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is phosphoric acid and/or disodium hydrogen phosphate.
The method according to any embodiment of the third aspect of the invention, wherein the acid-base regulator in the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is phosphoric acid and/or disodium hydrogen phosphate, and the amount of the acid-base regulator is such that when the pharmaceutical composition is dissolved in water and diluted to prepare a solution containing 10mg of adenosine cyclophosphate in each 1ml, the pH value of the solution is 5.5-7.0, for example, the pH value is 6.0-6.5.
The method according to any embodiment of the third aspect of the invention, wherein the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection further comprises sodium chloride.
The method according to any embodiment of the third aspect of the present invention, wherein the adenosine cyclophosphate lyophilized powder for injection further comprises sodium chloride, and the amount of the sodium chloride is 0.5-3 mg, for example 1-2 mg, per 10 parts by weight of adenosine cyclophosphate.
The method according to any embodiment of the third aspect of the invention, wherein the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is freeze-dried powder injection.
The method according to any embodiment of the third aspect of the invention, wherein the solution of the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection before freeze-drying comprises water for injection in addition to adenosine cyclophosphate, mannitol and optionally sodium chloride and optionally an acid-base regulator.
The method according to any embodiment of the third aspect of the invention, wherein the solution of the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection before freeze drying comprises water for injection in addition to adenosine cyclophosphate, mannitol, optional sodium chloride and optional acid-base regulator, and the solid content of the solution is 1-20% (w/v), preferably 2-15% (w/v), and still more preferably 2-10%.
The method according to any embodiment of the third aspect of the invention, wherein the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is re-dissolved 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 2-15% (w/v), and still more preferably 2-10%.
The method according to any embodiment of the third aspect of the present invention, wherein the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is a freeze-dried powder injection, and the weight of adenosine cyclophosphate contained in each bottle is 10-100 mg, such as 10-75 mg, such as 10-50 mg.
The method according to any embodiment of the third aspect of the invention, wherein the sodium chloride in the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is prepared into a solution with adenosine cyclophosphate in advance and is treated by activated carbon adsorption under the condition that the pH value is lower than 4.5 (for example, the pH value is 3.5-4.0). It has been unexpectedly found that when adenosine cyclophosphate is subjected to specific treatment in advance by using a proper amount of sodium chloride, the prepared freeze-dried adenosine cyclophosphate injection pharmaceutical composition for injection has excellent properties such as chemical stability.
The method according to any embodiment of the third aspect of the invention, wherein the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is prepared according to the method comprising the following steps:
(1) adding adenosine cyclophosphate and sodium chloride into room-temperature injection water with the preparation amount of 60%, stirring and dissolving, adjusting the pH value of the liquid medicine to 3.5-4.0 by using an acid-base regulator, adding active carbon for injection according to 0.05-0.15 w/v% of the volume of the liquid medicine, stirring and adsorbing for 20 minutes, and filtering and decarburizing for later use;
(2) adding mannitol into room-temperature injection water with the preparation amount of 20%, stirring for dissolving, adding active carbon for injection according to 0.05-0.15 w/v% of the volume of the liquid medicine, stirring for adsorbing for 20 minutes, filtering and removing carbon for later use;
(3) mixing the liquid medicines obtained in the step (1) and the step (2), adjusting the pH value of the liquid medicine to 6.0-6.5 by using an acid-base regulator, filtering by using a titanium rod filter with the aperture of 1um, supplementing water for injection at room temperature to a preparation amount, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0-6.5 by using the acid-base regulator;
(4) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22 mu m until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
The method according to any embodiment of the third aspect of the present invention, wherein the adding of room temperature water for injection to a preparation amount in step (3) means that the solid content in the obtained liquid medicine is 1-20% (w/v), preferably 2-15% (w/v), and more preferably 2-10%.
The method according to any embodiment of the third aspect of the present invention, wherein the step of measuring the adenosine cyclophosphate content and the related substances by high performance liquid chromatography comprises the following operations:
(1) the specification of the high performance liquid chromatography carried in section 0512 of the fourth part 59 of the Chinese pharmacopoeia 2015 edition is measured;
(2) chromatographic conditions and system applicability test: a column using octadecylsilane bonded silica as a packing (for example, a column specification of 250mm × 4.6mm, 5 μm), and a column prepared by mixing 0.01 phosphoric acid solution-acetonitrile in a volume ratio of 95: 5 is a mobile phase, the flow rate is 1ml/min, the column temperature is 30 ℃, and the detection wavelength is 259 nm; measuring by using a system applicability test solution, wherein the number of theoretical plates is not less than 5000 according to the adenosine cyclophosphate peak, and the separation degree between the adenosine cyclophosphate and the adenosine is more than 2;
(3) solution preparation:
taking a proper amount of adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection, adding a mobile phase for dilution, preparing into a solution containing 1mg of adenosine cyclophosphate in each 1ml of solution, and filtering to obtain a test sample solution (namely 1000 mu g/ml) for checking related substances;
precisely measuring 1ml of test solution for checking related substances, placing in a 100ml measuring flask, diluting with mobile phase, shaking, and making into solution containing adenosine cyclophosphate at concentration of 10 μ g/ml as reference solution (i.e. 10 μ g/ml);
precisely measuring 1ml of sample solution for checking related substances, placing in a 20ml measuring flask, diluting with mobile phase, shaking, and making into solution containing adenosine cyclophosphate at concentration of 50 μ g/ml as sample solution for content determination (i.e. 50 μ g/ml);
precisely weighing appropriate amount of adenosine cyclophosphate reference substance, dissolving with mobile phase to obtain solution with concentration of 50 μ g/ml, and determining adenosine cyclophosphate content with reference substance solution (50 μ g/ml);
accurately weighing appropriate amount of adenosine cyclophosphate reference substance and adenosine reference substance, adding mobile phase for dissolving and diluting, and making into mixed solution containing adenosine cyclophosphate 1000 μ g and adenosine 10 μ g in each 1ml solution as system applicability test solution (i.e. 1000 μ g/ml +10 μ g/ml);
(4) and (3) determination:
precisely measuring 20 mu l of system applicability test solution, injecting into a liquid chromatograph, recording a chromatogram, calculating the number of theoretical plates and the separation degree between adenosine cyclophosphate and adenosine separation degree peaks, and determining the retention time of the adenosine cyclophosphate and adenosine;
precisely measuring the sample solution for inspecting related substances and the reference solution for inspecting related substances respectively by 20 μ l, respectively injecting into a liquid chromatograph, recording chromatogram until the retention time of adenosine cyclophosphate is 3 times, reading the area of main peak formation peak and the area of peak of each impurity in the chromatogram of the sample solution, when the existence of acrobatics is detected, calculating the percentage content of each impurity relative to adenosine cyclophosphate in the chromatogram of the test solution by taking the peak area of the main component in the chromatogram of the control solution for checking related substances as 1.0%, and obtaining the content of a single impurity in the test sample (namely, for example, if the main peak area of the control solution is 100 and the peak area of a certain impurity in the chromatogram of the test solution is 115, the percentage content of the impurity relative to adenosine cyclophosphate is 1.15%, and the peak area of the certain impurity in the chromatogram of the test solution is 87, the impurity content is 0.87%);
respectively and precisely measuring 20 mu l of each of the test solution for content determination and the reference solution for content determination, respectively injecting into a liquid chromatograph, recording the chromatogram until the retention time of adenosine cyclophosphate is 2 times, obtaining two chromatograms, respectively reading the main peak area in the two chromatograms, and calculating the content of adenosine cyclophosphate in the test sample according to the peak area by an external standard method.
The above method is substantially the same as that disclosed in the literature of Haozai et al (Haozai, et al, HPLC method for measuring the content of adenosine cyclophosphate in freeze-dried powder injection for injection, Chinese pharmacist 2011, 14(5):682), and the present invention has the number of theoretical plates of adenosine cyclophosphate of 75000, the separation degree of adenosine cyclophosphate from adenosine of about 2.73, the tailing factor of adenosine cyclophosphate of 1.008, the retention time of adenosine cyclophosphate of about 6.69, and the relative retention time RRT of adenosine relative to adenosine cyclophosphate of 0.88, which are determined by the above method, and these results are substantially the same as those in the Haozai, et al. However, in the preparation of adenosine cyclophosphate, an obvious unknown impurity exists at a relative retention time of about RRT to 1.08, which is determined by the method, the separation degree between the impurity and the adenosine cyclophosphate peak is about 1.34, and the separation degree is unsatisfactory, and the calculation of the peak areas of the adenosine cyclophosphate and the unknown impurity is influenced. Therefore, the above-mentioned HPLC method still remains insufficient.
The method according to any one of the embodiments of the third aspect of the present invention, wherein 0.2 to 0.5w/v% of formic acid is further added to the mobile phase of the high performance liquid chromatography. In one embodiment, 0.3 w/v% formic acid is also added to the mobile phase. It has been found that when 0.3 w/v% formic acid is added to the mobile phase, the theoretical plate number, the degree of separation of adenosine cyclophosphate from adenosine, the adenosine cyclophosphate tailing factor, the adenosine cyclophosphate retention time, the adenosine RRT, and these parameters are substantially unchanged relative to the case where no formic acid is added, but the requirement for determination of the principal component and the unknown impurity is fully satisfied when the retention time of the unknown impurity is extended to about 1.17 RRT (which may be referred to as impurity RRT1.17 in the present invention) and the degree of separation from adenosine cyclophosphate reaches 2.42. In addition, it has been found that when formic acid is replaced with acetic acid, a similar organic acid, the above-mentioned separation effect is not achieved at all, i.e., the unknown impurity RRT is about 1.08 and the degree of separation from cyclic adenosine monophosphate is 1.39, and the remaining parameters are substantially the same.
In addition, it has been found that the above impurity RRT1.17 in the adenosine cyclophosphate formulation is substantially absent (or very low in content) in the drug substance and the initially prepared formulation, but gradually increases during long-term storage. It has been found that when a small amount of sodium chloride is added to the preparation and the sodium chloride is treated in a special manner of operation to prepare the preparation when preparing the adenosine cyclophosphate preparation of the present invention, the rate of increase of the impurity RRT1.17 during long-term storage of the resulting preparation is extremely low, which could not be expected at all in the prior art.
In the above-described steps of the preparation method of the present invention, although the specific steps described therein are distinguished in some detail or in language description from the steps described in the preparation examples of the detailed embodiments below, those skilled in the art can fully summarize the above-described method steps in light of the detailed disclosure throughout the present disclosure.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
Adenosine cyclophosphate is non-digitalis cardiotonic, has effects of positively correcting muscle strength, enhancing myocardial contraction force, improving myocardial blood pumping function, dilating blood vessel, and reducing myocardial oxygen consumption; improving myocardial cell metabolism, and protecting ischemic and anoxic myocardium; can improve the function of P cells in the sinus node. The adenosine cyclophosphate enters a human body, the half-life period in blood is 60-150 min, the adenosine cyclophosphate is better in hydrophilicity and particularly stronger in lipid solubility and can easily enter myocardial cells through lipid-soluble cell membranes to play a role, 5-AMP is formed through the decomposition of phosphodiester in the family, the 5-AMP is degraded into adenosine and phosphoric acid in the family, the adenosine cyclophosphate starts to act after 10-20 min after administration, the peak time of the effect is 1-2 h, and the disappearance time of the effect is 6-8 h.
The adenosine cyclophosphate preparation disclosed by the invention has the main component of adenosine cyclophosphate, is a non-digitalis cardiotonic, has the effects of positive inotropic action, enhancing myocardial contractility, improving myocardial blood pumping function, dilating blood vessels, reducing myocardial oxygen consumption, improving myocardial cell metabolism, protecting ischemic and anoxic myocardial cells, and improving p-cell function of sinoatrial node, and is clinically used for treating heart failure, coronary heart disease, cerebral infarction and other diseases.
The adenosine cyclophosphate preparation can be used for treating cardiovascular diseases.
The therapeutic effect on congestive heart failure. Congestive heart failure is commonly seen in coronary heart disease, dilated cardiomyopathy, rheumatic heart disease and the like, and 48 cases of congestive heart failure are treated by adenosine cyclophosphate injection preparation. In 48 cases, 28 men, 20 women, 30 cardiac II-III, 18 IV, 40 control, 24 men, 16 women, 28 cardiac II-III, and 16 IV were treated. The sex age and the cardiac function grading have no significance (p is more than 0.05). The adenosine cyclophosphate injection preparation for the treatment group is 90 mg, added into 250 ml of 3% glucose or 0.9% normal saline, and intravenously dripped, two weeks is a treatment course, and two treatment courses are used. The control group was given only cardiotonic diuretic and renin angiotensin converting enzyme inhibitor treatment. Treatment groups: 17 cases (35.4%) of significant effect, 26 cases (54.18%) of significant effect, 5 cases of no effect (10.42), control group: 6 cases (15%) of significant effect, 23 cases (57.5%) of effective effect, 11 cases (27.5) of ineffective effect, 89.58% of total effective rate of the treatment group, 72.5% of the control group, and the total effective rate of the treatment group is obviously higher than that of the control group.
The results show that the treatment group is obviously superior to the control group, the adenosine cyclophosphate injection preparation can obviously improve the myocardial contraction function of the patients with the heart failure in the blood flushing type, improve the exercise endurance and improve the life quality.
The adenosine cyclophosphate injection is used for treating 84 cases of congestive heart failure, two groups are used for cardiotonic, diuretic and vasodilator treatment, 60 mg to 180 mg of the adenosine cyclophosphate injection is added into the treatment group, 5 percent glucose or 250 mg of normal saline is added into the treatment group, the intravenous drip is carried out once a day, and 15 days are a treatment course. The treatment group showed 31 cases (73.8%), 10 cases (23.8%), 1 case (2.4%), 19 cases (45.2%), 6 cases (14.3%) and 36 cases (85.7%) of total effective rate. Compared to control group (p < 0.01).
The results show that the adenosine cyclophosphate injection treatment group has relieved symptoms, and the heart failure improvement degree is obviously better than that of a control group. The adenosine cyclophosphate injection can obviously improve the symptom and sign of a patient with heart failure by expanding peripheral blood vessels and reducing load before and after the heart, and has obvious curative effect.
39 cases of treating coronary heart disease and heart failure by using adenosine cyclophosphate injection preparation, wherein both a treatment group and a control group use cardiotonic, diuretic and vasodilator. The treatment group is added with adenosine cyclophosphate injection preparation 90 mg and 5% glucose or normal saline 250 mg, the injection is dripped out in about 90 minutes, once a day, and 14 days is a treatment course. The total effective rate of the treatment group is 92.3 percent, and the control group is 69.2 percent (p is less than 0.05). After the treatment group is used, the symptoms are obviously improved, the left ventricular function is obviously enhanced, the pulsation per stroke, the output per minute and the left ventricular ejection fraction are obviously different after the treatment group is used (p is less than 0.05), and no adverse reaction is caused.
Can be used for treating coronary heart disease. Dividing 58 cases of coronary heart disease into two groups, and 30 cases of treatment group, adding adenosine cyclophosphate 90 mg into 5% glucose or physiological saline 25mg, and dripping intravenously once a day, 15 days as a course of treatment. In 28 cases of the control group, 15mg of compound salvia miltiorrhiza injection is added into 250 mg of 5% glucose or normal saline, and the mixture is intravenously dripped once a day, and 15 days are a course of treatment. Compared with two groups of clinical treatment, the adenosine cyclophosphate injection has obvious effect on improving symptoms such as electrocardiogram, chest distress, angina, palpitation, short breath and the like, is used for a compound red sage root injection group, and has obvious total effective rate on improving cardiac function for a control group.
The result proves that the adenosine cyclophosphate injection preparation has positive inotropic effect, can enhance myocardial contractility, improve myocardial blood pumping function, dilate blood vessels, reduce myocardial oxygen consumption, improve myocardial cell metabolism, protect ischemic and anoxic cardiac muscle, and relieve the clinical symptoms of coronary heart disease better than the compound red sage root injection preparation.
The treatment effect on pulmonary heart disease. The adenosine cyclophosphate injection preparation is used for treating 45 cases of pulmonary heart disease, 39 cases of men, 6 cases of women, age 65-70 years and medical history 5-25 years. 90 mg of adenosine cyclophosphate injection is added into 5 percent glucose or 250 mg of normal saline, the intravenous drip is carried out once a day, 10 to 15 days are a treatment course, and other vasodilators and cardiotonic diuretics are simultaneously used during the medication period. Clinical observation shows that after the pulmonary heart disease is treated by the adenosine cyclophosphate injection preparation, the chest distress, the palpitation, the breathlessness, the liver function, the kidney function and the lung function have the electrocardiogram significant efficiency of more than 83 percent and the total effective rate of more than 95 percent. The medicine is considered to be a first-line medicine for treating pulmonary heart disease, particularly heart failure, can expand blood vessels, reduce pulmonary artery pressure, enhance myocardial contractility, improve heart, liver, lung and kidney functions, improve life quality and prolong life cycle. Is a positive inotropic drug which is safe and effective and has good application prospect.
The treatment effect on dilated cardiomyopathy is achieved. 44 cases of dilated cardiomyopathy are treated by using the adenosine cyclophosphate injection preparation, the adenosine cyclophosphate injection preparation is used for intravenous drip in a treatment group, and cardiotonic, diuretic and vasodilator treatment is added, and the control group is general treatment such as cardiotonic, diuretic and vasodilator treatment. The color cardiograph is used for measuring the left ventricular systolic function before treatment, and the results show that the blood flow peak speed of the left ventricular diastolic early stage of the treatment group is increased, the blood flow peak speed of the left ventricular diastolic late stage is decreased, the diastolic function is obviously changed, the stroke volume, the ejection fraction and the cardiac index are all improved, and the incidence rate of arrhythmia is reduced.
The treatment effect on hypertension. The adenosine cyclophosphate injection preparation is used for treating 48 cases of hypertension, 90 mg of the adenosine cyclophosphate injection preparation is added into 5% glucose or 250 mg of normal saline in a treatment group, and intravenous drip is carried out once a day for 15 days continuously. In 42 cases of the control group, 30mg of the benemine (produced by Bayer's corporation) is taken orally once a day for 15 days. The treatment combination control group uses other antihypertensive drugs and lipid-lowering drugs, and the effective rate of lowering blood pressure of the control group is 91.67 percent. The systolic pressure and diastolic pressure are obviously reduced, the symptoms such as dizziness, dim eyesight, headache and the like are obviously superior to those of a control group, and the adenosine cyclophosphate injection preparation is considered as a antihypertensive drug with obvious treatment effect and good safety.
Adenosine cyclophosphate preparation can be used for treating cerebral infarction. Adenosine cyclophosphate injection preparation is used for treating 32 cases of cerebral infarction. In 32 cases of treatment groups, 90 mg of adenosine cyclophosphate injection preparation is added into 250 mg of 5% glucose or normal saline, and the mixture is intravenously dripped once a day and continuously used for 20 days as a treatment course. In 32 control cases, 0.5 of citicoline is added to 250 mg of 5% glucose or physiological saline, and the solution is intravenously dripped once a day for 20 consecutive days as a treatment course. The total effective rate of the treatment group is 93.8 percent, the control group is 81.3 percent, and the two groups have obvious difference in treatment. The adenosine cyclophosphate injection preparation can promote energy metabolism in mitochondria in cells in the brain, increase the blood flow of the brain, improve the oxygen partial pressure of the brain, relieve encephaledema, reduce the range of cerebral infarction and promote the recovery of brain function. The treatment course of cerebral infarction is short, the nerve damage is light, and good curative effect is obtained.
The adenosine cyclophosphate preparation can be used for treating chronic renal failure. The adenosine cyclophosphate injection preparation is used for treating chronic renal failure, 20 cases of treatment groups are treated, 90 mg of adenosine cyclophosphate injection preparation is added into 250 mg of normal saline on the basis of conventional treatment, intravenous drip is carried out once a day, 15 days are continuously taken as a treatment course, and generally 1-2 treatment courses are adopted. Control group 20, given conventional treatment only. Results the treatment group showed 4 cases (20%), 8 cases (40%), 3 cases stable (15%), 3 cases ineffective (25%). The control group showed 3 cases (15%), 5 cases (25%), 6 cases of stability (30%), 6 cases of no effect (30%). By observing that the medicine has better curative effect on the treatment of renal insufficiency decompensation, the medicine is poor in the treatment of renal failure patients with creatinine more than 707 umol/l. The chronic renal failure in the period of failure can delay the development of the chronic renal failure by adopting the traditional dialysis treatment and matching with the adenosine cyclophosphate injection preparation for treatment.
According to the present invention, the term "excipient" may also be referred to as adjuvants, fillers, etc. As used herein, "pharmaceutically acceptable excipient" refers to an excipient that can be used to formulate a drug that has substantially no adverse effect on an organism and is generally tolerated by an organism.
The preparation of freeze-dried powder injections is a pharmaceutical process well known to those skilled in the art, for example, two illustrative lyophilization curves are shown as lyophilization curve a and lyophilization curve B below:
in the following specific examples in the preparation of freeze-dried powder injections, the lyophilization profile used is lyophilization profile a, unless otherwise specified.
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 appropriate adjustment of the freeze-drying program. The moisture content of the freeze-dried powder injection can be determined according to a number of known methods, such as loss-on-drying.
In the present invention, in order to adjust the pH of the drug solution as necessary, an appropriate pH adjuster may be added to the composition. Although the present inventors can adjust with strong acid or strong alkali solution without buffering ability such as aqueous sodium hydroxide solution and aqueous hydrochloric acid solution, those skilled in the art understand that if the treatment with such pH adjusting agent without buffering ability satisfies the pH requirement of the system, pH adjusting agent with buffering ability will more achieve the object of the present invention, and thus these buffering agents can not only adjust pH but also stabilize pH. Thus, any of the pH adjusting agents listed herein or combinations thereof are included within the spirit and scope of the present invention.
When the freeze-dried powder injection is prepared, the content of solid matters in the prepared liquid medicine is 1-20% (w/v), preferably 2-15% (w/v), and more preferably 2-10%. Since lyophilized injectable powder is usually obtained by lyophilization in a vial, it is understood by those skilled in the art that the product usually takes the shape of a cake before the final product is obtained even before it is used by a doctor, although the volume of the cake is theoretically smaller (slightly smaller) than the volume of the original aqueous solution, usually the volume of the cake is not reduced to 50% of the volume of the original aqueous solution, usually the volume of the cake is between 80-120% of the volume of the original aqueous solution, more usually the volume of the cake is between 90-100% of the volume of the original aqueous solution, the volume of the aqueous solution of the freeze-dried composition before freeze-drying can be estimated from the liquid level trace of the raw aqueous solution (the liquid level trace remained on the wall of the vial after the main cake is reduced by freeze-drying, and even if the freeze-dried product in the vial is powdery due to various reasons such as collision, the original liquid level trace can be usually remained). Therefore, although the invention provides a substantially anhydrous freeze-dried powder injection, the volume of the liquid medicine at least before the start of freeze-drying can be roughly estimated according to the powder injection, and the content of the solid in the prepared liquid medicine can be calculated according to the estimated volume and the weight of the dried final product in a penicillin bottle when the freeze-dried powder injection is prepared. Therefore, the solid content of the liquid medicine in the freeze-dried powder injection according to the first aspect of the invention is 1-20% (w/v), preferably 2-15% (w/v), and more preferably 2-10%.
The term "solid content" means that the solid substance (e.g. the active compound of the invention and all excipients used, weight/g) is added to a solvent (e.g. water for injection) and dissolved to give a solution, the weight of the solid substance being divided by the percentage of the final solution volume (weight/volume percentage, e.g. g/100 ml). For example, in the present invention, a solution having a final volume of 2ml, with a solids content of 6%, is prepared from 100mg of the active compound and a total of about 20mg of other solids, plus a suitable amount of aqueous injection solution.
In the present invention, the symbol%, depending on the context in which it is used, may have a meaning that is readily understood by a person skilled in the art. For example, where reference is made to solids content, the symbol indicates weight/volume percent (w/v, e.g., g/100 ml); also for example, where reference is made to "water content" in a freeze-dried powder injection, for example, the water content is below 8%, then the symbol% indicates weight/weight percent (w/w, g/100 g). Generally,% means weight/volume percent when a solid is dispersed in a liquid; where a solid is dispersed in a solid or a liquid is dispersed in a solid (e.g., the moisture content of a powder injection),% means weight/weight percent. In other cases, the symbol% represents weight/weight percent, unless otherwise indicated.
In preparing the drug solution of the present invention, it is known to those skilled in the art that rough filtration may be performed using, for example, a microfiltration membrane of about 0.45um, and fine filtration may be performed using, for example, a microfiltration membrane of about 0.22um to sterilize before filling the drug solution into vial, and that filtration may be performed several times if necessary.
The adenosine cyclophosphate preparation provided by the invention can be stored in a dry place below 25 ℃ for at least 24 months, and can meet the storage requirement of a common injection preparation.
The pharmaceutical composition is freeze-dried powder injection. In one embodiment, the lyophilized powder for injection is a single dose formulation (e.g., vial-loaded powder for injection) and the amount of active compound in each unit dose (which, as not otherwise specified in the present invention, is calculated as adenosine cyclophosphate) may be, for example, but not limited to, about 10mg, about 20mg, about 30mg, about 50 mg.
The pharmaceutical composition according to the invention, which is reconstituted with water for injection, is generally within 30 seconds, preferably within 20 seconds, more preferably within 15 seconds of reconstitution time.
According to the freeze-dried powder injection, 1ml of the freeze-dried powder injection is prepared into a solution containing 10mg of adenosine cyclophosphate, and the pH value of the solution is 5.5-7.0, for example, 6.0-6.5, measured according to the method in appendix VI H of the second part of the Chinese pharmacopoeia 2010 edition.
The freeze dried powder for injection, especially freeze dried powder for injection, is white or white-like freeze dried block or its crushed block or powder, and has no bad smell, bitter taste and easy water solubility.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it. In the following examples, the pH adjusting agent (i.e., the pH adjusting agent in the present invention) used was 1mo1/L disodium hydrogenphosphate solution or 0.1mol/L phosphoric acid adjusting solution, unless otherwise specified, in an amount to adjust the prepared formulation to a prescribed value or range.
The following preparation steps are given for the purpose of illustration and are based on the comparative nature of the respective examples and the person skilled in the art is fully enabled to generalize from the prior knowledge the process for preparing the formulations of the invention. In preparing various compositions in the following formulations, the total amount of formulation of each lot was 10000ml, as not otherwise specified, but when formulations were specified, they were each formulated in an amount relative to the amount of formulation of each 1ml (wherein the adenosine cyclophosphate concentration was about 10mg/ml), and dispensed into glass bottles in an amount of 20mg adenosine cyclophosphate contained in each bottle; the obtained preparation contained adenosine cyclophosphate 20mg in each bottle.
A quality control method for composition
The adenosine cyclophosphate preparation obtained by the invention is subjected to content determination and related substance determination by adopting a high performance liquid chromatography, and the method comprises the following steps:
(1) the specification of the high performance liquid chromatography carried in section 0512 of the fourth part 59 of the Chinese pharmacopoeia 2015 edition is measured;
(2) chromatographic conditions and system applicability test: column packed with octadecylsilane bonded silica (in this example, the column specification was 250mm × 4.6mm, 5 μm), purified with 0.01 phosphoric acid solution-acetonitrile in a volume ratio of 95: 5 and adding 0.3 w/v% formic acid as a mobile phase into the mixed solution, wherein the flow rate is 1ml/min, the column temperature is 30 ℃, and the detection wavelength is 259 nm; measuring by using a system applicability test solution, wherein the number of theoretical plates is not less than 5000 according to the adenosine cyclophosphate peak, and the separation degree between the adenosine cyclophosphate and the adenosine is more than 2;
(3) solution preparation:
taking a proper amount of adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection, adding mobile phase for dissolving and diluting, preparing into solution containing 1mg of adenosine cyclophosphate in each 1ml of solution, filtering, and using as test sample solution (namely 1000 μ g/ml) for related substance examination;
precisely measuring 1ml of test solution for checking related substances, placing in a 100ml measuring flask, diluting with mobile phase, shaking, and making into solution containing adenosine cyclophosphate at concentration of 10 μ g/ml as reference solution (i.e. 10 μ g/ml);
precisely measuring 1ml of sample solution for checking related substances, placing in a 20ml measuring flask, diluting with mobile phase, shaking, and making into solution containing adenosine cyclophosphate at concentration of 50 μ g/ml as sample solution for content determination (i.e. 50 μ g/ml);
precisely weighing appropriate amount of adenosine cyclophosphate reference substance, dissolving with mobile phase to obtain solution with concentration of 50 μ g/ml, and determining adenosine cyclophosphate content with reference substance solution (50 μ g/ml);
accurately weighing appropriate amount of adenosine cyclophosphate reference substance and adenosine reference substance, adding mobile phase for dissolving and diluting, and making into mixed solution containing adenosine cyclophosphate 1000 μ g and adenosine 10 μ g in each 1ml solution as system applicability test solution (i.e. 1000 μ g/ml +10 μ g/ml);
(4) and (3) determination:
precisely measuring 20 mu l of system applicability test solution, injecting into a liquid chromatograph, recording a chromatogram, calculating the number of theoretical plates and the separation degree between adenosine cyclophosphate and adenosine separation degree peaks, and determining the retention time of the adenosine cyclophosphate and adenosine;
precisely measuring the sample solution for inspecting related substances and the reference solution for inspecting related substances respectively by 20 μ l, respectively injecting into a liquid chromatograph, recording chromatogram until the retention time of adenosine cyclophosphate is 3 times, reading the area of main peak formation peak and the area of peak of each impurity in the chromatogram of the sample solution, when the existence of acrobatics is detected, calculating the percentage content of each impurity relative to adenosine cyclophosphate in the chromatogram of the test solution by taking the peak area of the main component in the chromatogram of the control solution for checking related substances as 1.0%, and obtaining the content of a single impurity in the test sample (namely, for example, if the main peak area of the control solution is 100 and the peak area of a certain impurity in the chromatogram of the test solution is 115, the percentage content of the impurity relative to adenosine cyclophosphate is 1.15%, and the peak area of the certain impurity in the chromatogram of the test solution is 87, the impurity content is 0.87%);
respectively and precisely measuring 20 mu l of each of the test solution for content determination and the reference solution for content determination, respectively injecting into a liquid chromatograph, recording the chromatogram until the retention time of adenosine cyclophosphate is 2 times, obtaining two chromatograms, respectively reading the main peak area in the two chromatograms, and calculating the content of adenosine cyclophosphate in the test sample according to the peak area by an external standard method.
All the formulations obtained in the following preparation examples 1 to 7 were measured using the above-mentioned method, and the results were: the number of theoretical plates of cyclic adenosine monophosphate is about 75000, the separation degree of cyclic adenosine monophosphate from adenosine is about 2.73, the tailing factor of cyclic adenosine monophosphate is about 1.008, the retention time of cyclic adenosine monophosphate is about 6.69, and the relative retention time of adenosine monophosphate relative to cyclic adenosine monophosphate is about RRT 0.88. In addition, if formic acid in the mobile phase of the HPLC method is removed or acetic acid of the same concentration is used, the above-mentioned measurement parameters are substantially unchanged.
The preparation example 1 was allowed to stand at 35 ℃ for 1 month, and the results of the measurement by the above-mentioned HPLC method showed that the theoretical plate number, the degree of separation of adenosine cyclophosphate from adenosine, the adenosine cyclophosphate tailing factor, the adenosine cyclophosphate retention time, and the adenosine RRT were not substantially changed, but a significant impurity peak (impurity RRT1.17) appeared at RRT1.17, and the degree of separation between the impurity RRT1.17 and adenosine cyclophosphate reached 2.42, which completely satisfied the requirements for the measurement of the main component and the unknown impurity. When formic acid in the mobile phase of the HPLC method is removed or acetic acid of the same concentration is used, when the preparation of preparation example 1 after being left at 35 ℃ for 1 month is measured, although the theoretical plate number, the separation degree of adenosine cyclophosphate from adenosine, the adenosine cyclophosphate tailing factor, the adenosine cyclophosphate retention time and the adenosine RRT are not changed, the RRT1.17 impurity is not present, an impurity peak whose peak area is substantially the same as that of the RRT1.17 impurity appears at about RRT1.08, both of them may be the same impurity and the retention time is changed due to the mobile phase change, and the separation degree between the impurity RRT1.08 and the adenosine cyclophosphate peak is calculated to be about 1.34, which cannot meet the measurement requirement. The above results show that the addition of a small amount of formic acid to the mobile phase is necessary for the efficient determination of the impurity RRT1.17, and that it is entirely surprising that the main component cannot be separated efficiently from this impurity RRT1.17 without the addition of formic acid or with the addition of acetic acid, which is a substance similar to formic acid.
The content of all the powder injections obtained in the preparation examples 1-7 is measured, and the result shows that the adenosine cyclophosphate content of all the powder injections is within 99-101% of the theoretical feeding amount.
For all the powder injections obtained in the preparation examples 1 to 7, relevant substances are determined, particularly the amount of RRT1.17 impurities is concerned, and the results show that each single impurity of the preparations is less than 0.1%, the sum of each impurity is less than 0.25%, and the RRT1.17 impurities of the preparations are less than 0.02%, so that the results show that all the powder injections obtained in the preparation examples 1 to 7 have good properties in the initial state.
For all the injections obtained in preparation examples 1 to 7 herein, they were left to stand at 35 ℃ for 5 months, and their contents and related substances were measured, and the results showed: these formulations varied substantially consistently in content as compared to their content at 0 months, with residual amounts (i.e., the percentage of 5 months content divided by 0 months content multiplied by 100%) ranging from 95-98%; in related substance determination, except RRT1.17 impurities, all preparations are basically consistent in other impurity changes, and each single impurity of each preparation is less than 0.1% in 5 months, and the sum of all impurities is less than 0.25%; in the related substance measurement, the change of the RRT1.17 impurity is obviously different between preparations, specifically, the RRT1.17 impurity of each injection in preparation examples 1-4 is increased by 0.18-0.23 times compared with the preparation at 0 month (namely, the value obtained by subtracting the impurity content at 0 month from the impurity content at 5 month and dividing the impurity content at 0 month), and the RRT1.17 impurity of each injection in preparation examples 5-7 is increased by 3.24-4.46 times compared with the preparation at 0 month. This result indicates that the formulations obtained by the different processes of the different recipes exhibit differences in stability, in particular as characterized by the RRT1.17 impurity.
In addition, for all the injections prepared in preparation examples 1 to 4 below, according to the standard of "adenosine cyclophosphate for injection" recorded in 588 of the second part of the edition of "Chinese pharmacopoeia" 2015, all the preparations were determined to meet the quality standards of the above pharmacopoeia at two time points at 0 month and after being left at room temperature for 2 years.
First, composition preparation example part
Preparation example 1 preparation of an injection containing adenosine cyclophosphate
Prescription: 10mg of adenosine cyclophosphate, 15mg of mannitol, 1.5mg of sodium chloride, a proper amount of acid-base regulator and a proper amount of water for injection are added to 1 ml.
The preparation method comprises the following steps:
(1) adding adenosine cyclophosphate and sodium chloride into room-temperature injection water with the preparation amount of 60%, stirring and dissolving, adjusting the pH value of the liquid medicine to 3.5-4.0 by using an acid-base regulator, adding active carbon for injection according to 0.1 w/v% of the volume of the liquid medicine, stirring and adsorbing for 20 minutes, and filtering and decarburizing for later use;
(2) adding mannitol into room temperature water for injection with a preparation amount of 20%, stirring for dissolving, adding active carbon for injection according to 0.05 w/v% of the volume of the liquid medicine, stirring for adsorbing for 20min, filtering and removing carbon for later use;
(3) mixing the liquid medicines obtained in the step (1) and the step (2), adjusting the pH value of the liquid medicine to 6.0-6.5 by using an acid-base regulator, filtering by using a titanium rod filter with the aperture of 1um, supplementing water for injection at room temperature to a preparation amount, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0-6.5 by using the acid-base regulator;
(4) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22um until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
Preparation example 2 preparation of an injection containing adenosine cyclophosphate
Prescription: adenosine cyclophosphate 9mg, mannitol 10mg, sodium chloride 2mg, an appropriate amount of pH regulator and an appropriate amount of water for injection are added to 1 ml.
The preparation method comprises the following steps:
(1) adding adenosine cyclophosphate and sodium chloride into room-temperature injection water with the preparation amount of 60%, stirring and dissolving, adjusting the pH value of the liquid medicine to 3.5-4.0 by using an acid-base regulator, adding active carbon for injection according to 0.05 w/v% of the volume of the liquid medicine, stirring and adsorbing for 20 minutes, and filtering and decarburizing for later use;
(2) adding mannitol into room temperature water for injection with a preparation amount of 20%, stirring for dissolving, adding active carbon for injection according to 0.15w/v% of the volume of the liquid medicine, stirring for adsorbing for 20min, filtering and removing carbon for later use;
(3) mixing the liquid medicines obtained in the step (1) and the step (2), adjusting the pH value of the liquid medicine to 6.0-6.5 by using an acid-base regulator, filtering by using a titanium rod filter with the aperture of 1um, supplementing water for injection at room temperature to a preparation amount, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0-6.5 by using the acid-base regulator;
(4) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22um until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
Preparation example 3 preparation of an injection containing adenosine cyclophosphate
Prescription: 11mg of adenosine cyclophosphate, 25mg of mannitol, 1mg of sodium chloride, a proper amount of acid-base regulator and a proper amount of water for injection are added to 1 ml.
The preparation method comprises the following steps:
(1) adding adenosine cyclophosphate and sodium chloride into room-temperature injection water with the preparation amount of 60%, stirring and dissolving, adjusting the pH value of the liquid medicine to 3.5-4.0 by using an acid-base regulator, adding active carbon for injection according to 0.15w/v% of the volume of the liquid medicine, stirring and adsorbing for 20 minutes, and filtering and decarburizing for later use;
(2) adding mannitol into room temperature water for injection with a preparation amount of 20%, stirring for dissolving, adding active carbon for injection according to 0.05 w/v% of the volume of the liquid medicine, stirring for adsorbing for 20min, filtering and removing carbon for later use;
(3) mixing the liquid medicines obtained in the step (1) and the step (2), adjusting the pH value of the liquid medicine to 6.0-6.5 by using an acid-base regulator, filtering by using a titanium rod filter with the aperture of 1um, supplementing water for injection at room temperature to a preparation amount, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0-6.5 by using the acid-base regulator;
(4) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22um until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
Preparation example 4 preparation of an injection containing adenosine cyclophosphate
Prescription: 10mg of adenosine cyclophosphate, 20mg of mannitol, 1.5mg of sodium chloride, a proper amount of acid-base regulator and a proper amount of water for injection are added to 1 ml.
The preparation method comprises the following steps:
(1) adding adenosine cyclophosphate and sodium chloride into room-temperature injection water with the preparation amount of 60%, stirring and dissolving, adjusting the pH value of the liquid medicine to 3.5-4.0 by using an acid-base regulator, adding active carbon for injection according to 0.15w/v% of the volume of the liquid medicine, stirring and adsorbing for 20 minutes, and filtering and decarburizing for later use;
(2) adding mannitol into room temperature water for injection with a preparation amount of 20%, stirring for dissolving, adding active carbon for injection according to 0.1 w/v% of the volume of the liquid medicine, stirring for adsorbing for 20min, filtering and removing carbon for later use;
(3) mixing the liquid medicines obtained in the step (1) and the step (2), adjusting the pH value of the liquid medicine to 6.0-6.5 by using an acid-base regulator, filtering by using a titanium rod filter with the aperture of 1um, supplementing water for injection at room temperature to a preparation amount, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0-6.5 by using the acid-base regulator;
(4) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22um until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
This preparation example 4 was carried out using the lyophilization curve B in lyophilization.
Preparation example 5 preparation of adenosine cyclophosphate preparation
Four batches of the formulation were prepared with reference to the formulations and methods of preparation examples 1-4, respectively, except that no sodium chloride was added.
Preparation example 6 preparation of adenosine cyclophosphate preparation
Four batches of the formulation were prepared with reference to the formulations of preparation examples 1-4, respectively, but during the preparation, instead of treating the sodium chloride and adenosine cyclophosphate separately in advance, they were treated together with mannitol. The preparation method comprises the following steps:
(1) adding adenosine cyclophosphate, mannitol and sodium chloride into room-temperature water for injection with the preparation amount of 80%, stirring for dissolving, adjusting the pH value of the liquid medicine to a specified value by using an acid-base regulator (the pH value of the liquid medicine is adjusted to 3.5-4.0 in reference to preparation example 1-2, and the pH value of the liquid medicine is adjusted to 6.0-6.5 in reference to preparation example 3-4), adding active carbon for injection according to 0.1 w/v% of the volume of the liquid medicine, stirring for adsorption for 20 minutes, filtering for decarbonization for later use;
(2) adjusting the pH value of the liquid medicine obtained in the step (1) to 6.0-6.5 by using an acid-base regulator, filtering the liquid medicine by using a titanium rod filter with the aperture of 1um, adding water for injection at room temperature to a prepared amount, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0-6.5 by using the acid-base regulator;
(3) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22um until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
Preparation example 7 preparation of adenosine cyclophosphate preparation
Four batches of formulations were prepared with reference to the formulations of preparation examples 1-4, respectively, but without the addition of sodium chloride and treatment of adenosine cyclophosphate with mannitol. The preparation method comprises the following steps:
(1) adding adenosine cyclophosphate and mannitol into room-temperature water for injection with the preparation amount of 80%, stirring for dissolving, adjusting the pH value of the liquid medicine to a specified value by using an acid-base regulator (the pH value of the liquid medicine is adjusted to 3.5-4.0 in reference to preparation example 1-2, and the pH value of the liquid medicine is adjusted to 6.0-6.5 in reference to preparation example 3-4), adding activated carbon for injection according to 0.1 w/v% of the volume of the liquid medicine, stirring for adsorption for 20 minutes, filtering for decarbonization for later use;
(2) adjusting the pH value of the liquid medicine obtained in the step (1) to 6.0-6.5 by using an acid-base regulator, filtering the liquid medicine by using a titanium rod filter with the aperture of 1um, adding water for injection at room temperature to a prepared amount, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0-6.5 by using the acid-base regulator;
(3) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22um until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
After the water content of the powder injection is removed by freeze drying, the water content of the freeze-dried product is less than 3 percent.

Claims (18)

1. A method for detecting the quality of an adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection comprises the following steps: adenosine cyclophosphate, mannitol, sodium chloride and acid-base regulator, the method comprises using high performance liquid chromatography to determine adenosine cyclophosphate content and/or related quality in the injection, including the following operations:
(1) the measurement was carried out according to the standard of high performance liquid chromatography described in section 0512 of section 59 of the fourth part of the pharmacopoeia 2015 edition;
(2) chromatographic condition and system applicability test, namely, a chromatographic column using octadecylsilane chemically bonded silica as a filler, a mixed solution of 0.01 phosphoric acid solution and acetonitrile in a volume ratio of 95: 5 as a mobile phase, and 0.2 ~ 0.5.5 w/v% of formic acid is added into the mobile phase, the flow rate is 1ml/min, the column temperature is 30 ℃, the detection wavelength is 259nm, the system applicability test solution is taken for determination, the number of theoretical plates is not less than 5000 according to the adenosine cyclophosphate peak, and the separation degree between the adenosine cyclophosphate and the adenosine is greater than 2;
(3) solution preparation:
dissolving appropriate amount of adenosine cyclophosphate lyophilized powder for injection in mobile phase to obtain 1mg adenosine cyclophosphate solution per 1ml solution, filtering, and making into test solution for related substance examination;
precisely measuring 1ml of test solution for checking related substances, placing in a 100ml measuring flask, diluting with mobile phase to obtain a solution containing adenosine cyclophosphate at a concentration of 10 μ g/ml, and shaking to obtain a reference solution for checking related substances;
precisely measuring 1ml of test sample solution for checking related substances, placing in a 20ml measuring flask, diluting with mobile phase to obtain a solution containing adenosine cyclophosphate at a concentration of 50 μ g/ml, and shaking to obtain a test sample solution for measuring content;
accurately weighing appropriate amount of adenosine cyclophosphate reference substance, dissolving with mobile phase to obtain solution with concentration of 50 μ g/ml, and using as reference substance solution for determining adenosine cyclophosphate content;
accurately weighing appropriate amounts of adenosine cyclophosphate reference substance and adenosine reference substance, adding mobile phase for dissolving and diluting, and making into mixed solution containing 1000 μ g adenosine cyclophosphate and 10 μ g adenosine per 1ml solution as system applicability test solution;
(4) and (3) determination:
precisely measuring 20 mu l of system applicability test solution, injecting into a liquid chromatograph, recording a chromatogram, calculating the number of theoretical plates and the separation degree between adenosine cyclophosphate and adenosine separation degree peaks, and determining the retention time of the adenosine cyclophosphate and adenosine;
respectively and precisely measuring 20 mu l of a test sample solution for checking related substances and 20 mu l of a reference solution for checking related substances, respectively injecting the test sample solution and the reference solution into a liquid chromatograph, recording the chromatogram until the retention time of the adenosine cyclophosphate is 3 times that of the chromatogram, reading the area of a main peak and the area of the peak of each impurity in the chromatogram of the test sample solution, and calculating the percentage content of each impurity in the chromatogram of the test sample solution relative to the adenosine cyclophosphate by taking the area of the main peak in the chromatogram of the reference solution for checking related substances as 1.0% when the impurity is detected to exist, thus obtaining the content of the single impurity in the test sample;
respectively and precisely measuring 20 mu l of each of the test solution for content determination and the reference solution for content determination, respectively injecting into a liquid chromatograph, recording the chromatogram until the retention time of adenosine cyclophosphate is 2 times, obtaining two chromatograms, respectively reading the main peak area in the two chromatograms, and calculating the content of adenosine cyclophosphate in the test sample according to the peak area by an external standard method;
the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection comprises 10 ~ 50 parts by weight of mannitol and 0.5 ~ 3 parts by weight of sodium chloride, wherein the materials are calculated by every 10 parts by weight of adenosine cyclophosphate, and the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is prepared by the following steps:
(1) adding adenosine cyclophosphate and sodium chloride into room-temperature water for injection with the preparation amount of 60%, stirring for dissolving, adjusting the pH value of the liquid medicine to 3.5 ~ 4.0.0 by using an acid-base regulator, adding active carbon for injection according to the volume of 0.05 ~ 0.15.15 w/v%, stirring for adsorbing for 20 minutes, and filtering for decarbonization for later use;
(2) adding mannitol into room temperature water for injection with a preparation amount of 20%, stirring for dissolving, adding active carbon for injection according to a volume of 0.05 ~ 0.15.15 w/v%, stirring for adsorbing for 20min, filtering, and removing carbon;
(3) mixing the liquid medicines obtained in the steps (1) and (2), adjusting the pH value of the liquid medicine to 6.0 ~ 6.5.5 by using an acid-base regulator, filtering the liquid medicine by using a titanium rod filter with the pore diameter of 1 mu m, adding water for injection at room temperature to a preparation amount, so that the content of solids in the obtained liquid medicine is 1 ~ 20w/v%, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0 ~ 6.5.5 by using the acid-base regulator;
(4) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22 mu m until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
2. The method according to claim 1, wherein the adenosine cyclophosphate lyophilized powder for injection comprises 10 ~ 25 parts by weight of mannitol per 10 parts by weight of adenosine cyclophosphate.
3. The method according to claim 1, wherein the acid-base modifier in the adenosine cyclophosphate lyophilized powder injection pharmaceutical composition for injection is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, or a combination thereof.
4. The method according to claim 1, wherein the acid-base regulator in the adenosine cyclophosphate lyophilized powder injection pharmaceutical composition for injection is phosphoric acid and/or disodium hydrogen phosphate.
5. The method according to claim 1, wherein the acid-base modifier in the adenosine cyclophosphate lyophilized powder for injection pharmaceutical composition is phosphoric acid and/or disodium hydrogen phosphate, and the amount is such that when the pharmaceutical composition is dissolved in water and diluted to make a solution containing 10mg of adenosine cyclophosphate per 1ml, the pH value of the solution is 5.5-7.0.
6. The method according to claim 1, wherein the solution of the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition before freeze drying comprises water for injection in addition to adenosine cyclophosphate, mannitol and optionally sodium chloride and optionally an acid-base regulator, and the solid content of the solution is 2 ~ 15 w/v%.
7. The method of claim 1, wherein the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is re-dissolved in water for injection to the same volume as the solution before freeze-drying, and the solid content in the obtained solution is 2 ~ 15% w/v.
8. The method according to claim 1, wherein the adenosine cyclophosphate lyophilized powder for injection pharmaceutical composition is lyophilized powder for injection, and the weight of adenosine cyclophosphate contained in each bottle is 10 ~ 100 mg.
9. The method of claim 1, wherein the chromatography column has a size of 250mm x 4.6mm, 5 μm.
10. The adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection comprises adenosine cyclophosphate, mannitol, sodium chloride and an acid-base regulator, wherein the amount of the mannitol is 10 ~ 50 parts by weight and the amount of the sodium chloride is 0.5 ~ 3 parts by weight of each 10 parts by weight of the adenosine cyclophosphate, and the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection is prepared by the method comprising the following steps:
(1) adding adenosine cyclophosphate and sodium chloride into room-temperature water for injection with the preparation amount of 60%, stirring for dissolving, adjusting the pH value of the liquid medicine to 3.5 ~ 4.0.0 by using an acid-base regulator, adding active carbon for injection according to the volume of 0.05 ~ 0.15.15 w/v%, stirring for adsorbing for 20 minutes, and filtering for decarbonization for later use;
(2) adding mannitol into room temperature water for injection with a preparation amount of 20%, stirring for dissolving, adding active carbon for injection according to a volume of 0.05 ~ 0.15.15 w/v%, stirring for adsorbing for 20min, filtering, and removing carbon;
(3) mixing the liquid medicines obtained in the steps (1) and (2), adjusting the pH value of the liquid medicine to 6.0 ~ 6.5.5 by using an acid-base regulator, filtering the liquid medicine by using a titanium rod filter with the pore diameter of 1 mu m, adding water for injection at room temperature to a preparation amount, so that the content of solids in the obtained liquid medicine is 1 ~ 20w/v%, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0 ~ 6.5.5 by using the acid-base regulator;
(4) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22 mu m until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
11. The pharmaceutical composition according to claim 10, wherein the amount of mannitol is 10 ~ 25 parts by weight per 10 parts by weight of adenosine cyclophosphate.
12. The pharmaceutical composition according to claim 10, wherein the ph modifying agent is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, hydrochloric acid, phosphoric acid, nitric acid, sulfuric acid, and combinations thereof.
13. The pharmaceutical composition according to claim 10, wherein the pH modifier is phosphoric acid and/or disodium hydrogen phosphate in an amount such that when the pharmaceutical composition is dissolved in water and diluted to a solution containing 10mg of adenosine cyclophosphate per 1ml, the pH of the solution is 5.5 to 7.0.
14. A pharmaceutical composition according to claim 10, which is reconstituted with water for injection to the same volume as the solution before freeze-drying and the resulting solution has a solids content of 1 ~ 20 w/v%.
15. The pharmaceutical composition according to claim 10, which is a freeze-dried powder injection comprising adenosine cyclophosphate in an amount of 10 ~ 100mg per bottle.
16. The pharmaceutical composition according to claim 10, wherein the addition of room temperature water for injection to a formulation amount in step (3) means that the solid content in the obtained liquid medicine is 2 ~ 15% w/v.
17. The method for preparing the adenosine cyclophosphate freeze-dried powder injection pharmaceutical composition for injection of any one of claims 10 to 16, comprising the following steps:
(1) adding adenosine cyclophosphate and sodium chloride into room-temperature water for injection with the preparation amount of 60%, stirring for dissolving, adjusting the pH value of the liquid medicine to 3.5 ~ 4.0.0 by using an acid-base regulator, adding active carbon for injection according to the volume of 0.05 ~ 0.15.15 w/v%, stirring for adsorbing for 20 minutes, and filtering for decarbonization for later use;
(2) adding mannitol into room temperature water for injection with a preparation amount of 20%, stirring for dissolving, adding active carbon for injection according to a volume of 0.05 ~ 0.15.15 w/v%, stirring for adsorbing for 20min, filtering, and removing carbon;
(3) mixing the liquid medicines obtained in the steps (1) and (2), adjusting the pH value of the liquid medicine to 6.0 ~ 6.5.5 by using an acid-base regulator, filtering the liquid medicine by using a titanium rod filter with the pore diameter of 1 mu m, adding water for injection at room temperature to a preparation amount, so that the content of solids in the obtained liquid medicine is 1 ~ 20w/v%, measuring the pH value of the solution, and adjusting the pH value of the liquid medicine to 6.0 ~ 6.5.5 by using the acid-base regulator;
(4) and (3) circularly sterilizing and filtering the solution by using a microporous filter membrane filter element with the aperture of 0.22 mu m until the filtrate is qualified after the inspection of visible foreign matters, then aseptically packaging the liquid medicine into penicillin bottles, freeze-drying to remove water, and pressing plugs to obtain the product.
18. The method according to claim 17, wherein said adding room temperature water for injection to a formulation amount in step (3) means that the solid content in the obtained liquid medicine is 2 ~ 15 w/v%.
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