CN102988305B

CN102988305B - Medicinal composition containing meglumine cyclic adenosine monophosphate compound

Info

Publication number: CN102988305B
Application number: CN201210303740.3A
Authority: CN
Inventors: 姚云
Original assignee: Individual
Current assignee: Individual
Priority date: 2012-07-12
Filing date: 2012-08-22
Publication date: 2014-04-16
Anticipated expiration: 2032-08-22
Also published as: CN102988305A

Abstract

The invention relates to a medicinal composition containing a meglumine cyclic adenosine monophosphate compound, and in particular relates to freeze-dried injection of meglumine cyclic adenosine monophosphate and a preparation method thereof. Each 1,000 injections are prepared from the following components: 20g of meglumine cyclic adenosine monophosphate, 100 to 200g of mannitol, 1 to 3g of ethylene diamine tetraacetic acid (EDTA) calcium, 1 to 2g of vitamin C, and 2,000ml of a buffer solution of disodium hydrogen citrate and trisodium citrate at a mole ratio of 1: 4.

Description

A kind of pharmaceutical composition that contains meglumine adenosine cycle phosphate compound

Technical field

The present invention relates to freeze-dried powder of a kind of meglumine adenosine cycle phosphate and preparation method thereof, belong to field of medicaments.

Background technology

Meglumine adenosine cycle phosphate, English name: Meglumine Adenosine Cyclophosphate is the salt of adenosine cyclophosphate and meglumine (1:1).Meglumine adenosine cycle phosphate is non-digitalis cardiac tonic, has positive inotropic action, can strengthen myocardial contraction, improves myocardium blood-pumping function, has blood vessel dilating effect, can reduce myocardial oxygen consumption; Improve myocardial cell metabolism, the cardiac muscle of protection ischemia, anoxia; Can improve sinuatrial node P cell function.

Meglumine adenosine cycle phosphate enters human body, half-life in blood is 60～150min, because it has good hydrophilic, especially fat-soluble stronger, easily through fat-soluble cell membrane, enter in myocardial cell and play a role, through phosphodiesterase, be decomposed to form 5-AMP, then be adenosine and phosphoric acid through 5-AMP enzymatic degradation.Meglumine adenosine cycle phosphate starts effect after medication after 10～20min, effective rush hour, drug effect extinction time was at 6～8 hours at 1～2 hour.

The meglumine adenosine cycle phosphate injection having gone on the market has lyophilization injectable powder, soluble in water because of meglumine adenosine cycle phosphate, in its formula, generally only use mannitol as filler, but find in practice, the problem that has color jaundice after existing medicament long storage time, needs low temperature storage.Some product dissolution velocity in clinical use procedure is undesirable, causes and uses inconvenience, the invention provides a kind of new prescription and preparation method, and medicament long storage time also can not turned to be yellow, and makes dissolution velocity improve simultaneously.

Summary of the invention

The invention provides a kind of pharmaceutical composition that contains meglumine adenosine cycle phosphate compound, is to take the injection freeze-dried pharmaceutical formulation that meglumine adenosine cycle phosphate is active component, every 1000 injections, and it is composed as follows:

Meglumine adenosine cycle phosphate 20g;

Mannitol 100-200g;

EDTA calcium 1-3g;

Vitamin C 1-2g,

Mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 1000ml of 1:4;

All the other are water for injection.

Compositions of the present invention, most preferred formula is: every 1000 injections, it is composed as follows:

Meglumine adenosine cycle phosphate 20g;

Mannitol 150g;

EDTA calcium 2g;

Vitamin C 1.5g,

Mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 2000ml of 1:4,

Wherein, the compound method of DisodiumHydrogen Citrate and trisodium citrate buffer is as follows: take DisodiumHydrogen Citrate 13g, trisodium citrate 60g is dissolved in the buffer solution that obtains pH value 7.0 in 1000ml water for injection.Compositions of the present invention, its preparation method is as follows: first prepare DisodiumHydrogen Citrate and trisodium citrate buffer 2000ml, then get meglumine adenosine cycle phosphate, mannitol, EDTA calcium, vitamin C adds mixed dissolution in DisodiumHydrogen Citrate and trisodium citrate buffer, the filter membrane of via hole diameter molecular cut off 20000 filters, fill, half tamponade, lyophilization, obtains.

The present invention has used DisodiumHydrogen Citrate and trisodium citrate buffer to make the solution pH value obtaining of the present invention remain on 6.9-7.1, and fluctuation range is minimum, guarantees its stability.

Adopt High-dose Mannitol that the powder dissolution speed after lyophilizing is accelerated, use EDTA calcium and vitamin C to guarantee that it places in use the long period and also can not change, guarantee its stability.

Compositions of the present invention, its formula obtains through screening, and wherein most preferred formula forms, referring to embodiment 1.Screening process is as follows:

Table 1: the formula screening experiment that the dissolution time of take is index

Experimental technique:

The above medicine of formula, wiring solution-forming, packing capacity into is 5ml ampulla, with the method for embodiment 1, is prepared into lyophilized formulations, carries out dissolution experiment again.

Sample:

Each 10 bottles, the sample of each formula, every bottle adds sodium chloride for injection solution 5ml, with hand moving.

Dissolve index:

Naked eyes are seen without floccule and are existed for whole dissolvings.

Table 2, investigates embodiment 1 and the indices result of the meglumine adenosine cycle phosphate sample that gone on the market

	Embodiment 1 sample	The meglumine adenosine cycle phosphate sample having gone on the market
			Mouldability	Good	Generally
Dissolubility	Good	Generally
			Water content	5.02%	4.89%
Condition of storage	Room temperature	4-8℃

As seen from table, embodiment 1 is better than reference substance.

Table, 3 investigate embodiment 1 and three batches, the meglumine cyclic adenosine for injecta sample that gone on the market, detection heavy metal and impurity content

From test data, the three batches of injection heavy metals and the impurity content of embodiment 1 are less than the medicine having gone on the market.

Another experimental group room temperature is placed 90 days, then detects three batches of heavy metal and impurity contents, and result is as following table:

From test data, the three batches of injection heavy metals and the impurity content of embodiment 1 are obviously less than the medicine having gone on the market.

Laboratory sample room temperature is placed 60 days in addition, and the fluctuation range of embodiment 1 solution pH value is 6.9-7.1, and the meglumine adenosine cycle phosphate having gone on the market is 6.7～7.4.

Dissolution velocity test:

The lyophilized injectable powder of the present invention of preparing by the method for the embodiment of the present invention 1 and the meglumine adenosine cycle phosphate lyophilized injectable powder having gone on the market carry out dissolution velocity test, result demonstration, and the product dissolution velocity of the embodiment of the present invention 1 is higher than matched group.

Storage-stable test

Embodiment 1 and the meglumine adenosine cycle phosphate lyophilized injectable powder that gone on the market, the lower storage of conventional refrigeration temperature (2-8 ℃) 18 months, be take to impurity as investigating index, carry out long-time stability and investigate test.The results are shown in following table:

Different prescriptions long-time stability under 2-8 ℃ of holding conditions

Minute	Embodiment 1	The meglumine adenosine cycle phosphate lyophilized injectable powder having gone on the market
			0 month	0.81％	0.62％
June	0.99％	0.94％
			December	1.05％	1.36％
18 months	1.19％	1.56％

Drug standard requires the content of impurity should not be greater than 1.5%.From table, the sample of the more commercially available formula preparation of the present invention is more stable, can at 2～8 ℃ of conventional refrigeration temperature, preserve 18 months, and product quality still meets the national drug standards, and contrast, can only store 12 months.

To the freeze dried injection that contains meglumine adenosine cycle phosphate of buying on market of the present invention.Carried out the research of stability test, result shows that stability of the present invention is better than the product on market.

New meglumine cyclic adenosine for injecta freeze-drying medicinal composition provided by the invention, has good stability, and invariant color does not stimulate during injection, and better tolerance is dissolved the multiple advantages such as rapid, easy to use, meets greatly patient's needs.

Specific implementation method

By following specific embodiment, the present invention is further detailed, but not as restriction.

Embodiment 1

Meglumine adenosine cycle phosphate 20g;

Mannitol 150g;

EDTA calcium 2g;

Vitamin C 1.5g,

Mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 2000ml of 1:4;

Preparation method

(1) by recipe quantity, take supplementary material

(2) mannitol, EDTA calcium, vitamin C being added to mol ratio is DisodiumHydrogen Citrate and the trisodium citrate buffer 2000ml of 1:4, stirring and dissolving.

(3) meglumine adenosine cycle phosphate that adds recipe quantity joins in solution, is stirred to dissolve completely.Stirring makes mix homogeneously.

(4) surveying solution pH value, is 7.0.

(5) with the microporous filter membrane fine straining of 0.2 μ m, check solution clarity.

(6) according to measurement result, with the volume of about 2ml by liquid medicine filling in the vial of XiLin.

(7) sample is put into the 18h of 35 ℃ of low-temperature vacuum dryings of 35 ℃ of pre-freeze 4h ， – of freeze dryer lyophilization ， –, 50 ℃ of intensifications are dried 4h again.

(8) lyophilizing finishes, and sample is jumped a queue, gland.

Embodiment 2

Meglumine adenosine cycle phosphate 20g;

Mannitol 100g;

EDTA calcium 1g;

Vitamin C 1g,

Preparation method

With embodiment 1

Embodiment 3

Meglumine adenosine cycle phosphate 20g;

Mannitol 200g;

EDTA calcium 3g;

Vitamin C 2g,

Preparation method

With embodiment 1.

Claims

1. a pharmaceutical composition that contains meglumine adenosine cycle phosphate, is freeze-dried pharmaceutical formulation, and every 1000 injections are made by the component of following proportioning:

Meglumine adenosine cycle phosphate 20g;

Mannitol 150g;

EDTA calcium 2g;

Vitamin C 1.5g;

The preparation method of described compositions is as follows: first prepare DisodiumHydrogen Citrate and trisodium citrate buffer 2000ml, then get meglumine adenosine cycle phosphate, mannitol, EDTA calcium, vitamin C adds mixed dissolution in DisodiumHydrogen Citrate and trisodium citrate buffer, and the filter membrane of via hole diameter molecular cut off 20000 filters, fill, half tamponade, lyophilization, obtains.