The injectable form of the drug, showing anti-ischemic activity

 

(57) Abstract:

The drug is made on the basis of adenosine-5'-triphosphate in isotonic. As a source of adenosine-5'-triphosphate drug contains TRACELEVEL salt of adenosine-5'-triphosphorylated (II) octahydrate in the amount of 10-20 g per 1000 ml isotonic. The preparation further comprises a pharmaceutically acceptable organic or inorganic acid or its acid salt in an amount necessary to achieve a pH of 7.0 to 7.4. Preferably as a pharmaceutically acceptable organic acid product contains citric acid in an amount of 0.6-1.2 g per 1000 ml isotonic. The drug in injectable form provides a high therapeutic effect and has an increased shelf life. 1 C.p. f-crystals, 5 PL.

The invention relates to medicine and can be used to obtain therapeutic agents with anti-ischemic activity in the prevention and treatment of ischemic heart disease.

Drugs, different biological activity and used for the prevention and treatment of coronary heart disease, are used in the form of tablets, capsules, powders, and economic damage to the myocardium is preferred.

It is now known that adenosine-5-triphosphates metals, in particular sodium, bimetallic have property enough to effectively protect the myocardium from ischemic damage (p. USSR 755201 and others).

However, there are certain problems associated with obtaining their injectable form required activity.

Closest to the claimed object is an injectable form of anti-ischemic drug containing as an active ingredient (substance) disodium salt of adenosine-5-triphosphate (Na2ATF), and isotonic. The concentration of the active component is 1% (Mashkovsky M. D.. Drugs, Minsk, Belarus", h 2, 1988, S. 125).

The known device has a membrane-stabilizing, energy-saving effect and to a much lesser extent exerts anti-ischemic activity. In the treatment of ischemic disease known means in injectable form is used in combination with other drugs. However, it should be noted that the tool prototype does not exhaust all the possibilities for protection of the myocardium from ischemic damage, which demonstrates his lack of biological activity. Upon the dissolution of Na2ATF

In the process of sterilization and preservation of known drug in injectable form, there is a noticeable reduction in ATF due to its hydrolysis to actinolite and inorganic phosphorus, which ultimately leads to some loss of activity of the dosage form.

The present invention is the creation of an injectable form of the drug that has anti-ischemic effect, by combining the most active substance and relevant additives, which results in high therapeutic effect injectable form of the drug and increases its shelf life.

The problem is solved by the fact that the injectable form of the drug, showing anti-ischemic activity, on the basis of adenosine-5'-triphosphate, isotonic, according to the invention as a source of adenosine-5-triphosphate contains TRACELEVEL salt of adenosine-5-tropospherestratosphere (II) octahedral and further comprises a pharmaceutically acceptable organic or inorganic acid, or its acid salt in an amount necessary to achieve a pH of 7.0 to 7.4, in the following ratio of components per 1000 isotonic:

- reorganisa or inorganic acid or its acid salt in the amount required to achieve a pH of 7.0 to 7.4

The authors of the present invention it is proposed to use as the active component similar in chemical nature to (Na2ATF) connection this formula K2Mg(His(ATF), hereinafter called the ATF-long, and in which His-anion histidine, ATF-anion adenosine-5'-triphosphate. However, the combination of ligands and biologically active metals - potassium, magnesium has significantly expanded the range of actions on myocardial ischemia, thereby determining the most high efficiency specified coordination compounds.

Connection ATF-long is new, the composition and structure of which is confirmed by the data of elemental analysis, Tg, IR and electronic spectroscopy in the UV region.

The data of elemental analysis and thermogravimetry coordination compounds ATF-long (see tab.1).

The structure of the compounds is presented below.

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The study of the toxicity of the above compounds showed that LD50= 850 mg/kg

Anti-ischemic activity of ATF-long was investigated in an experimental model of acute myocardial ischemia, played on the isolated, perfuziruemah on Langendorff CE is Uchaly on the solution, containing 0.3 g of tested compound. After 20 min perfusion of hearts this solution reproduces the limitation of the amount of coronary perfusion by 80%. The period of ischemia lasted 60 minutes

Already in the period of adequate perfusion adding ATF-long leads to changes in some indicators of ion and energy metabolism of the heart muscle, which generally indicate a moderate stimulation of redox processes (increased activity-ketoglutarates 15%, dehydrogenase 7%), improves the function of the ion-transport membrane properties (increase in the activity of Na+TO+-ATP-ASE at 17%, CA2+-binding capacity of the membrane by 9% compared with adequate perfusion). There is an increase in the energy capacity of the heart at the stage of adequate perfusion under the influence of this coordination compounds, as evidenced by the increase in the content of ATP and glycogen, respectively, 16% and 10% compared with the control. In these conditions there is an increase in intracellular potassium and magnesium on 12 and 15% and a reduction in sodium 85 compared to control.

Acute myocardial ischemia for 60 min resulted in inhibition of oxidant is Olam. Changing the bioenergetics of cardiac cells was accompanied by the lipid composition of their membranes (loss of phospholipids by 37%, the accumulation of fatty 27%), ion-transport membrane properties (inhibition of Na+TO+-ATP-ASE at 36%, CA2+-binding capacity of the membrane was decreased by 28%). Simultaneously, increased membrane permeability for calcium ions by 85%. The period of ischemia was accompanied by a sharp activation of anaerobic glycolysis and the development of acidosis in the myocardial tissue, which indicated an increase in the concentration of lactic acid in flowing from the heart of the perfusion fluid to the 60-th minute ischemia up to 320% of the original value. In cardiac cells has been a redistribution of electrolytes in the direction of decreasing potassium and magnesium, respectively, at 20 and 24%, and an increase of sodium and calcium, respectively, 17% and 23% compared to control.

In the case of therapeutic and prophylactic use ATF-long significantly expressed a degree of protection of cardiac cells from ischemic effects. Under the influence of the compounds decreased activity of Na+TO+-ATP-ASE was increased by 33% compared with ischemia. Most expressed normalization phospholipid and fatty acid composition of member is expressed was the activation of oxidative enzymes under the influence of this connection, in particular to 95 and 98% of the control level of the activity of succinate dehydrogenase and-Ketoglutarate respectively. While the least pronounced acidosis in the myocardium to 165% compared with control. The above changes were accompanied by increased levels of energy substrates in the heart, namely, to 89% control of ATP to 83% of control. With the introduction of ATF-long was observed more adequate correction of intracellular electrolytes.

Thus, the majority of the studied indicators ATF-long shows high anti-ischemic activity.

The authors of the present invention were identified appropriate additional components, which is inherent in the role of a buffer, which in turn allows you to increase the hydrolytic stability of the active anti-ischemic agents. These components, an organic acid or inorganic acid or acid salt, combine well with ATF-long and provide a pH of the injection solution concentration of 1-2% in the range of 7.0 to 7.4.

These supplements did not reduce the biological activity of the drug and did not impair its properties.

As can be seen from the data table. 2, in commercial preparator ATF for injection) 1% solution of disodium salt of ATF at pH 7,0-7,4 (notified by the NaOH solution according VFS) for 30 min in a sealed ampoule ( 2, 4, 6) about 10% ATF hydrolyzes to actinolite and inorganic phosphate. The same thing happens in the preparation of dosage forms in the factory ( 9).

When dissolved substance ATF-LONG in the water and getting a 1% solution ( 10) or 2-percent solution ( 12) pH respectively of 8.5 and 8.7. When sterilization of such solutions for 30 min loss ATF constitute only a few percent ( 1, 13). So to prepare injectable form ATF-LONG 2%-aqueous solution (pH 7.0 to 7.4) required partial neutralization of the acid. When neutralization, for example, phosphoric acid content of ATF in the solution remains practically unchanged ( 14), and when sterilization is reduced by only 5% ( 15) unlike the disodium salt of ATF.

Was tested a number of organic trekhosnovnykh, dibasic and monobasic acids as additives to neutralize the solution ATF-LONG and obtain a 2%-aqueous solution of ATF-LONG for injection with pH 7.0 to 7.4. The results are shown in table.3.

As can be seen from the data presented in table 3, all tested additives suitable for receiving injectable form ATF-LONG, because in the process of sterilization prepared using additives solutions content ATF in the solution is changed in the criterion values for the disodium salt ATF (PL. 2).

Thanks to the introduction of additives, acids or their acid salts (for example, phosphoric acid or its acid salts, citric or its acid salts, malic, tartaric, succinic, and others) is achieved by optimizing the pH of the solution for injection (pH 7.0 to 7.4). These buferiruemoi and complexes additives inhibit the processes of hydrolysis of ATP at room temperature and sterilization conditions.

The best results were obtained for solutions containing as an additive citric acid and tartaric acid.

The major advantage of citric acid is not only that the necessary amount to bring the pH minimum (because it is trehosnovnoy acid with a relatively low RK) and after sterilization, the product contains the largest number of ATF, but that citrate is known to be quite effective anticoagulation and desegregation blood and therefore prevents sguschaetsya. Therefore, from the point of view of practical application of additive citric acid is the most interesting.

During storage of the obtained solutions of the substance ATF-LONG (PL. 3) the rate of decrease of the content ATA compared with 1% solution of the disodium salt of the s showed that the proposed solutions ATF longer remains in its original form, which opens up the possibility of increasing the shelf life of the proposed injectable form, compared with 1% solution of Na2The ATF.

Given the fact that the substance of the drug ATF-LONG content ATF (including actinolite) is about 46%, and 2% solution of the drug ATF-LONG content ATF approximately the same as a 1% solution of disodium salt of ATF. However, the results of numerous biological tests showed that ATF-LONG significantly more effective (table. 4, 5). Even with the introduction of the same dose (0.3 mg/kg animal mass) disodium salt ATF and ATF-LONG (in this case, the content of ATP in the solution ATF-LONG two times less than in the solution of the disodium salt ATF) biological effects in the case of ATF-LONG were significantly higher.

In table. 4 shows some comparative data for solutions of Na2ATF (1% solution for injection) and ATF-LONG (1% solution with the addition of citrate, pH 7,37).

These data indicate that the injection solution ATF-LONG exhibits a pronounced energy-saving and stabilizing effect.

A preliminary introduction to perfuse the definition or ion myocardial metabolism in ischemia and hypoxia (table. 5). This is manifested, for example, to prevent reduction in the level of phospholipids membranes (35% of control) and the accumulation of free fatty acids (102% of control), which can be estimated as a membrane-stabilizing effect. The corresponding figures with the introduction of Na2ATF form 73 and 119%. When this membrane permeability for calcium ions in the case of ATF-LONG obviously did not differ from control (in the case of Na2ATF it is 22% higher than control). Thanks to the preservation of the lipid layer of the membrane with the introduction of ATF-LONG at a constant level (97% of control) supported by the activity of membrane-bound enzyme Na+TO+, ATF-basics sarcolemma (Na2ATF, the average is only 76%). Under the influence of ATF-LONG outer membrane of cardiomyocytes retains the ability to bind calcium ions (95%), improve process energy ion transport in cells. In the case of Na2ATF this figure is 22% lower than the control. The composition of the ATF and glycone in cardiac muscle with the introduction of ATF-LONG respectively 90 and 95% of the original level, which is higher than in the case of Na2ATF (79 and 72%, respectively). Thanks to the effects of Na2ATF-LONG during postischemic reperfusion flows more effectively and while the evidence from the original values (table. 5). However, a slight release of CPK in the perfusion fluid and the reduction in concentration of calcium ions, which indicates that maintaining the barrier properties of the membranes and to a lesser degree their defeat in the conditions of reperfusion.

From the data given in table. 4 and 5, it is seen that the injection solution ATF-LONG (1 and 2%) has a pronounced anti-ischemic effects, which is significantly more compared with 1% solution of Na2ATF for injection.

The invention is illustrated by specific example.

Example

10 g of ATF-LONG was placed in 1 l of isotonic saline solution (9 g NaCl in 1 l distilled water), then add the citric acid in the amount of 0.8 g, resulting in the solution has gained a pH of 7.2. Then the resulting solution was placed in vials 0.2 ml ampoules were soldered and spent their sterilization.

Properties of the obtained preparation is confirmed by the data given in table.2-5.

Thus, the proposed injection form of the drug with protiwaritmicescoy activity, exhibits a high therapeutic and prophylactic properties, has a high biochemical parameters needed stability and, consequently, elevated in a number of the here, on the basis of adenosine-5'-triphosphate in isotonic, characterized in that as a source of adenosine-5'-triphosphate contains TRACELEVEL salt of adenosine-5'-triphosphorylated (II) octahedral and further comprises a pharmaceutically acceptable organic or inorganic acid or its acid salt in an amount necessary to achieve a pH of 7.0 to 7.4, in the following ratio of the components in 1000 ml of isotonic: treculia salt adenosine 5'-tri-fosfatidiletanolamina (II) octahedral 10-20 g, pharmaceutically acceptable organic or inorganic acid or its acid salt in an amount necessary to achieve a pH of 7.0 to 7.4.

2. The injectable form of the drug under item 1, characterized in that as a pharmaceutically acceptable organic acid it contains citric acid in an amount of 0.6 to 1.2,

 

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