Antithrombotic negemorragicheskoy composition based on heparin, the method of production thereof and therapeutic use

 

(57) Abstract:

The invention relates to the field of medicine. The invention relates to heparin compositions exhibiting antithrombotic activity and almost devoid of hemorrhagic activity. The compositions according to the invention (S1, S2, S3) is composed of heparin fractions, such as those obtained by neutralization of heparin by Protamine in vitro. The invention also concerns the method of obtaining these compounds. These compounds are used to produce drugs with acceptable carrier. When using the claimed compounds do not experience bleeding while preserving the basic properties. 3 S. and 18 C.p. f-crystals, 2 ill., 13 table.

The invention relates to compositions based on heparin, and the method of their preparation and their therapeutic applications.

In particular it relates to compositions based heparins, neutralized by Protamine exhibiting antithrombotic activity, but markedly devoid of hemorrhagic activity.

Heparins are known and used for many decades to obtain medications with antiplatelet and/or anticoagulant activity, intended in particular for the prevention and treatment Enii.

For several years now, how can get low molecular weight heparins, which always exhibit antithrombotic activity, but anticoagulative properties are weakened.

However, with regard to nefrackzionirovannam heparins or low molecular weight heparin, the risk of bleeding remains a major complication in the treatment-based drug heparin. Due to this, there are significant restrictions on the use of heparin, which is particularly contraindicated in patients predisposed to bleeding, patients suffering from duodenal or gastric ulcers, and patients who have recently undergone surgery, have antithrombotic treatment with heparin can cause bleeding.

As a consequence, the useful properties of heparins and their antithrombotic or anticoagulant activity, cannot be used due to the significant side effects associated with the constant risk of bleeding.

When the treatment of heparin suddenly arise bleeding, use preteenslut that produces neutralization of heparin in vivo.

Thus, the problem that aims to solve the present invention is a significant reduction in the risk of bleeding described above, limiting therapeutic use of heparins.

More precisely, the aim of the invention is perhaps most elimination of the risk of bleeding during treatment with heparins while maintaining their basic properties, particularly an antithrombotic activity.

Also the aim of the present invention is to provide a heparin compositions with a very interesting pharmacological properties, particularly an antithrombotic, substantially equivalent to heparin compositions used up to the present time, but who are deprived of the basic disadvantage of a significant risk of bleeding.

Another goal of the infusion is in use, allowing, in addition, to expand their therapeutic applications.

Similarly, the invention is intended therapeutic application of these compounds.

These goals have been achieved using heparin compositions according to the invention, which possess antithrombotic activity and virtually devoid of hemorrhagic activity. These compositions are characterized in that they are composed essentially of fractions of heparin obtained by neutralization of heparin by Protamine in vitro.

Under the fraction of heparin neutralized by Protamine imply any fraction, obtained from natural or already fractionated heparin, synthetic heparin, hemorrhagic ability which was offset by the effect of Protamine, or any similar or equivalent with a similar ability to reduce hemorrhagic ability.

Compositions according to the invention is mainly composed of fractions of heparin obtained by neutralization nefrackzionirovannam or low molecular weight heparin by Protamine in vitro.

According to one variant of the invention, the composition consists of fractions of heparin, 25% of which have the realization of the invention the composition consists of only fractions of heparin, having a molecular weight of less than 2.5 KD.

In other compositions of the fractions of heparin have a range of molecular weights, depending on the used methods of neutralization by Protamine.

Compositions according to the invention substantially free of Protamine.

The invention also relates to a method for obtaining the above-mentioned compositions, characterized in that it includes a stage of neutralization of heparin by Protamine in vitro.

Applicants unexpectedly discovered that it is possible to neutralize the hemorrhagic activity of heparin, fully preserving its antithrombotic properties, in vitro especially with Protamine.

More precisely, the method according to the invention is that the heparin solution is injected into reaction with Protamine, especially in the form of a salt of Protamine, in accordance with the changing value of relationships heparin/Protamine.

According to a preferred method of implementation of the invention, the heparin solution is mixed with Protamine salt solution, preferably at room temperature, centrifuged the mixture and extract sucks.

According to the invention under the heparin solution implies the solution of the natural or already frieze of preteenlolita.

According to the invention can use any similar or equivalent Protamine with a similar ability to neutralize heparin and, consequently, to decrease hemorrhagic ability.

Sucks can later be liofilizovane.

Treated with heparin and Protamine can be used in different ratios, which lead essentially to eliminate the risk of bleeding associated with heparins.

The method comprises a stage of neutralization of heparin by Protamine or its equivalent preferably in a ratio of heparin/Protamine from 2/1 to 1/2.

According to one variant implementations of this method against the heparin/Protamine is about 1/1. In this case, receive heparin compositions containing fractions, at least 25% of which have a molecular weight of less than 2.5 KD and at least 40% have a molecular weight of more than 20 KD.

According to another implementation variant of the invention the ratio of heparin/Protamine is about 1/2. Then receive heparin compositions containing essentially the fraction with molecular weight less than 2.5 KD.

In a way appropriate to nestasnegodine heparin compositions according to the invention unexpectedly showed that they are virtually devoid of hemorrhagic activity and at the same time retain their antithrombotic properties.

This pharmacological study also unexpectedly showed that heparin fractions obtained by neutralization with Protamine according to the invention exhibit anti-thrombotic activity, which grows with the introduction of increasing doses without a parallel increase their hemorrhagic or anticoagulant activity. Experimental data showed that the compositions according to the invention are able to inhibit the hydrolytic activity of leukocyte elastase person more effectively than nefrackzionirovannam heparin. Elimination of the risk of bleeding allows us to consider the introduction of drugs parenterally or as an aerosol bronchopulmonary through in the treatment of some pulmonary diseases that may be associated with excess leukocyte elastase, such as syndromes of acute respiratory diseases, cystic fibrosis, chronic obstructive bronchopneumopathy.

Stable and non-toxic heparin compositions according to the invention can be used to produce medicines, prednaznachen the ski derivatives, including when heparin is contraindicated because of the risk of bleeding, which is sick. They can be especially for drugs for treatment and prophylaxis of venous or arterial thrombosis or to prevent clotting in the extracorporeal circulation.

Thus, the invention equally relates to pharmaceutical compositions containing a therapeutically effective amount of heparin compositions according to the invention, in combination with pharmaceutically acceptable basis for the preparation of medicines.

It could be, for example, about antithrombotic pharmaceutical compositions or pharmaceutical compositions to inhibit hydrolytic activity of leukocyte elastase person.

Heparin fractions of these songs can be transferred in the form of pharmaceutically acceptable salts in accordance with the classical methods.

The pharmaceutical compositions according to the invention preferably are suitable for injection of drugs intended, in particular, for administration parenterally.

For other applications, takim way.

Other characteristics and advantages of the compositions according to the invention is illustrated by the examples below for information and do not limit the invention, with reference to the accompanying drawings, on which: Fig. 1 - comparative curves hemorrhagic activity nefrackzionirovannam heparin, low molecular weight heparin and negemorragicheskoy heparin compositions according to the invention (S1, S2, S3); Fig. 2 - comparative curves of antithrombotic activity nefrackzionirovannam heparin, low molecular weight heparin and heparin compositions according to the invention (S1, S2, S3).

EXAMPLES

Products used: standard heparin (Leo), preteenslut (Soai) and low molecular weight heparin "Enoxaparine" under the trade name "Lovenox" (Farmaka).

Example 1. Preparation of sludge S1

Prepare to 14.4 ml of solution of standard heparin with a title 72000 international units (480 mg) and 48 ml of preteenlolita with a title 48000 UAH. These solutions are mixed at room temperature. In this case, the ratio of heparin/Protamine is equal to 1/1, that is, 1 mg of heparin neutralize 1 mg preteenlolita. Thus obtained mixture is centrifuged in those S2

Act as described in example 1, starting with 9 ml of solution of standard heparin (namely 45000 international units, 300 mg) and 60 ml of preteenlolita (namely 60000 UAH). In this case, the ratio of heparin/Protamine is equal to 1/2, that is, 1 mg of heparin neutralized 2 mg preteenlolita.

Example 3. Preparation of sludge S3

Act as described in example 1, starting with 4 ml of a solution of low molecular weight heparin, "Enoxaparine" (Lovenox) (namely 400 mg) and 40 ml of preteenlolita (namely 40000 UAH). In this case, the ratio of heparin/Protamine is equal to 1/1, that is, 1 mg of low molecular weight heparin neutralize 1 mg preteenlolita.

BIOLOGICAL CHARACTERIZATION

Molecular mass distribution (see tab.1, PL. 2).

Absorption spectrum in the ultraviolet region for sludge 1 (example 1)

The solution is diluted in a ratio of 1/20, has two maximum absorption at the following wavelengths: 212 nm : OP = 3,47 and to 271.5 nm : OP = 2,22.

Titration of sludge S1 (example 1)

Before lyophilization sludge S1, obtained according to example 1, each flask contains 0.7 ml of sludge. To check the reproducibility spend 12 identical quantitative definitions: the results are presented in table 3.

The results are presented in table 4.

Electrolyte composition (mekv/l)

Electrolyte composition of the sludge S1 and S2 is given in table 5.

Determination of pH (see table. 6).

PHARMACOLOGICAL RESEARCH

A. Experimental studies on rats in a model of venous thrombosis induced stasis, and model provoked bleeding

Studies are carried out according to the method described by C. Doutremepuich and other "Treatment of experimental venous thrombosis in rats heparin and low molecular weight heparin fraction", Haemostasis, 13, 109-112 (1983).

A. Medical model (subcutaneous injection two hours after induction of thrombosis).

Conduct two studies in accordance with the following Protocol:

: Ligature Vena cava

+2N: subcutaneous injection solutions

+NO: inducing bleeding

+6N: sampling (blood clots)

The data obtained in the first study are collected in tables 7 and 8.

This is the first study shows that heparin neutralized in vitro by Protamine against the heparin/Protamine equal to 1/1, leading tromboticescoy activity is not neutralized heparin and antithrombotic activity of heparin Lovenox (low molecular weight heparin), while anticoagulation activity and hemorrhagic activity only slightly increased.

Sucks S1 does not have any impact on blood cells.

At the same time sucks S2, obtained by neutralization with a ratio of heparin/Protamine equal to 1/2, exhibits no hemorrhagic activity, but has reduced antithrombotic activity.

The results of the second survey are presented in table 9.

The results imply that the antithrombotic activity of fractions S1, S2 and S3 according to the invention increases with the injected doses.

If we turn to the dependency of the dose-effect established for doses in the range from 2 mg/kg to 10 mg/kg, Fig. 1 shows that whatever the type of heparin-treated according to the invention, the received heparin fraction has hemorrhagic activity that is similar to the hemorrhagic activity of the control group, even at very high doses. Nefrackzionirovannam heparin and low molecular weight heparin (Lovenox), is not neutralized by Protamine according to the invention, exhibit high hemorrhagic activity compared to heparin fractions according to the invention.th antithrombotic activity. In the case of fractions S1 (heparin/Protamine equal to 1/1) this activity comparable to the activity of heparins, not neutralized in accordance with the invention.

B. Preventive model (subcutaneous injection one hour before induction of thrombosis)

The study was conducted with sludge S1 (example 1) in accordance with the following Protocol:

THEN: subcutaneous injection solutions

THE + 1 hour: inducing stasis

THE + 24 hours: sampling (blood clots)

The results are presented in table 10.

The results show that as a preventive measure, 24 hours after induction of thrombosis S1 shows antithrombotic activity, comparable with antithrombotic activity of heparin and Lovenox.

B. Experimental study on the rat model of thrombosis induced generation of free radicals

(reference: Doutremepuich - print - Annales de Cardiologi et Angiologie)

The study was conducted with S1 (example 1) in accordance with the following Protocol:

(THAT subcutaneous injection solutions)

THE + 25 min: injection of rose Bengal at a dose of 5 mg/kg

THE + 30 min: the induction of free radicals on the first level of the arterioles in polowanie free radicals at the level of the second arterioles

THEN + 85 min: injection of rose Bengal at the same dose

THE + 90 min: the induction of free radicals at the level of small veins.

After the last thrombosis produce sampling blood intracardiac way.

The time of excitation with 2 minutes, and the observation time is 10 minutes.

The results, presented in table 11.

In this model of thrombosis induced by free radicals, sucks S1 (example 1) exhibits antithrombotic activity, significant compared to the placebo group (indifferent substances), which continues after 90 minutes (+90 min). This activity is significantly greater than the activity of heparin entered in the same dose after 30 and 60 minutes (+30 and + 60 min).

C. Experimental study on the rat model of thrombosis induced by laser violation of the endothelium (link: Vesvres, Haemostasis 1993, 23, 8-12)

a) Study 1

The study was conducted according to the following Protocol:

THEN: subcutaneous injection of the test substance at a dose of 2 mg/kg

THE + 35 min: induction of arterial thrombosis under the action of the laser beam.

The observation time is set to 10 minutes. The results prirelsovogo heparin, entered at the same dose, and reduces the number of emboli, as well as the time of embolization in a statistically significant way.

b) Study 2

The study was conducted according to the following Protocol:

THE subcutaneous injection of the test substance at a dose of 2 mg/kg

THE + 1 hour: the induction of the first arterial thrombosis

THE + 3 h: induction of the second arterial thrombosis

THE + 6 hour: the third induction of arterial thrombosis.

The observation time is set to 10 minutes.

The results are presented in table 13.

S1 shows antithrombotic activity comparable to the activity of heparin is not neutralized by Protamine.

In conclusion, the studies described above show that the antithrombotic activity is observed in three experimental models of thrombosis, namely, models of venous thrombosis induced stasis, a model of arterial thrombosis induced by free radicals and model of arterial thrombosis induced by laser violation of the endothelium.

According to the invention heparin fraction is obtained on the basis of low molecular weight heparin "Enoxaparine" (Lovenox), proyavlyayuschego heparin, not treated in vitro with Protamine, and significantly greater than the antithrombotic activity of the fractions obtained on the basis of nefrackzionirovannam and not processed in vitro by Protamine heparins, not presenting any risk of bleeding.

The method according to the invention allows easy and cheap to virtually eliminate the hemorrhagic activity of heparins, keeping their antithrombotic activity.

1. The composition of heparin with antithrombotic activity and practically devoid of hemorrhagic activity, characterized in that it includes fractions of heparin contained in the supernatant obtained by centrifugation of the mixture neutralization in vitro heparin solution with a solution of Protamine.

2. The composition according to p. 1, characterized in that it contains fractions of heparin contained in the supernatant obtained by centrifugation of the mixture neutralization in vitro solution ungraded heparin solution of Protamine.

3. The composition according to p. 1, characterized in that it contains fractions of heparin contained in the supernatant obtained by centrifugation of the mixture neutralization in vitro solution of low molecular weight heparin concrete the shares, at least 25% of which have a molecular weight of less than 2.5 KD.

5. The composition according to p. 4, characterized in that it consists of fractions, at least 40% of which have a molecular weight of more than 20 KD.

6. Composition according to any one of paragraphs.1 to 4, characterized in that it consists of fractions with molecular weight less than 2.5 KD.

7. The composition according to p. 5, characterized in that it consists of a fraction having the following molecular weight distribution, expressed in %: fraction with a molecular weight of > 20 KD in the UV region 43,3, in the infrared region of 47.3; the fraction with a molecular mass of 16 - 20 KD in the UV region of 2.7, in the infrared region of 4.45; the fraction with a molecular mass of 12 to 16 KD in the UV region of 4.5, in the infrared region of 7.65; the fraction with a molecular mass of 8 - 12 KD in the UV region 9,7, in the infrared region 13,85; the fraction with a molecular weight of 5 - 8 KD in the UV region 8,13, in the infrared region of 11.8; the fraction with a molecular weight of 2.5 - 5 KD in the UV region 6,36, in the infrared region of 10.3; the fraction with a molecular weight < 2.5 CD in the UV region 25,16, in the infrared region 4,65.

8. Composition according to any one of paragraphs.1 to 7, characterized in that it contains almost no Protamine.

9. Composition according to any one of paragraphs.1 to 8, characterized in that it manifests inhibiting properties with respect to the hydrolytic activity of l is s, includes mixing a solution of heparin and Protamine salt solution to neutralize heparin in vitro and subsequent centrifugation of the mixture, characterized in that after centrifugation carry out removing the supernatant.

11. The method according to p. 10, characterized in that the salt of Protamine is preteenslut.

12. The method according to any of paragraphs.10 and 11, characterized in that the heparin and Protamine is used in a ratio of 1 : 1.

13. The method according to any of paragraphs.10 and 11, characterized in that the heparin and Protamine is used in a ratio of 1 : 2.

14. The method according to any of paragraphs.10 to 13, characterized in that use nefrackzionirovannam heparin.

15. The method according to any of paragraphs.10 to 13, characterized in that the use of low molecular weight heparin.

16. Composition according to any one of paragraphs.1 to 9, characterized in that it is used for drugs exhibiting antithrombotic activity and almost devoid of hemorrhagic activity.

17. Antithrombotic pharmaceutical composition, practically devoid of hemorrhagic activity, characterized in that it contains an effective amount of a composition according to any one of paragraphs.1 - 9 in combination with a headlight is 17, characterized in that it is in the form of a solution suitable for injection.

19. The pharmaceutical composition under item 17, characterized in that it is used for the inhibition of the hydrolytic activity of leukocyte elastase person.

20. The pharmaceutical composition according to p. 19, characterized in that it is in a form suitable for introduction bronchopulmonary way.

21. The pharmaceutical composition under item 17, characterized in that it comprises as active ingredient fraction of heparin contained in the supernatant obtained by centrifugation of the mixture neutralization in vitro heparin solution with a solution of Protamine in a ratio of heparin to the Protamine 1 : 1.

 

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