Haemostatic medication based on synthetic tripeptide plasmin inhibitor

FIELD: medicine.

SUBSTANCE: medication based on tripeptide Ac-Ala-Phe-Lys-Pip·AcOH or its pharmaceutically acceptable salts is applied. The claimed medication can be made in the form of a solution, gel, plate or sponge.

EFFECT: application of the said medication makes it possible to considerably reduce the volume of haemorrhage and reduce the time of bleeding stopping due to high anti-plasmin activity of the tripeptide Ac-Ala-Phe-Lys-Pip·AcOH with the absence of side effects.

2 cl, 8 ex, 2 tbl

 

The invention relates to chemical-pharmaceutical industry, namely to creation of drugs having hemostatic action, containing a Tripeptide inhibitor of plasmin and intended to stop bleeding, including bleeding from parenchymatous organs and trauma surgery. The use of the developed pharmaceutical drugs can significantly lower blood loss and reduce the time of stop of bleeding.

Providing effective hemostasis in surgery, trauma, ENT, dental and obstetric practice is an important problem of modern medicine. The use of traditional methods of hemostasis (mechanical, thermal hemostasis) can result in not only no effect, but to the development of serious complications associated with the additional injury of organs and tissues. Therefore, all the more widespread gentle ways to effect hemostasis with the use of drugs of biological origin (natural components of human blood and various biopolymers) and synthetic chemicals contributing to stop bleeding and having different mechanisms of action.

Hemostasis is a complex Rea�functions of the body, aimed at stopping the bleeding. Are vascular-platelet hemostasis, plays a leading role in the injury of capillaries and small vessels (100 µm), and plasma for halting bleeding in case of damage to larger vessels (V. M. Pokrovsky, 2003). Plasma hemostasis is an enzymatic cascade in which proenzymes, transitioning to the active state, acquire the ability to activate other coagulation factors. The result is the formation of a fibrin clot and its retraction, which provides the sealing and securing of a blood clot in a damaged vessel. Simultaneously with the retraction, but with less speed, begins the process of fibrinolysis is the destruction of formed clots serine protease by plasmin, which is formed from the proenzyme plasminogen by various activators, which are serine proteases. If damaged parenchymal organs-rich tissue activators, they release and increase blood fibrinolytic activity, resulting in high intensity of bleeding and significant blood loss. In the case of injuries, extensive burns or surgical operations on some organs (lungs, liver, thyroid, pancreatic and prostate glands), the obstetric bravoteen�ies, pancreatitis and others. Inhibition of components of the fibrinolytic system of the blood is the safest and most effective way to stop bleeding in surgery, trauma, ENT, dental and obstetric practice and is achieved by using separate groups of haemostatic drugs, Antifibrinolytics.

Antifibrinolytic drugs are presented:

first-synthetic structural analogues of lysine (ε-aminocaproic, tranexamic and p-aminobenzoic acid), which is based on binding of specific lysine-binding sites of the proenzyme plasminogen. Saturation and blocking of active sites of plasminogen inhibits the process of conversion of plasminogen to plasmin and leads to inhibition of fibrinolysis and hemostasis.

Secondly - nonspecific inhibitors of serine proteases (plasmin, plasma kallikrein and tissue) - constituting proteins, the main representative of which is Aprotinin. Aprotinin reduces fibrinolytic activity of blood, inhibits fibrinolysis and has a hemostatic effect, but has a number of adverse drug reactions and has a high allergenicity. Aprotinin, part of the hemostatic sponge "Tahoka�", because of allergenicity excluded from the composition.

A characteristic feature of Antifibrinolytics is to achieve a hemostatic effect at the site of bleeding, regardless of method of administration (oral, parenteral and local).

The actual problem is the search for specific inhibitors of fibrinolysis, which will operate only on enzymes target without affecting other components of the fibrinolytic system of the blood. Very promising from this point of view are low molecular weight peptide compounds, which should have a low toxicity.

In a number of publications and patents described synthetic inhibitors of fibrinolytic activity, representing organic compounds (WO 2012/047156, US 8569313), short peptides (Midura-Nowaczer K., et al., 2006; 2008 and EN 2017749) and peptidomimetics (WO 2013/004845). For some of them conducted studies of specific activity in vivo under different methods of application.

It is known that a peptide sequence-Ala-Phe-Lys - effectively binds to the active center of plasmin (RU2121690), this sequence was the basis for the synthesis having hemostatic activity of peptide inhibitors of plasmin, in the patent (RU 2341532) patented compound H-Ala-Phe-Lys-Pip, H-Ala-Phe-Lys-Mf For-Ala-Phe-Lys-Pip, For-Ala-Phe-Lys-Mf and their pharmaceutical�and acceptable salts (For - formyl, Pip is a piperidine-4-yl, Mf - morpholine-yl)

The closest analogue of the compounds which developed the inventive medicament is an inhibitor of For-Ala-Phe-Lys-Pip - has a number of disadvantages of technological nature, due to the included formyl group. This group is prone to lipid oxidation compounds that may be present in the solvents used during synthesis, leading to the necessity of additional purification at each stage. To improve the solubility of hydrophilic formulation when you scale synthesis requires multiple increase of the standard or the introduction of more effective but more toxic solvents. It was found that described in the aforementioned patents formulate hygroscopic and thermally unstable. These disadvantages are the closest analogue impede technological operations upon receipt of the finished dosage forms based on it.

The object of the present invention is to expand the Arsenal of haemostatic medicines to stop bleeding, including bleeding from parenchymatous organs for injuries and surgical operations.

The task is solved by obtaining hemostatic drugs, based on synthetic tripat�Yes Ac-Ala-Phe-Lys-Pip·AcOH or its pharmaceutically acceptable salts.

In the synthetic Tripeptide Ac-Ala-Phe-Lys-Pip·AcOH as the protective group used acetyl, which provides greater stability of the Tripeptide and does not have the disadvantages of the formyl group used in the closest analogue.

The claimed medicinal product is made in various dosage forms:

- aqueous solution,

gel on the basis of carboxymethyl cellulose sodium salt,

film based on the sodium salt of carboxymethyl cellulose and glycerin

- sponge on the basis of the mixed sodium alginate and calcium.

All of these dosage forms may additionally contain antiseptics and stabilizers.

The invention is illustrated by the following examples.

Example 1. Getting the Tripeptide Ac-Ala-Phe-Lys-Pip-AcOH

The peptide (Ac - acetyl, Pip is a piperidine-4-yl) receive consistent growth of the peptide chain, starting from the substituted amide of lysine.

Substituted amide of lysine HCl·H-Lys(Z)-Pip obtained by reaction of Boc-Lys(Z)-OH (20 g) with Ν,Ν'-dicyclohexylcarbodiimide (10,9 g) and N-hydroxysuccinimide (6.3 g) and piperidine (10 ml) chloride the methylene (Maxim E. Sergeev, Tatiana L. Voyushina. Convenient synthesis of novel natural amino acid cyclic amides for use as building blocks for proteinase inhibitors. Letters in Organic Chemistry, 2006, No. 3, 857). Boc-protective group is Boc-Lys(Z)-Pip removed the standard method by treatment with 4 M solution of hydrogen chloride in dioxane (A. A. Gershkovich, V. K. Chibirev. With�ntes peptides. Reagents and methods. Kiev, Naukova Dumka, 1987, p. 123). The yield of HCl·H-Lys(Z)-Pip 18,77 g (93%).

The activated ester Boc-Phe-OSu and Boc-Ala-OSu receive the standard method by reactions respectively Boc-Phe-OH and Boc-Ala-OH with Ν,Ν'-dicyclohexylcarbodiimide and N-hydroxysuccinimide in tetrahydrofuran, followed by crystallization of the product from isopropanol (A. A. Gershkovich, V. K. Chibirev. The synthesis of peptides. Reagents and methods. Kiev, Naukova Dumka, 1987, pp. 60-61).

Dipeptide HCl·H-Phe-Lys(Z)-Pip is produced by a method succinimide of the ester obtained in the previous stages of HCl·H-Lys(Z)-Pip (22,1 g) and Boc-Phe-OSu (22,0 g) in 200 ml of methylene chloride in the presence of Ν,Ν-diisopropylethylamine (12.5 ml). The reaction mixture was stirred for 3 h at room temperature. Was then added N-methylpiperazine (3 ml), stirred and evaporated on a vacuum rotary evaporator. The obtained oily residue was dissolved in a mixture of ethyl acetate (250 ml) and water (200 ml). Transfer the mixture into a separatory funnel, ethylacetate layer was washed successively with 200 ml twice with 5% aqueous H2SO415% solution of Na2SO4twice with 5% aqueous NaHCO3, 20% NaCl. Assembled ethylacetate the solution was dried over anhydrous Na2SO4. The desiccant was filtered off, the solution evaporated on a vacuum rotary evaporator to a state of viscous oil. Boc-protective group is Boc-Phe-Lys(Z)-Pip prowess�t standard method by treatment with 4 M solution of hydrogen chloride in dioxane (A. A. Gershkovich, V. K. Chibirev. The synthesis of peptides. Reagents and methods. Kiev, Naukova Dumka, 1987, p. 123). The yield of HCl·H-Phe-Lys(Z)-Pip of 28.9 g (94%)

Tripeptide HCl·H-Ala-Phe-Lys(Ζ)-Pip is produced by a method succinimide of the ester obtained in the previous stages of HCl·H-Phe-Lys(Z)-Pip (26,0 g) and Boc-Ala-OSu (16.0 g) in 200 ml of methylene chloride in the presence of equimolar quantities Ν,Ν-diisopropylethylamine (12 ml). Stirred for 3 h at room temperature, was then added N-methylpiperazine (3 ml) and evaporated on a rotary evaporator. The obtained oily residue was dissolved in a mixture of ethyl acetate (250 ml) and water (250 ml). Transfer the mixture into a separatory funnel, ethylacetate layer was washed successively with 200 ml twice with 5% aqueous H2SO415% solution of Na2SO4twice with 5% aqueous NaHCO3, 20% NaCl. Assembled ethylacetate the solution was dried over anhydrous Na2SO4. The desiccant was filtered off, the solution evaporated on a vacuum rotary evaporator to a state of viscous oil. Next, the substance is dried in vacuum, to the state of the cured foam. Boc-protective group Boc-Ala-Phe-Lys(Z)-Pip removed the standard method by treatment with 4 M solution of hydrogen chloride in dioxane (A. A. Gershkovich, V. K. Chibirev. The synthesis of peptides. Reagents and methods. Kiev, Naukova Dumka, 1987, p. 123). The yield of HCl·H-Ala-Phe-Lys(Z)-Pip 26,8 g (91%).

Protected Tripeptide Ac-Ala-Phe-Lys(Z)-Pip gain AC�melirovanie HCl·H-Ala-Phe-Lys(Z)-Pip acetic anhydride according to the method of obtaining acetylated amino acids (Z. I. Kuvaeva, D. V. Lopatin, T. A. Nikolayeva, A. N. Knizhnikov, V. Naidenov, M. M. Markovich. Pharmaceutical chemistry journal. 2010. Vol 44, No. 6. P. 22).

To obtain the target peptide Ac-Ala-Phe-Lys-Pip·AcOH protected Ac-Ala-Phe-Lys(Z)-Pip(24,3 r) was dissolved in methanol (250 ml) containing 5 ml of acetic acid, and is hydrogenated in the presence of palladium mobiles by well-known methods (J. Greenstein, M. of Vinnytsia, Mir, 1965, p. 695). After the reaction mixture was filtered through a filter paper, the solvent was removed in vacuo, the residue dissolved in water and freeze dried. The output of the hydrate product is 22,57 g (96% based on anhydrous substance).

Example 2. Evaluation of the stability of the Tripeptide Ac-Ala-Phe-Lys-Pip-AcOH

When comparing the properties of the Tripeptide Ac-Ala-Phe-Lys-Pip·AcOH with the closest analogue is established that during storage for 6 months Ac-Ala-Phe-Lys-Pip·AcOH remains crystalline, while the closest analogue due to the increased water absorption into the oil. According to data obtained by the method of Weeks UV detection, the claimed Tripeptide Ac-Ala-Phe-Lys-Pip·AcOH stable after incubation for 3 months at 65°C, while the closest analogue in such conditions is destroyed by 15-20%.

Example 3. Obtaining the claimed dosage forms of the drug - solution

The aqueous solution of the Tripeptide Ac-Ala-Phe-Lys-Pip-AcOH get in the traditional way. It has�next structure:

Ac-Ala-Phe-Lys-Pip·AcOH)0.5 to 10 g
Waterto 100 ml

To obtain dosage forms - 5% solution of 5 g of Ac-Ala-Phe-Lys-Pip·AcOH placed in a measuring cylinder and the volume was adjusted to 100 ml with water.

Example 4. Obtaining the claimed dosage forms drug - gel

The gel based on the Tripeptide Ac-Ala-Phe-Lys-Pip·AcOH has the following composition:

Ac-Ala-Phe-Lys-Pip·AcOH0.5 to 10 g
Karboksimetilcelljulozy sodium salt1-10 g
Waterto 100 ml

To obtain dosage forms of 2.5% gel 100 ml of a solution of Ac-Ala-Phe-Lys-Pip·AcOH to a concentration of 2.5% is poured into a glass Cup with a diameter of 20 cm On the surface of the solution evenly distribute 1 g of carboxymethyl cellulose in Na+ and leave for 1 hour at room temperature. After swelling of the polymer gel mix thoroughly and leave for several hours to remove air bubbles.

Example 5. Obtaining the claimed dosage forms drugs film

To obtain the pharmaceutical form film to 8.5 ml �of astora Ac-Ala-Phe-Lys-Pip·AcOH to a concentration of 1% is added 1.5 ml of glycerol, the mixture was thoroughly stirred and poured into glass Cup 5 cm in diameter On the surface of the solution evenly distribute 0.1 g of carboxymethyl cellulose in Na+ and leave for 1 hour at room temperature. After swelling of the polymer gel was thoroughly mixed, transferred into a plastic mould and dried in a thermostat at 37°C during the day.

Example 6. Obtaining the claimed dosage forms drug sponges

To obtain dosage forms - sponges to 70 ml of a solution of Ac-Ala-Phe-Lys-Pip·AcOH to a concentration of 1% is added 0.35 g of sodium salt of sodium alginate, the mixture was stirred under heating to 50°C before the formation of the solution, which is then freeze-dried in metal trays (12×12 cm). The resulting sponge is treated with a 0.3 M solution of calcium chloride and dried.

Experiments to study the haemostatic action of dosage forms of the proposed drug was carried out on Wistar rats, on the model of capillary-parenchymatous bleeding organ (liver). The effectiveness of the dosage forms was assessed by time stop bleeding and volume of blood loss, according to the "Guidance on preclinical drug discovery" edited by Mironov, A. N.

Example 7. Evaluation of hemostatic action of the claimed medicinal product in the form of a 5% solution of Ac-Ala-Phe-Lys-Pip·AcOH

About�the climate of bleeding is performed with the application of the wound surface gauze coated with a 5% solution of Ac-Ala-Phe-Lys-Pip·AcOH.

As a control, used gauze, containing 5% solution of Epsilon-aminocaproic acid, have a hemostatic effect. As a positive control was used gauze moistened with saline. The effectiveness of the dosage form was evaluated by mass of blood lost and time to stop bleeding.

From the results shown in table 1, it follows that the hemostatic efficacy of the action of a 5% solution on the basis of the Tripeptide Ac-Ala-Phe-Lys-Pip·AcOH in terms of blood loss corresponds to a solution of Epsilon-aminocaproic acid in the same concentration and time of bleeding exceeds this drug comparison.

Example 8. Evaluation of hemostatic action of the claimed medicinal product in the form of 2.5% gel Ac-Ala-Phe-Lys-Pip·AcOH

Hemostasis is performed with the application of the wound surface gauze coated with a gel, in an amount of 0.5 g to 1.0 cm2.

As a control used Napkin "ActiveX ACF containing Epsilon-aminocaproic acid. As a positive control was used gauze moistened with saline. The effectiveness of the dosage form was evaluated by mass of blood lost and time to stop bleeding.

Table 2
DrugWeight lost blood, gThe clotting time of blood,
Saline2,18±0,32305±27
Napkin "ActiveX ACF"0,79±0,08240±20
2.5% Gel Ac-Ala-Phe-Lys-Pip·AcOH0,62±0,08178±30

From the results shown in table 2, it follows that the effectiveness of hemostatic action of dosage forms of 2.5% gel on the basis of the Tripeptide Ac-Ala-Phe-Lys-Pip·AcOH - time control of bleeding and volume of blood loss exceeds the efficiency of the napkin "ActiveX ACF".

Thus, these hemostatic drug based on a synthetic Tripeptide Ac-Ala-Phe-Lys-Pip·AcOH, surpassing the closest analogue on the stability and containing formyl group, complicating the process of obtaining a peptide substances and medicinal products based on it. The effectiveness of hemostatic action of dosage forms of the proposed drug is comparable, and in some'hara�characteristics superior efficiency of well-known hemostatic means: solution of Epsilon-aminocaproic acid and napkins "ActiveX ACF".

Sources of information

1. Purwin M., Bruzdo M., Marcowska Α., Midura-Nowachek Κ. Short peptides containing L-lysine is an and ε-aminocaproic acid as potential plasmin inhibitors // Pharmacie, 2009, 64 (11), 765-7.

2. Marcowska Α., Bruzdo I., Surazynski A, Midura-Nowachek K. Tripeptides with non-code amino acids as potential serine proteases inhibitors // J Enzyme Inhib Med Chem. 2013 Jun; 28(3): 639-43.

3. Maxim E. Sergeev, Tatiana L. Voyushina. Convenient synthesis of novel natural amino acid cyclic amides for use as building blocks for proteinase inhibitors. Letters in Organic Chemistry, 2006, №3, 857.

4. A. A. Gershkovich, V. K. Chibirev. The synthesis of peptides. Reagents and methods. Kiev, Naukova Dumka, 1987.

5. Kuvaeva Z. I., D. V. Lopatin, T. A. Nikolayeva, A. N. Knizhnikov, V. Naidenov, M. M. Markovich. Preparation and use of N-acetyl - α-amino acids // pharmaceutical Chemistry journal. 2010. Vol 44, No. 6. P. 22.

6. J. Greenstein, M. Of Vinnytsia. Chemistry of amino acids and peptides // Mir, 1965.

7. "Guidelines for preclinical drug discovery" edited by Mironov A. N. M., Grif and, 2012.

8. Human physiology. The EDS V. M. Pokrovsky and G. F. Korotko. M, Medicine, 2003.

1. Hemostatic drug based on a synthetic Tripeptide Ac-Ala-Phe-Lys-Pip·AcOH or its pharmaceutically acceptable salts.

2. Hemostatic medicament according to claim 1, made in the form of a solution or gel, or plate, or sponge and containing 0.5-50% active ingredient.



 

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