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/kgTHE + 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.
FIELD: medicine, thoracic surgery, anesthesiology.
SUBSTANCE: as non-narcotic medicinal preparation one should apply heparin to be introduced intratracheally at the dosage of 300-500 IU/kg, moreover, heparin should be introduced during the first 30 min after the operation is over. The present innovation enables to create prolonged anesthetizing effect in combination with prophylaxis of postoperational thrombohemorrhagic complications due to heparin capacity to be kept in the body due to its accumulation by mast cells at blockade of their fermentative activity followed by its gradual release into the blood.
EFFECT: higher efficiency.
1 cl, 1 ex, 3 tbl
FIELD: chemistry of natural compounds, polymers.
SUBSTANCE: invention proposes a method for preparing low-molecular heparins from high-molecular heparins by the enzymatic fermentative depolymerization using the enzyme complex from Streptomyces kurssanovii immobilized on silochrome in the weight ratio heparin : immobilized enzyme = 1:1. Then suspension is stirred, the immobilized preparation is separated by centrifugation, washed out and washing liquid is combined with supernatant followed by desalting on column with Sephadex 6-10 and the obtained product is lyophilized.
EFFECT: improved preparing method, reduced cost of method.
FIELD: analytical methods in medicine.
SUBSTANCE: invention concerns hematological procedures and, in particular, can be used in heparin treatment practice. Method of invention is based on measuring rate of thrombin-mediated hydrolysis of a chromogenic substrate, thrombin having activity 0.5-0.6 unit/ml and chromogenic substrate being z-Ala0Ala-Arg-pNA·HBr.
EFFECT: extended assortment of home reagents, simplified preparation procedure, and increased sensitivity of method.
1 dwg, 3 tbl, 2 ex
FIELD: medicine, endocrinology, physiotherapy.
SUBSTANCE: the present innovation deals with introducing preparations of antioxidant, antiaggregate, antithrombotic and hypolipoedemic action as detralex and sulodexide along with the impact of low-intensity laser radiation (LILR) (at wave length of 0.97 mcm and power of 5-7 W). Moreover, LILR impact should be performed by contact since the 1st d of conservative therapy on projection of the main vessels of lower limbs in, at least, 2 o\points at every of them per 1-2 min/every point, and high-intensity laser radiation (HILR) impact should be carried out by contact-free technique from the distance of 1-3 cm for visually altered part of affected limb's skin in area of trophic disorders up to the border with intact tissue, beginning from toes towards talocrural joint and longitudinally towards knee joint, proximally up to the lower third of femur.
EFFECT: higher efficiency of therapy and decreased traumatism.
1 cl, 2 ex
FIELD: medicine, first aid, anesthesiology, resuscitation, surgery.
SUBSTANCE: along with conventional medicinal preparations applied to treat shock one should introduce crystalloids into central vein in certain sequence: 7.5% and 0.9%-sodium chloride solution, 5%-glucose solution, and, also, infucol and similar-group plasma; after stabilizing arterial pressure one should introduce, additionally, either mildronate, or dalargin at certain dosages. The present innovation enables to restore the volume of extracellular liquid in the shortest period of time at decreased volume of infusion that, in its turn, favors to remove shock and prevent other possible further complications.
EFFECT: higher efficiency.
FIELD: medicine, resuscitation.
SUBSTANCE: one should obtain the values on head's vertical position, pulmonary ventilation, efforts coming to organs of controlling and parameters of cabin's hermetic nature. A transport driver should get the information on irregular extreme situation, one should supply 100% oxygen. In case of acute respiratory insufficiency at the background of spontaneous respiration, in case of acute pain, high heart beating or gunshot wound it is necessary to perform additional electrostimulation of the muscles that actively participate in respiration act, with amplitude-frequency-modulated triangular series of impulses at impact duration being 1.5-2.0 sec at pause being about 3-4 sec. Moreover, electrostimulation should be combined with anesthesia performed due to automatic injection of medicinal preparation into biologically active point Tan'-Chzhun along with the intake of therapeutic dosage of an antiaggregant, a thrombolytic, a nitropreparation, beta-adrenoblocking agent and low-molecular heparin. Automatic pharmacoinjection should be conducted manually as a transport driver desired, and in critical situation - due to distance-controlled operation; moreover, injection should be fulfilled perpendicularly for the depth not exceeding 0.5-0.6 cm. The innovation increases the number of preparations applied in extreme situations to rescue a transport driver.
EFFECT: higher efficiency of rescue activity.
3 cl, 1 dwg
FIELD: medicine, surgery.
SUBSTANCE: one should perform Novocain blockade presacrally before operation and not less than one time after operation. Solution for blockade is being a 200 ml 0.25%-novocaine solution supplemented with 1.0 g antibiotic and 40 mg low-molecular heparin. The method enables to improve motor-evacuatory intestinal function, conduct microbiocenosis correction of small intestine, decrease the risk of the development of enterogenic purulent-septic complications, improve microcirculation and hemostasiological profile in mesenteric vessels of small intestine and its wall.
EFFECT: higher efficiency of therapy.
1 ex, 3 tbl
FIELD: medicine, phthisiology.
SUBSTANCE: for the purpose to treating tuberculosis it is necessary to carry out pathogenetic heparinotherapy at the background of antibacterial therapy, moreover, heparin should be introduced into tracheobronchial tree by inhalations or due to endobronchial spreading. Heparin dosage corresponds to 500-700 IU/kg. Introductions should be performed 3-6 times at 3-5-d-long intervals. The innovation enables to accelerate healing process, provide rapid regress of respiratory deficiency due to improving microcirculation in pulmonary tissue and bronchial drainage function in tuberculosis patients, in those with fibrous-cavernous tuberculosis, among them.
EFFECT: higher efficiency of therapy.
1 cl, 4 dwg, 1 ex, 2 tbl
SUBSTANCE: method involves making milled hole in Dandy point. Ventricular catheter is introduced into lateral cerebral ventricle, its distal end being connected to input opening of valve system. Venous mastoid outlet is exposed and externally threaded nipple is screwed to one half of its canal and filled with anticoagulation solution. Bone groove is manufactured in the vicinity of ventricular catheter bending, the catheter is laid into it and attached to dura mater. The valve system is connected to ventricular catheter distal end and to nipple outlet opening.
EFFECT: enhanced effectiveness of treatment; reduced risk of complications.
3 cl, 2 dwg
FIELD: medicine, pharmacology, pharmacy.
SUBSTANCE: invention relates to formulations comprising heparin as an active component and a base consisting of lipid and polymeric components for oral using. The lipid component is able preferably to enhance effect of the main component while the polymeric component possesses ability to dissolving or swelling, and at least part of the lipid component is incorporated into the polymeric matrix being in the molecular-dispersed state. Invention provides the sufficient complete absorption of active substance in digestive tract after its oral intake.
EFFECT: valuable properties of formulation.
9 cl, 2 dwg, 8 ex
FIELD: medicine, ophthalmology.
SUBSTANCE: the suggested ophthalmic composition contains ketothiphen salt, nonionic agent to regulate tonicity in the quantity that total tonicity of composition should correspond to osmolarity of 210-290 mOsm, a conserving agent, not obligatory, either acid or foundation to achieve pH value being slightly acid and water, moreover, if the mentioned conserving agent is not available, the concentration of ketothiphen salt should correspond to 0.01-0.04 weight%, or if the mentioned conserving agent is available, the concentration of ketothiphen salt should correspond to 0.01-0.03 weight%. As ketothiphen salt the suggested composition contains ketothiphen fumarate; tonicity should be controlled with nonionic agent - glycerol.
EFFECT: more prolonged action of the composition suggested.
15 cl, 2 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to a liquid pharmaceutical composition comprising pegilated erythropoietin as a conjugate in pharmaceutically acceptable buffer at pH from 5.5 to 7.0 and optionally one or some pharmaceutically acceptable excipients. Proposed composition is used in treatment and prophylaxis of diseases associated with erythropoiesis injury. The advantage of invention involves enhancing stability of the preparation.
EFFECT: improved and valuable property of preparation.
59 cl, 4 tbl, 11 dwg, 13 ex
SUBSTANCE: the present innovation deals with stable peroral solid composition of ramosetron or its pharmaceutically acceptable salt. The composition includes one or several components chosen out of the groups including aliphatic carboxylic acid or its ester, hydroxycarboxylic acid or its ester, acidic amino acid, enolic acid, aromatic carboxylic compound or its ester and high-molecular substance that contains carboxylic group. Such an innovation refers to the method for stabilizing ramosetron composition. The suggested innovation provides stability of ramosetron composition under conditions of increased temperature and humidity, especially at low content of active component.
EFFECT: higher efficiency of application.
14 cl, 10 ex, 6 tbl
SUBSTANCE: invention relates to a liquid composition used for recovery of hair growth. The composition comprises minoxidil and arginine in liquid mixture of water and alcohol and an agent used for prevention of development of coloring in the minoxidil-containing liquid preparation by effect of heat. Also, invention relates to a method for prevention of development of coloring in the minoxidil-containing liquid composition by effect of heat. Invention provides prevention of development of coloring in the minoxidil-containing liquid preparation by effect of heat with time, good stability in storage and the improved commercial value.
EFFECT: improved and valuable cosmetic properties of composition.
6 cl, 4 tbl, 9 ex
FIELD: organic chemistry, pharmacy, pharmacy.
SUBSTANCE: invention relates to novel compounds designated for delivery of active substances to tissues of the following formula: wherein values of radicals R1-R7 are determined in claim 1 of the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to compositions designated for delivery of active substances to tissues and containing: (A) active substance and (B) at least one compound designated for delivery of active substance to animal tissues of the formula: wherein values of radicals R1-R7 are determined in claims 3-5 of the invention claim. Also, proposed invention relates to a standard medicinal formulation designated for delivery of active substances to body tissues and to a method for preparing indicated compositions and administration of substances for their delivery to body tissues.
EFFECT: valuable properties of compounds.
23 cl, 11 tbl, 11 ex
FIELD: medicine, polymeric materials, pharmacy.
SUBSTANCE: invention describes biomaterial as a deposit comprising at least one suitable anion-active polymeric water-soluble component and amphiphilic component of ammonium type comprising a cationic surfactant. Deposit is prepared in the following steps: (1) contacting anion-active polymeric component and cyclodextrin component in aqueous medium, and (2) addition of the above said amphiphilic component of ammonium type to mixture prepared in the step (1) wherein components are taken in amounts providing formation of above said deposit. Biomaterial is used for preparing a depot-composition with regulated release and acceptable for prolonged feeding pharmaceutical substances. Also, invention describes a medicinal agent comprising biomaterial and representing a sheet material or film for closing and healing wounds, or surgery thread, and medicinal implant, or insert comprising the preliminary molded biomaterial.
EFFECT: improved preparing method, valuable properties of material.
27 cl, 34 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to drugs and concerns a pharmaceutical composition used for treatment or control of bacterial infections. Compositions used by parenteral administration route comprises the effective amounts of (a) piperacillin or its pharmaceutically acceptable salt; (b) tazobactam or its pharmaceutically acceptable salt, and (c) at least one chelate-forming agent chosen from group consisting of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), O,O'-bis-(2-aminoethyl)-ethylene glycol-N,N,N',N'-tetraacetic acid (EGTA), trans-1,2-diaminocyclohexane-N,N,N',N'-tetraacetic acid (CyDTA), and their pharmaceutically acceptable salts. Also, invention proposes a method for preparing a pharmaceutical composition to be subjected for dilution. Use of a chelate-forming agent in the combination piperacillin/tazobactam provides inhibition of formation of particles in its mixing with aminoglycoside antibiotics.
EFFECT: improved and valuable pharmaceutical properties of composition.
62 cl, 1 tbl
SUBSTANCE: invention refers to solution applied for nails and periungual area, containing agents improving active agent permeability. Solution for nails and periungual area includes mixed agents improving active agent permeability, including, at least, urea and ethoxydiglycol, containing urea and ethoxydiglycol in certain amounts. Nonaqueous solution for nails and periungual region includes mixed agents improving active agent permeability, urea including, at least, urea and lactic acid containing urea and lactic acid in certain amounts.
EFFECT: application of solution for nails and periungual area improving permeability active agent, for medical product intended for fungoid pathologies treatment, eg onychomycosis; solutions described above effectively improve active agent permeability and treat fungoid pathologies.
9 cl, 11 ex
FIELD: medicine; pharmacology.
SUBSTANCE: application of Sodium citratum dihydrate or potassium Citras dihydrate, or Sodium hydrogenum or bicarbonate of potassium, carbonate of sodium, arginine or their admixture as the antibiotic stabiliser fosfo-mitsina tromethamole, and their pharmaceutical structures for granulating is proposed. The invention allows for lowering destruction reaction of tromethamole fosfomicin in granulate by 35-70% (which provides stability of structure ready to use), and also in the presence of a gastric juice.
EFFECT: possess improved efficiencyof the structures.
8 cl, 3 ex