Pharmaceutical combination of atorvastatin and nicergolin for preventing or treating cerebrovascular disease

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for the correction of cerebrovascular disease accompanying cardiovascular diseases which contains the active ingredients presented by atorvastating or pharmaceutically acceptable salt thereof and nicergolin in the therapeutically effective amounts.

EFFECT: pharmaceutical composition is characterised by high stability and bioavailability.

8 cl, 8 tbl, 3 ex

 

The present invention relates to pharmaceutical compositions and combinations for the treatment of disorders of cerebral circulation.

Ischemic stroke is a major medical and social problem in our country. Brain disease - a leading cause of morbidity, mortality and disability. In Russia annually about 400-450 thousand of stroke, of which up to 200 thousand fatal and surviving patients at least 80% remain with disabilities of varying severity [Gusev E.I., Geht A.B. 2005].

Factors that contribute to the development of vascular diseases of the heart and brain, are the conditions of modern life, especially ecological imbalance, urbanization and accelerated pace of life, the nervous tension, ending with stress in work processes, insufficient physical activity, increased incidence of diabetes, particularly modern nutrition, excess alcohol consumption.

More and more children and young people in the United States fall in the number of victims of stroke, the incidence of stroke among persons aged 5-44 years less than 10 years has increased by approximately one third. At the same time the survivors of stroke, usually noted high blood pressure, diabetes, and obesity. According to the American heart Association, satr who you are on the medical care of stroke patients are 13.5 billion dollars a year.

Thus, prevention, treatment and rehabilitation of cerebrovascular pathology are presented not only a medical problem, but a medical social importance to the state and its economy.

The main reasons for the band and strokes (Lindsay DOE, Zhur. "The doctor" 9/1999).

TNMK (transit ischemic stroke)/cerebral infarctionPrimary intracerebral hemorrhage
Atherosclerosis of large arteries.Hypertension (usually in the basal ganglia, the bridge and the cerebellum).
Cardioembolism.
Atherosclerosis of small arteries.Aneurysm.
Unidentified (for example, if there are two or more possible causes).Malformation of the blood vessels.
Cerebral amyloid angiopathy.
Other (e.g., vasculitis, blood diseases).Abnormalities in the coagulation system.

Analyzing 26 statin trials (95000 patients) can make conclusion is, the risk of stroke when their appointment is reduced from 3.4% to 2.7% [Amarenco p, Labreuche J., Lavallee p, Touboul P.: Statins in stroke prevention and carotid atherosclerosis: Systematic review and up-to-datemeta-analysis. Stroke 2004; 35: 2902-2909]. For the most part, this is due to the reduction of risk, the so-called "non-fatal strokes" from 2.7% to 2.1%. Review included the results of the Heart Protection Study which assessed the results of the effectiveness of statins in secondary prevention [Heart Protection Study Collaborative Group: Mrc/bhf heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002; 360: 7-22]. This study revealed myopathy in one additional patient per 10,000 treated patients per year [Heart Protection Study Collaborative Group: Mrc/bhf heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002; 360: 7-22].

The first study showed a significantly lower rate of stroke with statins in patients without coronary heart disease (CHD), became ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm). In this study, 10305 patients with arterial hypertension without coronary heart disease (CHD), at the same time, with at least 3 risk factors for coronary heart disease, in addition to hypertension were randomized to receive 10 mg of atorvastatin (hypolipidemic agent) or placebo. 90% not identified cerebrovascular diseases in history. The use of atorvastatin in dose mg lowered LDL cholesterol levels by 29% compared with placebo (3.4 mmol/l [131 mg/DL] to 2.3 mmol/l [89 mg/DL]) and was associated with a reduction of 27% frequency of fatal or nonfatal stroke (95% CI 4-44; p=0,024).

It is known that diabetes mellitus is a severe cause of the risk of stroke. The study CARDS (Collaborative Atorvastatin Diabetes Study) 2838 patients with diabetes, with at least one risk factor for cardiovascular disease, and without the presence of cardiovascular disease or stroke in history were randomized to receive 10 mg of atorvastatin or placebo. The development of fatal or nonfatal stroke was observed in 21 patients in the atorvastatin group, compared with 39 in the placebo group, which corresponds to a relative risk reduction of stroke by 48% (95% CI 11-69; p=0,016). The average difference in the concentration of LDL cholesterol between groups was 1.2 mmol/l (46 mg/DL). In these previous studies would suggest that this difference would correspond to a reduction in the risk of stroke by approximately 25%, but the rate of decrease in risk in the study CARDS was nearly two times higher, although the 95% CI and included the value of 25%. Due to clearly demonstrated the benefits of using statins in patients with diabetes American heart Association and the Council of the American stroke Association in 2006 issued recommendations that reduce the risk of stroke for patients with diabetes, especially in the presence of other risk factors for cardiovascular diseases, with whom edue to prescribe statin treatment along with careful control of arterial hypertension.

Unlike HPS and other studies of statins, in which the primary goal was to evaluate the impact of statins on the incidence of clinically evident coronary heart disease, and stroke was a secondary endpoint, the study aims SPARCL (Stroke Preventionby Aggressive Reductionin Cholesterol Levels) was to study the effect of intensive statin therapy to reduce the risk of recurrent stroke.

Thus, we can conclude that the use of atorvastatin significantly improves the clinical picture of circulatory disorders, including cerebral circulation.

Nicergoline - derived substance from the ergot alkaloid, exhibits al-adrenoceptor blocking action. therapeutic efficacy of Nicergoline armywide two main pharmacological properties: 1) α-adrenoceptor blocking action - reducing vascular resistance, increase blood flow, improve blood circulation to the brain and other tissues, and 2) increases the activity of noradrenergic, dopaminergic and acetylcholinergic systems and thus a direct effect on cerebral neurotransmitter system.

In the action of nicergoline are important neurotransmitter effects. Nicergoline affects cholinergic processes in the nervous tissue. The weakening of the cholinergic neuromedicine is now the AK key player in the development of age-related memory disorders, cognitive functions in the pathogenesis of various neurodegenerative brain diseases. Nicergoline increases the synthesis of acetylcholine by activating cholineacetyltransferase, increases the release of acetylcholine from the presynaptic terminala, reduces the breakdown of acetylcholine by inhibiting acetylcholinesterase, also normalizes the content of postsynaptic M-cholinergic receptors in the Central nervous system. Nicergoline stimulates the reuptake of glutamate and prevents the development mediated by glutamate is neurotoxic effects during hypoxia exerts anti-apoptotic action, is antioxidant effects, stimulates the formation of nerve growth factor, the so-called neurotrophic effect, contributing to the preservation of cholinergic neurons, regulates the metabolism of calcium in the nervous tissue.

Contained in the molecule of nicergoline the rest of nicotinic acid has a direct myotropic antispasmodic effect on the muscle membrane resistance vessels, increases their permeability to glucose, with the most pronounced in relation to cerebral blood vessels and extremities.

Examining our own clinical experience, the experience of colleagues and literary sources, the authors assumed that professionals dealing with violations of cerebral circulation, which there is no remedy, that would have taken several properties that the authors can not only complement each other in their therapeutic effect, but also to be safe to use, as well as mutually potentiate multidirectional therapeutic effect of each, leading to a pronounced positive clinical outcome, with specific pathological situations.

Conducted a number of experiments to confirm or refute the alleged concepts.

Experiment 1 Determination of the severity of lipoidosis aorta.

Studies performed on rats male Wistar rats weighing 180-220, Experimental atherosclerosis induced by the feeding of animals with 1%cholesterol diet for 14 weeks. The diet consisted of 100 g/day atherogenic food and 60 g of a standard feed. Experimental group from the first day of experience on the background of atherogenic feed were treated orally with a combination of Atorvastatin (1 mg) + Nicergoline (1 mg)". The control group And received only atherogenic food, control group B consisted of intact animals. Conducted two series of experiments.

Carried out the euthanasia of animals by overdose of local anesthetic novocaine. Before that, the animals were fasted 18 hours.

Peeled aorta of rats were fixed in 10% solution of buffered formalin. Next, stained, etc who drove the layout. The extent of atherosclerotic lesions was determined in the aorta as a whole and in its three departments: the aortic arch, thoracic and abdominal.

The severity of atherosclerotic lesions was estimated percentage of square areas lipoidosis to the total area of the vessel or Department.

Statistical comparison of data was performed using two sample t-test t-test with different dispersions.

The results of the study:

The average percentage of lesions in the group of rats treated only cholesterol was 27.6±3.9%and in the group of rats treated with the investigational substance - 18.9±5.8%. A significant decrease in atherosclerotic lesions of 37% was observed in the aortic arch.

Table 1
Group% of lesion (M±m)
The entire aortaArch of aortaThoracic vertebraeAbdominal Department
"The control group And n=1027.6±3.943,4±6,121,7±4,718,6±3,8
"Experimental group n=1118.9±5.826,1±5,2 13,7±5,115,2±6,8

Experience 2. Assessment of therapeutic efficacy

The study was conducted on adult mice and adult rats male line Sprague-Dawley weighing 200-220 g, were grown in the nursery RAS "Rapolano".

Before the experiment, animals were subjected to 14-day quarantine. Experimental atherosclerosis induced by the feeding of animals with 1%cholesterol diet for 14 weeks. The diet consisted of 100 g/day atherogenic feed, 60 g of the standard feed. Experimental group from the first day of experience on the background of atherogenic feed were treated orally with a combination of Atorvastatin (1 mg) + Nicergoline (1 mg)". The control group consisted of intact animals (n=11), control group B (n=10) received only the atherogenic diet.

Model of acute circulatory hypoxia (gravitational overload). Longitudinal gravitational overload created by the centrifuge, lead to infringement of brain blood flow, the nature of which depends on the magnitude, duration and direction of radial accelerations. When the cranio-caudal vector of accelerations or so-called positive radial acceleration is the movement of blood in the caudal direction, which leads to ischemia in the brain tissue as a result of the fall in blood pressure in the vascular pool brain.

Qi is kastornoe hypoxia was simulated using gravitational overloads in the cranio-caudal direction. The value of the gravitational overloads were made so that the mortality of animals (mice-males) in the control group was close to 50%. The value of the gravitational overloads equal to 18 g for 10 minutes. The gradient of increase and decrease of the load was between 0.30 to 0.33 g per second [Methodical recommendations for a pilot study of drugs proposed for clinical studies as antihypoxic funds / Approved by FC the USSR Ministry of health 11.04.90,, order No. 7), 1990, to 18 C.].

The results of the studied drugs on the stability of mice males to circulatory hypoxia (gravitational overload) are presented in table 2.

Table 2
Study medicationDose, mg/kgSurvival (% to total)
Control group a40
Control group B<15*
Experienced group1 mg + 1 mg>70*
Note: * p≤0.05 compared to control

Presents the data is in the table show, that the introduction of an investigational combination has led to increased survival of animals compared with the control groups of animals, indicating the presence of therapeutic activity in conditions of induced ischemia cerebral blood vessels, caused by the gravitational overloads on the background of artificial atherosclerotic process.

After this has been verified the hypothesis about the possibility of reducing the effective dosage of the combinations of therapeutic agents. The study was held by titration of doses. Thus the investigated groups of animals were smaller, the number of animals in the group was 4.

Table 3
Study medicationDose, mg/kgSurvival (% to total)
Atorvastatin + Nicergoline1 mg + 1 mg>70*
Atorvastatin + Nicergoline0.8 mg + 0.8 mg<65*
Atorvastatin + Nicergoline0.5 mg + 0.5 mg<55*
Atorvastatin + Nicergoline0,3mg + 0.3 mg <50*

Experience 3. The study of therapeutic effects of acute circulatory disorders in the studied combinations in terms of local cerebral ischemia in rats, induced by bilateral occlusion of common carotid arteries in the background of artificial atherosclerotic process.

The experiments were performed on rats, which was modeled local ischemia by total ligation of the carotid arteries. Each group consisted of 9 survivors after surgery animals. As a positive control was used Nimodipine (INN) "Nimotop"™, as a vasodilator used in acute disorders of cerebral circulation.

In each group, after the beginning of the introduction of the studied solutions were killed and 1 rat. In the control group of intact animals, the death of the animal came within 1-2 minutes. In the treatment group Nimodipine animal died after the 1st hour after the start of treatment, the group receiving the combined preparation - 2 hours after the end of therapy.

One common focal neurological symptoms indicative of acute ischemia of the brain, is the development of ptosis. Table 4 shows that in animals, which was modeled acute local ischemia and not receiving treatment, developed ptosis of one eye in 75% of cases, the use of schemas combination led to a significant reduction in the percentage of animals with such violation.

Table 4
The experimental groupThe number of rats with ptosis
The control (intact animals)5/9 - 55%
Control (atherogenic diet)7/9 - 77,8%*
Nimodipine (INN) "Nimotop"™5/9 - 55%*
Atorvastatin (INN)4/9 - 44.4%*
Atorvastatin + Nicergoline3/9 - 33.3%*
Note: * p≤0.05 compared to control

Table 4
Data of neurological tests in points
The experimental groupNeurological status (M±m, points)
The control (intact animals)56,75±0.27
Control (atherogenic diet)58,60±0.34
Nimodipine (INN) "Nimotop"™Atorvastatin55,90±0.24
Atorvastatin + Nicergoline54,87±0.23

Table 5
Vegetative indicators indicators of Change in the respiratory system and rectal temperature in rats
The experimental groupRespiratory rate, min-1M±mRectal temperature (M±m °C)
The control (intact animals)85.6±12.637.8±0.3
Control (atherogenic diet)79.9±9.536.1±0.2
Nimodipine (INN) "Nimotop"™99.6±4.9*36.7±0.1*
Atorvastatin97.6±5.1*36.9±0.4*
Atorvastatin + Nicergoline110.7±5.7*37.4±0.I*
Note: * - p≤0.05 in respect of the control

In animals treated with a combination of vegetative indicators, such as respiratory rate and body temperature were significantly higher than in rats of the control group. This characterizes the recovery of thermoregulation and respiration (the level of performance in this case did not go beyond the generalized control standards and data of their own research). In the group Nimodipina (INN) and Atorvastatin changes the recorded data were somewhere in-between.

Table 6 presents the intervals of normal values of some vegetative indices in outbred rats (own research results):

Table 6
IndexThe average value X95% confidence interval of the true mean valueThe number of animals
M=x±t95*mx
T, °C37,437,3 of 37.5215
BH, min-1115111-119197

As the trail of the t presented in the table 6 data in animals with brain ischemia, there was a sharp decrease in locomotor and exploratory activity. Introduction and Nimodipina, and study the combination led to a change in the behavior of rats in the "open field" in the direction of activation compared to animals not receiving treatment. Rats were observed normalization of the duration of the latent period of the output in the center of the field and the number of zaglyadyvanie in mink.

Histological data serial frontal sections of the brain of animals from the control groups showed that the brain krovosnabjaemah branches of the middle cerebral artery has been most pronounced pathological changes in the frontal and parietal Department cerebral cortex and was characterized by wrinkling and hyperchromia neurons with initial crimp apical appendages.

To differentiate nuclear-cytoplasmic complex was impossible. Changes were widespread, with the inclusion of all nerve cells I, II and III of the layers. In subcortical (caudate nucleus, the outer third of the pale Orb) there was relatively no significant changes, as expressed by chromatolysis, and vacuolization of the cytoplasm of some neuronal cells. The cells were fixed pronounced swelling. There are isolated cases of neuronophagia. The average histological ball was equal to 2.6±0,3.

Note the imposition of the combination referatov of the drug and the combination has had a beneficial effect on brain structures. For example, in the frontal, parietal parts of the cerebral cortex hyperchromic wrinkling is observed only from the pyramidal cells of layer III. The neurons of the caudate nucleus was characterized by only weak changes. The average histological score of the group Nimodipina and combinations amounted to 1.7±0,18.

It was also found that adding in the claimed combination of Hydrochlorothiazide 0.5 mg to 1.5 mg improved neurological tests and histological data.

The objective of the invention is the creation of an effective pharmaceutical combination, improve the quality of life of patients, a reduction in the incidence of disability, expanding Arsenal of medicines, which has a complex effect in vascular disorders, detection and identification of therapeutic effectiveness of the combination.

To solve this problem was developed pharmaceutical composition comprising atorvastatin or its pharmaceutically acceptable salt, nicergoline and excipients, which allow producing means in the form of tablets.

As the target additives used lactose, potato starch, microcrystalline cellulose, kollidon and magnesium stearate in the following ratio, wt.%:

Atorvastatin2,0-5,5
Nicergoline2,0-5,5
Lactose47,0-51,5
Potato starch140-15,5
Microcrystalline celluloseof 20.0 to 23.5
Kollidon4.0 to 4.5
Magnesium stearate0,5-2,5

Thus, the authors were able to obtain an example of a pharmaceutical composition having good processing properties in the process of granulation and tableting. While tablets have properties that satisfy the requirements of the pharmaceutical agent. Namely, have the appearance, possess sufficient strength and raspadaemost, are stored for at least 2 years, we provide high clinical effect, convenient dosage and high bioavailability of its components.

A new pharmaceutical composition may be in the form of solid dosage forms coated, preferably in the form of a tablet, but not necessarily. The presence of a shell of the claimed composition gives, first, the stability of the composition during storage, and secondly improves its appearance and organoleptic properties.

As the shell serves composition based on polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable dyes or ready-mix brand "Opadry II".

Also the claimed pharmaceutical composition may be made in the form of capsules.

The most common ways of obtaining tablets are three technological scheme: wet granulation, dry granulation and direct pressing (Technology of medicinal forms / edited by Ivanova L.A. - M.: Medicine, 1991, vol. 2, p.142).

1. Pharmaceutical composition for correction of disorders of cerebral circulation in diseases of the cardiovascular system, characterized by the fact that as the active component contains atorvastatin or its pharmaceutically acceptable salt, nicergoline in therapeutically effective amounts.

2. The pharmaceutical composition according to claim 1, characterized in that as the target additives contains lactose, potato starch, microcrystalline cellulose, kollidon, magnesium stearate in the following ratio of ingredients, wt.%:

Atorvastatin2,0-5,5
Nicergoline2,0-5,5
Lactose 47,0-51,5
Potato starch14,0 is 15.5
Microcrystalline celluloseof 20.0 to 23.5
Kollidon4.0 to 4.5
Magnesium stearate0,5-2,5

3. The pharmaceutical composition according to claim 1, characterized in that the mammal is man.

4. The pharmaceutical composition according to claim 1, characterized in that it further comprises a therapeutically effective amount of hydrochlorothiazide.

5. The pharmaceutical composition according to claim 2, characterized in that it is made in the form of solid dosage forms.

6. The pharmaceutical composition according to claim 5, characterized in that it is made in the form of coated tablets.

7. The pharmaceutical composition according to claim 6, characterized in that the shell contains polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable dyes or ready-mix brand "Opadry II".

8. The pharmaceutical composition according to claim 2, characterized in that it is made in the form of capsules.



 

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12 cl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely a stable pharmaceutical composition of a water-soluble salt of vinorelbine. The composition contains approximately 56 wt % of a diluent, approximately 2.5 wt % of a binding agent, approximately 5 wt % of a disintegrant, approximately 0.25 wt % of a flow agent and approximately 0.5 wt % of a lubrication agent. The water-soluble salt of vinorelbine is preferentially vinorelbine ditartrate.

EFFECT: pharmaceutical composition is preferentially presented in the form of a gelatine capsule or a tablet.

5 cl, 6 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition applicable for oral administration contains an S1P receptor agonist and mannitol with the composition representing a solid dosage form. Mannitol has a particle specific surface area 1 to 7 m2/g, and the S1P receptor agonist is specified from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), its pharmaceutically acceptable salt and FTY720-phosphate.

EFFECT: compositions under the invention are characterised by a high level of distribution uniformity of said S1P receptor agonist, and applicable for oral administration in the solid dosage form, eg in the form of a tablet or a capsule.

14 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method for preparing a pharmaceutical composition consists in mixing an S1P receptor agonist - 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt with sugar alcohols; the mixture is milled and/or granulated, and then mixed with an oil agent. The method under invention is implemented on high-speed automated equipment and enables producing the compositions with high-level distribution uniformity of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

EFFECT: preparing the pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

15 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating and/or preventing depressions. The pharmaceutical composition contains an active substance presented by a selective serotonin reuptake inhibitor (SSRI) specified in a group of fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine differing by the fact that as an active substance, it additionally contains N-acetyl-5-methoxytryptamine (melatonin) in the following proportions, mg: selective serotonin reuptake inhibitor (SSRI) - 10-30 mg, melatonin - 3-8 mg. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a capsule, by a soft dosage form - a rectal suppository.

EFFECT: pharmaceutical composition provides treating depressions and has a number of additional therapeutic properties: easing falling asleep and relieving sleeping disorders, recovering circadian rhythm and seasonal rhythm with reducing a risk of side effects of SSRI.

3 cl, 14 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention describes a method for stabilising a sensitive ingredient for biological absorption in the oral intake in a therapeutic composition involving the stages of combining pregelatinised starch with at least one sensitive ingredient, and mixing the sensitive ingredient with pregelatinised starch. Pregelatinised starch is used in the amount of 5% to 80% of composition weight. The sensitive ingredient is specified in vitamin C, phenylephrine and their combinations. The sensitive ingredient is used in the amount of 0.1% to 20% of composition weight. Said sensitive ingredient is uniformly distributed in pregelatinised starch and adsorbed on pregelatinised starch.

EFFECT: stability of said sensitive ingredients and maintenance of their activity and availability for biological absorption in the oral intake of the therapeutic composition.

17 cl, 15 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns a pharmaceutical composition containing cholest-4-en-3-one oxime and oil specified in sesame oil, olive oil, soya oil, cottonseed oil or mixed medium-chain triglycerides (ESTASAN®, MYGLIOL®) or mixed oils, preferentially sesame oil, olive oil and soya oil, more preferentially sesame oil.

EFFECT: invention ensures chemical stability of the dosage form, higher concentration of the solubilised active ingredients, higher biological availability of the active ingredient.

6 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a stable pharmaceutical composition for treating cancer containing a water-soluble salt of vinflunine ditartrate and at least one diluent, one binding substance, one aerating agent and one lubricating agent wherein the composition is presented in a solid form for oral application wherein: the content of the water-soluble salt of vinflunine ditartrate makes 5 to 80 wt %, the content of the diluent makes 20 to 80 wt % of total weight of the composition, the content of the binding substance makes 1 to 10 wt % of total weight of the composition, the content of the lubricating agent makes 0.5 to 10 wt % of total weight of the composition, the content of the aerating agent makes 1 to 10 wt % of total weight of the composition.

EFFECT: invention provides storage stability at 5°C for 24 months in a sealed package.

19 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a solid dispersion wherein revaprazan particles are surface-modified by a water-soluble polymer, a water-soluble saccharide, a surfactant or their mixture wherein the water-soluble polymer is specified in a group consisting of polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, a water-soluble polyacrylic acid copolymer, polyvinyl alcohol or their mixture, and wherein the water-soluble saccharide is specified in a group consisting of lactose, white sugar, saccharose, mannitol, sorbitol, xylitol, trehalose, maltitol, dulcitol, inositol, dextrin, cyclodextrin and their mixture. The invention also refers to a method for preparing said solid dispersion. The present invention also presents a pharmaceutical composition containing the solid dispersion, and the method for producing the pharmaceutical composition.

EFFECT: invention provides improved solubility of revaprazan and reduced adhesion and agglutination properties.

16 cl, 4 dwg, 7 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns a pharmaceutical composition for prevention and treatment of thrombosis, containing (A) N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazol[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethandiamine, its pharmaceutically acceptable salt or hydrate, (B) sugar alcohol which is mannitol, xylitol or erythritol, and (C) a water-swellable additive.

EFFECT: composition has higher water solubility.

18 cl, 8 dwg, 4 tbl, 4 ex

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