RU2481124C1 - Pharmaceutical combination of atorvastatin and nicergolin for preventing or treating cerebrovascular disease - Google Patents

Abstract

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

Description

The present invention relates to pharmaceutical compositions and combinations for the treatment of cerebrovascular diseases.

Disturbance of cerebral circulation is the most important medical and social problem in our country. Brain diseases are a leading cause of morbidity, mortality and disability. About 400-450 thousand cerebral strokes are registered annually in Russia, of which up to 200 thousand are fatal, and of the surviving patients, at least 80% remain disabled of varying severity [Gusev E.I., Gekht AB 2005].

Factors that contribute to the development of vascular diseases of the heart and brain are the conditions of modern life, primarily environmental imbalance, urbanization and acceleration of the vital rhythm, nervous tension, which leads to overstrain in labor processes, inadequate motor activity, an increase in the incidence of diabetes mellitus, and features of modern nutrition, excess alcohol consumption.

More and more children and young people in the United States are among those affected by stroke, the frequency of strokes among people aged 5-44 years in less than 10 years increased by about a third. At the same time, people who survived a stroke usually had high blood pressure, diabetes and obesity. According to the American Heart Association, the cost of medical care for stroke patients is $ 13.5 billion per year.

Thus, the prevention, treatment and rehabilitation of cerebrovascular pathology is not only a medical task, but also a medical and social one, which is important for the state and its economy.

The main causes of TNMC and strokes (according to Lindsay Dow, journal. "The attending physician" 9/1999).

TNMK (cerebrovascular accident) / cerebral infarction Primary intracerebral hemorrhage Atherosclerosis of the large artery. Hypertension (usually in the basal ganglia, bridge and cerebellum). Cardioembolism. Atherosclerosis of the small arteries. Aneurysm. Unidentified (for example, if there are two or more possible causes). Vascular malformation. Cerebral amyloid angiopathy. Others (e.g., vasculitis, blood diseases). Violations in the coagulation system.

After analyzing 26 studies of statins (a total of 95,000 patients), it can be concluded that the risk of developing stroke when prescribed 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 a reduction in risk, the so-called Non-fatal strokes from 2.7% to 2.1%. The review included Heart Protection Study results that evaluated statin efficacy 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 randomized 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 randomized placebo-controlled trial. Lancet 2002; 360: 7-22].

The first study to show a significant decrease in stroke frequency with statins in patients without coronary heart disease (CHD) was ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm). In this study, 10305 patients with arterial hypertension, without coronary heart disease (CHD), while having at least 3 risk factors for CHD, in addition to arterial hypertension, were randomized to receive 10 mg of atorvastatin (a lipid-lowering drug) or placebo. 90% did not have a history of cerebrovascular disease. The use of atorvastatin at a dose of 10 mg led to a decrease in LDL cholesterol by 29% compared with placebo (from 3.4 mmol / L [131 mg / dl] to 2.3 mmol / L [89 mg / dl)) and was associated with a 27% decrease in the frequency of fatal or nonfatal stroke (95% CI 4-44; p = 0.024).

It is known that diabetes is a pronounced cause of stroke risk. In the CARDS (Collaborative Atorvastatin Diabetes Study) study, 2,838 patients with diabetes, at least one risk factor for cardiovascular disease, and without a history of cardiovascular disease or stroke were randomized to receive 10 mg of atorvastatin or placebo. Fatal or non-fatal stroke developed in 21 patients in the atorvastatin group compared with 39 in the placebo group, which corresponds to a 48% reduction in the relative risk of stroke (95% CI 11-69; p = 0.016). The average difference in LDL cholesterol concentration between the groups was 1.2 mmol / L (46 mg / dl). Based on the results of previous studies, it could be assumed that such a difference would correspond to a reduction in the risk of stroke by approximately 25%, however, the risk reduction rate in the CARDS study was almost two times higher, although 95% CI included a value of 25%. In connection with the clearly demonstrated benefits of using statins in patients with diabetes, the American Heart Association and the Council of the American Stroke Association issued recommendations in 2006 that, in order to reduce the risk of stroke, patients with diabetes, especially in the presence of other cardiovascular risk factors vascular diseases, statin treatment should be prescribed along with close monitoring of arterial hypertension.

Unlike HPS and other statin studies, in which the primary goal was to assess the effect of statins on the incidence of clinically evident coronary artery disease and stroke was a secondary endpoint, the goal of the SPARCL study (Stroke Preventionby Aggressive Reductionin Cholesterol Levels) was to study the effect of intensive statin therapy on reduced risk of re-stroke.

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

Nicergoline - a derivative of the ergot alkaloid, exhibits al-blocking effect. The therapeutic efficacy of Nicergoline is formed by two main pharmacological properties: 1) α-adrenergic blocking effect - reduction of vascular resistance, increased arterial blood flow, improved blood supply 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 systems.

In the action of nicergoline, its neurotransmitter effects are important. Nicergoline affects cholinergic processes in the nervous tissue. The weakening of cholinergic neuromediation is currently considered as a leading link in the development of age-related memory impairments, cognitive functions, and in the pathogenesis of various neurodegenerative diseases of the brain. Nicergoline increases the synthesis of acetylcholine by activating cholinacetyl transferase, increases the release of acetylcholine from presynaptic terminals, reduces the breakdown of acetylcholine by inhibiting acetylcholinesterase, and also normalizes the content of postsynaptic M-cholinergic receptors in the central nervous system. Nicergoline stimulates the reuptake of glutamate and prevents the development of glutamate-mediated neurotoxic effects during hypoxia, has an anti-apoptotic effect, exhibits 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.

The nicotinic acid residue contained in the nicergoline molecule has a direct myotropic antispasmodic effect on the muscle membrane of resistive vessels, increases their permeability to glucose, and is most pronounced in relation to the vessels of the brain and limbs.

Having studied their own clinical experience, the experience of colleagues and literary sources, the authors made the assumption that specialists dealing with cerebrovascular disorders have no drug that would contain several properties at the same time, which, according to the authors, can not only complement each other in its therapeutic effect, but also be safe to use, as well as mutually potentiate the multidirectional therapeutic effect of each, leading to a pronounced positive the clinical result, with a specific pathological situation.

A series of experiments have been conducted to confirm or refute the alleged concepts.

Experience 1 Determination of the severity of aortic lipoidosis.

Studies were performed on male Wistar rats weighing 180-220 years. Experimental atherosclerosis was induced by feeding the animals a 1% cholesterol diet for 14 weeks. The diet included 100 g / day of atherogenic food and 60 g of standard compound feed. The experimental group from the first day of the experiment against the background of atherogenic food received the oral combination “Atorvastatin (1 mg) + Nicergoline (1 mg)”. Control group A received only atherogenic food, control group B consisted of intact animals. Two series of experiments were carried out.

The animals were euthanized by an overdose of a local novocaine anesthetic. Before this, the animals were starving for 18 hours.

The purified rat aorta were fixed in a 10% buffered formalin solution. Then stained and planimetric. The degree of atherosclerotic lesion was determined in the aorta as a whole and in its three departments: the aortic arch, the thoracic and abdominal.

The severity of atherosclerotic lesions was assessed by the percentage of the area of the zones of lipoidosis to the total area of the vessel or department.

Statistical comparison of the data was performed using two sample t-student test with different variances.

The results of the study:

The average percentage of lesions in the group of rats receiving only cholesterol was 27.6 ± 3.9%, and in the group of rats receiving the test substance, 18.9 ± 5.8%. A significant decrease in atherosclerotic lesion by 37% was observed in the aortic arch.

Table 1 Groups % lesion (M ± m) Whole aorta Aortic arch Thoracic department Abdominal "Control group A" n = 10 27.6 ± 3.9 43.4 ± 6.1 21.7 ± 4.7 18.6 ± 3.8 "Experimental group" n = 11 18.9 ± 5.8 26.1 ± 5.2 13.7 ± 5.1 15.2 ± 6.8

Experience 2. Evaluation of therapeutic efficacy

The study was conducted on sexually mature mice and sexually mature male rats of the Sprague-Dawley line with a body weight of 200-220 g grown in the Rappolovo nursery.

Before the experiment, the animals were quarantined for 14 days. Experimental atherosclerosis was induced by feeding the animals a 1% cholesterol diet for 14 weeks. The diet included 100 g / day of atherogenic food, 60 g of standard compound feed. The experimental group from the first day of the experiment against the background of atherogenic food received the oral combination “Atorvastatin (1 mg) + Nicergoline (1 mg)”. Control group A consisted of intact animals (n = 11), control group B (n = 10) received only an atherogenic diet.

Model of acute circulatory hypoxia (gravitational overload). The longitudinal gravitational overloads created by the centrifuge lead to impaired blood circulation of the brain, the nature of which depends on the size, duration and vector of radial accelerations. With the cranio-caudal acceleration vector or the so-called positive radial acceleration, the blood moves in the caudal direction, which leads to ischemia in the brain tissue, as a result of a drop in blood pressure in the vascular basin of the brain.

Circulatory hypoxia was modeled using gravitational overloads in the cranio-caudal direction. The value of gravitational overloads was made so that the mortality of animals (male mice) in the control group was close to 50%. The value of gravitational overloads was 18 g for 10 minutes. The gradient of the rise and fall of the load was 0.30-0.33 g per second [Methodical recommendations for the experimental study of drugs proposed for clinical study as antihypoxic drugs / Approved by the Federal Ministry of Health of the USSR 11.04.90, order No. 7 - M., 1990, - 18 pp.].

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

table 2 Study drugs Dose mg / kg Survival rate (% of the total) Control Group A 40 Control Group B <15 * Experienced group 1 mg + 1 mg > 70 * Note: * - p≤0.05 in relation to control

The data presented in the table show that the introduction of the studied combination led to an increase in the survival of animals compared with control groups of animals, which indicates the presence of therapeutic activity in the conditions of induced cerebral ischemia caused by gravitational overloads, against the background of an artificial atherosclerotic process.

After that, the hypothesis was tested about the possibility of reducing the effective dosage of the therapeutic agents included in the combination. The study was carried out by titration of doses. Moreover, the studied groups of animals were smaller, the number of animals in the group was 4.

Table 3 Study drugs Dose mg / kg Survival rate (% of the total) Atorvastatin + Nicergoline 1 mg + 1 mg > 70 * Atorvastatin + Nicergoline 0.8 mg + 0.8 mg <65 * Atorvastatin + Nicergoline 0.5 mg + 0.5 mg <55 * Atorvastatin + Nicergoline 0.3 mg + 0.3 mg <50 *

Experience 3. The study of therapeutic effects in acute circulatory disorders of the studied combination in the conditions of local cerebral ischemia in rats caused by bilateral occlusion of the common carotid arteries against the background of an artificial atherosclerotic process.

The experiments were performed on rats that were used to simulate local ischemia by total ligation of the carotid arteries. Each group included 9 surviving animals after surgery. As a positive control, Nimodipine (INN) Nimotop ™ was used as a vasodilator used in acute cerebrovascular accidents.

In each group, after the start of the administration of the studied solutions, 1 more rat died. In the control group of intact animals, the death of the animal occurred within 1-2 minutes. In the Nimodipine treatment group, the animal died after 1 hour after the start of therapy, in the group receiving the combined drug, 2 hours after the end of therapy.

One of the common focal neurological symptoms indicative of acute brain ischemia is the development of ptosis. Table 4 shows that in animals that simulated acute local ischemia and did not receive treatment, ptosis of one of the eyes developed in 75% of cases, the use of the studied combination led to a significant decrease in the percentage of animals with a similar violation.

Table 4 Experimental groups The number of rats with ptosis 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 + Nicergoline 3/9 - 33.3% * Note: * - p≤0.05 in relation to control

Table 4 Neurological test scores Experimental groups Neurological status (M ± m, points) Control (intact animals) 56.75 ± 0.27 Control (atherogenic diet) 58.60 ± 0.34 Nimodipine (INN) Nimotop ™ 56.60 ± 0.19 Atorvastatin 55.90 ± 0.24 Atorvastatin + Nicergoline 54.87 ± 0.23

Table 5 Vegetative indicators Changes in the respiratory system and rectal temperature in rats Experimental groups Respiratory rate, in min ^-1 M ± m Rectal temperature (M ± m, ° С) Control (intact animals) 85.6 ± 12.6 37.8 ± 0.3 Control (atherogenic diet) 79.9 ± 9.5 36.1 ± 0.2 Nimodipine (INN) Nimotop ™ 99.6 ± 4.9 * 36.7 ± 0.1 * Atorvastatin 97.6 ± 5.1 * 36.9 ± 0.4 * Atorvastatin + Nicergoline 110.7 ± 5.7 * 37.4 ± 0.I * Note: * - p≤0.05 in relation to control

In animals treated with the combination, vegetative indicators, such as respiratory rate and body temperature, were significantly higher than in rats from the control group. This characterizes the restoration of thermoregulation and respiration systems (the level of indicators did not go beyond the generalized control of the norm and the data of our own studies). Moreover, in the Nimodipine group (INN) and Atorvastatin, the changes in the recorded data were intermediate in nature.

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

Table 6 Indicator The average value, X 95% confidence interval true average Number of animals M = x ± t ₉₅ * m _x T, ° C 37,4 37.3-37.5 215 BH, min ^-1 115 111-119 197

As follows from the data presented in table 6, in animals with brain ischemia there was a sharp decrease in motor and research activity. The introduction of Nimodipine and the studied combination led to a change in the behavior of rats in the conditions of the "open field" in the direction of activation compared with animals that did not receive treatment. In rats, a normalization of the duration of the latent period of reaching the center of the field and the number of peeps in minks was observed.

Histological data of serial frontal sections of the brain of animals of the control groups showed that the parts of the brain supplied by the branches of the middle cerebral artery underwent the most pronounced pathological changes in the frontal and parietal parts of the cerebral cortex and were characterized by wrinkling and hyperchromia of neurons with initial tortuosity of the apical processes.

It was impossible to differentiate the nuclear cytoplasmic complex. Changes were massive with the inclusion of all nerve cells of the I, II and III layers. Moreover, in the subcortical nodes (caudate nucleus, the outer third of the pale ball) there were relatively not pronounced changes expressed by chromatolysis and vacuolization of the cytoplasm of some neuronal cells. A pronounced edema was recorded in the cells. There are isolated cases of neuroophagy. The average histological score was 2.6 ± 0.3.

The use of a combination of an abstract preparation and a combination had a beneficial effect on brain structures. So, for example, in the frontal, parietal parts of the cerebral cortex, hyperchromic wrinkling is observed only from the side of the pyramidal cells of the III layer. The neurons of the caudate nucleus were characterized by only slight changes. The average histological score in the Nimodipine group and combination was 1.7 ± 0.18.

It was also found that the addition of 0.5 mg - 1.5 mg of hydrochlorothiazide to the claimed combination improved neurological tests and histological data.

The objective of the invention is the creation of an effective pharmaceutical combination, improving the quality of life of patients, reducing the incidence of disability, expanding the arsenal of drugs with a complex effect in vascular disorders, identifying and establishing therapeutic efficacy of the combination.

To solve this problem, a pharmaceutical composition has been developed, which includes atorvastatin or its pharmaceutically acceptable salt, nicergoline and auxiliary substances that make it possible to produce the drug in tablet form.

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

Atorvastatin 2.0-5.5 Nicergoline 2.0-5.5 Lactose 47.0-51.5 Potato starch 140-15.5 Microcrystalline cellulose 20.0-23.5 Collidon 4.0-4.5 Magnesium stearate 0.5-2.5

Thus, the authors were able to obtain an example of a pharmaceutical composition having good technological properties in the process of granulation and tabletting. At the same time, tablets have properties that satisfy the requirements for a pharmaceutical agent. Namely, they have a presentation, have sufficient strength and disintegration, are stored for at least 2 years, while providing a high clinical effect, convenient dosage and high bioavailability of incoming components.

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

As a shell, a composition based on polyvinyl alcohol, talc, polyethylene glycol, titanium dioxide, acceptable dyes or the ready-made mixture of the brand "Opadry II" is proposed.

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

The most common ways to obtain tablets are three technological schemes: with wet granulation, dry granulation and direct compression (Technology of dosage forms / Edited by Ivanova L.A. - M .: Medicine, 1991, v.2, p.142).

Claims (8)

1. A pharmaceutical composition for the correction of cerebrovascular accidents in diseases of the cardiovascular system, characterized in that it contains atorvastatin or a pharmaceutically acceptable salt and nicergoline in therapeutically effective amounts as active components. 2. The pharmaceutical composition according to claim 1, characterized in that as the target additives contains lactose, potato starch, microcrystalline cellulose, collidone, magnesium stearate in the following ratio of ingredients, wt.%:
Atorvastatin 2.0-5.5 Nicergoline 2.0-5.5 Lactose 47.0-51.5 Potato starch 14.0-15.5 Microcrystalline cellulose 20.0-23.5 Collidon 4.0-4.5 Magnesium stearate 0.5-2.5 3. The pharmaceutical composition according to claim 1, characterized in that the mammal is a human. 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 a solid dosage form. 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 colorants or the finished mixture of the brand "Opadry II". 8. The pharmaceutical composition according to claim 2, characterized in that it is made in the form of capsules.