RU2664439C2 - Pharmaceutical compositions based on 9-butylamino-3,3-dimethyl-3,4-dihydroacridine-1(2h)-one hydrochloride for the correction of cognitive and neurological disorders - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention relates to the field of medicine, in particular to a pharmaceutical composition for the correction of cognitive and neurological disorders caused by acute damage to the cerebral circulation containing 9-butylamino-3,3-dimethyl-3,4-dihydroacridine-1(2H)-one hydrochloride and pharmaceutically acceptable carrier.EFFECT: present pharmaceutical composition is effective in correcting cognitive and neurological disorders caused by acute damage to the cerebral circulation, in particular stroke, and also has low toxicity.7 cl, 4 tbl, 14 ex

Description

The invention relates to medicine and pharmacology and is based on the use of 9-butylamino-3,3-dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride as an independent or combined therapeutic agent for the correction of cognitive and neurological disorders.

9-butylamino-3,3-dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride

The search for remedies for cognitive and neurological disorders remains one of the most pressing problems of modern medicine. The importance of this problem is due to the great importance of cognitive and neurological functions in the processes of the human body and the fact that their violation can lead to dramatic consequences. The frequency of cognitive impairment increases in old age. According to statistics, from 3 to 20% of people over 65 have cognitive impairment in the form of dementia.

The current tendency to increase life expectancy and, accordingly, to increase the proportion of elderly people in the population, naturally increases the frequency of pathologies under consideration.

It should be noted that such disorders can be caused not only by factors associated with the aging of the body, but also be a consequence of damage to the brain as a result of cerebrovascular accidents, such as strokes or injuries. A significant number of strokes result in serious consequences, in particular, impaired memory, speech and motor function. 450,000 strokes are registered in Russia per year, of which more than 200,000 require rehabilitation.

It should be especially noted that currently there are no sufficiently effective means for the correction of cognitive and neurological disorders. Most drugs only alleviate the condition of patients and do not always lead to recovery.

The psychotropic, antiamnestic and lipid-regulating properties of 9-aminoacridine derivatives are known (RF patent No. 2024509).

Known antiamnestic properties of 9-butylamino-3,3-Dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride (J. Experimental and Clinical Pharmacology, published in 2013, No. 11, pp. 3-6, article " Anti-anamnestic effect of substances with nootropic activity in rats ”, author Yasnetsov VV, Krylova IN)

Known pharmaceutical compositions containing 9-butylamino-3,3-Dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride and having nootropic and anticholesterase activity (patents UA 93755, UA 46077).

The use of 9-butylamino-3,3-dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride for the correction of cognitive and neurological disorders in the prior art is absent.

Studies conducted for the first time found that 9-butylamino-3,3-Dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride is able to correct the cognitive and neurological impairment observed in various pathological conditions.

The problem solved by the invention is the creation of an effective pharmaceutical composition for the correction of cognitive and neurological disorders based on 9-butylamino-3,3-Dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride, in the form of various dosage forms.

The technical result from the use of the invention is to create a pharmaceutical composition with high efficiency in the correction of cognitive and neurological disorders.

The specified technical result is achieved by the proposed pharmaceutical composition containing 9-butylamino-3,3-dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride and a pharmaceutically acceptable carrier.

Preferably, the proposed pharmaceutical composition contains from 0.1 to 1.0 wt. % 9-butylamino-3,3-dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride and a pharmaceutically acceptable carrier that allows it to be performed in the form of an injection solution containing a stabilizer and a filler.

Preferably, the proposed pharmaceutical composition contains from 1.0 to 10.0 wt. % 9-butylamino-3,3-dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride (hereinafter compound I) and a pharmaceutically acceptable carrier that allows it to be made in the form of tablets, or granules, or pellets containing a binder, disintegrator, lubricant, filler.

It is preferable that the proposed pharmaceutical composition made in the form of tablets, or granules, or pellets, is coated on the basis of cellulose derivatives, or povidones, or cetyl alcohol, or acrylates.

Preferably, the mass of the shell relative to the mass of the core is not less than 1.0 wt. %

Preferably, a quantity of pellets or granules can be placed in a pharmaceutically acceptable hard capsule for oral administration.

Preferably, the capsule is filled with pellets or granules in such an amount that the content of the active substance in them is equivalent to a therapeutic dose.

Presumably, the pharmacological effect of compound I is based on its ability to have a complex effect on brain structures, which leads to inhibition of pathological processes. Firstly, it is the ability to selectively modulate potassium channels, leading to stabilization of the membrane potential and a decrease in the excitability of neurons. On the other hand, compound I is able to reduce the microviscosity of membranes, activating membrane-bound processes and prolonging the lifespan of a neuron.

The technical result achieved by the proposed composition is due to new properties of compound I, discovered during preclinical studies.

The ratio of the components in the proposed composition is selected experimentally and is optimal, which allows to obtain a technical result corresponding to the task.

A method of obtaining the proposed composition in the form of a solution.

The proposed dosage form in the form of a solution for injection is obtained by gradually dissolving the components in water for injection, followed by filtration and packaging of the resulting solution.

Examples of specific production of the proposed solution.

Example 1. Injection 0.1%.

To 400 ml of water for injection add 0.1 g of disodium edetate and mix. To the resulting solution was added 1.0 g of compound I and stirred until a clear solution was obtained. The solution was transferred to a 1 L volumetric flask and the solution was adjusted to 1 liter with water for injection. The resulting solution is filtered, packaged in sterile vials with a capacity of 1 ml and sterilized. The resulting solution meets the requirements of the State Pharmacopoeia XI and XII ed.

Example 2. Injection 0.5%

To 400 ml of water for injection add 0.5 g of disodium edetate and mix. To the resulting solution was added 5.0 g of compound I and stirred until a clear solution was obtained. The solution was transferred to a 1 L volumetric flask and the solution was adjusted to 1 liter with water for injection. The resulting solution is filtered, packaged in sterile vials with a capacity of 1 ml and sterilized. The resulting solution meets the requirements of the State Pharmacopoeia XI and XII ed.

Example 3. The injection for 1.0%

To 400 ml of water for injection add 1.0 g of disodium edetate and mix. To the resulting solution was added 10.0 g of compound I and stirred until a clear solution was obtained. The solution was transferred to a 1 L volumetric flask and the solution was adjusted to 1 liter with water for injection. The resulting solution is filtered, packaged in sterile vials with a capacity of 1 ml and sterilized. The resulting solution meets the requirements of the State Pharmacopoeia XI and XII ed.

A method of obtaining the proposed composition in the form of tablets.

A pharmaceutically acceptable excipient and disintegrant are added to the calculated amount of compound I, mixed, slip and lubricants are added to the mixture and mixed again. The resulting mass is tabletted by direct compression. A gastro-soluble coating of at least 1.0 wt.% May be applied to the tablets. % by weight of the tablet.

A method of obtaining the proposed composition in the form of granules or pellets.

A pharmaceutically acceptable excipient and disintegrant are added to the calculated amount of compound I, mixed, slip and lubricants are added to the mixture and mixed again. From the resulting mass, pellets or granules are obtained. On pellets or granules, a gastro-soluble coating of at least 1.0 wt. % by weight of pellets or granules.

The resulting pellets or granules can be placed in gastro-soluble hard capsules, for example made of gelatin, in such an amount that the content of active substances in them is equivalent to a therapeutic dose.

In the described methods for producing the proposed composition in the form of tablets, or pellets, or granules, compound I is used that meets the requirements of the pharmacopeia.

The filler may be used, in particular, either a mixture of microcrystalline cellulose (MCC) and starch, or a mixture of lactose and starch, or a mixture of MCC, lactose and starch, or calcium carbonate, or magnesium carbonate; as a lubricant, in particular, either stearic acid, or magnesium stearate, or calcium stearate, or talc, or silicon colloidal dioxide, or mixtures thereof can be used; as a disintegrant, in particular, either starch derivatives or crospovidone can be used; in particular, colloidal silicon dioxide may be used as a sliding one; as a gastrointestinal membrane, a membrane made in particular based on cellulose derivatives, or povidones, or cetyl alcohol, or acrylates can be used.

The following are specific examples of the manufacture of the proposed composition in the form of tablets.

Example 1

To 1.0 g (1.11%) of compound I, 43.8 g (48.67%) pregelatinized corn starch, 43.8 g (48.67%) microcrystalline cellulose were added and mixed. To the resulting mixture was added 0.5 g (0.55%) of colloidal silicon dioxide, 0.3 g (0.33%) of magnesium stearate, 0.6 g (0.67%) of stearic acid. The mixture is thoroughly mixed and tableted. The result is a tablet weighing 0.09 g with a content of compound I of 1.11%. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 2

To 5.0 g (5%) of compound I, 47.0 g (47.0%) pregelatinized corn starch, 46.5 g (46.5%) microcrystalline cellulose was added and mixed. To the resulting mixture was added 0.5 g (0.5%) of silicon dioxide colloidal, 0.3 g (0.3%) of magnesium stearate, 0.7 g (0.7%) of stearic acid. The mixture is thoroughly mixed and tableted. The result is a tablet weighing 0.1 g with a compound I content of 5%. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 3

To 20.0 g (10%) of compound I, 88.5 g (44.25%) of pregelatinized corn starch, 88.5 g (44.25%) of microcrystalline cellulose are added and mixed. To the resulting mixture was added 1.0 g (0.5%) of colloidal silicon dioxide, 0.6 g (0.3%) of magnesium stearate, 1.4 g (0.7%) of stearic acid. The mixture is thoroughly mixed and tableted. The result is a tablet weighing 0.2 g with a compound I content of 10%. The resulting tablets meet the requirements of the State Pharmacopoeia XI and XII ed.

Example 4

It is carried out as example 1, only a tablet weighing 0.09 g is coated with a polymer coating based on acrylates. The mass of the shell is 0.9 mg (1.0%) by weight of the core.

Example 5

It is carried out as example 2, only a tablet weighing 0.1 g is coated with a polymer coating based on cellulose derivatives. The mass of the shell is 3.6 mg (3.6%) of the mass of the core.

Example 6

It is carried out as example 3, only a tablet weighing 0.2 g is coated with a polymer coating based on povidones. The mass of the shell is 4.6 mg (2.3%) of the mass of the core.

Example 7

It is carried out as example 3, only a tablet weighing 0.2 g is coated with a polymer coating based on cetyl alcohol. The mass of the shell is 4.6 mg (2.3%) of the mass of the core.

The following are specific examples of the manufacture of the proposed composition in the form of granules and pellets.

Example 8

To 1.0 g (1.11%) of compound I, 43.8 g (48.67%) pregelatinized corn starch, 43.8 g (48.67%) microcrystalline cellulose were added and mixed. To the resulting mixture was added 0.5 g (0.55%) of colloidal silicon dioxide, 0.3 g (0.33%) of magnesium stearate, 0.6 g (0.67%) of stearic acid. The mixture is thoroughly mixed. Pellets or granules are obtained from the resulting mixture. The resulting cores are dried and calibrated. The result is granules or pellets with a compound I content of 1.11%.

Example 9

To 5.0 g (5%) of compound I, 47.0 g (47.0%) pregelatinized corn starch, 46.5 g (46.5%) microcrystalline cellulose was added and mixed. To the resulting mixture was added 0.5 g (0.5%) of silicon dioxide colloidal, 0.3 g (0.3%) of magnesium stearate, 0.7 g (0.7%) of stearic acid. The mixture is thoroughly mixed. Pellets or granules are obtained from the resulting mixture. The resulting cores are dried and calibrated. The result is granules or pellets with a compound content of 15%.

Example 10

To 20.0 g (10%) of compound I, 88.5 g (44.25%) of pregelatinized corn starch, 88.5 g (44.25%) of microcrystalline cellulose are added and mixed. To the resulting mixture was added 1.0 g (0.5%) of silicon dioxide colloidal, 0.6 g (0.3%) of magnesium stearate, 1.4 g (0.7%) of stearic acid. The mixture is thoroughly mixed. Pellets or granules are obtained from the resulting mixture. The resulting cores are dried and calibrated. The result is granules or pellets with a compound content of 110%.

Example 11

It is carried out as example 8, only a granule or pellet weighing 1.5 mg is coated with a polymer coating based on acrylates. The mass of the shell is 0.15 mg (10.0%) of the mass of the core.

Example 12

It is carried out as example 9, only a granule or pellet weighing 1.5 mg is coated with a polymer coating based on cellulose derivatives. The mass of the shell is 0.15 mg (10.0%) of the mass of the core.

Example 13

It is carried out as example 10, only a granule or pellet weighing 1.5 mg is coated with a povidone-based polymer coating. The mass of the shell is 0.15 mg (10.0%) of the mass of the core.

Example 14

It is carried out as example 10, only a granule or pellet weighing 1.5 mg is coated with a polymer coating based on cetyl alcohol. The mass of the shell is 0.15 mg (10.0%) of the mass of the core.

Studies have been conducted to study the effect of physical factors such as temperature and light on the pharmaceutical compositions described in Examples 1-14.

After conducting research, it was found that the best storage conditions for tablets: in a dry place at a temperature not exceeding 25 ° C; for capsules: in a dry place at a temperature of no higher than 20 ° C.

The test for microbiological purity of tablets and injection solution is carried out in accordance with the requirements of Global Fund XI, issue 2, p. 193 and Amendment No. 3 (category 2). The results obtained comply with regulatory requirements.

In order to study the effectiveness of the proposed pharmaceutical composition based on compound I, its preclinical trials were performed on a model of hemorrhagic brain stroke.

The studies were performed on white outbred male rats according to the Guidelines for the Preclinical Studies of Medicines, (T. Voronina et al. 2012 using a certified technique for stroke caused by intracerebral post-traumatic hematoma (hemorrhagic stroke model, GI).

Animals were divided into several groups:

Group I - intact rats (n = 10);

Group II - falsely operated animals (VALVE) (n = 10);

Group III - a group of animals with GI, control (n = 20);

Group IV - rats with HI who received the proposed pharmaceutical composition based on compound I at a dose of 1.0 mg / kg / 7 days (n = 10);

Group V - rats with GI, received the proposed pharmaceutical composition based on compound I at a dose of 2.5 mg / kg / 7 days (n = 10).

The dynamics of the development of disorders caused by post-traumatic hematoma was observed within 14 days after the operation with the recording of behavior indicators on the 1st, 7th and 14th days after the operation.

Registered the death of animals, neurological and motor deficits, the degree of change in cognitive functions. The death of animals was evaluated on the 1st and 7th and 14th days after the creation of a hemorrhagic stroke.

Neurological deficit in animals was determined on a Stroke-index McGrow scale in modification. The number of rats with mild symptoms (lethargy, weakness of the extremities, one- and two-sided semi-ptosis / ptosis) and with severe manifestations of neurological disorders (maneuvering movements, paresis of 1-4 limbs, paralysis of the lower extremities, lateral position, coma) was noted.

Cognitive functions were investigated on the model of the conditioned passive avoidance reflex (passive avoidance reaction) in the Passive avoidance setup, Lafauette Instrument Co (USA).

The results of the studies are presented in tables 1-4.

The effect of the proposed pharmaceutical composition based on compound I in different dosages on the death of animals with hemorrhagic stroke.

The results obtained indicate that the proposed pharmaceutical composition based on compound I at a dose of 1 mg / kg when administered 3 hours after a hemorrhagic stroke and then for 6 days significantly (P <0.05) decreases (by 40%) rat death rate compared with control (rats with hemorrhagic stroke), within 14 days after GI.

The effect of the proposed pharmaceutical composition based on compound I in various dosages on the indicators of neurological deficit in animals with hemorrhagic stroke.

The results show that the proposed pharmaceutical composition based on compound I at a dose of 1 mg / kg on the first day after a hemorrhagic stroke statistically reliably attenuates manifestations of neurological deficiency (according to the Stroke-index McGrow scale).

The effect of the proposed pharmaceutical composition based on compound I in various dosages on the development of motor deficiency in rats after HI in a rotating rod test.

The data presented indicate that the proposed pharmaceutical composition based on compound I at a dose of 1 mg / kg when administered 3 hours after a stroke once prevented the appearance of motor disorders by 100% after 24 hours of recording indicators in a rotating rod test. Re-administration of the composition (6 days) reduced the severity of motor deficiency on the 7th and 14th day, but not statistically significant. The proposed pharmaceutical composition based on compound I at a dose of 2.5 mg / kg did not have a positive effect on motor impairment.

The effect of the proposed pharmaceutical composition based on compound I in various dosages on the reproduction of passive avoidance reaction in rats with cognitive deficiency caused by hemorrhagic stroke

The table shows that the proposed pharmaceutical composition based on compound I at doses of 1 and 2.5 mg / kg corrected cognitive impairment caused by GI. At a dose of 1 mg / kg, the anti-amnestic effect was observed both a day and 7 days after the study of passive avoidance reaction, and at a dose of 2.5 mg / kg - a day after training.

Summarizing the above, it can be stated that the proposed pharmaceutical composition based on compound I at a dose of 1 mg / kg and weaker at a dose of 2.5, has the ability to reduce the severity of neurological and cognitive impairment and increase the survival of animals after hemorrhagic stroke. These studies were taken as the basis for determining the therapeutic dose of the active substance.

Claims (7)

1. A pharmaceutical composition for the correction of cognitive and neurological disorders caused by acute cerebrovascular accident, containing 9-butylamino-3,3-dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride and a pharmaceutically acceptable carrier. 2. The pharmaceutical composition according to claim 1, containing from 0.1 to 1.0 wt. % 9-butylamino-3,3-dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride and a pharmaceutically acceptable carrier that allows it to be performed in the form of an injection solution containing a stabilizer and a filler. 3. The pharmaceutical composition according to claim 1, containing from 1.0 to 10.0 wt. % 9-butylamino-3,3-dimethyl-3,4-dihydroacridin-1 (2H) -one hydrochloride and a pharmaceutically acceptable carrier that allows it to be made in the form of tablets, or granules, or pellets containing a disintegrant, a sliding lubricant, a filler . 4. The pharmaceutical composition according to claim 3, wherein the tablets, or granules, or pellets can be coated with a gastro-soluble coating based on cellulose derivatives, or povidones, or cetyl alcohol, or acrylates. 5. The composition according to p. 4, characterized in that the mass of the shell relative to the mass of the core is at least 1.0 wt. % 6. The composition according to paragraphs. 3-5, characterized in that a certain amount of pellets or granules can be placed in a gastro-soluble pharmaceutically acceptable hard capsule for oral administration. 7. The composition according to p. 6, characterized in that the capsule can be filled with pellets or granules in such an amount that the content of the active substance in them is equivalent to a therapeutic dose.