Neurotropic tacrolimus analogs

FIELD: medicine.

SUBSTANCE: method involves introducing tacrolimus derivative of known formula (1) for stimulating nerve cell growth or regeneration. Another method is suggested for repairing transected peripheral nerve or spinal cord by making contact of the transected peripheral nerve ends or spinal cord with the compound (1) or by introduced the compound (1) to the patient and transplanting a transplant into peripheral nerve or spinal cord.

EFFECT: sharp growth of regenerated myelinated axons; improved motor function of feet; high neurotropic and low immunosuppressive activity level.

17 cl, 8 tbl

 

This invention relates to a derivative of tacrolimus, with a high level of neurotropic activity and low levels of immunosuppressive activity.

It is known that certain macrolide compounds, such as tacrolimus and related compounds that help to prevent or treat cerebral ischemia (WO 94/14443). It is known that certain derivatives pipecolic acids, which have affinity for immunophilins type FKBP, such as tacrolimus, stimulate growth of damaged peripheral nerves or to promote neuronal regeneration (WO 96/40140). It is shown that certain is not immunosuppressive compounds, i.e. geldanamycin and its analogues, interrupting the complex of steroid receptors and promote the growth of nerves (WO 99/21552).

The authors of the present invention discovered that a certain analogue of tacrolimus, i.e. the compound (I)mentioned below, has excellent neurotropic activity, but in contrast to tacrolimus has little or no immunosuppressive activity. As shown below, the compound (I) has higher levels of neurotropic activity, compared with tacrolimus, for example, by measuring its ability to increase the length of Narita. Similarly, it was shown that the introduction of compound (I) causes axonal regeneration and accelerates the no the of after the crushing of the nerve or spinal cord injury. In addition, these pre-emptive neurotropic effects of compound (I) appear at little or no immunosuppressive activity in comparison with tacrolimus.

Accordingly, the present invention provides new methods of using the compound (I) as neurotropic tools with improved properties, as well as neurotropic tools with little or no immunosuppressive activity.

Further, the invention provides a neurotropic agent or a composition that includes the compound (I).

This invention also provides a method for prevention or treatment of damage/dysfunction of neurons, which includes an introduction to the mammal the compound (I).

Unexpectedly, the authors of the present invention have found that the compound (I) can be used to alleviate, prevent or treat neurological damage or dysfunction caused by disease or injury, disorder or disease of the nervous system, at the same time mainly providing small immunosuppressive effect or not providing it.

The compound (I) can be used to treat injury, disorder or dysfunction caused by physical trauma, eating disorders, ischemia, degenerative diseases, malignant diseases, infections the ion diseases and drug interactions, toxins or poisons. For example, the compound (I) can be used to treat neurological damage or dysfunction caused neurosurgical surgery, peripheral nerve injury, burns, encephalomyelitis, HIV, herpes, cancer, radiation therapy, drug interactions, lack of folic acid or vitamin b-12 and exposure to neurotoxins or chemicals, such as lead.

Accordingly, the compound (I) can be used to prevent or treat damage and dysfunction of neurons, such as polymyositis (multiple myositis, Guillain-Barre syndrome, a disease Miniera, polyneuritis (multiple neuritis), manometric (one nerve neuritis), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (als), Huntington's disease, radiculopathy, neuropathy (such as diabetic neuropathy, neuropathy caused by chemotherapy, etc), spinal cord injury, senile dementia, vascular dementia, multiple sclerosis, physical paralysis, etc.

The compound (I), analogue of tacrolimus used in the present invention, has the following chemical formula:

This compound can be obtained, as described in U.S. patent No. 5376663, example 29. In respect of the compound (I)used in this image the shadow, it should be understood that there may be conformers and one or more stereoisomers such as optical and geometrical isomers due to asymmetric atom (atoms) of carbon or double bonds (bonds), and such conformers and isomers are also included in the range of the claims compounds of the present invention.

The compound (I) may be in the form of a pharmaceutically acceptable salt, derivative, MES or prodrugs, which are all included in the scope of claims of the present invention. MES preferably includes hydrate and atenolol.

A preferred form of compound (I) is the following:

The compound (I) of the present invention can be introduced in the form of pure compounds or in the form of a mixture with another compound or other ingredients, preferably with pharmaceutical drive or media. When the compound (I) used in the form of a pharmaceutical preparation or composition, it can be mixed with organic or inorganic carrier, base or excipient suitable for topical (local), oral, enteral, subcutaneous, intravenous, intramuscular or parenteral use. For example, it may be present in solid, semi-solid or liquid composition that contains the compound (I) as active in the of radiant and one or more carriers, foundations or fillers. Typical carriers, bases or fillers include, but are not limited to, conventional pharmaceutical carriers, medicinal or pharmaceutical agents, buffers, dispersing agents, emulsifying agents and adjuvants.

The compound (I) can also be prepared into a composition with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pills, capsules, eye drops, suppositories, solutions (saline, for example), emulsions, suspensions (e.g., olive oil), ointments, aerosol sprays, creams, plasters, pads and any other form suitable for use.

Suitable carriers include water, saline and dextrose solutions, oils, including animal, vegetable and synthetic oils and oil products. Other media that can be used include glucose, lactose, resin acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition, you can use additional, stabilizing, emulsifying agents, thickeners, coloring agents, flavoring agents and fragrances.

The compound (I) of Staritsa pharmaceutical composition in a quantity effective to create the desired effect on a specific disease process or condition. Preferably, the compound (I) is introduced in a quantity effective to provide neurotropic effect or stimulate the growth of nerve cells.

To mammals, which can be treated using the method of the present invention, include livestock, such as cows, horses, pigs, etc., Pets allowed, such as dogs, cats, rats, mice, rabbits, hamsters, etc., primates and humans.

Preferred routes of administration or application of products or compositions containing compound (I)they include injection or oral administration.

Though therapeutically effective amount or dosage of compound (I) may vary among individual patients and also depends on the age and condition of each individual patient to be treated, for the treatment of diseases in General, prescribed daily dose in the range from approximately 0.0001 to 1000 mg, preferably from 0.001 to 500 mg, and preferably from 0.01 to 100 mg of active ingredient, and in General, enter the average single dose of about 0.001 to 0.01 mg, 0.2 to 0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg. Daily dose for chronic administration people should be in the range of about 1 to 30 mg/kg/d Compound (I) can also enter or use is at the same time, separately or sequentially with other tools, with neurotropic or stimulating the growth of nerve cell activity.

Pharmaceutical compositions in accordance with the invention can periodically enter the subject is a mammal (e.g. a human patient)in need of such treatment, to promote neuronal regeneration and functional recovery and to stimulate the growth of neuritis and, through this, to treat a variety of neurotic diseases States, including damage to the peripheral nerves and the Central nervous system caused by physical injury (for example, damage and spinal cord injury, loss, or injury of the sciatic or facial nerve grafting limbs after amputation); diseases (e.g. diabetic neuropathy), cancer chemotherapy (e.g., neuropathy caused by acrylamide, Taxol, alkaloids Winky and doxorubicin); consequences - for example, allopathie (such as articulation disorders), disorders of consciousness, dyskinesia, etc. associated with cerebral infarction, hemorrhagic infarction, etc.; and neurological disorders, including but not limited to, various peripheral neuropathic and neurological disorders, including but not limited to: trigeminal neuralgia, bell's palsy, g is nerealizovannoe myasthenia, muscular dystrophy, amyotrophic lateral sclerosis, progressive muscular atrophy, progressive bulbar inherited muscular atrophy syndromes hernial protrusion, rupture or prolapse of intervertebral disc, cervical spondylosis, plexus disorders, syndromes destruction of thoracic holes, peripheral neuropathy, such as neuropathy caused by lead, acrylamide, gamma-diketones (neuropathy sniff glue), carbon disulfide, Dapsone, ticks, porphyria, Guillain-Barre syndrome, Alzheimer's disease, Parkinson's disease and chorea Huntington.

The intersection of the peripheral nerve or spinal cord injury can be treated by administration of stimulating nerve growth amount to a mammal and a change in the peripheral nerve or spinal cord of nerve graft, such as an allograft (Osawa et al., J. Neurocytol. 19:833-849, 1990; Buttemeyer et al., Ann. Plastic Surgery 35:396-401, 1995) or artificial nerve graft (Madison and Archibald, Exp. Neurol. 128:266-275, 1994; Wells et al., Exp. Neurol. 146:395-402, 1997). The space between the severed ends of the peripheral nerve or spinal cord preferably fill noncellular, filling the gaps of material, such as collagen, methylcellulose, etc.; or cell suspensions, which promote the growth of nerve cells, such as Schwann cells (Xu et al., J.Neuroctol. 26:1-16, 1997), olfactory cells and cells of the nervous vagina (Li et al. Science 277:2000-2002, 1997). The tool, which promotes growth of nerve, you can include together with such cellular or non-cellular material filling the gaps, or system input before, during, or after transplantation of nerve.

In particular, the compound (I) can be used for treatment or prevention of polymyositis associated with damage/dysfunction of neurons (multiple myositis, Guillain-Barre syndrome, a disease Miniera, polyneuritis (multiple neuritis), mononeuritis (single neuritis), Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (als), Huntington's disease, radiculopathy, diabetic neuropathy, neuropathy caused by chemotherapy, senile dementia, vascular dementia, multiple sclerosis, paralysis or spinal cord injuries.

The following examples more illustrate the present invention. It should be understood that these examples describe certain aspects or implementations of the invention, but not intended to limit the scope of the claims of the invention.

Example 1: Treatment of compound (I) significantly increases the length of the neurites of hippocampal neurons

Obtaining cell cultures:

Embryonic hippocampal neurons were obtained in the rats 18.5 am the optional day ("E18,5"), in accordance with the method Banker and Cowan (Brain Research, 1977, 126: 397-425). Briefly, removed the hippocampus was passed through a meat grinder, and incubated in 100 IU of papain at 37°C for 45 min, and cells resuspendable in full neural environment: minimum, contain essential amino acids medium without L-glutamine (GIBCO, Grand Island, NY), 1.5 ml/100 ml of medium a minimum, contain essential amino acids medium with high glucose (GIBCO), 0.1 ml/100 ml medium serum filler (Hito + Tm; Collaborative Research Inc., Lexington, MA), glutamine (GIBCO)with 5% fetal calf reverse printing (GIBCO).

Cells were seeded on cover glasses (500 cells / cover glass)coated with poly-L-lysine. Cover glasses turned on cups, which were pre-coated with a monolayer of cortical astrocytes.

Analysis of the length of the axons of hippocampal neurons:

The neurons of the hippocampus (identified by their characteristic polarity and dendrites) investigated daily and photographed by random sampling (9-12 framework/cover glass) after 72 hours the Length of axons (defined as the longest process) was measured on photographic prints using transformative in figures Notepad Houston Instrument HI-PAD connected to the IBM XT computer with appropriate software (Bioquant IV, R&M Biometrics, Nashville, TN); measured only processes that have a length of three times reviewshow the length of the cell body. Data from identically treated cover glass (3 or 4 per group) did not differ and therefore were come together. Average values were calculated and compared using one-way (group treated with compound (Ia) or tacrolimus in comparison with the untreated control group) ANOVA analysis followed by the criterion of multiple comparisons Newman-Kuels (WINKS 4.62 professional edition).

The results:

After 72 h was not significant difference between the untreated control group and the group treated with 10 nmol of tacrolimus. However, the group treated with compound (Ia) at a concentration of 10 nmol, showed a significant increase in the length of neurites (see results presented in table 1):

Table 1

The effect of the compound (Ia) and tacrolimus on the average length of neurites in primary culutre cells of the hippocampus in rats at 72 h
The length of neurites (µm)
No processing372,3±18,23
Tacrolimus (10 nmol)423,4±19,50
The compound (Ia) (10 nmol)502,2±23,61*
*: P<0,05 in comparison with no treatment (one-way ANOVA analysis followed by the criterion m is divine comparisons Newman-Kuels)

Example 2: Treatment of compound (I) increases the average length of neurites in cells human neuroblastoma SH-SYSY

Obtaining cell cultures of human neuroblastoma SH-SYSY:

Cells human neuroblastoma SH-SYSY maintained in DMEM (GIBCO) supplemented with 10% fetal calf serum (SIGMA), 50 IU/ml penicillin and 50 µg/ml streptomycin (GIBCO) at 37°With 7% CO2. Cells were sown on sectionone tablets in the amount of 15,000 cells/well and treated with 0.4 mmol aphidicolin (SIGMA). After 5 days cells were washed and treated with nerve growth factor (NGF) at a concentration of 10 ng/ml (for the induction of the growth process) in the presence or absence of tacrolimus (10 nmol) or compound (IA). The medium was changed after 96 h and replaced with fresh medium for another 72 h (total time 169 h). Two wells were used in all experiments and data were averaged for each group processing.

Analysis of the length of neurites in cells neuroblastoma SH-SY5Y:

To analyze the length of the bone cells (20 fields per well) randomly photographed through 168 hours Length of neurites was measured on photographic prints using transformative in figures Notepad Houston Instrument HI-PAD connected to the IBM XT computer with appropriate software (Bioquant IV, R&M Biometrics, Nashville, TN); measured only processes that have a length, double offset the expansion of the length of the cell body. Data from identically treated wells was not different and so were combined. Average values were calculated and compared using one-way (group treated with compound (Ia) or tacrolimus compared with samples treated only NGF) variational analysis with the following criterion for multiple comparisons Newman-Kuels (WINKS 4.62 professional edition).

The results:

Length measurement processes of neurites showed that the compound (Ia) (1 nmol) and tacrolimus (10 nmol) significantly increased the length of the appendages of neurites through 168 h compared with one NGF (10 ng/ml). However, the effects of 1 nmol of compound (Ia) in combination with NGF were higher than the effects of 10 nmol of tacrolimus in combination with NGF.

Table 2

Effect of compound (Ia) and tacrolimus on the average length of neurites in cells human neuroblastoma SH-SY5Y through 168 h
The length of neurites (µm)
No processing94,75±3,734
NGF (10 ng/ml)198,8±8,991
Tacrolimus (10 nmol) + NGF (10 ng/ml)227,6±9,130*
The compound (Ia) (1 nmol) + NGF (10 ng/ml)256,0±9,067*
*: P<0,05 in comparison with NGF (one-way ANOVA anal is C with the following criterion for multiple comparisons Newman-Kuels)

Example 3: Treatment of compound (I) promotes functional recovery in models of crushing the sciatic nerve of rats

Animals and surgical procedure:

9 6-week-old male rats Sprague-Dawley was narcoticyou 2% halothane gas, provided the right sciatic nerve and the nerve of the double-crushed (just 60 seconds using jewelry forceps Dumont No. 7) at the level of the hips. Plot crushing celebrated by tying a sterile suture thread 9-through epinephelinae vagina.

Obtaining and introducing the compound (Ia):

The compound (Ia) was dissolved in medium containing 30% dimethyl sulfoxide (DMSO):70% salt solution. 3 rats, subjected axotomy received daily subcutaneous injections or compound (Ia) (1 or 5 mg/kg) or equivalent volume of vehicle (30% DMSO in saline) (5 mg/kg).

Behavioral assessment:

Animals were examined daily until the day of perfusion (18 days). The following semi-quantitative scale was used to assess functional recovery of animals:

0: paralysis of the foot, turning when walking and crooked toes;

1: the ability to straighten the foot and move the toes of the foot;

2: the ability to constantly walk on foot;

3: shows the fingers of the feet while walking;

4: goes from the heel and shows almost normal breeding fell the Germans stop.

Animals exhibiting intermediate was awarded partial marks: +, 0,25; ++, 0,5; +++, 0,75.

Fixation and preparation of tissue:

On the 18th day after the crushing of the nerve of the rat was deeply narcoticyou 4% halothane gas, Gaprindashvili and perfesional 4% paraformaldehyde in 0.1 M nutrifaster buffer (pH 7.4) for 10 seconds followed by perfusion with 5% glutaraldehyde (1 l) in 0.1 M nutrifaster buffer (pH 7.4) and fixed with 4°within 24 hours, tissue Samples were taken from the sciatic nerve at the famous (5 mm) distance from the site crushing. This study presents only the data obtained on the branches of the posterior tibial nerve, Innervate the plantar muscle. Tissue was placed in 0.1 M matrifocality buffer (pH 7.4)and then fixed with 1% osmium tetroxide (in 0.1 M phosphate buffer) for 2.5 h, dehydrational in ethanol and embedded in plastic. Half-thin sections were stained with uranylacetate and lead citrate, were mounted on grids with 75 holes in 1 square inch and examined in the electron microscope JEOL 100 CX.

Morphometric analysis:

Analysis caliber axons were performed on the plantar nerve. The number of regenerating liver myelination axons were counted using electron microscopy. Averages and standard errors were calculated for the group treated what setelem, the group treated with compound (Ia) (1 mg/kg) and groups treated with compound (Ia) (5 mg/kg).

Statistical analysis:

For behavioral analysis average recovery functions were compared using ANOVA analysis followed by the criterion of multiple comparisons Newman-Keuls for comparison of individual values. For morphometric analysis of the average values for the number of axons was compared using one-way ANOVA analysis followed by the criterion of multiple comparisons Newman-Keuls for comparison of individual values.

The results:

Functional recovery:

Functional recovery was observed on 15-17 day, and it has happened before and in rats treated with 1 mg/kg, and in rats treated with 5 mg/kg of the drug than in rats fed the media (see table 3).

Table 3

Effect of compound (Ia) on functional recovery after injury of the sciatic nerve in rats
Functional ball score
Carrier (SC) (30% DMSO in saline)The compound (Ia)
1 mg/kg (subcutaneously)5 mg/kg (subcutaneously)
day 151,67±0,082,58± 0,17*3,17±0,08*
16 day1,83±0,082,83±0,17*3,50±0,00*
17 day2,50±0,00is 3.08±0,22*3,50±0,00*
*: P<0,05 in comparison with vehicle (one-way ANOVA analysis followed by the criterion of multiple comparisons Newman-Kuels)

Electron microscopy

Morphological study of animals held on the 18th day after axotomy.

The number regeneriruyuschim myelination axons in the area of the nerve (5000 μm2) sharply increased from 5.5±2,7 (average ± standard error of the mean) in rats fed media up to 19±2,4 and 20±2,9-treated rats, respectively, 1 and 5 mg/kg of the drug (P<0,05) (see table 4).

Table 4

Effect of compound (Ia) on the number of regenerative myelination axons in the area of the nerve (5000 μm2in plantar nerve after 18 days after crushing the sciatic nerve in rats
Carrier (SC) (30% DMSO in saline)The compound (Ia)
1 mg/kg (subcutaneously)5 mg/kg (subcutaneously)
Regenerierbaren moulinsiana axons 5,5±2,719±2,4*20±2,9*
*: P<0,05 in comparison with vehicle (one-way ANOVA analysis followed by the criterion of multiple comparisons Newman-Kuels)

Example 4: Treatment of compound (I) promotes functional recovery in models of spinal cord injury in rats

(1) Methods

Animals and surgical procedure

28 6-week-old male rats Sprague-Dawley was narcoticyou 2% halothane gas, performed laminectomy at T10/T11 and produced damage half the dissection of the spinal cord at T10/T11 spinal cord.

Obtaining and introducing the compound (Ia)

The compound (Ia) was dissolved in medium containing 30% dimethyl sulfoxide (DMSO); 70% saline. Rats with lesions of the spinal cord received daily subcutaneous injections of compound (Ia) (2 mg/kg) or equivalent volume of vehicle (30% DMSO in saline solution) (5 ml/kg) for 7 weeks after the operation.

The evaluation of functional recovery

Functional recovery was assessed using the modified Tarlov scale/Kinger, test with a narrow beam and traces stop 2 weeks after the injury.

A. a Modified Tarlov scale/Kinger

The rats were given the possibility to move freely in an open field for 1 min and were rated from 0 to 6 with the accordance with the following scale.

0: No motion in the affected hind limb

1: Barely perceptible movement damaged hind limb

2: Active movement in joints damaged hind limb (hip, knee, or ankle), but the lack of coordination, lack of a support body mass

3: Alternating steps and movements tremors struck the hind limbs, lack of support body mass

4: you May provide a support to the body weight of the injured hind limb

5: Walks only with a slight deficit

6: Normal walking

C. Test with a narrow beam

Rats were tested on the wooden beams (length 1.5 m) with decreasing width: 7.7 cm, 4.7 cm, 2.7 cm and 1.7 see the Rats were given the opportunity to go to the bars and registered the narrow beam, by which they could pass without any slippage, at least two passes.

0: No walk on any beam

1: Can walk on a beam width 7.7 cm

2: Can walk on a beam width 4.7 cm

3: Can walk on a beam width of 2.7 cm

4: Can walk on a beam width of 1.7 cm

C. Test traces stop

The hind limbs of rats that had been dipped in ink and made the prints stop on the paper covering the narrow path length of 60 cm and a width of 7.5 see a Series of at least six sequential steps used to determine the 5-point ball is Inoi evaluation of the traces stop.

0: Constant back gait or dragging of the hind limbs, i.e. the traces of the feet are not visible

1: Has visible traces of the toes, at least, three toes, at least three tracks stop

2: Shows Exo - or androtation feet-more than double the value compared to its own baseline values

3: shows No signs of toes dragging, but the rotation stop

4: shows No evidence of Exo - or andromachi (less than twice the angle of the original values), but is seen more than one trace heel

5: Traces of heels are not visible

Statistical analysis

For behavioral analysis averages ball assess each functional test were compared using one-way ANOVA analysis followed by the criterion of multiple comparisons Newman-Keuls for comparison of individual values.

(2) the Results

Functional recovery

When all three dimensions of functional recovery carried out using a modified Tarlov scale/Klinger (table 5), the test distance along beam (table 6) and the test trace stop (table 7), the compound (Ia) improved movement ability when using the modified Tarlov scale/Klinger (table 5), the test distance along beam (table 6) and the test trace stop (table 7).

Table 5

Effect of compound (Ia) on a modified Tarlov score/Klinger spinal cord injury in rats
Modified Tarlov score/Klinger
Carrier (SC) (30% DMSO in saline)The compound (Ia) 2 mg/kg (subcutaneously)
Week 22,1±0,13,7±0,2*
*: P<0,05 in comparison with vehicle (one-way ANOVA analysis followed by the criterion of multiple comparisons Newman-Kuels)

Table 6

Effect of compound (Ia) the score of a walk on a beam with spinal cord injury in rats
The scoring walking beam
Carrier (SC) (30% DMSO in saline)The compound (Ia) 2 mg/kg (subcutaneously)
Week 20,9±0,12,0±0,3*
*: P<0,05 in comparison with vehicle (one-way ANOVA analysis followed by the criterion of multiple comparisons Newman-Kuels)
Table 7

Effect of compound (Ia) the scoring of the traces stop at the spinal cord injury in rats
The scoring marks stop
Carrier (SC) (30% DMSO in saline)The compound (Ia) 2 mg/kg (subcutaneously)
Week 21,7±0,43,6±0,3*
*: P<0,05 in comparison with vehicle (one-way ANOVA analysis followed by the criterion of multiple comparisons Newman-Kuels)

Example 5: Compound (Ia) binds to FKBP12, but unlike tacrolimus has a small immunosuppressive effect or not at all has it

(1) Analysis of binding to FKBP12

The analysis of binding was performed in accordance with the same method described Tamura, K., et al (Biochemical and Biophysical Research Communications, Vol. 202, No.1, 437-499, 1994). The results are shown in table 8.

(2) the Reaction of lymphocytes in a mixed culture (MRL)

The MRL test was carried out according to the method described in U.S. patent No. 4929611.

The results are shown in table 8.

Table 8

The pharmacological profile of the compounds (Ia) and tacrolimus in vitro
IR50binding to FKBP12 (nmol)IR50MLR (nmol)
The compound (Ia)<5>100
T is colimus <5<2

The above results show that compound (Ia) has immunosuppressive activity, although it can communicate with FKBP12.

The above results illustrate the powerful neurotropic effects of compound (I) using models and in vitro and in vivo. Two models of cell cultures compound (I) even at low concentrations increased the growth of neurites. Moreover, systemic injection of the compound (I) in low doses accelerated functional recovery after damage in the form of crushing of the nerve and promoted functional recovery after spinal cord injuries.

In addition, as shown above, compound (I) provides high neurotropic or stimulating the growth of nerve cells activity, although it does not possess immunosuppressive activity. Accordingly, the present invention provides a useful neurotropic agent to stimulate or promote growth or regeneration of neurons, in particular, when the immunosuppressive effect is not superior or undesirable.

Other aspects of the present invention include:

The product of manufacture, comprising packaging material and a compound (I)identified in the above description, contained within the specified upakovochnomu, moreover, the connection specified is (I) a therapeutically effective for the prevention or treatment of dysfunction of neurons, and with the specified packaging material includes a label or a written material which indicates that the compound (I) can or should be used for prevention or treatment of injury/dysfunction.

Intended for sale package comprising a pharmaceutical composition comprising the compound (I)identified in the above description, and written material, and written material indicates that the compound (I) can or should be used for prevention or treatment of injury/dysfunction.

Composition, such as cell suspensions, tissue or graft comprising a cell treated with compound (I). Such compositions can be used to repair damage to the nervous system. Such compositions may also include other means of stimulating the growth of nerve cells, such as other types of cell suspensions that facilitate and / or promote the growth of nerve cells, such as cells producing myelin, such as Schwann cells or oligodendrocytes, glial cells and cells of the vaginal nerve; extracellular matrix material such as collagen; or other specific neuroregulators, such as cytokines, mitogenic factors, immunophilins and atropine, such as NGF-1, BDNF, CNTF, NT-3, NT-4 and NT-5.

Grafts, such as homotransplantation, allografts or xenografts, can also be treated with a compound (I) to facilitate the growth of neurons and used as grafts for other uses.

The contents of each document, patent applications or patent publications, which are contained or referenced herein, were fully incorporated into it by reference. The content of any of the patent document, on which this application claims priority to, also fully incorporated here by reference. In particular, the content of the provisional application for U.S. patent No. 60/258500 included as references.

It is obvious that there are numerous modifications and variations of the present invention in light of the above provisions. Therefore, it should be understood that within the range of the claims appended claims the invention may be implemented otherwise than specifically described in this description. Various modifications and variations of the described compositions and methods, as well as the concept of the invention will be obvious to a person skilled in this field without departing from the range of the claims and the invention. Although the invention has been described in connection with specific preferred VA is Yantai implementation, it should be understood that the invention, in its present form is not intended to be limited to such specific choices of implementation. There is a view that various modifications of the described ways of carrying out the invention that are obvious to experts in the field of medicine, biology, chemistry or pharmacology or in related areas, are within the range of the claims of the present invention.

1. The method of promoting growth or regeneration of nerve cells, including the introduction of the compound (I) of the formula

needs it the subject.

2. The method according to claim 1, in which the specified subject is a mammal.

3. The method according to claim 1, in which the specified subject is people.

4. The method according to claim 1, characterized in that the growth or regeneration of nerve cells caused by traumatic injury, mechanical injury, surgical injury or pathological damage.

5. The method according to claim 4, characterized in that the said neuronal damage is a diabetic neuropathy, physical paralysis or spinal cord injury.

6. The method according to p. 5, characterized in that the neuronal damage is an injury of the spinal cord.

7. The method according to claim 5, characterized in that the neuronal damage is a diabetic who europathy.

8. The method according to any one of claims 1 to 7, in which the compound (I) is compound (Ia) of the formula

9. Method of increasing the rate of growth or regeneration of axons or length of nerve cells, including the provision of contact with the nerve cells with compound (I)defined in claim 1.

10. The method according to claim 9, characterized in that the nerve cells are cells from brain tissue, tissue of the spinal cord or peripheral nerve tissue.

11. Way to promote functional recovery of the nerve after traumatic, mechanical, surgical or pathological damage, including the introduction of an effective amount of compound (I), as defined in claim 1, needs it the subject.

12. Method of recovering rugged peripheral nerve or spinal cord, including the provision of contact of crossed ends of the specified peripheral nerve or spinal cord with an effective amount of compound (I), as defined in claim 1.

13. Method of recovering rugged peripheral nerve or spinal cord of a subject, comprising the introduction of stimulating the growth of peripheral nerve amounts of compound (I), as defined in claim 1, the specified subject and transplantation in peripheral nerve or spinal cord of nerve graft, collagen, IU is icellulse or cell suspension.

14. The method according to item 13, wherein said graft is an allograft.

15. The method according to item 13, wherein said transplant is a transplant of artificial nerve.

16. The method according to item 13, additionally comprising filling the space between the crossed ends of the peripheral nerve or spinal cord noncellular material that fills the gap.

17. The method according to item 13, additionally comprising filling the space between the crossed ends of the peripheral nerve or spinal cord cell suspension.



 

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4 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: medicine.

SUBSTANCE: method involves introducing recombinant human granulocytic colony-stimulating factor.

EFFECT: enhanced effectiveness of treatment; increased number of stem cells and their improved homing in lesion foci without polypragmasia effects.

5 tbl

FIELD: medicine.

SUBSTANCE: method involves introducing Hypoxen at a peroral dose of 0.5 g 40 min before premedication with Benzodiazepine series tranquilizer.

EFFECT: enhanced effectiveness in retaining psychic and motor functions after surgical intervention.

FIELD: medicine, veterinary science.

SUBSTANCE: invention relates to a method for improving the cognitive function in mammals and humans. Method involves administration in mammal needing in such treatment bis-[(2-hydroxyethyl)-N,N,N-trimethylaminium] succinate. This provides improving different cognitive functions in mammals being without the development of by-side effects and results to the improvement of the life quality and social adaptation in persons suffering with these disorders.

EFFECT: improved method for enhancing cognitive function.

2 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition possessing capacity to release the therapeutically effective dose of active substance rivastigmin and showing the time-controlled pattern. The pharmaceutical composition is designated for treatment of patients suffering with Alzheimer's diseases dementia from small to middle severity degree. Compositions show safety and time-controlled release pattern of active substance rivastigmin.

EFFECT: valuable medicinal and pharmaceutical properties of composition.

5 cl, 2 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method for treatment of diseases representing the result of cognitive disorders, in particular, Alzheimer's disease. Invention involves using (+)-enantiomer of fenserine - (+)-9-N-phenylcarbinoleseroline possessing the minimal anti-cholinesterase activity, or its pharmaceutically acceptable salt, for example, acid-additive salt, in particular, as an active component of a pharmaceutical composition. The dosed formulation of such composition comprises 20-500 mg of active component. The active component is given to a patient in the dose 0.5-10 mg/kg of body mass per a day. Invention provides achievement of clinic effect in said disorders in the absence of by-side toxic effect caused by anti-cholinesterase activity typical for agents that are used usually in these disorders.

EFFECT: improved method for treatment.

14 cl, 9 ex

FIELD: pharmacy.

SUBSTANCE: invention proposes a liquid pharmaceutical composition containing nicotine in any form for administration into the mouth cavity and alkalinized with a buffer and/or by regulation of pH value. Administration is carried out preferably by spraying and the most preferably by sublingual spraying. Also, invention relates to a method for preparing the indicated composition. Use of indicated composition in therapy, such as therapy for treatment of addiction to tobacco.

EFFECT: valuable pharmaceutical properties of composition.

51 cl, 11 ex

FIELD: medicine, cardiology, psychiatry.

SUBSTANCE: one should carry out traditional therapy of myocardial infarction and, additionally, prescribe perorally pyrasidol at the dosage of 25 mg twice daily for 21 d in combination with eglonyl at 1 ml (50 mg) once daily intramuscularly for 10 d. The present innovation enables to decrease the tension of regulatory systems due to decreasing sympathetic impacts and activation of parasympathetic department of autonomic nervous system.

EFFECT: higher efficiency of therapy.

1 ex, 3 tbl

FIELD: internal diseases.

SUBSTANCE: patient is administered diet including 0.3-0.5 g/kg/day animal for 10 days followed by increase to dose 0.8-1 g/kg/day during 1 month, after which 5% glucose solution is administered intravenously in dose 400-500 ml for 1 weak, lactulose in dose 60-90 ml divided into 2-3 intakes for 4 weeks, and probiotics over a 2-weak period 30 min before meal time. Simultaneously, L-ornithine-L-aspartate is given during 10 days in dose 30-40 g a day divided into 2-3 intakes followed by dose 5-7 g thrice a day during 10 days.

EFFECT: achieved involution of neurological and psychical manifestations of encephalopathy, reduced hepatic coma development incidence, and increased protein tolerance in patients.

4 cl, 3 ex

FIELD: medicine, orthopedics.

SUBSTANCE: one should fulfill certain tests, for example digital compression test, elevation test and others to evaluate pain syndrome according to a 5-point scale. If, as a result of these tests, the intensity of pain syndrome is increased up to 2-4 points and paresthesia occurs it is necessary to introduce about 25-35 mg kenalog 40 into painful site and at decreased pain syndrome up to 0-1 points one should diagnose peripheral tunnel syndrome. The innovation enables to differentiate peripheral tunnel syndromes against neurological manifestations of vertebral osteochondrosis.

EFFECT: higher efficiency and accuracy of diagnostics.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds 2,6-di-tert.-butyl-4-{2-[2-(methylamino)ethyl]-1,3-thiazole-4-yl}phenol, 2,6-di-tert.-butyl-4-[4-(hydroxymethyl)-1,3-oxazole-2-yl]phenol, 4-methylphenyl-2-[4-(1,1-biphenyl-4-yl)-1H-imidazole-2-yl]ethylcarbamate and others or their pharmaceutically acceptable salts. Also, invention relates to using these compounds for preparing a medicinal agent possessing one of the following three activities: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulating activity with respect to sodium channels. Proposed derivatives of thiazole, oxazole or imidazole possess one of the following species of pharmacological activity: inhibition of monoamine oxidases activity, inhibition of lipids peroxidation and modulation of sodium channels.

EFFECT: valuable biochemical and biological properties of derivatives.

34 cl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1-aminobutane-3-ol of the general formula (I): and their physiologically acceptable salts possessing analgesic effect and capacity for binding habapentin-site. In the general formula (I) R1 and R2 form in common (CH2)2-9-ring; each R3 and R4 independently of one another means (C1-C6)-alkyl that is branched or direct, saturated or unsubstituted, benzyl or phenethyl that are unsubstituted; R5 means (C1-C10)-alkyl that can be saturated, unsaturated, branched or direct or unsubstituted, (C3-C9)-cycloalkyl that is saturated, phenyl or 5-membered sulfur-containing heteroaryl possibly condensed with benzene ring, (C3-C6)-cycloalkyl bound through saturated or unsaturated (C1-C3)-alkyl, 5-membered possibly condensed with benzene ring sulfur-containing heteroaryl bound through saturated or unsaturated (C1-C3)-alkyl wherein each aryl, heteroaryl and cycloalkyl residue independently of one another can be unsubstituted or mono- or multi-substituted with residues chosen independently of one another from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct and can be mono- or multi-substituted with halogen atoms wherein R18 represents hydrogen atom (H), (C1-C10)-alkyl that is saturated, branched or direct or unsubstituted; R6 means H; R7 means (C1-C6)-alkyl that is branched or direct, saturated or unsaturated or unsubstituted, (C3-C9)-cycloalkyl that is saturated or unsubstituted, phenyl that is unsubstituted or mono- or multi-substituted or phenyl bound through saturated (C1-C3)-alkyl that can be unsubstituted or mono- or multi-substituted wherein these substitutes can be chosen independently from the group comprising atoms F, Cl, Br, J, -OR18, (C1-C10)-alkyl that is saturated or unsaturated, branched or direct, in free form as their physiologically acceptable salts. Proposed compounds can be used in treatment of pain and first of all neuropathic, chronic and acute pain. Also, invention relates to a method for synthesis of compounds and preparing a medicinal agent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

9 cl, 89 ex

FIELD: medicine, pharmacology.

SUBSTANCE: the suggested innovation deals with the method for obtaining a pharmaceutical composition being useful to decrease or remove pathological somnolence due to combining efficient quantity of nonlyophilized modaphinyl at particles diameter ranged 2-200 mcm and delivery means or pharmacologically acceptable carrier that improves bioavailability of modaphinyl.

EFFECT: higher efficiency of application.

8 cl, 9 dwg, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 2-pyridincyclohexane-1,4-diamine of the general formula (I): wherein R1, R2 and R3 mean independently of one another hydrogen atom (H), branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R4 means H, branched or linear (C1-C8)-alkyl or -C(X)R7 wherein X means oxygen atom (O); R7 means branched or linear (C1-C8)-alkyl or (C3-C8)-cycloalkyl; R5 means group -CHR11R12, -CHR11-CH2R12, -CHR11-CH-CH2R12, -CHR11CH2-CH2-CH2R12 wherein R11 means H, branched or linear (C1-C7)-alkyl or C(O)O-(C1-C6)-alkyl; R12 means H, (C3-C8)-cycloalkyl or five-membered nitrogen-containing heteroaryl optionally condensed with benzene ring as their racemates or pure stereoisomers being at first enantiomers or diastereomers, and as bases or physiologically compatible acid-additive salts. Compounds of the formula (I) elicit analgesic activity and can be used in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

15 cl, 1 tbl, 9 ex

FIELD: pharmaceutics, medicine, cosmetic and food industry.

SUBSTANCE: the present innovation deals with biologically active substance for obtaining medicinal preparations, curative-prophylactic cosmetic remedies, food biologically active additives being of anabolic and actoprotector actions. The innovation reveals the application of either homogenate or lyophilizate of drone breeding combs - the mixture of drone larvae and drone pre-pupae being of anabolic and actoprotector actions. The application of the declared substances enables to organize mass production of new cheap and high-efficient medicinal and curative-prophylactic remedies.

EFFECT: higher efficiency.

4 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention describes a pharmaceutical composition comprising a medicinal agent, wax-like substance and synthetic aluminum silicate and/or aqueous silicon dioxide, and oral pharmaceutical component comprising such composition. The pharmaceutical composition is prepared by granulation by spraying. Also, invention relates to an agent used for prevention in usage of granulated product to internal walls of granulator device during the granulation process by spraying. This agent represents synthetic aluminum silicate and/or aqueous silicon dioxide. Invention minimizes sticking granules in granulator device during granulation of the pharmaceutical composition and prevents caking granules.

EFFECT: improved preparing method, improved and valuable properties of composition.

13 cl, 4 tbl, 6 ex

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