Drug preparation for parkinson disease

FIELD: medicine.

SUBSTANCE: invention represents a drug preparation for Parkinson disease containing micronised L-DOPA (3-hydroxy-L-tyrosine) as an active ingredient, which represent stable particles containing poly(lactic-co-glycolic acid 50/50 (PLGA 50/50), or poly(lactic-co-glycolic acid 75/25 (PLGA 75/25), or poly(lactic-co-glycolic acid 50/50 with carboxyl group (PLGA-COOH 50/50), or lactic acid polymer (PLA) in an amount of 75.0÷79.0 wt %, D-mannitol in an amount of 7.5÷8.0 wt %, as well as either polyvinyl alcohol (PVA) or Tween 80.

EFFECT: treating Parkinson disease more effectively.

2 cl, 4 dwg, 2 ex


The invention relates to chemical-pharmaceutical industry and can be used to create a medicinal product on the basis of biodegradable polymers for the treatment of Parkinson's disease.

Parkinson's disease (PD) is a chronic progressive disease of the brain primarily associated with degeneration of dopaminergic neurons of the substantia nigra and is manifested by a combination of hypokinesia with rigidity, resting tremor and postural instability. BP is one of the most common neurological diseases in elderly: prevalence among persons over 65 years of age reaches 2%. The prevalence of PD is from 120 to 180 per 100,000 population, the incidence ranges from 12 to 20 cases per 100 000 population per year [1, 2]. Forecast conventionally unfavorable. Patients not receiving treatment, on average, lose the ability to care of themselves after 8 years from the onset of the disease, and in 10 years become bedridden [1]. Persons receiving adequate therapy, become dependent on their servicing persons on average in 15 years [1]. At a relatively early development of Parkinson's fastest progressing the symptoms of impaired motor activity, and with the appearance of the first symptoms of the disease in individuals 70 years and older at the forefront of mental disorders [3].In recent years, among patients with Parkinson's disease more and more young people. Obviously, this is due to the distribution of drugs that can be toxic to the neurons of a black body impurities. In Parkinson's disease in the striatum, one of subcortical parts of the brain involved in coordination of motor activity and the formation of emotional reactions, lowered maintenance of the neurotransmitter dopamine. In addition, affects the structures of the extrapyramidal system, basal nuclei and black stuff, blue stain and other [3]. The most pronounced changes are observed in the anterior part of the substantia nigra. Characteristic of Parkinson's disease symptoms (clinical manifestations) occur at the death of 60-80% of neurons of anatomical structures [4, 5].

Etiological risk factors for PD are considered as aging, genetic predisposition, exposure to environmental factors [4, 6, 7]. Pathology of normal aging is accompanied by a decrease in the number of neurons of the substantia nigra and by the presence Taurus Levi. Aging is also accompanied by neurochemical changes in the striatum - a decrease in the content of dopamine and the enzyme tyrosine hydroxylase, as well as reducing the number of dopamine receptors. Using positron emission tomography proved that the rate of degeneration of neurons of the substantia nigra in Parkinson's disease is much higher than in normal aging [6].About 15% of people with Parkinson's have a family history of this disease. However, the genes responsible for the development of Parkinson's disease that are not identified [6]. Reasons parkinsonopodobnyh manifestations can also be a viral infection, tumor, mechanical damage of the neurons of a black body (injury), the impact of environmental factors (pesticides, herbicides, heavy metals) [8], chronic cerebrovascular insufficiency, or the use of drugs that cause extrapyramidal side effects [9]. The oxidative hypothesis of the occurrence of the BP role of free radicals formed during the oxidative metabolism of dopamine and affecting the development and progression of Parkinson's disease. The increase in the content of substances which can serve as electron donors, in a black substance that promotes the formation of free radicals [6]. In addition, the oxidation of dopamine by the action of MAO formed hydrogen peroxide. If the peroxide is not associated with glutathione, there is an accumulation of highly reactive hydroxyl radicals, which react with the lipids of cell membranes, causing lipid peroxidation and cell death of the black substance.

Parkinson's disease for the second half of 2013 is incurable, all current treatments are aimed at relieving its symptoms (symptomatic treatment). To based�tion drugs, eliminates movement disorders include: 3,4-dihydroxy-L-phenylalanine - l-DOPA (often in combination with peripheral inhibitors of DOPA-decarboxylase or less with inhibitors COMT), dopamine receptor agonists and inhibitors of MAO-B [10].

Several decades after its inception, the drug levodopa remains the most effective antiparkinsonian agents, against which is measured the activity of all other tools [1, 11, 12]. Levodopa is effective against all three major symptoms of PD: hypokinesia, tremor, rigidity [1, 12]. Because the drugs levodopa remains the most effective remedy at all stages of PD, they are prescribed to almost all patients with this disease.

Levodopa (L-DOPA) is an amino acid, the immediate metabolic precursor of dopamine, which in contrast is capable of using a carrier to penetrate the blood-brain barrier and compensate for the dopamine deficiency in the brain that underlie many of the clinical manifestations of PD. Levodopa is absorbed in the proximal small intestine and is captured endings surviving dopaminergic nigrostriarnyh neurons, subjected to the decarboxylation, is converted into dopamine, which is released in the synaptic cleft, maintaining adequate functionally� the state of the neurons of the striatum and other basal ganglia [1, 11, 12]. The effectiveness of levodopa in the formulation of dopamine and its bioavailability is much higher compared to other precursors of dopamine - phenyl-alanine and tyrosine. The great advantage of the medication L-DOPA is the fact that using them in therapeutic doses does not violate the endogenous synthesis of dopamine, but rather enhances its production [1].

In our day levodopa is the main, but not the ideal drug for the treatment of Parkinson's disease. The disadvantages include the relatively low bioavailability of the drug, fluctuations in the degree of absorption of the drug in the gastro-intestinal tract, especially in violation of motor function of the intestine, and a short half-life in plasma (T1/2up to 3 hours). It penetrates not only in brain but also in other organs is not worse. As a result of these processes is often more than 50% of the medication is lost, not reaching target cells. Therefore, in order to create the desired concentration in the capillaries of the brain, requires a huge dose (initial dose of 0.25 g per day, which increased to 4-5 g, and good tolerability, the daily dose is 6 g). With the development of side effects reduce the dose or stop receiving the drug [11].

Important are two more features of levodopa. First, the product provides the most guaranteed e�effect in PD patients: has a therapeutic effect in more than 95% of patients [6]. Accordingly, the positive response to the drug levodopa is an important criterion for diagnosis of this disease. Levodopa in PD patients has a positive effect during the entire term of appointment: from the earliest to the final stages of the disease. Moreover, the magnitude of therapeutic effect during all the years of levodopa remains almost unchanged [6].

By reducing nigrostriarnyh terminalej of neurons in the striatum is lost their "buffer" function - the ability to store and gradually release the dopamine formed from exogenous levodopa. In the surviving neurons accelerates the circulation of dopamine cells faster release and not accumulate dopamine in the vesicles. Levodopa is increasingly being processed into dopamine in neighboring glial and mediumenergy (e.g., serotonergic) neurons, which contain DOPA-decarboxylase, but there is no mechanism regulating the release and reuptake of dopamine, leading to massive uncontrolled release of dopamine shortly after taking another dose. Newly synthesized dopamine penetrates into the intercellular space and diffuses into the synaptic cleft. As a result, the concentration of dopamine in the synapse is dependent on fluctuations in the level of levodopa in the blood and changes dramatically within wide limits. Shortly after Priya�and regular doses it increases, and then quickly falls. As a result, the stimulation of dopamine receptors from the tonic turns into a pulsating, non-physiological, which in turn alters the functional state of the receptor apparatus and striatal neurons [13, 14].

Thus, we can distinguish presynaptic mechanisms of fluctuations (critical decrease in the number nigrostriarnyh terminalej) and postsynaptic mechanisms initiated by a pulsatile stimulation of dopamine receptors. Postsynaptic mechanisms may be associated with changes in sensitivity of dopamine receptors or mediated intracellular signaling systems that control the state of the genes and production of proteins in the projection neurons of the striatum [13].

One of the approaches to eliminate the above drawbacks of the drug and reducing possible side effects and increase the efficiency and optimize the metabolism is change the dosage form of the drug levodopa, can reduce the dose required to achieve a given effect by using controlled release and optimize bearsdley.

Earlier, V. I. Shvets and others [15, 16] was shown the prospects of liposomes (phospholipid vesicles) for the protection of L-DOPA from the destructive action of enzymes. These microspheres ranging in size from 25 nm to 1 μm) served as a container for the drug, protecting it from premature decarboxylation and preventing a rapid decrease of the concentration of active substance in the blood, resulting in increased efficiency of action of the drug more than 10 times compared to its solution. A large activity of liposomal L-DOPA were also due to the ease of penetration of this dosage form through the blood-brain barrier. These experiments shows the principal viability of the use of DOPA in the form nanodomains dosage form for treatment of Parkinson's disease.

It should be noted that the use of liposomal dosage forms also provides the prolonged effect of drugs and decrease their toxicity. In the work During M. J., and others have shown that liposomes with incorporated DOPA, partially implanted into genererally striatum of rats showed a prolonged effect for 40 days. Small adnyamathanha vesicles were obtained by scoring liposomal dispersion. The results of these studies indicated a partial recovery of the deficiency of dopamine in animals with apomorphine-induced model of PD [17].

The significant disadvantages of liposomal drugs include high cost of the used phospholipids, as well as their low stability during storage.

As mentioned above, al�ternatively liposomal drugs are forms of medicinal substances on the basis of biocompatible, biodegradable polymers, for example based on copolymers of lactic and glycolic acids. These dosage forms are polymer particles of micron and submicron sizes with the active compound and stabilized from aggregation of surface-active substance (surfactant). In the composition also includes the cryoprotectant required for freeze-drying of the drug.

Attempt incorporating DOPA and dopamine in microspheres formed from a polyamide polymer [18]. However, the kinetics of the release of substance from the polymer particles in experiments in vitro showed the futility of their further use.

The known method [19] of receipt of the drug on the basis of L-DOPA in the composition of the polymer particles formed of a copolymer of lactic and glycolic acids. As emulsion stabilizer of polyvinyl alcohol is used. To obtain particles of the selected method of double emulsions, in contrast, used modificirovannogo method is simple emulsions.

Known composition of dry powder [RU 2484823, C2, A61K 31/485, A61K 9/14, A61K 9/16, A61K 9/12, A61K 9/72, A61P 25/16, 20.06.2013] containing apomorphine, for administration by pulmonary inhalation, for the treatment of pathological conditions of the Central nervous system, including Parkinson's disease, containing apomorphine and magnesium stearate, includes n�nominal dose of apomorphine from about 3 mg to 10 mg and provides the dose fraction of small particles (FPF), component of from about 2 to 6 mg when administered.

A disadvantage of the compositions is the relatively low efficiency of treatment.

The closest pharmaceutical composition is proposed pharmaceutical composition of [RU 2440100, C2, A61K 9/20, A61K 31/198, A61K 47/12, A61P 25/16, 20.01.2012] containing a food acid or a combination of food acids providing a pH of the composition in the range of 5.5 to 6.5, and a pharmacologically effective amount of micronized L-DOPA as the active ingredient, which active ingredient is present in the form of particles on the surface of larger carrier particles.

This composition is used to treat Parkinson's disease patient suffering from or susceptible to such disease. Treatment is aimed at elimination of motor fluctuations in patients receiving L-DOPA for treatment of Parkinson's disease.

A disadvantage of the compositions is the relatively low efficiency of treatment.

The problem to be solved by the present invention is to improve the treatment of Parkinson's disease.

The required technical result is the creation of pharmaceutical compositions that improve the efficacy of treatment of Parkinson's disease at lower doses, and thus reduce the risk of and degree of toxic effects and achieve the �of effecta prolongation of the action, reduce frequency reception during treatment.

The problem is solved, and the required technical result is achieved in that the proposed drug DOPA-based PCs micronized L-DOPA (3-hydroxy-L-tyrosine) as the active ingredient according to the invention, it is a stable particle, or a copolymer containing lactic and glycolic acids 50/50 (PLGA 50/50), or a copolymer of lactic and glycolic acid 75/25 (PLGA 75/25), or a copolymer of lactic and glycolic acids 50/50 with a carboxyl group (PLGA-COOH 50/50), or a polymer of lactic acid (PLA), D-mannitol, and polyvinyl alcohol (PVA), or tween-80 in the following ratio of components, wt.%:

PLGA 50/50 (or PLGA 75/25,
or PLGA-COOH 50/50,
or PLA)75,0÷79,0
PVA (or tween-80)else

In addition, the required technical result is achieved by use of stable particles of submicron size of from 100 to 400 nm.

In the proposed pharmaceutical compositions as an active ingredient use of L-DOPA (3-hydroxy-L-tyrosine), as the biodegradable polymer used, the copolymer of lactic and glycolic acids 50/50 (PLGA 50/50), or a copolymer of lactic and glycolic acid 75/25 (PLGA 75/25), or a copolymer of lactic and glycolic acids 50/50 with a carboxyl group (PLGA-COOH 50/50), or a polymer of lactic acid (PLA), as a cryoprotectant used D-mannitol, and as surface-active substances are used or polyvinyl alcohol, or tween-80.

In the drawings:

Fig.1 - graphs of the efficiency of DOPA-PC with chronic nasal injection in a dose of 0.35 mg/kg (L-DOPA), in comparison with the standard drug L-DOPA at the same dose;

Fig.2 - prolonged effect of DOPA-PC for chronic daily administration (test results after 0.5 and 24 hours after nasal administration of the drug at a dose of 0.35 mg/kg (L-DOPA) Wistar rats with a model of PD.

Fig.3 - the results of the study of animal behavior with BP in the test "open field" after the introduction of DOPA-PC at a dose of 0.35 mg/kg - study the number of stands (Fig.3, A), the number of incidents of grooming (Fig.3, B);

Fig.4 - comparative effectiveness of gastric reference DOPA-PC at a dose of 20 mg/kg (Fig.4, A) and nasal conducting DOPA-PC at a dose of 1 mg/kg (Fig.4, B) healthy Wistar rats in conditions of dynamic loads in the test "swimming with the weights".

The invention is illustrated by the following �the company.

Example 1. Preparation of polymer particles with embedded L-DOPA.

A mixture consisting of a solution of 500±5.0 mg PLGA 50/50 at 3.0±0.1 ml of chloroform and 100±0.5 mg L-DOPA, intensively stirred for 30 min on a magnetic stirrer, and then added, dropwise, 15±0.5 ml of 1% solution of polyvinyl alcohol saturated with L-DOPA. The resulting emulsion was stirred on a magnetic stirrer for 30 minutes and homogenized at 24000 rpm in a homogenizer Ultra-Turrax T-25 (CA®, Germany) 3 times for 60 sec with intervals of 1 minute.

The resulting emulsion is placed in a round bottom flask, which is connected to a rotary evaporator. Evaporation of chloroform is carried out at a slight vacuum and the temperature of the water in the bath ≈35°C. the Obtained colloidal solution is placed in test tubes for centrifugation. Particles precipitated at 13 000 rpm for 15 min at 4°C. Take the supernatant, the precipitate is suspended in 10 ml ± 30 µl of distilled water and filtered through a glass filter (pore diameter of 40-100 μm). After filtering in a round bottom flask with the filtrate add 50±0.2 mg D-mannitol and dissolve it. A colloidal solution and freeze-dried freeze-dried within 24 hours. Conduct the necessary tests of the drug.

The optimal composition, wt.%

PLGA 50/5075,0÷79,0

Example 2. Determination of particle size - DOPA-PC

The definition of particle size is carried out by autocorrelation spectroscopy. For analysis using submicron laser spectrometer Coulter N4MD company Coulter Electronics (USA). The measurement algorithm is based on the CONTIN program. The weight and composition of the drug 5÷5.5 mg was mixed with 5 ml of distilled water and suspend a few minutes by shaking. The obtained colloidal solution is transferred to a special cell and perform measurements. The scoring of the sample is not carried out. The particle size is 300÷400 nm. Thus, it follows from the foregoing that:

1. The best of the investigated surfactant is a 1.0% aqueous solution of PVA;

2. Optimum emulsification: 24 thousand rpm, 3 times for 1 min with intervals of 1 min;

3. The optimum volumetric ratio of organic to aqueous phase is 1:5.

Example 3. The study of the pharmacological efficiency of the drug DOPA-PC in rats with a model of Parkinson's disease.

The efficacy of therapy has been studied in 40 male rats Wistar (m=335±28r) with pharmacologically induced model of the disease �of Parkinsona.

a) Obtaining a model of rats with PD.

For the destruction of the compact part of the substantia nigra was selected as the standard technique using the neurotoxin 6-OHDA (6 - hydroxydopamine) [2, 20], which, having a structure similar to that of dopamine, shows high affinity with the membrane dopamine Transporter (DAT) and captured dopaminergic neurons. In the cage 6-OHDA undergoes oxidation with the formation of toxic products such as quinones and reactive oxygen species that damage the cell. The toxin was injected into the right hemisphere of zhivotnihe assistance stereotactic setup by coordinates AP -4.4; -1,2 L; H 7,8, three groups of rats (n=30). The operation was conducted under General anesthesia. For this purpose, rats were intraperitoneally injected with chloral hydrate at a dose of 400 mg/kg, dissolved in saline (100 mg/ml). An anesthetized rat was shaved away the hair on the top of the skull, then injected subcutaneously 0.3-0.5 ml of 2% R-RA of procaine as a local anesthetic. The skin of the skull was cut and stretched so that you can see the cranial sutures. The periosteum was removed. The animal was placed in a stereotactic setup, fixed head. The manipulator was inserted the needle and measuring the coordinates from bregma (the intersection of the sagittal and coronal sutures of the skull). Using the syringe needle drilled a hole in the skull, then changed the needle to the cannula, filled with a solution of 6-OHDA in tegatana physical�aStore (4 μg/μl). The needle cannula is immersed in the brain to the desired depth, then using a Hamiltonian of the syringe 10 ál attached to the cannula, has introduced a 2.5 µl (10 µg/rat) solution of the toxin at a rate of 1 μl/min. After injection the needle was left in the brain for 5 minutes to prevent reflux (backward flow of the drug). Control animals instead of the solution of the toxin were injected zagazovanny saline. After surgery, the incision on the skull was sutured, and the wound is decontaminated by levamisole and focaccina.

b) Confirmation of neurodegeneration

The development of the neurodegenerative process was confirmed three weeks after injection of the toxin, registering a unilateral rotation of rats in response to administration of apomorphine. Apomorphine was administered intraperitoneally, at a dose of 1.6 mg/kg (solution 0.4 mg/ml). After 10 minutes, the rat was placed in a glass cylinder with a radius of 30 cm and a height of 40 cm In the next 10 minutes were recorded the number of complete revolutions made by rat damaged the substantia nigra, in the opposite direction relative to the side of the injection of the toxin, in contrast to normal controls [21,2].

b) study of the effectiveness of DOF-PC.

As the comparison drug used substance L-DOPA. The drug DOPA-PC and the reference drug L-DOPA was administered chronically, daily, intranasally at a dose of 0.35 mg/kg (L-DOPA) (0.12 mg/rat 1 ascorbic acid solution, in volume - 20 µl/nostril). For control injections were used 1% solution of ascorbic acid with a pH of 7.0 in sterile water for injection. The drugs were prepared immediately prior to administration of L - DOPA was dissolved in 1% ascorbic acid solution rate of 3.2 mg/ml, after which the pH was adjusted to 7. Particles, with the inclusion of the drug 11±1,5%, suspended in the solvent in an amount necessary to obtain the concentration of L-DOPA - 3.2 mg/ml of the ascorbic acid Solution was prepared weekly and stored at +4°C.

The effectiveness of the drug DOPA-PC was determined by the improvement of coordination of movements in animal models of PD when performing standard tests for the study of animal behavior. The results obtained were compared with the standard drug L-DOPA at the same dose, as well as from healthy animals and control with PD who did not receive therapy.

g) Used tests

Animals were tested 30 min after drug administration. To assess motor coordination, motor functions, behavioral research and animal activity, and anxiety levels were conducted the following tests.

Statement of the limb. This test is used for weekly assessment of coordination of movements of animals from unilaterally destroyed in a black substance. The animal was holding one hand under the belly, the other on �neobhodimosti, held by the tail. The animal was kept parallel to the edge of the bench, below the surface. Then slowly raised so that the vibrissae (whiskers) touched the edge of the table, and at the endpoint of the lifting of the front leg of the corresponding side of the body was above the edge of the countertop. The criterion for correct execution attempts considered the statement of the forelimb near to the table side of the body on the table surface. The test was repeated 10 times for each side, bringing in the Protocol, the number of successful attempts [20].

An open field. This test is used to assess the possible effects of chronic drug administration on locomotor and exploratory activity of experimental animals under conditions of free behavior. The test was carried out twice - before drug administration and after 6 weeks of administration. The animal was placed in the center of the field square, evenly lit red lamp pad, size 80×80 cm, enclosed in an opaque wall height of 30 cm and the horizontal surface is divided into squares with sides of 20 cm.

The experimenters recorded the behavioral activity of the animal within 2 minutes. Were recorded the following parameters: horizontal activity of animals (the number of covered squares); number of outputs in the center of the "open field" (Central square, 20�20 cm); vertical activity (number of columns); the number of acts of grooming.

Grooming is an active animal behaviour, aimed at the body surface, i.e. washing, licking, cleaning the genitals, scratching. Strengthening of grooming observed in rodents when placed in a stressful situation and occurs in animals with a high emotional tension.

By the beginning of drug administration the results of animal groups with PD did not differ on the effectiveness of the test "setting the limbs and the efficiency was 81±15% of the test values from healthy controls.

Daily nasal administration of l-DOPA-PC at a dose of 0.35 mg/kg (L-DOPA) has led to a significant improvement of coordination of movements in the test "setting the limb in the group of animals with PD. The effectiveness of the action of the polymer composition DOPA-PC increased from the second day of drug administration within two weeks and remained unchanged throughout the experiment - 17 weeks of the introduction, and one week after discontinuation of the drug. The 22nd day of the experiment, 30 min after injection of drugs, indicators of coordination in the test "setting the limb in the group of animals with DOPA-PC was 94±12%, in the group with L-DOPA - 68±7% and for the group of control animals with BP - 58±15%, from the values of healthy controls. To the 120th day of the introduction of the indicator to�rdinatio animals in the group with DOPA-PC was 94±10% (p< 0.05) compared with L-DOPA - 62±13% and control BP - 51±28%. Standard reference drug is L-DOPA was significantly effective only after a single injection and 91±8% (p<0,05). One week after drug withdrawal, the value effectiveness test for the studied groups with DOPA-PC, L-DOPA and BP control was 77±15% (p<0,05), 60±15% and 47±29%, respectively.

The commentary to Fig.1.

It should also be noted that the effectiveness of the action of DOPA-PC after 30 min and 24 hours after its introduction in the test "setting the limb when the nasal introduction differed slightly. These results indicate a prolonged effect of DOPA-PC, which persists for 24 hours after administration of the drug in nanoform.

The commentary to Fig.2.

Study of the influence of the drug DOPA-PC on the behavior of animals in the test "open field" was performed twice. Prior to the introduction (day 0) and on day 42 (6 weeks). the introduction of the drug. The most informative were the following parameters: horizontal activity (number of columns) and the number of acts of grooming. While horizontal activity and the number of outputs in the center of the "open field" was not changed during the experiment and did not differ between groups. This fact suggests that the unilateral development of neurodegeneration has not substantially�impact on the studied parameters, as the animals from the control group of PD, none of the investigated parameters do not differ from the intact (healthy) control.

At the same time, the introduction of the drug DOPA-PC resulted in a significant increase in the number of racks and fewer acts of grooming, which indicates an increase in research activity, reducing anxiety and reducing the time of decision making.

The commentary to Fig.3.

Thus, the inclusion of L-DOPA in the polymer particles significantly increases the effectiveness of the drug in comparison with the effect of the same dose of the standard drug. Proven prolonged effect within 24 hours in a day DOPA-PC animal model of PD. In addition, nasal administration of L-DOPA in PLGA can significantly reduce the effective daily dose is 57 times for animals with BP and, accordingly, the cumulative dose of the drug.

The commentary to Fig.4.

A significant effect of DOPA-PC is the rapid restoration of motor functions in affected animals (within 1-2 weeks) saving effect in investigated for 17 weeks without an increase in the daily dose, and one week after discontinuation of drug administration that is of practical importance. These advantages reduce the side effects of L-DOPA. It is important to note that eff�aktivnosti drug DOPA-PC achieved in the absence of inhibitors copadichromis, used in standard treatment of L-DOPA, which also reduces the risk of side effects and shows a fundamentally new property of the drug DOPA-PC, was used to deliver the drug in the target organ is most effective.

Example 4. The study of the toxicity of the drug DOPA-PCs for the treatment of Parkinson's disease in rats after a single dose.

Assessment of the degree of toxic reactions to the drug DOPA-PC and comparison drug L-DOPA, was carried out with the intranasal route of administration of drug on white mice of the line Balbc and male rats of Wistar line.

The total duration of observation of the animals after administration of drugs and substances control (empty particles and the solvent) was 14 days, the first day the animals were under continuous observation.

The reference drug was administered at a dose of 1 mg/kg, DOPA-PC at a concentration of 10 mg/kg (L-DOPA) every 5 minutes in each nostril 20 μl for 5 hours. Animals of the control groups were injected with empty nanoparticles in 1% p-re of ascorbic acid in sterile water for injection (pH 7.0) in a volume corresponding to the volume of the drug DOPA-PC.

Revealed that administration of drugs was not accompanied by mortality. The introduction of 540 mg/kg of l-DOPA-PC mice of the line Balb/c weighing 19-21 g were recognized�s toxic manifestations. The condition of the animals was not different from the condition of the animals of the control groups. All behavioral responses to provoking effects: tactile, sound and light stimuli were. Of muscle tone disorders, manifestations of seizure activity was observed.

The introduction of 168 mg/kg of the drug solution comparison of L-DOPA led to the appearance of signs of toxicity. In animals, decreased spontaneous motor activity, short-term difficulty in breathing (respiratory motion rare, spastic), piloerection, developed intermittent clonic-tonic convulsions. Provoking effects: tactile, sound and light stimuli, as well as the impact of the air jet caused a riotous reaction, abnormal motor response (unsteady gait, and falling to one side). After 2-3 hours from the last administration, the level of spontaneous motor activity was recovered. And the subsequent monitoring of animals within the next 14 days have not found any changes of animal behavior.

The introduction of DOPA-PC and comparison drug L-DOPA to Wistar rats weighing 250 g were carried out according to the same scheme - within 5 hours. Observations of the animals showed signs of toxicity in the group of animals treated with L-DOPA, after administration of 75 mg/kg. When administered twice bolshej� number of DOF-PC (L-DOPA) - 150 mg/kg, did not lead to the appearance of any visible signs of toxic action of the drug during the first day and subsequent 14 days after drug administration.

Thus, in the study of acute toxicity found that intranasal (through multiple short intervals) the introduction of the composition DOPA-PC, as much as possible for the kind of volume and dose were not accompanied by deaths of the test animals. The highest total dose DOPA-PC, achieved by repeated intranasal routes of administration, respectively: in mice of the line Balb/c - 540 mg/kg (10 μl in each nostril, every 5 min); Wistar rats (150 mg/kg (20 μl in each nostril, every 5 min). Intranasal introduction according to the same scheme L-DOPA also was not accompanied by mortality of the test animals, but passing the toxic manifestations were found in significantly smaller doses and were more pronounced than the effect of "DOPA-PC". Observed good tolerance of the studied tools. Deaths or severe manifestations of toxic effects at the time of introduction and throughout the 14 days of observations were noted. The drug had no irritation at the injection site.

In the macroscopic examination of the organs and morphometric analysis, pathological studies have not found doscover�x changes in selected organs and tissues of animals treated with the test composition DOPA-PC relative to organs and tissues in animals of the control group and comparison drug L-DOPA.

Thus, the drug - DOPA-PC in the conditions of subacute experiment with and W/o administration to rats of 20 mg/kg and 50 mg/kg (on the active substance) caused no deaths, had no pronounced toxic effects. Observed tolerability of study medication. These data suggest the safety of nasal application of DOPA-PC.

Thus, a new technical result is achieved by the totality of all existing signs proposed pharmaceutical compositions on the basis of L-DOPA, which allows to achieve a positive pharmacological action at lower doses, thereby reducing the risk of and degree of occurrence of toxic effects and achieve the effect of prolongation of the operation, the lower frequency reception in treatment and a new method of administration.

The technical result of the invention is achieved by including a new pharmaceutical composition, built on the basis of L-DOPA, commercially available biodegradable polymers, authorized for medical use. As such, using a copolymer of glycolic and lactic acids (PLGA) with a molecular weight of from 10 to 300 kDa and a molar ratio of residues milk�Oh and glycolic acid of 50/50%. To obtain a stable dosage form is also applicable surface-active agent is polyvinyl alcohol and the cryoprotectant-D-mannitol. The proposed pharmaceutical composition is prepared by a modified method of simple (single) emulsification (water/oil).

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1. Drug for treatment of Parkinson's disease on the basis of micronized L-DOPA (3-hydroxy-L-tyrosine) as active ingredient, characterized in that it is a stable particle, or a copolymer containing lactic and glycolic acids 50/50 (PLGA 50/50), or a copolymer of lactic and glycolic acid 75/25 (PLGA 75/25), or a copolymer of lactic and glycolic acids 50/50 with a carboxyl group (PLGA-COOH 50/50), or a polymer of lactic acid (PLA), D-mannitol, and polyvinyl alcohol (PVA), or tween-80 in the following ratio of components, wt.%:

PLGA 50/50 (or PLGA 75/25, or PLGA-COOH 50/50,
or PLA)75,0÷79,0
D-mannitol 7,5÷8,0
PVA (or tween-80)else

2. Pharmaceutical composition according to claim 1, characterized in that one uses the stable particles of submicron size of from 100 to 400 nm.


Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and their pharmaceutically acceptable salts, wherein A is thiazolyl, oxazolyl, thienyl, furyl, imidazolyl, pyrazolyl or oxadiazolyl (structures of which are presented in cl.1 of the patent claim), R1 represents C1-6alkyl; R2 represents (i) phenyl substituted by halogen; C1-6alkyl optionally substituted by morpholine or C1-6dialkylamino; C1-6alkoxy optionally substituted by halogen; or heterocyclyl, wherein a heterocyclyl substitute is specified in morpholine; pyrazolyl optionally substituted by C1-6alkyl; piperidinyl; pyrrolidinyl; oxadiazolyl substituted by C1-6alkyl; furyl substituted by C1-6alkyl; dioxydoisothiazolidinyl; triazolyl; tetrazolyl substituted by C1-6alkyl, tridiazolyl substituted by C1-6alkyl; thiazolyl substituted by C1-6alkyl; pyridyl; or pyrazinyl; (ii) substituted or unsubstituted heterocyclyl specified in quinolinyl; pyridyl substituted by C1-6alkoxy or morpholinyl; or benzo [d] [1, 2, 3] triazolyl substituted by C1-6alkyl; R3 represents phenyl substituted by 2 or 3 substitutes specified in halogen; C1-6alkyl; C1-6alkoxy optionally substituted by halogen; hydroxy group; cyano; or -C(=O)ORa, wherein Ra represents phenyl; R4 represents hydrogen, C1-6alkyl or C1-6halogenalkyl. The invention also refers to a pharmaceutical composition containing the compounds of formula (I), a method for PDE10 inhibition, a method of treating neurological disorders, and to intermediate compounds: 2-(4-chlor-3,5-dimethoxyphenyl)furan and 4-(5-methyl-1,3,4-thiadiazol-2-yl)benzaldehyde.

EFFECT: compounds of formula (I) as PDE10 inhibitors.

39 cl, 13 ex, 2 tbl, 77 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents a pharmaceutical composition for treating Parkinson's disease, containing a pharmaceutically acceptable carrier and a combination of flat doses of controlled release pramipexole and controlled release rasagiline; the above combination of flat doses contains pramipexole in an amount of 0.06 mg to less than 1.5 mg and rasagiline in an amount of 0.05 mg to less than 1.0 mg.

EFFECT: invention provides the synergetic action of rasagiline and pramipexole in treating Parkinson's disease.

3 cl, 11 dwg, 3 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents a prolonged-release pharmaceutical composition containing entacapone, consisting of an immediate-release layer and a prolonged-release layer.

EFFECT: composition provides the prolonged release of the therapeutic agent, its uniform blood plasma concentration and lower rate of composition intake.

11 cl, 11 ex, 23 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and represents pharmaceutical compositions and oral dosage forms including granules prepared by wet granulation at a great shear force and containing an anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate and C6-18 alkylsulphate. The invention also consists in methods of treating Parkinson's disease, schizophrenia, cognitive disorder, restless leg syndrome, periodic limb movement disorder, delayed dyskinesia, Huntington disease, hypertension and daytime sleepiness by administering a therapeutically effective amount of the pharmaceutical composition or dosage form into the patient.

EFFECT: controlling the formation of crystalline (2R)-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate hydrate.

18 cl, 11 ex, 11 tbl, 9 dwg

FIELD: medicine.

SUBSTANCE: group relates to peptides or polypeptides inducing the anti-alpha-synuclein antibody production in vivo for producing medicaments for preventing and/or treating synucleinopathies.

EFFECT: producing the peptides or polypeptides, which induce the antibodies responsible for the removal of the alpha-synuclein involved in the production of alpha-synuclein aggregates, the Lewy bodies, or for the dissolution of alpha-synuclein aggregates, the Lewy bodies in the individual suffering from synucleinopathies.

22 cl, 3 ex, 5 tbl, 5 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and presents a pharmaceutical composition for injections for acute forms of parkinsonian syndrome characterised by the fact that an active substance is presented by a therapeutically effective amount of N-(2-adamantyl)-hexamethylenimine hydrochloride (hymantan), and additive substances are presented by water for injections or a physiological solution. The invention also concerns a method for preparing the pharmaceutical composition.

EFFECT: pharmaceutical composition possesses storage stability, releases the active substance easily that provides its high bioavailability and efficacy.

6 cl, 15 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a group of inventions involving a pharmaceutical composition, a method of preparing it, a method of treating Parkinson's disease and a method of reducing a 'wear' effect in the given patients by administering the same. The pharmaceutical composition in the form of a single oral dose for treating Parkinson's disease consists of a mixture of a) Levodopa or its salt in an amount of 50 mg to 300 mg in the form of prolonged release, b) Carbidopa or its salt in an amount of 10 mg to 100 mg in the form of prolonged release, wherein the prolonged release is ensured by coating or mixing Levodopa and Carbidopa with one or more rate control polymers, and c) Entacapone or its salt in an amount of 100 mg to 1000 mg in the form of prolonged release, optionally with other pharmaceutically acceptable excipients.

EFFECT: group of inventions promotes patient's treatment compliance; using it leads to a stable blood content of active antigens and to reducing administration rate that provides reducing the 'wear' effect in the patients with Parkinson's disease; besides, the additional technical effect ensured by the composition consists in its stability at high temperature and humidity.

9 cl, 15 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to using an oxadiazolyl compound of the formula I


wherein R1 and R2 mean hydrogen; X means a methylene group; Y represents an oxygen atom; n represents an integer of 0, 1, 2 or 3, and m represents an integer of 0 or 1; R3 means a group of N-oxide pyridine according to the formula B which is attached as shown by an unmarked bond: ,

wherein R4, R5, R6 and R7 are the same or different and mean hydrogen, lower alkyl, halogen, haloalkyl, trifluoromethyl; the term "alkyl" means carbon chains, unbranched or branched, containing one to six carbon atoms; the term "halogen" means fluorine, chlorine, bromine or iodine; or its pharmacologically acceptable salt for preparing a drug for preventing or treating diseases related to the central and peripheral nervous system, wherein the above drug is administered according to a dosage regimen characterised by a dosage rate within approximately twice a day to approximately once every two days.

EFFECT: optimising the dosage regimen.

84 cl, 3 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to chemical-pharmaceutical industry and presents using (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethinyloctahydroindole-1-carboxylic acid methyl ester for treating, preventing or arresting the development of dyskinesia caused by levodopa (L-dopa) in treating Parkinson's disease.

EFFECT: invention refers to a pharmaceutical composition, a kit and a foodstuff containing (-)-(3aR,4S,7aR)-4-hydroxy-4-m-tolylethinyloctahydroindole-1-carboxylic acid methyl ester.

5 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel imidazopyridine or imidazopyrimidine derivatives of formula (I) and to pharmaceutically acceptable salts and esters thereof, where A is N or C(R6); R1 is hydrogen, lower alkyl; R2 is halogen, C(O)NR7R8 or C(O)OR9; R3 is hydrogen, NR10R11; R4 is hydrogen, lower alkyl; R5 is phenyl or thiazolyl or pyridine, which can be substituted with one substitute independently selected from a group consisting of halogen; R6 is hydrogen, halogen, CN, C3-C6cycloalkyl; R7 and R8 are independently selected from a group consisting of hydrogen, lower alkyl, lower alkoxy-lower alkyl, fluoro-lower alkyl, C3-C6cycloalkyl, N(H,lower alkyl)-lower alkyl, hydroxy- lower alkyl, hydroxy-lower alkoxy- lower alkyl, N(lower alkyl2)C(O)- lower alkyl, lower alkoxy, hydroxy-lower alkyl-oxetanyl- lower alkyl, oxo-tetrahydrofuranyl, tetrahydrofuranyl-lower alkyl, hydroxy-fluoro-lower alkyl, tetrahydrofuranyl, phenyl and thiazolyl or pyridine, or R7 and R8 together with a nitrogen atom with which they are bonded form a heterocyclyl selected from a group consisting of pyrrolidinyl, azetidinyl, morpholinyl, 5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazinyl, 3,4-dihydro- 1H-pyrrolo[1,2-a]pyrazinyl, 2-oxa-6-aza-spiro[3.3]heptyl, 5,6-dihydro- 8H-imidazo[1,2-a]pyrazinyl, [1,4]oxazepanyl, piperazinyl, thiomorpholinyl and 2-oxa-5-aza-bicyclo[2.2.1]heptyl, where the heterocyclyl is optionally substituted with 1 or 2 substitutes independently selected from a group consisting of halogen, lower alkyl, lower alkyl-C(O), lower alkoxy-lower alkyl, oxo, hydroxy, hydroxy-lower alkyl, N(lower alkyl2); R9 is lower alkyl; R10 and R11 together with a nitrogen atom with which they are bonded form a heterocyclyl selected from a group consisting of piperidinyl, morpholinyl. The invention also relates to a pharmaceutical composition based on the compound of formula (I), a method of treating said pathological conditions and use of the compound of formula (I).

EFFECT: obtaining novel imidazopyridine or imidazopyrimidine derivatives which are PDE10A inhibitors.

24 cl, 94 ex

FIELD: medicine.

SUBSTANCE: agent contains a nanocomposite representing carbon-containing nanoparticles coated with organic alkyl functional groups presenting radicals -C4H9, -C6H11, -C8H15, -C10H21, -C16H33, -C18H35. The above groups are applied by covalent modification with using diazonium salts of the general formula XC6H4N2+ -Y, wherein X is an alkyl radical C4H9, -C6H11, -C8H15, -C10H21, -C16H33 or C18H35, Y-anion -HSO4, -Cl, -BF4 or -OTs.

EFFECT: reducing blood plasma cholesterol and triglycerides effectively.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: method of producing dry earthworm powder includes: contacting live earthworms with chloride(s) of at least one metal selected from a group consisting of potassium, sodium, magnesium and calcium; subsequently contacting the live earthworms with powder of a hydroxycarboxylic acid(s) (or aqueous solution) and diluting the obtained mixture with water to adjust pH to 2-5, followed by leaving the live earthworms to stand for 3-180 minutes, washing the live earthworms with water, grinding the washed live earthworms and freeze-drying the obtained ground product (version).

EFFECT: method enables to obtain powder with high enzymatic activity.

6 cl, 8 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: highly dispersive pharmaceutical composition contains from 5 to 100 mg of budesonide per 1 g of β-glycine. Composition is characterised by bulk density 0.008-0.035 g/cm3 and consists of porous spherical agglomerates with diameter to 50 mcm and separate fragments, formed in the process of destruction of agglomerates, which represent complex of joined into perforated layers separate particles. Composition is obtained by method, based on dispersing into tank with liquid nitrogen solutions of initial substances in mixed solvent tetrahydrofurane-water, in which concentration of tetrahydrofurane constitutes 20-25 wt %, solvents are removed from obtained by dispersion mixture of solid phases in dry nitrogen flow under pressure 100 Pa until pressure drop less than 2 Pa by step-by-step temperature increase in the interval from -196°C to -5°C to decompose clathrate hydrate formed in the system tetrahydrofurane-water and to remove components of used mixture of solvents by sublimation, then from -5°C to +30°C to remove residual moisture, with application of initial substances budesonide and α-glycine in mixed solvent tetrahydrofurane-water with ratio budesonide from 0.25 to 0.9 mg/g of solvent, α-glycine from 8 to 50 mg/g of solvent.

EFFECT: improved method of composition obtaining.

2 cl, 5 dwg, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: as medications composition includes beclomethazone dipropionate and salbutamol, with beta-glycine serving as carrier. Composition is obtained by dispersing solutions of initial medications in mixed solvent into tank with liquid nitrogen with further removal of solvents from obtained by dispersion mixture solid phases in dry nitrogen flow under pressure 600±20 mtorr to pressure drop less than 8 mtorr with stopping nitrogen supply by step-by-step increase of temperature: in the interval from -196°C to -15°C, then from -15°C to +30°C. As initial substances used are: beclomethazone dipropionate 1.9-5.1 wt %, salbutamol 1.9-10.2 wt %, alpha-glycin to 100%. Composition of mixed solvent includes tetrahydrofurane 5-15 wt %, tert-butyl alcohol 15-5 wt %, water 77-80 wt %.

EFFECT: invention provides obtaining highly dispersed pharmaceutical composition of salbutamol and beclomethazone dipropionate.

2 cl, 10 dwg, 3 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to medicine and concerns a method for preparing a spray-dried stable powder composition containing an antibody or its antigen-binding fragment; a pharmaceutical preparation containing an effective amount of the spray-dried stable powder composition containing the antibody or its antigen-binding fragment and prepared by the method described above; the spray-dried stable powder composition prepared by the method described above, containing the antibody or its antigen-binding fragment, and an excipient, wherein the composition contains residual moisture of 6% or less and the antibody or its antigen-binding fragment is specified in a group consisting of MAK 195F, ABT-325, ABT-308 or ABT-147.

EFFECT: group of inventions provides preparing the spray-dried high-stability powder composition.

44 cl, 11 dwg, 14 tbl

FIELD: biotechnologies.

SUBSTANCE: invention represents a producing method of cream containing fusidic acid, which involves a stage of application of sodium fusidate as an initial active ingredient and conversion of the above sodium fusidate in situ to fusidic acid in an oxygen-free medium by immediate addition of the acid to a cream base containing a preservative, an acid, a cosolvent, an emulsifier, a wax-like product and water.

EFFECT: obtaining cream having high stability at storage and smaller particles of an active ingredient.

9 cl, 11 tbl

FIELD: chemistry.

SUBSTANCE: invention represents pharmaceutical composition for correction and therapy of manifestations of amyloid intoxication in patients with brain pathologies, which are characterised by the fact that it contains melatonin 3-10 mg and memantine 5-300 mg.

EFFECT: effective treatment of patients, including cases of moderate cognitive disorders.

4 cl, 2 ex, 6 tbl, 7 dwg

FIELD: chemistry.

SUBSTANCE: group of inventions relates to a composite organic substance powder for use in medicine, a suspension for use in medicine in which the composite powder is dispersed in water and a method producing the composite powder. In the composite powder, the surface of particles of a poorly water-soluble crystalline organic substance are partially or completely coated with a carboxyvinyl polymer and the average diameter of particles coated with the carboxyvinyl polymer, obtained by calculating the BET specific surface is in the range of 50-400 nm. The method of producing the composite powder includes mixing a poorly water-soluble crystalline organic substance powder, a physiologically acceptable salt, a physiologically acceptable polyol and a carboxyvinyl polymer, pulverising the organic substance powder and removing the salt and the polyol after the pulverisation.

EFFECT: invention enables to obtain a medicinal preparation with a low degree of contamination with a pulverisation medium and with improved bioavailability.

6 cl, 8 dwg, 2 tbl, 38 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents an injectable form of 5α-androstane-3β,5,6β-triol containing a liquid injectable form, containing a solvent, or a solid injectable form containing at least one soluble additive with the above at least one soluble additive containing hydroxypropyl-β-cyclodextrine.

EFFECT: invention provides preparing the stable injectable form of 5α-androstane-3β,5,6β-triol.

10 cl, 7 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the chemical-pharmaceutical industry and represents a carrier for chewing gum in the form of particles for the controlled release of an active ingredient (ingredients), absorbed in the said carrier and/or adsorbed on it, characterised by the fact, that the said carrier contains 0.1-50 mcm of a calcium carbonate particle, preliminarily processed with an acid, selected from the group, which consists of H2SO4, HSO4-, H3PO4, oxalic acid and their mixtures, and gaseous CO2, and the specific area of surface of BET particles of calcium carbonate is increased to the level more than 15 m2/g according to the standard method of measuring the specific area of BET surface.

EFFECT: obtaining the carrier for chewing gum.

6 cl, 10 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine. What is described is a transdermally absorbable formulation prepared by dissolving donepezil in an adherent plaster base, which contains a hydrophobic polymer and an absorption enhancer. The absorption enhancer represents one substance, or two or more substances specified in lauryl alcohol, triethyl citrate, isopropylmyristate, cetyl lactate, oleyl alcohol, sorbitan monooleate, polyethyleneglycol monostearate, lauromacrogol, N-methyl-2-pyrroldone and triacetin.

EFFECT: transdermally absorbable formulation can administer donepezil stably for a relatively long period of time and can provide both blood donepezil increase, and the properties of sustained release of donepezil.

4 cl, 4 dwg, 6 tbl, 26 ex