Pharmaceutical composition of s1p receptor agonist for treatment of demyelinating diseases (versions) and method of its obtaining

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to field of pharmacology and clinical medicine and describes pharmaceutical compositions of 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diole in free form and/or in form of pharmaceutically acceptable salt, where as auxiliary substances they contain lactose, starch and/or starch derivatives, selected from acetylated starch, sodium salt of starch carboxymethyl ether, pregelatinised starch, sodium starch glycolate, gelatin, binding agent, and lubricant with specified ratio.

EFFECT: invention makes it possible to extend possibility for cheaper in industrial manufacturing preparation for treatment of disseminated sclerosis.

7 cl, 16 ex

 

The invention relates to the field of pharmacology and clinical medicine and relates to pharmaceutical compositions of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form and/or in the form of a pharmaceutically acceptable salt, or formerly known as FTY720 for treating, alleviating or delaying the flow and/or progression of multiple sclerosis. The present invention relates to pharmaceutical compositions that contain at least one agonist of S1P receptor for the treatment of demyelinated diseases, such as multiple sclerosis and associated with this pathology consequences.

Multiple sclerosis (PC) is a chronic autoimmune disease in which affected myelin sheath of nerve fibers in the brain and spinal cord. Multiple sclerosis is accompanied by a chronic inflammatory demyelination, leading to the extinction of motor and sensory functions and long-term disability. The disease occurs at the age of 15-40 years. Although at the moment there are known cases of this diagnosis in children three years and older. The peculiarity of this disease is the simultaneous defeat of several different parts of the nervous system, resulting in in patients with a variety of neurological symptoms. Morphological basis of this disease is the formation of so-called plaques is asianova sclerosis - lesions destruction of myelin (demyelination) of the white matter of the brain and spinal cord. The size of the plaques, usually from a few millimeters to a few centimeters, but with the progression of the disease, the formation of large fused plaques. The same patient special methods of research, you can identify plaques of varying degrees of activity of fresh and old.

The process could take four types of disease models of multiple sclerosis:

- Recurring-weakening (RR-MS). Manifested in the form of a separate motor, sensory, cerebellar or visual attacks of the disease. Can last more than 1-2 weeks and can weaken after about 1-2 months of treatment, or even without treatment. About 85% of patients initially suffer form recurring-weakening (RR) multiple sclerosis (MS), but within 10 years, approximately half of them develop a form of secondary progressive MS.

- Secondary progressive (SP-MS). Characterized by gradually increasing helplessness with recurrences, although perhaps without them. As a rule, in the period of secondary-progressive MS, there is a disability, expressed in disability, until irreversible.

- Primary progressive (PP-MS). Disease proceeds from the outset, without any relapses or remissions, the situation is about 15% of MS patients.

Progressive relapsing (PR-MS). Progressive disease, from the outset characteristic expressed by acute relapses. In the periods between relapses, there is a steady development of the disease.

As the disease itself, however, as the effects are accompanied by severe disturbances in the quality of life: reducing disability and human social activity, there is a high need for effective drugs for the treatment of demyelinization diseases - multiple sclerosis, Guillain-Barre syndrome. The use of such medicines should be characterized by clinical signs, which will manifest itself in the form of reduction, mitigation, stabilization or alleviate symptoms of the disease.

Already known drugs, combinations containing at least one agonist of S1P receptor and another therapeutically active agent, or a composition containing at least one agonist of S1P receptor and a pharmaceutically acceptable excipient. The proposed compositions have a therapeutically useful effect on demyelinization diseases such as multiple sclerosis.

Agonist S1P-receptor is a means of accelerating the migration of lymphocytes (CHL), which cause lymphopenia resulting redistribution in the core the main irreversible, lymphocytes from circulation to secondary lymphatic tissue, without General immunosuppression.

The agonist S1P-receptor are typical counterparts sphingosine, such as 2-amino-2-tetradecyl-1,3-propandiol or 2-aminopropanol. Especially preferred agonist S1P-receptor is the compound 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form or in the form of a pharmaceutically acceptable salt, for example in the form of hydrochloride.

Known following the publication describing this connection. International application WO 2006058316 "the dosage of the S1P modulator of the receptor or its agonists in the treatment of patients after transplantation or patients with autoimmune diseases or disorders; WO 2005123104 "Method of treating patients suffering from cancer"; WO 2004113330 "a New class of compounds of immunosuppressive drugs used in the treatment or prevention of diseases or disorders through effects on lymphocytes, particularly diseases associated with signal transmission through the EDG receptor"; RF application 2007136602 "Application of S1P receptor modulators in ophthalmology"; RF application 2009102278 describing the S1P receptor Modulators for the treatment of multiple sclerosis; RF application 2008117083 "Bicyclic aromatic compounds used as inhibitors proteinkinase, activated mitogenactivated protein kinase; RF application 2009115439 Pharmaceutical composition comprising an S1P modulator"; RF application 2007133561 "Induction antilimfocitarnyi antibody combination of agonist/modulator RECEPTOR S1P and immunosuppressive medicines; RF application 2007124327 "treatment with the use of agonist of S1P receptor; application US 2011124605 "the Use of agonist of S1P receptor"; application WO 2011041146 "the dosage of the S1P receptor modulators"; application US 2004235794 "tool for the treatment of respiratory diseases, which includes a controller sphingosine-1-phosphate receptors"; application EP 2209493 Composition comprising a modulator of the receptor S1P";

The following article.

Antagonism of Sphingosine-1-Phosphate Receptors by FTY720 Inhibits Angiogenesis and Tumor Vascularization, /Kenneth LaMontagne et al. Cancer Res. January 2006, 66, 221-231/; Seminars in Cell & Developmental /Biology Volume 15, Issue 5, October 2004, Pages 513-520 Timothy Hla, Biology of Lysophosphatidic Acid and Sphingosine 1-phosphate and Polarity in Mammalian Development; Effects of a novel immunomodulating agent, FTY720, on tumor growth and angiogenesis in hepatocellular carcinoma /Ho JW, Man K, Sun CK, Lee TK, Poon RT, Fan ST. Mol Cancer Ther. 2005 Sep; 4(9): 1430-8./; FTY720 in relapsing MS: results of a double-blind placebo-controlled trial with a novel oral immunomodulator /23/06/2005 Kappos L, Radue EW, Antel J, et al./; Developing therapeutics for the treatment of multiple sclerosis /David J Virley NeuroRx 2(4): 638-49 (2005) PMID 16489371/; Angiogenesis in multiple sclerosis: is it good, bad or an epiphenomenon? / Kirk S, Frank JA, Karlik S. J Neurol Sci. 2004 Feb 15; 217(2): 125-30.

Thus, the prior art known to use medical the practice in various diseases of the S1P receptor modulators. Effective representatives of this class are 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and its pharmaceutically acceptable salts.

However, when the dosage forms of the compounds belonging to aminodiol, there are considerable difficulties, especially when creating their solid forms, stable during storage. Known solid dosage forms are described, for example, in applications RF 2009115439 and RF 2009105403.

As the closest analogue may be specified in the application WO 2004089341 disclosing tablets and capsules containing the agonist of S1P receptors, such as FTY720, and excipients, including mannitol, cellulose derivatives, hydrogenated oil, lubricating, for example, magnesium stearate.

The purpose of the described invention is the provision of a stable pharmaceutical composition containing an effective amount of the active substance with cheap pharmaceutically permitted in the manufacture of excipients, and a more simple process implementation.

The proposed pharmaceutical composition has a high therapeutic efficacy in demyelinated diseases, especially multiple sclerosis or its associated effects and pathologies.

To implement the present invention, the composition that includes modulate the p receptor S1P, does not contain sugar alcohol and polyethylene glycol, which lead to the formation of unacceptable impurities during storage.

To ensure delivery of a therapeutically effective dose of a modulator of the receptor S1P pharmaceutically acceptable excipient is chosen to optimize the cost, ease, and stability of the production process. An important condition for the auxiliary substance is inert, chemical-physical compatibility with the active ingredient.

Thus, this invention proposes the inclusion in the composition of the first active agent or in free form and/or in the form of any pharmaceutically acceptable salt and the inclusion of related auxiliary substances for the formation of appropriate dosage forms and variants of the disintegration of the dosage form in the gastrointestinal tract.

To implement the present invention, the authors propose a pharmaceutical composition that includes a therapeutically active compound, namely 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and/or its pharmaceutically acceptable salt.

Important technological and pharmacological factor for excipients - unconditional moment is inert chemical-physical properties and also on the chemical-physical parameters is compatible with 2-amino-2-[2-(4-octylphenyl)ethyl]disappear to who -1,3-diola and/or its pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include inorganic salts such as hydrochloride, hydrobromide, phosphate and sulfate, salts with organic acids such as acetate, fumarate, maleate, benzoate, citrate, succinate, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with diskovnimi amino acids such as lysine.

Pharmaceutical excipients that are used in the claimed solid dosage forms such as tablets, capsules, granules, lozenges and the like, include milk sugar (lactose) in various forms: alpha-lactose or beta-lactose, monohydrate lactose monohydrate, alpha-lactose, anhydrous alpha-lactose and β-lactose and agglomerated lactose, starch and/or a derivative of starch, such as acetylated starch or sodium salt carboxymethylated ether starch, gelatinising starch, modified starches such as sodium starch glycolate, gelatin binder selected from the group including alginic acid, sodium salt of alginic acid, amylopectin, agar-agar or their mixtures, of a lubricant, such as talc, and/or paraffin, and/or twin, in particular tween-80.

Introduction starch having anti-slip properties, helps to reduce the content of other such aid is s substances talc - and eliminate calcium stearate.

The selected diluents, lactose (milk sugar), starch and derivatives of starch are property and dezintegriruetsja, and binders, and these additional factors are used according to the present invention, when the technology described pharmaceutical compositions. To ensure their rapid mechanical destruction in wet and/or liquid medium add dezintegriruetsja substances, including to facilitate dissolution and increase the bioavailability of the active component.

Binders used for granulation to increase the concentration of therapeutically active substance or substances, and other supporting ingredients in the formed granules. Binder ingredient contribute to increase the fluidity of the mixture and further pressing.

The lubricant in the manufacture of solid dosage forms used to exclude technological problems such as sticking of tablet mass production surface, and to reduce the buildup during the stages of pressing tablets, as well as to prevent "caking" mass storage in the case of other forms.

One of the preferred options is the use of two dezintegriruetsja substances, for example gelatinising starch and amylopectin.

According to the invention the composition may be in the form of options.

The first option provides for a pharmaceutical composition agonist of S1P receptor for the treatment of demyelinated diseases in the form of solid dosage forms for oral administration, which contains as active principle 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form and/or in the form of its pharmaceutically acceptable salts, as excipients lactose, starch and/or a derivative of a starch selected from the acetylated starch, sodium salt carboxymethylated ether starch, gelatinising starch, sodium starch glycolate, gelatin, a binder selected from the group including alginic acid, sodium salt of alginic acid, amylopectin, agar-agar, or their mixtures, of a lubricant selected from the group of talc and/or paraffin, in the following ratio, wt.%:

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
and/or its pharmaceutically acceptable salt0.25 to 1
actose 45-70
Starch and/or starch derivatives)20-38
Food gelatin1-2
Lubricating1-15
BinderRest

In the particular case of the talc can be contained in the amount of 1-1 .5 wt.%.

In the private case, the composition may contain as derived starch gelatinising starch, and as a binder amylopectin.

In preferred variants of the invention, the milk sugar (lactose) is about 45-65% by weight of the composition, gelatinising starch 5-15%, talc is from about 1-10% and paraffin, but not necessarily, approximately from 0.2 to 2.0%.

Another option is a pharmaceutical composition agonist of S1P receptor for the treatment of demyelinated diseases in the form of solid dosage forms for oral administration containing as active principle 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form and/or in the form of its pharmaceutically acceptable salts, as excipients lactose, starch and/or starch derivatives, selected from acetylated starch, sodium solidarnosciowa ether of starch, gelatinising starch, sodium starch glycolate, gelatin, talc in a mixture with the second lubricating agent selected from paraffin and/or tween-80 in the following ratio, wt%:

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
and/or its pharmaceutically acceptable salt1,0-2,0
Lactose30-45
Starch and/or starch derivatives)30-45
Food gelatin6-12
Talc1-6
Lubricating4-15

In some other embodiments, implementation of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol is 1.0% by weight of the composition, lactose (milk sugar) - 30,0-45,0%, twin, preferably tween-80, is 5-15%, most preferably at 10.5%, gelatinising starch - 11,0%, talc and gelatin - 6,0%, paraffin, not necessarily, is around 4.0%.

The pharmaceutical composition according to this invention is in the form of solid dosage forms, preferably, but not necessarily, in the form of tablets. This is ensures the accurate dosing of the active substance and the maximum adaptability subsequent packaging.

The ratio of auxiliary substances provides an indicator raspadaemosti 10-15 minutes, during which the optimal profile release 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol.

The method of obtaining the pharmaceutical composition is that 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and/or its pharmaceutically acceptable salt is mixed with a part of the lactose, then gradually with stirring, add the remaining quantity of lactose, enter the remaining excipients, provided that gelatin is used in the form of a 5% solution to obtain a solid dosage form.

A method of obtaining a solid dosage form according to this invention includes a step of preparing trituration mixture. This helps to ensure uniform mixing of the components. For the most uniform distribution of gelatin is added in the form of a 5%solution. These differences are the technological advantages of the claimed method in comparison with analogues and ensure optimal bioavailability of the active substance. The introduction of other auxiliary components depends on the desired form and may be made the conventional pharmaceutical methods. For example: granulation, powder and pressing - in the case of tablets, granulation or mix and napolneni the obtained granules or powder capsules, etc.

The invention is illustrated by the following examples.

Example 1. An example of a composition in the form of tablets, wt.% (the first option).

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol1
Milk sugar70
Acetylated starch20
Food gelatin2
Alginic acid6
Paraffin1

Example 2. A method of obtaining a composition in tablet form for treating, alleviating or delaying progression of multiple sclerosis.

1) Preparation trituration mixture. To ensure uniform mixing of small amounts of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol with other components initially prepare it blend in milk sugar, then add servings of milk sugar and mix thoroughly.

2) Obtain a wet granulate. In the reactor-mixer download milk sugar, pre-prepared mixture of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and milk sugar, Brahma is (and/or derivatives of starch) in an amount of about 95% of its total mass, the mixture is stirred for several minutes, then humidified 5%solution of gelatin in several portions until evenly moistened mass is stirred for several minutes. Next, the mixture mass is discharged from the mixer and granularit using pellet with diameter of the drum 1.5 mm and is passed to the drying of the granules.

3) Drying and dry granulation. The wet granulate is dried in a dryer at a temperature of (55±5)°C for 50-60 minutes residual moisture content preferably should be (3,0±0,5)%. Drying of the product by submitting a fan in the dryer warmed up to (60±5)°C air. After drying, the dried mass is passed through a granulator with a hole diameter of the drum 1,50 mm, the Dry granulate is passed the stage of formation of the tablet mass and further tableting.

4) Preparation of tablet mass.

In a reactor to obtain a pill-mass load of dry granules, talc, and the remaining quantity of starch, and, if necessary, grinding it into the granulator substandard tablet, everything is stirred for 15 min and discharged into the container.

The tabletting mixture is passed through tableting.

5) Tableting. Tableting is produced on the press. The mixture periodically serves every few minutes During tableting with a certain periodic the capacity of controlling the average weight of the tablets the appearance. The obtained tablets are sent to the stage of packing. Tablets are 0,00025; 0,0005; 0,001,

Example 3-4 are similar to examples 1 and 2, but as starch derivatives using sodium salt carboxymethylated ether of starch and sodium starch glycolate respectively.

Example 5. An example of a composition in the form of tablets, wt.%: (the first option).

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol0,50
Milk sugar68,57
Gelatinising starch26,81
Food gelatin1,67
The amylopectin1,0
Talc1,45

Example 6 Example of a composition in the form of pellets (composition in the first embodiment).

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol0,25
Lactose45,00
Starch38,00
VC is tin 1,00
A mixture of talc and wax15,00
A binder is a sodium salt of alginic acid0,75

Examples 7-8 are analogously to example 6, but as a binder to take one example, agar-agar, and the other a mixture of alginic acid sodium salt of alginic acid.

Example 9. An example of a composition in the form of granules (the second option).

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol1,00
Lactose39,18
Starch36,81
Gelatin11,60
Talc1,30
Tween-8010,11

Example 10. Hard gelatin capsules (the second option).

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol2,00
Lactose45,00
Starch + NAT the Oia starch, glycolate 35,71
Gelatin6,00
Talc1,30
Tween-809,99

Example 11

Hard gelatin capsules (the second option)

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol2,0
Lactose35,0
Sodium starch glycolate35,0
Gelatinto 12.0
Talc1,0
Tween-8015,0

Example 12.

Carried out analogously to example 11, but using gelatinising starch.

Example 13.

Hard gelatin capsules (the second option)

2-Amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol1,0
Lactose45,0
Sodium salt carboxymethylated ether of starch 38,0
Gelatin6,0
Talc6,0
Paraffin4,0

Example 14

Analogously to example 13, but using acetylated starch

Example 15

The study of stability of dosage forms.

The stability of the dosage forms was determined by the method of accelerated aging during storage for one month at 50°C. the characterization of the composition, including impurities, was carried out by the method of gradient liquid chromatography. The content of acetylated in the samples according to examples 1, 3, 4 was 0%. With the exception of gelatin from the formulation of example 1 - a 0.05%, and an average of more than 2% of other impurities. In the case example 3 on lactose mannitol - 3%.

The claimed pharmaceutical compositions are stable in storage and have a shelf life of more than 2.5 years.

Example 16.

The study of pharmacology.

Modulating activity of compounds was determined using conventional methods, namely using S1P receptors person: S1P1, S1P3, S1P2, S1P4and S1P5. Functional activation of the receptor was assessed by measuring the amount of GTP [Y-35S]associated with membrane protein derived from cord is tirovannyh cells SNO or RH7777, which stably Express the appropriate receptor S1P person. Used for the analysis acquired scintillation granules. Was prepared by serial dilution of the compounds of examples 1, 3, 4 from solutions in DMSO and added to the granules SPA (Amersham-Pharmacia) with immobilized S1P receptor expressing membrane protein (10-20 µg / well) in the presence of 50 mm Hepes, 100 mm NaCl, 10 mm MgCl210 μm (GDF), 0,1% BSA and 0.2 nm GTP [Y-35S] (1200 CI/mmol). After incubation in 96-well-microplate at RT for 120 min unbound GTP [Y-35S] was separated by centrifugation. Measured luminescence granules SPA, induced associated with membrane GTP [Y-35S], and the expected value EC50using standard software to approximate curves. The affinity in the binding with the receptor S1P was <50 nm on the results of the analysis of the binding of GTP [-35S] using receptors S1P1, S1P2, S1P3, S1P4or S1P5man. Thus, the data from the preparative form can be used as effective modulators of S1P.

The same affinity showed a form without content of gelatin. However, when assessing the bioavailability absolute bioavailability when administered such forms was 93%, and in the case of compositions according to the invention is 94%

The composition according to the invention can be used to enter to animalname pharmaceutical agents. The claimed compositions can be completed in a set, for example, with interferons in their content up to 1 MIU. They can also be combined with the mTOR inhibitor, which includes, but is not limited to rapamycin (sirolimus) or its derivatives in common for them therapeutic doses.

Thus, the invention enables the creation of secure dosage forms, characterized by the absence of degradation products of the active substance and high bioavailability.

1. The pharmaceutical composition of agonist S1P receptor for the treatment of demyelinated diseases in the form of solid dosage forms for oral administration containing as active principle 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form and/or in the form of its pharmaceutically acceptable salts and excipients, characterized in that the quality of excipients contains lactose, starch and/or starch derivatives, selected from acetylated starch, sodium salt carboxymethylated ether starch, gelatinising starch, sodium starch glycolate, gelatin binder, selected from the group including alginic acid, sodium salt of alginic acid, amylopectin, agar-agar, or their mixtures, of a lubricant selected from the group of talc and/or paraffin, in the following ratio com is onenow, wt.%:

2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
and/or its pharmaceutically acceptable salt0.25 to 1
Lactose45-70
Starch and/or starch derivatives)20-38
Food gelatin1-2
Lubricating1-15
BinderRest

2. The pharmaceutical composition according to claim 1, characterized in that it contains as lubricating talc in the amount of 1-1 .5 wt.%.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that it contains as derived starch gelatinising starch in the amount of 5-15% of the total amount of starch and a binder amylopectin.

4. The pharmaceutical composition according to claim 1, characterized in that the demyelinated disease represents multiple sclerosis.

5. The pharmaceutical composition of agonist S1P receptor for the treatment of demyelinated diseases in the form of solid dosage forms for oral administration, with the holding as the active agent 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol in free form and/or in the form of its pharmaceutically acceptable salts and excipients, characterized in that the quality of excipients contains lactose, starch and/or starch derivatives, selected from acetylated starch, sodium salt carboxymethylated ether starch, gelatinising starch, sodium starch glycolate, gelatin, talc in a mixture with the second lubricating agent selected from paraffin and/or tween-80, in the following ratio, wt.%:

2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol
and/or its pharmaceutically acceptable salt1,0-2,0
Lactose35-45
Starch and/or starch derivatives)35-45
Food gelatin6-12
Talc1-6
Lubricating4-15

6. The pharmaceutical composition according to claim 5, characterized in that the demyelinated disease represents multiple sclerosis.

7. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 6, characterized in that 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and/or Pharma is efticiency acceptable salt is mixed with a part of the lactose, then gradually with stirring, add the remaining quantity of lactose, enter the other auxiliary substances, provided that the gelatin used in the form of a 5%solution to obtain a solid dosage form.



 

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20 cl, 5 ex, 2 dwg, 16 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to physiotherapy, manual therapy. Method includes performing manual therapy with application "soft techniques" methods. Ischemic compression, postisometric relaxation of lumbar quadrate muscle, back erector, multifidus, iliolumbar, trapezoid muscles and mobilisation of blocked spine and peripheral joints. Session of manual therapy is carried out immediately after mud treatment. Mud treatment is carried out by application of mud on the area of back, at temperature 40° C, for 20 minutes. After 30 minutes after manual therapy session vibration massage is carried out. Impact is performed on the area of motor points of trapeziform, subspinous muscles, back erector at the level of breast and lumbar spine from both sides. Area of hypotrophic muscles is influenced with vibration with frequency 60 Hz, with application of notched applicator, for 2 minutes on each field, in accordance with labile method. Area of muscles in hypertonus is influenced with frequency 20 Hz, with application of multi-functional applicator, for 4 minutes on each field, by stable method. During one procedure 4 fields are influenced, each of which includes area of affected muscles from one side. Duration of procedure is 12 minutes. Course of treatment includes 10 procedures.

EFFECT: method increases efficiency of treatment by reducing spine curvature angle and forming muscle corset, which assists in preservation of obtained results of treatment, preventing possible progress of spine deformation degree, biomechanical and neurodystrophic abnormalities and formation of neurological complications.

1 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry, particularly a composition for preventing or treating peripheral neuropathy. The pharmaceutical composition for preventing or treating peripheral neuropathy containing a therapeutically effective amount of a compound presented by formula 1, or its salt and a pharmaceutically acceptable carrier: [Formula 1]

wherein R is a hydrogen atom, alkyl group C1-C4 or saccharide. A food composition for preventing or treating peripheral neuropathy containing the compound presented by formula 1, or its salt as an active ingredient.

EFFECT: compositions described above for preventing or treating peripheral neuropathy.

6 cl, 9 dwg, 1 tbl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a preparation having an effect on air passages, relieving coughing in a human and containing: 0.01%-40% of a polyethylene oxide film-forming agent; 0.01%-15% of a gelling material specific in sodium carboxymethyl cellulose, carboxymethyl cellulose and their mixture; and a number of excipients.

EFFECT: preparation is packed in spray bottles; it contains no active pharmaceutical substance, provides cough relief after 20 min after the use and as often as necessary.

4 cl, 13 dwg, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly a pharmaceutical composition for nasal introduction containing a hydrophilic biologically active substance and a peptide (a) having an amino acid sequence SEQ ID No:1 N0:1. (b) a peptide having the same amino acid sequence as shown in SEQ ID No:1, except that one or more amino acids are eliminated, substituted and/or added wherein the peptide is penetrable through nasal mucosa, (c) a peptide having an amino acid presented by a sequence reverse in relation to (a) or (b) wherein the peptide is penetrable through nasal mucosa; any of (a)-(c) provided the C-amidated peptide is eliminated. The hydrophilic biologically active substance is poorly absorbable through nasal mucosa which is commonly yet injectable, may be introduced nasally with the use of the declared peptide, particularly insulin or interferon beta.

EFFECT: invention provides injection-associated pain management and lower discomfort in the patients ensured by the nasal introduction of the composition.

7 cl, 5 ex, 8 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine, and concerns a method for therapeutic cell transportation into the disturbed, or degenerative, or injured animal's central nervous system, wherein the disturbances or degenerations are caused by a neurological disease or condition leading to cell apoptosis or death, involving application of at least one therapeutic cell in an upper one-third of mammal's nasal cavity.

EFFECT: invention provides non-invasive and high-directed therapeutic cell delivery.

30 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine, in particular to surgery, namely to means, used in treatment of bleeding traumatic injuries, flat granulating torpid wounds in stage of regeneration, burns of II and IIIa degrees, trophic ulcers, bedsores in healing of donor parts. Composition for wound treatment and products on its basis are made on the basis of natural biopolymers and represent polyelectrolyte protein-polysaccharide complex, covalently cross-linked with polyfunctional epoxy-compounds, containing as anionogenic protein collagen of type I, isolated from cattle skin, reindeer skin, and/or gelatin, and cationogenic polysaccharide is selected from a series of water-soluble powder-like heteropolymers of chitosonium salts. Product on the basis of composition can be made in form of colloid solvent, hydrogel, film, sponge, powder, cosmetic mask, cosmetic compress.

EFFECT: composition increases prolonged action, increases level of physicomechanical characteristics of finished products.

14 cl, 6 ex, 1 tbl

Silk proteins // 2467015

FIELD: medicine.

SUBSTANCE: there are produced silk polypeptides having a double-spiral structure and originated from honey bee, bumble bee, bulldog ant, green tree ant and golden-eyed fly. A recombinant method is used to produce a host cell, transgenic plant and animal which produce silk polypeptide. Antibodies are produced for prepared polypeptides.

EFFECT: invention enables using producing silk polypeptides in various fields of industry.

21 cl, 14 dwg, 14 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is application of an effective amount of the composition containing nanoparticles containing taxane and a carrier protein for preparing a drug for a proliferative disease in a combination with an effective amount of at least one other chemotherapeutic agent specified in a group consisting of antimetabolite, platinum agents, alkylating agents, tyrosine kinase inhibitors, anthracycline antibiotics, vinca alkaloids, proteasome inhibitors, macrolides, a therapeutic antibody, an antiangiogenic agent, geldanamycin, 17-AAG and topoisomerase inhibitors; a related composition and a kit.

EFFECT: shown higher clinical effectiveness in combined treatment of even hard-to-treat cancers, including cancer of lungs and pancreatic cancer with no new toxicity cases detected.

46 cl, 9 dwg, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention represents a composition and methods for production of stable docetaxel pharmaceutical compositions. In one implementation version the invention represents a pharmaceutical composition containing docetaxel nano-particles, dry form docetaxel used for the composition production. The average size of the nano-particles is no more than 200 nm. The composition additionally includes a biocompatible polymer representing the carrier protein which is albumin. In the second version the pharmaceutical composition includes docetaxel nano-particles and additionally contains a citrate. According to the invention, the compositions are physically stable and show no signs of sedimentation or precipitation during at least 8 hours after repeated recovery or repeated hydration.

EFFECT: composition is used for production of a medication for cancer treatment.

116 cl, 7 dwg, 6 tbl, 39 ex

FIELD: cosmetics.

SUBSTANCE: invention refers to cosmetic compositions for the care of mammal skin and people in particular. The compositions contain a) 1-40 wgh.% of the lipid depot from one or more modified lipids chosen among natural or synthetic lipids, oils, waxes, fatty alcohols, esters of complex fatty acids, glycerides, lecitins, sphingolipids, cholesterins, phospholipids, gangliosides, cerebrosides, ceramides and their mixtures; b) 0.01-12 wgh.% of one or more proteins with the average molecular mass 3500-8000 Da chosen among the proteins of buckwheat, millet, German wheat, tapioca; c) 0.01-10 wgh.% of one or more active agents chosen among the reduced nicotinamide-adenine dinucleotide (NADH), peroxydase, erythorbic acid, glutathione, alpha-liponic acid, green tea extract, cystus tea extract, apple meletin, blackberry extract, elderberry extract or their mixtures; d) 0.1-20 wgh.% one or more adjuvants; e) the rest is water.

EFFECT: invented composition can be used in cosmetic or cosmetic-bineal purposes, in particular, in the liquid, semi liquid or hard form, in the type of emulsion like "oil in the water", "water in the oil", gel emulsion, gel, cream, balsam, lotion, milk, face masks, aerosols, bath and shower additives.

7 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics. Composition contains botulinum toxin, polysorbate 20 and methionine, where methionine is present in amount from 25 to 75 mM, and polysorbate 20 is present in amount from 0.1 to 2.5 mg/ml.

EFFECT: composition possesses improved stability; application of liquid pharmaceutical composition in form of combination of polysorbate 20 and methionine as botulinum toxin stabilisers instead of proteins of animal origin albumin and gelatin eliminates risk of organism contamination by pathogens or microorganisms of serum origin and makes it possible to introduce into organism safely; in addition, composition is convenient for application in direct introduction to patients.

8 cl, 8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmacology and represents lyophilised medication for treatment of chronic viral hepatitis B or C and AIDS, which contains alpha fetoprotein (AFP) 60-150 mcg, interferon α 3000000-6000000 U and dextran 2-6 mg.

EFFECT: invention ensures improvement of treatment results, reduction of complications and treatment terms.

4 cl, 9 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine. Described is system of transdermal delivery of medication for passive transdermal delivery of one or more than one ionised active agent onto biological surface of subject. System of transdermal medication delivery includes carrying substrate and layer of active agent. Layer of active agent includes thickening agent, plasticiser and therapeutically efficient quantity of ionised active agent.

EFFECT: claimed is novel system of transdermal medication delivery for passive transdermal delivery of one or more than one ionised active agent onto biological surface of subject.

23 cl, 32 dwg, 7 ex

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