Tetrodotoxin-based lyophilised preparation and method of its production

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to methods of obtaining a lyophilised preparation of tetrodotoxin and to a tetrodotoxin preparation for relief of the drug withdrawal in case of addiction to opiates. The method of obtaining the lyophilised preparation of tetrodoxin includes the following stages: 0.1-20 mcg/dose of tetrodotoxin is dissolved with 0.1% solution of citric acid to regulate pH within the range of 3.5-4.5 in injection water and filtered to remove pyrogen; separately dissolved are: a stabiliser - dextran or trehalose - and a filling agent, representing an isotonic solution of sodium chloride or mannit in injection water. After that, 0.1% solution of citric acid is added to regulate pH within 3.5-4.5, then, activated carbon is added with keeping at a temperature of 60°C and mixing for more than 30 minutes, filtering to remove pyrogen and cooling to room temperature. After homogeneous mixing of the obtained solutions and realisation of ultrafiltration, lyophilic drying is carried out. Lyophilic drying consists in preliminary freezing, drying under vacuum at reduced temperature, drying under vacuum at increased temperature, with each drying being performed at a certain temperature for the specified time period. After that, filling with inert gas is performed with control of water content at 3% level, with further sealing. Another version includes addition of additional solution of lidocaine chloride to the solution of tetrodotoxin and citric acid at the first stage. Also disclosed is the tetrodotoxin preparation for relief of the drug withdrawal in case of addiction to opiates, obtained by the said method, which is characterised by the weight ratio tetrodotoxin:filling agent:stabiliser, equal to 1:(150-3000):(50-6000).

EFFECT: claimed group of inventions ensures obtaining the stable tetrodotoxin solution with accurate dosage, which is used for introduction into the human organism.

25 cl, 9 tbl, 14 dwg

 

1. The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to liofilizovannye powdered drug and the method of its production. In particular, the present invention relates to liofilizovannye the drug, including from the stabilizer and filler with a strictly defined number of specifications as the main active ingredient. Liofilizovannye powdered drug and the method thereof can be used to relieve withdrawal symptoms in dependent on opiates, such as ice and heroin, and drug amphetamine type with the rapid initial effect of habituation and strong impact. It provides fast and powerful influence in getting rid of drug addiction. Additionally, liofilizovannye drug TTH stable and secure and has a slight irritant effect on the human body.

2. The prior art PRIOR to the INVENTION of

Tetrodotoxin is a natural non-protein neurotoxin. Has the following chemical structure:

Chemical name: Octahydro-12-(hydroxymethyl)-2-imino-5,9: 7,10A-dimethano-an-[1,3] dioxolo[6,5-d]pyrimidine-4,7,10,11,12-pentol. English name tetrodotoxin (tetrodotoxin) and the abbreviation for specifications.

Studies show that TTX can be used in isulan to relieve withdrawal symptoms in dependent on opiates, such as ice and heroin, and drug amphetamine type. It can also be used to control excessive addiction to drugs and withdrawal symptoms and at the same time does not lead to addiction after cessation of the medication.

Crystal TTH relatively stable and essentially can keep the quality for six months at 40°C (see table 1). However, in aqueous solution tetrodotoxin sensitive to temperature and can easily break down more quickly at higher temperatures. At 40°C normal injection of tetrodotoxin collapses from content 99,20% to 65,57% after storage for 30 days, which is a significant destruction, components 33,63% (see table 2).

Table 1
The test results on the stability of tetrodotoxin at high temperature 40°C*
Time0 months1 month2 months3 months6 months
Content (%)to 100.4a 99.16 99,90100,6899,52
ImpuritiesPeak of the content in the test solutionPeak of the content in the test solutionPeak of the content in the test solutionPeak of the content in the test solutionPeak of the content in the test solution

Table 2
The test results on the stability of tetrodotoxin in acidic solution at different temperature conditions
TimeContent (%)Note
6°C25°C40°CThe solvent is a solution of acetic acid at a pH of 4.05
Day 099,299,2099,20
Day 597,8891,58
Day 1097,5486,30
Day 3096,9993,8869,57

For unstable in aqueous solution medicines used routine method in this area is to lyophilization to give the drug for injection stability. For example, in CN 1835754 describes A stable liofilizovannye powder tetrodotoxin, where the dosage form is selected from a disaccharide such as lactose, sucrose, maltose and cellobiose, along with proteoglycan, including polyglucose, dextran or its derivatives, including stabilizers, such as hydroxyarylalkyl and hydroxypropylcellulose applied within 5-100 mg for each dose. Additionally, the product also includes a solubilizer, such as citric acid, tartaric acid, malic acid or lactobionic acid. Each dose is within 0,00005-0,0005 mg In CN 1835754 A indicates that when used as a filler citrate or mannitol obtained liofilizovannye tetrodotoxin unstable and concentration of tetrodotoxin gradually decreases during storage.

Thus, the technical result provided by the invention, clochette in obtaining safe, providing quick and strong impact in their deliverance from drug addiction, and at the same time does not lead to addiction after stopping medication, stable and high quality products for medical use, rendering weak irritating effect on the human body that can be stored for a long period of time for subsequent clinical application of tetrodotoxin.

SHORT DESCRIPTION

To obtain stable tetrodotoxin, the applicant has conducted intensive research in the field of production of liofilizirovannogo powdered drug and the production technology. The results show that the Foundation, consisting of a filler, a stabilizer of tetrodotoxin, a solubilizer, and limits the pH of the deposition solution, the technology of freezing, sublimation and drying under vacuum and control the moisture content of tetrodotoxin have a significant impact on the stability of the powdered drug, in particular the absorption of moisture by the media that form the basis of the powdered drug. During long-term storage of auxiliary materials with high absorption of moisture gradually increase the moisture content in the product; and with increasing moisture content the content of tetrodotoxin in the drug gradually decreases.

Through what I extensive experimental studies of the author of the present invention have found, the use of leached sodium chloride or mannitol as auxiliary materials that form the basis of liofilizirovannogo powdered drug, and the use of dextran 20 or trehalose as a stabilizer of tetrodotoxin in the regulation of pH in the range 3.5 to 4.5 before freeze drying allows you to get liofilizovannye powdered preparation of tetrodotoxin in the form of a white and friable layer. Such a dosage form of the drug is accurately dosed white, has stable quality, safe and meets the requirements for injection, used for introduction into the human body.

Therefore, the present invention relates to civilizovannomu powdered drug of tetrodotoxin for safe injection injection into the body, where the product contains tetrodotoxin, a solubilizer, liofilizovannye filler and stabilizer. Purity specified tetrodotoxin is more than 96%, preferably 98%~99.8 per cent. Liofilizovannye filler is a sodium chloride or mannitol, or a mixture. The stabilizer is a dextran or trehalose, or their mixture, and the solubilizer is a citric acid.

In the present invention liofilizovannye powdered preparation of tetrodotoxin preferably has a ratio di is toxin: filler:the stabilizer is in the range of 1:150-3000:50-500 or 50-6000.

In the present invention liofilizovannye powdered preparation of tetrodotoxin has the content of tetrodotoxin in the range of 0.1~20,0 mg/dose, preferably in the range of 0.5~20,0 mg/dose, and more preferably in the range of 0.5~12,0 mg/dose.

In the present invention liofilizovannye powdered preparation of tetrodotoxin has a content of sodium chloride in the filler in the range of 1.0~30 mg/dose, preferably in the range of 5.0~30 mg/dose, and more preferably in the range of 5.0~0 mg/dose.

In the present invention liofilizovannye powdered preparation of tetrodotoxin has the content of mannitol filler in the range of 1.0~30 mg/dose, preferably in the range of 1.0~20 mg/dose, and more preferably in the range of 3.0~10 mg/dose.

In the present invention liofilizovannye powdered preparation of tetrodotoxin is the content of the dextran in the stabilizer in the range of 0.5-5.0 mg/dose, preferably in the range of 2.0~5.0 mg/dose, and more preferably in the range of 3.0~5.0 mg/dose.

In the present invention liofilizovannye powdered preparation of tetrodotoxin has the content of trehalose in the stabilizer of 0.5~60 mg/dose, preferably in the range of 2.0~60 mg/dose, and more preferably in the range of 10~60 mg/dose.

In the present invention liofilizovannye powdered preparation of tetrodotoxin has the content of citric acid is you in the range 0.001~0,080 mg/dose, preferably within 0,010~0,080 mg/dose, and more preferably within 0,020~to 0.060 mg/dose.

In the present invention liofilizovannye powdered preparation of tetrodotoxin preferably has a functional modulator, preferably lidocaine hydrochloride.

In the present invention liofilizovannye powdered preparation of tetrodotoxin preferably filled with inert gas, such as nitrogen, high cleaning or carbon dioxide high cleanup.

Preferably liofilizovannye powdered preparation of tetrodotoxin in the present invention are preferably administered by intramuscular or subcutaneous injection, for dissolution using water for injection, free from bacteria, the amount of water used is in the range of 0.5~2.0 ml/dose.

Additionally, the present invention also relates to a method of obtaining liofilizirovannogo powdered preparation of tetrodotoxin, which includes the following stages:

(1) Direct dissolving a fixed amount of tetrodotoxin in the solution of the solubilizer, the regulation of pH in the range of 3.0~6.0V, preferably a pH in the range of 3.5~4,5, and filtering to remove pyrogen.

(2) the Immediate dissolution of liofilizirovannogo filler, stabilizer and any selected modulator which functions in water for injection, free from bacteria, the addition of activated carbon and stirring for 30 minutes, then filtering to remove pyrogen.

(3) homogeneous mixing of the solution obtained in (1) and (2), filtration to remove bacteria and the injection volume of the bubbles, freeze drying under vacuum, inert gas filling, full clogging, closing with obtaining liofilizirovannogo powdered drug.

In stage 1 of the method according to the present invention the filtering is carried out preferably by ultrafiltration.

In stage 2 of the method according to the present invention the amount of activated carbon is preferably in the range of 0.1~6.0 g/100 ml

At stage 3 of the method according to the present invention the filtering is carried out using a sub-micron ultra-thin membranes of 0.05 μm~0,20 μm or charged ultra-filtration membranes.

BRIEF DESCRIPTION of FIGURES

Figure 1 - HPLC with fluorescence detection solution for injection of tetrodotoxin at 40°C on day 0.

Figure 2 - HPLC with fluorescence detection solution for injection of tetrodotoxin at 40°C on day 10.

Figure 3 - HPLC with fluorescence detection formulation A1 of liofilizirovannogo powdered preparation of tetrodotoxin at 40°C on day 0.

Figure - HPLC with fluorescence detection formulation A1 of liofilizirovannogo powdered preparation of tetrodotoxin at 40°C on day 10.

Figure 5 - HPLC with fluorescence detection formulation B1 of liofilizirovannogo powdered preparation of tetrodotoxin at 40°C on day 0.

Figure 6 - HPLC with fluorescence detection formulation B1 of liofilizirovannogo powdered preparation of tetrodotoxin at a temperature of 40°C on day 10.

Figure 7 - HPLC with fluorescence detection formulation of C1 liofilizirovannogo powdered preparation of tetrodotoxin at 40°C on day 0.

Figure 8 - HPLC with fluorescence detection formulation of C1 liofilizirovannogo powdered preparation of tetrodotoxin at 40°C on day 10.

Figure 9 - HPLC with fluorescence detection formulation D5 of liofilizirovannogo powdered preparation of tetrodotoxin at 40°C on day 0.

Figure 10 - HPLC with fluorescence detection formulation D5 of liofilizirovannogo powdered preparation of tetrodotoxin at 40°C on day 10.

Figure 11 - HPLC with fluorescence detection formulation of E5 liofilizirovannogo powdered preparation of tetrodotoxin when t is mperature 40°C on day 0.

Figure 12 - HPLC with fluorescence detection formulation of E5 liofilizirovannogo powdered preparation of tetrodotoxin at 40°C on day 10.

Figure 13 - HPLC with fluorescence detection formulation F5 of liofilizirovannogo powdered preparation of tetrodotoxin at 40°C on day 0.

Figure 14 - HPLC with fluorescence detection formulation F5 of liofilizirovannogo powdered preparation of tetrodotoxin at 40°C on day 10.

A DETAILED DESCRIPTION of the PREFERRED EMBODIMENT VARIANTS of the INVENTION

For determination of tetrodotoxin in liofilizirovannom powder preparation according to the present invention using high-performance liquid chromatography (Chinese Pharmacopoeia 2005 Editionm, Volume II, Appendix VII). Chromatography allows to obtain data on the content of the test substance, the retention time of the peak of the sample solution is consistent with the retention time of the peak of the control solution.

Chromatography is carried out under the following conditions: use the binder octyl silane silica as a filter and buffer solution containing 1-octane-sulfonic acid sodium and phosphate as mobile phase. The flow rate is 0.3 ml/min, wavelength upon excitation is 365 nm and the wavelength at emission costs is t 510 nm. It postalone-derived reagent is 4 mol/l solution of sodium hydroxide at a speed of current of 0.2-0.5 ml/min, the temperature in the column for the derivative is 100°C~140°C. the Number of theoretical plates is not less than 2000 based peak of tetrodotoxin.

A concrete method of test the following: take liofilizovannye powdered preparation of tetrodotoxin (containing 10(µg tetrodotoxin) of the present invention and add exactly 2.0 ml of water for dissolving accurately measure 20 ál injected sample ready chromatograph and record data chromatography with fluorescence detection. Also get a suitable control volume of tetrodotoxin. For detection use the same method. Calculation of the content of tetrodotoxin in each dose/vial carried out using the peak area of the external standard. Tetrodotoxin requirements liofilizovane drugs, if its content is 90%~110% of the labeled content.

Testing of impurities: take liofilizovannye powdered preparation of tetrodotoxin of the present invention, water is added to obtain a sample solution with 1 ml of 20 mg of tetrodotoxin. Accurately measure 1.0 ml and placed into a 25 ml volumetric flask and bring up to the mark, shake for uniform mixing and use in quality is the firmness of the control solution. Accurately measure 20 μl of each sample solution and the control solution and poured respectively into a liquid chromatograph, record data chromatography with fluorescence detection until the retention time of main peak content is doubled. The sample solution meets the medical requirements if the sum of the peak area of impurity does not exceed the peak area of control solution into the chromatograph.

In the present invention the authors used high-performance liquid chromatography as a fluorescent method of determining the content of tetrodotoxin and impurities. Compared with conventional high-performance liquid chromatography with UV detection HPLC with fluorescence detection, a more sensitive and accurate method, therefore, it determines the stability of the products of tetrodotoxin. For example, tetrodotoxin the lower threshold of detection using HPLC with UV detection is 8,14 ng, and when using HPLC with fluorescence detection the lower limit of 0.40 ng; which means that the lower limit of fluorescence detection is 20 times lower than ultraviolet. However, for the preparation of tetrodotoxin the limit of quantification for HPLC with UV detection is the Finance is 20,26 ng, while for HPLC with fluorescence detection, it is 0.81 ng, in other words, the set number in the limit of quantitation for fluorescent method 25 times lower than for the UV method.

As a rule, the norm of the product for injection of tetrodotoxin is 10 mg/vial. When the dissolution of the sample concentration for detection is in the range of 5 ág/ml 20 ág/ml If the sample quantity is 20 μl, and the sample contains 1% of impurities, the impurities content is only 1-4 ng; this is below the limits of detection using liquid chromatography with ultraviolet detection. If the sample contains 2% impurities, the impurities content is only in the range of 2-8 ng; well below the limit of detection liquid chromatography with ultraviolet detection. Therefore, it is clear that if a product has less than 5% of impurities, it is possible that the limits of detection in liquid chromatography with UV detection as a result, may lead to inaccurate detection. On the contrary, the limits of detection for liquid chromatography with fluorescence detection amount of 0.40 ng, and it fully meets the requirements for detection.

When using the above test conditions, the applicant is spruce searches of various factors, which may affect the stability of liofilizirovannogo powdered preparation of tetrodotoxin.

Screening filler and stabilizer of liofilizirovannogo powdered preparation of tetrodotoxin

The clinical application of tetrodotoxin measured in milligrams, hence the need to add filler as supporting material for getting the basics of liofilizirovannogo powdered drug. This screening of the stabilizer is also of great importance, because it is necessary for the stability of the powdered drug of tetrodotoxin. Through numerous experiments, the applicant has found that the best results can be obtained when using sodium chloride and/or mannitol as an auxiliary filler for liofilizirovannogo powdered preparation of tetrodotoxin and selecting as a stabilizer dextran 20 or trehalose. In Tables 3 and 4, below, shows the summarized test results for formulation of liofilizirovannogo powdered preparation of tetrodotoxin at 40°C when using a filler containing sodium chloride and/or mannitol and stabilizer containing dextran 20 or trehalose.

Table 3
Prescription composition of liofilizirovannogo powdered preparation of tetrodotoxin
Prescription composition123456
Tetrodotoxin (µg)101010101010
Auxiliary fillerSodium chloride (9 mg)Sodium chloride (9 mg)Mannitol (6 mg)Mannitol (10 mg)Sodium chloride (9 mg), Mannitol (6 mg)Sodium chloride (9 mg)
StabilizerDextran 20 (4 mg)Dextran 20 (4 mg)Dextran 20 (4 mg)Trehalose (4 mg)

By the looks of the product, using mannitol as filler, vig is edit well with a small absorption of moisture. Dextran has a significant protective function against liofilizovannye powdered drug of tetrodotoxin, but he has a strong absorption of moisture. To control the moisture content of the product of liofilizirovannogo powdered drug with the dense liofilizovannyh the basis of the content of dextran 20 in the preparation of the present invention is 4 mg/dose and mannitol 6 mg/dose. On the other hand, if isotonic sodium chloride is used as an auxiliary material filler to get the basics, and dextran or trehalose is used as a stabilizer to get prescription of composition, the water content of the product is low and it looks like a dense clump. In specific embodiments, the embodiments of the present invention the addition of water leads to rapid dissolution. Conduct a stability test that meets the medical requirements, at a high temperature of 40°C for 10 days.

The choice of solvent and pH formulation.

Tetrodotoxin is a nonprotein marine neurotoxin with a relative molecular mass 319,27 and often exists in the form of amphipatic molecules. Guanidyl shows the function of the base structure in accordance with its activity. It is not soluble in water or an organic solvent. It is easy on the hydrated or decomposes when exposed to a strong acid or strong alkali. It is relatively stable in solution weak acid, therefore, for liofilizirovannogo powdered preparation of tetrodotoxin should be selected suitable acidic solvent as a solubilizer. The Complainant refers to Chinese Pharmacopoeia 2005 edition, Handbook of Pharmaceutical Excipients and Chinese Pharmaceutical Necessities, he reviewed and selected the commonly used materials are weak acids for injection, such as citric acid, acetic acid, ascorbic acid, dihydrogen sodium phosphate. On the basis of the priority sampling Guiding Principle for Chemical and Pharmaceutical Preparation Technology Research acetic acid is a volatile acid, and its volatility is lost in the process of freeze drying. This is not conducive to control pH by dissolving powdered drug by adding water. Chemical and physical properties of ascorbic acid are not sufficiently stable when exposed to light and room temperature. Dihydrogen sodium phosphate is an acid salt with a weak acid svoistva, its pH is only 4.56 at 5% concentration. It regulate pH in a narrow range and it is not suitable for acidic solvent in liofilizovannyh powdered tetrodotoxin. Citric acid is non-volatile, has a slightly properties with a relatively wide range of pH control. Further, when performing analyses and compared the situation the authors of the present invention have chosen citric acid as a solubilizer in liofilizirovannom tetrodotoxin powder of the present invention. For liofilizirovannogo powdered drug of the present invention, it is preferable to use citric acid as a solubilizer in the range from 0.001 mg to 0,080 mg per dose.

The pH of the solution for injection is one of the most important factors closely related to the stability of the effective contents in medicine. The applicant uses the established prescription composition for liofilizirovannogo powdered drug and uses of 0.1% citric acid for regulating various pH. After freeze drying, powder products are subjected to study the appearance, dissolution, pH, and stability. The main test stability: maintain the product at a temperature of 40°C and examine samples at 0, 5 and 10 days, and for testing using liquid chromatography with fluorescence detection. The content and impurities of tetrodotoxin expect when using the standard squares. The results of the experiment are given in Table 5.

From the above results of the experiments shows that the pH of a solution of powdered drug of tetrodotoxin has a significant impact on the stability of tetrodotoxin. At 40°C, pH 5, and the exposure time 10 dnabased main peak destroyed impurities from tetrodotoxin more compared to a control solution and a new peak of impurities.

After repeated experiments, the applicant has found that the preferred pH of liofilizirovannogo powdered preparation of tetrodotoxin is in the range of 3.5-4.5 and the best pH is around 4.0.

The effects of different water content on the stability of liofilizirovannogo powdery product of tetrodotoxin

The applicant conducted a study on the impact of different water content, on the stability of liofilizirovannogo powdery product of tetrodotoxin. The results are shown in Table 6.

Table 6
The test results on the effect of different water contents on the stability of liofilizirovannogo powdery product of tetrodotoxin at 40°C
The batch number123
The water content in product (%)8,565,232,50
Limit content () 90-10090-10090-100
0 dayContent (%)100100100
Impurities<the area of the main peak of control solution<the area of the main peak of control solution<the area of the main peak of control solution
5 dayContent (%)97,6598,4399,21
Impurities>the area of the main peak of control solution<the area of the main peak of control solution<the area of the main peak of control solution
day 10Content (%)95,2897,8998,64
Impurities>the area of the main peak of control solution >the area of the main peak of control solution<the area of the main peak of control solution
Appearance

The experiment shows that at 40°C appearance powder is compressed and its stability is relatively poor when the content of water in liofilizovannyh powdered product more than 5%. With less water content in liofilizirovannom powdered product tetrodotoxin product more stable. In the present invention, the water content in liofilizirovannom powdered preparation of tetrodotoxin preferably should be controlled at the level of 3%.

The technology of freeze-drying

The technology of freeze-drying powder preparation of tetrodotoxin in the first place, consists of pre-freezing, primary drying and secondary drying. The authors of the present invention has been five liofilizovannyh methods for the experiment (see Table 7) according to the technology of freeze-drying with the use of screening Eutectic point, filler and stabilizer in prescription formulations products. Performing a comparative analysis of test results, the authors of the present invention have determined control parameters for nailo is our technology of freeze drying for this product (see Table 8).

Table 7
The technology of freeze-drying of liofilizirovannogo powdered preparation of tetrodotoxin
SolutionTechnology
Method 1Preliminary freezing at -35°C for 2.5 hours, drying under vacuum at -10°C for 15 hours, drying under vacuum at 40°C for 4 hours
Method 2Preliminary freezing at -35°C for 2.5 hours, drying under vacuum at low temperature -10°C to°C for 8 hours, drying under vacuum at a temperature of 10°C for 3 hours, dried under vacuum at a temperature of 20°C for 3 hours, dried under vacuum at 30°C for 4 hours
Method 3Preliminary freezing at -35°C for 2.5 hours, drying under vacuum at low temperature -10°C for 8 hours, drying under vacuum at a temperature of 10°C for 3 hours, dried under vacuum at a temperature of 20°C for 3 hours, dried under vacuum at 35°C for 4 hours
Method 4Preliminary freezing at -35°C for 2.5 hours, drying under vacuum at low temperature -10°C for 8 hours, drying under vacuum at a temperature of 10°C for 3 hours, dried under vacuum at a temperature of 20°C for 3 hours, dried under vacuum at 40°C for 4 hours
Method 5Preliminary freezing at -35°C for 2.5 hours, drying under vacuum at low temperature -10°C for 8 hours, drying under vacuum at a temperature of 10°C for 3 hours, dried under vacuum at a temperature of 20°C for 3 hours, dried under vacuum at 40°C for 410 hours

Table 8
The results of the evaluation technology of freeze drying of liofilizirovannogo powdered preparation of tetrodotoxin
SolutionThe evaluation results
Method 1The appearance of the Foundation is bad, the content of tetrodotoxin in the product is significantly reduced.
Method 2Method 3The appearance of the product is relatively good, the water content is a little high, the content of tetrodotoxin in the product slightly reduced.
Method 4The appearance of the product is relatively good, the water content of <3,0%, the process does not reduce the content of tetrodotoxin in the product.
Method 5The appearance of the product is relatively good, the water content of <2.0%) and the process does not reduce the content of tetrodotoxin in the product.

During the experiment it was found that upon receipt by the method 1 of the product prior to freezing to a temperature of -10°C, drying under vacuum for 15 hours, and the immediate increase in drying temperature up to 40°C tetrodotoxin in the product is significantly reduced. This shows that the sequence and conditions of the technology of freeze-drying have a significant impact on the quality of liofilizirovannogo powdered preparation of tetrodotoxin. Method 4 applies the optimal drying at a temperature gradient to study the primary drying stage of secondary drying at 40°C, and get low moisture content in the product. The technological process of freeze drying does not affect the contents of tetrodotoxin in the product. Therefore, the authors of the present invention have chosen option 4 as the preferred technology of freeze drying for this product.

Specific variants of embodiment of the invention

A variant embodiment of the invention 1: Liofilizovannye powdered preparation of tetrodotoxin includes as filler sodium chloride as a stabilizer - dextran 20 and as a solubilizer is citric acid.

The following composition to obtain liofilizirovannogo powdered preparation of tetrodotoxin:

Composition
Tetrodotoxin
(purity >98%) (μg/dose)
Sodium chloride (mg/dose)Dextran 20 (mg/dose)Before
freeze drying is used citric acid to regulate the pH of the solution
Prescription composition A11094,04,0
Prescription composition A25 94,03.5
Prescription composition A31094,03.8
Prescription composition A41594,54,0
Prescription composition A5894,54,2
Prescription composition A62095,03,5

Method: take the number of tetrodotoxin on prescription composition and use 10 ml of 0.1% solution of citric acid to dissolve, add the amount of sodium chloride on prescription composition and add water for injection for reconstitution up to 250 ml Using 0.1% solution of citric acid for adjustment to pH, filtered with the use of ultrafiltration for the removal of pyrogen and get the solution of group A. Also take the number of dextran 20 on prescription composition, add 200 ml of water for injection to dissolve, use a 0.1% solution of lemon is Oh acid for adjustment to pH, then add within 0.1%~1.0% ratio of mass:the amount of activated charcoal and incubated at 60°C, stirring during 30 minutes and then filtered to remove the charcoal and pyrogen and cooled to room temperature to obtain a solution of group B. Uniformly mixing the above solutions A and B groups, use water for injection to a final volume of 500 ml, then use 0.22 micron ultra-thin diaphragm for filtering, take samples for testing pH, transparency, and content to ensure compliance and conduct a sterile packaging. Then conduct a preliminary freezing to a temperature of -35°C for 2~6 hours, conduct primary drying at a temperature of -10°C~20°C for 10~20 hours and final drying at a temperature of 20°C~50°C for 6~10 hours from receipt of product. In appearance the product is kartoobrazny white layer.

With the above liofilizovane powdered preparation of tetrodotoxin you can also choose any of the hydrochloride lidocaine function of the modulator in the amount of 3.0 mg/dose.

Variant embodiments of the invention 2: Liofilizovannye powdered drug tetrodoxin includes as filler mannitol as a stabilizer dextran 20 and calulator citric acid.

The following composition p is zeptomole composition for liofilizirovannogo powdered preparation of tetrodotoxin:

TrackTetrodotoxin (purity >99%) (μg/dose)Sodium chloride (mg/dose)Dextran 20 (mg/dose)Before freeze drying is used citric acid to control pH
Prescription composition B11064,5the 3.8
Prescription composition B2201553,5
Prescription composition B35653,0
Prescription composition B43644,0
Prescription composition B515654,2
Prescription composition B61210 54,5

Method: take the number of tetrodotoxin on prescription composition and use 10 ml of 0.1% solution of citric acid to dissolve, add the amount of sodium chloride on prescription composition and add water for injection for reconstitution up to 250 ml Using 0.1% citric acid solution to regulate specific pH, filtered using a filtration membrane to remove pyrogen and get the solution of group A. Also take the number of dextran 20 and mannitol on prescription composition, add 200 ml of water for injection to dissolve, use a 0.1% solution of citric acid for adjustment to pH, then add in the range of 0.2% ratio mass:the amount of activated charcoal and incubated at 60°C, stirring during 30 minutes and then filtered to remove the charcoal and pyrogen and cooled to room temperature to obtain a solution of group B. Uniformly mixing the above solutions A and B groups, use water for injection to a final volume of 500 ml, then use 0.22 micron ultra-thin diaphragm for filtering, take samples for testing pH, transparency, and content to ensure compliance and conduct a sterile packaging. Then conduct a preliminary frosting is ugiwanie to a temperature of -35°C for 2~6 hours conduct primary drying at a temperature of -10°C~20°C for 10~20 hours and final drying at a temperature of 20°C~0°C for 6~10 hours from receipt of product. In appearance the product is kartoobrazny white layer.

With the above liofilizovane powdered preparation of tetrodotoxin you can also choose any of the hydrochloride lidocaine function of the modulator in the amount of 3.0 mg/dose.

Variant embodiments of the invention 3: Liofilizovannye powdered drug tetrodoxin includes as filler sodium chloride as a stabilizer trehalose and as a solubilizer citric acid.

The following composition formulation for liofilizirovannogo powdered preparation of tetrodotoxin:

Composition
Tetrodotoxin (purity >99%) (μg/dose)Sodium chloride (mg/dose)Dextran 20 (mg/dose)Before freeze drying is used
citric acid to regulate the pH of the solution
Prescription composition C1109104,0
159104,2
Prescription composition C3209204,5
Prescription composition C48930the 3.8
Prescription composition C559153,5
Prescription composition C639104,0

Method: take the number of tetrodotoxin on prescription composition and use 20 ml of 0.1% solution of citric acid to dissolve, add the amount of sodium chloride and trehalose on prescription composition and add water for injection for reconstitution to about 450 ml Using 0.1% solution of citric acid for adjustment to pH, filtered using a filtration membrane to remove pyrogen and use water for injection to obtain 500 ml, then use 0.22 micron ultra-thin diaphragm for Phi is Tracie, take samples for testing pH, transparency, and content to ensure compliance and conduct a sterile packaging. Then conduct a preliminary freezing to a temperature of -35°C for 2~6 hours, conduct primary drying at a temperature of -10°C~20°C for 10~20 hours and final drying at a temperature of 20°C~0°C for 6~10 hours from receipt of product. In appearance the product is kartoobrazny white layer.

With the above liofilizovane powdered preparation of tetrodotoxin you can also select any of the hydrochloride lidocaine function of the modulator in the amount of 3.0 mg/dose.

Variant embodiments of the invention 4: Liofilizovannye powdered drug tetrodoxin includes as filler mannitol as a stabilizer trehalose and as a solubilizer citric acid.

The following composition formulation for liofilizirovannogo powdered preparation of tetrodotoxin:

TrackTetrodotoxin (purity >99%) (μg/dose)Mannitol (mg/dose)Trehalose (mg/dose)Before freeze drying is used citric acid to regulate the pH, R is the target
Prescription composition D1355the 3.8
Prescription55104,0
the composition D2
Prescription composition D385204,0
Prescription composition D4155403,5
Prescription composition D5105304,0
Prescription composition D6205604,5

Way to obtain: b is Ruth amount of tetrodotoxin on prescription composition and use 20 ml of 0.1% solution of citric acid for dissolution, add the amount of trehalose on prescription composition and add water for injection for reconstitution to about 300 ml Using 0.1% solution of citric acid for adjustment to pH, filtered with the use of ultrafiltration for the removal of pyrogen and get the solution of group A. Also take the amount of mannitol on prescription composition, add 150 ml of water for injection to dissolve, use a 0.1% solution of citric acid for adjustment to pH, then add within 0.1%~1.0% ratio of mass:the amount of activated charcoal and incubated at 60°C, stirring in for 30 minutes and then filtered to remove the charcoal and pyrogen and cooled to room temperature to obtain a solution of group B. Uniformly mixing the solutions A and B groups, use water for injection to a final volume of 500 ml, then use 0.22 micron ultra-thin diaphragm for filtering, take samples for testing pH, transparency, and content to ensure compliance and conduct a sterile packaging. Then conduct a preliminary freezing to a temperature of -35°~ for 2~6 hours, conduct primary drying at a temperature of -10°C~20°C for 10~20 hours and final drying at a temperature of 20°C~50°C for 6~10 hours from receipt of product. In appearance the product PR is dstanley kartoobrazny white layer.

With the above liofilizovane powdered preparation of tetrodotoxin you can also select any of the hydrochloride lidocaine function of the modulator in the amount of 3.0 mg/dose.

Variant embodiments of the invention 5: Liofilizovannye powdered drug tetrodoxin includes as filler mannitol and sodium chloride as a stabilizer trehalose and as a solubilizer citric acid.

The following composition formulation for liofilizirovannogo powdered preparation of tetrodotoxin:

TrackTetrodotoxin (purity >99%) (μg/dose)Mannitol (mg/dose)Sodium chloride (mg/dose)Trehalose (mg/dose)Before freeze drying is used citric acid to regulate the pH of the solution
Prescription composition E135953,5
Prescription composition E2559104,
Prescription
part E3
85915the 3.8
Prescription composition E41559304,0
Prescription composition E51059204,0
Prescription composition E62059404,5

Method: take the number of tetrodotoxin on prescription composition and use 20 ml of 0.1% solution of citric acid to dissolve, add the amount of sodium chloride and trehalose on prescription composition and add water for injection for reconstitution to about 300 ml Using 0.1% solution of citric acid for adjustment to pH, filtered with the use of ultrafiltration for the removal of pyrogen and get the solution of group A. Also take the amount of mannitol on prescription composition, add 150 ml of water and is of jacci for its dissolution, use a 0.1% solution of citric acid for adjustment to pH, then add within 0.1%~1.0% ratio of mass:the amount of activated charcoal and incubated at 60°C, stirring during 30 minutes and then filtered to remove the charcoal and pyrogen and cooled to room temperature to obtain solution group Century. Uniformly mixing the solutions A and B groups, use water for injection to a final volume of 500 ml, then use 0.22 micron ultra-thin diaphragm for filtering, take samples for testing pH, transparency, and content to ensure compliance and conduct a sterile packaging. Then conduct a preliminary freezing to a temperature of -35°C for 2~6 hours, conduct primary drying at a temperature of -10°C~20°C for 10~20 hours and final drying at a temperature of 20°C~50°C for 6~10 hours from receipt of product. In appearance the product is kartoobrazny white layer.

With the above liofilizovane powdered preparation of tetrodotoxin you can also select any of the hydrochloride lidocaine function of the modulator in the amount of 3.0 mg/dose.

A variant embodiment of the invention 6: Liofilizovannye powdered drug tetrodoxin includes as filler mannitol and sodium chloride as a stabilizer dextran and as a solubilizer citric acid.

The following composition formulation for liofilizirovannogo powdered preparation of tetrodotoxin:

TrackTetrodotoxin (purity >99%) (μg/dose)Mannitol (mg/dose)Sodium chloride (mg/dose)Dextran 20 (mg/dose)Before freeze drying is used citric acid to regulate the pH of the solution
Prescription composition F133943,5
Prescription composition F253943,5
Prescription composition F3103944,0
Prescription
the composition of F4
153954,2
10394,54,0
Prescription composition F6203954,5

Method: take the number of tetrodotoxin on prescription composition and use 20 ml of 0.1% solution of citric acid to dissolve, add the amount of sodium chloride and mannitol on prescription composition and add water for injection for reconstitution to about 300 ml Using 0.1% solution of citric acid for adjustment to pH, filtered with the use of ultrafiltration for the removal of pyrogen and get the solution of group A. Also take the number of dextran 20 on prescription composition, add 150 ml of water for injection to dissolve, use a 0.1% solution of citric acid for adjustment to pH, then add within 0.1%~1.0% ratio of mass: the amount of activated charcoal and incubated at 60°C, stirring during 30 minutes and then filtered to remove the charcoal and pyrogen and cooled to room temperature to obtain solution group Century. Uniformly mixing the solutions A and B groups, use the coziness of water for injection to a final volume of 500 ml, then use 0.22 micron ultra-thin diaphragm for filtering, take samples for testing pH, transparency, and content to ensure compliance and conduct a sterile packaging. Then conduct a preliminary freezing to a temperature of -35°C for 2~6 hours, conduct primary drying at a temperature of -10°C~20°C for 10~20 hours and final drying at a temperature of 20°C~50°C for 6~10 hours from receipt of product. In appearance the product is kartoobrazny white layer.

With the above liofilizovane powdered preparation of tetrodotoxin you can also select any of the hydrochloride lidocaine function of the modulator in the amount of 3.0 mg/dose.

Variant embodiments of the invention 7: Test for stability.

Take liofilizovannye powdered drug TTX at the above variant of the embodiment of the present invention and conduct a stability test at 40°C for 10 days. When the test is conducted following a specific operation.

Put different liofilizovannye products in an experimental chamber at a temperature of 40±2°C and relative humidity of 75%±5% for testing the stability of the medicinal product. Products removed from the camera after 10 days and spend HPLC with fluorescence detection. Changes in purity TTX indicate stablestate.

In the above test the stability of liofilizovannye powdered drug TTX according to the present invention demonstrates a fairly good stability. Following the results of the tests are preferred preparations.

Table 9: test Results on the stability of the preferred formulation according to the present invention liofilizirovannogo powdered drug TTX at 40°C for 10 days.

Prescription compositionAppearance0 dayday 10
Purity (%)Related materialsPurity (%)Related materials
A1Kartoobrazny white layer99,20< the area of the main peak of the control98,56< the area of the main peak of the control
B1Kartoobrazny white layer99,20<the area of the main peak of the control 98,71<the area of the main peak of the control
C1Kartoobrazny white layer99,20<the area of the main peak of the controlto 99.00<the area of the main peak of the control
D5Kartoobrazny white layer99,20<the area of the main peak of the control99,06<the area of the main peak of the control
E5Kartoobrazny white layer99,20<the area of the main peak of the control99,10<the area of the main peak of the control
F5Kartoobrazny white layer99,20<the area of the main peak of the control98,63<the area of the main peak of the control

The use of variants of the embodiment of the invention

Only 80 persons suffering from drug addiction, accustomed to the use of drugs, use drugs is at the present invention for the treatment of abstinence: 49 men and 31 women, the oldest is 41 years old and the youngest is 18 years. The longest period of drug use is 13 years, while the shortest period of 2 years with the largest daily dose of the drug within 2~3 g and the smallest daily intake of 0.1, the drugs include heroin and heroin with sedative and hypnotic drugs, routes of administration include inhalation of combustion, intramuscular or subcutaneous injection of heroin. All 80 patients have a confirmed DSM-III-R mental disorders caused by substances that activate the psyche, the standard diagnosis of dependence on opiate positive test morphines in the urine without any other serious bodily diseases. Before treatment abstinence for drug dependence were selected only drug addicts with severe dependence. Dosage dosage of this drug is in the range of 10 μg-20 μg per day for 3~7 days.

Withdrawal symptoms of patients with opiate addiction caused by discontinuation of the drug may be different. Patients respectively injected injection according to the present invention in accordance with the seriousness of the forms of drug dependence and the degree of development of withdrawal symptoms. Statistics show that during the first medication the frame means 95% of patients had no withdrawal symptoms for 0.5~3 hours and patients remain reasonable and not feel pain. Withdrawal symptoms when you first receive may disappear in ~6 hours, and when it reappears, they are much softer, for patients with a prolonged form of addiction and drugs by intravenous injection, the authors present invention I propose to do two injections of this drug within 24 hours. All patients easily passed the strongest period of abstinence and patients remained sober and felt no pain. When getting rid of withdrawal symptoms, the patient's condition is rated as good, they have a good appetite and quickly restored the vital functions of the body. As a rule, there is no need for additional treatment after 3~6 times of reception of medicines. All patients were observed side effects or discomfort.

Typical variants of embodiment of the invention

Patient E. - man addict for 10 years with an average daily dose of 1.0 g of the drug like heroin, taken mainly by intramuscular or intravenous injection. The patient has stopped taking drugs and was on a voluntary treatment. 19:00 of the same day appeared withdrawal symptoms and 21:00 the symptoms became very serious with nasal discharge, lacrimation, yawning, pain in muscles and bones, chills, pain in the abdomen, diarrhea, nausea, vomiting, appearance of goose skin, the rise of body hair and body spasm, and the like. Immediately after intramuscular injection according to the present invention withdrawal symptoms reached "++"~"+++". After 0.5 hours the withdrawal symptoms is largely controlled, and after 2.5 hours the patient can sleep without pain. After about 10 hours the withdrawal symptoms again, but significantly relaxed. At 9:30 the next day the patient is back injection and after the injection, the patient feels well and does not feel any discomfort. After about 12 hours the patient again experiences the withdrawal symptoms, at 21:00 the patient receives an injection of a drug according to the present invention, the patient feels well enough and remains quiet all night. Next, the patient receives an injection of a drug according to the present invention every day until he feels a significant improvement in terms of the absence of diarrhea, restore appetite and normal stool. On the 5th day of the withdrawal symptoms have not appeared and the patient experienced no discomfort. The treatment lasted for 5 days with administration of a medicinal product according to the present invention a total of 6 times.

1. The method of receiving liofilizirovannogo preparation of tetrodotoxin, contains tetrodotoxin, a solubilizer, a filler and a stabilizer, where the specified tetrobot the Xin has a purity of> 96%, said filler is a sodium chloride or mannitol, or a mixture thereof; the stabilizer is a dextran, trehalose; and the solubilizer is a citric acid; also includes the following stages:
1) dissolve 0.1 to 20 μg/dose of tetrodotoxin with 0.1% citric acid solution to regulate pH in the range 3.5 to 4.5 in water for injection and filtered to remove pyrogen,
2) dissolve the stabilizer, representing the dextran in the amount of 0.5-5.0 mg/dose or trehalose in an amount of 0.5 to 60 mg/dose, and the filler, which represents an isotonic solution of sodium chloride in an amount of 1.0 to 30 mg/dose, or mannitol in amounts of 1.0-30 mg/dose, in water for injection, add 0.1% citric acid solution to regulate pH in the range 3.5 to 4.5, add activated carbon maintained at a temperature of 60°C, stirring for more than 30 minutes and filtered to remove pyrogen and cool to room temperature,
3) evenly mix obtained at stages 1 and 2 solutions are ultrafiltration,
4) conduct of freeze drying, which is in the preliminary freezing at -35°C for 2.5 hours, drying under vacuum at low temperature -10°C for 8 hours, drying under vacuum at a temperature of 10°C for 3 hours, dried under vacuum at a temperature of 20°C in ECENA 3 hours drying under vacuum at 40°C for 4 hours
5) is filled with an inert gas, control the water content to 3% and corked.

2. The method of receiving liofilizirovannogo preparation of tetrodotoxin according to claim 1, wherein said tetrodotoxin has a purity of preferably within 98%~99.8 per cent.

3. The preparation of tetrodotoxin to relieve withdrawal symptoms in dependent on opiates, obtained by lyophilization of tetrodotoxin, where the mass ratio of tetrodotoxin:filler, which represents an isotonic solution of sodium chloride in an amount of 1.0 to 30 mg/dose, or mannitol in amounts of 1.0-30 mg/dose, or their mixture, stabilizer, representing the dextran in the amount of 0.5-5.0 mg/dose or trehalose in an amount of 0.5 to 60 mg/dose, is 1:(150-3000):(50-6000)obtained by the method according to claim 1.

4. The preparation of tetrodotoxin according to claim 3, where the content of tetrodotoxin is within 0.1~20,0 mg/dose.

5. The preparation of tetrodotoxin according to claim 3, where the content of tetrodotoxin is preferably in the range of 0.5~20,0 mg/dose.

6. The preparation of tetrodotoxin according to claim 3, where the content of tetrodotoxin is more preferably in the range of 0.5~12,0 mg/dose.

7. The preparation of tetrodotoxin according to claim 3, where the concentration of sodium chloride in the filler is preferably in the range of 5.0-30 mg/dose.

8. The preparation of tetrodotoxin according to claim 3, g is e, the content of sodium chloride in the filler is more preferably in the range of 5.0-20 mg/dose.

9. The preparation of tetrodotoxin according to claim 3, where the content of mannitol filler is preferably in the range of 1.0~20 mg/dose.

10. The preparation of tetrodotoxin according to claim 3, where the content of mannitol filler is more preferably in the range of 3.0-10 mg/dose.

11. The preparation of tetrodotoxin according to claim 3, where the concentration of dextran in the stabilizer is preferably in the range of 2.0~5.0 mg/dose.

12. The preparation of tetrodotoxin according to claim 3, where the concentration of dextran in the stabilizer is preferably in the range of 3.0~5.0 mg/dose.

13. The preparation of tetrodotoxin according to claim 3, where the content of trehalose in the stabilizer is preferably in the range of 2-60 mg/dose.

14. The preparation of tetrodotoxin according to claim 3, where the content of trehalose in the stabilizer is preferably in the range of 10~60 mg/dose.

15. The preparation of tetrodotoxin according to claim 3, where the content of citric acid is in the range 0.001-~0,080 mg/dose.

16. The preparation of tetrodotoxin according to claim 3, where the content of citric acid is preferably within 0,010~0,080 mg/dose.

17. The preparation of tetrodotoxin according to claim 3, where the content of citric acid is more preferably within 0,020~to 0.060 mg/dose.

18. The preparation of tetrodotoxin according to any one of paragraphs. 3-17, where the composition also includes lidocaine hydrochloride.

19. The preparation of tetrodotoxin according to any one of paragraphs. 3-17, where the composition also includes an inert gas, such as highly purified nitrogen or carbon dioxide high cleanup.

20. The preparation of tetrodotoxin according to any one of paragraphs. 3-17, administered by injection subcutaneously or intramuscularly.

21. The method of receiving liofilizirovannogo preparation of tetrodotoxin, which includes the following stages:
1) dissolve 0.1 to 20 μg/dose of tetrodotoxin and lidocaine hydrochloride with 0.1% citric acid solution to regulate pH in the range of 3.0 to 6.0 in water for injection and filtered to remove pyrogen,
2) dissolve the stabilizer, representing the dextran in the amount of 0.5-5.0 mg/dose or trehalose in an amount of 0.5 to 60 mg/dose, and the filler, which represents an isotonic solution of sodium chloride in an amount of 1.0 to 30 mg/dose, or mannitol in amounts of 1.0-30 mg/dose, in water for injection, free from bacteria, add 0.1% citric acid solution to regulate pH in the range 3.5 to 4.5, add activated carbon maintained at a temperature of 60°C, stirring for more than 30 minutes and filtered to removal of pyrogen and cooled to room temperature,
3) evenly mix obtained at stages 1 and 2 solutions are ultrafiltration,
4) conduct of freeze drying, which is in the preliminary freezing at temperatures ranging from -20°C to -40°C for 2-3 hours, drying under vacuum at low temperature of -1°C for 6-10 hours, drying under vacuum at a temperature of 10°C for 2-5 hours, drying under vacuum at a temperature of 20°C for 2-5 hours, drying under vacuum at a temperature within 30-50°C for 6-10 hours,
5) is filled with an inert gas, control the water content to 3% and corked.

22. The method of receiving liofilizirovannogo preparation of tetrodotoxin on item 21, in which is dissolved 0.1 to 20 μg/dose of tetrodotoxin and lidocaine hydrochloride with 0.1% citric acid solution to regulate the pH is preferably in the range of 3.5 to 4.5.

23. The method according to item 21, where in stage 2 using activated carbon in the range of 0.1-6.0 g/100 ml

24. The method according to item 21, where at stage 3 carry out filtering using 0.05 µm of 0.20 micron, sub-micron ultra filtration membrane or charged ultrafine filter.

25. The method according to item 21, where at stage 3, preferably the pre-freezing temperature is -35°C for 2.5 hours, the temperature of the primary drying is -10°C for 8 hours, 10°C for 3 hours and 20°C for 3 hours; the temperature of the secondary drying is in the range of 40°C for 4 hours.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: a combination possessing analgesic action of at least one sigma ligand and at least one opioid or opiate compound specified in morphine and its structural derivatives, phentanyl and tramadol for simultaneous, separate or sequential administration; the sigma ligand has the general formula ;

using it for preparing a therapeutic agent potentiating analgesic action of morphine or its structural derivatives, phentanyl and tramadol and/or relieving addiction thereto. What is also presented is using the combination of at least one sigma ligand and at least one opioid or opiate compound for preparing the therapeutic agent for potentiating analgesic action of opioids or opiates and for relieving addiction thereto; the opiate is specified in a group of: hydromorphone, oxymorphone, desomorphine, diacetylmorphine, nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmorphine.

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16 cl, 10 dwg

FIELD: biotechnologies.

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10 cl, 11 ex, 4 tbl, 20 dwg

FIELD: medicine.

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1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine and describes a disulphiram implant for treating the alcohol or opiate addictive patients. The implant contains disulphiram 95.0-59.0 wt %, nitrogen polymer composition 4.8-40.5 wt % and stearic acid or magnesium stearate 0.2-0.5 wt %. The nitrogen polymer composition contains N-vinylpyrrolidone and 2-methyl-5-vinylpyridine copolymer or salts of branched oligomers hexamethylene diamine and guanidine, and polyvinylpyrrolidone.

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5 ex, 2 tbl

FIELD: medicine, pharmaceutics.

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33 cl, 23 dwg, 27 ex

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FIELD: medicine, pharmaceutics.

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2 cl, 3 ex, 2 tbl

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2 cl, 4 ex, 2 tbl

FIELD: medicine.

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FIELD: chemistry.

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32 cl, 501 ex, 21 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented: a combination possessing analgesic action of at least one sigma ligand and at least one opioid or opiate compound specified in morphine and its structural derivatives, phentanyl and tramadol for simultaneous, separate or sequential administration; the sigma ligand has the general formula ;

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FIELD: chemistry.

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19 cl, 47 tbl, 237 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to compound of general formula (1), where A1 represents -N= or -CR7=, A2 represents -N= or -CR8, A3 represents -N= or -CR9=, A4 represents -N= or -CR10=; on condition that not more than one of residues A1, A2, A3 and A4 represents -N=; Y1, Y1′, Y2, Y2′, Y3, Y3′, Y4 and Y4' in each case independently on each other represent -H or -C1-8-alkyl; W represents -NR4-, where R4 represents -H or -C1-8-alkyl; R1, R2 and R3 independently on each other in each case represent R0, where R0 represents non-substituted or monosubstituted -C1-8-alkyl; non-substituted or monosubstituted -phenyl; non-substituted or monosubstituted - heteroaryl or non-substituted or monosubstituted -C1-8-alkylphenyl; or R1 and R2 together represent -(CH2)3-6-; R5, R5' R6, R6' R7 R8, R9, R10, R18 and R19 in each case independently on each other are selected from group, including -H, -F, -Cl, -Br, -I and -R0; where "heteroaryl" represents 5-membered cyclic aromatic residue, which contains 1 heteroatom, where heteroatom represents sulphur; where "alkyl" in each case represents branched or non-branched, saturated, non-substituted or monosubstituted aliphatic hydrocarbon residue; where with respect to residues "phenyl", "-C1-8-alkyl", "heteroaryl" and "-C1-8-alkylphenyl" "monosubstituted" means monosubstitution of one hydrogen atom with substituents, selected from group, including -F, -Cl, -Br, -I or -OH, in form of single stereoisomer or their mixture, free compound and/or its physiologically compatible salts.

EFFECT: obtained is novel compound and medication based on thereof, which can be applied in medicine for pain treatment.

9 cl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds possessing a high effectiveness in modulation of NMDA receptor activity.

EFFECT: compounds are applicable in treating the diseases and disorders, such as disturbed learning, cognitive activities, as well as for relieving and/or reducing neuropathic pain.

26 cl, 21 dwg, 2 tbl, 9 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to ligands in the form of synthetic peptide amides of a kappa-opiate receptor, and namely to agonists of the kappa-opiate receptor, which show a low inhibition degree of P450 CYP and a low degree of penetration into brain. According to the invention, synthetic peptide amide is described by the following formula:

EFFECT: pharmaceutical compositions containing the above compounds are suitable for prophylaxis and curing of pain and inflammation, which are related to different diseases and states.

19 cl, 11 dwg, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a pharmaceutical combination for treating in pain conditions in the form of a solid dosage form for oral administration, characterised by the fact that it contains Mirtazapine 5 mg - 50 mg; Tizanidine 0.5 - 6 mg in ratio 20:1-5:1, and a pharmaceutically acceptable carrier.

EFFECT: invention provides creating an effective agent for preventing or treating a pain condition well-tolerated by patients.

6 cl, 2 ex

FIELD: chemistry.

SUBSTANCE: disclosed is use of a heptapeptide of general formula Tyr-D-Ala-Phe-Gly-Tyr-X-Ser-NH2, where X is D-Pro or Dh-Pro, or Dh-D-Pro, where Dh-Pro is 3,4-dehydroproline, as an antispasmodic, anxiolytic, central anti-inflammatory or anti-alcohol agent.

EFFECT: obtaining an agent used as an antispasmodic, anxiolytic, central anti-inflammatory or anti-alcohol agent.

3 cl, 8 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tevinol and orvinol derivatives of general formula I where R=OH; R1=H, CF3, C1-C4 alkyl, aryl, or (R+R1) stands for O=; R2=H, CH3; R3=H, CH3; R4=CH3, cyclopropylmethyl, allyl; Z~Z=CH2CH2, CH=CH. Invention also relates to method of obtaining formula I derivatives. Method lies in trifluoromethylation of respective aldehyde with formation of 21,21,21-trifluorotevinol, further oxidation of formed fluorine-containing alcohol with formation of respective ketone, which under influence of reagent, selected from the group, including R1Li, R1MgX, CF3Si(CH3)3, results in obtaining formula I tevinol derivatives. Orvinol derivatives are obtained by demethylation of tevinols.

EFFECT: formula I derivatives as ligands of opioid receptors with wide possibilities of varying their hydrophilic-hydrophobic balance.

9 cl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a combination for the prevention, correction and therapy of pain related to neurodegeneration and/or associated with somatoform disorders, characterised by the fact that it consists of buspirone and doxepin taken in therapeutically effective amounts.

EFFECT: invention provides creating the combination providing the prolonged analgesic effect, including in persistent chronic pains.

5 cl, 2 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular, to surgery and can be applied for prolonged anesthetisation in early post operational period of patients with haemorrhoids of III-IV stage. For this purpose 1% solution of morphine in dose 0.1 ml per 10 kg of weight is introduced one time per day in peridural space between vertebras L2-L3 , or L3-L4 through catheter. Said quantity is diluted with 6 ml of physiological solution. Such volume of narcotic medicine ensures effective anesthetisation within 18-20 hours. After that, after said time expiry, 6.0 ml of 2% solution of lidocaine are additionally introduced, which ensures anesthetisation effect within 4 hours. Claimed procedure is repeated on 2 and 3 day in the same succession.

EFFECT: invention ensures prolonged anesthetisation in early post operational period within 3 days, due to reduction of introduced narcotic analgesic (morphine) dose, which makes it possible to reduce probability of development of addiction and development of side effects in patients.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, namely to pharmacology and describes a histidine-free pharmaceutical composition containing high-purity factor VIII; arginine and saccharose, a surfactant for the prevention or at least the inhibition of a surface adsorption of factor VIII; 0.5 to 10 mM calcium chloride for the specific stabilisation of factor VIII, and sodium citrate or maleic acid as a pH buffer.

EFFECT: invention provides the protective function for preserve high-yield factor VIII over the whole cycle of pharmaceutical processing, long storage and end recovery and administration into the patient.

18 cl, 16 tbl, 8 ex

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