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WO2019203697A1 - Composition pour traiter des maladies virales (et variantes) - Google Patents

Composition pour traiter des maladies virales (et variantes) Download PDF

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Publication number
WO2019203697A1
WO2019203697A1 PCT/RU2019/050048 RU2019050048W WO2019203697A1 WO 2019203697 A1 WO2019203697 A1 WO 2019203697A1 RU 2019050048 W RU2019050048 W RU 2019050048W WO 2019203697 A1 WO2019203697 A1 WO 2019203697A1
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Prior art keywords
influenza
methoxy
benzylpiperazine
methyl
indol
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Ceased
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English (en)
Russian (ru)
Inventor
Рахимджан Ахметджанович РОЗИЕВ
Кенес Тагаевич ЕРИМБЕТОВ
Ксения Юрьевна ВЛАСОВА
Руслан Александрович ЗЕМЛЯНОЙ
Елена Сергеевна ФРОГ
Екатерина Валерьевна БОНДАРЕНКО
Анна Яковлевна ГОНЧАРОВА
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Publication of WO2019203697A1 publication Critical patent/WO2019203697A1/fr
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Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the invention relates to medicine, veterinary medicine, specifically to pharmacology, and for the use of a composition based on solid lipid particles of 1- ⁇ [6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-Z-yl hydrochloride ] carbonyl ⁇ -4 benzylpiperazine as targeted delivery agents for the treatment of influenza and SARS.
  • Viral infections are widespread in the human population and are able to infect almost all organs and systems of the host organism, causing latent, acute, chronic and slow forms of infection. High morbidity and mortality from viral infections necessitates the creation of etiotropic drugs. A significant part of the registered diseases of viral etiology falls on the flu and SARS.
  • Influenza is an infectious disease that is harmful to human health and leads to significant economic losses.
  • WHO World Health Organization
  • influenza etiotropic chemotherapy drugs that have a direct effect on the reproduction of the virus and aimed at a specific virus-specific target in its cycle.
  • H3N2 influenza A virus strains circulating during this period were resistant to amantadine / remantadine, and 98-100% of seasonal H1N1 influenza strains were resistant to oseltamivir, a neuraminidase inhibitor.
  • oseltamivir a neuraminidase inhibitor.
  • COPD chronic obstructive pulmonary disease
  • One of the methods of targeted delivery of a drug to the lesion is its transport through the lymphatic system. At the same time, it is possible not only to create and maintain adequate concentrations of drugs in the tissues -
  • SUBSTITUTE SHEET targets, but also act on pathogenic agents directly in the lymph.
  • lipids - solid lipid nanoparticles SSN
  • NLC nanostructured lipid carriers
  • LDC lipid-drug conjugates
  • Lipid dosage forms can increase the bioavailability of a lipophilic drug by improving its solubilization in the intestinal lumen (due to the formation of vesicles, mixed vesicles and micelles), as well as affecting transport and metabolic processes in enterocytes [Ipatova OM, Torkhovskaya TI, Medvedeva N.V., Prozorovsky V.N., Ivanova N.D., Shironin A.V., Baranova V.S., Archakov A.I. / Bioavailability of oral dosage forms and methods for increasing it // Biomedical Chemistry, 2010, Volume 56, no. 1, p. 101-119].
  • Dosage forms containing lipids, solid lipid nanoparticles, are homogeneous particles formed from lipids in identical aggregate states, while the drug molecules are dispersed in the space between the side chains of fatty acids.
  • the main materials for the synthesis of solid lipid nanoparticles are triglycerides and waxes.
  • the sizes of nanocarriers of this type range from 50 to 1000 nm.
  • the drug substance in them, as a rule, is highly lipophilic, dissolved in the core or dispersed throughout the matrix.
  • Solid lipid nanoparticles are well absorbed in the lymphatic vessels of the intestine and through the thoracic duct enter the pulmonary circulation without undergoing presystemic metabolism.
  • BBB blood-brain barrier
  • the technical problem to which the claimed invention is directed is that the existing means for the treatment of influenza and acute respiratory viral infections do not provide an improvement in the quality of therapy, are ineffective.
  • the technical result is the provision of targeted delivery and an increase in the concentration of the drug in the upper respiratory tract while reducing the dose of the drug.
  • the present invention provides a pharmaceutical composition based on solid lipid particles of 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indole- hydrochloride
  • SUBSTITUTE SHEET (RULE 26) 3-yl] carbonyl ⁇ -4 benzylpiperazine, which has the property of targeted delivery for the treatment of influenza and SARS, in the following ratio, wt.%:
  • Emulsifier 2 0
  • the pharmaceutical composition may further comprise a medium chain triglyceride in the following ratio of components, wt%:
  • Emulsifier 2 0
  • the long chain fatty acid glyceride may be selected from the group of, for example, glyceryl tristearate, glyceryl distearate, glyceryl monostearate, glyceryl palmitate, glyceryl dibehenate, glyceryl tribenegen, glyceryl monooleate, white wax or wax wax.
  • Vegetable oil is selected from the group of, for example, olive, peanut, sesame, linseed, rapeseed, soy, cotton, lemon, orange.
  • coconut or palm oil or palm kernel can be selected.
  • compositions based on solid lipid particles of 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl ⁇ -4 benzylpiperazine hydrochloride as targeted delivery vehicles for treatment of influenza and SARS was obtained as follows.
  • benzylpiperazine was prepared by the methods described in [Meghavi Patel, Development, Characterization and Evaluation of Solid Lipid Nanoparticles as a Potential Anticancer Drug Delivery System, University of Toledo, 2012], with modifications.
  • Method 1 hot homogenization method. 25 g of lipids were mixed in a 100 ml beaker with heating at 50-60 ° C, then a solution of 1- ⁇ [6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl hydrochloride was introduced ] carbonyl ⁇ -4
  • Method 3 through getting the bottom. 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-Z-yl] carbonyl ⁇ -4 benzylpiperazine was previously dissolved in alcohol and titrated with a 0.1 M sodium hydroxide solution to receiving the basis. Next, the procedure described in method 1 or method 2 was repeated.
  • Particles were characterized by the following physicochemical methods: particle size was determined using a PZO Worszava microscope and dynamic light scattering (Malvern Zetasizer). The content of 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl ⁇ -4 benzylpiperazine in compositions based on solid lipid particles was determined by HPLC (Ultimate Dionex 3000 , diode array detector on Waters Acquity BEN Cl 8 analytical columns (100x2.1 mm, 1.7 ⁇ m).
  • compositions based on solid lipid particles of 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-Z-yl] carbonyl ⁇ -4 benzylpiperazine hydrochloride were obtained. Their compositions are presented in tables 1 - 6.
  • compositions can be used in the form of tablets, gelatin capsules, in the following ratio of components:
  • Figure 1 shows the coefficient of tissue accessibility for the lungs and tracheitis bronchus of rats with a single intragastric administration of the inventive composition 1.1, 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl hydrochloride ] carbonyl ⁇ -4
  • Figure 2 shows the coefficient of tissue accessibility for the lungs and tracheitis of the rat bronchus with a single intragastric administration of the claimed composition 1.2, 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl hydrochloride ] arbonyl ⁇ -4
  • Figure 3 shows the coefficient of tissue accessibility for the lungs and tracheitis bronchus of rats with a single intragastric administration of the inventive composition 1.3, 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl hydrochloride ] carbonyl ⁇ -4
  • Figure 4 shows the tissue accessibility coefficient for rat lungs and tracheitis bronchus with a single intragastric
  • Figure 5 presents the coefficient of tissue accessibility for lungs and tracheitis of the bronchus of rats with a single intragastric administration of the claimed composition 2.2, 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl hydrochloride ] arbonyl ⁇ -4
  • Figure 6 shows the coefficient of tissue accessibility for the lungs and tracheitis bronchus of rats with a single intragastric administration of the inventive composition 2.3, 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl hydrochloride ] carbonyl ⁇ -4
  • Example 1 Determination of tissue accessibility of a composition based on solid lipid particles of 1- ⁇ [6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-Z-yl] carbonyl ⁇ -4 benzylpiperazine hydrochloride in the framework of studies of the pharmacokinetics of distribution in the organs and tissues of Wistar rats.
  • Blood samples were taken after decapitation of animals. Blood was collected from each animal in test tubes containing 100 ⁇ l of 5% ag-EDTA, at the following time intervals: 0.5, 1, 2, 4, 8, 24, 30 and 48 hours after intragastric administration of the claimed compositions, hydrochloride 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl ⁇ -4 benzylpiperazine and its clathrate complex with beta-cyclodextrin. Five rats were taken at each time point. Blood plasma was separated by centrifugation at 4000 rpm. within 15 minutes Blood plasma samples were frozen and stored until analysis at minus 70 ° C. To study the distribution in animals after their decapitation, fragments of the following organs and tissues were taken and frozen: lungs, trachea + bronchi.
  • Sample preparation of samples was carried out by precipitation of proteins and extraction of blood plasma and aqueous organ homogenates with acetonitrile.
  • the limit of quantification of 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] arbonyl ⁇ -4 benzylpiperazine in various tissues was 10 ng / ml.
  • benzylpiperazine in plasma (ng / ml) and the trachea and bronchi (ng / g tissue) were calculated area under the concentration-time curve from the time of administration to a specific time point (AUCo- t) ⁇ from this was calculated the coefficient of tissue availability by the following formula:
  • the coefficient of tissue availability AUC 0-t (tissue) / AUC 0-t (blood plasma).
  • the intragastric administration to rats of the proposed compositions based on solid lipid particles of 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-Z-yl] carbonyl ⁇ -4 benzylpiperazine provides its maximum penetration into the upper respiratory tract and suppression of virus reproduction in these organs, which is very important in the treatment of influenza and SARS.
  • the claimed composition based on solid lipid particles of 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-Z-yl] carbonyl ⁇ -4 benzylpiperazine hydrochloride as anti-influenza drugs due to targeted delivery and increase of its concentration in the upper respiratory tract, they will suppress the reproduction of the virus in these organs, which ultimately will reduce the severity of side effects and increase the effectiveness of treatment for influenza and SARS.
  • Example 2 The study of the effectiveness of the claimed compositions based on solid lipid particles of 1- ⁇ [6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl ⁇ -4 benzylpiperazine hydrochloride in a model experimental influenza pneumonia in mice.
  • the aim of the study was to study the effectiveness of the claimed compositions based on solid lipid particles of 1- ⁇ [6- bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-Z-yl] carbonyl ⁇ -4 benzylpiperazine in two doses on a viral influenza model
  • compositions based on solid lipid particles of 1- ⁇ [b-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-Z-yl] carbonyl ⁇ -4 benzylpiperazine hydrochloride were used; their compositions are given in tables 1-6, the pharmaceutical substance umifenovir.
  • the claimed compositions and umifenovir were prepared as a suspension in a 1% starch solution.
  • the injected doses of the studied drugs are indicated on the basis of the content of the pharmaceutical substance in the dosage form.
  • Samples of the studied preparations were prepared immediately before the experiment, animals were injected with 200 ⁇ l of the prepared preparations intragastrically. The substances were weighed to the nearest 0.1 mg on an analytical balance. Doses of drugs were calculated in relative mass units - mg / kg of animal body weight per day.
  • influenza virus strain A / California / 04/2009 (pndmH1141 2009) was used, provided by WHO, in a lyophilized state, stored at plus 4 ° C and adapted to mice.
  • the mice were infected with an intranasally diluted virus; after the onset of signs of the disease, they were humanely euthanized and opened. Under sterile conditions, homogenate of lung tissue was obtained.
  • the obtained lung tissue homogenate was used to infect 10-day-old chicken embryos from which the allantoic virus was obtained and, after titration on its mice (determination of MLD 50 (murine lethal dose 50) of the virus dose causing 50% death of infected mice), the animals were infected.
  • MLD 50 murine lethal dose 50
  • the animals were infected.
  • one pool of the virus was used, which was not frozen and stored at 4 ° C.
  • the same pool of virus was used in 2 experiments.
  • H1N1 influenza viruses - A / California / 04/2009
  • H1N1 seasonal virus A / Brisbane / 59/2007
  • RTGA 96-well microplates with V-wells were used. Serum in twice decreasing concentrations was diluted in isotonic sodium chloride solution and poured into wells. An equal amount of virus-containing liquid was added to each dilution. The control was a suspension of the virus in isotonic sodium chloride solution. Tablets with a mixture of sera and virus were kept in an incubator for 30 minutes or at room temperature for 2 hours, then a suspension of erythrocytes was added to each of them.
  • the reaction results were taken into account after 30 minutes. Conclusions about the results of typing the virus were made on the basis of the detected interaction of the test virus with one of the positive reference sera.
  • the virus was attributed to one or another type (subtype) of the virus, provided that it interacted with the corresponding reference serum of at least 1/4 of a homologous titer.
  • mice Females weighing 12-14 g. Were obtained from the Andreevka nursery (Moscow region) and kept on a standard diet. The animals were kept in regulated vivarium conditions under natural light conditions on a standard diet and
  • SUBSTITUTE SHEET (RULE 26) free access to water and food.
  • the animals were fed with briquetted feed in accordance with the approved standards.
  • the keeping of animals corresponded to the rules for the design, equipment and maintenance of experimental biological clinics (vivariums). Marking of animals in groups was carried out by dyeing the surface of the body.
  • the animals were weighed on an Ohaus Scout SPX222 scale (LEL 220g, resolution 0.01 g) every time at a specific time (12.00 p.m.).
  • Umifenovir was used as a comparison drug. The appropriateness of the choice of umifenovir was determined by the fact that it is the only licensed anti-influenza drug belonging to the class of indoles, which have proven their effectiveness and safety in preclinical and clinical trials,.
  • the hydrochloride 1- ⁇ [6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl ⁇ -4 benzylpiperazine included in the composition also belongs to this class.
  • Umifenovir was administered 24 hours and 1 hour before infection, then for 5 days 1 time per day after infection. For intragastric administration, a disposable insulin syringe with a special needle (lavage) was used.
  • mice The following groups of mice were formed for the experiment:
  • mice were from 8 to 15 animals. In some groups, 1 or 2 mice died during manipulations related to infection or treatment. Further, these groups were considered as containing one mouse less. Pre-weighed m and on the same day were infected intranasally under mild anesthesia with influenza virus
  • a / California / 04/2009 (pndmH11 ⁇ 11 2009) at a dose of 10 MLD BO - Treatment was performed according to the described schemes. Animals of the control group were infected with the influenza virus and did not receive any treatment, they were intragastrically injected with a suspension of 1% starch gel in a volume of 200 ⁇ l according to the scheme of application of the claimed compositions.
  • mice were weighed daily, in a subsequent period of time, every 1-2 days.
  • the chemotherapeutic activity of the studied drugs on the model of influenza pneumonia in mice was evaluated according to the following criteria:
  • mice The average life expectancy of mice was calculated by the following formula:
  • f is the number of mice dead on day d
  • mice are also included B i n d, in this case is 16, n is the number of mice in the group.
  • the decrease or increase in body weight was calculated separately for each mouse and expressed as a percentage, while the animal’s body weight before infection was taken as 100%. For all mice of the same group, the average percentage loss or increase in body weight of animals was determined.
  • lungs After visual assessment of the lungs, they were washed three times in a solution of 0.01 M phosphate-buffered saline (PBS), then homogenized and resuspended in 1 ml of cold sterile PBS. The suspension was clarified from cell debris by centrifugation at 2000 g for 10 min and the supernatant was used to determine the infectious titer of the virus in an MDCK cell culture.
  • PBS phosphate-buffered saline
  • MDCK cells transplantable dog kidney cells, weight 50-60
  • MEM minimal medium Needle
  • SUBSTITUTE SHEET (RULE 26) washed with serum-free MEM. 10-fold dilutions of each sample of the virus from the lungs (whole to 10 8 ) were prepared on medium supplemented with TRSC-trypsin (2 ⁇ g / ml). The resulting dilutions infected a monolayer of 4 wells of a 96-well plate. After incubation at 37 ° C in an atmosphere of 5% SDS for 72 hours, the cells were washed three times with PBS and fixed with 10% formaldehyde solution at a temperature of 18 - 23 ° C for 5 min.
  • infectious titer of the virus was determined by 4 replicates of each sample according to the method of Reed and Mench and expressed in loglO TCID 5 o / 0.1 ml (tissue cytopathic infectious dose 50 - the dose of the virus that causes the death of 50% of infected cells). Next, the average titer for three identical samples was calculated.
  • SUBSTITUTE SHEET (RULE 26) To determine the dose of the virus containing 10 MLD50 / groups consisting of 4-6 mice were infected with the obtained whole allantoic virus and its successive 10-fold dilutions (from 10 -1 to 10 5 ). An example of animal observation data for 16 days is shown in Table 8. From these data it is seen that 50% of the death of the animals causes infection with 10 3 virus, therefore, 50 ⁇ l of 10 2 dilution will contain approximately 10 MLD50 (Table 8).
  • mice of the control group infected with the influenza virus at a dose of 10 MLD50 and not receiving any treatment complete death of the animals was observed in accordance with the above infection dose.
  • the average life expectancy of mice in the first and second experiment in the viral control groups was 7.5 and 8.25 days, respectively.
  • the maximum loss was approximately 10% on day 7 in the first experiment and 30% on day 9 in the second experiment.
  • the treatment of the claimed compositions 1.1; 1.2; 1.3; 2.1; 2.2 and 2.3 at a dose of 3.7 mg / kg / day protected 33-45% of the animals from death, and increased their average life expectancy. Changing the treatment regimen and increasing its duration to 7 days did not lead to a significant increase in efficiency, which was almost the same as in the first experiment.
  • SUBSTITUTE SHEET (RULE 26) similar to the condition of the lungs in animals treated with the claimed compositions 1.1; 1.2; 1.3; 2.1; 2.2 and 2.3, pathological changes were observed in about half of the lungs and were evaluated on 2 crosses.
  • the results of a virological study of the lungs of animals confirmed the data obtained during the observation of mice and correlated with the clinical parameters of the effectiveness of treatment with a decrease in the reproduction of the virus in this organ.
  • the virus titers were 4.8312.89 and 3.610.36 1d TTsID50, respectively.
  • the titer of the virus in the lungs of animals during treatment with umifenovir and the claimed compositions 1.1; 1.2; 1.3; 2.1; 2.2 and 2.3 depended on the administered dose.
  • the treatment of the claimed compositions 1.1; 1.2; 1.3; 2.1; 2.2 and 2.3 at a dose of 15 mg / kg / day in a mouse influenza pneumonia model is effective.
  • a dose of 15 mg / kg / day there was a decrease in animal death, virus reproduction in the lungs and an increase in life expectancy compared with the control group of untreated animals.
  • solid dosage forms include, for example, tablets, pills, gelatine capsules, etc.
  • An example of a solid dosage form includes gelatin capsules.
  • colorants and stabilizers are commonly used.
  • dyes are used: tetrazine, indigo; as stabilizers can be represented: sodium metabisulfite, sodium benzoate.
  • the proposed gelatin capsules contain from 2 to 14% of the active ingredient.
  • 1 capsule 10 mg contains:
  • long chain fatty acid glyceride long chain fatty acid glyceride, medium chain triglyceride, vegetable oil, emulsifier, microcrystalline cellulose to a content weight of 350 mg
  • the active ingredient in free form such as powder or granules, in an amount of 100 g (the amount of substance required to obtain 10,000 capsules) is mixed with excipients (3400 g).
  • the dose of the active component to be administered is 1- ⁇ [6-bromo-1-methyl-5-methoxy-2-phenylthiomethyl-1-H-indol-3-yl] carbonyl ⁇ -4 benzylpiperazine formula 1 hydrochloride varies depending on many factors such as age, gender, patient’s body weight, symptoms and severity of the disease, the particular compound to be administered, the method of administration, the form of the preparation in which the active compound is administered.
  • the total prescribed dose is from 1 to 50 mg per day.
  • the total dose can be divided into several doses, for example, for taking from 1 to 4 times a day.
  • the range of total doses of the active substance is from 1 to 50 mg per day, preferably from 5 to 20 mg.
  • An effective therapeutic dose of the drug can be chosen by the attending physician.

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Abstract

L'invention concerne la médecine humaine et vétérinaire et plus particulièrement la pharmacologie et concerne une composition pharmaceutique sur la bse de particules lipidiques solides d'hydrochlorure de 1-{[6-brom-1-méthyl-5-méthoxy-2- phénylthiométhyl-1-N-indol-3-il]carbonyl}-4 benzylpipérazine (et variantes). La composition est proposée comme médicament à administration ciblée pour traiter la grippe et des maladies virales respiratoires aiguës.
PCT/RU2019/050048 2018-04-19 2019-04-19 Composition pour traiter des maladies virales (et variantes) Ceased WO2019203697A1 (fr)

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EA202092218A EA202092218A1 (ru) 2018-04-19 2019-04-19 Композиция для лечения вирусных заболеваний (варианты)

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RU2018114533 2018-04-19
RU2018114533A RU2018114533A (ru) 2018-04-19 2018-04-19 Композиция на основе твердых липидных частиц, обладающая свойством направленной доставки для лечения вирусных заболеваний (варианты)

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Citations (4)

* Cited by examiner, † Cited by third party
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