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WO2021211013A1 - Composition pharmaceutique pour traiter la tuberculose et comprenant de la makozinone - Google Patents

Composition pharmaceutique pour traiter la tuberculose et comprenant de la makozinone Download PDF

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Publication number
WO2021211013A1
WO2021211013A1 PCT/RU2020/050318 RU2020050318W WO2021211013A1 WO 2021211013 A1 WO2021211013 A1 WO 2021211013A1 RU 2020050318 W RU2020050318 W RU 2020050318W WO 2021211013 A1 WO2021211013 A1 WO 2021211013A1
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Prior art keywords
tablet
cyclodextrin
macosinone
tuberculosis
granules
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English (en)
Russian (ru)
Inventor
Борис Анатольевич РУДОЙ
Юрий Георгиевич КАЗАИШВИЛИ
Виктория Сергеевна ЩЕРБАКОВА
Наталия Александровна НИКИТИНА
Роман Николаевич БОЛГАРИН
Владимир Георгиевич НЕСТЕРЕНКО
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Obschestvo S Ogranichennoi Otvetstvennostyu "niarmedik Plyus"
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Obschestvo S Ogranichennoi Otvetstvennostyu "niarmedik Plyus"
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Priority to EA202192083A priority Critical patent/EA202192083A1/ru
Publication of WO2021211013A1 publication Critical patent/WO2021211013A1/fr
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    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • the present invention relates to pharmaceutical compositions for the treatment of mycobacteriosis based on 2- [4- (cyclohexylmethyl) piperazin-1-yl] -8-nitro-6- (trifluoromethyl) -4H-1, 3-benzothiazin-4-one ( makosinone), more specifically, the present invention relates to a solid oral gastro-retentive dosage form of makosinone and its use for the treatment of mycobacteriosis.
  • tuberculosis In terms of the burden of disease and mortality, tuberculosis (hereinafter TB) is undeniably the most important and complex threat to human health.
  • WHO World Health Organization
  • tuberculosis remains one of the 10 leading causes of death in the world, while mortality rates are significantly higher (about 2 times) than among widespread widespread HIV / AIDS.
  • the social significance and danger of this disease remains very high, especially due to the increase in the prevalence of primary resistance of the pathogen strains to known drugs.
  • MDR - M. tuberculosis strains have begun to acquire additional resistance mutations - already to second-line drugs, which has led to the emergence and spread of a new type (class) of pathogen mutants, designated as extensively drug-resistant strains (XDR - strains).
  • XDR - strains extensively drug-resistant strains
  • M. tuberculosis XDR strains are also resistant to fluoroquinolones and injectable aminoglycosides (Jassal M., Bishai WR.
  • drugs of the first and second line are currently exclusively oral solid forms (tablets, capsules).
  • the compound 2- [4- (cyclohexylmethyl) piperazin-1-yl] -8-nitro-6- (trifluoromethyl) -4H-1, 3-benzothiazin-4-one (PBTZ169 , INN Makosinon) (Makarov V, Lechartier B, Zhang M, Neres J, van der Sar AM, Raadsen SA, et al. Towards a new combination therapy for tuberculosis with next generation benzothiazinones. EMBO Mol Med. 2014; 6 (3) : 372-83; Shi J, Lu J, Wen S, Zong Z, Huo F, Luo J, Liang Q, Li Y, Huang H, Pang Y. 2018.
  • makosinone has a low level of toxicity for mammals, which is one of the conditions for newly synthesized promising drugs against mycobacteriosis, the treatment of which is carried out, as a rule, by very long courses lasting several months ...
  • Makosinone is practically insoluble in water, and at the same time is characterized by low lipophilicity (the substance is practically insoluble in most organic solvents, including hexane, heptane, chloroform).
  • macosinone has an extremely low oral bioavailability; in experiments on animals, the level of its bioavailability was recorded at a level of 1-2%.
  • makosinone should be classified as a class IV pharmacologically active substance according to the generally accepted BCS classification, that is, substances with poor water solubility and low permeability through biological membranes.
  • makosinone has such essential features for pharmaceutical development as low lipophilicity, a narrow window of bioavailability in the gastrointestinal tract.
  • makosinone has a relatively low (according to the results of clinical studies - less than 60%) level of metabolic transformation in the body. Taking this into account, macosinone cannot be assigned to any of the 4 known classes of another international classification based on distribution characteristics (BDDCS) widely used in pharmaceutical development.
  • DDCS distribution characteristics
  • the objective of the present invention is the development and creation of a new and effective pharmaceutical oral composition (dosage form) of the active substance of macosinone (PBTZ169), characterized by a sufficient level of bioavailability and therapeutic efficacy with predominantly once a day oral administration, which is promising for use in clinical practice.
  • PBTZ169 macosinone
  • the technical result of this invention is the development and production of containing macosinone - 2- [4- (cyclohexylmethyl) piperazin-1-yl] -8-nitro-6- (trifluoromethyl) -4H-1, 3-benzothiazin-4-one or its pharmaceutically acceptable salt, in particular the hydrochloride, of a pharmaceutical composition in the form of a gastro-retentive tablet with a modified release of the active substance, with an increased relative bioavailability, which provides, under single oral administration, for a long time, up to 24 hours, to maintain a therapeutically significant concentration of the active substance in organism with high compliance and suitability for use in the schemes of complex therapy of tuberculosis infection.
  • the technical result of the present invention is also the development of a technologically simple method for producing the specified dosage form (gastro-retentive tablet), suitable for scaling up on the traditional equipment used in the pharmaceutical production.
  • a gastro-retentive swellable mucoadhesive tablet for the controlled release of macosinone in the stomach and upper part of the small intestine which is a combined system comprising a complex of macosinone or a pharmaceutically acceptable salt thereof in a therapeutically effective amount and cyclodextrin in the form of gra - zero, additionally coated with a layer of mucoadhesive polymer and pressed into a polymer matrix based on at least two hydrophilic soluble and / or insoluble swellable and mucoadhesive polymers and at least one additional pharmaceutically acceptable excipient.
  • the macosinone or a pharmaceutically acceptable salt thereof is a fine crystalline powder with a particle size of 30 to 500 ⁇ m.
  • the pharmaceutically acceptable salt is a hydrochloride, hydrogen sulfate, ethanesulfonate, or methanesulfonate.
  • the cyclodextrin is 2-hydroxypropylp-cyclodextrin, 6-monodeoxy-6-monoamine N-cyclodextrin, y-cyclodextrin, 2-hydroxypropyl-y-cyclodextrin, and / or sulfobutyl N-cyclodextrin.
  • the cyclodextrin is 2-hydroxypropyl-N-cyclodextrin.
  • the mucoadhesive polymer coating the granules is a soluble carboxymethyl cellulose with a degree of substitution of at least 0.7.
  • the mucoadhesive polymer layer further comprises a solubilizer.
  • the solubilizer is a medium molecular weight polyethylene glycol, a monoester of polyoxyethylated sorbitan and higher fatty acids.
  • the polyethylene glycol is PEG 6000 or PEG 8000.
  • the polyoxyethylated higher fatty acid monoester is Polysorbate 80.
  • the hydrophilic soluble mucoadhesive matrix polymer is a soluble cellulose derivative or high molecular weight polyethylene oxide with a molecular weight in the range of 1,000,000 to 4,000,000 daltons.
  • the cellulose derivative is hydroxyethyl cellulose or hydroxypropyl methylcellulose.
  • the insoluble mucoadhesive matrix polymer is a high polymer carbomer.
  • the carbomer is carbopol.
  • the additional pharmaceutically acceptable substance is a filler, binder, glidant, or lubricant.
  • the weight ratio of macosinone or a pharmaceutically acceptable salt thereof to cyclodextrin in the complex is from 0.5: 1 to 1: 2.
  • the content of the complex of macosinone or its pharmaceutically acceptable salt with cyclodextrin is 50-80% by weight, based on the total weight of the tablet.
  • the amount of macosinone is 125-500 mg.
  • the tablet has an initial length of at least 20 mm and a width of at least 10 mm.
  • the tablet has an aqueous swelling index after 6 hours of 95-150%.
  • the tablet according to the invention has an in vitro adhesion force in 0.01 N hydrochloric acid solution, which ensures its retention on the mucosal surface for at least 5 hours.
  • the tablet has a crushing strength after tabletting of 190-210H.
  • the tablet is characterized in that the release rate of macosinone in vitro in 0.01 N hydrochloric acid solution is 25-50 mg / h.
  • the tablet is characterized in that the release of the active substance in vitro in the dissolution medium of 0.01 N HCI after 6 hours is 30-50%.
  • the specified technical result is also achieved through the use of a gastro-retentive swellable mucoadhesive tablet according to the invention for the prevention and / or treatment of a disease caused by mycobacteria.
  • the mycobacteria are M. tuberculosis.
  • the disease is tuberculosis.
  • the tuberculosis is in multiple and / or extensively drug resistant forms.
  • the tablet is administered orally to the subject once a day.
  • the subject is a human.
  • the invention also includes a method for preparing a gastro-retentive tablet according to the invention, comprising three steps: a) obtaining granules of macosinone or a pharmaceutically acceptable salt thereof in the form of a complex with cyclodextrin; b) incorporation of the granules obtained in stage a) into the composition of secondary granules with their coating with a layer of a mixture of a bioadhesive agent and a solubilizer; c) pressing dry secondary granules obtained in step b) into a tablet matrix based on one highly swellable and one strongly mucoadhesive polymer.
  • Macosinon The chemical compound macosinone (or PBTZ169) is 2- [4- (cyclohexylmethyl) piperazin-1-yl] -8-nitro-6- (trifluoromethyl) -4H-1, 3-benzothiazin-4-one, (CAS 1377239- 83-2) characterized by the following structural formula:
  • Macosinone in the compositions according to the invention may be present in amounts from 125 to 1000 mg, preferably from 250 to 500 mg.
  • Macosinone hydrochloride (2- [4- (cyclohexylmethyl) piperazin-1 - yl] -8-nitro-6- (trifluoromethyl) -4H-1, 3-benzothiazin-4-one hydrochloride) has the structural formula: gross formula - C20H24CIF3N4O3S, molecular weight 492.5; the properties of the compound are shown in more detail in Table 1.
  • modified release tablet in this document describes a composition (dosage form) characterized, after ingestion, by a sustained and controlled release of the active substance in a given area of the gastrointestinal tract, predominantly in the stomach and upper small intestine, as opposed to immediate dosage forms. release that after ingestion, uncontrollably and immediately occurs directly in the stomach.
  • pharmaceutically acceptable means a material, a component that is biocompatible with the human body.
  • pharmaceutically acceptable salt refers to those salts that, within the scope of the medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and correspond to a reasonable the balance of benefits and risks.
  • Some examples of the salts of the present invention are, in particular, the hydrochloride, hydrogen sulfate, ethane sulfonate or methanesulfonate.
  • therapeutically effective amount means that amount of a compound that, when administered as mono- or combination therapy, is sufficient to prevent and / or treat infectious diseases in humans or animals caused by mycobacteria.
  • dosage in this document means the content of the active (active) substance in quantitative terms per unit volume or unit of mass in accordance with the dosage form, namely a unit amount of the active ingredient in one unit of the dosage form, for example in a tablet.
  • Pharmacokinetic curve is a curve reflecting the change in time of the concentration of an active substance or its metabolite in blood plasma or any organ or tissue in the body.
  • the characteristics of the pharmacokinetic curve used in the present invention are indicators:
  • AUC is the area under the curve reflecting the time change in the concentration of an active substance or its metabolite in blood plasma or in any organ or tissue in the body at a certain time interval after drug administration;
  • Tm ah the moment recorded during the test from the injection of the drug to reaching the maximum concentration in the blood plasma (biological fluid of the body);
  • T 1/2 the moment of time from the beginning of the test, when the registered maximum concentration of the substance in the blood (biological body fluid) decreases by 2 times;
  • MRT is the duration of existence (retention) of a drug substance or metabolite in the body calculated from registered pharmacokinetic parameters
  • Cycpodextrins are a class of cyclic oligosaccharides obtained by enzymatic cleavage of starches and consisting of 6 (a-cyclodextrins, a-CD), 7 (b-cyclodextrins, b-CD) or 8 (g-cyclodextrins, g -CD) residues a- 0 (+) - glucoliranose (dextrose) linked into macrocycles aD-1 by 4-glycosidic bonds in such a way that the cyclodextrin molecule has the shape of a truncated cone with a hydrophobic inner cavity.
  • cyclodextrins When starch is treated with the microbial enzyme cyclodextringlucanotransferase, so-called large-ring cyclodextrins can also be obtained, containing nine, ten, eleven and more (up to 30-60) glucose residues in the cycle - the so-called b-cyclodextrins, e -cyclodextrins, x-cyclodextrins, etc.).
  • Structural formulas of the three main types of cyclodextrins (a-CD, b-CD, g-CD).
  • the conical shape of the cyclodextrin molecule is stabilized by hydrogen bonds between OH groups, as well as by aD-1, 4-glycosidic bonds.
  • cyclodextrins All OH groups in cycpodextrins are located on the outer surface of the molecule. Therefore, the inner cavity of cyclodextrins is hydrophobic and is capable of forming inclusion complexes with various molecules of organic and inorganic nature in aqueous solutions.
  • the cyclodextrin ring is a "host” molecule, the incorporated substance is called a "guest”.
  • Inclusion complexes in aqueous solutions dissociate into cyclodextrin and the initial substance, showing the basic properties of the latter. When heated above 50-60 ° C, the complexes usually disintegrate completely and usually restore their structure upon cooling.
  • Cyclodextrin suitable for the preparation of a pharmaceutical composition according to the invention can be, in particular, selected from 2-hydroxypropylp-cycpodextrin, 6-mono-deoxy-6-monoaminaph-cyclodextrin, g-cyclodextrin, 2-hydroxypropyl N-cyclodextrin, sulfobutylp ⁇ -cyclodextrin or mixtures thereof, while the quantitative ratio of macosinone and podextrin in the claimed pharmaceutical composition can be from 0.5: 1 to 1: 5.
  • Mycobacteriosis is an infectious disease of humans or animals caused by pathogenic strains of the genus Mycobacterium (Mycobacterium).
  • Mycobacterium pathogenic strains of the genus Mycobacterium
  • Within the scope of the present invention may be caused, inter alia, by one or more pathogens selected from Mycobacterium tuberculosis (the causative agent of human and animal tuberculosis), Mycobacterium bovis, Mycobacterium kansasii, Mycobacterium scrofulaceum, Mycobacterium avium, Mycobacterium complex ...
  • MDR strains are multidrug-resistant strains of the causative agent of tuberculosis that have acquired resistance to first-line drugs according to the WHO clinical guidelines.
  • XDR strains are extensively drug-resistant strains of the causative agent of tuberculosis that have acquired, in addition to MDR characteristics, resistance to drugs of the second and subsequent lines of therapy according to the WHO clinical guidelines.
  • a pharmaceutical composition is a combination of an active active (medicinal) substance and pharmaceutically acceptable excipients that ensure the creation of a medicinal product.
  • Medicinal product is a pharmaceutical composition in a specific dosage form that provides the use of a medicinal substance to achieve the desired therapeutic effect.
  • Matrix - polymer base of a modified release tablet can be based on hydrophilic (hydrophilic matrix) and / or hydrophobic polymers, which can be water-soluble or insoluble.
  • a gastro-retentive tablet is a dosage form in the form of a tablet, which, due to the design features, can linger in the stomach for a long time.
  • a monolithic (homogeneous) delivery system (tablet) is understood as a tablet obtained by simultaneous effective mixing of the active active ingredient (pharmaceutical substance) with the components that form the tablet matrix, followed by tabletting the resulting mixture with the formation of a system with components (substances) evenly distributed in it.
  • Dissolution media with pH 1.2, 4.5 and 6.8 - in accordance with the State Pharmacopoeia or the European Pharmacopoeia for testing the dissolution of dosage forms The temperature of the solutions is 37.5 ° C. Tests in an apparatus of the "paddle mixer" type (apparatus No. 2), rotation speed - 150 rpm; the volume of the dissolution medium is 1000 ml.
  • Figure 2. Target cumulative release curve of macosinone from a modified release gastro-reactive tablet for a 500 mg macosinone tablet. The fill marks the permissible range of variation of the experimentally recorded indicators.
  • Figure 3. Time release of macosinone HCI from an immediate release dosage form - hard gelatin capsules, dosage 80 mg (reference drug according to example 9), in solutions with different pH values.
  • Dissolution media with different pH values - in accordance with the State Pharmacopoeia or the European Pharmacopoeia for testing the dissolution of dosage forms The temperature of the solutions is 37.5 ° C. Tests in an apparatus of the "paddle mixer" type (apparatus No. 2). rotation speed - 150 rpm; the volume of the dissolution medium is 1000 ml.
  • Figure 4 Curves of changes in the content of makosinone in the blood plasma of animals when testing various oral dosage forms. Tests on dogs of the Beagle breed (5 dogs per group) under conditions of oral administration of drugs).
  • the ordinate is the concentration of makosinone in the blood plasma, ng / ml; the abscissa is the time after administration, hours.
  • the horizontal dashed line (7 and 8, respectively) marks the calculated minimum threshold of therapeutically effective concentration
  • composition GR10 500 mg (tablet according to the invention, example 6);
  • composition GR20 6 - gastro-retentive tablet of composition GR20, 500 mg (reference drug, example 11).
  • the present invention solves a complex problem, namely, the invention is directed to the development of an effective drug (pharmaceutical composition in a specific dosage form) based on macosinone hydrochloride for oral administration for the treatment of infectious diseases caused by mycobacteria, in particular M. tuberculosis (including resistant forms ), intended for a single dose during the day, and such a composition should ensure the maintenance of a therapeutically effective concentration of the indicated active substance in the body during the period between two successive doses of the drug.
  • an effective drug pharmaceutical composition in a specific dosage form
  • macosinone hydrochloride for oral administration for the treatment of infectious diseases caused by mycobacteria, in particular M. tuberculosis (including resistant forms )
  • tuberculosis therapy involves treatment with several drugs at the same time ("cocktail" of drugs), therefore, along with efficacy and bioavailability, an important factor is the compliance of the drug (suitability and acceptability for patients and medical personnel) when used in a hospital setting in combination with several drugs with different pharmacokinetic and pharmacodynamic properties.
  • bedaquiline can also include the presence of restrictions on the dosage of tablets and the need to take 4 tablets simultaneously (with a dosage of 100 mg), which impairs its compliance in complex therapy.
  • the disadvantages of delaminade can also include the need to take the drug twice a day.
  • the recently synthesized new class of chemical compounds - benzothiazinone derivatives, new in terms of the mechanism of antimicrobial action on mycobacteria (suppression of cell wall synthesis) - is currently being considered as a more promising candidate for the role of a drug for inclusion in the treatment regimen of drug-resistant forms of tuberculosis.
  • makosinone (PBTZ169) is characterized by a significantly higher efficiency of suppression of all tested XDR variants of the pathogen (the minimum inhibitory concentration (MIC) of makosinone is 80-110 ng / ml, while for bedaquiline it is of the order of 500-600 ng / ml).
  • MIC minimum inhibitory concentration
  • this compound has a relatively low lipophilicity, is characterized by a sharp decrease and so extremely low solubility in water in the zone of neutral pH values, and, as a consequence, low permeability through the membranes of intestinal epithelium cells, which does not depend on the presence of proteins or glycoproteins - carriers.
  • BCS Biopharmaceutics Classification System
  • class IV drugs with such low solubility and permeability indices are used in the clinic in the form of dosage forms for parenteral administration (injection or infusion preparations), such as the antibiotics carbopenems used in the treatment of tuberculosis.
  • parenteral administration injection or infusion preparations
  • the use of injectable drugs was recognized as low-compliant and such drugs are classified as reserve drugs (used when 4-5 - component therapy of resistant forms is ineffective).
  • the first-line drugs in all modern regimens of tuberculosis therapy are oral solid dosage forms (tablets or capsules). Tablet dosage forms are more preferable (they make up 96.2% of respondents' preferences) due to the duration of taking this group of drugs (Global drug facility product catalog / Global Drug Facility. Stop TV Partnership. World Health Organization, Geneva 2016; Anti-tuberculosis dosage forms: assortment, main advantages, prospects for technological improvement / ME Kim et al // Pharmacy and Pharmacology N ° 3, 2016. - pp. 38-55).
  • the dissolution rate of the substance of macosinone hydrochloride improved, mainly due to a decrease in the ability of crystals to aggregate, when small amounts (up to 0.005-0.01 %) tertiary ammonium detergents (for example, benzethonium chloride), but the use of such substances in pharmaceutical compositions is limited by the additional adverse side effects of such surfactants.
  • tertiary ammonium detergents for example, benzethonium chloride
  • makosinone in the body quickly and efficiently binds to blood plasma proteins and is unevenly distributed over organs and tissues, with a predominant delay in the lungs, spleen, and liver.
  • a negative aspect in this regard is the relatively fast metabolism found for makosinone even during the initial passage of the drug through the vasculature.
  • the detected and identified metabolites are significantly less active against the pathogen, which further reduces the therapeutic efficacy of the drug.
  • the present inventors have developed an immediate release dosage form in the form of a hard gelatin capsule containing granular macosinone powder (example 9).
  • the low suitability of this form of the drug for clinical use was revealed. So, according to the results of clinical pharmacokinetic studies of this dosage form (capsules with a dosage of 80 mg) with the participation of volunteers, it was shown that the time to reach the maximum concentration in the blood plasma of this substance, taken once per os in dosages of 320, 640 g, and 1280 mg is 1-2 hours, half-life is 10-12 hours.
  • a gastro-reactive swellable mucoadhesive tablet for the controlled release of macosinone in the stomach and upper small intestine which is a combined system comprising a complex of therapeutically effective the amount of macosinone or its pharmaceutically acceptable salt with cyclodextrin in the form of granules coated with a layer of mucoadhesive polymer and pressed into a polymer matrix based on at least two hydrophilic soluble and / or insoluble swellable and mucoadhesive polymers and at least one additional a pharmaceutically acceptable excipient.
  • this dosage form of makosinone (gastro-reactive tablet) is not only characterized by increased bioavailability, but also is able to maintain a concentration effective against M. tuberculosis bacteria and an effective therapeutic effect of makosinone on excitatory cells. - the body of tuberculosis in the human body in a single dose per day.
  • Example 1 The example describes the results of a study of the dependence of the solubility of macosinone hydrochloride on the pH values of the medium.
  • Figure 1 shows the dependence of the solubility of makosinone HCI ( ⁇ g / ml) on the pH of the medium.
  • the dissolution medium is 0.01 N HCI.
  • the volume of the dissolution medium is 1000 ml.
  • the temperature of the solutions is 37.5 ° C.
  • the tests were carried out in an apparatus of the "paddle mixer" type (apparatus No. 2). rotation speed - 150 rpm.
  • Example 2 This example describes the critical quality scores set and monitored in the development and testing of macosinone HCI gastro-retentive tablets.
  • Example 3 A method for evaluating the mucoadhesive properties of tablets by the force of detachment of the tablet from the mucous membrane.
  • the equipment used is a texture analyzer (TA.XT plus, Stable Micro Systems, Great Britain).
  • Each mucoadhesion test is performed on a freshly prepared porcine gastric mucosa preparation.
  • the tablet is attached to the flat end of a metal rod with a diameter of 10 ⁇ 1 mm using a piece of double-sided adhesive tape.
  • the probe of the texture analyzer with the tablet is lowered until it comes into contact with the mucosa at a speed of 0.5 mm / s, the tablet is pressed against the mucosa with a force of 100 g for 300 s, and then returned to its original position at a speed of 0.5 mm / s.
  • Tests are carried out on at least 3 samples at a temperature of 32 ⁇ 2 ° C. The readings of the instrument, recorded automatically in the Exponent program, are used to construct the stress-strain curves.
  • the maximum voltage about max is calculated by the formula:
  • CJmax F max / S, where F max is the maximum achieved value of the force at the stage of separation, S is the adhesive contact area (the surface area of the tablet in contact with the mucous membrane).
  • the work of destruction of the adhesive joint is calculated as: where F is the current value of the force, I is the movement of the rod. Integration is carried out numerically, for example, by the trapezoidal method.
  • Example 4 A method for assessing bioadhesive (mucoadhesive) ability by the "wash-off" method.
  • the equipment used is a "paddle stirrer” dissolution tester (USP, Apparatus 2); 1000 ml glasses. Special holders for the stirrer blades.
  • Biomaterial - fragments of the mucous membrane of the pig's stomach Biomaterial - fragments of the mucous membrane of the pig's stomach.
  • Fragments of the mucous membrane are glued back to the holders using cyanoacrylate glue.
  • a tablet In a laboratory stand, a tablet is placed on a mucosal fragment moistened with water and pressed under a weight of 10 g for 5 minutes. Attach the tablet holders to the stirrer blades, place it in the test medium in the beaker, and turn on the stirrer. The tests are carried out at a stirring speed of 25 rpm. The time to tear off each tablet is recorded.
  • Example 5 Determination of the degree of release of macosinone from modified release tablets.
  • the test is carried out in a 500 ml vessel using a dissolution tester with a paddle stirrer.
  • the dissolution medium is 0.01 N HCI.
  • the sampling mode is set in such a way that the concentration of the substance in the vessel during dissolution does not reach the saturating concentration ( ⁇ 100 ⁇ g / ml).
  • Ci the concentration of the substance in each of the selected aliquots of 300 ml
  • Ck the concentration of the substance in the last sample taken (for which the volume is not replenished).
  • the tablet according to the invention should provide a modified sustained release of makosinone in the gastric medium so that the concentration of makosinone in this medium does not reach the limit of its dissolution (80-100 ⁇ g / ml).
  • the rate of release of macosinone from the tablet calculated from the results of comparing in vitro and in vivo data on dissolution and pharmacokinetics of macosinone should be in the range of 25-50 mg / h.
  • Figure 2
  • Gastro-retentive tablet of composition GR 10 is a complex system using granules based on hydroxypropyl-beta cycpodextrin (inclusion complex) and an extra-granular matrix based on a mixture of carbopol + HEC.
  • GR10 gastro-retentive tablet
  • Carbopol + HEC + CMC mucoadhesive matrix
  • the gastro-retentive tablet is prepared in a separate method in three main stages:
  • humectant solution To prepare cyclodextrin granules, purified water is used as a humectant solution (the mixture-humectant ratio is 2.5: 1).
  • Macosinone hydrochloride (49g) and Hydroxypropylbetadex (hydroxypropyl-beta-cyclodextrin) (25g) are loaded into a granulator mixer and mixed at a rotation speed of 300 rpm until uniform (visual control).
  • a humidifier solution (purified water) is introduced into the mixer-granulator at a mixture-humidifier ratio of 2.5: 1. Stir at a stirrer speed of 600 rpm for 3-5 minutes until granules are formed (visual control).
  • the granules are dried in a drying oven. Residual moisture content of the mixture is 2.28%. Temperature when measuring humidity - 105 ° ⁇ .
  • the granules are sieved through a sieve with a mesh size of 0.5 mm. Residues are rubbed by hand through a 0.5 mm sieve.
  • the obtained cyclodextrin granules are introduced into the mixer-granulator, and sodium CMC, PEG is added. The components are mixed until homogeneous for about 1 minute (visual control).
  • a humidifier solution is introduced (an aqueous solution of Polysorbate-80 in the ratio Polysorbate-80: purified water 1: 16.9). Stir for no more than 2-3 minutes until a fine loose granulate is formed (visual control).
  • Residual moisture content of the mixture is not more than 1.2% (temperature when measuring moisture content - 105 ° C).
  • the granulate is sieved through a sieve with a mesh size of 0.71 mm.
  • the residues are rubbed by hand through a sieve with a mesh size of 0.71 mm.
  • the calibrated granulate, Carbopol and HEC are introduced into the mixer.
  • the lubricant is loaded with sieved sodium stearyl fumarate into the mixer and carried out mixing the components for 3 minutes until homogeneous (visual control).
  • the tabletting mixture is discharged into a labeled container.
  • the tableting process is carried out on a tablet press using an oval biconvex press tool measuring 20.00 mm x 10.00 mm.
  • the tablets obtained after pressing are controlled according to technological parameters: hardness, abrasion, height, deviations from the average weight of 20 tablets (deviation from the average weight of individual tablets should not exceed 5%), as well as according to the characteristics established by the specification for example 2 (Table 2) for the gastro-retentive form of tablets.
  • composition (tablet) according to the invention is the use for its creation of a separately prepared in the form of granules of a complex containing macosinone hydrochloride and beta-hydroxypropyl-cyclodextrin, capable of forming inclusion complexes with various molecules,
  • the mass ratio of the substance of makosinone hydrochloride and cyclodextrin can vary (for example, 2: 1, 1: 1 or 1: 2), but with the preservation of the quantitative ratio of the mass of cyclodextrin granules and other components, which, if necessary, makes it possible to obtain tablets with different to - dose of the active substance (for example, 500, 250 or 125 mg).
  • a fundamentally important distinguishing point in the design of a gastroreactive tablet according to the invention is the use of a combined base substance delivery system in which pre-prepared primary cyclodextrin granules (cyclodextrin complex of insoluble macosinone) are incorporated into secondary granules based on a mixture of a binder component with high bioadhesive properties (CMC) and an easily water-soluble solubilizer (PEG).
  • CMC bioadhesive properties
  • PEG easily water-soluble solubilizer
  • CMC - a capillary type disintegrant, which ensures rapid penetration of water into the secondary granules
  • PEG - a swelling type disintegrant accelerate the flow of water into the secondary granules, their destruction (erosion) and release of the complex from them active substance
  • the obtained granules of complex composition after the stage of dry mixing are pressed together with a mixture of highly hygroscopic, swellable and, at the same time, bio-adhesive polymer components that form the tablet carrier matrix.
  • - water-insoluble Carbopol - a polyacrylic cross-linked polymer of a swelling type with moderate bioadhesive properties and a partially water-soluble highly bioadhesive gel-forming polymer - hydroxyethyl cellulose (at the same time exhibiting the properties of a capillary disintegrant).
  • such a complex composition tablet When introduced into an aqueous medium, such a complex composition tablet swells rapidly due to the combined absorption of water, both by granules and by the components of the matrix (Carbopol and HEC).
  • Gastro-retentive tablet of composition GR 18 is a combined system using mucoadhesive-modified granules based on hydroxypropyl-beta cycpodextrin and an extra-granular matrix based on a combination of PEO and HPMC polymers.
  • Macosinone hydrochloride, hydroxypropyl-beta-cyclodextrin are loaded into the mixer-granulator. The components are mixed until homogeneous (visual control). o Granulation
  • the granules are dried in an oven (fluid bed dryer). Residual moisture content of the mixture is 2.28%. Temperature when measuring humidity - 105 ° ⁇ . o Calibration of pellets
  • the granules are sieved through a sieve with a mesh size of 0.5 mm. Residues are rubbed by hand through a 0.5 mm sieve.
  • a humidifier solution an aqueous solution of Polysorbate-80
  • Mixing is carried out for 2-3 minutes until fine friable granulate is formed (visual control) o Drying of the granulate
  • the granulate is dried in an oven (fluidized bed dryer). Residual moisture content of the mixture - 1.83%. Temperature when measuring humidity - 105 ° ⁇ . o Calibration of granulate
  • the granulate is sieved through a sieve with a mesh size of 0.71 mm.
  • the residues are rubbed by hand through a sieve with a mesh size of 0.71 mm.
  • Stage 3 Obtaining a tablet by pressing granules into a matrix Calibrated granulate, HPMC and PEO are introduced into the mixer. Stirring is carried out until uniform for 5 minutes (visual control). Then the sifted sodium stearyl fumarate is loaded into the mixer and the components are mixed for 3 minutes until homogeneous (visual control).
  • the tabletting mixture is discharged into a labeled container.
  • the tableting process is carried out on a tablet press using an oval biconvex press tool measuring 20.00 mm x 10.00 mm. At the beginning of the process, the tablet press is adjusted to produce tablets with an average weight of 1100.0 mg.
  • the tablets obtained after pressing are controlled according to technological parameters: hardness, abrasion, height, deviations from the average weight of 20 tablets (deviation from the average weight of individual tablets should not exceed 5%), as well as according to the characteristics established by the specification for example 2 (Table 2) for the gastro-retentive form of tablets.
  • This example describes a variant of the tablet according to the invention, obtained according to the same three-stage technology based on primary cyclodextrin granules with macosinone subjected to a second granulation stage followed by compression in a mixture with the components of the swellable-adhesive matrix, but in contrast to example 6 in this case as a highly swellable polymer, polyethylene oxide, is used for matrix components, the degree of swelling of which, unlike Carbopol, does not change with increasing pH values, and another highly adhesive cellulose derivative, HPMC.
  • a highly swellable polymer polyethylene oxide
  • the tablets according to this example have a lower degree of mucoadhesion, but swell more intensively when placed in an aqueous medium.
  • Example 8 The example characterizes the effect of the formation of a complex of the substance of makosinone hydrochloride with hydroxypropyl-beta-cyclodextrin (according to examples 6 and 7) on the dissolution parameters of the active substance from the cyclodextrin granules obtained according to the invention (stage 1 of the manufacturing method described in examples 6 or 7).
  • the solubility of macosinone significantly increases, with the most important increase (by more than 200%) in the solubility in the biorelevant FaSSIF medium, which imitates the composition of intestinal juice in the upper part of the duodenum. (the main absorption zone of the active substance). It is also important that the solubility of the complex with cyclodextrin in the FeSSIF medium (simulator of intestinal juice in the middle part of the small intestine) also remains 2-3 times higher than the initial salt of the active substance. In fact, this provides an expansion of the relatively narrow “bioavailability window” of makosinone in the complex with cyclodextrin.
  • Example 9 Preparation of a dosage form of immediate release macosinone - hard gelatin capsules with a dosage of 80 mg of macosinone hydrochloride (calculated as free base), a reference drug in experiments on pharmacokinetic studies in experiments on dogs. Table 6. Composition of the gelatin capsule according to the example. Brief description of technology:
  • Each type of raw material is sieved separately: makosinone hydrochloride, through a sieve with a mesh size of 0.5 mm; crospovidone, povidone, lactose monohydrate, colloidal silicon dioxide through a sieve with a mesh size of 1.0 mm; magnesium stearate through a sieve with a mesh size of 0.32 mm. Sifted raw materials are collected in production containers, weighed on scales
  • the resulting granulate is additionally subjected to dry granulation on a calibrator with a hole diameter of 1.2 mm.
  • Dry granules are powdered with a mixture (0.7 kg of crospovidone, 0.83 kg of colloidal silicon dioxide, 0.14 kg of magnesium sterate)
  • the finished mixture is filled into hard gelatin capsules (size N ° 0), up to a capsule content weight of 300 mg.
  • Example 10 Gastro-retentive tablet of composition GR 08, gastro-retentive swelling and bioadhesive (mucoadhesive) tablet with modified release of an active substance poorly soluble in water (reference drug analogous to the principle of gastro-retention).
  • This example describes a variant of a gastro-retentive tablet, based on an analogue known from the prior art, developed for a poorly soluble active substance with rapid (like macosinone) elimination from the body (acyclovir) and using the same as the tablet according to the invention, the principle of retention of the dosage form in the stomach - due to the combination in one tablet of the ability to significantly swell and the ability to mucoadhesion (Development and characterization of gastroretentive sus- tained-release formulation by combination of swelling and mucoadhesive approach: a mechanistic study / R. Sankar, Subheet Kumar Jain. // Drug Design, Development and Therapy 2013: 7 1455-1469).
  • composition according to example 10 differs from the composition according to the invention (GR10 or GR18 according to examples 6 and 7) both in the design principle and in the manufacturing technology of the dosage form, which uses a “mono-granular” (monolithic) system with the simultaneous inclusion of granules in the composition.
  • Table 7 Composition of GR08 (reference drug).
  • Macosinone hydrochloride, microcrystalline cellulose 101, Carbopol, PEO are loaded into the mixer-granulator. The components are mixed until homogeneous for 1 minute (visual control). o Granulation
  • the granulate is dried in an oven (or fluidized bed dryer). Residual moisture content of the mixture is 1.80%. Temperature when measuring humidity - 105 ° ⁇ . o Calibration of granulate
  • the granulate is sieved through a sieve with a mesh size of 1.0 mm (0.710 mm). Residues are rubbed by hand through a sieve with a mesh size of 0.710 mm.
  • the tabletting mixture is discharged into a labeled container.
  • the tableting process is carried out on a tablet press using an oval biconvex press tool measuring 20.00 mm x 10.00 mm. At the beginning of the process, the tablet press is adjusted to produce tablets with an average weight of 1100.0 mg.
  • the tablets obtained after pressing are controlled according to technological parameters: hardness, abrasion, height, deviations from the average weight of 20 tablets (deviation from the average weight of individual tablets should not exceed 5%), as well as according to the characteristics established by the specification for example 2 (Table 2) for the gastro-retentive form of tablets.
  • Example 11 Tablet of the GR 20 composition: a variant of a gastro-retentive tablet, according to the design scheme "monogranular" (monolithic) system with granules based on CMC + MCC and a matrix based on HPMC (comparison drug with a monolithic matrix used in a comparative experiment on the study of pharmacokinetics in dogs).
  • the tablet according to the invention is made, as in example 10, with a so-called “monolithic” matrix, all the components of which are included in the initially prepared granulate.
  • the release of the active substance in this case occurs due to a combination of diffusion processes through the matrix material and release due to the gradual destruction of the matrix.
  • Purified water with Polysorbate-80 is used as a humidifier solution (mixture: water ratio - 1, 55: 1).
  • Macosinone hydrochloride, microcrystalline cellulose 101, Povidone K-90, HPMC and sodium CMC are loaded into the mixer-granulator. The components are mixed until homogeneous for 1 minute (visual control). o Granulation
  • the granulate is dried in an oven (fluidized bed dryer). Residual moisture content of the mixture - 2.03%. Temperature when measuring humidity - 105 ° ⁇ . o Calibration of granulate The granulate is sieved through a sieve with a mesh size of 0.710 mm. The residues are rubbed by hand through a sieve with a mesh size of 0.710 mm. o Dusting
  • the mixer is loaded with calibrated granulate and sieved sodium stearyl fumarate, and the components are mixed until uniform for 3 minutes (visual control).
  • the tabletting mixture is discharged into a labeled container.
  • the tableting process is carried out on a tablet press using an oval biconvex press tool measuring 20.00 mm x 10.00 mm. At the beginning of the process, the tablet press is adjusted to produce tablets with an average weight of 1100.0 mg.
  • the tablets obtained after pressing are controlled according to technological parameters: hardness, abrasion, height, deviations from the average weight of 20 tablets (deviation from the average weight of individual tablets should not exceed 5%), as well as according to the characteristics established by the specification for example 2 (Table 2) for the gastro-retentive form of tablets.
  • Example 12 Gastro-retentive tablet of composition GR 12 a variant of the swelling-adhesive matrix tablet type with modified release of macosinone, similar to the tablet of the invention (GR10 or GR18 according to examples 6 and 7) according to the design scheme using a combined (non-monolithic) system and a polymer matrix, but in which primary granules are obtained without the use of cycpodextrin - based on cellulose derivatives (CMC + MCC).
  • CMC + MCC cycpodextrin - based on cellulose derivatives
  • a mixture of the same polymers was used as in the preparation of a tablet of the GR08 composition (example 10) carbopol + PEO.
  • the tablet of this example is intended to evaluate the effect of cyclodextrin on the release (solubility) of an active substance.
  • the tablet of composition GR12 is made according to a three-stage scheme for constructing a gastro-retentive tablet similar to the variant according to the invention (examples 6 or 7), in which separately prepared granules containing the active substance are included in the composition of secondary granules with mucoadhesive and solubilizer, which in the third stage by dry mixing and the presses are combined with the matrix-forming polymer components that are distributed between the granules.
  • the release of the active substance makosinone in this case occurs mainly through the initial erosion of the matrix (release of the granules) followed by dissolution of the substance from the released granules.
  • purified water is used as a humidifier solution (the mixture-humidifier ratio is 1, 1: 1).
  • Macosinone hydrochloride Crospovidone XL-10 is loaded into the mixer granulator. The components are mixed for 1 minute until homogeneous (visual control). o Granulation
  • the granules are dried in an oven (fluid bed dryer). Residual moisture content of the mixture - 2.79%. Temperature when measuring humidity - 105 ° ⁇ . o Calibration of pellets
  • the granules are sieved through a sieve with a mesh size of 0.5 mm. Residues are rubbed by hand through a 0.5 mm sieve. o Stage 2. Obtaining modified granules o Preparation of dry mix
  • the granulate is dried in an oven (fluidized bed dryer). Residual moisture content of the mixture - 2.95%. Temperature when measuring humidity - 105 ° ⁇ . o Calibration of granulate
  • the granulate is sieved through a sieve with a mesh size of 0.71 mm.
  • the residues are rubbed by hand through a sieve with a mesh size of 0.71 mm.
  • the tabletting mixture is discharged into a labeled container.
  • the tableting process is carried out on a tablet press using an oval biconvex press tool measuring 20.00 mm x 10.00 mm. At the beginning of the process, the tablet press is adjusted to produce tablets with an average weight of 1100.0 mg.
  • the tablets obtained after pressing are controlled according to technological parameters: hardness, abrasion, height, deviations from the average weight of 20 tablets (deviation from the average weight of individual tablets should not exceed 5%), as well as according to the characteristics established by the specification for example 2 (Table 2) for the gastro-retentive form of tablets.
  • Example 13 Comparison of the properties of gastro-retentive tablets of different compositions.
  • the tablets of the compositions GR08 (according to example 10) and GR12 (according to example 12) did not pass the tests for the parameters of swelling and mucoadhesion, respectively.
  • the tablet of the GR12 variant (according to example 12) also did not meet the requirements for the rate of release of the active substance.
  • the tablet of the GR20 composition (example 11) despite the lower level of cumulative release of macosinone for 6 hours of dissolution (at the level of the minimum permissible established values (table 2)) had the same high rates of swelling rate and degree and mucoadhesion, like the tablets of the invention (examples 6 and 7).
  • tablets according to the invention of compositions GR10 were selected, obtained according to the developed three-stage scheme using a complex combined matrix, and GR20 (according to example 11), as a comparison drug with no less, than the tablet according to the invention, with indicators that provide the tablet retention in the stomach, but manufactured according to an alternative scheme using a "monolithic" matrix and granules, obtained without the use of cyclodextrin.
  • Such a comparison drug allows one to experimentally, in in vivo experiments, evaluate the effect of the original method chosen according to the invention for preparing a gastro-retentive tablet based on the cyclodextrin complex of macosinone.
  • an immediate release dosage form (capsules) according to Example 9 was also used as a comparator.
  • the dosage forms were administered to the dogs as a single oral administration on an empty stomach.
  • the content of makosinone in blood plasma was determined by a previously validated bioanalytical method using equipment for HPLC / MS analysis.
  • both gastro-retentive tablets tested (variant according to the invention GR10 (example 6) and the comparison drug GR20 (example 11) significantly differed in pharmacokinetic parameters from the immediate release preparation (capsules according to example 9) in the form of the pharmacokinetic curve : after taking these tablets, the moment of reaching the maximum concentration of macosinone in the blood plasma significantly (by 2-4 hours) shifts in time, the excretion of the drug is significantly slowed down. - the amount of macosinone in the blood (Cmax) and, accordingly, is the parameter of the area under the AUC curve and
  • the tablet of the GR20 composition was characterized by the parameters of swelling and mucoadhesion similar to those of the GR10 tablet, providing a long retention in the stomach, and in terms of the rate of matrix erosion (recorded by the dissolution rate), the tablet of the GR20 composition was inferior formulation according to the invention GR10, which in turn reduces the likelihood of evacuation of this form from the stomach due to the rapid reduction in size compared to the tablet according to the invention.
  • the gastro-retentive nature of the GR20 tablet is confirmed by a significant (more than 2 hours) shift in time of the peak of the maximum concentration, as well as a significant decrease in the rate elimination of the active substance and an increase in the average indicator of the residence time of the active substance in the body (Table 11).
  • composition GR10 The effect of appearance 10-12 hours after administration of the tablet of a second sufficiently long period of increasing the concentration of macosinone in the blood, registered in an experiment on dogs for tablets according to the invention (example 6) of composition GR10, is unexpected, since the results of creating and in vivo testing of gastro-retentive tablets similar in design and gastro-retention methods, in particular for swellable mucoadhesive tablets of acyclovir, the method of manufacture of which was taken as an analogue in the preparation of gastro-retentive tablets according to Example 10, indicate that the retention time in the stomach of such dosage forms is usually no more than 4-8 hours due to the gradual degradation of the tablet matrix and the recurrent phenomena of periodic increased gastric motility (“migrating myoelectric complex”) at intervals of 2-4 hours.
  • a typical form in this sense for the case of testing gastro-retentive tablets was demonstrated by the composition comparison tablet GR20 according to example 11.
  • the tablet according to the invention provides an increase of at least 2 times (in terms of the total exposure of AUC) bioavailability and predicted therapeutic efficacy in comparison with the dosage form immediate release, which is due not only to an increase (also approximately 2 times) in the maximum concentration in blood plasma, but also a significant (approximately 3 times) increase in the time of the active substance in the body (MRT) (Table 11) ... It is important to emphasize that due to the unexpected, significantly delayed increase in the content of the active substance in the blood plasma, registered in these experiments, the concentration of makosinone in the blood plasma remains at a sufficiently high level for 22-24 hours after a single dose of the tablet.
  • the target level of the therapeutically effective concentration of makosinone in human blood plasma can be set at 60-90 ng / ml.
  • the indicator of the target minimum concentration in the blood plasma of dogs can be set at the level 20-25 ng / ml.
  • this minimum threshold of effective concentration is marked with a horizontal line (7,8).
  • inset B to this figure shows the predicted concentration of makosinone in the lung tissue, taking into account the coefficients of tissue bioavailability. From the data presented in Figure 4, it follows that under the conditions of a single administration of the tablet according to the invention to animals, in particular, the composition GR10, the predicted content of the active substance in the main target organ will exceed the established threshold for at least 24 hours.
  • a gastro-retentive dosage form according to the invention at a dosage of 500 mg is able to maintain a concentration effective against M. tuberculosis bacteria and, accordingly, an effective therapeutic effect of macosinone on cells of the causative agent of tuberculosis in the human body. in the conditions of a single dose of the drug.
  • the dosage of a 500 mg tablet taken once a day is promising for use in clinical practice, including when compared with the dosage level (about 640 - 1000 mg at least 2 times a day) required to achieve in the clinic therapeutic effect when using forms of immediate release. This will significantly reduce the total drug load on the patient's body, which is especially important for complex multicomponent treatment regimens for tuberculosis infection.
  • the developed gastro-retentive tablet according to the invention and the method for its preparation ensured the solution of the problem of the invention and the achievement of the claimed technical result.

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Abstract

L'invention concerne des compositions pharmaceutiques pour le traitement de mycobactérioses à base de 2-[4-(cyclohexyméthyl)pipérazone-1-yl]-8-nitro-6-(trifluoro-méthyl)-4Н-1,3-benzothiazine-4-one (makozinone), et concerne plus précisément une forme médicamenteuse gastrorétentive perorale solide et des procédés de production de telles compositions. Cette forme médicamenteuse obtenue de makozinone (cachet gastrorétentif) se caractérise non seulement par une biodiversité mais permet également de maintenir une concentration efficace agissant sur les bactéries M.tuberculosis et d'avoir une action thérapeutique efficace de la makozinone sur les cellules du déclencheur de tuberculose dans l'organisme d'une personne dans des conditions d'une prise quotidienne unique.
PCT/RU2020/050318 2020-04-06 2020-11-10 Composition pharmaceutique pour traiter la tuberculose et comprenant de la makozinone Ceased WO2021211013A1 (fr)

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RU2018123362A RU2751163C9 (ru) 2020-04-06 2020-04-06 Фармацевтическая композиция на основе макозинона для лечения туберкулеза, включая его формы с множественной и широкой лекарственной устойчивостью.

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WO2018214639A1 (fr) * 2017-05-24 2018-11-29 中国医学科学院药物研究所 Composé de 2-azacyclo-5-trifluorométhyl-8-nitrobenzo(thio)pyran-4-one, son procédé de préparation et son utilisation
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RU2325152C2 (ru) * 2001-07-04 2008-05-27 Сан Фармасьютикл Индастриз Лимитид Удерживаемая в желудке система регулируемой доставки лекарственного средства
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