WO2022106859A1 - Préparation pharmaceutique contenant du favipiravir, sa production et son utilisation - Google Patents

Préparation pharmaceutique contenant du favipiravir, sa production et son utilisation Download PDF

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Publication number
WO2022106859A1
WO2022106859A1 PCT/HU2021/050062 HU2021050062W WO2022106859A1 WO 2022106859 A1 WO2022106859 A1 WO 2022106859A1 HU 2021050062 W HU2021050062 W HU 2021050062W WO 2022106859 A1 WO2022106859 A1 WO 2022106859A1
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Prior art keywords
favipiravir
hpc
pharmaceutical preparation
granules
silicon dioxide
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PCT/HU2021/050062
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English (en)
Inventor
Pál FEKETE
Fruzsina NACSA
Lívia Gál
Zsolt ŐSZI
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Meditop Gyógyszeripari Kft.
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Publication of WO2022106859A1 publication Critical patent/WO2022106859A1/fr

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    • 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
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • 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 obj ect of the invention relates to a pharmaceutical preparation consisting of favipiravir, low-substituted hydroxypropyl cellulose ( L-HPC ) , silicon dioxide and, optionally, a lubricant , to a method for producing such pharmaceutical preparation, and to the use of the pharmaceutical preparation .
  • L-HPC low-substituted hydroxypropyl cellulose
  • Favipiravir is a pharmaceutical active ingredient for the treatment of serious influenza infections (Report on the Deliberation Results , 4 March 2014 ; Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Wel fare ; Japan (MHLW) ) , which has also proved to be ef fective in the treatment of patients of other viral disease epidemics , such as ebola ( CHMP assessment report ; Medicinal products under development for the treatment of Ebola ; 3 February 2016 ; EMA/ 204393/2016 ) and COVID- 19 (Anti-influenza drug Avigan® Tablet Meets Primary Endpoint in Phase I I I Clinical Trial in Japan for COVID- 19 patients ; Tokyo , 23 September 2020 ; FUJI FILM Toyama Chemical Co . Ltd) .
  • the active ingredient favipiravir was developed by FUJI FILM Toyama Chemical Co . Ltd, which has marketed it since 2014 under the brand name Avigan in the form of a film-coated tablet containing 200 mg of active ingredient (product information: AVIGAN Tablets 200 mg ( Favipiravir ) SmPC;
  • the main identifiers of favipiravir are the followings:
  • favipiravir molecule is metabolised in cells into favipiravir ribosyl triphosphate (favipiravir RTP) , which selectively inhibits RNA polymerase required for the replication of the influenza virus .
  • favipiravir RTP favipiravir ribosyl triphosphate
  • Favipiravir is absorbed quickly, its peak blood level time is two hours on average, and its terminal half-life is 2-4 hours (see: the CHMP assessment report referenced above) .
  • favipiravir into an oral pharmaceutical preparation, primarily into tablets or capsules, is a difficult task due to the unfavourable physical properties of the active ingredient (small particle size, low bulk density, bad compressibility and solubility, high dose) . Due to the high dose it is preferable if the active ingredient content of the pharmaceutical preparation is above 50%, it is particularly preferable if it is about or above 80%.
  • the binder it may be, for example, povidone, hydroxypropyl cellulose, hypromellose, carmellose sodium, methylcellulose, polyvinyl alcohol, gum arable, and dextrin. These binders may be used on its own, or a mixture of them may also be used . According to the speci fications the preferred binder is one of the various molecular weight types of povidone , such as K17 , K25 , K30 or K90 . On the other part , according to the patent speci fications , among the various disintegrating agents only L-HPC and croscarmellose ensured the fast dissolution of more than 85% of the active ingredient from the tablets within 15 minutes .
  • the composition of the Avigan 200 mg tablet falls within the scope of protection of the above patent No . EP2407166B1 .
  • the speci fication in addition to the L- HPC, povidone , and silicon dioxide it also contains crospovidone as supplementary disintegrating agent .
  • the disadvantage of the process disclosed in the patent speci fication of EP2407166B1 is that it contains five types of excipient , the integration of which into the granules demands the use of a large amount of water, which must be removed by drying after the granulation .
  • According to example 17 of the patent speci fication 8170 g of water was used for the granulation of 7400 g of favipiravir .
  • the use of the composition according to the preparation is very disadvantageous from the point of view of energy use .
  • a preparation is described in patent application No . CN107737128A that also contains the surfactant sodium lauryl sulphate in the interest of improving the dissolution speed .
  • the disadvantage of the composition is that the surfactant does not only facilitate dissolution of the favipiravir, but it also influences the absorption of other substances , therefore from a therapeutical point of view it is considered an excipient that is to be avoided .
  • a favipiravir tablet composition is described in patent application No . CN106667926A, in which microcrystalline cellulose coated with silicon dioxide is used .
  • the disadvantage of the composition is that it is not suitable for the production of a preparation with a greater active ingredient content of more than 50% , therefore with the use of this it is not possible to comply with an important subj ective requirement from the point of view of the patient , i . e . ease of swallowing .
  • a favipiravir tablet preparation is described in patent application No . CN105687152A, which also contains a surfactant in the interest of improving the dissolution speed, e . g . sodium lauryl sulphate , or polyoxyethylene sorbitan monooleate , or poloxamer .
  • a surfactant in the interest of improving the dissolution speed, e . g . sodium lauryl sulphate , or polyoxyethylene sorbitan monooleate , or poloxamer .
  • a favipiravir composition that may be used in a tablet or capsule that only contains a minimal number and amount of excipients and that may be produced in a simpler, quicker and more economical way than in the case of the current methods .
  • the desired obj ectives may be achieved by granulating favipiravir with low-substituted hydroxypropyl cellulose (hereinafter : L-HPC ) and a small amount of silicon dioxide ( 0 . 5 - 6% ) .
  • Granules containing favipiravir suitable for producing tablets or capsules may be produced by using water as the wetting agent in the presence of L-HPC and without the use of other, water-soluble binders .
  • low- substituted hydroxypropyl cellulose is an excipient that performs the role of both binder and disintegrant by itsel f as a sole excipient and is suitable for producing granules containing favipiravir, from which capsules or tablets , with the addition of a lubricant , may be formulated for oral administration .
  • the basis of our invention is the surprising recognition that the L-HPC in pharmaceutical preparations containing the active ingredient favipiravir does not only act as a disintegrant facilitating the appropriate degree of disintegration, but also as a binder displaying preferred binding properties , i . e . without the addition of other binding agents it performs the role of both disintegrant and binder as a single excipient .
  • the L-HPC adapts the mixture so that granules with a suitable particle si ze may be produced from it .
  • tablets made from these granules will have appropriate hardness , and the tablets and capsules formed from these granules will quickly disintegrate in an aqueous medium, i . e . after swallowing the medicine , as a result of the L-HPC and thereby ensure that the active ingredient is quickly released .
  • the amount of the single excipient used as both disintegrant and binder, i . e . the L-HPC is less than if a separate disintegrant and binder had to be used, therefore , at a given dose , the tablets obtained will be smaller too , which promotes better patient compliance .
  • the present invention relates to granules that consist of favipiravir, L- HPC and silicon dioxide , and that are suitable for the production of an oral pharmaceutical preparation, such as a tablet or capsule .
  • the amount of L-HPC is at least 4 % of the total mass of the granules .
  • the hydroxypropoxy content of the L-HPC in the granules is between 5% and 16% , preferably between 10% and 15% , or preferably 8 % , 11 % or 14 % .
  • the L- HPC in the granules is non- fibrous .
  • the hydroxypropoxy content of the L-HPC in the granules is 8% or 11 % and the particles are non- fibrous .
  • the obj ect of the present invention also relates to a pharmaceutical preparation that contains favipiravir, which contains granules consisting of favipiravir, L-HPC and silicon dioxide , and a lubricant .
  • the favipiravir content of the pharmaceutical preparation is preferably at least 80 mass% .
  • the pharmaceutical preparation preferably contains 200 mg - 900 mg of favipiravir, more preferably 200 mg - 800 mg, most preferably 200 mg or 400 mg of favipiravir .
  • the pharmaceutical preparation is preferably a tablet , which preferably contains 200 mg, 400 mg, 600 mg, 800 mg or 900 mg of favipiravir .
  • the tablet according to the invention particularly preferably contains 200 mg or 400 mg of favipiravir .
  • the pharmaceutical preparation is a capsule , preferably a hard capsule , which contains an amount of favipiravir in the range of 200 mg 400 mg, preferably 200 mg or 400 mg of favipiravir.
  • the lubricant used in the pharmaceutical preparation is preferably sodium stearyl fumarate, preferably at an amount of 0.2 - 4.0%.
  • the silicon dioxide in the pharmaceutical preparation is colloidal silicon dioxide with a specific surface area of at least 200 m 2 /g, or microporous colloidal silicon dioxide with a specific surface area of at least 100 m 2 /g.
  • the hydroxypropoxy content of the L-HPC in the pharmaceutical preparation is between 8% and 14%, preferably 8%, and even more preferably the L-HPC is of the NBD-022 type.
  • the pharmaceutical preparation contains at least 4% L-HPC and at least 0.5% silicon dioxide.
  • the present invention also relates to the use of the pharmaceutical preparation according to the above for the treatment or prophylaxis of viral diseases, where the pharmaceutical preparation is preferably a tablet or a capsule.
  • the viral disease is preferably influenza or COVID- 19, even more preferably COVID-19.
  • the object of the present invention also relates to a method for the production of the pharmaceutical preparation according to the above, which method contains the following steps : a) a part of the L-HPC powder is mixed with water to produce an aqueous dispersion, b) the favipiravir powder is mixed with the other part of the L-HPC and the silicon dioxide; c) the powder mixture obtained in step b) is granulated with the aqueous dispersion obtained in the first step; d) the granules are homogenised with sodium stearyl fumarate and, optionally, silicon dioxide, and then e) they are formulated into tablets or capsules.
  • % in the present specification is understood to mean mass percent (mass%) , and ratios are understood to mean the mass ratios of the individual components .
  • the object of the invention relates to granules (granulated form) consisting of favipiravir, L-HPC and silicon dioxide, as well as to a pharmaceutical preparation containing such granules and a lubricant.
  • the pharmaceutical preparation is for oral administration and may be a capsule, or preferably a tablet and which pharmaceutical preparation may be used for the treatment and prophylaxis of viral diseases.
  • the essence of the present invention is that tablets and capsules containing favipiravir may be produced from granules that consist of favipiravir, L-HPC and silicon dioxide, as, surprisingly, the L-HPC may be used to good effect in the preparation as both binder and as substance aiding disintegration (in other words disintegrant ) .
  • the amount of the disintegrant may also be reduced, therefore the pharmaceutical preparation according to the invention may be produced with a higher percentage of active ingredient content compared to the currently known pharmaceutical preparations containing favipiravir, and produced more cheaply and quickly.
  • those hydroxypropyl celluloses are called L-HPC that contain 5.0 mass! to 16.0 mass! hydroxypropoxy groups with respect to dry material (USP Stage 4 Harmonization Official May 1, 2019) .
  • those L-HPC types are preferred that have a hydroxypropoxy content of between 5% and 16%, preferably between 10% and 15%, or preferably a content of 8%, 11% or 14%.
  • HPC may not be used as an excipient.
  • Those hydroxypropyl celluloses are called HPC that contain 53.4 mass% to 80.5 mass% hydroxypropoxy groups with respect to dry material (USP, Stage 6 Harmonization Official December 1, 2014) .
  • L-HPCs are classed into various grades depending on the degree of substitution (i.e. hydroxypropoxy content) , particle shape and particle size.
  • degree of substitution i.e. hydroxypropoxy content
  • HPCMCAS HPCMCAS for Pharmaceutical Dosage Forms - Update- ExcipientFest Americas 2012. San Juan
  • Table 1 The characteristics of the various grades of L-
  • the non-fibrous types are primarily preferred as the viscosity of their aqueous dispersions is lower, so they may be dispersed in less water, and so they are better for use in granulation.
  • the non- fibrous L-HPCs those types with a more homogenous particle distribution are even more preferable .
  • L-HPCs used in the granules according to the invention are their hydroxypropoxy content ( see , for example , Table 1 ) .
  • L-HPCs with a hydroxypropoxy content between 5% and 16% are suitable for producing the granules according to the invention, within this range the L-HPCs with a hydroxypropoxy content of between 10% and 15% proved to be preferable .
  • those L-HCPs were the most suitable for the production of the granules according to the invention that have a hydroxypropoxy content of 8 % , 11 % or 14 % .
  • L-HPCs consisting of non- fibrous particles
  • NBD- 022 with a hydroxypropoxy content of 8 % proved to be particularly suitable
  • the ratio of favipiravir and L-HPC in the granules may even be greater than 20 : 1 , i . e . the active ingredient content of the preparation may even be higher than 90% .
  • the fracture toughness of the tablets compressed from granules containing favipiravir and L-HPC may be increased i f before compression 0 .
  • 5- 6% silicon dioxide is also added to the granules apart from the lubricant .
  • the silicon dioxide displayed a particularly preferable ef fect when added to the mixture of favipiravir and L-HPC before granulation and not to the finished granules .
  • a form of silicon dioxide proved to be suitable for this purpose that has a high external speci fic surface area (called colloidal silicon dioxide with a speci fic surface area of at least 200 m2 /g) , or a high internal speci fic surface area (called microporous silicon dioxide with a speci fic surface area of at least 100 m2 /g) .
  • Colloidal silicon dioxide is produced by hydrolysis of silicon dioxide , through which a form of silicon dioxide is obtained which has a greater speci fic surface area and that may be evenly distributed .
  • the internal speci fic surface area of microporous silicon dioxide increases as a result of the micropores .
  • the granules according to the invention consist of favipiravir, L-HPC and silicon dioxide .
  • the role of both the binder and of the disintegrant in the granules is performed by the L-HPC .
  • binders conventionally used for granulation, and the larger amount of disintegrant because of the presence of the binder beside the necessarily high dose of favipiravir increase the si ze of the pharmaceutical preparation, which has a negative effect on patient compliance (ability to swallow the tablets) .
  • the L-HPC content of the pharmaceutical preparation according to the present invention is preferably at least 4% of the total mass of the granules. The reason for this is that this is the minimum L-HPC amount that would ensure appropriate granulation of the granules. In addition it is preferable if the silicon dioxide content is at least 0.5%.
  • the pharmaceutical preparation according to the present invention contains the granules detailed above consisting of favipiravir, L-HPC and silicon dioxide, and a lubricant.
  • the favipiravir content of the pharmaceutical preparation is preferably at least 80 mass%.
  • the pharmaceutical preparation preferably contains 200 mg - 900 mg of favipiravir, more preferably 200 mg - 800 mg, most preferably 200 mg or 400 mg of favipiravir.
  • the pharmaceutical preparation is preferably a tablet, which preferably contains 200 mg, 400 mg, 600 mg, 800 mg or 900 mg of favipiravir.
  • an appropriate amount of lubricant with a friction-reducing effect is added to the granules according to the invention (e.g. usually 0.2 - 4.0% in the case of sodium stearyl fumarate) , then tablets are formed from this by compression.
  • the production of pressed tablets by wet granulation is known, e.g. according to that described in the following literature: Pharmaceutical Dosage Forms: Tablets, 2 nd edition, Marcel Dekker 1989, volume 1, pages 131-193) .
  • the tablet according to the invention contains 200 mg of favipiravir .
  • the currently administered dosage regimens may be realised and particularly with an active ingredient content of above 80% the tablets are of such a small si ze that swallowing them, even in the case of a larger number of them, does not cause any problem .
  • the tablet according to the invention contains 400 mg of favipiravir .
  • the currently administered dosage regimens may be realised and particularly with an active ingredient content of above 80% the tablets are still of such a small si ze that swallowing them does not cause any problem .
  • this dosage makes it possible for the doctor and the patient to select a more favourable dosage ( taking a smaller number of tablets ) .
  • the granules produced according to the above may also be used for filling two-part hard capsules with a wall material of , for example , gelatine or HPMC (hydroxypropyl methylcellulose ) .
  • the capsules may contain, for example , an amount of favipiravir in the range of 200 mg - 400 mg, for example 200 mg of favipiravir or 400 mg of favipiravir .
  • the lubricant may also be sodium stearyl fumarate also in the case of capsules , preferably at an amount of 0 . 2 - 4 . 0% .
  • the mass ratio of favipiravir and L-HPC in the granules may even be 25 : 1 , i . e . the active ingredient content of the preparation may even be as much as 96 mass% .
  • the mass ratio of the favipiravir and the L-HPC is preferably up to 20 : 1 , which means an active ingredient content in the preparation o f about 90% .
  • the production of the oral pharmaceutical preparation according to the present invention is signi ficantly simpler compared to other methods , as it contains fewer components , which may also result in more even distribution of the active ingredient content .
  • the tablets produced according to the invention may also contain a water-soluble film coating, which does not substantially reduce the speed of release of the active ingredient .
  • the polymer forming the film may be a polymer conventionally used in the coating of immediate release medicine tablets , such as methocel (methyl hydroxypropyl cellulose ) , PVA (polyvinyl alcohol ) , copovidone (vinylpyrrolidone-vinyl acetate copolymer ) , polyvinyl alcohol-polyethylene glycol graftcopolymer, or modi fied starch .
  • the coating of the film onto the tablets according to the invention may be implemented using methods conventionally used in the pharmaceutical industry .
  • Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms Drugs and the Pharmaceutical Sciences ) 3rd Edition by James W . McGinity (Editor ) , Linda A. Felton (Editor ) ; CRC Press ; 4th edition ( October 13 , 2016 ) .
  • the pharmaceutical preparation according to the invention made from this active ingredient is suitable for administration in the aforementioned indication .
  • the pharmaceutical preparation is preferably a tablet, film-coated tablet or capsule.
  • the granules containing favipiravir, and the tablets or capsules containing such granules are suitable for the treatment of all animals or humans who or which are suffering from a disease that may be treated with favipiravir.
  • animal is primarily understood to mean mammal.
  • the viral diseases that may be treated with favipiravir include, but are not limited to, influenza, ebola and COVID-19.
  • the pharmaceutical preparation according to the present invention is most preferably suitable for the treatment of persons suffering from COVID-19 disease, or for the prophylaxis of such a disease.
  • the production of the granules belongs to the obligatory knowledge of the person skilled in the art.
  • the starting materials are homogenised, then in the case of wet granulation they are aggregated with a suitable granulation liquid, the wet aggregate is dried, then milled by being pressed through a sieve with the appropriate mesh size.
  • the homogenised powder mixture is pressed into plates or large discs, otherwise known as slugs, and these are then milled to produce the granules.
  • Knowledge relating to this is discussed in detail in university textbooks and handbooks dealing with pharmaceutical production. E.g.
  • the granules according to the invention may be produced using wet granulation .
  • Pharmaceutical industry wet granulation processes are well known to the person skilled in the art ( see above ) .
  • There are three methods that may be used for the production of the granules according to the present invention are three methods that may be used for the production of the granules according to the present invention :
  • favipiravir powder, L-HPC powder and silicon dioxide powder are mixed together, and this powder mixture is granulated with water in the conventional way ( aggregated, dried, milled) ;
  • favipiravir powder a part of the L-HPC powder and the silicon dioxide are mixed, the other part of the L-HPC powder is mixed with water to produce an aqueous dispersion, then the powder mixture is granulated with the aqueous dispersion in the conventional way ( aggregated, dried, milled) .
  • the granules according to the invention are preferably produced with the above method 2 ) or 3 ) , as in these cases the use of 4 % L-HPC with respect to the mass of the granules is suf ficient , while in the case of the implementation of the first method it is necessary to use at least 20% L-HPC .
  • a particularly preferred method for the production of the pharmaceutical preparation according to the invention contains the following steps : a ) a part of the L-HPC powder is mixed with water to produce an aqueous dispersion, b) the favipiravir powder is mixed with the other part of the L-HPC and the silicon dioxide; c) the powder mixture obtained in step b) is granulated with the aqueous dispersion obtained in the first step; d) the granules are homogenised with sodium stearyl fumarate and, optionally, silicon dioxide, and then e) they are formulated into tablets or capsules.
  • the examination of the quality of the tablets was performed on the basis of the prescriptions of the European Pharmacopoeia (Ph. Eur.) , which correspond to the prescriptions of the Japanese Pharmacopoeia (JP) and the United States Pharmacopeia (USP) .
  • JP Japanese Pharmacopoeia
  • USP United States Pharmacopeia
  • the testing of the hardness of the tablets was performed with the device and method according to the prescriptions of the Ph. Eur. 2.9.8. RESISTANCE TO CRUSHING OF TABLETS monograph. The force required to crush the tablets was given in N. The tests were performed with the automatic Kraemer UTS 4.1 device .
  • the disintegration time of the tablets was tested with the device and method according to the prescriptions of the Ph. Eur. 2.9.1. DISINTEGRATION OF TABLETS AND CAPSULES monograph. The disintegration time of the tablets was considered to be that time when no fragments of any of the six tablets remain on the sieve. The tests were performed with an Erweka ZT 320 device .
  • the dissolution of the active ingredient of the tablets was tested using the paddle apparatus and method according to the prescriptions of the Ph. Eur . 2.9.3.
  • DISSOLUTION TEST FOR SOLID DOSAGE FORMS monograph 900 mL of 37 ⁇ 0.5 °C, pH 4.5 acetate buffer was used as the dissolution medium, the stirring rate was 50 rev/min.
  • the amount of active ingredient dissolved from the tablets is given as a percentage of the nominal active ingredient content (200 mg) of the tablets.
  • the tests were performed using an Erweka automatic tablet dissolving apparatus. The results are the averages of the measurement results for six tablets after 15 minutes of stirring .
  • the granules are passed through a sieve with a mesh size of 0.8 mm, 0.5 g sodium stearyl fumarate is mixed into it, then using a Korsch EXO tableting machine and an 8 mm round, biconcave punch tool, tablets with an average mass of 219 mg are compressed.
  • the tablets contain 200 mg favipiravir (91.3%) .
  • the tensile strength of the tablets is: 40-50 N. Structure of the tablets: scaly, not suitable for film coating or packaging. Disintegration time: 20 sec.
  • the composition is not suitable for industrial production because of the low tensile strength and the scaly tablet structure. The reason for this is that in the case of a scaly structure the tablets easily fall apart into scaly layers .
  • the granules are passed through a sieve with a mesh size of 0.8 mm, 0.5 g sodium stearyl fumarate and 0.5 mg silicon dioxide are mixed into it, then using a Korsch EXO tableting machine and an 8 mm round, biconcave punch tool, tablets with an average mass of 220 mg are compressed.
  • the tablets contain 200 mg favipiravir (90.1%) .
  • the tensile strength of the tablets is: 65-75 N.
  • the granules are passed through a sieve with a mesh size of 0.8 mm, 0.5 g sodium stearyl fumarate and 0.5 mg silicon dioxide are mixed into it, then using a Korsch EXO tableting machine and an 8 mm round, biconcave punch tool, tablets with an average mass of 220 mg are compressed.
  • the tablets contain 200 mg favipiravir (88.5%) .
  • the tensile strength of the tablets is: 65-80 N.
  • Disintegration time 27 sec.
  • Dissolution in 15 min 89.9%. Evaluation: the composition is suitable for industrial production, its dissolution is very fast.
  • the granules are passed through a sieve with a mesh size of 0.8 mm, 0.5 g sodium stearyl fumarate is mixed into it, then using a Korsch EXO tableting machine and an 8 mm round, biconcave punch tool, tablets with an average mass of 245 mg are compressed.
  • the tablets contain 200 mg favipiravir (81.6%) .
  • the tensile strength of the tablets is: 110-130 N.
  • the structure of the tablets homogenous. Disintegration time: 16 sec.
  • the granules are passed through a sieve with a mesh size of 0.8 mm, 0.5 g sodium stearyl fumarate is mixed into it, then using a Korsch EXO tableting machine and an 8 mm round, biconcave punch tool, tablets with an average mass of 245 mg are compressed.
  • the tablets contain 200 mg favipiravir (89.3%) .
  • the tensile strength of the tablets is: 120-130 N.
  • the structure of the tablets homogenous.
  • the tablets produced in example 4 are provided with a 3% film coating in a Procept 4M8 coating apparatus using a known method.
  • the Opadry II 85F18422 white coating of Colorcon Ltd was used for the coating, which contains polyvinyl alcohol, titanium dioxide, talc and triacetin.
  • the dissolution of the active ingredient from the film-coated tablets in 15 minutes is 86 . 8 % .
  • the tablets produced in example 5 are provided with a 3% film coating in a Procept 4M8 coating apparatus us ing a known method .
  • the Opadry I T 02B280009 white coating of Colorcon Ltd was used for the coating, which contains hypromellose , titanium dioxide , talc and polyethylene glycol .
  • the dissolution of the active ingredient from the film-coated tablets in 15 minutes is 85 . 4 % .
  • compositions containing favipiravir are provided in which the L-HPC ful fils the role of both disintegrant and binder, therefore less material has to be used than in the case of the use of a separate disintegrant and binder for the formulation of tablets or capsules with the same amount of favipiravir .
  • Better patient compliance is expected in connection with the smaller oral pharmaceutical preparations available due to this .

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
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  • Engineering & Computer Science (AREA)
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  • Inorganic Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
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  • Pulmonology (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des granules appropriés pour la production de préparations pharmaceutiques orales, comme des comprimés ou des gélules, caractérisés en ce qu'ils qui sont constitués de favipiravir, d'hydroxypropylcellulose faiblement substituée (L-HPC) et de dioxyde de silicium. L'invention concerne également une préparation pharmaceutique, caractérisée en ce qu'elle contient des granules constitués de favipiravir, de L-HPC ainsi que de dioxyde de silicium et d'un lubrifiant. Lesdites compositions sont destinées à être utilisées dans le traitement ou la prophylaxie de maladies virales, la préparation pharmaceutique étant préférablement un comprimé ou une capsule, et la maladie étant préférablement la grippe ou la COVID-19, même plus préférentiellement la COVID-19. L'invention concerne en outre un procédé pour la production de ladite préparation pharmaceutique, le procédé étant caractérisé en ce qu'il comprend les étapes suivantes : a) une partie de la poudre de L-HPC est mélangée avec l'autre partie du L-HPC et du dioxyde de silicium; c) le mélange de poudre obtenu à l'étape b) est granulé avec la dispersion aqueuse obtenue à la première étape; d) les granules sont homogénéisés avec du stéarylfumarate de sodium et, éventuellement, du dioxyde de silicium, et ensuite e) ils sont formulés sous forme de comprimés ou de gélules.
PCT/HU2021/050062 2020-11-17 2021-11-17 Préparation pharmaceutique contenant du favipiravir, sa production et son utilisation WO2022106859A1 (fr)

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Application Number Priority Date Filing Date Title
HU2000379A HUP2000379A1 (hu) 2020-11-17 2020-11-17 Favipiravir tartalmú gyógyszerkészítmény, ennek elõállítása és alkalmazása
HUP2000379 2020-11-17

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2407166B1 (fr) * 2009-03-13 2013-08-21 Toyama Chemical Co., Ltd. Comprimé et poudre granulée contenant du 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
JP2018076306A (ja) * 2016-10-31 2018-05-17 エスエス製薬株式会社 感冒薬
RU2731932C1 (ru) * 2020-05-07 2020-09-09 Общество с ограниченной ответственностью "Кромис" (ООО "Кромис") Противо-COVID-19 (SARS-CoV-2) вирусная фармацевтическая композиция

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2407166B1 (fr) * 2009-03-13 2013-08-21 Toyama Chemical Co., Ltd. Comprimé et poudre granulée contenant du 6-fluoro-3-hydroxy-2-pyrazinecarboxamide
JP2018076306A (ja) * 2016-10-31 2018-05-17 エスエス製薬株式会社 感冒薬
RU2731932C1 (ru) * 2020-05-07 2020-09-09 Общество с ограниченной ответственностью "Кромис" (ООО "Кромис") Противо-COVID-19 (SARS-CoV-2) вирусная фармацевтическая композиция

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