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EP4313155A1 - Orale formulierung von ivermectin und verwendungen davon - Google Patents

Orale formulierung von ivermectin und verwendungen davon

Info

Publication number
EP4313155A1
EP4313155A1 EP22717151.9A EP22717151A EP4313155A1 EP 4313155 A1 EP4313155 A1 EP 4313155A1 EP 22717151 A EP22717151 A EP 22717151A EP 4313155 A1 EP4313155 A1 EP 4313155A1
Authority
EP
European Patent Office
Prior art keywords
ivermectin
formulation
mini
micronized
formulation according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22717151.9A
Other languages
English (en)
French (fr)
Inventor
Pascal Suplie
Eléonore JOUANNY
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Substipharm
Original Assignee
Substipharm
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Substipharm filed Critical Substipharm
Publication of EP4313155A1 publication Critical patent/EP4313155A1/de
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/20—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
    • A61K9/20—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
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides

Definitions

  • the present invention relates to a galenic formulation, suitable for oral administration, comprising ivermectin, its method of preparation and its therapeutic uses.
  • Ivermectin belongs to the class of macrolide lactones; it is an avermectin derivative isolated from the fermentation of broths of Streptomyces avermitilis. This molecule has a high affinity for the glutamate-dependent chloride channels present in the nerve and muscle cells of invertebrates.
  • Ivermectin also interacts with other ligand-gated chloride channels such as the one involving the neuromediator GABA (gamma-amino-butyric acid).
  • Mammals do not have glutamate-gated chloride channels. In addition, avermectins do not easily cross the blood-brain barrier, which explains their relatively low toxicity in humans.
  • ivermectin is effective against many nematodes, mites and also certain insects such as anopheles; it is an old antiparasitic very widely used in veterinary medicine but also historically, because of its low toxicity, in humans in Africa in onchocerciasis or filariasis. Today it is also used more ubiquitously in the treatment of pediculosis and scabiosis commonly called scabies.
  • Scabies is an infection caused by a mite: scabies scabei var. Hominis. It is a contagious skin parasitosis that is very widespread throughout the world with approximately 300 million cases per year. It affects all social and economic backgrounds, however it is often associated with poverty, overcrowding and malnutrition. It is pandemic in tropical and developing countries. This parasitosis is very contagious and poses a significant problem for communities such as nursing homes, schools, homes, even hospitals. Scabies is manifested by a nocturnal recrudescent pruritus accompanied by specific lesions such as the scabious furrow; There are several forms of different severity, in particular depending on age, but in all cases contagion remains extremely problematic. Ivermectin is used orally in the form of 3 mg tablets, at the rate of 200 pg per kg. The dosage should be adjusted according to the weight of the patient; an adult weighing more than 80 kg will therefore need to take 6 tablets at once.
  • Ivermectin has been described in patent EP 0001689. It is a mixture of 22,23-dihydroavermectin Bla (CAS number: [71827-03-7]) and 22,23-dihydroavermectin Blb (CAS number : [70209-81-3]), with
  • Stromectol ® tablets contain 3 mg of ivermectin and the following excipients: anhydrous citric acid, modified corn starch, butylated hydroxyanisole, microcrystalline cellulose, magnesium stearate.
  • Ivermectin tablets are moreover in particular described in patent applications CN106619685, CN106852930, CN107028892, CN107669646, CN107837238 and CN 108079006.
  • Ivermectin gives good results in the treatment of malaria with substantially equivalent or slightly higher dosages and the implementation of a mass prophylactic treatment is under study. Ivermectin and other molecules of the macrolide lactone class also possess antibacterial and antiviral activity and recently many studies have been conducted to demonstrate antiviral activity.
  • ivermectin can also be used in bacterial infections, such as nosocomial diseases, infections with staphylococcus aureus [staphylococcus aureus) and viral infections such as influenza or coronavirus diseases, in particular COVID-19.
  • the doses tested are higher: between 24 mg and 70 mg minimum per day and over several days of treatment.
  • ivermectin and related molecules have a very broad spectrum of activity and in this very interesting, especially since the associated toxicity is quite low; however, the existing oral formulations require repeated and simultaneous intake of several tablets, which is not conducive to good compliance with the treatment.
  • the other problem generated is the phenomenon of resistance: stopping or poor compliance with treatment by the patient is likely to promote the appearance of the phenomenon of resistance, i.e. the emergence of parasites resistant to the molecule, or even to the therapeutic class. It is therefore essential to have effective and suitable drugs in the therapeutic arsenal.
  • the object of the invention presented here is to respond to this problem and therefore to allow the therapist to have a multi-particle and homothetic oral form allowing him to more easily adjust the dose to the weight of the patient and presenting improved pharmacokinetics. compared to the reference product, which is Stromectol ® . Summary of the invention
  • the subject of the invention is a galenic formulation, suitable for oral administration, comprising an envelope containing mini formulations in solid form, having a size of less than 4.5 mm, of micronized ivermectin.
  • the micronized ivermectin has a distribution of particle sizes in which the D50 varies between 1 ⁇ m and 30 ⁇ m, preferentially between 1 ⁇ m and 20 ⁇ m.
  • the galenic formulation comprising an envelope is advantageously chosen from capsules, sachets or sticks.
  • the galenic formulation according to the invention advantageously comprises 3 mg to 75 mg of ivermectin per formulation, more advantageously more than 3 mg to 75 mg of ivermectin per formulation, more advantageously more than 6 mg to 60 mg of ivermectin per formulation , even more preferably from 12 mg to 50 mg of ivermectin per formulation, even more preferably from 12 mg to 24 mg of ivermectin per formulation.
  • the solid mini formulation comprises from 2% to 50% by weight, relative to the total weight of the mini formulation, of micronized ivermectin.
  • the mini solid formulations are advantageously chosen from microgranules or mini tablets.
  • each microgranule comprises from the center towards the periphery
  • a support - at least one mounting layer comprising micronized ivermectin, optionally an antioxidant, and a pharmaceutically acceptable binding agent,
  • each mini tablet comprises a diluent, a binder, an antioxidant agent, a lubricant, and micronized ivermectin.
  • each mini tablet has a size of less than 3 mm.
  • a subject of the invention is also a process for the preparation of a galenic formulation according to the invention, comprising the following steps: a) preparation of a mini formulation in solid form, having a size of less than 4.5 mm, of micronized ivermectin; b) filling an envelope of the formulation with the desired quantity of solid mini formulation prepared in step a).
  • a subject of the invention is also the use of a galenic formulation according to the invention for homothetically adapting the dosage of ivermectin as a function of the dosage.
  • the invention also relates to the use of a galenic formulation according to the invention in the treatment or prevention of diseases due or induced by a parasite, a bacterium, a virus, in particular:
  • staphylococcus aureus in particular certain infections with staphylococcus aureus (staphylococcus aureus);
  • the subject of the invention is a galenic formulation, suitable for oral administration, comprising an envelope containing mini formulations in solid form, having a size of less than 4.5 mm, of micronized ivermectin.
  • the galenic formulation includes mini formulations of micronized ivermectin.
  • the mini formulations are contained in an envelope.
  • the mini formulations are in solid form and have a size less than 4.5 mm, advantageously less than or equal to 4 mm, advantageously less than or equal to 4.0 mm, more advantageously less than or equal to 3 mm, more advantageously less than or equal at 3.0mm.
  • This formulation makes it possible to offer several dosages of ivermectin and in particular makes it possible to administer a larger dose of ivermectin in a single dose.
  • This formulation also allows a homothetic adaptation of the quantity of mini formulations included in the envelope according to the desired dosage.
  • This formulation also allows an improvement in the pharmacokinetics of ivermectin, compared to a tablet comprising the same dose of ivermectin
  • the first manufacturing step comprises a step of micronizing the ivermectin
  • micronized it is meant that the size of the ivermectin particles is reduced, in particular either by wet grinding or by dry micronization.
  • micronized ivermectin is characterized by a distribution of particle sizes in which the D50 varies between 1 ⁇ m and 30 ⁇ m, preferentially between 1 ⁇ m and 20 ⁇ m, more preferentially between 1 ⁇ m and 15 ⁇ m, more preferentially between 2 ⁇ m and 12 ⁇ m, even more preferably between 3 ⁇ m and 10 ⁇ m.
  • micronized ivermectin is characterized by a particle size distribution in which the D10 is less than 10 ⁇ m, preferably less than or equal to 5 ⁇ m, more preferably less than or equal to 3 ⁇ m.
  • micronized ivermectin is characterized by a distribution of particle sizes in which the D90 is less than 100 ⁇ m, preferentially less than 80 ⁇ m, more preferentially less than or equal to 50 ⁇ m, preferentially less than or equal to 40 ⁇ m, more preferably less than or equal to 30 ⁇ m, even more preferably less than or equal to 20 ⁇ m.
  • the D50 is the 50th percentile of the particle size distribution, by volume, ie 50% of the particles have a size less than or equal to the D50 and 50% of the particles have a size greater than the D50.
  • the D10 is the 10th percentile of the particle size distribution, by volume, that is to say that 10% of the particles have a size less than or equal to the D10 and 90% of the particles have a size greater than the D10.
  • the D90 is the 90th percentile of the particle size distribution, by volume, ie 90% of the particles have a size less than or equal to the D90 and 10% of the particles have a size greater than the D90.
  • Particle size distributions and smaller particle sizes are measured by laser diffraction techniques, eg light scattering.
  • Light scattering equipment is well known in the art, for example a Mastersizer 3000 laser diffraction particle size analyzer.
  • Milling techniques are well known in the art and include media milling, such as ball milling, vibration milling; jet milling, for example using a micronizer, a jet mill or a jet atomizer; dispersion milling and colloidal milling; homogenization; and any other technique known to those skilled in the art.
  • the galenic formulation comprises an envelope making it possible to contain the mini formulations.
  • the envelope can be any galenic allowing to contain the mini formulations.
  • This envelope can be a device making it possible to contain, advantageously also to distribute, the mini formulations, such as sachets or sticks.
  • the envelope may also itself be suitable for oral administration and may thus for example be chosen from gelatin capsules and capsules, preferably gelatin capsules.
  • the gelatin capsules or capsules advantageously have a size suitable for oral administration, and in particular varying from one centimeter to a few centimeters.
  • the capsules are most often gelatin-based capsules, paraffin capsules, cellulose-based capsules (in particular hydroxypropylmethylcellulose), pullulan capsules, capsules based on unleavened leaves.
  • the pharmaceutical formulation advantageously comprises 3 mg to 75 mg of ivermectin per envelope, advantageously from more than 3 mg to 75 mg of ivermectin per envelope, advantageously from 6 mg to 60 mg of ivermectin per envelope, more advantageously from more than 6 mg to 50 mg of ivermectin per envelope, even more advantageously from 12 mg to 50 mg of ivermectin per envelope, even more advantageously from 12 mg to 24 mg of ivermectin per envelope.
  • each capsule or capsule advantageously comprises 3 mg to 75 mg of ivermectin per capsule or capsule, advantageously more than 3 mg to 75 mg of ivermectin per capsule or capsule , more preferably from more than 6 mg to 60 mg of ivermectin per capsule or capsule, more preferably from more than 6 mg to 50 mg of ivermectin per capsule or capsule, even more preferably from 12 mg to 50 mg of ivermectin per capsule or capsule, even more advantageously from 12 mg to 24 mg of ivermectin per capsule or capsule.
  • Ivermectin is formulated in the form of mini solid formulations which will be placed in the envelope. Each mini formulation constitutes a galenic unit.
  • the mini solid formulation that is to say each galenic unit, advantageously comprises 2 to 50% by weight, more advantageously 2 to 40% by weight, even more advantageously 2 to 30% by weight, relative to the total weight of the mini formulation, that is to say relative to the total weight of a galenic unit, of micronized ivermectin.
  • the mini solid formulation that is to say each galenic unit, advantageously comprises micronized ivermectin as the only active principle having its own therapeutic activity.
  • the mini solid formulation that is to say each galenic unit, advantageously also comprises an antioxidant such as butylhydroxyanisole (BHA), citric acid, 2,6-di-tert-butyl-4-methyl, propyl gallate, vitamin E, and combinations thereof, advantageously BHA.
  • BHA butylhydroxyanisole
  • the content of antioxidant agent advantageously varies from 0.005 to 0.05% by weight, relative to the total weight of the mini-formulation, that is to say relative to the total weight of a galenic unit.
  • the mini solid formulation that is to say each galenic unit, can comprise one or more excipients intended for example to support the micronized ivermectin, to promote the course of the preparation process such as anti-sticking agents, lubricants , to improve the cohesion such as binders, fillers, plasticizers, fillers, surfactants, disintegrants, sweeteners, colorants.
  • excipients intended for example to support the micronized ivermectin, to promote the course of the preparation process such as anti-sticking agents, lubricants , to improve the cohesion such as binders, fillers, plasticizers, fillers, surfactants, disintegrants, sweeteners, colorants.
  • the mini solid formulations are advantageously chosen from microgranules or mini tablets.
  • microgranules of the present invention relate to spherical galenic units, consisting in their center of a support, covered with at least one layer containing the active principle which is itself covered with at least one polymeric layer.
  • microgranules of the present invention can also be obtained by a method known per se such as, for example, extrusion-spheronization, wet or hot granulation.
  • microgranules can be obtained conventionally by depositing (mounting) micronized ivermectin on the surface of supports.
  • support means spherical or quasi-spherical supports of size between 50 ⁇ m and 800 ⁇ m and preferably between 100 ⁇ m and 600 ⁇ m such as those usually used in the pharmaceutical industry as base support for active principles for the constitution of microgranules such as microbeads based on cellulose, obtained for example by extrusion-spheronization, or a mixture of sugar and starch and sold under the term “sugar spheres” or even granules of other excipients, such as lactose for example, or other carriers suitable for pharmaceutical use obtained by extrusion-spheronization. These carriers are advantageously neutral, that is to say inert from a pharmaceutical point of view.
  • the support can also be chosen from the inert compounds previously described covered with a polymeric layer, the polymer possibly being chosen among sustained-release polymers and disintegrating polymers such as gums, in particular xanthan gum.
  • the process for depositing (mounting) the active ingredient is carried out in a conventional manner known to those skilled in the art.
  • the deposition (assembly) can be carried out by spraying a solution or suspension of micronized ivermectin on the surface of the support, alternating with the deposition by powdering of micronized ivermectin on the surface of the support previously moistened with the aid of of a binder solution.
  • the deposition (assembly) can also be carried out by spraying a solution or suspension comprising micronized ivermectin and a binder on the surface of the support.
  • At least one mounting layer comprising micronized ivermectin and a pharmaceutically acceptable binding agent, - at least one coating layer.
  • the editing layer is also called the active layer.
  • the micronized ivermectin is integrated into the active layer in combination with a pharmaceutically acceptable binding agent, such as those usually used in the pharmaceutical industry for fixing active principles to the surface of supports.
  • a pharmaceutically acceptable binding agent such as those usually used in the pharmaceutical industry for fixing active principles to the surface of supports.
  • pharmaceutically acceptable binders use will preferably be made of binders of a hydrophilic nature and in particular cellulose derivatives such as HPMC, in particular the Methocel ® E5 grades, or hydroxypropylcellulose or hydroxyethylcellulose, derivatives of polyvinylpyrrolidone, and also derivatives of polyethylene glycol, vinyl derivatives such as polyvinyl alcohol.
  • the content of pharmaceutical binder advantageously varies from 1% to 5% by weight, advantageously 1 to 3% by weight, relative to the total weight of the microgranule.
  • the active layer of the microgranules in accordance with the invention is applied by spraying with a dispersion of micronized ivermectin in a solvent (called assembly dispersion).
  • the solvent may for example be chosen from water, organic solvents, among them ethanol or hydro-alcoholic solutions of various concentrations. It is preferable to use solvents that are non-toxic and easily eliminated by evaporation during drying so that no trace of them remains in the microgranules.
  • the active layer can also comprise an antioxidant as described previously, in particular butylhydroxyanisole (BHA).
  • the coating makes it possible to protect the layer of ivermectin from the outside, and in particular from external humidity.
  • the microgranules are preferably coated with a coating agent chosen from the group consisting of shellac, polyvinylpyrrolidone, polyethylene glycol (PEG), cellulose derivatives such as hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC ), sucrose, alginate, fatty acid glycerides, methacrylic polymers, water-soluble polymers.
  • a water-soluble polymer mention may in particular be made of polyvinyl alcohol and its derivatives.
  • the coating layer is advantageously soluble in water.
  • the coating layer advantageously also comprises an inert filler.
  • the inert filler uniformly distributed in the coating layer is chosen from the group comprising in particular talc, titanium dioxide, magnesium stearate, glycerol monostearate, silica and silicate derivatives (magnesium silicate, aluminum silicate), magnesium stearylfumarate, mineral powders (gypsum, zeolite, stone, diatomaceous earth) and mixtures thereof.
  • a surfactant is optionally present in the coating.
  • the surfactant is preferably selected from the following group of products: alkaline or alkaline earth salts of fatty acids, sodium dodecyl sulphate and sodium docusate being preferred, polyoxyethylenated oils, preferably polyoxyethylenated hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylene sorbitan esters, polyoxyethylene castor oil derivatives, stearates, preferably of calcium, magnesium, aluminum or zinc, polysorbates, stearylfumarates, preferably of sodium , glycerol behenate, benzalkonium chloride, acetyltrimethyl ammonium bromide, cetyl alcohol and mixtures thereof.
  • a plasticizer is also optionally present in the coating.
  • the plasticizer is selected in particular from the following group of products: glycerol and its esters, preferably from the following subgroup: medium-chain triglycerides, acetylated glycerides, glyceryl-monostearate, glyceryl-thacetate, glyceryl -tributyrate, phthalates, preferably from the following subgroup: dibutylphthalate, diethylphthalate, dimethylphthalate, dioctylphthalate, citrates, preferably from the following subgroup: acetyltributylcitrate, acetylthethylcitrate, tributylcitrate, triethylcitrate, sebacates, preferably from the under- following group: diethylsebacate, dibutylsebacate, adipates, azelates, benzoates, chlorobutanoles polyethylene glycols,
  • excipients such as lubricants, colorants, sweeteners, anti-adherent agents.
  • the coating layer preferably comprises HPMC or a polymer such as polyvinyl alcohol.
  • HPMC high-density polyethylene
  • a polymer such as polyvinyl alcohol.
  • Commercial products of ready-to-use coating formulations comprising a polymer, a plasticizer and a pigment, such as the commercial products sold under the designation Opadry, can be used.
  • the commercial product Opadry AMB II is a ready-to-use coating formulation comprising polyvinyl alcohol, talc, titanium dioxide, glycerol monocaprylocaprate and sodium dodecyl sulfate.
  • Each microgranule advantageously has a diameter of less than 2 mm, ie less than 2000 ⁇ m, advantageously less than 1000 ⁇ m, even more advantageously varying from 0.35 ⁇ m to 1 mm, ie 1000 ⁇ m.
  • microgranules comprise, by weight relative to the total weight of microgranule:
  • a binder in an amount ranging from 1% to 3% by weight, relative to the total weight of microgranule
  • an antioxidant in an amount ranging from 0.005% to 0.05% by weight, relative to the total weight of microgranule
  • the support is advantageously made up of particles of sugar and starch and sold under the term “sugar spheres” having an average diameter of 500-600 ⁇ m. This is neutral support.
  • the binder is advantageously HPMC.
  • the antioxidant agent is advantageously BHA.
  • the coating may include HPMC or polyvinyl alcohol.
  • spherical supports s into a fluidized air bed enclosure, for example, - the spraying, in a fluidized air bed or in a perforated turbine for example, on these spherical supports of micronized ivermectin in suspension in a suitable solvent, in particular a hydro-alcoholic solvent, added with at least one binding agent and optionally with an antioxidant,
  • microgranules thus obtained, for example in a fluidized air bed or in a perforated turbine, then optionally sieving.
  • the mini tablets of the present invention relate to dosage units resulting from the compression of powders or granules and have a size of less than 4.5 mm, preferably less than 4 mm, preferably less than 4.0 mm, more preferably less to 3 mm, more preferably less than 3.0 mm.
  • Minitablets preferably have a size greater than 0.5 mm, preferably greater than 1 mm, preferably greater than 1.0 mm, more preferably greater than 2 mm, more preferably greater than 2.0 mm.
  • the various tablet manufacturing processes for example by direct compression or by compression after granulation by wet or dry process, are presented in particular in “Remington's pharmaceutical Sciences, 16th Ed, 1980, Mack Publ. Co. of Easton, PA, USA”.
  • the mini tablets in accordance with the invention can be prepared by compression after granulation.
  • the mini tablets according to the present invention are obtained by dry granulation then homogenization.
  • the homogenized mixture is then subjected to a compression force which gives the resulting tablet a satisfactory hardness.
  • the micronized ivermectin can be mounted on supports (obtaining microgranules) or by extrusion-spheronization or granulated by a wet or dry route (obtaining granules).
  • micronized ivermectin granulates can be obtained by dry or wet granulation, generally in the presence of at least one binding agent and a wetting liquid where appropriate, according to techniques well known to those skilled in the art. art. This granulation step improves the content uniformity of the manufactured tablets.
  • the mini tablet may include one or more excipients intended either to promote the progress of the compression process such as anti-sticking agents such as colloidal silica, talc, magnesium stearate, Polyethylene Glycol (PEG) or calcium stearate , or to improve the cohesion of the tablet during compression, such as the binding agents conventionally used in this function, in particular starches, cellulose derivatives, or bulking agents, or lubricants, or plasticizers, or agents fillers, either sweeteners or colorants.
  • each mini tablet according to the present invention comprises at least one pharmaceutically acceptable diluent.
  • maltodextrin anhydrous sugar powder, starch, cellulose derivatives, in particular microcrystalline cellulose, ethylcellulose and hydroxypropyl methylcellulose, polyols, in particular polyols of less than 13 carbon atoms, in particular mannitol, xylitol, sorbitol, maltitol, gums, silica derivatives, calcium or potassium derivatives, mineral compounds such as dicalcium phosphates, tricalcium phosphates and calcium carbonates, sucrose, glycine and other pharmaceutically compatible amino acids, and their derivatives, lactose and its derivatives, or mixtures thereof.
  • maltodextrin anhydrous sugar powder, starch, cellulose derivatives, in particular microcrystalline cellulose, ethylcellulose and hydroxypropyl methylcellulose, polyols, in particular polyols of less than 13 carbon atoms, in particular mannitol, xylitol, sorbitol, maltitol
  • each mini tablet according to the present invention comprises at least one pharmaceutically acceptable binder.
  • a binder such as starch, in particular pre-gelatinized starch, sucrose, gum arabic, polyvinylpyrrolidone (PVP or povidone), hydroxypropyl methylcellulose (HPMC ), shellac, hydroxypropyl cellulose (HPC), cellulose, polyols or alginates, polyglycolyzed glycerides (Gelucire ® ) or macrogolglycerides, in particular stearoyl macrogolglycerides, also acrylic derivatives, as well as mixtures of these.
  • each mini tablet according to the present invention comprises at least one pharmaceutically acceptable lubricant.
  • a lubricant mention may for example be made of talc, silica derivatives, in particular micronized silica gel, waxes, magnesium stearate, and mixtures thereof, advantageously magnesium stearate.
  • each mini tablet comprises a diluent, a binder, an antioxidant, a lubricant, and micronized ivermectin.
  • each mini-tablet comprises, by weight relative to the total weight of the mini-tablet: - micronized ivermectin, in the amounts described above;
  • diluent in an amount ranging from 70% to 90% by weight, relative to the total weight of the mini tablet
  • a binder in an amount ranging from 5% to 15% by weight, relative to the total weight of the mini tablet;
  • an antioxidant in an amount ranging from 0.005% to 0.05% by weight, relative to the total weight of the mini tablet;
  • the micronized ivermectin is mixed with the compression excipient(s), then this mixture is granulated by a dry or wet route in order to obtain directly compressible granules.
  • the mini tablets can be prepared by a process comprising the following steps: mixing the micronized ivermectin with the excipient(s), - optionally granulating and compressing said mixture, optionally coating the mini tablet.
  • Each mini tablet preferably comprises 0.5 to 2 mg ivermectin, preferably 0.5 to 2.0 mg ivermectin, more preferably 1 mg ivermectin, more preferably 1.0 mg ivermectin.
  • Each mini tablet advantageously has a hardness varying from 8 to 20 N, advantageously from 8 to 14 N.
  • mini formulations advantageously in the form of microgranules or mini tablets, which will fill an envelope, advantageously itself intended to be administered orally such as a capsule or capsule, preferably capsule, makes it possible to easily adapt the ivermectin content per dose according to the desired dose.
  • the preparation of a single-dose oral formulation having a higher concentration of ivermectin makes it possible to reduce the number of doses and thus improve compliance with the treatment.
  • the formulation consists of a formulation of microgranules or mini tablets; this formulation then being itself distributed in gelatin capsules or capsules of different sizes depending on the desired final dosage of ivermectin.
  • capsules or capsules advantageously dosed from 3 mg to 75 mg, advantageously from more than 3 mg to 75 mg, development of capsules or capsules advantageously dosed from 6 mg to 60 mg, more advantageously from more than 6 mg to 50 mg, more advantageously from 12 mg to 50 mg, more advantageously from 12 mg to 24 mg, of ivermectin makes it possible to administer the same formulation to patients while reducing the number of therapeutic units absorbed.
  • the other advantage of the formulation presented lies in the superior pharmacological effect observed compared to the reference oral tablet, stromectol ® ; indeed the formulation presented also allows an increase in bioavailability.
  • the formulation has a bioavailability greater than 100% compared to the stromectol ® tablet for the same ivermectin dosage.
  • taking a formulation for a given dosage of ivermectin has a bioavailability greater than 100% compared to taking an identical dose of ivermectin in the form of one or more stromectol ® tablets. .
  • the pharmacokinetic study carried out on the two formulations microgranules in capsules or capsules and mini tablets in capsules or capsules, each comprising 12 mg of ivermectin, respectively gave bioavailability values, in particular a maximum plasma concentration (Cmax) of 104% and 185% compared to the stromectol ® tablet for the same ivermectin dosage
  • the improvement in bioavailability is seen in particular through a reduced T max (time to reach maximum plasma concentration C max ) when the same dose of ivermectin is administered in the form of a formulation according to the invention compared to an administration in the form of one or more tablet(s) of stromectol ® .
  • a subject of the invention is also a process for the preparation of a galenic formulation according to the invention, comprising the following steps: a) preparation of a mini formulation in solid form, having a size less than
  • step a) filling an envelope of the formulation with the desired quantity of solid mini formulation prepared in step a).
  • step b) is a step of filling capsules with the desired quantity of solid mini formulation prepared in step a).
  • Stage b) makes it possible to vary the final content of ivermectin, by varying the quantity of mini-formulation, according to the desired dosage.
  • a particular subject of the invention is the preparation of a mini-formulation in solid form which is a set of microgranules prepared in step a) according to the method described above.
  • a method comprising the following steps: i) preparation of a suspension comprising micronized ivermectin, an antioxidant, a binder and a solvent; ii) spraying the suspension prepared in step ii) on a solid support with a size of less than 800 ⁇ m then drying the uncoated microgranules thus obtained; iii) spraying a coating suspension on the microgranules obtained following step ii) then drying the coated microgranules thus obtained.
  • the suspension is advantageously sprayed in a fluidized air bed at a temperature between 40°C and 55°C.
  • the solid support is advantageously preheated to a temperature between 40°C and 55°C.
  • the suspension is advantageously sprayed in a fluidized air bed at a temperature between 40°C and 55°C.
  • microgranules, the coating, the solid support, the antioxidant agent, the binder, the solvent, the micronized ivermectin and the devices involved are as described previously.
  • a particular subject of the invention is the preparation of a mini-formulation in solid form which is a mini-tablet prepared in step a) according to the process described previously, in particular a wet granulation process.
  • a method comprising the following steps: j) mixing an antioxidant agent and a part of the diluent; jj) addition to the mixture obtained following step j) of the micronized ivermectin, of the remainder of the diluent and of the binder then mixing of the whole; jjj) adding to the mixture obtained following step jj) part of the lubricant then mixing the whole; jjjj) dry granulation of the mixture obtained following step jjj); jjjjj) addition to the particles obtained following step jjj) of the remainder of the lubricant, mixing then compression to form the mini tablets.
  • a subject of the invention is also the use of a galenic formulation as described for homothetically adapting the dosage of ivermectin according to the dosage.
  • the invention makes it possible to offer the patient a galenic formulation adapted to his weight.
  • the treatment can be carried out by oral administration of a single galenic formulation per dose; instead of having to swallow several tablets with each intake. This treatment allows a finer adjustment of the dosage in relation to the weight of the patient. This treatment thus also improves compliance.
  • a subject of the invention is also a galenic formulation as described for its use in the treatment or prevention of diseases due or induced by a parasite, a bacterium, a virus.
  • the formulation can be used in the treatment or prevention of parasitosis, in particular onchocerciasis, filariasis, pediculosis, or scabies.
  • the formulation can be used in the treatment or prevention of bacterial infections, such as nosocomial diseases including certain infections with staphylococcus aureus (staphylococcus aureus).
  • the formulation can be used in the treatment or prevention of viral infections such as influenza or coronavirus diseases, in particular COVID-19.
  • viral infections such as influenza or coronavirus diseases, in particular COVID-19.
  • the viruses can be SARS-CoV or MERS-CoV.
  • a subject of the invention is also a galenic formulation as described for its use in the preparation of a medicament intended for the treatment or prevention of diseases due or induced by a parasite, a bacterium, a virus.
  • the medicament is intended for the treatment or prevention of parasitosis, in particular onchocerciasis, filariasis, pediculosis, or scabies.
  • the medicine is intended for the treatment or prevention of bacterial infections, such as hospital-acquired diseases and infections with staphylococcus aureus ( staphylococcus aureus).
  • the medicinal product is intended for the treatment or prevention of viral infections such as influenza or coronavirus diseases, in particular COVID-19.
  • the viruses can be SARS-CoV or MERS-CoV.
  • the invention also relates to a method of therapeutic treatment, or prevention, of diseases due or induced by a parasite, a bacterium, a virus comprising the administration, to a person in need thereof, of a galenic formulation such as previously described.
  • a galenic formulation such as previously described.
  • one formulation is administered per dose.
  • the invention allows a finer adjustment of the dosage in relation to the patient's weight, which is moreover favorable to compliance with the treatment.
  • the disease can be a parasitosis, in particular onchocerciasis, filariasis, pediculosis, or scabies.
  • the disease can be a bacterial infection, such as hospital-acquired illnesses and Staphylococcus aureus (staphylococcus aureus) infections.
  • the disease can be a viral infection such as influenza or coronavirus diseases, in particular COVID-19.
  • the viruses can be SARS-CoV or MERS-CoV.
  • the patient is advantageously the man.
  • the formulation described here makes it possible in particular to improve compliance with the treatment. Indeed, by a finer adjustment of the dosage in the formulation according to the weight of the patient, a single formulation per dose must be swallowed by the patient.
  • the recommended dose is advantageously 200 ⁇ g of ivermectin per kg in a single dose.
  • the single dose can be renewed 6 months later.
  • the recommended dose of ivermectin is advantageously from 24 mg to 70 mg minimum per day, advantageously over 5 to 15 days of treatment.
  • Two types of capsules according to the invention are prepared.
  • the capsules comprise microgranules and have the following composition:
  • microgranules are prepared according to the following process: a) preparation of an ivermectin dispersion according to the following successive steps:
  • the capsules comprise mini tablets and have the following composition: Table 2
  • mini tablets are prepared according to the following process: a) preparation of a BHA solution by adding BHA in 96% by volume ethanol until a clear solution is obtained; b) mixing in a granulator the BHA solution obtained in a) with a portion of the microcrystalline cellulose (55% by weight relative to the total weight of the microcrystalline cellulose); c) addition and sieving to 1 mm of: half by weight of the mixture obtained in b), then the micronized ivermectin, then the second half by weight of the mixture obtained in b), then the second part of the microcrystalline cellulose (45 % by weight relative to the total weight of the microcrystalline cellulose), then the pregelatinized starch; then mixing the whole; d) addition of a portion of the magnesium stearate to the mixture obtained in c) then dry mixing and granulation; e) adding the other part of the magnesium stearate to the mixture obtained in d) then mixing; f) compression of the mixture obtained in e) g) putting into capsules
  • the pharmacokinetics of type A capsules (capsule filled with microgranules) and type B capsules (capsule filled with mini tablets) is evaluated and compared with the reference product Stromectol ® after a single oral administration on an empty stomach in humans.
  • Each Stromectol ® tablet contains 3mg of ivermectin. 13 patients (healthy adult male and female human subjects) are included in the pharmacokinetic study.
  • a single oral dose of 12 mg ivermectin was administered on an empty stomach during each study period.
  • 22 blood samples were taken from each subject.
  • the first blood sample was collected before drug administration while the others were collected up to 36 hours after drug administration.
  • Subjects were confined to the clinical site at least 10 hours before each administration until at least 24 hours after each administration. Subjects return to the clinical site for the remaining blood sample.
  • Ivermectin Bla plasma concentrations were measured to determine the following pharmacokinetic parameters:
  • Non-compartmental analysis with a log-linear terminal phase assumption was used for PK analysis.
  • the trapezoidal rule was used to estimate the AUC.
  • - Plasma concentrations of ivermectin Bla were averaged per time and per treatment using the arithmetic mean, the geometric mean, the minimum, the median, the maximum, the standard deviation and the coefficient of variation (CV);
  • T max was analyzed using a nonparametric approach.
  • INV2 treatment one dose of type B capsule (12 mg of ivermectin)
  • the time to reach the maximum plasma concentration (T max ) is 2.67 hours for the INV1 treatment whereas it is 2 additional hours for the REF treatment at 4.67 hours.
  • the maximum plasma concentration of ivermectin Bla (C max ) for INV1 treatment is approximately 85% higher than the C max after administration of REF treatment.
  • the overall mean exposure to ivermectin Bla from Treatment INV1 is 70% higher than the overall exposure from Treatment REF.
  • T max The time to reach the maximum plasma concentration (T max ) is 3.67 hours for the INV2 treatment whereas it takes 1 hour more after the administration of the REF treatment at 4.67 hours.

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EP22717151.9A 2021-03-23 2022-03-23 Orale formulierung von ivermectin und verwendungen davon Pending EP4313155A1 (de)

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