WO2018087109A1 - Forme galénique multiparticulaire à libération de métamizole contrôlée - Google Patents

Forme galénique multiparticulaire à libération de métamizole contrôlée Download PDF

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Publication number
WO2018087109A1
WO2018087109A1 PCT/EP2017/078525 EP2017078525W WO2018087109A1 WO 2018087109 A1 WO2018087109 A1 WO 2018087109A1 EP 2017078525 W EP2017078525 W EP 2017078525W WO 2018087109 A1 WO2018087109 A1 WO 2018087109A1
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weight
minutes
dosage form
particles
composition
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PCT/EP2017/078525
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German (de)
English (en)
Inventor
Marc Schiller
Carlos Van Hemelrijck
Karl-Heinz Oedekoven
Elisabeth EBNER
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Grünenthal GmbH
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Publication of WO2018087109A1 publication Critical patent/WO2018087109A1/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
    • A61K9/14—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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • 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

Definitions

  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient metamizole or one of its physiologically acceptable salts, wherein the composition comprises a plurality of particles, each comprising a core which is coated with a retarding coating, wherein the active ingredient in the Core is contained and under controlled conditions released from the particles under physiological conditions.
  • Metamizole (also known as novamine sulfone, dipyrone, methampyrone or sodium [(1,5-dimethyl-3-oxo-2-phenylpyrazol-4-yl) -methylamino] methanesulfonate) is a pyrazolone derivative and analgesic from the group non-acidic nonopioid analgesics.
  • Metamizole which itself is a prodrug, is hydrolyzed to the pharmacologically active 4-N-methylaminoantipyrine (MAA). The bioavailability of 4-N-methylaminoantipyrine is about 90%.
  • Metamizole is metabolized in the liver (hepatic) and excreted mainly via the kidney (renal). Plasma half life and duration of action are approximately 2.5 hours. Concomitant ingestion may result in slower absorption of orally administered metamizole, resulting in a slightly delayed onset of action.
  • metamizole is usually administered in liquid form, for example as an infusion (drip).
  • metamizole in solid form, for example as tablets.
  • the commercially available tablets are relatively large and contain as a single tablet only 500 mg of active ingredient.
  • many patients require 1000 mg metamizole as a single dose for adequate analgesia.
  • metamizole must be taken as a tablet every 3 to 4 hours by the patient. Frequent use is very troublesome for many patients and also leads to compliance problems.
  • a retarded galenic opens up advantages for the patients, in particular a longer effectiveness, especially in chronic pain and better compliance. Other advantages can be more stable plasma levels and less side effects, especially less nausea due to the retardation.
  • EP 1 020 181 discloses a process for producing pellets consisting of at least 50% by weight of an active ingredient and at most 50% by weight of a combination of microcrystalline cellulose and low-substituted hydroxypropyl cellulose.
  • WO 00/25750 relates to solid, oral, controlled release formulations obtained by melt granulation of the active ingredient with a fatty component and mixing the resulting granules with a hydrophilic polymer and conventional excipients.
  • WO 00/66088 relates to a controlled release, solid, orally administered, pharmaceutical composition containing a therapeutically effective amount of metamizole and / or its pharmaceutically acceptable salts as active ingredients embedded in a controlled release matrix.
  • WO 2004/002398 discloses a process for the preparation of pellets containing an active ingredient and coated with a mixture of a polyvinyl alcohol-based polymer and a dispersion of ethyl cellulose.
  • the pellets contain from 0.1 to 50% by weight of the active ingredient relative to the total weight of the pellets.
  • US 2006/0003007 discloses tablets, pellets or beads which are coated and release the active ingredient prolonged.
  • the coating may consist of various materials, including a mixture of Eudragit ® S and Eudragit ® L is disclosed as a coating material.
  • WO 2008/101743 discloses pellets containing an active ingredient embedded in a polymer matrix and causing a delayed release of the active ingredient.
  • K.S. Kalchofner Guerro et al., The Veterinary Journal, 204 (1), 2015, 99-104, relates to a comparison of a formulation of metamizole and carprofen for extended postoperative analgesia in dogs after ovarian hysterectomy.
  • metamizole is not satisfactory in every respect.
  • matrix retardation requires comparatively large amounts of pharmaceutical auxiliaries, in particular of matrix material, which has an unfavorable effect on the total weight of the formulation.
  • the therapeutically effective dose of metamizole is often 500 mg or even 1000 mg, it would be desirable to know the amount of pharmaceutical excipients To keep as small as possible, so that the total weight of the formulation is not too large. Otherwise, this would have a negative impact on compliance.
  • this is difficult to achieve, especially in the case of multiparticulate administration forms, since the diffusion paths are comparatively short and therefore usually more matrix material is needed relative to the amount of active substance in order to achieve reliable retardation. Because of the very high daily doses, a multiparticulate form is to be preferred for reasons of swallowability.
  • a first aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient metamizole or one of its physiologically acceptable salts, the composition comprising a plurality of particles, each comprising a core which is coated with a retarding coating, wherein the Active ingredient is contained in the core and released in a controlled manner from the particles under physiological conditions.
  • composition of the invention contains as active ingredient metamizole or one of its physiologically acceptable salts, which may be in the form of solvates, e.g. Hydrates, and may be present in any modifications, i. in particular amorphous and / or crystalline, in the case of crystalline modifications all polymorphic forms come into consideration, as well as their mixtures.
  • solvates e.g. Hydrates
  • Physiologically acceptable salts of metamizole include in particular the sodium salt (ATC code N02BB02), which is particularly preferred according to the invention. Unless otherwise specified, for purposes of description, all amounts, dosages, and amounts are equivalent to metamizole sodium.
  • composition according to the invention may contain, in addition to metamizole or one of its physiologically acceptable salts, other active substances, for example different salts of metamizol or other analgesics.
  • metamizole or physiologically acceptable salt of metamizole is the only active ingredient included in the composition of the invention.
  • metamizol or physiologically acceptable salt of metamizole is in combination with another active ingredient or one of the physiologically acceptable salts of the other active ingredient, wherein the other active ingredient is preferably selected from
  • NSAIDs non-steroidal anti-inflammatory drugs
  • non-steroidal anti-inflammatory drugs in particular ketoprofen
  • Opioid analgesics in particular selected from the group consisting of tramadol, tapentadol, oxycodone, oxymorphone, hydrocodone, hydromorphone, sufentanil, tilidine, morphine and their physiologically acceptable salts.
  • composition of the invention is solid and multiparticulate, preferably dry, i. it is preferably not present as a suspension in a liquid.
  • the composition comprises different particles, which may differ, for example, in terms of their size, composition, active ingredient content and / or their coating with the retardant coating
  • Information according to the invention which relates to the total weight of the cores, particles or the retarding coating, should therefore always be understood as averages, unless expressly defined otherwise.
  • the composition of the invention comprises a plurality of particles comprising a core which is coated with a retarding coating. While it is fundamentally possible that the core itself is multi-layered or that one or more further layers are arranged around the core between the core and the retarding coating, it is preferred according to the invention for the core to consist of a homogeneous preparation and the retarding Coating directly adjacent to the core.
  • the core as the only coating on the retardant coating.
  • the retardant coating is not in addition to one or more surrounded by other coatings.
  • the retarding coating thus preferably forms or covers the outer surface of the particles or cores.
  • the entire surface of the cores is coated with the retarding coating, i. jacketed.
  • the layer thickness of the retarding coating is preferably as uniform as possible.
  • the core has as coating an enteric (enteric) coating.
  • the core has no enteric (enteric) coating as a coating.
  • the active ingredient is contained in the core.
  • the total amount of the active principle contained in the composition is contained in the cores of the plurality of particles, i. there is preferably no active ingredient outside the nuclei.
  • the weight fraction of the active ingredient based on the total weight of the particles is at least 20% by weight or at least 25% by weight, more preferably at least 30% by weight or at least 35% by weight, more preferably at least 40% by weight. -% or at least 45 wt .-%, most preferably at least 50 wt .-% or at least 55 wt .-%, and in particular at least 60 wt .-% or at least 65 wt .-%. More preferably, the weight fraction of the active ingredient based on the total weight of the particles is in the range of 65 ⁇ 18% by weight, more preferably 65 ⁇ 15% by weight, even more preferably 65 ⁇ 12% by weight, most preferably 65 ⁇ 9% by weight. -%, more preferably 65 ⁇ 6% by weight, and most preferably at 65 ⁇ 3% by weight.
  • the weight fraction of the active ingredient based on the total weight of the cores ie, without taking into account the weight of the retardant coating, at least 30% by weight or at least 35 wt .-%, more preferably at least 40 wt .-% or at least 45 wt %, more preferably at least 50% or at least 55%, most preferably at least 60% or at least 65%, and most preferably at least 70% or at least 75% by weight. %.
  • the weight fraction of the active ingredient based on the total weight of the cores in the range of 80 ⁇ 18 wt .-%, more preferably 80 ⁇ 15 wt .-%, more preferably 80 ⁇ 12 wt. -%, most preferably 80 ⁇ 9 wt .-%, and in particular 80 ⁇ 6 wt .-%.
  • the shape and size of the individual particles in the composition of the invention is not particularly limited.
  • the particles are substantially spherical.
  • the particles have an average weight per particle in the range of 0.1 to 50 mg.
  • the average weight per particle is in the range of 1.0 ⁇ 0.9 mg, or 2.0 ⁇ 1.9 mg, or 3.0 ⁇ 2.9 mg, or 4.0 ⁇ 3.9 mg , or 5.0 ⁇ 4.9 mg, or 6.0 ⁇ 5.9 mg, or 7.0 ⁇ 6.9 mg, or 8.0 ⁇ 7.9 mg, or 9.0 ⁇ 7.9 mg , or 10.0 ⁇ 9.9 mg, or 12.5 ⁇ 10.0 mg, or 15.0 ⁇ 10.0 mg, or 17.5 ⁇ 10.0 mg, or 20.0 ⁇ 10.0 mg , or 22.5 ⁇ 10.0 mg, or 25.0 ⁇ 10.0 mg, or 30.0 ⁇ 10.0 mg, or 35.0 ⁇ 10.0 mg, or 40.0 ⁇ 10.0 mg , or 45.0 ⁇ 10.0 mg, or 50.0 ⁇ 10.0 mg.
  • the release of the active ingredient from the composition according to the invention under physiological conditions is delayed according to the invention by the retarding coating.
  • the delayed release of the active ingredient is preferably based essentially exclusively on the retarding action of the retarding coating, i. the nucleus as such preferably does not cause additional matrix retardation.
  • the retarding coating is preferably based on a single layer.
  • retardation of the release of an active substance by a retarding coating is not trivial.
  • many materials for making retardant coatings are known in the art and are commercially available.
  • the function of retardant coatings can be based on different principles, in particular on controlled diffusion or controlled resolution.
  • a water-insoluble polymer composition may be admixed with water-soluble, fine particulate components as pore-forming agents which dissolve under physiological conditions and leave pores in the insoluble polymer film through which drug release thereafter occurs.
  • the properties of the active substance e.g. its solubility and its nature in the formulation (e.g., molecularly disperse or microcrystalline);
  • the amount of the active substance in particular its proportion by weight in the formulation
  • the properties of the coating such as its composition, its mode of action, its compatibility with the composition of the core, the number of possibly different layers and possibly their respective constituents;
  • the amount of coating i. their layer thickness.
  • the retarding coating according to the invention preferably contains no pore-forming agent, but is preferably based on a polymer which is permeable as such for the active ingredient.
  • the retarding coating of the invention preferably contains no ethylcellulose, more preferably no alkylcellulose ethers, more preferably no cellulose ethers, most preferably no polysaccharides.
  • the retarding coating of the invention preferably contains no polyvinylpyrrolidone, no waxes and / or oils.
  • the retarding coating is not based on a mixture of different acrylates, more preferably not on a mixture of different polymers.
  • the retarding coating is based on a single component, preferably on a single polymer.
  • the polymer on which the retarding coating is based is a synthetic polymer or a cationic polymer.
  • the retarding coating is based on a polymer, more preferably on a single polymer, wherein the polymer is prepared from a monomer, more preferably from two different monomers, and most preferably from three different monomers.
  • the retarding coating is based on a copolymer, preferably on an acrylate, more preferably on a cationic acrylate.
  • the retarding coating is based on a copolymer of ethyl acrylate and methyl methacrylate, optionally additionally of trimethylammonium ethyl methacrylate, this being preferably present as chloride.
  • the quaternary ammonium groups of the comonomer trimethylammonium ethyl methacrylate cause the polymer to become permeable to the active ingredient; a separate addition of pore formers is not required.
  • the permeability of the retarding coating has a significant influence on the extent of the retardation of the drug.
  • coating materials of this type with different relative composition of the three comonomers are commercially available (Eudragit ® RS and Eudragit ® RL).
  • Eudragit ® RS the relative weight ratio of ethyl acrylate is: methyl methacrylate: ethyl methacrylate trimethylammonium chloride 1: 2: 0.1.
  • Eudragit ® RL the relative weight ratio of ethyl acrylate is: methyl methacrylate: trimethylammonioethyl methacrylate chloride 1: 2: 0.2, so that Eudragit ® RL a greater proportion of quaternary ammonium groups containing as Eudragit ® RS. Both coating materials may also be mixed together in different mixing ratios to adjust the relative proportion of trimethylammoniumethyl methacrylate chloride in the mixture to values in the range of 0.1 to 0.2.
  • the relative weight ratio of ethyl acrylate is: methyl methacrylate: trimethylammoniumethyl methacrylate chloride (1.0 ⁇ 0.1): (2.0 ⁇ 0.2): (0.10 ⁇ 0.04), more preferably (1, 0 ⁇ 0.1): (2.0 ⁇ 0.2): (0.10 ⁇ 0.03), more preferably (1.0 ⁇ 0.1): (2.0 ⁇ 0.2) :( 0.10 ⁇ 0.02) and most preferably (1.0 ⁇ 0.1): (2.0 ⁇ 0.2): (0.10 ⁇ 0.01).
  • the relative weight ratio of ethyl acrylate: methyl methacrylate: trimethyl ammonium ethyl methacrylate chloride is 1: 2: (0.10 ⁇ 0.04), more preferably 1: 2: (0.10 ⁇ 0.03), even more preferably 1: 2: (0 , 10 ⁇ 0.02), and most preferably 1: 2: (0.10 ⁇ 0.01).
  • the layer thickness of the retardative coating has a significant impact on the extent of retardation of the drug.
  • the average layer thickness ultimately results from the proportion by weight of the retarding coating based on the total weight of the particles.
  • the weight fraction of the retarding coating based on the total weight of the particles at least 5.0 wt .-%, more preferably at least 7.5 wt .-%, more preferably at least 10.0 wt .-%, most preferably at least 12 , 5 wt .-%, and in particular at least 15.0 wt .-%.
  • the weight fraction of the retarding coating is based on the total weight of the cores, i. without regard to the weight of the retarding coating, at least 5.0% by weight, more preferably at least 7.5% by weight, even more preferably at least 10.0% by weight, most preferably at least 12.5% by weight, and in particular at least 15.0% by weight.
  • the weight fraction of the retarding coating based on the total weight of the particles is at most 40.0 wt .-%, more preferably at most 37.5 wt .-%, more preferably at most 35.0 wt .-%, most preferably at most 32 , 5 wt .-%, and in particular at most 30.0 wt .-%.
  • the weight fraction of the retarding coating based on the total weight of the cores ie, without taking into account the weight of the retardant coating, at most 40.0 wt .-%, more preferably at most 37.5 wt .-%, more preferably at most 35 0 wt%, most preferably at most 32.5 wt%, and most preferably at most 30.0 wt%.
  • the weight fraction of the retarding coating based on the total weight of the particles in the range of 10.0 ⁇ 7.5 wt .-%, or 15.0 ⁇ 7.5% by weight, or 20.0 ⁇ 7.5 wt%, or 25.0 ⁇ 7.5 wt%, or 30.0 ⁇ 7.5 wt%, or 10.0 ⁇ 5.0 wt%, or 12 , 5 ⁇ 5.0 wt%, or 15.0 ⁇ 5.0 wt%, or 17.5 ⁇ 5.0 wt%, or 20.0 ⁇ 5.0 wt%, or 22.5 ⁇ 5.0 wt.%, or 25.0 ⁇ 5.0 wt.%, or 27.5 ⁇ 5.0 wt.%, or 30.0 ⁇ 5.0 wt. %.
  • the weight fraction of the retarding coating is based on the total weight of the cores, i. without regard to the weight of the retarding coating, in the range of 10.0 ⁇ 7.5% by weight, or 15.0 ⁇ 7.5% by weight, or 20.0 ⁇ 7.5% by weight, or 25.0 ⁇ 7.5 wt%, or 30.0 ⁇ 7.5 wt%, or 10.0 ⁇ 5.0 wt%, or 12.5 ⁇ 5.0 wt% , or 15.0 ⁇ 5.0 wt%, or 17.5 ⁇ 5.0 wt%, or 20.0 ⁇ 5.0 wt%, or 22.5 ⁇ 5.0 wt%. %, or 25.0 ⁇ 5.0 wt%, or 27.5 ⁇ 5.0 wt%, or 30.0 ⁇ 5.0 wt%.
  • the core preferably comprises further auxiliaries, for example binders, fillers, antioxidants, etc., more preferably one or more binders.
  • Preferred binders include cellulose and cellulose derivatives, e.g. microcrystalline cellulose or cellulose ethers; Starches, e.g. Corn starch, rice starch, potato starch and wheat starch, modified (i.e., pre-gelatinized) starches; Gelatin; tragacanth; Polyvinyl pyrrolidone (e.g., povidone K12-K30); etc. as well as their mixtures.
  • cellulose and cellulose derivatives e.g. microcrystalline cellulose or cellulose ethers
  • Starches e.g. Corn starch, rice starch, potato starch and wheat starch, modified (i.e., pre-gelatinized) starches
  • Gelatin tragacanth
  • Polyvinyl pyrrolidone e.g., povidone K12-K30
  • Preferred cellulose ethers include methylcellulose, ethylcellulose, propylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose, and salts thereof.
  • Microcrystalline cellulose and hydroxypropyl cellulose are particularly preferred, the latter being preferably low substituted according to Ph. Eur.
  • the core contains microcrystalline cellulose in combination with preferably low substituted hydroxypropyl cellulose, wherein the relative weight ratio of microcrystalline cellulose to preferably low substituted hydroxypropyl cellulose is in the range of 3: 1 to 1: 3, more preferably 2: 1 to 2: 1 and especially 1.5: 1 to 1: 1.5.
  • the weight fraction of the binder based on the total weight of the particles is at most 40 wt .-%, more preferably at most 35 wt .-%, more preferably at most 30 wt .-%, most preferably at most 25 wt .-% and in particular at most 20% by weight.
  • the weight fraction of the binder is based on the total weight of the cores, i. without regard to the weight of the retarding coating, at most 40% by weight, more preferably at most 35% by weight, even more preferably at most 30% by weight, most preferably at most 25% by weight and especially at most 20% by weight.
  • the cores consist of active ingredient and one or more binders, preferably microcrystalline cellulose and hydroxypropylmethylcellulose.
  • the relative weight ratio of active ingredient to total weight of all binders in the core ranges from 7: 1 to 1: 1, more preferably 6.5: 1 to 1.5: 1, even more preferably 6: 1 to 2: 1, most preferably 5.5: 1 to 2.5: 1, more preferably 5: 1 to 3: 1, and especially 4.5: 1 to 3.5: 1.
  • Another aspect of the invention relates to an oral pharmaceutical dosage form comprising the above-described pharmaceutical composition according to the invention.
  • the dosage form of the invention comprises a limited amount of the pharmaceutical composition of the invention and thus also a limited amount of particles intended for substantially simultaneous oral administration so as to deliver a therapeutic drug dose to the patient.
  • the dosage form according to the invention preferably comprises the plurality of particles in non-compacted, free form.
  • the dosage form according to the invention comprises a large number of particles.
  • the dosage form according to the invention preferably comprises at least 10 particles, or at least 20 particles, or at least 30 particles, or at least 40 particles, or at least 50 particles, or at least 60 particles, or at least 70 particles, or at least 80 particles, or at least 90 particles, or at least 100 particles, or at least 125 particles, or at least 150 particles, or at least 175 particles, or at least 200 particles, or at least 250 particles, or at least 300 particles, or at least 400 particles, or at least 500 particles.
  • the dosage form of the invention contains the active ingredient in a total amount in the range of 50 mg to 2500 mg, more preferably more than 500 mg, even more preferably in the range of 500 mg to 2500 mg.
  • the total amount of the active ingredient in the dosage form of the invention is in the range of 250 ⁇ 200 mg, or 300 ⁇ 200 mg, or 350 ⁇ 200 mg, or 400 ⁇ 200 mg, or 550 ⁇ 200 mg, or 500 ⁇ 250 mg, or 600 ⁇ 250 mg, or 700 ⁇ 250 mg, or 750 ⁇ 250 mg, or 800 ⁇ 250 mg, or 900 ⁇ 250 mg, or 1000 ⁇ 250 mg, or 1100 ⁇ 250 mg, or 1200 ⁇ 250 mg, or 1250 ⁇ 250 mg, or 1300 ⁇ 250 mg, or 1400 ⁇ 250 mg, or 1500 ⁇ 250 mg.
  • the controlled release (release) is preferably selected from the group consisting of extended release, delayed release, repeated action release, sustained release and sustained release.
  • sustained release preferably defines a sustained release of the physiologically active substance for a defined, finite time (lag time), after the end of which the release is unimpeded.
  • sustained release preferably defines the initial release of a first subset of the physiologically active substance followed by at least one further subset, which is subsequently released.
  • sustained release preferably defines release at a reduced rate of release to maintain therapeutic efficacy, reduce toxic effects, or for other therapeutic reasons.
  • Uniform sustained release preferably defines sustained release over a relatively long period of time to reduce the frequency of administration.
  • the dosage form according to the invention under in vitro conditions according to European Pharmacopoeia (Paddle according to Ph.Eur 2.9.3, 37.0 ° C ⁇ 0.5 ° C, SIFsp pH 6.8, 900 mL, 50 rpm) after 6 hours at most 80% by weight, more preferably at most 70% by weight, even more preferably at most 67.5% by weight, most preferably at most 65% by weight, and especially at most 62.5% by weight of the original released in the dosage form contained active substance.
  • European Pharmacopoeia Paddle according to Ph.Eur 2.9.3, 37.0 ° C ⁇ 0.5 ° C, SIFsp pH 6.8, 900 mL, 50 rpm
  • the dosage form according to the invention is preferably suitable for once or twice daily administration.
  • the treatment of humans is preferred, but it can also mammals, especially pets such. Cats and dogs are treated.
  • Another aspect of the invention relates to the above-described dosage form according to the invention for therapeutic use, preferably for the relief of pain, wherein the dosage form is preferably administered orally once a day or twice daily.
  • the pain may be acute pain, especially postoperative pain, or chronic pain.
  • Types of pain that can be treated particularly effectively include headache, e.g. episodic tension-type headache episodic headache; visceral pain; Pain associated with neoplasms and pain associated with colic (colic pain).
  • the dosage form according to the invention u.a. also for the treatment of spastic states, including colic, affecting the gastrointestinal tract, the biliary system or the urinary tract.
  • Another aspect of the invention relates to the use of metamizole or one of its physiologically acceptable salts for the preparation of the above-described dosage form according to the invention for therapeutic use, preferably for the relief of pain, wherein the dosage form is preferably administered orally once a day or twice daily.
  • Another aspect of the invention relates to a therapeutic method, preferably a method of alleviating pain, comprising administering the above-described inventive dosage form to a patient preferably once or twice a day.
  • Another aspect of the invention relates to a package comprising the pharmaceutical dosage form according to the invention described above.
  • the packaging according to the invention is preferably in the form of a sachet. However, depending on the dose of active ingredient, filling in capsules may also be possible.
  • the following examples serve to illustrate the invention, but are not to be interpreted as limiting.
  • the cores thus produced were coated with the following coating materials in the following amounts:
  • the pellet cores were film-coated in a fluidized-bed plant from Wilsontlin Turbojet 05.
  • the product temperature when painted with Eudragit ® RS / RL varnish was 30 ° C and the volume flow was 33%.
  • the Eudragit ® RS30 D paints were film-coated at a product temperature of 52 ° C and a flow rate of 33%. All pellet cores were sprayed with a spray air of 0.3 bar.
  • the in vitro release was in each case for an amount of particles having a total weight in the range of 1250 to 1450 mg according to the paddle method according to Ph.Eur. 2.9.3, determined without sinker, 37.0 ° C ⁇ 0.5 ° C, SIFsp pH 6.8, 900 mL, 50 rpm. For comparison, the particle cores without coating were also examined.
  • the in vitro release profiles are shown in FIG.
  • the numerical numerical values (mean values) are additionally summarized in the following table:
  • the experimental data prove that in particular the particles according to Examples 3 and 4 show a significantly delayed release with sigmoidal course.
  • Within the first 2 hours less than 20% by weight of the amount of drug was released. This was achieved at a weight ratio of 19 and 24.5 wt .-% Eudragit ® RS30D, ie with a copolymer of ethyl acrylate: methyl methacrylate: trimethylammonioethyl methacrylate chloride in a relative weight proportion of 1: 2: 0.1.
  • the relative share of permeabilticians Montden quaternary ammonium groups by mixing Eudragit ® RL was increased, so was no sufficient retardation, even among larger amount of coating material (see. Examples 1 and 2).

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Abstract

L'invention concerne une composition pharmaceutique qui comprend en tant que principe actif du métamizole ou un de ses sels physiologiquement acceptables, ladite composition comprenant une pluralité de particules comprenant respectivement un cœur qui est recouvert d'un enrobage gastro-résistant, le principe actif étant contenu dans le cœur et libéré de manière contrôlée hors des particules dans des conditions physiologiques.
PCT/EP2017/078525 2016-11-08 2017-11-08 Forme galénique multiparticulaire à libération de métamizole contrôlée WO2018087109A1 (fr)

Applications Claiming Priority (2)

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EP16197675 2016-11-08
EP16197675.8 2016-11-08

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WO2018087109A1 true WO2018087109A1 (fr) 2018-05-17

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000025750A1 (fr) 1998-11-03 2000-05-11 Farmaceutici Formenti S.P.A. Compositions de metamizole a liberation prolongee
EP1020181A1 (fr) 1999-01-18 2000-07-19 Grünenthal GmbH Procédé pour la préparation de granules ayant une teneur en principe actif pharmaceutique allant jusqu'à 90% w/w
WO2000066088A1 (fr) 1999-05-04 2000-11-09 Hexal Ag Composition pharmaceutique a liberation controlee contenant du metamizol
WO2004002398A2 (fr) 2002-06-27 2004-01-08 Cilag Ag Preparations de granules spheriques
US20060003007A1 (en) 2004-07-01 2006-01-05 Isa Odidi Controlled extended drug release technology
WO2008101743A2 (fr) 2007-02-22 2008-08-28 Evonik Röhm Gmbh Granules pourvus d'une matrice comportant une substance active qui résiste au suc gastrique

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000025750A1 (fr) 1998-11-03 2000-05-11 Farmaceutici Formenti S.P.A. Compositions de metamizole a liberation prolongee
EP1020181A1 (fr) 1999-01-18 2000-07-19 Grünenthal GmbH Procédé pour la préparation de granules ayant une teneur en principe actif pharmaceutique allant jusqu'à 90% w/w
WO2000066088A1 (fr) 1999-05-04 2000-11-09 Hexal Ag Composition pharmaceutique a liberation controlee contenant du metamizol
WO2004002398A2 (fr) 2002-06-27 2004-01-08 Cilag Ag Preparations de granules spheriques
US20060003007A1 (en) 2004-07-01 2006-01-05 Isa Odidi Controlled extended drug release technology
WO2008101743A2 (fr) 2007-02-22 2008-08-28 Evonik Röhm Gmbh Granules pourvus d'une matrice comportant une substance active qui résiste au suc gastrique

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K.H. BAUER: "Lehrbuch der Pharmazeutischen Technologie", 1999, WVG
K.S. KALCHOFNER GUERRO ET AL., THE VETERINARY JOURNAL, vol. 204, no. 1, 2015, pages 99 - 104

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