Classifications

• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
• • 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

Definitions

• This invention relates to a pharmaceutical composition containing ribavirin as active substance and ensuring the perfect stability of the composition, even in case of high ratio of the active substance in it, and the immediate release of the active substance from a dosage form, when administered orally in the form of capsules or tablets.
• This invention also relates to a method of manufacturing of this pharmaceutical composition.
• Ribavirin its chemical name being l-beta-D-ribofuranosyl-l,2,4-triazole-3-carboxamide, is a substance having antiviral effects. It is a nucleoside analogue of formula I demonstrating, both in vitro and in vivo, an activity against certain DNA and RNA viruses.
• the dosage forms of the antiviral agent - ribavirin - used simultaneously with ⁇ 2b interferon or ⁇ 2b peg- interferon are used particularly for combined treatment of chronic hepatitis C.
• Ribavirin dosage forms having the form of topic preparations (gel, cream), parenteral preparations (hquid injections), oral solid and liquid dosage forms, and dosage forms intended for inhaling, have been described in literature.
• Ribavirin filled into capsules or tablets represents the dosage form particularly suitable for oral application.
• Virazole TM capsules and Rebetol ® capsules manufactured by the companies ICN and Schering-Plough, respectively, are particularly used in the current clinical practice.
• Ribavirin - the medicinal substance, both unprocessed and processed by milling and/or sieving to obtain the particle size suitable for pharmaceutical use - has a low tap density and a bad bulk density; this makes the preparation of the dosage form, particularly mixing of the active substance with suitable pharmaceutically acceptable excipients, and also particularly reproducible and sufficiently quick release of the active substance from the dosage form after being administered to the patient, rather complicated. Due to unsuitable physical characteristics of ribavirin, the capsule filled with Virazole preparation contains a badly flowing powder having a low and fluctuating tap density ranging between 0.320 and 0.449 g.cm "3 . Such fluctuation frequently results in a significant variability of capsule weights during filling, particularly when high-duty encapsulation machines are used.
• Virazole TM capsules have other deficiencies, namely, an unsuitable disintegration time of the said dosage form and an unsuitable release rate of the active substance during the dissolution test.
• the deficiencies mentioned above are partially solved in Rebetol ® preparation, the capsules of which, containing a high portion of the active component in the composition, are prepared using the dry granulation method according to WO 9932128.
• the substance of the solution of the problem consists in homogenization of an effective ribavirin quantity with an effective quantity of a pharmaceutically acceptable releasing agent and with at least one pharmaceutically acceptable filler.
• the homogeneous mixture is compacted using a compression force ranging between 50 and 75 kN for the time sufficient for manufacturing of appropriate compacts (aggregates).
• a granulate prepared using further milling of compacted agglomerates usually consists of fragments having uneven forms and sharp edges which affect adversely the liquidity of the composition, h addition, the granulate usually contains also a portion of superfine particles, the quantity of which depends on the agglomerate rigidity that affects significantly its bulk characteristics.
• the granulates manufactured using the dry granulation method also have a decreased porosity due to their compacting.
• the above mentioned facts result in a longer release time of the active substance from the composition like this.
• the cohesive properties advantageous for further possible processing into tablets are gradually lost during the processing of the granulate using the dry granulation method when compacting is also performed.
• the tablets have in this case a reduced cohesion (i.e. low radial strength) and a high abrasion.
• the invention relates to a pharmaceutical composition containing ribavirin as active substance in the mixture with at least one pharmaceutically acceptable excipient characterized in that it is a freely flowing granulate prepared using the wet granulation of a mixture, wetted with water, of ribavirin and at least one pharmaceutically acceptable filler selected from the group including cellulose and its derivatives and carbonates, phosphates, sulfates and silicates of metals, and optionally at least one pharmaceutically acceptable excipient.
• the mixture wetted with water and intended for the wet granulation contains advantageously ribavirin at the amount equal to at least 65 % by weight, and at least one pharmaceutically acceptable filler insoluble in water, at the amount equal to not more than 25 % by weight, related always to the dry-weight basis of the mixture mentioned.
• the composition contains advantageously microcrystalline cellulose, calcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate or hydrated forms thereof as the pharmaceutically acceptable fillers insoluble in water.
• the mixture advantageously contains at least one pharmaceutically acceptable binder and/or releasing agent.
• Polysaccharides and/or modified polysaccharides can be, for example, used as the releasing agent.
• the pharmaceutical composition according to the invention forms the granulate which is filled into capsules, particularly gelatine capsules, or into sacks.
• the granulate obtained can be also compacted into tablets.
• the pharmaceutical composition according to the invention forms the granulate having a predominantly regular and rounded shape and having the good liquidity.
• a pharmaceutically acceptable slipping agent for example, magnesium stearate, is advantageously added.
• a pharmaceutically acceptable external release agent for example, polysaccharide and/or modified polysaccharide, is added.
• the invention relates also to the method of manufacturing of the pharmaceutical composition according to the invention characterized in that the mixture of ribavirin wetted with water, at least one pharmaceutically acceptable filler insoluble in water selected from the group including cellulose and its derivatives and carbonates, phosphates, sulfates and silicates of metals, and at least one pharmaceutically acceptable excipient is granulated under wet conditions to obtain the granulate, then optionally at least one pharmaceutically acceptable external releasing agent and/or at least one pharmaceutically acceptable slipping agent are added to the granulate obtained, and the granulate, or optionally the mixture, obtained are optionally filled into capsules or sacks or compacted into tablets.
• the manufacturing method described is simple and has no special demands for the processing equipment.
• the granulate obtained has a high portion of the active substance - ribavirin - and a predominantly rounded shape and its particle size ensures the good liquidity of the composition.
• the composition according to the invention has also a very good disintegration and a good release of the active substance during the dissolution tests.
• the wet granulation method consists in that the liquid phase is added to the dry mixture while being simultaneously agitated in a suitable equipment.
• the wet granulate prepared using the process mentioned is optionally extruded, dried and then processed into the finished form.
• the mixture processed using the wet granulation has a significantly better aggregation and thus particularly drugs with high portions of the active substance in the composition obtain during the wet granulation the necessary bulk characteristics that represent one of the necessary conditions for their further processing into the final dosage forms because the formation of fragments of undefined shapes with sharp edges and a portion of superfine particles affecting adversely their uniform filling into capsules or matrixes of a tablet-making machine is thus eliminated.
• the granulates prepared using the wet granulation retain also their natural porosity, enhancing their plastic defor ability, enabling also their good compacting into tablets.
• fillers insoluble in water selected from the group including cellulose and its derivatives and carbonates, phosphates, sulfates and silicates of metals should be used in preparation of ribarivin dosage form in the wet granulation that in combination with a hydrophilic active substance ensures advantageously the instant release of the active substance at the amount equal to not more than 25 % by weight, related to the dry-weight basis of the mixture intended for the granulation.
• a hydrophilic active substance ensures advantageously the instant release of the active substance at the amount equal to not more than 25 % by weight, related to the dry-weight basis of the mixture intended for the granulation.
• at least 80 % by weight of the active substance were released within 30 minutes because the fillers mentioned above are not dissolved during the wet granulation and therefore no interactions with hydrophilic active substance occurs.
• a porous granulate By such unique combination of the hydrophilic active substance and the insoluble filler, a porous granulate, the porosity of which enables a quick penetration of the dissolution medium into the dosage form and thus the activation of the release agent, is formed during the process of the preparation.
• hydrophilic fillers as lactose
• the fillers insoluble in water also prevent an excessive wetting of the granulate and thus enable maintaining the standard production even during possible changes of the physical parameters of the active substance.
• the granulate amount in the individual dosage form is 300 mg.
• the granulate amount in the individual dosage form, a tablet or a capsule is 300 mg.
• the granulate amount in the individual dosage form, a tablet or a capsule is 300 mg.
• Amount of the active substance released is given in % by weight
• Amount of the active substance released is given in % by weight
• This dissolution profile is represented graphically in Fig. 2.

Applications Claiming Priority (2)

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• 2003
  • 2003-04-29 CZ CZ20031202A patent/CZ298224B6/cs not_active IP Right Cessation
• 2004
  • 2004-04-28 WO PCT/CZ2004/000023 patent/WO2004096187A1/en active Application Filing
  • 2004-04-28 EP EP04729818A patent/EP1617824A1/de not_active Withdrawn

Non-Patent Citations (1)

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