WO2006131790A2 - Composition pharmaceutique de ribavirine a administration par voie orale - Google Patents

Composition pharmaceutique de ribavirine a administration par voie orale Download PDF

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Publication number
WO2006131790A2
WO2006131790A2 PCT/IB2005/054434 IB2005054434W WO2006131790A2 WO 2006131790 A2 WO2006131790 A2 WO 2006131790A2 IB 2005054434 W IB2005054434 W IB 2005054434W WO 2006131790 A2 WO2006131790 A2 WO 2006131790A2
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Prior art keywords
ribavirin
composition
oral
modified release
mixtures
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PCT/IB2005/054434
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English (en)
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WO2006131790A3 (fr
Inventor
Gérard Soula
Rémi Meyrueix
Florence Guimberteau
Catherine Castan
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Flamel Technologies
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Application filed by Flamel Technologies filed Critical Flamel Technologies
Priority to PCT/IB2005/054434 priority Critical patent/WO2006131790A2/fr
Priority to PCT/EP2006/063070 priority patent/WO2006131566A2/fr
Priority to JP2008515226A priority patent/JP2009514784A/ja
Priority to CA002609998A priority patent/CA2609998A1/fr
Priority to EP06763633A priority patent/EP1888047A2/fr
Publication of WO2006131790A2 publication Critical patent/WO2006131790A2/fr
Publication of WO2006131790A3 publication Critical patent/WO2006131790A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • 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
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, 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
    • A61K9/50—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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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

Definitions

  • the invention relates to oral pharmaceutical compositions for the prevention and/or the treatment of viral diseases. This invention also addresses methods of prevention and/or treatment of these viral diseases, using these oral compositions.
  • Viral diseases of particular concern for the invention are notably viral infections such as hepatitis C infections.
  • ribavirin can be used in combination with active co-principle(s), such as interferon(s).
  • Ribavirin is known synthetic nucleoside analogs with broad spectrum antiviral activity. See e.g; US patent 3 927 216. It is colorles material with a water solubility as high as 140 g/liter, and is known to have two polymorphic forms.
  • Ribavirin is currently indicated for use as a combination therapeutic for Hepatitic C (HC) .
  • ribavirin is administered in large dosages, e;g; a dose as large as 1200 mg per day , together with interferon injections.
  • Dosing regimens involve 4 to 6 capsules per day for treatment of HC infections. The multiple capsules are taken twice a day. This dosage is continued daily for a number of months (typically 48 weeks).
  • the resulting efficacy of the treatment of HC, in conjunction either with interferon or long acting pegylated interferon is however limited.
  • sustained virologic response is obtained only for 30 to 55% of genotype I patients.
  • one of the main problems considered in the present invention is to enhance the efficiency of anti-viral treatments, especially against HC by means of ribavirin, for example in combination with interferon.
  • US-A-2005/0019406 discloses sustained release formulations of ribavirin based on coated pellets that reduce the dissolution rate of ribavirin in aqueous environment.
  • this patent application do not teach how to enhance the efficiency of anti-viral treatments, especially against HC by means of ribavirin 1.
  • WO- A-2005/016370 discloses a ribavirin-based method of treatment of viral infections based on low-dose and/ or slow release ribavirin formulation, possibly co-administered with interferon, to provide a clinically effective ribavirin blood level in the portal vein and less than required to provide clinically effective blood level in the systemic circulation.
  • This patent application do not disclose any particular slow release ribavirin formulation capable to enhance the efficiency of anti- viral treatments, especially against HC by means of ribavirin.
  • the viral focus is the liver and the portal vein.
  • ribavirin is rapidly bio-absorbed in the very upper part of the small intestine. This narrow window of absorption results in a sharp peak of bio- absorption, one hour after administration, followed by a rapid decline of the absorption rate.
  • liver first pass the drug entering the systemic circulation is rapidly distributed in red cells, a minor fraction being still present in plasma. Finally, portal vein and liver are fed only during the limited bio-absorption time plus the transit time of the drug through liver, this later being constant .
  • ⁇ to have considered that the transit time of ribavirin through portal vein and liver is fixed at a constant value and cannot be controlled; ⁇ and, then , to have proposed to increase the time during which portal vein and liver are fed with ribavirin, so as to increase the bio-absorption time of ribavirin using an appropriate dosage form.
  • ribavirin based therapies would be improved with a oral pharmaceutical composition feeding the portal vein and liver with ribavirin for extended period of time .
  • the known sustained release formulations that increase the in vitro dissolution time of the drug do not at all necessary increase the bio- absorption time and the duration of action of a drug such as ribavirine, whose window of absorption is narrow. For example, if the release time is too long, the majority of the drug is released too late, when the dosage form is out of the absorption window, resulting in a poor bioavailability without any significant increase of the bio-absorption time. On the contrary, if the release time is too short, the bioavailability is acceptable, but the bio- absorption time is short.
  • sustained release formulations of ribavirin do not necessarly remain and do not necessarly release ribavirin, in said very narrow window of ribavirin bio-absorption. Then, any sustained released ribavirin formulation does not make it possible to maintain constant and the therapeutically efficient concentration of ribavirin in the portal vein and in the liver for extended period of time.
  • Micropump® technology US-B-6,022,562
  • the Micropump® microparticulates are designed so as to be able to remain in the small intestine for an extended period of time, namely at least about 5 hours, and permitting so the absorption of the active principle during an extended bio-absorbtion time, namely at least part of their residence in the small intestine.
  • the active principle can be an antiviral drug, for example acyclovir, whose absorption window is limited to small intestine. This patent also discloses that it is beneficial to extend the release time of anti- viral drugs.
  • the Micropump® microparticles are 50 to 1000 ⁇ m microcapsules of API coated with at least one coating film of specific following composition (by weight of dry matter of the whole coating composition): 50 to 90% ethylcellulose; 2 to 25% polyvinylpyrrolidone; 2 to 20% castor oil and 2 to 20% magnesium stearate.
  • a first difficulty lies in the choice of the most appropriate range of in vitro release profiles.
  • a second difficulty is to maintain a high ribavirin loading within the dosage form.
  • the slow release of the active principle namely the ribavirin, is obtained by coating individually the reservoir-type microparticles by a polymeric membrane few microns thick. After oral administration, the microparticles come in contact with fluids of the gastrointestinal tract and the active principle is slowly released.
  • the driving force for the active principle release is the osmotic pressure of the active principle, directly proportionnal to its solubility.
  • Ribavirin being highly water-soluble, its sustained release requires thick coating, that reduces the loading rate of the particles. In the case of ribavirin, whose dosage is high: namely up to 3000 mg per day, it is crucial to maximise the drug loading and then to obtain a sustained release of ribavirin with limited amount of coating excipients.
  • the present invention relates to an oral ribavirin antiviral composition for increasing the bio-absorption time of ribavirin, and thus improving the treatment of the patients against viral infection.
  • composition comprises at least one modified release (MR) form of ribavirin which bio-absorption time BAT is greater than the bio-absorption time BAT* of a reference* immediate release (IR) form of ribavirin administered at the same dose.
  • BAT > BAT*.
  • the increase of the bio-absorption time BAT can be assessed by at least one of the following methods Ml and/or M2.
  • the BAT & BAT* of MR & IR* ribavirin are deduced from the bio-absorption plasma profile of ribavirin.
  • the bio-absorption plasma profile is computed by deconvolution of the mean plasma profile by the input response function of ribavirin, as explained in details in "Pharmacokinetics in drug discovery and development, R.D Schoenwald ED., CRC Press, 2002".
  • the BAT is arbitrarily defined as the time at which 90% of the bio-absorbable ribavirin has been bio-absorbed .
  • the increase of the bio-absorption time is reflected by a flat plasma profile after a mono- injection.
  • the flatness of the plasma profile is measured by the the peak and trought ratio, R, which is defined in the present invention as the ratio of the mean plasma concentration at peak, Cmax, divided by the mean plasma concentration 24 hours after dosing, C24.
  • R peak and trought ratio
  • an increase of the bio-absorption time will be establish if the peak and trought ratio, R, of the formulation according the present invention is less than the peak and trought ratio, R*, of a reference* immediate-release form of ribavirin containing the same dose of ribavarin administrated in the same conditions. So, when R ⁇ R*, then BAT > BAT*.
  • the oral ribavirin composition according to the invention can be characterized by the plasma concentration profile, obtained in a reference clinical test according to which the oral ribavirin composition is administered orally in a single administration, to a sample of N human individuals, preferably N>20 or 30 human individuals.
  • the individual plasma concentration profile is then measured on each of the patients, from where the individual pharmacokinetic parameters, such as the time Ti,max after which the plasma concentration reaches its maximum and the value of this maximum concentration Ci,max, are drawn. Based on these individual parameters, those skilled in the art conventionally calculate the mean values of these parameters and their standard deviations. Further details regarding the discussion of these parameters will be found in the work: Pharmacokinetics and pharmacodynamic Data Analysis 3rd ed., J. Gabrelsson et al., Kristianstads Bocktryckeri AB, Sweden, 2000.
  • the experimental conditions of the reference clinical test may for example be the following: administration of the form (gelatin capsule or tablet or suspension) once a day, one hour before the breakfast, to 20 normal human volunteers in the course of a cross trial study.
  • the plasma concentrations of ribavirin are measured at times: 0-0.25-0.5-0.75-1- 1.5-2-3-4-6-8-10-12-16-18-24-36-48 hours post-administration.
  • This clinical test defines the invention by virtue of the pharmacokinetic properties obtained specifically under the conditions of the test. Nevertheless, the invention is not limited to an implementation under the conditions of this reference clinical test.
  • modified release denotes, in the present disclosure, a prolonged or sustained release and/or a delayed release and/or a pulsed release of active principle (e.g. ribavirin) by an oral pharmaceutical composition.
  • a modified release oral pharmaceutical composition may, for example, comprise an immediate-release phase and a slow-release phase.
  • Modified-release oral compositions are well known in this field; see, for example, Remington: The Science and practice of pharmacy", 19th edition, Mack Publishing Co. Pennsylvania, USA.
  • the modified release may in particular be a prolonged and/or delayed release.
  • the active principle e.g. ribavirin
  • the active principle e.g. ribavirin
  • the active principle e.g. ribavirin
  • the active principle e.g. ribavirin
  • the bio-absorption time of the oral ribavirin composition according to the invention is, for example, preferably comprised between 2 and 15 h, and more preferably between 4 and 12 h.
  • the oral ribavirin composition according to the invention can include different MR forms of ribavirin, possibly one or several IR form(s) of ribavirin, as well as possibly at least one MR and/or IR form of one or several other active principle(s).
  • the inventors take credit to have identified the optimum release profile of ribavirin that lead to an extended bio-absorption time of ribavirin without any drastic decrease of the bioavailability.
  • optimum release profile of the modified release form of ribavirin could be the release profile obtained in a dissolutest in which the pH is maintained at pH 1.4 for 1.5h then increased at pH 6.8, such that 70% of the ribavirin is released over a period of time of between 1.5 and 16 h, preferably between 2 and 1O h, more preferably between 3 and 8 h.
  • the present invention also refers to, whether BAT > BAT* or not, an oral ribavirin composition wherein the modified release form of ribavirin has a release profile in a dissolutest in which the pH is maintained at pH 1.4 for 1.5h then increased at pH 6.8, such that 70% of the ribavirin is released over a period of time of between 1.5 and 16 hours.
  • the inventors take credit for demonstrating , after numerous trials, that a specific selection of coating compositions allow to obtain appropriate release profile of the drug with a limited amount of excipients..
  • ribavirin » as used herein includes ribavirin or any analogue or pro-drug, such as viramidine and levovirin thereof, that is found to have virucidal activity .
  • the present invention applies principally to the treatment of hepatitis C infection and to the use of combinations interferon and ribavirin.
  • the invention also applies to the treatment of any other form of viral infection in which the main tissue damage and the principle site of viral replication is in the liver.
  • a combination of oral ribavirin with interferon ⁇ -2b (INF) or peginterferon ⁇ -2b is now a standard therapy in treating patients with chronic hepatitis C, particularly with hepatitis C of genotype 1 b and high viral titers.
  • the daily oral dose of ribavirin is currently determined based on the patient's body weight, though approved ribavirin doses vary among countries. In Japan, for example, the dose is 600 mg/d for patients weighing less than 60 kg and 800 mg/d for patients weighing more than 60 kg in a combination therapy with INF.
  • ribavirin is, e.g., administered at a total daily dose of 1000 mg (under 75 kg) or 1200 mg (over 75 kg). Moreover, when ribavirin is combined with peginterferon ⁇ -2b, the dose is fixed at 800 mg/d in the United States but is 800 mg/d for patients under 65 kg, 1000 mg/d for patients 65-85 kg, and 1200 mg/d for patients over 85 kg in Europe.
  • the present invention also covers doses of both ribavirin and/or interferon other than the above given ones.
  • the interferon(s), possibly combined with the oral ribavirin composition according to the invention, can be:
  • oral ribavirin ⁇ co-administered, by any suitable route, with said oral ribavirin ⁇ and/or can be include in oral ribavirin composition in a therapeutically effective amount.
  • interferon alpha as used herein means the family of highly homologous species-specific proteins as defined in US 6,472,373 Bl column 4 line 39 to column 5 line 55.
  • modified interferons such as the novel genetic fusion protein, Albuferon fusion protein (Human Genome Science Inc.) are under development. Accordingly, the present invention contemplates the use of ribavirin with any form of interferon or any derivative thereof including the future oral forms of interferon or such derivatives.
  • the modified release form of ribavirin is a sustained release form with a release profile at pH 6.8, such that 70% of the ribavirin is released over a period of time, designed hereafter as t(70%), of between 1.5 and 15 hours, preferably 2 and 10 hours and even more preferably between 3 and 8 hours.
  • the modified release form of ribavirin has an in vitro release profile, in 0.05M potassium dihydrogeno phosphate/sodium hydroxide buffer medium at pH 6.8, such that, for any value of time t of between 2h and t(70%), preferably for any value of time t of between Ih and t(70%), the % of dissolved (released) ribavirin is greater or equal to 35 t / 1(70%).
  • the modified release form of ribavirin is a sustained release form with an in vitro dissolution behaviour such that:
  • the release of ribavirin is controlled by means of two distinct triggering mechanisms, one being based on a variation in pH and the other allowing the release of the active principle(s) after a predetermined period of residence in the stomach;
  • the dissolution profile comprises a lag phase of less than or equal to 7 hours, preferably less than or equal to 5 hours, and even more preferably of between 1 and 5 hours;
  • the modified release form of ribavirin according to this second embodiment has an in vitro dissolution behaviour, measured in an in vitro dissolution test, such that:
  • the modified release form of the oral ribavirin composition according to the invention can be:
  • reservoir type form is intended to denote, in the present disclosure, a form in which the volume of material containing the active principle(s) -e.g. ribavirin- is entirely coated by at least a film which controls the diffusion release speed of the active principle(s) -e.g. ribavirin- through the continous film (or membrane) which does not include the active principle(s) -e.g ribavirin.
  • the active principle(s) -e.g. ribavirin- containing material is, for example, the active principle(s) -e.g.
  • the reservoir form comprises, for example, a plurality of individually coated microcapsules or a monolithic system such as coated tablet(s), a tablet or any other pharmaceutical form containing a plurality of coated microcapsules.
  • matricial type form is intended to denote, in the present disclosure, a form in which the ribavirin is dispersed in a solid continous (polymeric) phase (the matrix) which controls the diffusion release speed of the active principle(s) -e.g. ribavirin-.
  • Said matrix can or cannot be erodable.
  • Said matrix e.g. consists of pharmaceutically acceptable excipients known by the man skilled in the art.
  • the matricial type form includes, for instance, a plurality of matricial microgranules (matricial elements) containing the active principle(s) -e.g. ribavirin-. These matricial elements are non coated or partially coated by at least one film.
  • the matricial type form can be, e.g., also a monolithic system (matricial element), such as a tablet(s) non-entirely coated by at least one continous film, which does not contain any reservoir form.
  • the matricial type form can be, e.g. a tablet containing a plurality of active principle(s) -e.g. ribavirin- IR granules or active principle(s) -e.g. ribavirin- SR granules, said granules being dispersed in a polymeric matrix.
  • the modified release form included therein is a gastric retentive system .
  • the modified release form included therein is a multiparticulate form.
  • a gastric retentive system can be defined, for instance, as a dosage form that swell in stomach, or float on the gastric fluids, and thus remains for prolonged period of time in stomach.
  • Polymers suitable for use in the gastric retentive system are, e.g. those that both swell upon absorption of gastric fluid and gradually erode over a time period of hours. Erosion initiates simultaneously with the swelling process, upon contact of the surface of the dosage form with gastric fluid.
  • Suitable polymers for use in the present dosage forms may be linear, branched, dendrimeric, or star polymers, and include synthetic hydrophilic polymers as well as semisynthetic and naturally occurring hydrophilic polymers.
  • the polymers may be homopolymers or copolymers, if copolymers, either random copolymers, block copolymers or graft copolymers.
  • Synthetic hydrophilic polymers useful herein include, but are not limited to:
  • Polyalkylene oxides particularly poly(ethylene oxide), polyethylene glycol and poly(ethylene oxide)-poly(propylene oxide) copolymers; - Cellulosic polymers;
  • Acrylic acid and metacrylic acid polymers, copolymers and esters thereof preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate; ethyl methacrylate, and copolymers thereof, with each other or with additional acrylate species such as aminoehtyl acrylate; - Maleic anhydride copolymers;
  • Poly(acrylamides) such as polyacrylamide per se, poly(methacrylamide), poly(dimethylacrylamide), and poly(N-isopropyl-acrylamide);
  • Poly(olefinic alcohol) such as poly(vinyl alcohol);
  • Poly(N-vinyl lactams) such as poly( vinyl pyrrolidone), poly(N-vynil caprolactam), and copolymers therof;
  • Polyols such as glycerol, polyglycerol (particularly highly branched polyglycerol), propylene glycol and trimethylene glycol substituted with one or more polyalkylene oxides, e.g., mono-, di-, and tri-polyoxyethylated glycerol, mono- and di-poly- oxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol;
  • polyalkylene oxides e.g., mono-, di-, and tri-polyoxyethylated glycerol, mono- and di-poly- oxyethylated propylene glycol, and mono- and di-polyoxyethylated trimethylene glycol;
  • Polyvinylacetates including polyvinylacetate per se as well as ethylene-vinyl acetate copolymers, polyvinyl acetate phthalate, and the like;
  • the oral ribavirin composition according to the invention is characterized by the fact that the microparticles have a volume mean diameter which is less or equal to 1000 microns, preferably comprised between 20 and 800 microns and more preferably comprised between 50 and 600 microns.
  • the oral ribavirin composition according to the invention is characterized by the fact that the microparticles have a mean diameter which is less than 2000 ⁇ m, and preferably between 50 and 800 ⁇ m, and even more preferably between 100 and 600 ⁇ m. .
  • the volume mean diameter could be measured, for example, with a particle laser sizer.
  • the present invention also encompasses a particular way of implementation of the multiparticulate form that is a reservoir type form, including a plurality of microcapsules with modified release of ribavirin, these microcapsules individually consisting of a microparticle including some ribavirin and coated with at least one coating for modified release of the ribavirin
  • This multimicroparticulate form can include, inter alia, microcapsules consisting of coated microparticles containing ribavirin.
  • microparticles containing ribavirin may, for example, be microparticles of the (pure) crude ribavirin in crystal form, matrix granules of ribavirin with various other ingredients, or alternatively neutral microspheres, for example made of cellulose or of sugar, coated with at least one layer comprising ribavirin.
  • the ribavirin microcapsules can also contain one or more active principles, different from ribavirin, that are identical to or different from one another.
  • the oral ribavirin composition according to the invention can also include, besides ribavirin MR microparticles (e.g. microcapsules), MR microparticles (e.g. microcapsules) of one or more active principles, different from ribavirin, and identical to or different from one another.
  • ribavirin MR microparticles e.g. microcapsules
  • MR microparticles e.g. microcapsules
  • these other active principles can be present in the composition in a MR form, such as a matricial form and/or a reservoir form and/or a multiparticulate form and/or a gastroretentive form.
  • a MR form such as a matricial form and/or a reservoir form and/or a multiparticulate form and/or a gastroretentive form.
  • the composition according to the invention may be made up of various populations of MR microparticles, these populations differing from one another at least through the nature of the active principle(s) (ribavirin) contained therein and/or through the composition of the coating or of the matrix.
  • the oral ribavirin composition according to the invention can also comprise IR form(s) of ribavirin, and possibly of other active principle(s).
  • these IR forms can be multimicroparticulate forms, namely e.g. noncoated microparticles of active principle(s) (ribavirin) that are of the same type as those used in the preparation of the microcapsules as above described.
  • microcapsules used in the composition according to the sub-embodiment b) of the invention
  • two preferred examples of the structure of the microcapsules are given in detail hereinafter, without any implied limitation.
  • at least some of the microcapsules with modified release of active principle(s) (ribavirin) each comprise:
  • the microparticle of active principle(s) (ribavirin) is a granule comprising the active principle(s) (ribavirin) and one or more pharmaceutically acceptable excipients.
  • microcapsules with modified release of active principle(s) each comprise: ⁇ a neutral core,
  • ⁇ at least one active layer comprising the active principle(s) and coating the neutral core
  • ⁇ at least one coating for modified release of the active principle(s) (ribavirin).
  • the neutral core contains sucrose and/or dextrose and/or lactose.
  • the neutral core is a cellulose microsphere.
  • the neutral core has a mean diameter of between 1 and 800 ⁇ m, and preferably of between 20 and 500 ⁇ m.
  • the active layer may optionally comprise, besides the active principle(s) (ribavirin), one or more pharmaceutically acceptable excipients.
  • this active layer can comprise active principle, at least one swelling agent, at least one binder and at least one surfactant.
  • the present invention has also consisted in selecting microcapsules having the hereinafter described specificities.
  • the microcapsule coating preferably comprises at least one layer which controls the modified release of ribavirin, and the composition of which is as follows:
  • D at least one plasticizer (D); E. optionally, at least one surfactant and/or lubricant (E).
  • * (A) is selected from the group of following products:
  • non-water-soluble derivatives of cellulose preferably ethylcellulose and/or cellulose acetate
  • (B) is chosen from water-insoluble charged acrylic derivatives, preferably from (copolymers of acrylic and methacrylic acid ester carrying at least one quaternary ammonium group, (B) even more preferably comprising at least one copolymer of alkyl (meth)acrylate and of trimethylammonioethyl methacrylate chloride, and more precisely the products sold under the trade marks EUDRAGIT ® RS and/or RL, e.g.
  • EUDRAGIT ® RL PO and/or EUDRAGIT ® RS PO and/or the granules EUDRAGIT ® RL 100 and/or EUDRAGIT ® RS 100 and/or the suspensions and/or solutions of these EUDRAGIT ® RL and RS namely, respectively, EUDRAGIT® RL 30D and/or EUDRAGIT® RS 30D and/or EUDRAGIT® RL 12.5 and/or EUDRAGIT® RS 12.5;
  • nitrogenous (co)polymers preferably from the group comprising polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly- N-vinyllactams;
  • PVAs polyvinyl alcohols
  • * (D) is chosen from the group comprising:
  • glycerol and its esters preferably from the following subgroup: acetylated glycerides, glyceryl monostearate, glyceryl triacetate, glyceryl tributyrate,
  • phthalates preferably from the following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate,
  • citrates preferably from the following subgroup: acetyl tributyl citrate, acetyltriethyl citrate, tributyl citrate, triethyl citrate, • sebacates, preferably from the following subgroup: diethyl sebacate, dibutyl sebacate,
  • malates preferably diethyl malate
  • oxalates preferably diethyl oxalate
  • succinates preferably dibutyl succinate
  • * (E) is chosen from the group comprising: • anionic surfactants, preferably from the subgroup of alkali metal or alkaline- earth metal salts of fatty acids, stearic acid and/or oleic acid being preferred,
  • o polyoxyethylenated oils preferably polyoxyethylenated hydrogenated castor oil, o polyoxyethylene-polyoxypropylene copolymers, o polyoxyethylenated esters of sorbitan, o polyoxyethylenated derivatives of castor oil, o stearates, preferably calcium stearate, magnesium stearate, aluminium stearate or zinc stearate, o stearyl fumarates, preferably sodium stearyl fumarate, o glyceryl behenates, o and mixtures thereof.
  • o polyoxyethylenated oils preferably polyoxyethylenated hydrogenated castor oil, o polyoxyethylene-polyoxypropylene copolymers, o polyoxyethylenated esters of sorbitan, o polyoxyethylenated derivatives of castor oil, o stearates, preferably calcium stearate, magnesium ste
  • composition of the modified-release layer is as follows:
  • the film- forming polymer(s) (A) is (are) present in a proportion of 10 to 90%, preferably 40 to 80% by weight on a dry basis relative to the total mass of the coating composition;
  • the optional water-insoluble hydrophilic film-forming polymer(s) (B) is (are) present in a proportion of 10 to 90%, preferably 40 to 80% by weight on a dry basis relative to the total mass of the coating composition;
  • the polymer(s) (C) that is (are) soluble in the fluids of the gastrointestinal tract is (are) present in a proportion of 2 to 25, preferably 5 to 20% by weight on a dry basis relative to the total mass of the coating composition;
  • the plasticizer(s) (D) is (are) present in a proportion of 2 to 20, preferably of 4 to 15% by weight on a dry basis relative to the total mass of the coating composition;
  • the optional surfactant(s) and/or lubricant(s) (E) is (are) present in a proportion of 2 to 20, preferably of 4 to 15% by weight on a dry basis relative to the total mass of the coating composition.
  • the coating of the microcapsules with modified release of active principle(s) -e.g. ribavirin- has the following characteristics: O the coating for modified release of the active principle(s) -e.g. ribavirin-comprises a composite material ⁇ ⁇ comprising:
  • ⁇ ⁇ representing a mass fraction (% weight relative to the total mass of the microcapsules) ⁇ 40
  • O their mean diameter is less than 2000 ⁇ m, and preferably between 50 and 800 ⁇ m, and even more preferably between 100 and 600 ⁇ m.
  • the composite material A"B" for the coating for modified release of the active principle with low solubility is such that:
  • the B 1 VA" weight ratio is between 0.2 and 1.5, preferably between 0.5 and 1.0, ⁇ ⁇ and the hydrophobic compound B" is selected from products that are crystalline in the solid state and that have a melting point M pB > 40°C, preferably M pB >
  • the hydrophilic polymer A" is chosen from: A". a copolymers of (meth)acrylic acid and of (meth)acrylic acid alkyl ester, and mixtures thereof;
  • cellulose derivatives preferably cellulose acetates, cellulose phthalates, cellulose succinates and mixtures thereof, and even more preferably hydroxypropylmethylcellulose phthalates, hydroxypropylmethylcellulose acetates, hydroxypropylmethylcellulose succinates and mixtures thereof; and mixtures thereof.
  • the polymers A" that are even more preferred are copolymers of (meth)acrylic acid and of (meth)acrylic acid alkyl (e.g. C 1 -C 6 alkyl) esters. These copolymers are, for example, of the type of those sold by the company Rohm Pharma Polymers under the registered trade marks EUDRAGIT ® , series L and S (such as, for example, EUDRAGIT ® LlOO, SlOO, L30 D-55 and Ll 00-55). These copolymers are anionic enteric copolymers that are soluble in aqueous medium at pHs above those encountered in the stomach.
  • the compound B" is chosen from the group of products below:
  • B.b hydrogenated plant oils taken on their own or as mixtures with one another; B.c mono- and/or di- and/or triesters of glycerol and of at least one fatty acid;
  • the compound B is chosen from the group of following products: hydrogenated cottonseed oil, hydrogenated soybean seed oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, tristearin, tripalmitin, trimyristin, yellow wax, hard fat or fat that is useful as suppository bases, anhydrous milk fats, lanolin, glyceryl palmitostearate, glyceryl stearate, lauryl macrogolglycerides, cetyl alcohol, polyglyceryl diisostearate, diethylene glycol monostearate, ethylene glycol monostearate, omega-3 and any mixture thereof, preferably from the subgroup of following products: hydrogenated cottonseed oil, hydrogenated soybean seed oil, hydrogenated palm oil, glyceryl behenate, hydrogenated castor oil, tristearin, tripalmitin, trimyristin and any mixture thereof.
  • the compound B" is preferable for the compound B" to be chosen: O from the group of products sold under the following trade marks: Dynasan ® , Cutina ® , Hydrobase ® , Dub ® , Castorwax ® , Croduret ® , Compritol ® , Sterotex ® , Lubritab ® , Apifil ® , Akofine ® , Softtisan ® , Hydrocote ® , Livopol ® , Super Hartolan ® , MGLA ® , Corona ® , Protalan ® , Akosoft ® , Akosol ® , Cremao ® , Massupol ® , Novata ® , Suppocire ® , Wecobee ® , Witepsol ® , Lanolin ® , Incromega ® , Estaram ® , Suppo Stamms ® , Gelucire
  • Emulcire ® Plurol diisostearique ® , Geleol ® , Hydrine ® and Monthyle ® , and mixtures thereof;
  • the coating for modified release of the active principle -e.g. ribavirin- is free of talc.
  • the oral ribavirin composition according to the invention is particularly advantageous in that it can be provided in the form of a single or twice daily oral dose comprising o from 5000 to 50 000 microunits containing active principle(s) -e.g. ribavirin-, or o from 5000 to 50 000 microcapsules with modified release of active principle(s) -e.g. ribavirin-.
  • This plurality of microcapsules illustrated by the numerical examples mentioned above constitutes a pharmaceutical form that is perfectly well tolerated by the mammalian organism.
  • microcapsules are all the more advantageous since the production thereof is carried out simply and economically according to techniques well known to those skilled in the art, for example the technique of spray coating in a fluidized air bed, wet granulation, compacting, extrusion-spheronization, etc.
  • the coating of the microcapsules may comprise, besides the essential constituents, other conventional ingredients known to those skilled in the art, such as in particular: pigments or colorants, plasticizers, (for instance dibutyl sebacate), hydrophilic compounds (for instance cellulose and its derivatives or polyvinylpyrrolidone and its derivatives and mixtures thereof), fillers, anti- foaming agents...
  • pigments or colorants for instance dibutyl sebacate
  • hydrophilic compounds for instance cellulose and its derivatives or polyvinylpyrrolidone and its derivatives and mixtures thereof
  • fillers for instance anti- foaming agents.
  • the composition of the invention is characterized in that the microcapsule coating responsible for the modified release of ribavirin consists of a single coating layer or a single coating film.
  • the coating monolayer can represent, for example, at most 40%, preferably at most 30%, by weight of the microcapsules.
  • Such a limited amount of coating makes it possible to produce pharmaceutical units each containing a high dose of active principle, without exceeding a size that is totally unacceptable with regard to swallowing.
  • Such limited coating levels make it possible to produce pharmaceutical units each containing a high dose of ribavirin, without exceeding a size that is totally unacceptable with regard to swallowing.
  • this coating A(B:optional)CD(E:optional) can be an impermeable coating having e.g. the following composition (in % by weight on a dry basis relative to the total mass of the coating composition): A. 50 to 90, preferably 40 to 80 ; B. 0
  • the active principle is deposited onto the core by means of techniques known to those skilled in the art, for example the technique of "spray coating' in a fluidized air bed, wet granulation, compacting, extrusion-spheronization, etc.
  • composition according to the invention may comprise, besides microunits consisting of microcapsules with modified release of ribavirin, microunits of ribavirin other than microcapsules. They could, for example, be microparticles with immediate release of ribavirin and/or of one or more other active principle(s). These immediate-release microparticles are advantageously noncoated and may be of the same type as those used in the preparation of the microcapsules according to the invention.
  • microunits (microparticles and/or microcapsules) constituting the composition according to the invention may be made up of various populations of microunits, these populations differing from one another at least through the nature of the active principle(s) other than ribavirin contained in these microunits and/or through the amount of ribavirin or of other optional active principle(s) that they contain and/or through the composition of the coating and/or through the fact that they are modified-release or immediate-release populations.
  • the microunits containing active principle(s) with immediate release are noncoated microparticles.
  • composition according to the invention can be provided in the form of a sachet of powder, of a powder for multidose suspension to be reconstituted of a liquide suspension, of a tablet or of a gelatin capsule.
  • the tablet can be advantageously an orally dispersible tablet.
  • the gelatin capsules can contain for example microcapsules.
  • These tablets, these gelatin capsules, these powders and these suspensions may consist of mixtures of the various populations of microunits, and in particular of microcapsules of active principle(s) according to the invention, preferably combining therewith microunits or microparticles with immediate release of active principle(s) -e.g. ribavirin- (for example granules).
  • active principle(s) e.g. ribavirin- (for example granules).
  • the invention can be directed towards the use of the microcapsules with modified release of the active principle(s) as defined above, and, optionally, of the microunits containing active principle(s) with immediate release, for preparing pharmaceutical or dietetic, microparticulate oral pharmaceutical forms, preferably in the form of tablets, that are advantageously orally dispersible, of powders or of gelatin capsules. It should be noted that it may be advantageous to mix, in the same gelatin capsule, the same tablet or the same powder for oral suspension, at least two types of microcapsules with different ribavirin release kinetics, but that are included within the characteristic framework of the invention.
  • composition containing or not the microcapsules with modified release of ribavirin also comprise pharmaceutically acceptable excipients that are conventional and known to those skilled in the art, useful for example for presenting the microcapsules in tablet form.
  • these excipients may in particular be:
  • ⁇ tableting agents such as microcrystalline cellulose or mannitol
  • ⁇ lubricants for instance glyceryl behenate
  • composition product When the composition product is in the form of a tablet, this can be coated according to the techniques and formulations known to those skilled in the art for improving its presentation: colour, appearance, taste masking, etc.
  • composition according to the invention can advantageously comprise a daily dose comprised between:
  • the daily dose can be chosen in the group of daily doses (mg) comprising: 400, 800, 1200, 2000 and 3000.
  • novel ribavirin-based compositions according to the invention are original in terms of their structure, their presentation and their composition and can be administered per os, in particular by means of single or twice daily doses, for example the doses as above defined.
  • the oral ribavirin composition according to the provided in the form of a unit dosage adapted for a single or a twice daily oral administration.
  • the invention also relates to the microcapsules per se as defined above.
  • the invention is also directed towards method of treating viral infections in a patient comprising administering to said patient the oral ribavirin composition according to the invention.
  • this method comprises co-administering to the patient, a therapeutically effective amount of at least an interferon.
  • this method is a method of treating hepatitis C.
  • the invention is directed towards the use of the oral ribavirin composition as defined above, for preparing pharmaceutical or dietetic, (e.g. microparticulate), oral galenical forms, preferably in the form of tablets, of powders for oral suspension, of stable liquid suspension or of gelatin capsules.
  • pharmaceutical or dietetic e.g. microparticulate
  • oral galenical forms preferably in the form of tablets, of powders for oral suspension, of stable liquid suspension or of gelatin capsules.
  • Example 1 Preparation of 200 mg ribavirin capsule
  • 720 g of ribavirin and 80 g of hydroxypropylcellulose (Klucel® EF) are dispersed in 1800 g of water.
  • the suspension is then sprayed onto 200 g of cellulose spheres in a Glatt® GPCGl fluidized air bed equipment.
  • step 1 850.0 g of granules obtained in step 1 are coated with 105 g of ethylcellulose
  • step 2 326 mg of microparticles obtained in step 2 are filled in size 1 gelatin capsule.
  • This capsule contains 200 mg of ribavirin and constitutes the final product.
  • ribavirin and 100 g of hydroxypropylcellulose are mixed in a high shear granulator (Aeromatic PMAl) during 5 minutes. This mix is then granulated by adding
  • step 2 247 mg of microparticles obtained in step 2 are filled in size 2el gelatin capsule.
  • This capsule contains 200 mg of ribavirin and constitutes the final product.
  • 920 g of ribavirin and 80 g of hydroxypropylcellulose (Klucel® EF) are mixed in a high shear granulator (Aeromatic PMAl) during 5 minutes. This mix is then granulated by adding 200 g of water. The product is dried at 40°C in a ventilated oven and shifted on a 500 ⁇ m grid.
  • fraction between 200 and 500 ⁇ m is selected by sieving.
  • step 2 271 g of microparticles obtained in step 2 are mixed with 12O g of microcrystalline cellulose
  • Tablets of 680 mg are produced from the above blend in a Korsch alternating press. These tablets contains 200 mg of ribavirin and constitutes the final product.

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Abstract

Cette invention concerne des compositions pharmaceutiques à administration par voie orale servant à la prévention et/ou au traitement des maladies virales. Cette invention concerne également des procédés de prévention et/ou de traitement de ces maladies virales utilisant de telles compositions à administration par voie orale. L'un des principaux problèmes considérés dans la présente invention est d'améliorer l'efficacité des traitements antiviraux, notamment contre l'hépatite C, au moyen de la ribavirine, par exemple associée à l'interféron. Une telle composition antivirale de ribavirine à administration par voie orale augmente le temps de bio-absorption de la ribavirine et, par conséquent, améliore le traitement des patients. Cette composition comprend au moins une forme posologique de ribavirine à libération modifiée dans le temps de bio-absorption BAT est supérieur au temps de bio-absorption BAT* d'une forme posologique de ribavirine à libération immédiate de référence* administrée à la même dose; le temps BAT étant de préférence compris entre 2 et 15 heures et plus préférablement entre 4 et 12 heures. Cette composition est constituée par une forme posologique de type réservoir ou par une forme posologique de type matriciel. Cette composition est constituée par un système de rétention gastrique ou par une forme posologique multiparticulaire.
PCT/IB2005/054434 2005-06-09 2005-06-09 Composition pharmaceutique de ribavirine a administration par voie orale WO2006131790A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/IB2005/054434 WO2006131790A2 (fr) 2005-06-09 2005-06-09 Composition pharmaceutique de ribavirine a administration par voie orale
PCT/EP2006/063070 WO2006131566A2 (fr) 2005-06-09 2006-06-09 Compositions pharmaceutiques orales a base de ribavirine
JP2008515226A JP2009514784A (ja) 2005-06-09 2006-06-09 経口リバビリン医薬組成物
CA002609998A CA2609998A1 (fr) 2005-06-09 2006-06-09 Compositions pharmaceutiques orales a base de ribavirine
EP06763633A EP1888047A2 (fr) 2005-06-09 2006-06-09 Compositions pharmaceutiques orales a base de ribavirine

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PCT/IB2005/054434 WO2006131790A2 (fr) 2005-06-09 2005-06-09 Composition pharmaceutique de ribavirine a administration par voie orale

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FR2945947B1 (fr) * 2009-05-29 2011-07-29 Flamel Tech Sa Compositions pharmaceutiques flottantes a liberation controlee
EP2959888A1 (fr) * 2014-06-23 2015-12-30 Sanovel Ilac Sanayi ve Ticaret A.S. Nouvelle composition pharmaceutique de sofosbuvir et ribavirine
EA201692514A1 (ru) * 2014-06-23 2017-04-28 Сановель Илач Санайи Ве Тиджарет А.Ш. Фармацевтические композиции на основе софосбувира и рибавирина с модифицированным высвобождением
CN108354000B (zh) * 2018-04-19 2021-12-28 西安工程大学 用于生鲜农产品保鲜的缓、控释微胶囊及其制备方法

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US6022562A (en) * 1994-10-18 2000-02-08 Flamel Technologies Medicinal and/or nutritional microcapsules for oral administration
US20030104056A1 (en) * 2000-10-13 2003-06-05 Rudnic Edward M. Delayed release anti-viral product, use and formulation thereof
US20050019406A1 (en) * 2002-09-19 2005-01-27 Three Rivers Pharmaceuticals, Llc Composition containing ribavirin and use thereof
WO2005016370A1 (fr) * 2003-08-13 2005-02-24 Howard J. Smith & Associates Pty Ltd Methode de traitement d'infections virales

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US8101209B2 (en) * 2001-10-09 2012-01-24 Flamel Technologies Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles
FR2837100B1 (fr) * 2002-03-18 2004-07-23 Flamel Tech Sa Comprimes a bases de microcapsules a liberation modifiee

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US6022562A (en) * 1994-10-18 2000-02-08 Flamel Technologies Medicinal and/or nutritional microcapsules for oral administration
US20030104056A1 (en) * 2000-10-13 2003-06-05 Rudnic Edward M. Delayed release anti-viral product, use and formulation thereof
US20050019406A1 (en) * 2002-09-19 2005-01-27 Three Rivers Pharmaceuticals, Llc Composition containing ribavirin and use thereof
WO2005016370A1 (fr) * 2003-08-13 2005-02-24 Howard J. Smith & Associates Pty Ltd Methode de traitement d'infections virales

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DATABASE CA [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; TAO, XIUMEI ET AL: "Preparation of ribavirin sustained - release pellets by centrifugal granulation technology" XP002395860 retrieved from STN Database accession no. 2005:500395 & ZHONGGUO YAOXUE ZAZHI (BEIJING, CHINA) , 39(12), 925-927 CODEN: ZYZAEU; ISSN: 1001-2494, 2004, *

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JP2009514784A (ja) 2009-04-09
CA2609998A1 (fr) 2006-12-14
EP1888047A2 (fr) 2008-02-20
WO2006131566A3 (fr) 2007-04-12
WO2006131790A3 (fr) 2007-07-05

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