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WO2010062996A2 - Composition de ribavirine - Google Patents

Composition de ribavirine Download PDF

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Publication number
WO2010062996A2
WO2010062996A2 PCT/US2009/065992 US2009065992W WO2010062996A2 WO 2010062996 A2 WO2010062996 A2 WO 2010062996A2 US 2009065992 W US2009065992 W US 2009065992W WO 2010062996 A2 WO2010062996 A2 WO 2010062996A2
Authority
WO
WIPO (PCT)
Prior art keywords
composition
ribavirin
granules
binder
dried
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2009/065992
Other languages
English (en)
Other versions
WO2010062996A3 (fr
Inventor
Ashok Katdare
Kavita Vermani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adamas Pharmaceuticals Inc
Original Assignee
Adamas Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Adamas Pharmaceuticals Inc filed Critical Adamas Pharmaceuticals Inc
Publication of WO2010062996A2 publication Critical patent/WO2010062996A2/fr
Publication of WO2010062996A3 publication Critical patent/WO2010062996A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K9/14—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

Definitions

  • the field of the invention is a method of making a ribavirin composition suitable for oral administration.
  • Ribavirin has been approved in the United States for the treatment of hepatitis C virus and respiratory syncytial virus.
  • the active pharmaceutical ingredient (API) is a white crystalline powder that is freely soluble in water.
  • ribavirin is typically processed with excipients to improve flowability and density properties. Examples of such processes include compaction (e.g. see US Pat. No. 6,335,032 to Schering et al.) and wet granulation (e.g. see US Pat. No. 6,720,000, to Kerrish et al, and US Pat Appl No. 2005/0123612 to Sobel et al.). These methods involve multiple processing steps and require the use of several types of excipients.
  • One aspect of the invention is a method of making a ribavirin composition, the method comprising: (a) combining ribavirin with a binder to produce ribavirin granules; and (b) drying the ribavirin granules.
  • the binder is selected from hydroxypropylmethyl cellulose and hydroxyethyl cellulose.
  • the dried ribavirin granules may consist essentially of the ribavirin and the binder.
  • the dried granules comprise less than 1.5 wt.% binder.
  • the method may further comprise passing the dried granules through a sieve or blending the ribavirin granules with excipients.
  • the excipients comprise less than 40 wt.% or 30 wt.% of the composition.
  • the granules may be filled into capsules or compressed into tablets.
  • Another aspect of the invention is a ribavirin composition comprising granules consisting essentially of ribavirin and a soluble binder. In various embodiments, the granules are less than 1.2 mm or 0.8 mm.
  • the composition may comprise one or more extragranular ingredients.
  • An extragranular ingredient may include an additional active pharmaceutical ingredient, such as an additional antiviral agent.
  • the extragranular ingredients comprise less than 40 wt.% or 30 wt.% of the composition.
  • the composition may be filled into a capsule or compressed into tablets.
  • One aspect of the invention is a method of making a ribavirin composition by combining ribavirin with a binder to make granules.
  • ribavirin refers to l-( ⁇ -D-Ribofuranosyl)-lH-l,2,4-triazole-3-carboxamide and salts and derivatives thereof (e.g. the 3-carboxamidine derivative, viramidine).
  • the binder can be prepared as a solution that is combined with the ribavirin by spraying or pouring over the ribavirin and mixed to form a wet mass. The wet mass is then dried using conventional drying equipment such as a fluidized bed drier, tray drier etc.
  • ribavirin is granulated with a binder solution in a fluidized bed drier where the binder solution is sprayed on ribavirin and the wet mass is dried simultaneously.
  • the binder solution is preferably prepared with a fully-soluble binder.
  • Suitable water- and/or alcohol-soluble binders include hydroxypropylmethyl cellulose, hydroxyethyl cellulose, povidone, gums such as acacia, tragacanth, xanthan gum, gelatin, ethyl cellulose and polymethacrylates. Sufficient amounts of water and/or alcohol are added to the binder to make a sprayable or pourable solution.
  • the binder can be partially soluble or swellable such as starch (starch paste).
  • starch starch paste
  • the amount of water and/or alcohol in the binder solution or paste will be about 10-40 wt.% or 15-35 wt.% of the total wet mass.
  • the binder solution or paste is preferably sprayed or poured directly onto ribavirin while mixing, without additional excipients, to result in granules that consist essentially of the ribavirin and the binder.
  • the granules are then dried.
  • large granules or clumps of granules can be removed by passing the granules through a sieve to obtain a granule size of less than 2.0 mm, and preferably less than 1.5 mm, 1.2 mm, 1.0 mm, 0.8 mm, or 0.6 mm.
  • the ribavirin granules may be filled directly into capsules or compressed into tablets.
  • the granules are blended with extragranular ingredients that improve the ability of the composition to be filled into capsules or compressed into tablets, or contribute to or impart other desired properties such as dissolution properties, stability, taste, etc.
  • Exemplary ingredients include soluble fillers (e.g. lactose, mannitol), insoluble fillers (e.g. calcium phosphate or dicalcium phosphate, microcrystalline cellulose typically in amounts of about 10-20% by weight of the total composition), polymers (e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, ethyl cellulose, EudragitTM, etc ), lubricants (e.g. talc, magnesium Stearate, sodium stearyl fumarate etc.), glidants (e.g. colloidal silicon dioxide), etc.
  • soluble fillers e.g. lactose, mannitol
  • insoluble fillers e.g. calcium phosphate or dicalcium phosphate, microcrystalline cellulose typically in amounts of about 10-20% by weight of the total composition
  • polymers e.g. hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, ethyl cellulose, Eu
  • the extragranular ingredients comprise less than 40 wt.%, and preferably less than 35 wt.%, 30 wt.%, or 25 wt.% of the total mass of the composition.
  • an extragranular ingredient may be one or more additional active pharmaceutical agent, such as an additional antiviral agent.
  • Another aspect of the invention is a ribavirin composition
  • a ribavirin composition comprising granules consisting essentially of ribavirin and a binder.
  • the granules preferably comprise less than 2.0 wt.%, 1.5 wt.%, or 1.0 wt.% binder.
  • the amount of binder in the granule is about 0.2 to about 2.0 wt.%, and preferably about 0.5 to about 1.0 wt.% .
  • substantially all the granules have a size less than 2.0 mm, 1.5 mm, 1.0 mm, 0.8 mm, or 0.6 mm.
  • the composition may additionally comprise one or more extragranular ingredients.
  • the extragranular ingredients comprise less than 40 wt.% of the composition, and more preferably, less than 35 wt.% , 30 wt.%, or 25 wt.% of the composition.
  • the drug composition comprises at least 70 wt.%, 75 wt.% or 80 wt.% ribavirin.
  • the composition has an in vitro dissolution profile for ribavirin of less than 80% in thirty minutes and more than 90% in sixty minutes as measured using a USP type 2 (paddle) apparatus at 50 rpm at a temperature of 37 ⁇ 5° C with 500 ml water as the dissolution medium.
  • the composition may be filled into capsules or sachets or compressed into tablets for oral administration.
  • an amount of the composition comprising at least 200 mg ribavirin is filled into a size 2 or 3 capsule.
  • the capsules or sachets may be opened and the contents sprinkled onto food such as applesauce or pudding for administration to patients who have difficulty swallowing pills.
  • the composition may be used for treatment of viral infections.
  • Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxypropylmethyl cellulose in water) in a high shear mixer and the resulting granules were dried in a fluidized bed drier. Extragranular excipients as shown in Table 1 below were added to the dried granules and the resulting blend was lubricated and filled in empty hard gelatin capsule shells.
  • Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixer and the resulting granules were dried in a fluidized bed drier. Extragranular excipients as shown in Table 2 below were added to the dried granules and the resulting blend was lubricated and filled in empty hard gelatin capsule shells. [023] Table 2
  • Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixer and the resulting granules were dried in a fluidized bed drier. Extragranular excipients as shown below were added to the dried granules and the resulting blend was lubricated and filled into empty hard gelatin capsule shells.
  • aqueous binder solution prepared by dissolving hydroxyethyl cellulose in water
  • Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixture. The wet mass (water content of 32.35%) was dried in a fluidized bed drier. The granules were sifted through mesh # 30 and had a bulk density - 0.56 g/ml, tapped density - 0.71 gm/ml and angle of repose - 37. The granules were blended with extragranular excipients as shown in table below and then lubricated.
  • the lubricated blend had a bulk density - 0.61 g/ml, tapped density - 0.75 gm/ml and angle of repose - 34.50.
  • the lubricated blend was filled into empty hard gelatin capsule shells of size 2.
  • Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixture. The wet mass (water content of 25.5%) was dried in a fluidized bed drier. The granules were sifted through #30 mesh and had a bulk density - 0.40 g/ml, tapped density - 0.60 gm/ml. The granules were blended with extragranular excipients as shown in table below, lubricated and filled into empty hard gelatin capsule shells of size 2.
  • Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixture. The wet mass (water content of 25.5%) was dried in a fluidized bed drier. The granules were sifted through #30 mesh and had a bulk density - 0.40 g/ml, tapped density - 0.60 gm/ml. The granules were blended with extragranular excipients as shown in table below, lubricated and filled into empty hard gelatin capsule shells of size 2.
  • Ribavirin was granulated using water as a granulating solvent in a high shear mixture. The wet mass was dried in a tray dryer. The granules were sifted through #30 mesh and had a bulk density - 0.50 g/ml. The granules were blended with extragranular excipients as shown in table below, lubricated and filled into empty hard gelatin capsule shells of size 2.
  • Ribavirin was granulated using water as a granulating solvent in a high shear mixture. The wet mass was dried in a tray dryer. The granules were sifted through #30 mesh and had a bulk density - 0.50 g/ml. The granules were blended with extragranular excipients as shown in table below, lubricated and filled into empty hard gelatin capsule shells of size 2. [045] Table 12
  • Ribavirin was granulated using an aqueous binder solution (prepared by dissolving hydroxyethyl cellulose in water) in a high shear mixer and the resulting granules were dried in a fluidized bed drier. Extragranular excipients as shown in Table 14 below were added to the dried granules and the resulting blend was lubricated and filled in empty hard gelatin capsule shells. [049] Table 14

Landscapes

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

Abstract

L’invention concerne une composition de Ribavirine de qualité pharmaceutique qui exige peu d’étapes de traitement et peu d’excipients, et qui assure une charge médicamenteuse élevée sous des formes pharmaceutiques par voie orale.
PCT/US2009/065992 2008-11-28 2009-11-25 Composition de ribavirine Ceased WO2010062996A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11858308P 2008-11-28 2008-11-28
US61/118,583 2008-11-28

Publications (2)

Publication Number Publication Date
WO2010062996A2 true WO2010062996A2 (fr) 2010-06-03
WO2010062996A3 WO2010062996A3 (fr) 2010-09-10

Family

ID=42226382

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/065992 Ceased WO2010062996A2 (fr) 2008-11-28 2009-11-25 Composition de ribavirine

Country Status (1)

Country Link
WO (1) WO2010062996A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106806345A (zh) * 2015-11-27 2017-06-09 北京科信必成医药科技发展有限公司 一种利巴韦林掩味颗粒及其制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6720000B2 (en) * 2001-03-19 2004-04-13 Three Rivers Pharmaceutical, Llc Process for producing wet ribavirin pellets
CA2465159A1 (fr) * 2001-11-02 2003-05-15 Sandoz Inc. Procede de preparation de compositions de ribavirine a charge elevee et a dissolution rapide
US7538094B2 (en) * 2002-09-19 2009-05-26 Three Rivers Pharmacueticals, Llc Composition containing ribavirin and use thereof
US20070166378A1 (en) * 2005-06-09 2007-07-19 Flamel Technologies, Inc. Oral ribavirin pharmaceutical compositions

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106806345A (zh) * 2015-11-27 2017-06-09 北京科信必成医药科技发展有限公司 一种利巴韦林掩味颗粒及其制备方法
CN106806345B (zh) * 2015-11-27 2020-10-13 北京科信必成医药科技发展有限公司 一种利巴韦林掩味颗粒及其制备方法

Also Published As

Publication number Publication date
WO2010062996A3 (fr) 2010-09-10

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