EP1904071A2 - Compositions de compose antiviral - Google Patents

Compositions de compose antiviral

Info

Publication number
EP1904071A2
EP1904071A2 EP06765637A EP06765637A EP1904071A2 EP 1904071 A2 EP1904071 A2 EP 1904071A2 EP 06765637 A EP06765637 A EP 06765637A EP 06765637 A EP06765637 A EP 06765637A EP 1904071 A2 EP1904071 A2 EP 1904071A2
Authority
EP
European Patent Office
Prior art keywords
ribavirin
free flowing
composition
combination
prepared
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.)
Withdrawn
Application number
EP06765637A
Other languages
German (de)
English (en)
Inventor
Amod Vishvanath Aurobindo Pharma Limited DHABU
Mohinder Paul Aurobindo Pharma Limited PAKHETRA
Ashish Aurobindo Pharma Limited GOGIA
Sivakumaran Aurobindo Pharma Ltd MEENAKSHISUNDERAM
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.)
Aurobindo Pharma Ltd
Original Assignee
Aurobindo Pharma Ltd
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 Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of EP1904071A2 publication Critical patent/EP1904071A2/fr
Withdrawn legal-status Critical Current

Links

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
    • 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

Definitions

  • the present invention relates to composition of an anti-viral compound. More particularly, the present invention relates to compositions comprising free flowing ribavirin.
  • the present invention also relates to a process for the preparation of compositions comprising free flowing ribavirin.
  • Ribavirin is a synthetic nucleoside analog with broad-spectrum antiviral activity and known to be useful in the treatment of hepatitis C as well as various other disease states. Chemically, ribavirin is l-( ⁇ )-D-ribofuranosyl-lH-l,2,4- triazole-3-carboxamide and is commercially available in the US as tablets under the trade name of Copegus®; as capsule and oral solution under the trade name of Rebetol® and as inhalation solution under the trade name of Virazole®. Ribavirin is currently indicated for use as a combination therapy with interferon for Hepatitis C.
  • Ribavirin is administered in large dosages, e.g., a dose as large as 1200 mg per day, together with interferon injections.
  • Ribavirin is a colorless, water-soluble, stable material and is known to have two polymorphic forms. It is very fluffy, non- free flowing powder, which makes it difficult for filling in capsules or as such compressing into tablets. Even after mixing ribavirin with fillers and lubricants, the composition cannot have sufficient flow and density of blend is not suitable for filling into capsules or compressing into tablets.
  • US patent Nos. 5,914,128; 5,916,594; 6,051,252; 6,335,032; and 6,337,090 disclose rapidly dissolving compacted ribavirin composition comprising ribavirin and disintegrant and further disclose the composition having a tap density of at least about 0.6 g/mL.
  • Dry compaction utilizes high pressure to form a ribbon of ribavirin that is subsequently reduced to a free flowing powder by milling.
  • the undesirable side effects of manufacturing ribavirin by dry compaction include creation of excessive dust, a potential health hazard, as well as the risk that high pressure, which can produce high heat, may change the polymorphic forms of ribavirin, which are unacceptable for obtaining health registration.
  • ribavirin is marketed in Canada as capsules under trade name Virazole®.
  • the ribavirin composition used in Virazole® capsules is a non-free flowing powder with low and variable tap densities in the range of 0.320 to 0.449 g/mL, and comprises lactose monohydrate, microcrystalline cellulose, and magnesium stearate as excipients. It is further disclosed that it would be desirable for the ribavirin composition to have a uniformly high tap density of at least 0.6 g/mL to fill any capsule and to avoid excessive weight variation and suggested the dry compaction method to improve the flow.
  • ribavirin formulation technologies some of them are as given below:
  • US patent No. 6,720,000 disclose a process for preparing ribavirin pellets by extrusion and spheronization. However, the pellets prepared by this method are costlier and time consuming.
  • US 2003/0104050 disclose quick dissolving ribavirin composition prepared by a process comprising mixing ribavirin, disintegrant, filler to form an homogenous mixture; granulating the mixture with water; drying the granules; and mixing the dried granules with disintegrant and lubricant.
  • WO 2004/096187 disclose 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 by wet granulation of a mixture of ribavirin, wetted with water, 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.
  • EP 1455801 discloses a process for preparing ribavirin granules, comprising preparing granulate solution which involves mixing of a binding agent with an isopropanol/water or ethanol/water-mixture, then stirring the granulate solution into a mixture of ribavirin-powder with sieving and drying the granulates.
  • the main objective of the present invention is to provide composition comprising free flowing ribavirin.
  • Another embodiment of the present invention is to provide simple, cost effective and efficient process for preparing ribavirin composition.
  • Yet another objective of the present invention is to provide ribavirin composition in such a way that it will comply with the reference product in terms of in vitro parameters like dissolution, disintegration, etc and in vivo parameters like bioequivalence.
  • the invention provides a composition comprising free flowing ribavirin and one or more pharmaceutically acceptable excipients, wherein the free flowing ribavirin is prepared by agglomerating the non-free flowing ribavirin using a solvent or by controlling the crystallization during synthesis of ribavirin.
  • the invention also provides a process for preparing ribavirin compositions wherein the composition is prepared by mixing free flowing ribavirin with one or more excipients and finally filling into capsules or compressing into tablets.
  • the present invention describes a composition comprising free flowing ribavirin prepared by a simple process from non free flowing ribavirin without using any excipients or procedures where high pressure is required such as compaction.
  • the free flowing ribavirin is prepared by dissolving ribavirin crude product in a mixture of water and methanol at 65 to 70 0 C. The resulting mixture is treated with charcoal and cooling the filtrate slowly at 50 to 70 0 C, at which temperature the product starts crystallizing resulting into a slurry. Maintaining such slurry at this temperature without agitation for 15-20 min for formation of crystals and stirring for 2.0 hrs and drying the product to obtain free flowing crystals of ribavirin.
  • the free flowing ribavirin is also prepared by adding solvent to non-free flowing ribavirin powder in a mixer, kneading the wet mass, sieving the wet agglomerate, and drying the wet agglomerate at 60 to 80 0 C. The dried granules are shifted through suitable sieves to obtain free flowing ribavirin.
  • the free flowing ribavirin used according to the present invention has bulk density not less than 0.36g/ml and not more than 0.66g/ml, tapped density of not less than 0.4g/ml and not more than 0.8g/ml.
  • the particle size of the free flowing ribavirin used is not more than 600 ⁇ m.
  • the ribavirin prepared by process of the present invention is uniform, free flowing, and have adequate bulk and tapped density for processing into capsules or tablets.
  • the ribavirin compositions are substantially free of polymorphic forms of ribavirin, i.e., there are no signs of change in polymorphic nature of ribavirin.
  • the ribavirin composition of the present invention may be filled into capsules, compressed into conventional or sustained release tablets.
  • the ribavirin composition of the present invention comprises one or more pharmaceutically acceptable excipients selected from fillers, disintegrants, binders, lubricants, glidants, polymers and the like.
  • the sustained release tablets further comprise polymers selected from hydoxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, and polyethylene oxide or a combination thereof.
  • the ribavirin composition of present invention complies with the reference product in terms of in vitro parameters like dissolution, disintegration, etc and in vivo parameters like bioequivalence.
  • Suitable solvents used for preparing free flowing ribavirin include water, acetonitrile, acetone, chloroform, methylene chloride, methanol, ethanol, and isopropanol or a combination thereof.
  • Suitable fillers used according to the present invention are selected from lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, dibasic calcium phosphate dihydrate, calcium carbonate, dextrose, sucrose, mannitol, and sorbitol or a combination thereof.
  • Suitable disintegrants used according to the present invention are selected from croscarmellose sodium, sodium starch glycolate, crospovidone, pregelatinized starch, and sodium carboxymethyl cellulose or a combination thereof.
  • Suitable binders of the invention are selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, starch, pregelatinized starch or a combination thereof.
  • Suitable lubricants used according to the present invention are selected from magnesium stearate, calcium stearate, zinc stearate, talc, stearic acid, vegetable oil, and sodium lauryl sulfate or a combination thereof.
  • Suitable glidants used according to the present invention are selected from magnesium trisilicate, talc, and colloidal silicon dioxide or a combination thereof.
  • ribavirin capsules The processing steps involved in manufacturing ribavirin capsules are : i) free flowing ribavirin was loaded in a blender, ii) lactose, microcrystalline cellulose, croscarmellose sodium and povidone were added to free flowing ribavirin and mixed, iii) lubricated the blend obtained from step (ii) with magnesium stearate, and iv) filled the uniform blend into capsules.
  • ribavirin immediate release tablets The processing steps involved in manufacturing ribavirin immediate release tablets are : i) free flowing ribavirin was loaded in a blender, ii) pregelatinized starch, microcrystalline cellulose, croscarmellose sodium and povidone were added to free flowing ribavirin and mixed the blend, iii) lubricated the blend obtained from step (ii) with magnesium stearate, and iv) compressed the blend to obtain tablets.
  • ribavirin sustained release tablets The processing steps involved in manufacturing ribavirin sustained release tablets are: i) free flowing ribavirin was loaded in a blender, ii) pregelatinized starch, microcrystalline cellulose, polymers, and povidone were added to free flowing ribivirin of step (i) and mixed the blend, iii) lubricated the blend obtained from step (ii) with magnesium stearate, and iv) compressed the blend to obtain sustained release tablets.
  • the dissolution studies were performed in 900 ml of water, at 100 RPM by USP I method.
  • the release profile (% of drug released in minutes) is given in table 1.

Landscapes

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

Abstract

L'invention concerne une composition pharmaceutique orale qui renferme de la ribavirine fluide et au moins un excipient acceptable sur le plan pharmaceutique. La ribavirine fluide est obtenue par agglomération de la ribavirine non fluide au moyen d'un solvant ou par la surveillance de la cristallisation au cours de la synthèse de la ribavirine.
EP06765637A 2005-07-08 2006-07-05 Compositions de compose antiviral Withdrawn EP1904071A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN906CH2005 2005-07-08
PCT/IB2006/001952 WO2007007183A2 (fr) 2005-07-08 2006-07-05 Compositions de compose antiviral

Publications (1)

Publication Number Publication Date
EP1904071A2 true EP1904071A2 (fr) 2008-04-02

Family

ID=37564409

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06765637A Withdrawn EP1904071A2 (fr) 2005-07-08 2006-07-05 Compositions de compose antiviral

Country Status (2)

Country Link
EP (1) EP1904071A2 (fr)
WO (1) WO2007007183A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60101056T2 (de) * 2001-07-30 2004-05-19 Clariant Life Science Molecules (Italia) S.P.A., Origgio Verfahren zur Herstellung von Ribavirin
ATE290387T1 (de) * 2001-12-21 2005-03-15 Biopartners Gmbh Ribavirin-granulat zur herstellung von filmtabletten
US20040258751A1 (en) * 2002-09-19 2004-12-23 Kerrish Donald J. Composition containing ribavirin and use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007007183A3 *

Also Published As

Publication number Publication date
WO2007007183A2 (fr) 2007-01-18
WO2007007183A3 (fr) 2007-08-23

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