EP1904071A2 - Compositions of antiviral compound - Google Patents
Compositions of antiviral compoundInfo
- 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- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims description 52
- 230000000840 anti-viral effect Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 title description 3
- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 claims abstract description 89
- 229960000329 ribavirin Drugs 0.000 claims abstract description 80
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 claims abstract description 80
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 7
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 5
- 238000002425 crystallisation Methods 0.000 claims abstract description 5
- 230000008025 crystallization Effects 0.000 claims abstract description 5
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 18
- 239000002775 capsule Substances 0.000 claims description 13
- 239000003826 tablet Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- 229920000881 Modified starch Polymers 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000008187 granular material Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- 239000007884 disintegrant Substances 0.000 claims description 7
- 239000000945 filler Substances 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical group [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 239000007939 sustained release tablet Substances 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 239000002002 slurry Substances 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- 229960001375 lactose Drugs 0.000 claims description 3
- 238000007873 sieving Methods 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 229940032147 starch Drugs 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- 235000012222 talc Nutrition 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 239000004368 Modified starch Substances 0.000 claims description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 239000003610 charcoal Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000004898 kneading Methods 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 235000019426 modified starch Nutrition 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 2
- 239000008158 vegetable oil Substances 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- 238000005054 agglomeration Methods 0.000 claims 2
- 230000002776 aggregation Effects 0.000 claims 2
- 239000008203 oral pharmaceutical composition Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 8
- 238000002156 mixing Methods 0.000 description 6
- 238000005056 compaction Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000011049 filling Methods 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- 229940100050 virazole Drugs 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- 208000005176 Hepatitis C Diseases 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229940033134 talc Drugs 0.000 description 2
- SJCDBQHCQSIZHN-UHFFFAOYSA-N 1,2-dihydrotriazole-3-carboxamide Chemical compound NC(=O)N1NNC=C1 SJCDBQHCQSIZHN-UHFFFAOYSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940055354 copegus Drugs 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 231100000206 health hazard Toxicity 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229940041682 inhalant solution Drugs 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940053146 rebetol Drugs 0.000 description 1
- 229940032154 ribavirin 200 mg Drugs 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 238000005563 spheronization Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
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
An oral pharmaceutical 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.
Description
COMPOSITIONS OF ANTIVIRAL COMPOUND
Field of the invention
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.
Background of the invention
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-(β)-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. As such, 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.
It is disclosed in US 5,914,128 patent that 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. There are few other patents/publications which disclose 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 above prior art references discloses various technologies for preparing ribavirin composition. However, still there is a need for making ribavirin composition, which involves simple process and does not involve high pressure compaction process and costlier pelletization technique. The inventors of the present invention during their continuous effort to develop ribavirin compositions, found that blending of free flowing ribavirin with other excipients produces composition which have uniform dissolution profile and does not cause the formation of undesired ribavirin polymorphic forms.
Objective of the invention
Accordingly, the main objective of the present invention is to provide composition comprising free flowing ribavirin.
Yet, 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. Summary of the Invention
Accordingly, to the main embodiment, 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.
Detailed description of the invention
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 0C. The resulting mixture is treated with charcoal and cooling the filtrate slowly at 50 to 70 0C, 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 0C. The dried granules are shifted through suitable sieves to obtain free flowing ribavirin.
In an embodiment of the present invention, 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.
In yet another embodiment of the present invention, the particle size of the free flowing ribavirin used is not more than 600 μm.
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. Furthermore, the ribavirin compositions are substantially free of polymorphic forms of ribavirin, i.e., there are no signs of change in polymorphic nature of ribavirin.
In an embodiment, the ribavirin composition of the present invention may be filled into capsules, compressed into conventional or sustained release tablets.
In an embodiment, 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.
The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.
Example 1
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.
The capsules disclosed in the following examples are prepared by similar process described in example 1.
Example 2
Ribavirin capsules
Example 3
Ribavirin capsules
Example 4
Immediate release ribavirin tablets
S. No. Ingredient Qty/capsule
1 Free flowing Ribavirin 200 mg
Pregelatinized starch 20 to 50 mg
Microcrystalline cellulose 50 to 100 mg
Sodium starch glycolate 6 to 30 mg
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.
The immediate release tablets disclosed in the following examples are prepared by similar process described in example 4.
Example 5
Immediate release ribavirin tablets
Example 6
Immediate release ribavirin tablets
Example 7
Sustained release Ribavirin 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.
Dissolution profile :
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.
Table I
Claims
1. 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.
2. The free flowing ribavirin as claimed in claim 1," prepared by crystallization process.
3. The crystallization process as claimed in claim 2, comprises the steps of dissolving ribavirin crude product in a mixture of water and methanol at 65 to 70 0C, treating the resulting mixture with charcoal, cooling the filtrate slowly at 50 to 70 0C to form a slurry, maintaining the slurry at this temperature without agitation for 15-20 min to form crystals, stirring for 2.0 hrs and drying the crystals.
4. The free flowing ribavirin as claimed in claim I5 prepared by agglomeration process.
5. The agglomeration process as claimed in claim 4, comprises the steps of adding solvent to non free flowing ribavirin powder in a mixer, kneading the wet mass, sieving the wet agglomerate, drying at 60 to 80 0C and sifting the dried the granules through sieves.
6. The process as claimed in claim 3, wherein the solvent used is selected from water, acetonitrile, acetone, chloroform, methylene chloride, methanol, ethanol, isopropanol or a combination thereof.
7. The free flowing ribavirin as claimed in claim 1, having 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 and
8. The free flowing ribavirin as claimed in claim 1, has a particle size of less than 600 μm.
9. The composition as claimed in claim 1, wherein pharmaceutically acceptable excipient is selected from fillers, disintegrants, binders, glidants and lubricants.
10. The composition as claimed in claim 9, wherein filler is selected from lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, dibasic calcium phosphate dihydrate, calcium carbonate, dextrose, sucrose, mannitol, sorbitol or a combination thereof.
11. The composition as claimed in claim 9, wherein disintegrant is selected from croscarmellose sodium, sodium starch glycolate, crospovidone, pregelatinized starch, sodium carboxymethyl cellulose or a combination thereof.
12. The composition as claimed in claim 9, wherein lubricant is selected from magnesium stearate, calcium stearate, zinc stearate, talc, stearic acid, vegetable oil, sodium lauryl sulfate or a combination thereof.
13. The composition as claimed in claim 1, is in the form of capsules, immediate release tablets or sustained release tablets.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN906CH2005 | 2005-07-08 | ||
| PCT/IB2006/001952 WO2007007183A2 (en) | 2005-07-08 | 2006-07-05 | Compositions of antiviral compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1904071A2 true EP1904071A2 (en) | 2008-04-02 |
Family
ID=37564409
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP06765637A Withdrawn EP1904071A2 (en) | 2005-07-08 | 2006-07-05 | Compositions of antiviral compound |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP1904071A2 (en) |
| WO (1) | WO2007007183A2 (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2208540T3 (en) * | 2001-07-30 | 2004-06-16 | Clariant Life Science Molecules (Italia) Spa | PROCEDURE FOR THE PREPARATION OF RIBAVIRINE. |
| JP4221299B2 (en) * | 2001-12-21 | 2009-02-12 | ビーオパルトナーズ ゲーエムベーハー | Ribavirin granules for film tablet production |
| WO2004026261A2 (en) * | 2002-09-19 | 2004-04-01 | Three Rivers Pharmaceuticals, Llc | Composition containing ribavirin and use thereof |
-
2006
- 2006-07-05 EP EP06765637A patent/EP1904071A2/en not_active Withdrawn
- 2006-07-05 WO PCT/IB2006/001952 patent/WO2007007183A2/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2007007183A3 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2007007183A2 (en) | 2007-01-18 |
| WO2007007183A3 (en) | 2007-08-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7642149B2 (en) | New pharmaceutical compositions | |
| US6511681B2 (en) | Aqueous solubility pharmaceutical formulations | |
| AU2009236289B2 (en) | Oral pharmaceutical compositions in a solid dispersion comprising preferably posaconazole and HPMCAS | |
| JP4875001B2 (en) | Wet granulation pharmaceutical composition of aripiprazole | |
| JP2020002149A (en) | High dosage strength tablets of rucaparib | |
| KR101613775B1 (en) | Fast release composition including melt granules of a moisture sensitive drug and process for manufacturing thereof | |
| AU2004238038A1 (en) | Bicalutamide forms, compositions, and processes thereof | |
| KR20230107902A (en) | Tablet formulation for cgrp-active compounds | |
| WO2008149338A2 (en) | Process for forming solid oral dosage forms of angiotensin ii receptor antagonists | |
| EP2203156A2 (en) | Candesartan cilexetil | |
| US6365196B1 (en) | Controlled release solid dosage forms of lithium carbonate | |
| JP3397385B2 (en) | Disintegration delay prevention tablets | |
| EP2946771B1 (en) | Water-dispersible tablet formulation comprising deferasirox | |
| WO2019012552A4 (en) | Compositions of ferric organic compounds | |
| EP1904071A2 (en) | Compositions of antiviral compound | |
| JP3896002B2 (en) | tablet | |
| CA3098208A1 (en) | Tablet compositions comprising abiraterone acetate | |
| WO2024030098A1 (en) | A tablet of tolvaptan and at least one binder processed with spray granulation | |
| EP4321154A1 (en) | A tablet of tolvaptan and at least one binder processed with spray granulation | |
| WO2023158411A1 (en) | A tablet of tolvaptan and at least one binder processed with wet granulation | |
| EP4479057A1 (en) | A tablet of tolvaptan and at least one binder processed with wet granulation | |
| WO2022029798A1 (en) | Pharmaceutical compositions comprising ribociclib | |
| JP2993321B2 (en) | Anticancer composition for oral administration | |
| JP2024531701A (en) | Bempedoic acid pharmaceutical composition | |
| WO2025018960A1 (en) | A film coated tablet of brivaracetam |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
| 17P | Request for examination filed |
Effective date: 20071221 |
|
| AK | Designated contracting states |
Kind code of ref document: A2 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR |
|
| DAX | Request for extension of the european patent (deleted) | ||
| 17Q | First examination report despatched |
Effective date: 20090812 |
|
| DAX | Request for extension of the european patent (deleted) | ||
| STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
| 18D | Application deemed to be withdrawn |
Effective date: 20140201 |