WO2004062552A2 - Pharmaceutical composition containing a nsaid and a benzimidazole derivative - Google Patents
Pharmaceutical composition containing a nsaid and a benzimidazole derivative Download PDFInfo
- Publication number
- WO2004062552A2 WO2004062552A2 PCT/BE2004/000003 BE2004000003W WO2004062552A2 WO 2004062552 A2 WO2004062552 A2 WO 2004062552A2 BE 2004000003 W BE2004000003 W BE 2004000003W WO 2004062552 A2 WO2004062552 A2 WO 2004062552A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- pharmaceutically acceptable
- derivative
- enteric coated
- oxicam
- Prior art date
Links
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 title description 10
- 239000003826 tablet Substances 0.000 claims abstract description 43
- 239000008188 pellet Substances 0.000 claims abstract description 35
- 239000002662 enteric coated tablet Substances 0.000 claims abstract description 34
- 238000000576 coating method Methods 0.000 claims abstract description 33
- 238000013270 controlled release Methods 0.000 claims abstract description 19
- 239000002552 dosage form Substances 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 95
- 150000001556 benzimidazoles Chemical class 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 49
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 41
- 239000002775 capsule Substances 0.000 claims description 40
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 28
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims description 27
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 27
- 229960000381 omeprazole Drugs 0.000 claims description 27
- 229960001929 meloxicam Drugs 0.000 claims description 26
- 239000011248 coating agent Substances 0.000 claims description 25
- 238000009505 enteric coating Methods 0.000 claims description 20
- 239000002702 enteric coating Substances 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 17
- 238000004090 dissolution Methods 0.000 claims description 14
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 claims description 13
- 229960002702 piroxicam Drugs 0.000 claims description 13
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 11
- 229940111133 antiinflammatory and antirheumatic drug oxicams Drugs 0.000 claims description 11
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 8
- 229960003943 hypromellose Drugs 0.000 claims description 8
- 229960003174 lansoprazole Drugs 0.000 claims description 7
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims description 7
- 239000007903 gelatin capsule Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 239000008203 oral pharmaceutical composition Substances 0.000 claims description 5
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 claims description 3
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 claims description 3
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 claims description 3
- 235000010385 ascorbyl palmitate Nutrition 0.000 claims description 3
- 238000007907 direct compression Methods 0.000 claims description 3
- 229960005019 pantoprazole Drugs 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 229960004157 rabeprazole Drugs 0.000 claims description 3
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims description 3
- 229960002871 tenoxicam Drugs 0.000 claims description 3
- WZWYJBNHTWCXIM-UHFFFAOYSA-N tenoxicam Chemical compound O=C1C=2SC=CC=2S(=O)(=O)N(C)C1=C(O)NC1=CC=CC=N1 WZWYJBNHTWCXIM-UHFFFAOYSA-N 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 2
- 230000003078 antioxidant effect Effects 0.000 claims description 2
- 238000001125 extrusion Methods 0.000 claims description 2
- 239000000473 propyl gallate Substances 0.000 claims description 2
- 235000010388 propyl gallate Nutrition 0.000 claims description 2
- 229940075579 propyl gallate Drugs 0.000 claims description 2
- 229940079593 drug Drugs 0.000 description 17
- 239000003814 drug Substances 0.000 description 17
- 230000002496 gastric effect Effects 0.000 description 14
- 230000003993 interaction Effects 0.000 description 11
- 230000000694 effects Effects 0.000 description 10
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229940126409 proton pump inhibitor Drugs 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 208000007107 Stomach Ulcer Diseases 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 208000000718 duodenal ulcer Diseases 0.000 description 5
- 239000000612 proton pump inhibitor Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- 229920003134 Eudragit® polymer Polymers 0.000 description 4
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 4
- 208000025865 Ulcer Diseases 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 4
- 231100000397 ulcer Toxicity 0.000 description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 239000011247 coating layer Substances 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 208000012895 Gastric disease Diseases 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- -1 benzimidazole compound Chemical class 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229940111134 coxibs Drugs 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 210000004877 mucosa Anatomy 0.000 description 2
- 239000002831 pharmacologic agent Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 2
- 229920000058 polyacrylate Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 208000018556 stomach disease Diseases 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229960002622 triacetin Drugs 0.000 description 2
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000010907 Cyclooxygenase 2 Human genes 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 102100028675 DNA polymerase subunit gamma-2, mitochondrial Human genes 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 206010062532 Erosive duodenitis Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920003163 Eudragit® NE 30 D Polymers 0.000 description 1
- 206010017865 Gastritis erosive Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 101000837415 Homo sapiens DNA polymerase subunit gamma-2, mitochondrial Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000023178 Musculoskeletal disease Diseases 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 102100032709 Potassium-transporting ATPase alpha chain 2 Human genes 0.000 description 1
- 229920003080 Povidone K 25 Polymers 0.000 description 1
- 108010083204 Proton Pumps Proteins 0.000 description 1
- 201000002661 Spondylitis Diseases 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 208000038016 acute inflammation Diseases 0.000 description 1
- 230000006022 acute inflammation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229920001688 coating polymer Polymers 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 230000002178 gastroprotective effect Effects 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 230000000642 iatrogenic effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229940112801 mobic Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 125000005498 phthalate group Chemical group 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
-
- 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
- A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
-
- 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
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- 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
Definitions
- composition containing a NSAID and a benzimidazole derivative
- Non steroidal anti-inflammatory drugs are among the most commonly prescribed and used drugs worldwide.
- NSAIDs gastrointestinal side effects
- their use is commonly limited by an increased risk of gastrointestinal (Gl) side effects, mainly upper gastro-intestinal side effects like peptic ulceration and dyspeptic symptoms.
- Gl gastrointestinal
- gastro-intestinal side effects of these drugs with enteric coatings have had limited success.
- the gastro-intestinal side effects of NSAIDs are in part attributable to their ability to inhibit the biosynthesis of gastroprotective prostaglandins, a significant amount of evidence exists that NSAIDs act locally on the mucosa to induce Gl ulcers and bleeding by a prostaglandin-independent mechanism.
- NSAIDs may be responsible of iatrogenic gastro-intestinal side effects which may lead to discontinuation of the treatment and in some cases necessitate hospital treatment.
- the term "NSAIDs-induced gastropathy” has been used to describe those adverse effects, which include haemorrhage, erosions and ulcers in the gastro-duodenal mucosa.
- the pathogenesis of NSAIDs-induced gastropathy is not fully understood, but both local and systemic effects are thought to contribute. Therefore, the galenical improvements consisting in gastro-resistant formulations have been of little influence on the frequence and severity of gastro-intestinal effects provoked by NSAIDs.
- cox 2 inhibitors A new generation of NSAIDs has been developed, called “cox 2 inhibitors" because they appear to act more specifically on the cyclooxygenase 2 and hence their administration result in a lower incidence of Gl side effects.
- cox 2 inhibitors are celecoxib and rofecoxib. But now, after several years of marketing of those drugs, they also appear to have significant Gl side effects (even if their incidence and/ or their severity is lower than with the old generation of NSAIDs ). That means that, at the moment there is no safe and efficient acute or chronic antiinflammatory treatment of inflammation disorders in people with potential Gl sensibility or people subjects to ulcers and / or gastritis.
- the aim of the present invention is to provide such a treatment
- the "oxicam" family of NSAIDs is a family of well-known efficient antiinflammatory drugs presenting as all the NSAID a relatively high risk of gastrointestinal side effects.
- the oxicam family contains, among others, piroxicam, meloxicam and tenoxicam. Administered orally, those molecules are indicated in several musculoskeletal disorders such as ankylosng spondylitis, osteoarthritis and rheumatoid arthritis. They are also prescribed in acute inflammation of soft tissues and in acute gout.
- the molecules owning to the oxicam family present the advantage to possess a relatively high elimination half-life what allows to administer them once daily. This is an important advantage in terms of posology and compliance of patients
- Benzimidazole derivatives also called proton pump inhibitors (PPIs) are widely known pharmacological agents used in the treatment of gastric and duodenal ulcers and other pathologies of the gastro-intestinal tract.
- Proton pump inhibitors have been shown to be able to prevent gastric and duodenal erosions in healthy volunteers during treatment with acetylsalicylic acid.
- Clinical studies have shown that omeprazole heals gastric and duodenal ulcers as fast and effectively in patients on a continuous NSAID treatment as in non NSAID uses (Walon A, Engl. S. Med, 1989;320,69).
- omeprazole significantly reduces the risk of developing gastric ulcers, duodenal ulcers and also dyspeptic symptoms in patients on continuous NSAID treatment.
- Physicians have already prescribed, in some cases, a therapy comprising a NSAID and proton pump inhibitor but the different active substances are administered separately. It is well known that patient compliance is a main factor in receiving a good result in medical treatments. Therefore, administration of two or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results.
- the benzimidazole derivative is formulated as enteric compositions since it is well known that this class of drugs are very sensitive to the acidic pH of the stomach.
- a further advantage of the composition of the invention is that a well predetermined amount of NSAID owning to the oxicam family is administered to the patient with a well predetermined amount of benimidazole derivative.
- US patent 6,365,184 describes a combination of a proton pump inhibitor with a NSAID under the form of a multiple unit tablet dosage form.
- the PPI is preferably under the form of compressible enteric coated beads.
- the present invention provides an oral pharmaceutical dosage form consisting in a capsule containing a non steroidal antiinflammatory drug (NSAID) owning to the family of oxicam derivatives or a salt thereof under the form of coated pellets or alternatively coated tablets, and an enteric coated tablet of a benzimidazole derivative, said pharmaceutical composition being suitable for a once a day administration
- NSAID non steroidal antiinflammatory drug
- the present invention provides an oral pharmaceutical dosage form consisting in a pharmaceutically acceptable capsule containing a non steroidal antiinflammatory drug (NSAID) owning to the family of oxicam derivatives or a salt thereof under the form of enteric coated or controlled released composition, advantageously enteric coated or controlled release pellets or alternatively one or more coated or controlled release tablets, and an enteric coated tablet of a benzimidazole derivative, both coatings presenting different release characteristics in order to minimize the possible interaction between both classes of drugs.
- NSAID non steroidal antiinflammatory drug
- a pharmaceutical composition combining in a single dosage form a NSAID from the oxicam family or salts thereof and a benzimidazole derivative or salts thereof is a new, advantageous and innovative method of treatment of inflammatory disorders, especially in patients presenting an history of gastro-intestinal pathologies line gastritis, Gl ulcers, etc,...
- the oxicam compound is thus advantageously selected from the group consisting of pharmaceutically acceptable oxicam derivatives, pharmaceutically acceptable salts of oxicam derivatives and mixtures thereof.
- Preferred oxicam compounds are meloxicam, piroxicam, tenoxicam, salts thereof, and mixtures thereof.
- the benzimidazole compound is advantageously selected from the group consisting of pharmaceutically acceptable benzimidazole derivatives, pharmaceutically acceptable salts of benzimidazole derivatives, and mixtures thereof.
- Preferred benzimidazole compounds are omeprazole, lansoprazole, rabeprazole, pantoprazole, pharmaceutically acceptable salts thereof, and mixtures thereof (omeprazole, pharmaceutically acceptable salts thereof and mixtures thereof being more preferred).
- Oxicam derivatives are usually poorly water soluble molecules. Piroxicam is a white to slightly yellow crystalline powder. It shows polymorphism. Practically insoluble in water, slightly soluble in dehydrated alcohol. Piroxicam is well absorbed from the gastro-intestinal tract. Piroxicam has a long elimination half-life of approximately 50 hours. Enterohepatic recycling occur. Meloxicam is well absorbed after oral administration and is 99% bound to plasma proteins. Meloxicam has a plasma elimination half-life of about 20 hours. The marketed oral compositions of oxicam available on the market until today are immediate release forms (uncoated)
- Benzimidazole compounds also called proton pump inhibitors (because their mechanism of action is to inhibit the so-called proton pump) are very effective drugs for the treatment of gastric and duodenal ulcers, gastroesophageal reflux diseases and Helicobacter pylori eradication, including the gastro-duodenal pathologies due to NSAID use.
- the main benzimidazole derivatives used are omeprazole, lansoprazole, rabeprazole and pantoprazole. All the benzimidazole compounds have the common properties of presenting very poor stability. They are sensitive to heat, moisture and light, and in aqueous solution or suspension, their stability decreases with decreasing pH.
- benzimidazole must be protected from gastric fluids since it is rapidly chemically degraded at acidic pH.
- Different oral compositions of benzimidazole compounds have been patented including our previous patent (WO 02/32425) describing a stable oral formulation containing a benzimidazole derivative.
- the main challenge(s) when combining two or more molecules in the same pharmaceutical form is (i) to guarantee the chemico-physical compatibility between the different active ingredients and/or between the active ingredients and the excipients used; and (ii) to insure the therapeutical compatibility between active ingredients regarding their pharmacokinetic and/or pharmaceutical properties in order that the posology of the combined composition allows to obtain safe and efficient plasma levels of both pharmacological agents.
- the metabolism of PPI is mainly due to cytochromes P450 2C19 system while the oxicams are mainly metabolized by P450 2C9 system. There are consequently no significant direct pharmacokinetic interactions described between those 2 family of drugs. But another kind of interaction may occur between two drugs, which can result in significant alteration of the bioavailability of the drugs. This interaction results from the physico- chemical properties of drugs. Oxicam derivatives present the properties of possessing a pH dependent solubility profile with a lower solubility at low pH than at higher pH.
- the oxicams are available on the market in immediate release uncoated forms (tablets or capsules) and benzimidazoles derivatives are available in enteric coated forms
- the oxicam de ⁇ vative will be released in first position in stomach and the beginning of intestine while the benzimidazole derivative will be released only after the passage of the pylori (i.e. after the stomach) because of the presence of the enteric coating.
- oxicam composition is released first, so releasing the alkaline excipients contained in the oxicam composition which present a pH between 6 to 9, may locally attack the enteric coating of the benzimidazole derivative, so provoking holes in the coating and then releasing the benzimidazole in the stomach where it is unstable and degrades very rapidly. This will result in a loss of bioavailability of oxicam derivative due to an early release and degradation of the benzimidazole derivative in the stomach.
- oxicams which are acidic molecule may also possibly provoke a direct degradation of benzimidazole compound by direct chemical contact in the gastro-intestinal tract.
- the present invention provides a solution to avoid this potential interaction between meloxicam and benzimidazole derivatives.
- the invention consists in avoiding, at the same time or at the same site, important release of both drugs.
- a possible aspect of this invention is to provide an oxicam composition form which is coated with an enteric release coating having a dissolution pH of at least 0.5 pH unit, advantageously comprised between 0.5 and 5 pH unit preferably comprised between 0.5 and 3 pH unit (such as about 0.5, about 1 , about 1.5, advantageously about 0.5 to about 1 ), superior to the enteric coating of the benzimidazole derivative, in order that when taken simultaneously, the oxicam derivative will be released after the benzimidazole derivative (due to its higher pH soluble coating), so avoiding possible interactions between meloxicam or alkaline excipients contained in the meloxicam composition and the benzimidazole derivatives.
- the dissolution pH of enteric coating formulations of benzimidazole derivatives is usually 5 to 5.5
- the dissolution pH of the meloxicam formulation is from 5.5 to 8, preferably between 6 to 7.
- Suitable enteric polymer for obtaining release at those pH are for example, but not limited to, acrylic derivatives such as EUDRAGIT ® L30D-55 (pH 5.5), EUDRAGIT ® L100 (pH 6), EUDRAGIT ® S100 (pH 7-8) or mixtures thereof.
- the tablet containing the benzimidazole derivative or salt thereof is advantageously provided with at least two coating layers, preferably two different coating layers, such as a precoating and an outer enteric coating.
- the tablet containing the benzimidazole derivative or salt thereof is preferably free of oxicam derivative.
- the composition of the invention is adapted (for example the control release coating or the enteric coating is adapted) so that the benzimidazole derivative starts to be released before the release of oxicam derivative.
- the peak of release of benzimidaole derivative is reached before the peak of release of oxicam derivative, preferably before reaching a level of release of oxicam derivative corresponding to less than 50% of the peak of release of oxicam.
- the composition of the invntion is adapted (for example the control release coating or the enteric coating is adapted) so that the release peak of oxicam derivative is retarded with respect to the release peak of benzimidazole derivative.
- the time between the two peaks is comprised for example between 5 minutes and 6 hours, advantageously between 15 minutes and 3 hours, for example 20 minutes, 30 minutes, 45 minutes, 1 hour, 90 minutes, 120 minutes.
- the oxicam derivative composition, pellets, beads or tablets
- the oxicam derivative may be coated with a controlled release coating in order to release the drug slowly all along the gastro-intestinal tract. In this manner, high concentrations of the oxicam derivative are never in contact with high concentration of the benzimidazole derivative.
- the controlled release of the oxicam derivative can be obtained by using well-known polymers films like acrylic (polyacrylate dispersions,%) or cellullosic (ethylcellulose,...) sustained release polymer.
- the oxicam derivative can also have the form of a controlled release matrix.
- the capsule used in the composition of the invention is advantageously a hard gelatin capsule, an hypromellose capsule, a starch capsule or any other pharmaceutically acceptable capsule.
- the oxicam derivative is present in said capsule for example as enteric coated pellets or alternatively as controlled release pellets and/or as an one or more enteric coated tablets or alternatively as on or more controlled release tablets, said oxicam derivative containing pellets or tablets being preferably free of benzimidazole derivative.
- the weight ratio between the pharmaceutically acceptable oxicam derivative or salt thereof and the pharmaceutically acceptable benzimidazole derivative is between 0.2 (w/w) and 5 (w/w), most preferably between 0.5 and 2.
- the composition of the invention comprises advantageously only two different pharmaceutically active agents, namely one pharmaceutically acceptable oxicam derivative and one pharmaceutically acceptable benzimidasole derivative.
- the pellets of the oxicam derivative or salt thereof have advantageously a diameter comprised between 0.2 and 3 mm, preferably between 0.5 and 2 mm, and most preferably between 0.7 and 1.6 mm
- the pellets containing the oxicam derivative or salt thereof are preferably manufactured by the process of extrusion - spheronisation
- the enteric coated tablets containing the benzimidazole derivative or salt thereof is advantageously manufactured by direct compression, coated with a pre-coating and subsequently coated with an enteric coating
- the enteric coated tablets containing the benzimidazole de ⁇ vative or salt thereof contains preferably at least one pharmaceutically acceptable lipophilic antioxidant, advantageously selected from the group consisting of ascorbyl palmitate, butylhydroxyanisole, butyl
- the oxicam derivative is selected from the group consisting of meloxicam, pharmaceutically acceptable salts thereof, and mixtures thereof, while the benzimidazole de ⁇ vative is selected from the group consisting of omeprazole, pharmaceutically acceptable salts thereof, and mixtures thereof.
- the oxicam derivative is selected from the group consisting of piroxicam, pharmaceutically acceptable salts thereof, and mixtures thereof, while the benzimidazole derivative is selected from the group consisting of omeprazole, pharmaceutically acceptable salts thereof, and mixtures thereof.
- the amount of the benzimidazole (determined as base for salts thereof) per capsule is advantageously between 5 and 80 mg, preferably between 5 and 40 mg
- the amount of the oxicam derivative per capsule is between 5 and 40 mg, preferably between 5 and 25 mg.
- the composition is preferably suitable for a once a day administration to patients in need in such a treatment.
- the invention relates also to a manufacturing process suitable to obtain a composition of the invention.
- a manufacturing process suitable to obtain a composition of the invention.
- an enteric coated tablet containing at least one pharmaceutically acceptable benzimidazole derivative or salt thereof and
- an enteric or controlled release composition containing a nonsteroidal antiinflammatory drug from the family of oxicams or pharmaceutically acceptable salt thereof, both coatings presenting different release characteristics in order to minimize the possible interaction between both classes of drugs
- said pharmaceutical composition being suitable for a once a day administration
- the tablet (a) and the composition (b) being filled together in a capsule.
- the tablet (a) and the composition (b) can be administered or released separately, but simultaneously orally absorbed.
- the invention relates also to an oral pharmaceutical composition or kit comprising (a) a first enteric coated tablet containing at least one pharmaceutically acceptable benzimidazole derivative or salt thereof and (b) a second enteric coated composition containing a nonsteroidal antiinflammatory drug from the family of oxicams and pharmaceutically acceptable salts thereof, the coating dissolution of the first enteric coated tablet (a) being at least 0.5 pH unit, advantageously between 0.5 pH unit and 3 pH unit (such as about 0.5 pH unit, 1 pH unit and 1.5 pH unit) lower than the coating dissolution of the second enteric coated composition (b), and the first enteric coated tablet (a) and the second enteric coated tablet (b) being in a form for being administered or released separately
- the invention further relates to the use of a composition of the invention for a once a day administration to patients in need in such a treatment.
- a composition of the invention for a once a day administration to patients in need in such a treatment.
- Different examples of formulations corresponding to the present invention are given hereinbelow together with examples of manufacturing process to obtain the composition of the invention.
- meloxicam sodium 200 g of microcrystalline cellulose (Avicel pH 101 , FMC), 25 g of sucroester (Crodesta, Gattefosse, France) and 10 g of Povidone (Plasdone K25, BASF, Germany) are introduced in a planetary mixer.
- the powders are mixed together for 10 minutes at speed 1.
- 200 g of demineralized water are then added, under mixing, to the powder blend in order to obtain granulates presenting adequate plastic properties.
- the granulates obtained are extruded through a 1.2 mm sieve of the extruder (Fuji-paudal, Japan).
- the extrudates obtained are then spheronized at 800 and 1000 rpm for 60 seconds in order to obtain pellets.
- the pellets obtained are dried in an oven at 60°C for 16 hours.
- the dried pellets are sieved between 0.7 and 1.4 mm.
- the enteric coating solution is obtained by dispersing 40 g hypromellose phthalate (HP55 ® , Shin-etsu) which has a dissolution pH of 5.5, 24 g of talc, 10 g of glycerol triacetate in a mixture alcohol 96 % - water 85/15 (w/w).
- the enteric coating is applied on the uncoated pellets with the following parameters :
- Omeprazole 100 g of Omeprazole, 10 g of ascorbyl palmitate, 765 g of lactose monohydrate, 250 g of cellulose microcrystalline, 85 g of crospovidone and 10 g of magnesium stearate, are blended together for 10 minutes at speed in a planetary mixer.
- the powder is then compressed directly to obtain tablets using round biconvex stamps of 6.5 mm of diameter.
- the tablets obtained are then coated with a precoating solution in order to avoid direct contact between the benzimidazole derivative and the enteric polymer, which could result in a degradation of omeprazole.
- the tablets will then be coated using (i) a pre-coating layer or insulating coating destined to avoid contact between omeprazole and the enteric coating polymer and (ii) an enteric coating layer
- the precoating solution is obtained by dissolving 15 g of povidone in absolute alcohol (100 g ethanol anhydrous).
- the coating process is preferably performed on a pan-coating machine (GS Pellegrini or Accela- Cota) but can alternatively be performed on fluidized bed apparatuses
- Glatt (Aeromatic or Glatt).
- the enteric coating layer is then applied on the precoated tablets using a
- the enteric coating solution is obtained by dispersing 40 g hypromellose phthalate (HP50 ® , Shin-etsu) which has a dissolution pH of 5.0, 24 g of talc, 10 g of glycerol triacetate and 10 g of red iron oxide in a mixture alcohol 96 % - water 85/15 (w/w).
- the final pharmaceutical form of the present invention is a
- capsules were filled with one enteric coated tablet
- the disintegration test is designed to control the enteric resistance of the tablet coating over time. It is performed according to the monograph "Gastro-resistant tablet” of the 4 th edition of the European Pharmacopoeia. No signs of either disintegration (apart from fragments of coating) or cracks that would allow the escape of the contents after 2 hours in HCI 0.1 M medium.
- Example 2 combination in a hard gelatin capsule of piroxicam pellets / lansoprazole coated tablets
- piroxicam pellets were similar as this described in example 1 for meloxicam.
- the pellets of piroxicam were not enteric coated but controlled release coated.
- the controlled release coating used was a polyacrylate dispersion at 30% (EUDRAGIT NE30D ® ) together with other excipients : talc, polysorbate 80, hypromellose, magnesium stearate. 12 % (w/w) of coating was applied on
- the precoating and the enteric coating applied on lansoprazole tablets have the same compostion as the coatings described in example 1 for omeprazole enteric coated tablets.
- the final pharmaceutical form of the present invention is a pharmaceutically acceptable capsule (hard gelatin capsule, Hypromellose capsule, starch capsule, polyethyleneglycol ).
- size 0 hard gelatin capsules were filled with one enteric coated tablet containing 30 mg of lansoprazole and 20 mg of controlled release pellets of piroxicam.
- Example 3 combination in a HPMC capsule of meloxicam enteric tablets / omeprazole enteric coated tablets
- Table 3 enteric coated tablets of meloxicam
- the enteric coated omeprazole tablets were the same as described in example 1 (with a dissolution pH of 5.0).
- One enteric coated tablet of meloxicam and one enteric coated tablet of omeprazole were then filled in a HPMC capsule to obtain the final pharmaceutical composition.
- enteric coated meloxicam pellets are filled in a capsule and the enteric coated tablet of benzimidazole de ⁇ vative remains as a tablet and both drugs are administered separately but simalteneously, without significant interaction.
Abstract
The present invention provides an oral pharmaceutical dosage form consisting in a combination, in the same dosage form, of an enteric coated or controlled release coated pellets and/or tablets, and an enteric coated tablet of a benzimidazole derivative, both coatings presenting different release characteristics.
Description
Pharmaceutical Composition containing a NSAID and a benzimidazole derivative
BACKGROUND OF THE INVENTION
Non steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed and used drugs worldwide. Despite the therapeutic benefits of NSAIDs, their use is commonly limited by an increased risk of gastrointestinal (Gl) side effects, mainly upper gastro-intestinal side effects like peptic ulceration and dyspeptic symptoms. Strategies to reduce the gastro-intestinal injurious effects of these drugs with enteric coatings, have had limited success. Although it is clear that the gastro-intestinal side effects of NSAIDs are in part attributable to their ability to inhibit the biosynthesis of gastroprotective prostaglandins, a significant amount of evidence exists that NSAIDs act locally on the mucosa to induce Gl ulcers and bleeding by a prostaglandin-independent mechanism.
NSAIDs may be responsible of iatrogenic gastro-intestinal side effects which may lead to discontinuation of the treatment and in some cases necessitate hospital treatment. The term "NSAIDs-induced gastropathy" has been used to describe those adverse effects, which include haemorrhage, erosions and ulcers in the gastro-duodenal mucosa. The pathogenesis of NSAIDs-induced gastropathy is not fully understood, but both local and systemic effects are thought to contribute. Therefore, the galenical improvements consisting in gastro-resistant formulations have been of little influence on the frequence and severity of gastro-intestinal
effects provoked by NSAIDs. A new generation of NSAIDs has been developed, called "cox 2 inhibitors" because they appear to act more specifically on the cyclooxygenase 2 and hence their administration result in a lower incidence of Gl side effects. Examples of cox 2 inhibitors are celecoxib and rofecoxib. But now, after several years of marketing of those drugs, they also appear to have significant Gl side effects (even if their incidence and/ or their severity is lower than with the old generation of NSAIDs ). That means that, at the moment there is no safe and efficient acute or chronic antiinflammatory treatment of inflammation disorders in people with potential Gl sensibility or people subjects to ulcers and / or gastritis. The aim of the present invention is to provide such a treatment The "oxicam" family of NSAIDs is a family of well-known efficient antiinflammatory drugs presenting as all the NSAID a relatively high risk of gastrointestinal side effects. The oxicam family contains, among others, piroxicam, meloxicam and tenoxicam. Administered orally, those molecules are indicated in several musculoskeletal disorders such as ankylosng spondylitis, osteoarthritis and rheumatoid arthritis. They are also prescribed in acute inflammation of soft tissues and in acute gout. The molecules owning to the oxicam family present the advantage to possess a relatively high elimination half-life what allows to administer them once daily. This is an important advantage in terms of posology and compliance of patients
Benzimidazole derivatives also called proton pump inhibitors (PPIs) are widely known pharmacological agents used in the treatment of gastric and
duodenal ulcers and other pathologies of the gastro-intestinal tract. Proton pump inhibitors have been shown to be able to prevent gastric and duodenal erosions in healthy volunteers during treatment with acetylsalicylic acid. Clinical studies have shown that omeprazole heals gastric and duodenal ulcers as fast and effectively in patients on a continuous NSAID treatment as in non NSAID uses (Walon A, Engl. S. Med, 1989;320,69). These results have been the basis for an amendment to the dose recommendation for the use of omeprazole in healing of gastric and duodenal ulcers during continuous NSAID treatment, approved by several European countries. Recent studies confirm that omeprazole significantly reduces the risk of developing gastric ulcers, duodenal ulcers and also dyspeptic symptoms in patients on continuous NSAID treatment. Physicians have already prescribed, in some cases, a therapy comprising a NSAID and proton pump inhibitor but the different active substances are administered separately. It is well known that patient compliance is a main factor in receiving a good result in medical treatments. Therefore, administration of two or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results. The benzimidazole derivative is formulated as enteric compositions since it is well known that this class of drugs are very sensitive to the acidic pH of the stomach.
A large amount of patents have been granted about pharmaceutical compositions of benzimidazole derivatives and especially about oral enteric formulations of benzimidazole derivatives and several patents about
compositions of NSAIDs but the combination, in the same pharmaceutical composition, of a NSAID owning to the oxicam family and a benzimidazole derivative has never been described. This combination allows to administer the NSAID molecule very safely in patients in need of such treatment by very significantly decreasing the possibility of Gl side effect. One particular advantage of the present invention is to minimize the possibility of drug-drug interaction once they are released in vivo. Another^ advantage of the invention is that a once a day administration of said composition is enough to maintain the activity for 24 hours, what is of considerable importance in terms of patient's compliance and comfort.
A further advantage of the composition of the invention is that a well predetermined amount of NSAID owning to the oxicam family is administered to the patient with a well predetermined amount of benimidazole derivative. US patent 6,365,184 describes a combination of a proton pump inhibitor with a NSAID under the form of a multiple unit tablet dosage form. In this invention, the PPI is preferably under the form of compressible enteric coated beads.
The present invention provides an oral pharmaceutical dosage form consisting in a capsule containing a non steroidal antiinflammatory drug (NSAID) owning to the family of oxicam derivatives or a salt thereof under the form of coated pellets or alternatively coated tablets, and an enteric
coated tablet of a benzimidazole derivative, said pharmaceutical composition being suitable for a once a day administration
SUMMARY OF THE INVENTION
The present invention provides an oral pharmaceutical dosage form consisting in a pharmaceutically acceptable capsule containing a non steroidal antiinflammatory drug (NSAID) owning to the family of oxicam derivatives or a salt thereof under the form of enteric coated or controlled released composition, advantageously enteric coated or controlled release pellets or alternatively one or more coated or controlled release tablets, and an enteric coated tablet of a benzimidazole derivative, both coatings presenting different release characteristics in order to minimize the possible interaction between both classes of drugs. The said pharmaceutical composition being suitable for a once a day administration.
DETAILED DESCRIPTION OF THE INVENTION
As explained before, it has been found out that a pharmaceutical composition combining in a single dosage form a NSAID from the oxicam family or salts thereof and a benzimidazole derivative or salts thereof, is a new, advantageous and innovative method of treatment of inflammatory disorders, especially in patients presenting an history of gastro-intestinal
pathologies line gastritis, Gl ulcers, etc,... The oxicam compound is thus advantageously selected from the group consisting of pharmaceutically acceptable oxicam derivatives, pharmaceutically acceptable salts of oxicam derivatives and mixtures thereof. Preferred oxicam compounds are meloxicam, piroxicam, tenoxicam, salts thereof, and mixtures thereof. The benzimidazole compound is advantageously selected from the group consisting of pharmaceutically acceptable benzimidazole derivatives, pharmaceutically acceptable salts of benzimidazole derivatives, and mixtures thereof. Preferred benzimidazole compounds are omeprazole, lansoprazole, rabeprazole, pantoprazole, pharmaceutically acceptable salts thereof, and mixtures thereof (omeprazole, pharmaceutically acceptable salts thereof and mixtures thereof being more preferred).
When developing a combination of drugs, a particular attention should be paid to the chemical and physical compatibility between active ingredients and/or between each active ingredient and the excipients used.
Oxicam derivatives are usually poorly water soluble molecules. Piroxicam is a white to slightly yellow crystalline powder. It shows polymorphism. Practically insoluble in water, slightly soluble in dehydrated alcohol. Piroxicam is well absorbed from the gastro-intestinal tract. Piroxicam has a long elimination half-life of approximately 50 hours. Enterohepatic recycling occur. Meloxicam is well absorbed after oral administration and is 99% bound to plasma proteins. Meloxicam has a plasma elimination
half-life of about 20 hours. The marketed oral compositions of oxicam available on the market until today are immediate release forms (uncoated)
Benzimidazole compounds also called proton pump inhibitors (because their mechanism of action is to inhibit the so-called proton pump) are very effective drugs for the treatment of gastric and duodenal ulcers, gastroesophageal reflux diseases and Helicobacter pylori eradication, including the gastro-duodenal pathologies due to NSAID use. The main benzimidazole derivatives used are omeprazole, lansoprazole, rabeprazole and pantoprazole. All the benzimidazole compounds have the common properties of presenting very poor stability. They are sensitive to heat, moisture and light, and in aqueous solution or suspension, their stability decreases with decreasing pH. The formulation of benzimidazole must be protected from gastric fluids since it is rapidly chemically degraded at acidic pH. Different oral compositions of benzimidazole compounds have been patented including our previous patent (WO 02/32425) describing a stable oral formulation containing a benzimidazole derivative.
The main challenge(s) when combining two or more molecules in the same pharmaceutical form is (i) to guarantee the chemico-physical compatibility between the different active ingredients and/or between the active ingredients and the excipients used; and (ii) to insure the therapeutical compatibility between active ingredients regarding their pharmacokinetic and/or pharmaceutical properties in order that the posology of the
combined composition allows to obtain safe and efficient plasma levels of both pharmacological agents.
The metabolism of PPI is mainly due to cytochromes P450 2C19 system while the oxicams are mainly metabolized by P450 2C9 system. There are consequently no significant direct pharmacokinetic interactions described between those 2 family of drugs. But another kind of interaction may occur between two drugs, which can result in significant alteration of the bioavailability of the drugs. This interaction results from the physico- chemical properties of drugs. Oxicam derivatives present the properties of possessing a pH dependent solubility profile with a lower solubility at low pH than at higher pH. This is particularly true for Meloxicam, which presents a solubility in water at 25°C of 0.037 mg/ 100 ml at pH = 2, of 2.7 mg/ 100 ml at pH = 6, and of 155 mg/ 100 ml at pH = 8. This means that to obtain a good bioavailability of an oxicam derivative, often a pH modifyer agent is added to the composition in order to confer a neutral to alkaline pH to the composition. For instance, the marketed form of meloxicam (Mobic®, Boehhnger Ingelheim) present a pH in water of 7.2 due to the presence in the tablet of sodium citrate, an alkaline excipient On the other hand, oxicam derivatives are acidic molecules. For instance, pKa values for meloxicam are 4.35 and 1.29 respectively.
Those two properties of oxicams are particularly important since they may result in an interaction between the oxicam composition and the benzimidazole composition when they are administered simultaneously.
Indeed, as today the oxicams are available on the market in immediate release uncoated forms (tablets or capsules) and benzimidazoles derivatives are available in enteric coated forms, when both classes of molecules will be administered simultaneously, the oxicam deπvative will be released in first position in stomach and the beginning of intestine while the benzimidazole derivative will be released only after the passage of the pylori (i.e. after the stomach) because of the presence of the enteric coating.
Two kinds of interactions may actually occur from this. First, an interaction due to the fact that oxicam composition is released first, so releasing the alkaline excipients contained in the oxicam composition which present a pH between 6 to 9, may locally attack the enteric coating of the benzimidazole derivative, so provoking holes in the coating and then releasing the benzimidazole in the stomach where it is unstable and degrades very rapidly. This will result in a loss of bioavailability of oxicam derivative due to an early release and degradation of the benzimidazole derivative in the stomach. On the other hand, oxicams which are acidic molecule may also possibly provoke a direct degradation of benzimidazole compound by direct chemical contact in the gastro-intestinal tract.
The present invention provides a solution to avoid this potential interaction between meloxicam and benzimidazole derivatives.
The invention consists in avoiding, at the same time or at the same site, important release of both drugs. A possible aspect of this invention is to provide an oxicam composition form which is coated with an enteric release coating having a dissolution pH of at least 0.5 pH unit, advantageously comprised between 0.5 and 5 pH unit preferably comprised between 0.5 and 3 pH unit ( such as about 0.5, about 1 , about 1.5, advantageously about 0.5 to about 1 ), superior to the enteric coating of the benzimidazole derivative, in order that when taken simultaneously, the oxicam derivative will be released after the benzimidazole derivative (due to its higher pH soluble coating), so avoiding possible interactions between meloxicam or alkaline excipients contained in the meloxicam composition and the benzimidazole derivatives.
As the dissolution pH of enteric coating formulations of benzimidazole derivatives is usually 5 to 5.5, it is proposed that the dissolution pH of the meloxicam formulation is from 5.5 to 8, preferably between 6 to 7. Suitable enteric polymer for obtaining release at those pH are for example, but not limited to, acrylic derivatives such as EUDRAGIT® L30D-55 (pH 5.5), EUDRAGIT® L100 (pH 6), EUDRAGIT® S100 (pH 7-8) or mixtures thereof.
Other suitable polymers are cellulose polymers such as cellulose acetophtalate (pH 6), hypromellose phtalate (pH = 5.5, HP50®, SHINETSU).
The tablet containing the benzimidazole derivative or salt thereof is advantageously provided with at least two coating layers, preferably two different coating layers, such as a precoating and an outer enteric coating.
The tablet containing the benzimidazole derivative or salt thereof is preferably free of oxicam derivative.
According to an embodiment, the composition of the invention is adapted (for example the control release coating or the enteric coating is adapted) so that the benzimidazole derivative starts to be released before the release of oxicam derivative. Advantageously the peak of release of benzimidaole derivative is reached before the peak of release of oxicam derivative, preferably before reaching a level of release of oxicam derivative corresponding to less than 50% of the peak of release of oxicam.
According to another embodiment, the composition of the invntion is adapted (for example the control release coating or the enteric coating is adapted) so that the release peak of oxicam derivative is retarded with respect to the release peak of benzimidazole derivative. For a human , the time between the two peaks is comprised for example between 5 minutes
and 6 hours, advantageously between 15 minutes and 3 hours, for example 20 minutes, 30 minutes, 45 minutes, 1 hour, 90 minutes, 120 minutes.
The presence of a coating also prevents from contact between both kinds of drugs within the final composition (capsule) so further guarantying the absence of chemical interaction between both kinds of drugs within the pharmaceutical composition, and hence making their compatibility more sure. Alternatively, the oxicam derivative (composition, pellets, beads or tablets) may be coated with a controlled release coating in order to release the drug slowly all along the gastro-intestinal tract. In this manner, high concentrations of the oxicam derivative are never in contact with high concentration of the benzimidazole derivative. The controlled release of the oxicam derivative can be obtained by using well-known polymers films like acrylic (polyacrylate dispersions,...) or cellullosic (ethylcellulose,...) sustained release polymer.
The oxicam derivative can also have the form of a controlled release matrix. The capsule used in the composition of the invention is advantageously a hard gelatin capsule, an hypromellose capsule, a starch capsule or any other pharmaceutically acceptable capsule.
The oxicam derivative is present in said capsule for example as enteric coated pellets or alternatively as controlled release pellets and/or as an one or more enteric coated tablets or alternatively as on or more controlled
release tablets, said oxicam derivative containing pellets or tablets being preferably free of benzimidazole derivative.
Advantageously, the weight ratio between the pharmaceutically acceptable oxicam derivative or salt thereof and the pharmaceutically acceptable benzimidazole derivative is between 0.2 (w/w) and 5 (w/w), most preferably between 0.5 and 2.
The composition of the invention comprises advantageously only two different pharmaceutically active agents, namely one pharmaceutically acceptable oxicam derivative and one pharmaceutically acceptable benzimidasole derivative. Preferably at least three layers or barriers separate the oxicam derivative from the benzimidazole. In case of pellets, the pellets of the oxicam derivative or salt thereof have advantageously a diameter comprised between 0.2 and 3 mm, preferably between 0.5 and 2 mm, and most preferably between 0.7 and 1.6 mm The pellets containing the oxicam derivative or salt thereof are preferably manufactured by the process of extrusion - spheronisation The enteric coated tablets containing the benzimidazole derivative or salt thereof is advantageously manufactured by direct compression, coated with a pre-coating and subsequently coated with an enteric coating The enteric coated tablets containing the benzimidazole deπvative or salt thereof contains preferably at least one pharmaceutically acceptable lipophilic antioxidant, advantageously selected from the group consisting of ascorbyl palmitate, butylhydroxyanisole, butylhydroxyanisole, propylgallate and mixtures thereof.
According to a specific preferred embodiment of a composition, the oxicam derivative is selected from the group consisting of meloxicam, pharmaceutically acceptable salts thereof, and mixtures thereof, while the benzimidazole deπvative is selected from the group consisting of omeprazole, pharmaceutically acceptable salts thereof, and mixtures thereof.
According to a specific preferred embodiment of a composition, the oxicam derivative is selected from the group consisting of piroxicam, pharmaceutically acceptable salts thereof, and mixtures thereof, while the benzimidazole derivative is selected from the group consisting of omeprazole, pharmaceutically acceptable salts thereof, and mixtures thereof.
The amount of the benzimidazole (determined as base for salts thereof) per capsule is advantageously between 5 and 80 mg, preferably between 5 and 40 mg
The amount of the oxicam derivative per capsule is between 5 and 40 mg, preferably between 5 and 25 mg.
The composition is preferably suitable for a once a day administration to patients in need in such a treatment. The invention relates also to a manufacturing process suitable to obtain a composition of the invention. In said process, (a) an enteric coated tablet containing at least one pharmaceutically acceptable benzimidazole derivative or salt thereof and (b) an enteric or controlled release composition containing a nonsteroidal antiinflammatory drug from the
family of oxicams or pharmaceutically acceptable salt thereof, both coatings presenting different release characteristics in order to minimize the possible interaction between both classes of drugs , said pharmaceutical composition being suitable for a once a day administration, and the tablet (a) and the composition (b) being filled together in a capsule. Alternatively, the tablet (a) and the composition (b) can be administered or released separately, but simultaneously orally absorbed.
The invention relates also to an oral pharmaceutical composition or kit comprising (a) a first enteric coated tablet containing at least one pharmaceutically acceptable benzimidazole derivative or salt thereof and (b) a second enteric coated composition containing a nonsteroidal antiinflammatory drug from the family of oxicams and pharmaceutically acceptable salts thereof, the coating dissolution of the first enteric coated tablet (a) being at least 0.5 pH unit, advantageously between 0.5 pH unit and 3 pH unit (such as about 0.5 pH unit, 1 pH unit and 1.5 pH unit) lower than the coating dissolution of the second enteric coated composition (b), and the first enteric coated tablet (a) and the second enteric coated tablet (b) being in a form for being administered or released separately
The invention further relates to the use of a composition of the invention for a once a day administration to patients in need in such a treatment.
Different examples of formulations corresponding to the present invention are given hereinbelow together with examples of manufacturing process to obtain the composition of the invention.
Examples
Example 1
A) meloxicam enteric coated pellets
30 g of meloxicam sodium, 200 g of microcrystalline cellulose (Avicel pH 101 , FMC), 25 g of sucroester (Crodesta, Gattefosse, France) and 10 g of Povidone (Plasdone K25, BASF, Germany) are introduced in a planetary mixer. The powders are mixed together for 10 minutes at speed 1. 200 g of demineralized water are then added, under mixing, to the powder blend in order to obtain granulates presenting adequate plastic properties. The granulates obtained are extruded through a 1.2 mm sieve of the extruder (Fuji-paudal, Japan). The extrudates obtained are then spheronized at 800 and 1000 rpm for 60 seconds in order to obtain pellets. The pellets obtained are dried in an oven at 60°C for 16 hours. The dried pellets are sieved between 0.7 and 1.4 mm.
500 g of the sieved pellets are introduced in a fluidized bed coater (Strea-1 , Aeromatic, Germany). The enteric coating solution is obtained by dispersing 40 g hypromellose phthalate (HP55® , Shin-etsu) which has a
dissolution pH of 5.5, 24 g of talc, 10 g of glycerol triacetate in a mixture alcohol 96 % - water 85/15 (w/w).
The enteric coating is applied on the uncoated pellets with the following parameters :
Flow rate : 10 g/min T° input air : 38°C T° output air : 28-30°C T° product : 25°C
10 % of coating, expressed as percentage of dry residue applied on the pellets, were sprayed on the pellets. The coated pellets were dried at 40°c for 16 hours and then sieved between 0.8 and 1.6 mm.
B) enteric coated omeprazole tablet
100 g of Omeprazole, 10 g of ascorbyl palmitate, 765 g of lactose monohydrate, 250 g of cellulose microcrystalline, 85 g of crospovidone and 10 g of magnesium stearate, are blended together for 10 minutes at speed in a planetary mixer. The powder is then compressed directly to obtain tablets using round biconvex stamps of 6.5 mm of diameter.
The tablets obtained are then coated with a precoating solution in order to avoid direct contact between the benzimidazole derivative and the enteric polymer, which could result in a degradation of omeprazole.
The tablets will then be coated using (i) a pre-coating layer or insulating coating destined to avoid contact between omeprazole and the enteric coating polymer and (ii) an enteric coating layer
The precoating solution is obtained by dissolving 15 g of povidone in absolute alcohol (100 g ethanol anhydrous). The coating process is preferably performed on a pan-coating machine (GS Pellegrini or Accela- Cota) but can alternatively be performed on fluidized bed apparatuses
(Aeromatic or Glatt).
The enteric coating layer is then applied on the precoated tablets using a
GS-Pellegrini pan coater.
The enteric coating solution is obtained by dispersing 40 g hypromellose phthalate (HP50® , Shin-etsu) which has a dissolution pH of 5.0, 24 g of talc, 10 g of glycerol triacetate and 10 g of red iron oxide in a mixture alcohol 96 % - water 85/15 (w/w).
Coating parameters : Pre-coating and coating:
• T° input air: 45°C
• T° out put air : 30-32°C
• T° product: 25-28°C
• Flow rate: +/- 35-40 g/min
The enteric coated tablets are then dried in an oven at 25°C for 16 hours.
Manufacturing of the final capsules
The final pharmaceutical form of the present invention is a
pharmaceutically acceptable capsule (hard gelatin capsule, Hypromellose
capsule, starch capsule, polyethyleneglycol ). The filling of the capsule
with the tablet(s) of omeprazole and enteric pellets of meloxicam has been
made manually in this case given the small size of the batch.
Nevertheless, some industrial capsule filling machines like the Futura
(Mg2, Italy) or the KFM (Haro Hofliger, Germany) are able to perform such a filling of one or more tablets together with pellets in a reliable way.
In the present example, capsules were filled with one enteric coated tablet
containing 10 mg of omeprazole and a weight of enteric pellets
corresponding to 7.5 mg meloxicam ( with 10 % of enteric coating).
- The results of the gastro-resistance dissolution test of omeprazole enteric tablets performed on this composition is given hereinbelow :
Gastro-resistance test on omeprazole tablets
The gastro-resistance on omeprazole tablets has been assessed by putting the 6 capsules containing the enteric tablet of omeprazole and the enteric coated pellets of meloxicam in a disintegration apparatus (European
Pharmacopoeia 4th edition). The disintegration test is designed to control the enteric resistance of the tablet coating over time. It is performed according to the monograph "Gastro-resistant tablet" of the 4 th edition of the European Pharmacopoeia. No signs of either disintegration (apart from fragments of coating) or cracks that would allow the escape of the contents after 2 hours in HCI 0.1 M medium.
All six tablets have disintegrated within 60 minutes in pH 6.8 buffer medium. Those results confirm (i) the efficacy of the enteric coating of the tablets and (ii) the adequate dissolution profile of omeprazole once the pH is increased.
Example 2 : combination in a hard gelatin capsule of piroxicam pellets / lansoprazole coated tablets
table 1 .uncoated piroxicam pellets
The manufacturing process of piroxicam pellets was similar as this described in example 1 for meloxicam. In this case the pellets of piroxicam were not enteric coated but controlled release coated. The controlled release coating used was a polyacrylate dispersion at 30% (EUDRAGIT NE30D®) together with other excipients : talc, polysorbate 80, hypromellose, magnesium stearate. 12 % (w/w) of coating was applied on
the pellets.
Table 2 : Formulation of uncoated Lansoprazole tablets
The precoating and the enteric coating applied on lansoprazole tablets have the same compostion as the coatings described in example 1 for omeprazole enteric coated tablets.
The final pharmaceutical form of the present invention is a pharmaceutically acceptable capsule (hard gelatin capsule, Hypromellose capsule, starch capsule, polyethyleneglycol ).
In the present example, size 0 hard gelatin capsules were filled with one enteric coated tablet containing 30 mg of lansoprazole and 20 mg of controlled release pellets of piroxicam.
Example 3 : combination in a HPMC capsule of meloxicam enteric tablets / omeprazole enteric coated tablets
Table 3 : enteric coated tablets of meloxicam
The ingredients of table were mixed together on al planetary mixer and the tablets were manufactured by direct compression on spheric punches of diameter 6.5 mm in order to obtain 15 mg of meloxicam / tablet. Those tablets were then coated using an enteric coating cotaining EUDRAGIT
S100® (which has a dissolution pH of about 7), triethylcitrate, ammonium and water .
10 % (expressed as dry residue deposited on the tablets) of coating were applied on the meloxicam tablets.
The enteric coated omeprazole tablets were the same as described in example 1 (with a dissolution pH of 5.0).
One enteric coated tablet of meloxicam and one enteric coated tablet of omeprazole were then filled in a HPMC capsule to obtain the final pharmaceutical composition.
Alternatively, enteric coated meloxicam pellets are filled in a capsule and the enteric coated tablet of benzimidazole deπvative remains as a tablet and both drugs are administered separately but simalteneously, without significant interaction.
Claims
1. An oral pharmaceutical dosage form consisting in a combination, in the same dosage form, of a Non Steroidal Antiinflammatory Drug
(NSAID) of the oxicam family and a benzimidazole deπvative, said dosage form containing a non steroidal antiinflammatory drug
(NSAID) owning to the family of oxicam derivatives or a salt thereof
under the form of enteric coated composition, advantageously
enteric coated or controlled release coated pellets or alternatively
one or more coated or controlled release coated tablets, and an
enteric coated tablet of a benzimidazole derivative, both coatings
presenting different release characteristics.
2. An oral pharmaceutical composition of claim 1 , in the form of a
capsule comprising (a) a first enteric coated tablet containing at
least one pharmaceutically acceptable benzimidazole derivative or
salt thereof and (b) a second enteric coated composition containing
a nonsteroidal antiinflammatory drug from the family of oxicams and
pharmaceutically acceptable salts thereof, the coating dissolution of
the first enteric coated tablet being at least 0.5 pH unit,
advantageously between 0.5 and 4 pH unit, preferably between 0.5 and 3 pH unit, lower than the coating dissolution of the second
enteric coated tablet.
3. An oral pharmaceutical composition of claim 2, in the form of a capsule comprising (a) an enteric coated tablet containing at least
one pharmaceutically acceptable benzimidazole derivative or salt
thereof and (b) a controlled release composition containing a nonsteroidal antiinflammatory drug from the family of oxicams and
pharmaceutically acceptable salts thereof
4. The composition of any one of the claims 1 to 3 wherein the
capsule is a hard gelatin capsule, an hypromellose capsule, a starch
capsule or any other pharmaceutically acceptable capsule.
5. The composition of any one of the claims 1 to 3, wherein the
oxicam deπvative is present in said capsule as enteric coated pellets
6. The composition of any one of the claims 1 to 3, wherein the oxicam derivative is present in the capsule as an enteric coated
tablet
7. The composition of any one of the claims 1 to 3, wherein the
oxicam derivative is present in said capsule as controlled release
pellets
8. The composition of any one of the claims 1 to 3, wherein the oxicam derivative is present in the capsule as controlled release
tablet
9. The composition of any one of the claims 1 to 3, wherein the weight ratio between the pharmaceutically acceptable oxicam derivative or
salt thereof and the pharmaceutically acceptable benzimidazole
derivative is between 0.2 (w/w) and 5 (w/w), most preferably
between 0.5 and 2.
10. The composition of any one of the claims 1 to 3, wherein the
benzimidazole derivative is selected from the group consisting of omeprazole, lansoprazole, rabeprazole, pantoprazole,
pharmaceutically acceptable salts thereof and mixtures thereof.
1 1. The composition of any one of the claims 1 to 3, wherein the
oxicam derivative is selected from the group consisting of
meloxicam, piroxicam, tenoxicam and mixtures thereof.
12. The composition of any one of the claims 1 to 3, wherein the weight
ratio between the oxicam derivative or salt thereof and the benzimidazole derivative or salt thereof is between 0.2 (w/w) and 5
(w/w), most preferably between 0.5 and 2.
13. The composition of claim 5 or 7, wherein the pellets of the oxicam
derivative or salt thereof have a diameter comprised between 0.2
and 3 mm, preferably between 0.5 and 2 mm, and most preferably
between 0.7 and 1 .6 mm
14. The composition of claim 5 or 7, wherein the pellets containing the
oxicam derivative or salt thereof are manufactured by the process of
extrusion - spheronisation
15. The composition of claim 6 or 8 , wherein the tablets containing the
benzimidazole derivative or salt thereof is manufactured by direct
compression, coated with a pre-coating and subsequently coated
with an enteric coating
16. The composition of any one of the claims 1 to 3 wherein the tablets
containing the benzimidazole deπvative or salt thereof contains at least one pharmaceutically acceptable lipophilic antioxidant,
advantageously selected from the group consisting of ascorbyl
palmitate, butylhydroxyanisole, butylhydroxyanisole, propylgallate and mixtures thereof.
17. The composition of any one of the claims 1 to 3 wherein the
benzimidazole derivative is selected from the group consisting of omeprazole, pharmaceutically acceptable salts thereof, and
mixtures thereof.
18. The composition of any one of the claims 1 to 3 wherein the
oxicam derivative is selected from the group consisting of
meloxicam, pharmaceutically acceptable salts thereof, and mixtures
thereof, while the benzimidazole derivative is selected from the
group consisting of omeprazole, pharmaceutically acceptable salts
thereof, and mixtures thereof.
19. The composition of any one of the claims 1 to 3 wherein the oxicam derivative is selected from the group consisting of piroxicam,
pharmaceutically acceptable salts thereof, and mixtures thereof,
while the benzimidazole derivative is selected from the group
consisting of omeprazole, pharmaceutically acceptable salts thereof, and mixtures thereof.
20. The composition of any one of the claims 1 to 3 wherein the
amount of the benzimidazole derivative (calculated as base) per capsule is between 5 and 80 mg, preferably between 5 and 40 mg
21 . The composition of any one of the claims 1 to 3 wherein the
amount of the oxicam derivative (calculated as base) per capsule is between 5 and 40 mg, preferably between 7 and 25 mg
22. The composition of any one of the claims 1 to 3 wherein said
composition is suitable for a once a day administration to patients in need in such a treatment.
23. The composition of any one of the claims 1 to 3, wherein the enteric
coated tablet containing at least one pharmaceutically
benzimidazole derivative is provided with at lest two coatings, preferably two different coatings.
24. A manufacturing process suitable to obtain the composition as
described in any one of the claims 1 to 3, in which (a) an enteric
coated tablet containing at least one pharmaceutically acceptable
benzimidazole derivative or salt thereof and (b) a nonsteroidal
antiinflammatory drug from the family of oxicams or
pharmaceutically acceptable salt thereof are placed in a capsule.
25. The manufacturing process of claim 23, in which the composition as
one or more characteristics mentioned in anyone of the claims 4 to
23.
26. The use of a composition of any one of the claims 1 to 3 for a once
a day administration to a patient in need in such a treatment.
27. An oral pharmaceutical composition or kit comprising (a) a first enteric coated tablet containing at least one pharmaceutically acceptable benzimidazole derivative or salt thereof and (b) a second enteric coated composition containing a nonsteroidal antiinflammatory drug from the family of oxicams and pharmaceutically acceptable salts thereof, the coating dissolution of the first enteric coated tablet (a) being at least 0.5 pH unit lower than the coating dissolution of the second enteric coated composition (b), and the first enteric coated tablet (a) and the second enteric coated tablet (b) being in a form for being administered or released separately.
28. An oral pharmaceutical composition in the form of a capsule comprising (a) a first enteric coated tablet containing at least one pharmaceutically acceptable benzimidazole derivative or salt thereof and (b) a second controlled release composition containing a nonsteroidal antiinflammatory drug from the family of oxicams and pharmaceutically acceptable salts thereof, and the first enteric coated tablet (a) and the second controlled release composition (b) being administered or released separately.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BE0300004 | 2003-01-09 | ||
BEPCT/BE03/00004 | 2003-01-09 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004062552A2 true WO2004062552A2 (en) | 2004-07-29 |
WO2004062552A3 WO2004062552A3 (en) | 2004-10-14 |
Family
ID=32686673
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/BE2004/000003 WO2004062552A2 (en) | 2003-01-09 | 2004-01-09 | Pharmaceutical composition containing a nsaid and a benzimidazole derivative |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2004062552A2 (en) |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1655026A1 (en) * | 2004-10-04 | 2006-05-10 | Espinosa Abdala, Leopoldo | Solid pharmaceutical formulations comprising diacereine and meloxicam |
WO2007064274A1 (en) * | 2005-11-30 | 2007-06-07 | Astrazeneca Ab | Oral pharmaceutical dosage form comprising as active ingredients a proton pump inhibitor together with acetyl salicyclic acid |
WO2007078874A2 (en) * | 2005-12-30 | 2007-07-12 | Cogentus Pharmaceuticals, Inc. | Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors |
WO2008018825A1 (en) * | 2006-08-10 | 2008-02-14 | Astrazeneca Ab | Oral polyvinyl alcohol capsules comprising proton pump inhibitors |
WO2008095263A1 (en) * | 2007-02-09 | 2008-08-14 | Alphapharm Pty Ltd | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
WO2008151415A1 (en) * | 2007-06-11 | 2008-12-18 | Nathan Bryson | Combination for treatment of diabetes mellitus |
EP2015731A2 (en) * | 2006-04-28 | 2009-01-21 | Wockhardt Limited | Pharmaceutical compositions comprising non-steroidal antiinflammatory drug, antipyretic- analgesic drug and proton pump inhibitor |
US8206741B2 (en) | 2001-06-01 | 2012-06-26 | Pozen Inc. | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
CN104208039A (en) * | 2014-08-26 | 2014-12-17 | 杭州新诺华医药有限公司 | Naproxen esomeprazole enteric preparation and preparation method thereof |
WO2016155786A1 (en) * | 2015-03-31 | 2016-10-06 | Laboratorios Bagó S.A. | Enteric-coated pellets containing a proton pump inhibitor |
US9801824B2 (en) | 2008-09-09 | 2017-10-31 | Pozen Inc. | Method for delivering a pharmaceutical composition to patient in need thereof |
US9987231B2 (en) | 2011-12-28 | 2018-06-05 | Pozen Inc. | Compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA201290026A1 (en) | 2009-06-25 | 2012-07-30 | Астразенека Аб | A METHOD FOR TREATING A PATIENT THAT HAS A RISK OF DEVELOPMENT OF ANALISM ASSOCIATED WITH THE RECEPTION OF NONSTEROID ANTI-INFLAMMATORY MEDIA |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997025064A1 (en) * | 1996-01-08 | 1997-07-17 | Astra Aktiebolag | Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a nsaid |
WO2002032425A2 (en) * | 2000-10-20 | 2002-04-25 | Galephar M/F | Stable oral formulation containing benzimidazole derivative |
WO2004060372A1 (en) * | 2002-12-20 | 2004-07-22 | Tap Pharmaceutical Products Inc. | Dosage forms containing a proton pump inhibitor, a nsaid, and a buffer |
-
2004
- 2004-01-09 WO PCT/BE2004/000003 patent/WO2004062552A2/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997025064A1 (en) * | 1996-01-08 | 1997-07-17 | Astra Aktiebolag | Oral pharmaceutical dosage forms comprising a proton pump inhibitor and a nsaid |
WO2002032425A2 (en) * | 2000-10-20 | 2002-04-25 | Galephar M/F | Stable oral formulation containing benzimidazole derivative |
WO2004060372A1 (en) * | 2002-12-20 | 2004-07-22 | Tap Pharmaceutical Products Inc. | Dosage forms containing a proton pump inhibitor, a nsaid, and a buffer |
Non-Patent Citations (1)
Title |
---|
ANDERSSON T ET AL: "Lack of drug-drug interaction between three different non-steroidal anti-inflammatory drugs and omeprazole" EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY, vol. 54, no. 5, July 1998 (1998-07), pages 399-404, XP002292866 ISSN: 0031-6970 * |
Cited By (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8206741B2 (en) | 2001-06-01 | 2012-06-26 | Pozen Inc. | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
US9707181B2 (en) | 2001-06-01 | 2017-07-18 | Pozen Inc. | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
EP1655026A1 (en) * | 2004-10-04 | 2006-05-10 | Espinosa Abdala, Leopoldo | Solid pharmaceutical formulations comprising diacereine and meloxicam |
WO2007064274A1 (en) * | 2005-11-30 | 2007-06-07 | Astrazeneca Ab | Oral pharmaceutical dosage form comprising as active ingredients a proton pump inhibitor together with acetyl salicyclic acid |
WO2007078874A2 (en) * | 2005-12-30 | 2007-07-12 | Cogentus Pharmaceuticals, Inc. | Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors |
WO2007078874A3 (en) * | 2005-12-30 | 2008-03-06 | Cogentus Pharmaceuticals Inc | Oral pharmaceutical formulations containing non-steroidal anti-inflammatory drugs and acid inhibitors |
EP2614818A1 (en) * | 2006-04-28 | 2013-07-17 | Wockhardt Limited | Pharmaceutical compositions comprising non-steroidal antiinflammatory drug, antipyretic- analgesic drug and proton pump inhibitor |
EP2015731A2 (en) * | 2006-04-28 | 2009-01-21 | Wockhardt Limited | Pharmaceutical compositions comprising non-steroidal antiinflammatory drug, antipyretic- analgesic drug and proton pump inhibitor |
EP2015731A4 (en) * | 2006-04-28 | 2010-05-12 | Wockhardt Ltd | Pharmaceutical compositions comprising non-steroidal antiinflammatory drug, antipyretic- analgesic drug and proton pump inhibitor |
WO2008018825A1 (en) * | 2006-08-10 | 2008-02-14 | Astrazeneca Ab | Oral polyvinyl alcohol capsules comprising proton pump inhibitors |
EP2120878A4 (en) * | 2007-02-09 | 2013-05-08 | Alphapharm Pty Ltd | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
WO2008095263A1 (en) * | 2007-02-09 | 2008-08-14 | Alphapharm Pty Ltd | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
EP2120878A1 (en) * | 2007-02-09 | 2009-11-25 | Alphapharm PTY LTD | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
AU2008213744B2 (en) * | 2007-02-09 | 2013-12-05 | Alphapharm Pty Ltd | A dosage form containing two or more active pharmaceutical ingredients in different physical forms |
JP2010518028A (en) * | 2007-02-09 | 2010-05-27 | アルファファーム ピーティーワイ リミテッド | Dosage form containing two or more active pharmaceutical ingredients in different physical forms |
CN101674811B (en) * | 2007-02-09 | 2015-08-19 | 阿尔法制药有限公司 | The dosage form of the active pharmaceutical ingredient containing two or more different physical aspects |
WO2008151415A1 (en) * | 2007-06-11 | 2008-12-18 | Nathan Bryson | Combination for treatment of diabetes mellitus |
US9801824B2 (en) | 2008-09-09 | 2017-10-31 | Pozen Inc. | Method for delivering a pharmaceutical composition to patient in need thereof |
US9987231B2 (en) | 2011-12-28 | 2018-06-05 | Pozen Inc. | Compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
US10603283B2 (en) | 2011-12-28 | 2020-03-31 | Genus Lifesciences, Inc. | Compositions and methods for delivery of omeprazole plus acetylsalicylic acid |
CN104208039A (en) * | 2014-08-26 | 2014-12-17 | 杭州新诺华医药有限公司 | Naproxen esomeprazole enteric preparation and preparation method thereof |
WO2016155786A1 (en) * | 2015-03-31 | 2016-10-06 | Laboratorios Bagó S.A. | Enteric-coated pellets containing a proton pump inhibitor |
RU2679652C1 (en) * | 2015-03-31 | 2019-02-12 | Лабораториос Баго С. А. | Method of obtaining enteric coated granules containing proton pump inhibitor, and pharmaceutical compositions, containing multiple particles and such granules |
US10786458B2 (en) | 2015-03-31 | 2020-09-29 | Laboratorios Bago S.A. | Procedure for preparing enteric-coated pellets containing a proton pump inhibitor and multi-particle pharmaceutical compositions containing them |
Also Published As
Publication number | Publication date |
---|---|
WO2004062552A3 (en) | 2004-10-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP4638964B2 (en) | Oral pharmaceutical dosage form comprising proton pump inhibitor and NSAID | |
AU2009200966B2 (en) | Pharmaceutical compositions for the coordinated delivery of NSAIDs | |
KR101752014B1 (en) | Orally disintegrating tablet compositions comprising combinations of high and low-dose drugs | |
EP1879566B1 (en) | Compositions and methods for inhibiting gastric acid secretion | |
US20120128764A1 (en) | Controlled-release compositions comprising a proton pump inhibitor | |
RU2325163C2 (en) | Lamotrigine-based compositions of prolonged release | |
US20070184109A1 (en) | Compositions comprising triptans and nsaids | |
KR20100126465A (en) | Modified release pharmaceutical compositions comprising mycophenolate and processes thereof | |
AU2008282900A1 (en) | Pulsatile gastric retentive dosage forms | |
JP2009517466A (en) | An oral pharmaceutical dosage form containing a proton pump inhibitor as an active ingredient together with acetylsalicylic acid | |
WO2004062552A2 (en) | Pharmaceutical composition containing a nsaid and a benzimidazole derivative | |
KR20190092805A (en) | Pharmaceutical composition comprising Acetylsalicylic acid and Lansoprazole | |
AU2005204014B2 (en) | Pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent | |
EP3377046A1 (en) | Pharmaceutical composition containing a non-steroidal antiinflammatory drug and a proton pump inhibitor | |
JP2019532960A (en) | Esomeprazole-containing composite capsule and method for producing the same | |
US20150224056A1 (en) | Pharmaceutical compositions of ibuprofen and famotidine | |
ZA200509860B (en) | Composition comprising triptans and NSAIDS | |
US20130236538A1 (en) | Pharmaceutical compositions of ibuprofen and famotidine | |
WO2008062320A2 (en) | Extended release formulations of a proton pump inhibitor | |
EA044361B1 (en) | COMPOSITE CAPSULE CONTAINING EZOMEPRAZOLE AND METHOD FOR ITS PREPARATION | |
MXPA06007779A (en) | Pharmaceutical compositions comprising a proton pump inhibitor and a prokinetic agent |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
122 | Ep: pct application non-entry in european phase |