MXPA05004999A - Oral dosage forms of delayed-release enteric coated risedronate - Google Patents
Oral dosage forms of delayed-release enteric coated risedronateInfo
- Publication number
- MXPA05004999A MXPA05004999A MXPA/A/2005/004999A MXPA05004999A MXPA05004999A MX PA05004999 A MXPA05004999 A MX PA05004999A MX PA05004999 A MXPA05004999 A MX PA05004999A MX PA05004999 A MXPA05004999 A MX PA05004999A
- Authority
- MX
- Mexico
- Prior art keywords
- risedronate
- dosage form
- composition
- active ingredient
- form according
- Prior art date
Links
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 title claims abstract description 79
- 229960000759 risedronic acid Drugs 0.000 title claims abstract description 77
- 229940089617 Risedronate Drugs 0.000 title claims abstract description 67
- 239000006186 oral dosage form Substances 0.000 title claims abstract description 20
- 230000003111 delayed Effects 0.000 title claims description 4
- 239000004480 active ingredient Substances 0.000 claims abstract description 49
- 239000002552 dosage form Substances 0.000 claims abstract description 30
- 239000000546 pharmaceutic aid Substances 0.000 claims abstract description 13
- 210000000214 Mouth Anatomy 0.000 claims abstract description 10
- 210000002784 Stomach Anatomy 0.000 claims abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 210000003800 Pharynx Anatomy 0.000 claims abstract description 8
- 239000004615 ingredient Substances 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 36
- 239000012055 enteric layer Substances 0.000 claims description 21
- 229910021320 cobalt-lanthanum-strontium oxide Inorganic materials 0.000 claims description 19
- 210000003238 Esophagus Anatomy 0.000 claims description 14
- -1 inorganic acid salt Chemical class 0.000 claims description 13
- 239000010410 layer Substances 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 229920000642 polymer Polymers 0.000 claims description 8
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 210000000813 small intestine Anatomy 0.000 claims description 7
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 229940108696 risedronate sodium Drugs 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 210000002429 large intestine Anatomy 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000008213 purified water Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims description 4
- 229940069328 Povidone Drugs 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 235000003599 food sweetener Nutrition 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- 239000003765 sweetening agent Substances 0.000 claims description 4
- 229960001681 Croscarmellose Sodium Drugs 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229960000913 Crospovidone Drugs 0.000 claims description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 3
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 3
- 230000003000 nontoxic Effects 0.000 claims description 3
- 231100000252 nontoxic Toxicity 0.000 claims description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 3
- 230000002829 reduced Effects 0.000 claims description 3
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-(1R,3R,4S)-menthol Chemical group CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000007792 addition Methods 0.000 claims description 2
- 125000002723 alicyclic group Chemical group 0.000 claims description 2
- 125000003342 alkenyl group Chemical group 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 150000007860 aryl ester derivatives Chemical class 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000001419 dependent Effects 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- 159000000011 group IA salts Chemical class 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000005644 linolenyl group Chemical group 0.000 claims description 2
- 238000005461 lubrication Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000005425 toluyl group Chemical group 0.000 claims description 2
- 125000005065 undecenyl group Chemical group C(=CCCCCCCCCC)* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 125000005023 xylyl group Chemical group 0.000 claims description 2
- 125000000129 anionic group Chemical group 0.000 claims 6
- 229960001375 Lactose Drugs 0.000 claims 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
- 239000000443 aerosol Substances 0.000 claims 1
- 239000003086 colorant Substances 0.000 claims 1
- 238000007906 compression Methods 0.000 claims 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 238000011068 load Methods 0.000 claims 1
- 125000005395 methacrylic acid group Chemical group 0.000 claims 1
- JMHRGKDWGWORNU-UHFFFAOYSA-M sodium;2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetate Chemical compound [Na+].CC1=C(CC([O-])=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 JMHRGKDWGWORNU-UHFFFAOYSA-M 0.000 claims 1
- 238000005507 spraying Methods 0.000 claims 1
- 238000003756 stirring Methods 0.000 claims 1
- 210000001519 tissues Anatomy 0.000 abstract description 10
- 241000124008 Mammalia Species 0.000 abstract description 7
- 208000006881 Esophagitis Diseases 0.000 abstract description 6
- 206010030216 Oesophagitis Diseases 0.000 abstract description 6
- 210000000981 Epithelium Anatomy 0.000 abstract description 5
- 230000003628 erosive Effects 0.000 abstract description 5
- 210000004877 mucosa Anatomy 0.000 abstract description 5
- 230000036269 ulceration Effects 0.000 abstract description 5
- 230000000968 intestinal Effects 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 14
- 238000004090 dissolution Methods 0.000 description 12
- 239000011575 calcium Substances 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 210000000988 Bone and Bones Anatomy 0.000 description 8
- 229910052791 calcium Inorganic materials 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 7
- 239000010452 phosphate Substances 0.000 description 7
- 235000021317 phosphate Nutrition 0.000 description 7
- 210000003750 Lower Gastrointestinal Tract Anatomy 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000036740 Metabolism Effects 0.000 description 3
- 208000010191 Osteitis Deformans Diseases 0.000 description 3
- 230000002159 abnormal effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000035786 metabolism Effects 0.000 description 3
- 230000001575 pathological Effects 0.000 description 3
- 206010065687 Bone loss Diseases 0.000 description 2
- 229920003134 Eudragit® polymer Polymers 0.000 description 2
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 2
- 208000003393 Mammary Paget's Disease Diseases 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 210000002438 Upper Gastrointestinal Tract Anatomy 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- RGNDKSSUUISHGP-UHFFFAOYSA-N 2,4,7-trimethyl-2,3-dihydro-1H-indene Chemical compound CC1=CC=C(C)C2=C1CC(C)C2 RGNDKSSUUISHGP-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N 2-methyl-2-propenoic acid methyl ester Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010000059 Abdominal discomfort Diseases 0.000 description 1
- 206010003246 Arthritis Diseases 0.000 description 1
- 210000001124 Body Fluids Anatomy 0.000 description 1
- 206010006811 Bursitis Diseases 0.000 description 1
- 208000004434 Calcinosis Diseases 0.000 description 1
- ACSIXWWBWUQEHA-UHFFFAOYSA-N Clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 210000001198 Duodenum Anatomy 0.000 description 1
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 1
- 206010068715 Fibrodysplasia ossificans progressiva Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010020583 Hypercalcaemia Diseases 0.000 description 1
- 235000017858 Laurus nobilis Nutrition 0.000 description 1
- 240000001422 Laurus nobilis Species 0.000 description 1
- 210000004470 MDP Anatomy 0.000 description 1
- 206010027476 Metastasis Diseases 0.000 description 1
- 210000004400 Mucous Membrane Anatomy 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 201000001146 Paget's disease of bone Diseases 0.000 description 1
- 210000001562 Sternum Anatomy 0.000 description 1
- 206010043255 Tendonitis Diseases 0.000 description 1
- 235000005212 Terminalia tomentosa Nutrition 0.000 description 1
- 210000002303 Tibia Anatomy 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical group [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002547 anomalous Effects 0.000 description 1
- 230000002917 arthritic Effects 0.000 description 1
- 230000033558 biomineral tissue development Effects 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000018678 bone mineralization Effects 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000002328 demineralizing Effects 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 201000008286 diarrhea Diseases 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 201000002980 hyperparathyroidism Diseases 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 235000009808 lpulo Nutrition 0.000 description 1
- 230000003211 malignant Effects 0.000 description 1
- 230000011164 ossification Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 230000003389 potentiating Effects 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000069 prophylaxis Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229940032399 risedronate sodium 35 MG Drugs 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000000152 swallowing Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
Abstract
The present invention refers to oral dosage forms containing risedronate as active ingredient, which has a novel enteric coat;the dosage form comprises a safe and effective amount of a pharmaceutical composition including risedronate as an active principle and pharmaceutically acceptable excipients. The present dosage form avoids the exposition of the risedronate active principle to the epithelial tissue as well as to the oral cavity mucosa tissue, the pharynx, oesophagus and stomach, thereby preventing said tissues from erosion, ulceration and further irritations. According to the aforesaid description, the dosage forms perform a release of the risedronate active principle in the lower intestinal tract of humans, or any other mammal, in an effective and safe amount, which will substantially relieve esophagitis or oesophagus irritation, said release being accompanied by the oral administration of the risedronate active principle ingredients.
Description
FORMS OF ORAL DOSAGE OF RISEDRONATE WITH ENTHRENE LAYER OF DELAYED DELAY
TECHNICAL FIELD OF THE INVENTION.
The present invention is directed to oral dosage forms containing risedronate as an active ingredient with a new enteric layer, the dosage form comprising a safe and effective amount of a pharmaceutical composition including risedronate as an active ingredient and pharmaceutically acceptable excipients. Said dosage form avoids the exposure of the active ingredient of risedronate with the epithelial tissue and the mucosa of the oral cavity, the pharynx, esophagus and stomach and therefore protects said tissues from erosion, ulceration and other irritations. According to the above, the dosage forms carry out the release in the lower intestinal tract of the human or other mammals of a safe and effective amount of the risedronate active ingredient, which substantially alleviates esophagitis or irritation of the esophagus, which usually accompanies the oral administration of risedronate active ingredients.
BACKGROUND OF THE INVENTION.
Polyphosphonic acids and their pharmaceutically acceptable salts have been proposed for use in the treatment and prophylaxis of a number of pathological conditions that
P05 / 028-LSC can affect humans and other mammals that involve the metabolism of calcium and phosphate. Such conditions can be divided into two broad categories: 1. Conditions that are characterized by abnormal mobilization of calcium and phosphate that lead to general or specific bone loss or to excessively high levels of calcium and phosphate in body fluids. Such conditions are associated with strongly pathological tissue demineralizations. 2. Conditions that cause or result in abnormal deposition in the body of calcium and phosphate. These conditions are often associated with pathological calcifications. The first category includes osteoporosis, a condition in which bone tissue is disproportionately lost by affecting the development of new bone tissue. Essential amounts of bone are lost, the marrow and spaces in the tissue become larger, resulting in a reduced force of the same. The bone also becomes less dense and more brittle. Osteoporosis can be subclassified as, senile, drug-induced (e.g., adrenocorticoid, as can occur with steroid therapy), induced disease (e.g., arthritic and tumor), etc., however, the manifestations are similar. Another condition in the first category is Paget's disease (osteitis deformans). In this disease, the dissolution of normal bone occurs that is replaced by soft, poorly mineralized tissue so that the bone is deformed by the pressure of body weight, particularly in the tibia and femur. Hyperparathyroidism, malignant hypercalcemia, and osteological bone metastasis are also included in the first category.
P0S / 028-LSC The second category, implies conditions that are manifested by the anomalous deposition of calcium and phosphate, includes myositis ossificans progressiva. calcinosis universalis, and afflictions such as arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions that predispose the tissue involved in the deposition of calcium phosphates. Particular diphosphonates, such as ethan-1-hydroxy-1,1-diphosphonic acid (EHDP), propan-3-amino-1-hydroxy-1, 1-diphosphonic acid (APD), and dichloromethane diphosphonic acid ( -2, MDP) have been the subject of considerable research efforts in this area. Paget's disease and heterotopic ossification are currently successfully treated with EHDP. Diphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss. However, EHDP, APD and many other diphosphonates of the prior art have the propensity to inhibit bone mineralization when administered at high dosage levels. Risedronate is the most potent biological compound of diphosphonate that can be administered at low dosage levels; These lower dosage levels have resulted in a wider margin of safety and cause little or no inhibition of mineralization. Low dosage levels are also desirable to avoid gastrointestinal discomfort, such as nausea, diarrhea, and abdominal pains, which are frequently associated with oral administration of disphosphonates. In spite of the low dosage level that is possible with risedronate, oral administration of the compound gives rise to complaints in patients shortly after dosing; complaints are usually characterized in patients with heartburn, burning in the esophagus, pain and / or difficulty in swallowing, and / or there is pain behind and / or in the middle of the sternum. It is believed that these complaints originate in esophagitis or irritation of the esophagus caused by erosion,
P05 / 028-LSC ulceration, or other irritation of the epithelial tissues and mucosa of the upper gastrointestinal tract, usually through the mouth of the stomach, most likely in the esophagus. It is presumed that the irritation results from the active ingredient of risedronate that is in direct contact with these epithelial and mucosal tissues, resulting in topical irritation thereof. Accordingly, it is desirable to develop novel oral dosage forms of the risedronate compound that provide for the release of risedronate compound in the area of the small intestine. In the state of the art, various compositions of an active ingredient of risedronate are described, such as those found in U.S. Patent Nos. 5,935,602; 6,096,342; and 6,569,460, however none of them provides the advantages that characterize the composition of the present invention. On the other hand, in publication WO 93/09785 published on May 19, 1993, a first risedronate composition with a release layer that differs significantly from that described in the present invention is described given the abundance of components of said layer. US Pat. Nos. 5, 622, 721 and 6,596,710 also describe risedronate compositions coated with enteric layers of delayed release, however the components and manufacturing processes thereof are less efficient, safer and more expensive than described in the present invention. .
SUMMARY OF THE INVENTION.
P05 / Q28-LSC "The novel oral dosage forms of the present invention are enterically coated and delay the initiation of the release of risedronate until a certain point in the small intestine or large intestine is reached, so that provides protection to the tissues of the mouth, pharynx, esophagus and stomach The present invention is directed to compositions of oral dosage forms that are enteric coated that provide protection to the tissues and mucosa of the mouth, pharynx, esophagus and stomach, as well as an enteric layer composition dependent on the pH that dissolves to a certain point in the small or large intestine, and the process of manufacturing them.
SPECIFICATION OF THE INVENTION
The present invention is directed to a novel enterally coated oral dosage form of an active ingredient of risedronate comprising a safe and effective amount of a pharmaceutical composition that includes an active ingredient of rise'dronate and pharmaceutically acceptable excipients. Dosage forms prevent the release of the active ingredient risedronate in the oral cavity, pharynx, esophagus, and stomach in such a way that it protects the epithelial tissues and the mucosa thereof against erosion, ulceration or other irritation. Accordingly, the novel dosage forms disclosed effect the delivery to the lower gastrointestinal tract of the human or other mammal of a safe and effective amount of the risedronate active ingredient, and substantially alleviate esophagitis or
P05 / 028-LSC irritation of the esophagus that usually accompanies the oral administration of risedronate active ingredients. The invention further comprises the use of said dosage forms in the treatment of diseases characterized by abnormal metabolism of calcium and phosphate which comprises administering to a human or other mammal afflicted with such a disease a novel oral dosage form as described below . The present invention is directed to a novel enterally coated oral dosage form of a risedronate active ingredient comprising a safe and effective amount of a pharmaceutical composition comprising a risedronate active ingredient and pharmaceutically acceptable excipients. In addition, the dosage forms inhibit the release of the risedronate active ingredient into the stomach and the anterior duodenum. Therefore, the dosage forms effect the delivery to the lower gastrointestinal tract of the human or other mammal of a safe and effective amount of the risedronate active ingredient, and substantially alleviate the esophagitis or irritation of the esophagus that usually accompany oral administration of the active ingredients of risedronate. The term "risedronate", as used herein, denotes 3-pyridyl-1-hydroxyethylidene-1, 1-bisphosphomachic acid and has the following structure:
P05 / 028-LSC The risedronate compound is described in greater detail in the following publication, incorporated by reference: EPO patent application 0186405 by Benedict et al., Assigned to Procter & Gamble Co., published July 2, 1986. The term "risedronate active ingredient" includes risedronate, risedronate salts, and risedronate esters, or any mixture thereof. Any pharmaceutically acceptable, non-toxic salt or ester of risedronate can be used as the active ingredient of risedronate in the novel oral dosage forms of the present invention. The risedronate salts can be addition salts of the acid, in particular hydrochloride, also the pharmaceutically acceptable, non-toxic organic or inorganic acid salt can be used. In addition, the alkaline salts (Ca, magnesium), the Ca and Na-salts are preferred. Particularly, other esters of risedronate which are suitable for use as an active ingredient in the disclosed invention are straight or branched chain alkyl esters Cj-C? 8, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl , isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, laurel, myristyl, cetyl, and stearyl; straight or branched chain C2-C? 8 alkenyl esters, including, but not limited to, vinyl, alkyl, undecenyl, and linolenyl; cycloalkyl esters of C3-Cs, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; aryl esters, including, but not limited to, phenyl, toluyl, xylyl, and naphthyl; alicyclic esters, including, but not limited to, menthyl; and aralkyl esters, including, but not limited to, benzyl, and phenethyl. Generally speaking, the appropriate selection of the risedronate active ingredient depends on the type of formulation selected, the disease pattern, especially the site and type of disease, and the desired degree of release of the active ingredient. In addition, physical characteristics and
P05 / 028-LSC active ingredient chemicals should be considered when selecting pharmaceutically acceptable excipients and suitable for use in dosage forms containing the risedronate active ingredient. Pharmaceutically acceptable excipients usually include polymers, resins, plasticizers, fillers, lubricants, solvents, surfactants, preservatives, sweetening agents, flavoring agents, buffers, dyes and pharmaceutical grade pigments and viscosity agents. Notwithstanding the foregoing, in the present invention it is demonstrated that only filling agents of the microcrystalline or lactose cellulose type are required; of viscosity agents such as povidone and crospovidone; of magnesium stearate as a lubricant and sweetening agents such as croscarmellose sodium, to obtain a composition with better dissolution characteristics. The effective oral dose of the risedronate active ingredient depends on the extent of the disease and for adults it is generally from about 20 mg to about 40 mg daily, preferably from about 30 mg to about 35 mg daily. When the dose is to be administered continuously, the preferred dose is from 30 to 35 mg / day, preferably 35 mg / day.
The human being or another mammal suffering from diseases or disorders involving the metabolism of calcium and phosphate can be successfully treated by delivery of the active ingredient of risedronate to the lower gastrointestinal tract, preferably to the small intestine. The enteric novel coated oral dosage forms of the present invention deliver to the lower gastrointestinal tract; at the same time that prevents the unwanted release of risedronate in the mouth, pharynx and / or
P05 / 028-LSC the esophagus, as well as inhibits the release of the risedronate active ingredient in the stomach, thereby preventing the erosion, ulceration or irritation of the epithelial or mucosal layers of these tissues. Although delivery to the small intestine is generally only preferred, in some cases, however, it may be desired to deliver the risedronate active ingredient to the entire lower gastrointestinal tract, beginning with delivery to the small intestine and continuing with delivery to the large intestine.; in other cases, it is desired that the delivery of the active ingredient of risedronate be made only to the large intestine. When using the enteric novel coated oral dosage forms described, the pharmaceutically acceptable excipients, the coating methods, the formulations, and / or the thickness of the layer can be easily varied by a person skilled in the art. The novel oral dosage forms are formulated for formulations that delay delivery of the active ingredient. Accordingly, the tissues of the upper gastrointestinal tract, especially epithelial and mucosal layers of the oral cavity, pharynx, esophagus and stomach do not come into direct contact with the risedronate active ingredient. The oral dosage form, therefore, substantially relieves esophagitis or irritation of the esophagus which usually occurs when orally administering pharmaceutical compositions containing a risedronate active ingredient. The pharmaceutical compositions described below comprise from 1 to 25%, preferably from 19 to 20% of an active ingredient of risedronate and from 85 to 75%, preferably from 79 to 81% of pharmaceutically acceptable excipients.
P05 / 028-LSC The term "oral dosage form" as used herein means any pharmaceutical composition intended to be administered to the gastrointestinal tract of an individual via the mouth of the individual, and for the purposes of the present invention, the form of delivery may be in the form of a tablet, (preferably enteric coated) containing the granules or the particles of the risedronate active ingredient. The "enteric coated oral dosage form" as used below relates to an oral dosage form containing a pharmaceutical composition as described below that uses an enteric layer to effect the release of the risedronate active ingredient in the gastrointestinal tract. low. The term "enteric coated" as used below relates to a mixture of pharmaceutically acceptable excipients to which the risedronate active ingredient is applied, combined, mixed or added.
TABLETS COVERED ENTELICALLY FROM RISEDRONATE
The enteric coated risedronate tablets are made by preparing a compressed layer and tablet composition containing the risedronate active ingredient separately, and then applying the layer composition to the tablets.
A. Sodium risedronate compressed tablets The composition containing the active ingredient is prepared from the following excipients:
P05 / 028-LSC Active ingredient Risedronate sodium 35 mg
Excipients Cellulose Microcrystalline PH 200 45 mg udipress * 92.8 mg Croscamellose sodium 5.5 mg Magnesium stearate 1.7 mg
* Ludipress: Lactose; crospovidone; povidone: 93%, 3.5%, 3.5%
The tablets are prepared by mixing the risedronate ingredient with microcrystalline cellulose PH 200, croscamellose sodium and Ludipress ® for 30 minutes in a "V" mixer, which have been previously screened in a No. 20 mesh. The stearate is added. magnesium and is mixed with the other ingredients until adequate lubrication is achieved. The tablets are obtained by compressing the mixture in a tabletting machine.
B. Suspension of Enteric Layer
The enteric layer composition is prepared from the following excipients:
P05 / 028-LSC Excipients
Euragit® L30 D 55 42 mg (manufactured by Rohm Pharma GmbH, Weiterstadt, West Germany) Eudragit ® blue 040 22.72 mg Purified Water 60.30 mg
The enteric layer is prepared using the following method: The Eudragit L-30-D-55 is added to a convenient container and Ql N sodium hydroxide is added until a pH of 5.0 to 5.2 is obtained and diluted with a portion of the purified water , homogenizing the mixture. The Eudracolor 040 is added with agitation to the diluted Eudragit solution and mixed until homogenized. In a container of suitable capacity, the risedronate sodium tablets prepared as described above are loaded, heated to about 30 ° to 35 ° C. The enteric suspension is sprayed onto the tablets at approximately 4 -8 mg / minute. When the spray cycle is completed, the temperature is reduced and the tablets are removed from the container. The applied layer is about 18 to 21 mg, that is, about 18 to 21 microns thick.
DISSOLUTION PROFILE OF RISEDRONATE. The dissolution profile of Risedronate sodium tablet with enteric layer of 35 mg was run, obtaining the following results:
P05 / 029-LSC SODIUM RISEDRONATE TABLET WITH ENTÉRICA LAYER OF 35 mg: To verify the effectiveness of the enteric layer in the tablet, the product was submitted to the acid resistance test under the following conditions: CONDITIONS: Dissolution medium: 750 mL of hydrochloric acid 0.1 N Apparatus: Pallets at 100 rpm. Temperature of the dissolution medium: 37 ° C ± 0.5 ° C Time: 2 hours.
The results were the following:
TABLE 1. RESULTS OBTAINED FROM THE ACID TEST RESISTANCE GRAGEA% DISSOLVED 1 6.9412 ~ 7.82? 0"
With the above results, the effectiveness of the enteric layer is demonstrated since the specification indicates that no more than 10% should dissolve.
PQ5 / 029-LSC Once the effectiveness of the enteric layer was verified, the dissolution profile was carried out using buffer pH 6.8 as dissolution medium. To perform the quantification of the dissolved percent of Risedronate sodium, a standard curve was made with supplier standard, which has a purity of 99.95%. Table 3 shows the results obtained from the curve (to make the dilutions, we used a buffer with an HOP of 6.8):
TABLE 2. RESULTS OBTAINED FROM THE PATTERN CURVE
CONCENTRATION ABSORBANCES mcg / mL AVERAGE
. 9920 0.1868 19.9900 0.2331 23.9880 0.2841 27.9860 0.3262 Tl "9840 ~ 0.3744
These results were graded as shown in Figure 1. Where the equation of the line is y = 0.0162x + 0.0017, with a linear correlation coefficient of 0.9998
P05 / 029-LSC The dissolution profile of Risedronate sodium tablet with enteric layer of 35 mg was carried out under the following conditions: CONDITIONS: Dissolution medium: 900 mL of Buffer pH 6.8 Apparatus: Paddles at 100 rpm. Temperature of the dissolution medium 37 ° C ± 0.5 ° C
The results obtained were the following:
TABLE 3. RESULTS OBTAINED FROM THE DISSOLUTION PROFILE OF
SODIUM RISEDRONATE TABLETS WITH ENTÉRICA LAYER OF 35 mg
These results were graded as shown in Figure 2.
P05 / 029-LSC
Claims (20)
1. A novel enteric-coated oral dosage form of an active ingredient of risedronate comprising from 15 to 25%, preferably from 19 to 20% of an active ingredient of risedronate and from 85 to 75%, preferably from 79 to 81% of pharmaceutically acceptable excipients.
2. A dosage form according to claim 1 wherein the pharmaceutical composition comprises from 19 to 20% of the risedronate active ingredient and from 80 to 81% of the pharmaceutically acceptable excipients.
3. A novel enteric-coated oral dosage form of an active ingredient of risedronate comprising from about 20 mg to about 40 mg, preferably from about 30 mg to about 35 mg, when the dose is to be administered continuously, the preferred dose is a from 30 to 35 mg, preferably 35 mg and the pharmaceutical excipients from 140 to 160 mg,.
4. A novel enteric-coated oral dosage form of an active ingredient of risedronate according to any of the preceding claims, wherein said dose is administered daily.
5. A dosage form according to any of the preceding claims wherein the active component of risedronate is selected from the group consisting of risedronate salts and esters, or any mixture thereof; the risedronate salts can be addition salts of the acid, in particular hydrochloride, the pharmaceutically acceptable, non-toxic organic or inorganic acid salt; the alkaline salts (Ca, magnesium), Na salt; Other esters of risedronate are the alkyl esters of P05 / 029- SC straight or branched chain C -C18, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl; straight or branched chain alkenyl esters C2-Clg, including, but not limited to vinyl, alkyl, undecenyl, and linolenyl; C3-C8 cycloalkyl esters, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; aryl esters, including, but not limited to, phenyl, toluyl, xylyl, and naphthyl; alicyclic esters, including, but not limited to, menthyl; and aralkyl esters, including, but not limited to, benzyl, and phenethyl.
6. A dosage form according to any of the preceding claims wherein the active component is sodium risedronate.
7. A dosage form according to any of the preceding claims wherein the pharmaceutically acceptable excipients include fillers, viscosity agents, sweetening agents and lubricants.
8. A dosage form according to any of the preceding claims wherein the filler is PH 200 microcrystalline cellulose, the viscosity agents are crospovidone, povidone and lactose; the lubricating agent is magnesium stearate and the sweetening agent is croscarmellose sodium.
9. A dosage form according to any of the preceding claims wherein the viscosity agent has 93% lactose, 3.5% crsopovidone and 3.5% povidone.
10. A dosage form according to any of the preceding claims wherein the risedronate active ingredient is present between 15% and 25% by weight of the P05 / 029-LSC composition, preferably between 19 and 20% by weight of the composition; the filling agent between 28% and 35% by weight of the composition, preferably between 30% and 32% by weight of the composition; the viscosity agent between 2.5% and 4.5% by weight of the composition, preferably between 3% and 4%; and the lubricating agent between 0.5% and 1.5%, by weight of the composition.
11. A dosage form according to any of the preceding claims wherein the enteric layer is a pH dependent layer and the dosage form is a delayed release pharmaceutical composition.
12. A dosage form according to any of the preceding claims wherein the enteric layer is insoluble at a pH below 5 but soluble at a pH of 6 or higher.
13. A dosage form according to any of the preceding claims wherein the enteric layer is insoluble in the oral cavity, the pharynx, esophagus and stomach, but soluble in the small and / or large intestine.
14. A dosage form according to any of the preceding claims wherein the enteric layer comprises an anionic carboxylic polymer.
15. A dosage form according to any of the preceding claims wherein the anionic carboxylic polymer of the enteric layer is a methacrylic acid polymer partially esterified with methyl wherein the ratio of free carboxylic groups to ester groups is about 1: 2.
16. A dosage form according to any of the preceding claims wherein the enteric layer comprises from 30 to 35% by weight of the composition of the anionic carboxylic polymer; from 16% to 20% by weight of the composition of a colorant Pharmaceutically acceptable P05 / 029-LSC and from 46% to 50% by weight of the purified water composition, preferably from 33 to 34% by weight of the composition of the anionic carboxylic polymer; 18% to 19% by weight of the composition of a pharmaceutically acceptable dye and 48% to 49%) by weight of the purified water composition
17. A dosage form according to any of the preceding claims wherein the enteric layer has a thickness between approximately 150 and 300 microns thick.
18. A manufacturing process of a tablet of a dosage form containing an active ingredient of risedronate sodium, said process comprises the steps of: - screening in a number 20 mesh, the risedronate ingredient with PH 200 microcrystalline cellulose, croscarmellose sodium and ludipress; - mixing the above components in a mixer "V" for 30 minutes; - add magnesium stearate and mix with the other ingredients until adequate lubrication is achieved. - transport the previous mixture to compression tablet machine.
19. A process for manufacturing an enteric layer composition for a dosage form containing as a composition an active ingredient of risedronate, said process comprising the steps of: - adding anionic carboxylic polymer in a convenient vessel sodium hydroxide 0.1 N until obtaining a pH of 5.0 to 5.2 dilute with a portion of the purified water and homogenize the mixture; P05 / 029-LSC add with stirring the dye 040 to the diluted suspension of the anionic carboxylic polymer and mix until homogenizing.
20. A process for the manufacture of an enteric-dose dosage form containing an active ingredient of risedronate, said process comprising the steps of - in a convenient layer container, loading the risedronate sodium tablets prepared as described in claim 18; cayenating said container with the tablets to about 30 ° to 35 ° C; spraying the enteric layer suspension obtained according to the process described in claim 19 on the tablets at approximately 4 to 8 milligrams per minute; - once the aerosol cycle is completed, the temperature is reduced and the tablets are removed from the container; - the applied layer is about 18 to 21 mg, that is, about 150 to 300 microns thick. P0S / 029-LSC
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| Publication Number | Publication Date |
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| MXPA05004999A true MXPA05004999A (en) | 2007-04-10 |
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