MXPA00003219A - Pharmaceutical compositions for oral administration of molecular iodine - Google Patents
Pharmaceutical compositions for oral administration of molecular iodineInfo
- Publication number
- MXPA00003219A MXPA00003219A MXPA/A/2000/003219A MXPA00003219A MXPA00003219A MX PA00003219 A MXPA00003219 A MX PA00003219A MX PA00003219 A MXPA00003219 A MX PA00003219A MX PA00003219 A MXPA00003219 A MX PA00003219A
- Authority
- MX
- Mexico
- Prior art keywords
- iodine
- iodide
- iodate
- sodium
- molecular
- Prior art date
Links
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 title claims abstract description 389
- 239000008194 pharmaceutical composition Substances 0.000 title description 8
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 204
- 239000011630 iodine Substances 0.000 claims abstract description 203
- 210000002784 Stomach Anatomy 0.000 claims abstract description 32
- 241000124008 Mammalia Species 0.000 claims abstract description 29
- 241000894007 species Species 0.000 claims abstract description 28
- 239000007800 oxidant agent Substances 0.000 claims abstract description 21
- 230000001590 oxidative Effects 0.000 claims abstract description 21
- 230000001225 therapeutic Effects 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 19
- 239000003638 reducing agent Substances 0.000 claims abstract description 19
- 210000004051 Gastric Juice Anatomy 0.000 claims abstract description 8
- 230000033116 oxidation-reduction process Effects 0.000 claims abstract description 5
- 238000006722 reduction reaction Methods 0.000 claims abstract description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 claims description 112
- 239000000203 mixture Substances 0.000 claims description 90
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M Sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 87
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 claims description 40
- 229940083599 Sodium Iodide Drugs 0.000 claims description 29
- 235000009518 sodium iodide Nutrition 0.000 claims description 29
- 239000012530 fluid Substances 0.000 claims description 22
- MHAJPDPJQMAIIY-UHFFFAOYSA-N hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 22
- WTCBONOLBHEDIL-UHFFFAOYSA-M Sodium iodate Chemical compound [Na+].[O-]I(=O)=O WTCBONOLBHEDIL-UHFFFAOYSA-M 0.000 claims description 20
- 239000011697 sodium iodate Substances 0.000 claims description 20
- 235000015281 sodium iodate Nutrition 0.000 claims description 20
- 229940032753 sodium iodate Drugs 0.000 claims description 20
- 208000000571 Fibrocystic Breast Disease Diseases 0.000 claims description 18
- 230000002496 gastric Effects 0.000 claims description 17
- 230000003647 oxidation Effects 0.000 claims description 17
- 238000007254 oxidation reaction Methods 0.000 claims description 17
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 14
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 12
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 claims description 11
- 235000010323 ascorbic acid Nutrition 0.000 claims description 11
- 239000011668 ascorbic acid Substances 0.000 claims description 11
- 229960005070 ascorbic acid Drugs 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 230000002354 daily Effects 0.000 claims description 9
- 239000008121 dextrose Substances 0.000 claims description 9
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 8
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 8
- 108090000437 Peroxidases Proteins 0.000 claims description 8
- 102000003992 Peroxidases Human genes 0.000 claims description 8
- -1 peroxide salts Chemical class 0.000 claims description 8
- 239000000600 sorbitol Substances 0.000 claims description 8
- 235000010356 sorbitol Nutrition 0.000 claims description 8
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 7
- 108010001336 Horseradish Peroxidase Proteins 0.000 claims description 7
- 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 7
- 229940072417 Peroxidase Drugs 0.000 claims description 7
- JLKDVMWYMMLWTI-UHFFFAOYSA-M Potassium iodate Chemical compound [K+].[O-]I(=O)=O JLKDVMWYMMLWTI-UHFFFAOYSA-M 0.000 claims description 7
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 7
- 239000000839 emulsion Substances 0.000 claims description 7
- 239000008101 lactose Substances 0.000 claims description 7
- 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 7
- 239000001187 sodium carbonate Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- 239000001230 potassium iodate Substances 0.000 claims description 6
- 235000006666 potassium iodate Nutrition 0.000 claims description 6
- 229940093930 potassium iodate Drugs 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 235000000346 sugar Nutrition 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- ZLNQQNXFFQJAID-UHFFFAOYSA-L Magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 5
- 229920002774 Maltodextrin Polymers 0.000 claims description 5
- 229920002472 Starch Polymers 0.000 claims description 5
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 230000037396 body weight Effects 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000008103 glucose Substances 0.000 claims description 5
- 239000001095 magnesium carbonate Substances 0.000 claims description 5
- 239000011776 magnesium carbonate Substances 0.000 claims description 5
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- 239000005720 sucrose Substances 0.000 claims description 5
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical class [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 5
- YDRWXKNFHCZTJF-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-N-methylethanamine;hydroiodide Chemical compound [I-].C[NH2+]CCC1=CC=C(OC)C(OC)=C1 YDRWXKNFHCZTJF-UHFFFAOYSA-N 0.000 claims description 4
- KGBXLFKZBHKPEV-UHFFFAOYSA-N Boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 4
- UHWJJLGTKIWIJO-UHFFFAOYSA-L Calcium iodate Chemical compound [Ca+2].[O-]I(=O)=O.[O-]I(=O)=O UHWJJLGTKIWIJO-UHFFFAOYSA-L 0.000 claims description 4
- 239000004151 Calcium iodate Substances 0.000 claims description 4
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 4
- 235000010469 Glycine max Nutrition 0.000 claims description 4
- BLQJIBCZHWBKSL-UHFFFAOYSA-L Magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 4
- 239000005913 Maltodextrin Substances 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 4
- 229940049964 Oleate Drugs 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 4
- 229940107816 ammonium iodide Drugs 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims description 4
- 239000004327 boric acid Substances 0.000 claims description 4
- 235000019390 calcium iodate Nutrition 0.000 claims description 4
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 4
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 4
- 229910001641 magnesium iodide Inorganic materials 0.000 claims description 4
- 229940035034 maltodextrin Drugs 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 4
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 4
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 4
- 230000003000 nontoxic Effects 0.000 claims description 4
- 231100000252 nontoxic Toxicity 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-M oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC([O-])=O ZQPPMHVWECSIRJ-KTKRTIGZSA-M 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 230000001603 reducing Effects 0.000 claims description 4
- 239000001488 sodium phosphate Substances 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 150000008163 sugars Chemical class 0.000 claims description 4
- 239000000454 talc Substances 0.000 claims description 4
- 235000012222 talc Nutrition 0.000 claims description 4
- 229910052623 talc Inorganic materials 0.000 claims description 4
- UNMYWSMUMWPJLR-UHFFFAOYSA-L Calcium iodide Chemical compound [Ca+2].[I-].[I-] UNMYWSMUMWPJLR-UHFFFAOYSA-L 0.000 claims description 3
- 229940046413 Calcium iodide Drugs 0.000 claims description 3
- ICIWUVCWSCSTAQ-UHFFFAOYSA-N Iodic acid Chemical compound OI(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-N 0.000 claims description 3
- 229940057428 LACTOPEROXIDASE Drugs 0.000 claims description 3
- 108010023244 Lactoperoxidase Proteins 0.000 claims description 3
- 102000028880 Lactoperoxidase Human genes 0.000 claims description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 229910001640 calcium iodide Inorganic materials 0.000 claims description 3
- 150000004694 iodide salts Chemical class 0.000 claims description 3
- 229960004839 potassium iodide Drugs 0.000 claims description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 229940072107 Ascorbate Drugs 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 206010036618 Premenstrual syndrome Diseases 0.000 claims description 2
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 201000009273 endometriosis Diseases 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 238000006479 redox reaction Methods 0.000 claims description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims 6
- 229920002678 cellulose Polymers 0.000 claims 6
- 239000001913 cellulose Substances 0.000 claims 6
- 235000010980 cellulose Nutrition 0.000 claims 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical class [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims 4
- 229960003563 Calcium Carbonate Drugs 0.000 claims 3
- 229950008138 Carmellose Drugs 0.000 claims 3
- 229940031574 HYDROXYMETHYL CELLULOSE Drugs 0.000 claims 3
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims 3
- 239000001506 calcium phosphate Substances 0.000 claims 3
- 235000011010 calcium phosphates Nutrition 0.000 claims 3
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims 3
- 239000001184 potassium carbonate Substances 0.000 claims 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 3
- 235000011008 sodium phosphates Nutrition 0.000 claims 3
- 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 claims 1
- 229960005069 Calcium Drugs 0.000 claims 1
- 239000004343 Calcium peroxide Substances 0.000 claims 1
- LHJQIRIGXXHNLA-UHFFFAOYSA-N Calcium peroxide Chemical compound [Ca+2].[O-][O-] LHJQIRIGXXHNLA-UHFFFAOYSA-N 0.000 claims 1
- 229940093915 Gynecological Organic acids Drugs 0.000 claims 1
- 229960003975 Potassium Drugs 0.000 claims 1
- XOLBLPGZBRYERU-UHFFFAOYSA-N Tin dioxide Chemical compound O=[Sn]=O XOLBLPGZBRYERU-UHFFFAOYSA-N 0.000 claims 1
- 235000019402 calcium peroxide Nutrition 0.000 claims 1
- 229910000389 calcium phosphate Inorganic materials 0.000 claims 1
- 150000007524 organic acids Chemical class 0.000 claims 1
- 235000005985 organic acids Nutrition 0.000 claims 1
- 235000021317 phosphate Nutrition 0.000 claims 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 claims 1
- 235000007686 potassium Nutrition 0.000 claims 1
- 229910000160 potassium phosphate Inorganic materials 0.000 claims 1
- 235000011009 potassium phosphates Nutrition 0.000 claims 1
- 235000019798 tripotassium phosphate Nutrition 0.000 claims 1
- 241000700159 Rattus Species 0.000 description 44
- 239000003814 drug Substances 0.000 description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 238000011065 in-situ storage Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 17
- 239000000126 substance Substances 0.000 description 17
- 210000001519 tissues Anatomy 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 235000005911 diet Nutrition 0.000 description 13
- 230000037213 diet Effects 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- 230000002950 deficient Effects 0.000 description 11
- 210000001685 Thyroid Gland Anatomy 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 230000001684 chronic Effects 0.000 description 9
- 229940079593 drugs Drugs 0.000 description 9
- 238000005755 formation reaction Methods 0.000 description 9
- 238000005259 measurement Methods 0.000 description 9
- 230000001988 toxicity Effects 0.000 description 9
- 231100000419 toxicity Toxicity 0.000 description 9
- 102000015728 Mucins Human genes 0.000 description 8
- 108010063954 Mucins Proteins 0.000 description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-M Perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 8
- 230000035492 administration Effects 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000008177 pharmaceutical agent Substances 0.000 description 8
- WRTMQOHKMFDUKX-UHFFFAOYSA-N triiodide Chemical compound I[I-]I WRTMQOHKMFDUKX-UHFFFAOYSA-N 0.000 description 8
- 210000000481 Breast Anatomy 0.000 description 7
- 206010016654 Fibrosis Diseases 0.000 description 7
- 206010020718 Hyperplasia Diseases 0.000 description 7
- 210000004293 Mammary Glands, Human Anatomy 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 230000004761 fibrosis Effects 0.000 description 7
- 206010067997 Iodine deficiency Diseases 0.000 description 6
- 230000001154 acute Effects 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 235000006479 iodine deficiency Nutrition 0.000 description 6
- 230000028327 secretion Effects 0.000 description 6
- 206010058314 Dysplasia Diseases 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 210000000038 chest Anatomy 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- DHCDFWKWKRSZHF-UHFFFAOYSA-L thiosulfate(2-) Chemical compound [O-]S([S-])(=O)=O DHCDFWKWKRSZHF-UHFFFAOYSA-L 0.000 description 5
- 241000282412 Homo Species 0.000 description 4
- 241000283984 Rodentia Species 0.000 description 4
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
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- 231100000331 toxic Toxicity 0.000 description 4
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- PAWIVBWALDNUJP-UHFFFAOYSA-N Iodine trichloride Chemical compound ClI(Cl)Cl PAWIVBWALDNUJP-UHFFFAOYSA-N 0.000 description 3
- 108090000284 Pepsin A Proteins 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
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- 239000011707 mineral Substances 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
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- 150000005527 organic iodine compounds Chemical class 0.000 description 3
- 229940111202 pepsin Drugs 0.000 description 3
- 230000003334 potential Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000011573 trace mineral Substances 0.000 description 3
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- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical class [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- YVPYQUNUQOZFHG-UHFFFAOYSA-N Diatrizoic acid Chemical compound CC(=O)NC1=C(I)C(NC(C)=O)=C(I)C(C(O)=O)=C1I YVPYQUNUQOZFHG-UHFFFAOYSA-N 0.000 description 2
- BJHIKXHVCXFQLS-UYFOZJQFSA-N Fructose Natural products OC[C@@H](O)[C@@H](O)[C@H](O)C(=O)CO BJHIKXHVCXFQLS-UYFOZJQFSA-N 0.000 description 2
- 210000004907 Glands Anatomy 0.000 description 2
- 229910004003 H5IO6 Inorganic materials 0.000 description 2
- WZUVPPKBWHMQCE-VYIIXAMBSA-N Haematoxylin Chemical compound C12=CC(O)=C(O)C=C2C[C@@]2(O)C1C1=CC=C(O)C(O)=C1OC2 WZUVPPKBWHMQCE-VYIIXAMBSA-N 0.000 description 2
- AQLJVWUFPCUVLO-UHFFFAOYSA-N Hydrogen peroxide - urea Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Iodoform Chemical compound IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 206010058667 Oral toxicity Diseases 0.000 description 2
- 210000003800 Pharynx Anatomy 0.000 description 2
- 239000004698 Polyethylene (PE) Substances 0.000 description 2
- 210000002966 Serum Anatomy 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M Sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000004809 Teflon Substances 0.000 description 2
- 229940036555 Thyroid hormones Drugs 0.000 description 2
- 206010070863 Toxicity to various agents Diseases 0.000 description 2
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- 210000004027 cells Anatomy 0.000 description 2
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Abstract
The invention is a method of administering therapeutic iodine for treating a disorder in a mammal. The invention comprises a step of feeding said mammal an effective amount of an oxidant for an iodine species and an iodine reductant which will cause oxidation-reduction reactions upon contact with the gastric juices present in the stomach of the mammal. This is done such that molecular iodine is generated in vivo at a ratio of molecular iodine to total iodine of above at least about 0.8.
Description
COMPUESTOS FARMACEUTIG¡j | »ARA THE ORAL ADMINISTRATION OF MOLECULAR IODINE
FIELD OF THE INVENTION This invention relates to a method for generating molecular iodine, in situ, in the stomach of a mammal to be used as an effective therapeutic agent, such as, in the treatment of fibrocystic breast syndrome, as well as other diseases that they require either chronic or acute dosage of therapeutic iodine at a controlled ratio of molecular iodine to total iodine above at least between 0.80 and 1.0, and preferably between 0.9 and 1.0. The present invention relates to a pharmaceutical composition that can be administered orally to a mammal to produce an effective iodine therapeutic agent, which has a ratio of molecular iodine to total iodine of at least 0.8 on contact with gastric juices in the stomach of a mammal. The method and oral pharmaceutical compositions of the present invention generally molecular iodine internally only upon contact with gastric juices in the stomach of a mammal and in a ratio of molecular iodine to total iodine above at least 0.8.
Background Iodine, including organically bound iodine, inorganic iodine and molecular iodine, ie, l2, has been used to treat human diseases. Iodine-containing compounds have been used extensively as expectorants. US Patents Nos.
i &a? a? sJ f & 4,187,294; 4,338,304 and 4,394,376 describe compositions containing iodine bound to protein for the treatment of hypercholesterolemia, diabetes and hyperlipidemia. U.S. Patent No. No. 4,259,322 describes tuberculosis medication containing sodium iodide. Plus
recently, US patents us. 4,816,255; 5,171,582; 5,250,304 and 5,389,385 describe compositions of "elemental iodine" (12) in water for oral administration in humans to treat a variety of human diseases. U.S. Patent No. 5,589,198 describes the benefits of using elemental iodine or "iodine metal" with
pharmaceutically acceptable carriers in the treatment of fibrocystic breast syndrome. Much of the prior art literature refers to "iodine" in an imprecise manner. The word iodine has been used in the literature to refer to several different chemical species that contain atoms of
iodine. Many different compounds with different and materially different properties contain iodine. For example, the literature on iodine disinfection clearly shows that the biocidal efficacy of various iodine species is profoundly different; molecular iodine (12) is an active biocide while iodide (1") has little, if any,
biocidal activity. Traditional beliefs in the field of toxicology (RC Haynes Jr and F. Murad, "Thyroid and Antithyroid Drugs", in Goodman and Gilman's the Pharmacological Basis of Therapeutics (The pharmacological basis of Goodman and Gilman), Eds. AG Gilman et al., 7th ed., Pp. 25 682-815, 1985, WB Saunders, Philadelphia) have argued that iodine
molecular and iodide have identical toxicity profiles; however, no direct experimental data was used to support this assumption. In fact, the toxicity and therapeutic efficacy of these different iodine species could vary dramatically just as their activity does
biocide. Unfortunately, the pharmaceutical literature on iodine has not indicated distinctions between the properties of many different chemical species that contain iodine atoms. The most serious concern for the administration of a pharmaceutical iodine refers to the potential for toxic reactions. To this
respect, it is believed that iodine is the form of iodine responsible for "poisoning by iodide" or "iodism". There is no way to predict which patient will react unfavorably to iodide, and an individual may vary in their sensitivity to iodine from time to time. A series of symptoms can result from iodism. Symptoms may include
Burns in the mouth and throat; acidity of the teeth and gum; increased salivation; coryza, irritation of the respiratory tract; cough; headache; enlarged glands; inflammation of the pharynx, larynx and amygdalas; skin lesions; gastric irritation; diarrhea; fever; anorexia and depression; and severe and sometimes fatal effects can occur.
(yoderma). In essence, the human consumption of iodide at levels in excess of the range (0.1 50 to 1.0 mg / day) established by the FDA researchers (J. A. Pennington, "A review of iodine toxicity reports". reports of iodine toxicity), J. Am. Dietetic Assoc, Vol. 90, pp. 1 571 - 1 581) presents a health risk.
Scientific studies on the relative oral toxicity of molecular iodide and iodide were conducted during the early 1990s (Karla Thrall, Ph. D. Thesis, "Formation of Organic By-Products Following Consumption of the Disinfected Drinking Water"). of organic byproducts 5 following the consumption of drinking water disinfected with iodine), Summary and Conclusion Section, Oregon State University, Department of Chemistry, 1992). These studies incorporated experiments to test the prevailing belief that iodide and molecular iodine were toxicologically and physiologically equivalent. The weight of a 10-thyroid thyroid is a key diagnostic measurement used in these studies to evaluate the toxicity of an iodine composition. Subchronic administration of iodide to male rats increased the weight of their thyroid to a iodide concentration of 10 mg / kg; Molecular iodine had no effect on the weight of the thyroid even at concentrations of 1000 mg / kg (Sherer et al., Journal of Toxicology and Environmental Health, Vol. 32, p. 89-1 01, 1 991). This study by Sherer did not measure an increase in steady state levels of the thyroid hormones until the animals were exposed to repeated daily doses of molecular iodine at 10 mg per kilogram of body weight. 20 It can be concluded from these studies that iodide can have an effect on thyroid weight in mammals at concentrations that are 10 times less than a comparable effect of molecular iodine. Another way of establishing this is that ten times more molecular iodine is required than iodide to affect the function of the animal thyroid with an orally administered iodine composition.
M ** »* ^^, ^^. ***** ^ ^, 3 ^, ^^ .... ^^^^^^ ^ ^^^^^^^^^^^^^^ J The human body contains approximately 1 8 to 20 mg of iodine. Iodine is an essential component of thyroxine and tri-iodothyronine. These hormones are essential for the maintenance of normal metabolic activity and have an effect on almost all mammalian tissue. Excess iodine can lead to an imbalance in thyroid hormones. The reduced toxicity in the thyroid gland exhibited by molecular iodine, as compared to iodide in the studies by Sherer et al. , has important implications for the design of an oral iodine pharmacist. These studies indicate that, all other factors being equal, molecular iodine is a preferred form of iodine for an oral medication. This would be especially true of disease states that require chronic administrations of said iodine pharmacist. In 1896, Dr. Beatson made an early observation of the association of iodine with the salt of the human female breast. He treated metastatic breast cancer using dried thyroid in large doses. The dried thyroid contains an abundance of iodine bound to protein. In 1966, an early association of a state of iodine deficiency and benign breast dysplasia was reported by a physician who reported an improvement rate of 71% in women with dysplastic mastodynia treated with iodine (Vishnyakova VV et al., " On the Treatment of Dyshormonal Hyperplasia of Mammary Glands "(On the treatment of mammary gland dishormonal hyperplasia), Vestin. Sakad. Med. Mauk. S. S. S. R., Vol. 21: p. 1 9, 1 966). The treatment of mammary dysplasia using traditional Chinese medicine such as Sargassum, which contains a high concentration of iodide, has provided a cure rate of 65.4 percent. Ghent (US Patent No. 5, 389, 385 and 5, 589, 1 98) explored the use of elemental iodine to treat a variety of human diseases. The scientific literature provides clear evidence that iodine in several different forms is an effective therapeutic agent against many different mammalian diseases. Animal models of fibrocystic breast syndrome have been studied for about 40 years. The "iodine-deficient rat model" has been used to correlate iodine deficiency with chest dysplasia. Several studies provide evidence that indicates that iodine can reverse chest dysplasia. Studies in humans have shown improvement or complete elimination of fibrocystic breast syndrome after several months of iodine therapy. Other conditions of mammalian diseases that have been treated with iodine include ovarian diseases, premenstrual syndrome, breast cancer, and endometriosis. For convenience, certain terms used in the specification, examples and appended claims are defined below. The term "molecular iodine" as used herein, refers to diatomic iodine, which is represented by the chemical symbol l2, which exists in a liquid. The term "elemental iodine" as used herein, refers to solid diatomic iodine, which is represented by the chemical symbol l2. The term "iodide" or "iodide anion" refers to the species that is represented by chemical symbol I. "Suitable counter-ions for the iodide ion include sodium, potassium, calcium, and similes.
The term "triiodide" refers to the species that is represented by chemical symbol I. One skilled in the art recognizes that triiodide is formed from the interaction of a iodide anion and a molecule of molecular iodine under the laws of mass action and that triiodide is rapidly dissociated into an iodide anion and a molecule of molecular iodine. The term "total iodine" as used herein, refers to the following iodine species: molecular iodine, iodide, organically complex forms of iodine, covalently linked iodine forms,
iodite, triiodide, polyiodods containing more than 5 iodine atoms and elemental iodine. The term "iodine generation ratio" as used herein, refers to the proportion at which molecular iodine (12) is formed to all other iodine species, such as iodide, triiodide and 15 polyiodides containing more of 5 iodine atoms. Elemental iodine is sold commercially as blue-black crystals with a high metallic luster. The greatest difficulty with the preparation of an adequate oral composition of molecular iodine is related to the basic physicochemical nature of this element. All 20 solid forms of elemental iodine are easily sublimated to generate a violet vapor. In fact, atmospheric iodine is a major component of the global iodine cycle. Unfortunately, the easy sublimation of elemental iodine introduces an inherent instability, which complicates or prevents its use, per se, as the active ingredient in a pharmaceutical preparation. Other chemicals combine in some way with iodine
^^ ¡£ ^ ¿^ £ ¿^^^^^^ ¡¡¡¡¡^ ^^ ts ^ zMÉ ^ ...?. '^ f > This is to provide stable preparations containing molecular iodine. There are three different types or categories of oral iodine compositions that have been used to treat disease states in mammals: (1) organically bound iodine including both covalent binding and hydrophobic / ionic complexes, (2) inorganic iodine, and (3) aqueous molecular iodine. Organic iodine compounds, which have been used "non-brand" as nutritional supplements of iodine, are designed for use in the area of radiographic contrast media (radiopaque compounds). For example, lymphography is used to detect and evaluate abnormalities of the lymphatic system and as a guide for the surgical dissection of lymph nodules. The radiopaque compounds based on iodine are used in different ways in several different diagnostic procedures, ie, cholecystography, myelography, urography, angiography, and angiography. A variety of organic iodine compounds different for this purpose have been used including β- (4-hydroxy-3,5-diiodophenyl) -a-phenylpropionic acid, β- (3-amino-2,4,6-triiodophenyl) acid ) -a propylene ion, iodophenylundecylate, 3,5-diacetamido-2,4,6-triiodobenzoate, 3,5-diacetamido-2,4,6-triiodobenzoic acid and etiodized oil. The iodine atoms in these compounds are covalently bound to organic molecules. Other forms of organic iodine have been used as therapeutic agents including iodine bound to protein, dried thyroid and iodine metabolically incorporated in chicken eggs.
^^ - ^ -teia ^^^ tMaá Inorganic iodine compositions that have been used as oral therapeutic agents include sodium or potassium iodide; iodine tincture or Lugol solution; and organic iodides that produce iodide. The aqueous compositions of these species inherently contain a very low and / or unpredictable proportion of molecular iodine to total iodine. In fact, these compositions usually contain less molecular iodine on a molar basis than other forms of iodine. For example, the Lugol solution contains approximately 129,000 ppm of total iodine but only 1 70 ppm of molecular iodine or a proportion of 0.001 3. Pure aqueous solutions of molecular iodine do not exist in the market. It is known that molecular iodine is unstable in water and this instability is a function of pH. Molecular iodine is hydrated by water and, in an aqueous system, undergoes the series of reactions shown below in equations 1 to 3. l2 + H2O = HOI + I "+ H + (1) 3HOI = IO + 21- + 3H + (2) l2 + I" = I (3) It is not possible to make and bottle a stable aqueous solution containing at least a molecular iodine ratio of 0.8. For clinical applications, this limitation has been previously addressed by preparing aqueous solutions of iodine immediately before use and then consuming them. Elemental iodine dissolves very slowly in water. The long time required to dissolve elemental iodine causes the loss of some of the newly formed molecular iodine due to its reaction with water, as shown in equation 1 above. As a result,
There are problems of consistency and ease of use with this method. Compositions containing several pharmacologically distinct active agents with various toxicity profiles are not preferred as pharmaceutical agents. 5 An ideal drug produces its desired effect in all patients without causing toxic effects. The relationship between the desired or undesired effects of a drug is called its therapeutic index or selectivity. The therapeutic index of a drug is frequently represented as the proportion of the average toxic dose
at the effective dose measured. In clinical studies, drug selectivity is frequently expressed indirectly by summarizing the pattern and nature of adverse effects produced by therapeutic doses of the drug and by indicating the proportion of patients with adverse side effects. Each species of separated iodine should be
considered as a single drug entity, since it has been shown to have different therapeutic index and oral toxicity profiles. Accordingly, a preferred "iodine" therapeutic agent is a composition wherein all or an overwhelming majority of the total iodine atoms present are in the desired form. The prior art demonstrates that molecular iodine is an effective therapeutic agent in a variety of disease states. For example, Eskin et al. (Biological Trace Element Research, Vol. 49, pp. 9-1,8, 1995) showed that molecular iodine is "clearly more effective in decreasing ductal hyperplasia and perilobular fibrosis in the glands
mammary than the iodide. "Scientific literature also indicates that the
; $$ & oral iodide toxicity is greater than that for molecular iodine. Another way to declare this is to say that the prior art in animals and humans shows that the most therapeutic form of iodine, when administered orally, is molecular iodine; in addition, the least toxic form of iodine when administered orally is molecular iodine. Accordingly, the prior art indicates that all iodine in a preferred oral iodine pharmaceutical agent should be molecular iodine. This distinction in toxicity is especially important for a treatment regimen that requires chronic dosing. Because the toxicity of an oral pharmaceutical iodine drug is directly related to the proportion and concentration of the different species of iodine present, the known instability of the l2 species presents a challenge for the development of an oral iodine pharmaceutical composition with a preferred therapeutic index. This application describes the methods for overcoming the problems that exist with the prior art and the delivery of molecular iodine in an acceptable stable oral pharmaceutical agent.
BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the concentration of free molecular iodine form of a 0.375 millimolar solution of sodium iodate as sodium iodide is added to a concentration of 20 μm ilimolar. Figure 1 also shows the concentration of iodide that is not oxidized to molecular iodine.
Brief description of the invention This application shows a novel pharmaceutical composition for oral administration to a mammal, which will become an effective iodine therapeutic agent. on contact with the stomach juices of the mammal and a proportion of molecular iodine to total iodine of 0.8 to 1.0. This application also shows a method for generating an effective iodine therapeutic agent, in situ, in the stomach of a mammal for the treatment of fibrocystic breast syndrome and other diseases that require chronic or acute therapeutic iodine dosing. The oral pharmaceutical compositions of the present invention generate molecular iodine upon contact with gastric juices in the stomach of a mammal and at a pharmaceutically acceptable dosage in a ratio of molecular iodine to total iodine above at least 0.8. it should be understood that it is not currently possible to make and / or bottle a stable aqueous solution containing molecular iodine in a proportion of molecular iodine relative to total iodine at or above 0.8 The iodine is sublimated at room temperature and reacts with water as described previously. These two properties make it very difficult to formulate molecular iodine; It is especially difficult to prepare compositions in which the majority of the iodine exists as a molecular iodine. The pharmaceutical composition of the present invention does not incorporate elemental iodine or molecular iodine in situ. The present invention provides dramatically improved stability to a composition incorporating molecular iodine. The control of molecular iodine is provided by the present invention, which results in generating molecular iodine in proportions of molecular iodine to total iodine between 0.8 and 1.0 and more preferably between 0.9 and 1.0 on contact with gastric juices. According to the method of the present invention, therapeutic iodine is administered to a mammal by feeding the mammal with an effective amount of an oxidant and a reductant for a species of iodine, which will cause oxidation-reduction reactions upon contact with the gastric juices present in the stomach of the mammal, so that molecular iodine is generated, in situ, at a proportion of molecular iodine to total iodine above at least about 0.8. The pharmaceutical composition of the present invention does not incorporate any elemental iodine or aqueous molecular iodine; The compositions described herein are based on the environment provided by gastric fluid to initiate the formation of molecular iodine. The composition of the present invention can be provided in the form of a set of unreacted components that react with stomach fluids to generate molecular iodine in situ. The pharmaceutical composition of the present invention can be incorporated into a simple powder, capsule, tablet, caplet, liquid, or emulsion, in addition to which combinations of these physical formats can be used. The advantages for generating molecular iodine in situ within the stomach upon contact with stomach fluids are: (1) production of pharmaceutically acceptable, stable composition; (2) production of a controlled dosage of molecular iodine in situ; and (3) the proportion of molecular iodine is controllable at levels above 0.8.
The methods described above allow a precise dosing regimen and the reduction of unwanted toxic side effects associated with iodide, triiodide and polyiodides to be achieved. In addition, therapeutic efficacy is increased for certain disease states such as fibrocystic breast syndrome.
DETAILED DESCRIPTION OF THE INVENTION The method described in this application describes a system for the in situ generation of molecular iodine in the stomach. It is necessary
Consider the composition of gastric fluid when such a composition is designed. The low pH of gastric fluids influences this type of chemistry. The main oxidation states of iodine are -1, + 1, +3, +5 and +7. Compounds that are representative of these states include Kl, Icl, ICI3, I F5 and Na5IO6, respectively. The IO2 oxide is known and
seems to be the only representative of the oxidation state +4. Molecular iodine (12) can be formed either by reducing a species of iodine with a positive oxidation state or by oxidizing the iodide anion (I ") Alternatively, it is possible to use an oxidizing or reducing agent, which can contain iodine, the oxidation potentials for
different oxidation states of iodine in an acid solution are represented below:
+ 1 .20V
H5IO6 - 1 7V I O2 + 1? and HOI + 1 5V + 0 5 V
There is a variety of iodine species in different oxidation states. Positive oxidation states are usually found in inorganic species, such as acids, salts, oxides or halides. Negative oxidation states appear in iodine species that are in the form of iodide salts or organic iodine compounds. The oxidation states of iodine and some iodine species that are representative of those states are shown below:
+7: periodic acid (H5IO6), potassium periodate (KIO), sodium periodate (NalO). +5 iodic acid (HIO3), potassium iodate (KIO3), potassium iodate acid (KHI2O6), sodium iodate (NalO3), iodine oxide (l2O5). +3: iodine trichloride (ICI3), + 1: iodine monobromide (Ibr), iodine monochloride (ICI). -1: hydriodic acid (Hl), sodium iodide, potassium iodide, ammonium iodide, aluminum iodide (All3), boron triiodide (Bl3), calcium iodide (Cal2), magnesium iodide (Mgl2), iodoform (CHI3), tetraiodoethylene (C2I), iodoacetic acid, iodoethanol, iodoacetic anhydride.
Molecular iodine can be formed from oxidation-reduction reactions according to the oxidation-reduction potentials indicated before the reaction half for a species of iodine. Another way to say this is as follows: substances with lower oxidation potentials
y- * .. & They can reduce a species of iodine to molecular iodine, and substances with a greater oxidation potential than iodide can oxidize iodide to molecular iodine. There are many chemicals known to one skilled in the art that will function in this way. A desired feature of the in situ generation method is to provide a composition that is non-toxic once it has come into contact with the gastric fluids contained in the stomach. Another parameter of this method is the speed at which molecular iodine is generated once the composition comes into contact with gastric fluids. Another important feature of this method is to provide a reproducible amount of molecular iodine. Suitable oxidants for the in situ generation method include hydrogen peroxide, iodate, other alkaline salts of peroxide such as calcium hydroperoxide and peroxidases which are capable of oxidizing iodide. A preferred oxidant for this invention is hydrogen peroxide. Any material that acts as a source of a peroxy oxidant functionality when ingested is suitable for the present invention. The term "source of hydrogen peroxide" for purposes of the present invention and as used herein shall mean any material alone or in combination, which is pharmaceutically acceptable to serve as a precursor to a peroxy-oxidizing functionality, including percarbonates, perfosphates, urea peroxide, peroxy acids, alkyloperoxides, peroxyacids and perborates. Mixtures of two or more of these substances can be used.
^ g sgi s ^^ «» ^. The preferred oxidant for this invention to be used in combination with the iodide anion is iodate. The iodate anion consists of an iodine atom and three oxygen atoms and has a negative charge associated with it at a pH of 7.0. Preferred sources of iodate include sodium iodate, calcium iodate and potassium iodate. The term "source of iodate", for purposes of the present invention and as used herein, shall mean any material alone or in combination, which is pharmaceutically acceptable to serve as a precursor for the release or delivery of iodate on the contact with stomach fluids Suitable reductants for the in situ generation method include iodide, sodium thiosulfate, ascorbate, simple reducing sugars, ales such as lactose, imidazole and other reductants well known to one skilled in the art. The oxidant and reductant used to generate molecular iodine can be combined in a dry state with other well-known pharmaceutical excipients to facilitate the manufacture of capsules, tablets and pills. Examples of such well-known non-toxic excipients include: various salts of phosphate, sucrose, lactose, maltodextrins, mannitol, dextrose, dextrose, glucose, citric acid, sorbitol, microcrystalline cellulose, starches, sodium carbonate, magnesium carbonate, carbonate of calcium, carboxymethylcellulose, polyethylene glycol, boric acid, leucine, sodium chloride, benzoate, acetate, oleate, magnesium stearate, stearic acid, talc and hydrogenated vegetable oils. Anyone skilled in the art will come up with other excipients and are incorporated for the purposes of this application. The preferred excipients should have the following characteristics: (1) not affect the stability of the oxidant and reducing agent; (2) not interfere with the interaction between the oxidant and the reductant; (3) does not affect the production of molecular iodine; (4) not reacting materially with molecular iodine in a manner that affects the absolute concentration of molecular iodine; and (5) not affect the ratio of molecular iodine to total iodine after it is formed in the stomach and during the time in which the molecular iodine is processed by the mammal in the stomach or intestines. Alternatively, it is possible to incorporate the components of the in situ generation method into a liquid that is swallowed before, after or together with a powder, capsule, tablet or other liquid. A variety of liquid compositions familiar to someone skilled in the art are acceptable, so long as the stability of the reactants to produce iodine is maintained. Examples of such liquid compositions would include (1) a suspension of powders in a viscous hydrophobic liquid, such as mineral oil, or (2) emulsions of hydrophobic molecules with an aqueous phase. Two dosing ranges for molecular iodine are contemplated in this application; a range for chronic dosing and a range for acute dosing. The treatment of stomach ulcers, which are caused by the presence of Helicobacter pylori in the lining of the stomach would be an example of a disease state that requires acute dosing. The treatment of chest dysplasia is an example of
a disease that requires chronic dosing. The amount of molecular iodine to be provided per day for treatment of chest dysplasia is between 0.5 and 12.0 mg per day for a female mammalia of 45.36 kg with a preferred range of iodine for consumption between 2.0 and 7.5 mg per day. . The amount of molecular iodine to be provided per day for the prevention of breast dysplasia is between 1 25 ug and 1.5 mg per day for a female female of 45.36 kg with a preferred range of iodine for consumption between 225 ug and 1 250 ug per day. The amount of molecular iodine delivered per day for acute dosing can be between 15 and 125 mg with a preferred range of iodine for consumption between 20 and 55 mg per day. An important parameter of any pharmaceutical iodine agent is its therapeutic index. The therapeutic index for a pharmaceutical iodine agent is proportional to the proportion of molecular iodine to total iodine provided by said pharmaceutical agent. The higher the proportion of molecular iodine to total iodine, the higher the therapeutic index for the iodine composition. The proportion of molecular iodine to total iodine that is generated by pharmaceutical iodine agents described in this application is between 0.8 and 1.0, with a preferred ratio of 0.90 to 1.0. For treatment of disease states requiring chronic iodine administration, such as fibrocystic breast syndrome, it is especially preferred to provide a composition that provides a ratio of 0.95 to 1.0. Because molecular iodine is the least toxic form of iodine, the chronic administration of an oral iodine therapeutic agent should be based on molecular iodine.
In order to limit the toxicity of unwanted iodide, it is necessary to limit the iodide concentration (which remains after in situ generation of molecular iodine). The amount of iodide in such a composition should provide no more than 1,000 ug / day of iodide 5 when administered acutely, and preferably should provide no more than 150 ug / day when it is administered chronically and highly. preferably it should provide no more than 50 ug / day. Therefore, as described in this application, the concentration of iodide in an iodine pharmaceutical agent for acute dosing containing 20 mg of total iodine, should be less than 1 mg or 5%, and preferably the concentration of iodide should be 1 50 ug (or 0.75%) or less of the total weight of iodine present. The ratio of molecular iodine to total iodine has a preferred ratio of between 0.80 and 1.0 and a most preferred proportion between 0.90 and 15 1.0. The higher the proportion of molecular iodine to total iodine, the higher the therapeutic index for the iodine composition. The rate of iodine generation should be rapid with at least 75% of the equilibrium concentration of molecular iodine being generated within the first 10 minutes of contact between the specific chemical agents that generate iodine and the stomach fluids. If tablets or capsules are used then at least 70% of the molecular iodine formation should occur within the first 45 minutes of contact with the gastric fluid and preferably within the first 20 minutes. The stability of the composition should be such that at least 90% of the molecular iodine generating capacity remains after the
»* •« * »^ ** s & ß ^ to &2 £ & * g * $ ¡& a *** ^^^ & * ... -gT. a ^^ S ^^^ storage in an appropriate package at 25 ° C in 75% relative humidity for at least 3 months and preferably 6 months. It is very important that the proportion of molecular iodine generated to total iodine does not change materially during storage.
EXAMPLES Example 1 An experiment was designed to determine if horseradish peroxidase (H RP) can be used to catalyze the oxidation of a
mixture of iodide / hydrogen peroxide under conditions that mimic the human stomach. A second objective for this experiment was to determine if such a composition can generate molar iodine in gastric fluid even in the presence of mucin. Total iodine was measured by thiosulfate titration as
describes in the United States Pharmacopoeia (USP). Molecular iodine was measured by the Gottardi method (Gottardi, W., Fresenius Z. Anal, Chem. Vol. 314, pp. 582-585, 1 983), which is based on the measurement of the redox potential, iodide concentration and pH. Two Corning Model 345 pH meters were used in combination with a reference electrode
platinum (Fisher Cat. No. 1 2-620-1 1 5), a Calomel electrode (Fisher Cat. No. 1 2-620-51) and a selective iodide ion electrode (Corni ng Model 4761 27); a saturated solution of elemental iodine at 25 ° C was used to calibrate the system. It is known that horseradish peroxidase catalyses the formation
of iodine in the presence of hydrogen peroxide via the oxidation of
I last. Simulated gastric fluid (SGF) was prepared, as described in USP, as follows: 2.0 grams of sodium chloride were dissolved in 750 ml of distilled water and then 7.0 ml of hydrochloric acid containing 3.2 grams of pepsin were added along with enough distilled water to bring the total volume to 1 000 ml. Horseradish peroxidase (H RP) was dissolved in SGF at a concentration of 1.0 mg / ml. The activity of horseradish peroxidase and its absorbance at 406 nm was monitored over the course of one hour. There was only a 20% decrease in absorbance at 406 nm, indicating that the tertiary structure of HRP is relatively stable in the presence of SG F. The rate at which horseradish peroxidase catalysed iodine formation was correspondingly reduced at the end of the hour by approximately 33%.
Five grams of citric acid and 1 gram of sodium citrate were combined in one liter of water to produce a buffer with a pH of 3.0. A second identical buffer containing 1.0% pig mucin was prepared. A mixture of two powders, sodium iodide (1 g bouquet) and H RP (5 mg) was made and subsequently used as a simple reagent. The next reaction began. Five hundred ml of buffer or five hundred ml of 10% mucin were mixed with 1.0 gram of the iodide / H RP mixture and 1.0 ml of 30% hydrogen peroxide. The concentration of molecular iodine was monitored as a function of time by the Gottardi method. In eight minutes, the buffer control had a molecular iodine concentration of 30.1 ppm; the same reaction in 1% pig mucin had a molecular iodine concentration of 38. 1 ppm.
Í & * > Z? Á * ± *? K ^ líiiM¿ ^ J ^ ** A ^? Sa This experiment demonstrates that H RP can be used to catalyze the oxidation of iodide by hydrogen peroxide in the stomach and can generate molecular iodine in fluid gastric and in the presence of mucin. Additional experiments using Lugol's solution diluted in simulated gastric fluid in various proportions in the presence of 10% mucin did not produce any medial molecular iodine. This experiment suggests that it may be advantageous to generate molecular iodine in situ in the stomach which is opposed to delivering molecular iodine to the stomach.
Example 2 An experiment was designed to compare the differences, if any, between generating molecular iodine in situ as opposed to delivering molecular iodine in an environment that simulates human gastric fluid. A secondary objective was to determine if it is possible to generate a concentration
significant molecular iodine in the environment found in the human stomach. The effect of SGF with 1% pig mucin was determined in three different types of iodine compositions. The three different types of iodine solutions were (1) diluted Lugol solution to deliver
about 150 ppm of titratable iodine; (2) 10% polyvinyl pyrrolidone iodine diluted to deliver approximately 50 ppm of titratable iodine; and (3) a mixture of HRP (1.5 mg / liter), sodium iodide (2 grams / liter) and hydrogen peroxide (0.08% w / v) that generates approximately 50 ppm of titratable iodine. The concentration of molecular iodine was determined
potentiometrically for these three different iodine compositions in
Ét ^ &^^^^^^ i ^ i ^ j ^ jj ^^^^^^^^ j ^^^^^ m ^^^ ^. ^^ to. ^ A ^^ a ^ absence and presence of pig mucin 1 0% and the results are shown below.
Compositions of iodine in simulated gastric fluid Compound of iodine Molar iodine SGF SGF + mucin 10% Polyvinylpyrrolidone 1 0% 9 0 Sol ution of Lugol 59 0 Mixture of H RP / iodide / peroxide 1 5 40
This experiment demonstrates that it is possible to generate significant concentrations of molecular iodine in the environment found in the stomach and that it may be preferable to generate said iodine in situ, as compared to delivering iodine to the stomach in an aqueous composition. Example 3 This experiment was designed to identify the preferred molar ratio of iodide to iodate to be incorporated into a suitable pharmaceutical composition, so that molecular iodine is the main form of iodine generated upon mixing with gastric fluid. SGF was prepared as described in USP and sodium iodate was dissolved in SGF at a final concentration of 0.375 millimolar. A sequential addition of sodium iodide was made to the iodate solution. Sodium iodide was added to the iodate solution in different amounts, so
^ «A« Mft .. i. ^ »- ^, AtfA, -» .- MjMj j, i ¿r ^. . ^^. -38ftafcfa.a that the concentration of iodide added varied between 0.25 and 3.0 millimolar. After each addition of iodide, the analytical chemistry of the resulting composition was determined. The concentration of molecular iodine increased in an almost 5 linear way between an iodide concentration of 0.0 and 1.75 μM and then flattened. The most obvious explanation for this observation is that once the majority of iodate had been reduced, a complementary addition of iodide produced no formation of molecular iodine material. Instead of an increase in molecular iodine, the concentration of
iodide increased. The concentration of sodium iodide increased in an almost linear manner between a sodium iodide concentration of 1.75 and 3.0 mM, whereas under identical conditions, the concentration of molecular iodine increased by less than 5%. Figure 1 shows the results of these tests. At a iodine entry of 1.75 mM, the concentration
of molecular iodine was 1.01 mM; this is equal to approximately 96% of the theoretical maximum yield of molecular iodine. This experiment was repeated using 2.5 mM sodium iodate and a sodium iodide concentration varying between 0 and 25 μM. The results were qualitatively identical. As iodide was added,
The concentration of molecular iodine increased in a linear manner between an iodide concentration of 0 and 1 2.5 M. Once the majority of iodate had been reduced, additional iodide did not produce any increase in material in the concentration of molecular iodine. The concentration of sodium iodide increased in an almost linear fashion
between a sodium iodide concentration of 1 2.5 and 25.9 mM without a
tt «gS-ji &f s.- ÉSt ti ^ a ^ *" ¿¿a ^^^ - ^ ¿l? aÉt ^^ corresponding increase in molecular iodine, at an iodide entry of 1 2.5 mM, the concentration of molecular iodine was 7. 1 7 mM, this is equal to 95% maximum theoretical yield of molecular iodine These results indicate that it is possible to generate molecular iodine in the environment found in the human stomach in such a way that a The concentration of iodide material does not result from chemicals supplied, for example, when 0.375 mM of iodate and 1.75 mM of sodium iodide are used, there is no detectable concentration of iodide, whereas the concentration of molecular iodine was approximately 1.1 mM correspondingly, with 2.5 mM of iodate and 1 2.5 mM of iodide, there was no detectable concentration of iodide while the concentration of molecular iodine was approximately 7.3 mM. molar preferred iodide to iodate, in order to provide a a composition that provides mainly molecular iodine and which therefore limits the iodide concentration. It is important to limit the iodide concentration for disease states that require chronic dosing.
Example 4 A mixture of powder containing magnesium stearate, sorbitol, sodium iodide and sodium iodate was prepared. The following quantities of each material were weighed on an analytical scale (AND Company Ltd, Model FX-3000); 25 grams of magnesium stearate; 1, 000 grams of sorbitol; 55 grams of sodium iodide; and 1 5.75 grams of sodium iodate. The standard gelatin capsules were filled with 1 gram of the mixed material and placed in polyethylene, wide-mouth, screwed bottles, containing a single disposable disposable cartridge (Fisher Cat. No. 08-594-14A). The polyethylene bottles were placed in an environmental chamber of constant temperature at 40 ° C at 75% relative humidity. Once a week for a period of three months, three capsules were removed, allowed to come to room temperature and dissolved in simulated gastric fluid. The concentration of molecular iodine was determined immediately after dissolution by a potentiometric measurement. The concentration of molecular iodine did not change over a period of three months. The percentage of the concentration measured on day 1 was plotted against time. No trend could be detected on a graph of molecular iodine concentration versus time.
Example 5 Soy peroxidase (E.C. 1.1.1.7) was used in conjunction with hydrogen peroxide and iodide to generate molecular iodine in situ. The ratio of molecular iodine to total iodine was calculated. Several different reaction conditions were established in a citrate / carbonate buffer at pH values of 1.7, 4.5 and 5.0. The concentrations of the different reactants at a pH of 5.0 are shown below in tabular form.
& amp; L - ^ *, A JBSS & ~ £ & $ * 3 & I
Reactions at pH 5.0 were initiated by adding 0.2 ml of soy peroxidase (5 mg / ml) and mixing gently. The concentration of molecular iodine was measured at 20 minutes by the potentiometric method of Gottardi. The concentration of molecular iodine for the three conditions at pH 5.0 was as follows: reaction 1 was 43 ppm; reaction 2 was 51 ppm and reaction 3 was 1 59 ppm. The ratio of molecular iodine to total iodine for the three reactions was 1.02, 1.0 and 0.94, respectively. 10 Another reaction was carried out at pH 4.5 using the following experimental conditions. The following chemicals were added to 1200 ml of water: 4.65 grams of citric acid, 2.0 grams of sodium carbonate, 0.252 grams of sodium iodide, 6 milligrams of lactoperoxidase (EC 1.1.1 .7) and 80 mg of urea hydrogen peroxide. After 20
minutes, it was determined that the concentration of molecular iodine was 172 ppm by the potentiometric method of Gottardi. The ratio of molecular iodine to total iodine was 0.97.
i | Example 6 An iodine pharmaceutical agent must be absorbed to provide a therapeutic benefit. Ghent (U.S. Patent 5 Nos. 4, 815, 255; 5, 1 71, 582) has shown that the Lugol solution is an effective therapeutic agent for the treatment of fibrocystic breast syndrome. This experiment was designed to demonstrate that the bioavailability of molecular iodine generated in situ is at least equal to that of the Lugol solution. 10 Sprague-Dawley female rats weighing 1 50-250 grams, 6-7 weeks old, were purchased from Charles River Canada, Inc. (Quebec, Canada). The rats were housed individually in rodent cages, with a mesh bottom, made of stainless steel, equipped with an automatic system for supplying water. Following the randomization, all the jau were
marked clearly with a cage card with color code, indicating the study number, group, animal number, sex and treatment. Each animal was uniquely identified by a tag on the ear individually upon arrival. The environment was controlled at 21 ± 3 ° C, 50 ± 20% relative humidity, 12 hours light, 12
hours of darkness and 1 0-1 5 air changes per hour were made. The animals were provided with Certified Rodent Diet (W) # 8728 from Teklad (Madison, Wl) ad libitum. Ad l ibitum municipal water was provided, which was purified by reverse osmosis and treated with ultraviolet light. The animals were allowed to acclimate to their environment
for at least two weeks before the start of the experiment.
The rats were dosed with 10 ml per 250 grams for each treatment group. The iodine-based drug concentration was either 0. 1 mg / kg (the low dose "L") or 1.0 mg / kg (the high dose "H"). different types of iodine-based medicines were dosed. It is known that Lugol is an effective treatment against fibrocystic chest syndrome and was used as the positive control. Compositions containing sodium iodide and sodium iodate alone, or in combination with other agents, were used as the experimental treatments. The ratio of iodide to iodate was controlled, so that essentially all of the iodide was converted to molecular iodine. Experimental treatments included (1) Nal / NalO mixed before priming; (2) Nal / NalO in 0.7% HCl primed separately; (3) Nal / NalO in 1% starch; and (4) Nal / NalO in 1% sorbitol. Blood was taken from the animals before treatment. The animals were primed and blood was taken two hours after the animals were sacrificed. The blood was processed to produce serum samples and these samples were frozen. The frozen samples were analyzed by using the oxidation-reduction reaction between ceric and arsenic catalyzed by iodide. This method provides a measurement of the total iodine that is absorbed in the serum. The results of these measurements are shown below in tabular form.
j ada,
The Nal / NalO compositions were absorbed by the rats at a rate which was equivalent to or greater than the Lugol solution. This indicates that iodine in these treatments is available for mammalian tissue.
Example 7 A seven-day dosing study was conducted at different
concentrations of iodine to determine the acute oral toxicity of a Na l / NalO composition. Twenty female Sprague-Dawley rats were divided into 4 groups with five animals in each group. Animals were selected and treated as described above in Example 6. The rats were dosed once each day with a Nal / NalO composition or
water (control groups). The composition of Nal / NalO was
so that essentially all iodine atoms were converted to molecular iodine upon use. The dose level used in the three treatment groups was (1) 0.1 mg / kg; (2) 1.0 mg / kg and (3) 10 mg / kg. Each animal was dosed with approximately 2 ml per 250 grams. 5 During the treatment period, clinical signs were evaluated
(bad health, behavior changes, etc.) next to the cage twice a day. Funduscopic and biomicroscopic examinations were performed for all animals during the pretreatment period and at the end of the treatment period. The animals were euthanized at the end of treatment with methoxyflurane. The necropsy examination of the corpses was carried out immediately after the sacrifice. None of the animals exhibited any clinically abnormal signs. No abnormal signs were observed during the necropsy. High doses of an iodide / iodate medication did not cause acute toxicity. Example 8 Female Sprague-Dawley rats (a total of 44) weighing 200-250 grams were purchased from Charles River Canada, Inc. (Quebec, Canada).
The rats were housed individually in rodent cages, 0 mesh bottom, stainless steel wire, equipped with an automatic water supply system. The environment was controlled at 21 ± 3 ° C,
50 ± 20% relative humidity, 12 hours of light, 12 hours of darkness and 10-15 air changes per hour were made. The animals were fed a diet deficient in iodine from Remington # 170360 (Tekiad, Madison, Wl) ad libitum. It was provided ad
^^^^^^^^ a ^ 3 | ^ í ^^ g ^ g ^ S ^^ ^ ^ ^^^^^^^ t > ^^^ g ^ ^^^ gggl ^^ gj ^^^^^ ^^^ ii Libitum municipal water treated with perchlorate (400 mg / dl NaCIO) during the first five days of the hospital. A group of rats received a normal diet (Tekiad Certified Rodent Diet (W) # 8728) and municipal water supply. All animals were then allowed to acclimate to their environment for two weeks before the initial experiment. Each day of the five days preceding the initiation of the test, the animals received estrogen (25 ug of 1 7-ß estradiol) suspended in 1000 ul of I M injected sesame oil. During the 2-week experiment, it was injected daily estrogen (2.5 ug of 17-ß
estradiol) suspended in 1 00 ul of sesame oil. Vaginal smears were taken every third day to ensure that the rats achieved constant estrus throughout the experiment. Molecular iodine was generated in situ in the rats by priming an aqueous solution containing sodium iodide and sodium iodate.
(molar ratio 5/1 of I7IO), so that essentially 1 00% of the administered iodide was converted to molecular iodine. The rats were dosed with molecular iodine once a day. Food was removed from the rats each morning and ten hours later, each rat was dosed with 80 ug / kg of molecular iodine. An equivalent dose of iodide was provided
(80 ug / kg) to a group of control rats. The negative control consisted of rats that were dosed with running water. The rats were weighed daily. At the end of the 2-week study, the rats were sacrificed and microscopic sections of the tissues of the breastmiras grafts were stained with hematoxylin and eosin before being
read by a pathologist. The breast tissue was registered according to the
methods described by Eskin et al. (Biological! Trace Element Research, 1995, volume 49, pages 9-1 8). Four groups of animals were examined: (1) normal diet without perchlorate treatment; (2) deficient in iodine with water priming; (3) 5 deficient in iodine with iodide priming; and (4) deficient in iodine with iodine priming. Each group contained 1 0 animals. There were small but statistically significant differences in the body weights of the different groups at the beginning and end of the experimental treatments. However, all body weights were within the range
normal. The average weight for the four groups was as follows (1) 208 ± 5.6 at the beginning, 237 ± 7.4 at the end; (2) 21 2 ± 6.3 at the beginning, 239 + 6.8 at the end; (3) 214 ± 6.5 at the start, 235 ± 7. 1 at the end; and (4) 216 ± 6.6 at the beginning, 241 +6.9 at the end. The breast tissue was classified by lobular hyperplasia,
secretions, periductal fibrosis and fibroadenomatous changes. The registration system for lobular hyperplasia, secretions, periductal fibrosis classified as positive only those animals showing moderate to severe conditions. Microscopic fibroadenomata were identified in some samples and quantified. The results of this classification
histological is shown below in tubular form.
É &bÉsi •? Í-tr - 1 íi - ilfilrTr "- * - - -" ** - - - *
It has been shown that iodine deficiency alters the structure and function of rat mammary glands, especially alveolar cells. When stimulated by estrogen, either physiologically or externally, the mammary glands appear to be highly sensitive to iodine deprivation. Extensive trials have shown that dysplasia and atypia caused by iodine deficiency in the mammary glands are reversible by treatment with iodine. The rat model has been used by several researchers as a model of the fibrocystic breast syndrome in humans. The group of rats that received the normal diet did not present any abnormal indication. The mammary tissue of rats in the iodine deficient diet, which received water priming, showed atypical breast tissue indicative of fibrocystic breast syndrome caused by an iodine deficiency. Iodine-deficient rats that received a iodide priming showed fibroadenomata and increased secretion. This increase in the secretion of mammary tissue and fibroadenomata from breast tissue
^^^^^ associated with iodide treatment has been previously observed in experiments by Eskin et al. (Biological! Trace Element Research, 1 995, volume 49, pages 9-1 8). In contrast to iodide, priming with the iodide / iodate mixture (ie, iodine priming) reduced the incidence of hyperplasia, secretion, periductal fibrosis and fibroadenomata. This indicates that in situ generation of molecular iodine can reverse the fibrocystic breast syndrome. The results of this experiment confirm that in situ generation of molecular iodine is an effective modality for the treatment of fibrocystic breast syndrome and other conditions of
iodine deficiency disease.
Example 9 A g ratation was prepared incorporating iodide anion with iodate anion and its stability at 40 ° C was evaluated. In a Kitchen Aid mixer,
The following chemicals were combined: 1 00 μl of deionized water; 1.0 gram of sodium iodate; 3.63 grams of sodium iodide; 5.0 grams of tribasic sodium phosphate; and a drop of sodium hydroxide. The materials were mixed well until they were amalgamated. Twenty-five grams of hydroxypropylmethyl cell were slugged and the material was
mixed until it was an iforme. An additional 450 grams of microcrystalline cellulose was slowly added while mixing. This g ranulation was passed through a number 5 tam and then dried in a vacuum oven at 50 ° C. After drying the material for 1 2 hours, it was passed through a No. 20 sieve.
Forty-five one-gram samples of the dried granulation were weighed into glass jars and then placed in an oven at 40 ° C. Three samples were withdrawn approximately every week for three months and the amount of titratable iodine was determined with thiosulfate after dissolution in 1 liter of simulated gastric fluid. The results of these measurements are shown below in tabular form.
Example 1 0 A solution of sodium iodate was prepared at a concentration of
m illimolar in 200 ml of SGF (without pepsin) in a glass bottle, with thread, coated with Teflon. A concentrated solution of ascorbic acid in the form of drops was added to this solution through a tube. The iodide concentration (determined by I SE) and free molecular iodine (determined potentiometrically) were determined after each addition of ascorbic acid. The electrodes used for the measurements of iodide and free molecular iodine were contacted through an airtight orifice made in the upper part of the container coated with Teflon. The concentration of molecular iodine increased in an almost linear manner as a function of the amount of ascorbic acid added until its concentration reached a maximum of 2.38 thousand imolar. After the molecular iodine reached a maximum, its concentration
, JHSt! & amp; ^ < The amount of ascorbic acid decreased as the concentration of ascorbic acid increased. No iodide was detected until the concentration of molecular iodine reached 2.38 millimolar. The concentration of iodide increased with increasing ascorbic acid until it reached a maximum of 4.82 m il imolar at which it remained constant, without considering any increase in ascorbic acid. The experiment was repeated using another oxidant-reducing pair. Iodine and sodium thiosulfate were replaced by iodate and ascorbic acid. The exact same experiment was repeated except that thiosu concentrated sodium phosphate in the form of drops was added to the sealed container. Again the concentration of molecular iodine reached a maximum value of 2.26 millimolar, and then decreased. As the molecular iodine concentration decreased from its maximum value, the iodide concentration increased from 0 to 4.7 millimolar.
Example 1 1 The proportion of molecular iodine to total iodine was determined as a function of the ratio of iodide anion to iodate anion in SGF (without pepsin). The following measurements were made to determine the presence of different iodine species: titrated iodine with thiosulfate, potentiometric analysis of molecular iodine and determination of selective electrode of iodide ions. It was found that essentially all the input mass of iodine atoms was considered when measuring these three species. Triiodide and other polyiodides were calculated from the thiosulfate values and molecular iodine values. The proportion of iodine
• The molecular iodine to total iodine was determined by dividing the mass of molecular iodine by the sum of the mass of iodide, molecular iodine and triiodide. The weight ratio of iodide anion to iodate anion was varied from 0.5 to 8. It was observed that the ratio of molecular iodine to total iodine varied as shown in the tabular form below.
Further experimentation indicated that a weight ratio for reagents, iodide and iodate, of about 0.78 (IOIO) yielded a ratio of molecular iodine to total iodine of 0.8.
Example 1 2 Female Sprague-Dawley rats were purchased weighing 200-250 grams from Charles River Canada, Inc. (Quebec, Canada). The rats were treated exactly as described in Example 8 and subjected to identical procedures with respect to perchlorate and dosage of estrogen. Each rat was dosed by priming an aqueous solution containing sodium iodide and sodium iodate (molar ratio 5/1 I7IO), so that essentially 1 00% of the iodide and iodate administered became molecular iodine upon contact. with stomach fluids The rats were dosed with molecular iodine once at
day . The feed was removed from the rats each morning and ten hours later, each rat was dosed with one of three concentrations 0.001 0, 0.01 0 or 0. 1 mg / kg molecular iodine. A dose of iodide (1000 μg / kg) was given to a group of control rats. The negative control consisted of rats that were dosed with running water. At the end of 4 weeks, the rats were sacrificed and microscopic sections of the tissues of the mammary glands were stained with hematoxylin and eosin before being read by a pathologist. Mammary tissue was recorded as described in Example 8. Six groups of animals were examined: groups 1-3 received daily doses of one of three concentrations of molecular iodine; (4) received the normal diet without perchlorate treatment; (5) received the diet deficient in iodine with a fattening of water; and (6) received a diet deficient in iodine and dosed with iodide (100 ug / kg). All body weights of the rats were within the normal range throughout the study. The breast tissue was classified by lobular hyperplasia, secretions, periductal fibrosis and fibroadenomatous changes as described in Example 8. Microscopic fibroadenomata were identified in some samples and quantified. The results of this histological classification are shown below in tabular form.
Rats maintained on a normal diet did not exhibit clinically abnormal signs. As expected, rats on an iodine-deficient diet that did not receive treatment (feed priming) had breast tissue whose histology is consistent with FBS. Daily treatment with iodide (100 ug / kg) did not substantially alleviate fibroadenomata formation. Daily treatment with molecular iodine at a concentration of 1 ug / kg did not substantially alleviate the formation of
fibroadenomata and periductal fibrosis. Daily treatment with molecular iodine at a concentration of 10 and 1000 μg / kg substantially reduced fibroadenomata formation and periductal fibrosis.
Example 1 3 Female Sprague-Dawley rats were purchased weighing 200-250 grams of Charles River Canada, I nc. (Quebec, Canada). The rats are
they were deficient in iodine using the same procedures previously described in Examples 8 and 1 2. The rats were dosed with five different com positions: (1) water; (2) iodide at 0. 1 mg / kg (delivered in the form of sodium iodide); (3) ineral oil emulsion that delivered molecular iodine at 0.01 mg / kg; (4) mineral oil emulsion that delivered molecular iodine at 0.001 mg / kg; and (5) mineral aeite emulsion that delivered molecular iodine at 0.10 mg / kg. Mineral oil (500 ml) was mixed thoroughly with powdered gum arabic (125 grams) in a dry mortar. Sodium carbonate (50 mg) and a mixture of sodium iodide / sodium iodate (molar ratio 5/1 I / IO) were added to sterilized distilled water (250 ml) and this solution was thoroughly mixed with the mixture. mineral ag ua / arabica. The resulting mixture was emulsified in a high speed mixing (Lightnin Model L1 U08). After emulsification, sterilized distilled water was added to bring a final volume of 1000 ml. The concentration of iodide / iodate added to the three different mineral emulsions was calculated, so that one ml contained one of the following three values: 0.25, 2.5 or 25 ug of iodine atoms. Each rat was dosed by priming once a day with each of the test items. The negative control consisted of rats dosed with water. The positive control consists of rats dosed with iodide. At the end of 4 weeks, the rats were sacrificed and microscopic sections of the tissues of the mammary glands were stained with hematoxyline and eosin before being read by a pathologist.
^ g¡ ^^^ ^ ¡^^^
The results of this experiment are broadly consistent with the observations made in the previous example, suggesting that an aqueous composition is a satisfactory vehicle for the delivery of the iodide / iodate mixture.
EXAMPLE 14 Oral pharmaceutical agents that are formulated as solid dosage forms must comply with specific regulatory guide lines with respect to their stability. The stability of such pharmaceutical agent is usually evaluated both at room temperature and at elevated temperatures, in order to assess the stability in the real world of such compositions. A solution of iodide and an iodate solution were granulated on several different sugars to evaluate the
The chemical stability of the combination of these two chemicals in the acceptable pharmaceutical dosage form The following were used
g ^ ^^^^^^^ ga ^ § j ^ gj ^ í > a ^ | j ^^ g¡b ^^^^^ a - * - * _, ttrifc * ... ... aa »? * ss? x- ~ fj¡ * t * sugars: sucrose, glucose , dextrose, galactose, sorbitol, maltodextrin, fructose and lactose. At each instant, the first agent to be granuted was sodium iodate. Each sugar was combined with sodium carbonate in a 50/50 mixture before granulation. After the granulation of sodium iodate, each sugar-carbonate mixture was dried under vacuum for at least 5 days at 40 ° C. The granulations were stored at room temperature in a vacuum desiccator. Then a highly concentrated iodide solution was atomized
of sodium on each of the sugar-carbonate mixtures that had been previously ranged with sodium iodate. Sodium iodide was atomized very slowly using an atomizer to deliver a volume of liquid that represented approximately 1% of the weight of the sugar. After the addition of sodium iodide, the sugar-carbonate mixtures were dried under vacuum at 40 ° C for at least one week. Sodium iodate was added at a concentration such that its final concentration in the dry sugar-carbonate was approximately 0.34% by weight. Sodium iodide was used at a concentration such that its final concentration in the dry sugar-carbonate was approximately
1 .32%. Each sugar-carbonate mixture was stored in an open glass container at 40 ° C and at room temperature in a sealed glass container. The concentration of iodide and iodate in each of the sugar-carbonate mixtures was measured every month for six months. HE
measured iodide using a selective electrode of ions. Iodate was measured by
medium of a titration with thiosulfate. The results of the measurements on the materials stored at 40 ° C are shown below in tabular form.
The data clearly suggests that the iodide / iodate can be stabilized in a manner suitable for use in a commercial pharmaceutical dosage form.
The invention should not be construed as limited to the foregoing examples. Other embodiments are within the scope of the following claims
a.jg ^ fefe
Claims (32)
- REVIVALATION IS 1 . A method for administering therapeutic iodine to treat a disorder in a mammal, comprising the steps of: feeding said mammal with an effective amount of a pharmaceutically acceptable oxidant for an iodine species and a pharmaceutically acceptable iodine reducing agent, containing at least one of these compounds a kind of iodine, which undergoes an oxidation-reduction reaction on contact with the gastric juices present in the stomach of said mammal and generates molecular iodine, in vivo, a proportion of molecular iodine to total iodine by above at least about 0.8.
- 2. The method of claim 1, wherein said molecular iodine is generated by feeding said mammal with an iodine reducer together with a species of iodine having a positive oxidation state.
- 3. The method of claim 1, wherein said molecular iodine is generated by feeding a mammal with an iodide oxidant and a source of an iodide anion. The method of claim 2, wherein said iodine species having a positive oxidation state is selected from the group consisting of calcium iodate, iodic acid, potassium iodate, potassium acid iodate, sodium iodate. The method of claim 4, wherein said iodine reductant is selected from the group consisting of iodide, sodium thiosulfate, ascorbate, lactose, reducing sugars and im idazole. + ± * 8 &asti & amp; amp. '^^^^^ ¿^ ^^^^^^^^^ 6. The method of claim 3, wherein said iodide oxidant is selected from the group consisting of hydrogen peroxide, iodate, alkaline peroxide salts, such as, calcium peroxide, peroxidase, ascorbic acid and / or other pharmaceutically acceptable organic acids 5 with an oxidation potential greater than -0.54 electron volts 7. The method of claim 6, wherein said source of the iodine anion is selected from the class consisting of sodium iodide, potassium iodide, ammonium iodide, iodide of calcium, magnesium iodide and other pharmaceutically acceptable iodide salts. 10. The method of claim 7, wherein said peroxidase is selected from the group consisting of horseradish peroxidase, soy peroxidase, lactoperoxidase, and mierloperoxidase. The method of claim 1, wherein said iodine reductant and oxidant is combined with a pharmaceutically acceptable non-aqueous medium. The method of claim 9, wherein said non-aqueous pharmaceutically suitable medium is a non-toxic excipient selected from the group consisting of sucrose, lactose, maltodextrin, mannitol, dextrose, dextrose, glucose, citric acid, sorbitol, cellulose microcrystalline slab, starch, sodium carbonate, magnesium carbonate, potassium carbonate, 20 calcium carbonate, carboxymethylcellulose, cross-linked carmellose cellulose, polyethylene glycol, boric acid, benzoate, acetate, oleate, magnesium stearate, stannic acid, talc, hydrogenated vegetable oils, hydroxymethylcellulose, cellulose, calcium phosphates, sodium phosphates, phosphates, potassium and combinations thereof. , .- .ft «. ^ vAH ^ -J. ^ - * - ***. .. ^ ...., aii- «ri.ar.Jrá ^^ eleven . A composition for administering therapeutic iodine to a mammal, consisting essentially of a pharmaceutically acceptable oxidant for an iodine species, a pharmaceutically acceptable iodine reducing agent, wherein at least one of these compounds contains a 5 species of iodine, and a pharmaceutically acceptable carrier with said oxidant and reductant selected to undergo oxidation-reduction reactions on contact with the gastric juices present in the stomach of said mammal in a sufficient amount to generate molecular iodine, in vivo , at a ratio of molecular iodine to total iodine 10 above at least about 0.8. 1 2. A non-aqueous composition of claim 1, wherein said pharmaceutically acceptable carrier is a non-toxic excipient selected from the group consisting of sucrose, lactose, maltodextrin, mannitol, dextrose, dextrose, glucose, sorbitol, microcrystalline cellulose, 15 starch, sodium carbonate, magnesium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, carboxymethylcellulose, cross-linked carmellose cellulose, polyethylene glycol, boric acid, benzoate, acetate, oleate, magnesium stearate, stearic acid, talcum, hydrogenated vegetable oils, hydroxymethylcellulose, cellulose, calcium phosphates, 20 sodium phosphates, potassium phosphates and combinations of the same. The composition of claim 1, wherein said oxidant and reductant comprise an iodate and an iodide respectively. 14. The composition of claim 1, wherein said iodide is selected from the group consisting of sodium iodide, iodide 25 potassium, ammonium iodide, calcium iodide and magnesium iodide. u »? m * ~ ,. . ^. 3 ^ ^ ütu aáfMmi 5. A non-aqueous composition of claim 14, wherein said iodate is selected from the group consisting of calcium iodate, potassium iodate and sodium iodate. The composition of claim 1, wherein the preferred inmate ratio of iodide anion to iodate anion is 3.63 to 1.0. The composition of claim 1, wherein the weight ratio of iodide anion to iodate anion ([I '] / [IO]) is between 0.78 and 6.0. The aqueous composition of claim 13, wherein the pH of the gastric fluid in the stomach of said mammal prior to the administration of said non-aqueous composition is less than 4.5. 9. The non-aqueous composition of claim 12, wherein the iodate anion and the iodide anion are dissolved in an aqueous composition and then applied to a pharmaceutically acceptable carrier before drying. The non-aqueous composition of claim 1, wherein said oxidant and reductant comprise a source of hydrogen peroxide, an iodide and a peroxidase selected from the group consisting of horseradish peroxidase, soy peroxidase, lactoperoxidase and ierloperoxidase. twenty-one . The method of claim 1, wherein said disorder to be treated is fibrocystic breast syndrome and the daily amount of iodine generated in vivo in the stomach of the mammal is between 0.01 mg per kilogram up to about 0.20 mg per kilogram of weight body of said animal. 22. The method of claim 21, wherein the prevention of fibrocystic breast syndrome is achieved by a daily amount of molecular iodine generated in vivo between 0.0025 mg per kilogram to about 0.01 mg per kilogram of body weight of said mammal. The method of claim 1, wherein at least 50% of the iodine is generated in vivo within a short interval of no more than about 20 minutes of intimate contact between a composition of said oxidant and reductant with the gastric fluid in the stomach of the mammal. The method of claim 23, wherein said composition further comprises a pharmaceutically acceptable carrier selected from the group consisting of sucrose, lactose, maltodextrin, mannitol, dextrose, dextrose, glucose, citric acid, sorbitol, microcrystalline cellulose, starch, Sodium carbonate, magnesium carbonate, potassium carbonate, calcium carbonate, carboxymethylcellulose, cross-linked carmellose cellulose, polyethylene glycol, boric acid, benzoate, acetate, oleate, magnesium stearate, stearic acid, talc, hydrogenated vegetable oils, hydroxymethylcellulose, cellulose, calcium phosphate, sodium phosphates, potassium phosphate and combinations thereof. The method of claim 1, wherein said disorder is selected from the group consisting of fibrocystic breast syndrome, breast cancer, premenstrual syndrome, endometriosis and stomach ulcers. G? ^^ 26. The method of claim 23, wherein said composition further comprises an inorganic or organic iodine composition. 27. The method of claim 1, wherein said oxidant and iodine reductant are combined with a pharmaceutically acceptable aqueous medium. 28 An aqueous composition of claim 1 1, wherein said oxidant and reductant comprise an iodate and an iodide respectively, contained in a solution or an emulsion. 29. The composition of claim 28, wherein said iodide is selected from the group consisting of sodium iodide, potassium iodide, ammonium iodide, calcium iodide, and magnesium iodide. 30. The composition of claim 28, wherein said iodate is selected from the group consisting of calcium iodate, potassium iodate, sodium iodate. 31 An aqueous composition of claim 28, wherein the preferred weight ratio of iodide anion to iodate anion is 3.63 to 1.0. 32. An aqueous composition of claim 28, wherein the weight ratio of iodide anion to iodate anion ([l '] / [I O]) is between 0.78 and 6.0.
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