WO2022118274A1 - Compositions for the use in the treatment and/or prevention of iron deficiency conditions or diseases - Google Patents
Compositions for the use in the treatment and/or prevention of iron deficiency conditions or diseases Download PDFInfo
- Publication number
- WO2022118274A1 WO2022118274A1 PCT/IB2021/061297 IB2021061297W WO2022118274A1 WO 2022118274 A1 WO2022118274 A1 WO 2022118274A1 IB 2021061297 W IB2021061297 W IB 2021061297W WO 2022118274 A1 WO2022118274 A1 WO 2022118274A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- iron
- nutraceutical
- pharmaceutical composition
- starch
- ranging
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 27
- 206010022971 Iron Deficiencies Diseases 0.000 title claims abstract description 16
- 238000011282 treatment Methods 0.000 title claims abstract description 16
- 201000010099 disease Diseases 0.000 title claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 6
- 230000002265 prevention Effects 0.000 title claims abstract description 6
- 229920002472 Starch Polymers 0.000 claims abstract description 31
- 235000019698 starch Nutrition 0.000 claims abstract description 31
- 239000008107 starch Substances 0.000 claims abstract description 29
- CADNYOZXMIKYPR-UHFFFAOYSA-B ferric pyrophosphate Chemical compound [Fe+3].[Fe+3].[Fe+3].[Fe+3].[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])([O-])=O CADNYOZXMIKYPR-UHFFFAOYSA-B 0.000 claims abstract description 19
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 18
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 11
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims abstract description 11
- 239000001116 FEMA 4028 Substances 0.000 claims abstract description 10
- 229960004853 betadex Drugs 0.000 claims abstract description 10
- 239000007787 solid Substances 0.000 claims abstract description 8
- 239000007788 liquid Substances 0.000 claims abstract description 5
- 239000002417 nutraceutical Substances 0.000 claims description 27
- 235000021436 nutraceutical agent Nutrition 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 24
- 230000000968 intestinal effect Effects 0.000 claims description 9
- 235000015872 dietary supplement Nutrition 0.000 claims description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 8
- 229940127557 pharmaceutical product Drugs 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 7
- 239000008187 granular material Substances 0.000 claims description 7
- 208000007502 anemia Diseases 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 210000001072 colon Anatomy 0.000 claims description 4
- 230000035935 pregnancy Effects 0.000 claims description 4
- 208000015943 Coeliac disease Diseases 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 208000032177 Intestinal Polyps Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 208000007107 Stomach Ulcer Diseases 0.000 claims description 3
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 3
- 208000029742 colonic neoplasm Diseases 0.000 claims description 3
- 208000014617 hemorrhoid Diseases 0.000 claims description 3
- 230000005906 menstruation Effects 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 206010046766 uterine cancer Diseases 0.000 claims description 3
- 230000004596 appetite loss Effects 0.000 claims description 2
- 206010003549 asthenia Diseases 0.000 claims description 2
- 230000000740 bleeding effect Effects 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000007902 hard capsule Substances 0.000 claims description 2
- 208000027866 inflammatory disease Diseases 0.000 claims description 2
- 235000021266 loss of appetite Nutrition 0.000 claims description 2
- 208000019017 loss of appetite Diseases 0.000 claims description 2
- 230000009245 menopause Effects 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000006186 oral dosage form Substances 0.000 claims 2
- 201000005917 gastric ulcer Diseases 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 15
- 238000009472 formulation Methods 0.000 abstract description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 111
- 229910052742 iron Inorganic materials 0.000 description 54
- 239000000546 pharmaceutical excipient Substances 0.000 description 15
- 229940079593 drug Drugs 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 238000000034 method Methods 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 9
- 235000005911 diet Nutrition 0.000 description 8
- 230000037213 diet Effects 0.000 description 8
- 229920000856 Amylose Polymers 0.000 description 7
- 229920000881 Modified starch Polymers 0.000 description 7
- 235000019426 modified starch Nutrition 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 102000008857 Ferritin Human genes 0.000 description 6
- 108050000784 Ferritin Proteins 0.000 description 6
- 238000008416 Ferritin Methods 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 229940097362 cyclodextrins Drugs 0.000 description 6
- 235000019640 taste Nutrition 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000013589 supplement Substances 0.000 description 5
- 102000004338 Transferrin Human genes 0.000 description 4
- 108090000901 Transferrin Proteins 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 230000007812 deficiency Effects 0.000 description 4
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 4
- 235000011180 diphosphates Nutrition 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 230000031891 intestinal absorption Effects 0.000 description 4
- 159000000014 iron salts Chemical class 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- -1 pyrophosphate Chemical class 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 239000012581 transferrin Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 208000015710 Iron-Deficiency Anemia Diseases 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 150000003278 haem Chemical group 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000000051 modifying effect Effects 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 229920000642 polymer Polymers 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
- 210000002784 stomach Anatomy 0.000 description 3
- 230000009469 supplementation Effects 0.000 description 3
- 229920001685 Amylomaize Polymers 0.000 description 2
- 229920000945 Amylopectin Polymers 0.000 description 2
- 229920001353 Dextrin Polymers 0.000 description 2
- 239000004375 Dextrin Substances 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000004368 Modified starch Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000036765 blood level Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 238000010668 complexation reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 235000019425 dextrin Nutrition 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 210000001198 duodenum Anatomy 0.000 description 2
- 210000002919 epithelial cell Anatomy 0.000 description 2
- 238000004299 exfoliation Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000007794 irritation Effects 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 2
- 229960001852 saquinavir Drugs 0.000 description 2
- 239000002356 single layer Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- XJOTXKZIRSHZQV-RXHOOSIZSA-N (3S)-3-amino-4-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[(2S)-2-[[(2S,3S)-1-[[(1R,6R,12R,17R,20S,23S,26R,31R,34R,39R,42S,45S,48S,51S,59S)-51-(4-aminobutyl)-31-[[(2S)-6-amino-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxohexan-2-yl]carbamoyl]-20-benzyl-23-[(2S)-butan-2-yl]-45-(3-carbamimidamidopropyl)-48-(hydroxymethyl)-42-(1H-imidazol-4-ylmethyl)-59-(2-methylsulfanylethyl)-7,10,19,22,25,33,40,43,46,49,52,54,57,60,63,64-hexadecaoxo-3,4,14,15,28,29,36,37-octathia-8,11,18,21,24,32,41,44,47,50,53,55,58,61,62,65-hexadecazatetracyclo[32.19.8.26,17.212,39]pentahexacontan-26-yl]amino]-3-methyl-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-4-oxobutanoic acid Chemical compound CC[C@H](C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1cnc[nH]1)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(O)=O)[C@@H](C)O)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@@H]4CSSC[C@H](NC(=O)[C@H](Cc5ccccc5)NC(=O)[C@@H](NC1=O)[C@@H](C)CC)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](Cc1cnc[nH]1)NC3=O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N2)C(=O)NCC(=O)N4)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O XJOTXKZIRSHZQV-RXHOOSIZSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- MNIPYSSQXLZQLJ-UHFFFAOYSA-N Biofenac Chemical compound OC(=O)COC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl MNIPYSSQXLZQLJ-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010049047 Chapped lips Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 108010025880 Cyclomaltodextrin glucanotransferase Proteins 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 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 description 1
- 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 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- PMVSDNDAUGGCCE-TYYBGVCCSA-L Ferrous fumarate Chemical group [Fe+2].[O-]C(=O)\C=C\C([O-])=O PMVSDNDAUGGCCE-TYYBGVCCSA-L 0.000 description 1
- 206010059024 Gastrointestinal toxicity Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000005232 Glossitis Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 206010053782 Hyposideraemia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 239000005569 Iron sulphate Substances 0.000 description 1
- 206010025476 Malabsorption Diseases 0.000 description 1
- 208000004155 Malabsorption Syndromes Diseases 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010060860 Neurological symptom Diseases 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010033546 Pallor Diseases 0.000 description 1
- 241001482237 Pica Species 0.000 description 1
- 208000005107 Premature Birth Diseases 0.000 description 1
- 108091006976 SLC40A1 Proteins 0.000 description 1
- 102100032008 Solute carrier family 40 member 1 Human genes 0.000 description 1
- 101710111423 Solute carrier family 40 member 1 Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000007216 Upjohn dihydroxylation reaction Methods 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000016383 Zea mays subsp huehuetenangensis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 229960004420 aceclofenac Drugs 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 238000004026 adhesive bonding Methods 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical group OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- AFYNADDZULBEJA-UHFFFAOYSA-N bicinchoninic acid Chemical compound C1=CC=CC2=NC(C=3C=C(C4=CC=CC=C4N=3)C(=O)O)=CC(C(O)=O)=C21 AFYNADDZULBEJA-UHFFFAOYSA-N 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000013553 cell monolayer Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 210000001842 enterocyte Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000010437 erythropoiesis Effects 0.000 description 1
- 230000000913 erythropoietic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 210000001156 gastric mucosa Anatomy 0.000 description 1
- 231100000414 gastrointestinal toxicity Toxicity 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 102000034238 globular proteins Human genes 0.000 description 1
- 108091005896 globular proteins Proteins 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000001033 granulometry Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 102000018511 hepcidin Human genes 0.000 description 1
- 108060003558 hepcidin Proteins 0.000 description 1
- 229940066919 hepcidin Drugs 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 125000001165 hydrophobic group Chemical group 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003870 intestinal permeability Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- OJZYRQPMEIEQFC-UAWLTFRCSA-N limaprost Chemical compound CCCC[C@H](C)C[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCC\C=C\C(O)=O OJZYRQPMEIEQFC-UAWLTFRCSA-N 0.000 description 1
- 229950009365 limaprost Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000009973 maize Nutrition 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000036997 mental performance Effects 0.000 description 1
- 230000026326 mitochondrial transport Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 230000021332 multicellular organism growth Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000813 peptide hormone Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 238000001782 photodegradation Methods 0.000 description 1
- 230000036314 physical performance Effects 0.000 description 1
- 210000002826 placenta Anatomy 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004032 porphyrins Chemical group 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000003867 tiredness Effects 0.000 description 1
- 208000016255 tiredness Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/16—Inorganic salts, minerals or trace elements
Definitions
- the present invention relates to a nutraceutical or pharmaceutical composition of substances effective in the prevention and/or treatment of conditions and pathologies characterized by iron deficiency both in man and animals .
- Iron is an essential oligo-element performing di f ferent vital functions in the human body and it is involved in several metabolic processes : it transports the oxygen through the bloodstream towards the body districts , it is a co- factor in the synthesis of DNA, of steroid hormones and of the bile acids , it transports the electrons in the mitochondrial transport chain and it detoxi fies the organism from foreign substances , since it belongs to p450 cytochrome . Iron is essential for several metabolic processes which occur at cellular level , also being able to be potentially dangerous , its biochemical ef fects and its levels are finely controlled by sophisticated mechanisms which regulate the homeostasis thereof at di f ferent levels .
- the haemoglobin is a globular protein formed by four polypeptide chains , each one thereof includes a Heme group, consisting of one porphyrin ring surrounding and complexes one iron atom.
- Each iron atom is capable of binding one oxygen molecule by allowing in this way the passage of the oxygen from the lungs to the bloodstream and its transportation to all districts of the organism .
- the remaining percentage of iron existing in the organism is bound to other tissue enzymes , to transportation systems , such as trans ferrin, and to not-heme proteins such as ferritin .
- the iron which the human organism succeeds in absorbing through feeding is of two types : heme iron, which does not create absorption problems , and non-heme iron, or inorganic iron, which instead has a very low bioavailability .
- heme iron which does not create absorption problems
- non-heme iron or inorganic iron, which instead has a very low bioavailability .
- Even i f it constitutes the greatest source of iron in diet the inorganic iron is absorbed only when it is in the reduced state ( Fe 2 + ) , which represents the form favoured by the acid pH of the stomach and of the proximal duodenum . At physiological pH, the inorganic iron is instead quickly oxidi zed to Fe 3 + .
- the human organism succeeds in maintaining the iron normal levels through a continuous recycling of the deposits existing in the cells and by avoiding the excretion thereof .
- the amount of iron which the body eliminates every day is very low ( « 1 mg/die ) .
- the iron elimination substantially takes place through exfoliation of the epithelial cells of the skin and mucous membranes of the genitourinary and gastrointestinal tract .
- the subj ects at risk there are : - Children and adolescents : iron is fundamental for the correct body growth, therefore in the absence of adequate supplementation, it is one of the main factors which could cause a deficiency thereof ;
- this category includes whoever suf fers from diseases characteri zed by malabsorption such as intestinal chronic inflammatory diseases , celiac disease or obesity .
- the latter is a condition accompanied by a chronic inflammatory state and by high levels of hepcidin, a peptide hormone inhibiting ferroportin 1 on the basolateral membrane of enterocytes and macrophage ferroportin, by inhibiting both the intestinal absorption, and the release from the macrophages of the iron already existing in the organism.
- an iron deficiency can appear with or without anaemia, but most iron deficit symptoms are, mainly, attributable to the anaemic picture.
- anaemia a condition is meant characterized by alterations in the number of red blood cells or haemoglobin in blood going down to a lower level than the one required to the correct transportation of oxygen to all districts and body tissues.
- the iron deficiency anaemia is defined "sideropenic anaemia" and it can appear in the subjects which do not succeed in reaching adequate levels of such essential element through the diet, or in subjects affected by morbid states characterized by chronic losses of blood (such as gastric ulcers, colon or uterine cancer, intestinal polyps and haemorrhoids) , pregnant women and obese subjects.
- the main symptoms characterizing an iron deficiency anaemia include: feeling of tiredness, weakness and reduced resistance; concentration difficulty and reduced physical and mental performances; pallor; shortness of breath; difficulty in maintaining an adequate body temperature (in particular at the ends which appear cool) ; during pregnancy it can lead to an increase in the risk of preterm birth .
- more serious deficiencies symptoms can appear such as : glossitis ( inflammation of the tongue which appears reddened, swollen and painful ) ; chapped lips ; neurological symptoms such as pica (need for eating substances such as dirt , ice and paints ) .
- the iron percentage absorbed through feeding is very low, therefore , under determined conditions or li fe phases , it is essential to have to recourse to a supplementation .
- This last strategy is not always easy to be implemented since the inorganic iron has several vehiculation problems .
- any iron salt has a characteristic rust odour and taste resulting extremely unpleasant by invalidating the compliance of any supplement including inorganic iron .
- Another important problem correlated to its vehiculation is the modest absorption which, as mentioned, is influenced by the iron redox state . The only form which can be absorbed at intestinal level is the reduced one ( Fe 2 + ) .
- the reduced state is favoured by acid pH values which can be found in the stomach and in the proximal duodenum . Therefore , the intestinal absorption of the inorganic iron is limited to this tract , considering that the pancreatic j uices , existing in the portion of remaining intestine , favour instead the oxidi zed state ( Fe 3 + ) .
- Some iron salts such as pyrophosphate , have a very bad suspensibility and a high tendency to sediment . This feature makes that , in contact with the gastric mucosa, on one side the iron is oxidi zed due to the contact with the basic mucus and, on the other side , it irritates the mucosa itsel f .
- the oral administration of iron in most patients , causes unwished ef fects at gastro-intestinal level , such as abdominal pain, diarrhoea or constipation, nausea and vomit .
- the purpose of the present invention is then to make available a nutraceutical or pharmaceutical composition apt to vehiculate iron to re-integrate the levels thereof in subj ects having a deficiency of such element .
- the iron pyrophosphate is one of the salts most used in the iron-based supplements .
- the pyrophosphate is a substance which participates in the energy cycle and it is produced by the hydrolysis of adenosine triphosphate . When it is combined with multivalent cations , it is capable of forming complexes insoluble in water which are characteri zed by a considerable chemical and structural complexity . This feature makes that pyrophosphate is among the most used compounds in chemical and biomedical industries .
- the selection of the most suitable inorganic salt is performed by taking into consideration several factors , the first thereamong is ef fectiveness .
- Many clinical studies have highlighted that the iron pyrophosphate is among the salts which provide best results , even in case of most serious deficiency .
- the iron deficiency i s among the most common nutritional deficits and it can be a secondary ef fect caused by the increase in erythropoiesis , by the decrease in the intestinal absorption capability, by the increase in the blood losses or in chronic bleeding, by the increased exfoliation of the gastrointestinal epithelial cells .
- iron inorganic salts (II) soluble in water such as iron sulphate
- iron pyrophosphate results to be extremely advantageous since it does not alter the colour of the supplements in which it is inserted.
- the iron salts (III) such as indeed the iron pyrophosphate, have the disadvantage of being less soluble in water and less bioavailable with respect to the iron salts
- (III) is correlated to their moderate solubility in the diluted acids, such as those existing in the gastric juices.
- nutraceutical or pharmaceutical composition characteri zed in that it comprises iron pyrophosphate as active principle and a combination of functional excipients , that i s beta-cyclodextrin and starch, capable of providing properties of gastro-resistance and of increasing iron bioavailability .
- the nutraceutical or pharmaceutical composition of the invention is particularly ef fective in the treatment and prevention of conditions and pathologies , including the related symptomatic states , caused by iron deficiency .
- the iron deficiency can be due to a reduced intake with diet or to an increased requirement .
- the pharmaceutical product or a food supplement comprising the nutraceutical or pharmaceutical composition according to the invention .
- the pharmaceutical product or food supplement of the invention can optionally include active principles and functional excipients which are easily selected by the person skilled in the art based upon the case needs . Even the selection of the vehicles, excipients and/or diluents required for the formulation of the pharmaceutical product or food supplement in an appropriate dosage form lies within the usual capabilities of the person skilled in the art .
- nutraceutical or pharmaceutical composition according to the invention is as defined in the enclosed claim 1 .
- the nutraceutical or pharmaceutical composition of the present invention comprises iron pyrophosphate as active principle and a combination of functional excipients which provide to the composition properties of gastro-resistance and increase the iron bioavailability .
- Such combination of functional excipients includes beta- cyclodextrin and starch .
- the nutraceutical or pharmaceutical composition of the invention is then particularly effective for the vehiculation and supplementation of iron in contrasting the typical symptomatology of the iron- deficiency states and to provide high levels of such element in periods of reduced intake with diet or of increased iron requirement .
- Examples of such conditions and pathologies are anaemia, sideropenia, pregnancy, breastfeeding, loss of appetite , asthenia, menstruation, haemorrhages , menopause , intestinal inflammatory diseases , celiac disease , obesity, gastric ulcers , colon or uterine cancer, intestinal polyps , haemorrhoids .
- the starch is an organic compound of polysaccharide nature consisting of the repetition of glucose units bound by a-glycosidic bonds . It consists of two types of polymers : amylose , which generally is equal to about 20% , and amylopectin, which generally is equal to about 80% .
- amylose constitutes the central portion of the starch granules , it is soluble in very hot water and it consists of molecules of glucose bound by a- 1 , 4 glycosidic bonds .
- the amylopectin is a polymer with a high degree of branching forming the external portion of the granules .
- the monomeric units constituting it are j oined, in the branching points , by a- 1 , 6 glycosidic bonds .
- a- 1 , 6 glycosidic bonds In nature it forms in the green portions of plants , to be then accumulated in the reserve elements , such as tubers , seeds and roots .
- the reserve elements such as tubers , seeds and roots .
- the starch is particularly important in food industry, which uses it as thickening agent and in the production of sweeteners such as maltitol and sorbitol . Thanks to its gluing properties it is also used in the production of paper and glues , under the form of solid starch . In the pharmaceutical industry the starch has always been used as excipient and for the formation of coatings , thanks to its binding properties .
- the starch is also used in its natural form, the interest of the firms is mainly directed to the modi fied starches , that is starch molecules suitably modi fied to meet the needs of the various productive processes in which the starch is used .
- modi fied starches can be obtained by using as source plants which mutated genetically naturally or induced and which then produce starches with altered features.
- Another strategy is that of modifying the starch, generally deriving from maize, tapioca and rice, by chemical treatments (addition of functional groups, treatment with acids and bases, physical treatments (gelatinization) or enzymatic treatments (partial hydrolysis) .
- Dextrins are an example of modified starches obtained by hydrolysis and repolymerization.
- Such reactions can be made by simple thermal degradation or by means of acid catalysis. The result is to obtain molecules characterized by shorter chains and then partially or wholly soluble in water.
- dextrins are cyclodextrins and maltodextrins, excipients widely used in nutraceutical and pharmaceutical field .
- HAS high amylose modified starches
- a starch in order to be defined as such, must have a percentage of amylose equal to at least 50%.
- the high amylose starch can be obtained from genetically modified plants or by enriching with amylose starches which have low percentages thereof.
- the strategies used by several firms provide the use of HAS for the preparation of solid pharmaceutical forms or in the coating processes .
- HAS have several advantages with respect to other types of starch, for example a better consistency, a greater thermal stability and a greater resistance to humidity and adhesion phenomena . Di f ferent strategies were put into practice to exploit HAS advantages in the most suitable way .
- di f ferent types of starch can be used .
- a not chemically modi fied starch of pregelatini zed mai ze or a starch of pregelatini zed acetylated mai ze with a high content of amylose which, in the specific case, can reach up to 90% by weight.
- the percentage of acetylic groups ranges from 0.5% to 2.5%.
- the acetylation is performed with acetic anhydride which guarantees to reach a percentage of acetylic groups higher than 0.5% but not higher than 2.5%.
- the starch pre-gelatinization treatment consists in dispersing the acetylated starch in water and in subjecting the so-obtained dispersion at temperatures ranging from 100 to 130 degrees and high pressures.
- the starch granules subjected to such procedure blow up and form a gel with a humidity content ranging from 5 and 10%.
- the thus obtained modified starch can be used in the processes for coating stiff, soft capsules and microgranules and it guarantees to obtain a coating which results resistant and adequately viscous at the same time, which is capable of masking unpleasant odours and tastes and which can be used even when one wants to obtain e a gastro-resistant pharmaceutical form or a form with modified release.
- the features of the pharmaceutical form can be modulated by modifying the amount of starch used in the coating.
- Tests performed by using the above-mentioned starch showed the gastro-resistant action, the action of protecting against humidity and the capability of releasing the active principle after few minutes in intestinal environment .
- the other functional excipient present in the nutraceutical or pharmaceutical composition of the invention is beta-cyclodextrin .
- Cyclodextrins ( CD) are cyclic oligosaccharides which are produced by the starch or by starch derivatives by using the cyclodextrin glycosyltrans ferase enzyme . These compounds are used as pharmaceutical excipients as they can form inclusion complexes by binding in a not covalent way (host -guest complexes ) several drugs in solution or in the solid state .
- cyclodextrins include units of a-D-glucopyranose with (a- 1-4 ) bond, having a central lyophile cavity and a hydrophile external surface ; from the spatial and three-dimensional point of view they have a truncated-conical shape or a donut-like shape .
- Cyclodextrins are used in the pharmaceutical industry for several purposes , such as : improving the aqueous solubility, the dissolution and the bioavailability of drugs , increasing the chemical- physical stability of the drug and improving the shel f-li fe of the drugs , modi fying the release , reducing to the minimum adverse reactions such as gastrointestinal and ocular irritation, reducing or removing unpleasant taste and odour, preventing drug-drug or drug-excipient interactions , converting liquid drugs into microcrystalline or amorphous powders .
- betacyclodextrins al f a-cyclodextrins and gammacyclodextrins .
- p-CDs and their derivatives from chemical modi fications are the ones most used by the pharmaceutical industry in the field of the controlled release of active principles .
- Hydrophobic ( diethyl- p -CD and triacetyl- p -CD) and ioni zable derivatives of p-CDs are used in the formulation of tablets with prolonged release and with delayed release , respectively .
- O-carboxymethyl-O-ethyl- p-CD causes a delayed dissolution of the included substances , not thanks to the presence of the ioni zable carboxymethyl groups but due to the presence of the ethylic hydrophobic groups .
- the ef fect of the CD complexes on the chemical stability of drugs was examined and it was highlighted that the complexation with CD can hinder hydrolysis , oxidation, photodegradation, isomeri zation and degradation catalyzed by enzymes of drugs dissolved in aqueous solution .
- the addition of p-CD as excipient to Limaprost-based tablets improved the stability of the derivative of El prostaglandin .
- CDs An additional application of CDs relates to their use with the purpose of masking the unpleasant taste of possible substances , the complexation of drugs with CDs constituting a coating method ( formation of a physical barrier ) or chemical modi fication .
- a coating method formation of a physical barrier
- chemical modi fication a coating method
- Aceclofenac a non-steroidal antiinflammatory drug
- CDs then, are used to reduce to the minimum the side ef fects of the drugs such as gastric, intestinal , nasal and ocular irritation .
- Naprossene for example has poor solubility in water and problems of gastrointestinal toxicity and ulceration i f administered by oral route , in order to overcome these critical issues coated tablets were developed containing Nanoprossene/HP-p-CD inclusion complexes to vehiculate the drug to the colon .
- CDs were used in the formulation of tablets as filler for the direct compression (p -CD) , disintegrating agents (polymers of CDs) , binding agents (p -CD) and osmotic pump agents (for example, SBE-p-CD) .
- Literature shows the development of a new multifunctional excipient, to be used in the production of tablets through direct compression, based upon citric acid and p -CD, in its forms insoluble (PCD-I) and soluble (PCD-S) in water.
- Other excipients such as binders, lubricants or disintegrating agents were not added.
- This project highlighted the multifunctional properties of this polymeric excipient, such as good flowing properties, compressibility, absence of toxicity and modular disintegration time.
- the present invention then allows to obtain :
- the present invention is a ready and valid intervention to contrast symptoms typical of the iron-deficiency states and to provide adequate levels of such element in periods of reduced intake with diet or of increased requirement .
- Such ef fect is ascribed to the combined action of the substances constituting it .
- the starch used in the present invention allows to mask the unpleasant taste which can be found in the iron-based supplements , as well as to protect iron from acid pH in the stomach, by guaranteeing the release at intestinal level .
- Beta-cyclodextrin thanks to the peculiar chemical structure is capable of incorporating iron pyrophosphate and favouring the bioavailability thereof by improving the solubility and stability thereof .
- the ef fectiveness of the nutraceutical or pharmaceutical composition of the present invention is evaluated by means of the experimental protocol described hereinafter .
- a disintegration test is performed, as provided by Pharmacopeia .
- a sample of the pharmaceutical form to be tested is placed in suitable instrument containing hydrochloric acid 0 . 1 N .
- the gastro-resistant pharmaceutical form in contact with the buf fer at pH 2 for two hours is not subj ected to disintegration .
- the sample is trans ferred into a buf fer at pH 6 . 8 wherein it disintegrates within ten minutes .
- the gastro-resistance can be evaluated even by means of a dissolution test by Pharmacopeia according thereto the pharmaceutical form is put in contact with a solution of 0 . 1 N-hydrochloric acid and for 2 hours .
- an in-vitro test is performed on Caco- 2 cells of human derivation .
- the cells put in culture , are prepared by using a suitable growth means (for example containing FBS , fetal bovine serum) and kept under controlled conditions (for example of 37 ° C, in an atmosphere having 5% of CO 2 and 100% of humidity) . After several passages the cells are washed and pre-incubated with PBS . After the treatment with the formulations of interest the collected samples are subj ected to analysis in order to quantify iron.
- a suitable growth means for example containing FBS , fetal bovine serum
- controlled conditions for example of 37 ° C, in an atmosphere having 5% of CO 2 and 100% of humidity
- a variant discussed by way of example of the above-mentioned in vitro test provides that the Caco-2 cells are incubated under the same conditions of temperature, CO 2 and humidity. After sucking the means the cells are washed twice with suitable buffer (for example 50 mM HEPES, 130 mM NaCl, 10 mM KC1, 5 mM glucose, 1 mM MgS0 4 , pH 7) and, subsequently, treated with the samples to be tested for one hour. At the end of the treatment the monolayer of cells is washed with a buffer which removes iron and it is dissolved in suitable means (for example Triton-X 2%) in order to be sonificated. The protein concentration is calculated by suitable method (for example of the bicinchoninic acid) . The iron concentration is obtained by atomic absorption and the uptake is expressed as pg of iron for mg of proteins.
- suitable buffer for example 50 mM HEPES, 130 mM NaCl, 10 mM KC1, 5 mM glucose, 1
- TEER transepithelial electric resistance
- the solution containing the composition, the present invention relates to , which is subj ected to gastric and intestinal digestion is then applied ( at the concentrations selected based upon the results of the preliminary cytotoxicity) from the apical side of the transwell (which in the model represents the intestinal lumen) .
- the apical side of the transwell which in the model represents the intestinal lumen
- the liquid is collected on the baso- lateral side which will be subsequently analysed for the iron pyrophosphate dosage by means of TCP or other accredited method .
- the iron uptake can be evaluated on still on Caco-2 cell model by evaluation after treatment with the samples of ferritin in cell .
- the percentage of ferritin is directly proportional to the iron amount inside the cell .
- the ef fectiveness of the present invention can be evaluated even by means of an in vi vo test on experiment animals in line with the directives of the European Community and of the Ministry of Health by an Ethical Committee .
- the test is performed on male mice , for example Sprague-Dawley, having an average weight of about 250-300 g .
- the iron level is evaluated after one single administration of the formulation under examination .
- the levels of plasmatic iron are measured by means of atomic absorption or other analytic technique suitable on blood samples collected at time zero and at determined time intervals after administration .
- the levels of plasmatic iron are evaluated after daily administration of the above- mentioned formulation for a prolonged period of time and, at the end of the treatment , the blood levels of iron, haemoglobin, trans ferrin and ferritin are evaluated .
- the ef fectiveness of the composition, the present invention relates to can be evaluated even by means of a clinical study on man by monitoring after a determined period of time the way in which the blood levels of iron, haemoglobin, trans ferrin, ferritin vary before and after administration of the formulation the present invention relates to .
- All mentioned experimental models represent only not limitative examples ; even variants thereof or other types of experimental models known to the person skilled in the art could be used with the purpose of evaluating the synergic action of the composition the present invention relates to .
- the nutraceutical or pharmaceutical composition of the present invention is particularly ef fective in contrasting the iron deficiency states thanks to the synergic action of its components .
- nutraceutical or pharmaceutical composition of the present invention is inserted within a pharmaceutical product or food supplement , which is formulated in a suitable dosage form, the composition and preparation thereof lies within the capability of the person skilled in the art .
- the iron pyrophosphate in the nutraceutical or pharmaceutical composition of the invention is present in an amount ranging from 0 . 1 and 90% , preferably between 1 and 80% , still more preferably between 5 and 70% , with respect to the total weight of the above-mentioned combination .
- additional percentages of iron pyrophosphate which can be used in the composition of the invention are : 2 % , 3% , 4 % , 6% , 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, or 85%.
- the starch in the nutraceutical or pharmaceutical composition of the invention is present in an amount ranging from 0.1 to 90%, preferably from 1 to 80%, still more preferably from 10 to 70% with respect to the total weight of the above-mentioned combination.
- additional percentage of starch which can be used in the composition of the invention are: 2%, 3%, 4%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, or 85%.
- betacyclodextrin in the nutraceutical or pharmaceutical composition of the invention is present in an amount ranging from 0.01 to 90%, preferably from 0.05 to 70%, still more preferably from 0.1 to 50% with respect to the total weight of the above- mentioned combination.
- additional percentages of beta cyclodextrin which can be used in the composition of the invention are: 0.02%, 0.03%, 0.04%, 0.06%, 0.07%, 0.08%, 0.09%, 0.2%, 0.3%, 0.4%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 15%, 20%, 25%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75 o 85%.
- the pharmaceutical product or food supplement comprising the pharmaceutical or nutraceutical composition of the invention, is formulated in a, preferably oral, pharmaceutical form which can be solid, half-solid or liquid.
- a powder, an orosoluble powder, a granulate, a hard capsule, a soft-gel capsule, a tablet, a sachet, a solution, a suspension or an emulsion can be mentioned.
- nutraceutical or pharmaceutical compositions are formulated as pharmaceutical products or food supplements and administered in a suitable form of oral dosage, in case divided into one or more dosage units, such as for example, a capsule, a tablet or a sachet.
- the working process consists in the following steps : a) Mixing:
- the raw materials previously loaded in the granulator basket are subjected to a first mixing phase on fluid bed, with process air having a pre- established temperature (for example of 80-90°C) , until obtaining a mixture having an average temperature for example of 44 °C.
- process air having a pre- established temperature (for example of 80-90°C)
- a homogeneous bulk from the point of view of the composition and of the temperature, pre-requirement necessary for the optimum course of the subsequent granulation phase.
- b) Granulation The granulation phase provides to graft an aqueous solution of a suitably selected binding or granulation agent , by means of direct nebuli zation on the bulk premixed and fluidi f ied on fluid bed .
- process air at 90 ° C is used by suitably selecting the speed for inletting the binding solution to obtain a granular structured according to expectations ( granulometry, bulk density, smoothness ) and homogeneous .
- the water content of the preformed granular is basically brought back to the conditions of the mixture of the starting raw materials .
- the temperature of the process air of the granulate at the end of the phase is suitably evaluated in the pilot testing phase depending upon such obj ective .
- the hal f- finished product obtained from the previous phase is trans ferred from the fluid bed granulator to a swinging granulator where it is calibrated through a sieve for reducing the particle si ze of the granules and of the agglomerates with coarser structure .
Abstract
The present invention relates to a composition of substances effective in the prevention and/or the treatment of conditions and diseases characterized by iron deficiency. The composition of the invention comprises iron pyrophosphate, beta-cyclodextrin and starch. Such formulation confers to the composition properties of gastro-resistance and a high bio-availability of the iron pyrophosphate active principle. The composition of the invention is prepared under the form of solid, half-solid or liquid pharmaceutical dosage, preferably for oral administration.
Description
COMPOSITIONS FOR THE USE IN THE TREATMENT AND/OR PREVENTION OF IRON DEFICIENCY CONDITIONS OR DISEASES
DESCRIPTION
The present invention relates to a nutraceutical or pharmaceutical composition of substances effective in the prevention and/or treatment of conditions and pathologies characterized by iron deficiency both in man and animals .
Iron is an essential oligo-element performing di f ferent vital functions in the human body and it is involved in several metabolic processes : it transports the oxygen through the bloodstream towards the body districts , it is a co- factor in the synthesis of DNA, of steroid hormones and of the bile acids , it transports the electrons in the mitochondrial transport chain and it detoxi fies the organism from foreign substances , since it belongs to p450 cytochrome . Iron is essential for several
metabolic processes which occur at cellular level , also being able to be potentially dangerous , its biochemical ef fects and its levels are finely controlled by sophisticated mechanisms which regulate the homeostasis thereof at di f ferent levels . 70% of the body iron is in the blood linked to haemoglobin on the red blood cells and it is involved in the erythropoietic process . The haemoglobin is a globular protein formed by four polypeptide chains , each one thereof includes a Heme group, consisting of one porphyrin ring surrounding and complexes one iron atom. Each iron atom is capable of binding one oxygen molecule by allowing in this way the passage of the oxygen from the lungs to the bloodstream and its transportation to all districts of the organism . When the red blood cells are subj ected to degradation, the iron is transported by trans ferrin in the bone marrow where it is re-used in the production of new red blood cells . The remaining percentage of iron existing in the organism is bound to other tissue enzymes , to transportation systems , such as trans ferrin, and to not-heme proteins such as ferritin . The iron which the human organism succeeds in absorbing through feeding is of two
types : heme iron, which does not create absorption problems , and non-heme iron, or inorganic iron, which instead has a very low bioavailability . Even i f it constitutes the greatest source of iron in diet , the inorganic iron is absorbed only when it is in the reduced state ( Fe 2 +) , which represents the form favoured by the acid pH of the stomach and of the proximal duodenum . At physiological pH, the inorganic iron is instead quickly oxidi zed to Fe 3 + .
Notwithstanding the iron amount absorbed with diet is very low, the human organism succeeds in maintaining the iron normal levels through a continuous recycling of the deposits existing in the cells and by avoiding the excretion thereof . The amount of iron which the body eliminates every day is very low ( « 1 mg/die ) . The iron elimination substantially takes place through exfoliation of the epithelial cells of the skin and mucous membranes of the genitourinary and gastrointestinal tract . However, there are determined categories of individuals who are more predisposed to develop more or less moderate forms of iron deficiency, substantially due to an inadequate iron intake with diet under conditions of increased requirement of the same . Among the subj ects at risk there are :
- Children and adolescents : iron is fundamental for the correct body growth, therefore in the absence of adequate supplementation, it is one of the main factors which could cause a deficiency thereof ;
- Women of productive age : the blood losses during menstruation increase , until almost doubling, the iron requirement which a woman of childbearing potential should assume with diet ;
- Pregnant women : there is a signi ficant increase in the iron requirement during pregnancy due to the quick growth of placenta and foetus ;
- Subjects with reduced intestinal absorption : this category includes whoever suf fers from diseases characteri zed by malabsorption such as intestinal chronic inflammatory diseases , celiac disease or obesity . The latter is a condition accompanied by a chronic inflammatory state and by high levels of hepcidin, a peptide hormone inhibiting ferroportin 1 on the basolateral membrane of enterocytes and macrophage ferroportin, by inhibiting both the intestinal absorption, and the release from the macrophages of the iron
already existing in the organism.
An iron deficiency can appear with or without anaemia, but most iron deficit symptoms are, mainly, attributable to the anaemic picture. Under the term "anaemia" a condition is meant characterized by alterations in the number of red blood cells or haemoglobin in blood going down to a lower level than the one required to the correct transportation of oxygen to all districts and body tissues. The iron deficiency anaemia is defined "sideropenic anaemia" and it can appear in the subjects which do not succeed in reaching adequate levels of such essential element through the diet, or in subjects affected by morbid states characterized by chronic losses of blood (such as gastric ulcers, colon or uterine cancer, intestinal polyps and haemorrhoids) , pregnant women and obese subjects. The main symptoms characterizing an iron deficiency anaemia include: feeling of tiredness, weakness and reduced resistance; concentration difficulty and reduced physical and mental performances; pallor; shortness of breath; difficulty in maintaining an adequate body temperature (in particular at the ends which appear cool) ; during pregnancy it can lead to an increase
in the risk of preterm birth . In case of more serious deficiencies symptoms can appear such as : glossitis ( inflammation of the tongue which appears reddened, swollen and painful ) ; chapped lips ; neurological symptoms such as pica (need for eating substances such as dirt , ice and paints ) .
As it was mentioned previously, the iron percentage absorbed through feeding is very low, therefore , under determined conditions or li fe phases , it is essential to have to recourse to a supplementation . This last strategy is not always easy to be implemented since the inorganic iron has several vehiculation problems . First of all , any iron salt has a characteristic rust odour and taste resulting extremely unpleasant by invalidating the compliance of any supplement including inorganic iron . Another important problem correlated to its vehiculation is the modest absorption which, as mentioned, is influenced by the iron redox state . The only form which can be absorbed at intestinal level is the reduced one ( Fe 2 + ) . The reduced state is favoured by acid pH values which can be found in the stomach and in the proximal duodenum . Therefore , the intestinal absorption of the inorganic iron is limited to this tract ,
considering that the pancreatic j uices , existing in the portion of remaining intestine , favour instead the oxidi zed state ( Fe 3 + ) . Some iron salts , such as pyrophosphate , have a very bad suspensibility and a high tendency to sediment . This feature makes that , in contact with the gastric mucosa, on one side the iron is oxidi zed due to the contact with the basic mucus and, on the other side , it irritates the mucosa itsel f . Moreover, the oral administration of iron, in most patients , causes unwished ef fects at gastro-intestinal level , such as abdominal pain, diarrhoea or constipation, nausea and vomit .
The purpose of the present invention is then to make available a nutraceutical or pharmaceutical composition apt to vehiculate iron to re-integrate the levels thereof in subj ects having a deficiency of such element .
The iron pyrophosphate is one of the salts most used in the iron-based supplements . The pyrophosphate is a substance which participates in the energy cycle and it is produced by the hydrolysis of adenosine triphosphate . When it is combined with multivalent cations , it is capable of forming complexes insoluble in water which are characteri zed by a considerable chemical and
structural complexity . This feature makes that pyrophosphate is among the most used compounds in chemical and biomedical industries .
The selection of the most suitable inorganic salt is performed by taking into consideration several factors , the first thereamong is ef fectiveness . Many clinical studies have highlighted that the iron pyrophosphate is among the salts which provide best results , even in case of most serious deficiency . Among the cancer patients the iron deficiency i s among the most common nutritional deficits and it can be a secondary ef fect caused by the increase in erythropoiesis , by the decrease in the intestinal absorption capability, by the increase in the blood losses or in chronic bleeding, by the increased exfoliation of the gastrointestinal epithelial cells . A clinical study, performed on 42 subj ects with advanced cancer and with plasmatic levels of iron lower than 60 pg/dL, has investigated about the ef fects on hyposideremia of a treatment with iron pyrophosphate for 30 days . The obtained results have highlighted that a dose of 30 mg/die of iron pyrophosphate improves the levels of sideremia, ferritin and haemoglobin without any
appearance of side effects.
Another factor to be considered is the alteration of the organoleptic features. Most iron inorganic salts (II) soluble in water, such as iron sulphate, in fact cause unpleasant alterations of taste and colour of supplements in which they are inserted. The iron pyrophosphate, instead, results to be extremely advantageous since it does not alter the colour of the supplements in which it is inserted. However, the iron salts (III) , such as indeed the iron pyrophosphate, have the disadvantage of being less soluble in water and less bioavailable with respect to the iron salts
(II) . The lower bioavailability of the iron salts
(III) is correlated to their moderate solubility in the diluted acids, such as those existing in the gastric juices.
Therefore, there is the need for making available a nutraceutical or pharmaceutical composition containing iron pyrophosphate as active principle which overcomes the drawbacks and disadvantages of the know art, in particular which is characterized by a high iron bioavailability.
There is further the need for making available a nutraceutical or pharmaceutical composition
containing iron pyrophosphate as active principle , which is provided with gastro-resistance features .
These and other needs are met by the present invention which, in a first aspect , makes available a nutraceutical or pharmaceutical composition characteri zed in that it comprises iron pyrophosphate as active principle and a combination of functional excipients , that i s beta-cyclodextrin and starch, capable of providing properties of gastro-resistance and of increasing iron bioavailability . The nutraceutical or pharmaceutical composition of the invention is particularly ef fective in the treatment and prevention of conditions and pathologies , including the related symptomatic states , caused by iron deficiency . The iron deficiency can be due to a reduced intake with diet or to an increased requirement .
Within the scope of the invention there are also a pharmaceutical product or a food supplement comprising the nutraceutical or pharmaceutical composition according to the invention . In addition to the iron pyrophosphate active principle and to starch and beta-cyclodextrin functional excipients , the pharmaceutical product or food supplement of the
invention can optionally include active principles and functional excipients which are easily selected by the person skilled in the art based upon the case needs . Even the selection of the vehicles, excipients and/or diluents required for the formulation of the pharmaceutical product or food supplement in an appropriate dosage form lies within the usual capabilities of the person skilled in the art .
The nutraceutical or pharmaceutical composition according to the invention is as defined in the enclosed claim 1 .
Additional features and advantages of the invention are defined in the depending claims . The claims form an integral part of the present description .
A detailed description of some preferred embodiments of the invention is provided hereinafter .
As shown, the nutraceutical or pharmaceutical composition of the present invention comprises iron pyrophosphate as active principle and a combination of functional excipients which provide to the composition properties of gastro-resistance and increase the iron bioavailability . Such combination of functional excipients includes beta-
cyclodextrin and starch .
The nutraceutical or pharmaceutical composition of the invention is then particularly effective for the vehiculation and supplementation of iron in contrasting the typical symptomatology of the iron- deficiency states and to provide high levels of such element in periods of reduced intake with diet or of increased iron requirement . Examples of such conditions and pathologies are anaemia, sideropenia, pregnancy, breastfeeding, loss of appetite , asthenia, menstruation, haemorrhages , menopause , intestinal inflammatory diseases , celiac disease , obesity, gastric ulcers , colon or uterine cancer, intestinal polyps , haemorrhoids .
The starch is an organic compound of polysaccharide nature consisting of the repetition of glucose units bound by a-glycosidic bonds . It consists of two types of polymers : amylose , which generally is equal to about 20% , and amylopectin, which generally is equal to about 80% . The amylose constitutes the central portion of the starch granules , it is soluble in very hot water and it consists of molecules of glucose bound by a- 1 , 4 glycosidic bonds . The amylopectin is a polymer with a high degree of branching forming the external
portion of the granules . The monomeric units constituting it are j oined, in the branching points , by a- 1 , 6 glycosidic bonds . In nature it forms in the green portions of plants , to be then accumulated in the reserve elements , such as tubers , seeds and roots . For its properties and features , it has been always largely used industrially .
The starch is particularly important in food industry, which uses it as thickening agent and in the production of sweeteners such as maltitol and sorbitol . Thanks to its gluing properties it is also used in the production of paper and glues , under the form of solid starch . In the pharmaceutical industry the starch has always been used as excipient and for the formation of coatings , thanks to its binding properties .
Although the starch is also used in its natural form, the interest of the firms is mainly directed to the modi fied starches , that is starch molecules suitably modi fied to meet the needs of the various productive processes in which the starch is used . Such modi fied starches can be obtained by using as source plants which mutated genetically naturally or induced and which then produce starches with
altered features. Another strategy is that of modifying the starch, generally deriving from maize, tapioca and rice, by chemical treatments (addition of functional groups, treatment with acids and bases, physical treatments (gelatinization) or enzymatic treatments (partial hydrolysis) . Dextrins are an example of modified starches obtained by hydrolysis and repolymerization. Such reactions can be made by simple thermal degradation or by means of acid catalysis. The result is to obtain molecules characterized by shorter chains and then partially or wholly soluble in water. Examples of dextrins are cyclodextrins and maltodextrins, excipients widely used in nutraceutical and pharmaceutical field .
The nutraceutical and pharmaceutical industry has shown much interest in the high amylose modified starches (HAS, high amylose starch) . A starch, in order to be defined as such, must have a percentage of amylose equal to at least 50%. The high amylose starch can be obtained from genetically modified plants or by enriching with amylose starches which have low percentages thereof. The strategies used by several firms
provide the use of HAS for the preparation of solid pharmaceutical forms or in the coating processes . HAS have several advantages with respect to other types of starch, for example a better consistency, a greater thermal stability and a greater resistance to humidity and adhesion phenomena . Di f ferent strategies were put into practice to exploit HAS advantages in the most suitable way . The use of soft gel capsules , for example , is attributed to Scherer Corporation, in which capsules a certain percentage of gelatine is replaced with the above-mentioned starch . The so- obtained capsules result to have a better aspect and greater resistance . Dow Chemical Company can boast the use of more uni form capsules , with a greater stability in water and at high temperatures thanks to the use of hydroxy-alkylated HAS . Upj ohn Company boasts the use of amylose acetate phthalate as coating agent in the gastro-resistant preparations .
In the present invention di f ferent types of starch can be used . By way of example , one can mention : a not chemically modi fied starch of pregelatini zed mai ze , or a starch of pregelatini zed acetylated mai ze with a high content of amylose
which, in the specific case, can reach up to 90% by weight. The percentage of acetylic groups ranges from 0.5% to 2.5%.
The acetylation is performed with acetic anhydride which guarantees to reach a percentage of acetylic groups higher than 0.5% but not higher than 2.5%. The starch pre-gelatinization treatment consists in dispersing the acetylated starch in water and in subjecting the so-obtained dispersion at temperatures ranging from 100 to 130 degrees and high pressures. The starch granules subjected to such procedure blow up and form a gel with a humidity content ranging from 5 and 10%. Once solidified and removed, the thus obtained modified starch can be used in the processes for coating stiff, soft capsules and microgranules and it guarantees to obtain a coating which results resistant and adequately viscous at the same time, which is capable of masking unpleasant odours and tastes and which can be used even when one wants to obtain e a gastro-resistant pharmaceutical form or a form with modified release. The features of the pharmaceutical form can be modulated by modifying the amount of starch used in the coating.
Tests performed by using the above-mentioned
starch showed the gastro-resistant action, the action of protecting against humidity and the capability of releasing the active principle after few minutes in intestinal environment .
As shown, the other functional excipient present in the nutraceutical or pharmaceutical composition of the invention is beta-cyclodextrin . Cyclodextrins ( CD) are cyclic oligosaccharides which are produced by the starch or by starch derivatives by using the cyclodextrin glycosyltrans ferase enzyme . These compounds are used as pharmaceutical excipients as they can form inclusion complexes by binding in a not covalent way (host -guest complexes ) several drugs in solution or in the solid state . As far as the chemical structure is concerned, cyclodextrins include units of a-D-glucopyranose with (a- 1-4 ) bond, having a central lyophile cavity and a hydrophile external surface ; from the spatial and three-dimensional point of view they have a truncated-conical shape or a donut-like shape . Cyclodextrins are used in the pharmaceutical industry for several purposes , such as : improving the aqueous solubility, the dissolution and the bioavailability of drugs , increasing the chemical-
physical stability of the drug and improving the shel f-li fe of the drugs , modi fying the release , reducing to the minimum adverse reactions such as gastrointestinal and ocular irritation, reducing or removing unpleasant taste and odour, preventing drug-drug or drug-excipient interactions , converting liquid drugs into microcrystalline or amorphous powders .
Among the main CDs there can be mentioned : betacyclodextrins , al f a-cyclodextrins and gammacyclodextrins . p-CDs and their derivatives from chemical modi fications are the ones most used by the pharmaceutical industry in the field of the controlled release of active principles .
Hydrophobic ( diethyl- p -CD and triacetyl- p -CD) and ioni zable derivatives of p-CDs ( for example , 0- carboxymethyl-O-ethyl- p -CD) are used in the formulation of tablets with prolonged release and with delayed release , respectively .
It is believed that O-carboxymethyl-O-ethyl- p-CD causes a delayed dissolution of the included substances , not thanks to the presence of the ioni zable carboxymethyl groups but due to the presence of the ethylic hydrophobic groups .
In literature the ef fect of the CD complexes on the chemical stability of drugs was examined and it was highlighted that the complexation with CD can hinder hydrolysis , oxidation, photodegradation, isomeri zation and degradation catalyzed by enzymes of drugs dissolved in aqueous solution . For example , the addition of p-CD as excipient to Limaprost-based tablets improved the stability of the derivative of El prostaglandin .
An additional application of CDs relates to their use with the purpose of masking the unpleasant taste of possible substances , the complexation of drugs with CDs constituting a coating method ( formation of a physical barrier ) or chemical modi fication . On this regard it is known that the bitter taste of Aceclofenac, a non-steroidal antiinflammatory drug, was masked by forming complexes with HP- p-CD .
CDs , then, are used to reduce to the minimum the side ef fects of the drugs such as gastric, intestinal , nasal and ocular irritation . Naprossene for example has poor solubility in water and problems of gastrointestinal toxicity and ulceration i f administered by oral route , in order to overcome these critical issues coated tablets
were developed containing Nanoprossene/HP-p-CD inclusion complexes to vehiculate the drug to the colon .
CDs were used in the formulation of tablets as filler for the direct compression (p -CD) , disintegrating agents (polymers of CDs) , binding agents (p -CD) and osmotic pump agents (for example, SBE-p-CD) .
Literature, in fact, shows the development of a new multifunctional excipient, to be used in the production of tablets through direct compression, based upon citric acid and p -CD, in its forms insoluble (PCD-I) and soluble (PCD-S) in water. Other excipients such as binders, lubricants or disintegrating agents were not added. This project highlighted the multifunctional properties of this polymeric excipient, such as good flowing properties, compressibility, absence of toxicity and modular disintegration time.
At last, in a study having the purpose of forming Saquinavir/CDs inclusion complexes in order to solve the problems of oral administration, as well as unfavourable pharmacokinetics related to such drug, an inhibitory effect of Methyl- p-
Cyclodex trins on glycoprotein-P, main outflow
system of Saquinavir, was observed .
The present invention then allows to obtain :
- Gastro-resistance
- Increase in iron bioavail ability
The present invention is a ready and valid intervention to contrast symptoms typical of the iron-deficiency states and to provide adequate levels of such element in periods of reduced intake with diet or of increased requirement . Such ef fect is ascribed to the combined action of the substances constituting it . The starch used in the present invention allows to mask the unpleasant taste which can be found in the iron-based supplements , as well as to protect iron from acid pH in the stomach, by guaranteeing the release at intestinal level . Beta-cyclodextrin thanks to the peculiar chemical structure is capable of incorporating iron pyrophosphate and favouring the bioavailability thereof by improving the solubility and stability thereof .
The ef fectiveness of the nutraceutical or pharmaceutical composition of the present invention is evaluated by means of the experimental protocol described hereinafter .
With the purpose of evaluating the gastro-
resistance a disintegration test is performed, as provided by Pharmacopeia . A sample of the pharmaceutical form to be tested is placed in suitable instrument containing hydrochloric acid 0 . 1 N . The gastro-resistant pharmaceutical form, in contact with the buf fer at pH 2 for two hours is not subj ected to disintegration . Subsequently the sample is trans ferred into a buf fer at pH 6 . 8 wherein it disintegrates within ten minutes .
The gastro-resistance can be evaluated even by means of a dissolution test by Pharmacopeia according thereto the pharmaceutical form is put in contact with a solution of 0 . 1 N-hydrochloric acid and for 2 hours .
In order to evaluate the intestinal permeability an in-vitro test is performed on Caco- 2 cells of human derivation . The cells , put in culture , are prepared by using a suitable growth means ( for example containing FBS , fetal bovine serum) and kept under controlled conditions ( for example of 37 ° C, in an atmosphere having 5% of CO2 and 100% of humidity) . After several passages the cells are washed and pre-incubated with PBS . After the treatment with the formulations of interest the collected samples are subj ected to analysis in
order to quantify iron.
A variant discussed by way of example of the above-mentioned in vitro test provides that the Caco-2 cells are incubated under the same conditions of temperature, CO2 and humidity. After sucking the means the cells are washed twice with suitable buffer (for example 50 mM HEPES, 130 mM NaCl, 10 mM KC1, 5 mM glucose, 1 mM MgS04, pH 7) and, subsequently, treated with the samples to be tested for one hour. At the end of the treatment the monolayer of cells is washed with a buffer which removes iron and it is dissolved in suitable means (for example Triton-X 2%) in order to be sonificated. The protein concentration is calculated by suitable method (for example of the bicinchoninic acid) . The iron concentration is obtained by atomic absorption and the uptake is expressed as pg of iron for mg of proteins.
Another variant provides that the Caco-2 cells are sown in the transwells and left to grow for at least 21 days. Once this period has elapsed, which is necessary so that a differentiated and polarized monolayer is formed, TEER ( transepithelial electric resistance) is measured, a parameter which provides information about the integrity of the epithelial
tight j unctions and of the cell monolayers cultivated on hal f-permeable supports . Only the transwells with a determined value ( for example TEER > 200 Q - cm2 ) are taken into consideration .
The solution containing the composition, the present invention relates to , which is subj ected to gastric and intestinal digestion is then applied ( at the concentrations selected based upon the results of the preliminary cytotoxicity) from the apical side of the transwell (which in the model represents the intestinal lumen) . At the pre- established time intervals ( for example after 1-2-
3-4 hours ) the liquid is collected on the baso- lateral side which will be subsequently analysed for the iron pyrophosphate dosage by means of TCP or other accredited method .
The iron uptake can be evaluated on still on Caco-2 cell model by evaluation after treatment with the samples of ferritin in cell . The percentage of ferritin is directly proportional to the iron amount inside the cell .
The ef fectiveness of the present invention can be evaluated even by means of an in vi vo test on experiment animals in line with the directives of the European Community and of the Ministry of
Health by an Ethical Committee . The test is performed on male mice , for example Sprague-Dawley, having an average weight of about 250-300 g . In the first part of the study the iron level is evaluated after one single administration of the formulation under examination . The levels of plasmatic iron are measured by means of atomic absorption or other analytic technique suitable on blood samples collected at time zero and at determined time intervals after administration . In the second part of the study the levels of plasmatic iron are evaluated after daily administration of the above- mentioned formulation for a prolonged period of time and, at the end of the treatment , the blood levels of iron, haemoglobin, trans ferrin and ferritin are evaluated .
The ef fectiveness of the composition, the present invention relates to , can be evaluated even by means of a clinical study on man by monitoring after a determined period of time the way in which the blood levels of iron, haemoglobin, trans ferrin, ferritin vary before and after administration of the formulation the present invention relates to . All mentioned experimental models represent only not limitative examples ; even variants thereof or
other types of experimental models known to the person skilled in the art could be used with the purpose of evaluating the synergic action of the composition the present invention relates to .
The nutraceutical or pharmaceutical composition of the present invention is particularly ef fective in contrasting the iron deficiency states thanks to the synergic action of its components .
As shown previously, the nutraceutical or pharmaceutical composition of the present invention is inserted within a pharmaceutical product or food supplement , which is formulated in a suitable dosage form, the composition and preparation thereof lies within the capability of the person skilled in the art .
In a preferred embodiment , the iron pyrophosphate in the nutraceutical or pharmaceutical composition of the invention is present in an amount ranging from 0 . 1 and 90% , preferably between 1 and 80% , still more preferably between 5 and 70% , with respect to the total weight of the above-mentioned combination .
By way of example , additional percentages of iron pyrophosphate which can be used in the composition of the invention are : 2 % , 3% , 4 % , 6% ,
7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, or 85%.
In another preferred embodiment, the starch in the nutraceutical or pharmaceutical composition of the invention is present in an amount ranging from 0.1 to 90%, preferably from 1 to 80%, still more preferably from 10 to 70% with respect to the total weight of the above-mentioned combination.
By way of example, additional percentage of starch which can be used in the composition of the invention are: 2%, 3%, 4%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 75%, or 85%.
In still another preferred embodiment, betacyclodextrin in the nutraceutical or pharmaceutical composition of the invention is present in an amount ranging from 0.01 to 90%, preferably from 0.05 to 70%, still more preferably from 0.1 to 50% with respect to the total weight of the above- mentioned combination.
By way of example, additional percentages of beta cyclodextrin which can be used in the composition of the invention are: 0.02%, 0.03%, 0.04%, 0.06%, 0.07%, 0.08%, 0.09%, 0.2%, 0.3%, 0.4%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%,
6%, 7%, 8%, 9%, 15%, 20%, 25%, 35%, 40%, 45%, 50%, 55%, 60%, 70%, 75 o 85%.
All above-mentioned preferred embodiments can be combined to one another.
The pharmaceutical product or food supplement, comprising the pharmaceutical or nutraceutical composition of the invention, is formulated in a, preferably oral, pharmaceutical form which can be solid, half-solid or liquid.
By way of example a powder, an orosoluble powder, a granulate, a hard capsule, a soft-gel capsule, a tablet, a sachet, a solution, a suspension or an emulsion can be mentioned.
Some not limitative examples of nutraceutical or pharmaceutical compositions, the present invention relates to, are mentioned hereinafter. As mentioned above, such nutraceutical or pharmaceutical compositions are formulated as pharmaceutical products or food supplements and administered in a suitable form of oral dosage, in case divided into one or more dosage units, such as for example, a capsule, a tablet or a sachet.
The following examples are provided by pure way of example and not for limiting the scope of the invention as defined by the enclosed claims.
EXAMPLES
EXAMPLE 1
EXAMPLE 2
EXAMPLE 3
EXAMPLE 4
EXAMPLE 5
For the preparation of the product "Granular pyrophosphate iron" it is possible to use the fluid bed granulation technique. A preparation example is provided hereinafter.
The working process consists in the following steps : a) Mixing:
The raw materials previously loaded in the granulator basket are subjected to a first mixing phase on fluid bed, with process air having a pre- established temperature (for example of 80-90°C) , until obtaining a mixture having an average temperature for example of 44 °C. During this phase one proceeds with implementing a homogeneous bulk from the point of view of the composition and of the temperature, pre-requirement necessary for the optimum course of the subsequent granulation phase. b) Granulation
The granulation phase provides to graft an aqueous solution of a suitably selected binding or granulation agent , by means of direct nebuli zation on the bulk premixed and fluidi f ied on fluid bed . Even in this phase process air at 90 ° C is used by suitably selecting the speed for inletting the binding solution to obtain a granular structured according to expectations ( granulometry, bulk density, smoothness ) and homogeneous . c ) Drying
During the drying phase the water content of the preformed granular is basically brought back to the conditions of the mixture of the starting raw materials . The temperature of the process air of the granulate at the end of the phase is suitably evaluated in the pilot testing phase depending upon such obj ective . d) Calibration
The hal f- finished product obtained from the previous phase is trans ferred from the fluid bed granulator to a swinging granulator where it is calibrated through a sieve for reducing the particle si ze of the granules and of the agglomerates with coarser structure .
Claims
1 . A nutraceutical or pharmaceutical composition for the use in the treatment or the prevention of an iron deficiency condition or disease , the composition comprising the combination of iron pyrophosphate , beta-cyclodextrin and starch .
2 . The nutraceutical or pharmaceutical composition for the use according to claim 1 , comprising an amount of iron pyrophosphate ranging from 0 . 1 to 90% , preferably ranging from 1 to 80% , still more preferably ranging from 5 to 70% with respect to the total weight of the above-mentioned combination .
3 . The nutraceutical or pharmaceutical composition for the use according to claim 1 or 2 comprising, preferably pregelatini zed acetylated, starch preferably in an amount ranging from 0 . 1 to 90% , more preferably ranging from 1 to 80% , still more preferably ranging from 10 to 70% with respect to the total weight of the above-mentioned combination .
4 . The nutraceutical or pharmaceutical composition for the use according to any one of claims 1 to 3 , comprising an amount of beta-cyclodextrin ranging from 0 . 01 to 90% , preferably ranging from 0 . 05 to
32
70%, still more preferably ranging from 0.1 to 50% with respect to the total weight of the above- mentioned combination.
5. The nutraceutical or pharmaceutical composition for the use according to any one of claims 1 to 4, wherein the iron deficiency condition or disease is chosen from the group consisting of anaemia, sideropenia, pregnancy or breastfeeding, loss of appetite, asthenia, menstruation, bleeding and menopause, intestinal inflammatory disease, celiac disease, obesity, gastric ulcer, colon or uterine cancer, intestinal polyp, haemorrhoids.
6. The pharmaceutical product or food supplement according to claim 5, formulated in a liquid, semisolid or solid oral dosage form.
7. The pharmaceutical product or food supplement according to claim 6, wherein the oral dosage form is a powder, an orosoluble powder, a granulate, a hard capsule, a soft-gel capsule, a tablet, a sachet, a solution, a suspension or an emulsion.
33
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT202000028934 | 2020-12-03 | ||
| IT102020000028934 | 2020-12-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2022118274A1 true WO2022118274A1 (en) | 2022-06-09 |
Family
ID=74592558
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB2021/061297 WO2022118274A1 (en) | 2020-12-03 | 2021-12-03 | Compositions for the use in the treatment and/or prevention of iron deficiency conditions or diseases |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2022118274A1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070065521A1 (en) * | 2005-09-19 | 2007-03-22 | Bala Venkataraman | Composition and method for treating iron deficiency anemia |
| US20170112178A1 (en) * | 2011-07-07 | 2017-04-27 | Chemo S.A. France | Compositions, kits and methods for nutrition supplementation |
| US20190105393A1 (en) * | 2012-07-31 | 2019-04-11 | Alesco S.R.L. | Solid composition comprising iron for use in iron deficient conditions |
| WO2019171236A1 (en) * | 2018-03-09 | 2019-09-12 | Frimline Private Limited | A pharmaceutical composition for anaemia |
-
2021
- 2021-12-03 WO PCT/IB2021/061297 patent/WO2022118274A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070065521A1 (en) * | 2005-09-19 | 2007-03-22 | Bala Venkataraman | Composition and method for treating iron deficiency anemia |
| US20170112178A1 (en) * | 2011-07-07 | 2017-04-27 | Chemo S.A. France | Compositions, kits and methods for nutrition supplementation |
| US20190105393A1 (en) * | 2012-07-31 | 2019-04-11 | Alesco S.R.L. | Solid composition comprising iron for use in iron deficient conditions |
| WO2019171236A1 (en) * | 2018-03-09 | 2019-09-12 | Frimline Private Limited | A pharmaceutical composition for anaemia |
Non-Patent Citations (6)
| Title |
|---|
| DATABASE GNPD [online] MINTEL; 12 May 2020 (2020-05-12), ANONYMOUS: "Iron & Multivitamin Supplement", XP055824782, retrieved from https://www.gnpd.com/sinatra/recordpage/7612483/ Database accession no. 7612483 * |
| DATABASE GNPD [online] MINTEL; 20 July 2020 (2020-07-20), ANONYMOUS: "Tropical Flavour Chewable Multivitamin & Mineral Food Supplement Tablets", XP055824781, retrieved from https://www.gnpd.com/sinatra/recordpage/7961093/ Database accession no. 7961093 * |
| DATABASE GNPD [online] MINTEL; 22 February 2017 (2017-02-22), ANONYMOUS: "Ferro Vital+ Dietary Supplement", XP055824788, retrieved from https://www.gnpd.com/sinatra/recordpage/4636435/ Database accession no. 4636435 * |
| DATABASE GNPD [online] MINTEL; 3 April 2018 (2018-04-03), ANONYMOUS: "Dietary Supplement for Pregnancy", XP055824786, retrieved from https://www.gnpd.com/sinatra/recordpage/5557275/ Database accession no. 5557275 * |
| DATABASE GNPD [online] MINTEL; 9 March 2020 (2020-03-09), ANONYMOUS: "Food Supplement with Sucrosomial Iron and Vitamin C", XP055824784, retrieved from https://www.gnpd.com/sinatra/recordpage/7423655/ Database accession no. 7423655 * |
| RAVIKIRAN PANAKANTI ET AL: "Impact of Excipient Interactions on Drug Bioavailability from Solid Dosage Forms", PHARMACEUTICAL RESEARCH, KLUWER ACADEMIC PUBLISHERS-PLENUM PUBLISHERS, NL, vol. 29, no. 10, 19 May 2012 (2012-05-19), pages 2639 - 2659, XP035111456, ISSN: 1573-904X, DOI: 10.1007/S11095-012-0767-8 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Gupta et al. | Inulin: A novel and stretchy polysaccharide tool for biomedical and nutritional applications | |
| US20230000907A1 (en) | Nutraceutical or pharmaceutical composition comprising iron pyrophosphate for treating and/or preventing iron deficiency conditions or diseases | |
| KR100516532B1 (en) | Inulin Products with Improved Nutritional Properties | |
| US4877774A (en) | Administration of steroid hormones | |
| CA2821312A1 (en) | Methods for facilitating muscle recovery after a period of disuse using beta-hydroxy-beta-methylbutyrate | |
| CN108902914A (en) | Promote the sticky wash swallowed safely in dysphagia patients | |
| JP2002508772A (en) | Health supplement | |
| CN104114039A (en) | Extensional viscosity to promote safe swallowing of food boluses | |
| CN109689035A (en) | Composition comprising choline | |
| CN103402371A (en) | Extensional viscosity to promote safe swallowing of food boluses | |
| CN112402397A (en) | Sustained-release oral disintegrating film with excellent oral mucosa adhesion and preparation method thereof | |
| CN113713084A (en) | Medicine and food dual purpose Chinese medicinal product for treating bone and joint pain and osteoporosis of middle aged and elderly people | |
| Chadha et al. | Inulin as a delivery vehicle for targeting colon-specific cancer | |
| WO2022118274A1 (en) | Compositions for the use in the treatment and/or prevention of iron deficiency conditions or diseases | |
| JP5349744B2 (en) | Mineral absorption promoter, food and feed | |
| WO2023082626A1 (en) | Method for preparing oyster shell calcium granules | |
| JP4001443B2 (en) | Phosphorus absorption inhibitor and therapeutic agent containing the same | |
| WO2022254414A2 (en) | Nutraceuticalor pharmaceutical composition for the use in the treatment and/or in the prevention of conditions or diseases characterized by magnesium deficiency | |
| AU5968900A (en) | Method for increasing propionate in the gastro-intestinal tract | |
| JP3993907B2 (en) | Calcium absorption promoter | |
| WO1998008877A1 (en) | Chitosan derivatives, process for producing the same and uses of the same | |
| EP1043022B1 (en) | Sodium ion absorption inhibitors and sodium ion excretion accelerators as preventive and therapeutic agents for diseases resulting from excessive intake of common salt | |
| WO2023112974A1 (en) | Hypertension-improving agent containing seaweed extract, and functional food, quasi-drug and drug containing hypertension-improving agent | |
| González Bermúdez | Anti-regurgitation infant formulas: in-vitro study about the effect of different thickering ingredients on their physicochemical characteristics across a digstive process, mineral availability and infant microbiota | |
| KR20100056329A (en) | Calcium compound and calcium compound fertilized rice for the prevention and treatment of osteoporosis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21835384 Country of ref document: EP Kind code of ref document: A1 |
|
| NENP | Non-entry into the national phase |
Ref country code: DE |
|
| 122 | Ep: pct application non-entry in european phase |
Ref document number: 21835384 Country of ref document: EP Kind code of ref document: A1 |