NZ622341B - Encapsulated metal ion nanoclusters - Google Patents
Encapsulated metal ion nanoclustersInfo
- Publication number
- NZ622341B NZ622341B NZ622341A NZ62234114A NZ622341B NZ 622341 B NZ622341 B NZ 622341B NZ 622341 A NZ622341 A NZ 622341A NZ 62234114 A NZ62234114 A NZ 62234114A NZ 622341 B NZ622341 B NZ 622341B
- Authority
- NZ
- New Zealand
- Prior art keywords
- water
- nanocluster
- combination
- carbohydrate
- polyol
- Prior art date
Links
- 229910052751 metal Inorganic materials 0.000 title claims abstract description 43
- 239000002184 metal Substances 0.000 title claims abstract description 43
- 150000002500 ions Chemical class 0.000 title claims description 19
- 238000005429 turbidity Methods 0.000 claims abstract description 70
- 150000001450 anions Chemical class 0.000 claims abstract description 32
- 150000001768 cations Chemical class 0.000 claims abstract description 32
- 239000003607 modifier Substances 0.000 claims abstract description 28
- 230000027455 binding Effects 0.000 claims abstract description 27
- 239000003446 ligand Substances 0.000 claims abstract description 27
- 201000010099 disease Diseases 0.000 claims abstract description 23
- 210000001519 tissues Anatomy 0.000 claims abstract description 18
- 239000002245 particle Substances 0.000 claims abstract description 17
- 206010061291 Mineral deficiency Diseases 0.000 claims abstract description 6
- 230000002496 gastric Effects 0.000 claims abstract description 6
- 238000010992 reflux Methods 0.000 claims abstract description 6
- 208000009863 Chronic Kidney Failure Diseases 0.000 claims abstract description 5
- 206010038444 Renal failure chronic Diseases 0.000 claims abstract description 5
- 239000000203 mixture Substances 0.000 claims description 155
- 150000001720 carbohydrates Chemical class 0.000 claims description 47
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 36
- 229920000570 polyether Polymers 0.000 claims description 36
- 229920005862 polyol Polymers 0.000 claims description 36
- 150000003077 polyols Chemical class 0.000 claims description 36
- 238000010494 dissociation reaction Methods 0.000 claims description 21
- 230000005593 dissociations Effects 0.000 claims description 21
- 239000007864 aqueous solution Substances 0.000 claims description 17
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 13
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- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 10
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K 2qpq Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 8
- 229940001468 Citrate Drugs 0.000 claims description 8
- GZCGUPFRVQAUEE-KCDKBNATSA-N D-(+)-Galactose Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C=O GZCGUPFRVQAUEE-KCDKBNATSA-N 0.000 claims description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 8
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims description 8
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- XPPKVPWEQAFLFU-UHFFFAOYSA-J Pyrophosphate Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 8
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 8
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K [O-]P([O-])([O-])=O Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 8
- 150000001479 arabinose derivatives Chemical class 0.000 claims description 8
- 229910052804 chromium Inorganic materials 0.000 claims description 8
- 235000019425 dextrin Nutrition 0.000 claims description 8
- 235000011180 diphosphates Nutrition 0.000 claims description 8
- 150000003045 fructo oligosaccharides Chemical class 0.000 claims description 8
- 229940107187 fructooligosaccharide Drugs 0.000 claims description 8
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- 229920001542 oligosaccharide Polymers 0.000 claims description 8
- 150000002482 oligosaccharides Polymers 0.000 claims description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 claims description 8
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- 229940086735 succinate Drugs 0.000 claims description 8
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 8
- WQZGKKKJIJFFOK-PHYPRBDBSA-N α-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 8
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 8
- 229940072107 Ascorbate Drugs 0.000 claims description 7
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 7
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- 229910052782 aluminium Inorganic materials 0.000 claims description 7
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- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- ZNCPFRVNHGOPAG-UHFFFAOYSA-L Sodium oxalate Chemical compound [Na+].[Na+].[O-]C(=O)C([O-])=O ZNCPFRVNHGOPAG-UHFFFAOYSA-L 0.000 description 1
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- 108060008443 TPPP Proteins 0.000 description 1
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- 240000000280 Theobroma cacao Species 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940035081 Venofer Drugs 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
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- 230000036626 alertness Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001449 anionic compounds Chemical class 0.000 description 1
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- 239000003963 antioxidant agent Substances 0.000 description 1
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- 239000008346 aqueous phase Substances 0.000 description 1
- 235000012791 bagels Nutrition 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium(0) Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 235000013527 bean curd Nutrition 0.000 description 1
- 230000035514 bioavailability Effects 0.000 description 1
- 239000007844 bleaching agent Substances 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- PUPZLCDOIYMWBV-UHFFFAOYSA-N butylene glycol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 235000016213 coffee Nutrition 0.000 description 1
- 235000013353 coffee beverage Nutrition 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 235000014510 cooky Nutrition 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 230000002939 deleterious Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- ZDQYSKICYIVCPN-UHFFFAOYSA-L disodium butanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CCC([O-])=O ZDQYSKICYIVCPN-UHFFFAOYSA-L 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 235000012489 doughnuts Nutrition 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229910001447 ferric ion Inorganic materials 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000021255 galacto-oligosaccharides Nutrition 0.000 description 1
- 150000003271 galactooligosaccharides Chemical class 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 150000004676 glycans Polymers 0.000 description 1
- 125000005456 glyceride group Chemical class 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 159000000011 group IA salts Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910001412 inorganic anion Inorganic materials 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229940032961 iron sucrose Drugs 0.000 description 1
- 229940097452 iron sucrose Injection Drugs 0.000 description 1
- 238000002356 laser light scattering Methods 0.000 description 1
- 230000002045 lasting Effects 0.000 description 1
- 239000011344 liquid material Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- RXVWSYJTUUKTEA-CGQAXDJHSA-N maltotriose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O[C@H]([C@H](O)CO)[C@H](O)[C@@H](O)C=O)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 RXVWSYJTUUKTEA-CGQAXDJHSA-N 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- QWIZNVHXZXRPDR-WSCXOGSTSA-N melezitose Chemical compound O([C@@]1(O[C@@H]([C@H]([C@@H]1O[C@@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O)CO)CO)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O QWIZNVHXZXRPDR-WSCXOGSTSA-N 0.000 description 1
- 235000019656 metallic taste Nutrition 0.000 description 1
- 230000000813 microbial Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 239000000346 nonvolatile oil Substances 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000002891 organic anions Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 235000016236 parenteral nutrition Nutrition 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000002694 phosphate binding agent Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- 235000009566 rice Nutrition 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 239000012056 semi-solid material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 235000009561 snack bars Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
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- 235000013618 yogurt Nutrition 0.000 description 1
- 239000011701 zinc Substances 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
-
- 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
- A23L33/165—Complexes or chelates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/26—Iron; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
Disclosed are nanoclusters having a particle size of from 2 nm to 500 nm a molecular weight of 3500 to 1000000 Dalton, and a formula of X(OH)aYbZcMd(H2O)e, in which X is a metal cation, Y is a water-soluble salt-forming anion, Z is a water-soluble ligand, M is a turbidity point modifier, a is 0.1 to 20, 5 b is 0 to 9, c is 0.1 to 10, d is 0.1 to 9, and 0 < e < 25, wherein the nanocluster has a turbidity point of 8 or lower. Also disclosed is the use of these nanoclusters in the treatment of mineral deficiency, gastric reflux disorder, chronic renal failure and tissue imaging. 20, 5 b is 0 to 9, c is 0.1 to 10, d is 0.1 to 9, and 0 < e < 25, wherein the nanocluster has a turbidity point of 8 or lower. Also disclosed is the use of these nanoclusters in the treatment of mineral deficiency, gastric reflux disorder, chronic renal failure and tissue imaging.
Description
ENCAPSULATED METAL ION NANOCLUSTERS
BACKGROUND
Many minerals useful for treating mineral deficiency are only soluble as metal
ions, which in general are irritating to tissues and have an unpleasant taste. Metal
complexes have been used instead to address this problem.
Metal complexes, usually having a high turbidity point and a low acid
dissociation rate, are unstable in neutral or acidic conditions desired for oral and
intramuscular applications. As such, they are typically formulated in a basic solution.
For example, Venofer, an iron sucrose commercial product that must only be
administered via the intravenous route, has a pH value as high as 11, making it unsuitable
for beverages and pharmaceutical formulations other than intravenous injections.
There is a need to develop metal complexes that are stable in neutral or acidic
conditions.
It is therefore an object of the present invention to provide a metal ion
nanocluster, a composition comprising said nanocluster, a use of an effective amount of
the nanoclusters in the manufacture of a medicament and/or a method of preparing a
nanoclusters that meets the above mentioned need or to at least to provide the public with
a useful choice of any one or more of the foregoing.
SUMMARY
This invention is based on the discovery of stable metal ion nanoclusters that have
a low turbidity point and a high acid dissociation rate.
In one broad aspect this invention provides a metal ion nanocluster having a
particle size of 2 to 500 nm, a molecular weight of 3500 to 1000000 Dalton, and a
formula of X(OH) Y Z M (H O) , in which X is a metal cation, Y is a water-soluble salt-
a b c d 2 e
forming anion, Z is a water-soluble ligand, M is a turbidity point modifier, a is 0.1 to 20,
b is 0 to 9, c is 0.1 to 10, d is 0.1 to 9, and e is 0 to 25. In one embodiment, the
nanocluster has a turbidity point of 8 or lower. In another embodiment, 0 < e < 25.
In one aspect, this invention features a metal ion nanocluster having a particle size
of 2 to 500 nm (e.g., 2 to 150 nm and 2 to 80 nm), a molecular weight of 3500 to
1000000 Dalton (e.g., 5000 to 300000 Dalton and 10000 to 180000 Dalton), a turbidity
point of 8 or lower (e.g., 7 or lower and 4.5 or lower), and a dissociation rate of 1 to
180minutes (e.g., 1 to 60 minutes). A turbidity point refers to a pH point at which
precipitation occurs during a pH titration. A dissociation rate refers to the time required
to dissociate greater than 75 % of nanoclusters into free metal ions in a 0.75 M HCl
aqueous solution at 37 °C with stirring.
VIA510407NZPR
303738480
The metal ion nanocluster of this invention has a formula of
X(OH) Y Z M (H O) .
a b c d 2 e
X is a metal cation. Examples include, but are not limited to, cations of Cr, Al,
Bi, Zn, Ba, Cu, Ti, Mg, Mn, Pt, Ca, Se, In, Fe, Co, Ni, V, La, Mo, Sr, Zr, and a
combination thereof. Preferably, the metal cation is Mg(II), Al(III), Ca(II), Cr(III),
Cu(II), Zn(II), Mn (II), Ti(IV), Fe(II/III), Co(II), Ni(II), Bi(III), V(V), La(III), Mo(VI),
Sr(II), Zr(IV) or a combination thereof. Y is a water-soluble salt-forming anion, which
can be an inorganic anion or an organic anion. Examples include, but are not limited to,
fluoride, chloride, bromide, iodide, nitrate, sulfate, acetate, and a combination thereof.
Preferably, it is chloride, nitrate, sulfate, acetate, or a combination thereof. Z is a water-
soluble ligand. Examples include, but are not limited to, a carbohydrate, a hydrogenated
carbohydrate, a hydrolyzed carbohydrate, a polyol, a polyether, and a combination
thereof. Preferably, it is xylitol, mannitol, ribose, mannose, xylose, galactose, fructose,
lactose, glucose, isomaltose, isomalt, sucrose, maltitol, trehalose, arabinose, sorbitol,
polyisomaltose, isomalto-oligosaccharide, dextrin, dextran, fructooligosaccharide, or a
combination thereof. M is a turbidity point modifier. Examples include, but are not
limited to, a complex-forming polyvalence anion, an oxidized carbohydrate (e.g.,
gluconic acid, sodium gluconate, and gluconate ester), a carboxylated polyol, a
carboxylated polyether, a sulfonated carbohydrate, a sulfonated polyol, a sulfonated
polyether, a phospholated carbohydrate, a phospholated polyol, a phospholated polyether,
an amino acid, a water-soluble polypeptide, a water-soluble protein, and a combination
thereof. Examples of the complex-forming polyvalence anion include, but are not limited
to, citrate, malate, fumarate, tartrate, lactate, oxalate, succinate, ascorbate, phosphate,
pyrophosphate, glycerophosphate, or a combination thereof.
The term “carbohydrate” refers to a monosaccharide (e.g., xylose, arabinose,
glucose, mannose, fructose, galactose, and ribose), a disaccharide (e.g., sucrose, lactose,
maltose, and isomaltose), an oligosaccharide (i.e., carbohydrates that are composed of 3-9
monosaccharide residues joined through glycosidic linkage, such as raffinose, melezitose,
maltotriose, acarbose, stachyose, fructooligosaccharide, and galactooligosaccharides), or
a polysaccharide (e.g., dextrin, dextran, poltisomaltose, and maltodextrin).
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Refering back to formula X(OH) Y Z M (H O) , a is 0.1 to 20 (e.g., 1 to 10), b is
a b c d 2 e
0 to 9 (e.g., 0.1 to 9, 0 to 3, and 0.1 to 3), c is 0.1 to 10 (e.g., 1 to 6) , d is 0.1 to 9 (e.g.,
0.1 to 6), and e is 0 to 25 (e.g., 0 to 10).
Another aspect of this invention relates to a composition containing the
nanocluster described above. This composition, for example a transparent aqueous
solution or a water-soluble solid for reconstitution into a transparent aqueous solution, is
free of unchelated ions, unreactive water-soluble ligands, and labile low-molecular-
weight ion complexes (i.e., below 3500 Dalton). The pH value of the composition (for
example a transparent aqueous solution) can be 3 to 11.5, e.g., 3.5 to 9. A transparent
aqueous solution refers to a clear or translucent aqueous solution, i.e., a colloidal solution
or a colloidal suspension.
Also within the scope of this invention is a method for treating a disorder or for
detecting a tissue image by administering to a subject in need thereof an effective amount
of the nanocluster described above. Examples of the disorder include a mineral
deficiency disorder, a gastric reflux disorder, and a chronic renal failure. The tissue
image is for use in differentiating an abnormal tissue from a normal tissue.
In another aspect the present invention relates to the use of an effective amount of
the nanocluster described above, in the manufacture of a medicament for treating a
disorder or for detecting a tissue image in a subject in need thereof, wherein the disorder
is a mineral deficiency disorder, a gastric reflux disorder, or a chronic renal failure and a
tissue image is for use in differentiating an abnormal tissue from a normal tissue.
The term “treating” or “treatment” refers to administering a nanocluster to a
subject, who has an above-described disorder, a symptom of such a disorder, or a
predisposition toward such a disorder, with the purpose to confer a therapeutic effect,
e.g., to cure, relieve, alter, affect, or ameliorate the above-described disorder, any
symptom of it, or the predisposition toward it.
Still within the scope of this invention is a method of preparing the nanocluster
described above. The method includes the steps of (1) providing an aqueous dispersion
containing X, Y, Z, and OH; (2) adjusting the pH of the aqueous dispersion to a
predetermined value to obtain a pH-adjusted aqueous dispersion; (3) heating the pH-
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adjusted aqueous dispersion to 50-180 °C so that a nanocluster is formed; and (4) adding
M after any of the above steps. Note that M becomes an integral part of the nanocluster
thus formed. The ratio of X : Y : Z : M, all of which are defined above, is 1 : 0-9 : 0.1-10
: 0.1-9. The nanocluster thus formed in an aqueous solution can be collected by
nanofiltration and then dried (e.g., in an oven, by vaccum, by spray, and by freeze) to
yield a solid nanocluster.
In another aspect the present invention provides a nanocluster when prepared by
method described above.
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The details of one or more embodiments of the invention are set forth in the
description below. Other features, objects, and advantages of the invention will be
apparent from the description and from the claims.
DETAILED DESCRIPTION
Described herein are metal ion nanoclusters each containing one or more metal
cations, one or more water-soluble salt-forming anions, one or more water-soluble
ligands, and one or more turbidity point modifiers.
Any metal cation having a dietary or health benefit can be used in a nanocluster of
this invention. Examples include Mg(II), Al(III), Ca(II), Cr(III), Cu(II), Zn(II), Mn (II),
Ti(IV), Fe(II/III), Co(II), Ni(II), Bi(III), V(V), La(III), Mo(VI), Sr(II), and Zr(IV). More
than one cations, e.g., Fe(III) and Mg(II), can be included in the nanocluster.
A suitable water-soluble salt-forming anion can be either organic or inorganic,
e.g., fluoride, chloride, bromide, iodide, nitrate, sulfate, and acetate.
A suitable ligand is soluble in water and binds to a metal cation to form a
nanocluster of this invention. Examples include xylitol, mannitol, ribose, mannose,
xylose, galactose, fructose, lactose, glucose, isomaltose, isomalt, sucrose, maltitol,
trehalose, arabinose, sorbitol, polyisomaltose, isomalto-oligosaccharide, dextrin, dextran,
and fructooligosaccharide. More examples are described in U.S. Patent Application
Publication 2012/0093898.
A turbidity point modifier is used to adjust the turbidity point of a nanocluster to a
predetermined range, e.g., 7 or lower, and thereby making the nanocluster stable in a
neutral or acidic solution, an important feature of intramuscular injections or oral
formulations. Further, a turbidity point modifier shortens the time for preparing a
nanocluster. It can also lower the temperature required in the preparation process.
turbidity point modifier, which interacts with a metal cation(s), an anion(s), or a
ligand(s), is an integrated part of a nanocluster. A turbidity point modifier in a
nanocluster can be a complex-forming polyvalent anion that is different from the water-
soluble salt-forming anion therein. Examples of a polyvalent anion include citrate,
malate, fumarate, tartrate, lactate, oxalate, succinate, ascorbate, phosphate,
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pyrophosphate, and glycerophosphate. Among them, citrate, oxalate, succinate, and
tartrate are preferred.
A nanocluster of this invention can be prepared using various methods. In one
embodiment, it is obtained by mixing a water soluble metal salt (e.g., ferric chloride), a
ligand (e.g., xylitol), an alkaline agent (e.g., sodium hydroxide), and a turbidity point
modifier (e.g., sodium citrate) in water at a suitable temperature (e.g., 50-180 C or
preferably 65-105 C) for a predetermined process time (e.g., 30 minutes to 10 hours).
Alternatively, the metal salt, the ligand, and the alkaline agent are mixed and heated to
form a nanocluster precursor. A turbidity point modifier is then introduced to the
precursor with or without heating (e.g., 50-180 C and 65-105 C). The type and amount
of the turbidity point can be adjusted to obtain the nanocluster having a predetermined
turbidity point.
The nanocluster thus formed is in an aqueous solution, which can be isolated
using nanofiltration to obtain a concentrated nanocluster-containing solution, free of
unchelated metal cations, unreactive ligands, and labile low-molecule-weight ion
complexes. Note that unchelated metal cations are irritating to tissues and have an
unpleasant metallic taste. They can also cause protein precipitation and interfere with
physiological functions. Unreactive ligands increase microbial contamination and
osmolarity of the solution. Labile low-molecular-weight ion complexes, which dissociate
and diffuse into tissues fast, cause oxidative damage. See Wyck, Journal of American
Society of Nephrology, 15, S107-11 (2004).
The concentrated nanocluster-containing solution is optionally dried to yield a
nanocluster solid using a suitable drying method, e.g., oven drying, vaccum drying, spray
drying, and freeze drying. The nanocluster solid can be reconstituted to a nanocluster
solution without changing the turbidity point and other properties.
Below is an exemplary procedure for preparing a nanocluster of this invention. A
metal cation and an anion, as a salt or a salt mixture, are mixed with a water-soluble
ligand in an aqueous solution to give a solution or dispersion. The pH is adjusted using
an alkaline salt or a base. The pH-adjusted solution or dispersion is heated until a
nanocluster precursor is formed or until the solution or dispersion turns clear. A turbidity
point modifier is then added to the precursor and heated to 50-105 C to yield the
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nanocluster, which is isolated through nanofiltration and then dried in an oven to obtain a
nanocluster solid. Other separation techniques such as solvent-induced precipitation
(e.g., using a water-soluble organic solvent such as ethanol) can also be applied. The
resulting solid product can be reconstituted into nanocluster colloidal solutions or
formulated into other dosage forms.
The nanocluster thus formed typically has a turbidity point of 8 or lower (e.g., 4.5
or lower), which can be determined by the procedure described in Example 1 below or by
analogous procedures, and a particle size of 2 nm to 500 nm (e.g., 2-80 nm), which can
be determined by dynamic laser light scattering technique as described in B. J. Berne et
al., “Dynamic Light Scattering,” J. Wiley and Sons, Inc., New York, 1976; P.J. Freud et
al., “A New Approach to particle Sizing by Dynamic Light Scattering,” Microtrac, Inc.;
and M.N. Trainer et al., “High-concentration submicron particle size distribution by
dynamic light scattering,” American Laboratory, July 1992.
Having a low turbidity point, a nanocluster of this invention is compatible with
many physiological and excipient components. It can be formulated with these
components in solid or liquid form. A solid composition containing a nanocluster can be
conveniently used to prepare beverage, paste, jelly, capsules, or tablets. On the other
hand, a liquid composition containing a nanocluster, which can be a transparent or
translucent solution, can be used to prepare injectable or oral formulations.
A composition containing a nanocluster of this invention can be a dietary
supplement, a cosmetic product, a contrast imaging product, or a pharmaceutical
formulation. As a dietary supplement, additional nutrients, such as minerals, amino acids,
or herb extracts, may be included. As a cosmetic product, additional ingredients, such as
humectants, whitening agents, anti-oxidants, or herb extracts, may be included. As a
contrast imaging product (e.g., for detecting a tissue image), it can be formulated into oral
or injection dosage form with suitable pharmaceutically acceptable carrier. Heavy metal
compositions and magnetic metal compositions are widely used for imaging purpose
(e.g., an iron-containing composition as an MRI contrast agent and a barium-containing
composition as an X-ray radio-contrast agent). As a pharmaceutical formulation (in
forms including but not limited to powder, capsule, tablet, emulsion, aqueous suspension,
dispersion, and solution), a nanocluster composition can be used alone or in combination
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with a pharmaceutically acceptable carrier. The carrier in a contrast imaging product or a
pharmaceutical composition must be “acceptable” in the sense of being compatible with
the active ingredient of the formulation (and, preferably, capable of stabilizing it) and not
deleterious to the subject to be treated. Examples include lactose, colloidal silicon
dioxide, magnesium stearate, sodium lauryl sulfate, and D&C Yellow # 10. A lubricating
agent, such as magnesium stearate, is typically added. For oral administration in a
capsule form, useful diluents include lactose and dried corn starch. When an aqueous
suspension or an emulsion is administered orally, a nanocluster composition can be
suspended or dissolved in an aqueous phase combined with an emulsifying or suspending
agent. If desired, a sweetening, flavoring, or coloring agent can be added.
A nanocluster composition can also be a food product, i.e., a liquid, solid, or semi-
solid material that is used for nourishing humans or animals, for sustaining normal or
accelerated growth, or for maintaining stamina or alertness. Examples include tea-based
beverages, juice, coffee, milk, jelly, cookies, cereals, bread, donut, bagel, chocolates,
snack bars, herbal extracts, dairy products (e.g., ice cream, and yogurt), soy bean product
(e.g., tofu), and rice products.
Nanocluster compositions that contain iron can be used to treat iron deficiency
disorders such as iron deficiency anemia. Compositions that contain chromium can be
used to treat diabetes (such as type II diabetes), lower cholesterol level, and treat obesity.
Those containing magnesium and aluminum/iron can be used as antacids, and those
containing Mg, Mn, Cr, Zn, and Cu ions, can be used as total parenteral nutrition
injections.
Further, this invention covers a method of administering an effective amount of a
nanocluster composition to a patient having a disease described in the summary section
above. The nanocluster composition can also be used for diagnosis (e.g., imaging), as a
phosphate binder, or as an antacid for gastric reflux disorder.
“An effective amount” refers to the amount of a nanocluster composition that is
required to confer a therapeutic effect on the treated subject. Effective doses will vary, as
recognized by those skilled in the art, depending on the types of diseases treated, route of
administration, excipient usage, and the possibility of co-usage with other therapeutic
treatment.
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The term “administering” covers oral, topical, or parenteral delivery to a subject a
composition of the invention in any suitable form, e.g., food product, beverage, tablet,
capsule, suspension, lotion, cream, gel, and solution. The term “parenteral” refers to
subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial,
intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection, as well as
various infusion techniques. A sterile injectable composition, e.g., a sterile injectable
aqueous or oleaginous suspension, can be formulated according to techniques known in
the art using suitable dispersing or wetting agents (such as Tween 80) and suspending
agents, if necessary. The sterile injectable preparation can also be a sterile injectable
solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for
example, as a solution in 1,3-butanediol, propylene glycol, or glycerine. Among the
acceptable vehicles and solvents that can be employed are xylitol, mannitol, water,
Ringer’s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or
diglycerides). Fatty acids, such as oleic acid and its glyceride derivatives are useful in
the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as
olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions
or suspensions can also contain a long-chain alcohol diluent or dispersant, or
carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants
such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers
which are commonly used in the manufacture of pharmaceutically acceptable solid,
liquid, or other dosage forms can also be used for the purposes of formulation.
The nanocluster described above can be preliminarily screened for their efficacy
in treating above-described diseases by an in vitro assay and then confirmed by animal
experiments and clinic trials. Other methods will also be apparent to those of ordinary
skill in the art.
The specific examples below are to be construed as merely illustrative, and not
limitative of the remainder of the disclosure in any way whatsoever. Without further
elaboration, it is believed that one skilled in the art can, based on the description herein,
utilize the present invention to its fullest extent. All publications cited herein are hereby
incorporated by reference in their entirety.
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EXAMPLE 1
Composition 1, an exemplary composition of this invention, was prepared
following the procedure described below. In a vessel equipped with a stirring and
heating device, an aqueous solution was obtained by dissolving in 87 grams of water the
following agents: (1) 13.68 grams of xylitol as a water-soluble ligand, (2) 2.18 grams of
sodium gluconate as a turbidity point modifier, and (3) 27 grams of ferric chloride
hexahydrate both as a metal cation and a water-soluble salt-forming anion. After the
aqueous solution was heated to between 75 and 80 °C, NaOH (12 grams in 54 grams of
water) was added followed by heating at 90 °C for 30 minute to yield composition 1
containing ferric hydroxide xylitol gluconate nanoclusters.
Comparative composition 1’ was prepared following exactly the same procedure
described above except that no sodium gluconate was added.
Turbidity Point Assay
The turbidity points of composition 1 and 1’ were measured by the method
described in the USP monograph of Iron Sucrose Injection, USP28–NF23, page 1064.
The pH value of composition 1 was adjusted to about 6.0 using 0.1 M hydrochloric acid
solution. A light source was applied to the solution such that the light beam shone
through the solution. More hydrochloric acid solution was added dropwise until a slight
but lasting turbidity had developed. The pH value at this point was the turbidity point.
The results are shown in the table below. As demonstrated in the table,
composition 1, which contained gluconate, a turbidity point modifier, had a turbidity
point unexpectedly much lower than that of comparative composition 1’, which did not
contain any turbidity point modifier.
Note that the table below also shows turbidity points of compositions 2-6, each of
which contains a turbidity point modifier, and comparative compositions 2’, 3’, 5’, and
6’, each of which does not contain any turbidity point modifier. Unexpectedly, each of
compositions 2-6 had a turbidity point much lower than that of its corresponding
comparative composition, i.e., one of comparative compositions 2’, 3’, 5’, and 6’. Note
that composition 3’ is the corresponding comparative composition for composition 4.
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Turbidity points of nanocluster compositions
Composition Turbidity point
1 Below 1
1A Below 1
Comparative 1’ 7.1
2 4.7
2’ 7.3
3 1.9
3’ 6.1
4 3.1
’ 7.2
6’ 5
EXAMPLE 1A
Composition 1A was prepared by separating the nanoclusters contained in
composition 1 from the aqueous solution via nanofiltration with a molecular weight cut-
off at 5000 Dalton. The separated nanoclusters were dried at 90 °C for 16 hours to yield
composition 1A as a solid.
To demonstrate that solid composition 1A could be reconstituted into a
nanocluster solution, composition 1A was dissolved in water to form a transparent
nanocluster solution, which had the same turbidity point as that of composition 1. See
the table above. Like composition 1, composition 1A unexpectedly has a turbidity point
much lower than that of comparative composition 1’.
EXAMPLE 2
Composition 2 was prepared following the procedure described below. In a
vessel equipped with a stirring and heating device, an aqueous solution was obtained by
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dissolving in 87 grams of water the following agents: (1) 18.2 grams of mannitol as a
water-soluble ligand, (2) 2.94 grams of sodium citrate dihydrate as a turbidity point
modifier, and (3) 27 grams of ferric chloride hexahydrate both as a metal cation and a
water-soluble salt-forming anion. After the aqueous solution was heated to between 75
and 80 °C, NaOH (12 grams in 54 grams of water) was added followed by heating at
90 °C for 30 minute to yield composition 2 containing ferric hydroxide mannitol
gluconate nanoclusters.
Comparative composition 2’ was prepared following exactly the same procedure
as composition 2 except that no sodium citrate dihydrate was added.
The turbidity points of both compositions 2 and 2’ were measured following the
procedure described in Example 1. The results, shown in the table above, unexpectedly
demonstrate that composition 2 had a turbidity point much lower than that of comparative
composition 2’.
EXAMPLES 3 AND 4
To obtain compositions 3 and 4, comparative composition 3’ was prepared
following the procedure described below. In a vessel equipped with a stirring and
heating device, a ferric hydroxide carbonate suspension was prepared by mixing a ferric
nitrate nonahydrate solution (102 grams in 250 grams of water) and a sodium carbonate
solution (55 grams in 350 grams of water). Solid sucrose (230 grams) and a NaOH
solution (5 grams in 13 gram of water) were added. The resulting mixture was heated at
92 °C for 3 hours to obtain comparative composition 3’ containing ferric hydroxide
sucrose nanoclusters.
Composition 3 was prepared by mixing 0.5 grams of comparative composition 3’
with 0.0683 grams of sodium oxalate.
On the other hand, composition 4 was prepared by mixing 0.5 grams of
comparative composition 3’ with 0.117 grams of sodium succinate.
The turbidity points of compositions 3, 3’, and 4 were measured following the
procedure described in Example 1. The results, shown in the table above, unexpectedly
demonstrate that compositions 3 and 4 each had a turbidity point much lower than that of
their comparative composition, i.e., composition 3’.
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EXAMPLE 5
Composition 5 was prepared following the procedure described below. In a
vessel equipped with a stirring and heating device, a ferric hydroxide carbonate
precipitate was obtained by mixing a ferric nitrate nonahydrate solution (25.6 grams in
62 grams of water) and a sodium carbonate solution (13 grams in 75 grams of water).
Solid sucrose (60.8 grams) and solid sodium tartrate (4.6 grams) were added. The
resulting mixture was heated at 92 °C for 1 hour to yield composition 5 containing ferric
hydroxide sucrose tartrate nanoclusters.
Comparative composition 5’ was prepared following exactly the same procedure
as composition 5 except that a NaOH solution (5.05 grams in 13 grams of water) was
used instead of solid sodium tartrate.
The turbidity points of both compositions 5 and 5’ were measured following the
procedure described in Example 1. The results, shown in the table above, unexpectedly
demonstrate that composition 5 had a turbidity point much lower than that of comparative
composition 5’.
EXAMPLE 6
To obtain composition 6, comparative composition 6’ was prepared following the
procedure described below. In a vessel equipped with a stirring and heating device, a
ferric chloride solution (150 grams in 1000 grams of water) and a sodium carbonate
solution (96 grams in 544 grams of water) were mixed to yield a ferric hydroxide
carbonate precipitate, which was isolated and washed by centrifugation to obtain 328
grams of a concentrated precipitate. Solid sucrose (545 grams) and a NaOH solution (12
grams in 108 grams of water) were added. The resulting mixture was heated at 105 °C
for 10 hours to obtain comparative composition 6’ containing ferric hydroxide sucrose
nanoclusters.
Composition 6 was prepared by mixing 10 grams of comparative composition 6’
with a sodium citrate dihydrate solution (0.5 grams in 1.5 grams of water) and heating at
80 °C for 30 minutes.
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The turbidity points of both compositions 6 and 6’ were measured following the
procedure described in Example 1. The results, shown in the table above, unexpectedly
demonstrate that composition 6 had a turbidity point much lower than that of comparative
composition 6’.
Dissociation Assay
In addition, the dissociation rates of both compositions 6 and 6’ were measured
following the procedure described below.
The acid dissociation rate of composition 6 was determined according to the
method described in US Patent 8,058,076. First, a solution of composition 6 was added
into a volumetric flask, followed by the addition of 0.75 M hydrochloric acid solution at
37 °C. After mixing, the solution was measured using a UV/VIS spectrophotometer at
450 nm every 5 minutes, starting at time 0 until a constant absorbance was observed by
the spectrophotometer. The percentage concentration was calculated using the equation
described at column 4 of US Patent 8,058,076. The acid dissociation rate (T75) was the
time in minutes required to release 75 % of the ferric ion from the composition.
Composition 6 had an acid dissociation rate of 32 minutes.
Following the same procedure described above, comparative composition 6’ had
an acid dissociation rate of 27.6 minutes.
Unexpectedly, composition 6 had a lower acid dissociation rate than that of
comparative composition 6’.
OTHER EMBODIMENTS
All of the features disclosed in this specification may be combined in any
combination. Each feature disclosed in this specification may be replaced by an
alternative feature serving the same, equivalent, or similar purpose. Thus, unless
expressly stated otherwise, each feature disclosed is only an example of a generic series
of equivalent or similar features.
From the above description, one skilled in the art can easily ascertain the essential
characteristics of the present invention, and without departing from the spirit and scope
thereof, can make various changes and modifications of the invention to adapt it to
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various usages and conditions. Thus, other embodiments are also within the scope of the
following claims.
Unless the context clearly requires otherwise, throughout the description and the
claims, the words “comprise”, “comprising”, and the like, are to be construed in an
inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense
of “including, but not limited to”.
The reference to any prior art in the specification is not, and should not be taken as,
an acknowledgement or any form of suggestion that the prior art forms part of the
common general knowledge in New Zealand.
Claims (31)
1. A metal ion nanocluster having a particle size of 2 to 500 nm, a molecular weight of 3500 to 1000000 Dalton, and a formula of X(OH) Y Z M (H O) , in which X a b c d 2 e is a metal cation, Y is a water-soluble salt-forming anion, Z is a water-soluble ligand, M 5 is a turbidity point modifier, a is 0.1 to 20, b is 0 to 9, c is 0.1 to 10, d is 0.1 to 9, and 0 < e < 25, wherein the nanocluster has a turbidity point of 8 or lower.
2. The nanocluster of claim 1, wherein the particle size is 2 to 150 nm. 10
3. The nanocluster of claim 2, wherein the particle size is 2 to 80 nm.
4. The nanocluster of claim 1, wherein the metal cation is a cation of Cr, Al, Bi, Zn, Ba, Cu, Ti, Mg, Mn, Pt, Ca, Se, In, Fe, Co, Ni, V, La, Mo, Sr, Zr, or a combination thereof; the water-soluble salt-forming anion is fluoride, chloride, bromide, 15 iodide, nitrate, sulfate, acetate, or a combination thereof; the water-soluble ligand is a carbohydrate, a hydrogenated carbohydrate, a hydrolyzed carbohydrate, a polyol, a polyether, or a combination thereof; and the turbidity point modifier is a complex- forming polyvalence anion, an oxidized carbohydrate, a carboxylated polyol, a carboxylated polyether, a sulfonated carbohydrate, a sulfonated polyol, a sulfonated 20 polyether, a phospholated carbohydrate, a phospholated polyol, a phospholated polyether, an amino acid, a water-soluble polypeptide, a water-soluble protein, or a combination thereof.
5. The nanocluster of claim 4, wherein the metal cation is Mg(II), Al(III), Ca(II), Cr(III), Cu(II), Zn(II), Mn (II), Ti(IV), Fe(II/III), Co(II), Ni(II), Bi(III), V(V), La(III), Mo(VI), Sr(II), Zr(IV) or a combination thereof; the water-soluble salt-forming anion is chloride, nitrate, sulfate, acetate, or a combination thereof; the water-soluble ligand is xylitol, mannitol, ribose, mannose, xylose, galactose, fructose, lactose, glucose, isomaltose, isomalt, sucrose, maltitol, trehalose, arabinose, sorbitol, polyisomaltose, 30 isomalto-oligosaccharide, dextrin, dextran, fructooligosaccharide, or a combination thereof; and the complex-forming polyvalence anion is citrate, malate, fumarate, tartrate, lactate, oxalate, succinate, ascorbate, phosphate, pyrophosphate, glycerophosphate, or a combination thereof. 5
6. The nanocluster of claim 5, wherein the nanocluster has a turbidity point of 4.5 or lower.
7. The nanocluster of claim 1, wherein a is 1 to 10, b is 0 to 3, c is 1 to 6, d is 0.1 to 6, and e is 0 to 10.
8. The nanocluster of claim 1, wherein the nanocluster has a molecular weight of 5000 to 300000 Dalton.
9. The nanocluster of claim 8, wherein the nanocluster has a molecular 15 weight of 10000 to 180000 Dalton.
10. The nanocluster of claim 1, wherein the nanocluster has a dissociation rate of 1 to 180 minutes. 20
11. The nanocluster of claim 10, wherein the nanocluster has a dissociation rate of 1 to 60 minutes.
12. The nanocluster of claim 1, wherein the nanocluster has a particle size of 2 to 150 nm, a turbidity point of 7 or lower, and a dissociation rate of 1 to 180 minutes; the metal cation is a cation of Cr, Al, Bi, Zn, Ba, Cu, Ti, Mg, Mn, Pt, Ca, Se, In, Fe, Co, Ni, V, La, Mo, Sr, Zr, or a combination thereof; the water-soluble salt-forming anion is fluoride, chloride, bromide, iodide, nitrate, sulfate, acetate, or a combination thereof; the water-soluble ligand is a carbohydrate, a hydrogenated carbohydrate, a hydrolysed carbohydrate, a polyol, a polyether, or a combination thereof; and the turbidity point 30 modifier is a complex-forming polyvalence anion, an oxidized carbohydrate, a carboxylated polyol, a carboxylated polyether, a sulfonated carbohydrate, a sulfonated polyol, a sulfonated polyether, a phospholated carbohydrate, a phospholated polyol, a phospholated polyether, an amino acid, a water-soluble polypeptide, a water-soluble protein, or a combination thereof.
13. The nanocluster of claim 12, wherein the nanocluster has a particle size of 2 to 80 nm, a turbidity point of 4.5 or lower, and a dissociation rate of 1 to 60 minutes; the metal cation is Mg(II), Al(III), Ca(II), Cr(III), Cu(II), Zn(II), Mn (II), Ti(IV), Fe(II/III), Co(II), Ni(II), Bi(III), V(V), La(III), Mo(VI), Sr(II), Zr(IV), or a combination 10 thereof; the water-soluble salt-forming anion is chloride, nitrate, sulfate, acetate, or a combination thereof; the water-soluble ligand is xylitol, robose, mannose, xylose, galactose, fructose, lactose, glucose, mannitol, maltitol, isomaltose, isomalt, sucrose, trehalose, arabinose, sorbitol, polyisomaltose, isomalto-oligosaccharide, dextrin, dextran, fructooligosaccharide, or a combination thereof; and the turbidity point modifier is 15 citrate, malate, fumarate, tartrate, lactate, oxalate, succinate, ascorbate, phosphate, pyrophosphate, glycerophosphate, an oxidized carbohydrate, a carboxylated polyol, a carboxylated polyether, a sulfonated carbohydrate, a sulfonated polyol, a sulfonated polyether, a phospholated carbohydrate, a phospholated polyol, a phospholated polyether, an amino acid, a water-soluble polypeptide, a water-soluble protein, or a combination 20 thereof.
14. A composition comprising a nanocluster of claim 1, wherein the composition has a pH value of 3 to 11.5 and is free of unchelated ions, unreactive water- soluble ligands, and labile low-molecular-weight ion complexes.
15. The composition of claim 14, wherein the nanocluster has a particle size of 2 to 150 nm, a turbidity point of 7 or lower, and a dissociation rate of 1 to 180 minutes; the metal cation is a cation of Cr, Al, Bi, Zn, Ba, Cu, Ti, Mg, Mn, Pt, Ca, Se, Fe, Co, Ni, V, La, Mo, Sr, In, Zr, or a combination thereof; the water-soluble salt-forming anion is 30 fluoride, chloride, bromide, iodide, nitrate, sulfate, acetate, or a combination thereof; the water-soluble ligand is a carbohydrate, a hydrogenated carbohydrate, a polyol, a polyether, or a combination thereof; and the turbidity point modifier is a complex- forming polyvalence anion, an oxidized carbohydrate, a carboxylated polyol, a carboxylated polyether, a sulfonated carbohydrate, a sulfonated polyol, a sulfonated 5 polyether, a phospholated carbohydrate, a phospholated polyol, a phospholated polyether, an amino acid, a water-soluble polypeptide, a water-soluble protein, or a combination thereof.
16. The composition of claim 15, wherein the nanocluster has a particle size 10 of 2 to 80 nm, a turbidity point of 4.5 or lower, and a dissociation rate of 1 to 60 minutes; the metal cation is Mg(II), Al(III), Ca(II), Cr(III), Cu(II), Zn(II), Mn (II), Ti(IV), Fe(II/III), Co(II), Ni(II), Bi(III), V(V), La(III), Mo(VI), Sr(II), Zr(IV), or a combination thereof; the water-soluble salt-forming anion is chloride, nitrate, sulfate, acetate, or a combination thereof; the water-soluble ligand is xylitol, robose, mannose, xylose, 15 galactose, fructose, lactose, glucose, mannitol, maltitol, isomaltose, isomalt, sucrose, trehalose, arabinose, sorbitol, polyisomaltose, isomalto-oligosaccharide, dextrin, dextran, fructooligosaccharide, or a combination thereof; and the turbidity point modifier is citrate, malate, lactate, fumarate, tartrate, oxalate, succinate, ascorbate, phosphate, pyrophosphate, glycerophosphate, an oxidized carbohydrate, a carboxylated polyol, a 20 carboxylated polyether, a sulfonated carbohydrate, a sulfonated polyol, a sulfonated polyether, a phospholated carbohydrate, a phospholated polyol, a phospholated polyether, an amino acid, a water-soluble polypeptide, a water-soluble protein, or a combination thereof.
17. The composition of claim 14, wherein the pH value is 3.5 to 9.
18. The composition of claim 17, wherein the nanocluster has a particle size of 2 to 150 nm, a turbidity point of 7 or lower, and a dissociation rate of 1 to 180 minutes; the metal cation is a cation of Cr, Al, Bi, Zn, Ba, Cu, Ti, Mg, Mn, Pt, Ca, Se, Fe, Co, Ni, 30 V, La, Mo, Sr, In, Zr, or a combination thereof; the water-soluble salt-forming anion is fluoride, chloride, bromide, iodide, carbonate, bicarbonate, hydroxide, nitrate, phosphate, pyrophosphate, sulfate, acetate, or a combination thereof; the water-soluble ligand is a carbohydrate, a hydrogenated carbohydrate, a polyol, a polyether, or a combination thereof; and the turbidity point modifier is a complex- forming polyvalence anion, an 5 oxidized carbohydrate, a carboxylated polyol, a carboxylated polyether, a sulfonated carbohydrate, a sulfonated polyol, a sulfonated polyether, a phospholated carbohydrate, a phospholated polyol, a phospholated polyether, an amino acid, a water-soluble polypeptide, a water-soluble protein, or a combination thereof. 10
19. The composition of claim 18, wherein the nanocluster has a particle size of 2 to 80 nm, a turbidity point of 4.5 or below, and a dissociation rate of 1 to 60 minutes; the metal cation is Mg(II), Al(III), Ca(II), Cr(III), Cu(II), Zn(II), Mn (II), Ti(IV), Fe(II/III), Co(II), Ni(II), Bi(III), V(V), La(III), Mo(VI), Sr(II), Zr(IV), or a combination thereof; the water-soluble salt-forming anion is chloride, nitrate, sulfate, acetate, or a 15 combination thereof; the water-soluble ligand is xylitol, robose, mannose, xylose, galactose, fructose, lactose, glucose, mannitol, maltitol, isomaltose, isomalt, sucrose, trehalose, arabinose, sorbitol, polyisomaltose, isomalto-oligosaccharide, dextrin, dextran, fructooligosaccharide, or a combination thereof; and the turbidity point modifier is citrate, malate, fumarate, tartrate, oxalate, succinate, ascorbate, phosphate, 20 pyrophosphate, glycerophosphate, an oxidized carbohydrate, a carboxylated polyol, a carboxylated polyether, a sulfonated carbohydrate, a sulfonated polyol, a sulfonated polyether, a phospholated carbohydrate, a phospholated polyol, a phospholated polyether, an amino acid, a water-soluble polypeptide, a water-soluble protein, or a combination thereof.
20. The composition of claim 14, wherein the composition is a transparent aqueous solution or a water-soluble solid capable of being reconstituted into a transparent aqueous solution, the transparent aqueous solution having a pH value of 3.5-9.5.
21. The composition of claim 20, wherein the nanocluster has a particle size of 2 to 150 nm, a turbidity point 7 or lower, and a dissociation rate of 1 to 180 minutes; the metal cation is a cation of Cr, Al, Bi, Zn, Ba, Cu, Ti, Mg, Mn, Pt, Ca, Se, Fe, Co, Ni, V, La, Mo, Sr, In, Zr, or a combination thereof; the water-soluble salt-forming anion is 5 fluoride, chloride, bromide, iodide, nitrate, sulfate, acetate, or a combination thereof; the water-soluble ligand is a carbohydrate, a hydrogenated carbohydrate, a polyol, a polyether, or a combination thereof; and the turbidity point modifier is a complex- forming polyvalence anion, an oxidized carbohydrate, a carboxylated polyol, a carboxylated polyether, a sulfonated carbohydrate, a sulfonated polyol, a sulfonated 10 polyether, a phospholated carbohydrate, a phospholated polyol, a phospholated polyether, an amino acid, a water-soluble polypeptide, a water-soluble protein, or a combination thereof.
22. The composition of claim 21, wherein the nanocluster has a particle size 15 of 2 to 80 nm, a turbidity point of 4.5 or lower , and a dissociation rate of 1 to 60 minutes; the metal cation is Mg(II), Al(III), Ca(II), Cr(III), Cu(II), Zn(II), Mn (II), Ti(IV), Fe(II/III), Co(II), Ni(II), Bi(III), V(V), La(III), Mo(VI), Sr(II), Zr(IV), or a combination thereof; the water-soluble salt-forming anion is chloride, nitrate, sulfate, acetate, or a combination thereof; the water-soluble ligand is xylitol, robose, mannose, xylose, 20 galactose, fructose, lactose, glucose, mannitol, maltitol, isomaltose, isomalt, sucrose, trehalose, arabinose, sorbitol, polyisomaltose, isomalto-oligosaccharide, dextrin, dextran, fructooligosaccharide, or a combination thereof; and the turbidity point modifier is citrate, malate, fumarate, tartrate, lactate, oxalate, succinate, ascorbate, phosphate, pyrophosphate, glycerophosphate, an oxidized carbohydrate, a carboxylated polyol, a carboxylated polyether, a sulfonated carbohydrate, a sulfonated polyol, a sulfonated polyether, a phospholated carbohydrate, a phospholated polyol, a phospholated polyether, an amino acid, a water-soluble polypeptide, a water-soluble protein, or a combination thereof.
23. Use of an effective amount of the nanocluster of claim 1, in the manufacture of a medicament for treating a disorder or for detecting a tissue image in a subject in need thereof, wherein the disorder is a mineral deficiency disorder, a gastric reflux disorder, or a chronic renal failure and a tissue image is for use in differentiating 5 an abnormal tissue from a normal tissue.
24. A method of preparing a nanocluster of claim 1, the method comprising: providing an aqueous dispersion containing X, Y, Z, and OH; adjusting the pH of the aqueous dispersion to a predetermined value to obtain a 10 pH-adjusted aqueous dispersion; heating the pH-adjusted aqueous dispersion to 50-180 °C so that nanoclusters are formed; and adding M after any of the above steps, wherein X is a metal cation, Y is a water-soluble salt-forming anion, Z is a water-soluble 15 ligand, M is a turbidity point modifier, and the ratio of X : Y : Z : M is 1 : 0-9 : 0.1-10 : 0.1-9.
25. The method of claim 24, further comprising, after M is added and the nanoclusters are formed, collecting the nanoclusters by nanofiltration and drying the 20 nanoclusters to form solid nanoclusters.
26. A nanocluster prepared by the method of claim 24 or claim 25.
27. A metal ion nanocluster as claimed in claim 1, substantially as hereinbefore described with particular reference to any one or more of the Examples.
28. A composition comprising a nanocluster as claimed in claim 14, substantially as hereinbefore described with particular reference to any one or more of the Examples.
29. Use of an effective amount of a nanocluster as claimed in claim 23, substantially as hereinbefore described with particular reference to any one or more of the Examples. 5
30. A method of preparing a nanocluster as claimed in claim 24, substantially as hereinbefore described with particular reference to any one or more of the Examples.
31. A nanocluster as claimed in claim 26, substantially as hereinbefore described with particular reference to any one or more of the Examples.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13/833,279 US9370202B2 (en) | 2013-03-15 | 2013-03-15 | Encapsulated metal ion nanoclusters |
| US13/833,279 | 2013-03-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ622341A NZ622341A (en) | 2015-09-25 |
| NZ622341B true NZ622341B (en) | 2016-01-06 |
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