US2816060A - Ferrous chelate compositions for oral administration - Google Patents
Ferrous chelate compositions for oral administration Download PDFInfo
- Publication number
- US2816060A US2816060A US446416A US44641654A US2816060A US 2816060 A US2816060 A US 2816060A US 446416 A US446416 A US 446416A US 44641654 A US44641654 A US 44641654A US 2816060 A US2816060 A US 2816060A
- Authority
- US
- United States
- Prior art keywords
- iron
- oral administration
- tablets
- elemental
- ferrous
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000000203 mixture Substances 0.000 title description 15
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 title description 12
- 239000013522 chelant Substances 0.000 title 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 95
- 229910052742 iron Inorganic materials 0.000 claims description 47
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical class [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims description 9
- 206010022971 Iron Deficiencies Diseases 0.000 claims description 6
- 239000002738 chelating agent Substances 0.000 claims description 5
- 239000008247 solid mixture Substances 0.000 claims description 5
- 238000011282 treatment Methods 0.000 claims description 5
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 16
- -1 alkali metal salts Chemical class 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- 229910052783 alkali metal Inorganic materials 0.000 description 9
- 102000018434 Iron-Regulatory Proteins Human genes 0.000 description 7
- 108010066420 Iron-Regulatory Proteins Proteins 0.000 description 7
- 230000002349 favourable effect Effects 0.000 description 7
- 239000000454 talc Substances 0.000 description 7
- 229910052623 talc Inorganic materials 0.000 description 7
- 235000021355 Stearic acid Nutrition 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 6
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000008117 stearic acid Substances 0.000 description 6
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 description 5
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000007086 side reaction Methods 0.000 description 5
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000011790 ferrous sulphate Substances 0.000 description 3
- 235000003891 ferrous sulphate Nutrition 0.000 description 3
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 238000009498 subcoating Methods 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 241000220479 Acacia Species 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 102000001554 Hemoglobins Human genes 0.000 description 2
- 108010054147 Hemoglobins Proteins 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- 206010028813 Nausea Diseases 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 2
- 206010047700 Vomiting Diseases 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 230000037406 food intake Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 150000002506 iron compounds Chemical class 0.000 description 2
- 230000008693 nausea Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 241001669696 Butis Species 0.000 description 1
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000237858 Gastropoda Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 101150076419 MT-CO3 gene Proteins 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 101100061105 Rattus norvegicus Mtco3 gene Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 229930003270 Vitamin B Natural products 0.000 description 1
- 206010047627 Vitamin deficiencies Diseases 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000010410 dusting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229940070385 intrinsic factor concentrate Drugs 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- 229960003284 iron Drugs 0.000 description 1
- 239000000797 iron chelating agent Substances 0.000 description 1
- 150000004698 iron complex Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 1
- 229960004172 pyridoxine hydrochloride Drugs 0.000 description 1
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 1
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229960002477 riboflavin Drugs 0.000 description 1
- 235000019192 riboflavin Nutrition 0.000 description 1
- 239000002151 riboflavin Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000019156 vitamin B Nutrition 0.000 description 1
- 239000011720 vitamin B Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/295—Iron group metal compounds
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S71/00—Chemistry: fertilizers
- Y10S71/02—Chelating agent
Definitions
- This invention relates to coiii" ositiohs useful for the oral administration of iron in therapeutic o'i' hylactic dosa e. More particularly it relates to compositi ns eontai'ning chelated iron in dial dosage u'nit form and to a method or compounding same.
- I p I r The need for iron in the daily diet brine average individual is fully established and the conditions which result from a failure to supply the necessary minimum amount of iron per day are wen known. Iron deficiency or iron anemia is a condition which occurs in a large segment of the population, particularly in females.
- Another object of the invention is to provide a convenient dosage unit form suitable for oral administration and capable of giving a high iron response.
- favorable iron res onse is meant a significant increase in the hemoglobin count of a blood sample.
- Other criteria are "also employed to show a favorable iron response and measured by any of these criteria the chelated iron composition of the present invention gives a highly favorable response.
- chelated iron as the term is used herein it is desired 1 2,816,060 Patented Dec. 10, 1957 to include iron derivatives of compounds which fall within the scope of the formula wherein n is 2 to 6 inclusive, m is O'to 2 inclusive, D is CH COOH, --CH CH COOH or the alkali metal salts thereof (sodium, potassium and -NH.;), and A is the same as D, or lower alkyl or hydroxy lower alkyl.
- carboxylic polyor diamino acids specifically included within ma nate formula may be mentioned ethylene a anine N,N' tetraacetic acid, propylene 1,2 -diamin N,N' tetraacetic acid, 1,3-diangii nopropanol-2-N,N' tetraace tic acid, diethylenetriamine N,N' tetraacetic acid, diethylenetriamine N,NN pentaacetic acid, hexamethylen'ediamine N,N' tetraacetic acid, [Hiydroxyethylethylenediarnine-N,N triacetic acid.
- the solid pharmaceutical carrier to which the invention pertains may take the form of tablets; powders; capsules or other dosage forms which are particularly useful for oral ingestion.
- Solid diluents and/or tablet adjuvants such as corn starch, lactose, t'alc, stcarieacid; magnesium stearate, gums and the like are all included in this class.
- any of the tableting materials used in ordinary pharmaceutical practice may be employed where there is no incompatibility with the chelated iron of this invention.
- the iron chelates used herein have between about 9% and 17% elemental iron and the bulk represented by the substantially inactive polycarboxylic amino acid residue may take the place of a diluent or filler in the oral dosage form.
- the material may be tableted with or without adjuvants but it will ordinarily be better practice to employ at least the lubricating compounds such as talc, stearic acid and magnesium stearate.
- the active material with or without its adjuvant materials may be placed in a capsule such as the usual gelatin capsule and administered in that form;
- the active chelated iron com position may be put with or without adjuvants into powder packets or in powdered forth and administered in this manner.
- the amount of chelated iron in the composition inthis' invention may be varied to suit certain individual situations. It is necessary, however, that the active ingredient constitute a proportion such that a suitable dosage will be obtained. It will be apparent that several unit dosage forms my be administered at the same time or in intervals. Hence, it will be apparent that any smallbut significant amount of chelated iron may be employed inacli dosage unit. As a practical matter i is desirable to have at least about 5 milligrams of ale tal iron present in each dosage unit and the amount iiiay be varied up: wardly from that point at will.
- One particularly useful dosage unit which will be described in detail in the following examples contains siifiicient chelated iron to provide about 16% milligrams of elemental iron per tablet.
- the patient may obtain 50 milligrams of elemental iron by taking one tablet three times 'a 'day. It has been found that this schedule of treatment will provide iron response comparable to that obtained with far greater amounts of elemental iron administered in the form of ferrous sulfateaccording to previously known practices.
- Example I mental ferrous iron 120 Talc 6 Stearic acid 4 Magnesium stearate 2 Add 3 grams of talc and 2 grams of stearic acid to the sequestrene H Fe (Alrose Chemical Company) through a 40-mesh screen. Mix well and slug. Grind the slugs through a 4-mcsh screen and then through a 16-mesh screen. Add the remainder of lubricants through a 40- mesh screen and blend well. Compress on a convex punch so that 10 tablets weigh about 1.1 grams.
- the tablets contain about 16 /3 milligrams of elemental ferrous iron per tablet and when taken three times daily to provide a daily dose of 50 milligrams of elemental iron the composition results in a high iron response as evidenced by a substantial increase in the hemoglobin count in the blood of patients taking the tablets.
- the response is equal to or superior to that obtained when 200 milligrams per day of elemental iron is given in the form of ferrous sulfate.
- the side reactions, vomiting and nausea, are far less in the composition of this invention.
- Lactose, corn starch and other diluents or adjuvants may also be added if desired, and if added, they do not substantially alter the response obtained.
- Example II 1200 tablets were made up according to the following directions:
- Example I Grams Sequestrene H Fe (containing about 17% elemental ferrous iron) 60 Talc 3 Stearic acid 2 Magnesium stearate 1
- the ingredients were compounded in the manner set forth in Example I and 10 such tablets weighed 0.55 gram.
- the tablets were sub-coated with gelatin and acacia solution and sub-coating powder. Then a suitable syrup coating was applied and polished.
- the tablets contained approximately 8 milligrams of elemental ferrous iron per tablet and three tablets per day were administered to provide a daily dose of 25 milligrams of elemental iron.
- Favorable iron response was noted and there were no important side reactions.
- Lactose, corn starch and other diluents and adjuvants may also be added if desired in order to make the tablet a desirable size and shape.
- Example III 1500 tablets were made up according to the following directions:
- the chelated iron' is passed through a 40-mesh screen and massed with the melted Carbowax. The mass is allowed to set for about 4 hours at about C. It is then granulated through a l6-mesh screen, talc, stearic acid, and magnesium stearate are added through a mesh screen and the composition is blended well. When compressed on an convex punch 10 such tablets weigh 2.2 grams.
- These tablets contain about 16% milligrams of elemental ferrous iron per tablet.
- Example IV A multiple viamin-mineral tablet was prepared according to the following directions:
- Sequestrene H Fe (containing about 10% elemental Blend the chelated iron, sodium ascorbate, nicotinamide and pyridoxine hydrochloride and pass through a 40-mesh screen. Mass with 10% polyvinylpyrrolidone in anhydrous alcohol. Granulate through a 4-mesh screen and dry at F. for 18 hours. Pass the dried granulation through a 16-mesh screen and blend in the intrinsic factor concentrate, vitamin B powder, folic acid, thiamin mononitrate, riboflavin, calcium pantothenate, talc, stearic acid and pass through a 40-mesh screen into the main granulation. Mix well and compress on a /2 convex punch. 10 such tablets weighed 6.91 grams.
- Tablets of this type are highly suitable for either therapeutic or prophylactic treatment of vitamin and iron deficiencies.
- the tablets can be marketed uncoated, or they can be sugar coated or enteric coated as desired.
- Example V 461 capsules were prepared according to the following directions:
- Lactose 26 Pass the chelated iron and the lactose through a 40- mesh screen and encapsulate into gelatin capsules. Each capsule contains about 333- milligrams of elemental ferrous iron.
- Example VI 2,000 tablets were prepared according to the following Charge the sequestrene iron and cane sugar into a mixer'and blend well. Prepare a hot starch paste, and
- the theoretical iron content may vary between about 9% and 17% in different samples.
- a solid composition for oral administration in dosage unit form for administering iron comprising at least about 5 mg. of a physiologically acceptable chelated ferrous iron in which the chelating compound is represented by the formula wherein n is 2 to 6 inclusive, m is to 2 inclusive, D is selected from the group consisting of -CH COOH, CH CH COOH, and the alkali metal salts thereof, A is selected from the group consisting of lower alkyl, hydroxy lower alkyl, CH COOH, CH CH COOH, and the alkalimetal salts thereof, and a non-toxic, solid pharmaceutical carrier.
- a solid composition for oral administration for treatment of iron deficiencies comprising at least about 5 milligrams of elemental iron in the form of a ferrous salt of a chelating compound represented by the formula wherein n is 2 to 6 inclusive, m is 0 to 2 inclusive, D is selected from the group consisting of -CH COOH, CH CH COOH, and the alkali metal salts thereof, A is selected from the group consisting of lower alkyl, hydroxy lower alkyl, CH COOH, CH CH COOH, and the alkali metal salts thereof.
- a solid composition for oral administration comprising a capsule of encapsulating material containing at least about 5 milligrams of elemental iron in the form of a ferrous salt of a chelating compound represented by the formula A A N(CH1),. N(CH:),. N D l l l.
- n 2 to 6 inclusive
- m 0 to 2 inclusive
- D is selected from the group consisting of CH COOH, CH CH CO0H, and the alkali metal salts thereof
- A is selected from the group consisting of lower alkyl, hydroxy lower alkyl, CH C0OH, CH CH COOH, and the alkali metal salts thereof.
- a tablet for oral administration for the treatment of iron deficiencies containing a non-toxic, solid pharmaceutical carrier and at least about 5 milligrams of elemental iron in the form of a ferrous salt of a chelating compound represented by the formula N( 0 H2) -.[N( 0 a) ,.]N D 15 ZD wherein n is 2 to 6 inclusive, m is 0 to 2 inclusive, D is selected from the group consisting of CH COOH, -CH CH COOH, and the alkali metal salts thereof, A is selected from the group consisting of lower alkyl, hydroxy lower alkyl, -CH COOH, -CH CH COOH, and the alkali metal salts thereof.
- a tablet for oral administration for therapeutic and prophylactic use containing a non-toxic, solid pharmaceutical carrier and at least about 5 milligrams of elemental iron in the form of a ferrous salt of ethylenediamine tetraacetic acid.
- a solid composition for oral administration of iron which comprises at least about 5 milligrams of elemental iron in dosage unit form, said iron being in the form of the ferrous salt of ,B-hydroxyethylethylenediamine-N,N' triacetic acid- References Cited in the file of this patent FOREIGN PATENTS Germany Mar. 3, 1952 Great Britain June 24, 1940 OTHER REFERENCES 5th Ed., 1952,
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Description
Uni e tate Patifi 7 2,816,060 FERROUS CHELATECOMPOSITIONS For: ORAL ADMINISTRATION Edgar ll. Carter, j Iji'ghlaridPark, Ill., Aliliiitt Laboratories, Ehicagd, 111., a corporation of Illinois No Drawing. Application ill; h3 4, Serial No. 446,416
6 Claims. (Cl. 167-68) This invention relates to coiii" ositiohs useful for the oral administration of iron in therapeutic o'i' hylactic dosa e. More particularly it relates to compositi ns eontai'ning chelated iron in dial dosage u'nit form and to a method or compounding same. I p I r The need for iron in the daily diet brine average individual is fully established and the conditions which result from a failure to supply the necessary minimum amount of iron per day are wen known. Iron deficiency or iron anemia is a condition which occurs in a large segment of the population, particularly in females. The treatment of iron deficiency 53'' injections of i roi'l compounds and oral administration of iron is widespread butis attended With disadvantages to the patient. In oral administration of iron compounds for example, the, in ci'dence or nausea and other undesirable side reactions is quite prevalent. It has been necessary iii order to obtain favorable iron response in an iron deficient patient to'administ'e'r a comparatively large amount of iron per day to the adult patient. This large amount of iron; usually administered in the forrri of ferrous sulfate, often results in undesirable side reactions such as nausea and vomiting. In order to overcome this tendency it has become common practice to administer tablets containin'g only'a small portion of the total dosage at intervals and to thereby spread the total intake of iron over the full day. This in itself is inconvenient 'to the patient and does not always solve the problem of eliminating the undesirable side reactions.
It is an object of this invention to provide a composition which will give a high iron response in relatively small dosage and with a minimum of side effects.
Another object of the invention is to provide a convenient dosage unit form suitable for oral administration and capable of giving a high iron response.
In the accomplishment of the foregoing objects and in accordance with the practice of the present invention there is now provided a new iron composition useful for oral administration and containing as the active ingredient a chelated iron compound which may be associated with a solid pharmaceutical carrier. It was an unexpected finding of this invention that a highly favorable response could be obtained in humans using a relatively small dosage of a chelated iron composition because experiments in rats had proved unsatisfactory. It was found, for example, that a favorable ir'o'n response comparable to that obtained when ferrous sulfate is used as the'source of elemental iron could be obtained using only A to 73 the amount of elemental iron in the form of a chelated iron complex or co-o'rdina'tion compound. I
By favorable iron res onse is meant a significant increase in the hemoglobin count of a blood sample. Other criteria are "also employed to show a favorable iron response and measured by any of these criteria the chelated iron composition of the present invention gives a highly favorable response.
By chelated iron as the term is used herein it is desired 1 2,816,060 Patented Dec. 10, 1957 to include iron derivatives of compounds which fall within the scope of the formula wherein n is 2 to 6 inclusive, m is O'to 2 inclusive, D is CH COOH, --CH CH COOH or the alkali metal salts thereof (sodium, potassium and -NH.;), and A is the same as D, or lower alkyl or hydroxy lower alkyl. As examples of the carboxylic polyor diamino acids specifically included within ma nate formula may be mentioned ethylene a anine N,N' tetraacetic acid, propylene 1,2 -diamin N,N' tetraacetic acid, 1,3-diangii nopropanol-2-N,N' tetraace tic acid, diethylenetriamine N,N' tetraacetic acid, diethylenetriamine N,NN pentaacetic acid, hexamethylen'ediamine N,N' tetraacetic acid, [Hiydroxyethylethylenediarnine-N,N triacetic acid. Iron forms a stable complex orco-ordination compound with the above identified polycarboxylic amino acids and salts thereof and the iron is readily released from such co mpositions upon oral ingestion. The compounds referred to in this paragraph may also be conveniently named allrylenepolyamine polyacetic acids. V The solid pharmaceutical carrier to which the invention pertains may take the form of tablets; powders; capsules or other dosage forms which are particularly useful for oral ingestion. Solid diluents and/or tablet adjuvants such as corn starch, lactose, t'alc, stcarieacid; magnesium stearate, gums and the like are all included in this class. In fact, any of the tableting materials used in ordinary pharmaceutical practice may be employed where there is no incompatibility with the chelated iron of this invention. The iron chelates used herein have between about 9% and 17% elemental iron and the bulk represented by the substantially inactive polycarboxylic amino acid residue may take the place of a diluent or filler in the oral dosage form. The material may be tableted with or without adjuvants but it will ordinarily be better practice to employ at least the lubricating compounds such as talc, stearic acid and magnesium stearate. Alternatively the active material with or without its adjuvant materials may be placed in a capsule such as the usual gelatin capsule and administered in that form; Iii still another embodiment the active chelated iron com position may be put with or without adjuvants into powder packets or in powdered forth and administered in this manner.
The amount of chelated iron in the composition inthis' invention may be varied to suit certain individual situations. It is necessary, however, that the active ingredient constitute a proportion such that a suitable dosage will be obtained. It will be apparent that several unit dosage forms my be administered at the same time or in intervals. Hence, it will be apparent that any smallbut significant amount of chelated iron may be employed inacli dosage unit. As a practical matter i is desirable to have at least about 5 milligrams of ale tal iron present in each dosage unit and the amount iiiay be varied up: wardly from that point at will. One particularly useful dosage unit which will be described in detail in the following examples contains siifiicient chelated iron to provide about 16% milligrams of elemental iron per tablet. In this manner the patient may obtain 50 milligrams of elemental iron by taking one tablet three times 'a 'day. It has been found that this schedule of treatment will provide iron response comparable to that obtained with far greater amounts of elemental iron administered in the form of ferrous sulfateaccording to previously known practices.
. The followingex'ample's arepresehted in order to define the invention more clearly but it will be understood that the invention is not intended to be limited in any way' by these examples. '1 Example I mental ferrous iron) 120 Talc 6 Stearic acid 4 Magnesium stearate 2 Add 3 grams of talc and 2 grams of stearic acid to the sequestrene H Fe (Alrose Chemical Company) through a 40-mesh screen. Mix well and slug. Grind the slugs through a 4-mcsh screen and then through a 16-mesh screen. Add the remainder of lubricants through a 40- mesh screen and blend well. Compress on a convex punch so that 10 tablets weigh about 1.1 grams.
Add suflicient coats of cellulose acetate phthalate in solution, dusting with talc, until the tablets meet the U. S. P. disintegration test for enteric coatings. Sub-coat with gelatin and acacia and sub-coating powder. Apply syrup and polish.
The tablets contain about 16 /3 milligrams of elemental ferrous iron per tablet and when taken three times daily to provide a daily dose of 50 milligrams of elemental iron the composition results in a high iron response as evidenced by a substantial increase in the hemoglobin count in the blood of patients taking the tablets. The response is equal to or superior to that obtained when 200 milligrams per day of elemental iron is given in the form of ferrous sulfate. The side reactions, vomiting and nausea, are far less in the composition of this invention.
Lactose, corn starch and other diluents or adjuvants may also be added if desired, and if added, they do not substantially alter the response obtained.
Example II 1200 tablets were made up according to the following directions:
' Grams Sequestrene H Fe (containing about 17% elemental ferrous iron) 60 Talc 3 Stearic acid 2 Magnesium stearate 1 The ingredients were compounded in the manner set forth in Example I and 10 such tablets weighed 0.55 gram. The tablets were sub-coated with gelatin and acacia solution and sub-coating powder. Then a suitable syrup coating was applied and polished.
The tablets contained approximately 8 milligrams of elemental ferrous iron per tablet and three tablets per day were administered to provide a daily dose of 25 milligrams of elemental iron. Favorable iron response was noted and there were no important side reactions.
Lactose, corn starch and other diluents and adjuvants may also be added if desired in order to make the tablet a desirable size and shape.
Example III 1500 tablets were made up according to the following directions:
The chelated iron'is passed through a 40-mesh screen and massed with the melted Carbowax. The mass is allowed to set for about 4 hours at about C. It is then granulated through a l6-mesh screen, talc, stearic acid, and magnesium stearate are added through a mesh screen and the composition is blended well. When compressed on an convex punch 10 such tablets weigh 2.2 grams.
A special clear, colored enteric coating of cellulose acetate phthalate resin was applied to the tablets until they would meet the U. S. P. test for enten'c coating. It is not necessary to apply sub-coating and sugar-coating to these tablets since their appearance is highly satisfactory.
These tablets contain about 16% milligrams of elemental ferrous iron per tablet.
Example IV A multiple viamin-mineral tablet was prepared according to the following directions:
Sequestrene H Fe (containing about 10% elemental Blend the chelated iron, sodium ascorbate, nicotinamide and pyridoxine hydrochloride and pass through a 40-mesh screen. Mass with 10% polyvinylpyrrolidone in anhydrous alcohol. Granulate through a 4-mesh screen and dry at F. for 18 hours. Pass the dried granulation through a 16-mesh screen and blend in the intrinsic factor concentrate, vitamin B powder, folic acid, thiamin mononitrate, riboflavin, calcium pantothenate, talc, stearic acid and pass through a 40-mesh screen into the main granulation. Mix well and compress on a /2 convex punch. 10 such tablets weighed 6.91 grams.
Tablets of this type are highly suitable for either therapeutic or prophylactic treatment of vitamin and iron deficiencies. The tablets can be marketed uncoated, or they can be sugar coated or enteric coated as desired.
Example V 461 capsules were prepared according to the following directions:
Grams Sequestrene H Fe (containing 12% elemental ferrous iron) Lactose 26 Pass the chelated iron and the lactose through a 40- mesh screen and encapsulate into gelatin capsules. Each capsule contains about 333- milligrams of elemental ferrous iron.
Example VI 2,000 tablets were prepared according to the following Charge the sequestrene iron and cane sugar into a mixer'and blend well. Prepare a hot starch paste, and
Percent Ethylenediamine tetraacetic acid 72.1 Total iron 13.3 Ferrous iron 13.2 Theoretical iron content for trihydrate 13.9
The theoretical iron content may vary between about 9% and 17% in different samples.
Others may practice the invention in any of the numerous ways which will be suggested to one skilled in the art. It is contemplated that all such practices of the invention shall be covered hereby provided they fall within the scope of the appended claims.
I claim:
1. A solid composition for oral administration in dosage unit form for administering iron comprising at least about 5 mg. of a physiologically acceptable chelated ferrous iron in which the chelating compound is represented by the formula wherein n is 2 to 6 inclusive, m is to 2 inclusive, D is selected from the group consisting of -CH COOH, CH CH COOH, and the alkali metal salts thereof, A is selected from the group consisting of lower alkyl, hydroxy lower alkyl, CH COOH, CH CH COOH, and the alkalimetal salts thereof, and a non-toxic, solid pharmaceutical carrier.
2. A solid composition for oral administration for treatment of iron deficiencies comprising at least about 5 milligrams of elemental iron in the form of a ferrous salt of a chelating compound represented by the formula wherein n is 2 to 6 inclusive, m is 0 to 2 inclusive, D is selected from the group consisting of -CH COOH, CH CH COOH, and the alkali metal salts thereof, A is selected from the group consisting of lower alkyl, hydroxy lower alkyl, CH COOH, CH CH COOH, and the alkali metal salts thereof.
3. As a new article of manufacture a solid composition for oral administration comprising a capsule of encapsulating material containing at least about 5 milligrams of elemental iron in the form of a ferrous salt of a chelating compound represented by the formula A A N(CH1),. N(CH:),. N D l l l.
wherein n is 2 to 6 inclusive, m is 0 to 2 inclusive, D is selected from the group consisting of CH COOH, CH CH CO0H, and the alkali metal salts thereof, A is selected from the group consisting of lower alkyl, hydroxy lower alkyl, CH C0OH, CH CH COOH, and the alkali metal salts thereof.
4. A tablet for oral administration for the treatment of iron deficiencies containing a non-toxic, solid pharmaceutical carrier and at least about 5 milligrams of elemental iron in the form of a ferrous salt of a chelating compound represented by the formula N( 0 H2) -.[N( 0 a) ,.]N D 15 ZD wherein n is 2 to 6 inclusive, m is 0 to 2 inclusive, D is selected from the group consisting of CH COOH, -CH CH COOH, and the alkali metal salts thereof, A is selected from the group consisting of lower alkyl, hydroxy lower alkyl, -CH COOH, -CH CH COOH, and the alkali metal salts thereof.
5. A tablet for oral administration for therapeutic and prophylactic use containing a non-toxic, solid pharmaceutical carrier and at least about 5 milligrams of elemental iron in the form of a ferrous salt of ethylenediamine tetraacetic acid.
6. A solid composition for oral administration of iron which comprises at least about 5 milligrams of elemental iron in dosage unit form, said iron being in the form of the ferrous salt of ,B-hydroxyethylethylenediamine-N,N' triacetic acid- References Cited in the file of this patent FOREIGN PATENTS Germany Mar. 3, 1952 Great Britain June 24, 1940 OTHER REFERENCES 5th Ed., 1952,
Claims (1)
- 2. A SOLID COMPOSITION FOR ORAL ADMINISTRATION FOR TREATMENT OF IRON DEFICIENCIES COMPRISING AT LEAST 5 MILLIGRAMS OF ELEMENTAL IRON IN THE FORM OF A FERROUS SALT OF A CHELATING COMPOUND REPRESENTED BY THE FORMULA
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US446416A US2816060A (en) | 1954-07-28 | 1954-07-28 | Ferrous chelate compositions for oral administration |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US446416A US2816060A (en) | 1954-07-28 | 1954-07-28 | Ferrous chelate compositions for oral administration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2816060A true US2816060A (en) | 1957-12-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US446416A Expired - Lifetime US2816060A (en) | 1954-07-28 | 1954-07-28 | Ferrous chelate compositions for oral administration |
Country Status (1)
| Country | Link |
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| US (1) | US2816060A (en) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2955981A (en) * | 1957-12-31 | 1960-10-11 | American Cyanamid Co | Prevention of iron-deficiency anemias in suckling mammals |
| US2982690A (en) * | 1958-05-26 | 1961-05-02 | Diamond Lab | Injectable veterinary iron compositions |
| US3027303A (en) * | 1958-06-04 | 1962-03-27 | Bristol Myers Co | Hematinic compositions |
| US3033646A (en) * | 1957-10-09 | 1962-05-08 | Dow Chemical Co | Method of separating rare earth metal ions |
| US3035978A (en) * | 1957-08-12 | 1962-05-22 | Ici Ltd | Ferrocene hematinic compositions and therapy |
| US3088868A (en) * | 1958-08-18 | 1963-05-07 | Riker Laboratories Inc | Orally-active therapeutic compositions and process for using same |
| US3091522A (en) * | 1959-04-27 | 1963-05-28 | Dow Chemical Co | Method and composition for improving soil |
| US3107260A (en) * | 1960-11-29 | 1963-10-15 | Geigy Chem Corp | Triaminopropane hexa-acetic acid and metal chelates thereof |
| US3115511A (en) * | 1957-04-17 | 1963-12-24 | Hampshire Chemical Corp | Iron chelate compositions |
| US3139447A (en) * | 1960-05-02 | 1964-06-30 | Prod Chim Billault Fab | Preparation of ferrous ferri-ethylenediamine-tetra-acetate and process |
| US3150160A (en) * | 1960-10-17 | 1964-09-22 | Geigy Chem Corp | Metal salts and chelates of cyclohexyl or cyclopentyl triamino penta-achetic acids |
| US3151107A (en) * | 1960-12-22 | 1964-09-29 | Central Pharmacal Company | Water-soluble iron complexes of carboxymethyl dextran |
| US3208995A (en) * | 1961-06-22 | 1965-09-28 | Cherokee Lab Inc | Method of depolymerizing alginic acid salts and esters by reaction with no2 |
| US3367834A (en) * | 1965-05-04 | 1968-02-06 | Dexter Martin | Method and compositions for enhancing the utilization of iron by mammals |
| US5159094A (en) * | 1991-05-15 | 1992-10-27 | W.R. Grace & Co.-Conn. | Process for the preparation of solid iron (III) complexes |
| US5274151A (en) * | 1991-05-15 | 1993-12-28 | Hampshire Chemical Corp. | Process for the preparation of solid iron (III) complexes |
| US5446179A (en) * | 1992-10-08 | 1995-08-29 | Hampshire Chemical Corp. | Process for the preparation of micronutrient blends |
| USRE37534E1 (en) * | 1982-10-22 | 2002-01-29 | Btg International Limited | Pharmaceutical compositions |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB522646A (en) * | 1937-12-20 | 1940-06-24 | Ig Farbenindustrie Ag | The manufacture of aqueous solutions having a high content of calcium |
| DE832889C (en) * | 1950-03-06 | 1952-03-03 | Cassella Farbwerke Mainkur Ag | Process for the production of cobalt compounds |
-
1954
- 1954-07-28 US US446416A patent/US2816060A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB522646A (en) * | 1937-12-20 | 1940-06-24 | Ig Farbenindustrie Ag | The manufacture of aqueous solutions having a high content of calcium |
| DE832889C (en) * | 1950-03-06 | 1952-03-03 | Cassella Farbwerke Mainkur Ag | Process for the production of cobalt compounds |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3115511A (en) * | 1957-04-17 | 1963-12-24 | Hampshire Chemical Corp | Iron chelate compositions |
| US3035978A (en) * | 1957-08-12 | 1962-05-22 | Ici Ltd | Ferrocene hematinic compositions and therapy |
| US3033646A (en) * | 1957-10-09 | 1962-05-08 | Dow Chemical Co | Method of separating rare earth metal ions |
| US2955981A (en) * | 1957-12-31 | 1960-10-11 | American Cyanamid Co | Prevention of iron-deficiency anemias in suckling mammals |
| US2982690A (en) * | 1958-05-26 | 1961-05-02 | Diamond Lab | Injectable veterinary iron compositions |
| US3027303A (en) * | 1958-06-04 | 1962-03-27 | Bristol Myers Co | Hematinic compositions |
| US3088868A (en) * | 1958-08-18 | 1963-05-07 | Riker Laboratories Inc | Orally-active therapeutic compositions and process for using same |
| US3091522A (en) * | 1959-04-27 | 1963-05-28 | Dow Chemical Co | Method and composition for improving soil |
| US3139447A (en) * | 1960-05-02 | 1964-06-30 | Prod Chim Billault Fab | Preparation of ferrous ferri-ethylenediamine-tetra-acetate and process |
| US3150160A (en) * | 1960-10-17 | 1964-09-22 | Geigy Chem Corp | Metal salts and chelates of cyclohexyl or cyclopentyl triamino penta-achetic acids |
| US3107260A (en) * | 1960-11-29 | 1963-10-15 | Geigy Chem Corp | Triaminopropane hexa-acetic acid and metal chelates thereof |
| US3151107A (en) * | 1960-12-22 | 1964-09-29 | Central Pharmacal Company | Water-soluble iron complexes of carboxymethyl dextran |
| US3208995A (en) * | 1961-06-22 | 1965-09-28 | Cherokee Lab Inc | Method of depolymerizing alginic acid salts and esters by reaction with no2 |
| US3367834A (en) * | 1965-05-04 | 1968-02-06 | Dexter Martin | Method and compositions for enhancing the utilization of iron by mammals |
| USRE37534E1 (en) * | 1982-10-22 | 2002-01-29 | Btg International Limited | Pharmaceutical compositions |
| US5159094A (en) * | 1991-05-15 | 1992-10-27 | W.R. Grace & Co.-Conn. | Process for the preparation of solid iron (III) complexes |
| US5274151A (en) * | 1991-05-15 | 1993-12-28 | Hampshire Chemical Corp. | Process for the preparation of solid iron (III) complexes |
| US5446179A (en) * | 1992-10-08 | 1995-08-29 | Hampshire Chemical Corp. | Process for the preparation of micronutrient blends |
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