Iron complexes and foodstuffs containing them

#My application Ser. No. 417,553, filed Nov. 20, 1973, now U.S. Pat. No. 3,901,874, issued Aug. 26, 1975, and all divisional or continuing applications related thereto, contains a disclosure regarding hydrolysis of pectin and other uronic moiety gums and use of the hydrolyzates in complexing iron.

#This invention relates generally to iron-containing compounds of the type often referred to in the medical and biological sciences as "hematinics". An aspect of this invention relates to the reaction product of a uronic acid (or the lactone form thereof or the neutralized, i.e., carboxylate form thereof) and a water soluble iron salt. Another aspect of this invention relates to a solid, iron-containing compound which has a high level of bioavailable iron, when tested according to the cyanomethemoglobin method of Drabkin for hemoglobin determination. Still another aspect of this invention relates to hematinic compounds or complexes in pharmaceutically acceptable extending media or as additives to foodstuffs. Still another aspect of this invention relates to an iron complex or compound containing in excess of 20 weight percent iron, which iron is in a substantially bioavailable form.

#It is well known that mammals require iron in their diets. Although the amount of iron required by a mammal is not large, in comparison, say, to protein requirements, the ingestion of iron appears to be essential to the maintenance of a high level of hemoglobin in the blood. Iron deficiency anemia can occur naturally and has been experimentally induced or created in a wide variety of mammalina species, including the typical experimental animals such as rodents. The occurrence of iron deficiency anemia in humans, of course, is well established.

#An aqueous iron solution was prepared containing 0.2 mol per liter of ferric chloride and 0.1 mol per liter of hydrochloric acid. The latter serves to prevent hydrolysis of the ferric chloride in the aqueous solution. Also, 2.546 grams of galacturonic acid monohydrate (molecular weight 212.16, Eastman Organic Chemicals) were dissolved in 50 ml of distilled water. The galacturonic acid solution was neutralized by slowing adding -- with good stirring -- solid sodium carbonate monohydrate until pH test paper showed a pH of 9 .+-. 1. Great precision is not needed for this step. Next, 120 ml of the above iron solution (containing 3.892 grams of ferric chloride) were added slowly, with moderate stirring, to the above solution of galacturonic acid. The resultant very acid mixture was again neutralized by the addition of solid sodium carbonate monohydrate. At one point during this latter addition, the solution became very turbid with an insoluble iron salt of the iron-galacturonic acid complex, but this turbidity disappeared completely when a pH of about 9 was reached. At this point, the solution was of a very deep red-brown color, and it was perfectly clear. It was gently warmed on a hot plate to about 40.degree. C. in order to expel the carbon dioxide formed in the neutralization process. The solution was then cooled to room temperature and added to 800 ml of isopropyl alcohol (aqueous, 70% by volume) with good stirring. A dark brown precipitate was then formed which settled readily to the bottom of the beaker upon cessation of the stirring. The supernatant liquid was substantially colorless. Precipitate and supernatant liquid were filtered off on a Buchner funnel. Filtration was rapid. The filter cake was washed three times with absolute isopropanol and dried. A dark, coffee-brown solid product was obtained which was loose and required no grinding. The size of the particles obtained was less than 200 mesh. Analysis by an independent academic laboratory showed the product to contain 29.5% iron and 7.6% sodium by weight. The product was easily soluble in water; the solution had a faint fruit flavor and was not astringent in low concentrations. The yield of solid product was 4.4 grams. The product was tested for hematinic activity; see Example 7.

#2.546 grams of the same galacturonic acid described in Example 1 were dissolved in 50 ml of distilled water, and 120 ml of the same ferric chloride solution described in the preceding example were added thereto slowly, with stirring, by means of a pipette. The acid mixture was then neutralized slowly by the addition of an aqueous solution of sodium carbonate monohydrate containing approximately 30 grams of the salt per 100 ml of distilled water. Addition was made by dropping the soda solution into the acid mixture from a burette at the rate of approximately 1 drop per second, until a pH of 9 .+-. 1 was reached. Because of the greater dilution of the reactants in this example, compared with that in Example 1, the reaction mixture was added from a dropping funnel to a beaker containing 1,800 ml of a 70:30 isopropanol:water mixture. A very fine -grained dark brown-red precipitate was obtained which settled to the bottom of the beaker very readily, leaving a clear and colorless supernatant which contains no iron as proven by a thiocyanate test. Filtration with the procedure described in Example 1 was fast, and the yield of dry, chocolate-brown product was 4.3 grams. Analysis proved the product to contain 29.0% iron and 8.1% sodium. Animal tests for bioavailability of the iron in this product gave substantially the same results as reported in Example 7 for the product of Example 1.

#Yields obtained in the two examples, the analyses of the two products, and the results of animal bioavailability tests leave no doubt that the two products are substantially identical, though the product of Example 2 seems to contain a very small amount of an impurity, most probably sodium chloride which is one of the products of reaction.