Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
1996-06-21
2004-11-16
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S646000, C424S647000, C424S648000, C514S904000, C514S905000
Reexamination Certificate
active
06818228
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to the fields of nutrition and obstetrics. More particularly, the present invention relates to a dietary supplement for use in humans, and in particular, in pregnant or lactating women, which supplement comprises calcium citrate and carbonyl iron. Compositions and methods for enhancing uptake of calcium, zinc, magnesium, or iron for a human are also provided.
BACKGROUND OF THE INVENTION
Vitamin and mineral compositions are commonly taken as dietary aids either as therapeutic preparations directed to a specific medical problem or as general nutritional supplements. Daily requirements for vitamins and minerals vary depending upon such factors as sex, body size, growth rate, exercise, disease, and age. Such compositions are especially provided for pregnant or lactating women to ensure provision of adequate nutrients for the developing fetus and for the mother.
Supplements pose a potential problem of nutrient—nutrient interactions. An excess of one nutrient in a supplement may interact with another nutrient in the supplement, thereby affecting absorption adversely, or less often, beneficially. For example, iron is reported to inhibit the absorption of zinc (Hambridge et al.,
Obstet. Gynecol.
4:593-596, 1987), zinc is reported to inhibit the absorption of copper (Festa et al.,
Am. J. Clin. Nutr.
41:285-292, 1985), calcium is reported to interfere with the absorption of both iron and zinc (Seligman et al.,
Obstet. Gynecol.
61:356-362, 1983), and protein is reported to increase urinary calcium losses (Allen et al.,
Am. J. Clin. Nutr.
32:741-749, 1979) and vitamin B6 requirements (National Research Council, Recommended Dietary Allowances, 10th ed., Natl. Acad. Press, Washington, D.C. 1989)
Calcium is required for adequate bone formation and maintenance, as well as for diverse metabolic functions. Approximately 99% of the calcium in the human body is located in the skeleton. Women are advised to increase their calcium intake substantially during pregnancy, and concern exists regarding many pregnant women who do not ingest enough calcium to maintain their own skeletons while providing for fetal needs. An estimated 600-800 mg of calcium is ingested in an average diet, far below the recommended dietary allowance. The efficiency of calcium absorption is determined by several factors, including the chemical form of ingested calcium. Part of the absorbed calcium is eliminated in urine, which poses a problem for certain people who are prone to the formation of calcium-containing kidney stones.
Ingested calcium is absorbed across the wall of the gastrointestinal tract and, in particular, the upper small intestine. To be absorbed across the intestinal wall, calcium must be soluble as an ionized form or as a salt form. Two major factors affect the amount of soluble calcium in the gastrointestinal tract. The first factor is gastric acid secretion, which increases the solubility of calcium by lowering the pH of intestinal fluids. This is important because ingested calcium is typically in the form of relatively insoluble salts, such as calcium carbonate and calcium phosphate. The second factor determining calcium absorption is the secretion of bicarbonate from the pancreas into the small intestine. The bicarbonate secreted into the small intestine alkalinizes fluid contained in the intestine, thereby decreasing the solubility of calcium. The absorption of calcium from the small intestine under a number of conditions varies with the form of ingested calcium salt. Minerals such as zinc and iron also depend upon stomach acid to become solubilized for intestinal absorption. Calcium in the form of calcium carbonate decreases the absorption of those minerals because of neutralization of the acidic environment.
Intestinal calcium absorption was reported to be increased almost 25% in women when the calcium was administered in the form of calcium citrate as compared to calcium carbonate (Harvey et al.,
J. Am. Coll. of Nutr.,
9(6):583-587, 1990.) In another study, performed in healthy, post-menopausal women, supplementation with calcium citrate was reported to be more effective than supplementation with equimolar amounts of calcium carbonate (Dossen-Use et al.,
N. Eng. J. Med.,
323:878-83, 1990.) In patients with decreased gastric acid secretion, intestinal calcium absorption was reportedly ten-fold higher when calcium was administrated as a citrate salt as compared to a bicarbonate salt (Recker et. al.,
N. Eng. J. Med.,
313:70-73, 1965.) Despite the higher intestinal absorption of calcium when administered in the form of calcium citrate, the use of calcium citrate actually was reported to decrease the propensity for the crystallization of calcium oxalate in the urine (Harvey et al.,
J. Clin. Endocrin. and Metab.,
61(6):1225-1233.
Calcium citrate is an efficiently absorbable chemical form of calcium. Because of improved absorption of calcium, osteoporosis development is precluded. Citrate is a known inhibitor of calcium stone formation, therefore, the risk of calcium nephrolithiasis (resulting from calcium supplementation) is reduced. An especially dense form of calcium citrate having advantageous properties regarding solubility and bioavailability is ULTRADENSE™ calcium citrate as described in U.S. Pat. Nos. 4,814,177; 4,851,221; and 4,772,467, incorporated by reference herein, and marketed under the tradename CITRACAL®. CITRACAL® with vitamin D is also available.
Accidental overdoses of iron-containing supplements are the most common cause of poisoning death in children under six. The FDA, Consumer Product Safety Commission, and American Association of Poison Control Centers are actively developing new regulations seeking to correct this significant public health issue which has seen the number of reported accidental iron ingestions in children more than double, to over 110,000, in the last decade.
Safety of iron supplements is a significant public health issue. Since 1986 at least 38 children between the ages of 9 months and 3 years have died from accidental ingestion of iron supplement products according to the American Association of Poison Control Centers. Over this same time frame, the FDA has recorded more than 110,000 incidents of pediatric iron overdose, and iron poisoning has become the number one cause of poisoning death in children. Ferrous salts, commonly used in prenatal vitamin preparations, can produce toxic symptoms at ingestion levels as low as 25 mg/kg and significant iron poisoning at levels as low as 60 mg/kg.
Alternatively, elemental iron may be supplied in a supplement as carbonyl iron. The term “carbonyl iron” is from a manufacturing process in which gaseous iron pentacarbonyl is heated under controlled conditions to extremely high temperatures resulting in the deposition of submicroscopic particles of 98% pure elemental iron that aggregate into spheres having a diameter of from about 2-8 microns (average of 5 microns). The importance of the small size is that carbonyl iron particles have very large surface areas since this property varies inversely with the size of a particle. The larger surface area results in higher reactivity of carbonyl iron particles with gastric acid in the stomach and consequently higher absorption rates. Thus, carbonyl iron exhibits 2-5 times higher bioavailability than other elemental iron forms (Sacks and Houchin,
Am. J. Clin. Nutr.
31:566-571, 1978). Studies in laboratory animals and humans show that carbonyl iron is as well absorbed as ferrous sulfate and ferrous fumarate without the attendant risk of iron toxicity. Carbonyl iron has been marketed under the name FERRONYL® IRON.
Within the stomach, carbonyl iron is oxidized to the ferrous form of iron using naturally produced stomach acids. This provides a delayed-release mechanism regulated by the body's own acid secretion. Because of its natural, self-regulated delayed release, carbonyl iron is significantly safer than other ferrous iron salts used in ordinary prenatal vitamins. In animal studies, carbonyl iron had an
Alexandrides George
Wabner Cindy L.
Walsdorf Neill B.
Badio Barbara P.
Fulbright & Jaworski L.L.P.
Mission Pharmacal Company
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