GB2212396A - Dietary supplement comprising calcium and delayed release coated iron - Google Patents

Abstract

A dietary calcium and iron supplement for oral ingestion comprises a nutritionally effective amount of a composition comprising iron, a delayed release coating surrounding said iron composition which delays release of said iron from said coating, and a nutritionally effective amount of a substantially immediate release composition comprising calcium. After the supplement reaches the stomach, the calcium is rapidly available for entry into the small intestine while the release of the iron in the small intestine is delayed for at least one hour after the entry of the calcium into the small intestine. As a result, calcium and iron can be simultaneously delivered without adverse mineral interactions.

Description

CALCfUM/IRON SUPPLEMENT TECHNICAL FIELD This application relates to dietary supplements useful for simultaneous oral ingestion of iron and calcium.

BACKGROUND OF THE INVENTION r Calcium and iron are important minerals in the human diet.

Calcium is the primary mineral in bone. Iron is a key mineral for a number of biologically important proteins, especially hemoglobin in blood. Chronic calcium deficiency can eventually result in the serious bone-loss disease osteoporosis. Failure to include enough iron in the diet can lead to a number of disorders, in particular iron-deficiency anemia.

Individuals who are significantly at risk for calcium and iron deficiencies need to increase their dietary intake of these minerals. Foods rich in calcium and iron can be included in the diet; however, compliance with such a diet is often difficult. Supplements containing these minerals are frequently used to insure adequate dietary intake of calcium and iron.

Certain population groups, in particular premenopausal women, are prone to both calcium and iron deficiencies. Alleviating such deficiencies by concurrently taking calcium and iron can lead to adverse interactions between these minerals. It is known that calcium supplementation can adversely affect iron absorption in animals. Davis, G. K., "Effects of High Calcium Intakes on the Absorption of Other Nutrients." Federation Proceeding, Vol.

18, (December 1959), pp. 1119-1124 discloses reduced iron absorption in the presence of calcium. A decrease in iron absorption due to calcium and iron interaction is also disclosed in Cook, T. D. and E. R. Monsen, "The Effects of Calcium and Phosphate Salts on the Absorption of Non-heme Iron", The American Journal of Clinical Nutrition, Vol. 29, (October 1976), pp. 1142-1148; Barton, J. C., M. E. Conrad, and R. T. Parmley, "Calcium Inhibition of Inorganic Iron Absorption in Rats", Gastroenterology, Vol. 84, (1983), pp. 90-101; and O'Neil-Cutting, M. A.

and W. tl. Crosby, "The Effects of Antacid on the Absorption of Simultaneously Ingested Iron", Journal of the American Medical Association, Vol. 255:11, (March 1986), pp. 1468-1470.

Simultaneous administration of calcium and iron results in decreased iron absorption. The U.S. Recommended Daily Allowance (USRDA) for calcium and iron is 1000 mg/day and 18 mg/day, respectively. Accordingly, a high calcium to iron weight ratio in a caicium/iron dietary supplement is required to meet human nutritional needs. However, a high calcium to iron ratio magnifies the adverse interaction between these minerals. Calcium in large excess interferes with iron absorption in the small intestine, resulting in a substantial decrease in the amount of iron absorbed.

This calcium-iron interaction can be avoided by administering calcium and iron supplements at different times. Taking a calcium supplement at least two hours after an iron supplement avoids the adverse mineral interactions. This time separated dose method is burdensome, however, because the individual must remember when to take the two separate supplements.

Reducing the amount of calcium in the supplement lessens the interference with iron absorption in the intestine. For exam ple, U.S. Patent 4,431,634, Ellenbogen, February 14, 1984, discloses enhanced bioavailability of iron by minimizing the level of calcium and magnesium carbonates and oxides in mineral supplements. However, such a supplement would not provide the USRDA for calcium.

It is known that absorption of iron from the intestine is generally enhanced in the presence of ascorbic acid: Cook, T.

D. and S. R. Lynch, "lnteraction of Vitamin C and Iron", The Annals of the New York Academy of Sciences, Vol. 355, (1980), pp. 32-34; Hungerford, D. M., and M. C. Linder, "Interactions of pH and Ascorbate in Intestinal Iron Absorption", Journal of Nutrition, Vol. 113, (1983), pp. 2615-2622; and Brune, M., L.

Hallberg and L. Rossander, "Effect of Ascorbic Acid on Iron Absorption from Different Types of Meals", Human Nutrition:Ap- plied Nutrition, Vol. 40, (1986) pp. 97-113. U.S. Patent 4,070,488, Davis, January 24, 1978, discloses a nutritive composition containing gelatin, metabolically available iron and ascorbic acid.

Dosage forms having delayed release coatings are known.

Lieberman, H. and L. Lachman, Pharmaceutical Dosage Forms Tablets, Copyright 1982 Marcel Dekker, Inc., New York, N.Y.

Vol. 3, pp. 108-110 discloses methods for making tablets with delayed release coatings. U.S. Patent Nos. 2,811,483, Alterno, Heyner, Leyden and Pindzola, October 29, 1957; 3,279,997, Schneyer, October 18, 1966; 4,079,125, Sipos, March 14, 1978; and 4,309,406, Guley, January 5, 1982; and European Patent Application 0,094,117, Close and Kelm, November 16, 1983, all disclose general delayed release and enterically-coated drug formulations. European Patent Application 0,208,362, Anastasia, Kelm, Smith and Boggs, January 14, 1987, discloses a calcium/iron supplement with enterically-coated calcium to delay entry of the calcium for approximately two hours from the stomach to the intestine.

U.S. Patent 3,975,513, Hecht, Laue and Kirchgebner, August 17, 1976, discloses a tablet wherein the size of the tablet delays its entry into the small intestine from the stomach while the tablet slowly releases a trace element.

While significant effort has been made to provide effective administration of iron and calcium, there is a continuing need for improved products and methods to achieve this end. Therefore, an object of the present invention is to provide a nutritionally effective supplement for oral ingestion comprising both iron and calcium.

A further object of this invention is to provide an iron/calcium supplement where calcium does not significantly inhibit the absorption of iron from the digestive tract.

Another object of this invention is to provide a method for administering calcium and iron concurrently, and additionally providing a nutritionally effective amount of both calcium and iron.

SUMMERY OF THE INVENTION The present invention includes a dietary calcium and iron supplement for oral Ingestion comprising a nutritionally effective amount of a composition comprising iron, a delayed release coating surrounding said iron composition which delays release of said iron from said coating, and a nutritionally effective amount of a substantially immediate release composition comprising calcium.

After the supplement reaches the stomach, the calcium is rapidly available for entry into the small intestine while the release of the iron in the small intestine is delayed for at least one hour after the entry of the calcium into the small intestine.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "pharmaceutically acceptable" or "pharmacologically acceptable" means the ingredients used in the supplements of the present invention are suitable for use by humans or other mammals, without undue toxicity, irritation, allergic response, or the like, commensurate with a reasonable benefit/risk ratio.

The dietary supplement of the present invention comprises: (1) a source of calcium; (2) a source of iron; and (3) a delayed release coating surrounding the iron.

Suitable sources of calcium are those calcium salts which are pharmaceutically acceptable, biologically absorbabie and provide bioavailable calcium. Generally, preferred calcium salts are those which are the most absorbable and bioavailable and which have the densest crystalline forms. Suitable calcium salts include calcium carbonate, calcium bicarbonate, calcium citrate, calcium malate, calcium citrate malate, calcium phosphate, calcium oxide, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium lactate, calcium chloride, calcium hydroxide, calcium sulfate, calcium gluconate, calcium hydroxyapatite, calcium polycarbophil, and mixtures thereof. The calcium salts can be obtained synthetically, from mineral sources, or from animal sources, e.g. oyster shell, bone meal or egg shells.

Preferred calcium salts are calcium carbonate, and mixtures of calcium citrate and calcium malate. A preferred mixture of calcium salts, herein "calcium citrate malate", comprises calcium salts of citric acid and malic acid. The calcium citrate malate may consist of a mixture of calcium citrate and calcium malate, a complex of calcium containing citrate and malate ligands, a mixture of a calcium salt with citric acid and malic acid, or combinations thereof. A preferred calcium citrate malate comprises a complex or a mixture of calcium salts having a ratio of moles citrate to moles malate of from about 1:0.16 to about 1:13.5. A preferred calcium citrate malate for use in the calcium/iron supplement has a molar composition of calcium:citrate:malate of about 6:2:3.

The calcium is included in the supplement in a nutritionally effective amount. As used herein, the term "nutritionally effective amount" with regard to the calcium refers to an amount of calcium sufficient to provide a nutritional benefit to the individual taking the supplement. The particular amount of calcium included in the supplement typically depends upon the calcium composition used and its density (usually determined by its crystalline form), as well as the nutritional benefits desired. Usually, the calcium is included in the supplement at from about 100 to about 1500 mg per unit dose. Preferably, the calcium is included in an amount from about 100 to about 1000 mg per unit dose. The amount of calcium included in the supplement can be a portion or all of the USRDA for calcium.

Iron sources which can be used in the supplement of the present invention are those which are pharmaceutically acceptable, biologically absorbable and provide bioavailable iron. Accordingly, both heme and nonheme iron sources can be used. Generally, suitable iron sources are those iron salts which are water-soluble, especially the ferrous salts. Suitable iron salts include ferrous sulfate, ferrous chloride, ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, ferric ammonium citrate, ferric pyrophosphate, and mixtures thereof. The preferred iron salts are ferrous ascorbate, ferrous sulfate, or ferrous fumarate.

The iron source is included in the supplement in a nutritionally effective amount. As used herein, the term "nutritionally effective amounts with regard to the iron source refers to an amount of iron sufficient to provide nutritional benefits to the individual taking the supplement. The amount of iron included in the supplement will typically depend upon the nutritional needs of the individual. Suitable amounts of iron range from about 1 to about 50 mg per unit dose. Preferred levels of iron range from about 6 to about 25 mg per unit dose. The amount of iron included in the supplement can be a portion or all of the USRDA for iron.

The suppiements of the present invention are particularly suitable for simultaneously delivering high weight ratios of calcium to iron. Typically, the weight ratio of calcium to iron in the supplements of the present invention is from about 10:1 to about 150:1. Preferably, the weight ratio of calcium to iron is from about 20:1 to about 90:1, with most preferred being the USRDA ratio of about 56:1.

As used herein, the term "delayed release coating" refers to a pharmaceutically acceptable coating which at least substantially prevents the release of the iron for absorption for at least about one hour after the release of calcium for absorption in the small intestine. As used herein, "substantially prevents" means that preferably greater than about 90% of the iron source has not been dissolved within an hour after the release of the calcium. (It is to be understood that the term "substantially prevents" can include situations where more than 108 of the iron source is dissolved, so long as the undesirable inhibition of the absorption of iron is avoided.) Preferred delayed release coatings fall into four categories: (1) pH-sensitive; (2) enzyme-sensitive; (3) diffusion; and (4) slowly soluble.

Providing a coating that will delay release of the iron source for at least about one hour is well within the purview of an artisan skilled in the art of dosage form development, and can be achieved in a variety of ways. Methods of achieving such coatings are described in Lieberman, H. A. and L. Lachman, Pharmaceutical Dosage Forms - Tablets, Vols. I-Ill, Copyright 1982, Marcel Dekker, Inc., and Lachman, L., H. A. Lieberman and T.

L. Kanig, The Theory and Practice of Industrial Pharmacy, 3rd Ed., Copyright 1986, Lea and Febiger, which are both hereby incorporated by reference in their entirety.

pH sensitive and enzyme sensitive delayed release coatings involve coating the center or core composition in a polymeric material. The dissolution rate of the polymer dictates the release of the core. By varying the coating thickness or layering concentric spheres of coating material over the core composition, different release time (or repeat action) forms can be produced.

Once the polymer has dissolved, all of the composition in the core is available for dissolution and absorption. Alternatively, the dissolution may involve an exterior coating where a portion of a composition is placed in the tablet coat and dissolves rapidly while the interior core provides controlled release of its contents.

In diffusion coatings the area and thickness of the coating are important parameters. They take on added importance because the dissolving fluid and the core composition must pass through the barrier represented by the film or coating before being available for absorption.

Slowly soluble coatings may utilize a combination of dissolution and diffusion to delay release of a composition. Gradual erosion of the coating, aided by pH and enzymatic hydrolysis of the fatty acid esters, causes slow release. The coating may contain a portion of the dose of one composition for quick release upon hydrolysis with subsequent slow release from erosion of the core composition.

The pH-sensitive delayed release coatings are referred to in the present application as "enteric coatings" and include any pharmaceutically acceptable coating insoluble at a pH in the range of from about 1 to about 3 while being soluble at a pH in the range of from about 4.5 to about 8.0. Suitable enteric coating materials include hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, acrylic and methacrylic anionic polymers (such as those available from Rohm GmbH, Darmstadt, West Germany, under the trade name EUDRAG IT L and S), and polyvinyl acetyl phthalate, as well as mixtures of these materials. A preferred enteric material is hydroxypropyl methylcellulose phthalate.Examples of optional components suitable for inclusion in the enteric coating are surface active agents, inert solids such as talc, and plasticizers such as triethyl citrate, triacetin, triglycerides and acetylated monog lycerides. The enteric coating composition and thickness is adjusted so that the iron composition of the calciumliron supplement is released about one hour or more after ingestion of the supplement.

The enzyme-sensitive delayed release coatings are referred to in the present application as "enteral enzyme degradable coatings" and refer to any pharmaceutically acceptable coatings which remain substantially intact in the stomach but which are degraded by enzymes in the small intestine. Suitable enteral enzyme degradable coating materials include lipids, such as naturally occurring fats and oils, as well as protein materials such as zein and albumin. Other suitable lipids include glyceryl tristearate, glyceryl tripalmitate, monopalmityl distearyl triglyceride, dipalmityl monostearyl triglyceride, sorbitan tristearate, hexaglycerol hexapalmitate, hexaglycerol hexastearate, decaglycerol decapalmitate, decaglycerol decastearate, and mixtures thereof.As with the enteric coatings, optional components such as plasticizers and binders can be included in the enteral enzyme degradable coatings.

As used herein, the term "diffusion coating" refers to any pharmaceutically acceptable coating which remains intact in the gastrointestinal tract, but permits the diffusion of digestive fluids to dissolve the iron. Suitable diffusion coating materials include ethyl cellulose, cellulose acetate, and quaternary ammonium substituted acrylic resins (such as those available from Rohm GmbH, Darmstadt, West Germany, under the trade names EUDRAGIT RL and RS). As with the enteric and enzyme degradable coatings, optional components such as plasticizers and soluble materials to enhance diffusion can be included in the diffusion coatings.

As used herein, the term "slowly soluble coating" refers to any pharmaceutically acceptable coating having a dissolution rate in digestive fluids which is such that the iron composition is not substantially released until at least about one hour after the release of the calcium. The slowly soluble coating composition and thickness are adjusted so that the iron is released about 1 hour or more after ingestion of the supplement. Suitable materials for slowly soluble coatings include polyethylene glycols, glycerol monostearate and beeswax.

The delayed release coating material is used in an amount sufficient to adequately surround the iron and prevent inhibition of the biological absorption of the iron by the calcium. The amount of delayed release material necessary to provide an adequate coating is highly dependent on the coating used and the surface area of the iron source which needs to be surrounded.

(The surface area of the iron source is highly dependent on the amount used as well as its form.) For tablet products, the amount of delayed release coating material necessary is typically from about 1 to about 20% by weight of the iron and preferably from about 5 to about 15% by weight of the iron. For capsule products, the amount of delayed release coating material necessary is typically from about 2 to about 25% by weight of the iron composition, and preferably from about 5 to about 15% by weight of the iron composition.

The iron is positioned in the supplement so that the delayed release coating can substantially prevent the calcium from inhibiting the biological absorption of iron. This usually means placing the iron out of contact with the calcium. For example, the coated iron can be formulated as a discrete component from the calcium. Typically, the calcium is adhered to the exterior surface of the delayed release coating.

A preferred dosage unit form of the present invention to ensure at least one hour delay between calcium and iron entry into the small intestine has the iron composition of a size of greater than about 1-2 mm. Particles of a size less than 1-2 mm generally pass directly from the stomach into the small intestine.

By maintaining a size of greater than about 1-2 mm for the iron and its surrounding coating, entry of iron into the small intestine is delayed until the next peristaltic or "housekeeper" wave in the stomach which occurs 2-3 hours after each meai. Therefore, the iron composition preferably consists of particles greater than about 1 mm in size, more preferably greater than about 1.5 mm in size, more preferably still from about 2 to about 4 mm in size, most preferably about 3 mm in size. In a preferred dosage form of the present invention, the calcium is preferably a composition which is rapidly soluble or disintegrable into small particles in acidic media so that the calcium rapidly dissolves or disperses as fine particles in the stomach fluid and passes rapidly into the small intestine where it is absorbed.The iron composition greater than about 1-2 mm in size, has a delayed release coating, (preferably an enteric coating), which prevents dissolution or dispersion of the iron in the stomach fluid. The iron composition is prevented from passing into the small intestine until the next peristaltic wave due to its size, and the iron is prevented from dissolving or dispersing in the stomach fluid by the enteric coating. Once the iron composition passes into the small intestine with the next peristaltic wave, the enteric coating dissolves or disintegrates thus releasing the iron which dissolves in the intestinal fluid and is absorbed. Since absorption of iron is most efficient in the duodenum, an enteric coating which releases the iron rapidly when the iron composition reaches the duodenum is preferred.

An iron absorption enhancer may be incorporated with the iron to enhance iron absorption after calcium absorption has occurred in the small intestine. Ascorbic acid is a preferred iron absorption enhancer. Other preferred enhancers of iron absorption include cysteine or glutathione. The typical iron portion of the tablet consists of an iron salt of sufficient quantity to provide a USRDA equivalent of elemental iron and ascorbic acid such that the molar ratio of ascorbic acid to elemental iron is 1:1 (i.e., 1 mg elemental iron to 3.154 mg ascorbic acid).

Other optional ingredients typically included in dietary supplements can be incorporated in the present invention. For example, vitamins and other minerals can be included in the calciumliron supplement. Suitable vitamins include A, D, E, C, B1 , B2 , 12' niacin, folic acid, thiamine, biotin and riboflavin.

Other minerals which can be included in the supplement include zinc, potassium, magnesium, manganese and copper. Those vitamins and minerals which adversely interact with calcium should be positioned in the supplement so that the delayed release coating can substantially prevent the calcium from interacting with them.

The calcium/iron supplement is administered by the oral route in a variety of pharmaceutical formulations, each with inherent advantages. Preferred dosage unit forms of the supplement include tablets, capsules, lozenges, and suspensions. Each preferred dosage form utilizes pharmaceutical carriers preferably to aid in the delivery and/or absorption of the calcium/iron supplement.

As used herein, the term "pharmaceutical carrier" denotes a solid or liquid filler, diluent, or encapsulating substance. Some exampies of the substances which can serve as pharmaceutical carriers are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as microcrystalline cellulose, sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulphate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of thiobroma; polyols, such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic salines; and phosphate buffer solutions; as well as other nontoxic compatible substances used in pharmaceutical formulations. Wetting agents and lubricants, such as sodium lauryl sulphate, as well as coloring agents, flavoring agents and preservatives, can also be present.

Solid dosage forms may be prepared by compression or molding of the calcium/iron supplement with or without suitable diluents, binders, disintegrants, lubricants, coatings, colorants and other pharmaceutical carriers. A tabletting excipient may be required if the mixture of the mineral source and other ingredients, if any, does not possess appropriate compressibility and flowability to be compressed, or appropriate disintegration or dissolution properties once compressed. Excipients to aid in compressibility and flowability may include, for example, lactose USP, lactose spray-dried USP, directly compressible starches, hydrolyzed starches, microcrystalline cellulose NF, other cellulose derivatives, mannitol USP, dextrose, etc.Binders may include, for example, starch paste, sodium alginate and alginate derivatives, acacia, cellulose derivatives, gelatin, polyvinylpyrrolidone (PVP), and others. Disintegrants may include, for example, starch, starch derivatives, clays, cellulose, alginates, polyvinylpyrrolidone cross-linked, etc. Lubricants may include, for example, stearic acid, stearic acid salts, etc.

Capsules are solid dosage forms in which the calcium/iron supplement and appropriate pharmaceutical carriers are enclosed in a shell which is, for example, composed of gelatin. Generally, hard gelatin capsules are used to encapsulate solid materials as dry powders, granules or pelletized materials. Soft gelatin capsules may encapsulate liquids, solids and solids in suspension, a "suspension" herein defined as a preparation in which the calcium/iron supplement is finely divided and held throughout a suitable pharmaceutical carrier vehicle. The iron in the calcium/iron supplement may be coated with a delayed release coat or incorporated with an iron enhancer such as ascorbic acid and coated with a delayed release coat. The calcium can either be unbound to the coated iron or applied directly to the exterior of the coated iron.The calcium/iron supplement may be encapsulated with any dilutents, lubricants or other inert excipients to fill the capsule. A suspension containing the calcium/iron supplement may also be dosed orally to directly reach the gastrointestinal tract for absorption.

The pharmaceutical carriers employed in conjunction with the calcium/iron supplement are used at a concentration sufficient to provide a practical size-to-dosage relationship. Preferably, the pharmaceutical carrier comprises from about 0.1% to about 99% by weight of the total composition.

The following, non-limiting Examples illustrate possible embodiments of the present invention.

EXAMPLE 1 Calcium/Iron Tablets A nutritional supplement comprising calcium and iron in tablet form is described below.

A. IRON-TABLET PORTION Ingredient Weight Weight (per 10,000 (per tablet) tablet batch) Ferrous Fumarate (32.87t Fe) (TOLERON TAC - Mallinckrodt 27.4 mg 274 g Chemical Works, St. Louis, Missouri) Ascorbic Acid, USP 28.4 mg 284 g Sodium Starch Glycolate 3.5 mg 35 g (EXPLOTAB - Edward Mendell Co., Inc., Carmel, New York) Magnesium Stearate, USP 0.3 mg 3 g Microcrystalline Cellulose 30.0 mg 300 g (AVICEL PH 102 - FMC Corp., Philadelphia, Pennsylvania) 89.6 mg 896 g A 10,000 tablet batch is prepared by adding weighed ascorbic acid, sodium starch glycolate, and magnesium stearate to the ferrous fumarate, and passing the composite of these components through a 20 mesh screen to break up any particle agglomerates.

The microcrystalline cellulose and the composite are mixed for 5 minutes in an appropriately sized (approximately 1 quart) Patterson-Kelley V-blender (Patterson-Kelley Company, Division of Harsco Corporation, East Stroudsburg, Pennsylvania). The mixture is then compressed, approximately 89.6 mg of the mixture at a time, using 1/8 or 3/16 in. diameter, flat-faced punch/die sets, on a Stokes Rotary Tablet Press, Model 511.6 (Sharples Stokes, Division of Pennwalt Corporation, Philadelphia, Pennsylvania).

B. ENTERIC COATING Weight (per Ingredient Weight % 2000 g Solution) Hydroxypropyl Methylcellulose Phthalate NF (HPMCP, Grade HP-50, Shin-Etsu Chemical Co., Ltd., Tokyo, Japan) 6% 120 g Acetone/Water Solution (95 parts acetone to 1 part water) 94% 1880 g 100% 2000 g A minimum of 2000 g of the above solution is prepared to coat a 10,000 iron tablet batch by dissolving the 120 g of the HMCP in 1880 g of the acetone/water solution. The iron/ascorbic acid tablets are then coated using a pan coating apparatus (Freund Hi-Coater, Vector Corporation, Marion, lowa). The coating solution is sprayed at a low rate, initially, to minimize hydrating the tablets.The inlet air temperature and flow are adjusted to maintain outlet temperature at about 300C and coat the tablets to approximately 10% solid (dry) weight gain. The weight is then determined by turning off the coater, removing the tablets, and weighing periodically.

C. CALCIUM TABLET PORTION Weight Weight (per 10,000 Ingredient (per tablet) tablet batch) Calcium Citrate Malate (6:2:3)* 1087 mg 10870 g (based on 23% Ca assay) Magnesium Stearate,- USP 3 mg 30 g 1090 mg 10900 g *(Made by dissolving 2 moles citric acid and 3 moles malic acid in water, heating, and adding 6 moles calcium carbonate in the form of a slurry of heated calcium carbonate and water while slowly stirring. A cake precipitate of calcium citrate malate is formed and then dried).

A 10,000 tablet batch is prepared by weighing and passing the calcium citrate malate material through a 10 mesh screen.

The magnesium stearate is then weighed and passed through a 30 mesh screen. The materials are mixed for five minutes with an appropriately sized (approximate 2 cu. ft.) Patterson-Kelley V-blender, and the enterically coated iron tablet is compressed within the calcium blend, utilizing the technique illustrated in U.S. Patent 3,096,248,, incorporated by reference herein in its entirety.

D. FILM COATING THE CALCIUM/IRON TABLET Weight (per Ingredient Weight s6 2600 g solution) Hydroxypropyl Methylcellulose (HPMC 6 cps) 10% 260 9 Polyethylene Glycol 3350 18 26 g White Pigment Solids (Opaspray White, Colorcon Formula M-1-7111-b, 338 pigment solids, - Colorcon, West Point, Pennsylvania) 10% 260 g Water (Distilled Water for 79% 2054 g Injection) 100% 2600 g A minimum of 2600 g of the above solution is prepared to coat a 10,000 tablet batch by suspending the HPMC in water and mixing until all the polymer is dispersed and no large lumps are visible. The polyethylene glycol is added to the polymer suspension and mixed for 20 minutes. The solution is then refrigerated for at least 10 hours at 3-100C.

The color concentrate suspension is mixed with a high shear mixer for 15 minutes; then the color concentrate suspension is added to the polymer solution and mixed for 20 minutes. Finally, the tablets are coated to 2-3% solids content (dry weight gain) using a suitable pan type coating apparatus (Freund Hi-Coater, Vector Corporation). The coating solution is sprayed at a low rate, initially, to minimize hydrating the tablets, maintaining the outlet temperature of the coater at about 40-500C. The tablets are packaged in clean moisture-free containers after the coating is completed to minimize hydration of tablets.

EXAMPLE li Calcium/lron Capsule A nutritional supplement comprising calcium and iron in capsule form is described below.

A. IRON - ASCORBIC ACID PELLETS Weight Weight (per 1,000 Ingredient (per capsule) capsule batch) Ferrous Fumarate (32.87% Fe) (TOLERON TAC) 27.4 mg 27.4 g Ascorbic Acid, USP 28.4 mg 28.4 g Microcrystalline Cellulose (AVICEL PH 102) 27.4 mg 27.4 g Methanol/Water(1:1) 55.2 1) 55.2 mg 55.2 g 138.4 mg 138.4 g A 1 ,000 capsule batch is prepared by making a paste by adding the methanol and water to the ferrous fumarate, dscorbic acid and microcrystalline cellulose and mixing. The paste is passed through a 10 mesh (2mm) screen, making pellets of about 2mm in size. Smaller sized pellets are screened out using a sieve. The pellets are dried in an oven at approximately 500C.

The particles are then coated with the same enteric coating formulation as in Example 1, using a Wurster fluidized bed coater.

The outlet air temperature is maintained at approximately 400C and the pellets are coated to approximately 4-626 solids content.

B. CAPSULE FILLING A 1000 capsule batch is prepared utilizing 1087 g of calcium citrate malate and 3 g of magnesium stearate. The calcium citrate malate and magnesium stearate are mixed with the enteric coated iron pellets in the proportion of nine (9) parts (by weight) of the calciumimagnesium stearate to one (1) part (by weight) of the enteric coated iron pellets, for five minutes, using an appropriately sized V-blender (Patterson-Kelley 2 quart V-blender). The blend is then loaded into appropriately sized capsules (#0), following the method for the specific capsule filling machine used (Parke Davis Model 8, Parke Davis and Company, Detroit,- Michi gan).

The present invention also relates to a method for concurrently administering dietary calcium and iron to mammals comprising the steps of orally administering a supplement comprising: (a) a nutritionally effective amount of a composition com prising iron surrounded by a delayed release coating which delays release of said iron from said coating; and (b) a nutritionally effective amount of a substantially imme diate release composition comprising calcium; whereby, after said supplement reaches the stomach said calcium is rapidly available for entry into the small intestine, while the release of said iron into the small intestine is delayed for at least one hour after entry of the calcium into the small intestine. The iron is positioned so that the delayed release coating substantially prevents the calcium from inhibiting biological absorption of the iron.

As used herein, the term "concurrent administration" refers to the administration of the calcium source and iron source simultaneously or substantially simultaneously, e.g., within a few minutes of each other.

While particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications to the compounds and compositions disclosed herein can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.

WHAT IS CLAIMED IS:

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (19)

**WARNING** start of CLMS field may overlap end of DESC **. blend is then loaded into appropriately sized capsules (#0), following the method for the specific capsule filling machine used (Parke Davis Model 8, Parke Davis and Company, Detroit,- Michi gan). The present invention also relates to a method for concurrently administering dietary calcium and iron to mammals comprising the steps of orally administering a supplement comprising: (a) a nutritionally effective amount of a composition com prising iron surrounded by a delayed release coating which delays release of said iron from said coating; and (b) a nutritionally effective amount of a substantially imme diate release composition comprising calcium; whereby, after said supplement reaches the stomach said calcium is rapidly available for entry into the small intestine, while the release of said iron into the small intestine is delayed for at least one hour after entry of the calcium into the small intestine. The iron is positioned so that the delayed release coating substantially prevents the calcium from inhibiting biological absorption of the iron. As used herein, the term "concurrent administration" refers to the administration of the calcium source and iron source simultaneously or substantially simultaneously, e.g., within a few minutes of each other. While particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications to the compounds and compositions disclosed herein can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention. WHAT IS CLAIMED IS:

1. A dietary calcium and iron supplement for oral ingestion comprising: (a) a nutritionally effective amount of a composition com prising iron; (b) a delayed release coating surrounding said iron compo sition which delays release of said iron from said coat ing; and (c) a nutritionally effective amount of a substantially imme diate release composition comprising calcium; whereby, after said supplement reaches the stomach said calcium is rapidly available for entry into the small intestine, while the release of said iron in the small intestine is delayed for at least one hour after the entry of the calcium into the small intestine.

2. The supplement of Claim 1 wherein said calcium composition comprises a calcium salt selected from the group consisting of calcium carbonate, calcium bicarbonate, calcium citrate, calcium malate, calcium citrate malate, calcium phosphate, calcium oxide, calcium hydrogen phosphate, calcium dihydrogen phosphate, calcium lactate, calcium chloride, calcium hydroxide, calcium sulfate, calcium gluconate, calcium hydroxyapatite, calcium polycarbophil and mixtures thereof.

3. The supplement of Claim 2 wherein said calcium salt consists of calcium carbonate.

4. The supplement of Claim 2 wherein said calcium salt consists of calcium citrate malate.

5. The supplement of Claim 1 wherein said iron composition comprises an iron salt selected from the group consisting of ferrous sulfate, ferrous chloride, ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, ferric ammonium citrate, ferric pyrophosphate, ferrous ascorbate, and mixtures thereof.

6. The supplement of Claim 5 wherein said iron salt is selected from the group consisting of ferrous sulfate and ferrous fumarate.

7. The supplement of Claim 1 wherein said delayed release coating is selected from the group consisting of enteric coatings, enteral enzyme degradable coatings, diffusion coatings and slowly soluble coatings.

8. The supplement of Claim l wherein said delayed release coating comprises an enteric coating.

9. The supplement of Claim 1 wherein said calcium composition comprises a calcium salt selected from the group consisting of calcium carbonate and calcium citrate malate; said iron composition comprises an iron salt selected from the group consisting of ferrous sulfate and ferrous fumarate; and said delayed release coating is an enteric coating.

10. The supplement of Claim 1 wherein said iron composition also comprises an iron absorption enhancer.

11. The supplement of Claim 9 wherein said iron composition also comprises an iron absorption enhancer comprising ascorbic acid.

12. The supplement of Claim 1 wherein said calcium composition is rapidly soluble or disintegrable in the stomach fluid, and wherein said iron composition is one or more coated particles of a size large enough to delay the passage of said iron composition from the stomach into the small intestine until a peristaltic wave occurs.

13. The supplement of Claim 12 wherein said iron composition consists of particles which are from about 1 mm to about 4 mm in size.

14. The supplement of Claim 12 wherein said supplement comprises a capsule wherein said calcium composition comprises a calcium salt selected from the group consisting of calcium carbonate and calcium citrate malate; said iron composition comprises an iron salt selected from the group consisting of ferrous sulfate and ferrous fumarate; and said delayed release coating is an enteric coating.

15. The supplement of Claim 12 wherein said supplement comprises a tablet wherein said iron composition is a coated tablet covered by said calcium composition.

16. The supplement of Claim 15 wherein said calcium composition comprises a calcium salt selected from the group consisting of calcium carbonate and calcium citrate malate; said iron composition comprises an iron salt selected from the group consisting of ferrous sulfate and ferrous fumarate; and said delayed release coating is an enteric coating.

17. A dietary calcium and iron supplement for oral ingestion comprising: (a) a nutritionally effective amount of an iron composition from about 2 mm to about 3 mm in size comprising ferrous fumerate and ascorbic acid; (b) an enteric coating comprising hydroxypropyl methyl cellulose surrounding said iron composition which delays release of said iron from said coating; and (c) a nutritionally effective amount of a composition com prising calcium citrate malate in a 6:2:3 molar ratio, which is rapidly soluble or disintegrable in stomach fluid; whereby said composition comprising calcium citrate malate is rapidly available for entry into the small intestine after reaching the stomach, while said enteric coated iron composition is delayed in the stomach until the next peristaltic wave which carries it into the small intestine.

18. A method for concurrently administering dietary calcium and iron to mammals comprising the steps of orally administering a supplement comprising: (a) a nutritionally effective amount of a composition com prising iron surrounded by a delayed release coating which delays release of said iron from said coating; and (b) a nutritionally effective amount of a substantially imme diate release composition comprising calcium; whereby, after said supplement reaches the stomach said calcium is rapidly available for entry into the small intestine, while the release of said iron into the small intestine is delayed for at least one hour after entry of the calcium into the small intestine.

19. The method of Claim 18 wherein said calcium composition comprises a calcium salt selected from the group consisting of calcium carbonate and calcium citrate malate; said iron composition comprises asoortic acid and an iron salt selected from the group consisting of ferrous sulfate and ferrous furnarate; and said delayed release coating comprises an enteric coating.