WO1986004815A2

WO1986004815A2 - Liquid dietary calcium supplementation

Info

Publication number: WO1986004815A2
Application number: PCT/US1986/000314
Authority: WO
Inventors: Charles Y. C. Pak
Original assignee: Board Of Regents, The University Of Texas System
Priority date: 1985-02-19
Filing date: 1986-02-19
Publication date: 1986-08-28
Also published as: EP0213181A1; JPS62501843A; DK497386A; AU576950B2; WO1986004815A3; JPS62501846A; AU5458786A; DK497386D0

Abstract

A process for dietary calcium supplementation. Oral dosage of a liquid or solid composition comprising calcium, in a form adapted to provide absorbable calcium ions in the intestine, and citrate, in a form adapted to provide absorbable citrate ions in the intestine is utilized to efficiently supply calcium while minimizing the occurrence of calcium nephrolithiasis. Calcium citrate, a preferred component of the composition may be replaced by various combinations of calcium salts and citric acid or citrate salts. The precluding of osteoporosis development and prevention or alleviation of calcium-repressible hypertension are accomplished by practice of the present invention.

Description

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LIQUID DIETARY CALCIUM SUPPLEMENTATION

Research leading to development of the present inven- tion was supported in part by grants P01-AM20543 and P01- AM16061 from the National Institutes of Health, Department of Health and Human Services, United States of America.

The mineral is an important human dietary component. Calcium is required for adequate bone formation and maintenance, as well as for diverse metabolic functions. These diverse metabolic functions of calcium are incom¬ pletely understood but likely to involve, at least in part, the alteration and functional. control of proteins such as enzymes.

An assurance of adequate dietary calcium intake is thus important for normal development, metabolism and maintenance. Dietary calcium intake alone however is insufficient to assure that adequate calcium levels are available for required body functions. Dietary calcium must be absorbed from the digestive tract before it may be utilized. Furthermore, the urinary excretion of absorbed calcium must be considered, particularly for individuals who may be subject to the formation of calcium-containing kidney stones. The intestinal absorption of calcium is enhanced by vitamin D and may also be affected by the particular chem¬ ical form of ingested calcium.

Among the conditions of particular relevance to cal¬ cium" dietary requirements is osteoporosis. Osteoporosis, a condition characterized by decreases in bone mass, ren¬ ders bones more fragile and susceptible to fracture. The increasingly older population of this country, since osteoporosis is usually an age-related phenomenon, further accentuates the significance of this condition. Post- menopausal women are generally agreed to be most suscep¬ tible to osteoporosis. As demonstrated by Heaney et al (J. Lab. Clin. Med. (1978) Vol. 92 No. 6 pp. 953 to 963), postmenopausal women, unless treated with estrogens, required an increased calcium intake to maintain a zero calcium balance. This increased required intake was ascribed as due to a decrease in the production of an active vitamin D compound and calcium absorption, both perhaps related to the absence of estrogens. Recker et al (Annals Int. Med. (1977) Vol. 87 No. 6 pp. 649 to 655) demonstrated that further bone losses in osteoporosis prone postmenopausal women ^'may be prevented by estrogen treatment or, to a lesser extent, by dietary calcium car- bonate supplementation.

In an additional study concerning osteoporosis of postmenopausal women, Nordin et al (Brit. Med. J. (1980) Vol. 280 pp. 451 to 454) found three treatments that succ- eeded in lessening or abolishing further bone deterior¬ ation. These three treatments were: dietary calcium sup¬ plementation; estrogenic hormone treatment; and, treatment with estrogenic hormone plus 1 alpha hydroxy vitamin D, .

Treatment of individuals with estrogenic hormones may have adverse effects, such as the stimulation of estrogen- dependent tumors. Treatment of individuals with vitamin D derivatives may be inadvisable because of potentially toxic effects when excess vitamin D is administered. An effective dietary calcium supplementation appears to be an advisable treatment for osteoporosis.

In certain individuals however, dietary calcium sup¬ plementation may increase urinary calcium and lead to formation of calcium-containing kidney stones (nephro- lithiasis) .

Kidney stone formation may result from a number of conditions, one of which is the presence of undue amounts of calcium in urine. Pak et al (N. Eng. J. Med. (1974) Vol. 290 pp. 175 to 180) have shown that urinary calcium levels and renal calcium stone formation are decreased when patients with a history of recurrent calcium nephro- lithiasis are fed low calcium diets and treated orally with cellulose phosphate. Pak (Urolithiasis Research (1976) ed. by H. Fleisch et al, Plenum Pub. Co., N.Y. ,

N.Y. pp. 213 to 224) demonstrated that' when patients with absorptive hypercalciuria are fed calcium gluconate, they exhibited increased urinary calcium, leading to an increased activity product ratio, a measure of the degree of urinary calcium oxalate saturation. Thus, calcium supplementation made them more prone to form kidney stones, since their urine became more supersaturated with respect to a common stone salt (calcium oxalate) .

The interrelation of calcium and hypertension has been the focus of much recent research. McCarron et al (Science (1982) Vol. 217 pp. 257 to 269) found that sub¬ jects with essential hypertension had a lower daily cal¬ cium intake (668 _+ ^'55 mg) than that (886 _ 89 mg) of nor- motensive subjects. McCarron (N. Eng. J. Med. (1982) Vol. 307 pp. 226 to 228) indicated that while normotensive sub- jects and hypertensive subjects had similar serum levels of total calcium, the hypertensive subjects had lower serum levels of ionized calcium. Ackley et al (Am. J. Clin. Nutr. (1983) Vol. 38 pp. 457 to 461) reported finding that hypertensive men consumed significantly less milk_., a major source of dietary calcium, than did normo- tensive men.

Belizan et al (J. Am. Med. Ass'n. (1983) Vol. 249 No. 9 pp. 1161 to 1165) indicated that young adults showed re¬ duction in blood pressure when their diets were supple¬ mented with 1 gm/day elemental calcium (calcium carbonate and calcium lactate-gluconate) . A similar observation was made with pregnant women (Belizan et al Am. J. Obstet. Gynecol (1983) Vol. 146 No. 2 pp. 175 to 180). Currently, a possibility exists that adequate calcium intake may be an important factor in control of blood pressure. Additionally, it has been proposed that the incidence of colon cancer may be lessened by increases in dietary calcium intake.

Chronic diarrheal syndrome, where bone loss may occur, also sometimes involves calcium nephrolithiasis. This syndrome may result from surgical resection or inflammation of the digestive tract. Bone disease may occur because patients with this condition absorb calcium poorly from intestines. Kidney stones may develop from different causes including concentrated urine, undue acidity of urine and low urinary citrate. While these patients require calcium supplements for prevention of bone loss, they face the danger of forming more kidney stones when they take more calcium.

Supplementation of the diet with calcium appears to be an important step for control of adverse conditions including osteoporosis, bone loss in chronic diarrheal syndrome, possibly hypertension and colon cancer. Such calcium supplementation however, may cause undesirable effects, particularly nephrolithiasis.

Dietary calcium supplementation is generally agreed as most effective when the calcium is efficiently absorbed from the digestive tract. Thus a method of providing efficiently absorbed calcium while inhibiting calcium nephrolithiasis is needed.

Dietary calcium supplementation without induction or enhancement of nephrolithiasis is accomplished by the daily supplementation of an individual's diet with a pharmaceutically acceptable composition comprising between about 0.5 gm and about 2.0 gm calcium. The pharmaceutic¬ ally acceptable composition comprises calcium in a chemical form adaptable to provide gastrointestinally absorbable calcium ions, said chemical form consisting essentially of at least one of: calcium carbonate, calcium chloride, calcium acetate, calcium fumarate, calcium gluconate, calcium glucobionate, calcium lactate, calcium malate, calcium oxide, calcium succinate, calcium tartrate, calcium hydroxide or calcium citrate; and citrate in a chemical form adapted to provide gastro- intestinally absorbable citrate ions, said chemical form consisting essentially of at least one of: citric acid, potassium salts of citric acid, ammonium salts of ci^'tric acid, magnesium salts of citric acid or calcium salts of citric acid, the calcium and citrate forms being in a molar ratio of about 1 to 2 to about 2 to 1. When in liquid form, the 'calcium to citrate ratio is between about 1 to 1 and about 1 to 7.

The present invention comprises processes for dietary calcium supplementation while lessening the likelihood of calcium-based kidney stone formation. Such calcium supplementation is particularly desirable for preventing or halting osteoporotic development. In addition, the processes of the present invention comprise the use of a form of calcium efficiently absorbed from the digestive tract.

A preferred form of calcium as well as citrate util¬ ized in processes of the present invention involving solid consists essentially of calcium citrate, (tricalcium dicitrate) illustrated by the formula:

O OH 0

II I it

Ca -+,(.-OC-CH,-C-CH_-CO ).

C = 0 0

or the hydrate thereof. The term "calcium:citrate" as used herein is defined as being any salt form of calcium with citrate. Combinations, however, such as those consisting essentially of calcium carbonate and potassium citrate or citric acid, for example, may be utilized to provide concomitant quantities of calcium and citrate in the intestine which may equilibrate therein to form calcium ions and citrate ions, in net effect this being essentially equivalent to calcium citrate. The calcium and citrate ions thus administered may be gastro- intestinally absorbed. The pharmaceutically acceptable compositions of the present invention include compounds or combinations of compounds without major amounts of sodium which may provide an intestinal supply of calcium, particularly in gastrointestinally absorbable form, and citrate, particularly in gastrointestinally absorbable form. When a liquid form calcium supplement is preferred, a most readily dissolvable calcium:citrate is a slurry or paste where water is combined with calcium:citrate, the calcium and citrate being in a ratio between about 1:1 and about 1:7.

Although calcium citrate itself is a preferred compound for administration of calcium and citrate, many combinations of calcium chemical forms and citrate chemical forms are viewed, when used in combination, as the functional equivalent of calcium citrate.

Chemical forms of calcium other than calcium:citrate utilizable in the composition of the present invention to provide an intestinal supply of gastrointestinally ab¬ sorbable calcium include those consisting essentially of calcium carbonate, calcium chloride, calcium acetate, cal- cium fumarate, calcium gluconate, calcium glucobionate, calcium lactate, calcium malate, calcium oxide, calcium succinate, calcium^' hydroxide ,and calcium tartrate, alone or in combination, anhydrous or hydrated.

Chemical forms of citrate other than calcium:citrate utilizable in the composition of the present invention to provide an intestinal supply of absorbable citrate include those consisting essentially of citric acid, potassium salts of citric acid, ammonium salts of citric acid, and magnesium salts of citric acid, in anhydrous or hydrated conditions, alone or in combination.

When separate calcium chemical solid forms and citrate chemical solid forms are concomitantly utilized instead of the combination form, calcium citrate, the molar ratio of calcium chemical form to citrate chemical form contained in the composition is preferably between about 1 to 2 and about 2 to 1. A particularly preferred concomitant mixture is one consisting essentially of calcium carbonate and potassium citrate in about a 1 to 1 molar ratio. Sodium should be avoided as a major ingredient of the present invention, particularly as a salt of citric acid, and a potassium salt of citric acid is analogously pre¬ ferred. Ammonium and metals besides sodium and potassium available as citrate salt components such as magnesium or calcium are generally known to be free of negative dietary effects although magnesium citrate may, at certain levels, have a laxative effect.

When normal subjects were given equivalent amounts of calcium as either calcium:citrate or calcium carbonate and their extents of calcium absorption measured, calcium was more efficiently absorbed with calcium citrate. It has further been found that calcium citrate dietary ad- ministration raises urinary pH, calcium content and citrate content while lowering ammonium content. When equivalent, levels of calcium carbonate were administered,

•» urinary calcium content similarly increased but other changes (pH and citrate levels) seen with calcium citrate administration did not occur. The rises in urinary pH and citrate are important because they provide protection against the formation of calcium nephrolithiasis. Thus, the stone-producing tendency of calcium supplements (from an increase in urinary calcium) is overcome when calcium citrate is given, because of this protective action.

Because it assures optimal calcium absorption without increasing the risk of nephrolithiasis, dietary calcium supplementation by oral administration of a composition consisting essentially of calcium:citrate is a desirable method of inhibiting osteoporosis and bone loss, of aiding in the control of blood pressure and of supplying adequate calcium levels for alleviation of any condition responsive thereto. Particular types of individuals are likely to opti¬ mally benefit from the dietary calcium supplementation according to methods of the present invention. These par¬ ticular individuals include, for example, those at risk for osteoporosis. Generally the older population, partic¬ ularly those often regarded as aged, or well beyond the age of retirement, are mere apt than most to incur at least a degree of osteoporosis, particularly if their calcium intake is inadequate. Postmenopausal women, particularly at risk for osteoporosis, are likely to be beneficiaries as subjects of dietary calcium supplementa¬ tion by the process of the present invention. In cases where a degree of osteoporosis has already occurred in a subject, dietary calcium supplementation according to the present invention should at least help to halt further osteoporotic^' development. Women approaching an age where menopause is likely to occur could begin dietary calcium supplementation by the process of the present invention to help avert any development of osteoporosis. Women subject to hysterectomies are also likely to benefit in analogous manner to calcium supplementation by the process of the present invention.

In one aspect, the present invention presents a composition and process for combatting development of osteoporosis. Individuals, such as those described above, who are susceptible to development of osteoporosis are identified. Those individuals already having a degree of osteoporosis are, of course, susceptible to further osteo- porosis development. A composition comprising calcium in a chemical form adapted to provide gastrointestinally absorbable calcium ions and citrate in a chemical form adapted to provide gastrointestinally absorbable citrate ions is then provided. The individuals are then admin- istered an effective amount of the composition on a con¬ tinuing basis, preferably on a daily basis. This procedure is also adapted for dietary calcium supplementation of any individuals where dietary calcium supplementation is desired.

Certain individuals with hypertension, particularly ^* essential hypertension, may have their hypertension relieved by dietary calcium supplementation according to the processes of the present invention. Individuals iden¬ tified as having calcium-repressible hypertension may also benefit by such calcium supplementation as described for those susceptible to development of osteoporosis. Such supplementation according to the present invention should help prevent or alleviate such calcium-repressible hyper¬ tension.

. Subjects with calcium nephrolithiasis or prone to calcium nephrolithiasis nevertheless require dietary calcium, specially, for example, when they also suffer from osteoporosis, low abso'rption of calcium from the digestive tract, or hypertension due to calcium deficiency. These subjects may particularly benefit from dietary calcium supplementation by the process of the present invention. The concomitant intestinal absorption of citrate and calcium provided by the compositions and processes of the present invention succeeds in calcium supplementation while maintaining urinary conditions un¬ favorable for calcium stone formation in the kidneys. Individuals with calcium nephrolithiasis or a previous incidence thereof then may be dietarily supplemented with calcium with minimal likelihood of worsening or causing renal calcium lithiasis. The process, once individuals susceptible to development of calcium nephrolithiasis are identified, is similar to that described herein for cal¬ cium supplementation in general or for preventing osteo- porosis or hypertension. In earlier studies described in the Detailed Descrip¬ tion of the Preferred Embodiment of U.S. Patent Applica¬ tion No. 483,678, incorporated by reference herein, by the same inventor and assigned to the same entity as the present application, the effectiveness of potassium citrate for treatment of calcium nephrolithiasis was described. Briefly, it was therein described that dietary potassium citrate treatment effectively lowered urinary calcium oxalate saturation while analogous sodium citrate treatment was found to increase urinary calcium oxalate saturation. Thus dietary calcium supplementation by con- comitantly supplying a composition comprising potassium salts of citric acid and readily available calcium car¬ bonate is one preferred aspect of the present invention.

A pharmaceutically acceptable composition according to the present invention may be, for example, a formula¬ tion comprising calcium citrate, pregelatinized starch, magnesium stearate and carboxymethyl cellulose. The term "pharmaceutically acceptable" as used herein is defined to indicate a general non-toxicity and lack of irritative intestinal effects commensurate with a favorable benefit/risk ratio.

It has also been noted that a palatable popular liquid formulation may be used to prepare a liquid form dosages of calcium with citrate. While tricalcium dicitrate is preferred for solid form dosages of calcium citrate, said tricalcium dicitrate is of limited solubility in popular beverages such as soda pop. It is herein revealed that a typical soft drink beverage, having a pH between about 3 and about 4 is an excellent solvent for calcium:citrate. By the term calcium:citrate, as used relating specifically to liquid calcium supplements, is meant a salt of calcium:citrate of particular ratios when the calcium: citrate molar ratio of between about 1:1 and about 1:7. It was further found that calcium and citrate in such ratios may be dissolved in any of numerous soft drink brands, diet or regular, cold and carbonated or warm and decarbonated. .Among the brands successfully tested were Pepsi±, Coke±, Slice±, Sprite± and Dr. Pepper±. Soft drink solutions of calcium and citrate in such ratios may be readily prepared so that a typical can (12 fl. oz. - 360 ml) contains about 200 mg of dissolved elemental calcium. It has further been found that such calcium citrate additions to soft drinks have no noticeable deleterious effects upon the flavor thereof.

Dietary calcium supplementation by administration of calcium: citrate dissolved in mildly acidic beverages both provides requisite calcium and also citrate, the later of which inhibits calcium nephrolithiasis. Such liquid supplementation also provides additional urine volume, another factor inhibiting nephrolithiasis. Also, such citrate-rich calcium supplement provide a calcium source where the calcium is efficiently absorbed by the intestine.

A generally effective amount of the liquid or solid composition of the present invention suitable for daily administration comprises from about 0.5 gm to about 2 gm elemental calcium.

The following examples are included to further de¬ scribe the present invention and are not intended to limit the invention unless otherwise specifically indicated herein.

EXAMPLE 1

Four subjects were fed a control diet containing

400 mg calcium, 800 mg phosphorus and 100 millequivalents sodium/day, and were given either calcium carbonate or calcium citrate (10 millequivalents) . The amount of cal¬ cium absorbed by the subjects on either supplementation was measured. It was found that calcium was more effi¬ ciently absorbed from the calcium:citrate supplement than from- the calcium carbonate supplement. All four subjects showed an increase in calcium absorption when supplemented with calcium:citrate, the mean increase in absorption being 16.2%.

EXAMPLE 2

Effects of calcium:citrate dietary supplementation were measured in five normal subjects and one subject with calcium nephrolithiasis while these subjects were main¬ tained on a control diet as described in Example 1. Tricalcium dicitrate supplementation was provided four times/day (40 millequivalents per day). Urinary pH and amount of calcium, oxalate, ammonium, and citrate were determined. The results are shown in Table 1.

Table 1

Calcium

Urinary Control Citrate ■PH . 5.88 + 0.41 6.15 + 0.40**

Ca (mg/day) 184 + 79 281 + 94

Oxalate (mg/day) 24.4 + 5.6 24.2 + 4.8 NH₄ (mg/day) 417 + 55 319 + 89**

Citrate (mg/day) 643 + 197 756 + 195**

Relative saturation 4.27 +_ 1.96 5.09 + 1.70 ratio of calcium oxalate

+ = p <0.001; ** = p <0.01

It was found that, compared to the control, there were significant increases in urinary pH, citrate and calcium, and a decrease in urinary ammonium. The level of urinary supersaturation with respect to calcium oxalate, measured by the relative saturation ratio, did not change. The relative saturation ratio was calculated as described in Pak, Calcium Urolithiasis, pgs. 5-20, Plenum Medical Book Co. , NY, NY (1978).

As shown from the data in Table 1 calcium:citrate as a calcium dietary supplement demonstrates properties adverse to the induction or worsening of calcium nephro¬ lithiasis. Urinary citrate complexes urinary calcium, lessening the probability of calcium oxalate precipitation as stones. Calcium oxalate stones are also less likely to form when urinary pH is elevated. These changes overcome the effect of the rise in urinary calcium, maintaining the level of supersaturation of urine unchanged. EXAMPLE 3

An individual was seguentially subjected to three diets (control, tricalcium dicitrate supplementation and -calcium- carbonate supplementation). The composition of the control diet was as in Example 1. The amount of calcium supplementation was 40 meg/day (in four divided doses). The subject was maintained on the control diet or the supplemental diet for 7 days. During the last 3 days of the diet the individual's urine was measured for pH, ammonium content, citrate content, calcium content and oxalate content. The relative saturation ratio (RSR) of calcium oxalate was determined as a measure of supersatur¬ ation as was the formation product (FP) which measures the degree of protection from calcium oxalate precipitation

(Pak, Calcium Nephrolithiasis (1978) pgs. 5 to 20, Plenum Medical Book Co., NY, NY).

Table 2

Calcium Calcium

Urinary Control Citrate Carbonate pH 6.27 + 0.08 6.72 + 0.12* 6.42 -_ 0.34

NH (mg/day) 400 + 32 319 + 21 374 + 2

Citrate 439 + 50 518 +_ 46* 477 + 118 (mg/day)

Ca (mg/day) 76 + 12 145 + 2** 151 + 22*

Oxala te (mg/day ) 30 + 4 21 + 2 27 + 1 RSR 2.31 + 0.55 3.02 + 0.07 4.64 + 0.93*

FP (calcium citrate(xl0 .-8.)) 3.04 + 0.18 3.88 + 0.09* 3.25 + 0.91 * p <0.05; ** p <0.01 As the data in Table 2 indicates, calcium citrate supplementation significantly increased urinary pH and citrate levels, but did not significantly change the level of urinary supersaturation (RSR) of calcium oxalate. In contrast, calcium carbonate supplementation did not change urinary pH and citrate levels, but increased both urinary calcium and level of supersaturation (RSR) . Moreover, the inhibitor activity (FP) was increased with calcium citrate supplementation, but not by calcium carbonate supple- mentation.

The data, presented in Table 2 again demonstrates the feasibility of dietary calcium supplementation by inclusion of calcium citrate without facilitation of calcium urolith- iasis.

The significant increase in RSR seen with calcium carbonate supplementation but not with calcium citrate supplementation further illustrates the superiority of calcium citrate as a calcium supplement not likely to pro¬ duce calcium renal stones. The significant increase in formation product ratio (FP) shown in urine from calcium citrate supplementation demonstrates that inhibitors of calcium oxalate precipitation are present.

EXAMPLE 4

A typical tricalcium dicitrate supplement, in capsule or tablet form with about 5 meq calcium (100 mg) contains: calcium-,citrate (415 mg) ; pregelatinized starch (24 mgs); magnesium stearate (5 mg) and sodium carboxymethylcellulose (6 mg) . EXAMPLE 5

A solid preparation of calcium:citrate having a citrate:calcium ratio of 3:1 was dissolved in the contents of a can (12 fl. oz.) of Sprite±. The net dissolved calcium was about 200 mg. A mixture of calcium:citrate having a molar ratio of 3:1 and water as a paste was found to be dissolvable in soft drinks such as Sprite± so that a 12 oz. amount of supplemented soft drink contained substantially more than 200 mg elemental calcium.

A group fo 12 subjects taste-sampled such soft drinks, both with and without calcium citrate added in this amount and from either type of source. The members of this group uniformly were unable to distinguish normal soft drink from calcium citrate supplemented soft drink.

Changes obvious to those skilled in the art may be made in the various components, steps and procedures described herein without departing from the concept and scope of the invention as defined in the following claims.

Claims

CLAIMS :

1. A process for dietary calcium supplementation without induction or enhancement of nephrolithiasis comprising the steps of:

providing a liquid having a pH between about 3 and about 4 and comprising calcium:citrate, the calcium and citrate being in a molar ratio between about 1: 1 and about 1:7;

supplementing an individual's diet with a daily amount of said liquid comprising from about 0.5 gm to about 2.0 gm calcium.

2. The process for producing a liquid dietary calcium supplement containing at least about 400 mg elemental calcium per 360 ml comprising, dissolving calcium:citrate having a molar ratio of calcium to citrate between about 1: 1 and about 1:7 in an aqueous fluid having a pH between about 3 and about 4.

3. A composition of matter comprising calcium:citrate in a molar ratio between 1:1 and 1:7 dissolved in an aqueous solution and having a pH between about 3 and about 4, the calcium content of said solution being at least about 200 mg/360 ml.