Liquid calcium supplementation from readily soluble mixtures of calcium compound and citric acid

The present invention comprises a composition of matter consisting essentially of citric acid and one or more calcium compounds selected from the group consisting of calcium hydroxide, calcium carbonate and calcium oxide. The composition of matter is preferably a substantially dry mixture which may be used, for example, as a powder for making an "instant" beverage of potable liquid. A preferred calcium compound/citric acid molar ratio in the composition of matter of the present invention is between about 0.6 and about 1.5. In a most preferred embodiment, the composition of matter of the present invention consists essentially of calcium hydroxide and citric acid having a calcium compound/citric acid or calcium hydroxide/citric acid molar ratio of about 1.25. The composition of matter of the present invention has a utility demostrated by dissolution in water to form a liquid dietary calcium supplement comprising soluble calcium citrate. This composition of matter may comprise one or more of a flavorant, lubricant, sweetener or colorant usable to maintain a powdery texture or to enhance the flavor of a beverage prepared therefrom.

The mineral calcium 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 incompletely 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 chemical form of ingested calcium. 
Among the conditions of particular relevance to calcium dietary 
requirements is osteoporosis. Osteoporosis, a condition characterized by 
decreases in bone mass, renders 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. Postmenopausal women are generally agreed 
to be most susceptible 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 carbonate 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 succeeded in lessening or abolishing further bone 
deterioration. These three treatments were: dietary calcium 
supplementation; estrogenic hormone treatment; and, treatment with 
estrogenic hormone plus 1 alpha hydroxy vitamin D.sub.3. 
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 supplementation may 
increase urinary calcium and lead to formation of calcium-containing 
kidney stones (nephrolithiasis). 
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 nephrolithiasis 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). 
Belizan et al., (J. Am. Med. Ass'n. (1983) Vol. 249 No. 9 pp. 1161 to 1165) 
indicated that young adults showed reduction in blood pressure when their 
diets were supplemented 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 and possibly at least certain types of 
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. 
The following is a more detailed clinical description of some of above 
conditions, as well as a description for additional conditions, in which 
calcium citrate (especially in the special liquid form as embodied in this 
invention) may be useful. 
Hypoparathyroidism. Hypoparathyroidism (either parathyroid 
hormone-deficient or resistant) is characterized clinically by 
hypocalcemia (low blood calcium from impaired skeletal mobilization and 
intestinal absorption of calcium) and hyperphosphatemia (high blood 
phosphate from defective renal phosphate clearance) (Breslau and Pak, 
Metabolism, Vol. 28, pp 1261-1276, 1979). It has been customary to provide 
calcium supplementation and exogenous vitamin D substances to correct 
these disturbances. 
While there has been considerable progress in the therapeutic management 
with the introduction of active vitamin D metabolite (1,25-(OH).sub.2 
vitamin D) in the marketplace, three areas continue to be of some concern. 
First, some patients may show variable response to 1,25-(OH).sub.2 vitamin 
D and may sometimes develop hypercalcemia/hypocalcemia. Second, 
substantial hypercalciuria (high urinary calcium) may ensue when normal 
serum calcium concentration is restored by treatment. Some patients may 
develop kidney stones. Third, serum phosphorus may remain high, especially 
when vitamin D substances are given. The need for a calcium supplement, 
which provides available calcium as well as bind phosphate, would seem to 
be clear. 
Postmenopausal Osteoporosis. Considerable interest has been generated 
recently concerning potential therapeutic role of calcium supplements in 
the prevention of postmenopausal osteoporosis. The rationale for the use 
of calcium supplements in postmenopausal osteoporosis is the finding that 
calcium absorption is often depressed, presumably because of the defective 
renal synthesis of 1,25-(OH).sub.2 vitamin D. Thus, a higher calcium 
intake is needed by postmenopausal women to prevent negative calcium 
balance. Heaney et al., (J. Lab. Clin. Med., Vol. 92, p 953, 1978), showed 
that the amount of calcium intake required to achieve zero calcium balance 
increased by approximately 500 mg/day to nearly 1500 mg/day with the onset 
of menopause. Their study provided experimental basis for the 
recommendation by the recent Consensus Development Conference on 
Osteoporosis that calcium intake of 1000-1500 mg/day be provided in order 
to "reduce the incidence of osteoporosis in postmenopausal women." Since 
the average dietary calcium intake of postmenopausal American women is 
only about 500 mg/day, the need for calcium supplementation would seem to 
be clear. 
End-stage Renal Disease. The pathogenetic mechanisms responsible for the 
development of renal osteodystrophy are multifactorial. They include renal 
phosphate retention, intestinal malabsorption of calcium, renal aluminum 
retention and acidosis. There is some evidence that these disturbances 
could be ameliorated by calcium citrate therapy. 
Considerable evidence supports the view that phosphate retention plays a 
major role in the development of secondary hyperparathyroidism in renal 
failure. Phosphate retention, resulting from a reduction in glomerular 
filtration rate, may cause a transient decline in serum calcium 
concentration in mild-moderate renal disease. In an attempt to normalize 
serum calcium and phosphorus levels, parathyroid hormone secretion is 
increased, leading to secondary hyperparathyroidism. When the glomerular 
filtration rate declines to less than 25% of normal, significant 
hyperphosphatemia may supervene because of inadequate compensation by 
parathyroid stimulation. Secondary hyperparathyroidism accounts for the 
development of osteitis fibrosa (bone destruction), whereas 
hyperphosphatemia contributes to soft tissue calcification. 
The intestinal calcium absorption is typically reduced in end stage renal 
disease, largely due to the defective renal synthesis of 1,25-(OH).sub.2 
vitamin D. The reduced intestinal calcium absorption contributes to the 
development of secondary hyperparathyroidism. Exogenous 1,25-(OH).sub.2 
vitamin D may restore normal intestinal calcium absorption, but may be 
complicated by frequent development of hypercalcemia (high blood calcium). 
Although aluminum metabolism in normal persons is poorly understood, 
previous studies have demonstrated that intestinal absorption and renal 
excretion normally play a key role in aluminum metabolism. Aluminum 
toxicity is rare in persons with normal renal function because of 
efficient renal elimination. With the loss of renal function, however, 
aluminum accumulates in the body, especially in bone. Bone biopsy 
specimens from dialysis patients demonstrated a strong correlation between 
the presence of osteomalacia (impaired mineralization of bone) and 
elevated levels of aluminum in bone (Hodsman et al., Ann. Int. Med., Vol. 
94, pp. 629-637, 1981). There is substantial experimental evidence 
supporting the view that aluminum accumulation in bone causes 
osteomalacia. 
Initial reports of aluminum intoxication resulting in osteomalacia were in 
patients undergoing dialysis with dialysate prepared from tap water 
containing high levels of aluminum. The establishment of standards for 
permissible levels of aluminum in dialysate (less than 10 ug per liter) 
resulted in a decrease in these diseases from previously epidemic 
proportions and it was believed that aluminum toxicity would no longer 
afflict patients on chronic hemodialysis. Unfortunately, this has not been 
the case. Phosphate binding gels, principally aluminum hydroxide, have 
been used to prevent the hyperphosphatemia in chronic renal failure and 
thus preventing the secondary hyperparathyroidism. Unfortunately, evidence 
now suggests that the aluminum load delivered to chronic renal failure 
patients from aluminum-containing phosphate binders results in aluminum 
accumulation in the body causing a vitamin D resistant osteomalacia. 
Metabolic acidosis frequently complicates the course of chronic renal 
disease because of defective renal elimination of acid. Loss of bone mass 
may ensue, possibly because of the need to buffer the acid load by bone 
mineral. It has been customary to provide soluble alkali to correct the 
acidosis. However, the typical alkali used, citrate or bicarbonate salts 
of sodium and potassium, impose a load of these cations which may not be 
advantageous or safe in patients with end stage renal disease. 
Essential Hypertension. There is some evidence that dietary calcium 
suplements may be beneficial in essential hypertension. Diet histories 
have disclosed a lower calcium intake among patients with essential 
hypertension. Serum ionized calcium has been reported to be low in the low 
renin subtype. Calcium supplements have been reported to reduce blood 
pressure in preliminary trials in control subjects, pregnant women, and 
patients with essential hypertension. 
There is some evidence for the varying vasopressor effects of the different 
types of monovalent cation and anions. The association of dietary sodium 
and hypertension is long recognized. On the other hand, potassium may have 
a protective role on blood pressure (Iimura et al., Clin. Sci., Vol. 61, 
pp 77-80, 1981). Recently, a hypertensive role of chloride ion has been 
implicated. In contrast, bicarbonate ion even when given as the sodium 
salt has been shown to be protective against the development of 
hypertension. The varying effect of anions may be explained by the 
retardation of calcium influx by alkali. 
SUMMARY OF THE INVENTION 
The present invention comprises a composition of matter consisting 
essentially of citric acid and one or more calcium compounds selected from 
the group consisting of calcium hydroxide, calcium carbonate and calcium 
oxide. This composition of matter preferably comprises citric acid and one 
or more calcium compounds selected from the group consisting of calcium 
hydroxide, calcium carbonate and calcium oxide. The composition of matter 
is preferably a substantially dry mixture which may be used, for example, 
as a powder for making an "instant" beverage of potable liquid. A 
preferred calcium compound/citric acid molar ratio in the composition of 
matter of the present invention is between about 0.6 and about 3.0. In a 
more preferred embodiment, the composition of matter of the present 
invention consists essentially of a mixture of calcium hydroxide and 
citric acid having a calcium compound/citric acid ratio of about 1.25, 
most preferably, a mixture of calcium hydroxide and citric acid having a 
calcium hydroxide/citric acid molar ratio of about 1.25. 
The composition of matter of the present invention has a utility 
demonstrated by dissolution in water to form a liquid dietary calcium 
supplement comprising soluble calcium citrate preferably enriched with 
citric acid. This composition of matter may comprise one or more of a 
flavorant, lubricant, sweetener or colorant usable to maintain a powdery 
texture or to enhance the flavor and appearance of a beverage prepared 
therefrom. 
The present invention also involves a method for preparing a mixture 
soluble in an aqueous solvent to form a potable liquid consisting 
essentially of calcium citrate and citric acid. This method comprises the 
steps of: mixing a calcium compound (preferably calcium hydroxide) and 
citric acid in a calcium compound/citric acid molar ratio of between about 
0.6 and about 3.0, preferably between about 0.6 and about 1.5 and most 
preferably about 1.25. 
This potable liquid consisting essentially of calcium citrate and citric 
acid may be prepared by dissolving a quantity of said above-described 
mixture in an amount of aqueous solvent such as tap water. Such a potable 
liquid is suitable for the dietary supplementation of calcium without 
substantial risk of calcium renal stone facilitation or enhancement. The 
potable liquid consists essentially of: citric acid; water; and a calcium 
compound selected from the group consisting of calcium hydroxide, calcium 
oxide and calcium carbonate. The potable liquid preferably has a pH 
between about 2 and about 7, more preferably between about 3 and about 5. 
The potable liquid preferably comprises calcium compound and citric acid 
are in a calcium compound/citric acid molar ratio between about 0.6 and 
about 1.5. This potable liquid preferably compries calcium in an 
concentration between about 500 mg/L and about 2000 mg/L and contains 
calcium hydroxide as the calcium compound. 
DESCRIPTION OF THE PREFERRED EMBODIMENT 
The present invention presents evidence that mixtures of citric acid and a 
calcium compound such as calcium hydroxide as a form of liquid calcium 
supplementation is more optimal than tricalcium dicitrate provided in a 
tablet form. Although calcium hydroxide is a preferred calcium compound, 
it is understood that calcium oxide and calcium carbonate may be equally 
useful in the practice of the present invention. 
In the original patent application No. 703,196 filed Feb. 15, 1985 it was 
shown that calcium citrate (tricalcium dicitrate) given orally in a solid 
form provides a greater calcium bioavailability (absorbability) and 
citraturic response (rise in urinary citrate) than calcium carbonate. 
Thus, more calcium was absorbable from calcium citrate than from a 
comparable amount of calcium carbonate (Nicar and Pak, J. Clin. Endo. 
Metab. Vol. 61, pp 391-393, 1985). Urinary citrate rose significantly 
during calcium citrate treatment, but not during calcium carbonate therapy 
(Harvey, Zobitz and Pak, J. Clin. Endo, Metab. Vol. 61, pp 1223-1225, 
1985). Since citrate is an inhibitor of calcium (kidney) stone formation, 
results suggested tat calcium citrate treatment would be less likely than 
calcium carbonate to cause such stones. 
Subsequent related patent application Nos. (807,530; 840,884 and 896,651), 
involved improved formulations of calcium citrate which possessed even 
greater bioavailability and citraturic effect than the original product (a 
solid preparation of tricalcium dicitrate). Since the solid form of 
calcium citrate must be dissolved in the intestinal tract before it is 
absorbed or raises urinary citrate, means to increase the solubility of 
tricalcium dicitrate were sought. Two successful approaches were discussed 
in these prior patent applications. 
First, it was found that solid preparations of calcium citrate made with an 
excess of citrate (calcium/citrate molar ratio of less than 1.5 where a 
value of 1.5 represents the ratio for tricalcium dicitrate) had greater 
aqueous solubility. Thus, in a synthetic solution which mimicked gastric 
juice (pH 3, 37.degree. C.), citrate-enriched calcium citrate (with 
calcium/citrate molar ratio of 0.67) in a solid form was 8.85 times more 
soluble than tricalcium dicitrate. This calcium-enriched calcium citrate 
was also found to be more absorbable from the intestinal tract. In three 
normal subjects, the rise in urinary calcium after taking this modified 
solid form of calcium citrate was 24% greater than following ingestion of 
an equivalent amount of tricalcium dicitrate. 
Second, a more soluble form of calcium citrate could be prepared by 
pre-mixing fixed amounts of calcium hydroxide and citric acid sufficient 
to achieve a desired molar ratio of calcium and citrate. When added to 
water, the mixture readily dissolved, yielding soluble calcium and citrate 
without elaboration of carbon dioxide. This "pre-mix" of calcium hydroxide 
and citric acid was much more suitable in preparing liquid calcium 
preparations, than pre-formed citrate-enriched calcium citrate which took 
longer to dissolve. 
In this continuation-in-part, additional data supporting utility of a 
pre-mix of calcium compound and citric acid in preparing a liquid 
preparation of calcium are presented. A readily soluble, powdered 
preparation of citric acid and a calcium compound such as calcium 
hydroxide, containing a desired amount of calcium, may be dissolved in an 
aqueous solvent such as water, fruit juice or soft drink prior to 
ingestion. Different mixtures with varying relative amounts of calcium 
compound and citric acid were tested in order to determine which 
demonstrated optimum solubility, calcium bioavailability and citraturic 
action. Such a preparation should be particularly useful in the correction 
of hypocalcemia in patients with hypoparathyroidism, in the prevention of 
bone loss in postmenopausal women, in the control of phosphate retention 
in patients with end-stage renal failure and in the treatment of essential 
hypertension. 
Liquid dietary calcium supplementation, useful in the prevention or 
treatment of hypoparathyroidism, postmenopausal osteoporosis, phosphate 
retention of chronic renal failure and essential hypertension, is 
accomplished by a readily soluble pre-mix of citric acid and a calcium 
compound, preferably calcium hydroxide. 
From the aforementioned actions of liquid calcium supplementation from 
readily solubilized premixes of calcium compound and citric acid, it 
should be apparent that these readily soluble mixtures should be more 
effective than tricalcium dicitrate (solid), or certainly calcium 
carbonate, in the management of various clinical disorders described 
earlier herein. 
Calcium carbonate is the most widely used calcium supplement. There is 
theoretical basis for the assertion that calcium citrate may be more 
optimal for the treatment of hypoparathyroidism. First, calcium is more 
absorbable from calcium citrate than from calcium carbonate. While calcium 
carbonate generally requires adequate gastric acid secretion for 
dissolution and absorption, the absorption of calcium citrate is less 
dependent on acid secretion especially in its modified (readily soluble 
pre-mix) form. The difference in calcium absorbability between the two 
salts may be more marked in hypoparathyroidism, because gastric acid 
secretion may be impaired owing to hypocalcemia. The improved calcium 
bioavailability of calcium citrate may reduce the requirement for vitamin 
D substances. 
Second, calcium citrate therapy should augment citrate excretion, 
especially when given in the citrate-rich form. There should be a reduced 
propensity for the crystallization of stone-forming calcium salts in urine 
due to the inhibitor activity of citrate. This action should help reduce 
the risk for stone formation which may sometimes complicate this 
condition. 
Third, calcium citrate is capable of binding dietary phosphate in the 
intestinal lumen. This binding capacity should be greater for mixtures of 
calcium hydroxide and citric acid than by calcium carbonate or solid 
tricalcium dicitrate because of the greater or more rapid solubility of 
pre-mixes and availability of calcium. Thus, there should be a better 
control of hyperphosphatemia. 
In recent reports, calcium carbonate has been shown to be ineffective in 
preventing vertebral bone loss in postmenopausal women (Christiansen et 
al., J. Bone Min. Res. 166A, 1986). Prior studies of the present inventors 
indicated that tricalcium dicitrate may be potentially more effective than 
calcium carbonate in preventing bone loss. Our prior patent application 
(Ser. No. 807,530) presented preliminary data showing that calcium citrate 
may avert further bone loss. This conclusion was derived from findings 
that calcium citrate (a) provides a modest but definite alkali load which 
may exert a protective effect against bone loss, (b) confers greater 
calcium bioavailability, and (c) may be associated with a reduced risk for 
the crystallization of stone-forming calcium salts because of citraturic 
response. Liquid calcium supplementation in the form of mixtures of 
calcium hydroxide and citric acid should be more effective than tricalcium 
dicitrate because of its greater solubility, bioavailability, provision of 
alkali load and citraturic action. 
There is a sound theoretical basis for the assertion that tricalcium 
dicitrate therapy should ameliorate complications of chronic renal 
failure. 
First, calcium citrate should prevent phosphate retention by binding 
phosphate in the intestinal tract. High doses of another calcium salt 
(calcium carbonate, 3-20 g calcium/day) has been shown to prevent the 
absorption of ingested phosphate (Clarkson et al., Clin. Sci., Sol. 30, pp 
524-438, 1966). Calcium citrate may be more effective than calcium 
carbonate in binding phosphate in the intestinal tract and in averting 
phosphate retention. Before calcium can bind phosphate in the gut, calcium 
must be dissociated from its associated anion. Calcium citrate has a 
greater aqueous solubility than calcium carbonate. This fact partly 
accounts for the higher calcium absorbability (bioavailability) from 
calcium citrate. Thus, more free calcium should be available from calcium 
citrate than from calcium carbonate to complex phosphate in the gut. This 
conclusion is supported by the study of McDonald et al., (Clin. Sci., Vo. 
26, pp 27-39, 1964), who found that a "modest" dose of calcium citrate (2 
g calcium/day) was effective in restoring normal serum phosphate 
concentration in patients with renal failure. Our own preliminary data has 
shown that a satisfactory control of hyperphosphatemia could be achieved 
in the majority of patients with tricalcium dicitrate at a dose of 
1.5-2.75 g calcium/day. Moreover, serum aluminum concentration declined 
from 127 ng/ml (before treatment) to 79 ng/ml after 8 weeks of treatment 
(p&lt; 0.05). 
Second, calcium citrate supplementation may provide sufficient calcium for 
absorption to avert malabsorption of calcium in patients with end stage 
renal disease. Calcium citrate may be more effective in this regard than 
calcium carbonate, the most widely-used calcium salt. Third, calcium 
citrate supplementation might obviate the need for the use of 
aluminum-containing antacids to bind phosphate, thus reducing aluminum 
load. The decline in serum aluminum concentration was previously 
enumerated. Finally, calcium citrate may ameliorate metabolic acidosis 
since it provides an alkali load. 
The above expectations for tricalcium dicitrate should be even more 
applicable for the liquid calcium supplementation with mixtures of calcium 
hydroxide and citric acid. Because of its rapid solubility, such pre-mixes 
should be more effective in binding phosphate and controlling 
hyperphosphatemia. They should be more effective in averting secondary 
hyperparathyroidism because of its greater calcium absorption. There 
should be a better control of metabolic acidosis since higher alkali load 
(citrate) would be delivered. 
The present invention derives in part from observations concerning the 
effects of calcium carbonate, tricalcium dicitrate (solid) and placebo in 
essential hypertension. Neither calcium carbonate nor tricalcium dicitrate 
(800 mg calcium/day) was effective in lowering blood pressure. It is 
expected that liquid calcium supplementation in the form of mixtures of 
calcium hydroxide and citric acid should show hypotensive action, because 
of its greater calcium absorbability and alkali load. 
Following is a summary of studies done with pre-mixes of calcium hydroxide 
and citic acid, showing superior solubility and absorbability. 
Several mixtures of calcium compound and citric acid were tested. Their 
calcium/citrate molar ratio ranged from 1.5 to 0.67. Solubility (defined 
as the amount of total calcium remaining in solution) was tested for these 
mixtures containing 500 mg calcium in 300 ml of water. The solubility was 
dependent on pH, time of incubation and the calcium/citrate molar ratio. 
All mixtures readily dissolved in water. All mixtures dissolved rapidly 
and remained in solution for at least 1 hour at a wide pH range (2-7). 
With a longer duration of incubation as well as at higher pHs, calcium 
precipitation occurred (as calcium citrate), leaving less calcium in 
solution. After 24 hours of incubation the final solubility approximated 
that found when corresponding solid form of calcium citrate and citric 
acid were used to formulate the same calcium/citrate compositions. The 
period required for the precipitation of calcium citrate after initial 
dissolution was more prolonged for citrate-rich mixtures with lower 
calcium/citrate ratios. The final solubility was higher for mixtures with 
lower calcium/citrate ratios. 
The absorption of calcium from the intestinal tract, tested in normal 
subjects, was greater from liquid calcium formulations prepared from 
mixtures of calcium compound and citric acid than from a solid preparation 
of preformed tricalcium dicitrate. The absorption of calcium from the 
mixture with a calcium/citrate molar ratio of 1.5 was 27-63% greater than 
that from the preformed solid preparation with same molar ratio 
(tricalcium dicitrate). The highest bioavailability among various 
preparations tested was obtained with the pre-mix of calcium compound and 
citric acid with a calcium/citrate molar ratio of 1.25. 
Ingestion of dissolved mixtures of calcium hydroxide and citric acid, 
especially those containing an excess of citric acid, caused a more 
prominent rise in urinary citrate (inhibitor of stone formation), than 
ingestion of a comparable amount (in terms of calcium content) of solid 
tricalcium dicitrate. 
Thus, mixtures of citric acid and a calcium compound such as calcium 
hydroxide represented effective means of providing liquid calcium 
supplementation. They could be dissolved rapidly in an aqueous liquid or a 
soft drink before ingestion. The pre-mix preparation with a 
calcium/citrate molar ratio of 1.25 was particularly suitable because of 
desired citrate content (60 meq/day assuming calcium intake of 1 g/day), 
adequate solubility and optimum calcium bioavailability. Other mixtures 
with different molar ratios may be useful under special circumstances. 
Owing to these properties, liquid calcium supplementation provided by 
mixtures of a calcium compound such as calcium hydroxide and citric acid 
may be more useful than tablet preparations of tricalcium dicitrate for 
raising serum calcium concentration in hypoparathyroidism, preventing bone 
loss in early postmenopausal women, controlling hyperphosphatemia in renal 
osteodystrophy and in lowering blood pressure in calcium-sensitive 
essential hypertension. Moreover, it is expected that such liquid calcium 
supplementation would be associated with a further reduction in the risk 
for stone formation, due to a more prominent citraturic action. 
The present invention relates to presented evidence that mixtures of citric 
acid and a calcium compound such as calcium hydroxide as a form of liquid 
calcium supplementation are more optimal than tricalcium dicitrate 
provided, for example, in a tablet form. Although calcium hydroxide is a 
preferred calcium compound, it is understood that calcium oxide and 
calcium carbonate may be equally useful in the practice of the present 
invention. A more detailed description follows. 
First, mixtures of calcium hydroxide and citric acid were found to be much 
more rapidly soluble than tricalcium dicitrate. Solubility was determined 
for 500 mg calcium (representing a typical prescribed dose) in 300 ml of 
water (representing gastric juice volume after ingestion of water with 
calcium supplement) at pH 2-7. The mixtures of calcium hydroxide and 
citric acid, ranging in calcium/citrate molar ratio of 0.67 to 1.5, 
rapidly and completely dissolved in water at all pHs. Subsequently, 
calcium citrate precipitated out of solution. The time required for 
initiation of precipitation depends on the citrate content and on pH. 
Thus, the precipitation took place within one hour of dissolution in the 
case of the mixture with a calcium/citrate molar ratio of 1.5 
(representing the molar ratio for tricalcium dicitrate). However, for the 
citrate-enriched mixture with a calcium/citrate molar ratio of 0.67, more 
than 2 hours were required to initiate calcium citrate precipitation. 
Moreover, for all mixtures, precipitation occurred at high pHs but not at 
low pHs. The total amount of calcium citrate precipitation was greatest 
for the mixture with highest calcium/citrate ratio (1.5), and smallest for 
the citrate-enriched mixture with calcium/citrate molar ratio of 0.67. 
When the precipitation was complete, the solubility of calcium citrate 
approximated that of the corresponding preformed calcium citrate (with 
same calcium/citrate ratio). 
In contrast, the preformed solid preparation of tricalcium dicitrate 
underwent only gradual dissolution, expecially at higher pHs. The 
preformed solid preparations of calcium citrate with an excess of citrate 
(to yield calcium/citrate molar ratio of less than 1.5) had enhanced 
solubility. However, for these preformed solid preparations, the rate of 
dissolution was too slow to be useful in making liquid calcium 
supplements. 
The final solubility of calcium citrate was the same for the precipitated 
material as was for the preformed compound. However, mixtures of calcium 
hydroxide and citric acid initially dissolved rapidly and gradually 
allowed precipitation of calcium citrate. In contrast, preformed solid 
preparations of calcium citrate gradually dissolved, yielding soluble 
calcium and citrate. Thus, the pre-mixes of calcium hydroxide and citric 
acid served as convenient means of rapidly providing calcium (and citrate) 
in a liquid form. By adding an excess of citric acid, the precipitation of 
calcium citrate could be delayed, and the preparation could be kept in a 
soluble form longer. 
Second, calcium bioavailability (absorbability from intestines upon oral 
ingestion) was greater from liquid formulations prepared from mixtures of 
calcium hydroxide and citric acid than from solid tricalcium dicitrate. 
Ten normal subjects underwent indirect measures of intestinal calcium 
absorption four times, after receiving orally 500 mg calcium as tricalcium 
dicitrate (solid form), and as pre-mixes of calcium hydroxide and citric 
acid with molar calcium/citrate ratios of 1.5, 1.25 and 0.67 (in liquid 
form). The pre-mixes yielded greater absorbability of calcium than 
tricalcium dicitrate. The increment in urinary calcium during the second 
two hours after taking liquid calcium supplements was 18-74% greater than 
that following ingestion of solid tricalcium dicitrate, with the highest 
value obtained for the pre-mix with calcium/citrate molar ratio of 1.25. 
The calcium absorption was also measured more directly from the recovery 
of radiocalcium after taking labeled calcium preparations in 6 normal 
subjects. The intestinal calcium absorption was greater from liquid 
preparations made from mixtures of calcium hydroxide and citric acid than 
from the solid preparation of trialcium dicitrate, with the highest value 
being obtained for the pre-mix with a calcium/citrate molar ratio of 1.25 
(70% higher). 
Third, the liquid calcium supplementation in the form of pre-mixes of 
calcium hydroxide and citric acid should be more efficient than as a solid 
or tablet preparation (tricalcium dicitrate) in binding phosphate in the 
intestinal tract. The binding of phospate in the diet more readily occurs 
with calcium in a soluble state rather than in a solid or precipitated 
form. As previously described, calcium and citrate may be kept in a 
soluble form metastably beyond the theoretical and actual final solubility 
by using readily soluble mixtures of calcium citrate and citric acid. 
Fourth, liquid calcium supplementation in the form of mixtures of calcium 
hydroxide and citric acid should provide a greater alkali load and 
citraturic response than the solid preparation of tricalcium dicitrate. 
Since these mixtures yield greater amounts of citrate in a soluble form, 
more citrate should be absorbed to provide an alkali load and to raise 
urinary citrate. Thus, urinary citrate rose from 107 mg/4 hours without 
calcium supplementation, to 137 mg/4 hours following ingestion of 500 mg 
calcium as pre-mix of calcium hydroxide and citric acid with a 
calcium/citrate molar ratio of 1.25, and to 174 mg/4 hours after taking 
the pre-mix with calcium/citrate molar ratio of 1.5. The citraturic 
response should reduce the risk for the crystallization of stone-forming 
calcium salts (Harvey, Zobitz and Pak, J. Clin. Endo. Metab. Vol. 62, pp 
1223-1225, 1985), albeit it may not totally eliminate the risk in some 
instances. The alkali load provided may also be beneficial for bone. In 16 
women with nephrolithiasis (due to causes other than absorptive 
hypercalciuria) studied, alkali load with potassium citrate therapy caused 
a stability of bone density in the distal third of the radius. The 
fractional change in bone density was -0.007 at 1 year, -0.005 at 2 
years, -0.002 at 3 years and +0.008 at 4 years to avoid impeding calcium 
absorption. Fifth, the ratio of citrate to phosphorous (primary as 
phosphate) is preferably above about 0.5, most preferably above about 5.6.

The following examples are presented to describe preferred embodiments and 
utilities of the present invention and are not meant to limit the present 
invention unless otherwise stated in the claims appended hereto. 
EXAMPLE 1 
Formulation of Pre-Mixes of Calcium Hydroxide and Citric Acid 
Two formulations of the pre-mix with a calcium/citrate molar ratio of 1.25 
were made in order to provide orange and lemon-lime flavor preparations. 
The orange flavored preparation (each 234.2 g) contained 153.6 g citric 
acid, 74.0 g Ca(OH).sub.2, 2.4 g orange flavoring, 4.0 g aspartame, 150 mg 
vitamin B.sub.2, and 22 mg of Red No. 40-89%. Each 2.927 g of this 
material, which could be placed in an individual sachet or scoop, 
contained 500 mg of elemental calcium. 
The lemon-lime flavored preparation (each 232.3 g) contained 153.6 g citric 
acid, 74.0 g Ca(OH).sub.2, 1.7 g lemon-lime flavoring, 2.85 g aspartame, 
and 115 mg of vitamine B.sub.2. Each 2.903 g of this material provided 500 
mg of elemental calcium. 
When 500 mg calcium amounts of above materials were suspended in 300 ml of 
water, they dissolved very rapidly and produced a well-tolerated drink of 
satisfactory flavor. 
In order to prevent clumping of powdered mixtures, Cabosil (fumed silica 
NF) may be added. 
EXAMPLE 2 
Solubility of Mixtures of Calcium Hydroxide and Citric Acid with a Calcium 
Citrate Molar Ratio of 1.25 
The aqueous solubility of a mixture of calcium hydroxide and citric acid 
with a calcium/citrate molar ratio of 1.25 was determined as follows. A 
sufficient amount of the mixture containing 500 mg of elemental calcium 
was suspended in 300 ml of water kept at 37.degree. C. and at various pHs 
(2-7) while the pH was maintained at the predetermined level. After 1, 2 
and 24 hours of incubation, the filtrate was analyzed for calcium. The 
amount of calcium recovered in the filtrate represented solubility, where 
100% recovery indicated complete solubility. 
The pre-mix dissolved in water very rapidly (within 2 minutes). It remained 
in solution after 1 hour of incubation (Table 1). After 2 hours of 
incubation, crystallization of calcium citrate occurred at pH greater than 
4.5, indicated by an appearance of visible precipitate and a decline in 
calcium recovery. Below pH 4.5, the pre-mix was completely soluble. After 
24 hours of incubation, precipitation was noticeable at pH greater than 
3.5. The filtrate concentration of calcium was much lower than at an 
earlier period of incubation (2 hours). The curve representing the 
solubility of precipitated calcium citrate from the dissolved pre-mix was 
indistiguishable from that of pre-formed calcium citrate (solid) of 
identical calcium/citrate ratio. The results suggested that at steady 
state conditions (24 hours of incubation), the final crystalline material 
(and its solubility) was the same whether it was obtained from dissolution 
of the preformed calcium citrate or from precipitation from dissolved 
pre-mix of calcium hydroxide and citric acid. The advantage of the pre-mix 
is that this device allows for a preparation of a liquid formulation of 
calcium citrate much more rapidly and at a higher calcium concentration 
than might be possible from preformed solid calcium citrate. 
TABLE 1 
______________________________________ 
Solubility of Pre-mix of Calcium Hydroxide and 
Citric Acid with Calcium/Citrate Molar Ratio of 1.25 
Percent of Calcium Recovered in the Filtrate 
pH 1 hr 2 hr 24 hr 
______________________________________ 
2.0 99.3 99.6 99.0 
2.5 99.3 99.0 97.8 
3.0 98.1 98.6 94.6 
3.5 97.8 98.4 95.9 
4.0 97.8 97.4 35.6 
4.5 97.5 95.4 17.2 
5.0 91.2 73.9 15.0 
6.0 95.7 63.8 19.1 
7.0 95.4 58.9 22.0 
______________________________________ 
EXAMPLE 3 
Relative solubility of Different Pre-Mixes of Calcium Hydroxide and Citric 
Acid 
The solubility of various pre-mixes (calcium/citrate molar ratio of 1.5, 
1.25 and 0.67) was determined as described in Example 2, and compared with 
that of tricalcium dicitrate (also 500 mg calcium per 300 ml). After 2 
hours of incubation, tricalcium dicitrate displayed expected solubility, 
with high dissolution at low pHs and reduced/limited dissolution at high 
pHs (Table 2). The pre-mix of calcium hydroxide and citric acid with an 
identical calcium/citrate molar ratio of 1.5 had a much higher solubility. 
Both preparations were completely soluble or nearly so at a pH of 2.0 and 
2.5. At higher pHs, the pre-mix gave a much greater calcium recovery at 
this early period of incubation. 
The pre-mixes with an excess of citric acid (calcium/citrate molar ratios 
of 1.25 and 0.67) had an even greater solubility. The preparation with the 
highest solubility was the pre-mix with calcium/citrate molar ratio of 
0.67. It was completely soluble even at high pHs. 
Thus, pre-mixes with an excess of citric acid (for example, calcium/citrate 
molar ratio of 1.25 and 0.67) allowed more calcium to remain in solution 
even in the neutral pH of the intestinal juice (where calcium absorption 
takes place), than the pre-mix with the calcium/citrate ratio of 
tricalcium dicitrate, i.e.-1.5. 
TABLE 2 
______________________________________ 
Solubility of Different Pre-Mixes 
After 2 Hours of Incubation 
Percent of Calcium Recovered in the Filtrate 
Pre-Mix Pre-Mix Pre-Mix 
Tricalcium 
pH (1.5) (1.25) (0.67) Dicitrate 
______________________________________ 
2.0 99.6 99.6 98.6 95.1 
2.5 99.5 99.0 99.7 95.0 
3.0 100.0 98.6 99.2 83.6 
3.5 99.5 98.4 99.4 61.3 
4.0 99.1 97.4 99.2 39.9 
4.5 -- 95.4 91.7 25.3 
5.0 98.7 73.9 52.1 16.9 
6.0 99.2 63.8 37.6 14.9 
7.0 96.3 58.7 38.8 14.3 
______________________________________ 
Numbers below Premix in parentheses indicate the calcium/citrate molar 
ratio in this and subsequent tables. 
EXAMPLE 4 
Absorption of Calcium from Different Pre-Mixes Assessed by an Indirect 
Method of Oral Calcium Loading 
Calcium adsorption was measured indirectly in 10 normal subjects from the 
rise in their urinary calcium after ingestion of 500 mg calcium as a 
liquid formulation of various pre-mixes or as a solid preparation of 
tricalcium dicitrate. The increment in urinary calcium during the second 
two hours following oral calcium load was substantially higher after 
taking dissolved pre-mixes than after ingestion of solid tricalcium 
dicitrate (Table 3). This indirect measure of calcium absorption was 
greatest for the pre-mix with a calcium/citrate molar ratio of 1.25 than 
for other pre-mixes. 
Thus, calcium was more bioavailable from liquid preparations of the 
pre-mixes than from solid tricalcium dicitrate. 
TABLE 3 
______________________________________ 
Indirect Measure of Calcium Absorption from Pre-Mixes 
Increment in Urinary Calcium 
Calcium (mg calcium/100 ml 
Preparation glomerular filtrate) 
______________________________________ 
Tricalcium dicitrate (1.5) 
0.087 .+-. 0.087 
Pre-mixes 
(1.5) 0.142 .+-. 0.061** 
(1.25) 0.151 .+-. 0.061** 
(0.67) 0.103 .+-. 0.059 
______________________________________ 
Values are presented as mean .+-. SD. Significant difference from 
triclcium dicitrate is shown by ** for p &lt; 0.01. 
EXAMPLE 5 
Calcium Absorption from Pre-Mixes Using a More Direct Method 
In 6 normal subjects, intestinal calcium absorption was indirectly measured 
from the fecal recovery of radioactive calcium after giving by mouth 
liquid preparations of various pre-mixes or tricalcium dicitrate (solid 
preparation) pre-labeled with radiocalcium. The calcium absorption from 
pre-mixes was higher than from tricalcium dicitrate (Table 4). The highest 
absorption was obtained with the mixture of calcium hydroxide and citric 
acid with a calcium/citrate molar ratio of 1.25. 
TABLE 4 
______________________________________ 
Radiocalcium Absorption from Pre-Mixes 
Calcium 
Preparation Calcium Absorption (%) 
______________________________________ 
Tricalcium dicitrate (1.5) 
19.1 .+-. 6.9 
Pre-mix 
(1.5) 24.3 .+-. 10.2 
(1.25) 32.5 .+-. 5.3* 
(0.67) 23.9 .+-. 13.5 
______________________________________ 
Values are presented as mean .+-. SD. Significant difference from 
tricalcium dicitrate is shown by * for p &lt; 0.05. 
EXAMPLE 6 
Effect of Pre-Mix Administration on Urinary Citrate 
Following oral administration of 500 mg calcium as various pre-mixes (in a 
liquid form) or as tricalcium dicitra te (solid), urinary citrate was 
measured over 4 hours in 10 normal subjects (Table 5). As compared to the 
control value obtained without taking any calcium, urinary citrate was 
greater after receiving liquid calcium supplements from pre-mix with 
calcium/citrate molar ratio of 1.25 and 0.67 (citrate-rich preparations). 
TABLE 5 
______________________________________ 
Urinary Citrate Following Oral 
Administration of Pre-Mixes 
Calcium 
Preparation Urinary Citrate (mg/4 hour) 
______________________________________ 
Tricalcium dicitrate (1.5) 
120 .+-. 33 
Pre-mix 
(1.5) 118 .+-. 33 
(1.25) 137 .+-. 50 
(0.67) 174 .+-. 35+ 
Control 120 .+-. 30 
______________________________________ 
Values are presented as mean .+-. SD. Significant difference from the 
control (without calcium supplementation) is shown by .+-. for p &lt; 0.001. 
EXAMPLE 7 
Summary of Properties of Various Calcium Preparations 
The mixture of calcium hydroxide and citric acid with a calcium/citrate 
molar ratio of 0.67 (citrate-rich) was most soluble, and had the greatest 
citrate content and citraturic action (Table 6). However, it had the 
lowest calcium bioavailability among the pre-mixes. The pre-mix with a 
calcium/citrate molar ratio for 1.25 had the highest calcium 
bioavailability, and had adequate solubility, citrate content and 
citraturic action. Assuming a recommended calcium intake of 1 g/day, the 
amount of citrate contained in this pre-mix was 60 meq/day, a safe level. 
These varying properties might be utilized to special advantage under 
different clinical conditions, to suit particular needs of those 
conditions. 
TABLE 6 
______________________________________ 
Order of Efficiency of Different Calcium Preparations 
Pre-Mixes Tricalcium 
(1.5) (1.25) (0.67) Dicitrate 
______________________________________ 
Solubility 3 2 1 4 
Ca bioavailability 
2 1 3 4 
Citraturic action 
3 2 1 3 
Citrate content 
3 2 1 3 
______________________________________ 
EXAMPLE 8 
Solubility of Ca(OH).sub.2 and CaCO.sub.3 in Orange Juice 
Since orange juice is rich in citric acid, addition of calcium hydroxide or 
calcium carbonate results in the formation of calcium citrate. The 
following general stoichiometric reaction formulas indicate appropriate 
reactions. 
______________________________________ 
3Ca(OH).sub.2 + 2H.sub.3 Citrate 
Ca.sub.3 Citrate.sub.2 + 6H.sub.2 O 
3CaCO.sub.3 + 2H.sub.3 Citrate 
Ca.sub.3 Citrate.sub.2 + 3H.sub.2 CO.sub.3 
3H.sub.2 O + 3CO.sub.2 
______________________________________ 
Solubility of calcium hydroxide was determined in Minute Maid orange juice 
(concentrate diluted 1:3 with distilled water) at 6.degree. C. 
(refrigerated). This "diluted" juice (hereafter called simply orange 
juice) contained 45 mmoles of total citrate/liter; pH was 3.91. Increasing 
amounts of calcium hydroxide were added to 180 ml (6 oz) of orange juice, 
and stirred for 30 minutes. The filtrate of the stirred mixture was 
assayed for pH and calcium content (Table 7). 
TABLE 7 
______________________________________ 
Solubility of Calcium Hydroxide in Orange Juice 
Amount of Ca 
added as Ca(OH).sub.2 
Final Filtrate Ca 
Sample (mg Ca) pH mg/180 ml 
______________________________________ 
1 100 4.15 106 
2 200 4.44 204 
3 300 4.83 305 
4 400 7.44 401 
5 500 9.16 418 
______________________________________ 
Calcium hydroxide readily dissolved (within 5 minutes) in samples 1 and 2. 
It dissolved more slowly (20 minutes) in sample 3. Samples 1-3 retained 
the original orange juice color. The final pH was less than 4.9 and final 
filtrate calcium closely approximated the amount added. However, in 
samples 4 and 5, final pH was much higher and there was grayish 
discoloration. Incomplete dissolution of calcium hydroxide was confirmed 
by the lower final filtrate concentration of calcium (compared to amount 
added) in Sample 5. 
The results suggested that there is sufficient amount of free citric acid 
in orange juice to convert up to 300 mg calcium as calcium hydroxide/180 
ml into soluble calcium citrate. 
Similar results were obtained when calcium carbonate was added to orange 
juice. For example, when 300 mg calcium as calcium carbonate was added to 
180 ml of Minute Maid orange juice (refrigerated), it dissolved rapidly 
(within 5 minutes). However, foam developed due to the elaboration of 
carbon dioxide. A mixture of calcium carbonate and calcium hydroxide (100 
mg Ca as calcium carbonate and 200 mg calcium as calcium hydroxide) was 
added to 180 ml of orange juice. Rapid dissolution (within 5 minutes) 
again took place. There was less foam. 
Thus, addition of calcium carbonate either alone or with calcium hydroxide 
provides rapid dissolution in orange juice. Unfortunately, the development 
of foam may limit the usefulness of calcium carbonate. Dissolution of 
calcium carbonate and citric acid in aqueous solutions or juices other 
than those as prone to foaming as orange juice is likely to be feasible to 
form a desired calcium compound/citric acid mixture analogously useful to 
the calcium hydroxide/citric acid combinations described earlier herein. 
Changes may be made in the compounds and procedures described herein 
without departing from the concept and scope of the invention as defined 
in the following claims.