Calcium is considered to be one of the most important minerals in the human body. It is required for maintaining bone mineral density, is essential for exocytosis of neurotransmitters, takes part in the contraction of muscle cells, replaces sodium as the depolarizing mineral in the heart, and participates in many other physiological functions. Calcium gastrointestinal absorption depends not only on the dietary calcium availability but on the absorptive capacity of the intestines, which is affected by physiological factors such as calcium reserves, hormonal regulation or previous dietary calcium supply. Dissolution of calcium salts (e.g. calcium carbonate) in the stomach is one step in the proper active and passive absorption of calcium as a calcium ion (Ca(2+)) in the proximal small intestine. Stomach acid markedly increases dissolution and ionization of poorly soluble calcium salts. If acid is not properly secreted, calcium salts are minimally dissolved (ionized) and, subsequently, may not be properly and effectively absorbed. Atrophic gastritis, gastric surgery, and high-dose, long-term use of antisecretory drugs markedly reduce acid secretion and may, therefore, be risk conditions for malabsorption of dietary and supplementary calcium, and may thereby increase the risk of osteoporosis in the long term (Sipponen et al., Scand J. Gastroenterol. 2010; 45(2):133-8).
Calcium gastrointestinal absorption may also be decreased in patients after bariatric surgery, patients suffering from hypoparathyroidism, Crohn's disease, cystic fibrosis, inflammatory bowel disease or celiac disease. Individuals, consuming additional types of drugs, such as proton pump inhibitors, anticonvulsants, and chronic corticosteroids, may also develop calcium malabsorption.
Bioavailability of calcium depends on its gastrointestinal absorption and the incorporation of absorbed calcium into bone. As for intestinal absorption, physiological factors, particularly hormones, play a major role in the incorporation of calcium into bone. The bioavailability of calcium may therefore be defined as the fraction of dietary calcium that is potentially absorbable by the intestine and can be used for physiological functions, particularly bone mineralization, or to limit bone loss (Gueguen et al, Am Coll Nutr, 2000 vol. 19 no. suppl 2 119S-136S).
Bone mineral density loss is associated with various metabolic bone diseases, such as: osteopenia, osteomalacia, Rickets, osteitis fibrosa cystica, and osteoporosis. Studies have shown that inadequate intake of dietary calcium can induce many bone-related diseases, such as osteoporosis.
A standard medication for prevention and treatment of certain types of bone loss (including osteoporosis) is an anti-resorptive agent. One non-limiting example for the anti-resorptive agents are bisphosphonates, e.g. the bisphosphonate Alendronate (ALN). Administration of ALN attenuates the decline in bone mineral density (BMD), as ALN has a bone resorption inhibiting effect. However, it is an acknowledged problem that ALN also suppresses bone formation and its administration is associated with a risk of adverse symptoms. Use of several drugs in combination has been suggested for the improvement of patients' compliance and the therapeutic effect.
The calcium used in supplements today, whether obtained from natural sources or synthetic precipitates, may comprise both organic and inorganic calcium salts. In specific conditions where calcium gastrointestinal absorption is limited, standard intake of the available supplements is insufficient to promote absorption, resulting in a need to increase intake doses. The requirement of consumption of higher calcium doses in malabsorption-associated conditions leads to adverse effects like constipation, kidney stones, vascular problems and subsequent reduced compliance. Moreover, most calcium supplements require low gastric pH in order to be efficiently dissolved and absorbed through the gut, and thus their bioavailability is superior in a fasting state.
Over the past 20 years, a rapidly growing scientific interest in the thermodynamically unstable amorphous polymorph of calcium carbonate, named amorphous calcium carbonate (ACC), has emerged. In nature, ACC is utilized by a small number of organisms, mainly crustaceans and other invertebrates that developed capabilities for stabilizing ACC in transient mineral deposition sites. These organisms require an exceptional efficient mineral source for the periodical mobilization, absorption and precipitation of calcium. In some crustaceans, such as the freshwater crayfish, ACC is stored in large quantities in specialized transient storage organs, named the Gastrolith.
In recent years, some of the inventors of the present invention have disclosed use of the gastrolith organs, ground to a fine powder useful as pharmaceutical and nutraceutical calcium compositions (WO 05/115414). It was disclosed that daily oral consumption of compositions comprising gastrolith components dramatically improves a range of conditions such as bone disorders, bone fractures, and cancer (WO 2008/041236). Pharmaceutical and nutraceutical compositions comprising ACC and phosphorylated peptides or amino acids for treating various disorders and conditions are disclosed in WO 2009/053967.
There is an unmet need for efficient treatment of calcium malabsorption, calcium malabsorption associated bone density loss and bone metabolism associated diseases.
USPTO Backgrounds
USPTO Backgrounds