Since the 1960s, when inhibitors of crystallisation were first talked about, many substances were classified as inhibitors due to their ability to prevent or reduce the formation of crystals. However, there is a shortage of substances that prevent the dissolution of already formed crystals, especially in living systems.
The dissolution of already formed salts is especially relevant in some disorders such as osteoporosis. Osteoporosis is a reduction of bone mass and mechanical strength leading to susceptibility to fractures. It is the main cause of bone fractures in post-menopausal women and in old people in general. Osteoporosis does not have a well-defined beginning and until recently, the first visible sign of the disease was often a fracture of the hip, wrist or of vertebrae that gave rise to pain or deformation. Menopause is the main cause of osteoporosis in women due to a reduction in estrogen levels. Osteoporosis affects one out of every five women over age 45 and four out of every ten over age 75.
The best treatment for osteoporosis is prevention. An adequate calcium intake and physical exercise during adolescence and youth can increase the density of bone mass, which results in a reduction in bone mass loss and in less risk of fractures in later years. Adequate consumption of calcium and vitamins during maturity is essential for bone health. Hormone replacement therapy requires strict gynecological control and careful selection of patients. In post-menopausal women with low bone mass or with established osteoporosis and for whom hormone replacement therapy is counterindicated, bisphosphonates (alendronate or etidronate) and calcitonin are effective medicaments for preventing bone loss.
Phytate or myo-inositol hexaphosphate is a molecule whose properties as a crystallisation inhibitor of calcium salts is well known (Grases F, Kroupa M, Costa-Bauzá A. Studies on calcium oxalate monohydrate crystallisation. Influence of inhibitors. Urol Res 1994; 22: 39-43. Grases F. Costa-Bauzá A. Potentiometric study of the nucleation of calcium oxalate in presence of several additives. Clin Chem Enzym Comms 1991; 3: 319-328. Grases F, Ramis M, Costa-Bauzá A. Effects of phytate and pyrophosphate on brushite and hydroxyapatite crystallization. Comparison with the action of other polyphosphates. Urol Res 2000; 28: 136-140). As it is a molecule with six phosphate groups, it shows a high affinity for divalent and trivalent metallic ions, such as calcium. It is precisely this affinity for calcium that leads to its property of inhibition of crystallisation of calcium salts, due to its high ability to adsorb on to surface of nuclei in formation or growing crystals. This ability gives phytate its properties for the prevention of the development of pathological calcifications, such as renal lithiasis (Conte A, Pizá P, García-Raja A, Grases F, Costa Bauzá, Prieto R M. Urinary lithogen risk test: usefulness in the evaluation of renal lithiasis treatment using crystallization inhibitors (citrate and phytate). Arch Esp Urol 1999; 52: 305-310) or cardiovascular calcifications (Grases F, Sanchis P, Perelló J, Isem B, Prieto R M, Fernández-Palomeque C, Fiol M, Bonnin O, Torres J J. Phytate (myo-inositol hexakisphosphate) inhibits cardiovascular calcifications in rats. Front Biosci 2006; 11: 136-142).
Surprisingly, the inventors of the present invention have found that the high adsorption capacity of phytate on calcium salts can be utilised to prevent the dissolution of already precipitated calcium salts, introducing a new property to phytate that has direct repercussions on certain disorders, such as osteoporosis, making it possible to utilise it to treat this disease.
The document that comes closest to the invention in the state of the art is the Chinese patent CN1295862. In summary, the patent discloses a method to treat osteoporosis based on the reaction between egg shell and acetic acid, forming calcium acetate that is used as a calcium supplement for the patient. At the same time, lysozyme and a protein of phytic acid (not phytate directly, but a different compound) were utilised to regulate the absorption of calcium, which is the agent utilised to act against osteoporosis.
In U.S. Pat. Nos. 5,057,507, 5,015,634 and WO9109601, isomers of inositol triphosphate are disclosed for the preparation of medicaments for treatment of bone disorders. As indicated in the description of this invention, the compound of the present invention, due to its structure, presents higher inhibitory potential on crystals of calcium salts and consequently provides more effective medicaments for the treatment of bone disorders, such as osteoporosis.
USPTO Backgrounds
USPTO Backgrounds