Modified phosphocalcic compound, injectable composition containing same

#The invention relates to a phosphocalcic compound modified with a gem-biphosphonic compound, to a process for preparing it and to its use for producing an injectable composition.

#Deregulation of bone activity of an individual is the cause of many bone pathologies such as osteoporosis, Paget's disease or osteolytic tumors. Taking into account, in particular, the increase in human life expectancy, osteoporosis has become a public health problem and much research has been undertaken to remedy it. Since the bone pathologies under consideration are caused by an imbalance in bone remodeling to the benefit of the activity of the osteoclasts, one of the routes of treatment envisioned consisted in reducing the activity of the osetoclasts, in order to slow down the degradation of the bone material.

#Studies performed on various gem-biphosphonic acids have shown their inhibitory power on osteoclast activity (G. A. Rodan et al., Therapeutic Approaches to Bone Diseases, 1 Sep. 2000, Vol. 289, Science, pp. 1508-1514). The use of some of them as medicaments, especially etidronate, clodronate, pamidronate, alendronate, risedronate, tiludronate and ibandronate, has been accepted in various countries. Data have been published for other gem-biphosphonic acid compounds, especially zoledronate, incadronate, olpadronate and neridronate. The gem-biphosphonic acids that are used at the present time for the treatment of bone lesions are used systemically and, as a result, give rise to a few undesirable side effects. They can cause renal disorders when they are administered intravenously, and digestive system disorders, especially esophagitis or stomach ulcers, when they are administered orally [(Lin J. H., Bone 1996; 18; 75-85) or (Thiébauld D. et al., Osteoporos Int. 1994; 76-73)]. Another drawback of the oral administration lies in the low level of absorption of the active principle onto bone material.

#FIG. 1 represents the liquid 31P NMR spectrum of the supernatant obtained in Example 1 after centrifugation of the reaction medium corresponding to the CDA precursor (NaOH route).

#FIG. 2 shows a photograph by scanning electron microscopy (SEM) performed on the compound obtained from β-TCP in Example 1.

#FIG. 3 shows solid 31P MAS NMR data for the compound obtained from β-TCP in Example 1.

#The present invention is described in greater detail by the examples that follow, which are given for illustrative purposes and to which the invention is not limited.

#The following compounds and reagents were used: ultrapure water: water with a resistivity in the region of 18 MΩ cm sodium zoledronate: gem-biphosphonic acid sold by the company Novartis sodium tiludronate: gem-biphosphonic acid sold by the company Sanofi-Synthélabo NaOH-route CDA: calcium-deficient hydroxyapatite obtained by hydrolysis of dicalcium phosphate dihydrate with aqueous NaOH solution (in the form of granules with a particle size of 40-80 μm) ammonia-route CDA (calcium-deficient hydroxyapatite obtained by hydrolysis of dicalcium phosphate dihydrate with aqueous ammonia), in the form of granules with a particle size of 40-80 μm β-TCP, in the form of granules with a particle size of 40-80 μm BCP (75% β-TCP/25% HA) in the form of granules with a particle size of 40-80 μm BCP (25% β-TCP/75% HA) in the form of granules with a particle size of 40-80 μm.

#A suspension of calcium phosphate was prepared by introducing 700 mg of BCP with a particle size of 40-80 μm into 3.5 ml of ultrapure water, and 56 mg (0.14 mmol) of zoledronate were added. The suspension was placed in a tube maintained at room temperature, and was stirred with a rotary stirrer at 15 rpm for 48 hours. The suspension was then centrifuged and the pellet was separated from the supernatant.