MXPA06002384A - Injectable calcium phosphate solid rods and pastes for delivery of osteogenic proteins - Google Patents

Abstract

Osteogenic proteins are delivered via an injectable solid rod or hardenable paste. The formulation comprises a calcium phosphate material, an osteogenic protein, and optional additives and active ingredients such as a bone resorption inhibitor. Methods of making injectable pharmaceutical compositions and methods of usingthe osteogenic compositions to treat bone defects are also disclosed.

Description

SOLID BAR AND PASTE OF INJECTABLE CALCIUM PHOSPHATE FOR SUPPLY OF OSTEOGENIC PROTEINS FIELD OF THE INVENTION The present invention relates to the field of osteogenic proteins and pharmaceutical formulations therefor.

BACKGROUND OF THE INVENTION Idiopathic osteoporosis is a disease of unknown etiology characterized by progressive loss of bone mass and increasing frailty, resulting in a marked increase in susceptibility to fracture. Osteoporosis is among the most prevalent skeletal muscle disorders that affect 56% of women over 45 years of age. Praemer et al., "Musculoskeletal Conditions in the United States", Amer. Acad. of Orthopedic Surgeons, Park Ridge, IL (1992). Because its incidence increases with age and the percentage of old people in the population increases, osteoporosis will become more common over time. Osteoporosis is difficult to treat locally and there is currently no known cure. Finally, and more significantly, osteoporosis is associated with substantial morbidity and mortality. The most severe fracture resulting from osteoporosis is that of Ref .: 170668 proximal femur in the region of the hip joint. With an annual incidence of more than 300,000 hip fractures, it is currently the most common fracture in old age. One in six Caucasian women will have a hip fracture during their lifetime (Cummings et al., Arch. Intern Med., Vol 149, pp. 2455-2458 (1989)), and those who reach the age of 90 , this proportion will become one in three. In addition to treating osteoporotic disease, there is a need for methods to treat or prevent fractures related to osteoporosis, for example by local administration of osteogenic proteins. Osteogenic proteins are those proteins capable of inducing or helping in the induction of cartilage and / or bone formation. In recent years many of these osteogenic proteins have been isolated and characterized and some have been produced by recombinant methods. In addition, various formulations designed to deliver osteogenic proteins have been developed at the site where induction of bone formation is desired. But despite substantial efforts in this field there is still a need for an effective method to repair and / or treat osteoporotic and osteopenic bone and to minimize or reduce the incidence or severity of fractures related to osteoporosis.

SUMMARY OF THE INVENTION The present invention relates to compositions for the injectable delivery of osteogenic proteins, i.e., osteogenic compositions. The compositions may take the form of a solid stick, preferably a cylindrical solid stick or a hardenable paste. The compositions comprise an osteogenic protein and a calcium phosphate material. In some preferred embodiments of the present invention, the osteogenic protein is a member of the family of bone morphogenetic proteins, most preferably one of BMP-2, BMP-4, BMP-5, BMP-6 ,. BMP-7, BMP-10, BMP-12 and BMP-13, more preferably BMP-2. The osteogenic protein is preferably present in an amount ranging from about 1% to about 90%, more preferably from about 15% to about 40% by weight of the solid bars of the , invention and in an amount ranging from approximately 0. 01% to about 2%, more preferably from about 0.03% to about 1% by weight of the paste of the invention. In some preferred embodiments of the present invention, the calcium phosphate material comprises a material that is selected from amorphous apatite calcium phosphate, sparingly crystalline apatite calcium phosphate, hydroxyapatite, tricalcium phosphate, fluoroapatite and combinations thereof. More preferably, the calcium phosphate material is sparingly crystalline apatite calcium phosphate. The calcium phosphate material is preferably present in an amount ranging from about 10% to about 99%, more preferably from about 40% to about 60% by weight of the osteogenic composition in stick form, and in an amount which ranges from about 30% to about 70%, more preferably from about 45% to about 55% by weight "of the hardenable paste osteogenic composition.Additional embodiments of the present invention relate to osteogenic compositions which also comprise a resorption inhibitor osseox The inhibitor of bone resorption is preferably a bisphosphonate which is selected from alendronate, cimadronate, clodronate, EB 1053, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate and salts, esters, acids and pharmaceutically acceptable mixtures thereof. Additional embodiments of the present invention relate to osteogenic compositions which also comprise an additive which is selected from the pharmaceutically acceptable forms of salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants and combinations thereof, more preferably they are selected from carboxymethylcellulose, hydropropylmethylcellulose, methylcellulose, polylactide, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol, dextran sulfate and combinations thereof. The additive is preferably present in an amount ranging from about 1% to about 90%, more preferably from about 20% to about 40% by weight of the osteogenic composition in bar form and in an amount ranging from about 1. % up to about 90%, more preferably from about 10% to about 20% by weight of the hardened paste osteogenic composition. When the osteogenic composition of the present invention takes the form of a solid cylindrical bar, the diameter of the cylindrical bar is preferably between about 0.1 mm and 3.0 mm,. more preferably between about 1.0 mm and the length of the cylindrical bar preferably is between about 0.5 cm and 5.0 cm. A further embodiment of the present invention relates to a method for preparing a rod-shaped composition for the injectable delivery of osteogenic proteins, the composition comprising an osteogenic protein and a calcium phosphate material, comprising the steps of: ) mix a dry form of the psteogenic protein with a dry form of the calcium phosphate material to produce a dry mixture; (b) reconstitute the dry mix by adding an aqueous buffer to form a paste; (c) molding the dough to form a stick-like composition; and (d) drying the bar-like composition of step (c) to form a rod-shaped composition for injectable delivery of osteogenic proteins. In preferred embodiments, the aqueous buffer is selected from phosphate buffered saline, glycine and glutamic acid based buffers and combinations thereof. The ratio of volume to weight (in ml: g) of the aqueous buffer relative to the dry mixture ranges from about 0.5: 1 to about 2: 1. The molding is preferably carried out by molding, extruding, pressing, perforating or combinations thereof. In some preferred embodiments, the stick-like composition is cut before or after step (d). In still another embodiment, the present invention relates to a method for preparing a paste composition for injectable delivery of osteogenic proteins, the composition comprising an osteogenic protein and a calcium phosphate material, comprising the step of mixing a dry form of the calcium phosphate material with an aqueous buffer containing an osteogenic protein to form a paste. In preferred embodiments of the present invention, the aqueous buffer is selected from phosphate buffered saline, saline, glycine and glutamic acid based buffers and combinations thereof. The ratio of aqueous buffer to calcium phosphate material ranges from about 0.5: 1 to about 2: 1. Additional embodiments of the present invention relate to methods of treating a mammal having a bone defect comprising administering to the site of the bone defect an effective amount of a composition for the injectable delivery of osteogenic proteins claimed herein. Additional embodiments of the present invention relate to methods of treating a mammal having a bone defect, comprising the steps of: (a) administering at the site of the bone defect an effective amount of a composition for injectable delivery of osteogenic proteins which are claimed herein, and (b) administering at the site of the bone defect an effective amount of a bone resorption inhibitor. The administration of the bone resorption inhibitor can be carried out before step (a), after step (a) or simultaneously with step (a).

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph showing the kinetics of in vitro release of rhBMP-2 from a-BSM bars using 125 I-rhBMP-2 as a tracer. Figure 2 is a graph showing the in vivo local retention of rhBMP-2 from a-BSM bars using 125I-rhBMP-2 as a tracer.

DETAILED DESCRIPTION OF THE INVENTION Generally, the methods and compositions of the present invention relate to the regeneration of bone tissue and the concomitant increase in bone mass, bone density and bone strength. More particularly, the present invention involves injectable solid sticks and pastes comprising an osteogenic protein, a calcium phosphate carrier and optional additives and active agents such as a bone resorption inhibitor as well as methods for preparing such osteogenic compositions and methods of treatment that they use said osteogenic compositions.

The solid calcium phosphate bars and hardenable pastes of the present invention are suitable for intraosseous delivery of osteogenic proteins. By using the methods and compositions of the present invention it is advantageous to reduce the severity of osteoporosis or the incidence of osteoporotic lesions, ultimately decreasing the incidence of bone bills. Other clinical uses include fracture repair, cartilage repair, repair of non-union defects, and spinal fusion. The injectable solid sticks and hardenable pastes of the present invention can also be used to promote bone growth as needed when using joint replacement implants as described in the provisional application of E. U. A. No. 60 / 502,526, ("Promotion of Bone ingrowth in Joint Replacement Implants Using Osteogenic Proteins"), the subject matter of this provisional application is hereby incorporated by reference in its entirety. A first embodiment of the present invention relates to a rod-shaped composition for the injectable delivery of osteogenic protein comprising an osteogenic protein and a calcium phosphate material. A composition according to a first embodiment of the present invention optionally includes other additives (binders, excipients) and / or active agents such as a bone resorption inhibitor. This composition in solid bar form is suitable for local intraosseous administration and can therefore be injected directly into the osteoporotic or osteopenic site to effectively induce bone formation and / or maintenance. In addition, the composition in the form of an injectable bar has a sustained release profile with respect to the osteogenic protein when administered in this manner. Preferably, the solid rods of the present invention are cylindrical and have a diameter ranging from about 0.1 mm to about 3.0 mm, more preferably from about 1.0 mm so as to allow their administration with a 16 gauge needle. solid bars preferably have a length ranging from about 1.0 mm to about 5.0 cm. Unlike existing injectable formulations, the osteogenic composition of this first embodiment of the present invention is administered in a solid form, whereby deficiencies inherent in liquid or viscous formulations are avoided. For example, using liquid or gel formulations, the osteogenic agent can be prematurely diluted by the body fluids before the bone promoter is indeed obtained. The present invention eliminates the effect of dilution by using a solid carrier which degrades slowly in vivo, whereby a sustained and delayed release of one or more of the active agents is provided. In addition, unlike liquid or viscous formulations which can be displaced from the administration site, the solid compositions of the present invention are housed and persisted at the desired bone growth site to carry out the bone growth promoting activity. In addition, they allow the placement ^ of the injectable ^ more precisely of a solid bar in areas of low bone mass. Typically, the composition must persist on the site for a period from about 5 days to about 2 months. If the composition is dispersed prematurely, the bone growth promoting effect that is desired will not occur or bone will be formed that does not have the desired strength. Finally, although the osteogenic composition of this embodiment of the present invention is administered as a solid, it is preferably formed as a cylindrical bar, whereby it is suitable for either injection or implantation in the body. Of course, if desired, other bar shapes can be used, for example hexagonal, square or semicircular bar shapes. In addition, the well-known surgical complication of inducing an embolism during an intraosseous injection procedure is considerably reduced by the use of solid bars (as compared to liquid or gel forms). The potential displacement of intraosseous bone fragments, fat or an embolus caused by a pressurized injection of a large volume of a liquid / gel carrier is reduced since the injected volume of the highly concentrated solid bar is much less than what is required if a similar dose is given in a liquid or gel form. The composition can be applied to the desired bone growth site in any convenient manner, including introduction through a conventional hypodermic needle or syringe. A second embodiment of the present invention relates to a method for preparing the composition in solid bar form for injectable administration of osteogenic proteins. In the first stage, the dry form of the osetogenic protein is mixed with a dry form of the calcium phosphate material to produce a dry mixture. In other words, the pulverized or dried forms of both the osteogenic protein and the calcium phosphate material are initially used in order to form a dry mixture. When additives and / or additional active sites are included in the composition, these materials can also be used in a dry or powdered form and can be included in the dry mix. In the second stage, the dry mix is reconstituted by adding an aqueous buffer to form a paste. Suitable aqueous buffers include, without limitation, phosphate buffered saline, saline, glycine based buffers and combinations thereof. When BMP-2 is used as the osteogenic protein, a glycine-based buffer having a pH of about 4.5 is preferred for use.; more preferably, a glycine-based buffer having a composition of 5 mmole of L-glutamic acid, 2.5% glycine, sucrose Q_.5%., "NaCl ..._ 5.-mmol.es _y_pp_Lis rbate_80 O .01 %. A ratio of volume to weight (ml: g) of aqueous buffer relative to the dry mixture ranges from about 0.5: 1 to about 2: 1. However, the lower limit of the proportion by weight is limited only by the concern that sufficient liquid is added to the dry mix so that it is sufficient to allow the formation of a paste which can be formed by injection through of a syringe or some other method. In addition, the upper limit of this weight ratio is limited only by the concern that too much liquid is not added to the dry mix so that, by subsequent drying, the geometry is obtained, that is, the shape of the bar; in other words, if too much liquid is used, then the bar form that is formed in the third stage of this method will be compromised when the osteogenic compound is dried. This step is carried out under conditions where substantially uniform mixing occurs. The mixing combines, the ingredients and can be used to regulate the spread of reactions between the ingredients. When all of the desired ingredients are preferably contained in the dry mixture, it is also possible to add an additive or an additional active agent immediately before the start of mixing or before completing the mixing. Such additional additive or active agent preferably is in dry form; however, a hydrated form of the additive or the additional active agent can also be added to the pulp. In the third step of the present method of the invention, the dough is molded to form a stick-like composition. The molding or shaping can be carried out using any of a number of known techniques such as molding, extrusion, pressing, perforation and / or cutting. In a preferred embodiment of this invention, the dough is packed inside and extruded through the end of the hub of a hypodermic syringe. In this case, the plunger of the syringe is inserted and a sufficient amount of pressure is applied to extrude a continuous length of paste onto a dry surface. The sections are then cut using a cutting tool such as a razor, a scalpel, a blade or the like, to form injectable rod-shaped compositions. The cutting can also be carried out after the drying step described below. Alternatively, the paste can be packaged in a cylindrical mold, catheter, air or gas permeable pipe (eg silastic or Teflon ^ / FEP) or any other extrusion type apparatus. In the final step, the bar-like composition obtained in the previous step is dried or hardened to form the rod-shaped composition for injectable administration of osteogenic proteins of the present invention (first mode). The drying can be carried out by air drying or incubation at elevated temperatures, i.e. at least 37 ° C. The drying temperature is limited only by the concern of degradation of the osteogenic protein, which typically occurs at some point in the range of 55 ° C and 60 ° C. When the drying is carried out in an oven at 37 ° C, the drying requires about at least one hour, and preferably the drying is carried out overnight. The bar-like composition preferably has a residual moisture of less than 10%. A third embodiment of the present invention relates to a hardenable paste composition for injectable administration of osteogenic proteins comprising an osteogenic protein and a calcium phosphate material. A composition according to this third embodiment of the present invention may optionally include other additives (binders, excipients) and / or active agents such as a bone resorption inhibitor.

This paste is suitable for local intraosseous administration and can therefore be injected directly into an osteoporotic or osteopenic site whereby the paste hardens to a solid form and effectively induces the formation and the maintenance of bone. Because the paste hardens upon injection into an environment at least 37 ° C, ie within a mammal, many of the disadvantages associated with the use of liquid or gel compositions are avoided. Similar to the injectable composition in solid bar form described above, the hardened paste composition has a sustained release profile with respect to the osteogenic protein. The injectable duration of the hardenable paste can be prolonged by cooling the paste. A fourth embodiment of the present invention relates to a method for preparing the paste composition for injectable administration of osteogenic proteins. In this method, a dry form of the calcium phosphate material is mixed with an aqueous buffer containing an osteogenic protein to form a paste. When additional additives and / or active agents are included in the composition, these materials can be used either in dry form or they can be premixed with the dry form of the calcium phosphate material or in a hydrated form to be mixed directly with the water buffer and calcium phosphate material. The mixing is carried out under conditions where mixing occurs . substantially uniform. Mixing combines the ingredients and can be used to regulate the spread of _5 _._ Q_reactions__between ^^ the_ ingredients. Suitable aqueous buffers include, without limitation, phosphate buffered saline, saline, glycine based buffers and combinations thereof. When BMP-2 is used as the osteogenic protein 0, a glycine-based buffer having a pH of about 4.5 is preferred for use; more preferably a glycine-based buffer having a composition of 5 mmoles of L-glutamic acid, 2.5% glycine, 0.5% sucrose, 5 mmoles of NaCl and polysorbate 5 80 0.01% is used. A weight ratio of aqueous buffer to dry calcium phosphate ranges from about 0.5: 1 to about 2: 1. Alternatively, a dry form of the osteogenic protein is mixed with a dry form of the calcium phosphate material to produce a dry mixture and the dry mixture is then reconstituted by adding an aqueous buffer to form a paste. These steps can be identical to the first and second steps of the method of preparing the composition in the form of solid bar above (second embodiment), except that the weight ratio of aqueous buffer to dry calcium phosphate varies from about 0.5: 1 to about 2: 1. Details regarding the active agent, carrier, additives and bone resorption inhibitors suitable for use in the present invention are provided in the following.

ACTIVE AGENT The active agent present in the osteogenic compositions of the present invention is preferably selected from the family of proteins known as the transforming growth factor (TGF-β) superfamily of proteins. This family includes activins, inhibins and bone morphogenetic proteins (BMPs). These BMPs include the BMP, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 and BMP-7 proteins, described, for example, in the U.S. Patents. Nos. 5,108,922, 5,013,649, 5,116,738, 5,106,748, 5,187,076 and 5,141,905, BMP-8, described in PCT WO 91/18098, BMP-9, described in PCT WO 93/00432, BMP-10, described in PCT WO 94/26893, BMP-11 described in PCT WO 94/26892, BMP-12 and BMP-13, described in PCT WO 95/16035, BMP-15, described in the US patent No. 5,635,372 and BMP-16, described in the US patent. 6,331,612. Other TGF-β proteins which may be useful as the active agent of the present invention include Vgr2, Jones et al. , Mol.

Endocrinol., Vol. 6, pp. 1961 1968 (1992) and any of the growth and differentiation factors (GDF) including those described in PCT WO 94/15965, WO 94/15949, WO 95/01801, WO 95/01802, WO 94/21681, __5_ WO 94/15966, WO 95/10539, WO 96/01845, WO 96/02559 and others. BIPs, described in WO 94/01557, HP00269, described in JP 7 250688 and MP52, described in PCT WO 93/16099 can also be useful in the present invention. Descriptions of all patents, periodicals and previous published international applications are incorporated herein by reference. Preferably, the active agent includes at least one protein that is selected from the subclass of proteins generally known as BMPs, which have been described that they have osteogenic activity and other activities of type of growth and differentiation. A 'subset of the BMPs which are currently preferred for use in the present invention include BMP-2, BMP-4, BMP-5, BMP-6, .BMP-7, BMP-10 and BMP-13, in a more preferable BMP-2, whose The sequence is described in the patent of E.U.A. 5,013,649, the disclosure of which is incorporated herein by reference. The active agent can be produced recombinantly or purified from a protein composition. The active agent, if it is a TGF-β such as a BMP or other dimeric protein, can be homodimeric or can be heterodimeric with other BMPs (for example a heterodimer composed of a monomer each of BMP-2 and BMP-6) or with other members of the TGF-β superfamily, such as activins , unhibines and TGF-β1 (for example, a heterodimer consisting of a monomer each of a BMP and a related member of the TGF-β superfamily). Examples of such heterodimeric proteins are described, for example, in PCT WO 93/09229, the disclosure of which is incorporated herein by reference. The active agent can comprise DNA encoding BMPs and cells transduced or transfected with genes encoding BMP proteins. The active agent may further comprise additional agents such as Hedgehog, Frazzled, Chordin, Noggin, Cerberus and Follistatin proteins. These protein families are generally described in Sasai et al., Cell, vol. 79, pp. 779-790 (1994) (Chordin); PCT WO 94/05800 (Noggin); and Fukui et al., Dev. Biol., vol. 159, pp. 131-139 , (1993) (Follistatin). The Hedgehog proteins (pig spin) are described in PCT WO 96/16668, EO 96/17924 and-WO 95/18856. The Frazzled protein family is a relatively recently discovered family of proteins with high homology by the extracellular binding domain of the family of receptor proteins known as Frizzled. The Frizzled family of genes and proteins is described in Wang et al., J. Biol. Chem., Vol. 271, pp. 4468-4476 (1996). The active agent may also include other soluble receptors, such as truncated soluble receptors described in PCT WO 95/07982. From the teachings of WO 95/07982, a person skilled in the art will recognize that truncated soluble receptors can be prepared for numerous additional receptor proteins. Such may also be encompassed within the present invention. The above publications are incorporated herein by reference in this document. The amount of active agent useful herein is that amount effective to stimulate. increased osteogenic activity of the current or infiltrating parent (osteoblast precursor cells) or other cells (hereinafter "effective amount") and will depend on the size and nature of the defect being treated as well as the composition of the calcium phosphate carrier used . Generally, the amount of osteogenic protein present in an osteogenic composition in solid bar form of the present invention ranges from about 1% to about 90%, more preferably from about 15% to about 40% by weight of the osteogenic composition. Generally, the amount of osteogenic protein present in an osteogenic hardened paste composition of the present invention ranges from about 0.01% to about 2%, more preferably from about 0.03% to about 1% by weight of the osteogenic composition.

CARRIER According to all embodiments of the present invention, a calcium phosphate material is used as a carrier. As used herein, a "calcium phosphate material" means any substitute bone synthetic material, which comprises calcium phosphate as the primcomponent, ie, having at least 90% by weight attributable to calcium and / or phosphate. The calcium phosphate material of the present invention can be any biocompatible calcium phosphate material known in the art. Suitable calcium phosphate materials can be produced by any of a variety of methods and can use any of the appropriate initial components. or they may be commercially available. In some preferred embodiments of the present invention, the calcium phosphate material is present in an amount ranging from about 10% to about 99%, more preferably from about 40% to about 60% by weight of the osteogenic composition in solid rod shape of the present invention. In some other preferred embodiments of the present invention, the calcium phosphate material is present in an amount ranging from about 30% to about 70%, more preferably, from about 45% to about 55% by weight of a composition Osteogenic of hardenable paste _5. present._invention. Preferably, the calcium phosphate material or carrier is used in dry form, i.e., pulverized. Calcium phosphate forms suitable for use in this invention include, without limitation, amorphous calcium or apatite phosphate (ACP), sparingly crystalline apatite calcium phosphate (PCA), hydroxyapatite. (HA, for its acronym in English), tricalcium phosphate and fluoroapatite. In a preferred embodiment, the calcium phosphate material is sparingly crystalline apatite solid calcium phosphate having a ratio of calcium to phosphate (Ca / P) comparable to naturally occurring bone minerals, more preferably , with a ratio of calcium to phosphate less than about 1: 1.5, more preferably about 1: 1.4. Suitable PCA materials can be identified by combining PCA precursors, hydrating with a limited amount of water (so that a paste or putty is formed), molding a cylindrical rod shape and allowing the molded material to harden into a material PCA. Desirable precursors are capable of hardening in a humid environment, at or about body temperature in less than 5 hours, and preferably within a period of 10-30 minutes. ... ... __ Of _ I agree with the "present. invention, the calcium phosphate carrier can comprise any bone substitute material containing one of the above forms of calcium phosphate as its primcomponent, ie having at least 90% by weight attributable to calcium and / or phosphate . The bone substitute material may comprise only one of the above forms of calcium phosphate, with or without additional components; The bone substitute may comprise a combination of the above forms of calcium phosphate, with or without additional components. In addition, one of the forms indicated above of calcium phosphate can be used to prepare a calcium phosphate material suitable for use in the present invention. Methods for producing such materials are well known in the art. However, any method that results in obtaining a dry, ie pulverized, calcium phosphate material is suitable. As used herein, the term "amorphous" means a material with a significant amorphous character. A significant amorphous character contemplates more than 75% amorphous content, preferably more than 90% amorphous content and is characterized by an X-ray diffraction pattern without characteristics, large. The terms "sparingly crystalline apatite calcium phosphate", "calcium phosphate PCA" and "PCA material" as those terms as used herein, describe a sparingly crystalline synthetic apatite calcium phosphate. The sparingly crystalline apatite material (PCA) is not necessarily limited to a single calcium phosphate phase with the proviso that it has the characteristic X-ray diffraction (XRD) and an infrared Fourier transform pattern ( FTIR, for its acronym in English). A calcium phosphate PCA has substantially the same XRD spectrum as bone. The XRD spectrum is generally characterized by. only two broad peaks in the 20-35E region with one centered at 26E and the other centered at 32E. The FTIR spectrum is characterized by peaks at 563 cm "1, 1034 cm" 1, 1638 cm "and 3432 cm" 1 (± 2. Cm "1); abrupt protrusions are observed at 603 cm "1 and 875 cm" 1 with a doublet that has a maximum at 1422 cm "1 and 1457 cm" 1. Preferred PCA materials for use in the present invention are described in the U.S.A. Us 5,650,176, 5,683,461 and 6,214,368 each of which is incorporated herein by reference. Suitable materials are also described in a set of related applications, entitled "Delivery Vehicle", "Conversion of Amorphous Calcium Phosphate to Form to Novel Bioceramic", "Orthopedic and Dental Ceramic Implants" and "Bioactive Ceramic Composites", each of the which was presented on October 16, 1997 and assigned to ETEX Corporation (Cambridge, MA) and is incorporated as a reference in this. Based on the scope of the description in each of the patent documents indicated above, the details of production of the appropriate PCA materials will not be included here. A summary of the characteristics of PCA will suffice. The PCA material is characterized by its ability to be bioabsorbable and its minimum crystallinity. Its crystalline character is substantially the same as that of natural bone. The PCA material is also biocompatible and is not harmful to the host. Crystalline hydroxyapatite (HA) is described, for example, in U.S. Patent Nos. 33,221 and 33,161, both of which are incorporated by reference herein. These patents describe the preparation of remineralization compositions of calcium phosphate and a gradually resorbable, non-ceramic, finely crystalline hydroxyapatite carrier material based on the same calcium phosphate composition. A similar calcium phosphate system, which consists of tetracalcium phosphate (TTCP, for its acronym in English) and monocalcium phosphate (MCP) or its monohydrated form (MCPM. describe in the US patents Nos. 5,053,212 and 5,129,905 both of which are incorporated herein by reference in this document. Additional crystalline HA materials (commonly referred to as dahllite) are described in the US patent. No. 5,962,028, the disclosure of which is incorporated herein by reference.

ADDITIVES The additives may be useful in the osteogenic compositions of the present invention. Many of the binders, which improve the cohesiveness and the excipients, which stabilize and / or modulate the release of the active ingredients, are well known in the art of formulations. Suitable additives include, without limitation, pharmaceutically acceptable forms of salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers and / or surfactants. Useful polymers include, for example, those described in the U.S.A. No. 5,171,579, the complete description of which is incorporated herein by reference. Preferred additives include cellulosic materials such as carboxymethylcellulose (CMC), hydroxypropylmethylcellulose (HPMC) and methylcellulose (MC), synthetic polymers such as polylactides and polyethylene glycols. , for example polylactide / polyethylene glycol, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), polyoxyethylene oxide, carboxyvinyl polyvinyl alcohol (PVA) and polyvinyl alcohol (PVA). dextran sulfate, and combinations thereof. Other useful additives include, without limitation, sodium alginate, chitosan, collagen, gelatin, hualuronan and various peptides, proteins and amino acids. The additives which have an effervescent effect are not currently designed for use in the present invention. In a preferred embodiment of the present invention an additive is used in a dry or powder form, which is mixed with one or more active agents, a carrier and an aqueous liquid in order to prepare an injectable composition of the present invention. In some preferred embodiments of the present invention, one or more of the additives are present in an amount ranging from about 1% to about 90%, more preferably from about 20% to about 40% by weight of the osteogenic composition of solid bar In some preferred embodiments of the present invention, one or more of the additives are present in an amount ranging from about 1% to about 90%, more preferably from about 10% to about 20% by weight of the osteogenic composition of Hardened paste ADDITIONAL ACTIVE AGENTS The injectable osteogenic compositions of the present invention may also include an additional active agent or additional active agents. Such additional active agents can be mixed, preferably in dry form although hydrated forms are also suitable for use, with the active agent, carrier and aqueous liquid for the purpose of preparing the injectable osteogenic compositions of the present invention. Alternatively, such additional active agents can be co-administered with the osteogenic compositions of the present invention, either in some way sequentially or simultaneously (hereinafter "co-administration scheme"). The additional active agents can be used herein in order to obtain additional desired effects or, in some cases they can be used to counteract the potential undesirable effects, such as infection, inflammation and transient resorption. For example, although much is known about the osteogenic potential of TGF-β proteins, recent reports show that local administration of certain osteoinductive agents, such as BMP-2, stimulates transient osteoclastic activity (local areas of bone resorption) in the administration site. This reaction, which occasionally precedes the formation of new bone _ induced by BPM, has been termed "transient resorption phenomenon". Agents that are known to inhibit bone resorption can therefore play an important role in delaying or reducing initial bone resorption related to the administration of local BMP, without inhibiting subsequent bone formation. Therefore, in the preferred embodiments of the present invention, a bone resorption inhibitor is used as an additional active agent present in the injectable osteogenic composition or coadministered with the injectable osteogenic composition in order to avoid or minimize the initial bone resorption. related to the intraosseous administration of an active agent such as BMP. As used herein, the term "inhibition of bone resorption" refers to the prevention of bone loss, especially the inhibition of existing bone separation through direct or indirect alteration of osteoclast formation or activity. Therefore, the term "bone resorption inhibitor", as used herein, refers to agents that prevent or inhibit bone loss by directly or indirectly altering the formation or activity of osteoclasts. In some preferred embodiments, the bone resorption inhibitor is a bisphosphonate. As used herein, the term "bisphosphonate" refers to acids and related salts, bisphosphonates. __? ___. to. various crystalline and amorphous forms of the bisphosphonate. Clinically, bisphosphonate therapy has been shown to markedly reduce bone turnover rates, increase bone mineral density and, in osteopenic women, reduce the risk of fractures in the hip and spine. (see, for example, H. Fleisch, Bisphosphonates in Bone Disease, from the Laboratory to the Patient, 3a. edition, Parthenon Publishing (1997), which is incorporated as a reference in the present). The bisphosphonates suitable for use in the present invention include, without limitation, alendronate, cimadronate, clodronate, EB 1053, etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate and pharmaceutically acceptable forms of salts. , esters, acids and mixtures thereof. The amount of bisphosphonate and indeed the amount of any useful bone resorption inhibitor is that amount effective to prevent or inhibit the transient bone loss occasionally associated with the local administration of an osteogenic protein such as BMP (hereinafter "effective amount"). ), through direct or indirect alteration of osteoclast formation or activity. The precise dosage needed will depend on the size and nature of the bone defect being treated as well as the amount of osteogenic agent ... that __se. supply Generally, the amount of bisphosphonate to be administered is preferably in a range from about 0.1 to about 3000 mg, more preferably from about 10 to about 1000 mg, and much more preferably from about 10 to about 500 mg per cubic centimeter of material. When the co-administration scheme of the present invention is used, the bone resorption inhibitor is typically delivered in a suitable carrier. The carrier can be any pharmaceutically acceptable carrier, a wide variety of which are well known and readily available in the art (see, for example, Martin, EW, Remington's Pharmaceutical Sciences (Mack Publ. Co., current edition), which is incorporated herein by reference in this document). Currently preferred carriers are formed into solid bars or pastes, as described elsewhere herein. In the co-administration scheme, the bone resorption inhibitor can be administered sequentially, either before or after, or concurrently with the compositions in solid bar or injectable paste form of the present invention. In addition, the bone resorption inhibitor can be applied locally (intraosseous), but it can be applied in other parenteral sites such as intramuscular or subcutaneous or it can be ingested orally or it can be injected intravenously for systemic delivery. Preferably, the bone resorption inhibitor, for example a bisphosphonate, is administered systemically, i.e., orally or intravenously, either before or concurrently with the solid stick or injectable paste composition of the present invention. In addition, the bone resorption inhibitor can be implemented at the site to be treated, by surgical implantation. However, it should be noted that despite. To their therapeutic benefit, bisphosphonates are poorly absorbed in the gastrointestinal tract when taken orally. To avoid this problem of low bioavailability, intravenous administration has been used; however, this modality is considered expensive and inconvenient due to the duration and frequency of dosing. Therefore, the present invention can correct this deficiency by incorporating the bisphosphonate into injectable osteogenic compositions of the present invention and by delivering them locally directly at the desired site of action.

The above description relates to the administration of a bone resorption inhibitor that is generally related to the administration of any additional active agent. Other suitable additional active agents include, but are not limited to, other osteogenic proteins, antibiotics, antiinflammatory agents, growth factors, peptides, proteins, cytokines, oligonucleotides, antisense oligonucleotides, DNA and polymers. These compounds can be added, preferably in dry form, by mixing them to form the paste in the preparation methods of the present invention.

ADMINISTRATION In accordance with the present invention, methods and compositions are provided for the treatment of patients who have bone defects. As used herein, "bone defects" include osteoporotic bones, osteopenic bones, bone fracture, cartilage defect and any other condition related to bone or cartilage that can be improved or corrected with stimulation of bone growth. or cartilage. Therefore, a fifth embodiment of the present invention relates to a method of treating a mammal having a bone defect by administering to the site of the bone defect an effective amount of an injectable rod or paste composition of the present invention. A sixth related embodiment of the present invention is directed to a method of treating a mammal having a bone defect by administering at the site of the bone defect an effective amount of a rod or injectable paste composition of the present invention and by administering an amount effective of a bone resorption inhibitor. The bone resorption inhibitor can also be administered to the defect site in the bone, but it can also be administered by some other route, i.e., parenterally, surgically, orally, or intravenously. In addition, the administration of the bone resorption inhibitor can occur before or concurrently or after administration of the injectable stick or paste composition of the present invention. More commonly, the methods and compositions of the present invention are provided for the treatment of patients who exhibit signs of osteoporosis or osteopenic conditions that include osteoporotic bone lesions. The identification of such patients can be carried out by procedures which are well known in the art. Such procedures provide the physician with information regarding the location and severity of osteoporotic or osteopenic bone lesions. In addition to locating one or more of the lesions that are to be treated, the physician may use this information to select the appropriate mode of administration and the dose of osteoinductive agent for the patient. The procedures of dia_gnóst_iso ... useful, include ... jaedición. Bone mass / density using double energy X-ray absorptiometry (DEXA), Kilgus, et al., J. Bone & Joint Surgery, vol. 75 B, p. 279-287 (1992); Markel, et al., Acta Orthop. Scand., Vol. 61, pp. 487 498 (1990); and Quantitative Computed Tomography (QCT, for its acronym in English), Laval Jeantet, et al., J. Comput. Assist. Tomogr. , vol. 17, pp. 915-921 (1993); Markel, Calcif. Tissue Int., Vol. 49, pp. 427-432 (1991); single photon absorptiometry, Markel, et al. Calcif. Tissue Int., Vol. 48, pp. 392-399 (1991); ultrasound transmission speed (UTV); Heaney, et al., JAMA, vol. 261, pp. 2986-2990 (1989); Langton, et al., Clin. Phys. Physiol. Meas., Vol. 11, pp. 243-249 (1990); and radiographic determination, Gluer, et al., J. Bone Min. Res., vol. 9, pp. 671-677 (1994). Other methods of identifying patients at risk of bone fracture include determination of age-related factors, such as knowledge, as well as previous presentation of fractures related to osteoporosis. Porter, et al., BMJ, vol. 301, pp. 638-641 (1990); Hui, et al., J. Clin. Invest., Vol. 81, pp. 1804-1809 < 1988). The above publications are incorporated herein by reference in this document. The particular dosage regimens will be determined by the clinical indications that are established as well as by various patient variables (eg weight, age, sex) and clinical presentation (eg extent of damage, site of damage, etc.). The injectable osteogenic compositions of the present invention can be administered in any clinically acceptable manner of injection. Many commercially available syringes may be suitable for use in the present invention and for administration of the compositions of the present invention Such syringes include, without limitation, the Calasept syringe "(JS Dental Manufacturing, Ridgefield CT); the syringe of aspiration Henke-Jct "11 and syringes / needles Hypo" dental (Smith &Nephew MPL, Franklin Park, IL); intraosseous needles for MPL, Inc., Chicago IL; and Luer-Lok syringes "11 (Becton Dickinson, Franklin Lakes, NJ) Any syringe capable of holding and supplying a paste or an injectable bar and / or an extrusion enable with a obturator is considered suitable for use. of the invention, solid stick-like compositions are delivered intraosseously using a hypodermic needle of the appropriate size and type either percutaneously or surgically replaced in the selected anatomical position Percutaneous placement of the hypodermic needle can be carried performed using hand palpation or well-known anatomical established markings, with or without the use of fluoroscopy to visualize placement.Fluoroscopy may also be used in conjunction with surgical implantation before, and / or concurrently with the placement of the hypodermic needle. In a preferred embodiment, it is first inserted percutaneously into the desired anatomical site. guide wire (commonly referred to as a "K wire") that serves as a guide for the hypodermic needle. The hypodermic needle is inserted over the guidewire, which is then removed leaving only the hypodermic needle in place. The solid bar-like composition is then inserted into the hub end of the hypodermic needle. After loading the composition, a second guidewire is inserted into the needle, which is used to advance the solid composition towards the tip of the needle. Then the needle is removed leaving the guidewire to anchor the composition into the bone at the desired location. Finally the guidewire is removed leaving the solid composition in place. In another embodiment, the solid bar composition of the invention is replaced within the barrel of the needle. After placement within the desired anatomical site, the plunger of the syringe is advanced into the barrel of the needle as the device is removed, leaving the composition in the form of a solid stick in the desired location. The compositions of the present invention allow the therapeutically effective amounts of the osteogenic protein to be delivered at a site of damage where cartilage and / or bone formation is desired. The formulations can be used as a substitute for autologous bone graft in fresh and non-union fractures, spinal fusions and repair of bone defects in the field, orthopedic, in skull / maxillofacial reconstructions, in osteomyelitis for bone regeneration and in the dental field. increase of the alveolar bridge and periodontal defects and extraction of receptacles of the teeth. The following examples are illustrative of the present invention and are not limiting in any way. Modifications and variations as well as minor improvements are contemplated which are considered to be within the scope of the present invention.

EXAMPLES All the materials used in these examples are pharmaceutical grade. The calcium phosphate material is the commercially available bone substitute material (hereinafter "V-BSM") sold under the tradename CEREDEX ™ by Etex Corporation, 38 Sydney Street, Cambridge, MA 02139 and described in detail in the patents of USA Nos. 5,683,461, 6,117,456 and 6,214,368 and PCT WO 98/16209. The osteogenic prpteína _ut.ilizada_ as an active agent is recombinant human bone morphogenetic protein-2 (rhBMP-2, for its acronym in English). The production and characterization of rhBMP-2 is well known. Wang, et al., Proc. Nat '1 Acad. Sci. E.U.A., vol. 87, pp. 2220-2224 (1990).

Example 1 - Formulation Several injectable solid bars (A-E) of V-BSM, rhBMP-2 and one of carboxymethylcellulose (CMC), polyvinylpyrrolidone (PVP) and dextran sulfate are prepared. The dry powders of each component are combined in a sterile mixing bulb and reconstituted to a rigid mastic by the addition of aqueous glycine-based buffer having a pH of about 4.5 and comprising 5. mmoles of L-glutamic acid, glycine 2.5%, sucrose 0.5%, 5 mmole NaCl and polysorbate 80 0.01% in a specified ratio of liquid (ml) to powder (g) (L / P) and knead for 1 minute to form a paste. The amounts of each ingredient as well as the particular L / P ratios used are as set forth in Table 1 below.

Table 1.

Each paste is loaded into a syringe and extruded to form cylindrical rods having a diameter of about 1 mm and a length of about 5 cm.

These 5 cm bars are then cut to the desired lengths for the following tests. After molding, the bars harden into a solid mass under simulated conditions in vivo, that is, in an incubator at 37 ° C, overnight. The hardening process can be delayed for several hours by storing the bars at a colder temperature, i.e., about 4 ° C. The theoretical dose of rhBMP-2 of bars A-E is 150 μg of rhBMP-2 per milligram of bar. All bars have a uniform, dense, cohesive and non-brittle appearance and are injectable through a 16 gauge needle.

Example 2 - Characterization in vi tro A relationship between additive content and particle formation is observed. Upon immersion in the aqueous glycine-based buffer described in Example 1 for 14 days, the bars containing a higher percentage of additive (40% CMC, 40% PVP or 40% dextran sulfate, ie the CE bars, respectively), are dispersed into smaller particles much faster, ie, within 1 day as compared to those containing an average amount (29% CMC, ie, bar B) and low (17% of CMC, that is, bar A) of additive. The bars containing low contents of additives (17% of CMC, ie bar A) maintain their bar-like structure for a much longer period, that is, from the order of days to weeks, compared to their counterparts with a higher concentration of CMC. In addition, the kinetics of in vitro release of rh.BMP-2 from the V-BSM bars containing either 17% (bar A), 29% (bar B) or 40% (bar C) of CMC were performed using 125I-rhBMP-2 as a tracer. Similar to general observations, bars containing a higher percentage of CMC release rhBMP-2 faster than those with a lower percentage of CMC, as shown in Figure 1.

Example 3 - Rat Biocompatibility and Efficacy Study The injectable rod-shaped calcium phosphate-based compositions (prepared as described in Example 1) were evaluated for biocompatibility and efficacy both intraosseous and ectopic, in a model in rat. Defects in the intraosseous nucleus were surgically generated in the distal femurs of six male CD rats. The rats are divided into two groups (A and B) of three. One extremity of each rat received a 2 mm segment test rod (calcium phosphate / rhBMP-2 / excipient), while the opposite extremity receives a 2 mm segment control rod (calcium phosphate / excipient). Group A rats received bar A (68/17/15 (w / w)% ACP / CMC / rhBMP-2) of Example 1 as the test bar, while rats of group B received bar B (56/29/15 (w / w)% ACP / CMC / rhBMP-2) of Example 1, as the test bar. In addition, a 10 mm bar was implanted subcutaneously, lateral to the midline of the ventral chest region, with one side receiving a test bar and the other side receiving a control bar. Here, again, the rats of group A received bar A (68/17/15 (w / w)% ACP / CMC / rhBMP-2) of Example 1 as the test rod, while the rats of group B received bar B (56/29/15 (w / w)% ACP / CMC / rhBMP-2) of Example 1, as the test bar. The animals are killed at 2 weeks after the determinations of the results consisting of faxitron radiographs and histomorphometry. Radiographs and histology of the 2-week distal femur explants indicate increased bone callus formation generally on the rhBMP-2 treated side compared with placebo. In particular, the bars (B) containing a higher concentration of CMC formed medium to large bony calli in comparison with the bars (A) that contain less amount of CMC, which formed callus with a size of small to medium. Radiographs and histology of the subcutaneous implants also indicated bone formation on the side treated with rhBMP-2, compared with placebo. In particular, bars (B) containing a greater amount of CMC formed a more robust ectopic bone response compared to bars (A) containing a smaller amount of CMC. Good biocompatibility is observed in all groups without inflammatory response for the implants.

Example 4 - Intraosseal local biodistribution study in rabbit The AD bars of Example 1 were injected percutaneously into the intraosseal spaces of the distal femur of rabbits (n = 4 sites per group) using a 14 gauge catheter with a 16 gauge needle. In particular, 10 mm AD bars containing approximately μCi of 125 I-rhBMP-2 were used. The amount of radioactivity in the synthetic bars is measured before injection using a Capintec dose calibrator. The retention of local rh.BMP-2 was monitored for 4 weeks using scintigraphy and. Local in vivo distribution data suggest a sustained release of rhBMP-2 from the bars and a higher percentage of the additive-containing bars which showed a faster in vivo release compared to those bars with a lower percentage of additive, such as it is shown in figure 2.

Example 5 - Formulation Curable pastes containing either 1 mg of rhBMP-2 per ml of paste or 4.5 mg of. rhBMP-2 per ml of paste are formulated by adding 2 ml of the appropriately concentrated solutions of rhBMP-2 in the glycine-based aqueous buffer of Example 1 to 2.5 g of V-BSM. The mixtures are kneaded in sterile bulbs for 1 minute to form a hardenable paste.

Example 6 - Intraosseous injection of paste into cynomolgus macaques An amount of 1 mg per ml and 4.5 mg per ml of hardened pastes of Example 5 are extracted from the sterile bulbs using a 3 ml syringe to which an 18 gauge needle is placed. and then injected under fluoroscopic control at various intraosseous sites of macaques. Sites include the distal femur, proximal femur, radiodistal, proximal tibia. After 1 month, a significant amount of new bone is observed at local sites where rhBMP-2 is injected. Although the invention has been described in terms of preferred embodiments and specific examples, those skilled in the art will recognize, by systematic experimentation, that various changes and modifications can be made without departing from the spirit and scope of the invention. Thus, it should be understood that the invention is not limited by the foregoing detailed description but is defined by the appended claims and their equivalents. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (123)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A composition for injectable administration of osteogenic proteins, characterized in that it comprises an osteogenic protein and a calcium phosphate material, wherein the composition is in the form of from a solid bar.
2. 2. The composition according to claim 1, characterized in that the osteogenic protein is selected from the group consisting of members of the family of bone morphogenetic proteins (BMP).
3. 3. The composition according to claim 1, characterized in that the osteogenic protein is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-10, BMP-12. , BMP-13 and MP52. 4. The composition according to claim 1, characterized in that the osteogenic protein is BMP-2. 5. The composition according to claim 1, characterized in that the osteogenic protein is BMP-12. 6. The composition according to claim 1, characterized by the osteogenic protein is BMP-13. The composition according to claim 1, characterized in that the osteogenic protein is BMP-52. 8. The composition according to claim 1, characterized in that the osteogenic protein is present in an amount ranging from about 1% to about 90% by weight of the composition. The composition according to claim 1, characterized in that the osteogenic protein is present in an amount ranging from about 15% to about 40% by weight of the composition. 10. The composition according to claim 1, characterized in that it further comprises a bone resorption inhibitor. 11. The composition according to claim 10, characterized in that the bone resorption inhibitor is a bisphosphonate. .12. The composition according to claim 11, characterized in that the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB 1053, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate and the forms pharmaceutically acceptable salts, esters, acids and mixtures thereof. The composition according to claim 1, characterized in that the calcium phosphate material comprises a material selected from the group consisting of amorphous apatite calcium phosphate, sparingly crystalline apatite calcium phosphate, hydroxyapatite, tricalcium phosphate, fluoroapatite and combinations thereof. The composition according to claim 13, characterized in that the calcium phosphate material comprises sparingly crystalline apatite calcium phosphate. 15. The composition according to claim 14, characterized in that the sparingly crystalline apatite calcium phosphate has a ratio of calcium to phosphate less than 1: 1.5. 16. The composition according to claim 14, characterized in that the sparingly crystalline apatite calcium phosphate has a ratio of calcium to phosphate of about 1: 1.
4. 4. The composition according to claim 1, characterized in that the calcium phosphate material is present in an amount ranging from about 10% to about 99% by weight of the composition. The composition according to claim 17, characterized in that the calcium phosphate material is present in an amount ranging from about 40% to about 60% by weight of the composition. 19. The composition according to claim 1, characterized in that it comprises an additive. which is selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants and combinations thereof. The composition according to claim 19, characterized in that the additive is selected from the group consisting of carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polylactide, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol, dextran sulfate and combinations thereof. The composition according to claim 19, characterized in that the additive is present in an amount ranging from about 1% to about 90% by weight of the composition. 22. The composition according to claim 21, characterized in that the additive is present in an amount ranging from about 20% to about 40% by weight of the composition. 23. The composition according to claim 1, characterized by comprising further a bone resorption inhibitor and an additive which is selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants. and combinations thereof. 24. The composition according to claim 1, characterized in that the bar is cylindrical and the diameter of the cylindrical bar is between approximately 0.1 mm and 3.0 mm. 25. The composition according to claim 1, characterized in that the length of the bar is between about 1.0 mm and 5.0 cm. 26. A composition for injectable administration of osteogenic proteins, characterized in that it comprises an osteogenic protein and a calcium phosphate material, wherein the composition is in the form of a hardenable paste. The composition according to claim 26, characterized in that the osteogenic protein is selected from the group consisting of members of the bone morphogenetic protein (BMP) family. The composition according to claim 26, characterized in that the osteogenetic protein is selected from the group consisting of BMP-2, BMP-4, _BMP-5, BMP-6, BMP-7, BMP-10, _ BMP- 12, BMP-13 and MP52. 29. The composition according to claim 26, characterized in that the osteogenic protein is BMP-2. 30. The composition according to claim 26, characterized in that the osteogenic protein is BMP-12. 31. The composition according to claim 26, characterized in that the osteogenic protein is BMP-13. 32. The composition according to claim 26, characterized in that the osteogenic protein is MP-52. The composition according to claim 26, characterized in that the osteogenic protein is present in an amount ranging from about 0.01% to about 2% by weight of the composition. 34. The composition according to claim 26, characterized in that the osteogenic protein is present in an amount ranging from about 0.03% to about 1% by weight of the composition. 35. The composition according to claim 26, characterized in that it also comprises a bone resorption inhibitor. 36. The composition according to claim 35, characterized in that the bone resorption inhibitor is a bisphosphonate. 37. The composition according to claim 36, characterized in that the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB 1053, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate and pharmaceutically acceptable forms of salts, esters, acids and mixtures thereof. 38. The composition according to claim 26, characterized in that the calcium phosphate material comprises a material selected from the group consisting of amorphous apatite calcium phosphate, sparingly crystalline apatite calcium phosphate, hydroxyapatite, tricalcium phosphate, fluoroapatite and combinations thereof. 39. The composition according to claim 26, characterized in that the calcium phosphate material comprises sparingly crystalline apatite calcium phosphate. 40. The composition according to claim 39, characterized in that the iapatitic calcium phosphate scarcely cri.stalino has a ratio of calcium to phosphate less than 1: 1.5. 41. The composition according to claim 40, characterized in that the sparingly crystalline apatite calcium phosphate has a ratio of calcium to phosphate of about 1: 1.4. 42. The composition according to claim 26, characterized in that the calcium phosphate material is present in an amount ranging from about 30% to about 70% by weight of the composition. 43. The composition according to claim 42, characterized in that the calcium phosphate material is present in an amount ranging from about 45% to about 55% by weight of the composition. 44. The composition according to claim 26, characterized in that it further comprises an additive which is selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants and combinations thereof. 45. The composition according to claim 44, characterized in that the additive is selected from the group consisting of carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polylactide, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol, dextran sulfate. and combinations thereof. 46. The composition according to claim 44, characterized in that the additive is present in an amount ranging from about 1% to about 90% by weight of the composition. 47. The composition according to claim 44, characterized in that the additive is present in an amount ranging from about 10% to about 20% by weight of the composition. 48. The composition according to claim 26, characterized in that it further comprises a bone resorption inhibitor and an additive that is selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants and combinations thereof. 49. A method for preparing a composition for injectable administration of osteogenic proteins, characterized in that it comprises the steps of: (a) mixing a dry form of an osteogenic protein with a dry form of a calcium phosphate material to produce a dry mixture; (b) reconstitute the dry mix by adding an aqueous buffer to form a paste; (c) molding the dough to form a stick-like composition; and (d) drying the bar-like composition of step (c) to form a rod-shaped composition for injectable administration of osteogenic proteins. 50. The method according to claim 49, characterized in that the osteogenic protein is selected from the group consisting of members of the bone morphogenetic protein family. 51. The method according to claim 49, characterized in that the osteogenic protein is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-10, BMP-12. , BMP-13 and MP52. 52. The method according to claim 49, characterized in that the osteogenic protein is BMP-2. 53. The method according to claim 49, characterized in that the osteogenic protein is BMP-12. 54. The method according to claim 49, characterized in that the osteogenic protein is BMP-13. 55. The method according to claim 49, characterized in that the osteogenic protein is MP-52. 56. The method according to claim 49, characterized in that an amount of the osteogenic protein ranging from about 1% to about 90% by weight of the composition is mixed with the calcium phosphate carrier. 57. The method according to claim 56, characterized in that an amount of the osteogenic protein ranging from about 15% to about 40% by weight of the composition is mixed with the calcium phosphate carrier. 58. The method according to claim 49, characterized in that the composition further comprises a bone resorption inhibitor and wherein a dry form of the bone resorption inhibitor is mixed in the dry mixture. 59. The method of compliance with the claim 58, characterized in that the bone resorption inhibitor is a bisphosphonate. .60. The method in accordance with the claim 59, characterized in that the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB 1053, etidronates, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate and the pharmaceutically acceptable forms of salts, esters, acids and mixtures thereof. 61. The method according to claim 49, characterized in that the calcium phosphate material _A_ comprises a material selected from the group consisting of amorphous apatite calcium phosphate, sparingly crystalline apatite calcium phosphate, hydroxyapatite, tricalcium phosphate, fluoroapatite and combinations thereof. 10 62. The method in accordance with the claim 49, characterized in that the calcium phosphate material comprises sparingly crystalline apatite calcium phosphate. 63. The method according to the claim 62, characterized in that the sparingly crystalline apatite calcium phosphate has a ratio of calcium to phosphate less than 1: 1.5. 64. The method of compliance with the claim 63, characterized in that the sparingly crystalline -apatitic calcium phosphate has a calcium content 20 relative to phosphate of about 1: 1.4. 65. The method according to claim 49, characterized in that an amount of the calcium phosphate material varying from about 10% to about 99% by weight of the composition is mixed with 25 the osteogenic protein. 66. The method according to claim 65, characterized in that an amount of the calcium phosphate material varying from about 40% to about 60% by weight of the composition is mixed with the osteogenic protein. 67. The method according to claim 49, characterized in that the composition further comprises an additive which is selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants and combinations of the and where a dry form of the additive is mixed in the dry mixture. 68. The method according to claim 67, characterized in that the additive is selected from the group consisting of carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polylactide, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol, dextran sulfate and combinations thereof . 69. The method according to claim 67, characterized in that an amount of the additive ranging from about 1% to about 90% by weight of the composition is mixed in the dry mixture. 70. The method according to claim 69, characterized in that an amount of the additive ranging from about 20% to about 40% by weight of the composition is mixed in the dry mixture. 71. The method according to claim 49, characterized in that the composition further comprises a bone resorption inhibitor and an additive which is selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers , surfactants and combinations thereof. 72. The method according to claim 49, characterized in that the aqueous buffer is selected from the group consisting of saline buffered with phosphate, saline, glycine-based buffers and combinations thereof. 73. The method according to claim 49, characterized in that the ratio of aqueous buffer to dry mixture ranges from about 0.5: 1 to about 2: 1. 74. The method of compliance with the claim 49, characterized in that the molding is carried out using a method that is selected from the group consisting of molding, extrusion, pressing, perforation and combinations thereof. 75. The method according to claim 49, characterized in that it further comprises a step of cutting the composition in the form of a bar before or after step (d). 76. The method according to claim 49, characterized in that the rod-shaped composition is cylindrical and the diameter of the cylindrical bar-shaped composition is between approximately O.l mm and 3.0 mm. 77. The method according to claim 49, characterized in that the length of the rod-shaped composition is between about 1.0 mm and 5.0 cm. 78. A method for preparing a composition for injectable administration of osteogenic proteins, characterized in that it comprises mixing a dry form of the calcium phosphate material with an aqueous buffer containing an osteogenic protein to form a paste. 79. The method according to claim 78, characterized in that the osteogenic protein is selected from the group consisting of members of the family of bone morphogenetic proteins. 80. The method according to claim 78, characterized in that the osteogenic protein is selected from the group consisting of BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-10, BMP-12. , BMP-13 and MP52. 81. The method according to claim 78, characterized in that the osteogenic protein is BMP-2. 82. The method according to claim 78, characterized in that the osteogenic protein is BMP-12. 83. The method according to claim 78, characterized in that the osteogenic protein is BMP-13. _ 84. The_conformity_method_ with the claim 78, characterized in that the osteogenic protein is MP-52. 85. The method according to claim 78, characterized in that the osteogenic protein is present in the pulp in an amount ranging from about 0.01% to about 2% by weight of the pulp. 86. The method according to claim 85, characterized in that the osteogenic protein is present in the pulp in an amount ranging from about 0.03% to about 1% by weight of the pulp. 87. The method according to claim 78, characterized in that the composition further comprises a bone resorption inhibitor and wherein a dry form of the bone resorption inhibitor is mixed in the paste. 88. The method according to claim 87, characterized in that the bone resorption inhibitor is a bisphosphonate. 89. The method according to claim 88, characterized in that the bisphosphonate is selected from the group consisting of alendronate, cimadronate, clodronate, EB 1053, etidronate, ibandronate, neridronate, olpadronate, pamidronate, risedronate, tiludronate, YH 529, zoledronate and pharmaceutically acceptable forms of salts, esters, acids and mixtures thereof. 90. The method according to claim 78, characterized in that the calcium phosphate material comprises a material selected from the group consisting of amorphous apatite calcium phosphate, sparingly crystalline apatite calcium phosphate, hydroxyapatite, tricalcium phosphate, fluoroapatite and combinations thereof. 91. The method according to claim 78, characterized in that the calcium phosphate material comprises sparingly crystalline apatite calcium phosphate. 92. The method of compliance with the claim 91, characterized in that the sparingly crystalline apatite calcium phosphate has a ratio of calcium to phosphate less than 1: 1.5. 93. The method of compliance with the claim 92, characterized in that the sparingly crystalline apatite calcium phosphate has a calcium to phosphate ratio of about 1: 1.4. 94. The method according to claim 78, characterized in that an amount of the calcium phosphate material ranging from about 30% to about 70% by weight of the composition is mixed with the aqueous buffer. 95. The method according to claim 94, characterized in that an amount of the calcium phosphate material varying from about 45% to about 55% by weight of the composition is mixed with the aqueous buffer. 96. The method according to claim 78, characterized. because the composition further comprises an additive which is selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers, surfactants and combinations thereof and wherein a dry form of the additive is mixed in Pasta. 97. The method according to claim 96, characterized in that the additive is selected from the group consisting of carboxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polylactide, polyethylene glycol, polyvinylpyrrolidone, polyoxyethylene oxide, carboxyvinyl polymer, polyvinyl alcohol, dextran sulfate and combinations thereof. 98. The method according to claim 96, characterized in that an amount of the additive ranging from about 1% to about 90% by weight of the composition is mixed in the paste. 99. The method according to claim 98, characterized in that an amount of the additive varying from about 10% to about 20% by weight of the composition is mixed in the paste. 100. The method according to claim 78, characterized in that the composition further comprises a bone resorption inhibitor and an additive which is selected from the group consisting of pharmaceutically acceptable salts, polysaccharides, peptides, proteins, amino acids, synthetic polymers, natural polymers , surfactants and combinations thereof. 101. The method according to claim 78, "characterized in that the aqueous buffer is selected from the group consisting of saline buffered with phosphate, saline, glycine-based buffers and combinations thereof. claim 78, characterized in that the ratio of aqueous buffer to calcium phosphate material ranges from about 0.5: 1 to about 2: 1. 103. A method for treating a mammal having a bone defect, characterized in that it comprises administering the bone defect site an effective amount of the composition for injectable administration of osteogenic proteins, according to claim 1. 104. The method according to claim 103, characterized in that the bone defect is an osteoporotic bone. to treat a mammal that has a bone defect, characterized because it nde the steps of: (a) administering on site of the bone defect an effective amount of the composition for injectable administration of osteogenic proteins in accordance with claim 1; and (b) administering at the site of the bone defect an effective amount of a bone resorption inhibitor. 106 .. The method according to the claim 105, characterized in that step (a) is carried out before step (b). 107. The method according to claim 105, characterized in that step (b) is carried out before step (a). 108. The method according to claim 105, characterized in that step (a) of step (b) are performed simultaneously. 109. A method for treating a mammal having a bone defect, characterized in that it comprises administering at the site of the bone defect an effective amount of the composition for injectable administration of osteogenic proteins, in accordance with claim 26. 110. A method for treating a mammal having a bone defect, characterized in that it comprises the steps of: (a) administering at the site of the bone defect an effective amount of the composition for injectable administration of osteogenic proteins, in accordance with claim 26; and (b) administering at the site of the bone defect an effective amount of a bone resorption inhibitor. 111. The method according to claim 110, characterized in that step (a) is performed before step (b). 112. The method according to claim 110, characterized in that step (b) is carried out before step (a). 113. The method according to claim 110, characterized in that step (a) and step (b) are performed simultaneously. 114. The use of an effective amount of a composition according to claim 1, for the preparation of a medicament for treating a mammal having a bone defect, wherein the use comprises administering to the site of the bone defect an effective amount of the composition for injectable administration of osteogenic proteins according to claim 1. 115. The use of an effective amount of a composition according to claim 1, for the preparation of a medicament for treating a mammal having a bone defect, wherein the use comprises the steps of: (a) administering at the site of the bone defect an effective amount of the composition for injectable administration of osteogenic proteins according to claim 1; and (b) administering at the site of the bone defect an effective amount of a bone resorption inhibitor. • - - 116. Use in accordance with the claim 115, wherein step (a) is performed before step (b). 117. The use according to claim 115, wherein step (b) is performed before step (a). 118. The use according to claim 115, wherein step (a) and step (b) are performed simultaneously. 119. The use of an effective amount of a composition according to claim 26, for the preparation of a medicament for the treatment of a mammal having a bone defect, wherein the use comprises administering at the site of the bone defect an amount Effectiveness of the composition for injectable administration of osteogenic proteins according to claim 26. 120. The use of an effective amount of an The composition according to claim 26 for the preparation of a medicament for treating a mammal having a bone defect, wherein the use comprises the steps of: (a) administering at the site of the bone defect an effective amount of the composition for injectable administration of osteogenic proteins according to claim 26; and (b) administering at the site of the bone defect an effective amount of a bone resorption inhibitor. 5 121. Use in accordance with the claim 120, wherein step (a) is performed before step (b). 122. The use according to claim 120, wherein step (b) is performed before step (a). 123. The use according to claim 0 120, wherein step (a) and step (b) are performed simultaneously.