MXPA97009904A - Biocompatible hydroxiapatita formulations and uses of mis - Google Patents

Abstract

A biocompatible hydroxyapatite formulation is provided, the formulation is precipitated from a mixture of a liquid phase, a bioactive or biocompatible additive which can be any of a number of bioreactive or other substances, and a base combination of calcium phosphate salts; the liquid phase and the additive can be combined to produce an increased liquid phase, which is then mixed with the base salt combination, the additive being chosen to achieve a desired effect during administration of the formulation to a plant or animal; it is released in the surrounding physiological place and the hydroxiapati component is reabsorbed

Description

HYDROXIAPATITA FORMULATIONS BIOCOMPATIBLES AND USES OF THE SAME BACKGROUND OF LFL INVENTION 1. FIELD OF THE INVENTION This invention relates generally to certain combinations of soluble calcium phosphates and applications thereof. More specifically, certain calcium phosphates 10 can be combined with a liquid to form a paste or suspension of hydroxyapatite, which has a variety of medical, dental and other uses. Various biocompatible additives can be incorporated into the paste or suspension for various applications. L5 2. DESCRIPTION OF THE RELATED TECHNIQUE Hydroxyapatite is a calcium phosphate mineral and is the primary constituent of human bones and teeth. Hydroxyapatite is only one of a number of said calcium phosphate minerals, which have different calcium to phosphate ratios, crystal structures, and physical characteristics. Apatite is a general term for a broad scale of compounds represented by the general formula 2+? O (ZO 3-) ßY ~ -) F. 2, in «where M is a metal atom, particularly alkaline or an alkaline earth metal atom, and ZO4 is an acid radical, where Z can be phosphorus, arsenic, vanadium, sulfur or silicon, or can replace all or part with carbonate (CO32-). and it is an anion, usually halide, hydroxy or carbonate. S A combination of soluble calcium phosphate salts, especially tetracalcium phosphate and another soluble calcium phosphate salt, both in their solid state, in equilibrium or near equilibrium in an aqueous or non-aqueous liquid phase so that both salts are in excess, can precipitate hydroxyapatite, that is, Cas (P0) 3 OH. Both calcium phosphate salts are almost in equilibrium with the same saturated solution which is also supersaturated with respect to hydroxyapatite, then the composition will continue to precipitate hydroxyapatite. The precipitated hydroxyapatite may be formed in vivo or ex vivo (in vitro) and may possess different mechanical and biological characteristics including, for example, hardness, flexibility, porosity, dissolution, bio-degradation, biodegradation, tissue adhesion, and replacement by soft and hard tissues. Hydroxyapatite, as well as modified forms thereof, is a material that occurs naturally in bones, teeth and some invertebrate skeletons. Hydroxyapatite crystals are embedded in the matrixes of teeth and bones along with cells and tissue matrix materials including fibrous proteins such as collagen and matrix binding proteins such as certain gla proteins, dentin and varnish.

All vertebrate and dentulose animals are capable of causing bone and tooth matrices through the precipitation of hydroxyapatite crystals under physiological conditions suitable for pH, temperature and ionic conditions. The resulting tissues are not highly cellular and show certain unique properties, such as mechanical effort, flexibility, physiological activity, and unique continuous self-renodelation. Due to its unique properties, hydroxyapatite is a highly biocompatible material. These unique hydroxyapatite properties present in bones have attempted efforts to develop implants made of hydroxyapatite, ceramics and other similar hard calcium phosphate materials such as a- and β-tricalcium phosphates. These implants have been used to fill a wide range of bone defects in orthopedic and reconstructive surgeries and in the incrustation of teeth into bones (for example, in periodontal, dental and orthodontic applications). Many physical and chemical variations have been attempted to create implants (i) with increased mechanical stress in order to allow the use of hydroxyapatite alone or mixed body implants of hydroxyapatite at loading bone effect sites; (ii) with altered porosity to allow for better bone growth so that the implant is effectively incorporated into the newly formed bone tissue; and (iii) as granulated forms to allow packing at sites of surgical defect. In addition to these applications, biological factors that are believed to cause the formation and growth of several cells implanted in the formation of bones have been used «Jo to produce implants of mixed body of hydroxyapatite with" inductive "properties. . Hydroxyapatite has other known applications, such as bone repair and remineralization of teeth. Such uses are shown in, for example, Patents of E.U.A. Nos. Re. 33.221 and Re. 33.161 to Brown and others. A specific example is the repair of injuries or cavities of teeth. When a lesion or incipient cavity develops on the surface of a tooth, the dentist traditionally fills the cavity that forms. This procedure can prevent decay from spreading further, but it does not restore the tooth to its original state. However, a considerable amount of research has been directed to the mineralization of incipient dental lesions. The purpose of the re-mineralization is to deposit hydroxyapatite in the caries lesion, so that the dental varnish incorporates the hydroxyapatite in its structure at the point of the lesion. In this way, remineralization prevents more tooth decay and restores the tooth. In general, the supersaturated solutions or suspensions used for remineralization have been prepared from a single form of calcium phosphate. However, these solutions or suspensions have been unsatisfactory for a variety of reasons. For example, the amount of calcium and phosphate ions available for remineralization in these supersaturated solutions is relatively low, thus requiring an excessive volume of fluid and an excessive number of applications. The use of a single calcium phosphate, ß-Ca3ÍP04) 2, was suggested for capped ends with pulp in Dpskell and others, "Development of Ceramic and Ceramic Composite Devices for Maxillofacial Application", 3. Bio ed. Mat. Res. 6: 345-361 (1972) and the use of Ca4 (0) 2 was suggested by the inventors in IADR Abstract No. 120, 3. Dent. Res. 54:74 (1975) as a possible capping agent at the ends with pulp. However, these individual calcium phosphate cements are not able to adjust to a hard consistency and suffer from the same disadvantages as individual calcium phosphate remineralizers. For example, they can not maintain a relatively constant pH and do not have sufficient remineralization capacity. For many years there has also been experience with calcium-based implants for the replacement of skeletal tissue. Many of these implants have been in the form of prefabricated hydroxyapatite, synthesized in granulated or block form. These preparations have several disadvantages, including a limited ability to form skeletal defects, particularly in the case of blocks; inadequate structural integrity of granules (which do not bind together); and difficulty in modeling in an implant that has the shape of missing skeletal tissues.

Various forms of hydroxyapatite, methods of its preparation, coating of metal dispoeitives or other prostatic devices with hydroxyapatite, coformulation with other polymeric substances, mixing with structural components of biological tissue such as collagen, combination with certain pharmaceutical agents of diagnostic uses and Therapeutics, and mixing with biologically active proteins or polypeptides have been described in the scientific and patent literature. Since all such descriptions will be very numerous to list, certain examples relevant to the present invention are cited herein. Patents of E.U.A. Nos. 4,795,467; 4,865,602; 4,992,226; 5,123,925 and 5,246,457 describe mixture preparations with mineral-collagen, including sterilization methods, for bone repair wherein the mineral component can be selected from a group of tricalcium phosphates or hydroxyapatites with preferred particle size of between 100-2000 uy the collagen is mixed to provide a moldable formulation or applied to coat the porous interstices within the ceramic particles. The Patent of E.U.A. No. 5,204,382 and International Application UO 93/16657 describe injectable compositions comprising materials of particle ceramics with sizes between 50-250 μm and collagen or other organic biocompatible polymer. These combinations are intended for the repair and improvement of hard or soft tissues through the dissipation of the biocompatible component leaving behind ceramic particles. The literature also describes mixing biological factors involved in bone regeneration with hydroxyapatites (including coral hydroxyapatite originally described by Holrnes and 5 others in 1979 - Plastic and Reconstructive Surgery volume 63, page 626) or tricalcium phosphate granules and the uses of said formulations in bone repair. All these descriptions refer to materials in which hydroxyapatite is preformed (such as octacalcium phosphate salts or ß-tricalcium phosphate U) and is substantially composed of or manufactured from contaminants or impurities present due to or arising from the source of material starting or manufacturing method. In Re. 33,221 and Re. 33,161, Brown and Chow have described 5 powders, pastes and suspensions comprising sparingly soluble calcium phosphate salts, one of which is tetracalcium anhydride phosphate, which are capable of precipitating hydroxyapatite under temperature conditions. environment on a wide scale of liquid phases. In the Patents of E.U.A. Nos. 0 4,880,610; 5,047,031; 5,053,212; 5,129,905; and 5,178,845 and in International Applications UO 92/02543, EP 0,347,028 A2, and EP 0,416,761 Al, Constantz et al., have described certain methods of calcium phosphate mineral in situ, intimate mixtures of calcium and phosphate, wherein the source of phosphate is *! "* phosphoric acid in a substantially anhydrous form, compositions thus obtained, and their use in bone repair, Constantz et al., have also described uses of said materials in the bone prosthesis coating. US Patent Nos. 5,164,187 and 5,188,670, and International Application EP 0,383,568 A2, US Patent No. 5,034,059 and 5,231,169, and International Application UO 92/12736 prescribe combining and / or mineralizing collagen to provide physical characteristics such as bones. 3P 1,111,762 discloses a powder or powder mixture containing racalcium phosphate and a tissue solution to produce a composition 1 f) hardened that produces hydroxyapatite on contact with water.

EP 436,499 provides a process for producing a calcium phosphate-type powder, as a highly active powder, as a component in calcium phosphate-type hardening materials. These materials can be used to obtain a highly plastic moldable material Lb that hardens under mild conditions. In the patent of E.U.A. No. 5,068,122, Ko ubo et al. Have described a process for forming a bioactive bone-type hydroxyapatite film on a desired substrate surface without the use of heat treatment and through of hydroxyapatite precipitation from solutions containing a certain scale of Ca2 + ions and HPO2-. Liu and others have described the use of tetracalcium phosphate alone, or together with a-tricalcium phosphate as a base, to produce calcium phosphate cements with surface pH '. *! *; relatively high that are considered beneficial for their biocompatibility in orthopedic, dental and maxillofacial applications. See, Patent of E.U.A. No. 5,149,368. Unlike preformed hydroxyapatites, calcium phosphate cements comprising the different precursor calcium phosphate salts and capable of precipitating hydroxyapatite provide the option of incorporating with bioactive substances such as proteins to produce implants that induce active tissue regeneration such as bones. Incorporation with tissue matrix proteins, such as collagen, can result in implants that are desirable matrices for tissue growth, including soft tissues and bones. However, these references only concern the incorporation of bioactive and biocompatible proteins and related substances as a means to improve the properties of hydroxyapatite as an implant material for tissue repair applications. Numerous patents, patent applications and publications describe instruments and their uses and methods for influencing tissue behavior, including curing by the use of electric and electromagnetic fields. Invasive implants that serve as electrodes as well as electrodes placed externally have been used to generate electric or electromagnetic fields of a direct or pulse nature in and around selected tissue sites. The recorded results include improvement or cure of bone fractures, relaxation of muscle fibers, regeneration of soft tissues, and the like. One of the first related patents is the U.S. Patent. No. 3,055,372. Several specific designs of devices with superior utility in specific applications have been described including, for example, devices used in the promotion of bone growth in pores of hydroxyapatite implants. See, for example, Shimizu et al., Journal of Orthopedic Research, vol. 6 pages 248-258. However, none of these references describe a formulation or device designed to modulate and / or improve the mechanical effects or the effects of electrical stimulation to cause healing.The available technologies and products, which utilize hydroxyapatite, suffer from other conceptual limitations. Thus, as practices, one of the main conceptual limitations arises from the approach of using hydroxyapatite for tissue replacement as described above: Typically, the implant must fill a tissue gap and provide structural support or be incorporated into newly formed tissue developed As a consequence, little effort has been devoted to using the biocompatible properties of hydroxyapatite and developing formulations in which hydroxyapatite is reabsorbed or degraded in a manner similar to certain synthetic polymers and functions primarily as a biocompatible matrix. to locate physiologically active materials at a predetermined site, or to achieve the presentation of said materials at a physiological site in a controlled manner resulting in improved utility. The practical limitations in the search for novel formulations of the present invention arise from several significant technological limitations. First, the current hydroxyapatite technology is limited by hard production methodology. Most hydroxyapatite implants are produced under extreme physical and chemical conditions resulting in hard implants composed of large acro-crystals, fused with pores and random voids, unlike material naturally formed in bones or other structures of the skeleton found in nature. Second, typical hydroxyapatite formulations are characterized by limited Jad compatibility and tissue resorption ability. For example, the hardness and nature of the crystal structure often makes them incompatible for application in the repair of soft tissues. These disadvantages are caused not only by the physical characteristics of the formulations, but also due to the inability of the body to completely reabsorb the material over an acceptable period. Third, the known formulations also suffer from limited co-formulation. Biologically active factors that can promote cell growth or biocompatible substances that offer better support for cell growth can only be applied to the conventional hydroxyapatite implant surface by spraying, cold drying or rinsing as the conditions used for producing the implants usually destroy the biological activities. Fourth, known formulations may have undesirable release characteristics. Biocompatible or bioactive materials applied to coat an hydroxyapatite implant surface can be readily washed away from a physiological site resulting in a rapid increase in local concentration of the substance with little or no remaining material available for the long-term action required to most of these substances. There are other disadvantages of current hydroxyapatite technology.

BRIEF DESCRIPTION OF THE INVENTION The biocompatibility of hydroxyapatite and the ability to precipitate hydroxyapatite crystals under ambient conditions leads to the production of novel bio-aterials where biologically active substances can be incorporated. These biomaterials can also be handled for co-formulation with or coating other polymer implants (eg, dacron, nylon, vinyl, Teflon, acrylic), elementals (eg, carbon, titanium), or alloy (eg, steel) . Novel biomaterials selected based on mechanical and biological properties are useful in providing structural support for the filling or covering of tissue, or the stabilization of other mechanical devices; in the promotion or support of tissue formation to repair, regenerate or improve tissues; Extract or release antigenic material for vaccination or genetic materials of pharmaceutically active agents such as antibiotics or '-. surgical or eubectanciae hor onalee for improved therapeutic effect; and provide a piezoelectric field to supply or amplify direct or pulse electromagnetic stimulation to improve healing or to generate controlled mechanical movement. These are simply examples of 0 applications of a biocopatible hydroxyapatite formulation. Based on the consistency and the desired site of application, the formulations and methods of this invention will be manageable for different administration means (for example, injection, implant, arthroscopic application, packaging, etc.) in different medical applications. As discussed above, the molecular composition of hydroxyapatite makes it highly biocompatible. A significant portion of the body weight of an adult vertebrate animal is composed of phosphate or calcium. Since bone is an active remodeling tissue, there is a substantial change in calcium phosphate in a continuous manner. Except for the conditions of significant hypercalcemia brought under certain pathological conditions, the main organs of the body are capable of supporting the physiological change of calcium phosphate, and the excretion system, mainly the kidney, is capable of processing the released calcium phosphate. . The hardness of the biocompatibility of calcium phosphate in creating implants (or calcium phosphate compositions that can form implants in situ), which are formed through the precipitation of hydroxyapatite under ambient or physiological conditions and are reabsorbed at different speeds Within the body, it has a broad scale of medical applications. Formulations based on such biocompatible materials are preferred over synthetic polymers such as polymethylmethacrylate, polyglycolic acid, polyacetic acid and copolymers of these substances which are not found in nature. Although many of these polymers are available on a scale of substances, the polymerization and depolymerization procedures of these materials are often accompanied by unacceptable changes in pH or temperature, may require the use of toxic organic solvents, or lead to inflammatory reactions not desirable in animals and humans. Hydroxyapatite crystals also possess unique piezoelectric characteristics that can be explored in the modulation of cell growth and metabolic activities. Therefore, the use of electrical and electromagnetic stimulation seeks tissue healing or the generation of controlled mechanical movement can improve > ! • * significantly through the use of implants made of hydroxyapatite dß crystals. Such implants can also be improved by the incorporation of other biocornpatible or bioactive subetancies involved in cell manipulation. Therefore, an object of the present invention is to provide controlled presentation of a wide variety of biologically active or biocompatible substances in selected locations and gradual assortment of said substances in the local place or systemically over desirable periods which may be appropriate to derive benefits. improved clinical features compared to other means of administration of such eubstances. Another object of the present invention is to provide a formulation of a versatile assortment matrix that is composed of a biocompatible additive., which can be managed by alterations to adjust the time under physiological conditions and environment, which can be managed to alterations in the speed of biodegradation or resorption in the body of an animal or human being, which is capable of producing materials with a wide scale of consistencies (for example, suspension, paste, large granule, block, powder, etc.), and which is capable of hardening as well as dissolving without significant changes in temperature or pH. Another object of the present invention is to provide a formulation of an implant or implantable composition that exhibits an appropriate combination of skillful resorption, ability to support cell growth, and piezoelectric conduction ability to be used in the improvement of electrical or electromagnetic stimulation. In order to achieve these and other objects, the present invention pr-ovee formulations of certain calcium phosphate salt combinations that are sparingly soluble, having the ability to precipitate hydroxyapatite under physiological conditions and / or environment, wherein a biocornpatible or bioactive material is incorporated during the precipitation process, so that the incorporated material is retained at the site of application of the formulation for extended periods or gradually released into the surrounding physiological site. The composition of the salt combination used in a formulation of the present invention is chosen, so that the physical properties (porosity, tensile stress and bending, consistency, etc.) and the resorption / biodegradation properties of the resultant hydroxyapatite precipitate they allow the formulation to improve the function of the incorporated biocompatible or bioactive material. In one embodiment of the present invention, a biocompatible hydroxyapatite formulation is provided wherein hydroxyapatite is precipitated under physiological conditions (including pH, temperature, ionic stress, etc.) or under conditions that (i) preserve the activity of a biocompatible substance or added bioactivity and (ii) allow the substance to be reasonably impregnated uniformly throughout the mixed precipitated body. One aspect of this 1, ' The method relates to formulations containing biologically compatible materials that support the growth or formation of different cells or tissues and biologically active substances that cause or induce the formation of said cells or tissues. Another aspect contemplates formulations containing biologically active substances that kill dead or undesirable cells or tissues, or activate certain cells or tissues wherein the activity can produce a therapeutic benefit. Biocornpatible hydroxyapatite formulations can be used in products and structures with other technologies to create novel, combined medical devices. In another embodiment, a method for preparing a biocompatible hydroxyapatite formulation is provided. A base combination of calcium phosphate salts is prepared. A liquid phase is prepared. A biocompatible additive is provided. These components are then combined to form a mixture. Then, a biocompatible hydroxyapatite formulation of this mixture is precipitated. To form the mixture, any two of the components can be combined first by suitable methods and then combined with the third component. Alternatively, the three ingredients can be combined simultaneously. In accordance with various aspects of this embodiment, the biocompatible additive can be any of several additives including, without limitation, growth factors, adhesive agents, immunogens, vaccines, genes, recombinant cells, antibiotics, pharmaceutical agents, hormones, fibers, gels, space-occupying particles, and electric stimulant enhancers. A formulation prepared in accordance with this method can also incorporate a pharmaceutically acceptable carrier. In another embodiment, a method for treating a patient is provided. In this embodiment, a biocompatible hydroxyapatite formulation is prepared as before. Then, the formulation is administered to a patient. I) Other objects, features and advantages of the present invention will be readily apparent to those skilled in the pertinent art from the detailed description of the preferred embodiments with reference to the appropriate figures. 15 BRIEF DESCRIPTION OF THE DRAWING Figure 1 is a graph of the isotherms of solubility dß Ca4ÍPO «) 2 ?; CaHPO «.2H2 ?; CaHP0 «; CaßH2 (PO «) 6.5H2 ?; β-Ca3 (PO «) 2; and Cas (POi) 3? H at 25 ° C in the 20 ternary system of Ca (OH) 2; H3PO4; and H2O.

DESCRIPTION OF THE PREFERRED MODALITIES The present invention is directed generally to selected mixtures of calcium phosphate salts formed as powders, suspensions or pastes and having various mechanical properties, porosities, characteristics m piezoelectric and bioreabsorption characteristics. These materials serve as novel assortment vehicles for various chemical agents used as traditional pharmaceutical drugs and for biological agents including glycoproteins, polymeric hydrocarbons, lipids, glycolipids, carbohydrates, proteins and nucleic acids. In addition, these materials improve the effects of electrical or electromagnetic stimulation in tissue healing. The resulting novel compositions have utility in a wide range of medical applications such as immunization or vaccination, gene therapy, therapeutic modalities mediated through selective elimination or modification of cells and removal of substances from a physiological site, repair or regeneration of biological structural material (eg, bone, muscle, skin, tendon, and ligament) fixation from tooth to bone, fixation of prosthetic devices, or improvement of soft tissues such as breast tissue. Other uses are contemplated and certain specific applications contemplated for the different compositions are discussed below. The major components for the biocompatible hydroxyapatite formulation comprise sparingly soluble calcium phosphate salts. Preferably, two salts are combined, one of which is preferably tetracalcium phosphate. The other salt can be selected from the group consisting of CaHPO * .2H2O; CaHPO «; Caß (PO4) e -5H2; β-Ca3 (P0 «) 2; α-Ca3 (PO4) 2; and Ca3 (P0 / i) 2; for example, tri-calcium phosphate modified by protons or up to about 10% by weight of magnesium. The fundamental principles on the selection of the second soluble calcium phosphate salt scarcely ee «Rubber mix with tetracalcium phosphate are described by Brown and Chow. See, for example, US Patents. Nos. Re. 33,221 and Re. 33,161; EU. Brown and L.C. Chow, "3. of Dental Research", vol. 63, p. 672 (1983); EU. Brown and L.C. Chow, "Cements Research Progress - 1986, American Ceramic Society," p. 352 (1986); and Y. Fukase, E.D. Eanes, S. Takagi, L.C.Chow and U.E. Brown, "3. of Dental Research", vol. 69, p. 1852 (1990). These materials are incorporated by reference. Basically, each of these calcium phosphate salts has a characteristic solubility behavior which can be represented by a plot of the total concentration of calcium ions at the saturation point against the pH of the solution at a constant temperature. A graph of the total concentration of phosphate ions against the pH would be equivalent for the purposes of the present invention since the concentrations of phosphate and calcium in solution are bound. The resulting curve is called an isotherm. When the isotherms for various calcium phosphate salts are plotted on the same axes, their relative solubility behavior can be determined one from the other.

Specifically, a calcium phosphate whose isotherm is on the isotherm of another calcium phosphate at a given pH is metastable with respect to the latter. The point where the isotherms of two calcium phosphates intersect is known as a singular point. In a solution that is saturated with respect to the two calcium phosphates, both calcium phosphates will be in equilibrium with the saturated solution at the singular point. This means that no calcium phosphate will precipitate out of solution, but another calcium phosphate whose isotherm is below the singular point can precipitate. The present invention in one aspect relates to combinations of calcium phosphate salts that form singular point solutions that are supersaturated with respect to hydroxyapatite. Figure 1 is a graph of the solubility isotherms for six calcium salts in the ternary system comprising Ca (0H) 2, H3PO4 and H2O at 25ßC. The axis and Figure 1 represents the total concentration of calcium ions in solution in moles per liter, while the x axis represents pH. The isotherms for CaHPO ".2H2 ?, CaHPO *, β-Ca3 (PO«) 2 and Cas (PO4) 3OH are based, respectively, on the following articles: Gregory et al., "Solubility of CaHP? 4.2H2? In the System Ca (OH) 2-H3P? 4-H2? At 5o, 15 °, 25 ° and 37.5 ° C. " 3. Res. Nat. Bur. Stand. 743: 461-475 (1970); McDowell et al., "Solubility Study of Calcium Hydrogen Phosphate Ion Pari Formation", Inorg. Chem. 10: 1638-1643 (1971); Gregory and? ? others, "Solubility of ß-Ca3 (PO4) 2 in the System Ca (0H) 2 -H3PO4- H2O at 5o, 15 °, 25 ° and 37.5 ° C", 3. Res. Nat. Bur. Stand. 781; 667-674 (1974); and McDowell et al., "Solubility of Cas (PO4) 3HH in the System Ca (0H2) -H3P04 -H2O at 5o, 15 °, 25 ° and 37.5 ° C", 5 3. Res. Nat. Bur. Stand. 81A: 273-281 (1977). The isotherm for CaßH2 (PO4) ß .5H2O is based on the solubility product described in Moreno et al., "Stability of Dicalciu Phosphate Dihydrate in Aqueous Solutions and Solubility of Octacalciu Phosphate", Soil Sci. Soc. Am. Proc. 21: 99-102 (1960). The isotherm of 0 C 4 (PO «) 2? is given in the approximate value of the solubility product calculated by Brown and Chow as referenced, for example, in Re. 33.221 and Re. 33.161. In the preferred embodiments of this invention, the ratio of tetracalcium phosphate to the other salt as well as the relative particle sizes vary in the different formulations contemplated in order to obtain those that meet the desired mechanical criteria and profiles of resorption and degradation. for the particular bioactive or biocornpatible substance incorporated as an additive. In addition, 0 the relative amount of a liquid phase (preferably chosen from the group consisting of water, saline, a weakly acidic solution, a biocompatible buffer, serum, plasma, and other body fluids) to the amount of the combination of salt may vary in order to alter >; the time of adjustment and the consistency of the resulting precipitated biocompatible hydroxyapatite formulation. The biocompatible or bioactive additive is preferably dissolved or uniformly mixed essentially in the liquid phase before adding the liquid phase to the dry salt combination and initiating the precipitation reaction of hydroxyapatite. Alternatively, the liquid phase can be combined first with the calcium phosphate salts, followed by incorporation of the additive into the mixture. In another alternative, the bioactive additive is first combined with the salts, and then the liquid phase is added. Still in another alternative, the salts, additives and liquids can be combined simultaneously. The liquid phase may additionally contain hydroxyapatite crystal adjustment or growth modifiers such as proteoglycan (e.g., hyaluronic acid), a protein (e.g., serum albumin), a carbohydrate (e.g., granulated sugar), a synthetic material (eg, polyethylene glycol), certain other ionic agents, and the like. Many representative examples of such materials can be found in the Patents of E.U.A. Nos. Re. 33,161 and Re. 33,221. The diester calcium phosphate component can be produced by any of the different suitable methods. In a method as such, tetracalcium phosphate is produced by a solid state reaction catalyzed by high temperature treatment (eg, 1500 ° C to 1700 ° C) of an equimolar mixture of dicalcium phosphate and calcium carbonate. The tetracalcium phosphate thus produced is then mixed with a 'JX, desired amount of another soluble calcium phosphate salt sparingly selected from the group cited above. Alternately, a mixture of α-Ca 2 + 2 and tetracalcium phosphate can be produced by calcining a 5-hydrophilapatite preparation having a molar ratio of Ca / P of between 1.5 and 1.8 at 1150 ° C at 1450 ° C under reduced pressure. This mixture is further enhanced by the addition of a sparingly soluble soluble calcium phosphate salt in order to provide the desired setting properties and consistency of the formulation.

Hydroxyapatite LU produced by precipitation in the mixture with the improved liquid phase containing a bioactive or biocompatible additive. Calcium phosphate salts and mixtures are preferably produced and stored under anhydrous conditions substantially in order to precipitate L5 hydroxylapatite foniMilations of consistent and superior quality in the addition of the liquid phase. The following embodiments include methods for producing formulations comprising the calcium phosphate salt combinations mentioned above and various additives. biaaw; ivos and biocompatibles, formulations thus obtained, and uses, dß the same. In the discussion of each modality, representative bioactive and biocompatible substances intended for certain medical applications are described. An expert in the art will be able to produce said R-materials as described in these embodiments and will also be able (where appropriate or desirable) to substitute or add bioactive or biocompatible substances with properties similar to those cited in any particular embodiment. Also, although the above discussion refers to calcium phosphate salt combinations such as those described by Brown and Chow, the technology is not so limited. The alidadee, characteristics and aspects of the present invention can be applied to other combinations of calcium phosphate salt. In addition, the characteristics of the biocompatible hydroxyapatite formulations allow precipitation in vivo, ex vivo or partially ex vivo and partially in vivo. Also, hydroxyapatite can be reabsorbed or degraded in vivo. 1. Incorporation of Growth Factors for Wound Healing and Soft Tissue Repair A first mode is aimed at healing wounds and repairing soft tissue, and addresses an important need that exists for materials that can be applied to soft wounded tissues (eg, skin, muscle, face, gum, periodontium, etc.). in order to provoke or promote (other than support) the healing of damaged tissue. Several biological factors have the potential to induce the growth of desired cells or formation of said non-compromised precursor cell cells in the area of the damaged site. The systemic application of said materials would require substantial amounts, making a proposal as such prohibitive of cost and impractical due to the limitations on the availability of the materials. Even in cases where problems have been resolved through the advent of recombinant DNA technology, other activities often shown by such factors and contaminants in preparations of this material may produce undesirable side effects when such high amounts are administered systemically. in order to achieve adequate concentration in a particular site. Local applications of such materials to date involve either the coating of a biodegradable membrane cover type material or multiple applications over extended periods. These proposals are ineffective, full of risks of infection and worrisome. A first embodiment of the present invention, which is directed to this medical application of improving or regenerating guided tissue, refers to a biocompatible hydroxyapatite formulation that incorporates one or more growth factors. The growth factor can be selected from the group consisting of epidermal growth factor (EGF), transform the growth factor alpha (TGF-a), transform the beta growth factor (TGF-ß), vaccine growth factor (VGF), growth factor «acid or basic fibroblasts (FGF), growth factor insulin type (IGF) ,, (for example, IGF-I and IGF-II), platelet-derived growth factor (PDGF), cartilage-derived growth factor (CDGF), interleukin-2, factor "* 7 nerve cell growth (NCGF), hemopoietic cell growth factor (HCGF), lymphocyte growth factor (LGF), bone morphogenic protein (BMP) and other members of the growing family of wound healing factors . In addition, the hemopoietic cell growth factor can be selected from the group consisting of interleukin-3, granulocyte-macrophage colony stimulating factor, angiogenesis factors, macrophage colony stimulating factor, colony stimulating factor of granulocyte and erythropoietin. Also, the lymphocyte growth factor can be selected from the group consisting of B cell growth factor, T cell growth factor, interleukin-4, interleukin-5 and interleukin-6. The formulation preferably shows the mechanical properties of a paste, a hydrogel, a film, or the like. The formulation preferably releases less than about 20% of the growth factor in about 1 day and greater than about 90% of the growth factor in about 30 days. More preferably, the release rate is equal to less than 20% in about 2 days and greater than about 90% in about 5 days. The amount of the growth factor is preferably from about 0.1 μg to about 10 μg volume per cubic centimeter of the formulation, and is more preferably in the range of about 3 μg to about 6 μg volume per cubic centimeter.

The biocompatible hydroxyapatite formulation can be prepared in accordance with the following steps. In a first step, a base combination of calcium phosphate salts is prepared. This step is preferably achieved by performing the following procedure. One or more calcium phosphate salt combinations are prepared as described above. Then, a liquid phase is formed by supplying a liquid, such as sterile water, saline or a regulator physiologically compatible with a crystal growth modifier, such as hyaluronic acid, non-crosslinked collagen, ethylene glycol, polyethylene glycol, glycerin, polylysine , or similar. The crystal growth modifier allows changes to the adjustment time and allows achievement of a desirable consistency, which depends on the method of administration. Then, the resulting liquid phase is added to one or more salt combinations, respectively, preferably at a solid to liquid weight to weight ratio between about 1: 1 and about 5: 1. The ratio of solid to liquid is more preferably between about 1.5: 1 and about 4: 1, and most preferred between about 2.5: 1 and about 3.5: 1. The respective hydroxyapatite samples are precipitated from these mixtures, which are each evaluated for their adjustment property as well as their consistency. Then, each respective sample is allowed to harden to one sheet, each sheet preferably having a thickness ranging from about 3 mm to about 7 mm. More preferably, the thickness varies from about 3 m to? approximately 5 mm. Parts of the respective hardened materials are implanted subcutaneously and intramuscularly in test animals, eg, ratae, guinea pigs, rabbits or pigs. A basic hydroxyapatite formulation, which allows the desired release rates, is then selected. The base combination of calcium phosphate salts is that combination that can be precipitated by this bax hydroxyapatite formulation. In a second step, a liquid phase is increased by the addition of a selected growth factor. This step is preferably achieved in accordance with the following procedure. First, a growth factor is selected, preferably from those already described. EGF, TGF-, TGF-β or VGF, for example, can be produced by the recombinant DNA technology of a transformed host cell substrate (e.g., mammalian cell culture, microbial, or insect), by chemical synthesis, or from cultured cell sources that elaborate these materials. The purified preparations are tested in cell culture systems to determine the potency to promote cell growth and receptor binding specificity (EGFR), and stored as lyophilized powders. Other wound healing factors can be produced by recombinant or synthetic means, and are characterized by potency and specificity using cell culture stimulation tests and specific receptor binding tests, respectively. One or more amounts that vary from the selected growth factor are then added to the supplemented liquid phase described in the first preceding step to provide one or more improved liquid phases, respectively, having a scale of finer concentrations of the selected growth factor. Deepuée, the respective improved liquid phases are mixed with the base salt combination described above to precipitate reelected improved hydroxyapatite samples. Preferably, this mixture results in a weight ratio of solid to liquid between about 1: 1 and about 5: 1 (more preferably between 1.5: 1 and 4: 1, most preferred between 2.5: 1 and 3.5: 1). These respective improved hydroxyapatite samples are then allowed to harden into sheets having granules that preferably range from about 1 mm to about 7 mm (more preferably between 3 mm and 5 mm). Alternatively, the samples are allowed to harden into test blocks. The test portions of the respective hardened samples are then immersed in water, saline, or other physiological fluids, such as serum or plasma, under sterile conditions at a temperature of about 25 ° C to about 42 ° C and portions of respective test are shaken with care. The test portions of the liquid medium are then tested at different times, by immunological techniques, for released amounts of the growth factor. A release kinetics diagram can be plotted from these test results. Formulations that show about 30% or less release in 5 days are chosen for subsequent live test. The chosen formulations are implanted subcutaneously and intramuscularly in vascularized eitios in test animals. The rate of growth factor release in the respective samples is determined by collecting serum samples as well as collecting, by aspiration, local fluid surrounding the implant. Afterwards, a final hydroxyapatite formulation is selected, which allows the desired release rates before mentioning "Jas. The improved liquid phase is that which allows the precipitation of this final improved hydroxyapatite formulation. In a third step, the improved liquid phase is mixed with the base combination of calcium phosphate salts. And, in a fourth step, the biocompatible hydroxyapatite formulation is precipitated from this mixture. 2. Incorporation of Immunogens The ability to incorporate an immunogen, for example a purified protein, glycoprotein, lipoprotein or eilary, into a biocompatible implant that reabsorbs and releases the immunogen over several weeks has several advantages over known technology. These include, without limitation, avoiding the need for multiple booster injections that require multiple visits to the clinic by the subject, and allowing the elicitation of a more potent immune response with less immunogen material that is required when said immunogens are mixed with various adjuvants. and administered by several conventional methods. In addition, the implant can be formulated to produce local inflammatory response of low Gram, G thus improving the potency of the immunogen. A slow release proposal may also allow immunization against materials that are moderately toxic and thus can not be managed for the development of an effective immune response by traditional immunization protocols. The second embodiment of the present invention of eeta way refers to a biocompatible hydroxyapatite formulation that incorporates an immunogen. For example, the ee immunogen can be selected from the group consisting of viral antigens, bacterial antigens, antigens L5 fungal, and parasitic antigens. The immunogen can also be any marker of specific malignancy including without limitation, tumor antigens, peptide fragments of tumor antigens, and metastitic antigens-speci fi c ones. The immunogen can be a d-subunit vaccine. The immunogen can be incorporated into a vaccine, which can be active or passive. Also, the vaccine can be a synthetic vaccine that can be made organically or recombinantly. Some specific examples of contemplated immunogens include HBV envelope antigen: HIV gpl20 / gpl60 / p4; protein immunogens recombinants or purified for vaccination against mumps, measles, blond or measles (vaccine); and similar.

Preferably, the formulation shows mechanical properties in a granule or plug. Preferably, the formulation releases approximately 20% or less of the immunogen in about 1 day and 90% or more in about 30 days. More preferably, the release rates are 20% or less in about 2 days and 90% or more in about 5 diae. The amount of the immunogen in the formulation is preferably between about 50 μg to about 500 μg volume per cubic centimeter packed. Eeta quantity is more preferably between 100 μg to about 400 μg per cubic centimeter, and most preferred between about 150 μg to apr-oximatjamente 300 μg per centimeter. A formulation according to this embodiment is preferably prepared in accordance with the following steps. In a first step, a base combination of calcium phosphate salts is prepared. This first step is preferably achieved in accordance with the following procedure. First, one or more combinations of soluble calcium phosphate salts is hardly prepared as previously described. Then, a liquid phase is formed as previously described by having a solid to liquid ratio as previously described. In several subsequent sub-steps, the liquid phases are mixed with the salt combinations to precipitate hydroxyapatite formulations which are each tested in connection with the first embodiment. Formulations are selected that provide the desired resorption rates indicated above. Eetae formulations should allow the desired release rates of the immunogen. In a second step, a liquid phase is improved by the addition of a selected immunogen. This step is preferably achieved in accordance with the following procedure. First, an immunogen is selected. The immunogen can be any of those already described. After, one or more amounts varying from the selected immunogen are added to the liquid phase described in the first step above to provide one or more improved liquid phases, respectively, having a final density scale of the selected immunogen. The respective improved liquid phases are then mixed with the salt combination described above to precipitate respective improved hydroxyapatite samples. In subsequent steps, these samples are tested as described in connection with the first mode. A final improved hydroxyapatite formulation is selected that allows the desired release rates. The improved liquid phase for the second embodiment is that it allows precipitation of this selected final improved hydroxyapatite formulation. In a third step, the improved liquid phase is mixed with the base combination of calcium phosphate salts. And, in a fourth step, the biocompatible hydroxyapatite formulation is a precipitate from this mixture. 3. Incorporation of Genes A third rno < The present invention relates to gene therapy. Recent advances in the understanding of genetic bases for diseases and the ability to manipulate functional genes are revolutionizing the field of medicine. The genetic material of humans and other animals, which is composed of deoxyribonucleic acid (DNA), can be managed to direct transfer in recipient cells along species barriers. As early as twenty years ago, a method of transferring DNA molecules to mammalian (including human) cells in tissue culture used a method to form DNA complex with calcium phosphate and applying this complex to the desired recipient cells. This resulted in recipient cells, albeit at a very low frequency, by taking the calcium-DNA phosphate complex and allowing part of the DNA to be incorporated into the crinoeomal material, thus allowing the product encoded by DNA to be produced in the recipient cells. . A major obstacle in the selection of genes in the form of naked DNA in intact organisms (animals or humans) is the susceptibility of DNA to degrade enzymes in body fluids and the propensity of DNA assortment to target sites, such as tissue of the muscle, to wash before the ability of the exposed cells to absorb a reasonable amount. Some attempts to solve these problems have involved the fixation of genetic sequences derived from certain viruses where the desired piece of DNA, 3 b even if it is absorbed only by some cells, it would be sufficient since the fixed viral sequences would allow reproduction of the piece of DNA in the recipient cells. The progenies of the recipients and transfer cells were expected to << Cell to cell would amplify the dose of DNA assorted in the animal (or human) in order to reach a desired clinical euperacy. However, a major safety concern arises from the use of virus-derived sequences to make the desired genes into virus-like self-reproducing elements. The concern is significant since most of the effective viral sequences that can provide the desired reproductive capacity arise from highly infectious viruses including certain viruses known to cause deadly diseases, such as AIDS and cancer. In the third embodiment of the present invention, a biocompatible hydroxyapatite formulation for gene therapy is provided, wherein the formulation incorporates a genetic material. The genetic material may comprise nucleic acids such as DNA or RNA (eg, antisense), modified proteins or proteins (eg, enzymes, transcription factors or translation factors), or cells expressing a desired protein or nucleic acid. The genetic material (eg, DNA) can be complexed in an orderly or random manner with hydroxyapatite. The cells physically adjacent to said complexes are allowed to absorb the complex and thus the gene. The purified DNA molecules (per 1 / example, concentrated form, circular or linear) representing a coding sequence operatively linked to regulatory and promoter sequences that allow favorable expression of a desired gene product in one or more types of mammalian cells. The formulation preferably exhibits mechanical properties of a soft paste or suspension, and should provide 20% or less of the genetic material approximately 1 day and 90% or more in about 30 days. More preferably, the assortment rates are 20% or less in about 2 days and 90% or more in about 5 days. The level of DNA is preferably in the range of about 10 μg to about 100 μg per cubic centimeter of the assortment vehicle produced in accordance with this embodiment. More preferably, the DNA level is preferably between 10 μg and 50 μg. The biocompatible hydroxyapatite formulation of this embodiment is preferably prepared in accordance with the following steps. In a first step, a base combination of calcium phosphate salts is prepared. This can be achieved in accordance with the following procedure, which is similar to that of the previous modalities. First, one or more combinations of calcium phosphate salts are prepared as previously described. Then, a liquid phase is prepared, also as previously described. Mixtures of these components, preferably having solid to liquid ratios as discussed in connection with previously described embodiments, are tested as discussed above. In a second step, a liquid phase is improved by the addition of the desired genetic material. This step can be accomplished in accordance with the following procedure. First, ee can select a desired gene ("coding sequence") that encodes the product intended to be expressed in the host. The gene can be cloned, propagated in a microbial host, and edited for expression in either a wide variety of recipient host cells or in a specific manner of tissue. Regulatory elements required for expression include general sequences or promoters of specific tissue, separation signals, polyadenylation signals and enhancer sequences. The genetic construction that will be incorporated in The hydroxyapatite formulation can be derived by combining the coding sequence with an appropriate series of regulatory elements in an operable ligature. The construct can then be propagated in a microbial host in order to avoid the risks of contaminating potentially dangerous or dangerous genetic sequences of a virus directed by a mammalian cell or a human cell. Preferably, all parts of the genetic construct are cloned from normal human cellular genetic material and then modified or edited and propagated in microbial host systems. Alternatively, where you want to express a As the viral or oncogenic sequence (eg, for immunotherapy purposes against certain cancers, AIDS, and the like), the coding sequence can be "derived from the virue or appropriate tumor cells. In certain cases, the coding sequence can be created by omitting "introns" from the original material derived from chromosome or through the creation of a DNA copy of the functional messenger RNA by a process called inverted transcription. In other cases, if the amino acid sequence of a desired polypeptide or protein product is known, the coding sequence for said protein or altered forms of said protein with predetermined changes can be produced by chemical gene synthesis. In these situations, where the coding sequence is modified or produced synthetically, the editing of the coding sequence may involve the predetermined addition of new separation signals, sites of start transcription / translation, or the like, in order to facilitate the production of the product encoded by the coding sequence in the recipient cells. The DNA purified for the biocompatible hydroxyapatite formulation of this embodiment preferably comprises the construction of The functional gene produced as described herein in a linear or circular form, in a single copy or multiple copy form linked in tandem, or in a mixed body of these forms. Various amounts of the desired gene, for example DNA The purified liquid is then dissolved in liquid phases of the type described in connection with the above embodiments. It is shown that the desired gene can be found in a cell, which can be a recombinant cell. The cell can be a cell derived from the myeloid or derived from the lymphoid. The cell can express a recombinant product including, without lipid, those selected from the group consisting of insulin, nucleic acid, viral antigens, bacterial antigens, fungal antigens, parasitic antigens, cytokines. , growth factors, hormones, pratrseinae cell surface, and enzymes. I also know where a protein or nucleic acid can be added directly to the liquid phase. The mixing of the genetic material with the liquid phase gives or preferably results in the weight ratios of solid to liquid described previously. These liquid phases auiwsintadas are mixed with the base salt combination to provide increased hydroxyapatite samples that are tested corso or previously described. A formulation of hi-ßlroxyapatite augmented final is selected, which allows the desired assortment rates. The increased liquid phase is that which Coraduce this formulation of the final absent hydroxyapatite test. In a third step, the increased liquid phase is mixed with the base combination of calcium phosphate salts. And, in a fourth step, the formulation of hydroxyapatite n r. Patchy biocous is precipitated from this mixture. 4. Extended or Controlled Assortment of Pharmaceutical Agents Traditional pharmaceutical agents typically comprise small chemical molecules that are eliminated from the relatively rapid circulatory system. An undesirable consequence of this feature is the need resulting from administering a compound containing the desired agent to the patient multiple times over several days or weeks. Also, every a <Administration involves the use of a large amount of the compound so that, after initial dilution, sufficient compound is present in the circulatory system to elicit a desired therapeutic effect. Current proposals to address these problems have mainly involved mechanical methods, for example, continuous intravenous infusion or the use of pumps that can be implanted. An implantable substance that contains the desired agent and degrades over different periods, thus releasing the agent and biocompatible ions such as calcium and phosphate, would improve upon known proposals. Among other advantages, a proposal as such reduces the complexity of the conventional administration of pharmaceutical agents, which is more expensive, carried with risks of infection, and subject to reduced patient consent. A substance that can be implemented in accordance with this embodiment would also reduce the total amount of pharmaceutical agent needed over the entire course of treatment, and avoid potential side effects caused by high concentrations of the pharmaceutical agent after each administration. Accordingly, the fourth embodiment refers to a biocompatible hydroxyapatite formulation that incorporates a pharmaceutical agent. Preferably, the agent is a b? Oc? < It is selected from the group consisting of anti-neoplastic agents, antibacterial agents, and anti-parasitic agents. An anti-neoplastic agent can be selected from the group consisting of cyclophosphamids, alkylating agents, purine analogues, pyrirnidic analogs, vinca alkaloids and vinca type, etopoeides and etoposide-like drugs, antibiotics, corticosteroids, nitrosoureas, antirnetabolites, cytotoxic drugs based on platinum, hormonal antagonists, antiestrogens, tamoxifen, doxorubicin, L-asparaginase, dacarbazine, amsacpna, procarbazm, hexamethylmelamine and mitroxanthrone. An antibacterial agent may comprise a heavy metal, an antibiotic, or other anti-bacterial agent. The pharmaceutical agent can also be an inflammatory agent, an analgesic, or a chemotherapeutic substance. Other contemplated pharmaceutical agents are known to those skilled in the art. The biocompatible hydroxyapatite formulation must show the mechanical properties of granules or a soft paste. The formulation must be able to release 20% or less of the agent in 1 day and 90% or more with approximately 30 days. More preferably, the release rates are 20% or less in about 20 days and 90% or more in about "10 days. The level of the agent comprises "Je preference of 10% to 20%" of the total dose conventionally prescribed for a total course of a specific treatment. The biocompatible hydroxyapatite formulation according to the method is preferably produced by the following steps. In a first step, a base combination of calcium phosphate salts is prepared by the following procedure similar to that in the previous modalities. In a second step, a liquid phase is increased by adding a desired pharmaceutical agent. This second step is preferably achieved by the following procedure. The desired agent is selected from the agents already "Jested. Then, one or more liquid phases, which are prepared as in the above embodiments, are augmented by adding varying amounts of the therapeutic agent. Each of the liquid phases is respectively mixed with the base salt combination preferably at a solid to liquid ratio as previously described, to form an increased formulation. The test samples of the respective augmented formulations (which have varying amounts of the pharmaceutical compound) are monitored subcutaneously, intramuscularly or intraperitoneally in test animals and characteristics such as serum levels of the therapeutic agent compound and reuptake rate of the implant formulation «ja. A final augmented formulation is selected that shows mechanical properties of granules or a paste, which allows the desired release rates of the agent, and which has an agent level of about 10% to about 50% of the total dose currently prescribed for a whole course of treatment. The increased liquid phase is that which leads to this final augmented test formulation. In a third step, the base combination of calcium phosphate salts is mixed with the increased liquid phase. And, in a fourth step, the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step. According to an example of this embodiment, antibiotic and anti-inflammatory compounds are incorporated into a hydroxyapatite formulation, wherein a final augmented formulation is selected that provides an adequate doeis for about 7 to about 14 days. In another example, a chemotherapeutic substance (or a combination thereof with other substances) is incorporated into a hydroxyapatite formulation to produce an increased formulation capable of delivering the chemotherapeutic substance over a period of from about 20 to about 30 days.

. Extensive or Controlled Hormone Assortment It is believed that small peptide hormones or their derivatives exert their physiological action on target cells 4iF; -L? specifics by binding to specific membrane receptors in said cells. As in the case of small chemical molecules that are incorporated into conventional pharmaceutical agents, the small peptides have only a half-life of "lirnite circulation" ja. This feature can be significantly improved by incorporating said molecules in a bio-jewel-like hydroxyapatite material. Thus, in accordance with a fifth embodiment of the present invention, a biocompatible hydroxyapatite formulation is provided as an assortment vehicle for hormones including peptide hormones and hormone-like agents. Preferably, the formulation comprises a hormone or peptide factor such as a regulatory type hormone selected from the group consisting of < Ineulin, atrial natriuretic factor (ANF), calcitonin, vasopressin, relaxin and the like. The hormone may also be a sex hormone selected from the group consisting of estrogen hormones, progestational hormones, androgenic hormones and any active derivatives thereof. The formulation must show mechanical properties of a paste suitable for subcutaneous placement and percutaneous application. Preferably, the formulation is capable of delivering the hormone at a rate of about 20% or less in about 1 day and about 90% or more in about 30 days. More preferably, the assortment rates are 20% or less in about 2 days and 90% or more in about 7 days. 4 b The concentration of the active material in the formulation is preferably from about 10% to about 50% (per cubic centimeter of the formulation administered) of the conventional recommended cumulative dose during a conventional treatment period from about 5 to about 100%. 30 days. The formation of biocompatible hydroxyapatite can be achieved by the following steps. In a first step, a base combination of calcium phosphate salts is preferably prepared following the procedure described in the fourth embodiment (ie, the embodiment incorporating a pharmaceutical agent) or similar steps thereto. In a second step, a liquid phase, such as that described in the above embodiments, is increased by adding the desired hormone (or peptide factor or hormone-like agent). This is preferably achieved by following the procedure described in the fourth embodiment. In a third step, the base salt combination is mixed with the increased liquid phase. And, in a fourth step, the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step. 6. Replacement, Repair and Regeneration of Bones Bone is unique in its ability to completely regenerate between complex tissues in larger organisms such as vertebrates. Due to the complex nature of bone tissue and the varied functions performed by the skeleton in different locations within the body, different proposals for intervention can provide greater therapeutic benefits at different locations. The respective roles played by the cellular component, the matrix component, and the interaction between these two phases of bone, contribute to the regenerative procedure and the functioning of the tissue. Certain proteins that are unique to bone have been identified with respect to their structural and mineral binding properties. In this way, a sixth embodiment of the present invention refers to the replacement, repair and regeneration of bone. An aspect of this modality deals with osteoconducting principles. A biocompatible hydro iapatite formulation that represents the main mineral component of bone in the presence of major structural and mineral binding proteins found in bones, they can be provided which has utility as a bone void filler with a matrix that resembles that of normal bone. This formulation is compatible with bones and capable of supporting resorption to be replaced by new bones that are remodeled between natural procedures. This novel formulation is useful for filling several damaged sites and is also useful for filling gaps between prosthetic devices and tissue surrounding the body, thus providing better fixation for orthopedic, periodontal and dental applications. The formulation is also useful as an autograft or allograft extender where 40 The quantities normally available are not enough. Thus, in accordance with this aspect, a biocompatible hydroxyapatite formulation is provided which is capable of supporting bone growth. Preferably, a formulation in accordance with this aspect contains one or more adhesive agents. The adhesive agent can be chosen from the group consisting of integrins, extracellular matrix proteins, leukocyte adhesion proteins, collagen, albumin, bone proteins, osteonectins, cell surface receptor proteins, bone gla protein, and protein. matrix gla. The biocompatible hydroxyapatite formulation must show mechanical properties of a paste that hardens on an implant. The implant preferably has a compression force of greater than 10 MPa, which is more preferably greater than about 50 MPa, and highly preferred greater than about 100 MPa. The implant should be approximately 45% porous with an average pore size of about 15 microns to about 30 microns. Most preferably, the average pore size is about 20 microns to about 25 microns. Most preferred, the average pore size is equal to about 23 micras. The maximum pore size should be less than 100 microns, preferably less than about 50 microns. The formulation can be reabsorbed preferably in about 60 days to about 2 years. More preferably, the formulation can be reabsorbed in about 60 days to about 90 days. The amount of the osteogenic protein should be about 10% to about 40% of the total weight of the formulation, and the relative amount of the proteins to each other (if more than one is incorporated) should be similar to that found in the tissues of the body at the application site. The biocompatible hydroxyapatite formulation may further contain (a) an antibiotic subenergy that is locally released from the formulation during the repair process and prevents infection that could prevent regeneration; or (b) a hormone, for example, calcitonin, which can be released locally during the repair procedure to inhibit bone loss due to a fundamental metabolic disease such as osteoporosis. The formulation of hydroxyapatite increased by this aspect of the sixth embodiment is preferably formed in accordance with the following method. In a first aspect, a base combination of calcium phosphate salts is prepared. This can be achieved in accordance with a procedure similar to that of previous modalities. In a second aspect, a liquid phase increases by adding an osteogenic adhesive type protein. This can be achieved by the following procedure. First, one or more proteins are selected from those already described. For example, human bone gla protein, human matrix gla protein and human osteonectin can be produced by recombinant and purified means. Then, a liquid phase is formed as previously described. The liquid phase can be supplemented (or supplemented more) with granulated sugar, at the time of mixing with the base salt combination, the final formulation will contain up to about 20% by weight of sugar. The selected proteins are then uniformly dissolved in the liquid phase supplemented to form an increased liquid phase. In a third step, the salt base combination is mixed with the increased liquid phase. In a fourth step, the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step. The paste thus formed is preferably allowed to harden under pressure (eg, from about 40,000 psi to about 80,000 psi) in vitro in desirable mold configurations for a period of about 12 hours to about 48 hours. The hardened formulation is then subjected to hot water at temperatures in the range of about 50 ° C to about 70 ° C., more preferably around 50 ° -55 ° C. This treatment should last for about 4 to about 10 hours, more preferably 4 to 5 hours, to remove most of the granulated sugar, thus creating a highly porous material. The material can then be implanted in a body, for example, in a selected amount of bone. Another aspect of the sixth modality deals with osteoinduction. Hydroxyapatite implants, including porous forms, often allow the growth of newly developed body tissue at sites of bone defect. As a result, the hydroxyapatite implant is incorporated into the newly formed bone that remodels naturally. A hydroxyapatite implant can actively perform the differentiation procedure that causes the cells of the pluripotent stem at the site of a trauma s? <The trajectory of bone formation, "osteogenesis", will provide ejod therapeutic benefits. A group of factors, usually called osteo factors < JEN cos, morphogenic bone protein, or chondrogenic factors, have been shown to mediate this phenomenon in animals and humans. Thus, this aspect of the sixth embodiment of the present invention provides a biocompatible hydroxyapatite formulation, which can cause active bone growth in implants. Preferably, the formulation is capable of inducing new bone formation and comprises one or more growth factors selected from the group consisting of osteogenic, morphogenic, bone, protein and chondrogenic factors. These growth factors can be included alone or in combination with one or more adhesive agents, which can be selected from the group consisting of integrins, extracellular matrix proteins, leukocyte adhesion proteins, collagen, albumins, bone proteins, osteonectins, cell surface receptor proteins, bone gla protein, and matrix gla protein. The formulation must show mechanical properties of a paste that hardens an implant that has a tensile stress of at least 20 MPa. More preferably, the tensile stress is greater than 60 MPa, and highly preferred greater than about 70 MPa. The preferred formulation is porous with average and maximum pore sizes as described above. The level of active growth factor "It should be on the scale of about 10 μg to about 100 μg per cubic centimeter" for an assortment vehicle containing the selected growth factor alone, or for an assortment vehicle it contains up to about 40% by weight of one or more of the adhesive agents. The final formulation may also contain a heparanase. This term generally means an enzyme that degrades heparin sulfate or causes the release of molecules in vivo that bind heparin or heparin sulfate. The final formulation may also contain an antibiotic substance. The formulation of this aspect of the sixth embodiment can be prepared in accordance with the following method. In a first step, a base combination of soluble calcium phosphate salts is hardly prepared as before. In a second step, a liquid phase is increased by adding one or more appropriate growth factors and the desired adhesive agents. Various suitable factors, including those already mentioned as examples, have been described in the art together with recombinant production media in genetically produced marine cells or microbial huéeed cells. In a third step, the increased liquid phase is mixed with the base salt combination. Preferably, this mixture has a solid to liquid o as previously described. In a fourth step, the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step. The formulation preferably has the characteristics described above. The final formulation can be hardened ex vivo or rapidly in vivo when applied in an open fracture such as an implant or a base material along with other implants. Yet another aspect of the sixth modality focuses on bone regeneon. Bone defects at sites other than the skeleton may require different balances between bone regeneon and short-term biomechanical support. The formulations described in the above aspect of the sixth embodiment can provide modest mechanical support and allow efficient bone growth, so that the implant is rapidly incorpod into newly formed bone for long-term mechanical support. Still, these formulations also provide capacity with reasonable stress within a short time post-opevely by virtue of their biomechanical effort. In other applications, where short-term load support is not an important factor (for example, [X. spinal fixation, radial and ulnar fracture, non-union, and the like), it is necessary to be able to provoke the rapid formation of new bone for long-term benefit with short-term support being provided by other fixation devices. Thus, in accordance with this aspect of the sixth embodiment of the present invention, a biocompatible hydroxyapatite formulation is provided which is capable of actively inducing bone repair in small defects. The formulation preferably comprises a growth factor selected from the group consisting of osteogenic factors, morphogenic bone proteins, and chondrogenic factors. The formulation may also comprise one or more adhesive agents, which may be selected from the group consisting of integrins, extracellular matrix proteins, leukocyte adhesion proteins, collagen, albumins, bone proteins, osteonectins, cell surface receptor proteins. , gla bone protein, and matrix gla protein. The formulation should be in the form of a soft paste or suspension that can be applied precutaneously. Preferably, the formulation is characterized by the resorption ability described in connection with the above aspects and preferably contains between about 50 μg and about 500 μg of the selected growth factor for each cubic centimeter of the formulation. If incorporated, the agent should be at a level of up to 40% by weight of the final formulation. ü b The formulation may also contain heparanase, which must generically mean an enzyme that degrades heparin substrate or induces the release of in vivo molecules that bind to heparin or heparin substrate. The formulation may also contain an antibiotic eubluency. In comparison with the formulation described in the previous aspects of this modality, this formulation should not have significant mechanical stress and should provide a faster local assortment of growth factors for a shorter duration. The formulation of this aspect of the sixth embodiment can be prepared in accordance with the following method. In a first step, a base combination of soluble calcium phosphate salts is hardly prepared as before. In a second step, a liquid phase increases with the addition of one or more appropriate growth factors and the adhesives "Jeseados. In a third step, the increased liquid phase is mixed with the base salt combination. In a fourth step, the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step. The formulation preferably has the aforementioned characteristics. Also, this mixture must have a solid to liquid ratio as previously described. Preferably, the final formulation is applied percutaneously and hardens in vivo. Examples of this and previous aspects of this embodiment include: (a) a formulation that incorporates a homodyne of BMP-2 produced in Chinese hamster ovary (CHO) cells; (b) a formulation using molecules designated C0P5 or C0P7 or Vgl produced in E coli cells; and (c) a formulation incorporating a heterodyne of BMP-4 and BMP-5 produced in a genetically produced honey host cell. 7. Enhancement of Electrical or Electromagnetic Stimulation of Bone Growth A seventh embodiment of the present invention relates to the improvement of osteogenesis around and in hydroxyapatite implants in response to electromagnetic stimulation. Electromagnetic stimulation has been reported to be effective in stimulating bone healing and bone growth in hydroxyapatite implants when the implants have an average size preferably on a scale of about 15 microns to about 30 microns (more preferably 20 microns). microns and 25 microns, more preferably equal to approximately 23 microns). The incorporation of paramagnetic, diamagnetic, conductive and insulating material in an implant can intensify or attenuate the electric and electromagnetic fields close to the implant when subjected to electromagnetic stimulation. This improved formulation can increase the speed of bone healing and reduce the field strength required for electromagnetic stimulation. This embodiment of the present invention relates to a formulation of b? Increased hydroxyapatite with altered magnetic and conductive properties that improve the effects of bone repair induced by electromagnetic field and bone formation. In this manner, the seventh embodiment of the present invention provides a biocompatible hydroxyapatite formulation, incorporating an electrical stimulus enhancer. The stimulus enhancer may be one or more of a paramagnetic material, a diamagnetic material, a conductive material, or an insulator. The paramagnetic material can It is selected from the group consisting of iron, iron ammonium, uranium, platinum and aluminum. The diamagnetic material can be selected from the group consisting of bismuth, mercury, silver, carbon (diamond), lead and copper. The conductive material can be selected from the group q? E consiete L5 silver, copper, aluminum and tungsten. And, the insulator can be selected from the group consisting of glass, lucite, mica, quartz, and polytetrafluoroethylene (PTFE). Preferably, the formulation is capable of causing new bone growth and promoting osteogenesis in the tissue surrounding the implant.

The formulation should show mechanical properties of a paste that hardens in an implant having a tensile stress greater than 20 MPa (more preferably greater than 60 MPa, highly preferred greater than 70 MPa). The formulation must be porous with average and maximum pore sizes as described above. The The formulation preferably has the resorption ability already described (ie, 60 days to 2 years, preferably 60-90 days). The hydroxyapatite formulation of the peptide modality can be prepared according to the following method. In a first step, a salt base combination of sparingly soluble calcium phosphate salts is prepared as before. In a second step, a liquid phase increases by adding one or more electromagnetic breeders selected from those already described. In cases where the material is toxic, it can be fitted in glass or PTFE. In a third step, the increased liquid phase is mixed with the base salt combination. And, in a fourth step, the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step. The hydroxyapatite formulation can harden iri vitro and is used as a bone replacement. In an example of treatment, an implant formed of the formulation can be implanted in the body of a human. The implant is then stimulated electrically or magnetically to induce bone growth in and around the implant. 8. Improvement of Electrical or Electromagnetic Pulse in Local Release of Materials Several embodiments of this invention generally refer to a hydroxyapatite formulation for the assortment d? a bioreactive substance. The application of an electromagnetic field can stimulate bone growth and 50 tissue and vascularization in and around a hydroxyapatite implant. The electromagnetic activation of an implanted hydrox apatite or implanted hydroxyapatite formulation can also regulate the assortment of bioreactive substances. They have been shown to poe eléctpcoe that cause the absorption of factors of a matrix that is exposed to the field. In addition to causing direct release, electromagnetic stimulation will also stimulate the growth of tissue in the implant, thereby increasing contact between the bioreactive substance and the tissue. In this manner, the eighth embodiment of the present invention relates to a biocompatible hydroxyapatite formulation that is subjected to electrical or electromagnetic stimulation after being inserted into a human or animal. The hydroxyapatite formulation is preferably prepared according to the following method. In a first step, a base combination of calcium phosphate salts is prepared as before. In a second step, a liquid phase increases by adding one or more bioreactive substances. The bioreactive substance can be any of the biocompatible additives described above. In a third step, the increased liquid phase is mixed with the base salt combination. In a fourth step, the biocompatible hydroxyapatite formulation is precipitated from the mixture of the third step. The precipitation can be in vivo. Alternately, the precipitation can be ex vivo. In accordance with this fai Alternatively, an additional step is required wherein the precipitated hydroxyapatite formulation is implanted in a human or animal. In a fifth step, the implant is electrically or electromagnetically stimulated to induce the growth of bone and tissue and vascularization in and around the hydroxyapatite implant and to induce the release of the bioreactive substance from the hydroxyapatite formulation. 9. Multicomponent Stratified Devices for Dual Tissue Interface The use of devices that can be implanted in guide tissue regeneration procedures would be significantly more beneficial if such devices can be constructed to allow a surface to be compatible with a second type of tissue. In periodontal defects, for example, the devices look at the soft tissue of the gum and the fundamental bone structure. Similarly, in joint joints such as hip, knee, elbow and ankle, where rheumatoid arthritis and osteoarthritis have caused cartilage damage or bone damage, a desirable device must have a surface compatible with bone and another compatible with cartilage. . It will be apparent to those skilled in the art that other examples may be readily identified with application throughout the human body, as well as animals. In this way, the ninth modality, which can be used hl for such dual-weave applications, it provides a stratified device having a first layer comprising a synthetic polymer (e.g., a glycolide / lactide / acrylic material selected for compatibility with soft tissue or cartilage) and a second layer of a Biocompatible hydroxyapatite formulation that is compatible with bones. The second layer can be created by applying a paste formed from a mixture of calcium phosphate salt sparingly, such as those previously described. This embodiment also contemplates the incorporation of a class of pharmaceutically active or biocompatible material in the first layer to facilitate the regeneration of soft tissue or cartilage although the hydroxyapatite layer incorporates one or more biologically active or biocompatible substances, which facilitates bone repair. as described in the previous modalities. A significant advantage of the stratified devices of this embodiment is that the biologically or pharmaceutically active subetancies that negate the formation of selected tissues can be incorporated in one layer while the other substances that encourage such formation can be incorporated in the other layer. This allows clear delineation of the dual tissue look created in the guided tissue regeneration procedure. For example, in the case of joint joints, the synthetic polymer layer which becomes compatible with cartilage may contain an anti-angiogenic factor to prevent the migration of bone tissue in this layer from the body tissue being regenerated in the layer «He hydroxyapatite. According to an example, the synthetic polymer layer is impregnated with type II collagen and hyaluronic acid to allow better cartilage compatibility, although the hydroxyapatite layer is impregnated with type I collagen, bone gla protein, osteonectin and the like, for the facilitation of previous regeneration.

. Other Characteristics and Aspects The embodiments thus described should be simply examples of the present invention, which should not limit the same. For example, as discussed previously, many of these embodiments described herein involve a procedure wherein a liquid phase increases with a biocompatible additive. Then, the increased liquid phase is mixed with a base combination of calcium phosphate salts. However, it is contemplated that the components of the mixture, which precipitates hydroxyapatite, may be combined in different orders or simultaneously. Also, although several release rates are described, those skilled in the art will note that the components of the hydroxyapatite formulations can be manipulated to achieve different release rates which may be more suitable for a given application. In accordance with a characteristic of the b Different embodiments of the present invention, the components of the mixture that precipitate a biocompatible hydroxyapatite formulation can be provided in a form of equipment. For example, a package comprises equipment that has three bottles. A first bottle preferably contains a measured amount of the base calcium phosphate salt combination. A second bottle contains preferably the selected additive, which can be any of the additives already described (for example, a growth factor).

Depending on the additive and the desired treatment criterion, the additive may be in any of several forms. For example, a growth factor can be provided in a lyophilized state. The third bottle contains the liquid phase. Alternately, the equipment contains two bottles. In a first In the option of two bottles, one bottle would contain the calcium phosphate salts and the other would contain a mixture of the liquid and the additive. In a second option of two bottles, one bottle contains a combination of the additive and the salee, and the other contains the liquid phase. In accordance with one aspect of the equipment characteristic, the contents of the bottles can be combined to produce a paste of the biocompatible hydroxyapatite material. The resulting paste can be administered by itself in a surgical site or can be used to increase suture, staples, membranes (which can be reabsorbed or not) or the like which are in widespread use for stabilization and wound closure. The paste can also be used to augment the artificial skin and membranes used to cover larger burn wounds. In accordance with another characteristic "je modalida" is above, hardened sheets pre-impregnated with a precipitated biocompatible hydroxyapatite formulation incorporating an additive may be provided in sterile form. Preferably, these sheets are capable of being cut into desired shapes and applied to cover wounded site and pack wounds deeply. Also, the sheets thus applied can be stabilized using known surgical closure techniques. Various procedures for producing sheets or similar structures are contemplated in this embodiment. The embodiments described above may also incorporate an antibiotic substance that prevents infection of the increased hydroxyapatite material. The antibiotic substance can also be released at the site of the wound to prevent infection of the wound site while the material is in place. Some of the types of antibiotics that may be used include, without limitation, aminglicosides, amphenicols (e.g., chloramphenicol), ß-lactam antibiotics, penicillins (e.g., anpicillin), peptide antibiotics, and tetracycline antibiotics (e.g. , tetracycline). In accordance with another feature, two or more formulations are independently prepared. For example, an ex vivo implant can be prepared by mixing the saltse, additives and liquid phase as described above to produce a paste. The paste can be allowed to harden into a component that can be reabsorbed more slowly than a separately prepared formulation. This paste can be extruded through w > a suitable opening to produce granules of such size that they can be applied through a large-scale hypodermic needle or other acceptable injection mechanism. A formulation formulation can be prepared freshly at the time of administration (e.g., by adding a liquid phase which contains about one third of the total intended dose of the additive to the base salt combination in a ratio that produces a softer paste, than it can harden in situ in a biodegradable implant more quickly.They can be mixed with the appropriate granule salts uniformly with the base salt combination before adding the liquid phase, as the granules contribute about three times as much of the immunogen as the softer paste contributed. Said sisttaaaa comprising a paste with mixed granules and a freshly prepared paste provides a two-component system where the freshly prepared dough releases a first dose of the selected additive relatively quickly and the mixture of dough and granules supplies more slowly over a period of time. extensive. In accordance with an aspect of this face * e * eristic, a mixed stratified body can be produced where the central core contains a formulation that can be reabsorbed more slowly, which is surrounded by a formulation that can be reabsorbed more quickly. In accordance with yet other features of these embodiments, the formulation can be administered intra-molecularly, intravenously, subcutaneously, or per-cutaneously (depending on the desired target tissue) in which the additive (eg, DNA) is to be delivered. The ratio of solid to liquid and the amounts of supplements cited herein for the liquid phase are selected on the basis of results from animal evaluations where various test formulations are administered, and the release of the additive and the biodegradation of hydroxyapatite. Those skilled in the art will note that other variations and modifications to the specific examples described herein can easily be achieved without departing from the scope and spirit of the present invention. Accordingly, the present invention is limited only by the following claims.

Claims (19)

1. NOVELTY OF THE INVENTION CLAIMS 1. - A method for preparing a biocompatible hydroxyapatite formulation comprising the steps of: a) preparing a base combination of calcium phosphate salts; b) prepare a liquid phase; c) provide a biocompatible additive; d) combining the base combination of calcium phosphate salts, the liquid fae and the biocompatible additive to form a mixture; and e) precipitating the biocompatible hydroxyapatite formulation from the mixture.
2. 2. The method according to claim 1, further characterized in that the combining step comprises: a) adding the biocompatible additive to the liquid phase to form an increased liquid phase; and b) mixing the increased liquid phase with the base combination of calcium phosphate salts.
3. 3. The method according to claim 1, further characterized in that the combining step comprises: a) adding the biocompatible additive to the base combination of calcium phosphate salts to form an increased combination of calcium phosphate salts; and b) mixing the liquid phase with the increased combination of phosphate salts.
4. 4. The method according to claim 1, further characterized in that the combining step comprises simultaneously combining the base combination of calcium phosphate salts, the biocompatible additive and the liquid phase.
5. 5. The method according to claim 1, further characterized in that said step of precipitation occurs in vivo.
6. 6. The method according to claim 1, further characterized in that said step of precipitation occurs ex vivo.
7. 7. The method according to claim 1, further characterized in that said step of precipitation occurs partially ex vivo and partially in vivo.
8. 8. The method according to claim 1, further characterized in that it comprises the step of allowing the formulation of precipitated biocompatible hydroxyapatite to be reabsorbed or degraded in vivo.
9. 9. The method according to claim 1, further characterized in that the base combination comprises two salts and wherein one of the two salts is tetracalcium phosphate and the other of the two salts is selected from the group consisting of CaHPO * .2H2 ?, CaHP0 «, CaßH2 (PO4) ß .5H20, ß-Ca3 (PO4) 2, α-Caß (PO4) 2, V Ca3 (PO4) 2 modified.
10. 10. The method according to claim 9, further characterized in that the modified C2 (P0") 2 is tetracalcium phosphate modified by protons or up to 0 next "10% by weight of magnesium.
11. 11. The method according to the claim I, further characterized in that the biocompatible additive is a growth factor.
12. 12. The method according to the claim II, further characterized in that the growth factor is selected from the group consisting of epidermal growth factors, transformation growth factor a, transformation growth factor B, vaccine growth factors, fibroblast growth factors, of insulin-like growth, platelet-derived growth factors, cartilage-derived growth factors, interleukin-2, nerve cell growth factors, growth factors of the hernapoietic cell, lymphocyte growth factors, rnorfogenic proteins. Je bone, osteogenic factors, chondrogenic factors.
13. 13. The method according to claim 12, further characterized in that the hemopoietic cell growth factor is selected from the group consisting of interleukin-3, granulocyte-macrophage colony stimulating factor, angiogenesis factors, stimulating factor of macrophage colony, granulocyte colony stimulating factor, and erythroprotein.
14. 14. The method according to the claim 12, further characterized in that the lymphocyte growth factor is selected from the group consisting of B cell growth factor., T cell growth factor, interleukin-4, interleukin-5 and interleukin-6.
15. 15. The method according to claim 1, further characterized in that the biocompatible additive is an immunogen.
16. 16. The method according to claim 15, further characterized in that the immunogen is selected from the group consisting of a viral antigen, a bacterial antigen, a fungal antigen, and a parasitic antigen.
17. 17. The method according to claim 15, further characterized in that the immunogen is a marker of specific malignancy.
18. 18. The method according to claim 17, further characterized in that the marker of specific malignancy is selected from the group consisting of tumor antigens, peptide fragments of tumor antigens, and metastatic-specie antigens.
19. 19. The method according to claim 15, further characterized in that the immunogen is a "subunit" vaccine. 20.- The method according to the claim 1, further characterized in that the biocompatible additive is a vaccine. 21. The method of compliance with the claim 20, further characterized in that the vaccine comprises an antigen selected from the group consisting of a viral antigen, a bacterial antigen, a fungal antigen and a parasitic antigen. 22. The method according to claim 20, further characterized in that the vaccine is a passive vaccine. 23.- The method according to the claim 20, further characterized in that the vaccine is an active vaccine. 24.- The method of compliance with the claim 20, further characterized in that the vaccine is a synthetic vaccine. 25. The method of conformity with claim 24, further characterized in that the synthetic vaccine is made by organic synthesis. 26. The method according to claim 24, further characterized in that the vaccine is made by recombinant techniques. 27. The method according to claim 1, further characterized in that the biocompatible additive is a nucleic acid. 28.- The method of compliance with the claim 1, further characterized in that the biocompatible additive is a protein. 29.- The method of compliance with the claim 28, further characterized in that the protein is selected from the group consisting of insulin, nucleic acid, viral antigens, bacterial antigens, fungal antigens, parasitic antigens, cytokines, factors < Growth, hormones, cell surface proteins and enzymes. 30. The method according to claim 1, further characterized in that the biocompatible additive is a cell comprising a gene. 31. The method according to claim 30, further characterized in that the cell is a recombinant cell. 32.- The method of conformity with claim 30, characterized in that the cell is a derived rhieloid cell. 33. The method according to claim 30, further characterized in that the cell is derived lymphoid. 34.- The method according to claim 30, further characterized in that the cell expresses a recombinant product. 35. The method according to claim 34, further characterized in that the recombinant product is selected from the group consisting of insulin, nucleic acid, viral antigens, bacterial antigens, fungal antigens, parasitic antigens, cytokines, growth factors, hormones, cell surface proteins and enzymes. 36. The method according to claim 1, further characterized in that the biocompatible additive is a pharmaceutical agent. r -J 37. - The method of compliance with the claim 36, further characterized in that the pharmaceutical agent is selected at p > Artir of the group that considers «anti-neoplastic agents, antibacterial agents, para-ethic agents, and derivatives and combinations thereof. 38.- The method according to the claim 37, characterized in that the anti-neoplastic agent is selected from the group consisting of cyclophosphates, alkylating agents, purine analogs, analogues of 10 pyrimidine, vinca and vinca type alkaloids, etoposides and etoposide-type drugs, antibiotics, corticosteroids, nitrosoureas, antimetabolites, cytotoxic drugs based on platinum, hormonal antagonists, antiestrogens, tamoxifen, doxorubicin, L-asparaginase, dacarbizine, amsacrine, 15 procarbazine, hexamethylmelamine and mitoxantrone. 39.- The method according to the claim 38, further characterized in that the antibacterial agent is selected from the group consisting of heavy metal and an antibiotic. 20 40.- The method according to the claim 36, further characterized in that the pharmaceutical agent is an inflammatory agent. 41.- The method according to claim 36, further characterized in that the pharmaceutical agent is? N :! = • analgesic. 42. The method according to claim 36, further characterized in that the pharmaceutical agent is a chemotherapeutic substance. 43.- The method according to claim 1, further characterized in that the biocompatible additive is a hormone. 44. The method according to claim 43, further characterized in that the hormone is selected from the group consisting of insulin, atrial natriuretic factor, calcitonin, vasopressin, and relaxin. 45.- The method of compliance with the claim 43, further characterized in that the hormone is selected from the group consisting of an estrogenic hormone, a progestational hormone, and an androgenic hormone. 46. The method according to claim 1, further characterized in that the biocompatible additive is an antibiotic. 47.- The method of compliance with the claim 46, further characterized in that the antibiotic is an aminoglycoside. 48.- The method of compliance with the claim 46, further characterized in that the antibiotic is an amphenicol. 49. The method according to claim 48, further characterized in that the anthfenicol is chloramphenicol. 50.- The method according to claim 46, further characterized in that the antibiotic is β-lactamase antibiotic. 51. - The method according to claim 46, further characterized in that the antibiotic is a penicillin. 52. The method according to claim 5 51, further characterized in that the penicillin is an icylme. 53. The method according to claim 46, further characterized in that the antibiotic is a peptide antibiotic. 54.- The method "conformity" with claim 10 46, further characterized in that the antibiotic is a tetracycline antibiotic. 55. The method according to claim 54, further characterized in that the tetracycline antibiotic is tetracycline. 5 56.- The method according to the claim 1, further characterized in that it comprises the step of combining the biocompatible hydroxyapatite formulation with an antibiotic. 57. The method according to claim 1, further characterized in that it comprises the step of combining the biocompatible hydroxyapatite formulation with heparanase. 58.- The method according to claim 1, further characterized in that said mixture has a solid to liquid ratio of about 1: 1 to about 5: 1. 59.- The method of compliance with the claim ••• R 1, further characterized in that the liquid phase comprises a liquid selected from the group consisting of water, saline, a weakly acid solution, a biocompatible buffer, serum and plasma. The method according to claim 1, further characterized in that the liquid phase is supplemented with one or more components selected from the group consisting of proteoglycan, hyaluronic acid, protein, albumin serum, carbohydrates, granulated sugar, a synthetic material, polyethylene glycol, ionic agents, non-interlaced collagen, and glycerin. 61.- The method according to the claim 1, further characterized in that the precipitation step occurs at a temperature on the scale of about 4 ° C to about 50 ° C. 62. The method according to claim 1, further characterized in that the precipitation step occurs at a temperature in the range of about 15 ° C to about 42 ° C. 63. The method according to claim 1, further characterized in that it comprises the step of hardening the biocompatible hydroxyapatite formulation to a substantially uniform crystallinity. 64.- The method according to claim 1, further characterized in that it comprises the step of hardening the biocompatible hydroxyapatite formulation to a substantially uniform porosity. 65.- The method according to claim 1, further characterized in that it comprises the steps of configuring the biocompatible hydroxyapatite formulation in a structure. 66. The method according to claim 65, further characterized in that the structure is a wound dressing, a bone substitute, a cartilage substitute, or a soft tissue substitute. 67.- The method according to claim 65, further characterized in that the structure is a sheet, a membrane, a coating, or a biological prosthesis. 68.- The method according to claim 67, further characterized in that the membrane has a thickness in the scale of about 1 mm to about 7 nm. 69.- The method according to claim 65, further characterized in that the structure is a granulated block. 70.- A biocompatible hydroxyapatite formulation prepared by the method according to claim 1. 71.- The formulation according to claim 1, further characterized in that the biocompatible additive is lyophilized in a powder. 72. The formulation according to claim 71, further characterized in that the powder is stable for more than about 3 months. 73.- The formulation according to claim 1, further characterized in that it comprises an r-8 pharmaceutically acceptable vehicle. 74. The formulation according to claim 73, further characterized in that the pharmaceutically acceptable carrier is selected from the group consisting of water, glycerol, glycols, saccharide, polycarbides, oils, salts and fatty acids. 75. A method for treating a patient comprising the steps of: a) preparing a base combination of calcium phosphate salts; b) preparing a liquid phase; c) provide a biocompatible additive; d) combining the base combination of calcium phosphate salts, the liquid phase and the biocompatible additive to form a mixture; e) precipitating the biocompatible hydroxyapatite formulation from the mixture; and f) administering the biocompatible hydroxyapatite formulation precipitated to the patient. The method according to claim 75, further characterized in that the step of combining comprises: a) adding the biocompatible additive to the liquid phase to form an increased liquid phase; and b) mixing the increased liquid phase with the base combination of calcium phosphate salts. The method according to claim 75, further characterized in that the combining step comprises: a) adding the biocompatible additive to the base combination of calcium phosphate salts to form an increased combination of calcium phosphate salts; and b) mix phase 7 q liquid with the increased combination of calcium foephate salt. 78. The method according to claim 75, further characterized in that the step of combining comprises combining simultaneously the base combination of phosphate salts, the biocompatible additive and the liquid phase. 79. The method according to claim 75, further characterized in that the precipitated biocompatible hydroxyapatite formulation is absorbed by the patient after administration. 80. The method according to claim 75, further characterized in that the precipitated biocompatible hydroxyapatite formulation is non-ininogenic for the patient. 15 81.- The method of compliance with the claim 75, further characterized in that the biocompatible additive is released from the hydroxyapatite formulation in a release mode with time measured. 82. The method according to claim 20 81, further characterized in that less than about 20% of said additive is released in about 24 hours. 83. The method according to claim 81, further characterized in that more than about 90% of said additive is released in about 30 days. • > r. 84.- The method according to claim 75, further characterized in that it comprises the step of forming the HO Biocompatible hydroxyapatite formulation precipitated in a paste. 85.- The method of compliance with the claim 84, further characterized in that the pulp is an adhesive, a bandage, a biological patch, a vehicle, an assortment, an absorbent, a coating or a protector. 86.- The method of compliance with the claim 85, further characterized in that the biological assortment vehicle is a contraceptive device. 87.- The method of compliance with the claim 85, further characterized in that the glue is bone glue. 88. The method according to claim 75, further characterized in that it comprises the steps of forming the biocompatible hydroxyapatite formulation in a form and administering the form to the patient. 89.- The method of compliance with the claim 88, further characterized in that the shape is a medical prosthesis. 90.- The method of compliance with the claim 89, further characterized in that the medical prosthesis is "administered cutaneously, subcutaneously, or intramuscularly. 91.- The method according to claim 75, further characterized in that the precipitated formulation is administered by covering, implanting or injecting. 92.- A device for precipitating a biocompatible hydrofoxyapatite formulation comprising: a predetermined quantity of a combination of calcium phosphate salts base; a predetermined amount of a liquid phase; and a predetermined amount of a biocompatible additive, in the base combination of calcium phosphate salts, the biocompatible mixture and the liquid phase can be combined to form a mixture that precipitates the biocompatible hydroxypatite formulation. The equipment according to claim 92, further characterized in that the base combination of the calcium phosphate salts, the biocompatible additive and the liquid phase can be combined simultaneously to precipitate the biocompatible hydroxyapatite formulation. 94.- The equipment according to claim 2 * further characterized in that the biocompatible additive can be added to the liquid phase to form a liquid phase, and wherein the increased liquid phase can be added to the base salt combination. of calcium phosphate to precipitate the biocompatible hydroxyapatite formulation. 95.- The equipment in accordance with the claim 92 »further characterized in that the biocompatible additive can be added to the base combination of calcium phosphate salts to form an increased combination of calcium phosphate salts, and wherein the increased combination of calcium phosphate salts can be added to the phase liquid to precipitate the formulation of biocompatible hydroxyapatite. 02 96. - The equipment according to claim 92, further characterized in that the biocompatible additive is in a lyophilized state. 97.- The equipment according to claim 92, further characterized in that the base combination of calcium phosphate salts is in a first container, wherein the liquid phase is in a second container, and wherein the biocompatible additive is present. in a third container. The equipment according to claim 92, further characterized in that two or more of the base combination of calcium phosphate salts, the liquid phase and the biocompatible additive are in the same container. 99.- A device for precipitating a biocompatible hydroxyapatite formulation comprising: a predetermined quantity of a base combination of calcium phosphate salts; a predetermined amount of an increased liquid phase; wherein the increased liquid phase comprises a liquid phase and a biocompatible additive, and wherein the liquid phase can be added to the base combination of calcium phosphate salts to precipitate the biocompatible hydroxyapatite formulation. 100.- The equipment according to claim 99, further characterized in that the base combination of calcium phosphate salts is in a first container, and wherein the liquid phase is in a second container. 101.- A team to precipitate a formulation of (13 biocopatible hydroxyapatite comprising: a predetermined amount of an increased combination of calcium phosphate salts; and a predetermined amount of a liquid phase, wherein the increased combination of calcium phosphate salts comprises a combination of phosphate-calcium salt base and a biocompatible additive, and wherein the liquid phase can be added to the augmented combination. of calcium phosphate salts to precipitate the biocompatible hydroxyapatite formulation. 102.- A method for preparing a biocompatible hydroxyapatite formulation comprising the steps of: a) preparing a base combination of calcium phosphate salts; b) preparing a liquid phase; c) provide an adhesive agent; d) combining the base combination of calcium phosphate, the liquid phase and the adhesive agent to form a mixture; and e) precipitating the biocompatible hydroxyapatite formulation from the mixture. 103. The method according to claim 102, further characterized in that the step of combining comprises: a) adding the adhesive agent to the liquid phase to form an increased liquid phase, -b) mixing the increased liquid phase with the combination of base of calcium phosphate salts. 104. The method according to claim 102, further characterized in that the combining step comprises: a) adding the adhesive agent to the base combination of calcium phosphate salts to form an increased combination "je 04 calcium phosphate salts; and b) mixing the liquid fae with the increased combination of calcium phosphate salts. 105. The method according to claim 102, further characterized in that the combining step comprises simultaneously combining the base combination of calcium phosphate salts, the adhesive agent and the liquid phase. 106. The method according to claim 102, further characterized in that said step of precipitation occurs in vivo. 107.- The method of compliance with the claim 102, further characterized in that said precipitation step occurs ex vivo. 108. The method according to claim 102, further characterized in that said step of precipitation occurs partially ex vivo and partially in vivo. 109. The method according to claim 102, further characterized in that it comprises the step of allowing the biocompatible hydroxyapatite formulation precipitated to be reabsorbed or degraded in vivo. 110.- The method of compliance with the claim 102, further characterized in that the base combination comprises two salts and wherein one of the two salts is tetracalcium phosphate and the other of the two salts is selected from the group consisting of CaHPO ".2H2 ?, CaHP0", Ca8H2 (P0u) 6.5H20, -Ca3 (PO4) 2, a-Ca3 (PO4 2, and Ca3 (P0 «) 2 modified. ¡Ib 111. The method according to claim 110, further characterized in that the modified C 2 (P 0.) 2 is tetracalcium phosphate modified by protons or up to about 10% by weight of magnesium. 112.- The method of compliance with the claim 102, further characterized in that the adhesive agent is selected from the group of integrins, extracellular matrix proteins, Luecocyte adhesion proteins, collagen, albumins, bone proteins, osteonectins, cell surface receptor proteins, protein gla bone, and matrix gla protein. 113. The method according to claim 102, further characterized in that it comprises the step of combining the biocompatible hydroxyapatite formulation with an antibiotic. 114. The method according to claim 102, characterized in that it comprises the step of combining the biocompatible hydroxyapatite formulation with heparanaea. The method according to claim 102, further characterized in that it comprises the step of combining the biocompatible hydroxyapatite formulation with a growth factor. 116.- The method of compliance with the claim 115, further characterized in that the growth factor is selected from the group consisting of an osteogenic factor, a morphogenic bone factor, a protein and a 96 cogenic factor. 117.- The method of compliance with the claim 115, further characterized in that the biocompatible hydroxyapatite formulation contains from about 10 μg to b about 100 μg of the growth factor per cubic centimeter of the biocompatible hydroxyapatite formulation. 118.- The method of compliance with the claim 115, further characterized in that the biocompatible hydroxyapatite formulation contains from about 100 μg to Approximately 500 μg of the growth factor per cubic centimeter of the biocompatible hydroxyapatite formulation is approximated. 119. The method according to claim 102, further characterized in that said mixture has a solid to liquid ratio of about 1: 1 to about 5: 1. 120.- The method of compliance with the claim 102, further characterized in that the liquid phase comprises a liquid selected from the group consisting of water, saline, weakly acid solution, a solution 20 biocompatible regulator, serum and plasma. 121. The method according to claim 102, further characterized in that the liquid phase is supplemented with one or more components selected from the group consisting of proteoglycan, hyaluronic acid, Ü Protein, albumin serum, carbohydrates, granulated sugar, a synthetic material, polyethylene glycol, ionic agents, non-interlaced collagen, and glycerin. 122. The method according to claim 102, further characterized in that the precipitation step occurs at a temperature in the range of about 4 ° C to about 50 ° C. 123. The method according to claim 102, further characterized in that the precipitation step occurs at a temperature in the range of about 15 ° C to about 42 ° C. 124.- The method according to the claim 102, further characterized in that it comprises the step of hardening the biocompatible hydroxyapatite formulation to a substantially uniform crystallinity. 125. The method according to claim 102, further characterized in that it comprises the step of hardening the biocompatible hydroxyapatite formulation to a substantially uniform porosity. 126. The method according to claim 102, further characterized in that it comprises the steps of configuring the biocompatible hydroxyapatite formulation in a structure. 127. The method according to claim 126, further characterized in that the structure is a bandage, a bone substitute, a cartilage substitute, or a soft tissue substitute. 128.- The method according to claim 00 126, further characterized in that the structure is a sheet, a membrane, a coating or a biological prosthesis. 129. The method according to claim 128, further characterized in that the membrane has a thickness in b the scale of about 1 mm to about 7 mrn. 130. The method according to claim 126, further characterized in that the structure is a granulated block. 131. The method according to claim LO 102, further characterized in that the precipitation step comprises precipitating a first component of the biocompatible hydroxyapatite formulation and precipitating a second component of the biocompatible hydroxyapatite formulation, wherein said first component has a resorption rate plus L5 slower than said second component. 132.- A biocompatible hydroxyapatite formulation prepared by the method according to claim 102. 133. The formulation according to claim 10, further characterized in that the adhesive agent is lyophilized in a powder. 134. The formulation according to claim 133, further characterized in that the powder is stable for more than about 3 months. 5 135.- The method of compliance with the claim 102, further characterized in that it comprises the step "hardening the biocompatible hydroxyapatite formulation. The method according to claim 135, further characterized in that the curable biocompatible hydroxyapatite formulation has a tensile stress of at least 20 MPa. 137. The method according to claim 135, further characterized in that the curable biocompatible hydroxyapatite formulation has a tensile stress of at least 60 MPa. 138.- The method of compliance with the claim 135, further characterized in that the biocompatible, hardenable hydroxyapatite formulation has a tensile stress of at least 10 MPa. 139. The method according to claim 135, further characterized in that the biocompatible hydroxyapatite formulation that can be hardened has a compression effort of at least 50 MPa. 140.- A stratified device comprising a first layer and a second layer, further characterized in that the first layer comprises a synthetic polymer, and the second layer comprises the biocompatible hydroxyapatite formulation according to claim 102. 141.- A method for treating a patient comprising the steps of: a) preparing the base combination of calcium phosphate salts; b) preparing a liquid phase; c) provide an adhesive agent; d) combine the salt base combination of 00 calcium phosphate, the liquid phase and the biocompatible additive to form a mixture; and e) precipitating the biocompatible hydroxyapatite formulation from the mixture; and f) administering the biocompatible hydroxyapatite formulation precipitated to the patient. 142.- The method of conformity with claim 141, further characterized in that the combination step comprises: a) adding an adhesive agent to the liquid phase to form an increased liquid phase; and b) mixing the increased liquid fae with the calcium phosphate ealee base combination. 143. The method according to claim 141, further characterized in that the combining step comprises: a) adding the adhesive agent to the calcium phosphate salee base combination to form an increased combination of calcium phosphate salts; and b) mixing the liquid phase with the increased combination of calcium phosphate salts. 144. The method according to claim 141, further characterized in that the step of combining comprises simultaneously combining the combination of calcium phosphate ealee base, the adhesive agent and the liquid phase. 145. The method according to claim 141, further characterized in that the precipitated biocompatible hydroxyapatite formulation is absorbed by the patient after administration. 146.- The method according to claim 141, further characterized in that the precipitated biocompatible hydroxyapatite formulation is non-immunogenic to the patient. 147. The method according to claim 141, further characterized in that the adhesive agent is released from the hydroxyapatite formulation in a release mode with measured time. 148.- The method of compliance with the claim 147, further characterized in that less than about 20% of said adhesive agent is released in about 24 hours. 149. The method according to claim 147, further characterized in that more than about 90% adhesive agent is released in about 30 days. 150. The method according to claim 141, further characterized in that it comprises the step of forming the biocompatible hydroxyapatite formulation precipitated in a paste. 151.- The method according to the claim 150, further characterized in that the pulp is an adhesive, a bandage, a biological patch, an assortment vehicle, an absorbent, a coating or a protector. 152.- The method of compliance with the claim 151, further characterized in that the biological assortment vehicle is a contraceptive device. 153.- The method according to the claim 151, further characterized in that the glue is a bone glue. 154. The method according to claim 141, further characterized in that it comprises the steps of forming the precipitated hydroxyapatite formulation into a form and administering the form to the patient. 155. The method according to claim 154, further characterized in that the shape is a medical prosthesis. 156. The method according to claim 155, further characterized in that the medical prosthesis is administered cutaneously, subcutaneously or intramuscularly. 157. The method according to claim 141, further characterized in that the precipitated formulation is administered by covering, implanting or injecting. 158.- A device for precipitating a biocompatible hydroxyapatite formulation comprising: a predetermined quantity of a liquid phase; and a predetermined amount of an adhesive agent, wherein the base combination of calcium phosphate salts, the adhesive agent and the liquid phase can be combined simultaneously to precipitate the formulation of biocompatible hydroxyapatite. 159.- The equipment in accordance with the claim 158, further characterized in that the base combination of calcium phosphate salts, the adhesive agent and the liquid phase can be combined simultaneously to precipitate the biocompatible hydroxyapatite formulation. 160. - The equipment according to claim 158, further characterized in that the adhesive agent can be added to the liquid phase to form an increased liquid phase, and wherein the increased liquid phase can be added to the salt base combination of phosphate calcium to precipitate the biocompatible hydroxyapatite formulation. 161. The equipment according to claim 158, further characterized in that the adhesive agent can be added to the base combination of calcium phosphate salts 10 to form an increased combination of calcium phosphate salts, and wherein the combination Increased calcium phosphate saltse can be added to the liquid phase to precipitate the biocornpatible hydroxyapatite formulation. 162. The equipment according to claim 15 158, further characterized in that the adhesive agent is in a lyophilized state. 163.- The equipment in accordance with the claim 158, further characterized in that the base combination of calcium phosphate salts is in a first container, in Wherein the liquid phase is in a second container, and wherein the adhesive agent is in a third container. 164. The equipment according to claim 158, further characterized in that two or more of the base combination of calcium phosphate salts, the adhesive agent and the liquid phase are in the same container. 165. A device for precipitating a biocompatible hydroxyapatite formulation comprising: a predetermined amount of a combination of low calcium phosphate salts; a predetermined amount of an increased liquid phase, wherein the increased liquid phase comprises a liquid phase and an adhesive agent, and wherein the liquid phase can be added to the base combination of calcium foephate salt to precipitate the biocompatible hydroxyapatite formulation. 166. The equipment according to claim 165, further characterized in that the base combination of calcium phosphate salts is in a first container, and wherein the increased liquid phase is in a second container. 167.- A device for precipitating a biocompatible hydroxyapatite formulation comprising: a predetermined amount of an increased combination of calcium phosphate salts; a predetermined amount of a liquid phase, wherein the increased combination of calcium phosphate salts comprises a combination of calcium phosphate salts base and a bonding agent, and in addition the liquid phase can be added to the augmented combination. of calcium phosphate salts to precipitate the biocompatible hydroxyapatite formulation. 168.- A method for preparing a biocompatible hydroxyapatite formulation comprising the steps of: a) preparing a base combination of calcium phosphate salts; b) preparing a liquid phase; c) provide an Ob improver electric stimulus; combine the base combination of phosphate salts with calcium, the liquid phase and the enhanced electrical stimulus to form a mixture; and e) precipitating the biocompatible hydroxyapatite formulation from the mixture. 169.- The method «In accordance with the claim 168, further characterized in that the combining step comprises: a) aggregating the electrical stimulus enhancer to the liquid phase to form an increased liquid phase; and b) mixing the increased liquid phase with the base combination of calcium phosphate salts. 170. The method according to claim 168, further characterized in that the combining step comprises: a) adding the electrical stimulus enhancer to the base combination of calcium phosphate salts to form an increased combination of phosphate salts of calcium; and b) mixing the liquid phase with the increased combination of calcium phosphate salts. 171. The method according to claim 168, further characterized in that the combining step comprises simultaneously combining the base combination of calcium phosphate salts, the stimulus enhancer and the liquid phase. 172. The method according to claim 168, further characterized in that said precipitation step occurs n vivo. 173.- The method according to the claim 168, further characterized in that said precipitation step occurs ex vivo. 174. The method according to claim 168, further characterized in that said step of precipitation occurs partially ex vivo and partially m vivo. 175.- The method of compliance with the claim 168, further characterized in that it comprises the passage of perrnitilla formulation of biocompatible hydroxyapatite precipitated to be reabsorbed or degraded n v vo. 176. The method according to claim 16, characterized in that the base combination comprises two salts and one of the two salts is tetracalcium phosphate and the other of the two salts is selected from the group consisting of CaHPO ".2H2 ?, CaHPO ^, CaßH2 (PO *) ß .5H20, ß-Ca3 (O4) 2, α-Ca3 (P0) 2, and modified Ca2 +. 177. The method according to claim 176, further characterized in that Ca3 (0) 2 is tetracalcium phosphate modified by protons or up to about 10% by weight of magnesium. 178.- The method of compliance with the claim 168, further characterized because the electrical stimulation enhancer is a paramagnetic material. 179. The method according to claim 178, is characterized by the fact that the paramagnetic material is selected from the group consisting of iron, ammonium of iron, uranium, platinum and aluminum. «D7 180. F. "The method" according to the indication rei 168, further characterized in that the improvement and stimulus is a diamagnetic material 181. - The method according to claim 180, further characterized by the diamagnetic material s from the group consisting of bismuth, mercury, silver, diamond, diamond, and charge, 182. The method in accordance with the indication 168, is also catered for because the electric stimulus generator is a conductive material. The method according to claim 182, further characterized in that the conductive material is selected from the group consisting of silver, copper, aluminum and tungsten, and the method in accordance with the claim. 168, further characterized because the improvement * of electrical stimulus is an insulator. 185. The method according to claim 184, further characterized in that the insulator is selected from the group consisting of glass, lucite, mica, quartz, and polytetrafluoroethylene. 186. The method according to claim 168, further characterized in that it comprises the step of combining the biocompatible hydroxyapatite formulation with an antibiotic. 187.- The method according to claim 08 168, further characterized in that it comprises the step of combining the biocompatible hydroxyapatite formulation with heparanase. 188. t-1 method in accordance with claim 168, further characterized in that the mixture has a "sun" to a liquid ratio of about "1: 1 to about 5: 1. 189.- The method of compliance with the reiviication 168, further characterized in that the liquid phase comprises a liquid selected from the group consisting of water, saline, a weakly acidic solution, a biocornpatible regulatory solution, serum and plasma. The method according to claim 168, further characterized in that the liquid phase is supplemented with one or more components selected from the group consisting of proteoglycan, hyaluronic acid, protein, albumin serum, carbohydrates, granulated sugar, synthetic material, polyethylene glycol, ionic agents, non-interlaced collagen, and glycerol. 191. The method according to claim 168, further characterized in that the precipitation step occurs at a temperature in the range of about 4 ° C to about 50 ° C. 192. The method according to claim 168, further characterized in that the precipitation step occurs at a temperature in the range of about 15 ° C to about 42 ° C. 193. The method according to claim 9 168, further characterized by comprising the step of hardening the biocompatible hydroxyapatite formulation to a substantially uniform crystallinity. 194. The method according to claim 168, further characterized in that it comprises the step of hardening the biocompatible hydroxyapatite formulation to a substantially uniform porosity. 195. The method according to claim 168, further characterized in that it comprises the steps of configuring the biocompatible hydroxyapatite formulation in a structure. 196. The method according to claim 195, further characterized in that the structure is a wound dressing, a bone substitute, a cartilage substitute, or a soft tissue substitute. 197. The method according to claim 195, further characterized in that the structure is a sheet, a membrane, a coating, or a biological prosthesis. 198. The method according to claim 197, further characterized in that the membrane has a thickness in the scale dβ of about 1 mm to about 7 mm. 199.- The method of compliance with the claim 195, further characterized in that the structure is a granulated block. 200 . - The method of compliance with the r eiv i ndi cation 168, characteristic «Jo also because the precipitation step 00 it comprises precipitating a first component of the biocopatible hydroxyapatite formulation and precipitating a second component of the biocompatible hydroxyapatite formulation, wherein said first component has a slower resorption rate than said second component. 201.- A biocornpatible hydroxyapatite formulation prepared by the method according to claim 168. 20? - the f-orrnula ion < 1e compliance < in claim 168, further characterized in that the electric stimulator is freeze dried in a powder 203. The formulation according to claim 202, further characterized by being stable for more than about 3 months. The formulation according to claim 168, further characterized in that it comprises a pharmaceutically acceptable carrier. 205. The formulation according to claim 204, further characterized in that the pharmaceutically acceptable carrier is selected from the group consisting of water, giicerol. , glycols, saccharin, polysaccharide, oils, salts and fatty acids 206.- Fl method in accordance with the claim 168, further characterized because it comprises the steps of: a) providing a biocopayable additive; and b) combining the biocompatible additive with a base combination of calcium phosphate salts, the electric stimulator enhancer and the 11 < ]or? «Ja. 207.- A method to treat a patient that includes the steps of: a) preparing a base combination of calcium phosphate salts; b) prepare * a liquid phase; c) provide an electric stimulation module; d) combining the base combination of calcium phosphate salts, the liquid phase and the electric stimulus enhancer to form a mixture; e) precipitating the biocompatible hydroxyapatite formulation from the mixture; and f) administering the biocornpatible hydroxyapatite formulation precipitated to the patient. 208. The method according to claim 207, further characterized in that the step of combining comprises: a) adding the electric stimulus enhancer to the liquid phase to form an increased liquid phase; and b) mixing the increased liquid phase with the base combination of calcium phosphate salts. 209. The method according to claim 207, further characterized in that the combining step comprises: a) adding the enhancer to the electrical stimulation of the calcium phosphate salts combination to form an increased salt combination. of phosphate «Je calcium; and b) mixing the liquid phase with the increased combination of calcium phosphate salts. 210.- The method of compliance with the claim 207, further characterized in that the combining step comprises simultaneously combining the base combination of calcium phosphate salts, the electric stimulus enhancer and the liquid phase. 211. The method of confi gnation with claim 207, further characterized in that the precipitated biocompatible hydroxyapatite formulation is absorbed by the patient after administration. 212. The method according to claim 207, further characterized in that the precipitated biocompatible hydroxyapatite formulation is not nnn? Nogem to the patient. 213. The method of compliance with the claim 207, further characterized in that it comprises the steps of: a) providing a biocompatible additive; and b) combining the biocopatible additive with the base combination of calcium phosphate salts, the electric stimulus enhancer and the liquid phase. 214.- The method of compliance with the claim 213, characterized by < Jernas because the biocompatible additive is released from the biocompatible hydroxyapatite formulation precipitated in a release mode with measured time. 215.- The method of compliance with the claim 214, further characterized in that less than about 20% of said additive is released in about 24 hours. 216. The method according to claim 214, further characterized in that approximately 90% of said additive is released in about 30 days. 217. - Fl m all in accordance with the claim 207, further characterized in that it comprises the step of forming the b-ocornpatible hydroxyapatite formulation precipitated in a paste. 218.- Fl rnetodo in accordance with the re vindication 217, further characterized in that the paste is glue, a bandage, biological patch, an assortment vehicle, an absorbent, a coating or a protector. 219. F. The method of conformity with claim 218, further characterized in that the assortment vehicle is a con- traceptive device. 220.- The method in accordance with the claim 218, further characterized in that the glue is a glue of bone., 221. The method according to the claim 207, further characterized in that it comprises the steps of forming the hydroxyapatite formulation precipitated in a form and administering it to the patient. 222. The method according to claim 221, further characterized in that it comprises the step of electrically or electromagnetically stimulating the forrna. 223.- The method in accordance with the claim 221, further characterized because The shape is a medical prosthesis. 224.- The method according to the claim 223, further characterized in that the medical prosthesis is administered cutaneously, subcutaneously or intramuscularly. 225. The method according to claim 207, further characterized in that the precipitated formulation is administered by covering, implanting or injecting. 226.- The method of compliance with the claim 207, further characterized by comprising the step of electrically or electromagnetically stimulating the biocornpatible hydroxyapatite formulation. 227.- A device for precipitating a biocompatible hydroxyapatite formulation comprising: a predetermined quantity of a base combination of calcium phosphate salts; a predetermined amount of an electrical stimulus enhancer; and a predetermined amount of a liquid phase, wherein the base combination of calcium phosphate salts, the electric stimulus enhancer and the liquid phase can be combined to form a mixture that precipitates the biocompatible hydroxyapatite formulation. 228. The equipment according to claim 227, further characterized in that the combination of salt base, calcium phosphate, electric stimulus enhancer and liquid phase can be combined simultaneously to precipitate the biocompatible hydroxyapatite formulation. 229.- The equipment according to claim 227, further characterized in that the electric stimulation-enhancer can be added to the liquid fae to form an increased liquid phase, and wherein the increased liquid phase can be added to the cornt >.Basement of calcium phosphate salts to precipitate the biocopatible hydroxyapatite formulation. 230. The equipment according to claim 227, further characterized by the fact that the electric stimulator can be added to the base combination of phosphate salts of calcium to form an increased combination of calcium phosphate salts, and wherein the increased combination of calcium phosphate salts can a < -re < jar < • * the phase i? Qu? La to precipitate * l to formulation of biocompatible hydroxyapatite. 231. The equipment according to claim 227, further characterized in that the base combination of calcium phosphate salts is in a first container-, wherein the liquid phase is in a second container, and wherein the buffer of electrical stimulus is in a third container. 232. A device for precipitating a biocompatible hydroxyapatite formulation comprising: a preterm amount of a combination of calcium phosphate salts bae; a predetermined amount of an increased liquid phase, in which the increased liquid phase comprises a liquid phase and an electric stimulus enhancer, and in which the increased liquid phase can be added to the base combination of salts of calcium to precipitate the biocompatible hydroxyapatite formulation. 233. The equation according to claim 232, further characterized in that the base combination of calcium phosphate salts is in a first container, and wherein the increased liquid phase is in a second container. 234. An etiology for precipitating a biocornpatible hydroxyapatite formulation comprising: a predetermined amount of an increased combination of calcium phosphate salts; a predetermined amount of a liquid phase, wherein the increased combination of phosphate salts; The calcium comprises a base combination of calcium phosphate salts and an electrical stimulus enhancer, and wherein the liquid phase can be added to the increased calcium phosphate salt combination to precipitate the biocompatible hydroxyapatite formulation. 235.- The equipment in accordance with the reiviication 227, further characterized in that it comprises a biocornpatible additive which can be combined with the base combination of calcium phosphate salts, the electric stimulus enhancer and the liquid fae. 236.- The equipment in accordance with the claim 227, further characterized in that two or more of the base combination of calcium phosphate salts, the electric stimulus enhancer and the liquid phase are in the same container. 237. The equipment according to claim 235, characterized by "jemás because the biocornpatible additive is in a fourth container. 238. - The equipment according to claim 235, further characterized in that the biocompatible additive is in a lyophilized state. 239. The equipment according to claim 235, further characterized in that two or more of the base combination of calcium phosphate salts, the liquid fae and the electric stimulator and the biococtable additive are in the same container. .