MXPA06004220A - Composite biomaterials for bone implants - Google Patents

Abstract

The invention relates to bone implant biomaterials comprising an inorganic phase which is formed by calcium salts, mainly by phosphates and hydroxy- and carbonate-apatites, and an organic phase containing polymers derived from vinyl acetate and crotonic acid. The inventive biomaterials, which can be dense or porous, have different reabsorption speeds when used as implants in living tissue depending on the type and proportion of the constituent phases thereof. Said biomaterials can also be used as supports in the production of systems for the controlled release of pharmaceuticals.

Description

COMPOSITE BIFOMATERIALS FOR BONE IMPLANTS Field of the Invention This invention is applied in the field of the synthesis and application of biomaterials, in particular of the biomaterials known as compounds or mixed ("composites") in this case formed by carbonate-phosphate ceramics. calcium and polymers derived from vinyl acetate capable of acting as substitutes for hard tissue when it has been damaged or lost or other biomedical applications such as drug carriers, controlled drug release systems, etc. BACKGROUND OF THE INVENTION The need to replace, reconstruct and / or regenerate damaged or lost bone tissue in different parts of the human body has been a challenge faced with greater or lesser success over the centuries since the very emergence of mankind. Although one of the first solutions found was the use of different types of bone grafts, these are now being replaced by other biomaterials due to their various limitations, mainly related to the difficulty in obtaining them, discomfort and surgical risks for patients and variable effectiveness among others. The materials used for these purposes make up a long list that covers different types of metals, polymers, ceramics and glass, which are known generically as bone graft substitutes (Senn N. On the healing of aseptic cavities by implantation of antiseptic decalcified bone. J. Med. Se, 98: 219-243; 1889., Weber JM, White EW Carbonate minerals as precursors of new ceramic, metal and polymer materials for biomedical applications, Min. Sci. Eng., 5: 151; 1973, Williams DF Challenges in materials for health care applications, Argew, Chem. Adv. Mater., 101 (5): 678, 1989, Hench LL, Wilson T. Suryace-active biomaterials, Science, 226: 630, 1984). It can be said that until now the ideal biomaterial that meets all the requirements of bone reconstructive surgery for different medical specialties has not been found, however, there is a consensus generalized among specialists, that from the point of view of their biocompatibility, tolerance for the organism and effectiveness in healing, calcium phosphates and in particular hydroxyapatites are the most perspective biomaterials in this field (Klein CPAT, Dreissen AA, by Groot K., van den Hooff A., Biodegradation behavior of various calcium phosphate materials in bone tissue, J. Biomed, Mater. Res., 17: 769-784, 1983, Shinazaki K., Mooney V., Comparative study of porous hydroxyapatite and calcium phosphate material in bone substitute J. Orthop. Res., 3: 301; 1985, Damien CJ, Parsons JR Bone great and bone great substitutes: A review of current technology and applications J. Appl. Biomat., 2: 187-208; 1991, Jallot E. Correlation between hydroxyapatite osseointegration and Young's Modulus, Med. Eng. Phys., 20: 697, 1998). This is because these substances have a great chemical and structural identity with the mineral support of the bone, known as the "biological apatite". Hence the successes achieved in the clinical use of these compounds, mainly in the last 30 years [Cottrell D.A., Wolford L.M. Long-term evaluation of the use of coralline hydroxyapatite in orthognatic surgery. J. Oral Maxillofac Surg., 56: 935; 1998 Ayers R.A., Simske S.J., Nunes C.R., Wolford L.M. Long-term bone ingrowth and residual mocrohardeness of porous block hydroxyapatite implants in human. J. Oral Maxillofac. Surg., 56: 1297; 1998. González R., Blardoni F., Maestre H., Pereda O., Pancorbo E., Ciénaga M.A. Long-term results of the coralline porous hydroxyapatite HAP-200 as bone implant's biomaterial in orthopedics and traumatology. Journal CENIC Biological Sciences, 32 (2): 97-101; 2001). But the investigations carried out by different specialists have allowed to verify that the bone is formed by an inorganic support (approximately 65%) constituted mainly by these calcium phosphates mentioned above and the rest (35%) is organic matter and water. The organic phase is composed mainly of collagen that is in close interrelation with biological apatite (Weiner S., Traub W.

Organization of hydroxyapatite crystals within collagen fibrils. FEBS, 206 (2): 262; 1986). This knowledge of the composition and structure of bone tissue has stimulated the research and development of calcium phosphate biomaterials with different composition, structure, porosities and with different "in vivo" behaviors in terms of biodegradation. Today there is a great variety of this type of implants, among which those described in patents US 4976736 (Dec, 1990), US 5900254 (May, 1999), FR 2776282 (Sept. 1999), US 6001394 can be cited. (Dec. 1999), US 6331312 (Dec. 2001). They have also been developed and applied to these purposes polymeric biomaterials both natural (collagen, chitosan, cellulose, etc) and synthetic of different nature and origin, simulating the organic part of the bone [US 5837752 (Nov. 1998), US 5919234 (Jul. 1999), US Patent Application 20031 14552 (June 2003)]. More recently, intensive work is being done in the manufacture of composite or mixed materials (composites), formed by calcium phosphates and hydroxyapatite with different types of natural and synthetic polymers in order to achieve products with chemical, physical and mechanical properties more similar to bone and with which better functional performance can be achieved as substitutes for bone grafting. A large number of combinations of this type of composite materials has been developed in recent years, among which the following may be mentioned: hydroxyapatite, collagen and a glycosaminoglycan (US 5071436, 1991), mixture of calcium phosphates with cellulose (FR2715853 , 1995), hydroxyapatite with polylactic acid (W09746178, 1997), hydroxyapatite with silicone (US5728157, 1998), calcium phosphate with cellulose and its derivatives (US6558709, 2003), various calcium salts with various polymer formulations (US6579532, 2003 ), hydroxyapatite, bone and various inorganic salts with polyethylene glycol, waxes, hydrogels and acrylic latexes (US 6605293, 2003).

No reports have been found on combinations of polymers derived from vinyl acetate and crotonic acid with any of the inorganic salts that could be used as an implant biomaterial. Notwithstanding the foregoing, although the products mentioned above have shown good results in some medical applications, they still do not satisfy the diverse and growing needs of reconstructive surgery of the bones of different regions of the human body. For some applications surgeons prefer that the biomaterial to be implanted is rapidly reabsorbed leaving new bone in place, in other cases requires that the implant remains unchanged for longer periods of time depending on the site and extent of the lesion to be treated. Additionally it is very favorable if the biomaterial is capable of releasing drugs or drugs in a controlled manner, because it allows at the same time to treat different bone pathologies such as infections, inflammatory processes, neoplasias, etc. On the other hand, many of the existing biomaterials for implants Bones are not economically viable to apply massively to the population. Recently, polymers derived from vinyl acetate and crotonic acid have been developed capable of acting as suitable supports for the manufacture of sustained-action drugs (Cuban Patents No. 22199 of 1993, 22880 of 2003, Int. Appl. PCT / CU99 / 00002 of 999). Summary of the Invention The present invention also contemplates new applications of these polymers in the manufacture of implantable biomaterials in humans to reconstruct bone tissue and other therapeutic or reconstructive surgery purposes.

The main objective of this invention is to obtain composite or mixed biomaterials ("composites") constituted by phosphates, carbonates and calcium hydroxide, hydroxyapatite, carbonate-apatites or mixtures thereof of different proportions bound to polymers derived from vinyl acetate and acid. crotónico with adequate properties to function as substitutes of the bone graft. It is also an objective of this invention that the developed biomaterials can be dense or porous and with different degrees of biodegradation according to the surgical needs for the site, type of bone and magnitude of the lesion to be treated. It is further sought that these biomaterials are formed by successive layers ceramic-polymer-ceramic or polymer-ceramic-polymer in such a way that contact surfaces of the biomaterial can be obtained with the living tissue formed only by the polymer, by the ceramic or by both .

As examples of application, clarifying the execution of our invention we put the following: The developed biomaterials are formed by two types of compounds, an inorganic phase (A) and an organic phase (B). The inorganic phase (A) is constituted by phosphates, hydroxide, calcium carbonates, hydroxyapatite and carbonate-apatite or mixture thereof in different proportions as shown in the following table: TABLE 1. Composition of some mixtures of inorganic compounds (A ) employed in the preparation of biomaterials.

The organic phase (B) consists of solutions of polyvinylacetate-co-vinyl alcohol (POVIAC) of composition between 1 and 25 mol% of monomer units of vinyl alcohol, of molecular mass and purity similar to that described for polyvinylacetate; polyvinylacetate of molecular mass between 10 000 and 250 000 D, with residual monomer content between 0 and 100 ppm, acidity less than 0.5% based on acetic acid, content of heavy metals referred to lead less than 20 ppm and free of peroxides (POVIAC1); polyvinylacetate-co-crotonic acid of composition between 1 and 40% by weight of monomeric units of crotonic acid, monomer content between 0 and 100 ppm, molecular mass between 10,000 and 25,000 D and free of peroxides (CROTAV) or mixtures thereof in ethanol or acetone in varying concentrations according to the% of the polymer that is desired to be incorporated into the biomaterial. Description of the Invention EXAMPLE 1. A homogeneous mixture of calcium salts with an approximate composition to that represented by No. 10 (Table 1) with a mean particle size of 0.1 mm, was gradually wetted with a POVIAC solution ( 25%) in acetone until a paste is obtained. The mixture was passed through a sieve to obtain particles between 1 and 2 mm in diameter and allowed to dry at room temperature. The dried granulate was passed through a conmissuring mill and the powder obtained was again wetted with acetone, it passed through the screen and dried to obtain a compact granulate with an average particle size of 1 to 2 mm. The product thus obtained with a content of about 20% of the polymer is suitable as a bone implant material for the filling of cavities in the bone as well as the sequelae of tumors and cysts. EXAMPLE 2. To the mixture of inorganic salts described in the previous example, acetylsalicylic acid (ASA) was added and properly mixed to obtain a homogenous mass, the same procedure was followed to obtain a granulate with 15% POVIAC1 and 2.5% of ASA. This "composite" behaves like a system of controlled release of the drug (Fig.1). EXAMPLE 3 A portion of porous hydroxyapatite granulate HAP-200. { González R .; Meló M.C .; Sloth.; Rodríguez A.C. Coral Porous Hydroxyapatite HAP-200. Main Physical-Chemical characteristics. Chemistry Nova, 16 (6) November-December: 509-512; 1993) of particle size between 2 and 2.5 mm and with a composition similar to mixture 2 is submerged in a suspension in acetone of 25% POVIAC and 10% of mixture No. 5 (Table 1) with particle size of 0.1 mm. Stir for 10 min. The granulate is separated and air dried. The product thus obtained retains its original porous structure with a polymeric layer adhered to the entire surface (Fig. 2).

EXAMPLE 4. The product obtained in the previous example was tested by implants in bone in the primate upper extremities after being sterilized with gamma radiation at 25 Kgy, showing excellent results in bone repair without the appearance of adverse local or general responses of 18 months (Fig. 3). EXAMPLE 5 A homogeneous mixture of calcium salts with an approximate composition to that represented by No. 10 (Table 1) with an average particle size of 0.1 mm was gradually moistened with a solution of CROTAV (26%) in ethanol until a pasta. The mixture was passed through a sieve to obtain particles between 1 and 2 mm in diameter and allowed to dry at room temperature. The dried granulate was passed through a conmissuring mill and the obtained powder was moistened again with ethanol, passed through the sieve and dried to obtain a compact granulate with an average particle size of 1 to 2 mm. The product thus obtained with a content of approximately 15% of the polymer is suitable as a bone implant material for the filling of cavities in the bone as well as the sequelae of tumors and cysts. EXAMPLE 6 Two types of granules prepared according to the procedure described in example 5, one with a composition similar to that of mixture 2 (G2) and another with that of mixture 5 (G5) were implanted in rat bone tissue (femur). ). One on the left side and one on the right side after being sterilized with gamma rays at 25 Kgy. The implants were removed and analyzed at different times of postoperative evolution, determining the variation in the composition of phases by FT-IR spectroscopy and the Ca / P molar ratio by chemical analysis. It was found that while the G2 granulate does not change its composition appreciably in 90 days, the G5 granulate degrades relatively quickly incorporating phosphorus to its structure to approach the average composition of the bone (Fig. 4). The present invention has the following advantages: 1- Biomaterials are obtained very stable physically and mechanically without causing collapse or detachment of isolated particles. 2- The obtained biomaterials can be dense or porous and have adequate biomechanical properties to function as substitutes for bone grafts.

- Biomaterials with different rates of degradation are obtained in correspondence with the composition of the present phases. - The developed biomaterials also function as controlled release systems of drugs, with which you can simultaneously restore damaged or lost bone, treat different bone diseases with drugs such as antibiotics, anti-inflammatory, etc. - The obtained biomaterials have such a porosity that they form viable matrices for the growth of new tissue in their interior when these are implanted the same in soft tissue that in the bone without forming "bottoms of sack".

Claims (1)

1. CLAIMS - Composite biomaterials for bone implants, characterized by having a multiphasic chemical composition comprising an inorganic phase composed of calcium salts and another organic phase constituted by polymers or copolymers or both derivatives of vinyl acetate and crotonic acid. - Compound biomaterials for bone implants, according to claim 1, characterized by indistinctly dense structures (without pores) or macro and microporous three-dimensionally connected with a pore diameter of 5 to 840 μm. - Composite biomaterials for bone implants, according to claims 1 and 2 characterized in that the inorganic phase is constituted by phosphates, hydroxide, calcium carbonates, hydroxyapatite and carbonate-apatite or mixture thereof in different proportions in which the molar ratio P / Ca varies between 0 and 99.9. - Composite biomaterials for bone implants, according to claims 1 and 3, characterized in that the inorganic salts can be of natural or synthetic origin, dense or porous and are physically formed to obtain the desired shape, either in blocks or granules. - Composite biomaterials for bone implants, according to claims 1 and 2 characterized by having in its composition a proportion of the organic phase between 0.1 and 99%, which is constituted by polyvinylacetate-co-vinyl alcohol of composition between 1 and 25 % molar of vinyl alcohol monomer units, of molecular mass and purity similar to that described for polyvinylacetate. - Composite biomaterials for bone implants, according to claims 1, and 2 characterized by having in its composition a proportion of the organic phase between 0.1 and 99%, which is constituted by poly-vinylacetate of molecular mass between 10,000 and 250,000 D , with monomer content residual between 0 and 100 ppm, acidity lower than 0.5% referred to acetic acid, content of heavy metals referred to lead less than 20 ppm and free of peroxides. 7- Composite biomaterials for bone implants, according to claims 1 and 2 characterized by having in its composition a proportion of the organic phase between 0.1 and 99%, which is constituted by poly-vinylacetate-co-crotonic acid of composition between 1 and 40% by weight of monomer units of crotonic acid, monomer content between 0 and 100 ppm, molecular mass between 10,000 and 25,000 D and free of peroxides or mixtures thereof. 8- Composite biomaterials for bone implants, according to claims 1, 2, 3, 4 and 5 characterized by having in its composition a proportion of the organic phase between 0.1 and 99%, which is constituted by mixtures of polymers derived from acetate vinyl and crotonic acid. 9- Composite biomaterials for bone implants, according to claims 1, 2, 3, 4, 5 and 6 characterized in that the organic phase can be homogeneous and uniformly distributed throughout the volume of the solid. 10-Composite biomaterials for bone implants, according to claims 1, 2, 3, 4, 5 and 6, characterized in that the organic phase can be homogeneous and uniformly distributed and coating the surface of the inorganic support. 11-Compound materials for bone implants, according to claims 1 and 8, characterized in that when the organic phase is coating the surface of the inorganic support, said surface is formed by successive layers ceramic-polymer-ceramic or polymer-ceramic-polymer such that contact surfaces of the biomaterial can be obtained with the living tissue formed only by the polymer, by the ceramic or both. 2-Composite biomaterials for bone implants, according to claims 1-1 1, characterized by presenting different rates of resorption between 10-5 and 3.2% per day, when it works as a bone implant depending on the chemical nature and relationship between the inorganic phases present in its composition. - Compound materials for bone implants, according to claims 1-12, characterized by their use as controlled release systems of drugs when they are loaded with them and implanted in both soft tissues and bones.