Carbonated hydroxyapatite-based microspherical composites for biomedical uses

Abstract

A composite material comprising of carbonated hydroxyapatite and biopolymer was synthesized in the form of microsphere for biomedical applications via a novel colloidal technique. Novel colloidal suspensions were prepared by mixing phosphate salts, calcium salts and carbonate precursors with size ranging from nanometer to submicrometer, together with sufficient amount of biocompatible polymers, following by spherorization to form microspheres of various sizes. Nanostructure of the constituents allows final apatitic phase to be developed upon moisture exposure. Biologically or therapeutically active drugs can be encapsulated directly into the microspherical composites upon synthesis for biomedical applications such as orthopedics, dentistry, and drug delivery.

What I claim as my invention is:  
     
         1 . A composite matrix consisted of a poorly-crystalline, calcium-deficient carbonated apatite (cHA) and biocompatible polymeric materials, and biologically or therapeutically active agents.  
     
     
         2 . The composite of  claim 1  wherein the cHA is prepared by thoroughly mixing a calcium phosphate system, sodium phosphate, calcium hydroxide, and carbonate precursors, in a mixture of non-aqueous liquid, to form a suspension.  
     
     
         3 . The calcium phosphate system of  claim 2  is monocalcium phosphate anhydrate.  
     
     
         4 . The calcium phosphate system of  claim 2  is a synthesized ultrafine dicalcium phosphate or more specifically, a surface-modified dicalcium phosphate powder.  
     
     
         5 . The carbonate precursors of  claim 2  are selected from a group of potassium bicarbonate and calcium bicarbonate.  
     
     
         6 . The composite of  claim 1  wherein the polymeric ingredients are selected from polylactic acid, polyglycolic acid, poly (DL-lactide-co-glycolide) copolymer, polyanhydrates, polyethylene glycol, polyethylene oxide, polyacrylates, polymethacrylates, dextran, polysaccharides, hyaluronic acid, and mixture thereof.  
     
     
         7 . The amount of polymeric materials selected from  claim 6  to form a composite entity of  claim 1  is ranging from 0.5% to 30% by weight, or more preferably, ranging from 3% to 20% by weight.  
     
     
         8 . The polymeric ingredients of  claim 6  are mixed with the colloidal suspension prepared in  claim 2  to from a polymer-powder suspension.  
     
     
         9 . The polymer-powder suspension of  claim 8  is prepared using ball miller and attrition miller.  
     
     
         10 . The composites of  claim 1  can be shaped into spherical geometry through a spherorization procedure by spray drying, freeze drying, drip casting, emulsification evaporation, and combination thereof.  
     
     
         11 . The microspheres of  claim 10  have a size ranging from 0.1 um to 1,000 um in diameter.  
     
     
         12 . The ultra-fine dicalcium phosphate of  claim 4  was prepared by 
 (a) dissolving calcium hydroxide into an aqueous solution containing small amount, 0.1%-10% by weigh, of surfactants  
 (b) preparing an aqueous phosphate solution from ammonia hydrogen phosphate or phosphoric acid.  
 (c) mixing the aqueous phosphate solution and aqueous calcium solution via titration, whereas a white precipitate forms.  
 (d) separating the precipitate via a cellulose paper filter  
 (e) drying the precipitates at temperature of 150-180° C. for 2 h.  
 
     
     
         13 . The dicalcium phosphate powder of  claim 12  has a particle size of 20 nm-2,000 nm in size.  
     
     
         14 . The surfactants of  claim 12  are a mixture of citric acid and polyacrylic acid  
     
     
         15 . The liquid phase of  claim 2  is selected from water, methanol, ethanol, acetone, methylene chloride, ethyl acetate, ethyl vinyl ether, dichloromethane, acetaldehyde dimethyl acetal, dioxane, hexane, toluene, and preferably, a combination thereof.  
     
     
         16 . The particle size of the starting inorganic powder mixture of  claim 2  is ranging from 50 nm to 2,000 nm, or more preferably, ranging from 50 nm to 1,000 nm.  
     
     
         17 . The amount of carbonate precursors used of  claim 5  is ranging from 0.1% to 50% by weight, or more preferably, ranging from 3% to 40% by weight, or most preferably, ranging from 5% to 30% by weight.  
     
     
         18 . The composites of  claim 1  with various amounts of carbonate as in  claim 17  allows dissolution behavior adjustable from weeks to months.  
     
     
         19 . The cHA of  claim 1  has an AB-type carbonated apatitic structure.  
     
     
         20 . The mcrospheres prepared according to  claim 10  can be transformed directly into apatitic phase under exposure of water or high moisture environment for a short time period from 4 to 16 h.  
     
     
         21 . The composites of  claim 1  have a poorly crystalline apatitic structure with X-ray diffraction of two broad peaks at 26° and 32° 2□ over the range of 20°-40° 2□.  
     
     
         22 . The microspheres of  claim 20  have a porosity ranging from 5% to 70% by volume.  
     
     
         23 . The microspheres of  claim 20  have a specific surface area ranging from 0.5 m 2 /g to 70 m 2 /g.  
     
     
         24 . The microspheres of  claim 20  have a pore size ranging from 1 nm to 1,000 nm.  
     
     
         25 . The microspheres of  claim 20  have a grain size ranging from 10 nm to 1,000 nm.  
     
     
         26 . The microspheres of  claim 20  have a mole ratio of Ca/P ranging from 1.10 to 1.65, or more preferably, ranging from 1.20 to 1.55.  
     
     
         27 . The microspheres of  claim 10  can be further shaped into monoliths, pellets, tablets, bulks, thin or thick sheets, by simply uni-axial compression or other means.  
     
     
         28 . Apatitic structure can be well developed in the composites according to  claim 27  by mixing with small amount of water or exposure to moisture at a temperature below 60° C.  
     
     
         29 . The microspheres of  claim 10  form a deformable paste by mixing with water, ethylene glycol, or Hank's solution, which can be used for a variety of clinical situations.  
     
     
         30 . The therapeutically or biologically active agents of  claim 1  are antibiotics, anti-cancer drugs, peptides, bone growth factors, proteins, and DNA.  
     
     
         31 . The therapeutically or biologically active agents of  claim 30  are added into the suspension of  claim 2  following a direct encapsulation process through spherorization according to  claim 10 .  
     
     
         32 . The biologically or therapeutically active agents of  claim 30  can be physically encapsulated within the composites of  claim 1  comprising an inorganic cHA phase and an organic polymeric phase.  
     
     
         33 . The encapsulated biologically or therapeutically active agents of  claim 30  can be released into a physiological solution over a time period from days to months.