Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1994-06-24
1996-04-16
Beisner, William H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 12, 530352, 530356, 530840, 424484, 427414, C07K 1478, C07K10102, A61K 3839, B05D 702
Patent
active
055082670
DESCRIPTION:
BRIEF SUMMARY
A material that does not produce adverse biological side effects when placed in the body is termed a biomaterial, and as such is classified as either bioinert or bioactive. Osteogenic bioactive materials stimulate bone regrowth, and are generally composed of natural materials. Implants of porous hydroxyapatite.sup.1, collagen combined with gelatin.sup.2, and hydroxyapatite immersed in a collagen gel.sup.3 have all shown excellent bone regenerative capacity, but unfortunately have been unable to provide the mechanical properties for use as implants in stressed regions. Bioinert materials, on the other hand, have mechanical properties superior to the bioactive materials but are not recognised by the immune system, allowing no interaction with the living tissue causing the implant to remain permanently within the body.
Calcium phosphate may precipitate out of aqueous solution as: dicalcium phosphate dihydrate (Ca/P ratio 1:1); octacalcium phosphate (Ca/P ratio 1.33:1) and hydroxyapatite (Ca/P ratio 1:67:1). (An amorphous calcium phosphate, of variable composition, sometimes precipitates initially.) The thermodynamic factors governing the nucleation and growth of calcium phosphate phases on both hydroxyapatite seed crystals and reconstituted collagen have been studied extensively by Nancollas.sup.4,5. The involvement of kinetic factors has been investigated by Boistelle.sup.6.
Glimcher.sup.7 and Endo.sup.8 have studied the effect of incorporating the amino acid residue o-Phosphoserine with collagen in the solid state prior to mineralisation and found that the lag-time occurring before mineral precipitation, decreased on adding the protein. The main distinctive feature of phosphoprotein is the presence of the residues of the phosphoserine amino ester unit. Many other experimenters have investigated the effect of proteins on mineralisation. Termine.sup.9 found osteonectin to enhance the mineralisation process and suggested that it formed a "link" between collagen and mineral, whereas Doi's.sup.10 experimentation deemed the same protein to inhibit mineralisation. Similar arguments have taken place over osteocalcin and osteopontin. Overall, the results of the effects of proteins on mineralisation are inconclusive due to conflicting information.
The mechanical properties of many different types of animal bone have been tested by Currey.sup.11, giving Young's Modulus and Ultimate Tensile Strength (UTS) values of 2 to 50 GPa and 40 to 200 MPa respectively. Mechanical properties of any bioactive materials so far produced have not been extensively tested, but those of bioinert materials have been shown to be far superior to natural bone. Stress shielding resulting in bone resorption is one of the main reasons why these mechanical properties are not conducive to implant longevity. Therefore, a biomaterial with mechanical properties closely matched to those of bone, with bioactive capacity, is required to stimulate bone regrowth. The present invention provides such a material. Accordingly, the present invention provides a self supporting composite bioactive material comprising a collagen substrate carrying a layer comprising a phosphoprotein and calcium phosphate deposited from a solution comprising the phosphoprotein and calcium phosphate.
The invention further provides a method of making a self supporting composite bioactive material which method comprises immersing a body of collagen in a solution comprising calcium phosphate and phosphoprotein for a period sufficient to deposit on the collagen a mineralised layer of calcium phosphate and phosphoprotein.
The collagen substrate may be, for example, in the form of fibrils or collagen sheet. However, the collagen should be continuous i.e. not powder or particles, in order to obtain the necessary strength characteristics when mineralised. The collagen may be obtained from demineralised bone, although this is not necessary.
Over a range of conditions from acidic to slightly basic, and depending on the calcium ion concentration in solution, the calcium phosphate of the calc
REFERENCES:
patent: 4563350 (1986-01-01), Nathan et al.
patent: 5171574 (1992-12-01), Kuberasampath et al.
Maier et al. "The Dynamics of Formation of a Collagen-Phosphophoryn Conjogate in Relation to Passage of the Mineralization Front in Rat Hicisor Dentin" J. Biol. Chem. 258(3): 1450-1455 1983.
Clarke Karen I.
Czernuszka Jan T.
Beisner William H.
Degen Nancy J.
Isis Innovation Limited
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