Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-08-28
2001-10-09
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C424S543000, C424S549000, C424S682000, C424S686000, C424S687000
Reexamination Certificate
active
06300315
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to the field of mineralized collagen materials and methods of producing the same and more particularly to mineralized collagen materials useful for guided tissue regeneration (GTR) procedures and methods for producing the same.
2. Background Discussion
By way of definition, collagen is an inert natural protein found in human and animal skin, connective tissue, bones and teeth; apatite is a calcium phosphate mineral and is the most important mineral constituent of bones and teeth. With respect to the latter, bone typically contains sixty to seventy-five percent by weight of biological apatite and teeth typically contain more than ninety-eight percent by weight of biological apatite.
Biological apatite has a crystal structure similar to that of pure hydroxyapatite, but contains some substitute ions for calcium, phosphate, and hydroxyl ions. Strictly speaking, synthetically produced, precipitated hydroxyapatite is more similar to biological apatite than are the hydroxyapatite ceramics.
It is already known that collagen can be mineralized by calcium phosphate minerals by inducing the precipitation of calcium phosphate in a collagen slurry. Several patents have disclosed the methods of preparation mineralized collagen by this precipitation of calcium phosphate.
As an example, my prior U.S. Pat. No. 5,320,844 discloses a mineralized collagen composite material produced by quickly adding a soluble calcium ion-containing solution and a phosphate ion-containing solution into a collagen slurry. The patent further discloses that the slurry is to be vigorously stirred while maintaining it at a pH of 7 or higher to thereby induce the mineralization of the collagen. The mineralized collagen is disclosed as being recovered by solid-liquid separation and by then being dried.
In addition, U.S. Pat. Nos. 5,455,231 and 5,231,169 and foreign patent WO 93/12736 to Brent R. Constantz et al. describe methods of mineralizing collagen by dispersing collagen in an alkaline solution and subsequently mixing soluble calcium and phosphate containing solutions to the collagen for over an hour while maintaining the resulting collagen slurry at a pH of 10 or higher.
It has been observed that mineralized collagen exhibits different physical and mechanical properties than those of pure collagen. Moreover, mineralized collagen is considered to provide better biocompatibility toward animal and human tissue than does pure collagen. As hard tissue implant material, mineralized collagen also has a conductivity effect that enhances hard tissue (e.g., bone) growth.
It is often necessary or desired to regenerate injured or defective animal or human tissue, including hard tissue such as bone and teeth. In order to assist such tissue generation, a so-called guided tissue regeneration (GTR) barrier material is typically applied to the tissue region to be regenerated
So far as is known to the present inventor, mineralized collagen has heretofore been prepared by freeze-drying to form a sponge structure or is alternatively prepared in solid block or granule form. However, none of these mineralized forms of collagen can be used as membrane barriers for GTR procedures, and no strong, mineralized collagen thin membranes that would be suitable for GTR applications are believed by the present inventor to have been used or disclosed
For more than a decade, thin polytetrafluoroethylene (PTFE) membranes have been used as barriers for GTR procedures in repairing periodontal defects. However, such known PTFE membrane barriers are non-resorbable. The use of such non-resorbable PTFE membranes for GTR procedures requires a two step tissue regeneration procedure. For example, in a first periodontal tissue regeneration step, the non-resorbable barrier material is inserted into or onto the periodontal defect. In a second step, after an initial healing period of about four to six weeks, the barrier material is surgically removed. This two step procedure associated with the use of a non-resorbable GTR barrier material is relatively costly, and the second, surgical-removal step increases the risk of patient infection and of other undesirable side effects.
In an attempt to simplify and reduce the cost of GTR procedures, thin, resorbable polymer membranes have recently been developed and tested in GTR applications. So far as is known to the present inventor, such resorbable polymers comprise either polylactic acid blended with a citric acid ester or a copolymer made of glycolide and lactide polymers. These polymers degrade directly to acid during the resorption process.
Examples of such resorbable polymer membranes are the GUIDOR product available from the John O. Butler Company and the CORE RESOLUTE XT product available from W. L. Core Associates.
However, medical devices made from the above types of resorbable polymer membranes have been associated with an inflammatory response, which may be caused by the accumulation of the acid of the degradation product.
More recently, membranes made from non-mineralized collagen (for example, BIOMED material available from Sulzer Medica) have been used in GTR applications for periodontal defect repair. However, membranes made from non-mineralized collagen is normally weak in strength and is therefore difficult to manipulate. Furthermore, the resorption rate of such non-mineralized membranes is difficult to match with the normal tissue-healing process.
A principle objective of the present invention is thus to provide, a thin, mineralized collagen membrane that is biocompatable with human tissue, is resorbable in GTR applications and which has a controllable resorption rate, and to provide a method for making the membrane.
Such a mineralized collagen membrane would eliminate the above-mentioned second step of surgically removing the GTR barrier and would thereby simplify and reduce the cost of the GTR procedures for both soft tissue and hard tissue repair.
SUMMARY OF THE INVENTION
In accordance with the present invention a strong, thin, flexible mineralized collagen membrane useful for medical applications comprises a substantially homogeneous mineralized collagen composite consisting essentially of about 30% to about 70% by weight of a collagen component and about 30% to about 70% by weight of a calcium phosphate minerals component precipitated from a collagen slurry by a soluble calcium ion-containing solution and a soluble phosphate ion-containing solution. The collagen component may include natural collagen and recombinant collagen.
The mineralized collagen membrane useful for medical applications preferably comprises a substantially homogeneous mineralized collagen composite of about 30% to about 70% by weight of collagen component and about 30% to about 70% by weight of calcium phosphate minerals. The calcium phosphate minerals component is preferably selected from the group consisting essentially of calcium phosphate, tri-calcium phosphate, octa-calcium phosphate, calcium deficient apatite, amorphous calcium phosphate, hydroxyapatite, substitute apatite, apatite-like minerals, and mixture thereof. Preferably the calcium phosphate minerals component has a mole ratio of calcium to phosphate in the range of about 1.0 to about 2.0; more preferably, the mole ratio of calcium to phosphate of about 1.67. Preferably, the mineralized collagen membrane will have a bulk density of about 1.0 g/cm
3
or higher.
A method of making or producing a substantially homogeneous mineralized collagen membrane comprises the steps of forming a collagen slurry, forming a soluble calcium ion-containing solution, forming a soluble phosphate ion containing solution, and adding the soluble calcium ion-containing solution and the soluble phosphate ion-containing solution to the collagen slurry while stirring the collagen slurry and maintaining the pH of said collagen slurry at least about 7, thereby inducing the precipitation of calcium phosphate mineral in the collagen slurry as mineralized collagen slurry.
The method includes the furth
Ceramedical, Inc.
Lambert Howard R.
Witz Jean C.
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