Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
1999-11-30
2002-08-06
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C623S016110, C523S114000, C523S115000
Reexamination Certificate
active
06428803
ABSTRACT:
The invention relates to a hydroxylapatite gel, to compositions and moldings containing the latter, and to the use thereof, especially in the area of bone surgery.
There is a need in the area of bone surgery for bone substitutes and implants which are tolerated by the body and easy to process. In order to facilitate taking of the bone implant in the body it should have a structure which is as similar as possible to that of bone. In addition, high mechanical stability is desirable. The implant material should moreover be suitable as carrier for active substances such as, for example, growth-promoting or -inhibiting substances.
One proven bone substitute material is a hydroxylapatite material obtained from the calcium carbonate skeleton of calcareous algae. A material of this type is described in DE 37 09 897 C2. To produce moldings, the granular hydroxylapatite material obtained by hydrothermal synthesis is shaken into a molding with slaked lime as binder and then subjected to another hydrothermal treatment. The bone implant obtained in this way has a high interconnective porosity and a high specific surface area. In its chemical makeup and crystalline structure it is considerably more similar to bone than are other bone substitute materials. However, in some specific applications, bone substitute materials having an even greater porosity and particularly high mechanical stability are necessary.
It is an object of the invention to indicate materials which are suitable for producing a bone substitute material which is as similar as possible in its chemical makeup and the crystalline structure to natural bone, has a very porous microstructure but, at the same time, has high mechanical stability. The materials should be simple to produce, cost-effective and easily processable. In addition, they should permit specific adjustment to the proportion of crystalline phases and the strength of the bone substitute material during their processing.
This object is achieved with the hydroxylapatite gel as claimed in claim 1. This hydroxylapatite gel is an essential constituent of the moldable hydroxylapatite composition as claimed in claim 9 and of the compacted hydroxylapatite composition as claimed in claim 15, which are in turn constituents of the novel hydroxylapatite molding as claimed in claim 16. The invention further relates to the use of the hydroxylapatite molding as claimed in claim 17. The hydroxylapatite molding is likewise present as coating in a metal implant as claimed in claim 20. The invention additionally relates to a process for producing the metal implant as claimed in claim 21, to a process for producing the hydroxylapatite gel as claimed in claim 23, and to a process for producing the hydroxylapatite molding as claimed in claim 28.
Further process variants and embodiments are evident from the dependent claims.
In a first aspect, the invention relates to a hydroxylapatite gel which is obtainable by a sol-gel process. This entails an alkaline aqueous solution of a calcium salt being reacted with an alkaline aqueous solution of a phosphate salt initially to give a sol. The stoichiometry is in this case chosen so that the ratio of calcium to phosphorus corresponds to the ratio in the hydroxylapatite. The molar ratio of calcium to phosphorus for producing the sol is thus in the region of about 1.67. Subsequently, the sol obtained in this way is converted into a gel by hydrothermal treatment.
The pH during the sol production is preferably in a range from 9 to 12 and particularly expediently between 10.5 and 11. The desired pH range can be adjusted by adding conventional bases. Ammonia is particularly suitable for this purpose. It has additionally emerged as advantageous initially to adjust the two aqueous solutions separately to the required pH and, if necessary, bring the pH into the desired range again after mixing the two solutions.
The sol is advantageously produced at a temperature in the range between 10° and 40° C., particularly expediently at room temperature (20° to 25° C.)
It is possible to use for producing the sol for example 0.1 to 1 N aqueous solutions of the calcium salt and of the phosphate salt. 0.3 to 0.5 N aqueous solutions of the salts are particularly suitable.
It is possible to employ as starting materials all soluble calcium and phosphate salts, which should where possible contain no constituents not tolerated by the body. An example of a suitable calcium salt is calcium nitrate. Diammonium hydrogen phosphate can be used as phosphate salt.
Under the stated conditions, after the two aqueous solutions have been mixed they are left to stand for a period of several days to form the sol. In a second step, the sol is then converted by hydrothermal treatment into a gel. The hydrothermal treatment expediently takes place at a temperature in the range from 180 to 200° C. It is particularly advantageously carried out in an autoclave. Autoclaves coated with polytetrafluoroethylene or similar inert linings are particularly suitable. It is advantageous for the autoclave to be no more than two-thirds full and for the hydrothermal treatment to be carried out under the saturation vapor pressure of the solution which is then set up. The pH during the conversion to the gel is advantageously in the same range as for the production of the sol, that is to say between 9 and 12 and, in particular, between 10.5 and 11.
During the hydrothermal treatment there is formation of crystal nuclei and fine crystals of hydroxylapatite in the sol. Specific control of the proportions of crystalline phases in the hydroxylapatite gel is possible depending on the duration of the hydrothermal treatment. The physical properties of the hydroxylapatite gel can be specifically influenced in this way. The hydrothermal treatment advantageously lasts until the proportion of crystal nuclei and microcrystalline hydroxylapatite in the gel is above 80% and, in particular, about 90%. Up to two-thirds of the water present in the sol remains in the gel composition. The novel gel normally contains up to 70% by weight of water after its production. An average water content is. about 60% by weight. If the hydroxylapatite gel is left to stand for a longer time, the gel separates out and an aqueous supernatant forms. The water content of the gel can, if desired, be reduced specifically by pouring off this supernatant.
The novel hydroxylapatite gel is outstandingly suitable as binder and can be employed, for example, for producing bone substitute materials and filter materials. Compared with conventional binders, the advantage of the novel hydroxylapatatite gel is that the crystalline phase structure adjusted during its production is retained in the final product, and final materials with a very porous microstructure are obtained. In addition, the novel hydroxylapatite gel ensures excellent moldability of the compositions containing it, whose density can be specifically influenced by compression.
In a further aspect, the invention relates to a moldable hydroxylapatite composition which, besides the novel hydroxylapatite gel which acts as binder, comprises a calcium-containing granular filler. Examples of suitable fillers are all those which are already employed in the area of bone surgery. Hydroxylapatite materials obtained from calcareous algae are particularly suitable as granular filler. Examples are described in German Patent 37 09 897. The calcium carbonate skeleton of the algae is retained in the materials described therein, so that the material has a high interconnective porosity and a large specific surface area.
It is also possible to use as granular filler for the moldable hydroxylapatite composition a modified tricalcium phosphate-containing hydroxylapatite material which is obtainable by reacting an algal hard tissue, from which organic compounds have been removed, in an alkaline aqueous phosphate solution with addition of Mg
2+
ions at elevated temperature. A material of this type is described in a parallel German patent application by the applicant. This tricalcium phosphate-containing hydro
Andreev Andrey Ivanov
Baumann Arnulf
Djerov Dimitar Assenov
Dramov Sava Assenov
Ewers Rolf
Azpuru Carlos A.
Pepper Hamilton LLP
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