Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Phosphorus or phosphorus compound
Reexamination Certificate
2000-01-11
2003-02-18
Pak, John (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Phosphorus or phosphorus compound
C424S601000, C424S604000, C424S605000, C424S606000, C424S057000, C424S422000, C424S423000, C424S426000, C514S054000, C514S055000, C514S075000, C514S129000, C514S143000, C514S557000, C423S305000, C423S307000, C423S311000, C423S315000, C106S035000, C106S690000, C106S691000, C606S076000, C606S077000, C433S228100, C427S002260, C427S002270
Reexamination Certificate
active
06521264
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a process for the production of a biomaterial essentially constituted of phosphocalcium hydroxyapatite of an atomic ratio of Ca/P comprised between 1.50 and 1.67. The invention relates to the obtained biomaterial and to uses of the latter, in particular for dental or bone filling or restoration. The invention also relates to surgical or dental set for practicing this invention.
BACKGROUND OF THE INVENTION
Phosphocalcium hydroxyapatites are well known and more and more used in the surgical or dental field because of their properties of biocompatibility and osteoconduction. They can be used in the dental field for periodontal filling, restoration of bone crests, filling cysts or recesses after dental extraction . . . and, in orthopedic surgery, for filling bone defects, interstitial filling between prosthesis and cortical bone, injection into vertebral bodies . . . The material thus emplaced can if desired contain active substances which, after hardening in situ of the material, are slowly diffused.
The preparation of phosphocalcium hydroxyapatites is essentially carried out according to two different ways each leading to specific applications:
on the one hand, an in situ preparation, in which the hardening of the hydroxyapatite is effected on the site of use at low temperature (in particular in vivo at body temperature), this preparation permitting the practice of the mentioned surgical or dental applications (this preparation which has a hardening phase at the site of utilization is designated hereafter as “preparation in situ” even if certain phases can be carried out apart from the utilization site),
on the other hand, an industrial preparation producing either pulverulent apatites or slightly bonded ones having limited mechanical properties, or ceramic apatites after high temperature thermal treatment or compression treatment in the presence of a binder.
The industrial apatites described above, which have good mechanical properties, are of course useless in applications in which a surgical or a bone operating site of any type must be filled or restored, because they require, to obtain their hardening, an industrial treatment under severe conditions. Moreover, industrial calcine apatites are always stoichiometric and have a low specific surface (less than 10 m
2
/g) and low solubility (solubility product equal to 10
−119
): these properties render the material difficultly bioresorbable, which represents a drawback in most of the surgical or dental applications (in which a slow replacement by bone of the implanted material is generally sought).
The present invention relates to apatites “prepared in situ”, that is whose hardening can be carried out at low temperature in situ at the utilization site. Of course, these apatites can, as the case may be, be used in other applications such as those of industrial apatites.
Known apatites for in situ preparation are generally prepared as cements by mixing with water a powder containing one or more calcium phosphates selected from known phosphates: monocalcium phosphate hydrated or not, dicalcium phosphate hydrated or not, tricalcium phosphate &agr; or &bgr;, tetracalcium phosphate (U.S. Pat. No. 461,053, EP 0 416 761, FR 2.693.716 . . . ). Certain authors have proposed first dissolving in water for mixing monocalcium phosphate so as to avoid untimely hydration of this phosphate in the powder (WO 95/083149). The apatites obtained by these known methods have essentially major drawbacks. In the first place, their mechanical properties are mediocre (compressive resistance of the order of 5 to 8 Megapascals), which, in numerous cases, is a major drawback (periodontal filling, injection in vertebral bodies, interstitial filling for sealing prostheses, osteotomy wedges hardened in situ . . . ).
Moreover, there is often seen with these known products the formation of “lumps”, of non-reproducible setup times, and an exfoliation of the material after its in vivo emplacement because of the biological liquids present; certain faults lead either to grave difficulties for emplacement, or to a mediocre quality of the obtained implant (bad filling, bad adherence at the operating site), or a very troublesome production of exfoliated particles outside the operating site. This is particularly serious in surgery and leads many surgeons to reject this type of product after one or more unfortunate experiences.
SUMMARY OF THE INVENTION
The present invention provides a process for the in situ preparation of an apatite biomaterial, having good reproducibility and more certain and easy use than the known processes (homogeneity of the product, constant setup time, ease of shaping and modeling, absence of exfoliation).
Another object is to permit obtaining a biomaterial having improved mechanical properties relative to the known apatite materials prepared in situ.
Another object is to permit obtaining a biomaterial having a solubility and a specific surface significantly greater than the existing apatite biomaterials.
An object of the invention is in particularly to provide an apatite material which combines excellent properties of resistance to compression, good solubility in life media and a high specific surface.
To this end, the process contemplated by the invention for preparing a biomaterial whose hardening takes place at the site of utilization, in particular cold on a surgical or dental operating site (temperature below about 40° C.), is of the type in which are mixed calcium phosphates to obtain a hydroxy apatite within an atomic ratio Ca/P comprised between 1.50 and 1.67; the process of the invention is characterized in that:
a) there is first prepared a solid pulverulent product from a tricalcium phosphate powder and from a tetracalcium phosphate powder by mixing said powders so that the atomic ratio Ca/P of the obtained product will be substantially comprised between 1.40 and 1.90,
b) there is prepared an aqueous solution or aqueous solutions to mix with said solid pulverulent product, said solution or solutions containing calcium ions and phosphate ions such that the overall atomic ratio Ca/P of the solutions will be greater than 0.20 and that the atomic ratio Ca/P of each solution will be less than 0.50,
c) the aqueous solution or solutions and the solid pulverulent product are mixed, with the addition of water as the case may be, such that the liquid/solid weight ratio of the final mixture obtained will be comprised between 0.30 and 0.65 so as to obtain a homogeneous paste of an atomic ratio Ca/P comprised between 1.50 and 1.67, said paste being emplaced at the utilization site for its hardening in situ.
Experience has shown that this preparation from, on the one hand, a solid pulverulent product containing tricalcium phosphate and tetracalcium phosphate, on the other hand, from an aqueous solution containing calcium ions and phosphate ions, results in obtaining a naturally homogeneous pasty mixture having no tendency to lump, and having progressive and regular setting up and a constant setup time (for a given composition), with the four-fold condition that:
The Ca/P ratio of the solid pulverulent product be comprised in the above-indicated range (preferably between 1.70 and 1.85),
The Ca/P ratio of the solution or of each solution if several solutions are used, will be less than 0.50 (preferably less than 0.40),
The Ca/P ratio of the solution, or the overall Ca/P ratio of the assembly of the solutions if several solutions are used, be greater than 0.20 (preferably greater than 0.35),
The liquid/solid weight ratio of the produced mixture is comprised between 0.30 and 0.65.
The malleable pasty mixture thus obtained is deposited at the utilization site at which it undergoes setting and at which it then proceeds to harden. The utilization site can be a surgical or dental operating site and the setting up and hardening take place at body temperature (temperature below 40° C.). The site can also be a mold to produce a piece, the setting up and hardening being accomplished cold or at low temperature
Frache-Botton Michele
Hatim Zinèb
Lacout Jean-Louis
Pak John
Teknimed
LandOfFree
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