Compositions: coating or plastic – Coating or plastic compositions – Dental
Reexamination Certificate
1999-04-16
2001-03-27
Koslow, C. Melissa (Department: 1755)
Compositions: coating or plastic
Coating or plastic compositions
Dental
C433S228100, C427S002260, C427S002270, C424S687000, C424S602000, C424S603000
Reexamination Certificate
active
06206957
ABSTRACT:
SUMMARY OF THE INVENTION
The invention relates to biocement pastes based on tricalcium phosphate and materials which are suitable for preventing or reducing the tendencies of the settable pastes to disintegrate and for improving their cohesion properties, with the result that improved processing of pastes in the preparation of synthetic bone cements is ensured. The invention relates further to biocement pastes comprising cohesion promoters. The cohesion promoters are preferably selected from the following compounds or classes of compounds: hydroxyethyl starch, cyclodextrins, alginates, dextran sulphates, polyvinylpyrrolidone and hyaluronic acid.
The advantage of the pastes according to the invention is that they do not become inhomogeneous or dissolve when they come into contact with aqueous solutions, such as saline solutions, and body fluids, such as, for example, blood. Furthermore, such pastes do not disintegrate or do so only to a greatly reduced extent when they are injected by means of syringes, as a rule at superatmospheric pressure, into the defective bone space.
Naturally occurring bone material consists of calcium phosphate having the hydroxyapatite structure. However, the composition of bone minerals does not correspond to the ideal stoichiometric composition of crystalline hydroxyapatite (Ca
10
(PO
4
)
6
(OH)
2
) but as a rule has a nonstoichiometric composition which is due to the incorporation of other anions, such as carbonate or hydrogen phosphate, instead of orthophosphate, but also of other cations, such as sodium, potassium or magnesium, instead of calcium.
For some years it has been possible to prepare synthetic bone material based on hydroxyapatite-like calcium phosphate compounds which, owing to its qualitative and structural similarities, very closely resembles natural bone. The known disadvantages which may occur as a result of acquiring natural autogenous or heterogeneous bone can thus be avoided. Synthetic calcium phosphate cements can be used in diverse and different ways, for example for bone fractures, fixation of metal prostheses and bone screws, in the dental sector and in plastic surgery.
The properties of these synthetic hydroxyapatites or calcium phosphate cements (CPC), in particular their physiological acceptance, the required bioabsorbability and the ability to be replaced by newly generated natural bone tissue or stimulation of the growth thereof, depend on the more or less strongly pronounced crystallinity, on the particle size and on the porosity which can be achieved in the preparation. Furthermore, these materials have the advantage that they withstand mechanical loads virtually as well as the natural bone, which suggests their use for relatively large bone defects or bone fractures.
The main components of these materials are, for example, tricalcium phosphate (alpha- and beta-TCP), dicalcium phosphate (DCP) and tetracalcium phosphate (TTCP), which, in the presence of water, react to give hydroxyapatite, the end product of the cement formation reaction. Since hydroxyapatite formed in this manner has formed in an aqueous environment, it resembles the biological apatites to a far greater extent than the hydroxyapatite which is produced at high temperatures. Such cements are therefore osteotransductive and hence very suitable for repairing and reconstructing bones. They are rapidly integrated in bone structures and then converted into new bone tissue by the cellular activity of the osteoblasts.
Such cements are disclosed, for example, in U.S. Pat. No. 4,518,430, U.S. Pat. No. 4,612,053, U.S. Pat. No. 4,880,610, U.S. Pat. No. 5,053,212, U.S. Pat. No. 5,152,836, U.S. Pat. No. 5,605,713, EP 0416 761, EP 0 543 765, EP 0664 133 or WO 96/36562. WO 96/36562 discloses a hydroxyapatite bone cement (&agr;-BSM) which, owing to its virtually amorphous structure, has excellent bioabsorbability and, in spite of its porosity, good mechanical stability. This and many of the materials described in the above-mentioned publications can be prepared in the form of settable pastes which can be easily introduced into the defective bone by means of a syringe.
However, it has now been found that such pastes often partially or completely disintegrate or exhibit inhomogeneous behavior as soon as they come into contact with body fluids or other aqueous solutions (Jansen et al., 1995, J. Mater. Sci. Mat. Med. 6, 653; Ishikawa et al., 1995, J. Mater. Sci. Mat Med. 6, 528; Kurashina et al., 1997, Biomaterials 18, 539). Furthermore, such pastes readily separate during extrusion from syringes, the more liquid part being forced out of the syringe while the more solid part remains in the syringe and cannot be removed from it even by means of higher pressures. As a result of the separation, a material which is no longer suitable for the intended purpose may thus be obtained.
Cherng et al. (J. Biomed. Mat. Res. 35, 1997, page 273) and Chow et al. (Innov. Techn. Biol. Med. 18, 1997, page 11) report the use of hydroxypropylmethylcellulose and carboxymethylcellulose and chitosan derivatives in calcium phosphate cements based on tetracalcium phosphate (TTCP). The additives lead to improved processing properties with regard to the cohesion of the cement pastes used but frequently result in poorer setting kinetics and reduced mechanical strength of the set cements.
It was therefore an object of the invention to provide cement pastes which lead to settable, biocompatible synthetic bone cements and which not only have substantially improved cohesion properties but also possess sufficient or advantageous injectability, mechanical hardness and setting times.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
These objects are achieved by the pastes of the present invention.
The invention therefore relates to a processible, settable paste, suitable for the preparation of biocompatible bone cements, which can be obtained by mixing a cement powder which contains tricalcium phosphate (TCP) and at least one further calcium phosphate-containing compound with an aqueous solution of a cohesion promoter and a setting accelerator. As used herein, the term “processible” means a paste which can be processed or treated, e.g., injected with a syringe.
According to the invention, the cohesion promoters are used in a concentration of about 0.1 to 10% (wt/wt), preferably about 1 to 6% (wt/wt), based on the aqueous solution before the paste is formed. The corresponding compounds are dissolved in water. If required, small amounts of organic solvents may be present if the cohesion promoter is poorly soluble in pure water.
Suitable cohesion promoters are in principle all compounds known for this object, in particular oligomeric and/or polymeric compounds. Preferably, compounds for use as cohesion promoters are selected from the celluloses, for example hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose, preferably hydroxyethyl starch and soluble starch, cyclodextrins, such as &agr;-, &bgr;- or &ggr;-cyclodextrin, alginates, such as sodium alginate, dextransulphates, such as sodium dextransulphate, polyvinylpyrrolidone and hyaluronic acid. According to the invention, several cohesion promoters can also be used.
The pastes according to the invention furthermore contain setting accelerators, for example Na
2
HPO
4
, NaH
2
PO
4
, KH
2
PO
4
, K
2
HPO
4
, or mixtures thereof, in concentrations of about 0.5 to 5% (wt/wt). The concentration depends on the choice of the cohesion promoter but especially on the composition of the calcium phosphate cement in conjunction with the desired medical application.
Furthermore, the ratio of liquid to cement powder which are mixed with one another affects the cohesion and injectability properties of the pastes according to the invention. Preferably, the ratio of aqueous solution to cement powder is about 0.30 to 0.45 ml/g, in particular about 0.35 to 0.40 ml/g.
Surprisingly, it has been found that one can avoid or red
Driessens Ferdinand C. M.
Wenz Robert
Koslow C. Melissa
Merck Patent Gesellschaft mit beschrankter Haftung
Millen White Zelano & Branigan
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