Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Phosphorus or phosphorus compound
Reexamination Certificate
2000-01-18
2002-11-26
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Phosphorus or phosphorus compound
C424S405000, C424S409000, C424S422000, C424S423000, C424S426000, C424S489000, C424S601000, C514S025000, C514S027000, C514S769000, C514S772000
Reexamination Certificate
active
06485754
ABSTRACT:
The invention relates to an injectable curable bone cement paste based on bioresorbable hydroxyapatite-like compounds comprising calcium phosphate, which contains a cationic antibiotic in the form of a salt, preferably of its sulfate, the curable biodegradable bone cement releasing the antibiotic with depot-like action over a long period of time. The bone cements according to the invention are suitable for the treatment of infectious inflammations of the bone and of the bone marrow, in particular as a result of bone defects and bone fractures.
Naturally occurring bone mineral consists of calcium phosphate of hydroxyapatite structure. The composition of bone minerals here, however, does not correspond to the ideal stoichiometric composition of crystalline hydroxyapatite (Ca
10
(PO
4
)
6
(OH)
2
), but as a rule has a non-stoichiometric composition which is caused by the incorporation of other anions such as carbonate or hydrogenphosphate instead of ortho-phosphate 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 substitute material based on hydroxyapatite-like calcium phosphate compounds, which on account of its qualitative and structural similarity approaches natural bone. Thus the known disadvantages which can arise due to the obtainment of natural autogenic or allogenic bone can be avoided.
The properties of these synthetic hydroxyapatites, in particular the physiological acceptance, the demanded bioresorbability and the ability to be replaced by newly generated natural bone tissue, or stimulation of the growth thereof, depend on the degree of crystallization, which is pronounced to a greater or lesser extent, the particle size and the porosity which can be achieved in the preparation. These materials furthermore have the advantage that they resist mechanical stresses virtually exactly as well as natural bone, which suggests their use in the case of relatively large bone defects or fractures.
Such materials are disclosed, for example, in EP 0416 761, U.S. Pat. Nos 4,880,610, 5,053,212, EP 0664 133, EP 0 543 765 or WO 96/36562. WO 96/36562 discloses a hydroxyapatite bone cement which, on account of its almost amorphous structure, has an excellent bioresorbability and, despite its porosity, a good mechanical stability. This material, called &agr;-BSM, can be prepared in the form of curable pastes which can easily be introduced into the defective bone by means of a syringe.
In the case of injuries to the bone, in particular in the case of open breaks or comminuted fractures, as a rule there is a considerable risk of infection. In principle, this can be combatted by addition of antibiotics. A local, single and limited-dose administration in the surgical care of the bone fracture merely causes only a small part of the infectious bacteria which have established themselves in the bone tissue and are very poorly accessible as a result of inadequate circulation to be killed. As a result, severe and life-threatening inflammations of the bone marrow or of the bone tissue can therefore occur in some cases.
In order to avoid this, antibiotic-containing polymer beads (DE 23 20 373, DE 26 51 441), for example, are introduced into the wound or medullary cavity in the wound-toilet and first dressing of the defective bone. The antibiotic can diffuse out of this polymer material over a relatively long period of time and thus display its bacteriocidal action in an adequate concentration. The disadvantage of this method is that the polymer material suitable for the release of the antibiotic is mostly not biodegradable or inadequately biodegradable such that after the healing of the bone it has to be removed again by means of a fresh operation.
The incorporation of the antibiotic directly into the synthetic bone cement used failed until now on the fact that no possiblities were found to release the antibiotic from the cement in delayed form over an adequately long period of time in biologically active concentrations including a toxicologically still justifiable total dose. As a rule, in such cases a very rapid release of the entire amount of antibiotic takes place.
It has now surprisingly been found that bone cements based on bioresorbable hydroxyapatite-like compounds comprising calcium phosphate release certain antibiotics which are present as certain salts over a long period of time in adequately high biologically active concentrations continuously from the cured bone cement into the medullary cavity and the surrounding tissue in the manner of an active compound depot having controllable release.
The great advantage of such a system according to the invention is that a second specific surgical intervention to remove non-biodegradable polymer materials which until now were widely used as an active compound depot for applications of this type is superfluous. Inflammatory processes in the bone marrow or bone tissue can thus be treated very simply at the same time as the reconstruction of the bone or else even prevented. This is time-saving, inexpensive and saves the patient the bother of a further surgical intervention including in-patient treatment.
Appropriate bone cements which cure in vivo using cationic antibiotic salts are particularly suitable here. According to the invention, the cement materials which are disclosed in EP 0 543 765 or WO 96/36562 are particularly preferred, but in particular &agr;-BSM from WO 96/36562.
By “amorphous” as that term is used here, it is meant a material with significant amorphous character. Significant amorphous character contemplates greater than 75% amorphous content and preferably greater than 90% amorphous content and is characterized by a broad, featureless X-ray diffraction pattern. It is recognized that a small degree of crystallinity may exist in the material, however, it is anticipated, in the case of the amorphous components of the invention, that such crystallinity will not be greater than the degree of crystallinity desired in the product poorly crystalline hydroxyapatitic calcium phosphate.
“Reactive” is used herein to refer to the reactivity of the amorphous calcium phosphate of the present invention and with other calcium phosphates. The reactivity is characterized by the ability of the amorphous calcium phosphate to harden at 37 degrees C. in less than five hours and substantially harden in about one to five hours in the presence of a calcium phosphate or crystallization promoter. Completeness of the reaction, the rate of the reaction, homogeneity of the resultant product and ability to react with otherwise inert compounds are characteristic of the reactive ACP (amorphous calcium phosphate) of the invention.
The invention thus relates to a plastic, injectable, curable bone cement paste based on bioresorbable hydroxyapatite-like compounds comprising calcium phosphate, which contain a cationic antibiotic salt. The invention likewise relates to an appropriate active compound depot for use for the treatment and prophylaxis of osteomyelitis and osteitis, in particular as a result of bone defects and bone fractures. The system according to the invention is especially suitable, in particular for larger fractures and comminuted fractures having open and therefore easily infectable wounds.
It has been found that, of the group consisting of the cationic antibiotics, especially the aminoglycosides or certain peptide antibiotics, have the desired advantageous release properties.
Suitable aminoglycosides are, for example: amikacin, butirosin, dideoxykanamycin, fortimycin, gentamycin, kanamycin, lividomycin, neomycin, netilmicin, ribostamycin, sagamycin, seldomycin and epimers thereof, sisomycin, sorbistin, spectinomycin and tobramycin. The aminoglycosides not only exhibit outstanding release properties in the sense according to the invention but as a rule additionally exhibit a wide concentration-dependent spectrum of action. A preferred aminoglycoside in the sense of the invention is gentamycin.
Especially polymyxin B is to be emphasised from the series of s
Nies Berthold
Wenz Robert
Choi Frank
Dees Jose′ G.
Merck Patent GmbH
Millen White Zelano & Branigan P.C.
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