Chemical compositions

The invention provides a pharmaceutical composition for filling into bone cavities comprising an agueous paste formed from powdered calcium phosphate and an antibacterial substance, if necessary together with one or more binders. The antibacterial substance is preferably taurolidine and the calcium phosphate is preferably .beta.-tricalcium phosphate.

This invention relates to a novel composition of use in the treatment of 
osteitis and osteomyelitis. 
In the treatment of osteitis and osteomyelitis, where infection has led to 
necrosis of bone, it is essential that the necrotic bone (sequester) is 
removed from the infected site before further treatment can take place. 
Relatively large cavities are formed in this way and the regeneration of 
the bone tissue, including the spongeosa, is the primary objective of such 
further treatment. In our European Patent Application No. 48558 we have 
described resorbable gel formulations (which may contain antibacterial 
substances and other materials which assist bone regeneration and prevent 
re-infection) to be inserted in granulated form into such cavities to 
promote tissue growth. 
In our above patent application we described gel formulations which 
contained up to about 20% by weight of calcium phosphate to provide 
calcium and phosphorus needed for bone formation. However, the granulated 
gel provided the main bulk of material required to fill the cavity, the 
voids between the gel granules permitting new tissue to grow into the mass 
which is gradually resorbed. Eventually, all the gel resorbed and the 
cavity is filled by bone tissue. Even calcium phosphate is largely 
resorbed and regenerated in the physiological form in the new bone. 
We have now found that an alternative composition for filling into bone 
cavities of human or animal subjects resulting from the surgical treatment 
of osteomyelitis and osteitis comprises an aqueous paste formed from 
powdered resorbable calcium phosphate and an antibacterial substance 
resorbable together with one or more binders. 
The calcium phosphate may be secondary or tertiary calcium phosphate or a 
more complex form such as hydroxyapatite. Other forms of calcium phosphate 
which can be used include tetra calcium phosphate and octa calcium 
phosphate. Tertiary calcium phosphate (i.e. tricalcium phosphate) is 
preferably in the .beta.-form since this has been found to be more 
compatible with the growing bone cells and is more efficiently resorbed 
than the .alpha.-form. The particle size of the calcium phosphate is 
preferably above 200 microns, for example in the range 200-500 microns. 
The preferred form of calcium phosphate is thus .beta.-tricalcium phosphate 
in substantially pure form. The purity of the product can be determined by 
X-ray diffraction; however small quantities up to 2.3% of the .alpha.-form 
may be undetectable. 
The antibacterial substances employed may be antibiotics and other 
microbiocidal or microbiostatic substances. In addition, further 
medicaments, for example analgesic agents may be used. In addition, the 
compositions can also contain other dissolved additives which promote 
healing of the wound and/or favourably influence the physical and 
biochemical properties of the composition. These are, for example, amino 
acids, sugar, polyhydric alcohols, common salt and others. 
When the antibacterial substance is an antibiotic, it is preferably a broad 
spectrum antibiotic active against both gram-negative and gram-positive 
bacteria, for example, a .beta.-lactam antibiotic such as a penicillin or 
cephalosporin, a tetracycline antibiotic, a macrolide antibiotic such as 
erythromycin, a polypeptide antibiotic such as bacitracin, novobiocin, or, 
more preferably, an aminoglycoside antibiotic such as streptomycin, 
neomycin, lincomycin, kanamycin, vancomycin, gentamicin or sisomycin. 
Typical infecting bacteria include Staphylococcus aureus, Proteus, 
Pseudomonas, Streptococcus, E. coli, as well as Enterococci, Klebsiella 
and Staphylococcus albus. However, antibiotics are often contraindicated 
for use in surgical treatment, due to their tendency to produce resistant 
strains, and a preferred type of antibacterial substance is a methylol 
transfer agent, especially noxytiolin or, more preferably taurolidine or a 
close analogue thereof. Taurolidine is 
bis-(1,1-dioxo-perhydroxy-1,2,4-thiadiazin-4-yl)methane and this compound 
and its close analogues can be represented by the formula: 
##STR1## 
where R.sup.1 is hydrogen or a methyl, ethyl, propyl, butyl or pentyl 
group and R.sup.2 is hydrogen or a group 
##STR2## 
where R.sup.1 has the above meaning. Where R.sup.1 and R.sup.2 are both 
hydrogen, the compound is the methylol transfer antibacterial taurultam. 
The preferred active substances are broad spectrum antibiotics and methylol 
transfer agents such as taurolidine. Taurolidine and its analogues are 
active against both gram-negative and gram-positive organisms, as well as 
against the toxins produced by gram-negative bacteria. 
The complex of elemental iodine and polyvinyl pyrrolidone may also be 
advantageously be used as a microbiocidal substance. 
It is important that the binder for the calcium phosphate should be 
resorbable, so that it does not remain and give rise to tissue reactions 
after the remains of the composition has been resorbed. 
In general, polyvinylpyrrolidone can be used as a binder in the 
formulations. A molecular weight in the range of 200-30,000 is preferred. 
Kollidone 17 (sold by BASF) is one suitable form. Other useful binding 
agents include gelatin, e.g. edible gelatin, and dextran; the molecular 
weight of the dextran is preferably about 70,000. The binding agent will 
commonly comprise 2-10% by weight of the composition e.g. 4-6%. 
The compositions of the invention will normally contain a relatively large 
amount of water, e.g. in the range of 30-60%, preferably 40-50%. In 
general, the proportions of water and binding agent will depend on the 
consistency which is required. Relatively fluid compositions may be useful 
in that they can be introduced into the cavity via a post-operative 
drainage tube. In other instances, however, it may be preferable to pack 
the cavity with a more solid composition before closing the wound. 
The quantity of calcium phosphate in the compositions will in general be 
above 30% and preferably about 40% by weight, they will normally contain 
up to 60% or even up to 70% by weight. This contrasts with the quantities 
of calcium phosphate incorporated into the gels as described in our above 
patent application which were always less than 20%. 
The quantity of antibacterial substance may conveniently be in the range 
0.5-5% by weight. Where taurolidine is used, it is preferably present in 
the range 1-4% by weight. In large cavities, 2% taurolidine may be 
sufficient; in small cavities, e.g. in bones in the wrist, 4% by weight of 
taurolidine is preferred.

The following Examples are given by way of illustration only: 
EXAMPLE 1 
______________________________________ 
Weight % 
______________________________________ 
.beta.-Tricalcium phosphate (200 microns) 
40,00 
Taurolidine 4,00 
Kollidone 17 PF 5,00 
Distilled water 51,00 
______________________________________ 
The above components are blended to give a relatively fluid suspension 
which can be administered via a drainage tube. 
EXAMPLE 2 
______________________________________ 
Weight % 
______________________________________ 
.beta.-Tricalcium phosphate 
50,00 
Taurolidine 4,00 
Kollidone 17 PF 5,00 
Distilled water 41,00 
______________________________________ 
The above components were blended together to yield a thick but still fluid 
paste which could be administered via a drainage tube and would remain in 
the cavity. 
EXAMPLE 3 
______________________________________ 
Weight % 
______________________________________ 
.beta.-Tricalcium phosphate 
50,00 
Taurolidine 4,00 
Dextran 70,000 5,00 
Distilled water 41,00 
______________________________________ 
The above components were blended together to give a relatively thick but 
fluid paste which could be introduced into a bone cavity via a drainage 
tube or directly, and would remain in the cavity. 
EXAMPLE 4 
______________________________________ 
Weight % 
______________________________________ 
Tricalcium phosphate 
55,00 
Taurolidine 4,00 
Dextran 70,000 5,00 
Distilled water 36,00 
______________________________________ 
The above components were blended together to provide a plastic paste 
particularly suitable for direct application into an open cavity. 
EXAMPLE 5 
______________________________________ 
Weight % 
______________________________________ 
Dicalcium phosphate 
50,00 
Dextran 70,00 5,00 
Taurolidine 4,00 
Distilled water 41,00 
______________________________________ 
The above components were blended together to give a rather fluid 
suspension. 
EXAMPLE 6 
______________________________________ 
Weight % 
______________________________________ 
Dicalcium phosphate 
60,00 
Dextran 70,000 5,00 
Taurolidine 4,00 
Distilled water 31,00 
______________________________________ 
The above components were blended together to give a relatively thick paste 
.