COMPOSITIONS FOR THE PROPHYLACTIC TREATMENT OF OSTEITIS AND OSTEOMYELITIS

Abstract: Compounds of formula (I) [wherein R¹ represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and R² represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a group of formula (II) in which R¹ is as defined above] and pharmaceutical compositions thereof may be administered prophylactically to humans or warm-blooded animals to combat the occurr­ ence of osteitis or osteomyelitis, especially in patients suffering from bone injuries of traumatic origin.

Description: This invention relates to compositions for use in prophylactic treatment against osteitis and osteomyelitis. In spite of intensive reseach both in the clinic and the laboratory, osteitis, that is bone infection following injury or surgery, remains a feared complication in traumatology and orthopaedics. Although antibiotics can be helpful, they cannot be relied upon for certain to prevent or heal osteitis, whether given therapeutically or prophylactically (G. Hierholzer and G. Lob "Antibiotikatherapie in der Unfallchirurgie" Unfallchir. 81,64 (1978); D. Stolle et al "Antibioticaprophylaxe in der Traumatologie" Hefte Unfallheilk. 143 (1980); G. Lob and C. Burri "Perioperative Infektionsprophylaxe mit Antibiotika oder Disinfektionsmitteln" page 157 ff in 2. Saarbruecker Gespraeche, P. Eckert Ed., Zuckschwerdt, Munich 1982). A case of acute post-traumatic osteitis may be successfully treated by immediate specific therapy, but acute osteitis often proceeds into a chronic, therapy-resistant stage. Chronic post-traumatic osteitis may at any time, even after many years, flare up and become active once again so that, at most, it is possible to speak of "a state of suspended activity" in a case of osteitis. It is not possible, by definition, to speak of a "cure" in chronic post-traumatic osteitis (C. Kaufmann "Handbuch der Unfallmedizin" Enke, Stuttgart 1925; C. Burri "Posttraumatische Osteitis" 2nd Edition, Huber, Bern/Stuttgart/Vienna, 1979; I. Schweiberer "Verheutung und Behandlung von Infektionen nach Osteosynthesen" Chirurg. 48, 1 (1977)). Similarly osteomyelitis, which is a bone infection of haematogenous origin, is extremely difficult to cure by conventional methods. It seems possible that osteomyelitis does, in fact, arise from traumatic incidents such as cracked bones which may not be thought serious at the time (Morrissy et al, 26th Annual ORS, Atlanta, Georgia, 1980). In the treatement of osteitis and osteomyelitis, necrotic bone (sequester) is normally rigorously removed since it has been found to promote the return of the disease even after antibiotic treatment. The mechanism of this reactivation has not hitherto been clear but we have now established that such necrotic bone contains a very high concentration e.g. up to about 5%, of bacterial toxins, including both endotoxins of lipopolysaccharide character and exotoxins which are essentially proteins. The infected site also contains bacteria but it has not previously been recognised that large toxin concentrations were present. Bacteria and their toxins found to be present in such infected bone include aerobic bateria such as Staphylococcus, Klebsiella, Proteus, Pseudomonas, Escherichia, and Citrobacter as well as anaerobic bacteria such as Peptococcus, Streptococcus Enterococcus, Peptostreptococcus, Veillonella, Bacteroides, Fusobacterium, Clostridium, Propionibacterium and Eubacterium. We have further established that certain methylol transfer antibacterial substances, and in particular taurolidine and its analogues, are effective against such toxins not only in the necrotic bone but also in the extracellular fluid of the body, where the toxins are commonly released by both gram-positive and gram-negative bacteria; endotoxins are commonly liberated by gram-negative bacteria on treatement with antibacterial agents, such as antibiotics or povidone-iodine, which cause cell lysis. Gram-positive and gram-negative bacteria are commonly present in the human body even though at levels too low to produce symptoms associated with a disease. It thus appears that an important feature of the establishment of osteitis or osteomyelitis in bone is the build-up in the bone of toxins from bacteria which may be of exogenous or haematogenous origin which build-up induces necrosis and provides a reservoir of toxic material leading to further necrosis, often over relatively long periods of time. While the treatment of existing osteitis and osteomyelitis can be greatly improved by the use of such methylol transfer antibacterials, our discovery leads to the possibility of prophylaxis against these diseases by systemic administration of such drugs wherever bone damage is known or suspected. The work of Morrissy referred to above has established that even a cracked bone can provide a nucleus for haematogenous infection of the bone. Thus, if the bacterial toxins can be prevented from gaining a foothold in damaged bone tissue by systemic administration of an effective amount of the methylol transfer agent, osteomyelitis can be avoided. According to one aspect of the present invention there is provided the use of compounds of formula (I) [wherein R¹ represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and R² represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a group of formula (II) in which R¹ is as defined above] for the preparation of pharmaceutical compositions for the systemic prophylactic treatment of human or warm-blooded animal patients suffering from bone injuries to combat subsequent occurrence of osteitis or osteomyelitis, by preventing build-up of bacterial toxins in the damaged bone tissue- In the present invention, of the compounds of formula (I), the compounds taurolidine (R¹=H; R²=formula II) and taurultam (R¹=R²=H) are particularly preferred. A particular advantage of the compounds of formula (I) is their very low toxicity; thus methylol transfer activity results in the production of taurine which is found naturally in the body and is particularly non-toxic. A further advantage of taurolidine is its stability in aqueous solution, enabling the solutions to be pre-packed and stored over relatively long periods. Furthermore, it has recently shown to be non-teratogenic in mice. The compositions prepared in accordance with the invention may be in forms suitable for systemic, e.g. oral or, more particularly, parenteral administration. Oral forms include tablets, capsules, and fluid compositions such as solutions and suspensions. Parenteral forms include sterile aqueous solutions for injection or infusion. Solutions will commonly contain a solubilising agent such as polyvinylpyrrolidone which helps maintain the active substance in solution and also contributes to the isotonicity of the solution. The polyvinylpyrrolidone (PVP) is preferably incorporated into the solution, e.g. at a concentration in the range 4 to 7% by weight, in order to achieve relatively high concentrations of taurolidine and the relatively insoluble compounds of formula (I). The molecular weight of the PVP should not be greater than 30,000 and is preferably less than 10,000, for example between 200 and 3500. Kollidone 17 (registered Trade Mark) sold by BASF is especially suitable. Such PVP is relatively quickly resorbed and excreted renally. The daily dose of the active compound depends, in part, on such factors as the body weight of the subject, the extent of the bone injury and any haematogenous infection known to be present but in general will be in the range 10 g to 40 g, more preferably 20g to 30 g per day. A suitable dosage regime is four 250 ml bottles of a 2% solution of the active compound by i.v. drip infusion with a 4 hour pause or 3 such bottles per day with a 6 hour pause. The concentration of the substance of formula (I) in such solutions is preferably in the range 0.5 to 5% by weight, depending, at the maximum, on the solubility of the compound. Solutions of 1.0 to 2.0% taurolidine are particularly preferred. Where the compositions prepared according to the invention are in solid form, e.g. as tablets or capsules, they conveniently contain 400 to 700mg, preferably about 500mg of the compound of formula (I). As with iv administered solutions, the daily dosage will depend in part upon such factors as the body weight of the subject, the extent of the bone injury and any haematogenous infection known to be present; however oral daily dosages will generally be at least about 10g, preferably 10 to 30g. The following Examples are provided to illustrate further the present invention:- Example 1 - Solution Bis-(1,1-dioxo-perhydro-1,2,4-thiadiazin-4-yl)-methane (taurolidine) 400 g Polyvinylpyrrolidone (Kollidone 17) 1000 g Sterile water to 20 litres 15 Litres double distilled pyrogen free water are filled into a 25 litre glass vessel with stirrer and intensive reflux device and heated to 50°C with stirring. The taurolidine (400 g) is added followed by PVP (Kollidone 17; 1000 g). After dissolution, the solution is cooled and the pH adjusted to 6.0 with a few drops of 0.1 N hydrochloric acid. The solution is then passed through an adsorption filter to remove microorganisms and pyrogens and through a sterilising millipore filter before being filled into 100 ml vials which are finally autoclaved. Example 2 - Solution Taurultam 990g Sterile water ad 22 litres The taurultam is dissolved in the sterile water and filled into sterile bottles, 250ml in each. Example 3 - Tablet Taurolidine 500g Amylum maydis 60g Kollidone 25 (polyvinylpyrrolidone) 50g Plasdon XL 20g Magnesium stearate 6g Distilled water 200g 1000 tablets each containing 500mg taurolidine are produced by conventional means using the above formulation. In an alternative tablet formulation, the amylum maydis is replaced by 60g amylum orizae. Example 4 - Solution Taurolidine 440g Pharmaceutical gelatin 88g Sodium chloride 99g Sterile water to 22 litres The components are dissolved in the sterile water, if necessary using gentle warming and sonication. The solution is then filled into sterile bottles, 500ml in each.

Claims: The use of compounds of formula (I) [wherein R¹ represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms and R² represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a group of formula (II) in which R¹ is as defined above] for the preparation of pharmaceutical compositions for the systemic prophylactic treatment of human or warm-blooded animal patients suffering from bone injuries to combat subsequent occurrence of osteitis or osteomyelitis, by preventing build-up of bacterial toxins in the damaged bone tissue. Use as claimed in claim 1 in which the compound of formula (I) is taurolidine, taurultam. Use as claimed in either of claims 1 and 2 in which the prophylactic treatment is treatment of patients suffering from bone injuries of a traumatic origin. Use as claimed in any of claims 1-3 in which the pharmaceutical composition is in tablet, capsule or sterile solution form. Use as claimed in any one of claims 1 to 4 in which the pharmaceutical composition is in tablet or capsule form containing from 400 to 700mg of the compound of formula (I) per tablet or capsule.

Inventors: PFIRRMANN, ROLF WILHELM
Applicants: ED. GEISTLICH SOEHNE AG FUER CHEMISCHE INDUSTRIE
Application year: 1984
Main classification: A61K31
IPC codes: C07D285, A61P43, A61K31