TAUROLIDINE IN PREOPERATIVE COLON-DISINFECTION

Abstract: Use of an antibacterial and anti-toxaemic compound of the general formula (I), where R<1> is hydrogen or a C1-5 alkyl group and R<2> is hydrogen or a group of formula (II), for the preparation of an aqueous solution for the orthograde or retrograde preoperative disinfection of the colon. The preferred compound is taurolidine.

Description: Taurolidine in preoperative colon-disinfection This invention relates to a novel method of disinfection of the colon in preparation for surgery. Surgery carried out on the large bowel or colon is very frequently complicated by post-operative sepsis deriving from faecal organisms inhabiting the gut. In recent years, this problem has been reduced in part by mechanical cleaning of the colon, that is by washing.out its contents using retrogade irrigation (enemas) or orthgrade irrigation through a tube into the stomach via the nose or mouth. (J. Hewitt et al The Lancet, p.337, 1973). It has also been recommended to disinfect the colon using antibiotics such as neomycin and kanamycin in the irrigation fluid. Organisms present in the colon include such gram-negative bacteria as Escherioσhia Coli, Proteus spp. Streptococcus faeσalis, Bacteroides spp and anaerobic streptococci. These organisms carry endotoxins which are largely responsible for many of the harmful effects of sepsis and when released in large quantities, can produce endotoxic shock. Since most antibiotics, such as those previously used, tend to cause lysis of the bacterial cells, sterilisation using antibiotics can give rise to release of large quantities of endotoxin due to the high concentrations of bacteria present in the faeces (40-60%) . We have found that a particularly effective way of avoiding this is to use as antibacterial substance a methylol transfer antibacterial of the general formula [wherein R represents a hydrogen atom or an alkyl 2 group having from 1 to 6 carbon atoms and R represents a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or a group of formula II in which R is as defined above] . "Particularly useful compounds of formula I are taurolidine (R 1=H, R2=Formula II) and taurultam (R 1 =R 2 =H) . The invention thus includes the use of a compound of formula I as defined above, in particular taurolidine or taurultam, in the pre-operative disinfection of the interior of the colon. Although it may be virtually impossible to kill all pathogens in the colon, the active compound will in general convert invasive pathogens into non-invasive forms, as well as combatting bacterial toxins deriving from such pathogens. The cleansing of the interior of the colon may be effected by the retrograde or, more preferably, by the orthograde technique. In the retrograde technique, laxatives are generally required, followed by a series of enemas. This procedure may be carried out over several days. It is preferred, therefore. to use the orthograde technique, in which about 8-12 litres of an irrigation fluid are passed through the colon via the stomach, and such irrigation may be completed within 2-3 hours. The irrigant is passed into the stomach continuously via a tube through the nose or mouth. The enema solution or the irrigant may thus comprise, at least in part, a solution of the compound of formula I in water. However, it is desirable to give the active compound at relatively high concentration after all or the greater part of the faeces has been washed out of the colon. It is thus preferable to give the active compound of formula I after the main body of irrigant has been administered, most simply by drinking an aqueous solution of the compound although it is also possible for the last litre or so of the irrigant to contain the active compound. The solution will advantageously be approximately isotonic. A solubilising agent for the compound of formula I may be present, for example a water- soluble long chain material such as polyvinyl pyrrolidone or gelatin. In the case of taurolidine, a 2% solution containing about 7.5% of Povidone BP (polyvinyl pyrrolidone) has been found to be approximately isotonic. Where it is desired to adjust the isotonicity of the solution, sodium chloride may be added (possibly together with a minor proportion of potassium chloride) . In the case of solution for drinking, one or more sweetening and/or flavouring agents are advantageously present. According to a further feature of the invention we therefore provide an irrigant solution for orthograde disinfection of the colon comprising an aqueous solution containing 1-5% by weight of a compound of formula I as defined above, a long-chain solubiliser therefor and one or more sweetening and/or flavouring agents. In general, in the case of taurolidine the overall dose administered will be about 20-30 gms. Thus, where a 2% solution of taurolidine is given, •one litre will provide 20 grams while 1.5 litres will be required to provide 30 grams. If desired, however, it is possible to provide part of the overall dose of the active compound in solid form, e.g. in tablets or capsules, in order to reduce the amount of liquid to be drunk by the patient. Such tablets or capsules will commonly contain 400 to lOOOmg, e.g. 500-700mg of the compound of formula I. In the case of taurultam, dosages stated for taurolidine should be multiplied by 1.5. The compound of formula I will be absorbed systemically as well as acting locally against bacteria and toxins in the colon and will serve to combat any bacterial infections or toxaemia in the vascular system. Thus, the active compound is effective prophylactically against post operative sepsis both locally and systemically. In general, orthograde -irrigation will be effected by passing a 3mm rubber or plastic tube into the stomach via the nose or mouth. The patient is in a semi-sitting position on a so-called cholera- couch. The irrigant solution will normally be isotonic saline or Ringer solution warmed to 37 β C and may be delivered through the stomach tube via a peristaltic pump. The total quantity of irrigant will be 8-13 litres given over 2-3 hours. If the compound of formula I is given by drinking a further litre or more of liquid, somewhat less irrigant is preferable so that the total quantity of liquid does not exceed 13 litres. In irrigation studies in cats, the effect of a 2% solution of taurolidine was compared with that of a standard coloscopy solution in sterilising the colon in respect of Staphylococci, Streptococci, Enterobacteria, Lactobacillae, Clostridium perfringens, Bifidobacteria, anaerobic bacilli and the total anaerobic bacteria. It was found that a single retrograde irrigation with the 2% taurolidine solution was significantly more effective than a single and also a double orthograde irrigation with coloscopy solution. A double retrograde irrigation with taurolidine was even more effective. No adverse histological changes in the mucosa of the colon were observed. The taurolidine solution was particularly effective against the anaerobic bacteria, especially the gram negative bacteria. The following Examples are given by way of illustration onlys- Example 1 - Oral solution for orthograde sterilisation of the colon Taurolidine 5.00g Povidone BPC 18.75g Saccharine Flavouring Distilled water ad 250ml Example 2 - Tablets Taurolidine 500g Am lum aydis 60g Kollidone 25 50g (pol vinylpyrrolidone) 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.

Claims: - 6 - Claims 1. The use of an antibacterial and anti-toxaemic compound of the general formula (I) where R is hydrogen or a C, - alkyl group and R 2 is hydrogen or a group of the formula R' for the preparation of an aqueous solution for the orthograde or retrograde preoperative disinfection of the colon. 2. The use as claimed in claim 1 in which the compound of formula (I) is taurolidine. 3. The use as claimed in claim 1 or claim 2 in which the aqueous solution contains 1-5% by weight of the compound of formula (I) , a long-chain stabiliser therefor and one or more sweetening and/or flavouring agents. 4. An irrigant solution for orthograde disinfection of the colon comprising an aqueous solution of 1-5% of a compound of formula (I) as defined in claim 1, a long chain stabiliser therefor and one or more sweetening and/or flavouring agents. 5. An irrigant solution as claimed in claim 4 comprising an aqueous solution contining taurolidine as the compound of formula (I) and polyvinyl pyrrolidone as the long chain stabiliser. 6. A compound of the general formula (I) as claimed in claim 1 for use in the orthograde or retrograde preoperative disinfection of the colon. 7. A method of preoperative disinfection of the colon in which the colon is irrigated by the orthograde or rectograde route with an aqueous solution of an effective amount of a compound of general formula (I) as claimed in claim 1. 8. A method as claimed in claim 1 in which the compound of formula (I) is taurolidine. 9. A method as claimed in claim 8 in which 20-30 g. of taurolidine is administered by the orthograde route. 10. A method as claimed in claim 9 in which a proportion of the compound of formula (I) is administered in solid form while the remainder is administered as an aqueous solution.

Inventors: PFIRRMANN ROLF WILHELM, PFIRRMANN, ROLF, WILHELM
Applicants: GEISTLICH SOEHNE AG, HOLMES MICHAEL JOHN, ED GEISTLICH SOHNE AG FUR CHEMISCHE INDUSTRIE, HOLMES, MICHAEL, JOHN
Application year: 1985
Main classification: A61K31
IPC codes: A61K31