WO2008017814A1

WO2008017814A1 - Prevention and treatment of microbial infection

Info

Publication number: WO2008017814A1
Application number: PCT/GB2007/002963
Authority: WO
Inventors: Jonathan Lane
Original assignee: Sinclair Pharmaceuticals Limited
Priority date: 2006-08-09
Filing date: 2007-08-03
Publication date: 2008-02-14
Also published as: GB0615814D0; EP2051713A1

Abstract

Use of a compound of formula (I) in the manufacture of a medicament for the prevention or treatment of a microbial infection caused by contacting the body with a medical device.

Description

Prevention and Treatment of Microbial Infection

Field of the Invention

The present invention relates to the prevention and treatment of microbial infection. Background to the Invention

The insertion of any foreign object into a living body has the potential to cause an infection, where a pathogenic microbe enters the body. These microbial infections, often referred to as nosocomial, post-operative or postsurgical infections, are a major healthcare issue and can, in the most severe cases, be fatal.

Delmopinol is a morpholino compound that has utility in the treatment of the oral cavity, especially the tooth surface, and for the removal or inhibition of dental plaque. The compound and its manufacture are disclosed in US 4,894,221 , the content of which is incorporated herein by reference. Delmopinol, and its derivatives, are not thought to have antibacterial activity.

WO-A-2006/082393 describes the use of delmopinol in the prevention of bacterial contamination caused by biofilm formulation on a surface. However, there is a very large spectrum of microbial infections that are problematic to humans and animals. There is, therefore, an ongoing need to identify methods of reducing and preventing infection.

Summary of the Invention

The present invention is based on the realisation that delmopinol, and its derivatives, can be used to prevent microbial infections caused by contacting the body with a medical device. According to a first aspect of the invention, a compound of formula (I)

(I) wherein Ri is a straight or branched alkyl group containing 8 to 16 carbon atoms at the 2- or 3-position of the morpholino ring, and R₂ is a straight or branched alkyl group containing 2 to 10 carbon atoms, substituted with a hydroxy group except in the alpha-position, is used in the manufacture of a medicament for the prevention or treatment of a microbial infection caused by contacting the body with a medical device.

According to a second aspect of the invention, a compound of formula (I) is used to treat a medical device prior to contact with the body, to prevent a microbial infection that is caused by contacting the body with the device.

According to a third aspect of the invention, a kit for the prevention or treatment of a microbial infection caused by contacting the body with a medical device comprises a compound of formula (I) and instructions that it is to be used for prevention or treatment of a microbial infection caused by contacting the body with a medical device.

Description of the Invention

The invention is based on the surprising discovery that delmopinol, and its derivatives, can prevent microbial infections caused by contacting the body with a medical device.

The compounds for use in the present invention have the general formula (I)

wherein Ri is a straight or branched alkyl group containing 8 to 16 carbon atoms at the 2- or 3-position of the morpholino ring, and R₂ is a straight or branched alkyl group containing 2 to 10 carbon atoms, substituted with a hydroxy group except in the alpha-position. In a preferred embodiment the sum of the carbon atoms in the groups Ri and R₂ is at least 10 and is preferably 10 to 20. Preferably, the R₂ group terminates with the hydroxy group. In a further preferred embodiment, the compound is delmopinol, i.e. 3- (4-propyl-heptyl)-4-(2-hydroxyethyl) morpholine (CAS No.79874-76-3).

The claimed morpholino compounds are known per se as disclosed in US4,894,221 and US5,082,653, which are incorporated herein by reference.

The morpholino compounds of the present invention can be used in their free base form or as a pharmaceutically acceptable salt thereof. Some examples of pharmaceutically acceptable salts are the salts of acids such as acetic acid, phosphoric, acid, boric acid, hydrochloric acid, maleic acid, benzoic acid, citric acid, malic acid, oxalic acid, tartaric acid, succinic acid, glutaric acid, gentisic acid, valeric acid, gallic acid, beta-resorcyclic acid, acetyl salicylic acid, salicylic acid, perchloric acid, barbituric acid, sulfanilic acid, phytic acid, p-nitro benzoic acid, stearic acid, palmitic acid, oleic acid, myristic acid, lauric acid and the like. The most preferred salt form is of hydrochloric acid. A preferred compound is delmopinol hydrochloride (CAS No. 98092-92-3).

The claimed compounds can be manufactured by any known method, for example, that disclosed in US 4,894,221 , US 5,082,653 and WO 90/14342, which are incorporated herein by reference.

The invention relies on the discovery that microbial infections, that are caused when the body is contacted with a medical device, can be reduced or prevented by contacting the body of the patient, or the medical device, or both, with a compound of formula (I) prior to, during or after, preferably immediately after, initial contact between the medical device and the body. Preferably, the area of the body that is contacted with a compound of formula (I) is the site of contact between the body and the medical device, and the immediate surrounding area. Infections that can be reduced or prevented using a compound of formula (I) are caused by a microbe. The term "microbe" includes bacteria, funghi and yeast. Bacteria that are known to cause infections arising from medical devices can be gram-positive or gram-negative. Bacteria that are known to cause infections relating from medical devices include Streptococci such as Group A beta-hemolytic Streptococci, Group B Streptococci, Streptococcus pneumoniae, Viridans Streptococci, Enterococci, Pneumococci and Streptococcus Bovis, Staphylococci including Coagulase negative Staphylococci (CoNS), Coagulase positive Staphylococci, Staphylococcus aureus, Staphylococcus epidermidis and Staphylococcus capitus, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, E.coli, Klebsiella including Klebsiella pneumoniae, enterobacteria, Proteus including Proteus mirabilis, Serratia, coryneforms, Enterococcus faecalis, Bacterioides spp., Gardenerella spp., Corynebacterium spp., Enterococci, coccobacilli including gram-negative coccobacilli, Providencia stuartii, M.Morganii, Propionibacterium acne, Acinetobacter calcoaceticus, Enterobacter aerogenes, Lactobacilli including anaerobic lactobacilli, lactobacillus plantarum, and Micrococcus. In a preferred embodiment, the bacteria is drug resistant, preferably antibiotic resistant, more preferably penicillin resistant. Drug resistant bacteria are known in the art; preferred examples of drug resistant bacteria are methicillin-resistant Staphylococcus aureus and multiple-resistant Staphylococcus aureus (MRSA) Non-bacterial microbes that are known to cause infections arising from medical devices include Candida spp., for example Candida Albicans, and Aspergillus spp.

In a preferred embodiment, a compound of formula (I) is used according to the invention to prevent or reduce infection caused by planktonic microbes. As used herein, the term "planktonic" refers to microbes that are not attached to a surface; planktonic microbes are free-floating. These microbes are not part of a biofilm. A compound of formula (I) can be used to act on the microbes before they attach to any one surface.

In a preferred embodiment, the infection that is prevented or treated using a compound of formula (I) is a nosocomial infection. As used herein, the term "nosocomial" is given its normal definition in the art, i.e. an infection that is caused by a treatment (for a different condition). For example, a catheter may be inserted to deliver drugs to treat a cancer, and a nosocomial infection occurs in the tissue surrounding the catheter.

Conditions that can be caused by contacting the body with a medical device and can be prevented or treated using a compound of formula (I) include peri-implantitis, septic thrombosis, endocarditis including native valve endocarditis, candidal endocarditis, early and late prosthetic valve endocarditis, osteomyelitis, catheter tunnel infection, catheter port abcess, sepsis including septicaemia, bacteraemia, phlebitis, candidiasis including invasive candidiasis, candidaemia, cystic fibrosis and related infections in particular bronchial infections such as pseudomonas aeruginosa infections, otitis media (acute or chronic), prostatitis including chronic bacterial prostatitis and pelvic inflammatory disease including pelvic inflammatory disease resulting from inter-uterine devices. The skilled person will realise that the most likely way for a specific body part to become infected is by contacting that body part with a medical device, thereby allowing microbes access to that body part.

Table 1 lists a number of preferred microbial infections, together with microbes that are known to cause each infection that can be prevented, reduced or treated by contacting a medical device and/or body with a compound of formula (I). It should be noted that an infection listed in the first column of Table 1 can be prevented, reduced or treated using a compound of formula (I), irrespective of the specific microbe that causes the infection. Table 1

As used herein, the term "medical device" refers to any device, implant or implement that contacts the body with the aim of treating or preventing a medical condition, diagnosing a medical condition or monitoring the general health of a patient.

In one embodiment, the term "medical device" refers to a surgical implant. Implants may be used to replace a missing or defective biological structure, for example artificial joints such as artificial hip joints. Implants can be bioactive, such as subcutaneous drug delivery devices in the form of implantable pills or drug-delivery stents. In orthopaedic surgery, implants such as pins, plates and screws are often used to ensure correct healing of a fractured or broken bone. Cosmetic implants, such as breast implants, are also within the scope of the invention. Examples of implants that are within the scope of the invention are artificial joints such as hips, orthopaedic hardware such as pins, plates and wires, dental implants such as a pin or screw, cosmetic implants such as breast implants, artificial/prosthetic limbs, heart valves, stents, contact lenses, intra-uterine devices (IUD) and devices for delivering fluids, nutrients and medicines, or for the removal of fluids and waste, e.g. catheters, in particular cardiovascular catheters (CVC). Infection of the tissue surrounding an implant is often referred to as peri-implantitis, which may be defined as an inflammatory reaction caused by microbial infection that results in the loss of tissue, preferably bone, in the tissues surrounding an implant. Prevention or treatment of peri-implantitis using a compound of formula (I) is therefore a preferred embodiment. For the avoidance of doubt, the term "medical device", as used herein, includes devices, implants and implements used in cosmetic procedures. The term "medical device" also includes identification and information tags, or electronic chips, that are implanted into a subject. In one embodiment, the term "medical device" refers to a surgical implement, e.g. surgical knives, saws, scalpels, forceps or any other instrument used in an invasive surgical procedure.

The medical device may be an implant, i.e. a device that is inserted into the body of a subject. In a preferred embodiment, the device is a surgical implant that requires an incision to be made into the body to allow implantation.

In a particularly preferred embodiment, the device to be treated is a dental implant, e.g. a tooth-retaining dental pin or screw. The prevention of infection in dental implants is particularly problematic as they are one of the few medical devices that permanently cross the boundary between the inside and outside of the body. A typical dental screw is screwed into the bone of the mandible or maxilla, leaving an exposed surface in the mouth, onto which an artificial tooth can be attached. Coating or impregnating a dental implant with a compound of formula (I) will reduce the probability of infection occurring, thereby improving the chance of osseointegration.

In an alternative embodiment, the medical device contacts the body but does not enter it, for example a prosthetic limb, plaster cast, contact lens or external hearing aid. In the context of a contact lens, a compound of the invention may be impregnated onto the surface of the contact lens. Alternatively, in the context of hydrogel contact lenses, the compound may be impregnated into the hydrogel matrix. Alternatively, the compound may be present in the solution used to store or clean contact lenses. The subject into (or onto) which the medical device is implanted (or contacted) may be human or animal, i.e. veterinary applications are within the scope of the invention.

The compound of formula (I) will usually be applied onto the region of the patient that is to be exposed to the medical device, and/or onto the medical device itself.

The compound of formula (I) can be applied to a medical device by contacting the device directly with the compound. A medical device comprising a compound of formula (I) is therefore within the scope of the invention. In a preferred embodiment, a solution comprising or consisting of a compound of formula (I) is applied to a medical device. The solution may be poured or sprayed onto the device, or the device may be dipped into the solution. Other methods of contacting the device are within the scope of the invention. The device may be coated or impregnated with a compound of formula (I).

There are many ways in which compounds can be coated onto a medical device, including spray coatings, irradiation and ultra violet curing. The technologies for coating medical devices with biomaterials are now advanced, and these technologies may be applied in the present invention. Accordingly, the present invention encompasses coated medical devices coated with the compound of formula (I). The material to be coated, i.e. the medical device, is preferably a bioinert material, i.e. it is non-reactive in the body. The medical device may be metal such as titanium, polymer (plastic) such as polyethylene, ceramic, polystyrene or glass. Preferably, the material to be coated is metal, more preferably stainless steel. The medical device can comprise a mixture of materials described above.

The compound of the invention may be bound to the treated surface in a covalent or non-covalent attachment. If bound covalently, a linker molecule may be used to bind the compound to the surface. For example, polyethylene glycol (PEG) is a useful linker substrate that may be used in the present invention. Amination may also be used to provide an effective linker molecule.

Alternatively, the compound may be impregnated within a matrix, e.g. a polymer matrix. Conventional biocompatible poylmer matrices may be used to retain the compound on the surface. For example, poly(organo)phophazene, hydrophilic hydrogels (e.g. 2-hydroxyethyl methacrylate; HEMA) or silicon-based coatings (e.g. fluorosilicone) are all used as conventional coatings on medical devices and may be used to retain a compound of the invention. A suitable method of coating is disclosed in US2005/0187611 , the content of which is hereby incorporated by reference.

In a preferred embodiment, a medical device is contacted with a compound of formula (I) prior to or during insertion into (or contact with) the subject into (or onto) which the implant is to be deposited. More preferably, the device is rinsed in the compound prior to or during contact with the subject. Most preferably, rinsing occurs immediately prior to contact with the subject, with subsequent drying to coat the compound onto the device. For the avoidance of doubt, where reference is made herein to coating or contacting a medical device with a compound of formula (I), the skilled person will realise that coating or contacting the raw material required to make the device, or an intermediate between the raw material and final device, is within the scope of the invention. For example the metal required to produce a hip implant can be coated or contacted with a compound of formula (I) prior to machining to form the final implant.

A preferred embodiment of the invention comprises an amount of the compound of formula (I) suitable for a single application to the medical device, within a container. Preferably, the internal surfaces of the container, it's internal environment and contents (e.g. delmopinol) are aseptic, i.e. sterile and substantially free from pathogens, and therefore suitable for use in a medical (or cosmetic) operation such as surgery. More preferably, the external surfaces are also sterile. Any container suitable for holding a liquid may be used, it is preferred that the container can be sealed. A preferred container is a sachet, or pouch, that can be sealed aseptically on production and is cut or torn open when required. Preferably, the sachet is made from a flexible plastic or metal material; suitable sachets are known in the art. Other suitable containers include bottles, jars and tubes of any material, preferably glass or plastic. In a preferred embodiment, the container is a holder for the storage or cleaning of a contact lens. The size of the container (and therefore the pre-determined dosage of compound stored within) suitable for different applications will be apparent to one skilled in the art, for example a hip implant will require a larger amount of delmopinol than a (standard) catheter. It is preferred that each container is "single-use", i.e. once it has been opened and the contents used, it is disposed of, irrespective of whether all of the contents have been used. This has the advantage of minimising any potential contamination. In an alternative preferred embodiment, the container is a multiple-use container. For example, a container capable of dispensing multiple aliquots, preferably sterile aliquots, of a compound of formula (I) is preferred.

The compound of the invention may be present in the container in any suitable concentration. Typically, the compound is present in a concentration of from 0.01% (w/v) to 10% (w/v), preferably from 0.1 % (w/v) to 5% (w/v) and most preferably from 1% (w/v) to 3% (w/v) e.g. 2% (w/v). The compound will typically be present in aqueous solution, although any other suitable solvent may be used, including alcohol.

The compounds of formula I may be impregnated onto a material that is used to contact the medical device or area of the body where infection is to be prevented. The material may be woven or non-woven. A woven material will typically be used to wipe the surface; non-limiting examples of suitable woven materials include a swab, cloth, wipe or mop. The woven material may comprise natural (eg cotton) or synthetic fibres (eg nylon), or a combination of both. In a preferred embodiment, the impregnated material is an aseptic/sterile "single-use" material, suitable for use in a medical environment e.g. a bandage. Most preferably, the material is supplied in a container as described above; the container may comprise the impregnated material only, or the impregnated material and an excess of the compound suitable for rinsing the surface (in addition to, or instead of, contacting it with the impregnated material).

In another preferred embodiment, the medical device itself is coated or impregnated with a compound according to the invention. This embodiment is particularly suitable for medical devices that will remain in situ for a prolonged period of time, for example medical implants.

The compounds may be brought into contact with the medical device or patient in a conventional way. For example, the compounds may be prepared in solution and the solution brought into contact with the relevant area.

The compounds may be used to rinse or wipe the medical device or patient, as described above. In a further preferred embodiment, the compound is sprayed onto the medical device or patient. In this embodiment, the compound may be prepared in an aerosol canister, atomiser spray bottle or other similar device, suitable for producing a droplet-based mist containing the compound. This is an effective method of contacting large surfaces with the compound. This is also particularly effective for contacting awkwardly shaped surfaces, or delicate surfaces such as contact lenses.

The compounds may be delivered in any suitable form that achieves the desired effect. The compounds may be included in a controlled release formulation or stored within a device that permits the controlled release of the compound. A controlled release formulation may be used in combination with any other embodiment described herein, for example a controlled release formulation may be impregnated into a surface, or delivered using a spray. The amount effective to prevent infection will be readily apparent to the skilled person and may be determined based on the surface to be treated.

Claims

1. Use of a compound of formula (I)

wherein Ri is a straight or branched alkyl group containing 8 to 16 carbon atoms at the 2- or 3-position of the morpholino ring, and R₂ is a straight or branched alkyl group containing 2 to 10 carbon atoms, substituted with a hydroxy group except in the alpha-position, in the manufacture of a medicament for the prevention or treatment of a microbial infection caused by contacting the body with a medical device.

2. Use according to claim 1 , wherein the microbial infection is septic thrombosis, osteomyelitis, catheter tunnel infection, catheter port abcess, catheter-associated sepsis, phlebitis, endocarditis, otitis media, chronic bacterial prostatitis, cystic fibrosis - associated infection or an intra-uterine device infection.

3. Use according to claim 1 , wherein the microbial infection is peri- implantitis.

4. Use according to claim 1 , wherein the microbial infection is caused by Streptococci such as Group A beta-hemolytic Streptococci, Group B Streptococci, Streptococcus pneumoniae, Viridans Streptococci, Enterococci, Pneumococci and Streptococcus Bovis, Coagulase negative Staphylococci (CoNS), Coagulase positive Staphylococci, Staphylococcus aureus, Staphylococcus capitus, Haemophilus influenzae, Moraxella catarrhalis, Pseudomonas aeruginosa, E.coli, Klebsiella including Klebsiella pneumoniae, enterobacteria, Proteus including Proteus mirabilis, Serratia, coryneforms, Enterococcus faecalis, Bacterioides spp., Gardenerella spp., Corynebacterium spp., Enterococci, coccobacilli including gram-negative coccobacilli, Providencia stuartii, M.Morganii, Acinetobacter calcoaceticus, Enterobacter aerogenes, Lactobacilli including anaerobic lactobacilli, lactobacillus plantarum, and Micrococcus.

5. Use according to claim 4, wherein the microbial infection is caused by Staphylococcus aureus.

6. Use according to claim 1 , wherein the microbial infection is caused by Staphylococci, Staphylococcus epidermidis or Propionibacterium acne.

7. Use of a morpholino compound according to any preceding claim wherein the sum of the carbon atoms in the groups R₁ and R₂ is at least 10, preferably between 10 and 20.

8. Use or a morpholino compound according to any preceding claim wherein R₂ terminates with the hydroxy group.

9. Use or a morpholino compound according to any preceding claim wherein the morpholino compound is 3-(4-propyl-heptyl) -4-(2-hydroxyethyl) morpholine.

10. Use according to any preceding claim, wherein the medical device is an implant.

11. Use according to claim 10, wherein the implant is a dental implant.

12. Use of a compound of formula (I)

wherein Ri is a straight or branched alkyl group containing 8 to 16 carbon atoms at the 2- or 3-position of the morpholino ring, and R₂ is a straight or branched alkyl group containing 2 to 10 carbon atoms, substituted with a hydroxy group except in the alpha-position, for treating a medical device prior to contact with the body, to prevent a microbial infection that is caused by contacting the body with the device.

13. A kit for the prevention or treatment of a microbial infection associated with insertion of an implant into the body, comprising a compound of formula (I)

wherein Ri is a straight or branched alkyl group containing 8 to 16 carbon atoms at the 2- or 3-position of the morpholino ring, and R₂ is a straight or branched alkyl group containing 2 to 10 carbon atoms, substituted with a hydroxy group except in the alpha-position and instructions that it is to be used for prevention or treatment of a microbial infection caused by contacting the body with a medical device.