WO2016159859A1

WO2016159859A1 - Mannan oligosaccharides for the treatment of urinary tract infection

Info

Publication number: WO2016159859A1
Application number: PCT/SE2016/050244
Authority: WO
Inventors: Roland STENUTZ
Original assignee: Stenutz Roland
Priority date: 2015-03-27
Filing date: 2016-03-24
Publication date: 2016-10-06

Abstract

The present invention relates to the general field of using mannan oligosaccharides (MOS) in non-oral therapeutic formulations for the prophylaxis and treatment of urinary tract infec- tion (UTI) and more particularly to the use of said MOS formulations for the prophylaxis and treatment of catheter-associated UTI (CAUTI). The formulations are administered topically, locally,intraurethrally and/or to a medical device.

Description

MANNAN OLIGOSACCHARIDES FOR THE TREATMENT OF URINARY TRACT INFECTION

TECHNICAL FIELD

The present invention relates to the general field of using mannan oligosaccharides (MOS) in non-oral therapeutic formulations for the prophylaxis and treatment of urinary tract infection (UTI) and more particularly to the use of said MOS formulations for the prophylaxis and treatment of catheter-associated UTI (CAUTI). The formulations are administered topically, locally, intraurethrally and/or to a medical device.

BACKGROUND

In the medical literature UTI is defined as microbial infiltration of pathogens of the otherwise sterile urinary tract. UTIs include infections of the urethra (urethritis), bladder (cystitis - also referred to as lower UTI), ureters (urethritis) and kidney (pyelonephritis - also referred to as upper UTI). UTI is a major cause of morbidity with about 4 million cases per annum in the US alone.

Urinary catheterization is a necessary medical procedure. However, urinary catheterization is a major cause of UTI. Commensal bacteria such as uropathogenic Escherichia coli (UPEC) infect the urinary tract which results in severe UTIs. A large number of about 560 00 cases, are CAUTI with a mortality of 13 000 per year. Thus, many of the cases are nosocomial, i.e. acquired during hospital visits. Typical symptoms range from painful urination to kidney failure (pyelonephritis) and death. The preferred method for treatment of these CAUTI is the removal of the contaminated urinary catheter.

The ability of bacteria to both establish and maintain infections is directly related to biofilm formation on indwelling devices within the urinary tract itself [Hatt]. The risk of developing a urinary tract infection increases significantly with the use of indwelling devices such as catheters. Indwelling catheters are the primary contributing factor in the development of these infections [Hatt]. The use of catheters to manage urinary incontinence in nursing home and spinal cord injury patients makes these populations especially vulnerable to these infections. Remarkably, the risk of developing catheter-associated urinary tract infections increases 5% with each day of catheterization and virtually all patients are colonized by day 30 [Hatt]. Unfortunately, bacteria forming biofilm are difficult to eradicate due to antibiotic and antimicrobial resistance.

The main infective agent representing 80% of infections is UPEC originating from fecal con- tamination. Other bacteria associated with UTI are Staphylococcus saprophyticus, Klebsiella species, Proteus mirabilis, and Enter^•ococcusfaecalis. As the occurrence of antibiotic resistance in E. coli has risen drastically over the past decade it is becoming increasingly difficult to treat UTI effectively. The rate of recurrence is high, 10-20%, and recurrent UTI (rUTI) cause high frequencies of morbidity as well as lowering the patients quality of life. Despite administration of antibiotics which cure the infection, the probability that a patient will develop a second UTI is about 25% [Aydin].

It has long been recognized that attachment of a bacterium to the urothelial surface is an essential step in establishing UTI infection since it allows the bacteria to establish a site for colonization and subsequent infection and invasion of the urothelial surface. The attachment of bacteria is mediated by fimbriae which are selective for surface structures on the cells of the targeted organ. If the attachment can be prevented by inhibiting the binding of the fimbriae then infection cannot take place and the bacterium will be removed by mechanical means. UTI in particular has been studied in great detail with regard to bacterial adhesion.

It is known that a major virulence factor in E. coli, as well as other enterobacteriae causing UTI, are Type 1 fimbriae which are also referred to as Type 1 pili in the art. Type 1 fimbriae which are filamentous attachment structures help the bacteria to adhere to the urothelial surface by binding N-glucans present on uroplakins. This binding is mediated by FimH adhesin which is a lectin located at the tip of the Type 1 fimbriae [Zhou].

It has been shown that a-mannosides can prevent binding of bacteria to the urothelial sur- face and thereby interfere with UTI [Hartman]. This prevention involves the inhibition of Type 1 fimbriated E. coli by α-mannosides which are small molecules comprising a-mannose as well as optional benzyl groups. Although, α-mannosides have been seen to have some effect, there is a need in the art to use (i) more effective mannose containing molecules, (ii) mannose containing molecules not comprising potentially toxic benzyl groups, (iii) mannose containing molecules which are cheaper and easier to produce, and (iv) non-oral routes of administration of mannose containing molecules.

Additionally, the oral administration of MOS for the treatment of UTI has been disclosed in US8063026. However, there is a need in the art to provide more effective routes of administration than oral administration of MOS. OBJECT OF THE INVENTION

As indicated in US8063026, MOS have potential as pharmaceutical compounds for use in the treatment of UPIs. One of the biggest advantages is that the use of mannan oligosaccharides may help to avoid inducing antibiotic and antimicrobial resistance in microorganisms. Antibiotic resistance (against e.g. fluoroquinolones) is an increasing problem but is not induced by MOS.

However, a major concern with systematic oral administration of mannan oligosaccharides is the potential adverse effects on commensal E. coli strains and other members of the intesti- nal microbiota which express type 1 fimbriae. Hence, the object of the present invention is to provide a route of administration which does not give rise to adverse effects of commensal bacterial strains.

As described in the previous section, a-mannosides appear to prevent binding of bacteria to the urothelial surface. However, they appear to be intended for oral use and there is a need for more effective mannose containing molecules as well as non-oral routes of administration. Moreover, the a-mannosides are synthetically produced and derivatized by aromatic groups, i.e. expensive to produce and potentially toxic for animals and environment. Thus, a further object of the invention is to provide more effective mannose containing molecules which are also non-synthetic, cheaper to produce as well as non-toxic for the environment. A further concern is the oral administration of mannan oligosaccharides in chronic cases of UTI since very high therapeutic oral dosages have to be provided, either as a big single dose administered daily or multiple smaller doses administered daily. However, the oral administration of high doses of mannan oligosaccharides would pose a big risk of adverse effects on commensal bacteria. Hence, a further object of the present invention is to provide a route of administration of high daily or systematic doses of mannan oligosaccharides which does not give rise to adverse effects of commensal bacterial strains.

Although the molecular weight of mannan oligosaccharides is quite large, they are soluble in water and are therefore not suitable for topical, local and intraurethral administration to the site of UTI since they can easily be washed away by bodily fluids. Hence, a further object of the present invention is to provide mannan oligosaccharides in a formulation which can be administered topically, locally and/or intraurethrally at the site or vicinity of UTI. Although urinary catheterization is a necessary medical procedure, the contaminated urinary catheter is removed due to CAUTIs. Hence, a further object of the present invention is to provide means for administering mannan oligosaccharides to the catheter so that the risk of CAUTIs are reduced when urinary catheters are used. UTI-causing bacteria form biofrlms on catheters and thereby cause severe infections which are difficult to treat. Hence, it is a further object of the present invention to provide mannan oligosaccharides in a formulation which can eliminate the formation of biofilms in uretic catheters (i.e. urinary catheters), particularly in indwelling catheters.

Uretic catheters, in particular indwelling catheters, are used over long periods of time. Hence, it is a further object of the present invention to provide means of application an composition comprising MOS on a catheter which is effective against principal pathogens involved in CAUTIs over a long duration typically the whole period of catheter implantation (up to 12 weeks).

Many antibacterial agents and disinfectants applied to the urinary tract, such as triclosan (antibacterial agent), are harmful for animals as well as being environmentally hazardous. It is a further object of the invention to provide an agent which can be administered to the urinary tract but is not harmful for animals and the environment.

Various antibacterial metals such as silver, as well as antibiotics and antibacterial agents, are expensive to produce. Hence it is a further object of the invention is to provide an agent which is relatively cheaper to produce.

SUMMARY OF INVENTION

The objects of the present invention are attained by a preferred embodiment being a composition comprising MOS of microbial origin wherein said composition is a gel, cream, foam, lotion, paste or ointment formulation.

The composition is used for the prophylaxis and treatment of diseases, in particular for the prophylaxis and treatment of UTI such as urethritis, cystitis (lower UTI), urethritis and pyelonephritis (upper UTI). In a further preferred embodiment the composition is used for the prophylaxis and treatment of CAUTI. The advantage of using gel, cream, foam, lotion, paste and ointment formulations is that such formulations may be administered to the site of bacterial colonization and infection without having to be ingested orally. Hence, the risk of having an adverse effect on commensal bacterial strains is avoided. In a preferred embodiment, the composition comprises a gel formulation comprising MOS. Our studies have shown that a composition comprising MOS formulated as a gel is an optimal vehicle for MOS delivery. MOS formulated in the composition are derived from the cell wall of yeast, such as from the Saccharomycetales order, preferably from yeast of the Saccharomyces genus such as Sac- charomyces cerevisiae. MOS from Pichia guilliermondii may also be used. Such MOS molecules are high-molecular and may have a molar mass ranging from 25 000 - 500 000 g/ mol, but usually they have a molar mass of 75 000 - 300 000 g/mol. However, MOS with a molar mass ranging from 1 000 g/mol to 1 000 000 g/mol may also be utilized. Although the MOS molecules maybe non-covalently bound within a gel material, the MOS molecules are instead in preferred embodiments cross-linked to each other and thereby form a gel material. It appears as if cross-linking enhances binding efficiency of the bacteria to MOS thereby inhibiting bacterial adhesion to urethral cells. The composition is in a preferred embodiment adminis- tered to a medical device in order to prevent bacterial biofilm formation and thereby prevent and treat CAUTI. Preferred medical devices are catheters and stents, more preferably catheters, most preferably uretic catheters. The administration of the composition to a medical device is preferably achieved by known techniques in the art such as coating or matrix loading techniques. Furthermore, a medical device prepared by coating and matrix loading, as well as a method of preparing catheter by coating and matrix loading, also achieves the objects of the present invention. Preferred medical devices are catheters and stents, more preferably catheters, most preferably uretic catheters.

In further preferred embodiments of the invention, the composition is administered topi- cally, locally and/or into the urethra (i.e. intraurethral administration) for the prophylaxis and treatment of UTI. A topical administration is drug delivery to body surfaces such as the skin or mucous membranes wherein mucous membranes include the urethra since the urethra is lined with mucous membranes. Hence, intraurethral administration is also a type of topical administration. The object of the present invention is also achieved by a method of preparing a composition comprising MOS formulated as a gel, characterized by the steps of:

• Cross-linking MOS to each other in the presence of a cross-linking agent,

• Optionally removing excess cross-linking agent

• Subjecting the mixture optionally to dialysis to remove salts, • Optionally lyophilizing to give a cross-linked product as a powder,

• Adding a liquid to the product, preferably up to 10 times the product's weight, wherein said liquid is preferably water, glycerol and/ or propylene glycol. wherein said MOS are of microbial origin, preferably derived from the cell wall of yeast, more preferably derived from the cell wall of Saccharomyces genus, most preferably derived from the cell wall of Saccharomyces cerevisiae.

FIGURE

Figure l. Bacterial growth (E. coli ATCC 117 75 in LB medium) in the presence and absence of cross-linked MOS (as measured by optical density (a.u.) versus time (min)).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compositions comprising MOS of microbial origin for use in the prophylaxis and treatment of UPI such as urethritis, cystitis, urethritis and pyelonephritis, as well as CAUTI. MOS of microbial origin are MOS which originate from fungi (such as yeast), bacteria, archea and protists.

Although MOS maybe present in cream, foam, lotion, paste or ointment formulations, the preferred formulation for topical, local and intraurethral drug delivery is gel formulations. We have discovered that gel formulations according to the present invention facilitate the absorption of MOS to the urothelial surface. The urothelial surface, also referred to as urothe- lium and uroepithelium is an example of transitional epithelium and is the type of epithelium that lines much of the urinary tract including the renal pelvis, the ureters, the bladder, and parts of the urethra.

A gel can be defined as a semi-solid, jelly-like material that can have properties ranging from soft and weak to firm and tough. Moreover, gels are defined as a substantially dilute cross- linked system, which exhibit high viscosity. By weight, gels are composed mostly of a liquid component, yet they may behave like solids due to a three-dimensional cross-linked network within the liquid. It is the crosslinking within the fluid that give a gel its structure and contribute to the adhesive properties. Furthermore, we have also discovered that a gel formulation is optimal for administration to medical devices such as catheters and stents, particularly to catheters such as uretic catheters, i.e. catheters used for draining urine from the urinary bladder as in urinary catheterization. In urinary catheterization a latex, polyurethane, or silicone tube known as a urinary catheter is inserted into a patient's bladder via the urethra. Catheterization allows the patient's urine to drain freely from the bladder for collection. Catheterization maybe used to inject liquids used for treatment or diagnosis of bladder conditions. The catheter maybe a permanent one (indwelling catheter), or an intermittent catheter (also known as Robinson catheter) removed after each catheterization. The composition according to the present invention is in preferred embodiments of the invention applied to uretic catheters such as intermittent catheters and Foley catheters (indwelling urinary catheter), as well suprapubic catheterization when the urethra is damaged. Moreover, the composition may also be administered to Texas catheters (also referred to as urisheat or condom catheter) which are catheters made of silicone or latex and cover the pe- nis just like a condom but with an opening at the end to allow the connection to the urine bag.

The main requirements which must be considered in the development of a composition for use as a long term indwelling urinary catheter are that it should be effective against principal pathogens involved in CAUTIs over a long duration typically the whole period of catheter im- plantation (up to 12 weeks). These requirements are fulfilled by the composition according to the present invention.

To inhibit bacterial colonization and biofrlm formation within and outside of a uretic catheter, the composition comprising MOS may be used to cover the inner and/ or outer surface of the catheter. Moreover, MOS remain stable upon sterilization and storage, and the incorpora- tion of them into the catheter material does not adversely affect the mechanical performance of the catheter or balloon. Importantly, a MOS covered catheter prevents (i) bacterial attachment, (ii) colonization, and (iii) subsequent biofilm formation.

A composition according to the present invention is preferably administered to the above described medical devices by coating. The coat is applied by dip coating and spray coating tech- niques, i.e. dipping or spraying of the composition onto and/or into the medical device. The coated catheter is subsequently allowed to dry, either at room temperature or at a controlled temperature or both. The resulting coating forms a protective anti-infective layer over the catheter which hinders biofilm formation in the catheter as well as around the catheter. As a result, the risk of infection in the urinary tract is reduced. A further advantage with coating the catheter with a gel formulation comprising MOS is that the coating improves the patient's comfort since the friction between the catheter and the urethral tissue is decreased.

MOS are relatively inexpensive since they are available as by-products from fermentation, e.g. citric acid production. Moreover, they are used as food additives in animal husbandry and they therefore have a clean clinical history with low risk of toxicity for animals. More importantly, MOS are not associated with any environmental issues. Hence, MOS used as food additives for animals may also be used for the subject-matter of the present invention.

MOS can be prepared by known methods in the art such as alkaline extraction or detergent extraction (etyltrimethylammonium bromide (cetavlon) extraction method). These methods provide MOS molecules which have been released from their linkages to serine and threonine of the yeast cell wall and therefore only comprise carbohydrate components. These types of MOS typically have a molar mass ranging from 75 000 - 300 000 g/mol [Kath]. However, MOS having a molar mass of 1 000 - 1 000 000 g/mol and 25 000 - 500 000 g/mol may also be attained by various methods in the art. Moreover, other known methods in the art such as selective acid hydrolysis, selective alkaline degradation, selective acetolysis and/or enzymatic degradation are further options for preparing MOS [Ballou, sections ILB-ILE]. Additionally, mild enzymatic isolation and other related methods maybe used to prepare MOS having native structures [Ballou, sections ILB-ILE].

The following examples 1-5 relate to a gel formulation comprising cross-linked MOS. The gel formulation is comprised in a composition according to the present invention. As indicated in Figure 1, MOS shows a bacteriostatic effect. It should be noted that the examples 1-5 are presented to illustrate specific embodiments of the present invention, but is in not construed as limiting the scope of the invention. Moreover, the gels in Examples 1-5 may be modified to promote sterility and antibacterial activity by including additives such as pharmaceuticals and/or chemical agents such as disinfectants, humectants and plasticizers. An example of an anti-bacterial compound which can be included in the gels according to Examples 1-5 is chlorhexidine.

EXAMPLE 1 Mannan, o.2-2g, (from Saccharomyces cerevisiae) was dissolved in 2ml alkaline water

(pH>7). The mixture was heated to 40-90°C and epichlorohydrin (0.1-1 ml) added. Heating was continued for 90 min. After cooling, the reaction mixture was aerated to remove excess epichlorohydrin, subjected to dialysis to remove salts and lyophilized to give the cross-linked product as a white powder that swells but is insoluble in water. A gel is formulated by adding a liquid to the white powder. A suitable liquid for preparing the gel formulation is preferably selected from water, glycerol and/or propylene glycol.

The final compound retains 10-50 times its weight in water and at least five times their weight in glycerol producing a viscous gel.

EXAMPLE 2

500 mg mannan oligosaccharide from Saccharomyces cerevisiae (SIGMA, CAS 9036-88-8) is dissolved in 2 ml 2.5 M aqueous sodium hydroxide. The mixture is heated to 6o°C and epichlorohydrin (1 ml) is added. The mixture is kept at 6o°C for 90 min. After cooling, the reaction mixture is aerated to remove excess epichlorohydrin, subjected to dialysis to remove salts and lyophilized to give the cross-linked product as a white powder (490 mg) that swells but remains insoluble in water. A gel is formulated by adding a liquid to the white powder. A suitable liquids for preparing the gel formulation is preferably selected from water, glycerol and/ or propylene glycol.

The final compound retains 10 times its weight in water. The hardness of the gel can be modified by adding less epichlorohydrin in the above described process. Amounts as low as 1-10 μΙ/500 mg maybe added to make the gel softer.

EXAMPLE 3

Mannan, o.2-2g, was dissolved in a concentrated aqueous solution of o.5-2g of sodium dihy- drogenphosphate to give a thick syrup. The syrup was heated to a temperature 80-150 °C for 1-2 hours. After cooling the reaction mixture was subjected to dialysis to remove salts and lyophilized to give the cross-linked product as an off-white powder. A gel is formulated by adding a liquid to the off-white powder. A suitable liquid for preparing the gel formulation is preferably selected from water, glycerol and/or propylene glycol.

EXAMPLE 4

Mannan, o.2-2g, was mixed with citric acid (o.i-o.5g) and a trace of water and heated to 100- 150 °C for approximately 1 hour. The reaction mixture was dissolved in a small volume of water and subjected to dialysis to remove salts and lyophilized to give the cross-linked product as an off-white powder. A gel is formulated by adding a liquid to the off-white powder. A suitable liquid for preparing the gel formulation is preferably selected from water, glycerol and/or propylene glycol.

EXAMPLE 5

Mannan, o.2-2g, was mixed with 10-200% (w/w) pectin and 0.5-10 mL water to give a semi solid. The mixture was heated to 80-120 °C for 0.5-2 hours to allow for effective mixing and cross-linking of the polymers. The product was recovered by lyophilization as a powder. A gel is formulated by adding a liquid to the powder. A suitable liquid for preparing the gel formu- lation is preferably selected from water, glycerol and/ or propylene glycol.

EXAMPLES of non-cross-linked MOS

The present invention may also be realized with ointments, creams, lotions, foams and pastes for applying MOS topically, locally and intraurethrally. The ointments, creams, lotions, foams and pastes according to the present invention may comprise MOS in a wide range of concentrations and variety of bases (i.e. principle ingredients or elements which are not pharmaceutically active) wherein the choice of bases depend partly on the concentration of MOS, partly on the method of application and partly on the desired mode of action of the final product. Bases rarely consist of one component and are usually mixtures or emulsions of several sub- stances which may differ widely from one another in chemical and physical properties.

Ointments according to the present invention comprise anhydrous preparations, of a fairly firm consistence, usually (but not essentially) with a greasy, water insoluble base. MOS concentration is usually less than 25 %.

Creams according to the present invention comprise emulsion (water-in-oil or oil-in-water) and usually softer than ointments.

Pastes according to the present invention comprise relatively high concentrations (about

50 %) of powdered MOS or pharmaceutical excipient. The base may be oily or water-miscible.

Lotions according to the present invention are either liquid or semiliquid preparations that comprise MOS in an appropriate vehicle and excipients. Said lotions may be suspensions of solids in an aqueous medium, either as emulsion or solution. Apart from the cross-linked MOS gels described in Examples 1-5, the present invention may also be realized with MOS which is not cross-linked but instead contained in a pharmaceutical gel suitable for topical and local administration. Two classes of pharmaceutical gels exist, namely: · Hydrophobic gels wherein the bases of the hydrophobic gels (oleogels) usually consist of liquid paraffin with polyethylene or fatty oils gelled with colloidal silica or aluminum or zinc soaps.

• Hydrophilic gels wherein the bases of bases hydrophilic gels (hydrogels) usually consist of water, glycerol, or propylene glycol gelled with suitable gelling agents such as tragacanth, starch, cellulose (as well as derivatives of tragacanth, starch, cellulose), carboxyvinyl polymers, and magnesium-aluminum silicates.

REFERENCES

Hatt, J.K. et al. (2008) Role of bacterial biofilms in urinary tract infections. Current Topics in Microbiology and Immunology, 322, pp. 163-192

Aydin, A. et a. (2014) Recurrent urinary tract infections in women. International Urogynecol- ogy Journal and Pelvic Floor Dysfunction, Article in press.

Zhou, G. et al. (2001) Uroplakin la is the urothelial receptor for uropathogenic: Escherichia coli: Evidence from in vitro FimH binding. Journal of Cell Science, 114 (22), pp. 4095-4103 Pieters, R.J. (2007) Intervention with bacterial adhesion by multivalent carbohydrates. Medicinal Research Reviews, 27 (6), pp. 796-816

Ballou, C. (1976) Structure and Biosynthesis of the Mannan Component of the Yeast Cell Envelope. Advances in Microbial Physiology, 14 (C), pp. 93-158

Kath, F. et al (1999) Mild enzymatic isolation of mannan and glucan from yeast Saccharomy- ces cerevisiae. Angewandte Makromolekulare Chemie, 268, pp. 59-68

Claims

1. Composition characterized in that said composition is a non-oral formulation comprising mannan oligosaccharides (MOS) in a gel formulation, and wherein said MOS are of microbial origin.

2. Composition according to claim l or 2, characterized in that said MOS are high-molecular MOS, preferably high-molecular MOS having a molar mass of ι ooo - l ooo ooo g/mol, 25 000 - 500 000 g/mol, preferably 75 000 - 300 000 g/mol.

3. Composition according to any one of the previous claims, characterized in that said high-molecular MOS is derived from the cell wall of yeast, preferably derived from the cell wall of Saccharomycetales order, preferably derived from Saccharomyces genus, preferably derived from the cell wall of Saccharomyces cerevisiae, or preferably derived from Pichia guilliermondii.

4. Composition according to anyone of the previous claims, characterized in that said MOS have been prepared by selective acid hydrolysis, selective alkaline degradation, selective acetolysis, enzymatic degradation, mild enzymatic isolation, alkaline extraction or detergent extraction, preferably alkaline extraction or detergent extraction.

5. Composition according to anyone of the previous claims, characterized in that said MOS are MOS with preserved native structure.

6. Composition according to anyone of the previous claims, characterized in that said MOS are cross-linked, preferably said mannan oligosaccharide molecules are cross- linked to each other or cross-linked with pectin, more preferably said MOS have been cross-linked by using (i) epichlorohydrin, (ii) sodium dihydrogenphosphate, and/or (iii) citric acid, as cross-linker.

7. Composition according to anyone of the previous claims, characterized in that said formulation comprises cross-linked MOS and a liquid, wherein said liquid is preferably water, glycerol and/or propylene glycol.

8. Composition according to anyone of the previous claims, characterized in that said composition comprises additives, wherein said additives are selected from:

a) one or more viscosity adjusting additives, b) pharmaceuticals, and/or

c) chemical agents such as disinfectants, humectants and plasticizers.

9. Composition according to the previous claim, wherein said additive is chlorhexidine.

10. Composition according to any one of the previous claims, characterized in that said composition is administered topically, locally, intraurethrally and/or to a medical device, wherein said medical device is selected from the group catheter and stents, preferably catheter, most preferably uretic catheters.

11. Composition according to anyone of the previous claims, characterized in that said composition is administered to a medical device, preferably by coating a medical device, more preferably by coating the inside and/ or outside of the medical device, wherein said medical device is selected from the group catheter and stents, preferably catheter, most preferably uretic catheters.

12. Composition according to anyone of the previous claims, characterized in that said composition is administered via a medical device by dip-coating, spray-coating and/or matrix loading said device, wherein said medical device is selected from the group catheter and stents, preferably catheter, most preferably uretic catheters.

13. Composition according to any one of the previous claims, characterized in that said catheters are chosen from the group comprising intermittent catheters, Foley catheters (indwelling urinary catheter), suprapubic catheterization and Texas catheters (also referred to as urisheat or condom catheter), preferably intermittent catheters, Foley catheters (indwelling urinary catheter) and suprapubic catheterization, more preferably intermittent catheters and Foley catheters (indwelling urinary catheter).

14. Composition according to any one of claims 1-10, characterized in that said gel is administered topically, locally and/or intraurethrally.

15. Composition comprising a composition according to any of previous claims for use in the prophylaxis and/ or treatment of disease.

16. Composition comprising a composition according to claimi4 for use in the prophylaxis and/ or treatment of urinary tract infection (UTI), preferably urethritis, cystitis (lower UTI), urethritis and pyelonephritis (upper UTI), more preferably CAUTI.

17. Composition comprising a composition according to the previous claim for use in the prophylaxis and/or treatment of catheter associated urinary tract infection (CAUTI).

18. Composition comprising a composition according to any one of claims 1-13 and 15 for use in the prophylaxis and/or treatment of urinary tract infection (UTI), preferably urethritis, cystitis (lower UTI), urethritis and pyelonephritis (upper UTI), more preferably CAUTI.

19. Composition comprising a composition according to the previous claims for use in the prophylaxis and/or treatment of catheter associated urinary tract infection (CAUTI).

20. A medical device characterized in comprising a composition according to claims 1-9, wherein

a) said medical device is preferably a catheter or stent, more preferably a catheter, most preferably a uretic catheter, and wherein

b) said medical device has been dip-coated, spray-coated and/ or matrix loaded by said composition.

21. A method of coating a medical device characterized by the steps of:

a) Providing a medical device uretic and applying a composition according to claims 1-9 to at least a portion of the medical device to form a solid coat, wherein the composition is applied by dip-coating, spraying coating and/or or matrix loading, and

b) Optionally repeating step a. one or more times.

c) wherein said medical device is preferably a catheter or stent, more preferably a catheter, most preferably a uretic catheter.

22. A method of preparing a composition according to claims 1-9, characterized by the steps of:

a. Reacting MOS with a cross-linking agent, wherein said crosslinking agent is preferably chosen from

i. Epichlorohydrin in the presence of an alkaline solution, ii. Aqueous solution of sodium dihydrogenphosphate,

iii. Citric acid and water, or

iv. Pectin and water b. Heating the mixture, preferably 40-150 °C, for a period of time, preferably 0.5-2 hours,

c. After cooling, optionally removing excess epichlorohydrin,

d. Subjecting the mixture optionally to dialysis to remove salts,

e. Optionally lyophilizing to give a cross-linked product as a powder, and f. Adding liquid to the product, preferably up to 10 times the product's weight, wherein said liquid is preferably selected from water, glycerol and/or propylene glycol,

wherein said MOS are of microbial origin, preferably derived from the cell wall of yeast, more preferably derived from the cell wall of Saccharomycetales order, preferably derived from Saccharomyces genus, preferably derived from the cell wall of Saccharomyces cerevisiae, or preferably derived from Pichia guillier- mondii, and wherein

said cross-linked MOS gel formulation is used for therapeutic non-oral administration.