SE538140C2

SE538140C2 - Treatment of urinary tract infection

Info

Publication number: SE538140C2
Application number: SE1450829A
Authority: SE
Inventors: Constantin Raduti
Original assignee: Biomedicals Sweden Ab
Priority date: 2014-07-02
Filing date: 2014-07-02
Publication date: 2016-03-15
Also published as: CN107073018A; EP3164138A1; ES2880794T3; CN107073018B; US10525069B2; EP3164138A4; EP3164138B1; SE1450829A1; DK3164138T3; WO2016003358A1; US20170173058A1

Description

538 140 Administration of antibiotics to patients suffering from UTI is not without problems. Firstly, more and more UTI-causing bacterial strains show resistance to the antibiotics traditionally used when treatingUTl as mentioned above. Secondly, the antibiotics do not only affect the UTI-causing bacteria but also have side effects in terms of negatively affecting the normal body micro flora.

WO 2009/089442 discloses the usage of a human dietary supplement composition comprising a cranberry derivative or proanthocyanidin containing concentrate and D-mannose for preventing, controlling and ameliorating UTI caused by E. coli. WO 2011l073112 discloses mannose derivatives useful for the prevention and treatment of bacterial infections, in particular of urinary infections caused by E. coli.

Research in Microbiology, 201 1, 162(3): 249-252 investigates the effect of modification of pH on bacterial growth of E. coli ATCC 25922 and Klebsiella oxytoca ATCC 700324 as well as on activity of modern fluoroquinolones in urine in vitro. There was no difference in bacterial growth of E. coli and K. oxytoca observed at pH values between 5.0 and 8.0. However, acidification of urine led to a major impairment of the antimicrobial activity of the tested fluoroquinolones. lt was postulated that the reduction in pH impaired uptake of fluoroquinolones into the bacterial cells.

There is still need for an efficient treatment for UTI that is not marred by the problems and shortcomings of traditional antibiotics-based treatment regimens.

SUMMARY It is a general objective to provide an efficient treatment for UTI.

This and other objectives are met by embodiments as disclosed herein.

Briefly, an aspect of the embodiments relates to a composition comprising a pH increasing agent, a pH decreasing agent and mannose or an analogue thereof for use in treatment or prevention of urinary tract infection in a subject.

Another aspect of the embodiments relates to use of a composition comprising a pH increasing agent, a pH decreasing agent and mannose or an analogue thereof for the manufacture of a medicament for treatment or prevention of urinary tract infection in a subject. 538 140 A further aspect of the embodiments relates to a method for treatment or prevention of urinary tract infection in a subject. The method comprises alternately administering a pH increasing agent in combination with mannose or an analogue thereof and a pH decreasing agent in combination with the mannose or the analogue thereof to the subject.

The present embodiments achieve an efficient treatment or prevention of UTI in subjects without the shortcomings of traditional antibiotics-based treatment regimens. Thus, the present embodiments do not contribute towards multi-resistant bacteria and do not negatively affect the micro flora in the gastrointestinal tract.

DETAILED DESCRIPTION The present embodiments generally relate to treatment or prevention of urinary tract infection (UTI) in a subject, and in particular to treatment or prevention of UTI by using mannose as anti-adhesion agent in combination with administration of pH increasing and decreasing agents to a subject suffering from UTI.

Cranberry comprising the sugar mannose has traditionally been employed for treatment of UTI since mannose seems to prevent UTI-causing bacteria from attaching and binding to the walls of the urinary tract and bladder. Mannose binds to lectin molecules on the cell walls of UTI-causing bacteria, and in particular Escheria coli, thereby preventing the lectin molecules from attaching the E. coli bacteria to carbohydrate molecules in the walls of the urinary tract system. This anti-adhesion effect of mannose causes the E. coli bacteria to be flushed away from the urinary tract system.

The present invention is based on the unexpected discovery that the effect of mannose and analogues thereof with regard to UTI can be significantly improved by exposing the UTI-causing bacteria to a stress to inhibit cell growth. This inhibition of cell growth is, according to the embodiments, achieved by exposing the UTI-causing bacteria to changes in pH in the urinary tract system in connection with mannose administration. ln particular, the embodiments provide alternate increases and decreases in pH in the urinary tract system in connection with mannose administration to achieve treatment and/or prevention of UTI in a subject, preferably a mammalian subject, and more preferably a human subject.

Urinary tract system as used herein encompasses the urinary bladder (vesica urinaria) and the urinary tract (urethra). The urinary tract system is part of the urinary or renal system additionally comprising the kidneys (ren) and the ureters. UTI may occur in the urinary tract, the urinary bladder or indeed also the 538 140 ureters and kidneys. Thus, UTI-bacteria may be present not only in the urinary tract system but indeed in all or at least some of the tissues or organs of the renal system.

Hence, an aspect of the embodiments relates to a composition comprising a pH increasing agent, a pH decreasing agent and mannose or an analogue thereof for use in treatment or prevention of UTl in a subject.

The components of the composition can be provided as separate ingredients, i.e. the pH increasing agent, the pH decreasing agent and the mannose or the analogue thereof. Alternatively, the mannose or the analogue thereof can be mixed with the pH increasing agent and/or the pH decreasing agent, preferabiy with both the pH increasing agent and the pH decreasing agent. in such a case, the composition comprises first dosage units comprising the pH increasing agent and the mannose or the analogue thereof, preferabiy in the form of a mixture of the pH increasing agent and the mannose or the analogue thereof. The composition also comprises second dosage units comprising the pH decreasing agent and the mannose or the analogue thereof, preferabiy in the form of a mixture of the pH decreasing agent and the mannose or the analogue thereof. ln the former case, i.e. separate ingredients, the pH increasing agent and the pH decreasing agent can be administered separately from administration of the mannose or the analogue thereof. Alternatively, the pH increasing agent could be administered substantially at the same time as the mannose or the analogue thereof and/or, preferabiy and, the pH decreasing agent could be administered substantially at the same time as the mannose or the analogue thereof. ln an embodiment, an administration pattern or protocol of the composition comprises alternately administering the pH increasing agent and the pH decreasing agent to the subject and administering the mannose or the analogue thereof to the subject.

The alternate administration of the pH increasing agent and the pH decreasing agent causes a change or switch in pH in the urinary tract system, which in turn stresses any bacteria present therein. The pH- induced stress will inhibit or at least reduce the growth rate of the bacteria, thereby potentiating the anti- adhesion effect of the mannose or the analogue thereof. 538 140 Changing pH by the composition of the embodiments in the urinary tract system encompasses changing pH in the urinary tract of the subject, changing pH in the urinary bladder of the subject or changing pH in the urinary tract and bladder of the subject.

The administration pattern preferably specifies that the pH increasing agent is administered to the subject at every second administration occasion and that the pH decreasing agent is administered to the subject at the other administration occasions. For instance, the pH increasing agent could be administered at the 1st, 3fd, 5"), etc. administration occasion (odd numbered administration occasions) and the pH decreasing agent is administered at the Z?d, 4ih, 6"), etc. administration occasion (even numbered administration occasions. Also the opposite case is possible with administration of the pH increasing agent at the even numbered administration occasions and administration of the pH decreasing agent at the odd numbered administration occasions.

Although it is generally preferred to switch between the pH increasing agent and the pH decreasing agent at every administration occasion, the embodiments are not limited thereto. For instance, the pH increasing agent (or the pH decreasing agent) could be administered to the subject at the first N administration occasions, followed by administering the pH decreasing agent (orthe pH increasing agent) at the following M administration occasions, followed by N administration occasions of the pH increasing agent (or the pH decreasing agent), and so on. ln an embodiment, N, M are positive number equal to or larger than one, preferably N, M e [1, 3], more preferably N, M =1 or 2, such as N=M=1. ln an embodiment, M is preferably equal to N.

The values of the parameters N, M typically depend on the frequency of the administration occasions. ln an embodiment, the values of the parameters N, M are preferably smaller for a low frequency of administration occasion, i.e. long time between two administration occasions, as compared to a high frequency of administration, i.e. shorter time between two administration occasions. ln an embodiment where the administration is taking place over multiple days, the administration pattern may be repeated each day. Thus, the administration pattern at day 1 could be administering the pH increasing agent (or the pH decreasing agent) to the subject at the first N administration occasions, followed by administering the pH decreasing agent (or the pH increasing agent) at the following M administration occasions, followed by N administration occasions of the pH increasing agent (or the pH decreasing agent), and optionally further on. The administration pattern at day 2 could then be the same as the administration pattern at day, i.e. starting with N administration occasions with the pH increasing 538 140 agent (or the pH decreasing agent) regardless of which agent that was administered at the last administration occasion at the previous day. ln another embodiment, the administration pattern extends over multiple days so that if the previous day ended with the last administration of the pH decreasing agent (or the pH increasing agent), the next day starts with administration of the pH increasing agent (or the pH decreasing agent).

The pH increasing agent is preferably a base and the pH decreasing agent is preferably an acid. The pH increasing agent thereby preferably has a pH value higher than 7 in an aqueous solution and the pH decreasing agent preferably has a pH value lowerthan 7 in an aqueous solution.

The pH value in the urinary tract system is preferably changing between a more basic pH value and a more acidic pH value with regard to the baseline or normal pH level in the urinary tract system when administrating the pH increasing agent and the pH decreasing agent and if not countered by any buffering action. This change between more basic and acidic pH values induces the growth-inhibiting effect to any UTI-causing bacteria that may be present in the urinary tract system.

Administration of the mannose or the analogue thereof can be made independent of the administrations of the pH increasing agent and the pH decreasing agent. For instance, the mannose or the analogue thereof could be administered in between the administration occasions for the pH increasing and decreasing agents.

However, it is generally preferred to co-administer the mannose or the analogue thereof and the pH increasing agent or the pH decreasing agent or administer the mannose or the analogue thereof at least substantlally at the same time as administering the pH increasing agent or the pH decreasing agent. ln such a case, the mannose or the analogue thereof and the pH increasing agent could be administered as two separate dosage units taken at substantlally the same time and the mannose or the analogue thereof and the pH decreasing agent could be administered as two separate dosage units taken at substantlally the same time. ln an embodiment, the composition comprises a pH increasing part composition comprising the pH increasing agent and the mannose or the analogue thereof and a pH decreasing part composition comprising the pH decreasing agent and the mannose or the analogue thereof. ln such a case, the 538 140 administration pattern preferably comprises alternately administering the pH increasing part composition and the pH decreasing part composition to the subject.

The alternate administration of the pH increasing part composition and the pH decreasing part composition to the subject preferably induces an alternation of the pH value in the urinary tract system of the subject.

The pH increasing part composition comprises the pH increasing agent and the mannose orthe anaiogue thereof as separate dosage units that are, however, co-administered or at least administered substantialiy at the same time to the subject. Correspondingly, the pH decreasing part composition comprises the pH decreasing agent and the mannose or the anaiogue thereof as separate dosage units that are co- administered or at least administered substantialiy at the same time to the subject. ln another embodiment, the composition comprises first dosage units comprising the pH increasing part composition, such as in the form of a mixture of the pH increasing agent and the mannose orthe anaiogue thereof. The composition also comprises second dosage units comprising the pH decreasing part composition, such as in the form of a mixture of the pH decreasing agent and the mannose or the anaiogue thereof. This means that administration of a first/second dosage unit implies that both mannose or the anaiogue and the pH increasing/decreasing agent will be co-administered, preferably as a mixture, to the subject.

Each first dosage unit preferably comprises 0.1 to 2 g of the pH increasing agent and 0.5 to 4 g of the mannose or the anaiogue thereof. Correspondingly, each second dosage unit preferably comprises 0.1 to 2 g of the pH decreasing agent and 0.5 to 4 g of the mannose or the anaiogue thereof. ln an embodiment, each first dosage unit preferably comprises 0.25 to 1 g of the pH increasing agent and 1.5 to 2.5 g of the mannose or the anaiogue thereof. Correspondingly, each second dosage unit preferably comprises 0.25 to 1 g of the pH decreasing agent and 1.5 to 2.5 g of the mannose or the anaiogue thereof. ln a particular example, each first dosage unit preferably comprises about 0.5 g of the pH increasing agent and about 2 g of the mannose or the anaiogue thereof. Correspondingly, each second dosage unit preferably comprises about 0.5 g of the pH decreasing agent and about 2 g of the mannose or the anaiogue thereof. 538 140 The first and second dosage units may be provided in various administration formuias or forms suitable for oral administration, intravenous administration or subcutaneous administration, preferabiy oral administration. ln particular for oral administration, the first and second dosage units may be powder mixtures to be dissolved in water or another drinkabie liquid, tablets, pills, Iozenges, capsules, drops, liquid syrups, oral sprays, gels, etc.

The first and second dosage units may comprise the active ingredients alone or the active ingredients and at least one excipient. For instance, if the first and second dosage units are provided as powder mixtures silica can be added as an excipient to prevent the powder from aggregating or compacting upon exposure to moisture.

Non-limiting examples of excipients that can be used according to the embodiments include antiadherents, binders, coatings, disintegrants, filers, flavours, colors, lubricants, glidants, sorbents, preservatives and sweeteners.

An example of dosage units that can be used for oral administration is to provide the first dosage units as sachets comprising the pH increasing part composition as a powder mixture of the pH increasing agent and the mannose or the analogue thereof and the second dosage units as sachets comprising the pH decreasing part composition as a powder mixture of the pH decreasing agent and the mannose or the analogue thereof.

The sachets are then opened prior to administration and the powder mixture present therein is preferabiy added to water or another drinkabie liquid to form a solution or a suspension.

Another example of dosage units that can be used for oral administration is to provide the first dosage units as tablets or lozenges comprising the pH increasing part composition as a mixture of the pH increasing agent and the mannose or the analogue thereof and the second dosage units as tablets or lozenges comprising the pH decreasing part composition as a mixture of the pH decreasing agent and the mannose or the analogue thereof. 538 140 ln an embodiment, the sachets, tablets or Iozenges may have a respective number specifying an administration order according to the administration pattern. For instance, the sachets, tablets or Iozenges may be numbered 1, 2, 3, and so forth to inform the subject that the sachet, tablet or Iozenge number 1 should be taken at the first administration occasion, the sachet, tablet or Iozenge number 2 should be taken at the second administration occasion, and so on. in such a case, it is not necessary for the subject to mind which sachets, tablets or Iozenges that comprise the pH increasing part composition and which sachets, tablets or Iozenges that comprise the pH decreasing part composition. Hence, the subject mereiy has to make sure that the sachets, tablets or lozenges are taken according to the administration order specified by the respective numbers.

Numbering dosage units can of course be applied to other dosage forms than sachets with powder mixtures, tablets and Iozenges.

Alternatively, or in addition, different colors or patterns can be used to simplify discriminating the first dosage units from the second dosage units. For instance, the first dosage units may have a first color or pattern and the second dosage units may have a second color or pattern that is different from the first color or pattern.

This coloring can be achieved by adding colors to the pH increasing and decreasing part compositions.

Alternatively, or in addition, the package units, such as sachets, blister packets, etc. containing the pH and increasing and decreasing part compositions may be colored or patterned differently to simplify telling the first and second dosage units apart. l.v. and s.c. formulations could be in the form of injection solutions, such as water, saline or buffered aqueous injection solutions in vvhich the pH increasing part compositions and the pH decreasing part compositions are dissolved. ln an embodiment, the administration pattern comprises administering a part composition to the subject every 2?d to 4fh hour 3 to 7 times a day. ln a preferred embodiment, every second administered part composition is a pH increasing part composition and the other administered part compositions are a respective pH decreasing part composition. 538 140 ln a particular embodiment, the administration pattern comprises administering a part composition to the subject every Znd to 411 hour 3 to 7 times a day during 2 to 6 days. ln a preferred embodiment, every second administered part composition is a pH increasing part composition and the other administered part compositions are a respective pH decreasing part composition.

For instance, the administration pattern comprises administering a part composition to the subject every third hour tive times a day during four or ?ve days.

For continuous or long-term administration, such as in the case of preventing UTl, fewer number of administration occasions may be used as compared to transient administration, such as in the case of treating a subject suffering from UTI. For instance, if about five administrations are used per day in the administration pattern for treatment application then about three administrations could be used per day in the administration pattern for preventive application.

The pH increasing agent is preferably administered to the subject at a dosage of 0.1 to 20 g per day, the pH decreasing agent is preferably administered to the subject at a dosage of 0.1 to 20 g per day and the mannose or the analogue thereof is preferably administered at a dosage of 0.1 to 50 g per day. ln a particular embodiment, the pH increasing agent is preferably administered to the subject at a dosage of 1 to 1.5 g per day, the pH decreasing agent is preferably administered to the subject at a dosage of 1 to 1.5 g per day and the mannose or the analogue thereof is preferably administered at a dosage of 5 to g, preferably about 10 g per day.

The pH increasing agent is preferably selected from a group consisting of a carbonate, a lactate, a hydroxide, an amine, an amide, an ammonium salt, ammonium, alanine and pyridine.

The carbonate is preferably selected from a group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, magnesium carbonate and calcium carbonate. ln a preferred embodiment, the carbonate is calcium carbonate.

The lactate is preferably selected from a group consisting of sodium lactate, potassium lactate and calcium lactate. ln a preferred embodiment, the lactate is potassium lactate. 538 140 The hydroxide is preferably selected from a group consisting of sodium hydroxide, potassium hydroxide, barium hydroxide, ammonium hydroxide, calcium hydroxide, Iithium hydroxide, magnesium hydroxide and beryllium hydroxide.

The amine is preferably methylamine, the amide is preferably acetazolamide and the ammonium salt is preferably ammonium chloride. ln an embodiment, the pH increasing agent is calcium carbonate or potassium Iactate.

The pH decreasing agent is preferably selected from a group consisting of citric acid, a straight-chain, saturated carboxyiic acid, lactic acid, ascorbic acid, tartaric acid, mandelic acid, acetylsalicyiic acid, benzoic acid, boric acid, ethylenediaminetetaacetic acid (EDTA), carbonic acid, maleic acid, hydrochloride, hypochlorous acid, a hypochlorite, such as sodium hypochlorite, potassium chlorite or calcium hypochlorite.

The straight-chain, saturated carboxyiic acid is preferably selected from a group consisting of fumaric acid, acetic acid, propionic acid, butyric acid and valeric acid. ln an embodiment, the pH decreasing agent is lactic acid or citric acid.

The mannose (CßHnOß) can be in in a diastereomer form, i.e. D-mannose or L-mannose, or be in the form of a mixture of D-mannose and L-mannose, such as a racemate of D-mannose and L-mannose.

Mannose commonly exists as two different sized rings, the pyranose (six-membered) form and the furanose (five-membered) form. Each ring closure can have either an alpha or beta configuration at the anomeric position. The chemical rapidly undergoes isomerization among these four forms.

The D-mannose can therefore be in the form of or-D-manopyranose, ß-D-mannopyranose, or-D- mannofuranose, ß-D-mannofuranose, a mixture of the pyranoses, a mixture of the furanoses, a mixture of at least one pyranose and at least one furanose, or a mixture of the pyranoses and the furanoses.

Generally, D-mannose is in the form of a mixture of about 67 % ot-D-manopyranose, 33 % ß-D- mannopyranose, < 1 % oi-D-mannofuranose and < 1 % ß-D-mannofuranose. 11 538 140 The L-mannose can be in the form of ot-L-manopyranose, ß-L-mannopyranose, ot-L-mannofuranose, ß- L-mannofuranose, a mixture of the pyranoses, a mixture of the furanoses, a mixture of at least one pyranose and at least one furanose, or a mixture of the pyranoses and the furanoses.

Mannose is sometimes also referred to as semonose or carubinose.

The mannose is preferabiy in the form of D-mannose.

A preferred analogue of mannose is mannitol (CGH14O6). Mannitoi is classified as a sugar alcohol that is derived from mannose by reduction. Other analogues of mannose that can be used according to the embodiments are disclosed in WO 2011/073112 and defined by formula (I) H O OH Ho /O Ho R O_(CH2)n wherein n is O, 1 or 2; Rt is phenyl connected to the phenyl ring of formula (I) in meta- or para-position and substituted by one, two or three substituents selected from the group consisting of lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, cyclohexyl, cyclopropyl, aryl, heteroaryl, heterocyclyl; para-hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, cycloalkyloxy, hydroxysulfonyloxy; mercapto, alkylmercapto, hydroxysulfinyl, alkylsulfinyl, halo-lower alkylsulfinyl, hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aminosulfonyl wherein amino is unsubstituted or substituted by one or two substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted phenyl-lower alkyl and optionally substituted heteroaryl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; amino optionally substituted by one or two 12 538 140 substitutents selected from lower alkyl, cycloalkyl-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl and di-lower alkylamino-lower alkyl, or by one substituent cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, alkylcarbonyl, optionally substituted phenylcarbonyl, optionally substituted pyridylcarbonyl, alkoxycarbonyl or aminocarbonyl, orwherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resultlng substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resultlng acyl group corresponds to one of the 20 naturally occurring standard amino acids; lower alkylcarbonyl, halo-lower alkylcarbonyl, para-carboxy, lower alkoxycarbonyl, lower alkoxy-lower alkoxycarbonyl; aminocarbonyl wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two su bstitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted phenyl-lower alkyl and optionally substituted heteroaryl-lower alkyl, or wherein the two substituents on nitrogen form together with the nitrogen heterocyclyl; cyano, halogen, and nitro; and wherein two substituents in ortho-posltion to each other can form a 5- or 6-membered heterocycllc ring containing one or two oxygen atoms and/or one or two nitrogen atoms, wherein the nitrogen atoms are optionally substituted by lower alkyl, lower alkoxy-lower alkyl or lower alkylcarbonyl; or Rl is alyl other than optionally substituted phenyl, heteroaryl, heterocyclyl with 5 or more atoms, optionally substituted phenylamino, or optionally substituted phenyl- thioureido; and R2 and Rß are, independent of each other, hydrogen, lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, optionally substituted alkenyl, optionally substituted alkinyl, cycloalkyl, hydroxy, lower alkoxy, halo-lower alkoxy, lower alkoxy-lower alkoxy, phenoxy, hydroxysulfonyloxy; mercapto, alkylmercapto, hydroxysulfinyl, alkyl-sulfinyl, halo-lower alkylsulfinyl, hydroxysulfonyl, alkylsulfonyl, arylsulfonyl, heteroaryl- sulfonyl, aminosulfonyl, amino optionally substituted by one or two substitutents selected from lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl; lower alkylcarbonylamino, alkoxycarbonylamino, benzoylamino, pyridinylcarbonylamino, carboxymethylamino or lower alkoxycarbonylmethylamino substituted at the methyl group such that the resultlng substituent corresponds to one of the 20 naturally occurring standard amino acids, aminomethylcarbonylamino substituted at the methyl group such that the resultlng acyl group corresponds to one of the 20 naturally occurring standard amino acids; carboxy, lower alkylcarbonyl, benzoyl, pyridlnecarbonyl, pyrimidinecarbonyl, lower alkoxycarbonyl, aminocarbonyl, wherein amino is unsubstituted or substituted by one hydroxy or amino group or one or two substitutents selected from lower alkyl, hydroxy-lower alkyl or lower alkoxy-lower alkyl; tetrazolyl, cyano, halogen, or nitro; or wherein two substituents in ortho- position to each other form a 5- or 6-membered heterocycllc ring containing one or two oxygen atoms 13 538 140 and/or one or two nitrogen atoms, wherein the nitrogen atoms are optionally substituted by lower alkyl, lower alkoxy-Iower alkyl or lower alkylcarbonyl. ln a particular embodiment, the composition comprises calcium carbonate, lactic acid and the mannose or the analogue thereof, preferably D-mannose. ln another particular embodiment, the composition comprises potassium lactate, lactic acid and the mannose or the analogue thereof, preferably D-mannose. ln a further particular embodiment, the composition comprises calcium carbonate, citric acid and mannose or the analogue thereof, preferably D-mannose. ln yet another particular embodiment, the composition comprises potassium lactate, citric acid and mannose or the analogue thereof, preferably D-mannose. ln an embodiment, 0.5 g calcium carbonate and 2 g D-mannose are mixed to form a respective first dosage unit. 0.5 g lactic acid and 2 g D-mannose are mixed to form a respective second dosage unit. ln another embodiment, 0.5 g calcium carbonate and 2g D-mannose are mixed to form a respective first dosage unit. 0.5 g citric acid and 2 g D-mannose are mixed to form a respective second dosage unit. ln a further embodiment, 0.5 g potassium lactate and 2 g D-mannose are mixed to form a respective first dosage unit. 0.5 g lactic acid and 2 g D-mannose are mixed to form a respective second dosage unit. ln yet another embodiment, 0.5 g potassium lactate and 2 g D-mannose are mixed to form a respective first dosage unit. 0.5 g citric acid and 2 g D-mannose are mixed to form a respective second dosage unit. ln an embodiment, the first and second dosage units according to any of the above mentioned embodiments is alternative administered to the subject during four days, every three hours for a total of five times per day. ln another embodiment, the first and second dosage units according to any of the above mentioned embodiments is alternative administered to the subject every five to six hours for a total of three times a day during multiple consecutive days, preferably as part of prevention of UTI in a subject. 14 538 140 The present embodiments can therefore be used to treat a subject suffering from UTl or at least reduce the symptoms of UTI or inhibit UTI in the subject. The present embodiments can also be used to prevent UTI in a subject having a risk of suffering from UTI, such as a subject that will have a urinary catheter and/or a subject suffering from a urinary tract disorder, such as men having enlarged prostate or women with prolapse.

The subject is preferabiy a human subject. However, the composition of the embodiments can also be used within veterinary care to treat or prevent UTI in animals, and in particular mammals. Non-limiting examples of such mammals include horse, cow, pig, cat, dog, rabbit, guinea pig, rat and mice.

Another aspect of the embodiments relates to use of a composition comprising a pH increasing agent, a pH decreasing agent and mannose or an analogue thereof for the manufacture of a medicament for treatment or prevention of UTI in a subject.

A further aspect of the embodiments relates to a method for treatment or prevention of UTI in a subject.

The method comprises alternately administering a pH increasing agent in combination with mannose or an analogue thereof and a pH decreasing agent in combination with the mannose or the analogue thereof to the subject. ln a particularembodiment, the method comprises alternately administering a first dosage unit comprising the pH increasing agent and the mannose or the analogue thereof and a second dosage unit comprising the pH decreasing agent and the mannose or the analogue thereof to the subject.

EXPERIMENTS Example 1 Four women (between the ages of 60 and 70) with recurrent UTI (UTI 1-2 times per month) were treated according to an embodiment of the invention. Prior to the treatment, the urine of the four women was tested using bacteria test strips (NlTRlSTlC®, RAERAD Products, Sweden) following the instructions of the manufacturer. All women showed bacteria in the urine (strips indicating red instead of blue). The women were given a composition with 1 g calcium carbonate (pH-KALK, pH Balans AB, Sweden) together with 2 g D-mannose (DM, BECKMAN-KENKO GMBH, Germany) or 1 g citric acid (SANTA MARIA AB, Sweden) together with 2 g D-mannose (DM, BECKMAN-KENKO GMBH, Germany) and these compositions were taken in an alternating administration pattern 5 times per day (see Table 1 for details). The treatment lasted for 4 days and after completed treatment all four women displayed undetectable levels of bacteria in their urine using the same type of bacteria test strips as before the 538 140 initiation of the treatment (strips showing blue color).

Table 1 -Administration protocol Time of day Day 1 Day 2 Day 3 Day 4 7:00 Used test strip to test urine prior test 7:30 1 g CaCOg + 2 g DM 1 g citric acid + 2 1 g CaCOß + 2 g 1 g citric acid + 2 g in 1/2 glass of water g DM in 1/2 glass DM in 1/2 glass of DM in 1/2 glass of of water water water :30 1 g citric acid + 2 g 1 g CaCOa + 2 g 1 g citric acid + 2 g 1 g CaCOs + 2 g DM in 1/2 glass of DM in % glass of DM in 1/2 glass of DM in 1/2 glass of water water water water 13:30 1 g CaCOß + 2 g DM 1 g citric acid + 2 1 g CaCOg + 2 g 1 g citric acid + 2 g in 1/2 glass of water g DM in 1/2 glass DM in % glass of DM in 1/2 glass of of water water water 16:30 1 g citric acid + 2 g 1 g CaCOs + 2 g 1 g citric acid + 2 g 1 g CaCOs + 2 g DM in 1/2 glass of DM in 1A glass of DM in 1/2 glass of DM in 1/2 glass of water water water water 19:30 1 g vCaCOg + 2g DM 1 g citric acid + 2 1 g CaCOß + 2 g 1 g citric acid + 2 g in i/z glass of water g DM in 1/2 glass DM in 1/2 glass of DM in ß glass of of water water water :00 Used test strip to test urine Example 2 One wheelchair-bound woman (age 62), with recurrent UTl (UTl every week) was treated according to an embodiment of the invention. Prior to the treatment, the urine of the woman was tested using bacteria test strips (NlTRlSTlC®, RAERAD Products, Sweden) following the instructions of the manufacturer. The woman showed bacteria in the urine (strips indicating red instead of blue). The woman was given a composition with 1 g calcium carbonate (pH-KALK, pH Balans AB, Sweden) togetherwith 2 g D-mannose (DM, BECKMAN-KENKO GMBH, Germany) or 1 g citric acid (SANTA MARIA AB, Sweden) together with 2 g D-mannose (DM, BECKMAN-KENKO GMBH, Germany). The compositions were taken in an alternating administration pattern 5 times per day (see Table 2 for details). The initial treatment lasted for 16 538 140 4 days. At the completion of the initial treatment the woman displayed undetectable levels of bacteria in the urine using the same type of bacteria test strips as before the initiation of the treatment (strips showing blue color). After the initial treatment, the woman continued with the treatment to prevent UTI according to Table 2 alternating pH 3 times a day for 5 months. The woman did not get any UTl during the 5 months.

Table 2 - Administration protocol After discontinuing the treatment, the woman relapsed with UTl within 3 weeks.

Time of day Day 1 Day 2 Day 3 Day 4 Day 5 and five months daily 7:00 Used test strip to test urine prior test 7:30 1 g CaCOg + 2 g 1 g citric acid 1 g CaCOa + 2 1 g citric acid 1 g CaCOs + 2 DMint/zglassof +2gDMin1/2 gDll/linl/z +2gDl\/lin% gDlVlin% water glass of water glass of water glass of water glass of water :30 1 g citric acid + 2 1 g CaCOa + 2 1 g citric acid 1 g CaCOß + 2 gDh/lini/zglass gDlVlin1/2 +2gDl\/lin% gDMinVz of water glass of water glass of water glass of water 13:30 1 g CaCOg + 2 g 1 g citric acid 1 g CaCOa + 2 1 g citric acid 1 g citric acid Dll/lint/zglassof +2gDMin“/2 gDMinl/z +2gDl\/lin% +2gDl\/lin'/2 water glass of water glass of water glass of water glass of water 16:30 1 g citric acid + 2 1 g CaCOa + 2 1 g citric acid 1 g CaCOe, + 2 gDlvlinl/zglass gDMinl/z +2gDl\/lin'/2 gDl\/lin% of water glass of water glass of water glass of water 19:30 1 g CaCOg + 2 g 1 g citric acid 1 g CaCOß + 2 1 g citric acid 1 g CaCOg + 2 DMint/zglassof +2gDMin% gDMinl/z +2gDl\/lin% gDl\/lin% water glass of water glass of water glass of water glass of water :00 i Used test strip to test urine The embodiments described above are to be understood as a few illustrative examples of the present invention. lt will be understood by those skilled in the art that various modifications, combinations and changes may be made to the embodiments without departing from the scope of the present invention. ln particular, different part solutions in the different embodiments can be combined in other configurations, where technically possible. The scope of the present invention is, however, defined by the appended claims. 17

Claims

538 1 PATE NTKRAV

1. En sammansattning innefattande ett pH-hojande amne, ett pH-sankande amne och mannos eller en analog darav for anvandning i behandling eller forbyggande av urinvagsinfektion i en patient, van ett administreringsmonster has sammansattningen innefattar vaxelvis administrering av det pH-hojande amnet och det pH-sankande amnet till patient och administrering av mannos eller analogen darav till patienten.

2. Sammansattningen for anvandning enligt patentkrav 1, van sammansattningen innefattar: en pH-hojande delsammansattning innefattande det pH-hojande amnet och mannos eller 10 analogen darav; samt en pH-sankande delsammansattning innefattande det pH-sankande amnet och mannos eller analogen darav, van i administreringsmonstret innefattar vaxelvis administrering av den pH-hojande delsammansattningen och den pH-sankande delsammansattningen till patienten.

3. Sammansattningen for anvandning enligt patentkrav 2, van i administreringsmonstret innefattar vaxelvis administrering av den pH-hojande delsammansattningen och den pH-sankande delsammansattningen till patienten for att inducera en forandring av pH-vardet i patientens urinvagssystem.

4. Sammansattningen for anvandning enligt patentkrav 2 eller 3, van i sammansattningen innefattar: forsta dosenheter innefattande den pH-hojande delsammansattningen; samt andra dosenheter innefattande den pH-sankande delsammansattningen, vani administreringsmonstret innefattar vaxelvis administrering av en forsta dosenhet och en andra dosenhet till patienten.

5. Sammansattningen for anvandning enligt patentkrav 4, vani vane forsta dosenhet innefattar 0,1 till 2 g pH-hojande amne och 0,5 till 4 g mannos eller analogen darav; samt vane andra dosenhet innefattar 0,1 till 2 g pH-sankande amne och 0,5 till 4 g mannos eller analogen darav.

6. Sammansattningen for anvandning enligt patentkrav 5, vani varje forsta dosenhet innefattar 0,25 till 1 g pH-hojande arnne och 1,5 till 2,5 g mannos eller analogen darav; samt 538 1 varje andra dosenhet innefattar 0,25 till 1 g pH-sankande arnne och 1,5 till 2,5 g mannos eller analogen darav.

7. Sammansattningen for anvandning enligt patentkrav 6, vani varje forsta dosenhet innefattar 0,5 g pH-hojande amne och 2 g mannos eller analogen darav; samt varje andra dosenhet innefattar 0,5 g pH-sankande amne och 2 g mannos eller analogen darav.

8. Sammansattningen for anvandning enligt nagot av patentkrav 4 till 7, vani de forsta dosenheterna an portionspasar innefattande den pH-hojande delsammansattningen som en pulverblandning av det pH-hojande amnet och mannos eller analogen darav; de andra dosenheterna är portionspasar innefattande den pH-sankande delsammansattningen som en pulverblandning av det pH-sankande amnet och mannos eller analogen darav; varje portionspase har ett respektive nummer som specificerar en administreringsordning enligt administreringsmonstret.

9. Sammansattningen for anvandning enligt nagot av patentkrav 4 till 7, vani de forsta dosenheterna är tabletter eller pastiller innefattande den pH-hojande delsammansattningen som en blandning av det pH-hojande amnet och mannos eller analogen darav; de andra dosenhetema är tabletter eller pastiller innefattande den pH-sankande delsammansattningen som en blandning av det pH-sankande amnet och mannos eller analogen darav; varje tablett eller pastill har ett respektive nummer som specificerar en administreringsordning enligt administreringsmonstret.

10. Sammansattningen for anvandning enligt nagot av patentkrav 4 till 9, vani de forsta dosenheterna har en forsta farg eller monster; samt de andra dosenheterna har en andra fang eller monster som skiljer sig fran den forsta fargen eller monstret.

11. Sammansattningen for anvandning enligt nagot av patentkrav 2 till 10, vani administreringsmonstret innefattar administrering av en delsammansattning till patienten var andra till fjarde timme 3-7 ganger per dag, van i var andra administrerade delsammansattning an en pH-hojande delsammansattning och de andra administrerade delsammansattningarna är en respektive pH-sankande delsammansattning. 538 1

12. Sammansattningen for anvandning enligt patentkrav 11, van i administreringsmonstret innefattar administrering av en delsammansattning till patienten var andra till fjarde timme 3-7 ganger per dag under 2-6 dagar, van i var andra administrerade delsammansattning är en pH-hojande delsammansattning och de andra administrerade delsammansattningarna är en respektive pH-sankande delsammansattning.

13. Sammansattningen for anvandning enligt patentkrav 12, van i administreringsmonstret innefattar administrering av en delsammansattning till patienten var tredje timme 5 ganger per dag under 4 dagar, vari var andra administrerade delsammansattning ar en pH-hojande delsammansattning och de andra 10 administrerade delsammansattningarna är en respektive pH-sankande delsammansattning.

14. Sammansattningen for anvandning enligt nagot av patentkrav 1 till 13, van i det pH-hojande amnet administreras till patienten vid en dos pa 0,1 till 20 g per dag, det pH-sankande amnet administreras till patienten vid en dos pa 0,1 till 20 g per dag och mannos eller analogen darav administreras till patienten vid en dos pa 0,1 till 50 g per dag.

15. Sammansattningen for anvandning enligt patentkrav 14, van i det pH-hojande amnet administreras till patienten vid en dos pa 1 till 1,5 g per dag, det pH-sankande amnet administreras till patienten vid en dos pa 1 till 1,5 g per dag och mannos eller analogen darav administreras till patienten vid en dos pa 0,1 till 10 g per dag.

16. Sammansattningen for anvandning enligt nagot av patentkrav 1 till 15, van i det pH-hojande amnet är valt fran en grupp som bestar av ett karbonat, ett laktat, en hydroxid, en amin, en amid, ett ammoniumsalt, ammonium, alanin och pyridin.

17. Sammansattningen for anvandning enligt patentkrav 16, van i karbonatet an valt frail en grupp som bestar av natriumbikarbonat, natriumkarbonat, kaliumbikarbonat, kaliumkarbonat, magnesiumkarbonat och kalciumkarbonat.

18. Sammansattningen for anvandning enligt patentkrav 16, van i laktatet är valt fran en grupp som bestar av natriumlaktat, kaliumlaktat och kalciumlaktat. 538 1

19. Sammansattningen for anvandning enligt patentkrav 16, van i hydroxiden är vald fran en grupp som bestar av natriumhydroxid, kaliumhydroxid, bariumhydroxid, ammoniumhydroxid, kalciumhydroxid, litiumhydroxid, magnesiumhydroxid och berylliumhydroxid.

20. Sammansattningen for anvandning enligt patentkrav 16, vari aminen är metylamin.

21. Sammansattningen for anvandning enligt patentkrav 16, vari amiden är acetazolamid.

22. Sammansattningen for anvandning enligt patentkrav 16, vari ammoniumsaltet ar ammoniumklorid.

23. Sammansattningen for anvandning enligt nagot av patentkrav 1 till 22, van i det pH-sankande amnet är valt fra' n en grupp som bestk av citronsyra, en rak, mattad karboxylsyra, mjolksyra, askorbinsyra, vinsyra, mandelsyra, acetylsalicylsyra, bensoesyra, borsyra, etylendiamintetraattiksyra (EDTA), kolsyra, maleinsyra, saltsyra, hypokloritsyra, en hypoklorit, sasom natriumhypoklorit, kaliumklorit eller kalciumhypoklorit.

24. Sammansattningen for anvandning enligt patentkrav 23, van i den raka, mattade karboxylsyran an vald fr6 n en grupp som besthr av fumarsyra, attiksyra, propansyra, smorsyra och valeriansyra.

25. Sammansattningen for anvandning enligt nagot av patentkrav 1 till 24, van i analogen av mannos är mannitol.

26. Sammansattningen [Or anvandning enligt nagot av patentkrav 1 till 15, van i sammansattningen innefattar kalciumkarbonat, mjolksyra och mannos eller analogen darav.

27. Sammansattningen for anvandning enligt nagot av patentkrav 1 till 15, van i sammansattningen innefattar kaliumlaktat, mjolksyra och mannos eller analogen darav.

28. Sammansattningen [Or anvandning enligt nagot av patentkrav 1 till 15, van i sammansattningen innefattar kalciumkarbonat, citronsyra och mannos eller analogen darav.

29. Sammansattningen [Or anvandning enligt nagot av patentkrav 1 till 15, van i sammansattningen innefattar kaliumlaktat, citronsyra och mannos eller analogen darav.