Inhibiting crystallization and / or biofilm formation on indwelling catheters

Abstract

The present invention relates to a composition for inhibiting crystallization and / or biofilm formation on an indwelling catheter. Likewise, the present invention relates to the use of a composition as provided herein for the preparation of a medicament for inhibiting crystallization and / or biofilm formation on an indwelling catheter. The composition applied according to the invention contains trimagnesium citrate and tripotassium citrate, and the application of the composition reduces the risk of catheter blockage, reduces the risk of catheter-related urinary tract infection, reduces the risk of bladder calculus formation, reduces the risk of urethral mucosa injury caused by replacement of the indwelling catheter, and reduces the risk of urinary tract mucosa damage caused by replacement of the indwelling catheter. And allows the catheter to be used over an extended period of time.

Description

Technical Field

[0001] This invention relates to a composition for inhibiting crystal and / or biofilm formation on indwelling urinary catheters. Similarly, this invention relates to the use of the compositions provided herein in the preparation of medicaments for inhibiting crystal and / or biofilm formation on indwelling urinary catheters. The compositions administered according to the invention comprise trimagnesium citrate and tripotassium citrate, and their administration reduces the risk of catheter occlusion, reduces the risk of catheter-related urinary tract infections, reduces the risk of bladder stone formation, reduces the risk of urethral mucosal damage due to catheter replacement, and allows for extended use of the catheter. Background Technology

[0002] Urinary catheters are among the most commonly used medical devices worldwide and can be characterized as indwelling catheters or intermittent catheters depending on their mode of use and the duration of insertion. Catheters are necessary when there are problems in the lower urinary tract, such as nerve damage or muscle atrophy leading to urinary incontinence, or prostatic enlargement or urethral stricture causing urinary retention. A catheter is typically a long tube inserted into the urethra until urine begins to flow. An indwelling catheter (e.g., inserted through the urethra) is a catheter that remains in place for an extended period. Two other commonly used types of catheters are suprapubic catheters and pigtail catheters.

[0003] In clinical practice, biofilm formation and / or crystal formation (also referred to herein as crystallization) on indwelling catheters can significantly complicate the care of patients undergoing prolonged bladder catheterization. As discussed herein, a biofilm is defined as a microorganism bound to each other's surfaces in the presence of an extracellular matrix, preferably comprising secretory products of the organism and / or components of the microorganism itself and / or other components (e.g., proteins). Cells within the biofilm can irreversibly bind to the surface and to each other via secreted adhesive substances. Biofilms may contain one or more microbial species, including both Gram-negative and Gram-positive bacteria and yeast. It should be noted that while biofilm formation on catheters occurs in 10% to 50% of patients with short-term (no more than 7 days) catheterization, in practice, all patients with long-term (more than 28 days) catheterization will develop biofilms on their indwelling catheters.

[0004] The advantages of microorganisms within biofilms include resistance to antimicrobial resistance, protection against physical forces, and safety from phagocytosis by immune cells. The ability of biofilms to resist antimicrobial agents is particularly concerning because resistance mechanisms (such as genes encoding antimicrobial resistance) can be transferred throughout the community and even further as microorganisms leave the biofilm to spread and multiply. It should be noted that once a biofilm has formed, preventing or inhibiting biofilm formation may therefore be a more efficient biofilm management strategy than biofilm removal, for example, using antimicrobial agents.

[0005] When functioning normally, the lower urinary tract flushes the urethra during bladder emptying, preventing bacteria from entering the urethra from the skin around the urethra and then into the bladder. It should be noted that the long-held idea that the bladder and urine themselves are sterile is a misconception, and those skilled in the art know that the body's complex microbiome is also present in the bladder and urine. These bacteria include Corynebacterium species in the male urinary tract and Lactobacillus species in the female urinary tract. The cellular structure of the bladder and the regular emptying of its contents normally prevent bacteria from multiplying to dangerous levels or adhering to the surrounding mucosa. Excessive bacterial contamination can occur when foreign objects such as catheters are introduced.

[0006] Biofilm formation can be accompanied by crystallization on the surface of catheters, particularly indwelling catheters. Without being limited by theory, it should be noted that the alkaline urine produced by bacterial urease is thought to cause calcium phosphate and magnesium phosphate to precipitate from the urine and accumulate in the catheter biofilm. Ultimately, this can lead to obstruction of urine flow from the bladder. It should be noted that while both calcium and magnesium are present in the crystalline precipitates on indwelling catheters, calcium has been shown to play a significant role in this process.

[0007] Therefore, the presence of certain bacteria in the urinary tract can lead to crystallization. However, in some patients, crystallization can also occur in the catheter due to metabolic dysfunction. As mentioned in this article, crystallization can also manifest as the formation of bladder stones, historically also known as infection stones.

[0008] Biofilms and / or crystallization can also affect and alter various aspects of the surrounding environment, particularly the flow of urine through a catheter. Indwelling catheters can become blocked during biofilm formation and crystallization, leading to urinary retention, which is not only painful for the patient but also constitutes a medical emergency. If a catheter becomes blocked during biofilm formation and crystallization, it must be removed to avoid damage to the bladder, ureters, and kidneys; if the pressure in the bladder reaches a sufficiently high level, ureteral reflux may occur, where urine is forced backward and upward into the ureter and then into the kidney. In some patients, catheter crystallization can be so severe that emergency surgery may be required to remove the catheter.

[0009] Citrate acts as a chelating agent for divalent metal ions, and thus can retain calcium and magnesium in solution. Furthermore, citrate can be used to control the pH of urine, thereby preventing the precipitation and / or crystallization of calcium and magnesium salts. However, to date, formulating citrate into a suitable form for administration to subjects / patients has been challenging.

[0010] Stickler et al. (J. Med. Microbiol., 2006, 55, 489-494) published a model study in which they tracked the formation of crystalline biofilms in a laboratory model of a catheter-inserted bladder infected with P. mirabilis and exposed to citrate-containing urine.

[0011] Wang et al. (British Journal of Urology, 1994, 74, 409-415) demonstrated that oral intake of sodium citrate and potassium citrate reduces crystal growth and precipitation in urine. Summary of the Invention

[0012] The objective technical problem of the present invention is to provide an improved means for inhibiting the formation of crystals and / or biofilms on indwelling urinary catheters.

[0013] The embodiments disclosed herein, and those characterized by the claims, solve objective technical problems.

[0014] The inventors have surprisingly demonstrated that the compositions of the present invention, comprising magnesium (preferably in ionic form), potassium (preferably in ionic form), and citrate (preferably in ionic form), can effectively inhibit biofilm formation and / or crystallization on indwelling urinary catheters. The inventors have further surprisingly demonstrated that the compositions of the present invention are well-tolerated by patients, particularly by limiting the extent of potential side effects that may result from the administration of said compositions.

[0015] The present invention will be summarized in the following embodiments.

[0016] In a first embodiment, the present invention relates to the use of a composition in the preparation of a medicament for inhibiting crystallization and / or biofilm formation on an indwelling urinary catheter, wherein the composition comprises trimagnesium citrate and tripotassium citrate, wherein the tripotassium citrate comprises 70-80% by weight of the citrate in the composition, and wherein the trimagnesium citrate comprises 20-30% by weight of the citrate in the composition, wherein a single dose of the composition comprises 35 mEq to 45 mEq of citrate, and wherein administration of the composition to a subject is initiated substantially simultaneously with the insertion of the urinary catheter into the subject.

[0017] In a second embodiment, the present invention relates to a composition used as a medicament for inhibiting crystallization and / or biofilm formation on an indwelling urinary catheter, wherein the composition comprises trimagnesium citrate and tripotassium citrate, wherein the tripotassium citrate comprises 70-80% by weight of citrate in the composition, and wherein trimagnesium citrate comprises 20-30% by weight of citrate in the composition, wherein a single dose of the composition comprises 35 mEq to 45 mEq of citrate, and wherein administration of the composition to the subject is substantially simultaneous with the insertion of the subject's urinary catheter.

[0018] In a third embodiment, the present invention relates to a method for inhibiting crystal and / or biofilm formation on an indwelling urinary catheter, the method comprising administering to a subject with the indwelling urinary catheter inserted an effective amount of a composition comprising trimagnesium citrate and tripotassium citrate, wherein the tripotassium citrate comprises 70-80% by weight of the citrate in the composition, and wherein the trimagnesium citrate comprises 20-30% by weight of the citrate in the composition. The effective amount of the composition comprises 35 mEq to 45 mEq of citrate, and the administration of the composition to the subject begins substantially simultaneously with the insertion of the subject's urinary catheter. Attached Figure Description

[0019] The invention is further illustrated in the following figures. These are for illustrative purposes only and are not intended to limit the scope of protection as defined by the appended claims in any way.

[0020] Figure 1 Comparison of an indwelling urinary catheter blocked by biofilm formation and crystallization (left) and a normal, unblocked urinary catheter (right).

[0021] Figure 2 Urease-induced biofilm and crystal formation led to bladder catheter stenosis, which was subsequently assessed by flow rate measurement of crust formation and the inhibition of Pro24c (in vitro study).

[0022] Figure 3 Blood concentrations of bicarbonate and potassium, and urine concentrations of potassium, were measured before and after Pro24c administration (in vivo study).

[0023] Figure 4 Urine pH measured before and after Pro24c administration (in vivo study).

[0024] Figure 5 Urinary concentrations of magnesium and citrate were measured before and after administration of Pro24c (in vivo study). Detailed Implementation

[0025] The present invention will now be described in detail. It should be understood that all possible combinations of the features described herein are also contemplated.

[0026] In a first embodiment, the present invention relates to the use of a composition in the preparation of a medicament for inhibiting crystallization and / or biofilm formation on an indwelling urinary catheter.

[0027] In a second embodiment, the present invention relates to a composition for inhibiting crystallization and / or biofilm formation on an indwelling urinary catheter.

[0028] In a third embodiment, the present invention relates to a method for inhibiting crystallization and / or biofilm formation on an indwelling urinary catheter, the method comprising the step of administering an effective amount of the composition provided herein to a subject with the indwelling urinary catheter inserted. It should be understood that an effective amount of the composition will be administered.

[0029] The provided composition for use according to the invention and the application of the composition according to the invention are described below.

[0030] In the context of this invention, "prevention" (e.g., prevention of medical conditions) refers to a reduction in the risk, likelihood, or severity of a condition that causes a subject to illness, including complete suppression of the occurrence of the condition. Therefore, prevention encompasses both the complete avoidance of the condition and any measurable reduction in the likelihood or severity of the condition. As described herein, prevention also includes delaying the onset of the disease.

[0031] As understood herein, the compositions provided herein comprise magnesium, potassium, and citrate, and are compositions for inhibiting crystallization and / or biofilm formation on indwelling urinary catheters. Preferably, magnesium, potassium, and / or citrate are present as ions. As understood herein, magnesium ions (also known as Mg ions) 2+ Potassium ions (also known as K+) are present in the compositions of the present invention in the form of salts. Furthermore, as understood herein, potassium ions (also known as K+) are present in the compositions of the present invention. +The citrate ion exists in the composition of the present invention in the form of a salt. Further, as understood herein, the citrate ion exists in the composition of the present invention in the form of a salt. The citrate ion (the term preferably refers to complete deprotonation of citric acid) can be represented by the following chemical formula:

[0032] However, as will be apparent to those skilled in the art, all possible tautomer forms of citrate besides those depicted in the foregoing formulas are also covered within the scope of this invention. Those skilled in the art will recognize that citrate ions can exist in different protonated states, including the fully deprotonated form shown above, which can also be referred to as citrate. 3- And the partially protonated form of H-citrate. 2- and H2-citrate - As understood herein, unless otherwise specified, whenever citrate is mentioned, it means the completely deprotonated form of citrate. 3- .

[0033] Preferably, the composition to be used according to the invention is a solid composition. A solid composition comprising magnesium, potassium, and citrate ions for inhibiting crystallization and / or biofilm formation on an indwelling urinary catheter can be understood herein as a composition comprising a salt made of magnesium, potassium, and citrate ions, as defined herein. The definition of the composition of the invention does not exclude the presence of ions other than magnesium, potassium, and citrate ions. However, preferably, the composition according to the invention substantially does not contain ions other than magnesium, potassium, and citrate ions. As understood herein, particularly in the context, "substantially" and "substantially does not contain other ions" means "may contain no more than 10% of other ions, preferably no more than 5% of other ions." In other words, the composition to be used according to the invention contains only a salt made of ions selected from magnesium, potassium, and citrate ions, wherein the citrate ions are preferably in a fully deprotonated form of citrate ions.

[0034] The inventors have surprisingly discovered that compositions characterized by a specific molar ratio of magnesium to potassium ions are particularly useful when used to inhibit crystallization and / or biofilm formation on indwelling urinary catheters. Therefore, in a particular embodiment, the molar ratio of potassium to magnesium ions in the composition is between 3.2:1 and 5.5:1. In a preferred embodiment, the molar ratio of potassium to magnesium ions in the composition is between 3.5:1 and 5.0:1. More preferably, the molar ratio of potassium to magnesium ions in the composition is between 3.8:1 and 4.5:1. Even more preferably, the molar ratio of potassium to magnesium ions in the composition is about 4:1, and most preferably, the molar ratio of potassium to magnesium ions in the composition is 4:1.

[0035] In another preferred embodiment, as discussed herein, the composition is substantially free of ions other than magnesium, potassium, and citrate ions. Therefore, those skilled in the art can assume the composition of the invention is charge-neutral to calculate the amount of citrate ions relative to the amounts of potassium and magnesium ions. Thus, within the scope of the invention, a particularly preferred embodiment is one in which the molar ratio of potassium ions to magnesium ions to citrate ions in the composition is about 4:1:2, preferably 4:1:2. In other words, a particularly preferred embodiment is one in which the molar ratio of potassium ions to magnesium ions is about 4:1, the molar ratio of potassium ions to citrate ions (preferably completely deprotonated) is about 2:1 (which may also be referred to as 4:2), and the molar ratio of magnesium ions to citrate ions (preferably completely deprotonated) is about 1:2. In a further or even more preferred embodiment, the molar ratio of potassium ions to magnesium ions is 4:1, and the molar ratio of potassium ions to citrate ions (preferably completely deprotonated) is 2:1 (which may also be referred to as 4:2), wherein the molar ratio of magnesium ions to citrate ions (preferably completely deprotonated) is 1:2.

[0036] The composition used according to the present invention may contain different salts, as long as the salts meet the requirements described above.

[0037] Particularly preferred is that the composition used according to the invention comprises trimagnesium citrate, which may also be referred to as Mg3citrate2, dimagnesium citrate, trimagnesium citrate, or magnesium citrate (3:2). Preferably, the trimagnesium citrate is present in the composition in the form of anhydrous trimagnesium citrate.

[0038] Preferably, the composition used according to the present invention comprises tripotassium citrate, which may also be referred to as K3 citrate. More preferably, as mentioned herein, tripotassium citrate is present in the composition as a monohydrate, which may also be referred to as K3 citrate × H2O.

[0039] Preferably, the salt contained in the composition as disclosed herein will be provided to meet quality standards suitable for an active pharmaceutical ingredient (API), as known to those skilled in the art. Preferably, trimagnesium citrate or anhydrous trimagnesium citrate as used herein refers to trimagnesium citrate provided as an API quality standard. More preferably, tripotassium citrate monohydrate as used herein refers to tripotassium citrate monohydrate provided as an API quality standard.

[0040] Preferably, according to the invention, the composition comprises trimagnesium citrate, preferably anhydrous trimagnesium citrate, and / or the composition comprises tripotassium citrate, preferably tripotassium citrate monohydrate. More preferably, the composition comprises trimagnesium citrate, preferably anhydrous trimagnesium citrate, and tripotassium citrate, preferably tripotassium citrate monohydrate. Even more preferably, the invention relates to an embodiment in which the composition as described herein comprises anhydrous trimagnesium citrate and tripotassium citrate monohydrate. In a particularly preferred embodiment of the invention, the composition consists of anhydrous trimagnesium citrate and tripotassium citrate monohydrate. In other words, according to this particularly preferred embodiment of the invention, there are substantially no other components in the composition thus defined. More preferably, there are no other components in the composition thus defined according to the invention.

[0041] The inventors have surprisingly discovered that compositions of the present invention, comprising anhydrous trimagnesium citrate and tripotassium citrate monohydrate (characterized by a specific relationship between the contents of the two salts), are particularly useful when used to inhibit crystallization and / or biofilm formation on indwelling urinary catheters. Therefore, in another particularly preferred embodiment, tripotassium citrate comprises 70-80% by weight of the citrate in the composition, and trimagnesium citrate comprises 20-30% by weight of the citrate in the composition. More preferably, tripotassium citrate monohydrate comprises 70-80% by weight of the citrate in the composition, and trimagnesium citrate (preferably understood as anhydrous trimagnesium citrate) comprises 20-30% by weight of the citrate in the composition. The term "% by weight of citrate in the composition" preferably refers to the ratio of the weight of a particular citrate (including any water of crystallization present in the salt) in the composition to the total weight of all citrates in the composition. According to the present invention, the composition is preferably a composition consisting of anhydrous trimagnesium citrate and tripotassium citrate monohydrate. Therefore, for a composition consisting of anhydrous trimagnesium citrate and tripotassium citrate monohydrate, it can be understood that the two weight percentages of citrate in the composition will refer to the weight percentage of each component in the composition. Therefore, preferably, the weight percentages given above preferably total 100%.

[0042] In a preferred embodiment, the present invention relates to compositions for use as described herein and the use of such compositions, wherein tripotassium citrate monohydrate comprises 74.2% by weight of citrate in the composition, and wherein anhydrous trimagnesium citrate comprises 25.8% by weight of citrate in the composition. Since the invention preferably relates to embodiments in which the composition consists of anhydrous trimagnesium citrate and tripotassium citrate monohydrate, it is preferred that the composition as described herein consists of 74.2% by weight of tripotassium citrate monohydrate and 25.8% by weight of anhydrous trimagnesium citrate.

[0043] The inventors have surprisingly discovered that a preferred ratio of tripotassium citrate monohydrate to anhydrous trimagnesium citrate allows for maximizing the possible dosage of citrate while minimizing the risks of side effects caused by potassium ion administration (i.e., hyperkalemia, cardiac complications, bitter or metallic taste leading to decreased compliance) and / or the risks of side effects caused by magnesium ion administration (laxative effect at elevated doses). It should be noted that these side effects will be discussed below.

[0044] The compositions of the present invention are preferably prepared as a mixture of two salts, as discussed herein, and may be in powder and / or granular form. Preferably, in some embodiments, the compositions are solid compositions and will be packaged in waterproof pouches so that the contents of a single pouch corresponding to a single dose of the composition of the present invention can be dissolved in water immediately prior to administration. It is noted herein that while solid form of the compositions of the present invention is preferred, liquid galenic forms comprising magnesium, potassium, and citrate ions according to the present invention are also covered by the present invention, as described above.

[0045] As understood herein, whenever the composition is provided in solid form, a single dose of the composition of the present invention should preferably be dissolved in a volume of 50 ml to 150 ml of water, more preferably in a volume of about 100 ml of water. It should be noted that when the composition is dissolved in water, the pH should be between 6.0 and 9.0.

[0046] It should be noted that the powder of the present invention is preferably characterized in that the particle size (preferably referred to as the average particle size of the particles of the granules of the present invention, such as preferably measured by sieving) is less than 0.8 mm.

[0047] The inventors have surprisingly discovered that the compositions of the present invention, as defined herein, are not only effective in inhibiting crystallization and / or biofilm formation on indwelling urinary catheters, but also exhibit optimal proportions of the components (understood herein as weight ratios or molar ratios) and allow for minimization of potential side effects associated with the administration of potassium and / or magnesium ions. Increased doses of potassium can lead to hyperkalemia, i.e., elevated levels of potassium ions in the blood, which in some cases can cause palpitations, muscle pain, muscle weakness or numbness, or cardiac arrhythmias that can lead to cardiac arrest or death. The risk of cardiac arrest and potential death due to cardiac arrhythmias is particularly pronounced in subjects with a pre-existing heart condition. As is known to those skilled in the art, the daily dose of potassium (adults) should not exceed 100 mEq, as higher doses may lead to cardiac complications.

[0048] Although potassium ions in the composition have cardiology-related side effects, it should be noted that an unpleasant metallic and / or bitter taste may develop as the potassium concentration in the solution increases, which may negatively impact patient / subject compliance when taking the compositions of the present invention, especially over extended periods (preferably at least once daily, preferably for more than 1 month, more than 2 months, more than 3 months, or more than 6 months). Furthermore, the inventors have surprisingly discovered that the compositions of the present invention are characterized by solubility, which ensures oral administration of the compositions and improves patient compliance.

[0049] Conversely, higher doses of magnesium salts are also not recommended, as this may lead to side effects. The most common side effect reportedly associated with high doses of magnesium salts is diarrhea, due to their laxative effect. This article assumes that the daily dose of magnesium ions should not exceed 27 mEq.

[0050] An equivalent (referred to as Eq) is the amount of one substance that reacts with one mole (or the equivalent of one mole) of another substance in a given chemical reaction. In this text, since an equivalent refers to the amount of magnesium ions, potassium ions, and citrate ions, the amount of each ion, expressed as Eq, is defined as its amount (in moles) multiplied by its valence. For illustrative purposes only, it should be noted that one mole of magnesium ions corresponds to two Eq of magnesium ions, one mole of potassium ions corresponds to one Eq of potassium ions, and one mole of citrate ions (completely deprotonated) corresponds to three Eq of citrate ions.

[0051] The compositions of the present invention may further comprise additional pharmaceutically acceptable excipients, including sweeteners, taste enhancers, anti-adhesion agents, binders, coatings, colorants, disintegrants, flow aids, lubricants, and / or mediators. Therefore, in another embodiment, the present invention relates to compositions as described herein, wherein said compositions further comprise pharmaceutically acceptable excipients.

[0052] The compositions of the present invention are preferably administered orally to subjects, particularly patients in need. It should be noted that, as the inventors have surprisingly discovered, certain compositions of the present invention, particularly those having the molar ratio of magnesium to potassium ions as described herein, or the weight content of tripotassium citrate monohydrate and anhydrous trimagnesium citrate as described herein, are optimal for oral administration of the compositions of the present invention.

[0053] The compositions of the present invention can be administered to subjects, particularly patients, in a single dose or over several doses during a day. Within the scope of the invention, it is preferred that a single dose of the composition comprises citrate between 35 mEq and 45 mEq. Therefore, a single dose of the compositions of the present invention may comprise 35 mEq, 36 mEq, 37 mEq, 38 mEq, 39 mEq, 40 mEq, 41 mEq, 42 mEq, 43 mEq, 44 mEq, or 45 mEq of citrate. The inventors have surprisingly found that such dosing regimens can improve compliance on the subject (i.e., patient) side because any side effects associated with the presence of counterions (potassium and magnesium, as described herein) are reduced to acceptable levels. Preferably, a single dose of the composition comprises citrate between 39 mEq and 41 mEq. More preferably, a single dose of the composition comprises about 40 mEq of citrate. Particularly preferred is that a single dose of the composition comprises 40 mEq of citrate. Preferably, the single dose is an oral dose, and in this document, it is a single oral dose.

[0054] As understood herein, the term "comprising" indicates the presence of the desired element but does not exclude the presence of additional elements. However, if this term is used in this invention, it also includes direct and specific references to embodiments described using the phrase "consisting of," which expressly excludes the presence of additional elements other than those specifically referenced.

[0055] As described herein, a single dose may be administered to the subject (i.e., the patient) once or more daily. Preferably, a single dose as described herein is administered to the subject once or twice daily. More preferably, a single dose as described herein is administered to the subject once daily. In other words, a single dose as mentioned herein may also be referred to as a daily dose. Such administration regimens do not impose an undue burden on the subject / patient and allow for optimal compliance. As understood herein, the daily dose of the composition of the present invention is preferably the sum of the daily doses administered to the subject (or patient) throughout the day. Preferably, the daily dose of the composition comprises a citrate between 35 mEq and 45 mEq. Therefore, the daily dose of the composition of the present invention may comprise citrate of 35 mEq, 36 mEq, 37 mEq, 38 mEq, 39 mEq, 40 mEq, 41 mEq, 42 mEq, 43 mEq, 44 mEq, or 45 mEq. Preferably, the daily dose of the composition comprises a citrate between 39 mEq and 41 mEq. More preferably, the daily dose of the composition comprises about 40 mEq of citrate. Particularly preferred is that the daily dose of the composition comprises 40 mEq of citrate.

[0056] As further understood herein, the single dose (preferably the daily dose of the composition applied according to the invention) can also be referred to as the effective amount of the composition of the invention. Therefore, as preferably provided herein, the daily dose of the composition comprises citrate (preferably composed of said citrate) between 35 mEq and 45 mEq. Thus, the daily dose of the composition of the invention may comprise 35 mEq, 36 mEq, 37 mEq, 38 mEq, 39 mEq, 40 mEq, 41 mEq, 42 mEq, 43 mEq, 44 mEq, or 45 mEq of citrate (preferably composed of said citrate). Preferably, the daily dose of the composition comprises citrate (preferably composed of said citrate) between 39 mEq and 41 mEq. More preferably, the daily dose of the composition comprises about 40 mEq of citrate (preferably composed of said citrate). Particularly preferred is that the daily dose of the composition comprises 40 mEq of citrate (preferably composed of said citrate).

[0057] The inventors have surprisingly discovered that applying the compositions of the present invention as defined herein reduces the risk of indwelling catheter occlusion. As described above, crystallization and / or biofilm formation on indwelling catheters can affect the flow of urine through the catheter and lead to its blockage. As understood herein, inhibiting these processes reduces the associated risks and may potentially prevent indwelling catheter occlusion.

[0058] As a result of the administration of this composition, biofilm formation and / or crystallization on the indwelling catheter are reduced and / or inhibited. Therefore, as covered by this invention, administration of the composition of this invention allows for the use of the indwelling catheter in a patient for an extended period, which may be understood herein as longer than 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, or even longer. The administration of the composition of this invention for an extended period is particularly recommended for subjects / patients requiring long-term catheterization.

[0059] It should be further noted that when the compositions of the present invention are administered to subjects or patients requiring long-term catheterization, the indwelling catheter does not need to be changed as frequently as is commonly done in contemporary clinical practice. Therefore, complications associated with frequent indwelling catheter changes can be avoided. Thus, again in another specific embodiment, the present invention relates to compositions as described herein, wherein administration of said compositions reduces the risk of urethral mucosal damage due to indwelling catheter changes.

[0060] The present invention further includes an embodiment in which application of the composition can reduce the risk of catheter-associated urinary tract infection.

[0061] Therefore, this invention relates to a composition of the invention as described herein for the prevention of catheter-associated urinary tract infections (CATIs). Similarly, this invention relates to the use of the compositions provided herein in the preparation of medicaments for the prevention of CATIs. Furthermore, this invention relates to a method for the prevention of CATIs, the method comprising the step of administering an effective amount of the composition provided herein to a subject with the indwelling catheter inserted. It should be understood that an effective amount of the composition will be administered. The composition to be administered according to the invention and the administration of the composition are as described herein.

[0062] As discussed above, the presence of an indwelling urinary catheter constitutes a foreign body in the urinary tract, which may increase the predisposition to urinary tract infections. Furthermore, it should be noted that the presence of biofilms (as a microenvironment that promotes the presence and / or growth of microorganisms) can further promote urinary tract infections. Such infections associated with the presence of an indwelling urinary catheter may also be referred to by those skilled in the art as catheter-associated urinary tract infections (CAUTIs) and can be caused by any microorganism capable of growing in the urinary tract. These microorganisms may also be referred to as urethropathogenic microorganisms. A non-exhaustive list of microorganisms that may cause catheter-associated urinary tract infections (CATTIs) includes *Escherichia coli*, *Pseudomonas aeruginosa*, *Staphylococcus aureus*, *Klebsiella pneumoniae*, *Morganella morganii*, *Proteus mirabilis*, *Proteus vulgaris*, *Providentia rettgeri*, and yeast. However, this list is not intended to be restrictive. It should be noted that the risk of infection increases from 3% to 7% for each day the catheter remains in place. It should also be noted that other types of catheters, including suprapubic catheters and pigtail catheters, are also associated with an increased risk of CATTIs.

[0063] Therefore, this invention relates to a composition of the invention as described herein for the prevention of catheter-associated urinary tract infections (CATIs). Similarly, this invention relates to the use of the compositions provided herein in the preparation of medicaments for the prevention of CATIs. Furthermore, this invention relates to a method for the prevention of CATIs, the method comprising the step of administering an effective amount of the composition provided herein to a subject with the indwelling catheter inserted. It should be understood that an effective amount of the composition will be administered. The composition to be administered according to the invention and the administration of the composition are as described herein.

[0064] Several types of bacteria exist in the urinary tract, either as members of the normal human microbiome or originating from external sources and causing infection. *Escherichia coli* is primarily found in the gastrointestinal tract, but due to the urethra's proximity to the anus (especially in female patients), it is a major cause of catheter-associated urinary tract infections, particularly for intermittent catheter users. Specifically, strains of *E. coli* that cause urinary tract infections are called urethropathogenic *E. coli* strains.

[0065] Many urethral pathogenic bacteria produce urease, which hydrolyzes urea, ultimately leading to calcium precipitation in the urine and the formation of crystalline biofilms on indwelling catheters. One example of such bacterial species is *Proteus mirabilis*, a member of the Enterobacteriaceae family. *Proteus* is widely distributed in the environment and opportunistically associated with several types of hospital-acquired infections. Hospitalization is understood here as relating to the length of hospital stay, typically beginning within 72 hours of admission. *Proteus mirabilis* is generally not associated with urinary tract infections in healthy individuals with unobstructed urinary tracts. However, it can colonize the urinary tract in individuals with structural or functional abnormalities, with patients with inserted catheters, particularly those with indwelling catheters, at the greatest risk. *Proteus mirabilis* has been shown to typically exhibit the strongest tendency to bind to the surfaces of catheters and urological devices, likely due to the production of a variety of adhesion factors. Importantly, *Proteus mirabilis* produces urease, which hydrolyzes urea and is crucial for the formation of crystalline biofilms in the urinary tract. It should be noted that Proteus mirabilis exhibits the highest urease production among all urethral pathogens, and the urease it produces is highly reactive and can hydrolyze urea faster than urease from other species.

[0066] Furthermore, according to the present invention, catheter-associated urinary tract infections cause crystallization biofilm deposition. Crystallization may be caused by the presence of any urease-producing bacteria in the urinary tract, or by infection of the urinary tract by any urease-producing bacteria. Other species of the genus *Proteus* (e.g., *Proteus vulgaris*) are known to have similar effects, in addition to *Proteus mirabilis*. Besides *Proteus*, other urease-producing bacterial species exist, such as *Providencera reticularis*. All species mentioned herein are isolated from biofilms, particularly crystallization biofilms, formed in the urinary tract of a patient. Therefore, the present invention relates to compositions as described herein, wherein inhibition of crystallization and / or biofilm formation is caused by the presence of *Proteus mirabilis*, *Proteus vulgaris*, or *Providencera reticularis*, preferably *Proteus mirabilis*.

[0067] Many other bacterial species that do not form crystalline biofilms may form them because their urease output is much lower than that of *Proteus mirabilis* or other species mentioned above. These species include *Pseudomonas aeruginosa*, *Staphylococcus aureus*, *Klebsiella pneumoniae*, *Morganella morganii*, and *Providencia stuarii*. Additionally, fungal species, including *Candida albicans*, may also participate in the formation of non-crystalline biofilms. It should be noted that this list is not intended to be restrictive, and other microbial (particularly bacterial) species may also form non-crystalline biofilms. Typically, bacterial species listed herein produce large amounts of mucus material. While this mucus material usually does not (completely) block the catheter, it certainly affects the flow of urine through it and is therefore highly undesirable. Therefore, as described herein, it is essential to prevent the formation of such biofilms. Therefore, again in another specific embodiment, the present invention relates to compositions as described herein, wherein inhibition of biofilm formation is caused by the presence of Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Citrobacter spp., and / or Candida albicans.

[0068] As those skilled in the art know, the processes of biofilm formation and crystallization are closely related. This can also refer to the process of crystalline biofilm formation. The inventors have further and surprisingly discovered that the compositions of the present invention are effective against biofilm formation, crystallization, and / or crystalline biofilm formation. Therefore, it should be noted that, in another embodiment, the present invention relates to the use of the compositions described herein for inhibiting crystallization and / or biofilm formation on indwelling urinary catheters.

[0069] The inventors have further and surprisingly discovered that application of the compositions described herein effectively inhibits crystallization in the urinary tract. Crystallization, as understood herein, includes crystals of calcium phosphate, magnesium phosphate, and calcium oxalate. It should be understood herein that, upon application of citrate, calcium can be chelated by citrate rather than oxalate, thereby reducing the risk of bladder stone formation. Therefore, it should be understood herein that the invention further relates to compositions as described herein, wherein application of said compositions reduces the risk of bladder stone formation.

[0070] Preferably, the administration of the composition of the present invention to the subject begins substantially simultaneously with the insertion of the subject's urinary catheter. More preferably, the administration of the composition of the present invention to the subject shall begin no later than the insertion of the subject's urinary catheter. "Substantially simultaneously" can preferably be understood as occurring within 1 hour of each other, more preferably within 30 minutes of each other, and even more preferably within 15 minutes of each other. The inventors have demonstrated that adding the composition of the present invention to urine yields significantly better results in inhibiting crystallization and / or biofilm formation on indwelling urinary catheters than subsequent application, as shown in Example 2.

[0071] As further illustrated in Example 2, the compositions of the present invention are particularly effective in inhibiting crystallization and / or biofilm formation on indwelling urinary catheters, wherein the concentration of citrate ions in the urine is maintained at a specific level upon administration. Therefore, preferably, the compositions of the present invention are administered to a subject at a dose such that the concentration of citrate ions in the subject's urine reaches at least 1 mmol / L, more preferably at least 2 mmol / L, even more preferably at least 3 mmol / L, even more preferably about 4 mmol / L, and most preferably 4 mmol / L. It should be understood that physicians will be able to determine the optimal dosing regimen based on the specific physical and / or clinical data of the subject to ensure that this condition is met.

[0072] In another embodiment, the present invention relates to the use of the compositions described above for inhibiting crystal and / or biofilm formation on indwelling urinary catheters. The invention further relates to treatment methods covering the application of the compositions of the invention as defined above to persons in need, particularly those undergoing prolonged catheter insertion with indwelling urinary catheters, to inhibit crystal and / or biofilm formation on the indwelling urinary catheters.

[0073] In Example 3 (which discusses limited human findings of the compositions of the invention), the inventors further demonstrated that, as described herein, a single dose of the compositions of the invention, and particularly 40 mEq of citrate, resulted in a citrate concentration in urine exceeding 3 mM, preferably reaching a level between 3 mM and 4 mM, which had been shown in Example 2 to be effective in preventing catheter crusting in the model in which the invention was applied.

[0074] Various modifications and variations of the invention will be apparent to those skilled in the art without departing from its scope. Although the invention has been described in conjunction with specific preferred embodiments, it should be understood that the claimed invention should not be unduly limited to such specific embodiments. Indeed, various modifications for carrying out the described modes of the invention will be apparent to those skilled in the art and are intended to be covered by the invention.

[0075] The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention as defined by the appended claims.

[0076] Example Example 1: The composition of the present invention consisting of only two salts The composition was obtained by mixing 1441.8 mg of tripotassium citrate monohydrate and 501.2 mg of anhydrous trimagnesium citrate. Both salts were of API quality and supplied by Jungbunzlauer Ladenburg GmbH (Dr.-Albert-Reimann-Str. 18, DE-68526 Ladenburg). The composition is also known as Pro24c.

[0077] Example 2: Urease-induced biofilm and crystal formation led to bladder catheter stenosis, followed by crust formation measured by flow rate, and the inhibition of stenosis by Pro24c (in vitro study). introduction In vitro studies were conducted using Pro24c (a drug composed of anhydrous trimagnesium citrate and tripotassium citrate monohydrate, see Example 1) to demonstrate that this drug can reduce or inhibit urease-induced biofilm formation and crystallization on bladder catheters.

[0078] Urease (produced by microorganisms in vivo or in commercially available synthetic forms) leads to different stages of biofilm formation and crystallization (nucleation, growth, aggregation) in urine and catheters. This process on / inside the catheter can cause crusting and loss of catheter patency (blockage).

[0079] In this in vitro study, the process was quantified by measuring the time required for a defined volume of water to flow through a catheter (also known as flow time).

[0080] Design and Methodology In this study, synthetic urine and urease (a high-purity preparation of sword bean dissolved in 0.1 M TRIS, producing 109.09 mmol NH3 activity per ml urine / min at 37°C) were used. Four large sterile glass containers (2 L each) were filled with 1.5 L of synthetic urine. The urine was adjusted to pH 5.5 (using 32% HCl). Container 1 served as a control. Container 2 was prepared with 1 mmol / L Pro24c, and container 3 with 4 mmol / L Pro24c, respectively. Urease solution (0.1 ml / 100 ml urine) was then added to all containers. Pro24c (at a higher concentration of 4 mmol / L) was added to container 4 no earlier than 72 hours before the start of the experiment.

[0081] The glass containers were placed on a heatable magnetic stirrer at 37°C. During incubation, continuous, slow stirring was provided by a Teflon-coated stirring rod. Forty bladder catheters (CH-14; 18 cm; PharmaPlast) were suspended in each glass container and secured to a triangular mesh while the urease solution was added.

[0082] The study duration was set to a maximum of 14 days. pH was controlled at the same time each day. Five catheters were removed from each glass container at time points of 2, 4, 6, 8, and 10 days. Flow rate was measured for each catheter. To do this, the catheter was secured in a funnel, allowing 150 ml of properly calibrated water to flow freely through the catheter (without adding pressure, solely by gravity). The duration of this procedure (flow time) was measured and recorded.

[0083] result After day 1, the pH in each glass container rose from 5.5 to above 8 and remained at this level throughout the study period. The results of the average flow time (in seconds) recorded as 150 ml of water passed through the catheter are shown in Table 1 and... Figure 2 Presented in the middle.

[0084] In glass container #1 (control), the average flow time increased from 15.93 seconds (at day 0) to 20.62 seconds (at day 10), an increase of 29.4%.

[0085] In glass containers No. 2 and No. 3 (containing 1 mmol / L and 4 mmol / L Pro24c, respectively), the average flow times increased by 7% and decreased by 3.4%, respectively.

[0086] In glass container #4 (Pro24c added only after 72 hours), the average flow time increased by 42.5% at time point 8. (Results at time point 10 could not be evaluated due to technical issues).

[0087] Table 1. Flow time of 150 mL of water under each condition is the average for 5 catheters at each time point, as described above.

[0088]

[0089] These differences were striking and significant. Catheters suspended in untreated urine showed a marked tendency to crystallize and crust over a 10-day period, resulting in loss of patency. Pro24c at a concentration of 4 mmol / L inhibited this blockage. The experiments in glass container #4 demonstrate that administering Pro24c at the beginning of catheter insertion (i.e., when the catheter is placed in the patient) rather than immediately after a certain delay is reasonable.

[0090] in conclusion As is known from the literature, in vitro studies as described above have demonstrated and validated the value of the drug in preventing biofilm formation, crystallization, and crusting on bladder catheters, thereby inhibiting these catheter blockages and corresponding complications. Pro24c is a drug used to prevent biofilm formation and crystallization on indwelling catheters.

[0091] To verify that a concentration of 4 mmol / L Pro24c (Example 2) also has a significant effect in vivo, a study was conducted in humans (see Example 3).

[0092] Example 3: Changes in the concentrations of different parameters in blood and urine after a single oral administration of 40 mEq Pro24c: a proof-of-concept study in humans. A proof-of-concept study was conducted to demonstrate changes in parameters / concentrations such as blood bicarbonate, urine citrate, and pH following a single oral administration of Pro24c (a mixture of two citrates in a predefined ratio). The study showed significant and promising changes in blood bicarbonate levels and urine citrate concentrations, laying the foundation for further development of new treatments or therapies superior to those currently used.

[0093] method A cohort of 16 participants (comprising 12 healthy subjects and 4 patients with chronic kidney disease, 10 men and 6 women) were enrolled in this study. Baseline testing was conducted on the morning before breakfast, following a 12-hour overnight fast. Blood and urine samples (first morning urine the following day) were collected. Blood potassium and bicarbonate concentrations, as well as urine pH, creatinine, potassium, magnesium, calcium, and citrate parameters were measured; the corresponding potassium / creatinine, magnesium / creatinine, calcium / creatinine, and citrate / creatinine ratios were calculated.

[0094] After a period of at least 2 days (but no more than 1 week), each person must take 2 Pro24c strips at night. This dose corresponds to 40 mEq (powder dissolved in 2 dl of water). Afterward, the same procedure as at baseline was performed. To assess deviation from baseline, the mean was calculated for each blood and urine parameter across the entire group (baseline and test day).

[0095] result Figures 3 to 5 The main results are shown in the figure.

[0096] Figure 3 The blood concentrations of bicarbonate and potassium, as well as the urine concentration of potassium, were shown before and after the administration of Pro24c.

[0097] Potassium remained unchanged, while bicarbonate increased slightly. This latter effect demonstrates the reabsorption of citrate and its partial metabolic conversion to bicarbonate. Figure 3 It can also be seen that potassium excretion in urine has increased significantly, which is the effect required to maintain blood potassium levels within the normal range.

[0098] Figure 4 The pH values ​​of urine were depicted before and after the administration of Pro24c.

[0099] The pH value increased significantly, approaching a value close to six, and this occurred after a single dose of Pro24c.

[0100] exist Figure 5 The figure shows the urinary concentrations of magnesium and citrate before and after Pro24c intake.

[0101] Significant increases were detected for both parameters, demonstrating the salt absorption and elimination of Pro24c.

[0102] in conclusion The results of this study provide evidence of relevant changes in parameters in blood and urine induced by a single oral dose of 40 mEq Pro24c. They also confirm the hypothesis that Pro24c, as a drug, can deliver pharmacological effects for its intended medical indications. The results are promising for patients requiring restoration of environmental imbalances in their blood and / or urine due to chronic diseases. Therefore, Pro24c may be a treatment option for different patient populations, as demonstrated in controlled clinical trials.

Claims

1. Use of a composition in the preparation of a medicament for inhibiting crystallization and / or biofilm formation on an indwelling urinary catheter, wherein the composition comprises trimagnesium citrate and tripotassium citrate, wherein the tripotassium citrate comprises 70-80% by weight of the citrate in the composition, and wherein anhydrous trimagnesium citrate comprises 20-30% by weight of the citrate in the composition, wherein a single dose of the composition comprises 35 mEq to 45 mEq of citrate, and wherein administration of the composition to a subject is initiated substantially simultaneously with catheter insertion in the subject.

2. The use according to claim 1, wherein the molar ratio of potassium ions to magnesium ions to citrate ions in the composition is about 4:1:2, preferably 4:1:

2.

3. The use according to claim 1, wherein the composition comprises anhydrous trimagnesium citrate, and / or wherein the composition comprises tripotassium citrate monohydrate.

4. The use according to claim 3, wherein the tripotassium citrate monohydrate accounts for 70-80% by weight of the citrate in the composition, and wherein the anhydrous trimagnesium citrate accounts for 20-30% by weight of the citrate in the composition.

5. The use according to claim 4, wherein the tripotassium citrate monohydrate accounts for 74.2% by weight of the citrate in the composition, and wherein anhydrous trimagnesium citrate accounts for 25.8% by weight of the citrate in the composition, preferably wherein the composition consists of 74.2% by weight of tripotassium citrate monohydrate and 25.8% by weight of anhydrous trimagnesium citrate.

6. The use according to claim 1, wherein when the composition is dissolved in water, the pH is between 6.0 and 9.0, and / or The composition described herein will be administered orally, and / or The composition further comprises a pharmaceutically acceptable excipient, and / or The single dose mentioned above refers to a single oral dose.

7. The use according to claim 1, wherein a single dose of the composition comprises about 40 mEq of citrate, preferably wherein a single dose of the composition comprises 40 mEq of citrate.

8. The use according to claim 1, wherein the composition is administered once daily, preferably wherein the daily dose of the composition comprises 40 mEq of citrate.

9. The use according to claim 1, wherein the application of said composition reduces the risk of obstruction of the indwelling urinary catheter, and / or The application of the composition allows the indwelling catheter to be used over an extended period of time, and / or The application of the aforementioned composition reduces the risk of catheter-associated urinary tract infections, and / or The inhibition of crystallization and / or biofilm formation is caused by the presence of Proteus mirabilis, Proteus vulgaris, and / or Providenia rettgeri, preferably Proteus mirabilis, and / or The inhibition of biofilm formation is caused by the presence of the following: Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Citrobacter spp., and / or yeast, especially Candida albicans, and / or The application of the aforementioned composition reduces the risk of bladder stone formation, and / or The application of the composition reduces the risk of urethral mucosal damage caused by replacement of the indwelling catheter.

10. The use according to claim 1, wherein the composition is administered to a subject such that the concentration of citrate ions in the subject's urine reaches at least 3 mmol / L, more preferably about 4 mmol / L, and most preferably 4 mmol / L.

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