Pharmaceutical composition for preventing or treating interstitial cystitis / bladder pain syndrome

Abstract

The present invention provides a pharmaceutical composition for preventing or treating interstitial cystitis / bladder pain syndrome (IC / BPS), the pharmaceutical composition containing polyphosphoric acid or a salt thereof. The salt of polyphosphoric acid may be a metal salt of polyphosphoric acid. The metal salt may contain at least one of sodium, potassium, magnesium, calcium, and zinc as a constituent metal and is preferably calcium polyphosphate or zinc polyphosphate. The present invention enables the prevention or treatment of IC / BPS based on a new mechanism of action with a high level of safety for a living body.

Description

Pharmaceutical composition for preventing or treating interstitial cystitis / bladder pain syndrome

[0001] The present invention relates to a pharmaceutical composition for preventing or treating interstitial cystitis-bladder pain syndrome, which comprises polyphosphoric acid or a salt thereof.

[0002] Interstitial cystitis / bladder pain syndrome (IC / BPS) is defined as "a condition characterized by chronic pelvic pain, pressure, or discomfort related to the bladder, accompanied by lower urinary tract symptoms such as increased urinary urinary urinary urinary frequency, and the absence of any other potentially confounding diseases" (Non-Patent Document 1). Among these, IC / BPS accompanied by erosive lesions (Hanna lesions) is called Hanna-type interstitial cystitis. Hanna-type interstitial cystitis has clear abnormal findings both endoscopically and pathologically, and is considered to be symptomatically more severe. It has been designated an intractable disease by the Ministry of Health, Labor, and Welfare as designated intractable disease 226.

[0003] There is no established treatment for IC / BPS, and currently only symptomatic measures are available. Surgical treatment involves endoscopic hydrodistention of the bladder, and if Hanna lesions are found in the bladder, electrical or laser ablation is also performed. Pharmacological treatments include oral administration of centrally acting sensitizing drugs such as amitriptyline and immunosuppressants such as cyclosporine A, as well as intravesical instillation of drugs such as heparin, DMSO, and steroids, and intrabladder wall injection of botulinum toxin.

[0004] Currently, hydrodistention of the bladder or ablation of Hanna lesions results in symptomatic relief in approximately half of cases, but long-term remission is only achieved in a small proportion of cases. Furthermore, pharmaceutical treatment has not yet led to a complete cure for IC / BPS. IC / BPS is thus an intractable disease affecting quality of life (QOL) and requires long-term medical management due to repeated relapses and remissions, and the development of effective therapeutic agents is highly desirable.

[0005] Polyphosphate is known to be utilized as an energy source by microorganisms and to have various physiological activities, such as being involved in the coagulation reaction of human blood. The present inventors have identified long-chain polyphosphate derived from malt-derived lactic acid bacteria as a molecule that strengthens the intestinal barrier function. They have demonstrated that long-chain polyphosphate improves the deterioration of intestinal barrier function and intestinal injury caused by dextran sulfate sodium treatment (Patent Document 1), and further demonstrated that long-chain polyphosphate promotes mucosal healing in patients with refractory ulcerative colitis (Non-Patent Document 2). They have also reported that calcium salts of polyphosphate act on damaged gastrointestinal mucosa in inflammatory bowel disease and exert a platelet aggregation effect specific to the damaged mucosa (Patent Document 2), and that zinc polyphosphate, which exhibits a characteristic X-ray diffraction peak, has an excellent intestinal barrier-enhancing effect (Patent Documents 3 and 4).

[0006] Polyphosphate is known to have wound healing and anti-inflammatory effects, and there are hopes for the development of wound dressings and dental materials using amorphous or nanoparticles composed of calcium polyphosphate salts (Patent Document 5).

[0007] Polyphosphate is also known as a blood coagulation-inducing factor. When polyphosphate is released from blood platelets, it activates factor XII protease in the blood, inducing a coagulation reaction. Natural polyphosphate is thought to exist in various salts, such as calcium salt, magnesium salt, sodium salt, and potassium salt, and amorphous nanoparticles are also known to exist (Non-Patent Documents 3 and 4). Donovan et al. prepared nanoparticles from polyphosphates of different chain lengths and reported on the size of polyphosphates and their effect on blood coagulation (Non-Patent Document 5).

[0008] WO2011 / 125619WO2021 / 141066WO2024 / 090537WO2024 / 090538WO2016 / 079006

[0009] Interstitial Cystitis / Bladder Pain Syndrome Treatment Guidelines, edited by the Japan Interstitial Cystitis Study Group / Japan Urological Association, published April 25, 2019 Fujita et al., “Long-Chain Polyphosphate Is a Potential Agent for Inducing Mucosal Healing of the Colon in Ulcerative Colitis.” Clin Pharmacol Ther. 2019 Sep.Feng et al., “Biogenic Polyphosphate Nanoparticles from a Marine Cyanobacterium Synechococcus sp. PCC 7002: Production, Characterization, and Anti-Inflammatory Properties In Vitro.” Mar Drugs. 2018 Sep 10;16(9).Feng et al., “Biogenic Polyphosphate Nanoparticles from Synechococcus sp. PCC 7002 Exhibit Intestinal Protective Potential in Human Intestinal Epithelial Cells In Vitro and Murine Small Intestine Ex Vivo.” J Agric Food Chem. 2018 Aug 1;66(30):8026-8035.Donovan et al., “Size-controlled synthesis of granular polyphosphate nanoparticles at physiologic salt concentrations for blood clotting.” Biomacromolecules. 2014 Nov 10;15(11):3976-84.

[0010] The present invention provides a new means for preventing or treating IC / BPS that is highly safe for the living body.

[0011] The present inventors have found that salts of polyphosphate are useful for the prevention and treatment of IC / BPS, particularly for the improvement of frequent urination.

[0012] The present disclosure provides the following: Item 1. A pharmaceutical composition for preventing or treating IC / BPS, comprising polyphosphoric acid or a salt thereof. Item 2. The pharmaceutical composition according to Item 1, wherein the polyphosphoric acid or a salt thereof is poorly soluble or insoluble in water. Item 3. The pharmaceutical composition according to Item 1 or 2, wherein the polyphosphoric acid or a salt thereof has an average particle size of 1 to 3,000 nm. Item 4. The pharmaceutical composition according to any one of Items 1 to 3, wherein the polyphosphoric acid or a salt thereof has a zeta potential of 0 mV or less. Item 5. The pharmaceutical composition according to any one of Items 1 to 4, comprising linear polyphosphoric acid or a salt thereof. Item 6. Item 6. The pharmaceutical composition according to any one of Items 1 to 5, wherein the average chain length of the polyphosphate or a salt thereof is at least 1.1 phosphate units, at least 1.2 phosphate units, at least 1.3 phosphate units, at least 1.4 phosphate units, at least 1.5 phosphate units, at least 1.6 phosphate units, at least 1.7 phosphate units, at least 1.8 phosphate units, at least 1.9 phosphate units, at least 2 phosphate units, at least 2.5 phosphate units, at least 3 phosphate units, at least 4 phosphate units, at least 5 phosphate units, at least 6 phosphate units, at least 7 phosphate units, at least 8 phosphate units, at least 9 phosphate units, or at least 10 phosphate units. Item 7. The pharmaceutical composition according to any one of Items 1 to 6, wherein the average chain length of the polyphosphoric acid or a salt thereof is 10,000 phosphate units or less, 1,000 phosphate units or less, 900 phosphate units or less, 800 phosphate units or less, 700 phosphate units or less, 600 phosphate units or less, 500 phosphate units or less, 400 phosphate units or less, 300 phosphate units or less, 200 phosphate units or less, 100 phosphate units or less, 90 phosphate units or less, 80 phosphate units or less, 70 phosphate units or less, 60 phosphate units or less, 50 phosphate units or less, 40 phosphate units or less, 30 phosphate units or less, 20 phosphate units or less, or 15 phosphate units or less. Item 8. The pharmaceutical composition according to any one of Items 1 to 5, wherein the average chain length of the polyphosphoric acid or a salt thereof is 1.1 phosphate units or more, 1.2 phosphate units or more, 1.3 phosphate units or more, or 1.4 phosphate units or more. Item 9. The pharmaceutical composition according to any one of Items 1 to 5 and 8, wherein the average chain length of the polyphosphate or a salt thereof is 10 phosphate units or less, 5 phosphate units or less, 4 phosphate units or less, 3.5 phosphate units or less, 3 phosphate units or less, 2.5 phosphate units or less, 2 phosphate units or less, or 1.5 phosphate units or less.Item 10. The pharmaceutical composition according to any one of Items 1 to 5, wherein the average chain length of the polyphosphoric acid or a salt thereof is at least 1.5 phosphate units, at least 1.6 phosphate units, at least 1.7 phosphate units, at least 1.8 phosphate units, at least 1.9 phosphate units, at least 2 phosphate units, or at least 2.5 phosphate units. Item 11. The pharmaceutical composition according to any one of Items 1 to 5 and 10, wherein the average chain length of the polyphosphoric acid or a salt thereof is at most 15 phosphate units, at most 10 phosphate units, at most 5 phosphate units, at most 4 phosphate units, or at most 3.5 phosphate units. Item 12. The pharmaceutical composition according to any one of Items 1 to 11, which contains a metal salt of polyphosphate, wherein the metal salt of polyphosphate contains at least one of sodium, potassium, magnesium, calcium, and zinc as its constituent metal. Item 13. The pharmaceutical composition according to any one of Items 1 to 12, which contains calcium polyphosphate. Item 14. The pharmaceutical composition according to any one of Items 1 to 12, which contains zinc polyphosphate. Item 15. Item 14. The pharmaceutical composition according to Item 14, wherein the zinc polyphosphate exhibits a broad peak at 2θ=4 to 7° in an X-ray diffraction chart. Item 16. The pharmaceutical composition according to Item 14 or 15, wherein the zinc polyphosphate has a zinc content of 10 to 60%, preferably 20 to 55%, more preferably 30 to 50%. Item 17. The pharmaceutical composition according to any one of Items 1 to 12, which contains sodium polyphosphate. Item 18. The pharmaceutical composition according to any one of Items 1 to 17, for improving frequent urination in IC / BPS patients. Item 19. The pharmaceutical composition according to any one of Items 1 to 18, which is for oral administration. Item 20. The pharmaceutical composition according to any one of Items 1 to 18, which is for intravenous administration or intravesical instillation.

[0013] According to the present invention, it is possible to prevent or treat IC / BPS based on a new mechanism of action.

[0014] Figure 1 shows an X-ray diffraction pattern of zinc polyphosphate. Figure 2 shows the protocol for an intravenous administration study of long-chain sodium polyphosphate using the cyclophosphamide-induced IC / BPS model. Figure 3 shows the results of an intravenous administration study of long-chain sodium polyphosphate (cystometrogram, urine weight, micturition interval, and voided volume). Figure 4 shows the results of an intravenous administration study of long-chain sodium polyphosphate (basal intravesical pressure, maximum intravesical pressure, and micturition threshold). Figure 5 shows the results of an intravenous administration study of long-chain sodium polyphosphate (bladder weight and bladder weight / body weight ratio). Figure 6 shows the results of an intravesical instillation study of long-chain sodium polyphosphate using the hydrochloric acid-induced IC / BPS model (cystometrogram, micturition interval, and maximum intravesical pressure). Figure 7 shows the protocol for an oral administration study of zinc polyphosphate using the cyclophosphamide-induced IC / BPS model. Figure 8 shows the results of an oral administration test of zinc polyphosphate (cystometrogram, urine weight, urination interval, and single urination volume). Figure 9 shows the results of an oral administration test of zinc polyphosphate (basal intravesical pressure, maximum intravesical pressure, and urination threshold). Figure 10 shows the results of an oral administration test of zinc polyphosphate (bladder weight and bladder weight / body weight ratio). Figure 11 shows the results of an oral administration test of zinc polyphosphate (KRT8 immunofluorescent stained images of bladder tissue). Figure 12 shows the results of an oral administration test of zinc polyphosphate (proportion of bladder epithelium in the bladder lumen).

[0015] The following description may be based on representative embodiments or specific examples, but the present invention is not limited to such embodiments or specific examples. In this specification, numerical ranges expressed using "to" or "-" mean ranges that include the numerical values ​​at both ends as upper and lower limits, unless otherwise specified. The upper and lower limits of each numerical range exemplified in this specification can be combined in any way.

[0016] [Polyphosphoric acid and its salts] In the present disclosure, the term "polyphosphoric acid" refers to a compound having a plurality of phosphate units (formula -[P(=O)(O - )-O]-).

[0017] In the present disclosure, the term "salt of polyphosphate" refers to a substance containing multiple phosphate units and cations as constituent units. In the salt of polyphosphate, the cation is bonded to an oxygen anion. The salt of polyphosphate may contain one or more types of cations. Examples of cations contained in the salt of polyphosphate include metal ions (e.g., monovalent metal ions such as sodium and potassium, and divalent metal ions such as calcium, zinc, and magnesium) and organic ions (e.g., ammonium ions).

[0018] The polyphosphate salt used in the present disclosure may be any pharmaceutically acceptable salt, and is preferably a metal salt containing a metal ion as a cation. The polyphosphate metal salt preferably contains at least one of sodium, potassium, magnesium, calcium, and zinc as its constituent metal, more preferably at least one of sodium, calcium, and zinc, and even more preferably at least one of calcium and zinc.

[0019] The individual phosphate units contained in polyphosphoric acid and salts thereof may be bonded to each other directly or via an atom or functional group other than the phosphate unit, for example, a divalent or higher valent cation (e.g., a divalent metal ion such as calcium or zinc). In this specification, when matters common to both polyphosphoric acid and salts of polyphosphoric acid are explained, they are collectively referred to as "polyphosphoric acid and salts thereof."

[0020] The polyphosphoric acid and salts thereof may be linear or cyclic, and may have one or more branches. Preferably, the polyphosphoric acid and salts thereof are linear.

[0021] Polyphosphates and salts thereof may contain only one type of molecule having the same structure and chain length, or may contain multiple types of molecules having different structures or chain lengths. The chain length of polyphosphates and salts thereof is expressed in terms of the number of consecutive phosphate units directly bonded to each other in the linear portion. For example, a chain length of 10 phosphate units or more (n=10) means that the linear portion of the polyphosphate molecule contains 10 or more consecutive phosphate units.

[0022] When polyphosphoric acid and its salts contain only one type of molecule having the same structure and chain length, the average chain length of the polyphosphoric acid and its salts is the same as the chain length of the molecule. When polyphosphoric acid and its salts contain multiple types of molecules having different structures or chain lengths, the average chain length of the polyphosphoric acid and its salts can be calculated by multiplying the chain length of each molecule by the proportion of that molecule in all molecules, and then adding up the obtained values ​​for all types.

[0023] The average chain length can be determined, for example, by size exclusion chromatography or, in the case of linear chains, by 31 It can be determined by known analytical methods such as P NMR, or electrospray ionization mass spectrometry (ESI-MS) when the chain length is relatively short. For analytical methods, see, for example, Christ et al., Anal. Chem. 2020, 92, 4167-4176, DOI: 10.1021 / acs.analchem.9b05144.

[0024] for example, 31 Using P NMR, the average chain length of polyphosphates and their salts can be determined as follows: 31 From the P NMR spectrum, the integral value of the signal corresponding to P in the terminal phosphate group of the polyphosphate molecule (terminal phosphate signal) and the total integral value of all signals corresponding to P in the phosphate groups of the polyphosphate molecule (total phosphate group signals) are obtained, and the ratio of the total integral values ​​of all phosphate group signals is calculated when the integral value of the terminal phosphate group signal is set to 2. This ratio corresponds to the average chain length of linear polyphosphate. The solvent used for sample preparation may contain a pH adjuster such as a buffer, as long as it does not contain a phosphate-containing compound.

[0025] The average chain length of polyphosphates and salts thereof used in the present disclosure is not limited, and may be, for example, 1.1 phosphate units or more, 1.2 phosphate units or more, 1.3 phosphate units or more, 1.4 phosphate units or more, 1.5 phosphate units or more, 1.6 phosphate units or more, 1.7 phosphate units or more, 1.8 phosphate units or more, 1.9 phosphate units or more, 2 phosphate units or more, 2.5 phosphate units or more, 3 phosphate units or more, 4 phosphate units or more, 5 phosphate units or more, 6 phosphate units or more, 7 phosphate units or more, 8 phosphate units or more, 9 phosphate units or more, or 10 phosphate units or more, and may be, for example, 10,000 phosphate units or less, 1,000 phosphate units or less, 900 phosphate units or less, or 10,000 phosphate units or less. The phosphate units may be less than 800 phosphate units, less than 700 phosphate units, less than 600 phosphate units, less than 500 phosphate units, less than 400 phosphate units, less than 300 phosphate units, less than 200 phosphate units, less than 100 phosphate units, less than 90 phosphate units, less than 80 phosphate units, less than 70 phosphate units, less than 60 phosphate units, less than 50 phosphate units, less than 40 phosphate units, less than 30 phosphate units, less than 20 phosphate units, less than 15 phosphate units, less than 10 phosphate units, less than 5 phosphate units, less than 4 phosphate units, less than 3.5 phosphate units, less than 3 phosphate units, less than 2.5 phosphate units, less than 2 phosphate units, or less than 1.5 phosphate units.

[0026] The polyphosphoric acid and salts thereof used in the present disclosure may have a mass of greater than 10 kDa. Polyphosphoric acid and salts thereof having a mass of greater than 10 kDa can also be expressed as polyphosphoric acid and salts thereof that do not permeate an ultrafiltration membrane with a molecular weight cutoff of 10 kDa when subjected to ultrafiltration. Here, ultrafiltration refers to the process of adding a sample to a spin column equipped with an ultrafiltration membrane made of PES (polyethersulfone) and centrifuging the sample to filter out molecules in the sample.

[0027] The polyphosphoric acid and its salts used in the present disclosure may be readily soluble, sparingly soluble, or insoluble in water. Sparingly soluble or insoluble polyphosphoric acid salts have the advantages of being easy to recover, wash, dry, and otherwise handle, and of having low hygroscopicity and excellent storage stability.

[0028] The polyphosphoric acid and salts thereof used in the present disclosure are not limited in their molecular arrangement, and may be crystalline, quasicrystalline, or amorphous.

[0029] The polyphosphate and its salts used in the present disclosure may form microparticles (hereinafter also referred to as polyphosphate microparticles). The average particle size of the polyphosphate microparticles may be, for example, 1 nm or more, 10 nm or more, 20 nm or more, 50 nm or more, 100 nm or more, 200 nm or more, or 500 nm or more, and may be, for example, 3000 nm, 2500 nm, 2000 nm, 1500 nm, 1000 nm, 800 nm, 600 nm, or 500 nm or less. The polyphosphate microparticles may be aggregates of fine polyphosphate particles, and the aggregates may have an average particle size within the above numerical range. Polyphosphate microparticles with a particle size on the order of nanometers are also called polyphosphate nanoparticles.

[0030] The average particle size refers to the harmonic mean particle size (diameter) based on scattered light intensity, and can be obtained by dynamic light scattering (DLS) measurement and cumulant analysis. Measurement by dynamic light scattering and cumulant analysis can be performed using a commercially available DLS device or the like according to the methods described in JIS Z 8828:2019, ISO 22412:2017, etc.

[0031] The polyphosphoric acid and salts thereof used in the present disclosure may have a zeta potential of, for example, 0 mV or less, preferably -20 mV or less, and more preferably -30 mV or less. The polyphosphoric acid and salts thereof used in the present disclosure may have a zeta potential of, for example, -100 to 0 mV or less, preferably -80 to -20 mV, and more preferably -60 to -30 mV. The zeta potential can be measured by electrophoretic light scattering (ELS, also known as laser Doppler electrophoresis).

[0032] In one embodiment, the metal salt of polyphosphate is zinc polyphosphate. Zinc polyphosphate is primarily composed of polyphosphoric acid and zinc, with zinc being the most abundant constituent metal. Zinc polyphosphate may be composed solely of polyphosphoric acid and zinc, or may be composed of polyphosphoric acid, zinc, and other metals, such as sodium, calcium, and magnesium. The zinc content in zinc polyphosphate is preferably 10-60%, more preferably 20-55%, and even more preferably 30-50%. Here, the zinc content refers to the mass % of zinc element in zinc polyphosphate. Furthermore, the content of other metals in zinc polyphosphate is in the range of 0-30%, preferably 0-20%, more preferably 0-10%, and even more preferably 0-7%. Here, the content of other metals refers to the mass % of metal elements other than zinc in zinc polyphosphate.

[0033] The zinc polyphosphate may further contain various inorganic salts such as inorganic zinc salts (e.g., zinc hydroxide, zinc oxide, zinc phosphate, etc.) and calcium phosphate, and may also contain inorganic carbon compounds such as calcium carbonate.

[0034] The zinc polyphosphate preferably exhibits a broad peak at 2θ = 4 to 7° in an X-ray diffraction chart. In the present disclosure, a broad peak refers to a peak having a half-width of 1 degree or more in an X-ray diffraction chart, and is clearly distinguishable from a sharp linear peak. In addition to the broad peak at 2θ = 4 to 7°, the zinc polyphosphate preferably exhibits a broad peak at either 2θ = 30 to 36° or 56 to 62°, and more preferably exhibits broad peaks at both of these positions. Furthermore, the zinc polyphosphate preferably further exhibits a plateau-like, gentle signal spanning at least the range of 2θ = 10 to 36° in an X-ray diffraction chart, in addition to the one or more broad peaks described above.

[0035] The zinc polyphosphate is preferably in the form of fine particles. The zinc polyphosphate fine particles may have an average particle size of preferably 1 nm to 1000 nm, more preferably 20 nm to 800 nm, even more preferably 20 nm to 500 nm, and even more preferably 100 nm to 500 nm. The zinc polyphosphate fine particles may have a zeta potential of, for example, -100 to 0 mV or less, preferably -80 to -20 mV, and more preferably -60 to -30 mV.

[0036] The average chain length of the zinc polyphosphate can be 1.1 to 1000 phosphate units, 1.1 to 50 phosphate units, 1.1 to 30 phosphate units, 1.1 to 15 phosphate units, 1.1 to 5 phosphate units, 1.1 to 4 phosphate units, 1.1 to 3.5 phosphate units, 1.1 to 3 phosphate units, 1.1 to 2.5 phosphate units, or 1.1 to 2 phosphate units. The zinc polyphosphate is preferably sparingly soluble in water.

[0037] The zinc polyphosphate may be one disclosed in WO2024 / 090537 A1 or WO2024 / 090538 A1, which has both intestinal barrier function and excellent storage stability.

[0038] In one embodiment, the metal salt of polyphosphate is calcium polyphosphate. Calcium polyphosphate is mainly composed of polyphosphate and calcium, with calcium being the most abundant constituent metal. Calcium polyphosphate may be composed only of polyphosphate and calcium, or may be composed of polyphosphate and calcium and other metals, such as sodium, magnesium, and zinc.

[0039] The calcium polyphosphate may further contain calcium inorganic salts (for example, calcium hydroxide, calcium oxide, calcium phosphate, etc.), and may also contain inorganic carbon compounds such as calcium carbonate.

[0040] Calcium polyphosphate is preferably in the form of fine particles. The average particle diameter of the calcium polyphosphate fine particles may be preferably 10 nm to 3000 nm, more preferably 100 nm to 2500 nm, even more preferably 200 nm to 2000 nm, and even more preferably 500 nm to 1500 nm. The zeta potential of the calcium polyphosphate fine particles may be, for example, -100 to 0 mV or less, preferably -80 to -20 mV, and more preferably -60 to -30 mV.

[0041] The average chain length of calcium polyphosphate can be 1.1 to 1000 phosphate units, 1.1 to 200 phosphate units, 1.1 to 50 phosphate units, 1.1 to 30 phosphate units, 1.1 to 20 phosphate units, or 1.1 to 15 phosphate units. Calcium polyphosphate is preferably poorly soluble in water. Calcium polyphosphate is preferably amorphous.

[0042] The calcium polyphosphate may be that disclosed in WO2021 / 141066 A1, which has both intestinal barrier function and excellent storage stability.

[0043] In one embodiment, the metal salt of polyphosphate is sodium polyphosphate. Sodium polyphosphate is mainly composed of polyphosphate and sodium, with sodium being the most abundant constituent metal. Sodium polyphosphate may be composed only of polyphosphate and sodium, or may be composed of polyphosphate and sodium and other metals, such as calcium, magnesium, and zinc.

[0044] The average chain length of the sodium polyphosphate can be 1.1 to 10,000 phosphate units, 1.1 to 1,000 phosphate units, 3 to 1,000 phosphate units, 10 to 750 phosphate units, or 10 to 500 phosphate units. The sodium polyphosphate is preferably readily soluble in water.

[0045] Polyphosphoric acid and salts thereof can be produced by known chemical synthesis techniques, biochemical techniques, or biological techniques.

[0046] An example of a chemical synthesis method is a method in which a reaction solution containing a phosphate such as sodium phosphate is heated to a dehydration condensation temperature of, for example, 150 to 350°C.

[0047] An example of a biochemical method is synthesis by reacting adenosine triphosphate (ATP) with polyphosphate kinase (PPK). Commercially available PPK may be purchased, or PPK produced by known microorganisms capable of producing polyphosphate, such as Lactobacillus rhamnosus, Lactobacillus brevis, and Propionibacterium freudenreichii subsp. shermanii, may be used.

[0048] Although the enzymatic reaction catalyzed by PPK is reversible, when a large amount of ADP is present in the reaction solution relative to ATP, the decomposition reaction of polyphosphate becomes dominant so that the ADP / ATP ratio reaches equilibrium. Therefore, for efficient polyphosphate synthesis, it is preferable to maintain a low ADP concentration in the reaction solution. For example, a continuous ATP regeneration reaction system using creatine kinase or pyruvate kinase may be coupled. Other conditions, such as the composition of the reaction solution, reaction temperature, and reaction time, can be appropriately set to optimize PPK activity and depending on the synthesis scale.

[0049] As an example, the reaction conditions for coupling polyphosphate synthesis using PPK from Propionibacterium freudenreichii subsp. shermanii with a continuous ATP regeneration reaction using pyruvate kinase are shown below. Mix 680 μL of 2 mol / L Tris-HCl (pH 9.0), 0.1 g of phosphoenolpyruvate, 72 mg of adenosine 5'-triphosphate disodium trihydrate, 160 μL of 1 mol / L phosphate buffer (pH 6.0), 60 μL of 2 mol / L magnesium chloride, 1 mL of 2 mol / L acetate buffer (pH 6.0), and 2.1 mL of purified water in a 10 mL sample tube and incubate at 40°C for 30 minutes. After incubation, add 2.5 μL of 240 U / mL polyphosphate kinase and incubate at 40°C for an additional 5 minutes. Subsequently, 2.5 μL of 1690 U / mL pyruvate kinase is added, and the mixture is reacted for 0.5 to 36 hours at 40° C. The reaction time may be appropriately set depending on the molecular weight and yield of the target polyphosphate. For example, to obtain high-molecular-weight polyphosphate in good yield, the reaction time is preferably about 20 hours.

[0050] An example of a biological method is to culture a microorganism capable of producing polyphosphate under appropriate culture conditions to produce polyphosphate. Examples of microorganisms capable of producing polyphosphate include strains belonging to the genera Lactobacillus, Bifidobacterium, Enterococcus, Lactococcus, Pediococcus, Leuconostoc, Streptococcus, Bacteroides, Eubacterium, and Clostridium, such as Lactobacillus rhamnosus GG and Lactobacillus brevis SBC8803. Polyphosphate can be recovered from the culture medium, supernatant, or precipitate after culturing a microorganism capable of producing polyphosphate under conditions suitable for polyphosphate production.

[0051] The salt of polyphosphate can be obtained by allowing a cation to coexist in the reaction system during the production of polyphosphate by the above-mentioned chemical synthesis method, biochemical method, or biological method. Alternatively, the salt of polyphosphate can be obtained by reacting polyphosphate with a chloride salt of the cation under alkaline conditions.

[0052] For example, zinc polyphosphate can be obtained by adjusting the pH of a polyphosphoric acid solution to 7.5 or higher, preferably 8 to 11, to prepare an alkaline solution of polyphosphoric acid, and then adding zinc chloride to the solution and allowing it to react. Alternatively, zinc polyphosphate can be obtained by adding zinc chloride to a polyphosphoric acid solution having a pH of 4 or higher (e.g., pH 4 to 7.5), and then adjusting the solution to an alkaline pH, for example, to 7.5 or higher, preferably 8 to 11, and allowing it to react. For details, see WO2024 / 090537 A1 and WO2024 / 090538 A1.

[0053] For example, calcium polyphosphate can be obtained by adding calcium chloride to an alkaline solution of polyphosphoric acid and reacting it, similar to zinc polyphosphate. For details, see WO2021 / 141066 A1.

[0054] Polyphosphoric acid and salts thereof can be purified by separation and concentration methods such as size exclusion chromatography, ion exchange chromatography, affinity chromatography, high performance liquid chromatography (HPLC), dialysis, salting out, ammonium sulfate precipitation, precipitation, and crystallization.

[0055] Pharmaceutical Compositions The pharmaceutical compositions of the present disclosure contain polyphosphate or a salt thereof, preferably a metal salt of polyphosphate, as an active ingredient and can be used for the prevention or treatment of IC / BPS. As used herein, the term "prevention" encompasses all types of medically acceptable preventative interventions aimed at preventing or suppressing the onset or development of a disease. The term "treatment" encompasses all types of medically acceptable therapeutic interventions aimed at curing or temporarily alleviating a disease or condition. Therefore, prevention or treatment of IC / BPS encompasses medically acceptable interventions for various purposes, including improving symptoms of IC / BPS, such as frequent urination, increased urgency, urinary urgency, and pain, slowing or halting progression, preventing the onset, or preventing recurrence. In particular, the pharmaceutical compositions of the present disclosure can be used to improve frequent urination in IC / BPS.

[0056] The pharmaceutical composition of the present disclosure contains an amount of polyphosphate or a salt thereof effective for the prevention or treatment of IC / BPS. The effective amount of polyphosphate or a salt thereof can be determined appropriately depending on the dosage, the age, sex, weight, severity, and other factors of the subject. The pharmaceutical composition may contain only polyphosphate, only a salt of polyphosphate, or both polyphosphate and a salt of polyphosphate.

[0057] The pharmaceutical composition of the present disclosure may contain, in addition to polyphosphoric acid or a salt thereof, pharmaceutically acceptable additives. Examples of pharmaceutically acceptable additives include excipients, binders, lubricants, solvents, disintegrants, solubilizers, suspending agents, emulsifiers, isotonicity agents, stabilizers, preservatives, antioxidants, flavoring agents, coloring agents, buffers, and flow enhancers. Pharmaceutically acceptable additives are well known to those skilled in the art, and those skilled in the art can appropriately select and use them within the scope of their ordinary skill.

[0058] Specific examples of excipients include organic excipients such as sugars such as lactose, glucose, and D-mannitol, starches, and celluloses such as crystalline cellulose, and inorganic excipients such as calcium carbonate and kaolin.

[0059] Examples of binders include pregelatinized starch, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, D-mannitol, trehalose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol.

[0060] Examples of lubricants include stearic acid, fatty acid salts such as stearates, talc, silicates, and the like.

[0061] Examples of the solvent include purified water, physiological saline, and phosphate buffer solution.

[0062] Disintegrants include low-substituted hydroxypropyl cellulose, chemically modified celluloses and starches.

[0063] Examples of solubilizing agents include polyethylene glycol, propylene glycol, trehalose, benzyl benzoate, ethanol, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.

[0064] Examples of suspending agents or emulsifying agents include sodium lauryl sulfate, gum arabic, gelatin, lecithin, glycerin monostearate, polyvinyl alcohol, polyvinylpyrrolidone, celluloses such as sodium carboxymethylcellulose, polysorbates, and polyoxyethylene hydrogenated castor oil.

[0065] Examples of isotonic agents include sodium chloride, potassium chloride, sugars, glycerin, and urea.

[0066] Stabilizers include polyethylene glycol, dextran sodium sulfate, other amino acids, and magnesium carbonate, which also acts as an acidity regulator.

[0067] Examples of preservatives include parahydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

[0068] Antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; fat-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0069] Flavoring agents include sweeteners, fragrances, and the like that are commonly used in the pharmaceutical field, and coloring agents include coloring agents that are commonly used in the pharmaceutical field.

[0070] The pharmaceutical composition of the present disclosure may contain other drugs for the prevention or treatment of IC / BPS. Examples of other drugs for the prevention or treatment of IC / BPS include drugs described in Non-Patent Document 1 (Guidelines for the Treatment of Interstitial Cystitis / Bladder Pain Syndrome). In particular, when the pharmaceutical composition is administered intravesically, drugs suitable for intravesical administration, such as heparin, DMSO, or steroids, are preferred.

[0071] The pharmaceutical composition of the present disclosure may be in any dosage form suitable for the route of administration, and can be formulated into dosage forms such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, and orally disintegrating tablets), powders, granules, capsules (including soft capsules and microcapsules), liquids, troches, syrups, emulsions, suspensions, injections (e.g., intravenous injections, subcutaneous injections, intramuscular injections, intraperitoneal injections, etc.), topical preparations (e.g., nasal preparations, transdermal preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories), foams (enemas), pellets, nasal preparations, pulmonary preparations (inhalants), and the like.

[0072] The pharmaceutical composition of the present disclosure can be administered orally or parenterally (e.g., intravenously, intravesically, rectally, etc.), and is preferably administered orally or by transurethral or transvesically intravesically.

[0073] Pharmaceutical compositions for oral administration may be in the form of oral preparations, such as tablets, powders, granules, capsules, liquids, troches, syrups, emulsions, suspensions, and the like.

[0074] The pharmaceutical composition for intravesical instillation may be, for example, a liquid. The liquid contains an effective amount of polyphosphate or a salt thereof and a pharmaceutically acceptable vehicle. Examples of pharmaceutically acceptable vehicles include aqueous media such as water, saline, and phosphate-buffered saline (PBS). The unit dose of the liquid can be determined depending on the route of administration, the effective amount of polyphosphate or a salt thereof, and the like. For example, in the case of intravesical instillation, the unit dose is 30 to 50 mL, and the liquid can be administered to a subject at appropriate intervals, such as once a week, once every two weeks, or once a month.

[0075] The pharmaceutical composition of the present disclosure may be a controlled-release formulation such as an immediate-release formulation or a sustained-release formulation. Furthermore, when formulated as an oral preparation, coating may be performed as necessary for the purposes of masking, enteric coating, or sustained release. Examples of coating bases used for coating include sugar-coating bases, water-soluble film-coating bases, enteric film-coating bases, and sustained-release film-coating bases.

[0076] The pharmaceutical composition of the present disclosure is administered to a subject at risk of developing or currently developing IC / BPS. The subject may be a human or a non-human animal. Non-human animals may include mammals such as rodents including mice, rats, hamsters, and guinea pigs; primates including chimpanzees and rhesus monkeys; livestock including pigs, cows, goats, horses, and sheep; and pets including dogs and cats. The pharmaceutical composition is preferably administered to humans.

[0077] The dosage of the pharmaceutical composition when administered to humans (excluding intravesical instillation) can be selected, for example, from the range of 0.005 mg / kg to 15 mg / kg, preferably 0.01 mg / kg to 15 mg / kg, more preferably 0.05 mg / kg to 15 mg / kg, even more preferably 0.05 mg / kg to 5 mg / kg, and even more preferably 0.05 mg / kg to 2.5 mg / kg, in terms of polyphosphate per administration per day. Alternatively, the pharmaceutical composition can be administered, for example, in the range of 0.3 to 900 mg / day, preferably 0.6 to 900 mg / day, more preferably 3 to 900 mg / day, even more preferably 3 to 300 mg / day, and even more preferably 3 to 150 mg / day, in terms of polyphosphate per patient, once a day or in divided doses.

[0078] When administered to humans (excluding intravesical instillation), the dosage of a pharmaceutical composition containing zinc polyphosphate can be selected, for example, from the range of 0.005 mg / kg to 5 mg / kg, preferably 0.01 mg / kg to 4 mg / kg, more preferably 0.01 mg / kg to 2.5 mg / kg, even more preferably 0.015 mg / kg to 2 mg / kg, still more preferably 0.03 mg / kg to 1 mg / kg, and even more preferably 0.05 mg / kg to 1 mg / kg, in terms of zinc polyphosphate per day. Alternatively, the pharmaceutical composition can be administered, for example, in the range of 0.3 to 300 mg / day, preferably 0.6 to 240 mg / day, more preferably 0.6 to 150 mg / day, even more preferably 0.9 to 120 mg / day, still more preferably 1.8 to 60 mg / day, and even more preferably 3 to 60 mg / day, in terms of zinc polyphosphate per patient, once a day or in divided doses.

[0079] The dosage of the pharmaceutical composition when administered intravesically to humans is, for example, 10 μg to 1500 mg, preferably 30 μg to 500 mg, more preferably 300 μg to 50 mg in terms of polyphosphate per administration.

[0080] [Food and Beverage Compositions] Polyphosphoric acid and its salts can be safely ingested orally, and therefore can be used as ingredients in foods and beverages, such as foods for specified health uses, foods for special dietary uses, dietary supplements, health foods, functional foods, and foods for medical patients. Thus, the present disclosure provides food and beverage compositions containing polyphosphoric acid or a salt thereof for preventing or treating IC / BPS. The present disclosure also provides food and beverage compositions containing polyphosphoric acid or a salt thereof for improving frequent urination in IC / BPS.

[0081] [Method for preventing or treating IC / BPS] The present disclosure further provides a method for preventing or treating IC / BPS, comprising administering to a subject at risk of developing or currently developing IC / BPS the pharmaceutical composition containing the polyphosphate or a salt thereof. The present invention also provides a method for improving frequent urination in IC / BPS, comprising administering the pharmaceutical composition containing the polyphosphate or a salt thereof.

[0082] In addition, the present invention provides use of the above-mentioned polyphosphoric acid or a salt thereof in the manufacture of a pharmaceutical composition for the prevention or treatment of IC / BPS; use of the above-mentioned polyphosphoric acid or a salt thereof in the manufacture of a pharmaceutical composition for ameliorating frequent urination in IC / BPS; use of the above-mentioned polyphosphoric acid or a salt thereof for the prevention or treatment of IC / BPS; and use of the above-mentioned polyphosphoric acid or a salt thereof for ameliorating frequent urination in IC / BPS.

[0083] The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

[0084] Example 1. Preparation of Polyphosphates (A) Preparation of Long-Chain Sodium Polyphosphate: 680 μL of 2 mol / L Tris-HCl (pH 9.0), 0.1 g of phosphoenolpyruvic acid, 72 mg of adenosine 5'-triphosphate disodium trihydrate, 160 μL of 1 mol / L phosphate buffer (pH 6.0), 60 μL of 2 mol / L magnesium chloride, 1 mL of 2 mol / L acetate buffer (pH 6.0), and 2.1 mL of purified water were mixed in a 10 mL sample tube and heated at 40°C for 30 minutes. After heating, 2.5 μL of 240 U / mL polyphosphate kinase was added and the mixture was further heated at 40°C for 5 minutes. 2.5 μL of 1690 U / mL pyruvate kinase was then added and the mixture was incubated at 40°C for 20 hours. 1.7 mL of 2 mol / L sodium chloride was added to the reaction mixture and stirred at 10°C for 10 minutes. After stirring, the supernatant was removed, and 400 μL of purified water was added to the precipitate to dissolve it. 400 μL of 3 mol / L sodium chloride was then added to precipitate the precipitate. 400 μL of purified water was added to dissolve the precipitate, and 400 μL of 3 mol / L sodium chloride was added to precipitate the precipitate. After removing the supernatant, the precipitate was lyophilized to obtain long-chain sodium polyphosphate (also known as Poly-P Na or PPA-Na). From the chromatogram obtained by HPLC using a gel filtration column, the average chain length of the long-chain sodium polyphosphate was estimated to be 600-800.

[0085] (B) Preparation of Zinc Polyphosphate: 1 g of long-chain sodium polyphosphate (average chain length 600 or greater; Kamui Pharma Co., Ltd.) prepared in the same manner as in (A) above was added to 50 g of water to prepare an aqueous solution. A 1 mol / L aqueous sodium hydroxide solution was added to adjust the pH to 10, and 50 mL of a 1 mol / L zinc chloride solution was added dropwise over approximately 30 minutes. During the dropwise addition, sodium hydroxide solution was added periodically to maintain the pH at approximately 10. After the dropwise addition, the mixture was stirred at room temperature for 4 hours, then allowed to stand at a temperature below 10°C for 16 hours. The precipitate was then centrifuged (12,000 × g, 4°C, 10 minutes) to recover the precipitate. The precipitate was washed with aqueous ethanol (33% v / v ethanol) and centrifuged twice. This process was repeated twice, followed by lyophilization to obtain zinc polyphosphate (also known as Poly-P Zn or PPA-Zn) as a white powder.

[0086] (C) Confirmation of the degree of polymerization of zinc polyphosphate by NMR measurement Approximately 10 mg of zinc polyphosphate was dissolved in approximately 0.7 mL of approximately 190 mmol / L citrate-sodium buffer solution (DO), pH 5.5, and used as an analytical sample. 31 P NMR was measured. (i) Instrument: Bruker BioSpin 400 MHz. (ii) Analysis Conditions: The signal at -5 ppm represents the terminal phosphate group, and the signals between -15 and -25 ppm represent internal phosphate groups. The total integral value of the terminal phosphate group was calculated by setting the integral value of the terminal phosphate group to 2. Zinc polyphosphate is prepared from linear sodium polyphosphate in aqueous solution. Cyclized polyphosphate is rare, and most polyphosphates are linear. Therefore, the calculated total integral value of the phosphate group is considered to be close to the degree of polymerization of zinc polyphosphate. Furthermore, since zinc polyphosphate is linear, the degree of polymerization is equal to the average chain length. (iii) Results: The degree of polymerization of the zinc polyphosphate prepared in (B) above was calculated to be 8.5 by NMR measurement. Based on the manufacturing method in (A), zinc polyphosphate with a degree of polymerization ranging from 5.6 to 12.0 could be produced by varying detailed conditions such as the stirring time after sodium hydroxide addition and the collection, washing, and drying of the precipitate.

[0087] (D) Powder X-ray crystal diffraction of zinc polyphosphate (i) Instrument: Rigaku MiniFlex II (ii) Analysis conditions: Anticathode: Cu, tube voltage: 30 kV, tube current: 15 mA, monochromator: Ni filter, sampling width: 0.020°, scanning speed: 10° / min, wavelength: 1.541836 Å, diffraction angle range (2θ): 2–60°, divergence slit: 1.25°, scattering slit: 8.0 mm, receiving slit: open (iii) Results: The zinc polyphosphate prepared in (B) above exhibited broad signal peaks at 2θ = 4–7°, 30–36°, and 56–62° (Figure 1). Zinc polyphosphate with a degree of polymerization ranging from 5.6 to 12.0, prepared by the method in (A) but varying the stirring time after sodium hydroxide addition and the recovery, washing, and drying of the precipitate, also exhibited broad signal peaks at the same positions. Such a signal peak is not observed with conventionally known polyphosphates such as sodium polyphosphate and calcium polyphosphate.

[0088] (E) Elemental Analysis of Polyphosphates. 20 mg of sodium polyphosphate and zinc polyphosphate prepared in (A) and (B) were weighed on a precision electronic balance and subjected to elemental analysis at Nogai Kagaku Co., Ltd. (Sapporo). Water content was determined by loss on drying (105°C, 2 hours). The test solution was prepared by adding nitric acid and hydrogen peroxide to the sample, decomposing it in a microwave sample pretreatment device, and then adjusting the volume to 20 ml with distilled water. Sodium, calcium, and magnesium contents were determined by flame atomic absorption spectrometry using an atomic absorption spectrometer (PerkinElmer, Analist 200). Zinc content was determined by inductively coupled plasma mass spectrometry (Agilent, Agilent 7500cx). Phosphorus content was determined by molybdenum reduction blue absorptiometry using a spectrophotometer (Shimadzu, UV-1800). The elemental contents (mass%) are shown in Table 1.

[0089] (F) Measurement of pH, zeta potential, and particle size of zinc polyphosphate. Five mg of zinc polyphosphate was suspended in 1 mL of purified water. The suspension was allowed to stand, and the pH of the supernatant was measured. After pH measurement, the suspension was ultrasonically dispersed and diluted to 2 mg / mL with purified water. This was used as an analytical sample to measure the zeta potential and particle size. Instrument: Malvern, ZEN3600. Analysis conditions: Dispersant: Water, Dispersant RI: 1.330, Viscosity (cp): 0.8872, Dispersant Dielectric Constant: 78.5, Temperature: 25°C. The pH of zinc polyphosphate was 9.46, and the zeta potential was -33.0 mV. The mean particle size based on intensity was 175.9 (d.nm).

[0090] (G) Preparation of Calcium Polyphosphate. 1.2 g of long-chain sodium polyphosphate (average chain length ≥ 600; Kamui Pharma Co., Ltd.) prepared in the same manner as in (A) above was added to 60 g of water to prepare an aqueous solution. 1 mol / L sodium hydroxide solution was added to adjust the pH to 10. 0.865 g of calcium chloride hydrate was added to 7.5 mL of purified water to prepare a calcium chloride solution. The entire amount was added dropwise to the long-chain sodium polyphosphate solution using a peristaltic pump at a rate of approximately 0.2 g / min. During the addition, sodium hydroxide solution was added periodically to maintain the pH at approximately 10. After the addition, the mixture was stirred at room temperature for 4 hours. The resulting suspension was then transferred to a centrifugal ultrafiltration unit (Amicon Ultra-15, nominal molecular weight cutoff: 3 kDa, sample volume: 15 mL) and concentrated and desalted by centrifugation (3,040 × g, 20 °C, 3 hours). The filter unit containing the concentrated precipitate was redispersed by adding 2 mL of ethanol (99.5%), followed by centrifugation at 3,040 × g and 20°C for 1 hour, after which the ethanol wash was removed. This ethanol washing procedure was repeated twice. After washing, the precipitate was vacuum-dried together with the filter unit, and the resulting solid was sieved through a sieve (mesh opening: 500 μm) to obtain calcium polyphosphate (also known as Poly-P Ca or PPA-Ca) as a white powder.

[0091] (H) Zeta Potential and Particle Size Measurement of Calcium Polyphosphate. The average particle size and zeta potential of the prepared calcium polyphosphate particles were measured using a dynamic light scattering (DLS) particle size analyzer (Zetasizer model Nano-ZS, Ver. 6.01, Malvern Instruments). Calcium polyphosphate was suspended in distilled water at a concentration of approximately 1 mg / mL and filtered through a PVDF membrane filter (Millex-SV Filter Unit, Low Protein Binding Durapore (PVDF) Membrane, pore size: 5.0 μm, Merck Millipore Ltd.). After vortexing, the supernatant dispersion was subjected to both dynamic light scattering and zeta potential measurements. Measurements were performed at 25°C using a disposable collapsible capillary cell (DTS1070). The average particle size of calcium polyphosphate was 1252 nm, and the zeta potential was -36.2 mV.

[0092] Example 2. Effect of Intravenous Administration of Long-Chain Sodium Polyphosphate Ten-week-old female Wistar / ST rats were divided into a sham group (n = 12), IC group (n = 11), and IC + Poly-P Na group (n = 12). Physiological saline was administered intraperitoneally to the sham group, and cyclophosphamide (CYP) 200 mg / kg was administered intraperitoneally to the IC and IC + Poly-P Na groups to induce cystitis. Subsequently, physiological saline was administered intravenously to the sham and IC groups, and 1 mg / body of long-chain sodium polyphosphate prepared in Example 1 (A) was administered intravenously to the IC + Poly-P Na group via the tail vein. The day after administration, urinary function was evaluated by cystometry. Under isoflurane anesthesia, a PE-50 tube was placed at the bladder vertex of each rat. The tube was passed subcutaneously and exited from the back (under the neck) and connected to a pressure transducer (MLT0699, ADInstruments Ltd, Dunedin, New Zealand) and a syringe pump (YSP-101, YMC Co., Ltd., Kyoto, Japan). After surgery, the rats were immobilized, and saline was infused into the bladder at a rate of 40 μl / min while measuring intravesical pressure and voided volume. Ten stable voiding data points were obtained at least two hours after the start of perfusion and were used for analysis. The pressure at the voiding peak on the cystometric curve was defined as the maximum intravesical pressure, the interval between peaks as the voiding interval, the pressure immediately after the peak as the basal intravesical pressure, the pressure immediately before the peak as the voiding threshold, and the volume voided at the peak as the single voided volume. After the test, the rats were euthanized, and the bladders were removed and their wet weights were measured. The test protocol for this example is shown in Figure 2, and the results are shown in Figures 3-5.

[0093] The IC group showed a shorter urination interval and a smaller voided volume compared with the sham group. Meanwhile, the IC+Poly-P Na group, which received intravenous sodium polyphosphate, showed a significant improvement in urination interval compared with the IC group. A trend toward improvement in voided volume was observed (Figure 3). Basal intravesical pressure and micturition threshold were significantly higher in the IC group, while a trend toward improvement was observed in the IC+Poly-P Na group. Maximum intravesical pressure was higher in both the IC and IC+Poly-P Na groups, but no significant difference was observed (Figure 4). Bladder weight and bladder weight / body weight ratio (both indicators of tissue thickening) significantly increased in the IC and IC+Poly-P Na groups, but no significant difference was observed between the IC and IC+Poly-P Na groups (Figure 5).

[0094] Example 3. Effect of Intravesical Instillation of Long-Chain Sodium Polyphosphate. Eight-week-old female Fisher 344 rats (weight: 151.3-172.6 g) had polyethylene catheters inserted into their urethras and left in place. 300 μL of 0.1 M HCl was instilled into the bladder through the catheter and allowed to sit for 1 minute, after which the bladder was irrigated twice with saline. The rats were divided into two groups (n = 3 / group). On the day following HCl injection (Day 1), Day 2, and Day 3, one group received 300 μL of PBS, and the other group received 300 μL of a 0.1 mg / mL solution of long-chain sodium polyphosphate (average chain length: 450-700; Kamui Pharma Co., Ltd.) in PBS. The other group received a transurethral instillation of the catheter and allowed to sit for 30 minutes. On Day 4, bladder function was evaluated using the same method as in Example 2.

[0095] In the groups injected with sodium polyphosphate (HCl + PolyP or 3PolyP in the figure), the micturition interval was prolonged and the mean maximum intravesical pressure during micturition was lower than in the groups injected with PBS (HCl + PBS or 3PBS in the figure) (Figure 6).

[0096] Example 4. Effect of Oral Administration of Zinc Polyphosphate Ten-week-old female Wistar / ST rats were divided into four groups: sham group (n = 12), IC group (n = 12), IC + Poly-P Zn(0.1) group (n = 10), and IC + Poly-P Zn(1) group (n = 11). Physiological saline was intraperitoneally administered to the sham group, while CYP 150 mg / kg was intraperitoneally administered to the IC, IC + Poly-P Zn(0.1), and IC + Poly-P Zn(1) groups. Subsequently, zinc polyphosphate (average chain length 8.5) prepared in Example 1 (B) was orally administered at 0.1 mg / kg and 1 mg / kg to rats in the IC + Poly-P Zn(0.1) and IC + Poly-P Zn(1) groups. The day after administration, bladder function was evaluated and weight was measured in the same manner as in Example 2.

[0097] The excised bladder tissue was fixed in 10% formalin, embedded in paraffin, and sliced ​​(5 μm). The slices were deparaffinized and immunofluorescently stained using a primary antibody against the bladder epithelial marker Cytokeratin 8 (KRT8) (Cosmo Bio Co., Ltd.: Catalog No. 10384-1-AP) and an anti-rabbit IgG secondary antibody (Cell Signaling Technology: Catalog No. 4412). The entire bladder lumen was traced from the bright-field image using Adobe Photoshop 2024 (Adobe Inc.), and the KRT8 expression area was traced from the merged image. The length of the traced area was calculated using ImageJ (public domain image analysis software), and the proportion of KRT8 expression in the bladder epithelial lumen was quantified and evaluated as the proportion of bladder epithelium. The test protocol for this example is shown in Figure 7, and the results are shown in Figures 8-12.

[0098] The IC group showed a shorter urination interval and a smaller voided volume compared to the sham group. While no improvement was observed in the IC+Poly Zn(0.1) group, which received 0.1 mg / kg of zinc polyphosphate, the IC+Poly-P Zn(1) group, which received 1 mg / kg of zinc polyphosphate orally, showed significant improvements in urination interval and voided volume (Figure 8). No significant differences were observed among the four groups in basal bladder pressure, maximum bladder pressure, or micturition threshold (Figure 9). Bladders were removed from these animals and analyzed. The IC group showed significantly increased bladder weight and bladder weight / body weight ratio compared to the sham group. Meanwhile, the IC+Poly-P Zn(1) group, which received 1 mg / kg of zinc polyphosphate orally, showed a decrease in bladder weight / body weight ratio compared to the IC group, demonstrating improvement (Figure 10). In the IC group (referred to as CYP in Figure 12), the epithelial occupancy rate in the bladder lumen was reduced to approximately 70%, whereas in the IC + Poly-P Zn(1) group, the bladder epithelium was almost completely preserved in many individuals (Figures 11 and 12).

[0099] These results indicate that polyphosphate salts can improve the deterioration of bladder function, particularly urinary frequency, and inflammatory changes in IC / BPS.

[0100] Example 5. Effect of Oral Administration of Calcium Polyphosphate Ten-week-old female Wistar / ST rats were divided into three groups: a sham group, an IC group, and an IC+Poly-P Ca group. Physiological saline was administered intraperitoneally to the sham group, and 150 mg / kg of CYP was administered intraperitoneally to the IC and IC+Poly-P Ca groups. Subsequently, 1 mg / kg of calcium polyphosphate prepared in (G) of Example 1 was orally administered to the rats in the IC+Poly-P Ca group. The following day, bladder function was evaluated and weight was measured in the same manner as in Example 2. Furthermore, the proportion of bladder epithelium in the bladder epithelial lumen was evaluated in the same manner as in Example 4. This confirmed that calcium polyphosphate can also improve bladder function decline, particularly frequent urination and inflammatory changes, in IC / BPS.

[0101] All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A pharmaceutical composition for preventing or treating interstitial cystitis / bladder pain syndrome (IC / BPS), comprising polyphosphate or a salt thereof.

2. The pharmaceutical composition according to claim 1, wherein the polyphosphoric acid or a salt thereof is poorly soluble or insoluble in water.

3. The pharmaceutical composition according to claim 1, wherein the average particle size of the polyphosphoric acid or a salt thereof is 1 to 3,000 nm.

4. The pharmaceutical composition according to claim 1, wherein the zeta potential of the polyphosphoric acid or a salt thereof is 0 mV or less.

5. The pharmaceutical composition according to claim 1, which contains linear polyphosphate or a salt thereof.

6. The pharmaceutical composition according to claim 1, wherein the average chain length of the polyphosphate or a salt thereof is not less than 1.1 phosphate units and not more than 10,000 phosphate units.

7. The pharmaceutical composition according to claim 1, which contains a metal salt of polyphosphate, wherein the metal salt of polyphosphate contains at least one of sodium, potassium, magnesium, calcium, and zinc as its constituent metal.

8. The pharmaceutical composition according to claim 1, which contains calcium polyphosphate.

9. The pharmaceutical composition according to claim 1, containing zinc polyphosphate.

10. The pharmaceutical composition according to claim 9, wherein the zinc polyphosphate exhibits a broad peak at 2θ=4 to 7° in an X-ray diffraction chart.

11. The pharmaceutical composition according to claim 9, wherein the zinc content of the zinc polyphosphate is 10 to 60%.

12. A pharmaceutical composition according to any one of claims 1 to 11 for improving frequent urination in IC / BPS.

13. A pharmaceutical composition according to any one of claims 1 to 11, for oral administration.

14. The pharmaceutical composition according to any one of claims 1 to 11, which is for intravenous administration or intravesical instillation.

Images