Urinary Disorder Reliever

Abstract

The present invention addresses the problem of developing a dysuria-alleviating agent that demonstrates sufficient dysuria-alleviating effects and can be administered over a long period of time.　The invention relates to a dysuria-alleviating agent, which comprises acotiamide or a salt thereof as an active ingredient, and which is characterised by being used such that the acotiamide or a salt thereof is orally administered to an adult in an amount of 600 mg to 900 mg per day, each dose consisting of 200 mg to 300 mg.

Description

1 / 22 “URINATION DISTURBANCE RELIEF AGENT” Technical Field

[001] The present invention relates to a pharmaceutical agent for relieving voiding disorders caused by conditions such as underactive bladder. Background of the Technique

[002] Voiding disorders are broadly classified into urinary storage dysfunction and urinary emptying dysfunction. Urine storage dysfunction is a disorder of urine storage function and includes frequent urination and urinary incontinence (such as urge urinary incontinence and stress urinary incontinence). Meanwhile, urinary emptying dysfunction is a disorder during urination, including difficulty urinating, residual urine, and urinary retention. Each pathogenesis can be classified as neurogenic or non-neurogenic, but can be considered a functional abnormality, such as excessive contraction or incomplete contraction of the bladder smooth muscle (detrusor smooth muscle).

[003] Among urine storage dysfunctions, “the syndrome characterized primarily by urinary urgency, usually accompanied by frequent urination and nocturia and, in some cases, resulting in urge urinary incontinence,” was defined as overactive bladder (OAB) by the International Continence Society (ICS) in 2002. Meanwhile, underactive bladder (UAB) is a condition in which “bladder contraction during urination is incomplete, resulting in symptoms such as difficulty urinating,” which is a symptom syndrome that suggests detrusor underactivity.

[004] For the treatment of voiding disorders due to hypoactive and hyperactive bladder, cholinergic agents (muscarinic receptor agonists and cholinesterase inhibitors) are used, since aging reduces the expression level of muscarinic M3 receptors in the smooth muscle of the bladder and decreases the Petition 870250082209, dated 12 / 09 / 2025, page 7 / 43 2 / 22 amount of acetylcholine secretion. That is, it is known that cholinergic agents increase the contraction of the detrusor muscle and exhibit an effect of improving voiding function, acting directly or indirectly on the muscarinic M3 receptors of the bladder smooth muscle. When no effect is observed with cholinergic agents or when the physician determines that the use of cholinergic agents is not appropriate, treatment is performed by intermittent self-catheterization or permanent catheterization.

[005] The chemical name of acotiamide is N-[2-[bis(1-methylethyl)amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazol-4-carboxamide and the molecular formula is C21H30N4O5S. Acotiamide is known to improve gastrointestinal motility disorders by significantly increasing gastrointestinal motility (Patent Literature 1), and its hydrochloride hydrate (Acofide) is commercially available as a therapeutic agent for functional dyspepsia.

[006] Furthermore, as a result of conducting a pilot study in which acotiamide (100 mg, administered orally three times daily for two weeks) was used in combination with an α1 receptor blocker in patients with underactive bladder, the mean residual urine volume after administration did not fall below 100 mL, which is considered to require specialized treatment according to clinical guidelines for lower urinary tract symptoms (Non-Patent Literature 1 to 3). The effect of acotiamide in the rat model of underactive bladder was investigated only at doses (up to 100 mg / kg, subcutaneous administration) that exhibit gastrointestinal motility-enhancing action, and the efficacy and tolerability of administering high doses that greatly exceed this dose were not examined (Non-Patent Literature 4). List of Citations Patented Literature Patented Literature 1: WO 1996 / 36619 A Non-Patented Literature Petition 870250082209, dated 12 / 09 / 2025, page 8 / 43 3 / 22 Non-Patented Literature 1: Res. Rep. Urol. 2015; 7:81-83 Non-Patented Literature 2: Res. Rep. Urol. 2017; 9:141-143 Non-Patented Literature 3: Int. J. Urol. 2019; 26(8):848-849 Non-Patented Literature 4: The Journal of Japanese Continence Society. 2022; 33(1):224 Summary of the Invention Technical Problem

[007] However, with conventional therapy using cholinergic agents, there are problems such as insufficient improvement in voiding function, attenuation of the voiding-enhancing effect with long-term administration, decreased urine storage capacity due to reduced bladder compliance, and the possibility of worsening overactive bladder symptoms in patients with voiding disorders accompanied by overactive bladder. Furthermore, cholinergic agents are known to commonly cause cholinergic side effects such as diarrhea, abdominal pain, and sweating, and can induce cholinergic crisis as a serious adverse effect, therefore requiring caution in their use. Cholinergic crisis refers to a sudden deterioration in the state of excess acetylcholine accompanied by respiratory distress that occurs during the administration of cholinesterase inhibitors (ChE) and indicates a condition requiring mechanical ventilation.

[008] Therefore, the aim is to develop an agent that relieves voiding disorders that has a sufficient effect in relieving voiding disorders and that can be administered chronically. Solution to the Problem

[009] The present inventors, as a result of various investigations to solve the above problems, concluded the present invention by discovering, quite unexpectedly, that acotiamide or a salt thereof, which did not exhibit a sufficient effect even when used in combination with a Petition 870250082209, dated 12 / 09 / 2025, p. 9 / 43 4 / 22, an α1 receptor blocker, as described above, exhibited excellent relief of voiding disorders when administered alone at a high oral dose, without causing serious adverse effects and being suitable for long-term administration.

[010] That is, the present invention offers the following inventions [1] to

[16] .

[011] [1] A voiding disorder reliever comprising acotiamide or a salt thereof as the active ingredient, wherein the acotiamide, or a salt thereof, is administered orally in an amount of 200 to 300 mg per administration for a total of 600 to 900 mg per day to an adult.

[012] [2] The micturition disorder relief agent according to [1], wherein the subject of administration is a patient selected from the group consisting of patients with hypoactive bladder and patients with hypoactive bladder accompanied by hyperactive bladder.

[013] [3] The micturition disorder reliever according to [1] or [2], wherein the number of oral administrations of acotiamide or a salt thereof per day is 2 to 3.

[014] [4] The micturition disorder reliever according to any of items [1] to [3], wherein the subject of administration is a patient with hypoactive bladder.

[015] [5] The use of acotiamide or a salt thereof to produce a micturition-relieving agent, wherein acotiamide, or a salt thereof, is administered orally in an amount of 200 to 300 mg per administration, for a total of 600 to 900 mg per day to an adult.

[016] [6] Use in accordance with [5], wherein the subject of administration is a patient selected from the group consisting of patients with hypoactive bladder and patients with hypoactive bladder accompanied by hyperactive bladder.

[017] [7] The use according to [5], where the number of oral administrations Petition 870250082209, dated 12 / 09 / 2025, page 10 / 43 5 / 22 of acotiamide or a salt of the same per day is 2 to 3.

[018] [8] Use in accordance with any of items [5] to [7], where the subject of administration is a patient with an underactive bladder.

[019] [9] Acotiamide or a salt thereof for use in the relief of voiding disorder, wherein acotiamide, or a salt thereof, is administered orally in an amount of 200 to 300 mg per administration, for a total of 600 to 900 mg per day to an adult.

[020]

[10] Acotiamide or a salt thereof according to [9], wherein the subject of administration is a patient selected from the group consisting of patients with hypoactive bladder and patients with hypoactive bladder accompanied by hyperactive bladder.

[021]

[11] Acotiamide or a salt thereof according to [9] or

[10] , wherein the number of oral administrations per day is 2 to 3.

[022]

[12] Acotiamide or a salt thereof, according to any of items [9] to

[11] , wherein the subject of administration is a patient with an underactive bladder.

[023]

[13] A method for relieving micturition disorder, comprising the oral administration of acotiamide or a salt thereof in an amount of 200 to 300 mg per administration, to a total of 600 to 900 mg per day, to an adult.

[024]

[14] The method according to

[13] , in which the subject of administration is a patient selected from the group consisting of patients with hypoactive bladder and patients with hypoactive bladder accompanied by hyperactive bladder.

[025]

[15] The method according to

[13] , in which the number of oral administrations of acotiamide or a salt thereof per day is 2 to 3.

[026]

[16] The method according to

[13] , in which the subject of administration is a patient with hypoactive bladder. Advantageous Effects of the Invention

[027] When acotiamide, or a salt thereof, is administered orally to Petition 870250082209, dated 12 / 09 / 2025, page 11 / 43 6 / 22 In an adult, a dose of 200 to 300 mg per administration for a total of 600 to 900 mg noticeably improves voiding disorders in patients with underactive and / or overactive bladders, no serious adverse effects occur, and long-term administration is also possible. Brief Description of the Drawings

[028] Figure 1 is a view showing a sketch of the innervation of the lower urinary tract.

[029] Figure 2 shows a nervous response of the lower urinary tract after administration of acotiamide.

[030] Figure 3 shows the results of bladder contraction pressure during micturition in Example 1 (0 to 90 minutes after administration). In the drawing, the bar graph shows the values ​​for a normal group (Normal), acotiamide administration groups (30 to 200 mg / kg), and distigmine administration groups (0.01 to 0.1 mg / kg), respectively, from left to right. The vertical axis represents the rate of change in bladder contraction pressure during micturition (micturition amplitude index, %) (mean value and standard error of 4 to 5 animals in each group).

[031] Figure 4 shows the results of maximum contraction pressure during urination in Example 1 (0 to 90 minutes after administration). In the drawing, the bar graph shows the values ​​for a normal group (Normal), acotiamide administration groups (30 to 200 mg / kg), and distigmine administration groups (0.01 to 0.1 mg / kg), respectively, from left to right. The vertical axis represents the rate of change in maximum contraction pressure during urination (maximum micturition pressure index, %) (mean value and standard error of 4 to 5 animals in each group).

[032] Figure 5 shows the results of the urine flow rate in Example 1. In the drawing, the bar graph shows the values ​​of a normal group (Normal), Petition 870250082209, dated 12 / 09 / 2025, page 12 / 43 7 / 22 acotiamide administration groups (30 to 200 mg / kg) and one distigmine administration group (0.1 mg / kg), respectively, from left to right. The vertical axis represents the maximum urine flow rate (maximum flow rate, g / s) (mean value and standard error of 6 animals in each group).

[033] Figure 6 shows the bladder compliance results in Example 1 (0 to 90 minutes after administration). In the drawing, the bar graph shows the values ​​for a normal group (Normal), acotiamide administration groups (30 to 200 mg / kg), and distigmine administration groups (0.01 to 0.1 mg / kg), respectively, from left to right. The vertical axis represents the rate of change in bladder compliance (bladder compliance index, %) (mean value and standard error of 4 to 5 animals in each group). The dashed line shows a lower limit value of the rate of change in bladder compliance (mean value) for the normal animal group in this study.

[034] Figure 7 shows the results of the loss pressure on exertion in Example 3. In the drawing, the bar graph shows the values ​​of a normal group (Normal), acotiamide administration groups (30 to 300 mg / kg), a distigmine administration group (0.1 mg / kg) and a bethanechol administration group (3 mg / kg), respectively, from left to right. The vertical axis represents the rate of change (%) in loss pressure on exertion (mean value and standard error of 6 to 7 animals in each group).

[035] Figure 8 shows the results of bladder contraction pressure during micturition in Example 4 (0 to 30 minutes after administration). In the drawing, the bar graph shows the values ​​for a normal group (Normal), acotiamide administration groups (0.1 to 10 mg / kg), and a distigmine administration group (1 mg / kg), respectively, from left to right. The vertical axis represents the rate of change in bladder contraction pressure during micturition (micturition amplitude index, %) (mean value and standard error of 8 animals in each group). Petition 870250082209, dated 12 / 09 / 2025, page 13 / 43 8 / 22

[036] Figure 9 shows the results of maximum contraction pressure during urination in Example 4 (0 to 30 minutes after administration). In the drawing, the bar graph shows the values ​​for a normal group (Normal), acotiamide administration groups (0.1 to 10 mg / kg), and a distigmine administration group (1 mg / kg), respectively, from left to right. The vertical axis represents the rate of change in maximum contraction pressure during urination (micturition amplitude index, %) (mean value and standard error of 8 animals in each group).

[037] Figure 10 shows the results of urine flow rate (maximum urine flow rate) in Example 4 (0 to 30 minutes after administration). In the drawing, the bar graph shows the values ​​for a normal group (Normal), acotiamide administration groups (0.1 to 10 mg / kg), and a distigmine administration group (1 mg / kg), respectively, from left to right. The vertical axis represents the rate of change in maximum urine flow rate during urination (maximum flow rate index, %) (mean value and standard error of 8 animals in each group).

[038] Figure 11 shows the results of urine flow rate (mean urine flow rate) in Example 4 (0 to 30 minutes after administration). In the drawing, the bar graph shows values ​​for a normal group (Normal), acotiamide administration groups (0.1 to 10 mg / kg), and a distigmine administration group (1 mg / kg), respectively, from left to right. The vertical axis represents the rate of change in mean urine flow rate (mean flow index, %) (mean value and standard error of 8 animals in each group).

[039] Figure 12 shows the results of detrusor muscle contraction pressure in Example 5. Detrusor muscle contraction pressure traces are shown for a sham operation group, a pelvic nerve crush injury group, acotiamide administration groups (30 to 200 mg / kg) and a distigmine administration group (0.1 mg / kg), respectively (30 to 60 minutes after drug administration). Petition 870250082209, dated 12 / 09 / 2025, p. 14 / 43 9 / 22

[040] Figure 13 shows the results of the bladder M3 receptor (protein) expression level in Example 6.

[041] Figure 14 shows the results of a voiding interval in Example 7. In the drawing, the bar graph shows the values ​​for a vehicle administration group, acotiamide administration groups (100 and 200 mg / kg), a distigmine administration group (0.1 mg / kg), and a mirabegron administration group (3 mg / kg), respectively, from left to right. The vertical axis represents the rate of change in voiding interval (intercontraction interval, %) (mean value and standard error of 6 to 7 animals in each group).

[042] Figure 15 shows the results of a NVC frequency from Example 7. In the drawing, the bar graph shows the values ​​for a vehicle administration group, an acotiamide (200 mg / kg) administration group, and a distigmine (0.1 mg / kg) administration group, respectively, from the left (under co-administration with mirabegron at 3 mg / kg). The vertical axis represents the rate of change in NVC (non-voiding contraction, %) (mean and standard error of 7 animals in each group). Description of the Modalities

[043] The present invention provides a voiding disorder relief agent comprising acotiamide or a salt thereof as the active ingredient.

[044] According to a preferred aspect of the urinary disorder-relieving agent of the present invention, acotiamide or a salt thereof is administered orally in an amount of 200 to 300 mg per administration, for a total of 600 to 900 mg per day to an adult.

[045] As described above, the chemical name of acotiamide is N-[2-[bis(1-methylethyl)amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]thiazol-4-carboxamide. Acotiamide is known to improve gastrointestinal motility disorders by significantly increasing gastrointestinal motility (Patent Literature 1), and Petition 870250082209, dated 12 / 09 / 2025, page 15 / 43 10 / 22 its hydrochloride hydrate (Acofide) is commercially available as a therapeutic agent for functional dyspepsia.

[046] More specifically, the therapeutic agent for functional dyspepsia containing acotiamide exhibits efficacy and effect on postprandial fullness, upper abdominal bloating and early satiety due to functional dyspepsia, and the administration and dosage are 100 mg of acotiamide hydrochloride hydrate orally, three times a day, before meals, for an adult.

[047] Examples of the active ingredient of the voiding disorder reliever of the present invention include acotiamide and a salt thereof. Examples of acotiamide salts include acid addition salts, and specific examples include acid addition salts with inorganic acids such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide and hydroiodide, and acid addition salts with organic acids such as acetate, oxalate, malonate, succinate, maleate, fumarate, lactate, malate, citrate, tartrate, methanesulfonate and ethanesulfonate. Among these, acotiamide hydrochloride is most preferred. In addition, various solvents, such as acotiamide hydrate or a salt thereof, are also included. Acotiamide hydrochloride hydrate is also preferred. This acotiamide or its salts can be produced, for example, by the method described in Patent Literature 1.

[048] With regard to acotiamide or a salt thereof, detrusor muscle contraction pressure, urine flow rate and urethral pressure were examined by administering a high dose that greatly exceeds the dose that exhibits a gastrointestinal motility-enhancing action, and acotiamide or a salt thereof was found not to affect urethral pressure at a dose that exhibits a detrusor muscle contraction action, unlike the existing cholinergic agent.

[049] As a result of verifying the effect of acotiamide or its salt on the expression level of the M3 receptor in bladder smooth muscle, it was discovered Petition 870250082209, dated 12 / 09 / 2025, p. 16 / 43 11 / 22 that the existing cholinergic agent decreases the level of M3 receptor expression in the bladder with repeated administration, while acotiamide or a salt thereof does not decrease the level of M3 receptor expression in the bladder with repeated administration. It has not been previously reported and is unexpected that repeated administration of acotiamide or a salt thereof does not reduce the level of M3 receptor expression in the bladder.

[050] As a result of verifying the effect of acotiamide or one of its salts on the voiding interval and the frequency of non-voiding contractions (non-voiding contraction, NVC) in the filling phase, it was found that in rats with partial bladder outlet obstruction (BOO) exhibiting overactive bladder, the existing cholinergic agent shortens the voiding interval and increases the frequency of NVC in the filling phase, while acotiamide or one of its salts does not affect the voiding interval and the frequency of NVC. It has not been previously reported and is unexpected that acotiamide or a salt thereof does not affect the voiding interval or the frequency of NVC in an overactive bladder model.

[051] Furthermore, it was found that the existing cholinergic agent reduces bladder compliance and induces a cholinergic crisis at a dose close to the dose at which pharmacological effects occur, whereas acotiamide or a salt thereof does not affect bladder compliance and does not induce a cholinergic crisis at a dose close to the dose at which pharmacological effects occur.

[052] In this document, these doses of acotiamide or its salt correspond to an amount of 200 to 300 mg per administration, for a total of 600 to 900 mg per day for oral administration in an adult.

[053] Therefore, the urinary disorder relief agent comprising acotiamide or a salt thereof as the active ingredient of the present invention is preferably used in such a way that the acotiamide or a salt thereof is administered orally in an amount of 200 to 300 mg per administration, in Petition 870250082209, dated 12 / 09 / 2025, p. 17 / 43 12 / 22 a total of 600 to 900 mg per day for an adult.

[054] The number of oral administrations of acotiamide or its salt per day is preferably 2 to 3.

[055] As described in Non-Patented Literature 1 to 3, a pilot study was conducted in a patient with underactive bladder using acotiamide (100 mg orally 3 times daily for 2 weeks) in combination with an α1 receptor blocker, and as a result, a sufficient reduction in residual urine volume was not obtained. Furthermore, as described in Non-Patented Literature 4, the efficacy and tolerability of administering high doses that greatly exceed the dose that exhibits an action of improving gastrointestinal motility were not examined. Considering these facts, the effect of the therapeutic agent for voiding disorder of the present invention could not be expected in any way.

[056] Examples of voiding disorders to be treated with the therapeutic agent for voiding disorders of the present invention include the hypoactive bladder described above and the hypoactive bladder accompanied by an overactive bladder. Therefore, any voiding disorder due to a hypoactive bladder, voiding disorder due to an overactive bladder, and voiding disorder due to both a hypoactive and an overactive bladder is included. Specific symptoms include frequent urination, nocturia, urinary incontinence (urge urinary incontinence, stress urinary incontinence, and the like), difficulty urinating, residual urine, urinary retention, and the like.

[057] Acotiamide or a salt thereof is effective when used alone, as described above, or when used in combination with a urethral relaxant at a different time or simultaneously. In this document, examples of urethral relaxants that can be used in combination include urapidil, tamsulosin, naftopidil, silodosin, terazosin, and prazosin. Petition 870250082209, dated 12 / 09 / 2025, page 18 / 43 13 / 22

[058] Furthermore, the voiding enhancer of the present invention provides a non-invasive treatment that is safe and effective compared to existing cholinergic agents, thus avoiding the transition to invasive treatments such as intermittent self-catheterization and permanent catheterization (when the muscarinic M3 receptor is increased by acotiamide, improvement in urinary function is also expected without drug dependence). In addition, the voiding enhancer of the present invention allows treatment of voiding disorders without worsening the symptoms of overactive bladder in patients with hypoactive bladder accompanied by overactive bladder (refer to Figures 1 and 2).

[059] The micturition-relieving agent of the present invention is preferably an orally administered composition obtained by mixing a pharmaceutically acceptable carrier with acotiamide or a salt thereof. As an orally administered composition, acotiamide or a salt thereof may be formulated into tablets, powders, granules, or capsules using appropriately suitable additives such as excipients (e.g., lactose, mannitol, corn starch, and crystalline cellulose), binders (e.g., cellulose derivatives, gum arabic, and gelatin), disintegrants (e.g., calcium carboxymethylcellulose), and lubricants (e.g., talc and magnesium stearate). In addition, these solid preparations may be transformed into an enteric preparation using a coating base such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, or a methacrylate copolymer. Examples

[060] The present invention will now be described in more detail with reference to the Examples, but the present invention is not limited to those Examples. Example 1 (Bladder Test Using Normal Rats) Cystometry (detrusor muscle contraction pressure) and rate measurement Petition 870250082209, dated 12 / 09 / 2025, page 19 / 43 14 / 22 urine flow (1) Cystometry (measurement of detrusor muscle contraction pressure)

[061] A polyethylene (PE50) catheter for cystometry was inserted and fixed into the bladder of male rats (strain: Crl:CD (SD), 8 weeks old, Jackson Laboratory Japan, Inc.). The catheter inserted into the bladder was connected to a pressure transducer (Nihon Kohden Corporation) to measure intravesical pressure. Physiological saline was injected into the bladder using an infusion pump, and changes in intravesical pressure were recorded on a polygraph system (RMT-1000, Nihon Kohden Corporation) and an analysis system (Lab Chart Pro, ADInstruments). Changes in detrusor muscle contraction pressure when distigmine (0.01 to 0.3 mg / kg), acotiamide (3 to 200 mg / kg), or vehicle were administered subcutaneously (5 mL / kg) were measured over 90 minutes. (2) Uroflowmetry (measurement of urine flow rate)

[062] Changes in urine flow rate when distigmine (0.1 mg / kg), acotiamide (30, 100, and 200 mg / kg) or vehicle were administered subcutaneously (5 mL / kg) to male rats (strain: Crl:CD (SD), 8 weeks old, Jackson Laboratory Japan, Inc.) were measured for 12 hours. Changes in urine flow rate were recorded using the PowerLab (ADInstruments), placing a digital scale under the voiding measurement cage to cumulatively collect excreted urine into a container on the scale and measure the change in weight. (3) Results

[063] As Figures 3, 4, and 5 show, acotiamide increased bladder contraction pressure during urination and maximum contraction pressure during urination, and also showed an effect of increasing urine flow rate. The effect of acotiamide on bladder contraction pressure was extremely strong in the 200 mg / kg administration group compared to the 30 and 100 mg / kg administration groups. Meanwhile, distigmine increased bladder contraction pressure. Petition 870250082209, dated 12 / 09 / 2025, page 20 / 43 15 / 22 during urination and the maximum contraction pressure during urination, but the urine flow rate decreased. Furthermore, distigmine significantly reduced bladder compliance, while acotiamide did not affect bladder compliance, even at a dose that greatly increased detrusor muscle contraction pressure (200 mg / kg) (Figure 6). Regarding drug tolerability in the cystometry test, acotiamide was well tolerated up to the highest dose (200 mg / kg), but the highest dose of distigmine (0.3 mg / kg) induced a cholinergic crisis (hypersecretion, respiratory abnormalities, seizures (clonic / tonic seizures)), and tolerability was extremely low.

[064] Based on the above results, distigmine is considered to increase detrusor muscle contraction pressure but decrease bladder compliance and does not exhibit a urine flow rate increase. A cholinergic crisis was induced at a dose close to the dose at which pharmacological effects occur, and tolerability was extremely low. Meanwhile, acotiamide increases detrusor muscle contraction pressure and showed a strong effect at the highest dose (200 mg / kg), but unlike distigmine, acotiamide does not affect bladder compliance and is considered to have a urine flow rate increase effect. Furthermore, acotiamide did not induce a cholinergic crisis even when the highest dose (200 mg / kg) was administered and, unlike distigmine, also showed good tolerability. Example 2 (Test to Confirm Tolerability) Investigation into the induction of cholinergic crisis (rat)

[065] Distigmine (0.1, 0.2, 0.3 and 0.4 mg / kg) or acotiamide (200 and 300 mg / kg) was administered subcutaneously to female rats (strain: Crl: CD (SD), Jackson Laboratory Japan, Inc.) (5 mL / kg) under urethane anesthesia, and the presence or absence of cholinergic crisis induction was observed within 120 minutes after administration. Petition 870250082209, dated 12 / 09 / 2025, p. 21 / 43 16 / 22

[066] Cholinergic crisis (hypersecretion, respiratory abnormalities) was induced after distigmine administration, with 1 of 3 animals in the 0.2 mg / kg group, 5 of 6 animals in the 0.3 mg / kg group and all animals (3 of 3) in the 0.4 mg / kg group resulting in death.

[067] Acotiamide did not induce cholinergic crisis at any dose, and no cases of death were observed.

[068] Based on the above results, distigmine induced cholinergic crisis at doses close to the dose at which pharmacological effects occur, and its tolerability was extremely low. Meanwhile, as acotiamide showed good tolerability even when high doses were administered, including the dose (200 mg / kg) that exerts a strong pharmacological action, the potential of acotiamide to induce cholinergic crisis was considered low. Example 3 (Urethra Test Using Normal Rats) Measurement of LPP (Urethral Pressure)

[069] Using female rats (strain: Crl:CD (SD), 9 weeks old, Jackson Laboratory Japan, Inc.), under isoflurane anesthesia, the spinal cord was transected at the Th8 vertebra and, after ligation and excision of the ureters, a catheter (Becton Dickinson: PE-90, PE-50) was inserted and fixed in the bladder dome to prepare the animal for measurement. Physiological saline solution was injected through the catheter, and the maximum intravesical pressure (stress loss pressure (SLP)) leaking from the external urethral opening was recorded by PowerLab (ADInstruments). Changes in stress loss pressure were measured when distigmine (0.1 mg / kg), bethanechol (3 mg / kg), acotiamide (30 to 300 mg / kg) or a vehicle were administered subcutaneously (5 mL / kg).

[070] Acotiamide and distigmine did not alter stress leakage pressure and did not affect urethral pressure (Figure 7). Meanwhile, bethanechol showed an increase in stress leakage pressure and increased urethral pressure. Petition 870250082209, dated 12 / 09 / 2025, page 22 / 43 17 / 22 Example 4 (Bladder Test Using Normal Guinea Pigs) Cystometry (detrusor muscle contraction pressure) and urine flow rate measurement

[071] A polyethylene catheter (Becton Dickinson: PE50) was inserted and secured into the bladder of a guinea pig (male, strain: Slc:Hartley, 7 weeks old, Japan SLC, Inc.). A catheter placed in the bladder was connected to a pressure transducer to measure intravesical pressure. Physiological saline was injected into the bladder using an infusion pump, and intravesical pressure was recorded on the PowerLab (ADInstruments). Urine flow rate was recorded on the PowerLab (ADInstruments) by placing a digital scale under the cage to cumulatively collect excreted urine in a container on the scale and measure the change in weight. Changes in detrusor muscle contraction pressure and urine flow rate when distigmine (1 mg / kg), acotiamide (0.1 to 10 mg / kg), or a vehicle was administered intravenously (1 mL / kg) were measured over 30 minutes.

[072] Distigmine increased bladder contraction pressure during urination and maximum contraction pressure during urination, but decreased urine flow rate (maximum urine flow rate and mean urine flow rate). Acotiamide increased bladder contraction pressure during urination and maximum contraction pressure during urination, and also showed a urine flow rate-increasing effect at the same dose (detrusor muscle contraction pressure; Figure 8, Figure 9, urine flow rate; Figure 10, Figure 11).

[073] Based on the results above, distigmine is considered to increase the contraction pressure of the detrusor muscle, but it has an effect of decreasing the urine flow rate. Meanwhile, acotiamide increases the contraction pressure of the detrusor muscle, but, unlike distigmine, acotiamide is considered to have an effect of increasing the urine flow rate. Example 5 (Bladder Test Using Rats with Voiding Disorder) Petition 870250082209, dated 12 / 09 / 2025, page 23 / 43 18 / 22 [Underactive Bladder] Cystometry measurement (detrusor muscle contraction pressure)

[074] Under isoflurane anesthesia, female rats (strain: Crl:CD (SD), 8 weeks old, Jackson Laboratory Japan, Inc.) underwent pelvic nerve injury surgery to prepare rats with pelvic nerve crush (PNC). Cystometry was performed awake, 2 to 4 weeks post-surgery. A polyethylene (PE50) catheter for cystometry was inserted into the bladder and fixed in place. The catheter inside the bladder was connected to a pressure transducer (Nihon Kohden Corporation) to measure intravesical pressure. Saline solution was injected into the bladder via an infusion pump, and changes in intravesical pressure were recorded on a polygraph system (RMT-1000, Nihon Kohden Corporation) (RMT-1000MG, Miyuki Giken Co., Ltd.) and an analysis system (Lab Chart Pro, ADInstruments).

[075] Changes in detrusor muscle contraction pressure when distigmine (0.01 to 0.3 mg / kg), acotiamide (3 to 200 mg / kg) or vehicle were administered subcutaneously (5 mL / kg) to PNC rats were measured for 60 minutes.

[076] Acotiamide and distigmine increased detrusor muscle contraction pressure (Figure 12). The action of acotiamide on detrusor muscle contraction pressure was extremely strong in the 200 mg / kg administration group compared to the 30 and 100 mg / kg administration groups.

[077] Regarding drug tolerability, acotiamide showed good tolerability up to the highest dose, while at the highest dose of distigmine (0.3 mg / kg), a cholinergic crisis was induced (hypersecretion, respiratory abnormality, seizures [clonic / tonic seizures]).

[078] Based on the above results, in the hypoactive bladder model, distigmine increased detrusor muscle contraction pressure but induced seizures. Petition 870250082209, dated 12 / 09 / 2025, page 24 / 43 19 / 22 cholinergic at doses close to the dose at which pharmacological effects occur. Meanwhile, acotiamide increased the contraction pressure of the detrusor muscle, but, unlike distigmine, did not cause a cholinergic crisis. Example 6 (Receptor Expression (Normal Rats)) (Analysis of Gene and Protein Expression)

[079] Distigmine (0.1 mg / kg), acotiamide (100 mg / kg), or vehicle were administered subcutaneously twice daily for two weeks (5 mL / kg per dose) to normal rats (males, strain: Crl:CD (SD), 8 weeks old, Jackson Laboratory Japan, Inc.), and the bladder was collected. The level of M3 receptor expression in the collected bladder was examined by quantitative gene analysis by real-time PCR (Chrm3) and protein expression analysis by Western blotting (CHRM3).

[080] The results for the expression level of the bladder M3 receptor (gene) are shown in Table 1. The results for the expression level of the bladder M3 receptor (protein) are shown in Figure 13.

[081] Repeated administration of distigmine reduced the level of bladder M3 receptor expression. Meanwhile, repeated administration of acotiamide did not reduce the level of bladder M3 receptor expression. [Table 1] Group Dose (mg / kg / day) Number of Animals Relative gene expression of Chrm3 (mean ± SE) Vehicle 6 106.3 ± 15.5 Acotiamide 200 6 107.0 ± 12.9 Distigmine 0.2 6 79.1 ± 11.8 Example 7 (Bladder Test Using Partial BOO Model Rats) Voiding range and frequency of non-voiding contractions (non-voiding contractions, NVC) during the filling phase.

[082] Under isoflurane anesthesia, female rats (strain: Crl:CD (SD), 6 weeks old, Jackson Laboratory Japan, Inc.) underwent bladder outlet obstruction surgery to prepare rats with partial bladder outlet obstruction. Petition 870250082209, dated 12 / 09 / 2025, p. 25 / 43 20 / 22 bladder (BOO). The sham surgery group was operated on similarly, except for partial BOO. Six weeks after surgery, cystometry was performed while awake. A polyethylene catheter (Becton Dickinson: PE50) for cystometry was inserted and secured in the bladder. The catheter in the bladder was connected to a pressure transducer (Nihon Kohden Corporation) to measure intravesical pressure. Physiological saline solution was injected into the bladder using a syringe pump, and changes in intravesical pressure were recorded on the PowerLab (ADInstruments). (Evaluation of Therapeutic Effect Using Rats with Partial BOO) (1) Single Agent Effect on Micturition Interval

[083] Distigmine (0.1 mg / kg), acotiamide (100 and 200 mg / kg) or vehicle were administered subcutaneously (5 mL / kg), or a β3-adrenergic receptor agonist (β3 agonist mirabegron, a therapeutic agent for overactive bladder) (3 mg / kg) was administered intravenously (1 mL / kg), and the voiding interval was measured for up to 2 hours. (2) Combination with β3 Agonist

[084] The β3 agonist mirabegron (3 mg / kg, intravenous administration [1 mL / kg]) was co-administered with distigmine (0.1 mg / kg) or acotiamide (200 mg / kg) by subcutaneous administration (5 mL / kg), and the frequency of NVC was measured.

[085] In rats with partial BOO (6 weeks after surgery), the frequency of NVC in the filling phase was increased compared with rats operated on with sham, and overactive bladder was exhibited.

[086] Regarding the effect of a single agent in rats with partial BOO, distigmine significantly reduced the voiding interval, while acotiamide and the β3 agonist had no effect on the voiding interval (Figure 14).

[087] Regarding the combined effect with the β3 agonist in rats with partial BOO, the frequency of NVC increased in the distigmine combination group compared to the β3 agonist single administration group. The frequency of Petition 870250082209, dated 12 / 09 / 2025, p. 26 / 43 21 / 22 NVC in the acotiamide combination group was different from that in the distigmine combination group and similar to that in the single β3 agonist administration group (Figure 15).

[088] Based on the above results, it has been shown that in rats with partial BOO exhibiting overactive bladder, distigmine shortens the voiding interval and increases the frequency of NVC in the filling phase, even under the combined use of the β3 agonist, while acotiamide does not affect the voiding interval and the frequency of NVC. Example 8 (Clinical Trial)

[089] Acotiamide at a dose of 600 to 900 mg per day or placebo is administered for 12 weeks to male or female patients with symptoms of underactive bladder.

[090] Provided that the dosage and administration are not altered during the clinical study, an α1 blocker, a therapeutic agent for benign prostatic hyperplasia, a diuretic, an agent with an anticholinergic effect and a Chinese medicine to be administered with the aim of improving urinary symptoms may be administered simultaneously or at different times from acotiamide.

[091] During clinical trials, as items relating to the efficacy of the present agent, the International Prostate Symptom Score, commonly used to measure the symptoms of patients with underactive bladder, uroflowmetry parameters (evacuated volume, evacuation time, maximum urine flow rate, average urine flow rate), post-void residual urine volume, voiding efficiency, parameters recorded in the bladder diary (urine discharge time, urine volume, presence or absence of urgency sensation, presence or absence of slow stream, presence or absence of delayed voiding and presence or absence of straining to urinate) are investigated.

[092] During the execution of the clinical trial, as items that refer to Petition 870250082209, dated 12 / 09 / 2025, page 27 / 43 22 / 22 safety of the present agent, clinical examinations (hematology, blood biochemistry, general urine tests), vital signs, 12-lead electrocardiogram and the occurrence of adverse events are investigated. Petition 870250082209, dated 12 / 09 / 2025, page 28 / 43

Claims

1 / 3 CLAIMS 1. A micturition disorder reliever comprising acotiamide or a salt thereof as the active ingredient, CHARACTERIZED in that the acotiamide or a salt thereof is administered orally in an amount of 200 to 300 mg per administration, for a total of 600 to 900 mg per day to an adult.

2. A micturition disorder relief agent, according to claim 1, CHARACTERIZED in that the subject of administration is a patient selected from the group consisting of patients with hypoactive bladder and patients with hypoactive bladder accompanied by hyperactive bladder.

3. Urinary disorder relief agent, according to claim 1, CHARACTERIZED in that the number of oral administrations of acotiamide or a salt thereof per day is 2 to 3.

4. A micturition disorder relief agent, according to claim 1, CHARACTERIZED in that the subject of administration is a patient with an underactive bladder.

5. Use of acotiamide or a salt thereof to produce a micturition-relieving agent, CHARACTERIZED in that acotiamide or a salt thereof is administered orally in an amount of 200 to 300 mg per administration, for a total of 600 to 900 mg per day to an adult.

6. Use according to claim 5, CHARACTERIZED in that the subject of administration is a patient selected from the group consisting of patients with underactive bladder and patients with underactive bladder accompanied by overactive bladder.

7. Use according to claim 5, CHARACTERIZED in that the number of oral administrations of acotiamide or a salt thereof per day is 2 to 3.

8. Use, according to claim 5, CHARACTERIZED by the fact that Petition 870250082209, dated 12 / 09 / 2025, page 29 / 43 2 / 3 the subject of administration is a patient with an underactive bladder.

9. Acotiamide or a salt thereof for use in relieving micturition disorders, CHARACTERIZED in that acotiamide or a salt thereof is administered orally in an amount of 200 to 300 mg per administration for a total of 600 to 900 mg per day to an adult.

10. Acotiamide or a salt thereof, according to claim 9, CHARACTERIZED in that the subject of administration is a patient selected from the group consisting of patients with underactive bladder and patients with underactive bladder accompanied by overactive bladder.

11. Acotiamide or a salt thereof, according to claim 9 or 10, CHARACTERIZED in that the number of oral administrations per day is 2 to 3.

12. Acotiamide or a salt thereof, according to any one of claims 9 to 11, CHARACTERIZED in that the subject of administration is a patient with an underactive bladder.

13. Method for relieving urinary disturbance, CHARACTERIZED by the fact that it comprises administering acotiamide or a salt thereof orally in an amount of 200 to 300 mg per administration, for a total of 600 to 900 mg per day, to an adult.

14. Method, according to claim 13, CHARACTERIZED in that the subject of administration is a patient selected from the group consisting of patients with hypoactive bladder and patients with hypoactive bladder accompanied by hyperactive bladder.

15. Method according to claim 13, CHARACTERIZED in that the number of oral administrations of acotiamide or a salt thereof per day is 2 to 3.

16. Method, according to claim 13, CHARACTERIZED by the fact that the subject of administration is a patient with an underactive bladder. (Petition 870250082209, dated 12 / 09 / 2025, p. 30 / 43 3 / 3)

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