JP2013049653A - Therapeutic agent of dysuria of female - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a safe drug applicable to treatment of dysuria of female with fewer side effects.SOLUTION: The dysuria therapeutic agent contains silodosin or a pharmacologically allowable salt thereof or a solvate thereof as an active constituent, and is administered to a female dysuria patient, especially a female dysuria patient with disturbance of urinary collection, preferably a female dysuria patient with disturbance of urinary collection and excretory disorder, more preferably such a female dysuria patient complicated by hypotension, for instance, orthostatic hypotension.

Description

  The present invention relates to a therapeutic agent for dysuria, comprising silodosin or a pharmacologically acceptable salt thereof or a solvate thereof as an active ingredient, which is administered to female dysuria patients. More specifically, the present invention relates to dysuria, comprising silodosin or a pharmacologically acceptable salt thereof or a solvate thereof as an active ingredient and administered to a female dysuria patient having urinary storage disorder It relates to a therapeutic agent. More specifically, the present invention relates to a female urination disorder patient having urinary storage disorder and having hypotension, comprising silodosin or a pharmacologically acceptable salt thereof or a solvate thereof as an active ingredient. The present invention relates to a therapeutic agent for dysuria characterized by administration.

  Urination is composed of a urine storage function for collecting urine in the bladder and a discharge function for discharging the accumulated urine out of the body. The urinary storage function and the drainage function are controlled by the lumbosacral spinal cord urination center existing in the spinal cord, the pontine micturition center (abbreviated as PMC) existing in the brain stem, and the pelvis under the control of the higher urination center existing above the brain stem. The peripheral nervous system is composed of parasympathetic nerves such as nerves, sympathetic nerves such as hypogastric nerves, and somatic nerves such as pudendal nerves, and various neurotransmitters such as acetylcholine, noradrenaline, adenosine triphosphate (ATP) ), Substance P, neuropeptide Y and the like are implicated. When urine near the maximum volume accumulates in the bladder, afferent neurotransmission from the bladder ascends the spinal cord and communicates to the higher micturition center and the PMC through the paraquatral gray, thalamus. The higher urination center judges the situation and stimulates the descending branch (motor nerve) of the spinal nerve via PMC to promote urine drainage. Normally, the higher micturition center suppresses (or stimulates) PMC, but when it decides to drain urine, this suppression is released (or stimulation is transmitted), and efferent neurotransmission from PMC is the parasympathetic nerve of the sacral cord. Stimulates the center and suppresses the sympathetic nerve center and the Onuf nucleus. As a result, two urethral sphincters, namely the inner urethral sphincter (smooth muscle) and the outer urethral sphincter (striated muscle) relax in coordination with bladder contraction, and urine drainage is smoothly promoted until the bladder is empty. .

  Urinary dysfunction is called lower urinary tract disorder in a broad sense, and is roughly divided into urinary storage disorder and discharge disorder. Symptoms caused by dysuria are referred to as lower urinary tract symptoms (LUTS), and can be divided into urinary storage symptoms, voiding symptoms, and post voiding symptoms. However, the urine storage symptom does not necessarily reflect the urinary storage disorder and the discharge symptom does not reflect the discharge disorder, and there are not a few patients who have both disorders and symptoms.

  In urinary storage disorders, urinary storage symptoms such as daytime frequent urination, nocturia, urgency, urinary incontinence, abnormal sensations such as bladder appear. Frequent urination is a condition in which the number of urinations is abnormally high. The frequency of urination for normal persons is large between day and individual, but as a guideline, frequent urination is 8 or more times a day and one or more times during sleep. Frequent urination may be accompanied by a sense of urgency, increased bladder perception (sustained urine from an early stage), bladder pain, pelvic pain and urination pain. Urinary urgency is a sudden, uncontrollable urinary urgency that is difficult to endure. Usually accompanied by frequent urination and incontinence. Urinary incontinence is a state of involuntarily leaking urine. There are several types. Incontinence that overflows when the bladder fills the urine and becomes urinary retention (excessive urinary incontinence), incontinence that occurs because urination cannot be suppressed when feeling urine (imminent urinary incontinence), only when abdominal pressure rises Incontinence that occurs (stress urinary incontinence), loss of urinary sphincter function, and incontinence that occurs continuously without urine collecting in the bladder (urethral relaxation incontinence).

  In discharge disorders, discharge symptoms such as difficulty in urination, pain in urination, urinary retention, and residual urine sensation appear. Difficult urination is a general term for the state in which it is difficult to urinate during urination. It takes a long time to start urination even when trying to urinate (delayed urination), the momentum of urine is weak (decrease in urine), and the urinary line is in urination One or more interruptions occur (intermittent urination), and urine is difficult to output unless abdominal pressure is applied (abdominal pressure urination). Urinary pain is pain that is felt in the urethra during urination and may be felt only in the early stage or the last stage of urination. Urinary retention is a condition where the bladder cannot be completely emptied or evacuation stops. Moreover, residual urine sensation and post-urination dripping appear as symptoms after urination.

  There are various causes of dysuria, but it has been broadly divided into organ abnormalities of the bladder and urethra and abnormalities of the urinary control nerve. Examples of organic abnormalities of the bladder and urethra include prostatic hypertrophy, urethral stricture, bladder diverticulum, stones, and tumors. The dysuria due to abnormalities in the urinary control nerve is a dysuria that occurs in both men and women due to a malfunction of the sympathetic nerve that controls the function of the urethra, the parasympathetic nerve that controls the function of the bladder, and is collectively called neurogenic bladder. Major diseases that cause neurogenic bladder include cerebrovascular disorders, Parkinson's disease, and brain tumors such as brain tumors, spinal cord injury, spina bifida, posterior longitudinal ligament ossification, adult T-cell leukemia virus-related myelopathy (HAM) ), And spinal cord disorders such as spinal tether syndrome, peripheral neuropathy such as diabetes, intrapelvic surgery, and lumbar spinal stenosis, and multiple sclerosis and spinocerebellar degeneration.

  Known treatment methods for urinary storage disorders include pharmacotherapy centered on anticholinergic drugs and surgical treatment such as bladder dilatation. However, currently no treatment has been reported that does not affect bladder contraction (excretion function).

  As a therapeutic agent for drainage disorders, particularly a therapeutic agent for dysuria, a drug that enhances the contractile force of the bladder muscle (detrusor muscle) or a drug that relaxes prostate / urethral smooth muscle and attenuates urethral resistance is used. For example, cholinergic agents such as besanecol and acetylcholinesterase inhibitors such as distigmine are used as drugs that act on the bladder muscles and increase their contractile force. For example, besanecol also contracts bladder muscles in the urine storage phase. It impairs the urinary storage function of the bladder and has side effects such as tearing, sweating, gastrointestinal disorders, and abdominal pain. It is contraindicated for pregnant women, peptic ulcer, organic intestinal obstruction, asthma, hyperthyroidism, and the like. As an agent that relaxes prostate / urethral smooth muscle and attenuates urethral resistance, α1 adrenergic receptor antagonists such as tamsulosin, prazosin, alfuzosin, naphthopidyl, urapidil are used. It has been reported that it is effective in improving subjective symptoms. Tamsulosin and naphthopidil are selective α1 adrenergic receptor antagonists and are used as therapeutic agents for dysuria associated with prostatic hypertrophy because they selectively act on prostate and urethral smooth muscle. On the other hand, α1 adrenergic receptor antagonists have an antihypertensive action because they block the effects of adrenergic sympathetic nerves, and thus have side effects such as hypotension and exacerbation of orthostatic hypotension.

  In cases with both urinary storage disorder and discharge disorder, the urine storage function and the discharge function are exactly the opposite functions, so using drugs that assist urine storage may lead to the occurrence or exacerbation of discharge disorders, In addition, the use of a drug that assists the discharge may lead to the occurrence or deterioration of urine storage disorders. Therefore, it is difficult to treat a case having both urinary storage disorder and discharge disorder.

  On the other hand, urination disorders that do not fall into any obvious organic disorder or neurological abnormality in the lower urinary tract have been reported in men and women in recent years, and dysuria, bladder neck sclerosis, bladder neck Examples include cervical obstruction, urethral syndrome, prostate pain, Hinman syndrome, Fowler syndrome, psychogenic dysuria, drug-induced dysuria, and aging-related dysuria. For these and other causes of dysuria in men and women, the mechanism of the disease has not been fully elucidated, and no cure has yet been established.

  In women's dysuria, hitherto, attention has been focused only on urinary storage disorders in which symptoms such as urinary incontinence occur, and it has been considered that there are few discharge disorders, but in practice, discharge disorders are often recognized. The frequency of drainage disorders is particularly high in neurogenic bladder. Since urination disorder lowers the quality of life (Quality of Life, hereinafter abbreviated as QOL) of patients, it is an important problem to be solved. However, there are few studies on the treatment of female dysuria, and in addition, there are a limited number of drugs that can be used for female discharge disorders, so the development of new therapies is required.

  In recent years, it has been reported that α1 adrenergic receptor inhibitors are effective against female discharge disorders (Non-patent Documents 1-6). α1 adrenergic receptors are divided into three subtypes: α1A receptors, α1B receptors, and α1D receptors. The expression of each subtype differs depending on the tissue. Α1A receptors are expressed in the prostate and urethra, α1B receptors are expressed in blood vessels, and α1D receptors are expressed in the prostate and bladder detrusor muscle. Therefore, α1 adrenergic receptor inhibitors with low or non-selectivity for α1 adrenergic receptor subtypes also act on α1B receptors expressed in blood vessels to inhibit contraction of peripheral vascular smooth muscle. As a result, side effects such as exacerbation of hypotension, dizziness and dizziness may be observed.

  Women often have low blood pressure, and in cases of neurological disorders, orthostatic hypotension is often associated. Therefore, there is a problem that α1 adrenergic receptor inhibitors are difficult to use for female cases. For example, in addition to the use of urapidil (trade name: Ebranbu), which is indicated for neuropathic bladder, female α-adrenergic receptor inhibitors currently used as antihypertensive drugs are currently being used for female discharge disorders. . However, since these α1 adrenergic receptor inhibitors are low or non-selective for α1 adrenergic receptor subtype, side effects such as exacerbation of hypotension, dizziness and dizziness may be observed. There was a safety problem.

  Silodosin is a selective inhibitor of α1A receptor, which is a subtype of α1 adrenergic receptor, and is used as an active ingredient of a therapeutic agent for dysuria that treats dysuria due to prostatic hypertrophy (Non-patent Document 7). And 8). Silodosin is highly selective for the α1A receptor compared to other α1 adrenergic receptor inhibitors such as tamsulosin, prazosin, alfuzosin, naphthopidyl, urapidil (Non-patent Documents 8-10).

JP-A-6-220015

T. Yamanishi et al., "Improvement of urethral resistance after the administration of an alpha-adrenoceptor blocking agent, urapidil, for neuropathic voiding disfunction", Paraplegia, Vol.32, pp.271-276 (1994) K. Yasuda et al., "The effect of urapidil on neurogenic bladder: a placebo controlled couble-blind study", The Journal of Urology, Vol.156, pp.1125-1130 (1996) H. Kakizaki et al., "Urodynamic effects of alpha1-blocker tamsulosin on voiding dysfunction in patients with neurogenic bladder", International Journal of Urology, Vol. 10, pp. 576-581 (2003) L. O. Olujide et al., "Female voiding dysfunction", Best Practice & Research Clinical Obstetrics and Gynaecology, Vol.19, No.6, pp.807-828 (2005) T. M. Kessler et al., "The effect of terazosin on functional bladder outlet obstruction in woman: a pilot study", The Journal of Urology, Vol.176, pp.1487-1492 (2006) K. Lee et al., "Efficacy and safety of tamusulosin for the treatment of non-neurogenic voiding dysfunctionvin females: a 8-week prospective study", Journal of Korean Medicinal science, Vol.25, pp.117-122 (2010) S. Schilit et al., "Silodosin: a selective alpha1A-adrenergic receptor antagonist for the treatment of benign prostatic hyperplasia", Clinical Therapeutics, Vol.31, No.11, pp.2489-2502 (2009) Kawatsuki Kazuki, “The Forefront of Drug Treatment for Prostatic Hypertrophy”, Pharmaceutical Journal, Vol. 126, 199-206, 2006 Muramatsu Yunobu et al., “Classification of α1 Adrenergic Receptors and Latest Information on α1 Blockers”, Pharmaceutical Journal, Vol. 126, pp. 187-198, 2006 Tachimichi et al., “Α1-adrenergic receptor subtype selectivity and organ specificity of silodosin (KMD-3213)”, Pharmaceutical Journal, Vol. 126, 199-206, 2006

  An object of the present invention is to provide a safe drug that can be applied to the treatment of female dysuria and has few side effects. Urination problems are an important issue to be solved because they lower the patient's QOL. There are various diseases that cause dysuria, such as overactive bladder, neurogenic bladder, benign prostatic hyperplasia, and interstitial cystitis. Especially in elderly people, various causes overlap, and aging and lifestyle-related diseases. It itself has been reported to cause symptoms of dysuria. In particular, for dysuria in women, the mechanism of the disease has not yet been elucidated, and a therapeutic method has not yet been established.

  Conventionally, only urinary storage disorders that cause symptoms such as urinary incontinence have attracted attention as dysuria in women, and there are few studies on the treatment of discharge disorders that were considered to be few, and good results were not obtained even if they were examined . Many women have low blood pressure, and the conventional therapies used for women's dysuria are urapidil (brand name Ebranchle) and antihypertensive drugs, which may cause exacerbation of hypotension, dizziness, dizziness, etc. There were occasional side effects, and there were safety issues.

  In order to solve the above-mentioned problems, the present inventor has conducted an exploratory study on the usefulness and safety of urination disorder in women, and in the process, a selective α1A adrenergic receptor which is an active ingredient of a therapeutic agent for urination disorder due to prostatic hypertrophy. Focusing on the fact that the inhibitor silodosin has little effect on blood pressure, we conducted an exploratory study (voluntary clinical study) on the usefulness and safety of women with dysuria.

  And, the present inventor has shown that silodosin can improve QOL by reducing both urine storage symptoms and discharge symptoms in female dysuria patients, and does not affect the basal blood pressure and orthostatic blood pressure of the patients. This was confirmed for the first time in clinical practice and the present invention was completed.

That is, the present invention relates to:
1. A therapeutic agent for dysuria, comprising silodosin or a pharmacologically acceptable salt thereof or a solvate thereof as an active ingredient, which is administered to female dysuria patients,
2. 1. The female urination disorder patient is a female urination disorder patient with urinary storage disorder, Dysuria treatment agent,
3. 1. The female dysuria patient is a female dysuria patient with urinary storage disorder and discharge disorder. Dysuria treatment agent,
4). 2. A female dysuria patient who is associated with hypotension. Or 3. Dysuria treatment agent,
5. 4. The hypotension is orthostatic hypotension. Dysuria treatment agent,
6). Use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof in the treatment of female dysuria patients.
7). 5. The female urination disorder patient is a female urination disorder patient with urinary storage disorder. Use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof,
8). 6. The female dysuria patient is a female dysuria patient with urinary storage disorder and discharge disorder. Use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof,
9. 6. The female dysuria patient is a patient with hypotension. Or 8. Use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof,
10. 8. The hypotension is orthostatic hypotension. Of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof.

  ADVANTAGE OF THE INVENTION According to this invention, the urination disorder therapeutic agent administered to a female urination disorder patient can be provided. Since the therapeutic agent for dysuria according to the present invention exhibits an excellent effect that is clinically effective in a female dysuria patient with urinary storage disorder, preferably a female urinary disorder patient with urinary storage disorder and excretion disorder, This is useful for women with dysuria who have few options. Furthermore, the therapeutic agent for dysuria according to the present invention has no side effects related to hypotension such as orthostatic hypotension, and therefore can be administered to patients with dysuria who have such hypotension. Thus, the present invention relates to dysuria patients, particularly female dysuria patients with urinary storage disorders, preferably female urinary disorder patients with urinary storage disorders and excretion disorders, and even female urinary disorder patients with low blood pressure. It is useful in the medical field related to the treatment.

It is a figure which shows the result of having evaluated the micturition symptom before a silodosin administration and after the administration start by an international prostate symptom score (IPSS). ■ indicates the evaluation result of discharge symptoms, ▲ indicates the evaluation result of urine accumulation symptoms, and ◆ indicates the evaluation result based on the total score. * Indicates that a significant difference (P <0.05) was observed in statistical analysis by Student's t test. Example 1 It is a figure which shows the result of having evaluated QOL before and after the administration of silodosin by IPSS-QOL. * Indicates that a significant difference (P <0.05) was observed in statistical analysis by Student's t test. Example 1 It is a figure which shows the result of having evaluated the urinary storage symptom before administration of silodosin and after administration start with an overactive bladder symptom questionnaire (OABSS). * Indicates that a significant difference (P <0.05) was observed in statistical analysis by Student's t test. Example 1 It is a figure which shows the result of having evaluated the state of urinary incontinence before administration of silodosin, and after administration start by the international urinary incontinence meeting questionnaire short form (ICIQ-SF). ■ indicates urine leakage frequency, ▲ indicates discomfort, and ◆ indicates urine leakage. Example 1 It is a figure which shows the result of having evaluated QOL before a silodosin administration and after the administration start with a King health questionnaire (KHQ). Example 1 It is a figure which shows the result of having evaluated the residual urine amount before silodosin administration and after the start of administration. * Indicates that a significant difference (P <0.05) was observed in statistical analysis by Student's t test. Example 1 It is a figure which shows the result of having measured orthostatic hypotension before and after the administration of silodosin by the Shelong test. ● indicates systolic blood pressure (SBP) and diastolic blood pressure (DBP) before silodosin administration, □ indicates SBP and DBP at the beginning of silodosin administration, ▲ indicates SBP and DBP at 4 weeks after silodosin administration, and ◆ indicates silodosin SBP and DBP at the 8th week from the start of administration are shown, and ■ indicates SBP and DBP at the 12th week from the start of administration of silodosin. Example 1 It is a figure which shows the result of having measured the pulse at the time of the Shelong test implementation before silodosin administration and after administration start. ● indicates systolic blood pressure (SBP) and diastolic blood pressure (DBP) before silodosin administration, □ indicates SBP and DBP at the beginning of silodosin administration, ▲ indicates SBP and DBP at 4 weeks after silodosin administration, and ◆ indicates silodosin SBP and DBP at the 8th week after the start of administration, and SBP and DBP at the 12th week after the start of administration of silodosin. (Example 1) ● represents systolic blood pressure (SBP) and diastolic blood pressure (DBP) before silodosin administration, □ represents SBP and DBP at the beginning of silodosin administration, and ▲ represents SBP and DBP at 4 weeks after silodosin administration started. , ♦ indicates SBP and DBP at 8 weeks after the start of silodosin administration, and ■ indicates SBP and DBP at 12 weeks after the start of silodosin administration. Example 1

  The present invention relates to a therapeutic agent for dysuria, comprising silodosin or a pharmacologically acceptable salt thereof or a solvate thereof as an active ingredient, which is administered to female dysuria patients.

  The therapeutic agent for dysuria according to the present invention is preferably administered to female dysuria patients with urinary storage disorders. The range of female dysuria patients with urinary storage disorders includes female dysuria patients with urinary storage disorders and discharge disorders, and female dysuria patients with urine storage disorders but no urinary disorders.

  The therapeutic agent for dysuria according to the present invention is preferably administered by female dysuria patients with urinary storage disorders and discharge disorders. In urination disorders that have both urinary storage disorder and discharge disorder, the urine storage function and the discharge function are exactly the opposite functions, so using a drug that assists in urine storage may lead to the occurrence or deterioration of the discharge disorder. In addition, the use of a drug that assists the discharge may cause urinary storage disorder or exacerbation. Therefore, it is difficult to treat dysuria having both urinary storage disorder and discharge disorder. Silodosin not only improves drainage disorders in cases where only discharge disorders are observed, but also confirms not only improvements in drainage disorders but also improvements in urinary storage disorders in cases with both urine storage disorders and discharge disorders. The possibility of improving the urinary storage symptoms in the observed cases was also recognized. Thus, silodosin showed an excellent effect that was clinically effective in female dysuria patients with urinary storage disorders and discharge disorders.

  The therapeutic agent for dysuria according to the present invention is more preferably administered to a female dysuria patient with urinary storage disorder who is associated with hypotension. Silodosin showed no reduction in basal blood pressure, worsening orthostatic hypotension, or other side effects in female dysuria patients. Therefore, silodosin is a safe drug that can be administered to female dysuria patients with urinary storage disorders, preferably female dysuria patients with urinary storage disorders and discharge disorders, and patients with low blood pressure .

  The term “dysuria” refers to a state in which normal urination function is impaired by preventing either or both of the two processes of urination function, the urine accumulation phase and the elimination phase. That is, dysuria is roughly classified into three categories: dysuria having only urine storage disorder, dysuria having urine storage disorder and discharge disorder, and dysuria having only discharge disorder.

  The term “urine storage disorder” refers to a disorder in which there is some disorder in the urine accumulation process and the urine cannot be collected in the bladder sufficiently. Urinary storage disorders result in urinary storage symptoms such as daytime frequent urination, nocturia, urgency, and urge incontinence.

  The term “excretion disorder” refers to a disorder in which there is some disorder in the elimination process, and the urine collected in the bladder cannot be sufficiently discharged. Discharge disorders may cause discharge symptoms such as delayed urination, decreased urination, intermittent urination, itching, and residual urine sensation.

  The term “agent for treating dysuria” means a drug that exerts an effect of reducing, improving, or curing dysuria by being administered to a patient having dysuria.

  The term “hypotension” refers to a decrease in systemic arterial pressure and refers to systolic blood pressure of 100 mgHg or less, more preferably systolic blood pressure of 80 mgHg or less. Hypotension is broadly classified into essential hypotension, secondary hypotension (also referred to as symptomatic hypotension), and orthostatic hypotension. Essential hypotension is hypotension of unknown cause, and secondary hypotension is hypotension that occurs as one of the symptoms caused by the causative disease that can be identified. Orthostatic hypotension refers to transient hypotension that occurs when posture changes such as standing. In the present invention, the term “low blood pressure” refers to a blood pressure equal to or lower than the systolic blood pressure regardless of such classification.

  The term “orthostatic hypotension” refers to transient hypotension that shows a decrease in systolic blood pressure of 20 mmHg or more when the body position changes, for example, when standing from sitting or sitting. Orthostatic hypotension causes symptoms such as darkness in front of the eyes, dizziness, fainting, palpitation, and nausea as well as a decrease in blood pressure during standing. Orthostatic hypotension can occur in all humans regardless of whether the sitting blood pressure is normal blood pressure, hypotension or hypertension. Since autonomic nerves, particularly sympathetic nerves, play a very important role in blood pressure regulation, diseases that cause sympathetic nerve dysfunction and inhibitors of sympathetic nerve function can cause hypotension, particularly orthostatic hypotension.

  Silodosin has the chemical name (-)-1- (3-hydroxypropyl) -5-[(2R) -2-({2- [2- (2,2,2-trifluoroethoxy) phenoxy] ethyl. } Amino) propyl] -2,3-dihydro-1H-indole-7-carboxamide ((-)-1- (3-Hydroxypropyl) -5-[(2R) -2-({2- [2- ( 2,2,2-trifluoroethoxy) phenoxy] ethyl] amino) propyl] -2,3-dihydro-1H-indole-7-carboxamide), an indoline derivative with urethral smooth muscle contraction inhibitory treatment It was developed as an agent (Patent Document 1). Silodosin can be produced, for example, by the method described in Patent Document 1 and the like.

  Silodosin is a selective α1A adrenergic receptor inhibitor, and among α1 adrenergic receptor subtypes such as α1A, α1B, and α1D, it has high affinity for α1A receptor, and other subtypes of α1 adrenergic receptors Compared to the α1A receptor more strongly compared. The α1A receptor is expressed more in the urethra than the α1D receptor. On the other hand, α1B receptors are highly expressed in blood vessels. Therefore, the selective α1A adrenergic receptor inhibitor has less effect on the blood vessels, that is, side effects such as hypotension, compared with the α1B adrenergic receptor inhibitor and the like, and has a selective effect on the urethra.

  Silodosin contained as an active ingredient of the therapeutic agent for dysuria according to the present invention may be a free form or a pharmacologically acceptable salt. Examples of pharmacologically acceptable salts include acid addition salts and base addition salts. Acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, or phosphate, and citrate, oxalate, acetate, formate, Examples thereof include organic acid salts such as propionate, benzoate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, or paratoluenesulfonate. Examples of the base addition salt include inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, or ammonium salt, and organic base salts such as triethylammonium salt, triethanolammonium salt, pyridinium salt, and diisopropylammonium salt. . Silodosin may be a solvate of these in addition to a free form and a salt. Examples of solvates include hydrates and ethanol solvates, but any solvate may be used as long as it is a solvate with another solvent acceptable as a pharmaceutical product.

  The therapeutic agent for dysuria according to the present invention can be produced as a pharmaceutical composition containing a pharmaceutically acceptable carrier (pharmaceutical carrier) as necessary.

  Examples of the pharmaceutical carrier include fillers, fillers, binders, moistening agents, disintegrating agents, lubricants, diluents and excipients that are usually used depending on the form of use of the preparation. These are appropriately selected and used depending on the administration form of the resulting preparation. More specifically, water, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, xanthan gum, gum arabic, casein, Examples include gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, and lactose. These may be used alone or in combination of two or more according to the dosage form of the drug. In addition, stabilizers, bactericides, buffers, isotonic agents, chelating agents, surfactants, pH adjusters, and the like can be used as appropriate. Examples of the stabilizer include human serum albumin, ordinary L-amino acids, saccharides, and cellulose derivatives. The L-amino acid is not particularly limited, and may be any of glycine, cysteine, glutamic acid and the like. The saccharide is not particularly limited, for example, monosaccharides such as glucose, mannose, galactose, and fructose, sugar alcohols such as mannitol, inositol, and xylitol, disaccharides such as sucrose, maltose, and lactose, dextran, hydroxypropyl starch, chondroitin sulfate, Any of polysaccharides such as hyaluronic acid and their derivatives may be used. The cellulose derivative is not particularly limited, and may be any of methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose sodium and the like. There is no particular limitation on the surfactant, and either an ionic surfactant or a nonionic surfactant can be used. Examples of the surfactant include polyoxyethylene glycol sorbitan alkyl ester, polyoxyethylene alkyl ether, sorbitan monoacyl ester, and fatty acid glyceride. Buffers include boric acid, phosphoric acid, acetic acid, citric acid, ε-aminocaproic acid, glutamic acid and / or their corresponding salts (for example, alkali metal salts such as sodium salts, potassium salts, calcium salts, magnesium salts thereof, An alkaline earth metal salt). Examples of the isotonic agent include sodium chloride, potassium chloride, saccharides and glycerin. Examples of the chelating agent include sodium edetate and citric acid.

  The amount of the active ingredient contained in the therapeutic agent for dysuria according to the present invention is appropriately selected from a wide range. Usually, it is in the range of about 0.00001-70% by weight, preferably about 0.0001-5% by weight.

  The dose range of the therapeutic agent for dysuria according to the present invention is not particularly limited, and the effectiveness of the contained components, administration form, administration route, type of disease, nature of the subject (weight, age, medical condition and use of other medicines) Or the like) and the judgment of the doctor in charge. In general, an appropriate dose is, for example, in the range of about 0.01 μg to 100 mg, preferably about 0.1 μg to 1 mg, per kg of the subject's body weight. However, these dose modifications can be made using general routine experimentation for optimization well known in the art. The above dose can be administered once to several times a day. As for the preferred dose, when administered orally, it is appropriate to administer 2 mg-4 mg twice a day as the weight of silodosin.

  As the administration route, either systemic administration or local administration can be selected. In this case, an appropriate administration route is selected according to the disease, symptoms and the like. The medicament according to the present invention can be administered by either oral route or parenteral route, but oral administration is more preferred. Examples of parenteral routes include normal intravenous administration and intraarterial administration, as well as subcutaneous, intradermal and intramuscular administration.

  The dosage form is not particularly limited and can be various dosage forms. For example, in addition to being able to be used as a solution preparation, it can be lyophilized and stored, and after use, it can be dissolved in a buffer solution containing water, physiological saline, etc. and adjusted to an appropriate concentration. You can also Further, it may be a sustained dosage form or a sustained release dosage form.

  Specifically, for oral administration, tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, spirits, syrups, extracts, elixirs should be used. Can do. Examples of parenteral agents include subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, transdermal administration or patches, ointments or lotions, sublingual agents for buccal administration. , Oral patches, and aerosols and suppositories for nasal administration, but are not limited thereto. These preparations can be produced by known methods usually used in the preparation process.

  When an oral solid preparation is prepared, an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, a flavoring agent, and the like are added to the above active ingredients, and then tablets are prepared by a conventional method. Coated tablets, granules, powders, capsules and the like can be produced. Such additives may be those commonly used in the art. For example, excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid As a binder, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc. Disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, and lubricants such as purified talc, stearin Salts, borax, polyethylene glycol and the like, as the corrigent sucrose, orange peel, citric acid, can be exemplified tartaric acid.

  When an oral liquid preparation is prepared, an oral solution, a syrup, an elixir or the like can be produced by a conventional method by adding a corrigent, a buffer, a stabilizer, a corrigent and the like to the above compound. In this case, the flavoring agent may be those listed above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing injections, add pH regulators, buffers, stabilizers, tonicity agents, local anesthetics, etc. to the above compounds to produce subcutaneous, intramuscular and intravenous injections by conventional methods. can do. In this case, examples of the pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, ethylenediaminetetraacetic acid (EDTA), thioglycolic acid, and thiolactic acid. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

  The present invention also provides a method for treating dysuria, comprising administering a therapeutic agent for dysuria containing silodosin or a pharmacologically acceptable salt thereof or a solvate thereof as an active ingredient to a female dysuria patient. About. The method of treating dysuria according to the present invention is preferably intended for female dysuria patients with urinary storage disorders, and more preferably for female dysuria patients with urine storage disorders and discharge disorders. More preferably, the therapeutic agent for dysuria according to the present invention is intended for female dysuria patients with urinary storage disorders, preferably female dysuria patients with urinary storage disorders and excretion disorders, and patients with low blood pressure. And

  The invention further relates to the use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof in the treatment of female dysuria patients. Silodosin or a pharmacologically acceptable salt thereof or a solvate thereof is preferably used for the treatment of female dysuria patients with dysuria, more preferably female dysuria patients with dysuria and drainage disorders Is done. More preferably, silodosin or a pharmacologically acceptable salt thereof or a solvate thereof is a female urination disorder patient with urinary storage disorder, preferably a female urination disorder patient with urinary storage disorder and discharge disorder. Used for patients with low blood pressure.

  By the administration of the therapeutic agent for dysuria according to the present invention, QOL can be improved in the treatment of female dysuria. Therefore, according to the present invention, it is possible to provide an agent for improving QOL in female dysuria, comprising silodosin or a pharmacologically acceptable salt thereof or a solvate thereof as an active ingredient. According to the present invention, there is also provided a method for improving QOL in dysuria of women, comprising administering a therapeutic agent for dysuria comprising silodosin or a pharmacologically acceptable salt thereof or a solvate thereof as an active ingredient. Can provide. Furthermore, according to the present invention, it is possible to provide use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof in improving QOL of female dysuria patients.

  Hereinafter, the present invention will be described more specifically with reference to examples. The present invention is not limited by the following examples.

[subject]
Silodosin was administered to 15 women with discharge symptoms and residual urine, and the effect of silodosin on dysuria was examined. Prior to this clinical study, we received approval from the Ethics Committee and obtained written consent from the subject patient. None of the subjects received medications that affect urination.

[Drug]
First, after observing the urination state for 4 weeks, silodosin was administered for 12 weeks. As silodosin preparations, Yurief (registered trademark) tablets manufactured by Kissei Pharmaceutical Co., Ltd. were used, and 4 mg was orally administered twice a day. Half of the patients increased the dosage of silodosin after 4 weeks, and 8 mg was orally administered twice a day.

[Evaluation method]
The effect of silodosin was evaluated before and after the observation period, and after 2, 4, 8, and 12 weeks of oral administration, International Prostate Symptom Score (IPSS), IPSS-QOL, Overactive Bladder Symptom Questionnaire (OASS), International Urinary Incontinence Meeting Questionnaire Short form (ICIQ-SF), King Health Questionnaire (KHQ), questionnaire, urine flow and residual urine were measured. Moreover, the side effect to the orthostatic blood pressure fluctuation was measured by the Shelong test, and the pulse was also measured at the time of measurement. The measurement results were analyzed by student t-test.

  IPSS is a method for evaluating urination symptoms related to both irritation (urine storage) symptoms and obstruction (excretion) symptoms, and it is determined that the lower the score, the milder the symptoms. Evaluation of irritation (urine accumulation) symptoms is performed by scoring each of urination within 2 hours, urgency, and night urination. The evaluation of the obstruction (excretion) symptom is performed by scoring each of the feeling of residual urine, urinary line disruption, urinary gland momentum and urination. In addition, the evaluation of urination symptoms is performed based on the total score by summing up the scores relating to the irritating (urine accumulation) symptom and the scores relating to the obstruction (excretion) symptom.

  IPSS-QOL is a method for evaluating the degree of satisfaction with urinating symptoms, in other words, the degree of dissatisfaction, and it can be interpreted that the lower the level, the higher the degree of satisfaction with QOL.

  OABSS is a method for evaluating overactive bladder symptoms, that is, urine storage symptoms, and it is determined that the lower the score, the milder the symptoms. Scores are given for daytime urination frequency, nighttime urination frequency, urgency, and urinary incontinence. The lower the score, the milder the symptom.

  ICIQ-SF is a method for evaluating urinary incontinence, and it is determined that the lower the score, the milder the symptoms. Evaluation is performed by scoring each of the frequency of urine leakage, the amount of urine leakage, and the level of confusion caused by urine leakage.

  KHQ is a method for evaluating QOL due to dysuria, and the lower the score, the better the QOL. The evaluation is performed by scoring each of the physical and social activity limits, sleep and vitality (energy), and calculating the total score.

  The urinary flow measurement was performed using a urofluorometric instrument for the maximum urinary flow rate (Qmax, ml / sec) and the average urinary flow rate (ml). Both are test values that show the momentum of urine, and the higher the value, the faster the urine excretion, and therefore it is judged that the excretion disorder is mild or normal.

  The amount of residual urine was measured by transabdominal ultrasonic tomography, and the amount of urine remaining in the bladder after self-urine was measured. The larger the amount of residual urine, the more serious the discharge disorder.

  The Shelong test is a method for evaluating orthostatic hypotension due to autonomic neuropathy. Generally, stand for 10 minutes after resting for 10 minutes, measure blood pressure before and after standing, and conduct questions about standing upset symptoms such as dizziness, lightheadedness, darkness and cloudiness in front of the eyes. . If the patient has a standing ataxic symptom and has a systolic hypotension of 20-30 mmHg or more when standing, a diagnosis of orthostatic hypotension is made.

[result]
The results of IPSS evaluation and IPSS-QOL evaluation are shown in FIG. 1 and FIG. 2, respectively, and the results of OABSS evaluation and ICIQ-SF evaluation are shown in FIG. 3 and FIG. The results of KHQ evaluation are shown in FIG. The results of the residual urine volume measurement evaluation are shown in FIG. Moreover, the result of a Shelong test is shown to FIG. 7-A, and the measurement result of a pulse is shown to FIG. 7-B.

  In the observation before oral administration of silodosin and after 2 weeks, 4 weeks, 8 weeks, and 12 weeks, the excretion symptom score (IPSS obstruction symptom score) significantly decreased after 8 weeks and 12 weeks. Residual urine decreased in almost all cases, and the average values of maximum and average urinary flow rates increased. In addition, the urine accumulation symptom score (IPSS irritation symptom score and OASS score) also decreased significantly after 8 weeks. Therefore, it was observed that silodosin improves not only the discharge symptoms but also the urine storage symptoms after the 8th week. On the other hand, there was no change in the frequency, degree and incentive of urinary incontinence.

  On the other hand, silodosin had no effect on standing-induced changes in blood pressure by the Shelong test (standing load test), nor showed any effects on basal blood pressure or pulse. It was also observed that there were no other adverse events and it could be used safely.

  From the above clinical results, it was found that silodosin safely improves women's urinary storage symptoms (disorders) and discharge symptoms (disorders) and does not show side effects related to lowering blood pressure. Thus, silodosin was considered to be an effective and safe drug for both neurogenic and non-neuropathic dysuria.

  The present invention relates to the medical field of dysuria patients, particularly female dysuria patients with urinary storage symptoms, preferably female dysuria patients with urinary storage symptoms and excretion symptoms, and female dysuria patients with low blood pressure. Useful.

Claims (10)

A therapeutic agent for dysuria, comprising silodosin or a pharmacologically acceptable salt thereof or a solvate thereof as an active ingredient, which is administered to female dysuria patients. The therapeutic agent for urination disorder according to claim 1, wherein the female dysuria patient is a female urinary disorder patient having a urine storage disorder. The therapeutic agent for dysuria according to claim 2, wherein the female dysuria patient is a female dysuria patient having urinary storage disorder and discharge disorder. The therapeutic agent for dysuria according to claim 2 or 3, wherein the female dysuria patient is a patient with hypotension. The therapeutic agent for dysuria according to claim 4, wherein the hypotension is orthostatic hypotension. Use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof in the treatment of female dysuria patients. The use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof according to claim 6, wherein the female dysuria patient is a female urinary disorder patient having a urinary storage disorder. 8. Use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof according to claim 7, wherein the female dysuria patient is a female urinary disorder patient having urinary storage disorder and discharge disorder. Use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof according to claim 7 or 8, wherein the female dysuria patient is a patient with hypotension. Use of silodosin or a pharmacologically acceptable salt thereof or a solvate thereof according to claim 9, wherein the hypotension is orthostatic hypotension.

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