JP2012219075A - Medicine containing naftopidil - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine having efficacy to treatment of a disease in which functions of a serotonin 2A receptor and/or a serotonin 2B receptor are enhanced.SOLUTION: This medicine contains naftopidil for treating a disease in which at least either function of the serotonin 2A receptor and the serotonin 2B receptor is enhanced.

Description

  The present invention relates to a medicament for treating a disease containing at least one of serotonin 2A receptor and serotonin 2B receptor, which contains naphthopidyl as an active ingredient.

  Serotonin (5-hydroxytryptamine; 5-HT) is an in vivo monoamine known to function as a biotransmitter, and is the most abundant in the intestinal tract. Intestinal motility, vascular tone, platelet function In addition, it is involved in various physiological actions such as regulation of nerve function, central action such as sleep and mood disorders (Non-patent Document 1).

  Receptors on which serotonin acts are classified into seven subtypes. Among these subtypes, serotonin 2 receptor is further divided into three subtypes: serotonin 2A receptor, serotonin 2B receptor and serotonin 2C receptor. (Non-Patent Document 2).

  Compounds that bind to and block the serotonin 2A receptor are irritable bowel syndrome, peripheral circulatory disturbance, platelet aggregation, pulmonary hypertension, hot flush, gastroesophageal reflux disease, hyperalgesia, pancreatitis, asthma, sleep disorder, or Since they alleviate symptoms of diseases such as depression, these are considered as diseases related to hyperfunction of serotonin 2A receptor (Patent Document 1, Patent Document 2, Patent Document 3, Patent Document 4, Non-Patent Document) Document 3, Non-Patent Document 4, Non-Patent Document 5). In addition, it is known that ketanserin, which is a serotonin 2A receptor blocker, exhibits an action of reducing the internal pressure in the ureter that has been increased by an agonist of serotonin 2A receptor (Non-patent Document 6). In addition, it has been reported that salpololelate, a serotonin 2A receptor blocker, was effective even in cases in which anticholinergic drugs used as a therapeutic drug for frequent urination were not effective for diabetic urinary symptoms. There exists patent document 7).

  As for serotonin 2B receptor, since a drug showing its blocking effect is effective, irritable bowel syndrome, dyspepsia, reflux esophagitis (GERD), migraine, pain, fibrosis, etc. are associated with serotonin 2B receptor. It is mentioned as a disease related to hyperfunction (Patent Document 5).

  On the other hand, naphthopidil (Naftopidil: (±) -1- [4- (2-methoxyphenyl) piperazinyl] -3- (1-naphthyloxy) propan-2-ol) is a substance disclosed in Patent Document 6, and The publication discloses that naphthopidyl or a salt thereof is useful for treating dysuria in prostatic hypertrophy. Naftopidil has been proven to improve dysuria associated with benign prostatic hyperplasia in a number of clinical studies, and has already been used for oral tablets ("Frivus Tablets", "Frivus OD Tablets"); Manufacturer: Asahi Kasei Pharma ). Frivus tablets or Frivus OD tablets are administered as naphthopidil once daily from 25 mg to adults with dysuria due to benign prostatic hyperplasia. If the effect is insufficient, it is 50 to 75 mg at intervals of 1 to 2 weeks. From clinical trial results, it is set to be taken once a day. Examples of prescription and component amount of naphthopidyl preparation are described in Patent Document 6 and Example 12 of Patent Document 7.

  It is known that naphthopidyl has a blocking action on α1A and α1D adrenergic receptors and suppresses the contraction of noradrenaline on prostate tissue or smooth muscle tissue of prostate urethra (Non-Patent Document). 8). Moreover, it has been shown that naphthopidyl is effective not only for dysuria associated with prostatic hypertrophy but also for urinary storage symptoms such as frequent urination and nocturia in patients with benign prostatic hyperplasia (Non-patent Document 9). However, there is no report that naphthopidyl is effective for lower urinary tract symptoms such as frequent urination due to diabetes.

  It is known that naphthopidyl has an action on other than α1 receptor, for example, there is a report that it acts on serotonin 1A receptor (Non-patent Document 10). Rather, it has been suggested that it may act as an agonist on the serotonin 1A receptor. In addition, there is a report that naphthopidyl has an inhibitory effect on serotonin contraction of the ileum extracted from guinea pigs (Non-patent Document 11).

  However, there is no report that naphthopidyl suppresses serotonin-induced contraction of tissues such as ureters, blood vessels, intestinal tracts other than the ileum, or bladder. Furthermore, there is a report that naphthopidyl suppresses human platelet aggregation when the adrenergic action is enhanced by serotonin (Non-patent Document 12). Although this report discusses the relationship between the inhibition of platelet aggregation by naphthopidil and the serotonin 2 receptor, it does not specifically identify the receptor on which naphthopidil acts, and other than platelet aggregation. Is not mentioned. Therefore, there is no report that naphthopidyl directly binds to or acts on the serotonin 2A receptor or serotonin 2B receptor. That is, the possibility that naphthopidyl is a therapeutic agent for a disease considered to be caused by the enhancement of the serotonin 2A receptor and the serotonin 2B receptor has not been shown so far.

JP 2000-239163 A Special table 2007-510701 gazette WO2006 / 118212 pamphlet Special Table 2002-542287 JP 2005-526720 A Japanese Patent Publication No. 60-29712 JP 2001-288115 A

Mohammad-Zadeh LF et al. , J .; Vet. Pharmacol. Ther. 31: 187-199 (2008) Nichols DE and Nichols CD, Chem. Rev. 108: 1614-1641 (2008) Amprag Tablets 50mg, Amprag Tablets 100mg, Amprag Fine Granules 10%, Drug Interview Form Revised August 2010 (14th Edition) Hironaka E et al. Cardiovasc. Res. 60: 692-699 (2003). Yukie Sato et al. Journal of Geriatrics 43 (4): 492-497 (2006) Hauser DS et al. Br. J. et al. Pharmacol. 135: 1026-1032 (2002) Takimoto Shitoku et al. The Japanese Journal of Urology 90 (8): 731-740 (1999) Takei R et al. Jpn. J. et al. Pharmacol. 79: 447-454 (1999). Kakizaki H et al. , LUTS, 1: 35-39 (2009). Borbe HO et al. Eur. J. et al. Pharmacol. 205 (1): 105-107 (1991) Koji Yamamoto et al., Basic and Clinical Studies 26 (1): 229-246 (1992) Alaryyed NA et al. Br. J. et al. Clin. Pharmac. 39: 369-374 (1995).

  The subject of this invention is providing the therapeutic agent of the disease which arises when the function of at least one of a serotonin 2A receptor and a serotonin 2B receptor is enhanced.

  As a result of extensive studies on naphthopidyl, it has been surprisingly found that naphthopidyl binds to serotonin 2A receptor and serotonin 2B receptor and has a blocking action on these receptors. Various α1 blockers have also been found to have no effect on these receptors. Further, in an experimental animal model in which the urethra is partially occluded in a rat and the bladder is thickened, the bladder was examined. As a result, the reactivity to serotonin was increased and serotonin 2A receptor and serotonin 2B receptor increased. I found out. And in this experimental animal model, it was found that naphthopidyl suppresses the contractile reaction due to the enhancement of at least one of the functions of serotonin 2A receptor and serotonin 2B receptor.

The present invention has been completed based on the above findings. That is, the present invention
(1) The present invention relates to a drug containing naphthopidyl for treating a disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced.

  Furthermore, 1) the serotonin 2A receptor blocker was effective against cases in which anticholinergic drugs used as a therapeutic agent for frequent urination were ineffective against frequent urinary symptoms in diabetic patients; 2) Irritable bowel syndrome, peripheral circulatory disorder, pulmonary hypertension, hot flush, gastroesophageal reflux disease, hyperalgesia, pancreatitis, asthma, sleep disorder, or depression are considered as diseases related to hyperfunction of serotonin 2A receptor 3) Since the serotonin 2A receptor blocker lowers the internal pressure in the ureter, which is increased by the serotonin 2A receptor agonist, it is considered promising as a therapeutic agent for ureteral stones; 4 ) Irritable bowel syndrome, dyspepsia, reflux esophagitis (GERD), migraine, pain, fibrosis, etc. are considered as diseases associated with hyperfunction of serotonin 2B receptor; (1) The present invention as claimed; Given the current clinical indications and 6) naftopidil, the present invention further relates to the following.

(2) An overactive bladder having an anticholinergic drug-resistant overactive bladder, an overactive bladder associated with diabetes and / or accompanied by diabetes, wherein the function of at least one of serotonin 2A receptor and serotonin 2B receptor is enhanced Or a drug containing naphthopidil that is frequent urination, irritable bowel syndrome, ureteral stones, peripheral circulation disorder, pulmonary hypertension, gastroesophageal reflux disease, hyperalgesia, pancreatitis, migraine, fibrosis, or pain;
(3) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is an anti-cholinergic resistant overactive bladder;
(4) The disease according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is overactive bladder associated with diabetes or overactive bladder associated with diabetes Medicine;
(5) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is irritable bowel syndrome;
(6) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is ureteral stones;
(7) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is peripheral circulation disorder;
(8) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is pulmonary hypertension;
(9) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is hot flash;
(10) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is gastroesophageal reflux disease;
(11) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is hyperalgesia;
(12) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is pancreatitis;
(13) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is migraine;
(14) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is fibrosis;
(15) The medicament according to (2) above, wherein the disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced is pain;
(16) The function of at least one of serotonin 2A receptor and serotonin 2B receptor is enhanced by combining naphthopidyl with a serotonin 2A receptor blocker and / or a serotonin 2B receptor blocker other than naphthopidyl. Medicines for treating certain diseases;
(17) Serotonin 2A receptor blockers and / or serotonin 2B receptor blockers other than naphthopidyl are sarpogrelate, clozapine, olanzapine, quetiapine, risperidone, mirtazapine, ziprazidone, iloperidone, avaperidone, lurasidone, aripiprazole, paliperidone, asenapine , Blonanserin, ziprasidone, diclonapine, ITI-007, teruclide, pimavanserin, temanocrel, iferanserine, SB-742457, CYR-101, R-167154, TNX-102, TNX-105, YKP-1447, ACP-106, SEL -73, GSK-2054757, SB-742888, GSK-1742942, GSK-160260, GSK-1645888, GSK-2080 17, ER-21027, AR246686, MT-500, RQ-00310941, Babicaselin, PRX-8066, BF-1, SB-206553, R-1, MDL-100,907, ketanserin, ritanserin, and cycloheptazine The medicament according to (17) above, which is one or more blockers selected from the group;
(18) A medicament containing a serotonin 2A receptor blocker and / or a serotonin 2B receptor blocker other than naphthopidil for treating anticholinergic resistant hyperactive bladder;
(19) A serotonin 2A receptor blocker and / or a serotonin 2B receptor blocker other than naphthopidil for treating overactive bladder or frequent urination associated with diabetes or overactive bladder or frequent urination associated with diabetes Contains medicines.

  Another aspect of the present invention provides use of naphthopidyl for the manufacture of the above medicament for treating a disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced.

  Furthermore, from another aspect of the present invention, there is provided a method for treating a disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced, comprising at least one of serotonin 2A receptor and serotonin 2B receptor. There is provided a method comprising the step of administering a therapeutically effective amount of naphthopidyl to a mammal, including a human who has developed a disease having an enhanced function of

  As shown in Examples 1 to 3, the medicament of the present invention contracts with serotonin on the bladder in which the function of at least one of serotonin 2A receptor and serotonin 2B receptor is enhanced by occluding the urethra portion. It is extremely effective for the treatment of diseases in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced because the reaction can be suppressed and safety is high as already used in clinical practice. It can be used as a unique medicine.

Figure 3 shows the effects of naphthopidyl and various α1 blockers on serotonin-induced contractions in normal rat isolated bladder. The horizontal axis represents the serotonin concentration (M). The vertical axis (Developed tension) represents the degree of serotonin-induced contraction response converted to 100% as the contraction response due to 40 mM KCl. Data are mean ± standard error (n = 5-6). Figure 6 shows the contractile effect of serotonin in normal and BOO rat isolated bladders. The horizontal axis represents the serotonin concentration (M). The vertical axis (Developed tension) represents the degree of contraction reaction converted to contraction force (g / 100 mg tissue) per unit tissue weight (100 mg). Data are mean ± standard error. Figure 3 shows the effect of naphthopidyl on serotonin-induced contraction in BOO rat isolated bladder. The horizontal axis represents the serotonin concentration (M). The vertical axis (Developed tension) represents the degree of contraction reaction converted to contraction force (g / 100 mg tissue) per unit tissue weight (100 mg). Data are mean ± standard error (n = 9). Figure 2 shows the expression of serotonin 2A receptor (A) and serotonin 2B receptor (B) mRNA in normal and BOO rat bladders. The ordinate (Expression level) uses ribosomal protein 19 (RPL19) as an internal standard gene, corrected the expression levels of serotonin 2A receptor and serotonin 2B receptor, and expressed the average value of control values as 1. Data are mean ± standard error.

  The active ingredient in the medicament of the present invention is a blocker of at least one of serotonin 2A receptor and serotonin 2B receptor, preferably naphthopidil ((±) -1- [4- (2-methoxyphenyl). ) Piperazinyl] -3- (1-naphthyloxy) propan-2-ol).

  The medicament of the present invention is a medicament comprising naphthopidyl or a physiologically acceptable salt thereof as an active ingredient and one or more pharmaceutical additives. Naftopidyl is a substance described in Japanese Patent Publication No. 60-29712, and can be easily obtained by those skilled in the art. As an active ingredient of the medicament of the present invention, a physiologically acceptable salt of naphthopidyl (for example, hydrochloride) may be used, but a free form substance can be preferably used.

  In this specification, when the pharmaceutical additive is in contact with naphthopidyl, for example, if it is a liquid form of the drug, the pharmaceutical additive present in a solution state or suspension state is dissolved or suspended in the naphthopidyl molecule or In the case of a solid state medicine, for example, in the case of a mixture containing naphthopidyl and a pharmaceutical additive, the powder and granulation of the pharmaceutical additive contained in the mixture This means that the product comes into contact with naphthopidyl powder or granulated product. In the medicament of the present invention, it is preferable that lactose is not included as an additive for preparation that comes into contact with naphthopidyl among one or more additives for preparation used for preparation of the medicament. And it is very preferable that the pharmaceutical of this invention does not contain lactose at all as an additive for formulation.

  In the present specification, the hardness of the tablet and the degree of compression at the time of manufacture can be appropriately determined according to the shape of the tablet and the like. As the medicament of the present invention, a tablet is particularly preferable. Tablets can be classified according to use, but the term “tablet” used in this specification includes, for example, oral tablets (troches) that are dissolved in the mouth and applied to the oral mucosa and pharyngeal mucosa, and dissolved in the mouth from the oral mucosa. Oral tablets that absorb drugs (buccal tablets, sublingual tablets), orally disintegrating tablets that disintegrate tablets in the mouth, swallow with water or saliva, and absorb drugs from the digestive organs, implanted tablets that are implanted subcutaneously Also included are dissolved tablets that take a liquid in which tablets are dissolved or are used for external use.

  Moreover, a tablet can be classify | categorized into a plain tablet and a coated tablet from a structural viewpoint, for example. The uncoated tablet means a tablet in which the surface of the tablet obtained by compression molding is not coated. Typically, the whole tablet is a tablet composed of a continuous phase containing naphthopidyl. Usually, it can be understood that it is a tablet itself obtained by compressing a powder or granulated product containing a drug with a tableting machine. The coated tablet means a tablet in which a coating layer containing no drug is formed on the surface of the uncoated tablet. Examples of the coated tablet include a film-coated tablet, a sugar-coated tablet, and a dry-coated tablet. Furthermore, the multilayer tablet which forms the layer which does not contain a drug in a part of tablet is illustrated. It goes without saying that these tablets are included in the term “tablet” as used herein.

  An orally disintegrating tablet is, for example, an active ingredient in which a formed tablet disintegrates rapidly in the oral cavity and is suspended and dispersed into fine particles, or a part or all of the tablet components are dissolved and then swallowed. Is a tablet absorbed from the digestive tract. As the disintegration time of the orally disintegrating tablet provided by the present invention, for example, the disintegration time by saliva can be measured in the oral cavity, but as a simpler method, as described in the examples of the present specification, It can be measured by a measurement method according to the Japanese Pharmacopoeia disintegration test method (using water as a test solution). The disintegration time is not particularly limited, but is, for example, within 3 minutes, usually within 1 minute, preferably within 40 seconds, more preferably within 30 seconds, and particularly preferably within 20 seconds. Orally disintegrating tablets can also be classified by manufacturing method, more specifically, non-compressible type orally disintegrating that can be manufactured using a freeze-drying method after filling a suspension-dispersed solution in a mold It can be classified into tablets and compression-type orally disintegrating tablets that can be produced by compressing powder using a tableting machine or the like. In the present invention, a compression type orally disintegrating tablet is a preferred example.

  The pharmaceutical additive used in the production of the pharmaceutical of the present invention is added for imparting functions such as a shaping effect, a coating effect, a binding effect, a disintegration effect, and a lubrication effect when the pharmaceutical is prepared. It is a substance and includes all substances except for the active ingredient among the ingredients contained in the medicine. Additives for pharmaceutical preparation can be classified according to the purpose of use, for example, excipients if it has a shaping effect, coating agents if it has a coating effect, binders if it has a binding effect, disintegration A substance having an effect can be classified as a disintegrant, and a substance having a lubrication effect can be classified as a lubricant. As the additive for preparation used in the present specification, a substance listed in “Pharmaceutical Additives Dictionary 2000” (edited by the Japan Pharmaceutical Additives Association, Yakuji Nippo) can be used, preferably other than lactose Substances can be used.

  For example, sugar alcohols and / or saccharides other than lactose can be used as pharmaceutical additives. Sugar alcohols are polyhydric alcohols obtained by reducing carbonyl groups of saccharides, such as glycerin, D-sorbitol, D-mannitol, erythritol, maltitol, xylitol, and D-mannitol, erythritol, Tolu and xylitol are preferable examples. One type or two or more types may be selected as sugar alcohols. Examples of saccharides other than lactose include glucose, sucrose, fructose, maltose, and candy powder obtained by saccharifying starch with an enzyme. Glucose and sucrose are preferable examples.

  A water-soluble polymer binder can be used for the preparation of the medicament of the present invention. The water-soluble polymer binder is an additive for pharmaceutical preparations composed of a water-soluble polymer that exhibits viscosity by dissolving in water and exhibits adhesive properties such as glue. A water-soluble polymer binder is used when granulating a powder mixture using this property. Although the addition method is not particularly limited, for example, it can be added as a solution at the time of granulation or can be added as a powder. Examples of the water-soluble polymer binder include hydroxypropylcellulose, methylcellulose, povidone, polyvinyl alcohol, hydroxypropylmethylcellulose, pregelatinized starch, gelatin, pullulan, sodium carboxymethylcellulose, gum arabic powder and the like. As the water-soluble polymer binder, one type or two or more types may be selected. Of these, hydroxypropylcellulose, povidone, and hydroxypropylmethylcellulose are particularly preferred examples.

  In preparing the medicament of the present invention, a binder other than the water-soluble polymer binder may be used. Examples of such binders include crystalline cellulose, corn starch, anhydrous precipitated calcium carbonate, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like. Of these, one type or two or more types may be selected. Lubricants used to avoid the phenomenon that the compression molded product adheres to the tableting parts and is difficult to be discharged (sticking: generated during tableting) include, for example, magnesium stearate and stearyl fumarate. Examples include sodium, talc, sucrose fatty acid ester, calcium stearate, stearic acid, L-leucine and the like. Of these, one type or two or more types may be selected. As the lubricant, magnesium stearate and sodium stearyl fumarate are particularly preferable. Disintegrants for rapidly disintegrating compressed tablets in saliva and gastric juice include low-substituted hydroxypropylcellulose, carmellose, carmellose calcium, croscarmellose calcium, partially pregelatinized starch, and light anhydrous silica. Examples thereof include acid, magnesium carbonate, calcium hydrogen phosphate, and synthetic hydrotalcite. Of these, one type or two or more types may be selected. A sweetener may be used to impart sweetness to the tablet and improve the dosage. Examples of the sweetener include saccharin, sodium saccharin, aspartame, monoammonium glycyrrhizinate, reduced maltose water candy, purified honey, and the like. Of these, one type or two or more types may be selected. A fragrance may be used to impart a good odor to the tablet and improve the dosage. Examples of the fragrance include L-menthol, vanillin, mint oil, lemon oil, vanilla flavor, fruit flavor, mint flavor and the like.

  The manufacturing method and manufacturing apparatus of a tablet are not specifically limited, The method and apparatus normally used in this industry can be used. More specifically, in the mixing step, a V-type mixer, a cross rotary mixer, or the like is used. In the granulation step, a fluidized bed granulator / dryer, a tumbling fluidized granulation coating apparatus, a stirring granulator, a cylindrical extrusion granulator, or the like is used. A compression molding (tablet) machine is an apparatus generally used for producing tablets, and examples thereof include a single-shot tablet machine.

  In the medicament of the present invention, the lower limit value of the content ratio of naphthopidyl which is an active ingredient is not particularly limited. For example, it is preferably 3% by weight or more, and preferably 4% by weight or more with respect to the total weight of the medicament. More preferably, it is more preferably 5% by weight or more. The upper limit of the content is not particularly limited, but is preferably 60% by weight or less, more preferably 55% by weight or less, and particularly preferably 50% by weight or less based on the total weight of the medicine. The lower limit value of the content ratio of the excipient is, for example, preferably 45% by weight or more, more preferably 50% by weight or more, and particularly preferably 55% by weight or more with respect to the total weight of the medicine. The upper limit of the content of the excipient is, for example, preferably 96% by weight or less, more preferably 94% by weight or less, and particularly preferably 92% by weight with respect to the total weight of the medicine.

  Although the content of naphthopidyl in the unit dosage form is not particularly limited, for example, it is preferably an amount reflecting the clinical dose. For example, the lower limit of the content in a tablet as a unit dosage form is preferably 20 mg or more, more preferably 22 mg or more, and particularly preferably 25 mg or more. The upper limit of the naphthopidyl content in one tablet is preferably 100 mg or less, more preferably 80 mg or less, and particularly preferably 75 mg or less.

  The shape of the tablet is not particularly limited as long as it is easy to take. Examples of the shape include a circle, an ellipse, a polygon, and a caplet (capsule type). Moreover, the size should just be easy to hold with a finger | toe and it is easy to include in a mouth, and the upper limit of a long diameter (in the case of circular) is preferable about 25 mm or less, about 22 mm or less is more preferable, About 20 mm or less is especially preferable. The lower limit is preferably about 5 mm or more, more preferably about 6 mm or more, and particularly preferably about 7 mm or more.

  The packaging form in the case of packaging a medicine is not particularly limited. For example, a light shielding process using a light shielding film or the like may be performed, and pillow packaging is applied to PTP (Press Through Package) packaging, strip packaging, or PTP packaging. Packaging etc. can be adopted. Examples of the packaging material include aluminum foil, polyvinyl chloride, cyclic polyolefin, polyvinylidene chloride, polychlorotrifluoroethylene, and polyethylene. Moreover, as a packaging container, the polyethylene bottle and glass bottle which performed the light-shielding process are illustrated.

In addition, the daily dose of naphthopidyl contained in the medicament of the present invention is appropriately determined according to individual cases in consideration of the administration route, the disease, the symptoms of the disease, the age of the administration subject, sex, and the like. In the case of oral administration, about 10 to 100 naphthopidyl per adult
mg / day, most preferably 25 to 75 mg / day, which is orally administered once or twice daily after meals.

  The medicament of the present invention can be used for the purpose of treating a disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced. Non-limiting examples of such diseases include anticholinergic resistant overactive bladder, overactive bladder or frequent urination associated with and / or associated with diabetes, irritable bowel syndrome, ureteral stones, Includes peripheral circulatory disturbances, pulmonary hypertension, gastroesophageal reflux disease, hyperalgesia, pancreatitis, migraine, fibrosis, and pain. In particular, the medicament of the present invention can be effectively used for the treatment of patients with diseases associated with overactive bladder, frequent urination, etc. for which other α1A adrenergic receptor blockers and / or blockers for α1D adrenergic receptors are not effective. it can.

  EXAMPLES Hereinafter, although this invention is demonstrated in more detail based on an Example, it cannot be overemphasized that this invention is not limited to an Example.

[Test Example 1] Inhibitory effect of naphthopidyl and various α1 blockers on serotonin-induced contraction of isolated bladder An untreated normal female CD (SD) rat was anesthetized by intraperitoneal administration of pentobarbital sodium 40-60 mg / kg, The bladder was removed under anesthesia, a bladder specimen was prepared in ice-cooled Krebs-Henseleit solution, and the bladder specimen was filled with 10 mL of Krebs-Henseleit solution aerated with a mixed gas of 95% O ₂ and 5% CO _2. Suspended in an organ bus. The bladder specimen was loaded with 1 g of static tension, the bladder specimen was contracted with a final concentration of 40 mM KCl, the condition of the bladder specimen was confirmed, washed out, and a drug (naphthopidyl, tamsulosin, silodosin or prazosin) was placed in the organ bath. In addition, after pretreatment for 10 minutes, serotonin was cumulatively added and the tension of each bladder specimen was recorded. The tension is measured using an FD pickup (manufactured by Nihon Kohden), and CARRIER
Recording was performed with LINEARCODER (manufactured by GRAPHTEC) through AMPLIFIER (manufactured by Nihon Kohden). The contraction reaction by serotonin was analyzed by converting the contraction reaction of 40 mM KCl as 100%. When the isolated urinary bladder of normal rats was stimulated with serotonin, a concentration-dependent contraction response was observed from 10 ⁻⁸ M, and the maximum contraction response was shown at 10 ⁻⁵ M. In response to the contraction response of serotonin in the isolated rat urinary bladder, naphthopidyl translated the serotonin concentration-response curve to the right in a concentration-dependent manner (0.3, 1 and 3 μM). The contraction reaction by serotonin was suppressed. On the other hand, tamsulosin (0.1 μM), silodosin (0.1 μM), and prazosin (1 μM) did not suppress the contractile reaction caused by serotonin at a sufficiently high concentration as an α1 blocker. The inhibitory effect on serotonin contraction was an action specifically observed for naphthopidyl among α1 blockers. (See Figure 1)
[Test Example 2] Effect of naphthopidyl on serotonin-induced contraction using the bladder of partially urethral obstructed rats A Blader outlet obstruction (BOO) model was used as an animal model for dysuria due to lower urinary tract obstruction. The method for preparing the BOO rat was as follows. Female CD (SD) rats with pentobarbital sodium 30
Anesthesia was performed by intraperitoneally administering mg / kg, and the following treatment was performed under anesthesia. After inserting and indwelling 22G Surfflow (without needle) retrogradely into the urinary bladder from the outer urethral orifice of the rat, the urethra was exposed by incising about 1 cm in the lower abdomen. Attach 4-0 blade silk to the suture needle, scoop only the urethra with a needle, thread the thread at one location, remove the surf flow that was left in the bladder, and place a stainless steel wire with a diameter of 1.1 mm on the urethra. The urethra was ligated with 4-0 blade silk together with the stainless wire and the stainless wire was removed to narrow the urethra. Thereafter, the muscle layer, peritoneum and skin were sutured to close the wound. The sham operation group (control group) exposed the bladder in the same manner as the operation group, and then sutured the wound without ligating the urethra. After the operation, the animals were fed with drinking water containing antibiotics for 1 week. Usually, the weight of the bladder of normal rats of the same age is about 60 mg, but the bladder was enlarged by BOO treatment, and the weight became 160 to 350 mg. In addition, the animal which 150 mg or more of bladder enlargement was not recognized was judged to be unsuccessful operation, and was not used for experiment.

Rats one week after BOO treatment were anesthetized by intraperitoneal administration of pentobarbital sodium 40-60 mg / kg, the bladder was removed under anesthesia, and a bladder specimen was prepared in ice-cooled Krebs-Henseleit solution, The bladder specimen was suspended in an organ bath filled with 10 mL of Krebs-Henseleit solution aerated with a mixed gas of 95% O ₂ and 5% CO ₂ . Apply 1g of static tension to the bladder specimen, contract the bladder specimen with KCl at a final concentration of 40mM, confirm the state of the bladder specimen, wash out, and add serotonin cumulatively into the organ bath. The tension was recorded. When investigating the effect of naphthopidyl on serotonin contraction, 1 μM naphthopidyl was added, pretreated for 10 minutes, then serotonin was added cumulatively, and the tension of the bladder specimen was recorded. The tension is measured using an FD pickup (manufactured by Nihon Kohden), and CARRIER
Recording was performed with LINEARCODER (manufactured by GRAPHTEC) through AMPLIFIER (manufactured by Nihon Kohden). Since the bladder of BOO rats is enlarged, the contraction response by serotonin is the contractile force per unit tissue weight (100 mg) (g / 100 mg) in order to compare the contraction response with normal animals.
evaluation). When the isolated bladder of BOO rats was stimulated with serotonin, a concentration-dependent contraction response was observed from 10 ⁻⁸ M, and the maximum contraction response was shown at 10 ⁻⁵ M. The contractile response of 10 ⁻⁶ , 10 ^−5, and 10 ⁻⁴ M serotonin was enhanced about 2-fold compared to the control (see FIG. 2).

  In contrast to the contraction response of serotonin in the BOO rat-excised bladder, naphthopidyl (1 μM) translated the concentration-response curve to the right and suppressed the contraction response due to serotonin. The pKB value was calculated to be 6.36 (see FIG. 3).

[Test Example 3] Affinity of naphthopidil for serotonin 2A receptor and serotonin 2B receptor Recombinant cells expressing human serotonin 2A receptor in HEK293 cells and recombinant cells expressing human serotonin 2B receptor in CHO cells Was used. These cells were homogenized in 50 mM Tris-HCl (pH 7.4) buffer, centrifuged at 48,000 g for 15 minutes, and the precipitate was again homogenized and centrifuged to prepare a membrane preparation. Stored at 70 ° C. or lower until testing.

In the binding test for serotonin 2A receptor, 50 mM Tris-HCl (pH 7.4) buffer was used. The buffer was placed in a reaction tube, and [ ³ H] -ketanserin was added to a final concentration of 0.5 nM. In addition, to the tube for measuring non-specific binding, ketanserin was added to a final concentration of 1 μM, and in other cases, DMSO dissolution of buffer or naphthopidyl was performed with a final concentration of naphthopidyl of 10 ⁻⁸ M to 10 ⁻⁵ M. I added. Membrane preparations that were thawed and suspended in a buffer were added to the tube, reacted at room temperature for 60 minutes, filtered with suction through a GF / B (Packard) glass filter treated with 0.3% polyethylenimine, and cooled on ice. The filter was washed several times with 50 mM Tris-HCl buffer, dried, and radioactivity was measured with a scintillation counter (Topcount, Packard).

In the binding test for serotonin 2B receptor, 50 mM Tris-HCl (pH 7.4) buffer supplemented with 5 mM MgCl ₂ , 10 μM pargyline and 5 mM ascorbic acid was used. The buffer was placed in a reaction tube, and [ ³ H] -mesulazine was added to a final concentration of 2 nM. In addition, mesulamine is added to a tube for measuring non-specific binding so that the final concentration is 10 μM, and in other cases, DMSO dissolution of buffer or naphthopidyl is performed at a final concentration of naphthopidyl of 3 × 10 ⁻⁹ M to 3 × 10 5. ^-6 M was added. The membrane preparation which was thawed and suspended in the buffer was added to the tube, reacted at room temperature for 60 minutes, suction filtered through a 0.3% Polyethyleneimine-treated GF / B (Packard) glass filter, and then ice-cooled 50 mM Tris. The filter was washed several times with HCl buffer, dried, and the radioactivity was measured with a scintillation counter (Topcount, Packard).

［試験例４］尿道部分閉塞ラット膀胱でのセロトニン２Ａ受容体及びセロトニン２Ｂ受容体
ｍＲＮＡの発現量の解析
ＢＯＯモデル作製１週間後のラットにペントバルビタールナトリウム
４０〜６０ｍｇ／ｋｇを腹腔内投与して麻酔し、開胸して心臓からの全採血及び大動脈切断による放血で安楽死させた後、直ちに腹部を切開して膀胱を摘出した。摘出した膀胱は余分な組織を取り除いた後、生理食塩水にて洗浄し、ＲＮａｓｅによるＲＮＡ分解を防ぐためＲＮＡｌａｔｅｒ（Ｑｉａｇｅｎ社製）に浸して保存した。膀胱からのＲＮＡ抽出はＲＮｅａｓｙ ｆｉｂｒｏｕｓ ｔｉｓｓｕｅ ｋｉｔ（Ｑｉａｇｅｎ社製）を用い、キットの手順書に従って、ＤＮａｓｅ処理を行い、ＲＮＡ ａｆｆｉｎｉｔｙカラムによりＲＮＡを抽出した。抽出したＲＮＡ量はＮＤ−１０００分光光度計（Ｔｈｅｒｍｏ Ｆｉｓｈｅｒ Ｓｃｉｅｎｔｉｆｉｃ社製）を用いて測定し、ＲＮＡ ０．５μｇを用いて、ＳｕｐｅｒＳｃｒｉｐｔ ＶＩＬＯ ｃＤＮＡ Ｓｙｎｔｈｅｓｉｓ ｋｉｔ（Ｉｎｖｉｔｒｏｇｅｎ社製）によりｃＤＮＡを作製した。５倍希釈したｃＤＮＡ ２μＬに２５μＬのＰｌａｔｉｎｕｍ Ｑｕａｎｔｉｔａｔｉｖｅ ＰＣＲ ＳｕｐｅｒＭｉｘ−ＵＤＧ ｗｉｔｈＲＯＸ（Ｉｎｖｉｔｒｏｇｅｎ社製）と表２に示したセロトニン２Ａ受容体あるいはセロトニン２Ｂ受容体のプライマーペア（１０μＭ、１μＬ）及びプローブ（１０μＭ、０．５μＬ）を加え、ＤＥＰＣ−ｔｒｅａｔｅｄ
ｗａｔｅｒ（Ｉｎｖｉｔｒｏｇｅｎ社製）を加えて全量を５０μＬとして反応させた。プライマー及びプローブのデザインはＰｒｉｍｅｒ Ｅｘｐｒｅｓｓ ｖｅｒｓｉｏｎ ２．０（Ａｐｐｌｉｅｄ
Ｂｉｏｓｙｓｔｅｍｓ社製）にて行い、ＢＬＡＳＴ ｓｏｆｔｗａｒｅ（Ｎａｔｉｏｎａｌ Ｃｅｎｔｅｒ ｆｏｒ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ Ｉｎｆｏｒｍａｔｉｏｎ提供）によりデザインした配列の目的遺伝子に対する特異性を確認した。反応及び検出はＡＢＩ７０００（Ａｐｐｌｉｅｄ
Ｂｉｏｓｙｓｔｅｍｓ社製）にて行った。反応条件は５０°Ｃで２分間、９５°Ｃで２分間処理した後、９５°Ｃで１５秒、６０°Ｃで３０秒間処理するサイクルを４０サイクル行った。内部標準遺伝子としてｒｉｂｏｓｏｍａｌ
ｐｒｏｔｅｉｎ １９（ＲＰＬ１９）を用い、セロトニン２Ａ受容体及びセロトニン２Ｂ受容体の発現量を補正し、コントロールの値の平均値を１として示した。その結果、ＢＯＯラット膀胱ではセロトニン２Ａ受容体およびセロトニン２Ｂ受容体のｍＲＮＡの発現がそれぞれコントロールの３．２倍及び３．９倍に増加した（図４を参照）。この結果より、下部尿路閉塞による排尿障害時の過活動膀胱の発症にセロトニン２Ａ受容体及びセロトニン２Ｂ受容体の発現増加によるセロトニン誘発膀胱収縮の増加が関与していることが明らかとなった。

As a result, as shown in Table 1, it was shown that naphthopidyl binds to the serotonin 2A receptor and the serotonin 2B receptor.

Test Example 4 Analysis of Serotonin 2A Receptor and Serotonin 2B Receptor mRNA Expression Levels in Urinary Partially Obstructed Rat Bladder One week after preparation of the BOO model, 40 to 60 mg / kg of pentobarbital sodium was intraperitoneally administered. After anesthesia, the chest was opened, and blood was collected from the heart and euthanized by exsanguination by cutting the aorta, and the abdomen was immediately opened to remove the bladder. After removing the excess tissue, the excised bladder was washed with physiological saline and stored in RNAlater (Qiagen) in order to prevent RNA degradation by RNase. RNA extraction from the bladder was performed using DNase treatment using an RNeasy fiber tissue kit (manufactured by Qiagen), and RNA was extracted using an RNA affinity column. The amount of extracted RNA was measured using an ND-1000 spectrophotometer (Thermo Fisher Scientific), and cDNA was prepared using SuperScript VILO cDNA Synthesis kit (Invitrogen) using 0.5 μg of RNA. Primer pair (10 μM, 1 μM) of a serotonin 2A receptor or a serotonin 2B receptor shown in Table 2 and 25 μL of Platinum Quantitative PCR SuperMix-UDG withROX (manufactured by Invitrogen) and probe (10 μM, 1 μM) and probe (10 μM, 1 μM) .5 μL), DEPC-treated
Water (manufactured by Invitrogen) was added to make the total volume 50 μL. Primer and probe design is Primer Express version 2.0 (Applied
Biosystems) and the specificity of the sequence designed by BLAST software (provided by National Center for Biotechnology Information) for the target gene was confirmed. Reaction and detection were performed using ABI7000 (Applied
Biosystems). The reaction conditions were 50 ° C for 2 minutes and 95 ° C for 2 minutes, followed by 40 cycles of 95 ° C for 15 seconds and 60 ° C for 30 seconds. Ribosomal as an internal standard gene
The expression level of serotonin 2A receptor and serotonin 2B receptor was corrected using protein 19 (RPL19), and the average value of control values was shown as 1. As a result, in the BOO rat bladder, the expression of serotonin 2A receptor and serotonin 2B receptor mRNA increased 3.2 times and 3.9 times that of the control, respectively (see FIG. 4). From this result, it became clear that the increase in serotonin-induced bladder contraction due to increased expression of serotonin 2A receptor and serotonin 2B receptor is involved in the development of overactive bladder during dysuria due to lower urinary tract obstruction.

  Since the medicament of the present invention has a remarkable effect of blocking serotonin 2A receptor and serotonin 2B receptor, for the treatment of diseases in which serotonin 2A receptor and / or serotonin 2B receptor function is enhanced, It can be used clinically safely. Therefore, the present invention can be used in the pharmaceutical manufacturing industry and the like.

Claims (8)

A pharmaceutical comprising naphthopidyl for treating a disease in which at least one of the functions of serotonin 2A receptor and serotonin 2B receptor is enhanced. The disease is an anticholinergic resistant overactive bladder, an overactive bladder or frequent urination associated with and / or associated with diabetes, irritable bowel syndrome, ureteral stones, peripheral circulation disorder, or pulmonary hypertension The medicament according to claim 1, wherein The medicament according to claim 2, wherein the disease is an anti-cholinergic resistant overactive bladder. The medicament according to claim 2, wherein the disease is overactive bladder or frequent urination associated with diabetes and / or accompanying diabetes. The medicament according to claim 2, wherein the disease is irritable bowel syndrome. The medicament according to claim 2, wherein the disease is ureteral calculus. The medicament according to claim 2, wherein the disease is peripheral circulation disorder. The medicament according to claim 2, wherein the disease is pulmonary hypertension.

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