Vasopressin-like action enhancer

Abstract

A problem to be solved by the present invention is to provide a method for ameliorating pollakiuria and nocturia, in particular, nocturia caused by nocturnal polyuria by finding a composition that enhances the antidiuretic action of vasopressin or a vasopressin V2 receptor agonist. As a result of the studies, it has been found that imidafenacin enhances the antidiuretic action of vasopressin or the vasopressin V2 receptor agonist, whereby the present invention has been completed. According to the present invention, a composition containing imidafenacin can enhance the antidiuretic action of vasopressin or the vasopressin V2 receptor agonist, making it possible to ameliorate pollakiuria and nocturia, in particular, nocturia caused by nocturnal polyuria.

Claims

1. A pharmaceutical composition comprising imidafenacin and vasopressin or a vasopressin V2 receptor agonist.

2. The pharmaceutical composition according to claim 1, wherein the vasopressin V2 receptor agonist is desmopressin or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier.

4. A method of enhancing the antidiuretic action of vasopressin or a vasopressin V2 receptor agonist, comprising administering a therapeutically effective amount of imidafenacin to a patient in need thereof.

5. The method according to claim 4, wherein the imidafenacin is administered in the form of a pharmaceutical composition comprising the imidafenacin and a pharmaceutically acceptable carrier.

6. The method according to claim 4, further comprising administering a therapeutically effective amount of vasopressin or a vasopressin V2 receptor agonist to the patient.

7. The method according to claim 6, wherein the vasopressin V2 receptor agonist is desmopressin or a pharmaceutically acceptable salt thereof.

8. The method according to claim 4, wherein the imidafenacin is administered at a dose of 0.05 to 1.0 mg per day.

9. The method according to claim 4, wherein the imidafenacin is administered at a dose of 0.1 to 0.4 mg per day.

10. The method according to claim 4, wherein the imidafenacin is administered twice per day.

11. The method according to claim 4, wherein the imidafenacin is administered orally.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 is a diagram illustrating an antidiuretic action of imidafenacin.

(2) FIG. 2 is a diagram illustrating an antidiuretic action of desmopressin.

(3) FIG. 3 is a diagram illustrating a combination effect of imidafenacin and desmopressin.

(4) FIG. 4 is a diagram illustrating an effect of mozavaptan on the antidiuretic action of imidafenacin.

(5) FIG. 5 is a diagram illustrating an enhancing effect of imidafenacin on the antidiuretic action of desmopressin.

DESCRIPTION OF EMBODIMENTS

(6) In the present invention, imidafenacin is orally administered at a dose of preferably 0.05 to 1.0 mg per day, further preferably 0.1 to 0.4 mg per day, and particularly preferably 0.2 mg per day.

(7) In the present invention, as an administration method of imidafenacin, the same dose as the above may be orally administered daily in two portions after breakfast and dinner or orally administered daily at one time after dinner.

(8) In the present invention, the term vasopressin V2 receptor agonist refers to a compound that binds to the V2 receptor, a receptor of vasopressin, and induces a vasopressin-like action (the antidiuretic action). In the present invention, the particularly preferable vasopressin V2 receptor agonist is desmopressin or a pharmaceutically acceptable salt thereof. In the present specification, a vasopressin V2 receptor agonist and a V2 receptor agonist have the same definition.

(9) In the present invention, the expression enhancing the antidiuretic action of vasopressin or the vasopressin V2 receptor agonist refers to a state in which the antidiuretic action becomes higher than that obtained by using vasopressin or the vasopressin V2 receptor agonist alone.

(10) The composition of the present invention may include any pharmaceutically acceptable carrier. Further, the composition of the present invention may include an optional pharmaceutically acceptable additive. Examples of the additive may include an excipient, a disintegrant, a binder, a lubricant, a coating agent, a coloring agent, and a brightening agent.

(11) Examples of the excipient may include sugars such as lactose and glucose, sugar alcohols such as D-sorbitol and mannitol, celluloses such as a crystalline cellulose, and starches such as partially pregelatinized starch and cornstarch.

(12) Examples of the disintegrant may include celluloses such as carboxymethylcellulose calcium, a low substituted hydroxypropyl cellulose, croscarmellose sodium, and a methyl cellulose, and crospovidone.

(13) Examples of the binder may include celluloses such as a crystalline cellulose, a hydroxypropyl cellulose, a hydroxypropyl methyl cellulose, an ethyl cellulose, and a methyl cellulose, gelatin, a polyvinyl alcohol, a partially saponified polyvinyl alcohol product, and polyvinylpyrrolidone.

(14) Examples of the lubricant may include stearic acid and metal salts thereof, talc, hydrogenated oil, light anhydrous silicic acid, hydrated silicon dioxide, and a sucrose ester of fatty acid.

(15) Examples of the coating agent may include celluloses such as a hydroxypropyl cellulose, a hydroxypropyl methyl cellulose, an ethyl cellulose, and a methyl cellulose, hydroxypropyl methyl cellulose phthalate, a methacrylic acid copolymer, polyvinylpyrrolidone, a stearyl alcohol, an ammonio methacrylate copolymer, an aminoalkyl methacrylate copolymer E, polyvinyl acetal diethyl aminoacetate, and a methacrylic acid copolymer (L, S).

(16) Examples of the coloring agent may include titanium oxide, and iron sesquioxide.

(17) Examples of the brightening agent may include carnauba wax.

(18) The composition of the present invention may be administered, for example, in an oral dosage form, such as a tablet, a capsule, a granule, a powder, an inhalant, a syrup, a jelly, or the like, or in a parenteral dosage form, such as an injection, a suppository, a patch, or the like.

(19) The composition of the present invention can be produced by a conventional method in the art. For example, if the composition of the present invention is in a dosage form of a film-coated tablet, it can be produced by a method described in WO2001/034147. Further, if the composition of the present invention is in a dosage form of an intraoral disintegrable tablet, it can be produced by a method described in WO2009/096559.

EXAMPLE

Example 1 Antidiuretic Action of Imidafenacin

(20) A method according to Watanabe et al. (Watanabe et al 2013 Antidiuretic effect of antimuscanrinic agents in rat model depends on C-fibre afferent nerves in the bladder. BJU Int 112(1) 131-6) was carried out with a partial modification.

(21) Female rats (10 to 11-week-old, obtained from Charles River Laboratories Japan) were intravenously administered (1 mL/kg) with a vehicle (saline) or imidafenacin (3, 10, 30, 100, and 300 g/mL) and subjected to an oral water load (25 mL/kg). After the rats were transferred to Bollmann cages, urine was collected for 2 hours from each rat via a catheter previously inserted and fixed to the bladder apex of the rat (8 rats in each group).

(22) The antidiuretic action of imidafenacin is shown in FIG. 1. As shown in FIG. 1, imidafenacin exhibited the antidiuretic action in a dose-dependent manner. Further, imidafenacin reduced the urinary volume by about 50% at the maximum.

Example 2 Antidiuretic Action of Desmopressin

(23) The method according to Watanabe et al. (Watanabe et al 2013 Antidiuretic effect of antimuscanrinic agents in rat model depends on C-fibre afferent nerves in the bladder. BJU Int 112(1) 131-6) was carried out with a partial modification. Female rats (10 to 11-week-old, obtained from Charles River Laboratories Japan) were intravenously administered (1 mL/kg) with a vehicle (saline) or desmopressin (0.001, 0.003, 0.01, 0.03, and 0.1 g/mL) and subjected to an oral water load (25 mL/kg). After the rats were transferred to Bollmann cages, urine was collected for 2 hours from each rat via a catheter previously inserted and fixed to the bladder apex of the rat (8 rats in each group).

(24) The antidiuretic action of desmopressin is shown in FIG. 2. As shown in FIG. 2, desmopressin exhibited the antidiuretic action in a dose-dependent manner. Further, desmopressin reduced the urinary volume by about 100% at the maximum.

Example 3 Combination Effect of Imidafenacin and Desmopressin

(25) The method according to Watanabe et al. (Watanabe et al 2013 Antidiuretic effect of antimuscanrinic agents in rat model depends on C-fibre afferent nerves in the bladder. BJU Int 112(1) 131-6) was carried out with a partial modification. Female rats (10 to 11-week-old, obtained from Charles River Laboratories Japan) were intravenously administered (1 mL/kg) with a vehicle (saline), imidafenacin (10 g/mL), desmopressin (0.003 g/mL), or both imidafenacin and desmopressin, and subjected to an oral water load (25 mL/kg). After the rats were transferred to Bollmann cages, urine was collected for 2 hours from each rat via a catheter previously inserted and fixed to the bladder apex of the rat (8 rats in each group).

(26) The antidiuretic action obtained by co-administration of imidafenacin and desmopressin is shown in FIG. 3. As shown in FIG. 3, the antidiuretic action was enhanced more by the co-administration of imidafenacin and desmopressin as compared to the case where imidafenacin or desmopressin was administered alone. The present invention found, for the first time, that the antidiuretic action was enhanced by the co-administration of imidafenacin and desmopressin. Further, such an enhancing effect is unexpected and surprising conclusion considering that these drugs have different action mechanisms. Further, desmopressin is an analogue of vasopressin, thus it is expected that the antidiuretic action of vasopressin is also enhanced by combination with imidafenacin as with the case of desmopressin.

Example 4 Effect of Mozavaptan on Antidiuretic Action of Imidafenacin

(27) The method according to Watanabe et al. (Watanabe et al 2013 Antidiuretic effect of antimuscanrinic agents in rat model depends on C-fibre afferent nerves in the bladder. BJU Int 112(1) 131-6) was carried out with a partial modification. Female rats (10 to 11-week-old, obtained from Charles River Laboratories Japan) were intravenously administered with a vehicle (dimethylformamide or saline); mozavaptan (a dose of 0.1 mL/kg of a 30 mg/mL solution); 3 mg/kg of mozavaptan and imidafenacin (10 g/kg or 300 g/kg); 3 mg/kg of mozavaptan and desmopressin (0.003 g/kg or 0.1 g/kg); or 3 mg/kg of mozavaptan, imidafenacin (10 g/kg or 300 g/kg) and desmopressin (0.003 g/kg or 0.1 g/kg), and subjected to an oral water load (25 mL/kg). After the rats were transferred to Bollmann cages, urine was collected for 2 hours from each rat via a catheter previously inserted and fixed to the bladder apex of the rat (8 rats in each group).

(28) Mozavaptan is a V2 antagonist that competes with vasopressin and desmopressin and inhibits their antidiuretic action. FIG. 4 shows an inhibitory action of mozavaptan on the antidiuretic action of imidafenacin or desmopressin. As shown in FIG. 4, the antidiuretic action of imidafenacin, even at the maximum reaction dose of 300 g/kg, was completely suppressed by mozavaptan. On the other hand, although the antidiuretic action of desmopressin was also suppressed by the mozavaptan, the antidiuretic action of desmopressin was recovered by using desmopressin at the maximum reaction dose of 0.1 g/kg. Further, as shown in FIG. 5, addition of imidafenacin at the dose of 300 g/kg further enhanced the antidiuretic action in the group in which mozavaptan and 0.1 g/kg desmopressin were co-administered. That is, the study showed that the administration of imidafenacin did not exhibit the antidiuretic action in a state where the antidiuretic action of endogenous vasopressin was almost completely suppressed by mozavaptan (FIG. 4), whereas the administration of imidafenacin enhanced the antidiuretic action in a state where the antidiuretic action via the vasopressin system was recovered by desmopressin (FIG. 5). These results and the result shown in FIG. 3 suggest that the vasopressin system is involved in the antidiuretic action of imidafenacin and imidafenacin exhibits its antidiuretic action by enhancing the vasopressin activity. The present invention found, for the first time, that the vasopressin system was involved in the antidiuretic action of imidafenacin. Further, the previous report (Watanabe et al 2013 Antidiuretic effect of antimuscanrinic agents in rat model depends on C-fibre afferent nerves in the bladder. BJU Int 112(1) 131-6) showed that release of vasopressin was not affected by imidafenacin in rat, leading to the conclusion that vasopressin was not involved in the antidiuretic action of imidafenacin. Thus, the present invention has unexpected advantageous effects with surprising results.

INDUSTRIAL APPLICABILITY

(29) According to the present invention, it is expected that pollakiuria and nocturia, in particular, nocturia caused by nocturnal polyuria can be prevented or treated by enhancing the antidiuretic action of vasopressin or the vasopressin V2 receptor agonist using imidafenacin.