JPH11106334A - Therapeutic agent for urinary incontinence - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject therapeutic agent having lowering action of pressure in bladder due to direct relaxation of vesical smooth muscle and especially effective to urinary incontinence due to abdominal pressure and impending incontinence by including formoterol and its salt as active ingredients. SOLUTION: This therapeutic agent contains formoterol (3-formylamino-4- hydroxy-α-[N-(1-methyl-2-p-methoxyphenylethyl)aminomethyl]benzyl allcohol) and/or its salt (especially preferably an acid addition salt of fumaric acid) as an active ingredient. The agent is preferably each administered at a dose of 2-1,000 μg/man/time in the case of intravenous injection and at a divided dose of 10-1,000 μg/man/kg once to three times per day in the case of oral administration and at a divided dose of 10-14,000 μg/man/skin once to 7 times per day in the case of dermal administration. The therapeutic agent enables treatment of almost urinary incontinences which are different in symptom thereby.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel therapeutic agent for urinary incontinence.

[0002]

2. Description of the Related Art Urinary incontinence is characterized by differences in its symptoms, such as stress (strain) urinary incontinence, urge urinary incontinence, false stress incontinence, reflex incontinence, overflow urinary incontinence, extraurethral incontinence. , Functional urinary incontinence, dementia urinary incontinence, nocturnal enuresis type incontinence, total urinary incontinence, iatrogenic incontinence, etc. Among them, stress urinary incontinence is particularly common and is often seen in women aged 30 to 60 years. Stress urinary incontinence occurs because the detrusor muscle does not function normally and the intravesical pressure increased by the abdominal pressure overcomes the urethral closure pressure.

Heretofore, these therapeutic agents for urinary incontinence include ephedrine hydrochloride and mitodrine hydrochloride as sympathetic α-receptor stimulants, imipramine hydrochloride and anticholine as tricyclic antidepressants, and oxybutynin hydrochloride as smooth muscle stimulants. Propiverine hydrochloride, serimevelin hydrochloride, and clenbuterol hydrochloride were the sympathetic beta-receptor stimulants.

[0004]

However, the therapeutic effect of clenbuterol hydrochloride on urinary incontinence cannot be said to be sufficient, and there are tachycardia, palpitations, tremors as side effects, and the administration route is limited due to the nature of the drug. There are disadvantages such as being limited,
There has been a demand for the development of a therapeutic agent for urinary incontinence which has a stronger effect and is superior in safety and pharmacokinetics.

[0005] The present invention has been made in view of such circumstances, and an object thereof is to provide Clenbutero hydrochloride.
And to provide a more effective therapeutic agent for urinary incontinence than that of urine.

[0006]

SUMMARY OF THE INVENTION Formoterol (3-formylamino-4-hydroxy-α- [N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl])
Benzyl alcohol) is a compound represented by the following formula (1), which is known to have a direct bronchodilator effect by stimulating the β-adrenergic receptor of the sympathetic nerve (Japanese Patent Publication No. Sho 5).
9-9542).

[0007]

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For this reason, formoterol and its typical acid addition salts formoterol fumarate (3-formylamino-4-hydroxy-α- [N
-(1-Methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol.1 / 2 fumaric acid monohydrate) has been used as a therapeutic agent for asthma.

[0009]

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However, formoterol or a salt thereof developed as a bronchodilator has been used for the treatment of asthma, but has not been applied to urinary incontinence at all.
In addition, it has not been known so far that it has an effective action for treating urinary incontinence, and has not been disclosed or suggested at all.

The present inventors have focused on the fact that formoterol and its salts selectively act on the β receptor, and as a result of intensive studies, found that formoterol is mainly involved in the intravesical pressure due to the direct bladder smooth muscle relaxation. It has been found that the present invention has a reducing effect, and the present invention has been completed.

That is, the present invention provides a therapeutic agent for urinary incontinence comprising formoterol and / or a salt thereof as an active ingredient. As mentioned above, urinary incontinence has different symptoms, such as stress incontinence, urge incontinence, reflex incontinence,
Includes overflow incontinence, extraurethral incontinence, functional incontinence, dementia incontinence, nocturnal urinary incontinence. The urinary incontinence treated in the present invention includes all of them and is not particularly limited, but the therapeutic agent of the present invention is particularly useful for stress urinary incontinence and urge incontinence.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION Since formoterol has two asymmetric carbon atoms in its molecular structure, there are a total of four optical isomers derived from them. In the therapeutic agent for urinary incontinence of the present invention, formoterol or a salt thereof may be a mixture of these optically different organisms or may be an isolated one.

The salt of formoterol that can be used in the therapeutic agent for urinary incontinence of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, inorganic acids such as phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid,
Examples include acid addition salts with organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, aspartic acid, and glutamic acid, and especially formoterol fumarate, which is an acid addition salt with fumaric acid. Is a preferred salt.

Further, the therapeutic agent for urinary incontinence of the present invention may contain various hydrates or solvates of formoterol or a salt thereof and a polymorphic substance.

The therapeutic agent for urinary incontinence of the present invention is usually used in the art or formoterol or a salt thereof, or a pharmaceutically acceptable carrier, excipient or the like. Can be prepared by the following methods. Oral administration by powder, tablet, pill, capsule, granule, powder, liquid, etc., intravenous injection,
Transdermal and transmucosal preparations such as intramuscular injections, cataplasms, plasters, salves, creams, ointments, solutions, suppositories, buccals, buccal preparations, sprays, etc. Any form of parenteral administration may be used.

As the solid composition for oral administration, for example, tablets, powders, granules and the like are used. In such a solid composition, the one or more active substances include
At least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylmethylcellulose;
, Microcrystalline cellulose, starch, polyvinylpyrrolidone and magnesium aluminate metasilicate.
The composition may contain, in a conventional manner, additives other than the inert diluent, for example, a lubricant such as magnesium stearate and a solubilizing agent such as calcium cellulose glycolate. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose-phthalate or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents. , For example, purified water and ethanol.
This composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, preservatives and the like.

Injections for parenteral administration may contain sterile aqueous or non-aqueous solutions, suspensions, emulsions and the like. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Water-insoluble solutions,
Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 and the like. It may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), and solubilizers (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be prepared as a sterile solid composition and dissolved in sterile water or a sterile injection solvent before use.

As the external preparation, solid or semi-solid, semi-solid or liquid for transdermal administration or transmucosal (intraoral, nasal, vaginal, anal, etc.) administration, and affixed to a support or the like Preparations such as patches and the like can be mentioned. Liquid compositions for external use include liquid preparations such as pharmaceutically acceptable emulsions, emulsions such as lotions, tinctures for external use, and solutions for transmucosal administration. These compositions may contain inert diluents such as water, ethanol, oils, emulsifiers. These compositions are obtained by adding other additives such as transdermal absorption enhancers, stabilizers, solubilizers, fragrances, preservatives, etc., in addition to the inert diluent. You may.

Semi-solid preparations for external use include ointments such as oily ointments and hydrophilic ointments and the like, and generally used inert carriers such as water, petrolatum, polyethylene glycol and carboxyvinyl polymer. -(Trade name: Carbopol, manufactured by BF Goodrich), an oil component, and a surfactant may be used. Further, in addition to the inert diluent, other additives such as a transdermal absorption enhancer, a stabilizer, an auxiliary agent such as a solubilizer, an aromatic agent, a preservative, and the like may be contained.

Examples of semi-solid to solid preparations for external use include transdermal administration of plasters (rubber, plaster), films, tapes, cataplasms and the like or transmucosal (intraoral, nasal) , Vagina, anus, etc.) and other commonly used inert carriers, for example, rubber-based polymers composed of synthetic rubber such as natural rubber, butadiene rubber, SBR, SIS; gelatin, kaolin , Zinc oxide and the like; sodium polyacrylate, α · β-unsaturated carboxylic acid copolymer and / or a derivative thereof and α ·
hydrophilicity such as polycarboxylic acid-based cross-linked copolymers obtained by polymerizing mixed monomers of alkali metal salts of β-unsaturated carboxylic acids, methyl vinyl ether / maleic anhydride copolymer, sodium carboxymethyl cellulose, etc. High molecular;
It can be prepared by blending an acrylic resin; water; other oil components and a surfactant. Further, other additives such as a cross-linking agent such as aluminum hydroxide gel, a transdermal absorption promoter, a stabilizer, an auxiliary agent such as a solubilizer, an aromatic agent, and a preservative may be contained.

The dose is appropriately determined depending on the individual case in consideration of the symptoms, age, sex, etc. of the administration subject. For intravenous injection, the dose is preferably 2 to 1000 μg / man / dose. In oral administration, once to three times a day, 10 to 10 times
It is preferable to administer 1000 μg / man / kg. In the case of transdermal administration, once every 1 to 7 days,
It is preferred to administer 14000 μg / man / skin.

[0024]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. [Example 1] Formoterol and formoterol fumarate
Was produced as follows. 3-formylamino-4-
Benzyloxy-α- [N-benzyl-N- (1-methyl-2-p-methoxyphenylethyl) aminomethyl]
0.52 g of benzyl alcohol was dissolved in 10 ml of ethanol, 0.2 g of 10% palladium on carbon was added, and the mixture was catalytically reduced at normal temperature and pressure until 48 ml of hydrogen was absorbed. After removing the catalyst by filtration, the mixture was concentrated under reduced pressure and concentrated with formoterol (3-formylamino-4-hydroxy-α- [N- (l-methyl-
0.35 g of white crystalline powder of 2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol) was obtained.

The formoterol 0.3 obtained above
5 g and 0.06 g of fumaric acid in 7 ml of 95% ethanol
, And the precipitated crystals are collected by filtration to give formoterol fumarate (3-formylamino-4).
0.35 g of -hydroxy-α [N- (l-methyl-2-p-methoxyphenylethyl) aminomethyl] benzyl alcohol · 1/2 fumaric acid monohydrate was obtained.

The melting point and elemental analysis values of the obtained formoterol fumarate are as follows. Melting point: 138 to 140 ° C. (decomposition) Elemental analysis value (as C ₁₁ H ₂₆ N ₂ O ₆ .H ₂ O): Theoretical value C: 59.99%, H: 6.71%, N: 6.66 % Experimental value C: 59.63%, H: 6.65%, N: 6.71%

Example 2 8.39 mg of formoterol fumarate obtained in Example 1 was added to a physiological saline solution (20 m).
In addition, the mixture was dissolved by heating at 50 ° C. for 15 minutes to prepare a ^10-3 mol / l formoterol fumarate injection solution as a therapeutic agent for urinary incontinence.

Example 3 10 ^-3 prepared in Example 2
A 1 mol / l formoterol fumarate solution was diluted with 9 ml of physiological saline to prepare a 10 ^-4 mol / l injection solution.

Example 4 10 ^-4 prepared in Example 3
A 1 mol / l formoterol fumarate solution was diluted with 9 ml of physiological saline to prepare a 10 ^-5 mol / l injection solution.

Example 5 10 ^-5 prepared in Example 4
A 1 mol / l formoterol fumarate solution was diluted with 9 ml physiological saline to prepare a 10 ^-6 mol / l injection solution.

Example 6 10 ^-6 prepared in Example 5
A 1 mol / l formoterol fumarate solution was diluted with 9 ml of physiological saline to prepare a 10 ^-7 mol / l injection solution.

Example 7 7.32 mg of formoterol fumarate obtained in Example 1 were dissolved in 20 ml of physiological saline by heating at 50 ° C. for 15 minutes, and 300 μg / ml of formotelo fumarate was dissolved. To prepare injection solutions.

Example 8 300 prepared in Example 7
18 ml of physiological saline was added to 2 ml of the μg / ml injection solution to prepare a 30 μg / ml formoterol fumarate injection solution.

Example 9 30 μm prepared in Example 8
18 ml of physiological saline was added to 2 ml of the g / ml injection solution to prepare a 3 μg / ml formoterol fumarate injection solution.

Example 10 3 μm prepared in Example 9
18 ml of physiological saline was added to 2 ml of the g / ml injection solution to prepare a 0.3 μg / ml formoterol fumarate injection solution.

Example 11 18 ml of physiological saline was added to 2 ml of the 0.3 μg / ml injection solution prepared in Example 10, and 0.03 μg / ml of formotelotrate fumarate was added.
The injection solution was prepared.

Example 12 In a solution of 0.248 g of formoterol fumarate obtained in Example 1 in N-methyl-2-pyrrolidone, 4.0 g of ethanol and 1-menthol were added.
4.0 g of water, 4.112 g of water and 0.4 g of polyvinylpyrrolidone were added and mixed. This liquid was added to and mixed with 27.24 g of an acrylic adhesive, and the obtained adhesive mixture was applied on a polyester film to a thickness of 150 μm,
It was dried to prepare a patch as a therapeutic agent for urinary incontinence.

Example 13 0.5 g of formoterol fumarate obtained in Example 1 was added to 10 g of N-methyl-2-pyrrolidone, 46.5 g of oleyl alcohol, 28% of N, N-dimethylstearylamine. Of sorbitan fatty acid ester, and 850 g of glycerin fatty acid ester.
C. The mixture was heated and dissolved in C, stirred, heated, dispensed into a shell-shaped mold, and cooled from the outside to obtain a suppository as an external preparation for urinary incontinence.

Comparative Example 1 Formoterol fumarate
A ^10-3 mol / l injection of clenbuterol hydrochloride was prepared in the same manner as in Example 2 except that 39 mg was changed to 6.28 mg of clenbuterol hydrochloride.

Comparative Example 2 A 10 ^-4 mol / l injection of clenbuterol hydrochloride was prepared in the same manner as in Example 3 except that formoterol fumarate was changed to clenbuterol hydrochloride.

Comparative Example 3 An injection solution of 10 ⁻⁵ mol / l clenbuterol hydrochloride was prepared in the same manner as in Example 4 except that formoterol fumarate was used as clenbuterol hydrochloride.

Comparative Example 4 An injection solution of 10 ^-6 mol / l clenbuterol hydrochloride was prepared in the same manner as in Example 5 except that formoterol fumarate was changed to clenbuterol hydrochloride.

Comparative Example 5 An injection solution of 10 ^-7 mol / l clenbuterol hydrochloride was prepared in the same manner as in Example 6 except that formoterol fumarate was used as clenbuterol hydrochloride.

Comparative Example 6 Formoterol fumarate
A 300 μg / ml injection of clenbuterol hydrochloride was prepared in the same manner as in Example 7, except that 6.78 mg of clenbuterol hydrochloride was used instead of 32 mg.

Comparative Example 7 An injection solution of 30 μg / ml of clenbuterol hydrochloride was prepared in the same manner as in Example 8 except that formoterol fumarate was changed to clenbuterol hydrochloride.

Comparative Example 8 A 3 μg / ml injection solution of clenbuterol hydrochloride was prepared in the same manner as in Example 9 except that formoterol fumarate was used as clenbuterol hydrochloride.

Comparative Example 9 A 0.3 μg / ml injection solution of clenbuterol hydrochloride was prepared in the same manner as in Example 10 except that formoterol fumarate was changed to clenbuterol hydrochloride.

Comparative Example 10 A 0.03 μg / ml injection solution of clenbuterol hydrochloride was prepared in the same manner as in Example 11 except that formoterol fumarate was changed to clenbuterol hydrochloride.

Test Example 1 The formoterol fumarate injection solution prepared in Examples 2 to 6 and the clenbuterol hydrochloride injection solution prepared in Comparative Examples 1 to 5 were used as samples.
Potassium chloride (KCl) from an isolated bladder specimen in vitro
The relaxation effect on the evoked contractile response was examined by the following method.

Method: After leaving the rat to die, the rat's bladder was excised and a 2 × 10 mm tissue-sliced specimen was prepared.
The suspension was suspended in a Tylode liquid tank (10 ml of Tylode liquid in a Magnus tank in a Magnus tube) ventilated with ° C and 95% O ₂ + 5% CO ₂ , and a 0.5 g weight was loaded. . Next, KCl was added to the tank and the concentration was adjusted to 40.
mM, and the tissue slice of the bladder muscle was contracted. After the specimen was stabilized, the bladder muscle contracted by 40 mM KCl
The sample solutions prepared according to Examples 2 to 6 were administered by dropping 100 μl into the Tylode's liquid tank in ascending order of concentration, and potassium chloride (KCl) -induced contraction reaction of the isolated bladder specimen in vitro in rats. The relaxation effect on was investigated. Bladder muscle stretch was detected by an isotonic transducer and recorded on a recorder. Moreover, it carried out similarly about the sample solution prepared in Comparative Examples 1-5.

Results: The results of the measurement are shown in FIG. As shown in FIG. 1, both formoterol and clenbuterol relax KCl-induced contractile bladder in rats in a concentration-dependent manner. However, IC ₅₀ is Horumotero - Le 5.1
At × 10 ⁻⁸ M, a significant difference was observed from 2.8 × 10 ⁻⁶ M of clenbuterol, and
It has a higher effect of relaxing KCl-induced constrictive bladder than that of nicotine, indicating that it is excellent as a therapeutic agent for urinary incontinence.

Test Example 2 Formotero fumarate prepared in Examples 7 to 11
Using the injection solution for injection and the injection solution for clenbuterol hydrochloride prepared in Comparative Examples 6 to 10 as samples, the effect on in vivo rat bladder pressure was examined by the following method.

Method: Rats were treated with urethane (500 mg / k
g, i. p. ) And α-chloralose (50 mg / k
g, j. p. ), Anesthesia in the trachea and femoral vein
Inserted. After laparotomy, a cannula for pressure measurement was inserted from the bladder apex and connected to the transducer. Fill the bladder gradually with physiological saline, internal pressure is about 8-13mmH
After stabilization in the range of g, the infusion was stopped and the urethra was ligated. After administering physiological saline as a control and confirming that it did not affect the intravesical pressure, Examples 7 to 11 were used.
Were administered by intravenous injection at a dose of 0.1 ml per 100 g of rats in order of decreasing concentration,
The change value with respect to the reference value was evaluated using the intravesical pressure before administration as the reference value. The same applies to the samples prepared in Comparative Examples 6 to 10.

Results: FIG. 2 shows the results of the evaluation. As shown in FIG. 2, formoterol fumarate and clenbuterol hydrochloride reduced rat bladder pressure in a concentration-dependent manner.
However, clenbuterol hydrochloride caused a decrease in rat bladder pressure of 2.5 mmHg when administered at 30 μg / ml, whereas formoterol fumarate at 3 μg / ml.
ml caused a drop in rat bladder pressure of 5.1 mmHg. From these results, it can be seen that ormotelol fumarate has a stronger effect of reducing intravesical pressure in rats than clenbuterol hydrochloride and is excellent as a therapeutic agent for urinary incontinence.

[0055]

As described above, the relaxing action of formoterol in the in vitro test is stronger than that of clenbuterol hydrochloride used in the clinical practice of urinary incontinence. Also, in an in vivo test by intravenous administration in rats, formoterol has a stronger effect of reducing intravesical pressure in rats than clenbuterol hydrochloride. Therefore, the therapeutic agent for urinary incontinence according to the present invention is extremely effective for treating urinary incontinence.

[Brief description of the drawings]

FIG. 1 is a graph showing the inhibitory effect of formoterol on KCl-induced contractile bladder in rats.

FIG. 2 is a graph showing the effect of formoterol on reducing intravesical pressure in rats.

Claims (3)

[Claims] 1. A therapeutic agent for urinary incontinence comprising formoterol and / or a salt thereof as an active ingredient. 2. The urinary incontinence to be treated is stress urinary incontinence, urge incontinence, pseudo stress incontinence, reflex incontinence, overflow urinary incontinence, extraurethral incontinence, functional urinary incontinence, dementia 2. The therapeutic agent according to claim 1, which is one or more of urinary incontinence, nocturnal enuresis type incontinence, total urinary incontinence and iatrogenic incontinence. 3. The therapeutic agent according to claim 1, wherein the formoterol salt is formoterol fumarate.