JP2017002044A - Stable amorphous powders containing solifenacin or pharmaceutically acceptable salt thereof and lactose, and preparation method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide stable novel agents containing solifenacin represented by chemical formula (1), or a pharmaceutically acceptable salt thereof.SOLUTION: The invention provides stable amorphous powders containing lactose as a stabilizer, a preparation method thereof, and a pharmaceutical composition for the prevention or treatment of urologic disease, respiratory disease, or digestive system disease. Since the stable amorphous powders not only exhibit excellent thermal stability but also can be produced with homogeneous quality and high purity, a method for use in the preventive or treating agent of the diseases is also provided.SELECTED DRAWING: Figure 1

Description

  The present invention relates to a stable amorphous powder comprising solifenacin or a pharmaceutically acceptable salt thereof and lactose as a stabilizer, a preparation method thereof, and a pharmaceutical composition containing the amorphous powder as an active ingredient. It is about.

In the international application publication WO96 / 20144, solifenacin of the following chemical formula 1 is represented by the compound name 1-azabicyclo [2.2.2] oct-3-yl (1R) -1-phenyl-3,4-dihydro- 1H-isoquinoline-2-carboxylic acid, urinary diseases such as urinary incontinence and frequent urination in neurogenic pollakiuria, neurogenic bladder, nocturnal urine, unstable bladder, bladder neck contraction, chronic cystitis, etc., chronic obstructive lung It is disclosed that it is useful as a preventive or therapeutic agent for diseases, respiratory diseases such as chronic bronchitis, asthma and rhinitis, irritable bowel syndrome, convulsive colitis, diverticulitis and the like.
(Chemical formula 1)

  A series of quinuclidine derivatives, including solifenacin or its salts, have excellent selective antagonism against muscarinic M3 receptors, urinary diseases such as neurogenic urination, neurogenic bladder, nocturia, unstable bladder, bladder spasm and chronic cystitis It is reported to be useful as a preventive or therapeutic agent for respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma and rhinitis.

  Example 8 of EP 0810667 describes a process for the preparation of solifenacin hydrochloride, wherein crystals crystallized in a mixed solvent containing acetonitrile and diethyl ether have a melting point of 212 ° C to 214 ° C. It is described that it shows specific rotation ([α] 25D is 98.1 (c = 1.00, EtOH)).

  However, when formulating solifenacin or its salt in an amorphous form, or when formulating solifenacin succinate by a general formulation method, in the prepared preparation, solifenacin succinate as the main drug is There was no mention or even suggestion in the European patent that it was significantly degraded.

  On the other hand, in June 2003, published by the Japanese Ministry of Health, Labor and Welfare No. 0624001, the Ministry of Health, Labor and Welfare published information regarding the degradation products (impurities) in pharmaceutical preparations that have been confirmed by standard setting of pharmaceutical preparations, that is, stability tests. ing. According to this, when the amount of drug substance administered per day is less than 10 mg, the threshold value for the safety confirmation of the decomposition product in the preparation is 1% of the decomposition product contained in the drug substance. 0.0% or the total daily intake of degradation products is 50 μg, whichever is lower, and the amount of drug substance administered daily is 10 mg or more and 100 mg or less. The threshold that required safety confirmation was recorded as the lower of the percentage of degradation products contained in the drug substance, either 0.5% or the total daily intake of degradation products of 200 μg. Therefore, as a standard value of the amount of decomposition product that can be generally set without confirming the safety of the decomposition product, for example, in the case of a preparation having a drug content of 5 mg, the decomposition product contained in the drug substance The ratio is 1.0% or less. For example, in the case of a preparation having a drug content of 10 mg, the ratio of degradation products contained in the drug substance is 0.5% or less.

  Currently, there are 2.5 mg tablets, 5 mg tablets and 10 mg tablets among solifenacin preparations to be marketed based on the results of clinical trials.

  On the other hand, in order to prepare pharmacologically superior salt and crystal forms, (1) excellent solubility, (2) excellent stability, (3) non-hygroscopicity, and (4) tablet dosage form. Must meet physicochemical criteria such as processability. Drugs with high stability have the advantage that they do not change even when stored for a long time, and drugs with high solubility are absorbed quickly in the stomach and intestine when taken orally, so that they show high blood levels even at low doses High effect can be expected. In general, amorphous forms of pharmaceuticals have high solubility and fast absorption in the stomach and intestine, but have the disadvantage of being less stable than crystalline forms. Accordingly, there is a need for a stable amorphous pharmaceutical composition comprising solifenacin or a salt thereof in order to improve the solubility of solifenacin or a salt thereof and ensure stability.

International application WO96 / 20144 European Patent No. 0801667

Japanese Medical Examination No. 0624001

  The object of the present invention is to provide a stable novel substance comprising solifenacin or a pharmaceutically acceptable salt thereof.

  Another object of the present invention is to provide a process for the preparation of said substance.

  Another object of the present invention is to provide a pharmaceutical composition comprising the substance as an active ingredient.

  In accordance with the above objects, the present invention provides an amorphous powder comprising solifenacin or a pharmaceutically acceptable salt thereof and lactose.

  The present invention also includes (1) a step of dissolving solifenacin or a pharmaceutically acceptable salt thereof and lactose in water or a mixed solvent of water and an organic solvent, and (2) a solution produced in step 1. And lyophilizing to obtain a solid-phase powder. A method for preparing an amorphous powder comprising solifenacin or a pharmaceutically acceptable salt thereof and lactose is provided.

  The present invention also provides a pharmaceutical composition comprising the amorphous powder as an active ingredient.

  Amorphous powder containing solifenacin or pharmaceutically acceptable salt thereof and lactose according to the present invention has excellent thermal stability and high solubility, so that bioavailability is good, so a pharmaceutical containing this as an active ingredient The composition is useful as a preventive or therapeutic agent for urinary disease, respiratory disease or digestive disease.

FIG. 1 shows the X-ray powder diffractometry (XPRD) of the amorphous powder containing solifenacin and lactose prepared in Example 1. FIG. 2 shows the X-ray powder diffraction degree measured after the amorphous powder containing solifenacin and lactose prepared in Example 1 was stored at 60 ° C. for 10 days.

  The present invention provides an amorphous powder comprising solifenacin or a pharmaceutically acceptable salt thereof and lactose as a stabilizer.

  In the amorphous powder of the present invention, lactose can greatly increase the stability of solifenacin, such as the thermal stability, by forming an amorphous powder with solifenacin.

Lactose used in the present invention is also called lactose as a disaccharide in which galactose and glucose are bound, and has a structure of s-D-galactosyl- (1,4) -D-glucose. The molecular formula is C ₁₂ H ₂₂ O ₁₁ and there are two types of α and s types depending on the form. Lactose is a component of mammalian milk, and is a safe stabilizer that is mainly used as a raw material for formulating infant formula and as a medical nutrient.

The lactose used in the present invention can have a structure represented by the following chemical formula (2).
(Chemical formula 2)

As the “pharmaceutically acceptable salt of solifenacin” used in the present invention, solifenacin and an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, or formic acid, With organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid Examples include acid addition salts and quaternary ammonium salts. Among these, solifenacin succinate of the following chemical formula 3 is preferable from the viewpoint of its medicinal effect.
(Chemical formula 3)

  The amorphous powder of the present invention comprises 10% to 70%, 15% to 65%, or 20% to 60% by weight of solifenacin or a pharmaceutically acceptable salt thereof based on the total weight. The lactose can be included in an amount of 30% to 90%, 35% to 85%, or 40% to 80% by weight.

  The amorphous powder of the present invention exhibits amorphous characteristics in X-ray powder diffraction analysis (XPRD). As specific examples, the amorphous powder prepared in Example 1 of the present application and the X-ray powder diffraction degree after storing the amorphous powder at 60 ° C. for 10 days are shown in FIGS. 1 and 2, respectively.

  The amorphous powder of the present invention has a water content of 1% by weight to 10% by weight as measured by Karl-Fischer titration (hereinafter referred to as KF). Preferably, the amorphous powder has a moisture content of about 2.6% by weight.

  Even when the amorphous powder according to the present invention is allowed to stand at 60 ° C. for 10 days, it maintains a stable amorphous form without melting while maintaining the water content at around 2.6%.

  The stable amorphous powder of the present invention includes (1) a step of dissolving solifenacin or a pharmaceutically acceptable salt thereof and lactose in water or a mixed solvent of water and an organic solvent, and (2) in step 1. The resulting solution can be prepared by a preparation method including lyophilizing to obtain a solid phase powder.

  In one embodiment, the pharmaceutically acceptable salt of solifenacin that can be used in the preparation method of the present invention may be solifenacin succinate.

  In step (1) of the preparation method of the present invention, solifenacin or a pharmaceutically acceptable salt thereof and lactose are dissolved in water or a mixed solvent of water and an organic solvent. Can be arbitrarily determined. For example, solifenacin or a pharmaceutically acceptable salt thereof is dissolved in water or a mixed solvent of water and an organic solvent, and then lactose is added to the resulting solution, or lactose is mixed with water or water and an organic solvent. Then, solifenacin or a pharmaceutically acceptable salt thereof is added to the resulting solution, or solifenacin or a pharmaceutically acceptable salt thereof and lactose are added to water or water and an organic solvent. It can be simultaneously added to and dissolved in the mixed solvent.

  The lactose can be used in an amount of 1 equivalent to 4 equivalents, preferably 1 equivalent to 2 equivalents, relative to 1 equivalent of solifenacin or a pharmaceutically acceptable salt thereof.

  The water or mixed solvent can be used in an amount of 1 to 100 times, preferably 5 to 50 times based on the volume of solifenacin or a pharmaceutically acceptable salt thereof.

  The mixed solvent of water and organic solvent is a mixed solvent of water and an organic solvent selected from the group consisting of methanol, ethanol, acetone, and acetonitrile, and the mixing ratio of water and organic solvent is a volume ratio. 1: 100 to 100: 1.

  In step (2) of the preparation method of the present invention, lyophilization can be performed at -90 ° C to -10 ° C for 1 day to 10 days.

  By recovering and drying a solid material produced through the freeze-drying in Step 2 such as a solid phase powder by a usual method, the stable amorphous powder of the present invention can be obtained.

  The present invention also provides a pharmaceutical composition comprising the amorphous powder as an active ingredient. Such a pharmaceutical composition can be prepared by appropriately adding various pharmaceutically acceptable additives to the amorphous powder. Any additive can be used as long as it is pharmaceutically acceptable and pharmacologically acceptable as long as it does not impair the object of the present invention. For example, a disintegrating agent, a sour agent, a foaming agent, an artificial sweetener, a fragrance, a lubricant, a coloring agent, a stabilizer, a buffering agent, an antioxidant, a surfactant, and the like can be used, and are not particularly limited thereto. Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, and low-substituted hydroxypropylcellulose. Examples of the acidulant include citric acid, tartaric acid, malic acid and the like. Examples of the foaming agent include sodium bicarbonate. Examples of artificial sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, and thaumatin. Examples of the fragrances include lemon, lemon lime, orange, menthol and the like. Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, talc, stearic acid and the like. Examples of the colorant include yellow ferric oxide, red ferric oxide, edible yellow No. 4, No. 5, edible red No. 3, No. 102, edible blue No. 3, and the like. Buffers include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, phosphoric acid Boric acid or a salt thereof. Examples of the antioxidant include ascorbic acid, sodium nitrite, sodium sulfite, sodium hydrogen sulfite, sodium edetate, erythorbic acid, tocopherol acetate, tocopherol, butylhydroxyanisole, dibutylhydroxytoluene, propylgallate and the like. Examples of the surfactant include sodium lauryl sulfate, polyoxyethylene sorbitan aliphatic ester (polysorbate 80), polyoxyethylene hydrogenated castor oil, and the like.

  The said additive can be used suitably individually or in combination of 2 or more types.

  In the pharmaceutical composition of the present invention, the amorphous powder as an active ingredient is 0.1% to 99% by weight, preferably 0.1% to 95% by weight, more preferably 1%, based on the total weight of the composition. It can be included in an amount of from 70% to 70% by weight.

  On the other hand, the pharmaceutical composition of the present invention can be formulated as various forms of pharmaceutical preparations according to any pharmaceutical method known in the art.

  For example, the pharmaceutical compositions of the present invention can be formulated in oral dosage forms such as capsules, tablets, dispersions and suspensions. The capsule or tablet may be in enteric coated form or contain enteric coated amorphous powder pellets. The formulations according to the invention can be administered to the patient in an effective amount via various routes, for example oral or parenteral routes.

  The dosage of the stable amorphous powder of the present invention is usually appropriately selected depending on the pharmaceutical use (indication), but is not particularly limited as long as it is a therapeutically effective amount or a prophylactically effective amount. A typical daily dose may be a corresponding amount of solifenacin 0.01 mg to 100 mg, 0.5 mg to 50 mg, 0.5 mg to 10 mg, or 0.5 mg to 4 mg based on an adult. The formulations of the present invention can be administered daily in single or divided dose forms. However, the actual dosage of the active ingredient should be determined in light of various relevant factors such as the route of administration, patient age, sex, weight, and severity of the disease, and the dosage should be determined in any aspect. That is not intended to limit the scope of the present invention.

(Example)
Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

[Reference example: Equipment used and measurement conditions]
The analytical values described in the following examples were measured as follows.

1) Chemical purity (%): high-performance liquid chromatography (HPLC) using a column for the harvested product obtained in each example.
(Column: Develosil ODS-UG-5 column, inner diameter 4.6 mm × length 150 mm,
Detection wavelength: 210 nm
・ Flow rate: 1.0 ml / min,
・ Eluent: Acetonitrile: Potassium dihydrogen phosphate buffer
= 50: 50 (v / v),
・ Oven temperature: 40 ℃
The chemical purity was calculated from all peak areas excluding the solvent peak appearing in the chromatogram and the peak area of the amorphous powder.
At this time, the potassium dihydrogen phosphate buffer was prepared by adding 0.1 M phosphoric acid to a 0.064 M potassium dihydrogen phosphate aqueous solution and adjusting the pH to 6.0.

  2) Thin film X-ray diffraction spectrum: Cu-Kα radiation (wavelength λ) using a D8 Advance X-ray powder diffraction spectrometer (Bruker, Germany) = 1.54050 mm) and measured.

  3) The differential scanning calorific value (DSC) was measured at a rate of + 1 ° C./min using a differential scanning calorimeter (STA S-1000, Scinco, Korea).

  4) Nuclear magnetic resonance spectrum (NMR): measured using a 300 MHz FT-NMR spectrometer (Bruker, Germany).

  5) Melting point: Measured using a melting point apparatus (Auto melting point apparatus, Buchi / Swiss, B-545).

  6) Water content: measured by Karl Fischer titration (KF).

Example 1: Preparation of amorphous powder I
After mixing 20 g of solifenacin succinate and 200 ml of water, the mixture was stirred and dissolved at room temperature. After 14.2 g of lactose was added and dissolved in this solution, membrane (0.45 μm HV, source: Durapore) was filtered. The filtrate was put into a conflat flask, rapidly cooled and frozen, and then lyophilized at −80 ° C. for 3 days in a lyophilizer. The obtained solid was recovered to obtain 32.3 g (yield: 94.5%) of solid phase powder.

  The analysis values of the prepared solid phase powder are as follows.

Purity: 99.96% (measured by HPLC)
¹ H-NMR (D2O, 300 MHz) d 6.8 to 7.2 (m, 10H), 6.06 (d, 1H), 4.61 (d, 1H), 4.39 (d, 1H), 3.45 to 3.90 (m, 15H), 3.11 ~ 3.24 (m, 5H), 2.68 (t, 3H), 2.45 (s, 4H), 2.08 (s, 1H), 1.86 (m, 1H), 1.73 (m, 2H)
Water content: about 2.6%
The XRD spectrum of the prepared solid phase powder is shown in FIG.
As can be seen from FIG. 1, the solid-phase powder showed an amorphous characteristic peak.

<Example 2: Preparation of amorphous powder II>
After mixing 10 g of solifenacin succinate and 50 ml of water, the mixture was stirred and dissolved at room temperature. After 7.1 g of lactose was added to this solution and dissolved, membrane filtration was performed. The filtrate was put into a conflat flask, rapidly cooled and frozen, and then freeze-dried at −80 ° C. for 3 days in a freeze dryer. The obtained solid was recovered to obtain 15.7 g (yield: 91.8%) of solid phase powder.

  The analysis values of the prepared solid phase powder are as follows.

Purity: 99.91% (measured by HPLC)
¹ H-NMR and moisture content results are the same as in Example 1.

<Example 3: Preparation III of amorphous powder>
After mixing 10 g of solifenacin succinate and 200 ml of water, the mixture was stirred and dissolved at room temperature. After 7.1 g of lactose was added to this solution and dissolved, membrane filtration was performed. The filtrate was put into a conflat flask, rapidly cooled and frozen, and then freeze-dried at −80 ° C. for 3 days in a freeze dryer. The obtained solid was recovered to obtain 15.8 g (yield: 92.8%) of solid phase powder.

  The analysis values of the prepared solid phase powder are as follows.

Purity: 99.94% (measured by HPLC)
¹ H-NMR and moisture content results are the same as in Example 1.

<Example 4: Preparation IV of amorphous powder>
After mixing 20 g of solifenacin succinate and 800 ml of water, the mixture was stirred and dissolved at room temperature. After 14.2 g of lactose was added to this solution and dissolved, membrane filtration was performed. The filtrate was put into a conflat flask, rapidly cooled and frozen, and then freeze-dried at −80 ° C. for 4 days in a freeze dryer. The obtained solid was recovered to obtain 31.4 g (yield: 91.2%) of solid phase powder.

  The analysis values of the prepared solid phase powder are as follows.

Purity: 99.93% (measured by HPLC)
¹ H-NMR and moisture content results are the same as in Example 1.

<Example 5: Preparation of amorphous powder V>
After mixing 10 g of solifenacin succinate and 100 ml of water, the mixture was stirred and dissolved at room temperature. After adding 14.2 g (2.0 eq.) Of lactose to this solution and dissolving it, membrane filtration was performed. The filtrate was put into a conflat flask, rapidly cooled and frozen, and then freeze-dried at −80 ° C. for 3 days in a freeze dryer. The obtained solid was recovered to obtain 21.4 g (yield: 88.6%) of solid phase powder.

  The analysis values of the prepared solid phase powder are as follows.

Purity: 99.93% (measured by HPLC)
<Example 6: Preparation VI of amorphous powder>
After mixing 10 g of solifenacin succinate and 100 ml of water, the mixture was stirred and dissolved at room temperature. After adding 21.3 g (3.0 eq.) Of lactose to this solution and dissolving it, membrane filtration was performed. The filtrate was put into a conflat flask, rapidly cooled and frozen, and then freeze-dried at −80 ° C. for 4 days in a freeze dryer. The obtained solid was recovered to obtain 23.5 g (yield: 75.2%) of solid phase powder.

  The analysis values of the prepared solid phase powder are as follows.

Purity: 99.92% (measured by HPLC)
<Example 7: Preparation of amorphous powder VII>
After mixing 10 g of solifenacin succinate and 100 ml of water, the mixture was stirred and dissolved at room temperature. Lactose 28.4 g (4.0 eq.) Was added to this solution and dissolved, and then membrane filtration was performed. The filtrate was put into a conflat flask, rapidly cooled and frozen, and then freeze-dried at −80 ° C. for 3 days in a freeze dryer. The obtained solid was recovered to obtain 30.1 g (yield: 78.4%) of solid phase powder.

  The analysis values of the prepared solid phase powder are as follows.

Purity: 99.91% (measured by HPLC)
<Comparative Example 1: Preparation of amorphous solifenacin>
After mixing 20 g of solifenacin succinate and 200 ml of water, the mixture was stirred and dissolved at room temperature, followed by membrane filtration. The filtrate was placed in a conflat flask, rapidly cooled and frozen, and then freeze-dried at −80 ° C. for 2 days in a freeze dryer, and 19.7 g of amorphous solifenacin (yield: 98.4%) Was obtained as an individual.

Purity: 99.94% (measured by HPLC)
DSC endothermic peak: 145 ° C
Water content: 1.5%
XRD: Amorphous <Comparative Example 2: Preparation of a mixture of solifenacin succinate and lactose>
A mixture was prepared by simply mixing 20 g solifenacin succinate and 14.2 g lactose.

Purity: 99.88% (measured by HPLC)
Melting point: 155 ° C to 160 ° C
Water content: 2.4%
<Test example: Thermal stability test>
In order to compare the thermal stability of the materials prepared in Example 1 and Comparative Examples 1 and 2, the materials were placed in a stability chamber and stored at 60 ° C. for 10 days. retention time) The impurity content was measured. The results are shown in Tables 1 to 3 below.

  As can be seen from the results shown in Tables 1 to 3, the amorphous powder of Example 1 was found to have the amorphous solifenacin of Comparative Example 1 and the amorphous solifenacin of Comparative Example 1 when stored under severe conditions at 60 ° C. It was found that excellent thermal stability was exhibited as compared with the mixture of solifenacin succinate and lactose of Comparative Example 2.

  In particular, the amorphous solifenacin of Comparative Example 1 and the mixture of solifenacin succinate and lactose of Comparative Example 2 all showed a result that the crystallinity could not be confirmed by dissolving all within one day at 60 ° C. The amorphous powder containing solifenacin succinate and lactose of Example 1 can maintain a stable amorphous form without melting while maintaining a moisture content of about 2.6% even at 60 ° C. for 10 days or more. It could be confirmed.

  Therefore, the amorphous powder comprising solifenacin succinate and lactose according to the present invention has, of course, improved stability as compared with the conventional amorphous solifenacin or the mixture of solifenacin succinate and lactose, and higher purity. Can be provided to patients as a drug.

Claims (14)

(Chemical formula 1)
An amorphous powder comprising solifenacin of Formula 1 or a pharmaceutically acceptable salt thereof and lactose.   The solifenacin or a pharmaceutically acceptable salt thereof is 10 wt% to 70 wt% and lactose is 30 wt% to 90 wt% based on the total weight of the powder. Amorphous powder. (Chemical formula 3)
The amorphous powder according to claim 1, wherein the pharmaceutically acceptable salt of solifenacin is the solifenacin succinate of Formula 3.   Amorphous powder according to claim 1, characterized in that it exhibits amorphous in X-ray powder diffraction analysis (XPRD) using Cu-Kα radiation. (1) dissolving solifenacin or a pharmaceutically acceptable salt thereof and lactose in water or a mixed solvent of water and an organic solvent;
(2) A method for preparing an amorphous powder comprising the step of freeze-drying the solution produced in the step (1) to obtain a solid phase powder. (Chemical formula 3)
[6] The preparation method according to claim 5, wherein the pharmaceutically acceptable salt of solifenacin is the solifenacin succinate of Formula 3.   In the step (1), the water or a mixed solvent of water and an organic solvent is used in an amount of 1 to 100 times based on the volume of solifenacin or a pharmaceutically acceptable salt thereof. The preparation method according to claim 5.   The preparation method according to claim 5, wherein in the step (1), the organic solvent is selected from the group consisting of methanol, ethanol, acetone, and acetonitrile.   The preparation method according to claim 5 or 8, wherein a mixing ratio of water and the organic solvent in the mixed solvent is 1: 100 to 100: 1 as a volume ratio.   The preparation method according to claim 5, wherein in the step (1), the lactose is used in an amount of 1 equivalent to 4 equivalents per equivalent of solifenacin or a pharmaceutically acceptable salt thereof. .   The preparation method according to claim 5, wherein the freeze-drying in the step (2) is performed at -90 ° C to -10 ° C for 1 day to 10 days.   A pharmaceutical composition comprising the amorphous powder according to any one of claims 1 to 4.   The pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is used for prevention or treatment of urological diseases, respiratory diseases or digestive diseases.   The urological disease is selected from the group consisting of urinary incontinence and frequent urination in neurogenic pollakiuria, neurogenic bladder, nocturnal urine, unstable bladder, bladder neck contraction, chronic cystitis, etc., and the respiratory disease is chronic obstructive A pharmaceutical composition characterized by being selected from the group consisting of pulmonary disease, chronic bronchitis, asthma and rhinitis, wherein the digestive system disease is selected from the group consisting of irritable bowel syndrome, convulsive colitis and diverticulitis object.