WO2019013403A1

WO2019013403A1 - Agents for preventing or treating urinary disease and preparing the same

Info

Publication number: WO2019013403A1
Application number: PCT/KR2017/013385
Authority: WO
Inventors: Yun-Sik Kim; Ji-Won Son; Yun-Young Kim; Eui-Jin Choo; Ju-hee YOUN; Hye-Jin Kim; Ji-Eun Lee
Original assignee: Dongkoo Bio & Pharma Co., Ltd.
Priority date: 2017-07-11
Filing date: 2017-11-23
Publication date: 2019-01-17
Also published as: KR101879133B1

Abstract

The present disclosure provides an agent for preventing or treating urinary disease, which contains tamsulosin or a pharmaceutically acceptable salt thereof, a PDE-5 inhibitor and a muscarinic receptor antagonist, and a method for preparing the same. The pharmaceutical agent according to the present disclosure, which contains tamsulosin, a PDE-5 inhibitor and a muscarinic receptor antagonist, is capable of treating benign prostatic hypertrophy, erectile dysfunction and bladder disease at the same time. In addition, the pharmaceutical agent according to the present disclosure provides a sustained-release effect and reduces treatment period and side effects.

Description

AGENTS FOR PREVENTING OR TREATING URINARY DISEASE AND PREPARING THE SAME

The present disclosure relates to an agent for preventing or treating urinary disease, which contains tamsulosin or a pharmaceutically acceptable salt thereof, a PDE-5 inhibitor and a muscarinic receptor antagonist, and a method for preparing the same.

Urinary diseases are representative diseases that can occur frequently in men older than 50 years of age, followed by cardiovascular diseases and metabolic diseases. Representative male urinary diseases include benign prostatic hypertrophy, urinary incontinence and erectile dysfunction. They occur frequently and, in many cases, one disease is accompanied by another disease. They have negative effects on the quality of life of patients by inducing very uncomfortable symptoms.

Benign prostatic hypertrophy refers to a condition where the prostatic gland just below the bladder is enlarged and compresses the urethra, thereby resulting in various voiding dysfunctions. Although the exact cause is not known yet, the change in male sex hormones due to aging is presumed to be the most plausible cause at present.

There are various treatment methods for treating the benign prostatic hypertrophy. The two main methods are medication and surgery. The main medications primarily selected for the treatment are α-blockers and 5α-reductase inhibitors. α-Blockers treat benign prostatic hypertrophy via a mechanism of selectively binding to α1 receptors present mainly in the smooth muscle of the prostatic gland, thereby relaxing the smooth muscle and reducing the size of the prostatic gland. Representative examples include doxazosin, terazosin, alfuzosin, tamsulosin, silodosin, etc. 5α-Reductase inhibitors act via a mechanism of inhibiting 5α-reductase which produces dihydrotestosterone, a hormone enlarging the prostatic gland, thereby reducing the size of the prostatic gland. Examples include finasteride, dutasteride, etc.

Tamsulosin is a selective α1 blocker for the smooth muscle of the prostatic gland, which is effective in the treatment of not only the symptoms of benign prostatic hypertrophy but also the symptoms of chronic prostatitis and chronic abdominal pain syndrome. It is also effective in treating urolithiasis via a muscle relaxation mechanism through α1 blocking and a recommended daily dosage is 0.2-0.8 mg. Unlike other αα blockers such as doxazosin or terazosin, tamsulosin is highly selective for the prostatic gland smooth muscle and greatly reduces side effects such as orthostatic hypotension, etc. because it exhibits low activity for the blood vessel. However, the administration dosage is very small because its medicinal efficacy is very strong and it is absorbed very quickly in the body. Therefore, despite the high selectivity for the prostatic gland smooth muscle, side effects such as orthostatic hypotension, etc. may occur if the initial blood drug level is increased exceedingly.

In order to solve this problem, US Patent No. 4,772,475 discloses a controlled-release formulation containing tamsulosin. According to this patent, a tamsulosin-containing controlled-release granule is prepared by mixing tamsulosin with 50 wt% or more of a unit-forming substance selected from a group consisting of crystalline cellulose, chitin and chitosan, adding a release controlling agent selected from a group consisting of an aqueous suspension, an aqueous emulsion, an aqueous gel or a water-containing organic solution of a water-insoluble polymer such as an acrylic acid polymer, an acrylic acid copolymer or a cellulose derivative to the resulting mixture and then granulating the same. However, if a controlled-release formulation is prepared according to the patent, the drug is released from a minimum amount of 16.2% to a maximum amount of 60.4% within 1 hour after the beginning of dissolution in a first solution under an acidic condition (pH 1.2) and in an amount of 90% or more within 1 hour after the beginning of dissolution in a second solution under a neutral condition (pH 6.8). Therefore, controlled release cannot be achieved satisfactorily.

And, Korean Patent No. 531,612 discloses a method for preparing a sustained-release tamsulosin tablet. According to this patent, a tamsulosin tablet is prepared by using a release-controlling polymer. However, it is disadvantageous in that the polymer used in the tamsulosin tablet is glyceryl dibehenate as an enteric, hydrophobic polymer having a phthalic acid enteric polymer, which can exhibit toxicity in the human body.

Erectile dysfunction is generally defined as a condition where erection is not developed or maintained sufficiently for sexual activity. Although the causes of erectile dysfunction are diverse as old age, smoking, drinking, diabetes, hypertension, cerebrovascular diseases, etc., it is a urinary disease that can frequently occur in aged men like benign prostatic hypertrophy.

There are several methods of treating erectile dysfunction. Medication is used primarily and phosphodiesterase type 5 inhibitors (hereinafter, PDE-5 inhibitors) are mainly used. Phosphodiesterases degrade cGMP, which is essential in erection by relaxing the smooth muscle of the penile corpus cavernosum to 5'-GMP and, thereby, cause erectile dysfunction. The PDE-5 inhibitors treat erectile dysfunction by interrupting this process.

The PDE-5 inhibitors include tadalafil, sildenafil citrate, udenafil and mirodenafil hydrochloride. Among them, tadalafil has a half-life which is 3 times or longer than that of sildenafil citrate or vardenafil. Tadalafil was first developed by ICOS and, at present, a tadalafil-containing erectile dysfunction medication first developed by Eli Lilly and Company is marked under the name Cialis. Cialis　was also approved in 2011 by the FDA for treatment of benign prostatic hypertrophy.

Urinary incontinence is one of the symptoms of hypersensitive bladder disease together with frequent urination, urinary urgency, urinary incontinence, etc. The cause of hypersensitive bladder is also unclear but is related with urinary tract infection, hormone deficiency, drug side effects, excessive water intake, constipation, obesity, etc.

Medication is considered primarily for the treatment of overactive bladder, too. Muscarinic receptor antagonists which are a type of anticholinergic agents are widely used. The muscarinic receptor antagonist competitively binds to the muscarinic receptor which binds to acetylcholine, thereby inhibiting the excitatory action of the neurotransmitter acetylcholine and relieving the symptoms of the overactive bladder disease.

Examples of the muscarinic receptor antagonist include solifenacin, tolterodine, oxybutynin, etc. Solifenacin or solifenacin succinate exhibits superior selective antagonistic action on the muscarinic receptor and is reported be effective in preventing urinary diseases such as neurogenic frequent urination, neurogenic bladder, nocturnal enuresis, unstable bladder, bladder spasm, chronic cystitis, etc. or respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, rhinitis, etc.

Solifenacin is mainly used for frequent urination, neurogenic bladder, nocturnal enuresis, etc. Because these patients also have benign prostatic hypertrophy, a combination therapy with tamsulosin is prescribed as a once-daily dosage.

Meanwhile, because tadalafil exhibits therapeutic effect for not only erectile dysfunction but also benign prostatic hypertrophy despite having a different mechanism of action from tamsulosin, superior preventive and therapeutic effect and decreased side effects can be expected from co-administration of tadalafil and tamsulosin.

Because benign prostatic hypertrophy is usually accompanied by lower urinary tract symptoms (LUTS) such as urinary incontinence, erectile dysfunction, etc. as described above due to the compression of the urethra below the bladder, it is highly likely that they occur in the same patient and co-administration is not uncommon. Therefore, development of a new combination drug which exhibits preventive and therapeutic effect for benign prostatic hypertrophy, erectile dysfunction and urinary incontinence at the same time and exhibits superior patient convenience and patient compliance is necessary.

In addition, whereas combination drugs containing two active ingredients are studied actively at present, there is no combination drug containing three active ingredients yet. Accordingly, development of a combination drug containing three ingredients is necessary.

[References of Related Art]

[Patent Documents]

US Patent No. 4,772,475 (registered on September 20, 1988).

Korean Patent No. 531,612 (registered on November 22, 2005).

The present disclosure is directed to providing an agent for preventing or treating urinary disease, which contains tamsulosin, a PDE-5 inhibitor and a muscarinic receptor antagonist, the drug release amount of which can be controlled depending on pH environments and which allows solubilization of the hardly soluble PDE-5 inhibitor and immediate release of the muscarinic receptor antagonist, and a method for preparing the same.

An agent for preventing or treating urinary disease according to a suitable exemplary embodiment of the present disclosure contains a first drug layer containing a granule formed by mixing tamsulosin or a pharmaceutically acceptable salt thereof, a release-controlling polymer and an enteric polymer, at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof and at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof.

The first drug layer may contain the muscarinic receptor antagonist and a second drug layer may contain the PDE-5 inhibitor.

A second drug layer may contain the PDE-5 inhibitor and a third drug layer may contain the muscarinic receptor antagonist.

The agent for preventing or treating urinary disease may contain a second drug layer containing the PDE-5 inhibitor and a third drug layer containing the muscarinic receptor antagonist.

The agent for preventing or treating urinary disease may contain a second drug layer which coats the outside of the first drug layer with the PDE-5 inhibitor and the muscarinic receptor antagonist.

The release-controlling polymer may be one or more compound selected from hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polypropylene oxide, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polymethacrylate, glycerol monostearate and poloxamer.

The enteric polymer may be one or more selected from hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethylhydroxyethyl cellulose phthalate, a styrene-acrylic acid copolymer, a methyl acrylate-acrylic acid copolymer, a methyl methacrylate-acrylic acid copolymer, a butyl acrylate-styrene-acrylic acid copolymer, a methacrylic acid-ethyl acrylate copolymer, a methyl acrylate-methacrylic acid-octyl acrylate copolymer, a vinyl acetate-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, a vinyl butyl ether-maleic anhydride copolymer, an acrylonitrile-methyl acrylate-maleic anhydride copolymer, a butyl acrylate-styrene-maleic anhydride copolymer, polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butylate phthalate and polyvinyl acetate acetal phthalate.

A method for preparing an agent for preventing or treating urinary disease according to the present disclosure includes: a step of preparing a tamsulosin granule by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer; a step of preparing a mixture by mixing the tamsulosin granule with at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof and an excipient; a step of preparing a PDE-5 inhibitor granule by mixing at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof with an excipient; a step of preparing a first drug layer by tableting the mixture; and a step of preparing a second drug layer by tableting the PDE-5 inhibitor granule.

Another method for preparing an agent for preventing or treating urinary disease according to the present disclosure includes: a step of preparing a tamsulosin granule by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer; a step of preparing a PDE-5 inhibitor granule by mixing at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof with an excipient; a step of preparing a muscarinic receptor antagonist mixture by mixing at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof with an excipient; a step of preparing a first drug layer by tableting the tamsulosin granule; a step of preparing a second drug layer by tableting the PDE-5 inhibitor granule or the mixture; and a step of preparing a third drug layer by tableting the muscarinic receptor antagonist mixture.

Another method for preparing an agent for preventing or treating urinary disease according to the present disclosure includes: a step of preparing a tamsulosin granule by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer; a step of preparing a first coating solution containing at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof; a step of preparing a second coating solution containing at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof; a step of preparing a tablet by tableting the tamsulosin granule; and a step of coating the first coating solution and the second coating solution on the tablet.

Another method for preparing an agent for preventing or treating urinary disease according to the present disclosure includes: a step of preparing a tamsulosin granule by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer; a step of preparing a coating solution containing at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof and at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof; a step of preparing a tablet by tableting the tamsulosin granule; and a step of coating the coating solution on the tablet.

A pharmaceutical agent according to the present disclosure, which contains tamsulosin, a PDE-5 inhibitor and a muscarinic receptor antagonist, is capable of treating benign prostatic hypertrophy, erectile dysfunction and bladder disease at the same time.

In addition, the pharmaceutical agent according to the present disclosure provides a sustained-release effect and reduces treatment period and side effects.

FIG. 1 shows a result of comparing the dissolution rate of tamsulosin hydrochloride in Test Example 1.

FIG. 2 shows a result of comparing the dissolution rate of tadalafil in Test Example 2.

Hereinafter, the present disclosure is described in detail. Prior to the description, the terms or words used in the present specification and claims should not be interpreted as being limited to their typical meaning based on the dictionary definitions thereof but should be interpreted to have the meaning and concept relevant to the technical spirit of the present disclosure, based on the fundamental notion that the present inventor can suitably define the concept of the terms to describe the invention using the best method. Therefore, the constructions in the embodiments described in the present specification are only specific exemplary embodiments of the present disclosure and do not represent the entire technical spirit of the present disclosure. Therefore, those skilled in the art will understand that there may be various equivalents and modifications capable of replacing the constructions at the time of filing the present disclosure.

The agent for preventing or treating urinary disease of the present disclosure contains:

a first drug layer containing a granule formed by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer;

at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof; and

at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof.

The tamsulosin or a pharmaceutically acceptable salt thereof, the PDE-5 inhibitor and the muscarinic receptor antagonist used in the present disclosure are mixed at a weight ratio of specifically 1 : 1-100 : 1-100, more specifically 1 : 5-80 : 5-80, most specifically 1 : 10-50 : 10-50.

As the release-controlling polymer used in the present disclosure, a pH-independent polymer or a pH-dependent polymer is used and serves to control the optimal drug release.

As the release-controlling polymer, any pharmaceutically acceptable polymer may be used. Specifically, one or more compound selected from hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polypropylene oxide, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polymethacrylate, glycerol monostearate and poloxamer may be used. More specifically, one or more compound selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone and polyvinyl alcohol may be used. Most specifically, one or more compound selected from hydroxypropylmethyl cellulose and hydroxymethyl cellulose may be used.

In the present disclosure, the dissolution rate of tamsulosin may be controlled by controlling the viscosity of the release-controlling polymer. For example, hydroxypropylmethyl cellulose with a high viscosity, specifically a viscosity of 10-10,000 cps, more specifically 50-4,000 cps, may be used. When the viscosity is lower than the above range, the size of the tablet may increase. And, when the viscosity is higher than the above range, uniform mixing with the drug may be difficult.

And, the tamsulosin or a pharmaceutically acceptable salt thereof and the release-controlling polymer may be mixed at a weight ratio of specifically 1 : 10-1500, more specifically 1 : 50-1250.

The pH-dependent polymer used as the enteric polymer in the present disclosure serves to delay drug release by affecting the dissolution of the drug in response to pH change.

As the enteric polymer, any pharmaceutically acceptable polymer may be used. Specifically, one or more selected from hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethylhydroxyethyl cellulose phthalate, a styrene-acrylic acid copolymer, a methyl acrylate-acrylic acid copolymer, a methyl methacrylate-acrylic acid copolymer, a butyl acrylate-styrene-acrylic acid copolymer, a methacrylic acid-ethyl acrylate copolymer, a methyl acrylate-methacrylic acid-octyl acrylate copolymer, a vinyl acetate-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, a vinyl butyl ether-maleic anhydride copolymer, an acrylonitrile-methyl acrylate-maleic anhydride copolymer, a butyl acrylate-styrene-maleic anhydride copolymer, polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butylate phthalate and polyvinyl acetate acetal phthalate may be used. Most specifically, hydroxypropylmethyl cellulose acetate succinate may be used.

The hydroxypropylmethyl cellulose acetate succinate is available as various grades depending on pH selectivity or type such as granule or fine powder. Examples include Shin-Etsu AQOAT AS-LF (Shin-Etsu Chemical Co., Ltd., soluble at pH 5.5, fine powder), Shin-Etsu AQOAT AS-LG (Shin-Etsu Chemical Co., Ltd., soluble at pH 5.5, granule), Shin-Etsu AQOAT AS-MF (Shin-Etsu Chemical Co., Ltd., soluble at pH 6.0, fine powder), Shin-Etsu AQOAT AS-MG (Shin-Etsu Chemical Co., Ltd., soluble at pH 6.0, granule), Shin-Etsu AQOAT AS-HF (Shin-Etsu Chemical Co., Ltd., soluble at pH 6.5, fine powder) and Shin-Etsu AQOAT AS-HG (Shin-Etsu Chemical Co., Ltd., soluble at pH 6.5, granule).

The release-controlling polymer and the enteric polymer may be mixed at a weight ratio of specifically 1 : 0.5-5, more specifically 1 : 1-3.

Because the tamsulosin used in the present disclosure may have a nonuniform content due to low unit dosage, a method for resolving the nonuniformity of the active ingredient is necessary. In the present disclosure, a uniform content may be maintained superiously by including the release-controlling polymer and the enteric polymer without the need of a complex process, an expensive excipient or an expensive special equipment.

The tamsulosin used in the present disclosure is mixed with the release-controlling polymer and the enteric polymer to form a matrix, which allows sustained release by preventing quick contact with biological fluid. Specifically, the tamsulosin in the agent according to the present disclosure exhibits a dissolution rate of 20-30% within 2 hours under a gastric juice condition (pH 1.2) and 50-70% within 3 hours and 80-90% within 5 hours under an intestinal juice condition (pH 7.2) and consistent drug release is possible without being affected by the PDE-5 inhibitor or the muscarinic receptor antagonist.

Specifically, the granule containing the tamsulosin or a pharmaceutically acceptable salt thereof and the release-controlling polymer may have a particle size of 500-2000 μm. For example, the granule may exhibit a particle size distribution of 70% or more of particles passing through 850 μm meshes. The granule of this size is suitable for uniform release of the drug.

When the granule has a particle size which is greater than the above range, it may take time until medicinal efficacy is manifested and a sufficient therapeutic effect may not be achieved because of delayed drug release. In addition, there may occur the problem of nonuniform content when preparing a tablet or a capsule. And, when the particle size is smaller than the above range, side effects may occur due to high initial blood level of the drug because the effect of controlling drug release is not exerted enough. In addition, the therapeutic effect may be reduced as a consistent medicinal efficacy is not achieved with a once-daily dosage. Besides, the small particle size may result in interruption of the intrinsic drug release profile of each active ingredient due to interactions with the ingredients PDE-5 inhibitor and muscarinic receptor antagonist.

The agent for preventing or treating urinary disease according to the present disclosure may further contain at least one of an excipient, a disintegrant, a surfactant, a binder, a lubricant and a diluent.

The disintegrant is used to improve dissolution by absorbing water and thereby facilitating disintegration. As the disintegrant, any commonly used orally administrable polymer may be used. Specifically, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium starch glycolate, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, starch, microcrystalline cellulose, etc. may be used. More specifically, sodium starch glycolate may be used. The disintegration effect may be enhanced when two disintegrants are used in admixture. Specifically, the tamsulosin or a pharmaceutically acceptable salt thereof and the disintegrant may be mixed at a weight ratio of 1 : 5-300.

The lubricant is used to improve the formability of a formulation. As the lubricant, any commonly used orally administrable polymer may be used. Specifically, magnesium stearate, glyceryl behenate, colloidal silicon dioxide, silicon dioxide, talc, stearic acid, sodium stearyl fumarate, etc. may be used. Specifically, the tamsulosin or a pharmaceutically acceptable salt thereof and the lubricant may be mixed at a weight ratio of 1 : 1-100.

Hereinafter, specific examples of the agent for preventing or treating urinary disease according to the present disclosure are described in detail.

As an example, the agent for preventing or treating urinary disease according to the present disclosure may contain:

a first drug layer containing a granule formed by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer and a muscarinic receptor antagonist; and

a second drug layer containing a PDE-5 inhibitor.

As another example, the agent for preventing or treating urinary disease according to the present disclosure may contain:

a second drug layer containing a PDE-5 inhibitor; and

a third drug layer containing a muscarinic receptor antagonist.

a first drug layer containing a granule formed by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer; and

a second drug layer which is formed by coating the outside of the first drug layer and contains a PDE-5 inhibitor and a muscarinic receptor antagonist.

The agent for preventing or treating urinary disease according to the present disclosure may be in the form of various pharmaceutical formulations. Specifically, it may be prepared into a tablet, a hard capsule or a granule. Most specifically, it may be prepared into a tablet.

Hereinafter, a method for preparing an agent for preventing or treating urinary disease of the present disclosure is described. The characteristics of the agent such as type, composition, contents, etc. are the same as described above.

A method for preparing an agent for preventing or treating urinary disease of the present disclosure includes:

a step of preparing a tamsulosin granule by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer;

a step of preparing a mixture by mixing the tamsulosin granule with at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof and an excipient;

a step of preparing a PDE-5 inhibitor granule by mixing at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof with an excipient;

a step of preparing a first drug layer by tableting the mixture; and

a step of preparing a second drug layer by tableting the PDE-5 inhibitor granule.

Another method for preparing an agent for preventing or treating urinary disease of the present disclosure includes:

a step of preparing a muscarinic receptor antagonist mixture by mixing at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof with an excipient;

a step of preparing a first drug layer by tableting the tamsulosin granule;

a step of preparing a second drug layer by tableting the PDE-5 inhibitor granule or the mixture; and

a step of preparing a third drug layer by tableting the muscarinic receptor antagonist mixture.

a step of preparing a first coating solution containing at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof;

a step of preparing a second coating solution containing at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof;

a step of preparing a drug layer by tableting the tamsulosin granule; and

a step of coating the first coating solution and the second coating solution on the drug layer.

a step of preparing a coating solution containing at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof and at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof;

a step of preparing a drug layer by tableting the tamsulosin granule; and

a step of coating the coating solution on the drug layer.

The granule described in the present disclosure may be prepared by wet or dry granulation. The wet granulation may be performed by uniformly mixing the main ingredients, a diluent, a disintegrant, etc. in a powder mixer and then kneading, granulating, drying and tableting the mixture.

And, the dry granulation may be performed by slugging a mixture of the main ingredients and an additive into a 1-inch wide, flat pellet, grinding the same with a grinder, passing the resulting powder through a sieve and then compressing the same into a tablet after adding a lubricant (slugging method) or by compressing the powder between rollers of a powder compressor and then tableting the compressed powder via various methods after lubrication (roller compression method).

In the preceding description, the present disclosure is described with reference to specifically exemplary embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the present disclosure, as set forth in the claims. The specification and drawings are, accordingly, to be regarded as illustrative and not as restrictive. It is understood that the present disclosure is capable of using various other combinations and embodiments and is capable of any changes or modifications within the scope of the inventive concept as expressed herein.

Hereinafter, the present disclosure will be described in detail through examples. However, the following examples are for illustrative purposes only and it will be obvious to those of ordinary skill in the art that the scope of the present disclosure is not limited by the examples.

Examples 1-8. Double-layered formulations

Tamsulosin hydrochloride was dissolved in a mixed solvent of ethanol and methylene chloride and a binder solution was prepared by dissolving hydroxypropylmethyl cellulose acetate succinate in the resulting solution. A tamsulosin granule was prepared by adding the binder solution to an excipient mixture containing hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, microcrystalline cellulose, lactose and sodium starch glycolate and kneading the same. The tamsulosin granule was tableted using a Comil grinder equipped with a screen having a mesh size of 1.016-1.27 mm.

A post-mixture was prepared by adding an excipient containing solifenacin, lactose hydrate, magnesium stearate, pregelatinized starch, silicon dioxide and colloidal silicon dioxide to the tamsulosin granule.

A tadalafil granule was obtained by mixing tadalafil with lactose hydrate and kneading the same using a binder solution obtained by dissolving hydroxypropyl cellulose and sodium lauryl sulfate in a mixed solvent of ethanol and water. Then, a tadalafil post-mixture was obtained by performing post-mixing by adding microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide.

A circular double-layered tablet was obtained by forming a first layer by primarily tableting the granule containing tamsulosin and solifenacin and then forming a second layer by secondarily primarily tableting the granule post-mixture containing tadalafil.

The ingredients and compositions used for the preparation are described in Table 1.

Ingredients (mg)	Ex. 1	Ex. 2	Ex. 3	Ex. 4	Ex. 5	Ex. 6	Ex. 7	Ex. 8
First layer containing tamsulosin hydrochloride and solifenacin succinate (Uncoated tablet)
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Solifenacin succinate	5	5	5	5	5	5	5	5
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Second layer containing tadalafil
Tadalafil	5	5	5	5	5	5	5	5
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
Silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01

Examples 9-16. Wet granule formulations

A post-mixture was prepared by adding an excipient containing solifenacin, magnesium stearate, pregelatinized starch, silicon dioxide and colloidal silicon dioxide to the tamsulosin granule.

A tadalafil granule was obtained by mixing tadalafil with lactose hydrate and kneading the same using a binder solution obtained by dissolving hydroxypropyl cellulose and sodium lauryl sulfate in a mixed solvent of ethanol and water.

After adding an excipient containing microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide to the granule and performing post-mixing, the mixture was filled in a capsule.

The ingredients and compositions used for the preparation were the same as in Examples 1-8.

Examples 17-24. Minitablet-filled capsule formulations

A mixture was prepared by adding an excipient containing solifenacin succinate, lactose hydrate, pregelatinized starch, magnesium stearate and colloidal silicon dioxide to the tamsulosin granule.

A minitablet containing tamsulosin and solifenacin was prepared by tableting the mixture.

A mixture was obtained by mixing the tadalafil granule with microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide.

After tableting the tadalafil mixture into a minitablet, it was filled in a capsule together with the minitablet containing tamsulosin and solifenacin.

The ingredients and compositions used for the preparation are described in Table 2.

Ingredients (mg)	Ex. 17	Ex. 18	Ex. 19	Ex. 20	Ex. 21	Ex. 22	Ex. 23	Ex. 24
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	5	9	13	17	21	25	29	33
Hydroxypropylmethyl cellulose acetate succinate	10	16	22	28	34	40	46	50
Microcrystalline cellulose	20	20	20	20	20	20	20	20
Lactose	70	60	50	40	30	20	10	5
Sodium starch glycolate	15	15	15	15	15	15	15	15
Magnesium stearate	1	1	1	1	1	1	1	1
Colloidal silicon dioxide	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.03	0.03	0.03	0.03	0.03	0.03	0.03	0.03
Solifenacin succinate	5	5	5	5	5	5	5	5
Tadalafil	5	5	5	5	5	5	5	5
Hydroxypropyl cellulose	5	5	5	5	5	5	5	5
Microcrystalline cellulose	4.5	4.5	4.5	4.5	4.5	4.5	4.5	4.5
Sodium lauryl sulfate	0.2	1	1.5	2	2.5	3	3.5	4
Lactose hydrate	68	68	68	68	68	68	68	68
Sodium starch glycolate	7	7	7	7	7	7	7	7
Magnesium stearate	1	1	1	1	1	1	1	1
Silicon dioxide	1	1	1	1	1	1	1	1
Pregelatinized starch	20	20	20	20	20	20	20	20

Examples 25-120. Triple-layered tablet formulations

Tamsulosin hydrochloride was dissolved in a mixed solvent of ethanol and methylene chloride and a binder solution was prepared by dissolving hydroxypropylmethyl cellulose acetate succinate in the resulting solution. A tamsulosin granule was prepared by adding the binder solution to an excipient mixture containing hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, microcrystalline cellulose, lactose hydrate and sodium starch glycolate and kneading the same. The tamsulosin granule was tableted using a Comil grinder equipped with a screen having a mesh size of 1.016-1.27 mm.

A post-mixture was obtained by mixing the tamsulosin granule with magnesium stearate and colloidal silicon dioxide.

A PDE-5 inhibitor granule was obtained by adding a binder solution in which hydroxypropyl cellulose and sodium lauryl sulfate are dissolved in dilute ethanol to an excipient mixture containing one of tadalafil, sildenafil citrate, udenafil and mirodenafil hydrochloride and lactose hydrate and then kneading the mixture.

A post-mixture was obtained by adding an excipient containing microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide to the PDE-5 inhibitor granule and mixing the same.

A mixture containing a muscarinic receptor antagonist was obtained by dispersing one or more muscarinic receptor antagonist selected from solifenacin, tolterodine, oxybutynin, etc. in an excipient mixture containing lactose hydrate.

A post-mixture was obtained by mixing the muscarinic receptor antagonist mixture with lactose hydrate and pregelatinized starch and then mixing with an excipient containing magnesium stearate and silicon dioxide.

A circular triple-layered tablet was obtained by tableting the tamsulosin granule, the PDE-5 inhibitor granule and the muscarinic receptor antagonist mixture into a triple-layered tablet.

The ingredients and compositions used for the preparation are described in Tables 3-14.

Table 3 shows cases where tadalafil and solifenacin succinate were used.

Ingredients (mg)	Ex. 25	Ex. 26	Ex. 27	Ex. 28	Ex. 29	Ex. 30	Ex. 31	Ex. 32
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	5	5	5	5	5	5	5	5
Sildenafil citrate	-	-	-	-	-	-	-	-
Udenafil	-	-	-	-	-	-	-	-
Mirodenafil hydrochloride	-	-	-	-	-	-	-	-
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
Silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	5	5	5	5	5	5	5	5
Tolterodine tartrate	-	-	-	-	-	-	-	-
Oxybutynin hydrochloride	-	-	-	-	-	-	-	-
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 4 shows cases where sildenafil citrate and solifenacin succinate were used.

Ingredients (mg)	Ex. 33	Ex. 34	Ex. 35	Ex. 36	Ex. 37	Ex. 38	Ex. 39	Ex. 40
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	-	-	-	-	-	-	-	-
Sildenafil citrate	5	5	5	5	5	5	5	5
Udenafil	-	-	-	-	-	-	-	-
Mirodenafil hydrochloride	-	-	-	-	-	-	-	-
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
Silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	5	5	5	5	5	5	5	5
Tolterodine tartrate	-	-	-	-	-	-	-	-
Oxybutynin hydrochloride	-	-	-	-	-	-	-	-
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 5 shows cases where udenafil and solifenacin succinate were used.

Ingredients (mg)	Ex. 41	Ex. 42	Ex. 43	Ex. 44	Ex. 45	Ex. 46	Ex. 47	Ex. 48
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	-	-	-	-	-	-	-	-
Sildenafil citrate	-	-	-	-	-	-	-	-
Udenafil	5	5	5	5	5	5	5	5
Mirodenafil hydrochloride	-	-	-	-	-	-	-	-
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	5	5	5	5	5	5	5	5
Tolterodine tartrate	-	-	-	-	-	-	-	-
Oxybutynin hydrochloride	-	-	-	-	-	-	-	-
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 6 shows cases where mirodenafil hydrochloride and solifenacin succinate were used.

Ingredients (mg)	Ex. 49	Ex. 50	Ex. 51	Ex. 52	Ex. 53	Ex. 54	Ex. 55	Ex. 56
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	-	-	-	-	-	-	-	-
Sildenafil citrate	-	-	-	-	-	-	-	-
Udenafil	-	-	-	-	-	-	-	-
Mirodenafil hydrochloride	5	5	5	5	5	5	5	5
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	5	5	5	5	5	5	5	5
Tolterodine tartrate	-	-	-	-	-	-	-	-
Oxybutynin hydrochloride	-	-	-	-	-	-	-	-
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 7 shows cases where tadalafil and tolterodine tartrate were used.

Ingredients (mg)	Ex. 57	Ex. 58	Ex. 59	Ex. 60	Ex.61	Ex. 62	Ex. 63	Ex. 64
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	5	5	5	5	5	5	5	5
Sildenafil citrate	-	-	-	-	-	-	-	-
Udenafil	-	-	-	-	-	-	-	-
Mirodenafil hydrochloride	-	-	-	-	-	-	-	-
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	-	-	-	-	-	-	-	-
Tolterodine tartrate	5	5	5	5	5	5	5	5
Oxybutynin hydrochloride	-	-	-	-	-	-	-	-
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 8 shows cases where sildenafil citrate and tolterodine tartrate were used.

Ingredients (mg)	Ex. 65	Ex. 66	Ex. 67	Ex. 68	Ex. 69	Ex. 70	Ex. 71	Ex. 72
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	-	-	-	-	-	-	-	-
Sildenafil citrate	5	5	5	5	5	5	5	5
Udenafil	-	-	-	-	-	-	-	-
Mirodenafil hydrochloride	-	-	-	-	-	-	-	-
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	-	-	-	-	-	-	-	-
Tolterodine tartrate	5	5	5	5	5	5	5	5
Oxybutynin hydrochloride	-	-	-	-	-	-	-	-
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 9 shows cases where udenafil and tolterodine tartrate were used.

Ingredients (mg)	Ex. 73	Ex. 74	Ex. 75	Ex. 76	Ex. 77	Ex. 78	Ex. 79	Ex. 80
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	-	-	-	-	-	-	-	-
Sildenafil citrate	-	-	-	-	-	-	-	-
Udenafil	5	5	5	5	5	5	5	5
Mirodenafil hydrochloride	-	-	-	-	-	-	-	-
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	-	-	-	-	-	-	-	-
Tolterodine tartrate	5	5	5	5	5	5	5	5
Oxybutynin hydrochloride	-	-	-	-	-	-	-	-
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 10 shows cases where mirodenafil hydrochloride and tolterodine tartrate were used.

Ingredients (mg)	Ex. 81	Ex. 82	Ex. 83	Ex. 84	Ex. 85	Ex. 86	Ex. 87	Ex. 88
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	-	-	-	-	-	-	-	-
Sildenafil citrate	-	-	-	-	-	-	-	-
Udenafil	-	-	-	-	-	-	-	-
Mirodenafil hydrochloride	5	5	5	5	5	5	5	5
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	-	-	-	-	-	-	-	-
Tolterodine tartrate	5	5	5	5	5	5	5	5
Oxybutynin hydrochloride	-	-	-	-	-	-	-	-
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 11 shows cases where tadalafil and oxybutynin hydrochloride were used.

Ingredients (mg)	Ex. 89	Ex. 90	Ex. 91	Ex. 92	Ex. 93	Ex. 94	Ex. 95	Ex. 96
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	5	5	5	5	5	5	5	5
Sildenafil citrate	-	-	-	-	-	-	-	-
Udenafil	-	-	-	-	-	-	-	-
Mirodenafil hydrochloride	-	-	-	-	-	-	-	-
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	-	-	-	-	-	-	-	-
Tolterodine tartrate	-	-	-	-	-	-	-	-
Oxybutynin hydrochloride	5	5	5	5	5	5	5	5
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 12 shows cases where sildenafil citrate and oxybutynin hydrochloride were used.

Ingredients (mg)	Ex. 97	Ex. 98	Ex. 99	Ex. 100	Ex. 101	Ex. 102	Ex. 103	Ex. 104
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	-	-	-	-	-	-	-	-
Sildenafil citrate	5	5	5	5	5	5	5	5
Udenafil	-	-	-	-	-	-	-	-
Mirodenafil hydrochloride	-	-	-	-	-	-	-	-
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	-	-	-	-	-	-	-	-
Tolterodine tartrate	-	-	-	-	-	-	-	-
Oxybutynin hydrochloride	5	5	5	5	5	5	5	5
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 13 shows cases where udenafil and oxybutynin hydrochloride were used.

Ingredients (mg)	Ex. 105	Ex. 106	Ex. 107	Ex. 108	Ex. 109	Ex. 110	Ex. 111	Ex. 112
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	-	-	-	-	-	-	-	-
Sildenafil citrate	-	-	-	-	-	-	-	-
Udenafil	5	5	5	5	5	5	5	5
Mirodenafil hydrochloride	-	-	-	-	-	-	-	-
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	-	-	-	-	-	-	-	-
Tolterodine tartrate	-	-	-	-	-	-	-	-
Oxybutynin hydrochloride	5	5	5	5	5	5	5	5
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Table 14 shows cases where mirodenafil hydrochloride and oxybutynin hydrochloride were used.

Ingredients (mg)	Ex. 113	Ex. 114	Ex. 115	Ex. 116	Ex. 117	Ex. 118	Ex. 119	Ex. 120
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06	0.06	0.06	0.06	0.06	0.06	0.06	0.06
Tadalafil	-	-	-	-	-	-	-	-
Sildenafil citrate	-	-	-	-	-	-	-	-
Udenafil	-	-	-	-	-	-	-	-
Mirodenafil hydrochloride	5	5	5	5	5	5	5	5
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	-	-	-	-	-	-	-	-
Tolterodine tartrate	-	-	-	-	-	-	-	-
Oxybutynin hydrochloride	5	5	5	5	5	5	5	5
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Examples 121-128. Triple-layered tablet formulations with different proportion of mixed organic solvent

Tamsulosin hydrochloride was dissolved in a mixed solvent of ethanol, methylene chloride and purified water and a binder solution was prepared by dissolving hydroxypropylmethyl cellulose acetate succinate in the resulting solution. A tamsulosin granule was prepared by adding the binder solution to an excipient mixture containing hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, microcrystalline cellulose, lactose hydrate and sodium starch glycolate and kneading the same. The tamsulosin granule was tableted using a Comil grinder equipped with a screen having a mesh size of 1.016-1.27 mm.

A tadalafil granule was obtained by adding a binder solution in which hydroxypropyl cellulose and sodium lauryl sulfate are dissolved in dilute ethanol to an excipient mixture containing tadalafil and lactose hydrate and then kneading the mixture.

A post-mixture was obtained by adding an excipient containing microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide to the tadalafil granule and mixing the same.

A mixture was obtained by dispersing solifenacin in an excipient mixture containing lactose hydrate.

A post-mixture was obtained by mixing the solifenacin mixture with lactose hydrate and pregelatinized starch and then mixing with an excipient containing magnesium stearate and silicon dioxide.

A circular triple-layered tablet was obtained by tableting the tamsulosin granule, the tadalafil granule and the solifenacin mixture into a triple-layered tablet.

The ingredients and compositions used for the preparation are described in Table 15.

Ingredients (mg)	Ex. 121	Ex. 122	Ex. 123	Ex. 124	Ex. 125	Ex. 126	Ex. 127	Ex. 128
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	34	34	34	34	34	34	34	34
Hydroxypropylmethyl cellulose acetate succinate	56	56	56	56	56	56	56	56
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose hydrate	85	85	85	85	85	85	85	85
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Ethanol	0.055	0.042	0.03	0.018	0.005	0.03	0.042	0.048
Methylene chloride	0.005	0.018	0.03	0.042	0.055	-	-	-
Purified water	-	-	-	-	-	0.03	0.018	0.012
Tadalafil	5	5	5	5	5	5	5	5
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	6.5	6.5	6.5
Lactose hydrate	138.5	137	135.5	134	132.5	132.5	132.5	132.5
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
Silicon dioxide	2	2	2	2	2	2	2	2
Mixed organic solvent (70% ethanol)	0.01	0.01	0.01	0.01	0.01	0.01	0.01	0.01
Solifenacin succinate	5	5	5	5	5	5	5	5
Lactose hydrate	90	90	90	90	90	90	90	90
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Magnesium stearate	3	3	3	3	3	3	3	3

Examples 129-136. Dry granule compositions

Tamsulosin hydrochloride was mixed with an excipient mixture containing hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, microcrystalline cellulose, lactose hydrate and sodium starch glycolate and prepared into a flat tablet or pellet through slugging or compression. A tamsulosin granule was obtained by grinding with a grinder and it was tableted using a Comil grinder equipped with a screen having a mesh size of 1.016-1.27 mm.

The tamsulosin granule was post-mixed with magnesium stearate and colloidal silicon dioxide.

A tadalafil granule was obtained by mixing tadalafil with an excipient mixture containing hydroxypropyl cellulose, sodium lauryl sulfate and lactose hydrate, preparing the same into a flat tablet or pellet through slugging or compression and then grinding with a grinder.

The tadalafil granule was post-mixed with an excipient containing microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide.

A granule was obtained by mixing solifenacin with an excipient mixture containing lactose hydrate and pregelatinized starch, preparing the same into a pellet through slugging or compression and then grinding with a grinder.

The solifenacin granule was post-mixed with an excipient containing magnesium stearate and silicon dioxide.

The tamsulosin, tadalafil and solifenacin granules were filled in a capsule.

The ingredients and compositions used for the preparation are described in Table 16.

Ingredients (mg)	Ex. 129	Ex. 130	Ex. 131	Ex. 132	Ex. 133	Ex. 134	Ex. 135	Ex. 136
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Solifenacin succinate	5	5	5	5	5	5	5	5
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Tadalafil	5	5	5	5	5	5	5	5
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
Silicon dioxide	2	2	2	2	2	2	2	2

Examples 137-144. Simple-mix tadalafil formulations

Tamsulosin hydrochloride was dissolved in a mixed solvent of ethanol, methylene chloride and water and a binder solution was prepared by dissolving hydroxypropylmethyl cellulose acetate succinate in the resulting solution. A tamsulosin granule was prepared by adding the binder solution to an excipient mixture containing hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, microcrystalline cellulose, lactose hydrate and sodium starch glycolate and kneading the same. The tamsulosin granule was tableted using a Comil grinder equipped with a screen having a mesh size of 1.016-1.27 mm.

A mixture was obtained by mixing the tamsulosin granule with magnesium stearate and colloidal silicon dioxide.

A tadalafil mixture was obtained by homogeneously mixing tadalafil, lactose hydrate, hydroxypropyl cellulose, sodium lauryl sulfate, microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide.

A post-mixture was obtained by mixing the muscarinic receptor antagonist mixture with lactose hydrate and pregelatinized starch and then adding an excipient containing magnesium stearate and silicon dioxide.

A circular triple-layered tablet was obtained by tableting the tamsulosin granule, the tadalafil mixture and the solifenacin mixture into a triple-layered tablet.

The ingredients and compositions used for the preparation are described in Table 17.

Ingredients (mg)	Ex. 137	Ex. 138	Ex. 139	Ex. 140	Ex. 141	Ex. 142	Ex. 143	Ex. 144
Tamsulosin hydrochloride	0.2	0.2	0.2	0.2	0.2	0.2	0.2	0.2
Hydroxypropylmethyl cellulose	10	18	26	34	42	50	58	65
Hydroxypropylmethyl cellulose acetate succinate	20	32	44	56	68	80	92	100
Microcrystalline cellulose	65	65	65	65	65	65	65	65
Lactose	145	125	105	85	65	45	25	10
Sodium starch glycolate	25	25	25	25	25	25	25	25
Magnesium stearate	10	10	10	10	10	10	10	10
Colloidal silicon dioxide	7.5	7.5	7.5	7.5	7.5	7.5	7.5	7.5
Solifenacin succinate	5	5	5	5	5	5	5	5
Lactose hydrate	99	99	99	99	99	99	99	99
Pregelatinized starch	40	40	40	40	40	40	40	40
Silicon dioxide	3	3	3	3	3	3	3	3
Tadalafil	5	5	5	5	5	5	5	5
Hydroxypropyl cellulose	4	4	4	4	4	4	4	4
Microcrystalline cellulose	9	9	9	9	9	9	9	9
Sodium lauryl sulfate	0.5	2	3.5	5	6.5	8	9.5	11
Lactose hydrate	138.5	137	135.5	134	132.5	131	129.5	128
Sodium starch glycolate	14	14	14	14	14	14	14	14
Magnesium stearate	2	2	2	2	2	2	2	2
Silicon dioxide	2	2	2	2	2	2	2	2

Examples 145-152. Multiple-layered tablet compositions

A tamsulosin hydrochloride granule prepared in the same manner as in Example 13 was tableted by post-mixing. A coating solution prepared by mixing tadalafil with hydroxypropyl cellulose and sodium lauryl sulfate and dissolving in a mixed solvent of ethanol and water was coated on the tamsulosin hydrochloride tablet.

In addition, a coating solution prepared by dissolving solifenacin succinate in a mixed solvent of ethanol and water with hydroxypropyl cellulose was spray-coated on the tablet.

The ingredients and compositions used for the preparation are described in Table 18.

Ingredients (mg)	Ex. 145	Ex. 146	Ex. 147	Ex. 148	Ex. 149	Ex. 150	Ex. 151	Ex. 152
Tamsulosin hydrochloride plain tablet	O	O	O	O	O	O	O	O
Tadalafil coating solution	O	O	-	-	O	O	-	-
Blocking layer	-	O	-	O	-	O	-	O
Solifenacin coating solution	O	O	-	-	O	O	-	-
Tadalafil + solifenacin coating solution	-	-	O	O	-	-	O	O
Outer blocking layer	-	-	-	-	O	O	O	O

Comparative Example 1. Simple-mix tablet

Tamsulosin hydrochloride 0.2 mg

Solifenacin succinate 5.0 mg

Tadalafil 5.0 mg

Hydroxypropylmethyl cellulose 30.0 mg

Hydroxypropylmethyl cellulose acetate succinate 45.0 mg

Microcrystalline cellulose 50.0 mg

Lactose 40.0 mg

Magnesium stearate 3.0 mg

Colloidal silicon dioxide 3.0 mg

A PDE-5 inhibitor such as tamsulosin hydrochloride and tadalafil, a muscarinic receptor antagonist such as solifenacin succinate, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, microcrystalline cellulose and lactose were homogeneously mixed for 5 minutes. After adding magnesium stearate and colloidal silicon dioxide and mixing for 5 minutes, the mixture was tableted directly into a circular tablet.

Comparative Example 2. Simple-mix formulation containing tamsulosin hydrochloride

Tamsulosin hydrochloride was homogeneously mixed with an excipient mixture containing hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose, microcrystalline cellulose, lactose and sodium starch glycolate for 5 minutes.

The tamsulosin mixture was post-mixed with magnesium stearate and colloidal silicon dioxide.

A tadalafil granule was prepared by adding a binder solution in which hydroxypropyl cellulose and sodium lauryl sulfate are dissolved in dilute ethanol to an excipient mixture containing tadalafil and lactose hydrate and kneading the same.

A post-mixture was obtained by mixing the tadalafil granule with an excipient containing microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide.

A mixture containing solifenacin was obtained by dispersing solifenacin in an excipient mixture containing lactose hydrate.

A circular triple-layered tablet was obtained by tableting the tamsulosin mixture, the tadalafil granule and the solifenacin mixture into a triple-layered tablet.

The ingredients and compositions used for the preparation were the same as in Example 13.

Comparative Example 3. Tamsulosin hydrochloride formulation using hydroxyethyl cellulose

Tamsulosin hydrochloride was dissolved in a mixed solvent of ethanol and methylene chloride and a binder solution was prepared by dissolving hydroxypropylmethyl cellulose acetate succinate. A tamsulosin granule was obtained by adding the binder solution to an excipient mixture containing hydroxyethyl cellulose, microcrystalline cellulose, lactose hydrate and sodium starch glycolate and then kneading the same.

The ingredients and compositions used for the preparation are described in Table 19.

Ingredients (mg)	Comparative Example 3
Tamsulosin hydrochloride	0.2
Hydroxypropylmethyl cellulose acetate succinate	56
Hydroxyethyl cellulose	38
Microcrystalline cellulose	65
Lactose hydrate	65
Sodium starch glycolate	20
Magnesium stearate	7.5
Colloidal silicon dioxide	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06
Tadalafil	5
Hydroxypropyl cellulose	4
Microcrystalline cellulose	9
Sodium lauryl sulfate	2
Lactose hydrate	137
Sodium starch glycolate	14
Magnesium stearate	2
Silicon dioxide	2
Mixed organic solvent (70% ethanol)	0.01
Solifenacin succinate	5
Lactose hydrate	90
Pregelatinized starch	40
Silicon dioxide	3
Magnesium stearate	3

Comparative Example 4. Tamsulosin hydrochloride formulation using EudragitL 100-55

Tamsulosin hydrochloride was dissolved in a mixed solvent of ethanol and methylene chloride and a binder solution was prepared by dissolving EudragitL 100-55. A tamsulosin granule was obtained by adding the binder solution to an excipient mixture containing Eudragit　L 100-55, hydroxypropylmethyl cellulose, microcrystalline cellulose, lactose hydrate and sodium starch glycolate and then kneading the same.

The ingredients and compositions used for the preparation are described in Table 20.

Ingredients (mg)	Comparative Example 4
Tamsulosin hydrochloride	0.2
Eudragit L 100-55	56
Hydroxypropylmethyl cellulose	38
Microcrystalline cellulose	65
Lactose hydrate	65
Sodium starch glycolate	20
Magnesium stearate	7.5
Colloidal silicon dioxide	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06
Tadalafil	5
Hydroxypropyl cellulose	4
Microcrystalline cellulose	9
Sodium lauryl sulfate	2
Lactose hydrate	137
Sodium starch glycolate	14
Magnesium stearate	2
Silicon dioxide	2
Mixed organic solvent (70% ethanol)	0.01
Solifenacin succinate	5
Lactose hydrate	90
Pregelatinized starch	40
Silicon dioxide	3
Magnesium stearate	3

Comparative Example 5. Tamsulosin hydrochloride formulation using hydroxyethyl cellulose and Eudragit L 100-55

Tamsulosin hydrochloride was dissolved in a mixed solvent of ethanol and methylene chloride and a binder solution was prepared by dissolving EudragitL 100-55. A tamsulosin granule was obtained by adding the binder solution to an excipient mixture containing hydroxyethyl cellulose, microcrystalline cellulose, lactose hydrate and sodium starch glycolate and then kneading the same.

The ingredients and compositions used for the preparation are described in Table 21.

Ingredients (mg)	Comparative Example 5
Tamsulosin hydrochloride	0.2
Eudragit L 100-55	56
Hydroxyethyl cellulose	38
Microcrystalline cellulose	65
Lactose hydrate	65
Sodium starch glycolate	20
Magnesium stearate	7.5
Colloidal silicon dioxide	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06
Tadalafil	5
Hydroxypropyl cellulose	4
Microcrystalline cellulose	9
Sodium lauryl sulfate	2
Lactose hydrate	137
Sodium starch glycolate	14
Magnesium stearate	2
Silicon dioxide	2
Mixed organic solvent (70% ethanol)	0.01
Solifenacin succinate	5
Lactose hydrate	90
Pregelatinized starch	40
Silicon dioxide	3
Magnesium stearate	3

Comparative Example 6. Tamsulosin hydrochloride formulation using Eudragit L 30 D-55

Tamsulosin hydrochloride was dissolved in a mixed solvent of ethanol and methylene chloride and a binder solution was prepared by dissolving EudragitL 30 D-55. A tamsulosin granule was obtained by adding the binder solution to an excipient mixture containing hydroxypropylmethyl cellulose, microcrystalline cellulose, lactose hydrate and sodium starch glycolate and then kneading the same.

The ingredients and compositions used for the preparation are described in Table 22.

Ingredients (mg)	Comparative Example 6
Tamsulosin hydrochloride	0.2
Eudragit L 30 D-55	56
Hydroxyethyl cellulose	38
Microcrystalline cellulose	65
Lactose hydrate	65
Sodium starch glycolate	20
Magnesium stearate	7.5
Colloidal silicon dioxide	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06
Tadalafil	5
Hydroxypropyl cellulose	4
Microcrystalline cellulose	9
Sodium lauryl sulfate	2
Lactose hydrate	137
Sodium starch glycolate	14
Magnesium stearate	2
Silicon dioxide	2
Mixed organic solvent (70% ethanol)	0.01
Solifenacin succinate	5
Lactose hydrate	90
Pregelatinized starch	40
Silicon dioxide	3
Magnesium stearate	3

Comparative Examples 7-9. Tamsulosin hydrochloride formulations with different particle sizes

Tamsulosin hydrochloride was dissolved in a mixed solvent of ethanol and methylene chloride and a binder solution was prepared by dissolving hydroxypropylmethyl cellulose acetate succinate. A tamsulosin granule was obtained by adding the binder solution to an excipient mixture containing hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, microcrystalline cellulose, lactose hydrate and sodium starch glycolate and then kneading the same. The tamsulosin granule was tableted using Comil grinders equipped with screens having various mesh sizes.

The ingredients and compositions used for the preparation were the same as in Example 28. The mesh sizes of the screens of the Comil grinders are described in Table 23.

	Comparative Example 7	Comparative Example 8	Comparative Example 9
Mesh size of screen	3.692 mm	1.575 mm	0.610 mm
Particle size distribution	≥ 3.35 mm81.5%	≥ 1.4 mm72.9%	≤ 500 μm90.1%

Comparative Example 10. Simple-mix tadalafil formulation prepared without using sodium lauryl sulfate

Tamsulosin hydrochloride was dissolved in a mixed solvent of ethanol and methylene chloride and a binder solution was prepared by dissolving hydroxypropylmethyl cellulose acetate succinate. A tamsulosin granule was obtained by adding the binder solution to an excipient mixture containing hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate succinate, microcrystalline cellulose, lactose hydrate and sodium starch glycolate and then kneading the same.

A tadalafil mixture was obtained by homogeneously mixing an excipient mixture containing tadalafil and lactose hydrate for 5 minutes.

A post-mixture was obtained by mixing the tadalafil mixture with an excipient containing hydroxypropyl cellulose, microcrystalline cellulose, sodium starch glycolate, magnesium stearate and silicon dioxide.

The ingredients and compositions used for the preparation are described in Table 24.

Ingredients (mg)	Comparative Example 10
Tamsulosin hydrochloride	0.2
Hydroxypropylmethyl cellulose	35
Hydroxypropylmethyl cellulose acetate succinate	60
Microcrystalline cellulose	65
Lactose hydrate	65
Sodium starch glycolate	20
Magnesium stearate	7.5
Colloidal silicon dioxide	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06
Tadalafil	5
Hydroxypropyl cellulose	4
Microcrystalline cellulose	9
Lactose hydrate	137
Sodium starch glycolate	14
Magnesium stearate	2
Silicon dioxide	2
Solifenacin succinate	5
Lactose hydrate	90
Pregelatinized starch	40
Silicon dioxide	3
Magnesium stearate	3

Comparative Example 11. Tadalafil formulation prepared by wet granulation without using sodium lauryl sulfate

A tadalafil granule was prepared by adding a binder solution in which hydroxypropyl cellulose is dissolved in dilute ethanol to an excipient mixture containing tadalafil and lactose hydrate and kneading the same.

The ingredients and compositions used for the preparation are described in Table 25.

Ingredients (mg)	Comparative Example 11
Tamsulosin hydrochloride	0.2
Hydroxypropylmethyl cellulose	35
Hydroxypropylmethyl cellulose acetate succinate	60
Microcrystalline cellulose	65
Lactose hydrate	65
Sodium starch glycolate	20
Magnesium stearate	7.5
Colloidal silicon dioxide	7.5
Mixed organic solvent (ethanol:methylene chloride = 1:1)	0.06
Tadalafil	5
Hydroxypropyl cellulose	4
Microcrystalline cellulose	9
Lactose hydrate	137
Sodium starch glycolate	14
Magnesium stearate	2
Silicon dioxide	2
Mixed organic solvent (70% ethanol)	0.01
Solifenacin succinate	5
Lactose hydrate	90
Pregelatinized starch	40
Silicon dioxide	3
Magnesium stearate	3

Test Example 1. Tamsulosin hydrochloride dissolution test

Dissolution test was conducted to evaluate the dissolution behavior of tamsulosin for the examples and comparative examples. The result is given in Tables 26-30 and FIG. 1.

Table 26 shows the test result for Examples 1-24.

Sample		Ex. 1	Ex. 2	Ex. 4	Ex. 5	Ex. 7	Ex. 8	Ex. 9	Ex. 10	Ex. 17	Ex. 24
Tamsulosin dissolution rate (%)	2 hr	35.1	29.7	25.2	23.3	21.2	20.1	23.1	27.4	34.8	25.6
	3 hr	70.3	67.2	61.3	59.8	58.9	51.1	57.5	56.6	69.4	56.4
	5 hr	92.3	89.4	85.1	82.9	81.5	81.6	80.3	79.5	91.2	79.6

Table 27 shows the test result for Examples 25-122.

Sample		Ex. 25	Ex. 26	Ex. 27	Ex. 28	Ex. 29	Ex. 30	Ex. 31	Ex. 32	Ex. 121	Ex. 122
Tamsulosin dissolution rate (%)	2 hr	33.4	30.9	27.2	24.1	22.3	21.7	20.1	19.8	25.0	26.2
	3 hr	69.8	67.7	63.2	60.9	58.9	54.9	51.5	50.6	60.7	61.5
	5 hr	92.1	89.1	85.4	81.4	81.5	80.1	80.7	79.9	84.3	83.3

Table 28 shows the test result for Examples 123-135.

Sample		Ex. 123	Ex. 124	Ex. 125	Ex. 126	Ex. 127	Ex. 128	Ex. 129	Ex. 130	Ex. 134	Ex. 135
Tamsulosin dissolution rate (%)	2 hr	25.7	27.9	27.1	34.1	32.2	29.7	27.2	25.3	27.6	24.9
	3 hr	61.8	61.2	61.3	62.1	66.9	65.6	64.7	60.8	61.0	63.7
	5 hr	82.2	80.1	84.2	89.3	86.3	85.1	81.3	80.7	83.4	81.7

Table 29 shows the test result for Examples 137-152.

Sample		Ex. 137	Ex. 140	Ex. 145	Ex. 146	Ex. 147	Ex. 148	Ex. 149	Ex. 150	Ex. 151	Ex. 152
Tamsulosin dissolution rate (%)	2 hr	26.8	27.1	26.2	25.8	26.1	25.7	25.1	25.9	25.1	25.0
	3 hr	62.7	61.9	60.8	59.1	61.2	60.7	59.7	62.8	60.2	59.3
	5 hr	83.1	81.2	82.5	82.8	83.1	81.1	81.5	82.7	82.1	81.2

Table 30 shows the test result for Comparative Examples 1-9.

Sample		Comp. Ex. 1	Comp. Ex. 2	Comp. Ex. 3	Comp. Ex. 4	Comp. Ex. 5	Comp. Ex. 6	Comp. Ex. 7	Comp. Ex. 8	Comp. Ex. 9
Tamsulosin dissolution rate (%)	2 hr	42.5	49.5	40.4	51.6	51.2	49.7	11.2	18.4	40.7
	3 hr	72.8	75.1	78.9	71.8	70.1	79.5	41.2	43.2	71.2
	5 hr	98.7	89.9	98.9	90.6	99.7	98.8	67.8	71.1	97.6

As seen from Tables 26-30, the tablets of the examples showed the dissolution rate maintained low under acidic conditions as the contents of the enteric polymer hydroxypropylmethyl cellulose acetate succinate and the release-controlling polymer hydroxypropylmethyl cellulose are higher. They exhibited suitable dissolution rates of 12-39%, 44-70% and 70% or higher at 2, 3 and 5 hours, respectively.

Test Example 2. Tadalafil dissolution test

Dissolution test was conducted to evaluate the dissolution behavior of tadalafil for the examples and comparative examples. The result is given in Tables 31-35 and FIG. 2.

Table 31 shows the test result for Examples 1-24.

Sample		Ex. 1	Ex. 2	Ex. 4	Ex. 5	Ex. 7	Ex. 8	Ex. 9	Ex. 10	Ex. 17	Ex. 24
Tadalafil dissolution rate (%)	10 min	61.5	60.1	62.1	59.8	60.2	61.7	59.9	64.1	60.1	65.1
Tadalafil dissolution rate (%)	30 min	91.5	90.7	92.8	91.0	90.1	88.9	92.9	93.1	91.6	94.3

Table 32 shows the test result for Examples 25-122.

Sample		Ex. 25	Ex. 26	Ex. 27	Ex. 28	Ex. 29	Ex. 30	Ex. 31	Ex. 32	Ex. 121	Ex. 122
Tadalafil dissolution rate (%)	10 min	62.4	65.1	68.3	69.8	65.7	62.4	64.7	65.4	62.8	62.2
Tadalafil dissolution rate (%)	30 min	90.2	95.1	93.1	92.4	91.2	92.2	93.5	92.7	93.2	91.2

Table 33 shows the test result for Examples 123-135.

Sample		Ex. 123	Ex. 124	Ex. 125	Ex. 126	Ex. 127	Ex. 128	Ex. 129	Ex. 130	Ex. 134	Ex. 135
Tadalafil dissolution rate (%)	10 min	62.1	61.7	62.5	61.3	61.4	63.4	61.4	64.4	67.1	63.2
Tadalafil dissolution rate (%)	30 min	90.3	92.4	94.3	91.5	95.1	98.1	93.4	93.3	94.2	96.5

Table 34 shows the test result for Examples 137-144.

Sample		Ex. 137	Ex. 138	Ex. 139	Ex. 140	Ex. 141	Ex. 142	Ex. 143	Ex. 144
Tadalafil dissolution rate (%)	10 min	62.7	62.1	60.8	61.1	60.1	64.7	61.8	63.5
Tadalafil dissolution rate (%)	30 min	91.2	91.7	93.3	93.2	91.3	97.8	91.9	92.2

Table 35 shows the test result for Comparative Examples 10-11.

Sample		Comp. Ex. 10	Comp. Ex. 11
Tadalafil dissolution rate (%)	10 min	20.1	19.5
Tadalafil dissolution rate (%)	30 min	52.8	55.1

As seen from Tables 31-35, the tablets of the examples exhibited tadalafil dissolution rates of 40% at 10 minutes and 75% or higher at 30 minutes.

Test Example 3. Solifenacin succinate dissolution test

Dissolution test was conducted to evaluate the dissolution behavior of solifenacin succinate for the examples and comparative examples. The result is given in Tables 36-39.

Table 36 shows the test result for Examples 1-24.

Sample		Ex. 1	Ex. 2	Ex. 4	Ex. 5	Ex. 7	Ex. 8	Ex. 9	Ex. 10	Ex. 17	Ex. 24
Solifenacin dissolution rate (%)	30 min	92.7	91.8	96.4	95.1	95.9	94.8	95.7	92.9	93.2	94.1

Table 37 shows the test result for Examples 25-122.

Sample		Ex. 25	Ex. 26	Ex. 27	Ex. 28	Ex. 29	Ex. 30	Ex. 31	Ex. 32	Ex. 121	Ex. 122
Solifenacin dissolution rate (%)	30 min	94.5	92.4	93.7	99.1	94.5	94.5	94.5	96.5	98.1	91.7

Table 38 shows the test result for Examples 123-135.

Sample		Ex. 123	Ex. 124	Ex. 125	Ex. 126	Ex. 127	Ex. 128	Ex. 129	Ex. 130	Ex. 134	Ex. 135
Solifenacin dissolution rate (%)	30 min	91.7	93.7	91.4	93.7	92.6	94.2	94.1	93.1	93.5	96.7

Table 39 shows the test result for Comparative Example 1.

Sample		Comparative Example 1
Solifenacin dissolution rate (%)	30 min	71.5

As seen from Tables 36-39, the tablets of the examples exhibited solifenacin dissolution rates of 90% or higher at 30 minutes. Accordingly, it can be seen that the tablets of the examples exhibit immediate release behaviors as compared to the tablets of the comparative examples.

Test Example 4. Tamsulosin hydrochloride dissolution rate depending on granule particle size

The tamsulosin hydrochloride dissolution rate of the tablets tableted with Comil grinders of different mesh sizes was evaluated.

Sample		Ex. 25	Ex. 27	Ex. 29	Ex. 31	Ex. 32	Ex. 121	Ex. 122	Comp. Ex. 7	Comp. Ex. 8	Comp. Ex. 9
% of granules 850 μm or smaller		90.9	91.3	74.8	89.1	81.0	78.9	83.5	7.5	15.3	99.5
Tamsulosin dissolution rate (%)	2 hr	33.4	27.2	22.3	20.1	19.8	25.0	26.2	11.2	18.4	40.7
	3 hr	69.8	63.2	58.9	51.5	50.6	60.7	61.5	41.2	43.2	71.2
	5 hr	92.1	85.4	81.5	80.7	79.9	84.3	83.3	67.8	71.1	97.6

As seen from Table 40, the tablets of the examples showed 70% or more granules with particle size of 850 μm or smaller and exhibited sustained release behaviors in the tamsulosin hydrochloride dissolution rate.

Claims

An agent for preventing or treating urinary disease, comprising:

a first drug layer comprising a granule formed by mixing tamsulosin or a pharmaceutically acceptable salt thereof, a release-controlling polymer and an enteric polymer;

at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof; and

at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof.
The agent for preventing or treating urinary disease according to claim 1, wherein the first drug layer comprises the muscarinic receptor antagonist and a second drug layer comprises the PDE-5 inhibitor.
The agent for preventing or treating urinary disease according to claim 1, wherein a second drug layer comprises the PDE-5 inhibitor and a third drug layer comprises the muscarinic receptor antagonist.
The agent for preventing or treating urinary disease according to claim 1, which comprises the PDE-5 inhibitor and the muscarinic receptor antagonist and comprises a second drug layer coated outside the first drug layer.
The agent for preventing or treating urinary disease according to claim 1, wherein the release-controlling polymer is one or more compound selected from hydroxypropylmethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, polypropylene oxide, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate, polymethacrylate, glycerol monostearate and poloxamer.
The agent for preventing or treating urinary disease according to claim 1, wherein the enteric polymer is one or more selected from hydroxypropylmethyl cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate, hydroxymethylethyl cellulose phthalate, cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methyl cellulose phthalate, carboxymethylethyl cellulose, ethylhydroxyethyl cellulose phthalate, a styrene-acrylic acid copolymer, a methyl acrylate-acrylic acid copolymer, a methyl methacrylate-acrylic acid copolymer, a butyl acrylate-styrene-acrylic acid copolymer, a methacrylic acid-ethyl acrylate copolymer, a methyl acrylate-methacrylic acid-octyl acrylate copolymer, a vinyl acetate-maleic anhydride copolymer, an ethylene-maleic anhydride copolymer, a vinyl butyl ether-maleic anhydride copolymer, an acrylonitrile-methyl acrylate-maleic anhydride copolymer, a butyl acrylate-styrene-maleic anhydride copolymer, polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butylate phthalate and polyvinyl acetate acetal phthalate.
A method for preparing an agent for preventing or treating urinary disease, comprising:

a step of preparing a tamsulosin granule by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer;

a step of preparing a mixture by mixing the tamsulosin granule with at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof and an excipient;

a step of preparing a PDE-5 inhibitor granule by mixing at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof with an excipient;

a step of preparing a first drug layer by tableting the mixture; and

a step of preparing a second drug layer by tableting the PDE-5 inhibitor granule.
A method for preparing an agent for preventing or treating urinary disease, comprising:

a step of preparing a tamsulosin granule by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer;

a step of preparing a PDE-5 inhibitor granule by mixing at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof with an excipient;

a step of preparing a muscarinic receptor antagonist mixture by mixing at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof with an excipient;

a step of preparing a first drug layer by tableting the tamsulosin granule;

a step of preparing a second drug layer by tableting the PDE-5 inhibitor granule or the mixture; and

a step of preparing a third drug layer by tableting the muscarinic receptor antagonist mixture.
A method for preparing an agent for preventing or treating urinary disease, comprising:

a step of preparing a tamsulosin granule by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer;

a step of preparing a first coating solution comprising at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof;

a step of preparing a second coating solution comprising at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof;

a step of preparing a tablet by tableting the tamsulosin granule; and

a step of coating the first coating solution and the second coating solution on the tablet.
A method for preparing an agent for preventing or treating urinary disease, comprising:

a step of preparing a tamsulosin granule by mixing tamsulosin or a pharmaceutically acceptable salt thereof with a release-controlling polymer and an enteric polymer;

a step of preparing a coating solution comprising at least one PDE-5 inhibitor of tadalafil, sildenafil citrate, udenafil, mirodenafil and a pharmaceutically acceptable salt thereof and at least one muscarinic receptor antagonist of solifenacin, tolterodine, oxybutynin and a pharmaceutically acceptable salt thereof;

a step of preparing a tablet by tableting the tamsulosin granule; and

a step of coating the coating solution on the tablet.