Pharmaceutical composition comprising tadalafil or pharmaceuticallly acceptable salt thereof and dutasteride or pharmaceuticallly acceptable salt thereof exhibiting novel dissolution rate

Abstract

To provide a pharmaceutical composition comprising, as active ingredients, tadalafil and dutasteride, having a strong in vitro in vivo correlation under specific dissolution conditions between in vitro dissolution test results and in vivo absorption pattern.SOLUTION: Provided is a pharmaceutical composition comprising as active ingredients: 5 mg of tadalafil or a pharmaceutically acceptable salt thereof and 0.5 mg of dutasteride or a pharmaceutically acceptable salt thereof, wherein the dissolution rate of tadalafil under the dissolution conditions of a paddle rate of 50 rpm in 500 mL of a dissolution solution having a pH of 1.2 and containing 0.25% of SLS is 60-75% after 5 minutes and 80% or more after 30 minutes, and the dissolution rate of dutasteride under the dissolution conditions of a paddle rate of 50 rpm in 500 mL of a dissolution solution containing water and 0.1% of SLS is 50% or more after 15 minutes and 85% or more after 30 minutes.SELECTED DRAWING: Figure 5

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition exhibiting a novel dissolution rate. More specifically, the present invention relates to a pharmaceutical composition containing tadalafil or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as "tadalafil") and dutasteride or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as "dutasteride") as active ingredients. Further, in the present invention, in a pharmaceutical composition containing tadalafil and dutasteride as active ingredients, a method capable of easily predicting in vivo absorption through an in vitro dissolution test is also provided. Furthermore, the present invention relates to a pharmaceutical composition containing tadalafil-containing granules and dutasteride-containing granules having a specific particle size distribution in order to exhibit such a dissolution rate.

Background Art

[0002] Korean Registered Patent No. 1745425 discloses an oral composite emulsion composition containing dutasteride and tadalafil. The emulsion composition disclosed in the same document contains two types of drugs, dutasteride and tadalafil, in one unit dosage form, but has no problem of reduced stability, is convenient for production, reduces an unpleasant pill burden, shows drug dissolution equivalent to that of each single preparation and the same medicinal effect, and enables simultaneous treatment of erectile dysfunction and benign prostatic hyperplasia, and thus has an effect of enhancing the compliance of patients with taking medicine.

[0003] Korean Registered Patent No. 1712524 relates to a composite preparation composition containing a tadalafil preparation and a dutasteride preparation, and a method for producing the same. In the same document, a mixed solution containing dutasteride, diethylene glycol monoethyl ether, mono / diglyceride, and polyoxyl castor oil and an adsorbent are included, and the mixed solution is adsorbed to the adsorbent, and a suspension containing tadalafil, a surfactant, a water-soluble polymer, and a solvent is produced and granulated, and a composite preparation composition produced by mixing the granulated tadalafil preparation is disclosed, and a method for producing the same.

[0004] Korean Patent Registration No. 1780739 discloses a combined preparation containing a phosphodiesterase 5 inhibitor, such as tadalafil, as a first active ingredient and a 5-α-reductase inhibitor, such as dutasteride, as a second active ingredient. In this document, it is a technical feature to include a 5-α-reductase inhibitor in the coating layer, and by including both two types of therapeutic drugs for benign prostatic hyperplasia with different pharmacological mechanisms in one preparation to provide a synergistic effect in the treatment and relief of benign prostatic hyperplasia, the effect is to increase the medication compliance of patients.

[0005] However, in any of the above documents, there is no specific mention of the correlation between in vitro dissolution tests and in vivo absorption behavior in a pharmaceutical composition containing tadalafil and dutasteride as active ingredients, nor is there a disclosure of the configuration for this.

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Patent Document 3

Non-Patent Documents

[0007]

Non-Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0008] By investigating the correlation between the in vitro dissolution pattern and the in vivo absorption profile of a pharmaceutical composition (combination agent) containing tadalafil and dutasteride as active ingredients, the in vivo absorption patterns of each active ingredient from a single agent containing tadalafil as an active ingredient and a single agent containing dutasteride as an active ingredient are made the same as those of each active ingredient from the combination agent composition. The problem to be solved is to derive the dissolution conditions and dissolution rates. Thereby, it aims to provide a pharmaceutical composition containing tadalafil and dutasteride as active ingredients that has a strong correlation (hereinafter abbreviated as "IVIVC (in vitro in vivo correlation)") between the results of in vitro dissolution tests and in vivo absorption profiles under specific dissolution conditions.

Means for Solving the Problems

[0009] In a pharmaceutical composition containing 5 mg of tadalafil or a pharmaceutically acceptable salt thereof and 0.5 mg of dutasteride or a pharmaceutically acceptable salt thereof as active ingredients, the dissolution rate of tadalafil is 60 - 75% in 5 minutes and 80% or more in 30 minutes under dissolution conditions where the paddle speed is 50 rpm in 500 mL of a dissolution medium containing 0.25% sodium lauryl sulfate (SLS) at pH 1.2, and the dissolution rate of dutasteride is 50% or more in 15 minutes and 85% or more in 30 minutes under dissolution conditions where the paddle speed is 50 rpm in 500 mL of a dissolution medium containing water and 0.1% SLS. The above problems are solved by providing a pharmaceutical composition characterized by this. As one specific means for showing the dissolution rate, the particle size of the tadalafil-containing granules may be adjusted so that D10 is 30 μm or less, D50 is 70 - 130 μm, and D90 is 250 - 350 μm, and the particle size of the dutasteride-containing granules may be adjusted so that D10 is 15 μm or less, D50 is 25 - 40 μm, and D90 is 90 - 150 μm.

Effects of the Invention

[0010] When manufacturing a pharmaceutical composition containing tadalafil and dutasteride as active ingredients, by deriving dissolution conditions and dissolution rates that can accurately predict in vitro absorption profiles, the formulation and development period of pharmaceuticals can be shortened. Furthermore, by improving the dissolution rate of each single component, the therapeutic effect is maximized.

Brief Description of the Drawings

[0011]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Modes for Carrying Out the Invention

[0012] In the process of pharmaceutical development, in vitro tests, animal tests, and in vivo tests on humans are involved. This is the same not only in the development process of new drugs but also when developing so-called dossier pharmaceuticals or generic pharmaceuticals called improved new drugs.

[0013] Efforts to reduce in vivo tests on humans are actively being made based on scientific grounds. As part of this, efforts to replace in vivo tests with in vitro tests are being actively carried out both at home and abroad. However, the drug elution and absorption processes from pharmaceuticals administered in vivo occur in a complex system involving various physiological substances, and the in vivo influencing factors on drug absorption are also very diverse. Therefore, there are limitations to evaluating the pharmacokinetics of drugs only by in vitro test methods. Accordingly, research on in vitro test conditions that can most appropriately reflect the in vivo state through the study of in vivo-in vitro correlations is necessary. The results of the development and evaluation of IVIVC correlations should be able to establish the method of dissolution test as a surrogate indicator for bioequivalence tests on humans, and based on this, reduce the number of bioequivalence tests to be conducted in the process of scale-up production, post-approval changes, and the initial approval process. In vitro dissolution tests are important for process control and quality assurance, confirmation of the stable release characteristics of products over the entire time period, and making certain regulatory decisions in the case of minor formulation changes or changes in the manufacturer. In the case of orally administered controlled-release formulations, dissolution tests can also be used as an indicator for quality control in the manufacturing process and the in vivo pharmacokinetic aspects of the formulation.

[0014] The present invention relates to a pharmaceutical composition containing tadalafil and dutasteride as active ingredients. Tadalafil is the active ingredient of a pharmaceutical product commercially available as Cialis (registered trademark) (trade name) and has the structure of Chemical Formula 1 below.

[0015] [Chemical Formula]

[0016] Tadalafil is a selective and reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (hereinafter, PDE-5). Tadalafil is said to be usable for the treatment of erectile dysfunction and benign prostatic hyperplasia or for the treatment of patients with a combination of erectile dysfunction and benign prostatic hyperplasia.

[0017] Dutasteride is the active ingredient of a pharmaceutical product marketed as Avodart (registered trademark) (trade name) and has the structure of Chemical Formula 2 below.

[0018]

Chemical formula

[0019] Dutasteride is a dual 5-α reductase inhibitor that inhibits both type 1 and type 2 of 5-α reductase, and is known to be effectively usable for the treatment of benign prostatic hyperplasia, prostate cancer, and male pattern hair loss by inhibiting the conversion of testosterone to dihydrotestosterone (DHT).

[0020] Benign prostatic hyperplasia is a very common disease in which the size of the prostate increases with age and causes abnormalities in various urinary functions. For the treatment of benign prostatic hyperplasia, although it is effective to administer a 5-α reductase inhibitor, which is a drug that reduces the size of the prostate, the improvement effect may not appear immediately. As a result, it may be administered in combination with other drugs for symptom improvement, and tadalafil is included in other drugs. Therefore, by providing a composite agent containing dutasteride and tadalafil as active ingredients, it is possible to reduce the size of the prostate and expect an effect of improving symptoms.

[0021] In the production of a combined preparation that combines the active ingredients of two single preparations, which are already known and commercially available under the approval of a pharmaceutical regulatory authority, into one dosage form, it is necessary to ensure that the in-vivo absorption profile of the active ingredients contained in the combined preparation is equivalent to that of the active ingredients of the single preparations that have already obtained approval. And such matters must be confirmed by clinical trials involving human subjects. However, even if they are the same active ingredient, the patterns of drug elution and absorption from a single preparation and from a combined preparation are often not the same. Therefore, even if a dissolution test is simply conducted to adjust the dissolution rate of the active ingredient from the single preparation and the dissolution rate of the active ingredient from the combined preparation to be equivalent, the in-vivo absorption profiles in actual clinical trials often differ. As a result, it becomes necessary to repeatedly conduct formulation design through multiple clinical trials, and the associated cost and time consumption become one of the most significant obstacle factors encountered in the development process of combined preparations.

[0022] According to the guidance of the US Food and Drug Administration (FDA) published in September 1997, the purpose of conducting research on IVIVC is to enable dissolution, solubility, and intestinal membrane permeability tests to be used as alternative methods for bioavailability tests. That is, if IVIVC is established, after the approval of a pharmaceutical product, it is possible to ensure biological equivalence between the two formulations through dissolution tests when expanding production volume or changing additives. On the other hand, although dissolution tests are widely used for the quality control of oral solid preparations in domestic testing institutions, in many cases, it is not possible to accurately predict in-vivo pharmacokinetics based solely on such in-vitro dissolution test data. Moreover, in the case of combined preparations, it is still far from reality to predict the in-vitro absorption profile based on the in-vitro dissolution test results.

[0023] Under such circumstances, the inventors of the present invention have obtained the finding that in a pharmaceutical composition containing tadalafil and dutasteride, the dissolution rate under specific dissolution conditions has a strong correlation with the in-vitro absorption profile, and thus have completed the present invention.

[0024] Specifically, in a pharmaceutical composition containing tadalafil and dutasteride as active ingredients, under the dissolution conditions where the paddle speed is 50 rpm in 500 mL of a dissolution medium containing pH 1.2 and 0.25% SLS, the dissolution rate of tadalafil is 60 - 75% in 5 minutes and 80% or more in 30 minutes, and under the dissolution conditions where the paddle speed is 50 rpm in 500 mL of a dissolution medium containing water and 0.1% SLS, the dissolution rate of dutasteride is 50% or more in 15 minutes and 85% or more in 30 minutes. In this case, a novel finding was obtained that the in vitro absorption profiles of a single agent containing tadalafil as an active ingredient, a single agent containing dutasteride as an active ingredient, and the said pharmaceutical composition are equivalent.

[0025] In other words, when deviating from the above dissolution conditions, the pharmaceutical composition containing tadalafil and dutasteride will not have the same in vivo absorption profile as each active ingredient of the single agents containing tadalafil and dutasteride, respectively. Therefore, in the case of a pharmaceutical composition that meets the specific dissolution conditions disclosed in the present invention, it has the merit that pharmaceutical development can be carried out by investing a minimum of cost and time without repeated clinical trials.

[0026] As one technical means to exhibit the above dissolution conditions, the particle size distribution of the granules containing tadalafil and dutasteride can be adjusted. The pharmaceutical composition of the present invention contains granules containing tadalafil (hereinafter referred to as "tadalafil granules") and granules containing dutasteride (hereinafter referred to as "dutasteride granules"). Specifically, the tadalafil preparation is obtained by granulating a suspension containing tadalafil, a surfactant, a water-soluble polymer, and a solvent, and the dutasteride granules are obtained by dissolving them in a solution such as mono / diglyceride and / or diethylene glycol monoethyl ether, adsorbing them on an adsorbent, and granulating them.

[0027] The inventors have obtained the finding that the particle size distributions of the tadalafil granules and dutasteride granules affect the fine dissolution profiles of the pharmaceutical composition according to the present invention. Specifically, the dissolution conditions disclosed in the present invention finely adjust the dissolution profile released during a relatively short time of 30 minutes, and such a dissolution pattern can be achieved by more precisely adjusting the particle size distributions of the granules containing each active ingredient. Specifically, when the particle size of the tadalafil-containing granules is adjusted so that D10 is 30 μm or less, D50 is 70 to 130 μm, and D90 is 250 to 350 μm, and the particle size of the dutasteride-containing granules is adjusted so that D10 is 15 μm or less, D50 is 25 to 40 μm, and D90 is 90 to 150 μm, the dissolution pattern of the present invention can be expressed. D10 refers to the diameter of particles corresponding to the lower 10% of the volume cumulative in the cumulative particle size distribution by a particle size distribution meter, and D50 and D90 respectively mean the diameters of particles corresponding to 50% and 90%. The adjustment and measurement of the particle size distribution are performed by micronization methods and measurement methods widely known in this technical field. For example, as a common method known for adjusting the particle size distribution, methods such as pulverization using a microfluidizer, jet mill, Co-mill, ball mill, etc., and sizing of wet or dry granules can be mentioned. In order to confirm the adjustment of the particle size distribution, it can be measured by a laser diffraction particle size analyzer (for example, HELOS (H0184)&RODOS, R5: 0.5 / 4.5...875 μm) dry measurement method.

[0028] The pharmaceutical composition according to the present invention includes steps of manufacturing tadalafil granules by manufacturing a suspension containing tadalafil, a surfactant, a water-soluble polymer, and a solvent, dissolving dutasteride in a mixed solution of mono / diglyceride and diethylene glycol monoethyl ether, then adsorbing it on an adsorbent to produce a dutasteride adsorbate and granulating it to produce dutasteride granules, and after mixing the tadalafil granules and dutasteride granules, mixing a pharmaceutically acceptable excipient, disintegrant, and additive and filling or tableting them.

[0029] The surfactant, water-soluble polymer, adsorbent, and pharmaceutically acceptable excipient, disintegrant, diluent, and additive contained in the pharmaceutical composition of the present invention are not particularly limited as long as they satisfy the elution conditions defined in the present invention, or as long as they satisfy the particle size conditions of the granules defined in the present invention while satisfying the elution conditions, and are produced by adopting ordinary pharmaceutical dosage form techniques. For example, they can be formulated into various pharmaceutical compositions using standard pharmaceutical techniques disclosed in Remington’s The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), etc. Preferably, they may be tablets or capsules. For the surfactant, water-soluble polymer, adsorbent, and pharmaceutically acceptable excipient, disintegrant, diluent, and additive contained in the pharmaceutical composition of the present invention, reference may be made to documents such as [Handbook of PH armaceutical Excipients (Rowe, Ed., APH A Publications, 2017)]. The excipient may be present intragranularly (i.e., mixed into the granules) or extragranularly (i.e., outside the granules).

[0030] The surfactant contained in the pharmaceutical composition of the present invention can be a pharmaceutically acceptable surfactant without particular limitation. Preferably, those selected from polyoxyethylene stearates, palmitic acid esters, sodium lauryl sulfate, poloxamer, and combinations thereof can be used. More preferably, sodium lauryl sulfate can be used, but it is not necessarily limited thereto. The water-soluble polymer contained in the pharmaceutical composition of the present invention can be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and combinations thereof. The solvent referred to in the present invention can be selected from methanol, ethanol, isopropyl alcohol, purified water, and combinations thereof.

[0031] In this specification, the "mono / diglyceride" is a general term for monoglyceride, diglyceride, and mixtures thereof. In the present invention, as the adsorbent, a pharmaceutically acceptable adsorbent can be used without particular limitation. Preferably, those selected from silicon dioxide, colloidal silicon dioxide, magnesium aluminum silicate, calcium silicate, magnesium aluminometasilicate, and combinations thereof can be used. More preferably, magnesium aluminum silicate can be used.

[0032] In addition to the above components, the pharmaceutical composition according to the present invention may further contain ordinary additional pharmaceutically acceptable components, such as excipients, disintegrants, additives, and the like. Examples of pharmaceutically acceptable excipients, disintegrants, additives, etc. include, but are not limited to, calcium diphosphate, calcium sulfate, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; kaolin, powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid, magnesium stearate, and calcium stearate; calcium sulfate; mineral oil; vegetable oils such as hydrogenated vegetable oil, poppy oil, cottonseed oil, sesame oil, olive oil, corn oil, and cocoa butter; polyols such as propylene glycol, glycerin, sorbitol, inositol, mannitol, and polyethylene glycol; alginic acid; emulsifiers such as polysorbate; wetting agents such as sodium lauryl sulfate, poloxamer; coloring agents; flavoring agents; tabletting agents; stabilizers; antioxidants; preservatives, and the like.

[0033] Hereinafter, specific embodiments of the present invention will be described with examples. These examples are merely illustrative for helping the understanding of the present invention, and the scope of the rights of the present invention is not limited thereby.

[0034] Manufacture of Examples 1 to 3

[0035] A pharmaceutical composition was manufactured according to the composition described in Table 1 below. For the tadalafil granules, hydroxypropyl cellulose, sodium lauryl sulfate, and poloxamer were added to purified water and completely dissolved, and then tadalafil was added and dispersed to produce a suspension. Microcrystalline cellulose, lactose hydrate, and D-mannitol as diluents, and low-substituted hydroxypropyl cellulose and croscarmellose sodium as disintegrants were mixed, and then kneaded with the above suspension so that no problem occurred in the uniformity of the content of tadalafil through the granulation process. After drying the granulated product at a temperature of 60°C and sizing, granules containing tadalafil were produced. For the dutasteride granules, first, dutasteride was dissolved in a mixed solution of mono / diglycerides and diethylene glycol monoethyl ether to produce a solution. The mixed solution produced above was adsorbed onto colloidal silicon dioxide as an adsorbent and sodium lauryl sulfate to produce an adsorbate containing dutasteride. After mixing the tadalafil granules and dutasteride granules produced above, D-mannitol, croscarmellose sodium, and magnesium stearate were added and tableted.

[0036]

Table 1

[0037] (The numerical values described in the above table indicate the content per tablet in mg.)

[0038] The particle sizes of the tadalafil granules and dutasteride granules produced in Examples 1 to 3 are as shown in Table 2 below.

[0039]

Table 2

[0040] Manufacture of Comparative Examples 1 to 3

[0041] TIFF2025106557000006.tif122170

[0042] (The numerical values described in the above table indicate the content per tablet in mg.)

[0043] Comparative Examples 1 to 3 were produced in the same manner as in Examples 1 to 3, but the particle size distributions of the tadalafil granules and dutasteride granules in Comparative Examples 1 to 3 were adjusted as described in Table 3.

[0044]

Table 3

[0045] Experimental Example 1

[0046] Using Avodart tablets (dutasteride 0.5 mg) and Cialis tablets (tadalafil 5 mg) as Example 1, Comparative Example 1, and the reference example, dissolution was carried out under the following conditions, and the results of the dissolution rate of dutasteride are shown in Figure 1 and Table 4, and the results of the dissolution rate of tadalafil are shown in Figure 2 and Table 5.

[0047] Dissolution conditions

[0048] Water, 0.25% SLS 900 mL, 50 rpm

[0049]

Table 4

[0050]

Table 5

[0051] As is clear from Tables 4 and 5 and Figures 1 and 2 above, under the dissolution conditions of the normal base test method, there was no difference in the dissolution rate among the reference example, Example 1, and Comparative Example 1. Therefore, it is presumed that an ordinary formulation researcher would assume that both Example 1 and Comparative Example 1 are biologically equivalent to the reference example.

[0052] Experimental Example 2

[0053] PK (pharmacokinetic profile) was measured using beagle dogs as the subjects, with reference example, Example 1 and Comparative Example 1, and the changes in the blood drug concentration of tadalafil were described in Figure 3 and Table 6, and the changes in the blood drug concentration of dutasteride were described in Figure 4 and Table 7.

[0054] For the pharmacokinetic evaluation of the drug, 15 beagle dogs (5 dogs per group) were administered the following each group in a 3X3 crossover manner. However, at this time, the washout period was set to 2 weeks considering the half-life of the drug. Blood sampling was performed every 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 48 hours considering the highest blood concentrations of dutasteride and tadalafil.

[0055] [Information on test drugs]

[0056] Control group: combined administration of 1 tablet of Cialis and 1 capsule of Avodart

[0057] Test group 1: 1 tablet of Example 1

[0058] Test group 2: 1 tablet of Example 2

[0059] As is clear from Figure 3, Figure 4, Table 6, and Table 7, Example 1 was biologically equivalent to the reference example, while Comparative Example 1 was not equivalent to the reference example. Considering the results of Experimental Example 1 in which there was no difference in the dissolution rate among the reference example, Example 1, and Comparative Example 1, it can be understood that in a pharmaceutical composition containing tadalafil and dutasteride as active ingredients, there is no strong correlation between the in vitro dissolution profile and the in vivo absorption profile under the dissolution conditions of the normal base test method.

[0060] [Table 6]

[0061] [Table 7]

[0062] Experimental Example 3

[0063] Under the following elution conditions, dissolution tests were performed on Example 1, Comparative Example 1, and Reference Examples (Avodart and Cialis tablets), and the dissolution rates of tadalafil are shown in Table 8 and Figure 5, and the dissolution rates of dutasteride are shown in Table 9 and Figure 6.

[0064] Tadalafil Elution Conditions

[0065] pH 1.2, 0.25% SLS, 50 rpm, 500 mL

[0066] Dutasteride Elution Conditions

[0067] Water, 0.1% SLS, 50 rpm, 500 mL

[0068]

Table 8

[0069]

Table 9

[0070] As is clear from Table 8, Table 9, Figure 5, and Figure 6, it was confirmed that Example 1 showed dissolution rates of 60 - 75% at 5 minutes and 80% or more at 30 minutes under the tadalafil elution conditions of pH 1.2, 0.25% SLS, 50 rpm, and 500 mL, and it was found that under the dutasteride elution conditions of water, 0.1% SLS, 50 rpm, and 500 mL, it showed dissolution of 50% or more at 15 minutes and 85% or more at 30 minutes.

[0071] Experimental Example 4

[0072] Under the dissolution test conditions according to the present invention, the dissolution rates of tadalafil were measured for Example 1 and Comparative Examples 1, 2, and 3, and the results are shown in Table 10 and FIG. 7.

[0073]

Table 10

[0074] From Table 10 and FIG. 7, it was confirmed that when the particle size distribution presented in the present invention cannot be satisfied, the dissolution conditions of the present invention cannot be satisfied.

Industrial Applicability

[0075] When producing a pharmaceutical composition containing tadalafil and dutasteride as active ingredients, when using the dissolution conditions and dissolution rates disclosed in the present invention, the in-vivo absorption profiles of each active ingredient from the pharmaceutical composition can be adjusted to be equivalent to those of the active ingredient from an existing approved single agent.

Claims

1. A pharmaceutical composition comprising 5 mg of tadalafil or a pharmaceutically acceptable salt thereof, 0.5 mg of dutasteride or a pharmaceutically acceptable salt thereof, as an active ingredient, wherein the dissolution rate of tadalafil is 60 - 75% in 5 minutes and 80% or more in 30 minutes under dissolution conditions where the paddle speed is 50 rpm in 500 mL of a dissolution medium containing 0.25% SLS at pH 1.2, and the dissolution rate of dutasteride is 50% or more in 15 minutes and 85% or more in 30 minutes under dissolution conditions where the paddle speed is 50 rpm in 500 mL of a dissolution medium containing water and 0.1% SLS.

2. The pharmaceutical composition according to claim 1, characterized in that it comprises granules containing tadalafil or a pharmaceutically acceptable salt thereof, and granules containing dutasteride or a pharmaceutically acceptable salt thereof.

3. The pharmaceutical composition according to claim 2, characterized in that the particle size of the granules containing tadalafil or a pharmaceutically acceptable salt thereof is such that D10 is 30 μm or less, D50 is 70 - 130 μm, and D90 is 250 - 350 μm.

4. The pharmaceutical composition according to claim 2, characterized in that the particle size of the granules containing dutasteride or a pharmaceutically acceptable salt thereof is such that D10 is 15 μm or less, D50 is 25 - 40 μm, and D90 is 90 - 150 μm.

5. The pharmaceutical composition according to claim 3 or 4, characterized in that the tadalafil granules are granules obtained by granulating a suspension containing tadalafil, a surfactant, a water-soluble polymer, and a solvent.

6. The pharmaceutical composition according to claim 3 or 4, characterized in that the dutasteride granules are obtained by dissolving dutasteride in an oil mixture containing diethylene glycol monoethyl ether and mono / diglyceride, adsorbing the resulting solution onto an adsorbent, and then granulating.

7. The pharmaceutical composition according to claim 6, characterized in that the dutasteride granules do not contain polyoxyl castor oil.

8. The pharmaceutical composition according to claim 6, characterized in that the adsorbent is selected from silicon dioxide, colloidal silicon dioxide, magnesium aluminum metasilicate, calcium silicate, magnesium aluminosilicate, and combinations thereof.

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