Pharmaceutical compositions comprising tadalafil or a pharmaceutically acceptable salt thereof and dutasteride or a pharmaceutically acceptable salt thereof exhibiting a new dissolution rate

Abstract

There is provided 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 is 60-75% after 5 minutes and 80% or more after 30 minutes under dissolution conditions of a paddle speed of 50 rpm in 500 mL of a dissolution solution having a pH of 1.2 and containing 0.25% of SLS, and the dissolution rate of dutasteride is 50% or more after 15 minutes and 85% or more after 30 minutes under dissolution conditions of a paddle speed of 50 rpm in 500 mL of a dissolution solution containing water and 0.1% of SLS.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions exhibiting novel dissolution rates. More specifically, this invention relates to pharmaceutical compositions comprising 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. The invention also provides a method for readily predicting in vivo absorption by in vitro dissolution testing in pharmaceutical compositions comprising tadalafil and dutasteride as active ingredients. Furthermore, this invention relates to pharmaceutical compositions comprising tadalafil-containing particles and dutasteride-containing particles, the particles having a specific particle size distribution to exhibit such dissolution rates. Background Technology

[0002] Korean Patent No. 1745425 discloses a combined emulsion composition containing dutasteride and tadalafil for oral administration. The emulsion composition disclosed in this document contains both drugs (dutasteride and tadalafil) in a single unit formulation, but it does not have the problem of stability degradation, is easy to manufacture, reduces the burden of pills, and exhibits equivalent drug dissolution and the same drug effect as in single formulations, allowing for the simultaneous treatment of erectile dysfunction and benign prostatic hyperplasia, and thus increasing patient drug compliance.

[0003] Korean Patent No. 1712524 relates to a composite formulation composition comprising a tadalafil formulation and a dutasteride formulation, a composite formulation composition comprising tadalafil and dutasteride, and methods for preparing the same. This document discloses a composite formulation composition prepared by mixing a dutasteride formulation and a tadalafil formulation, and a method for preparing the same. The dutasteride formulation comprises a mixed solution containing dutasteride, diethylene glycol monoethyl ether, monoglyceride / diglyceride, and polyoxyethylene castor oil; and an adsorbent onto which the mixed solution is adsorbed. The tadalafil formulation (in particulate form) is prepared by preparing a suspension comprising tadalafil, a surfactant, a water-soluble polymer, and a solvent.

[0004] Korean Patent No. 1780739 discloses a compound formulation comprising a phosphodiesterase-5 inhibitor (e.g., tadalafil) as the first active ingredient and a 5-α-reductase inhibitor (e.g., dutasteride) as the second active ingredient. This document discloses the inclusion of a 5-α-reductase inhibitor in the coating layer as a technical feature, and its purpose is to provide a synergistic effect in treating and alleviating benign prostatic hyperplasia by containing two types of drugs with different pharmacological mechanisms in one formulation, thereby increasing patient drug compliance.

[0005] However, none of the aforementioned documents specifically mention or disclose the characteristics of the correlation between in vitro dissolution tests and in vivo absorption behavior in pharmaceutical compositions containing tadalafil and dutasteride as active ingredients.

[0006] [Primary Technology]

[0007] [Patent Literature]

[0008] Korean Patent No. 1745425

[0009] Korean Patent No. 1712524

[0010] Korean Patent No. 1780739

[0011] [Non-patent literature]

[0012] Efficacy of tadalafil treatment on erectiledysfunction in patients under dutasteride treatment: A prospective non-randomized comparative study (Turk J Urol. 2018Jul; 44(4):294-297.) Summary of the Invention

[0013] Technical issues

[0014] The technical problem to be solved is to study the correlation between the in vitro dissolution patterns and in vivo absorption behavior of pharmaceutical compositions (combination formulations) containing tadalafil and dutasteride as active ingredients, in order to obtain dissolution conditions and dissolution rates that make the in vivo absorption patterns of each active ingredient from a single formulation containing tadalafil and a single formulation containing dutasteride as active ingredients equal to the in vivo absorption patterns of each active ingredient from the combination composition. In this way, the present invention provides pharmaceutical compositions containing tadalafil and dutasteride as active ingredients, which exhibit a strong in vitro-in vivo correlation (hereinafter referred to as "IVIVC") between in vitro dissolution test results and in vivo absorption patterns under specific dissolution conditions.

[0015] Technical solution

[0016] The above technical solution is achieved by providing a pharmaceutical composition comprising 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, wherein the dissolution rate of tadalafil is 60 to 75% within 5 minutes and greater than 80% within 30 minutes under dissolution conditions of 500 mL of elution buffer containing 0.25% SLS at pH 1.2 and a paddle rate of 50 rpm, and the dissolution rate of dutasteride is 50% or higher within 15 minutes and 85% or higher within 30 minutes under dissolution conditions of 500 mL of elution buffer containing water and 0.1% SLS and a paddle rate of 50 rpm. As a specific means of demonstrating the above dissolution rate, the particle size of the tadalafil-containing particles can be adjusted such that D10 can be 30 μm or smaller, D50 can be 70 to 130 μm, and D90 can be 250 to 350 μm; and the particle size of the dutasteride-containing particles can be adjusted such that D10 can be 15 μm or smaller, D50 can be 25 to 40 μm, and D90 can be 90 to 150 μm.

[0017] Beneficial effects

[0018] In preparing pharmaceutical compositions containing tadalafil and dutasteride as active ingredients, the drug formulation development cycle can be shortened by obtaining dissolution conditions and dissolution rates that allow for accurate prediction of in vitro absorption patterns. Furthermore, therapeutic efficacy can be maximized by improving the dissolution rate of each individual component. Attached Figure Description

[0019] Figure 1 This is a graph showing the results of dissolution testing performed according to the conventional instructions and test methods of Example 1, Comparative Example 1, and Reference Example (Avodart).

[0020] Figure 2 This is a graph showing the results of dissolution testing performed according to the conventional instructions and test methods of Example 1, Comparative Example 1, and Reference Example (Cialis).

[0021] Figure 3 This is a diagram showing the PK of the beagle dogs in Example 1, Comparative Example 1, and Reference Example (Avodart).

[0022] Figure 4 This is a diagram showing the PK of the beagle dogs of Example 1, Comparative Example 1, and Reference Example (Cialis).

[0023] Figure 5 This is a graph showing the dissolution test results of Example 1, Comparative Example 1, and Reference Example (Cialis) under the dissolution conditions of the present invention.

[0024] Figure 6 This is a graph showing the dissolution test results of Example 1, Comparative Example 1, and Reference Example (Avodart) under the dissolution conditions of the present invention.

[0025] Figure 7 The graph shows the dissolution test results of Examples 1, Comparative Examples 2 and 3, and Reference Example (Cialis) under the dissolution conditions of the present invention. Detailed Implementation

[0026] The drug development process includes in vitro testing, animal testing, and in vivo testing in human subjects. This applies not only to the development of new drugs but also to the development of generic drugs, also known as incrementally modified drugs, which require data submission.

[0027] Based on scientific evidence, efforts are actively underway to reduce in vivo testing in human subjects. As part of this effort, a global effort is actively pursuing the replacement of in vivo testing with in vitro testing. However, the dissolution and absorption processes of drugs administered in vivo occur within complex systems involving various physiological substances, and the in vivo factors contributing to drug absorption are highly diverse. Therefore, there are limitations to assessing the in vivo pharmacokinetics of drugs using only in vitro testing methods. Consequently, it is necessary to investigate in vitro testing conditions that can most appropriately reflect the in vivo state through in vivo and in vitro correlation studies. The development and predictive assessment results of IVIVC correlation can establish dissolution testing methods as a substitute index for human bioequivalence testing, and based on this, the number of bioequivalence tests performed during scaling up manufacturing, post-approval changes, and obtaining initial approval can be reduced. In vitro dissolution testing is important in process control and quality assurance, confirming the stable release characteristics of products over time, and making certain regulatory decisions in the event of minor changes in formulation or changes in the manufacturer. For controlled-release formulations intended for oral administration, dissolution testing can also serve as an indicator to control the quality of the manufacturing process and represent the in vivo pharmacokinetics of the formulation.

[0028] This invention relates to pharmaceutical compositions comprising tadalafil and dutasteride as active ingredients. Tadalafil is a brand name... The active ingredient of the drug sold below, and has the structure of the following chemical formula 1.

[0029] [Chemical Formula 1]

[0030]

[0031] Tadalafil is a selective and reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (hereinafter referred to as PDE-5). Tadalafil is known to be used to treat erectile dysfunction and benign prostatic hyperplasia, or to treat patients with both erectile dysfunction and benign prostatic hyperplasia.

[0032] Dutasteride is a brand name The active ingredient of the drug sold below, and has the structure of the following chemical formula 2.

[0033] [Chemical Formula 2]

[0034]

[0035] Dutasteride is a dual 5-alpha reductase inhibitor that inhibits both type I and type II 5-alpha reductase. Dutasteride is known to be used to treat benign prostatic hyperplasia, prostate cancer, and male pattern baldness because it inhibits the conversion of testosterone to dihydrotestosterone (DHT).

[0036] Benign prostatic hyperplasia (BPH) is a very common condition in which the prostate gland increases in size with age, causing various urinary dysfunctions. While 5-alpha reductase inhibitors (a type of medication that reduces prostate size) are effective in treating BPH, the improvement may not be immediate. Therefore, they can be used in combination with other medications used to improve symptoms, including tadalafil. Thus, by providing a combination formulation containing dutasteride and tadalafil as active ingredients, the simultaneous effects of reducing prostate size and improving symptoms can be expected.

[0037] In the preparation of compound formulations (which are formulated as single formulations of two types of active ingredients (known and approved for sale by drug regulatory authorities)), it is necessary to ensure that the in vivo absorption pattern of the active ingredient contained in the compound formulation is equivalent to that of the active ingredient in the approved single formulation. Furthermore, equivalence must be verified through clinical testing in human subjects. However, it is common for the dissolution and absorption patterns of the same active ingredient from the single formulation to differ from those from the compound formulation. Therefore, even when the dissolution rate of the active ingredient from the single formulation is simply adjusted to be equivalent to its dissolution rate from the compound formulation by performing dissolution tests, the absorption patterns observed in humans during actual clinical trials are often different. Therefore, it is necessary to repeat the formulation design during several clinical trials. Thus, the associated costs and time consumption are among the biggest obstacles encountered in the development of compound drugs.

[0038] According to US FDA guidance published in September 1997, the purpose of IVIVC research was to enable dissolution, solubility, and intestinal permeability testing to be used as alternative methods for bioavailability testing. Therefore, once IVIVC is established, bioequivalence between two formulations can be ensured through dissolution testing when scaling up production or changing additives after drug approval. Furthermore, although Korean testing agencies widely use dissolution testing for quality control of orally administered solid dosage forms, in vitro dissolution test data alone often cannot accurately predict in vivo pharmacokinetics. In the case of combined formulations, predicting in vitro absorption patterns based on in vitro dissolution test results is even more difficult.

[0039] In this context, the inventors have achieved the present invention by acquiring the knowledge that in pharmaceutical compositions comprising tadalafil and dutasteride, the dissolution rate under specific dissolution conditions is strongly correlated with the in vitro absorption pattern.

[0040] Specifically, the inventors have obtained the following new knowledge: In a pharmaceutical composition containing tadalafil and dutasteride as active ingredients, when the dissolution rate of tadalafil is 60 to 75% within 5 minutes and greater than 80% within 30 minutes under dissolution conditions of 500 mL of an eluent containing 0.25% SLS at pH 1.2 and a dissolution rate of dutasteride is 50% or higher at 15 minutes and greater than 85% or higher at 30 minutes under dissolution conditions of 500 mL of an eluent containing water and 0.1% SLS and a dissolution rate of 50 rpm, the in vitro absorption pattern of the pharmaceutical composition is equivalent to the in vitro absorption patterns of a single formulation containing tadalafil as an active ingredient and a single formulation containing dutasteride as an active ingredient.

[0041] In other words, when the dissolution conditions are not those described above, the in vivo absorption pattern of a pharmaceutical composition containing tadalafil and dutasteride differs from the in vivo absorption pattern of each active ingredient in a single formulation containing tadalafil and dutasteride. Therefore, pharmaceutical compositions that meet the specific dissolution conditions described herein have the advantage of allowing for drug development with minimal investment of cost and time, without the need for repeatable clinical trials.

[0042] As a technical means to demonstrate the above-mentioned dissolution conditions, the particle size distribution of particles containing tadalafil and dutasteride can be controlled. The pharmaceutical composition of the present invention comprises particles containing tadalafil (hereinafter referred to as "tadalafil particles") and particles containing dutasteride (hereinafter referred to as "dutasteride particles"). Specifically, the tadalafil formulation is granulated by preparing a suspension containing tadalafil, a surfactant, a water-soluble polymer, and a solvent, and the dutasteride particles are granulated by dissolving in a solution such as monoglyceride / diglyceride and / or diethylene glycol monoethyl ether and adsorbing onto an adsorbent.

[0043] The inventors have learned that the particle size distribution of tadalafil particles and dutasteride particles affects the microdissolution pattern of the pharmaceutical composition according to the invention. Specifically, the dissolution conditions described in this invention are obtained by finely controlling a dissolution pattern released over a relatively short period of 30 minutes, and this dissolution pattern can be achieved by more precisely controlling the particle size distribution of the particles containing each active ingredient. Specifically, the dissolution pattern of the invention can be exhibited when the particle size of the tadalafil-containing particles is adjusted such that D10 can be 30 μm or less, D50 can be 70 to 130 μm, and D90 can be 250 to 350 μm, and the particle size of the dutasteride-containing particles is adjusted such that D10 can be 15 μm or less, D50 can be 25 to 40 μm, and D90 can be 90 to 150 μm. D10 refers to the particle size corresponding to less than 10% of the cumulative volume in the cumulative particle size distribution according to the particle size distribution system, and D50 and D90 refer to the particle sizes corresponding to 50% and 90%, respectively. Particle size distribution is controlled and measured using grinding and measurement methods well-known in the art. For example, commonly known methods for controlling particle size distribution include grinding using microfluidicators, zet mills, co-mills, ball mills, etc., and granulation using wet or dry granulation methods. To confirm control of particle size distribution, it can be measured using a dry measurement method with a laser diffraction particle size analyzer (e.g., HELOS (H0184) & RODOS, R5: 0.5 / 4.5...875 μm).

[0044] The pharmaceutical composition according to the invention comprises: preparing tadalafil particles by preparing a suspension comprising tadalafil, a surfactant, a water-soluble polymer, and a solvent; dissolving dutasteride in a mixed solution of monoglyceride / diglyceride and diethylene glycol monoethyl ether and adsorbing it onto an adsorbent to prepare a dutasteride adsorbent, and granulating it to prepare dutasteride particles; and mixing tadalafil particles and dutasteride particles, and then filling or compressing them by mixing pharmaceutically acceptable excipients, disintegrants, and additives.

[0045] The surfactants, water-soluble polymers, adsorbents, and pharmaceutically acceptable excipients, disintegrants, diluents, and additives contained in the pharmaceutical compositions of the present invention are not limited, as long as they meet the dissolution conditions specified in the present invention, or meet the dissolution conditions and the particle size conditions specified in this application, and the pharmaceutical compositions are prepared using formulation techniques commonly used in the pharmaceutical field. For example, the pharmaceutical compositions can be prepared into various pharmaceutical compositions, preferably as tablets or capsules, using standard formulation techniques disclosed in Remington's *The Science and Practice of Pharmacy*, 21st Ed., Lippincott Williams & Wilkins (2005), etc. For information on the surfactants, water-soluble polymers, adsorbents, and pharmaceutically acceptable excipients, disintegrants, diluents, and additives contained in the pharmaceutical compositions of the present invention, please refer to references such as [Handbook of Pharmaceutical Excipients (Rowe, Ed., APhA Publications, 2017)], etc., and the excipients can be in-particle (i.e., bound in the particle) or out-of-particle (i.e., outside the particle).

[0046] As surfactants included in the pharmaceutical compositions of the present invention, pharmaceutically acceptable surfactants may be used without any particular limitation, and preferably, a selection from polyoxyethylene stearate, palmitate, sodium lauryl sulfate, poloxamer, and combinations thereof may be used, and more preferably, sodium lauryl sulfate may be used, but is not limited thereto. Water-soluble polymers included in the pharmaceutical compositions of the present invention may be selected from hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and combinations thereof. Solvents mentioned in the present invention may be selected from methanol, ethanol, isopropanol, purified water, and combinations thereof.

[0047] As used herein, the term "monoglyceride / diglyceride" refers comprehensively to monoglycerides, diglycerides, and mixtures thereof. In this invention, pharmaceutically acceptable adsorbents can be used without particular limitation, and preferably, a selection from silica, colloidal silica, magnesium aluminum silicate, calcium silicate, magnesium aluminum metasilicate, and combinations thereof can be used, and more preferably, magnesium aluminum silicate can be used.

[0048] In addition to the components described above, the pharmaceutical compositions according to the present invention may further include other common pharmaceutically acceptable ingredients, such as excipients, disintegrants, additives, etc. Pharmaceutically acceptable excipients, disintegrants, and additives may 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, peanut 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 and poloxamer); colorants; flavoring agents; tableting agents; stabilizers; antioxidants; and preservatives.

[0049] In the following description, specific embodiments of the invention will be described with reference to examples. These examples are merely illustrative to aid in understanding the invention, and the scope of the invention is not limited thereto.

[0050] Preparation of Examples 1-3

[0051] The pharmaceutical composition was prepared according to the composition shown in Table 1 below. For tadalafil granules, hydroxypropyl cellulose, sodium lauryl sulfate, and poloxamer were added to purified water and completely dissolved, and then tadalafil was added to disperse the resulting solution to prepare a suspension. After mixing microcrystalline cellulose, lactose hydrate, D-mannitol as a diluent, low-substituted hydroxypropyl cellulose, and croscarmellose sodium as a disintegrant, the resulting mixture was incorporated into the above suspension to prevent problems with the uniformity of tadalafil content during granulation. The granulated material was dried at 60°C to prepare tadalafil-containing granules. Dutasteride granules were prepared by first dissolving dutasteride in a mixed solution of monoglycerides / diglycerides and diethylene glycol monoethyl ether. A dutasteride-containing adsorbent was prepared by adsorbing the above-prepared mixed solution onto colloidal silica (which is the adsorbent) and sodium lauryl sulfate. After mixing the tadalafil granules and dutasteride granules prepared above, D-mannitol, croscarmellose sodium and magnesium stearate are added and the mixture is compressed into tablets.

[0052] [Table 1]

[0053]

[0054] (The values ​​described in the table above indicate the content of each tablet, in mg.)

[0055] The particle sizes of the tadalafil particles and dutasteride particles prepared in Examples 1 to 3 are shown in Table 2 below.

[0056] [Table 2]

[0057]

[0058] Preparation of Comparative Examples 1-3

[0059]

[0060] (The values ​​described in the table above indicate the content of each tablet, in mg.)

[0061] Comparative Examples 1 to 3 were prepared in the same manner as in Examples 1 to 3, except that the particle size distribution of the tadalafil particles and dutasteride particles in Comparative Examples 1 to 3 was adjusted as described in Table 3.

[0062] [Table 3]

[0063]

[0064] Experimental Example 1

[0065] For Example 1, Comparative Example 1, and Reference Example, dissolution was performed using Avodart tablets (dutasteride 0.5 mg) and Cialis tablets (tadalafil 5 mg) under the conditions described below, and the dissolution rate results for dutasteride were shown in... Figure 1 The results in Table 4, as well as the dissolution rate of tadalafil, show... Figure 2 And in Table 5.

[0066] Dissolution conditions

[0067] Water, 0.25% SLS 900mL, 50rpm

[0068] [Table 4]

[0069]

[0070]

[0071] [Table 5]

[0072]

[0073] As shown in Tables 4 and 5 above, and Figure 1 and Figure 2As shown, under the general description and test methods, there was no difference in dissolution rates among the Reference Example, Example 1, and Comparative Example 1. Therefore, researchers of pharmaceutical formulations can expect that both Example 1 and Comparative Example 1 are bioequivalent to the Reference Example.

[0074] Experiment Example 2

[0075] Using the reference example, example 1, and comparative example 1, beagle dogs were used as subjects to measure pharmacokinetic (PK), and the trend of tadalafil blood concentration was observed. Figure 3 As shown in Table 6, the trend of dutasteride blood concentrations in Figure 4 As shown in Table 7.

[0076] For pharmacokinetic evaluation, 15 beagle dogs (5 in each group) were cross-administered in a 3x3 manner in each group described below. The drug withdrawal period was set at 2 weeks to account for the drug half-life. Blood sampling intervals were 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, and 48 days to account for the peak blood concentrations of dutasteride and tadalafil.

[0077] [Test Drug Information]

[0078] Control group: Combined administration of 1 Cialis tablet and 1 Avodart capsule

[0079] Test group 1: 1 piece of Example 1.

[0080] Test group 2: 1 piece of Example 2.

[0081] like Figure 3 and Figure 4 As shown in Tables 6 and 7, Example 1 is biologically equivalent to the Reference Example, but Comparative Example 1 is not equivalent to the Reference Example. Considering the results of Experimental Example 1, in which there is no difference in dissolution rate between the Reference Example, Example 1, and Comparative Example 1, the results described above indicate that in pharmaceutical compositions containing tadalafil and dutasteride as active ingredients, there is no robust IVIVC between the in vitro dissolution mode and the in vivo absorption mode under the dissolution conditions of the general description and test methods.

[0082] [Table 6]

[0083]

[0084] [Table 7]

[0085]

[0086]

[0087] Experimental Example 3

[0088] Dissolution tests were performed using Example 1, Comparative Example 1, and Reference Example (Avodart and Cialis tablets) under the dissolution conditions described below, and the dissolution rates of tadalafil are shown in Table 8 and... Figure 5 The dissolution rates of dutasteride and other compounds are shown in Table 9 and 1. Figure 6 middle.

[0089] Tadalafil dissolution conditions

[0090] pH 1.2, 0.25% SLS, 50rpm, 500mL

[0091] Dutasteride dissolution conditions

[0092] Water, 0.1% SLS, 50 rpm, 500 mL

[0093] [Table 8]

[0094]

[0095] [Table 9]

[0096]

[0097]

[0098] As shown in Tables 8 and 9, and Figure 5 and 6 As shown, under the tadalafil dissolution conditions of pH 1.2, 0.25% SLS, 50 rpm, and 500 mL, Example 1 showed a dissolution rate of 60 to 75% within 5 minutes and a dissolution rate of more than 80% within 30 minutes, and under the dutasteride dissolution conditions of water, 0.1% SLS, 50 rpm, and 500 mL, it showed a dissolution rate of 50% or higher within 15 minutes and a dissolution rate of 85% or higher within 30 minutes.

[0099] Experiment Example 4

[0100] Under the dissolution test conditions according to the present invention, the dissolution rates of tadalafil in Example 1 and Comparative Examples 1, 2 and 3 were measured, and the results are shown in Table 10 and... Figure 7 middle.

[0101] [Table 10]

[0102]

[0103] From Table 10 and Figure 7 It can be confirmed that the dissolution conditions of this invention may not be met when the particle size distribution shown in this invention is not satisfied.

[0104] Industrial applicability

[0105] When the dissolution conditions and dissolution rates described in this invention are used to prepare a pharmaceutical composition comprising tadalafil and dutasteride as active ingredients, the in vivo absorption patterns of each active ingredient from the pharmaceutical composition and the in vivo absorption patterns of active ingredients from previously approved single formulations can be adjusted to be equivalent.

Claims

1. A pharmaceutical composition comprising: 5 mg of tadalafil or a pharmaceutically acceptable salt thereof; and 0.5 mg of dutasteride or a pharmaceutically acceptable salt thereof, as the active ingredient. In 500 mL of eluent containing 0.25% SLS at pH 1.2, under dissolution conditions of 50 rpm, the dissolution rate of tadalafil was 60-75% within 5 minutes and greater than 80% within 30 minutes. In 500 mL of eluent containing water and 0.1% SLS, under dissolution conditions of 50 rpm slurry rate, the dissolution rate of dutasteride was 50% or higher at 15 minutes and 85% or higher at 30 minutes. The pharmaceutical composition comprises particles containing tadalafil or a pharmaceutically acceptable salt thereof, and particles containing dutasteride or a pharmaceutically acceptable salt thereof. The particle size of the particles containing tadalafil or its pharmaceutically acceptable salt is such that D10 is 30 μm or less, D50 is 70 to 130 μm, and D90 is 250 to 350 μm. The particle size of the particles containing dutasteride or a pharmaceutically acceptable salt thereof is such that D10 is 15 μm or less, D50 is 25 to 40 μm, and D90 is 90 to 150 μm. Tadalafil particles are prepared by granulating a suspension containing tadalafil, a surfactant, a water-soluble polymer, and a solvent. Dutasteride particles are prepared by dissolving in a mixed oil solution containing dutasteride, diethylene glycol monoethyl ether, and glycerol monoester / diglyceride, adsorbing the resulting solution onto an adsorbent, and then granulating the solution.

2. The pharmaceutical composition according to claim 1, wherein the dutasteride particles do not contain polyoxyethylene castor oil.

3. The pharmaceutical composition according to claim 1, wherein the adsorbent is selected from silica, colloidal silica, magnesium aluminum silicate, calcium silicate, magnesium aluminum metasilicate, and combinations thereof.

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