UDENAFIL CONTAINING PHARMACEUTICAL COMPOSITION

Description

Technical Field Cross Reference to Related Application

[0001] This application claims the benefit of priority based on Korean Patent Application No. 10-2019-0091056, filed on July 26, 2019.Technical Field

[0002] The present invention relates to a pharmaceutical composition containing udenafil as an active ingredient.Background Art

[0003] Udenafil is a compound having the name 5-[2-propyloxy-5-(1-methyl-2-pyrrolidinyleneamidosulfonyl)phenyl]-1-methyl-1-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one, is a phosphodiesterase type 5 inhibitor, and is a drug currently marketed for the treatment of erectile dysfunction. Udenafil has a structure of the following Formula:

[0004] Korean Patent Nos. 10-0792126 and 10-0496372 disclose the use of udenafil for the treatment of pulmonary arterial hypertension, portal vein hypertension, and benign prostatic hyperplasia, and Korean Patent Application Publication No. 10-2017-0066334 discloses a method of improving myocardial performance in patients, who have had a Fontan procedure, using an udenafil composition.

[0005] The Fontan procedure is a palliative surgical procedure for a child born with a functional single ventricle congenital heart disease, and started as a procedure to connect the right atrium directly to the pulmonary artery in the case in which the right ventricle could not be used. This procedure was based on the discovery that, unlike the left ventricle, the right ventricle is not essential for maintaining pulmonary arterial blood flow. The Fontan procedure has been applied to patients with right ventricular hypoplasia, patients with tricuspid valve atresia, and single ventricle patients with only one ventricle. Recently, the surgical procedure has been significantly modified, and a technique of connecting the vena cava to the pulmonary arteries directly or through a conduit has been used.

[0006] A formulation of udenafil, which is currently used as a treatment for erectile dysfunction, is commercially available as a tablet formulation that is difficult to administer to patients with dysphagia and infants.

[0007] In the case of the Fontan patients mentioned above, the main age group for whom udenafil is used consists of children at the infant stage, it is preferable to formulate udenafil as a liquid or syrup rather than a tablet in order to improve the convenience of administration. However, when udenafil is formulated as a liquid or syrup, a problem arises in that the inherent strong bitter taste of udenafil or the numbing sensation caused by udenafil appears.[Prior Art Documents][Patent Documents]

[0008] (Patent Document 1) Korean Patent No. 10-0792126 (Patent Document 2) Korean Patent No. 10-0496372 (Patent Document 3) Korean Patent Application Publication No. 10-2017-0066334 DISCLOSURE Technical Problem

[0009] Accordingly, the present inventors have found that, when udenafil or a pharmaceutically acceptable salt thereof is formulated as a liquid or syrup, it is possible to improve the medication compliance of infant patients by masking the bitter taste and numbing sensation, thereby completing the present invention.

[0010] Therefore, an object of the present invention is to provide an oral liquid formulation (as defined in the Korean Pharmacopoeia 11th edition; for example, including liquid formulations, suspension formulations, lemonade formulations, etc.) or syrup formulation containing udenafil or a pharmaceutically acceptable salt thereof.

[0011] Another object of the present invention is to provide an oral liquid or syrup formulation containing udenafil or a pharmaceutically acceptable salt thereof, in which the active ingredient has improved uniformity.Technical Solution

[0012] The present invention is directed to a pharmaceutical composition containing: udenafil or a pharmaceutically acceptable salt thereof; a pH adjusting agent; and cyclodextrin or a derivative thereof, wherein the cyclodextrin derivative is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, sulfobutylether-7-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, (2-carboxymethoxy)propyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin, and 2-hydroxypropyl-γ-cyclodextrin, wherein the pharmaceutical composition is a liquid or syrup formulation for oral administration, wherein the pharmaceutical composition further comprises a viscosity modifier, wherein the pharmaceutical composition has a viscosity of 0.4 Pa·s [400 cPs] to 4 Pa·s [4,000 cPs] measured with a Brookfield DV-E viscometer, Model LVDVE using spindle S62 at a rotation speed of 30 rpm, and wherein the pharmaceutical composition has a pH ranging from 3 to 6.

[0013] The composition of the present invention is intended for administration to patients, who have undergone a Fontan procedure, and is preferably in a liquid or syrup formulation which is convenient to administer to infant patients.

[0014] The composition of the present invention contains a viscosity modifier. In the present invention, the viscosity of the composition is 0.4 Pa·s [400 cPs] to 4 Pa·s [4,000 cPs] . In addition, the pH of the composition of the present invention is in the range of 3 to 6.

[0015] In the present invention, the cyclodextrin derivative is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, sulfobutylether-7-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, (2-carboxymethoxy)propyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin, and 2-hydroxypropyl-γ-cyclodextrin.

[0016] In the present invention, the weight ratio between the udenafil or a pharmaceutically acceptable salt thereof and the cyclodextrin or a derivative thereof is preferably 1: 0.1 to 10.

[0017] In the present invention, the viscosity modifier may be at least one selected from the group consisting of agar, xanthan gum, locust bean gum, guar gum, tragacanth gum, arabic gum, gellan gum, karaya gum, ghatti gum, tamarind gum, tara gum, acacia gum, chitosan, carrageenan, gelatin, pectin, alginic acid, sodium alginate, propylene glycol, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, polyethylene glycol, polyvinyl alcohol, povidone, and polyethylene oxide.

[0018] In the present invention, the pH adjusting agent may be at least one selected from the group consisting of citric acid, fumaric acid, succinic acid, adipic acid, aspartic acid, glutamic acid, maleic acid, lactic acid, tartaric acid, phosphoric acid, hydrochloric acid, and acetic acid.Advantageous Effects

[0019] The pharmaceutical composition containing udenafil or a pharmaceutically acceptable salt thereof according to the present invention minimizes the inherent bitter taste of the drug and the numbing sensation caused by the drug, thereby improving the medication compliance of infant patients and dysphagia patients, who are main subjects. In addition, it is possible to provide a liquid or syrup composition containing udenafil, which does not undergo layer separation due to ensured uniformity of the liquid or syrup and has excellent quality due to good flowability.Brief Description of Drawings

[0020] FIG. 1 is a photograph of the appearance of a composition according to an embodiment of the present invention, taken after a stability test.Best Mode

[0021] Hereinafter, the present invention will be described in detailPharmaceutical Composition

[0022] The present invention is directed to a pharmaceutical composition containing: udenafil or a pharmaceutically acceptable salt thereof; a pH adjusting agent; and cyclodextrin or a derivative thereof, wherein the cyclodextrin derivative is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, sulfobutylether-7-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, (2-carboxymethoxy)propyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin, and 2-hydroxypropyl-γ-cyclodextrin, wherein the pharmaceutical composition is a liquid or syrup formulation for oral administration, wherein the pharmaceutical composition further comprises a viscosity modifier, wherein the pharmaceutical composition has a viscosity of 0.4 Pa·s [400 cPs] to 4 Pa·s [4,000 cPs] measured with a Brookfield DV-E viscometer, Model LVDVE using spindle S62 at a rotation speed of 30 rpm, and wherein the pharmaceutical composition has a pH ranging from 3 to 6.

[0023] As used herein, the term "pharmaceutically acceptable salt" means salts that are commonly used in the pharmaceutical industry. Examples of the salts include: inorganic ion salts formed with calcium, potassium, sodium, magnesium, etc.; inorganic acid salts formed with hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, etc.; organic acid salts formed with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; sulfonic acid salts formed with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; amino acid salts formed with glycine, arginine, lysine, etc.; and amine salts formed with trimethylamine, triethylamine, ammonia, pyridine, picoline, etc. However, the types of salts meant in the present invention are not limited to the above listed salts.

[0024] The composition of the present invention relates to a pharmaceutical composition intended for administration to a patient who has undergone a Fontan procedure, and may treat or prevent conditions, symptoms and / or side effects related to a patient who has undergone a Fontan procedure, thereby, for example, improving cardiac output, or reducing pulmonary vascular resistance, or increasing exercise capacity, improving myocardial performance, or improving aerobic exercise performance.

[0025] In addition, the composition of the present invention relates to a pharmaceutical composition for the prevention or treatment of erectile dysfunction, and improves the medication compliance of erectile dysfunction patients (particularly, patients with difficulty in swallowing).

[0026] As used herein, the term "prevention" means delaying onset of a disease, disorder or disease. Prevention may be considered complete when onset of a disease, disorder or condition has been delayed for a predefined period of time.

[0027] As used herein, the term "treatment" refers to partially or completely alleviating, ameliorating, relieving, delaying onset of, inhibiting progression of, reducing severity of, or reducing incidence of one or more symptoms or features of a particular disease, disorder, and / or condition.

[0028] In one embodiment of the present invention, the pharmaceutical composition of the present invention may be may be prepared in a unit dose form or prepared to be contained in a multi-dose container by formulating the composition with a pharmaceutically acceptable carrier according to a method that a person skilled in the art can easily perform.

[0029] As used herein, the term "carrier" means a compound that facilitates the addition of the compound into a cell or tissue, and the term "pharmaceutically acceptable" refers to an additive which is physiologically acceptable and, when administered to the human beings, does not cause allergic reactions such as gastrointestinal disorders and dizziness, or similar reactions.

[0030] In one embodiment of the present invention, the pharmaceutically acceptable carrier is one that is commonly used in formulation, and examples thereof include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. The pharmaceutical composition of the present invention may further contain, in addition to the above-described components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like.

[0031] In one embodiment of the present invention, the content of the additives in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the content range that is commonly used in formulation.

[0032] The composition of the present invention is in the form of a liquid formulation or syrup formulation so that it may be conveniently administered orally to infant patients, who have undergone a Fontan procedure, according to the intended administration method.

[0033] As used herein, the term "administration" means providing a predetermined substance to a subject or patient in any suitable manner. Depending on the method as desired, the substance may be administered parenterally (for example, applied as an injectable formulation intravenously, subcutaneously, intraperitoneally or topically) or orally. Dosage may vary according to the patient's weight, age, sex, health condition and diet, the time of administration, the mode of administration, the rate of excretion, and the severity of the disease. The composition of the present invention is administered orally.

[0034] As used herein, the term "oral administration" means that a substance prepared so that the active substance is digested is administered into the gastrointestinal tract for absorption. In order to formulate the pharmaceutical composition of the present invention into a form for oral administration, it is possible to use a binder such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; an excipient such as dicalcium phosphate; a disintegrant such as corn starch or sweet potato starch; and a lubricant such as magnesium stearate, calcium stearate, sodium stearyl fumarate or polyethylene glycol, and it is also possible to use a sweetener, fragrance, syrup or the like. Furthermore, for capsules, it is possible to additionally use a liquid carrier such as fatty oil, in addition to the above-mentioned substances.

[0035] A preferred dosage of the pharmaceutical composition of the present invention may vary depending on the patient's condition, weight, age, sex, health condition, diet, and constitution specificity, the nature of the formulation, the severity of the disease, the time, mode, duration or interval of administration of the composition, the excretion rate, and the form of drug, and may be appropriately selected by those skilled in the art. For example, the dosage may be in the range of about 0.1 to 10,000 mg / kg, but is not limited thereto, and may be administered once or several times a day.

[0036] The pharmaceutical composition of the present invention may include two separate formulations, or may consist of a single formulation, but is not limited thereto.

[0037] As used herein, the term "liquid formulation" refers to a liquid medicine for oral administration obtained by dissolving a pharmaceutical drug in water or an organic solvent. The liquid formulation has an advantage over a suspension or solid formulation in that drug absorption into the systemic circulation from the gastrointestinal tract is more effective. The liquid formulation may contain, in addition to, the pharmaceutical drug, an additional solute, and may also contain additives that give color, smell, sweetness or stability.

[0038] As used herein, the term "syrup" refers to a concentrated aqueous solution of sugar or a sugar substitute. In the present invention, the syrup is a formulation obtained by formulating a drug having an unpleasant taste, for example, a bitter taste, so that the drug is easy to take. The syrup is a formulation that is particularly suitable for children to take. In the present invention, the syrup may contain, in addition to purified water and extract, sugar or a sugar substituent that is used to give sweetness and viscosity, an antibacterial preservative, a sweetener, a flavoring agent, or a coloring agent, but is not limited thereto. Examples of a sweetener that may be contained in the syrup include, but are not limited to, sucrose, mannitol, sorbitol, xylitol, aspartame, stevioside, fructose, lactose, sucralose, saccharin, or menthol.

[0039] The composition of the present invention contains a viscosity modifier. In the present invention, the viscosity of the composition is 0.4 Pa·s [400 cPs] to 4 Pa·s [4,000 cPs]. In addition, the pH of the composition of the present invention is in the range of 3 to 6.

[0040] As used herein, the term "cps" means centipoise, which is a unit of viscosity. It is noted that 1 cps is equal to 1 mPa·s.

[0041] As used herein, the term "cyclodextrin derivative" refers to a compound that may be derived from cyclodextrin, or a part of the compound.

[0042] In the present invention, the cyclodextrin derivative is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, sulfobutylether-7-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, (2-carboxymethoxy)propyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin, and 2-hydroxypropyl-γ-cyclodextrin. Specifically, γ-cyclodextrin is preferably used alone or in combination with α-cyclodextrin.

[0043] In the present invention, the weight ratio between the udenafil or pharmaceutically acceptable salt thereof and the cyclodextrin or derivative thereof is preferably 1: 0.1 to 10. Specifically, the weight ratio between the udenafil or pharmaceutically acceptable salt thereof and the cyclodextrin or derivative thereof is more preferably 1:1 to 5.

[0044] As used herein, the term "viscosity modifier" refers to a substance which is used to maintain the pharmaceutical composition at a stable state without layer separation by combining the liquid phase with the solid phase in the pharmaceutical composition and to increase the viscosity of the pharmaceutical composition.

[0045] In the present invention, the viscosity modifier may be at least one selected from the group consisting of agar, xanthan gum, locust bean gum, guar gum, tragacanth gum, arabic gum, gellan gum, karaya gum, ghatti gum, tamarind gum, tara gum, acacia gum, chitosan, carrageenan, gelatin, pectin, alginic acid, sodium alginate, propylene glycol, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, polyethylene glycol, polyvinyl alcohol, povidone, and polyethylene oxide, but is not limited thereto.

[0046] As used herein, the term "pH adjusting agent" refers to an excipient which is used to adjust the pH of the pharmaceutical composition to a desired value.

[0047] In the present invention, the pH adjusting agent may be at least one selected from the group consisting of citric acid, fumaric acid, succinic acid, adipic acid, aspartic acid, glutamic acid, maleic acid, lactic acid, tartaric acid, phosphoric acid, hydrochloric acid, and acetic acid, but is not limited thereto.Method for Preventing or Treating Fontan Disease and Pulmonary Hypertension or Erectile Dysfunction Related to Fontan Disease (not claimed)

[0048] Disclosed, but not claimed, is a method for preventing or treating Fontan disease and pulmonary hypertension or erectile dysfunction related to Fontan disease, the method comprising a step of administering a therapeutically effective amount of the pharmaceutical composition to mammals including humans.

[0049] As used herein, the term "therapeutically effective amount" refers to an amount effective for preventing or treating Fontan disease and pulmonary hypertension or erectile dysfunction related to Fontan disease, for example, the amount of the pharmaceutical composition that is administered to the subject to be treated. The term may encompass an amount of the pharmaceutical composition that prevents the occurrence or recurrence of Fontan disease and pulmonary hypertension or erectile dysfunction related to Fontan disease, or alleviates a symptom of the disease, or diminishes any direct or indirect pathological consequences of the disease, or prevents metastasis of the disease, or decrease the rate of disease progression, or ameliorates or palliates the disease state, or achieves remission or improved prognosis. That is, the therapeutically effective amount may be interpreted as encompassing all doses at which Fontan disease and symptoms of pulmonary hypertension or erectile dysfunction related to Fontan disease are ameliorated or cured by the pharmaceutical composition.

[0050] The method (not claimed) for preventing or treating Fontan disease and pulmonary hypertension or erectile dysfunction related to Fontan disease also encompass inhibiting or averting symptoms of the disease as well as addressing the disease itself, prior to the onset of symptoms by administering the pharmaceutical composition. The magnitude of a prophylactic or therapeutic dose of a particular active ingredient in the management of a disease will vary depending on the nature and severity of the disease or condition, and the route by which the active ingredient is administered. The dose and the dose frequency will also vary according to the age, body weight, and response of the individual patient. Suitable dosing regimens can be readily selected by those skilled in the art with due consideration of such factors. In addition, the prevention or treatment method may further comprise administering a therapeutically effective amount of an additional active agent that is helpful in the prevention or treatment of Fontan disease and pulmonary hypertension or erectile dysfunction related to Fontan disease, together with the pharmaceutical composition. The additional active agent may exhibit a synergistic or additive effect with the pharmaceutical composition.

[0051] As used herein, the expression "mammals including humans" includes mammals such as humans, monkeys, cattle, horses, dogs, cats, rabbits, and rats.Uses of Pharmaceutical Composition (not claimed)

[0052] Disclosed, but not claimed, is the use of the pharmaceutical composition for use in the preparation of a formulation for Fontan disease and pulmonary hypertension or erectile dysfunction related to Fontan disease.

[0053] Disclosed, but not claimed, is the use of the pharmaceutical composition for the treatment of Fontan disease and pulmonary hypertension or erectile dysfunction related to Fontan disease.

[0054] The pharmaceutical composition for the preparation of a formulation for Fontan disease and pulmonary hypertension or erectile dysfunction related to Fontan disease may contain an acceptable carrier, and may further contain other agents.

[0055] Details mentioned above with respect to the pharmaceutical composition, prevention or treatment method and use are equally applied as long as they do not contradict each other.[Examples]

[0056] Hereinafter, the present invention will be described in detail with reference to examples in order to help the understanding of the present invention. However, the following examples serve merely to illustrate the content of the present invention, and the scope of the present invention is not limited by the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.

[0057] Test Example 1: Udenafil Solubility Test at Different pHs

[0058] In order to evaluate the solubility of udenafil (free base) depending on pH, Preparation Examples 1 to 8 shown in Table 1 below were prepared and subjected to a solubility test. The results of the test are shown in Table 2 below. [Table 1]FunctionComponent namePrep. Ex. 1Prep. Ex. 2Prep. Ex. 3Prep. Ex. 4Prep. Ex. 5Prep. Ex. 6Prep. Ex. 7Prep. Ex. 8Active ingredientUdenafil5g5g5g5g5g5g5g5gpH adjusting agentCitric acid27.5mg45mg------Phosphoric acid (purity: 35%)--0.05ml0.3ml0.5ml0.7ml1ml1.5mlSolventPurified water5ml5ml5ml5ml5ml5ml5ml5mlpH6.836.676.546.105.763.191.871.36 Preparation method for Preparation Examples 1 to 8:

[0059] A pH adjusting agent was added to 5 ml of purified water, and the mixture was stirred for 10 minutes, and then udenafil was added thereto, thus preparing the solutions shown in Table 1 above. Each solution was stirred for 2 hours, and then a sample was taken therefrom, filtered using a 0.45 µm PVDF syringe filter, and subjected to a solubility test, and the pH was measured (pH measuring device: pH2700, EUTECH, USA). HPLC analysis conditions Detector: UV detector (292 nm) Column: Aegispak C18-F 5 µm, 4.6x150 mm Column temperature: 30°C Mobile phase: 2.72 g of KH 2 PO 4 dissolved in 1 L of purified water (A); acetonitrile (B); A: B = 700: 300 Flow rate: 1.0 mL / min Injection volume: 10 µL [Table 2] pH of solutionSolubility (mg / ml)Preparation Example 16.83About 39.4Preparation Example 26.67About 60.0Preparation Example 36.54About 94.0Preparation Example 46.10About 426.6Preparation Example 55.76About 474.8Preparation Example 63.19About 467.5Preparation Example 71.87About 359.0Preparation Example 81.36About 347.5

[0060] Udenafil has a water solubility of about 0.12 mg / mL (Comparative Example 1) and is very poorly soluble in water, and it was confirmed in the above-described test that the solubility of udenafil changed depending on the pH of the solution. It was seen that the solubility was improved in Preparation Example 1 having a pH of 6.83, and the solubility greatly increased in Preparation Example 4 (pH 6.1) having a low pH. However, in Preparation Examples 7 and 8 in which the pH was lower than 2, the solubility was slightly lower than those in the Preparation Examples having a pH ranging from 3 to 6.

[0061] From these results, it can be confirmed that udenafil has the highest solubility in the range of pH 3 to 6.Preparation of Comparative Examples 1 and 2

[0062] Using the components and contents shown in Table 3 below, a composition (Comparative Example 1) was prepared by adding udenafil added to purified water, and a composition (Comparative Example 2) was prepared by completely dissolving udenafil through pH adjustment with a pH adjusting agent. [Table 3]Per 100 ml of compositionComparative Example 1Comparative Example 2FunctionComponent nameActive ingredientUdenafil1,000mg1,000mgpH adjusting agentCitric acid-180mgSolventPurified water100ml100ml

[0063] Preparation method: each of the compositions shown in Table 3 was prepared according to the following preparation method.

[0064] Comparative Example 1 was prepared by adding udenafil to 100 ml of purified water, followed by stirring for 20 minutes.

[0065] Comparative Example 2 was prepared by adding a pH adjusting agent to 100 ml of purified water and adding udenafil to the solution, followed by stirring for 20 minutes.Preparation of Comparative Examples 3 and 4

[0066] Udenafil syrup compositions (Comparative Examples 3 and 4) containing no cyclodextrin were prepared using the compositions shown in Table 4 below. Since the composition of Comparative Example 3 contained no pH adjusting agent, udenafil did not completely dissolve therein. [Table 4]Per 100 ml of compositionComparative Example 3Comparative Example 4FunctionComponent namemg / 100mlmg / 100mlActive ingredientUdenafil1,0001,000pH adjusting agentCitric acid-180SolventPurified water20mL20mLSweetenerSucrose45,00045,000SweetenerSucralose5050SweetenerStevioside5050PreservativeMethyl paraoxybenzoate3030PreservativePropyl paraoxybenzoate2020PreservativeSodium benzoate5050SolventPurified waterq.s.q.s.

[0067] Preparation method: each of the compositions shown in Table 4 above was prepared according to the following preparation method. (i) add a pH adjusting agent to 20 ml of purified water, followed by stirring for 10 minutes (however, this step is omitted in the preparation of Comparative Example 3 containing no pH adjusting agent). (ii) add udenafil to the solution, followed by stirring for 20 minutes. (iii) add sweeteners and preservatives to about 40 mL of separate purified water, and then dissolve them by stirring for 1 hour or more while heating at 90°C or higher. (iv) mix the solution, mixed in step (ii), with the solution prepared in step (iii), and then stir and cool the mixture, and then add purified water to the mixture to reach a final volume of 100 ml, thereby preparing each composition. Preparation of Comparative Examples 5 to 15

[0068] Udenafil syrup compositions containing cyclodextrin were prepared using the compositions shown in Tables 5-1 and 5-2 below. Since the composition of Comparative Example 5 contained no pH adjusting agent, udenafil did not completely dissolve therein. [Table 5-1]Per 100 ml of compositionComp. Example 5Comp. Example 6Comp. Example 7Comp. Example 8Comp. Example 9Comp. Example 10FunctionComponent namemg / 100m1mg / 100mlmg / 100mlmg / 100m1mg / 100m1mg / 100m1Active ingredientUdenafil1,0001,0001,0001,0001,0001,000Excipientα-cyclodextrin--2,0004,0006,000-Excipientβ-cyclodextrin-----2,000Excipientγ-cyclodextrin4,0004,000---pH adjusting agentCitric acid-113180180180180SolventPurified water20mL20mL20mL20mL20mL20mLSweetenerSucrose45,00045,00045,00045,00045,00045,000SweetenerSucralose505050505050SweetenerStevioside505050505050PreservativeMethyl paraoxybenzoate303030303030PreservativePropyl paraoxybenzoate202020202020PreservativeSodium benzoate505050505050SolventPurified waterq.s.q.s.q.s.q.s.q.s.q.s. [Table 5-2] Per 100 ml of compositionComp. Example 11Comp. Example 12Comp. Example 13Comp. Example 14Comp. Example 15FunctionComponent namemg / 100mlmg / 100mlmg / 100mlmg / 100mlmg / 100mlActive ingredientUdenafil1,0001,0001,0001,0001,000Excipientα-cyclodextrin-----Excipientβ-cyclodextrin4,000----Excipientγ-cyclodextrin-2,0004,0006,0008,000pH adjusting agentCitric acid180180180180180SolventPurified water20mL20mL20mL20mL20mLSweetenerSucrose45,00045,00045,00045,00045,000SweetenerSucralose5050505050SweetenerStevioside5050505050PreservativeMethyl paraoxybenzoate3030303030PreservativePropyl paraoxybenzoate2020202020PreservativeSodium benzoate5050505050SolventPurified waterq.s.q.s.q.s.q.s.q.s.

[0069] Preparation method: each of the compositions shown in Table 5 above was prepared according to the following preparation method. (i) add a pH adjusting agent to 20 ml of purified water, followed by stirring for 10 minutes (however, this step is omitted in the preparation of Comparative Example 5 containing no pH adjusting agent). (ii) add udenafil to the solution, followed by stirring for 20 minutes. (iii) adding cyclodextrin to the solution while heating to a temperature of 60°C, followed by stirring for 20 minutes. (iv) add sweeteners and preservatives to about 40 mL of separate purified water, and then dissolve them by stirring for 1 hour or more while heating at 90°C or higher. (v) mix the solution, mixed in step (iii), with the solution prepared in step (iv), and then stir and cool the mixture, and then add purified water to the mixture to reach a final volume of 100 ml, thereby preparing each composition. Preparation of Comparative Examples 16 to 23

[0070] Udenafil syrup compositions shown in Table 6 below, which contain cyclodextrin and a pH adjusting agent, were prepared. [Table 6]Per 100 ml of compositionComp. Example 16Comp. Example 17Comp. Example 18Comp. Example 19Comp. Example 20Comp. Example 21Comp. Example 22Comp. Example 23FunctionComponent namemg / 100 mlmg / 100 mlmg / 100 mlmg / 100 mlmg / 100 mlmg / 100 mlmg / 100 mlmg / 100 mlActive ingredientUdenafil1,0001,0001,0001,0001,0001,0001,0001,000Excipientγ-cyclodextrin4,0004,0004,0004,0004,0004,0004,0004,000pH adjusting agentCitric acid180180180180180180180180SolventPurified water20mL20mL20mL20mL20mL20mL20mL20mLSweetenerSucrose45,00045,00045,00045,00045,00045,00045,00045,000SweetenerSucralose5050505050505050SweetenerStevioside5050505050505050Viscosity modifierAgar300--300300300300300Viscosity modifierHydroxypropyl cellulose-100------Viscosity modifierHydroxyethyl cellulose--4004004,0003,5003,2003,000PreservativeMethyl paraoxybenzoate3030303030303030PreservativePropyl paraoxybenzoate2020202020202020PreservativeSodium benzoate5050505050505050SolventPurified waterq. s.q.s.q.s.q.s.q. s.q.s.q.s.q. s.

[0071] Preparation method: each of the compositions shown in Table 6 above was prepared according to the following preparation method. (i) add a pH adjusting agent to 20 ml of purified water, followed by stirring for 10 minutes. (ii) add udenafil to the solution, followed by stirring for 20 minutes. (iii) add cyclodextrin to the solution while heating to a temperature of 60°C, followed by stirring for 20 minutes. (iv) add sweeteners, viscosity modifiers and preservatives to about 40 mL of separate purified water, and then dissolve them by stirring for 1 hour or more while heating at 90°C or higher. (v) mix the solution, mixed in step (iii), with the solution prepared in step (iv), and then stir and cool the mixture, and then add purified water to the mixture to reach a final volume of 100 ml, thereby preparing each composition. Preparation of Examples 1 to 20

[0072] The udenafil syrup compositions shown in Tables 7-1, 7-2 and 7-3 were prepared. [Table 7-1]Per 100 ml of compositionExample 1Example 2Example 3Example 4Example 5Example 6FunctionComponent namemg / 100m1mg / 100mlmg / 100mlmg / 100mlmg / 100mlmg / 100m1Active ingredientUdenafil100010001000100010001000Excipientα-cyclodextrin------Excipientβ-cyclodextrin------Excipientγ-cyclodextrin400040004000400040004000pH adjusting agentCitric acid180180180180180180pH adjusting agentHydrochloric acid (purity: 35 to 37%)------pH adjusting agentPhosphoric acid (purity: 35%)------SolventPurified water20mL20mL20mL20mL20mL20mLSweetenerSucrose450004500045000450004500045000SweetenerSucralose505050505050SweetenerStevioside505050505050Viscosity modifierAgar----300300Viscosity modifierHydroxypropyl cellulose250500----Viscosity modifierHydroxyethyl cellulose--80012008001200PreservativeMethyl paraoxybenzoate303030303030PreservativePropyl paraoxybenzoate202020202020PreservativeSodium benzoate505050505050SolventPurified waterq.s.q.s.q.s.q.s.q.s.q. s. [Table 7-2] Per 100 ml of compositionExample 7Example 8Example 9Example 10Example 11Example 12Example 13FunctionComponent namemg / 100mlmg / 100mlmg / 100mlmg / 100mlmg / 100 mlmg / 100 mlmg / 100 mlActive ingredientUdenafil1000100010001000100010001000Excipientα-cyclodextrin---1000200010002000Excipientβ-cyclodextrin-------Excipientγ-cyclodextrin4000400040001000200020001000pH adjusting agentCitric acid180180180180180180180pH adjusting agentHydrochloric acid (purity: 35 to 37%)-------pH adjusting agentPhosphoric acid (purity: 35%)-------SolventPurified water20mL20mL20mL20mL20mL20mL20mLSweetenerSucrose45000450004500045000450004500045000SweetenerSucralose50505050505050SweetenerStevioside50505050505050Viscosity modifierAgar300300300300300300300Viscosity modifierHydroxypropyl cellulose-------Viscosity modifierHydroxyethyl cellulose2000250016001200120012001200PreservativeMethyl paraoxybenzoate30303030303030PreservativePropyl paraoxybenzoate20202020202020PreservativeSodium benzoate50505050505050SolventPurified waterq.s.q.s.q.s.q.s.q.s.q.s.q.s. [Table 7-3] Per 100 ml of compositionExample 14Example 15Example 16Example 17Example 18Example 19Example 20FunctionComponent namemg / 100mlmg / 100mlmg / 100mlmg / 100mlmg / 100 mlmg / 100 mlmg / 100 mlActive ingredientUdenafil1000100010001000100010001000Excipientα-cyclodextrin-------Excipientβ-cyclodextrin-------Excipientγ-cyclodextrin4000400040004000400040004000pH adjusting agentCitric acid140320----180pH adjusting agentHydrochloric acid--0.2 mL0.12mL-0.3mL-pH adjusting agentPhosphoric acid----0.2 mL--SolventPurified water20mL20mL20mL20mL20mL20mL20mLSweetenerSucrose450004500045000450004500045000-SweetenerSucralose505050505050-SweetenerStevioside505050505050-Viscosity modifierAgar300300300300300300300Viscosity modifierHydroxypropyl cellulose-------Viscosity modifierHydroxyethyl cellulose1200120012001200120012002400PreservativeMethyl paraoxybenzoate30303030303030PreservativePropyl paraoxybenzoate20202020202020PreservativeSodium benzoate50505050505050SolventPurified waterq.s.q.s.q.s.q.s.q.s.q.s.q.s.

[0073] Preparation method: each of the compositions shown in Table 7 above was prepared according to the following preparation method. (i) add pH adjusting agents to 20 ml of purified water, followed by stirring for 10 minutes (ii) add udenafil to the solution, followed by stirring for 20 minutes. (iii) adding cyclodextrin to the solution while heating to a temperature of 60°C, followed by stirring for 20 minutes. (iv) add sweeteners and preservatives to about 40 mL of separate purified water, and then dissolve them by stirring for 1 hour or more while heating at 90°C or higher. (v) mix the solution, mixed in step (iii), with the solution prepared in step (iv), and then stir and cool the mixture, and then add purified water to the mixture to reach a final volume of 100 ml, thereby preparing each composition. Test Example 2: Flowability and Precipitation Degree Evaluation for Compositions

[0074] The viscosity, pH value, relative flowability and precipitation degree of each of the compositions of the Comparative Examples and the Examples were measured, and the results were compared and shown in Table 8 below.A. Viscosity measurement

[0075] The viscosity of each composition was measured using a viscometer, and the results of the measurement are shown in Table 8 below. Device used: LVDV-E, Brookfield, USA Spindle: S62 Rotation speed: 30 rpm B. pH measurement

[0076] The pH of each composition was measured using a viscometer, and the results of the measurement are shown in Table 8 below. Device used: pH2700, EUTECH, USAC. Comparison of flowability

[0077] In order to compare relative flowability, 1 ml of each sample was allowed to flow along a ramp under the following conditions, and the time taken to reach the bottom was compared between the samples, and the results are shown in Table 8 below. Ramp material: polypropylene Ramp angle: 45° Ramp length: 10 cm D. Evaluation of layer separation

[0078] In order to evaluate layer separation, each sample was left to stand at room temperature for 1 month, and then whether layer separation would occur was determined by visual observation. The results are shown in Table 8 below. [Table 8] (Examples 18 and 19 are not in the scope of the claims)pHViscosity (cps)Layer separationFlowabilityComparative Example 37.633O1 secComparative Example 45.331O1 secComparative Example 57.634O1 secComparative Example 66.633O1 secComparative Example 75.333O1 secComparative Example 85.335O1 secComparative Example 95.337O1 secComparative Example 105.331O1 secComparative Example 115.335O1 secComparative Example 125.333O1 secComparative Example 135.333O1 secComparative Example 145.435O1 secComparative Example 155.431O1 secComparative Example 165.2297O2 secComparative Example 175.3191O2 secComparative Example 185.365O1 secComparative Example 195.3131O2 secComparative Example 205.338690XAlmost no flowComparative Example 215.313080XAlmost no flowComparative Example 225.39840X3 min and 40 secComparative Example 235.35210X1 min and 40 secExample 15.3689X5 secExample 25.31196X12 secExample 35.3431X3 secExample 45.3849X7 secExample 55.3420X3 secExample 65.3890X6 secExample 75.32714X55 secExample 85.33310X1 min and 10 secExample 95.31221X15 secExample 105.3831X7 secExample 115.3894X7 secExample 125.3811X6 secExample 135.3856X6 secExample 146.03842X6 secExample 154.07887X6 secExample 163.06854X6 secExample 174.85857X6 secExample 182.14813X6 secExample 192854X6 secExample 205.2738X5 sec

[0079] As a result of examining the viscosity, pH, flowability, and degree of layer separation for each sample, it was confirmed that layer separation was observed in Comparative Examples 3 to 19 having a viscosity of 297 cps or less, indicating that the stability of the solution in each of Comparative Examples 3 to 19 was not good.

[0080] It was confirmed that the sample having a viscosity of 431 cps or more was stable without layer separation. However, it was confirmed that, in the case of Comparative Examples 20 to 21 having a viscosity of 13000 cps or more, the syrup hardly flowed even on the ramp. It was confirmed that the compositions of Comparative Examples 22 and 23 having a viscosity of 5210 cps or more flowed, but the times taken to reach the bottom were 1 min and 40 sec and 3 min and 40 sec, respectively, suggesting that these compositions had very poor flowability. If a liquid or syrup formulation having poor flowability as described above, inconvenience may cause when the liquid or syrup formulation is taken in small portions, and the dosage may not be constant, suggesting that the liquid or syrup formulation is not suitable.Test Example 3: Sensory Evaluation

[0081] A sensory test for bitter taste and numbing sensation for each composition was performed on 10 healthy adults. The results of the test were evaluated according to the evaluation criteria shown in Table 9 below, and the average values of 10 people are shown in Tables 10 and 11 below. [Table 9]ScoreBitter tasteNumbing sensation0No bitter tasteNo numbing sensation1Slight bitter taste that is almost indistinguishableSlight numbing sensation that is almost indistinguishable2A little bitter tasteA little numbing sensation3Moderately bitterModerately numbing4Strong and repulsive bitter tasteStrong and repulsive numbing sensation5Very strong bitter tasteVery strong numbing sensation [Table 10] No.12345678910AverageComp. Example 155555555555Comp. Example 255555555555Comp. Example 333444334343.5Comp. Example 433343434333.3Comp. Example 533434343333.3Comp. Example 633434343433.4Comp. Example 733223332322.6Comp. Example 832322223222.3Comp. Example 922222222322.1Comp. Example 1033332333232.8Comp. Example 1133232323232.6Comp. Example 1232323223232.5Comp. Example 1322222232222.1Comp. Example 1422232222222.1Comp. Example 1522222322322.2Comp. Example 1622322322222.2Comp. Example 1723323222222.3Comp. Example 1822232322232.3Comp. Example 1922322223222.2Comp. Example 2032322332232.5Comp. Example 2132332233232.6Comp. Example 2223322323222.4Comp. Example 2322322332222.3Example 123222232322.3Example 232222322232.3Example 322322222222.1Example 422322232222.2Example 532223222322.3Example 632222223222.2Example 732232232222.3Example 822322322222.2Example 923222323222.3Example 1033233323332.8Example 1122332322322.4Example 1223222232232.3Example 1323232222322.3Example 1423223222232.3Example 1522232232222.2Example 1622323222222.2Example 1722222222322.1Example 1823223222232.3Example 1922322322222.2Example 2042323423322.8 [Table 11] No.12345678910AverageComp. Example 155555555555Comp. Example 255555555555Comp. Example 355555455454.8Comp. Example 454554555554.8Comp. Example 555554555554.9Comp. Example 655455545454.7Comp. Example 712212221221.7Comp. Example 811011011010.7Comp. Example 910100011110.6Comp. Example 1012122222221.8Comp. Example 1112122212221.7Comp. Example 1221211221211.5Comp. Example 1301010011010.5Comp. Example 1411010101010.6Comp. Example 1510011011000.5Comp. Example 1611010110110.7Comp. Example 1710110110100.6Comp. Example 1810110010110.6Comp. Example 1900101101100.5Comp. Example 2010110101110.7Comp. Example 2110111011110.8Comp. Example 2211010110110.7Comp. Example 2310110101100.6Example 111011001010.6Example 200111011000.5Example 310011101000.5Example 400011010100.4Example 500101001100.4Example 601011101010.6Example 710101101100.6Example 810110101100.6Example 900110110100.5Example 1001211212121.3Example 1101010110100.5Example 1210110101100.6Example 1301010110110.6Example 1411101100100.6Example 1510101010100.5Example 1601110011010.6Example 1711011110100.7Example 1810011011110.7Example 1910110011010.6Example 2010101110110.7

[0082] As a result of sensory evaluation, Comparative Example 1 containing udenafil dispersed in purified water and Comparative Example 2 containing udenafil completely dissolved by pH adjustment all showed a strong bitter taste and numbing sensation.

[0083] Comparative Examples 3 and 4 prepared as the syrup formulations had a slightly decreased bitter taste, but the numbing sensation caused thereby did not significantly differ from that caused by Comparative Examples 1 and 2.

[0084] The compositions of Comparative Examples 5 and 6 contained γ-cyclodextrin, but the evaluation values of bitter taste and numbing sensation thereof did not significantly differ from those of Comparative Examples 2 and 3 due to the udenafil particles dispersed without being completely dissolved.

[0085] It was confirmed that, in the case of the compositions of the remaining Comparative Examples and Examples, due to the addition of the cyclodextrins, the bitter taste and numbing sensation decreased, and in particular, the numbing sensation significantly decreased.

[0086] The test results were comprehensively evaluated according to the criteria shown in Table 12 below, and the results of the evaluation results are shown in Table 13 below. [Table 12]Layer separationFlowabilityBitter tasteNumbing sensationCriteria for suitabilityNo layer separationWithin 1 min and 30 secScore of 3 or lessScore of 3 or less [Table 13] Layer separationFlowabilityBitter tasteNumbing sensationComparative Example 1--UnsuitableUnsuitableComparative Example 2--UnsuitableUnsuitableComparative Example 3UnsuitableSuitableUnsuitableUnsuitableComparative Example 4UnsuitableSuitableUnsuitableUnsuitableComparative Example 5UnsuitableSuitableUnsuitableUnsuitableComparative Example 6UnsuitableSuitableUnsuitableUnsuitableComparative Example 7UnsuitableSuitableSuitableSuitableComparative Example 8UnsuitableSuitableSuitableSuitableComparative Example 9UnsuitableSuitableSuitableSuitableComparative Example 10UnsuitableSuitableSuitableSuitableComparative Example 11UnsuitableSuitableSuitableSuitableComparative Example 12UnsuitableSuitableSuitableSuitableComparative Example 13UnsuitableSuitableSuitableSuitableComparative Example 14UnsuitableSuitableSuitableSuitableComparative Example 15UnsuitableSuitableSuitableSuitableComparative Example 16UnsuitableSuitableSuitableSuitableComparative Example 17UnsuitableSuitableSuitableSuitableComparative Example 18UnsuitableSuitableSuitableSuitableComparative Example 19UnsuitableSuitableSuitableSuitableComparative Example 20SuitableUnsuitableSuitableSuitableComparative Example 21SuitableUnsuitableSuitableSuitableComparative Example 22SuitableUnsuitableSuitableSuitableComparative Example 23SuitableUnsuitableSuitableSuitableExample 1SuitableSuitableSuitableSuitableExample 2SuitableSuitableSuitableSuitableExample 3SuitableSuitableSuitableSuitableExample 4SuitableSuitableSuitableSuitableExample 5SuitableSuitableSuitableSuitableExample 6SuitableSuitableSuitableSuitableExample 7SuitableSuitableSuitableSuitableExample 8SuitableSuitableSuitableSuitableExample 9SuitableSuitableSuitableSuitableExample 10SuitableSuitableSuitableSuitableExample 11SuitableSuitableSuitableSuitableExample 12SuitableSuitableSuitableSuitableExample 13SuitableSuitableSuitableSuitableExample 14SuitableSuitableSuitableSuitableExample 15SuitableSuitableSuitableSuitableExample 16SuitableSuitableSuitableSuitableExample 17SuitableSuitableSuitableSuitableExample 18SuitableSuitableSuitableSuitableExample 19SuitableSuitableSuitableSuitableExample 20SuitableSuitableSuitableSuitable

[0087] From the above results, it was confirmed that, the viscosity of the composition was 0.4Pa·s [400 cPs] or more, no layer separation appeared, but when the viscosity of the composition was excessively high, the flowability thereof was very low, which causes difficulties in commercialization, suggesting that a suitable viscosity range is 0.4 Pa·s [400 cPs] to 4 Pa·s [4,000 cPs].

[0088] As a result of sensory evaluation, it was confirmed that the bitter taste and the numbing sensation significantly decreased in the compositions containing the cyclodextrins, but when udenafil was not dissolved due to a high pH of the composition, the bitter taste and the numbing sensation hardly decreased even when the cyclodextrins were used. Therefore, the most suitable pH of the composition is in the range of pH 3 to 6, at which the solubility of udenafil is the highest.

[0089] The compositions of Examples 1 to 20, which satisfied these criteria, showed satisfactory results in all items, including layer separation, flowability, bitter taste and numbing sensation, compared to the compositions of Comparative Examples 1 to 23.Test Example 4: Stability Test for Composition

[0090] In the above results, Example 6, which showed all suitable results, was selected. In order to evaluate the stability thereof, Example 6 was evaluated for its appearance (layer separation), content, impurities, pH and viscosity under stress conditions (60°C) and accelerated conditions (40°C and 75% RH). The test results are shown in Table 14 below and FIG. 1.A. Appearance

[0091] Visual observation was performed.B. Content and impurities

[0092] Udenafil concentration of syrup composition: 10 mg / ml Sample preparation: 20 mg of the syrup composition as udenafil was taken and placed in a 100-ml-volume flask, 80% of which was then filled with a diluent, followed by stirring for 1 hour. Then, the solution was diluted to the volume mark with a diluent, and then filtered through a 0.45-µm PVDF syringe filter, and the filtrate was used as a test sample. HPLC analysis conditions Detector: UV detector (292 nm) Column: Aegispak C18-F 5um, 4.6 x 150 mm Column temperature: 30°C Mobile phase: 2.72 g KH 2 PO 4 dissolved in 1 L of purified water (A); acetonitrile (B); A: B = 700: 300 Flow rate: 1.0 mL / min Injection volume: 10 µL C. pH measurement

[0093] pH was measured using a pH meter. Device used: pH2700, EUTECH, USAD. Viscosity measurement

[0094] Viscosity was measured using a viscometer. Device used: LVDV-E, Brookfield, USA Spindle: S62 Rotation speed: 30 rpm [Table 14] Test itemsCriteriaInitialStress for 4 weeksAccelerated for 1 monthAppearance (layer separation)Uniform without layer separationSuitableSuitableSuitableContent95 to 105%100.4±0.1100.9±1.1100.9±1.0ImpuritiesTotal impurity content of 2.0% or less0.110.130.14pH3 to 65.154.985.12Viscosity400 to 4,000 cps864920867

[0095] As a result of the stability test, the composition of the Examples showed suitable results in all items, including appearance, content, impurities, pH and viscosity.Industrial Applicability

[0096] The pharmaceutical composition containing udenafil or a pharmaceutically acceptable salt thereof according to the present invention minimizes the inherent bitter taste of the drug and the numbing sensation caused by the drug, thereby improving the medication compliance of infant patients who are main subjects. In addition, it is possible to provide a liquid or syrup composition containing udenafil, which does not undergo layer separation due to ensured uniformity of the liquid or syrup and has excellent quality due to good flowability.

Claims

1. A pharmaceutical composition containing: udenafil or a pharmaceutically acceptable salt thereof; a pH adjusting agent; and cyclodextrin or a derivative thereof, wherein the cyclodextrin derivative is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin, 2,6-dimethyl-β-cyclodextrin, sulfobutylether-7-β-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, (2-carboxymethoxy)propyl-β-cyclodextrin, 2-hydroxyethyl-γ-cyclodextrin, and 2-hydroxypropyl-γ-cyclodextrin, wherein the pharmaceutical composition is a liquid or syrup formulation for oral administration, wherein the pharmaceutical composition further comprises a viscosity modifier, wherein the pharmaceutical composition has a viscosity of 0.4 Pa·s [400 cPs] to 4 Pa·s [4,000 cPs] measured with a Brookfield DV-E viscometer, Model LVDVE using spindle S62 at a rotation speed of 30 rpm, and wherein the pharmaceutical composition has a pH ranging from 3 to 6.

2. The pharmaceutical composition of claim 1, intended for administration to patients who have undergone a Fontan procedure.

3. The pharmaceutical composition of claim 1, wherein a weight ratio between the udenafil or pharmaceutically acceptable salt thereof and the cyclodextrin or derivative thereof is 1: 0.1 to 10.

4. The pharmaceutical composition of claim 1, wherein the viscosity modifier is at least one selected from the group consisting of agar, xanthan gum, locust bean gum, guar gum, tragacanth gum, arabic gum, gellan gum, karaya gum, ghatti gum, tamarind gum, tara gum, acacia gum, chitosan, carrageenan, gelatin, pectin, alginic acid, sodium alginate, propylene glycol, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methyl cellulose, polyethylene glycol, polyvinyl alcohol, povidone, and polyethylene oxide.

5. The pharmaceutical composition of claim 1, wherein the pH adjusting agent is at least one selected from the group consisting of citric acid, fumaric acid, succinic acid, adipic acid, aspartic acid, glutamic acid, maleic acid, lactic acid, tartaric acid, phosphoric acid, hydrochloric acid, and acetic acid.

6. The pharmaceutical composition of claim 1, intended for prevention or treatment of Fontan disease and pulmonary hypertension related to Fontan disease.

7. The pharmaceutical composition of claim 1, intended for prevention or treatment of erectile dysfunction.