Pharmaceutical compositions containing udenafil

Abstract

Pharmaceutical compositions comprising udenafil are disclosed.

Description

[Technical Field]

[0001] Cross-Citation of Related Applications This application claims the benefit of priority based on Korean Patent Application No. 10-2019-0091056, filed on July 26, 2019, the entire disclosure of which is incorporated herein by reference.

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

[0003] Udenafil, a compound named 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 a currently marketed drug for the treatment of erectile dysfunction. Udenafil has the following chemical structure: [ka]

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

[0005] The Fontan procedure began as a palliative surgical procedure for children born with a functional single ventricle congenital heart disease, in which the right atrium was directly connected to the pulmonary artery when the right ventricle was not functional. This procedure was based on the discovery that the right ventricle, unlike the left ventricle, is not necessary to maintain pulmonary artery blood flow. The Fontan procedure has been used in patients with right ventricular hypoplasia, tricuspid atresia, and single-ventricle heart disease. More recently, the surgical technique has been significantly improved, using a direct or conduit connection to the pulmonary artery via the vena cava.

[0006] Currently, udenafil, which is used to treat erectile dysfunction, is commercially available in tablet form, which makes it difficult to administer to patients with swallowing difficulties and to infants.

[0007] In the case of Fontan patients, the primary age group for udenafil use is infants and young children, and for ease of administration, udenafil is preferably formulated as a liquid or syrup rather than as a tablet. However, when udenafil is formulated as a liquid or syrup, problems arise, such as the strong bitterness inherent to udenafil or the numbness caused by udenafil. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] Republic of Korea Patent No. 10-0792126 [Patent Document 2] Republic of Korea Patent No. 10-0496372 [Patent Document 3] Republic of Korea Patent Application Publication No. 10-2017-0066334 Summary of the Invention [Problem to be solved by the invention]

[0009] As a result, the present inventors discovered that when udenafil or a pharmaceutically acceptable salt thereof is formulated as a liquid or syrup, the bitterness and numbness can be masked, thereby improving the compliance of infant patients with medication, and thus completed the present invention.

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

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

[0012] The present invention relates to a pharmaceutical composition containing udenafil or a pharmaceutically acceptable salt thereof, a pH adjuster, and a cyclodextrin or a derivative thereof.

[0013] The compositions of the present invention are for administration to patients who have undergone the Fontan procedure and are preferably in the form of a liquid or syrup that is convenient for administration to infants and young children.

[0014] The composition of the present invention may further contain a viscosity modifier. The viscosity of the composition of the present invention is preferably 400 to 4000 cps. The pH of the composition of the present invention is preferably within the range of 3 to 6.

[0015] In the present invention, the cyclodextrin derivative may be 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 of the udenafil or a pharmaceutically acceptable salt thereof to the cyclodextrin or a derivative thereof is preferably 1:0.1-10.

[0017] In the present invention, the viscosity adjuster may be at least one selected from the group consisting of agar, xanthan gum, locust bean gum, guar gum, tragacanth gum, gum arabic, gellan gum, karaya gum, gum ghatti, 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 adjuster 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. [Effects of the Invention]

[0019] The pharmaceutical composition containing udenafil or a pharmaceutically acceptable salt thereof according to the present invention minimizes the inherent bitterness of the drug and the numbness caused by the drug, thereby improving compliance among infants and patients with dysphagia, who are the primary target users. Furthermore, by ensuring the uniformity of the liquid or syrup, layer separation does not occur, and the liquid or syrup composition has good flowability, making it possible to provide a high-quality liquid or syrup composition containing udenafil. [Brief explanation of the drawings]

[0020] [Figure 1] 1 is a photograph of the appearance of a composition according to an embodiment of the present invention taken after a stability test. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention will be described in detail below.

[0022] Pharmaceutical Compositions The present invention relates to a pharmaceutical composition containing udenafil or a pharmaceutically acceptable salt thereof, a pH adjuster, and a cyclodextrin or a derivative thereof.

[0023] The term "pharmaceutically acceptable salt" used in the present invention means a salt commonly used in the pharmaceutical industry, and includes, for example, 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.; 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, glucuronolic acid, acetic ... Examples of suitable salts include organic acid salts formed with carboxylic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; sulfonate 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., but the types of salts meant in the present invention are not limited to these listed salts.

[0024] The compositions of the invention relate to pharmaceutical compositions for administration to patients who have had a Fontan procedure to treat or prevent conditions, symptoms and / or side effects associated with patients who have had a Fontan procedure, which may, for example, improve cardiac output, decrease pulmonary vascular resistance, increase exercise capacity, improve myocardial performance, or improve aerobic exercise performance.

[0025] Furthermore, the composition of the present invention relates to a pharmaceutical composition for preventing or treating erectile dysfunction, and improves compliance with medication in patients with erectile dysfunction (especially patients who have difficulty swallowing).

[0026] The term "prevention" as used herein means delaying the onset of a disease, disorder, or condition. Prevention can be considered complete if the onset of the disease, disorder, or condition has been delayed for a predetermined period of time.

[0027] The term "treatment" as used herein refers to partially or completely alleviating, ameliorating, mitigating, delaying the onset of, inhibiting the progression of, reducing the severity of, or reducing the occurrence of at least one symptom or characteristic of a particular disease, disorder, and / or condition.

[0028] In one embodiment of the present invention, the pharmaceutical compositions of the present invention may be prepared in unit dose form or may be prepared to be contained in multi-dose containers by formulating them with a pharmaceutically acceptable carrier by methods readily practiced by those skilled in the art.

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

[0030] In one embodiment of the present invention, the pharmaceutically acceptable carrier is one commonly used in pharmaceutical formulations, including, but not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. The pharmaceutical composition of the present invention may further contain, in addition to the above ingredients, lubricants, wetting agents, sweeteners, flavoring agents, emulsifiers, suspending agents, preservatives, etc.

[0031] In one embodiment of the present invention, the content of the additive contained in the pharmaceutical composition is not particularly limited and may be appropriately adjusted within the range of the content normally used in formulations.

[0032] Due to the intended mode of administration, the compositions of the present invention are preferably in the form of a liquid or syrup for convenient oral administration to infants and young children who have undergone the Fontan procedure.

[0033] The term "administration" as used in the present invention means providing a predetermined substance to a subject or patient by any suitable method. Depending on the intended method, the substance may be administered parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or locally in an injectable form) or orally. The dosage may vary depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and disease severity. The composition of the present invention is preferably administered orally.

[0034] The term "oral administration" used in the present invention means that a substance prepared so that the active substance is digested is administered to the gastrointestinal tract for absorption.To formulate the pharmaceutical composition of the present invention into a form for oral administration, binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose, or gelatin, excipients such as dicalcium phosphate, disintegrants such as corn starch or sweet potato starch, lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, or polyethylene glycol, etc., can be used, and sweeteners, flavorings, syrups, etc. can also be used.Furthermore, in the case of capsules, in addition to the above-mentioned substances, liquid carriers such as fatty oils can also be used.

[0035] The preferred dosage of the pharmaceutical composition of the present invention may vary depending on the patient's condition, body weight, age, sex, health condition, diet, and constitutional characteristics, the nature of the formulation, the severity of the disease, the administration time, administration method, administration period or interval, excretion rate, and drug form, 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 a day or in divided doses.

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

[0037] The term "liquid formulation" as used in the present invention refers to a liquid medicine for oral administration obtained by dissolving a pharmaceutical agent in water or an organic solvent. The liquid formulation has the advantage of more effective absorption of the drug from the gastrointestinal tract into the systemic circulation compared to a suspension or solid formulation. The liquid formulation may contain additional solutes in addition to the pharmaceutical agent, and may also contain additives that impart color, odor, sweetness, or stability.

[0038] The term "syrup" as used herein refers to a concentrated aqueous solution of sugar or a sugar substitute. In the present invention, the syrup is a dosage form formulated to make it easier to take drugs with an unpleasant taste, such as a bitter taste. The syrup is particularly suitable for children. In the present invention, the syrup may contain, in addition to purified water and extracts, sugar or a sugar substitute used to impart sweetness and viscosity, an antibacterial preservative, a sweetener, a flavoring agent, or a coloring agent, but is not limited thereto. Examples of sweeteners that may be contained in such syrups 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 may further contain a viscosity modifier. In the present invention, the viscosity of the composition is preferably 400 to 4000 cps, but is not limited thereto. In addition, the pH of the composition of the present invention is preferably within the range of 3 to 6, but is not limited thereto.

[0040] The term "cps" as used in the present invention means centipoise, a viscosity unit.

[0041] The term "cyclodextrin derivative" as used herein refers to a compound or a portion of a compound derived from cyclodextrin.

[0042] In the present invention, the cyclodextrin derivative may be 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, it is preferred to use γ-cyclodextrin alone or in combination with α-cyclodextrin.

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

[0044] The term "viscosity modifier" as used herein refers to a substance used to bind the liquid and solid phases in a pharmaceutical composition to maintain the pharmaceutical composition in a stable state without phase separation and to increase the viscosity of the pharmaceutical composition.

[0045] In the present invention, the viscosity adjuster may be at least one selected from the group consisting of agar, xanthan gum, locust bean gum, guar gum, tragacanth gum, gum arabic, 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] The term "pH adjusting agent" as used herein refers to an excipient used to adjust the pH of a pharmaceutical composition to a desired value.

[0047] In the present invention, the pH adjuster 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.

[0048] Methods for preventing or treating Fontan disease and pulmonary hypertension or erectile dysfunction associated with Fontan disease The invention provides a method for preventing or treating Fontan disease and pulmonary hypertension or erectile dysfunction associated with Fontan disease, comprising the step of administering a therapeutically effective amount of the pharmaceutical composition to a mammal, including a human.

[0049] The term "therapeutically effective amount" as used herein refers to an amount effective for preventing or treating pulmonary hypertension or erectile dysfunction associated with Fontan disease, for example, the amount of a pharmaceutical composition administered to a subject to be treated. This term may include an amount of a pharmaceutical composition that prevents the occurrence or recurrence of pulmonary hypertension or erectile dysfunction associated with Fontan disease, alleviates the symptoms of the disease, reduces any direct or indirect pathological consequences of the disease, prevents the metastasis of the disease, reduces the rate of progression of the disease, alleviates or temporarily alleviates the disease state, or achieves remission or improved prognosis. In other words, the therapeutically effective amount may be interpreted as encompassing all doses of the pharmaceutical composition that improve or completely cure the symptoms of pulmonary hypertension or erectile dysfunction associated with Fontan disease.

[0050] The method for preventing or treating Fontan disease and pulmonary hypertension or erectile dysfunction associated with Fontan disease by administering the pharmaceutical composition not only addresses the disease itself before symptoms appear, but also inhibits or prevents the symptoms. In disease management, the magnitude of the prophylactic or therapeutic dose of a particular active ingredient will vary depending on the nature and severity of the disease or condition, as well as the route by which the active ingredient is administered. The dose and dose frequency will also vary depending on the age, weight, and response of the individual patient. An appropriate dosage regimen can be easily selected by those skilled in the art after due consideration of such factors. The method for preventing or treating Fontan disease and pulmonary hypertension or erectile dysfunction associated with Fontan disease may also include administering a therapeutically effective amount of an additional active ingredient together with the pharmaceutical composition, which is useful for preventing or treating Fontan disease and pulmonary hypertension or erectile dysfunction associated with Fontan disease. The additional active ingredient may exhibit a synergistic or additive effect with the pharmaceutical composition.

[0051] The expression "mammals including humans" used in the present invention includes mammals such as humans, monkeys, cows, horses, dogs, cats, rabbits, and rats.

[0052] Uses of the Pharmaceutical Composition The present invention provides the use of the pharmaceutical composition for the manufacture of a medicament for treating Fontan disease and pulmonary hypertension or erectile dysfunction associated with Fontan disease.

[0053] The present invention provides the use of said pharmaceutical composition for the treatment of Fontan disease and pulmonary hypertension or erectile dysfunction associated with Fontan disease.

[0054] Pharmaceutical compositions of the invention for the manufacture of Fontan disease and pulmonary hypertension or erectile dysfunction associated with Fontan disease medications may include an acceptable carrier and may further include other active agents.

[0055] The matters mentioned in the pharmaceutical composition, the prophylactic or therapeutic method, and the use of the present invention are equally applicable unless they contradict each other.

[0056] [Example] The present invention will be described in detail below with reference to examples to aid in understanding the present invention. However, the following examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art.

[0057] Test Example 1: Solubility test of udenafil at different pH levels To evaluate the solubility of udenafil (free base) at different pH levels, Preparation Examples 1 to 8 in Table 1 below were prepared and subjected to a solubility test. The test results are shown in Table 2 below.

[0058] [Table 1]

[0059] Production methods for Production Examples 1 to 8: A pH adjuster was added to 5 ml of purified water, and the mixture was stirred for 10 minutes, after which udenafil was added to prepare the solutions shown in Table 1. After stirring each solution for 2 hours, a sample was taken and filtered through a 0.45 μm PVDF syringe filter. A solubility test was performed to measure the pH (pH measuring device: pH2700, EUTECH, USA).

[0060] HPLC analysis conditions Detector: UV detector (292 nm) Column: Aegispak C18-F 5 μm, 4.6 × 150 mm Column temperature: 30℃ Mobile phase: Dissolve 2.72 g of KH2PO4 in 1 L of purified water (A); acetonitrile (B); A:B = 700:300. Flow rate: 1.0mL / min Injection volume: 10μL

[0061] [Table 2]

[0062] The aqueous solubility of udenafil was approximately 0.12 mg / mL (Comparative Example 1), making it extremely poorly soluble in water. The above test confirmed that the solubility of udenafil varied depending on the pH of the solution. In Preparation Example 1, where the pH was 6.83, the solubility improved, while in Preparation Example 4, where the pH was low (pH 6.1), the solubility increased significantly. However, in Preparation Examples 7 and 8, where the pH was lower than 2, the solubility was slightly lower than in the Preparation Examples in the pH range of 3 to 6.

[0063] These results demonstrate that udenafil has the highest solubility in the pH range of 3 to 6.

[0064] Preparation of Comparative Examples 1 and 2 Using the ingredients and contents in Table 3 below, a composition (Comparative Example 1) was prepared by adding udenafil to purified water, and a composition (Comparative Example 2) was prepared by adjusting the pH with a pH adjuster to completely dissolve the udenafil.

[0065] [Table 3]

[0066] Manufacturing method: Each composition in Table 3 was manufactured according to the following manufacturing method.

[0067] Comparative Example 1: Udenafil was added to 100 ml of purified water and stirred for 20 minutes to produce a tablet.

[0068] Comparative Example 2: A pH adjuster was added to 100 ml of purified water, and udenafil was added to this solution, followed by stirring for 20 minutes to prepare a pharmaceutical preparation.

[0069] Preparation of Comparative Examples 3 and 4 Udenafil syrup compositions (Comparative Examples 3 and 4) containing no cyclodextrin were prepared according to the compositions shown in Table 4. The composition of Comparative Example 3 did not contain a pH adjuster, and therefore, udenafil was not completely dissolved.

[0070] [Table 4]

[0071] Manufacturing method: Each composition in Table 4 was manufactured according to the following manufacturing method. (i) A pH adjuster is added to 20 ml of purified water and stirred for 10 minutes (however, this step is omitted when producing Comparative Example 3 which does not contain a pH adjuster). (ii) Add udenafil to the solution and stir for 20 minutes. (iii) Add the sweetener and preservative to approximately 40 mL of purified water, heat to 90°C or higher, and stir for at least 1 hour until all the ingredients are dissolved. (iv) The solution mixed in step (ii) is mixed with the solution prepared in step (iii), stirred, cooled, and then purified water is added to a final volume of 100 ml to prepare each composition.

[0072] Preparation of Comparative Examples 5 to 15 Udenafil syrup compositions containing cyclodextrin were prepared according to the compositions shown in Tables 5-1 and 5-2 below. The composition of Comparative Example 5 did not contain a pH adjuster, so udenafil was not completely dissolved.

[0073] [Table 5-1]

[0074] [Table 5-2]

[0075] Manufacturing method: Each composition in Table 5 was manufactured according to the following manufacturing method. (i) A pH adjuster is added to 20 ml of purified water and stirred for 10 minutes (however, this step is omitted when producing Comparative Example 5 which does not contain a pH adjuster). (ii) Add udenafil to the solution and stir for 20 minutes. (iii) The solution is heated to 60°C, and cyclodextrin is added thereto, followed by stirring for 20 minutes. (iv) Add the sweetener and preservative to approximately 40 mL of purified water, heat to 90°C or higher, and stir for at least 1 hour until completely dissolved. (v) The solution mixed in step (iii) is mixed with the solution prepared in step (iv), stirred, cooled, and then purified water is added to a final volume of 100 ml to prepare each composition.

[0076] Preparation of Comparative Examples 16 to 23 The udenafil syrup compositions shown in Table 6 below containing cyclodextrin and a pH adjuster were prepared.

[0077] [Table 6]

[0078] Manufacturing method: Each composition in Table 6 was manufactured according to the following manufacturing method. (i) Add a pH adjuster to 20 ml of purified water and stir for 10 minutes. (ii) Add udenafil to the solution and stir for 20 minutes. (iii) While heating the solution to 60°C, cyclodextrin is added, and the mixture is stirred for 20 minutes. (iv) Add the sweetener, viscosity adjuster, and preservative to approximately 40 mL of purified water, heat to 90°C or higher, and stir for at least 1 hour until all are dissolved. (v) The solution mixed in step (iii) is mixed with the solution prepared in step (iv), stirred, cooled, and then purified water is added to a final volume of 100 ml to prepare each composition.

[0079] Preparation of Examples 1 to 20 The udenafil syrup compositions shown in Tables 7-1, 7-2, and 7-3 below were prepared.

[0080] [Table 7-1]

[0081] [Table 7-2]

[0082] [Table 7-3]

[0083] Manufacturing method: Each composition in Table 7 was manufactured according to the following manufacturing method. (i) Add a pH adjuster to 20 ml of purified water and stir for 10 minutes. (ii) Add udenafil to the solution and stir for 20 minutes. (iii) While heating the solution to 60°C, cyclodextrin is added, and the mixture is stirred for 20 minutes. (iv) Add the sweetener and preservative to approximately 40 mL of purified water, heat to 90°C or higher, and stir for at least 1 hour until completely dissolved. (v) The solution mixed in step (iii) is mixed with the solution prepared in step (iv), stirred, cooled, and then purified water is added to a final volume of 100 ml to prepare each composition.

[0084] Test Example 2: Evaluation of flowability and sedimentation of the composition The viscosity, pH value, relative flowability, and sedimentation of each of the compositions of the comparative examples and examples were measured, and the results are shown in Table 8 below for comparison.

[0085] A. Viscosity measurement The viscosity of each composition was measured using a viscosity measuring device, and the measurement results are shown in Table 8 below. Equipment used: LVDV-E, Brookfield, USA Spindle: S62 Rotation speed: 30 rpm B. pH Measurement The pH of each composition was measured using a viscosity meter, and the results are shown in Table 8 below. Equipment used: pH2700, EUTECH, USA C. Comparison of flowability To compare the relative flowability, 1 ml of each sample was poured onto an inclined path under the following conditions, and the time it took for the samples to reach the bottom was compared. The results are shown in Table 8 below. Ramp material: Polypropylene Ramp angle: 45° Ramp length: 10cm D. Evaluation of Layer Separation To evaluate layer separation, each sample was left at room temperature for one month, and then visually observed to determine whether layer separation occurred. The results are shown in Table 8 below.

[0086] [Table 8]

[0087] The viscosity, pH, flowability, and degree of layer separation of each sample were confirmed. As a result, layer separation was observed in Comparative Examples 3 to 19, which had a viscosity of 297 cps or less, and it was confirmed that the solution stability was poor in each of Comparative Examples 3 to 19.

[0088] It was confirmed that samples with a viscosity of 431 cps or higher were stable without phase separation. However, in Comparative Examples 20 and 21, which had a viscosity of 13,000 cps or higher, the syrup hardly flowed even on an inclined plane. The compositions of Comparative Examples 22 and 23, which had a viscosity of 5,210 cps or higher, flowed, but the time to reach the bottom was 1 minute 40 seconds and 3 minutes 40 seconds, respectively, confirming extremely poor flowability. Such liquid or syrup preparations with poor flowability cause inconvenience when divided into small portions for administration and may result in inconsistent dosage, making them unsuitable for use as liquid or syrup preparations.

[0089] Test Example 3: Sensory Evaluation A sensory test was conducted on 10 healthy adults to evaluate the bitterness and numbness of each composition. The test results were evaluated according to the evaluation criteria in Table 9 below, and the average scores of the 10 people are shown in Tables 10 and 11 below.

[0090] [Table 9]

[0091] [Table 10]

[0092] [Table 11]

[0093] As a result of the sensory evaluation, both Comparative Example 1, in which udenafil was dispersed in purified water, and Comparative Example 2, in which udenafil was completely dissolved by adjusting the pH, exhibited a strong bitter taste and a numbing sensation.

[0094] Comparative Examples 3 and 4, which were prepared in the form of a syrup, had a slightly reduced bitter taste, but the numbness they caused was almost the same as that caused by Comparative Examples 1 and 2.

[0095] The compositions of Comparative Examples 5 and 6 contained γ-cyclodextrin, but due to the udenafil particles remaining dispersed without being completely dissolved, the evaluation scores for bitterness and numbness were almost the same as those of Comparative Examples 2 and 3.

[0096] In the remaining comparative examples and examples, it was confirmed that the bitterness and numbness were reduced by adding cyclodextrin, and in particular, the numbness was significantly reduced.

[0097] The test results were comprehensively evaluated according to the criteria shown in Table 12 below, and the evaluation results are shown in Table 13 below.

[0098] [Table 12]

[0099] [Table 13]

[0100] From the above results, it was found that when the viscosity of the composition was 400 cps or more, no layer separation was observed, but when the viscosity was extremely high, the flowability was extremely poor, which made it difficult to commercialize the composition. Therefore, the viscosity range of 400 to 4000 cps is suitable.

[0101] Sensory evaluation confirmed that compositions containing cyclodextrin significantly reduced bitterness and numbness, but when the pH of the composition was high and udenafil was not fully dissolved, the bitterness and numbness were barely reduced even with the use of cyclodextrin. Therefore, the pH of the composition is most suitable in the range of pH 3 to 6, which is the range in which udenafil has the highest solubility.

[0102] The compositions of Examples 1 to 20, which met these criteria, showed satisfactory results in all aspects including layer separation, flowability, bitterness, and numbness compared to the compositions of Comparative Examples 1 to 23.

[0103] Test Example 4: Stability test of the composition Example 6 was selected because it showed all the appropriate results. To evaluate stability, the appearance (phase separation), content, impurities, pH, and viscosity of Example 6 were evaluated under stress conditions (60°C) and accelerated conditions (40°C, 75% RH). The test results are shown in Table 14 below and Figure 1.

[0104] A. Appearance Visually observe. B. Content and Impurities Udenafil concentration in syrup composition: 10 mg / ml Sample preparation: 20 mg of udenafil from the syrup composition was taken and placed in a 100 ml flask, which was filled to 80% with diluent and stirred for 1 hour. The solution was then diluted to the mark with diluent and filtered using a 0.45 μm PVDF syringe filter, and the filtrate was used as the test sample. HPLC analysis conditions Detector: UV detector (292 nm) Column: Aegispak C18-F 5 μm, 4.6 × 150 mm Column temperature: 30℃ Mobile phase: Dissolve 2.72 g of KH2PO4 in 1 L of purified water (A); acetonitrile (B); A:B = 700:300. Flow rate: 1.0mL / min Injection volume: 10μL C. pH Measurement The pH was measured using a pH meter. Equipment used: pH2700, EUTECH, USA D. Viscosity Measurement The viscosity was measured using a viscometer. Equipment used: LVDV-E, Brookfield, USA Spindle: S62 Rotation speed: 30 rpm

[0105] [Table 14]

[0106] As a result of the stability test, the compositions of the examples showed suitable results in all items including appearance, content, impurities, pH, and viscosity. [Industrial Applicability]

[0107] The pharmaceutical composition containing udenafil or a pharmaceutically acceptable salt thereof according to the present invention minimizes the inherent bitterness of the drug and the numbness caused by the drug, thereby improving compliance among infants, who are the primary target patients. Furthermore, by ensuring the uniformity of the liquid or syrup, it is possible to provide a high-quality udenafil-containing liquid or syrup composition with no layer separation and good flowability.

Claims

1. A pharmaceutical composition comprising udenafil or a pharmaceutically acceptable salt thereof, a pH adjusting agent, and a cyclodextrin or a derivative thereof, wherein the cyclodextrin derivative is at least one selected from the group consisting of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin; the pharmaceutical composition is a liquid or syrup for oral administration and further comprises a viscosity adjusting agent; The viscosity of the pharmaceutical composition is 400-4000 cps and the pH is in the range of 3-6; and the weight ratio of the udenafil or its pharmaceutically acceptable salt to the cyclodextrin or its derivative is 1:1 to 5; Pharmaceutical compositions.

2. 10. The pharmaceutical composition of claim 1 for administration to a patient who has undergone the Fontan procedure.

3. 2. The pharmaceutical composition of claim 1, wherein the viscosity adjuster is at least one selected from the group consisting of agar, xanthan gum, locust bean gum, guar gum, tragacanth gum, gum arabic, 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.

4. 2. The pharmaceutical composition of claim 1, wherein the pH adjuster 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.

5. 10. The pharmaceutical composition of claim 1, for the prevention or treatment of Fontan disease and pulmonary hypertension associated with Fontan disease.

6. The pharmaceutical composition according to claim 1, which is for the prevention or treatment of erectile dysfunction.

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