KR20210126515A - Composition for preventing and treating pulmonary hypertension comprising niclosamide - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating pulmonary hypertension, comprising a delayed-release composition of niclosamide or a pharmaceutically acceptable salt thereof. The pharmaceutical composition for the prevention or treatment of pulmonary hypertension of the present invention solves the problems of existing formulations of niclosamide and maintains effective blood concentration and drug concentration in a target organ for a long time to be effective in preventing or treating pulmonary hypertension.

Description

Composition for the prevention and treatment of pulmonary hypertension comprising niclosamide

The present invention relates to a pharmaceutical composition for preventing or treating pulmonary hypertension, comprising a delayed-release composition of niclosamide or a pharmaceutically acceptable salt thereof.

Pulmonary hypertension is a disease in which the blood pressure of blood vessels from the heart to the lungs rises. There are 250,000 patients with pulmonary hypertension in Korea, of which 4,500-6,000, or 2-3%, are estimated to be patients with pulmonary arterial hypertension.

Patients with pulmonary arterial hypertension may show symptoms such as shortness of breath (dyspnea), fainting, dizziness, peripheral edema (eg, lower extremity edema), weakness, loss of appetite, increased heart rate, headache, anterior chest pain, and cyanosis. In addition, it may be accompanied by Raynaud's phenomenon, in which the hands and toes become easily cold in the cold and discolored blue. Pulmonary arterial hypertension patients are often misdiagnosed at first, such as asthma or the effects of excessive stress.

Pulmonary arterial hypertension has not been the subject of clinical interest for a long time due to its relatively infrequent incidence and no specific treatment method. In 2019, the domestic pulmonary arterial hypertension treatment market was worth KRW 30.7 billion, a growth of 20% compared to the previous year.

Pulmonary arterial hypertension drugs are divided into three categories: oral, inhaled, and injection. Among them, oral therapeutics are again divided into three types according to the mechanism. The class of endothelin receptor (ERA) antagonists include traclear (bosentan), obsumit (marcitentan), and bolibris (ambrisentan). Phosphodiesterase-5 inhibitors (PDE5i) include Partition (sildenafil) and Cialis (tadalafil). Lastly, there is the prostacyclin class, and the representative drug is Uptravi (Celexifac).

Despite the existence of such therapeutic agents, the results of the analysis of the status of pulmonary arterial hypertension treatment by the HIRA from 2008 to 2016 show that the 3-year survival rate in Korea is 54%, which is lower than that of the United States (2006-2007) 68%. The development and introduction of drugs for the treatment of pulmonary arterial hypertension is continuously required.

Korean Patent Publication No. 10-2018-0081936

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating pulmonary hypertension, comprising a delayed-release composition of niclosamide or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preventing or treating pulmonary hypertension using the composition.

One aspect of the present invention for achieving the above object relates to a pharmaceutical composition for preventing or treating pulmonary hypertension, comprising a delayed-release composition of niclosamide or a pharmaceutically acceptable salt thereof.

In the present invention, “niclosamide” is an oral salicyl anilide derivative that was approved by the FDA in 1960 and used to treat various parasitic infections for nearly 50 years. These existing niclosamide formulations had very low water solubility and intestinal permeability, so bioavailability was extremely low, so it was impossible to achieve and maintain a blood drug concentration to exhibit effective pharmacological effects in the body. Drugs with these physicochemical properties are usually attempted to increase bioavailability using various solubilization techniques, but niclosamide is reduced by microorganisms in the intestine and a large amount of the drug is distributed in the gastrointestinal tract. It is difficult to expect the drug effect by systemic exposure of In addition, recently, it has been reported that it can be used for anticancer therapy for various types of cancer, but it has not been reported that it can exhibit therapeutic and ameliorating effects on pulmonary hypertension depending on the dosage form, especially when administered orally. was found to have an extremely fast clearance, so there was a problem in that it was impossible to apply niclosamide to the body for the treatment of hypertension, such as pulmonary hypertension, with the existing formulation.

The delayed-release composition of the present invention solves the problems of the existing formulations of niclosamide as described above and exhibits PK profile characteristics that can show the effect of treating or improving pulmonary hypertension. The treatment or improvement effect was allowed to appear.

In the present invention, “Pulmonary hypertension” refers to various diseases having common clinical features of elevated pulmonary arterial pressure and right ventricular dysfunction along with clinical symptoms of dyspnea.

The pulmonary hypertension is pulmonary arterial hypertension, pulmonary venous occlusive disease (PVOD) and /or Pulmonary capillary hemangiomatosis (PCH), pulmonary hypertension due to left heart disease owing to left heart disease; pulmonary hypertension owing to lung disease and/or hypoxia; chronic thromboembolic pulmonary hypertension (CTEPH); It is classified as pulmonary hypertension with unclear multifactorial mechanisms.

Specifically, the pulmonary hypertension of the present invention may be pulmonary arterial hypertension (PAH).

The 'pulmonary arterial hypertension' may occur idiopathically or secondary to various causes such as chronic obstructive pulmonary disease, congenital heart disease, respiratory distress syndrome, and chronic hypoxia. Pulmonary arterial hypertension is a pathophysiology characterized by increased pulmonary vascular tone, vascular response, and proliferation of pulmonary smooth muscle cells, and secondaryly increases pulmonary vascular resistance, resulting in right ventricular hypertrophy. Pathological findings of pulmonary arterial hypertension include thickening of the vessel wall and accumulation of extracellular matrix due to hypertrophy and proliferation of endothelial cells, fibroblasts, and smooth muscle cells.

More specifically, the pulmonary arterial hypertension is idiopathic PAH, hereditable PAH, pulmonary arterial hypertension associated with congenital heart disease, and pulmonary arterial hypertension associated with connective tissue disease (PAH). associated with connective tissue diseases, PAH associated with HIV infection, PAH associated with portal hypertension, PAH associated with drugs and toxins It may be one or more selected from the group consisting of drugs and toxins, PAH associated with hemoglobinopathies, and PAH associated with pulmonary venous or capillary abnormalities. it is not

Also, specifically, the delayed-release composition may include niclosamide or a pharmaceutically acceptable salt thereof, and an anionic polysaccharide cellulose derivative.

More specifically, the anionic polysaccharide may be a carboxy polysaccharide, and the anionic polysaccharide cellulose derivative may be carboxymethyl cellulose, carboxyethyl cellulose, carboxymethyl chitosan or carboxymethyl dextran, but is not limited thereto. More specifically, the anionic polysaccharide cellulose derivative may be carboxymethyl cellulose, but as an anionic polysaccharide cellulose derivative, it can be applied without limitation as long as it is applied as an excipient of a pharmaceutical preparation to exhibit the effects of the present invention.

In addition, specifically, the composition may further include a phosphate salt and a sodium salt. The phosphate and sodium salt may be derived from sodium phosphate monobasic monohydrate, but is not limited thereto.

In addition, specifically, the delayed-release composition may further include mannitol, but is not limited thereto, and as long as it is an excipient that can be applied to the injection formulation as a sugar alcohol, it can be changed and applied as needed.

In one embodiment of the present invention, a delayed-release composition of niclosamide was prepared including an anionic polysaccharide cellulose derivative, and it was confirmed that the prepared composition showed a therapeutic effect on an increase in pulmonary arterial pressure, which is one of the effective symptoms of pulmonary hypertension.

Specifically, in pulmonary hypertension, an increase in systolic pressure, right ventricular hypertrophy, vascular occlusion in the pulmonary artery, and vascular muscle muscle appear while the pulmonary arterial pressure rises. .

In particular, similar or improved right ventricular systolic pressure (RSVP) reduction, right ventricular weight reduction, right ventricular hypertrophy, vascular occlusion, and vascular muscle muscle reduction effects were exhibited, particularly compared to niclosamide, compared to the positive control, Macitentan. It was confirmed that it exhibits a significantly superior therapeutic effect compared to the conventional niclosamide formulation and oral administration route. did.

Macitentan, a drug administered as the positive control, is a drug approved for treatment of pulmonary arterial hypertension, and is one of endothelin receptor antagonists. In pulmonary hypertension disease, endothelin-1 (endothelin-1, ET-1) produced and secreted from vascular endothelial cells is a peptide that causes strong and long-lasting vasoconstriction and is associated with changes in pulmonary blood vessels. Serum ET-1 is also produced and secreted by macrophages, mast cells, and polymorphonuclear leukocytes, and it is known that secretion from cells is stimulated by angiotensin II, which in turn causes ventricular hypertrophy and fibrosis. An endothelin receptor antagonist has been developed as a drug that modulates the cellular mechanism of action of ET-1, which acts competitively on the endothelin receptor to block the binding of ET-1.

In one embodiment of the present invention, even when macitentan, one of the endothelin receptor antagonists approved as a treatment for pulmonary arterial hypertension, is used in combination with the composition of the present invention, significant right ventricular systolic pressure (RSVP) reduction, right ventricular weight reduction, right ventricular hypertrophy inhibition, vascular occlusion It was confirmed that the effect of reducing and reducing vascular muscle was observed, and in particular, in the inhibition of right ventricular hypertrophy, as the synergistic effect was shown by the combined administration, it was confirmed that the inhibitory effect of right ventricular hypertrophy was significantly increased.

Accordingly, the pharmaceutical composition of the present invention may further include an endothelin receptor antagonist. Specifically, the endothelin receptor antagonist may be macitentan, bosentan, or ambrisentan, but is not limited thereto. Applicable.

In addition, specifically, the pharmaceutical composition of the present invention may be a formulation for parenteral administration, and more specifically, may be administered intramuscularly or subcutaneously.

In addition, the pharmaceutical composition of the present invention may be applied in a pharmaceutically effective amount, and "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and effective Dosage levels depend on the patient's sex, age, type of disease, severity, drug activity, drug sensitivity, administration time, administration route and excretion rate, duration of treatment, factors including concomitant drugs, and other factors well known in the medical field. It may depend on factors.

Another aspect of the present invention relates to a method for preventing or treating pulmonary hypertension, comprising administering the pharmaceutical composition to a subject. Specifically, the pulmonary hypertension may be pulmonary arterial hypertension, and more specifically, the pharmaceutical composition may be administered in combination with an endothelin receptor antagonist.

'Pulmonary hypertension', 'pulmonary arterial hypertension', and 'endothelin receptor antagonist' are the same as described above.

The term "subject" of the present invention includes animals or humans with pulmonary hypertension whose symptoms can be improved by administration of the pharmaceutical composition according to the present invention. By administering the therapeutic composition according to the present invention to an individual, pulmonary hypertension can be effectively prevented and treated.

The term "administration" of the present invention means introducing a predetermined substance into a human or animal by any suitable method, and the administration route of the therapeutic composition according to the present invention is through any general route as long as it can reach the target tissue. It may be administered orally or parenterally. In addition, the therapeutic composition according to the present invention may be administered by any device capable of moving the active ingredient to the target cell.

The preferred dosage of the pharmaceutical composition according to the present invention varies depending on the patient's condition and body weight, the degree of disease, drug form, administration route and period, but may be appropriately selected by those skilled in the art.

The pharmaceutical composition for preventing or treating pulmonary hypertension of the present invention is effective in preventing or treating pulmonary hypertension by solving the problems of the existing formulations of niclosamide and maintaining the effective blood concentration and drug concentration in the target organ for a long time. made to appear.

The formulation of the present invention allows the effective blood concentration of poorly soluble drug to be maintained for a long time. can increase

1 schematically shows the flow of an animal experiment confirming the pharmacological effect in the present invention.
Figure 2 shows the results of right ventricular systolic pressure analysis according to the administration of the test substance (* p <0.05, ** p <0.01, *** p <0.001).
3 shows the results of measuring the weight of the right ventricle according to the administration of the test substance.
4 shows the results of confirming the right ventricular hypertrophy index according to the administration of the test substance.
5 shows the results of confirming the blood vessel occlusion ratio according to the administration of the test substance.
6 is a micrograph showing the degree of blood vessel occlusion according to the administration of the test substance.
7 shows the results of confirming the change in the ratio of muscled blood vessels according to the administration of the test substance.
8 shows the results of confirming the change in the ratio of fully muscled blood vessels according to the administration of the test substance.
9 is a micrograph showing the degree of vascular muscle muscularization according to the administration of the test substance.

Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples are merely illustrative of the present invention, and the present invention is not limited by the following examples.

Example 1. Preparation of niclosamide delayed-release composition

Niclosamide formulations were prepared according to the composition of Table 1 below. Specifically, sodium carboxymethylcellulose, sodium phosphate monobasic monohydrate, and mannitol were added to water for injection and completely dissolved by stirring, and then niclosamide was added and stirred. After homogeneous mixing using a homomixer, the sterilization process was performed by autoclaving at 121° C. for 15 minutes. Thereafter, the drug particle size was adjusted to a target particle size through a wet milling method, and post-sterilization was completed as necessary. The average particle size of niclosamide of the prepared niclosamide delayed-release composition was 1 to 3 μm.

ingredient function Content (%, w/w) niclosamide active ingredient 21.87 Carboxymethylcellulose sodium
(Sodium carboxymethylcellulose) suspending agent 0.80 Sodium phosphate monobasic
monohydrate) buffer 0.07 mannitol suspending agent 4.37 water water for injection 72.89 Sum 100

Comparative Example 1. Comparative formulation of niclosamide The oral administration solution was 15 mg/mL by weighing an appropriate amount of niclosamide and dispersing it in a vehicle solution (0.2 v/v% Tween 80, 0.5 w/v% Methylcellulose). By preparing as much as possible, an oral administration solution was prepared.

Experimental Example 1. Pulmonary Arterial Hypertension (PAH) animal model production

Six-week-old male SD white rats (Coatec, Inc.) were obtained and had an acclimatization period to check their health for 7 days. The kennel was set at a temperature of 23±3 ℃, a relative humidity of 55±15%, a ventilation frequency of 10 to 20 times/hr, a lighting time of 12 hours (lights on at 8 am to off at 8 pm), and an illuminance of 150 to 300 Lux. Then, the body weight of animals determined to be healthy during the acclimatization period was measured, and white mice with an average body weight (g) ± 20% were selected. 10 mice were used as G1, and SUGEN (SU5416, DC chemicals) was injected subcutaneously at a concentration of 20 mg/kg and bred in a hypoxic chamber for 3 weeks to induce pulmonary arterial hypertension.

SU5416 was dissolved in DMSO and then diluted with a dilution buffer (dilution buffer, 0.5% sodium carboxymethylcellulose, 0.9% sodium chloride, 0.4% polysorbate 80 and 0.9% benzyl alcohol in deionized water). The oxygen concentration was continuously monitored with the ProOx P360 Oxygen SingleChamber Controller, and the oxygen concentration inside the chamber was maintained at about 10% through nitrogen injection for 3 weeks. Pulmonary arterial hypertension was induced by maintaining the humidity and ammonia concentration in the chamber at appropriate levels using a dehumidifier and ammonia remover.

After administration of SU5416 and induction of pulmonary arterial hypertension in a hypoxic chamber for 3 weeks, animals were bred for 2 weeks in normal oxygen (normoxia) for 2 weeks, and the test substance was administered.

Experimental Example 2. Test group composition and dosage setting

The main component, niclosamide, was contained at 240 mg/mL, and the composition of the test group and the dosage setting of the administered material are shown in Table 2 below, respectively.

G1 was a normal control without inducing disease, and Macitentan was administered as a positive control. The macitentan was previously approved as a treatment for pulmonary arterial hypertension, and was prepared at a concentration of 10 mg/mL of macitentan using 0.5% (w/v) sodium carboxymethylcellulose, and orally administered at a concentration of 30 mg/kg. (PO; per os).

In the case of oral administration, the animals were fixed by the method of fixing the skin of the dorsal region and administered directly into the stomach using a sonde for oral administration. The composition of Comparative Example 1 was administered orally daily by dividing the dose of 150 mg/10mL/kg/day into twice a day in consideration of the actual amount of oral agent used in the human body and the short half-life of the drug during body surface area-based conversion.

The composition of Example 1 of the present invention was administered intramuscularly (IM), and in the case of intramuscular administration, the administration site was disinfected using 70% alcohol before administration. Animals were carefully calibrated and administered to the right thigh of the animal using a syringe equipped with a 22 gauge needle. In the case of intramuscular administration once a week, intramuscular injection was performed using the right thigh for the 1st session and the left thigh for the 2nd time.

army Whether PAH is induced number of animals
(number of animals) dosing substance Dosage dosing cycle route of administration G1 N 10 - - - - G2 Y 13 Comparative Example 1 150 mg/10mL/kg/day dose
Divide into twice a day and administer daily Oral (PO) G3 Y 7 Example 1 0.42ml/kg
(100mg/kg as niclosamide) once a week muscle (IM) G4 Y 12 Example 1 0.63ml/kg
(150mg/kg as niclosamide) once a week muscle (IM) G5 Y 10 mashentan 30mg/kg Once a day Oral (PO) G6 Y 10 Example 1
+ Marcitentan Example 1: 0.42 ml/kg
Masitentan: 30mg/kg Example 1: Once a week
Masitentan: Once a day Example 1: Muscle (IM)
Maritentan: Oral (PO)

Experimental Example 3. Confirmation of pharmacological effect

3-1. Analysis of right ventricular systolic pressure (RVSP)

With the day of subcutaneous administration of SU5416 as D ₀ , pulmonary arterial hypertension induction was completed in a hypoxic hypoxic chamber for 3 weeks (D ₂₁ ), the test substance according to Table 2 was administered for 2 weeks, and an analysis was performed to confirm the pharmacological effect on _{D 35} (refer to the flowchart of FIG. 1).

RVSP was _{measured by measuring the weight of the experimental animal on D 35} , anesthetized using isoflurane, and then inserting a rat pressure catheter (Millar Instruments) through the right jugular vein. RVSP values were measured and analyzed using LabChart 8 software (ADInstruments).

As a result, as shown in FIG. 2 , when Example 1 was administered, a pharmacological effect similar to that of the positive control group, macitentan, was exhibited, and it was confirmed that RVSP was remarkably reduced compared to Comparative Example 1 (G2). In addition, it was confirmed that RVSP can be further reduced even in Example 1 and in combination with macitentan, an endothelin receptor antagonist (G6). Existing niclosamide exhibits reduction by microorganisms in the gastrointestinal tract when administered orally, and a large amount of drug is distributed to the gastrointestinal tract. It is difficult to maintain a blood concentration that can be effective. In the case of Comparative Example 1, due to the above-mentioned shortcomings in absorption distribution and metabolism of the drug, a very rapid clearance was observed, and accordingly, it appears that it is difficult to achieve the in vivo exposure required for the treatment of pulmonary hypertension, but the composition of Example 1 In this case, it was confirmed that effective pulmonary hypertension, particularly pulmonary arterial hypertension, was effective.

3-2. Right ventricle weight (RV weight) measurement

After completing the RVSP measurement in 3-1 above, the experimental animals were _{quickly sacrificed using CO 2} , and then laparotized to remove blood by perfusion with PBS, and some lobes of the lungs were removed and immediately cryopreserved in liquid nitrogen. After that, 10% neutral buffered formalin (NBF) was put through the airway of the experimental animal, and the remaining lobes of the lungs and heart tissue were extracted and fixed by immersion in 10% NBF. Then, the weight of the right ventricle was measured.

As a result, as shown in FIG. 3 , it was confirmed that the weight of the right ventricle was significantly reduced in G3 when Example 1 was administered. On the other hand, in the case of G4 administered at a relatively high dose of Example 1 and G5 administered with macitentan as a positive control, a significant decrease in right ventricular weight was not observed.

In addition, in the case of Example 1 and the combined use of macitentan (G6), the increase in right ventricular weight was almost completely inhibited, and in particular, when administered in Example 1, pulmonary hypertension, It was confirmed that it can exhibit an effective therapeutic effect on pulmonary arterial hypertension.

3-3. Confirmation of indicators of right ventricular hypertrophy

The heart fixed in 10% NBF was cut along the right ventricle wall, and the weight ratio was calculated after quantification of the right ventricle and left ventricle + septum. The right ventricle hypertrophy index expressed as a right ventricle/(left ventricle+ventricular wall) weight ratio (Heart (RV/LV+S) mass ratio) was confirmed by the above calculation.

As a result, as shown in FIG. 4 , it was confirmed that the increase in the right ventricular hypertrophy index was suppressed at a level similar to that of the positive control macitentan when Example 1 was administered, and the increase in the right ventricular hypertrophy index was noticeably higher than that of Comparative Example 1 (G2). It was confirmed that it was significantly suppressed. In addition, in the case of Example 1 and the combined use of macitentan (G6), it was confirmed that the increase in the right ventricular hypertrophy index was more significantly suppressed compared to the macitentan alone group (G5) by a synergistic effect.

3-4. histopathological examination

After sectioning the lungs fixed in 10% NBF with paraffin blocks, two types of tissue staining were performed to analyze vascular remodeling.

The degree of occlusion of blood vessels was analyzed by staining with hematoxylin & eosin (H&E), and the degree of muscleization of blood vessels was analyzed by co-staining with vascular endothelial cell marker (vWF) and smooth muscle cell marker (SMAα). .

3-4-1. Analysis of the degree of vascular occlusion

After hematoxylin & Eosin (H&E) staining, 34 to 140 small pulmonary arteries with a diameter of less than 50 μm per section were observed and photographed under a microscope (Olympus BX53, Japan). The degree of occlusion of each blood vessel was analyzed as no occlusion (open; no occlusion), partial occlusion (partial), and closed (occluded).

As a result, as shown in FIG. 5 , in the normal group G1, there was no vascular occlusion, whereas in the G2 group, about 70% or more of the blood vessels were partially or completely occluded. On the other hand, it was confirmed that when Example 1 was administered, vascular occlusion was significantly reduced to a level similar to that of the positive control, macitentan, and it was confirmed that the vascular occlusion was significantly reduced even when Example 1 and macitentan were used in combination.

Even in the photomicrograph of observing blood vessels with a diameter of 50 μm or less after H&E staining according to FIG. 6, completely occluded blood vessels appeared in G2, whereas occluded blood vessels in Example 1, Masitentan, Example 1, and the combination of Masitentan. It was confirmed that the number of blood vessels decreased significantly and the number of open blood vessels increased without occlusion.

3-4-2. Analysis of the degree of vascular muscleization

In order to confirm the degree of muscleization of blood vessels in the lung tissue, vWF-FITC (abcam), a vascular endothelial cell marker, and SMAα-Cy3 (abcam), a smooth muscle cell marker, were fluorescently stained. After paraffin removal and hydration, the tissues that had undergone antigen retrieval and blocking were incubated with primary antibody, followed by DAPI staining and mounting. At least 100 blood vessels with a diameter of 50 μm or less were observed and photographed under a microscope. The analysis was divided into non-muscularized, partially muscularized, and fully muscularized.

As a result, as shown in FIG. 7 , the ratio of fully muscled blood vessels in the G2 group treated with Comparative Example 1 after disease induction was rapidly increased, and when Example 1 was administered, the vascular muscle was increased to a level similar to that of the positive control, Masitentan. was confirmed to be inhibited.

In addition, in FIG. 8, it was confirmed that the proportion of fully muscled blood vessels decreased to a level similar to that of the positive control, macitentan, when Example 1 was administered.

In addition, in the micrograph of FIG. 9 in which blood vessels stained simultaneously with vWF, a marker of vascular endothelial cells, and SMAα, a marker of smooth muscle cells, were stained to confirm the degree of pulmonary arterial muscleization, Comparative Example 1 was treated after disease induction. In the G2 group, the number of muscled blood vessels was significantly increased, and it was confirmed that the proportion of fully muscled blood vessels was significantly decreased in Example 1, Masitentan, Example 1, and the combined use of Masitentan.

In confirming the pharmacological effect, statistical analysis was performed using GraphPad Prism 8 Software, and unpaired Student t- test was used.

The above results show that when the niclosamide delayed-release composition of the present invention is administered by the parenteral route, it is possible to achieve and maintain a blood drug concentration that could not be achieved by oral administration, which is a conventional formulation, thereby preventing pulmonary hypertension, particularly pulmonary arterial hypertension. and/or exhibit a therapeutic effect. This improved therapeutic effect is shown in both doses of Example 1, and further, the niclosamide delayed-release composition of the present invention may exhibit a synergistic effect with an endothelin receptor antagonist such as macitentan.

The description of the present invention described above is for illustration, and those of ordinary skill in the art to which the present invention pertains can understand that it can be easily modified into other specific forms without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. For example, each component described as a single type may be implemented in a dispersed form, and likewise components described as distributed may be implemented in a combined form.

The scope of the present invention is indicated by the following claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included in the scope of the present invention.

Claims (14)

A pharmaceutical composition for preventing or treating pulmonary hypertension, comprising a delayed-release composition of niclosamide or a pharmaceutically acceptable salt thereof. According to claim 1,
The pulmonary hypertension is pulmonary arterial hypertension, a pharmaceutical composition of pulmonary hypertension. The method of claim 1,
The delayed-release composition is a pharmaceutical composition for the prevention or treatment of pulmonary hypertension, comprising niclosamide or a pharmaceutically acceptable salt thereof and an anionic polysaccharide cellulose derivative. 4. The method of claim 3,
The anionic polysaccharide is a carboxypolysaccharide, a pharmaceutical composition for the prevention or treatment of pulmonary hypertension. 4. The method of claim 3,
The anionic polysaccharide cellulose derivative is at least one selected from the group consisting of carboxymethyl cellulose, carboxyethyl cellulose, carboxymethyl chitosan and carboxymethyl dextran, a pharmaceutical composition for preventing or treating pulmonary hypertension. 4. The method of claim 3,
The anionic polysaccharide cellulose derivative is carboxymethyl cellulose, a pharmaceutical composition for the prevention or treatment of pulmonary hypertension. 4. The method of claim 3,
The composition further comprises a phosphate and sodium salt, a pharmaceutical composition for the prevention or treatment of pulmonary hypertension. 4. The method of claim 3,
The composition further comprises mannitol, a pharmaceutical composition for the prevention or treatment of pulmonary hypertension. According to claim 1,
The pharmaceutical composition further comprises an endothelin receptor antagonist (Endothelin receptor antagonist), a pharmaceutical composition for the prevention or treatment of pulmonary hypertension. 10. The method of claim 9,
The endothelin receptor antagonist is macitentan (Macitentan), bosentan (Bosentan) or ambrisentan (Ambrisentan), a pharmaceutical composition for the prevention or treatment of pulmonary hypertension. According to claim 1,
The delayed-release composition is a pharmaceutical composition for the prevention or treatment of pulmonary hypertension, which is administered parenterally. A method of treating pulmonary hypertension, comprising administering the composition of claim 1 to a non-human subject. 13. The method of claim 12,
The method of treating pulmonary hypertension, wherein the pulmonary hypertension is pulmonary arterial hypertension. 13. The method of claim 12,
The pharmaceutical composition is to be administered in combination with an endothelin receptor antagonist, the therapeutic method.

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