Highly concentrated liquid aqueous pyronaridine preparations

Abstract

The present invention relates to a liquid aqueous formulation of pyronaridine for use in medical treatment, wherein the liquid aqueous formulation comprises at least 70% by weight of water and at least 40 μmol / mL of dissolved pyronaridine, has a pH in the range of 2.5 to 5.8, and is characterized in that the ratio of the osmotic pressure (Osm / kg) of the formulation to the pyronaridine concentration (mmol / mL) of the formulation is less than 2.0. The present invention also relates to a sterile liquid aqueous formulation comprising at least 70% by weight of water and at least 40 μmol / mL of dissolved pyronaridine, has an osmotic pressure in the range of 0.15 to 0.60 Osm / kg and a pH in the range of 2.5 to 5.8, and is characterized in that the ratio of the osmotic pressure (Osm / kg) of the formulation to the pyronaridine concentration (mmol / mL) of the formulation is less than 2.0. The concentrated aqueous pyronaridine preparation of the present invention is fully suitable for intramuscular administration, but can also be suitably administered subcutaneously, nasally, orally, intraperitoneally, or intravenously.

Description

Technology Field

[0001] The present invention relates to a highly concentrated liquid aqueous pyronaridine formulation particularly suitable for, for example, intramuscular or intranasal administration.

[0002] The present invention also relates to the use of the aforementioned pyronaridine preparation in medical treatments, such as the treatment of malaria. Background Technology

[0003] Malaria is a severe, sometimes fatal, disease caused by parasites that typically infect certain types of mosquitoes that bite humans. People infected with malaria usually become very ill with high fever, chills, and flu-like symptoms. There are four types of malaria parasites, namely Plasmodium palsipharum ( Plasmodium falciparum ), P. Bbox( P. vivax ), P. Ovalle( P. ovale ), and Blood. To malaria ( P. malariae ) infects humans. Additionally, blood, a type of malaria that naturally infects macaque monkeys in Southeast Asia. Noulesi ( P. knowlesi ) also infects humans and causes zoonotic malaria, which is transmitted from animals to humans. Blood. Palsipalum ( P. falciparum ) is the type of malaria most likely to cause severe infection, and if not treated quickly, it can lead to death.

[0004] Globally, the World Health Organization estimates that in 2020, there were 241 million clinical cases of malaria and 627,000 deaths, the majority of which were children in Africa. Because malaria causes massive disease and mortality, it places a significant burden on the economies of many countries. Since many malaria-affected nations are already impoverished, the disease perpetuates a vicious cycle of disease and poverty.

[0005] Pironaridine is an antimalarial drug. It was first manufactured in 1970 and has been used clinically in China since the 1980s. In a small (n=88) malaria study in Cameroon, pironaridine showed a 100% cure rate compared to 60% for chloroquine. It has also been studied as a potential anticancer agent and a treatment for Ebola.

[0006] Trademark name Pyramax ® Artesunate / pyronaridine commercially available is a fixed-dose combination product for the treatment of malaria administered orally. Each Pyramax tablet contains 180 mg of pyronaridine tetraphosphate and 60 mg of artesunate. Pyramax tablets should be administered orally at a once-daily dose (1 to 4 tablets per day depending on body weight) for 3 consecutive days.

[0007] The combination of pyronaridine and artesunate is being studied as a possible treatment for moderate to severe SARS-COV-2.

[0008] Shao( A review of the antimalarial drug pyronaridine , Chin Med J (Engl) 1990, 103:428-434) reported that intramuscular injection of 48 μmol / kg of pyronaridine in a 4% solution induced a mild local irritation reaction in rabbits that completely disappeared within 2 weeks.

[0009] Adegoke and others ( Determination of the phyiscochemical properties of pyronaridine - a new antimalarial drug , Pak. J. Pharm. Sci. 2006, Vol. 19(1), 1-6) investigated the physicochemical properties of pyronaridine. It was found that pyronaridine tetraphosphate is slightly soluble in water and very slightly soluble in other solvents. At the end of the paper, the authors concluded that there is a need to improve the properties of pyronaridine to enhance its utility in their study, and hypothesized that selecting other salt forms with superior solubility, distribution, and distribution characteristics could help improve the poor bioavailability of this drug already observed.

[0010] Croft and others ( Review of pyronaridine anti-malarial properties and product characteristics Malaria Journal 2012, 11:270) reported that pyronaridine has high efficacy against Plasmodium falciferum, including chloroquine-resistant strains. The authors reported that pyronaridine tetraphosphate (base 56.89%) is administered as a bitter-tasting, odorless yellow powder, and that this drug is produced in China as a tablet for oral administration and as an injectable solution for intramuscular administration, and has also been administered intravenously. The authors also observed that while the free base of pyronaridine is 'extremely' soluble in water, the tetraphosphate salt is 'slightly' soluble (1.46%) in water, which aids in oral absorption.

[0011] Literature [Chu et al., Pyronaridine: a review of its clinical pharmacology in the treatment of malaria [J Antimicrob Chemother 2023; 78: 2406-2418] provides a comprehensive overview of the clinical pharmacology of pyronaridine in the treatment of malaria. This paper states that pyronaridine tetraphosphate as a monotherapy is sold in the Chinese market under the trade name Malaridine and is formulated as an enteric-coated tablet (pyronaridine base 100 mg) for oral administration and an injectable drop solution (pyronaridine base 80 mg / 2 mL) for intramuscular administration.

[0012] Currently, there are no available pyronaridine preparations concentrated enough to be administered intramuscularly or intranasally to humans.

[0013] The inventors have developed a liquid aqueous pyronaridine formulation that is sufficiently concentrated and has a sufficiently low osmotic pressure so as to be administered intramuscularly. The liquid aqueous pyronaridine formulation of the present invention contains at least 40 μmol / mL of dissolved pyronaridine, has a pH in the range of 2.5 to 5.8, and has a ratio of the osmotic pressure (Osm / kg) of the formulation to the pyronaridine concentration (mmol / mL) of the formulation to less than 2.0.

[0014] Accordingly, one aspect of the present invention relates to a liquid aqueous formulation of pyronaridine for use in medical treatment, wherein the liquid aqueous formulation comprises at least 70 weight% water and at least 40 μmol / mL of dissolved pyronaridine, has a pH in the range of 2.5 to 5.8, and is characterized in that the ratio of the osmotic pressure (Osm / kg) of the formulation to the pyronaridine concentration (mmol / mL) of the formulation is less than 2.0.

[0015] The inventors have discovered that a highly concentrated liquid aqueous formulation of pyronaridine that can be safely administered intramuscularly can be obtained by dissolving a pyronaridine base in water with a strong acid such that the resulting formulation has a pH in the range of 2.5 to 5.8 and a ratio of osmotic pressure to pyronaridine concentration of less than 2.0. For example, by using a pyronaridine base instead of pyronaridine tetraphosphate, the inventors were also able to prepare an isotonic highly concentrated pyronaridine solution.

[0016] Accordingly, another aspect of the present invention relates to a sterile liquid aqueous formulation comprising at least 70 weight% water and at least 40 μmol / mL of dissolved pyronaridine, having an osmotic pressure in the range of 0.15 to 0.60 Osm / kg and a pH in the range of 2.5 to 5.8, and having a ratio of the osmotic pressure (Osm / kg) of the formulation to the pyronaridine concentration (mmol / mL) of the formulation of less than 2.0.

[0017] The concentrated aqueous pyronaridine preparation of the present invention is fully suitable for intramuscular administration, but can also be suitably administered nasally, orally, or intravenously. Specific details for implementing the invention

[0018] A first aspect of the present invention relates to a liquid aqueous formulation of pyronaridine for use in medical treatment, wherein the liquid aqueous formulation comprises at least 70 weight% water and at least 40 μmol / mL of dissolved pyronaridine, has a pH in the range of 2.5 to 5.8, and is characterized in that the ratio of the osmotic pressure (Osm / kg) of the formulation to the pyronaridine concentration (mmol / mL) of the formulation is less than 2.0.

[0019] Used at this institution The term "pyronaridine" refers to the substance 4-[(7-chloro-2-methoxy-1,5-dihydrobenzo[b][1,5]naphthiridine-10-yl)imino]-2,6-bis(pyrrolidine-1-ylmethyl)cyclohexa-2,5-dien-1-one (CAS number: 74847-35-1). The molar mass of pyronaridine is 518.05 g / mol.

[0020] The term "malaria" used here refers to Plasmodium falsifalum, Plasmodium bibox ( Plasmodium vivax ), Plasmodium Ovale( Plasmodium ovale ), Plasmodium malaria ( Plasmodium malariae ) and Plasmodium noulesi( Plasmodium knowlesi It refers to an infection caused by malaria parasites selected from ).

[0021] The medical treatment of the present invention is preferably a human medical treatment.

[0022] The treatment of the present invention preferably comprises administering a liquid aqueous pyronaridine preparation to provide pyronaridine in a dose of at least 1 μmol / kg (body weight), more preferably 2 to 100 μmol / kg (body weight), and most preferably 3 to 60 μmol / kg (body weight).

[0023] Treatment may suitably involve the administration of aqueous pyronaridine preparations by various modes of administration, including intramuscular, subcutaneous, intravenous, intranasal, oral, or intraperitoneal administration. More preferably, treatment includes intramuscular, intranasal, or intravenous administration of aqueous pyronaridine preparations.

[0024] In a preferred embodiment of the present invention, treatment comprises intramuscular administration of an aqueous pyronaridine preparation. According to a particularly preferred embodiment, the aqueous pyronaridine preparation is administered intramuscularly to provide pyronaridine at a dose of at least 1 μmol / kg (body weight), more preferably at a dose of 2 to 30 μmol / kg (body weight), and most preferably at a dose of 3 to 20 μmol / kg (body weight).

[0025] In another preferred embodiment of the present invention, treatment involves intranasal administration of an aqueous pyronaridine preparation. According to a particularly preferred embodiment, the aqueous pyronaridine preparation is administered intranasally to provide pyronaridine at a dose of at least 0.5 μmol / kg (body weight) / day, more preferably at a dose of 1 to 30 μmol / kg (body weight) / day, and most preferably at a dose of 2 to 20 μmol / kg (body weight) / day.

[0026] The treatment of the present invention preferably comprises intranasal administration of an aqueous pyronaridine preparation at least once a day for 2 to 10 days, preferably 3 to 6 days.

[0027] In another preferred embodiment, treatment involves oral administration of an aqueous pyronaridine preparation. According to a particularly preferred embodiment, the aqueous pyronaridine preparation is administered orally to provide pyronaridine at a dose of at least 2 μmol / kg (body weight) / day, more preferably at a dose of 4 to 50 μmol / kg (body weight) / day, and most preferably at a dose of 5 to 20 μmol / kg (body weight) / day.

[0028] The treatment of the present invention preferably comprises oral administration of an aqueous pyronaridine preparation at least once a day for 2 to 10 days, preferably 3 to 6 days.

[0029] A preferred embodiment of the present invention relates to the treatment of a disease caused by a parasite or virus, more preferably a disease caused by a parasite.

[0030] Examples of diseases caused by parasites that can be treated according to the present invention include malaria and diseases caused by metazoan parasites, such as schistosomiasis and cysticercosis. Preferably, the disease to be treated is malaria or Echinococcus granulosus ( Echinococcus granulosus It is cystic cerebrospinal infection caused by )

[0031] Examples of viral diseases that can be treated according to the present invention include SARS-cov-1, SARS-cov-2, Ebola, and Marburg virus diseases.

[0032] According to a particularly preferred embodiment, the medical treatment according to the present invention includes the treatment of malaria, particularly malaria caused by Plasmodium falciparum.

[0033] The treatment of the present invention is particularly suitable for the treatment of severe malaria. Severe malaria occurs when the infection is accompanied by severe organ failure or abnormalities in the patient's blood or metabolism. Clinical signs of severe malaria include the following:

[0034] · Cerebral malaria with abnormal behavior, impaired consciousness, seizures, coma, or other neurological abnormalities

[0035] · Severe anemia caused by hemolysis (destruction of red blood cells)

[0036] · Hemoglobinuria due to hemolysis (hemoglobin in urine)

[0037] · Acute respiratory distress syndrome (ARDS), an inflammatory response in the lungs characterized by inhibited oxygen exchange that can occur even after the number of parasites has decreased in response to treatment

[0038] · Blood clotting disorders

[0039] · Hypotension induced by cardiovascular collapse

[0040] · Acute kidney injury

[0041] · Hyperparasitosis, in which more than 5% of red blood cells are infected with malaria parasites

[0042] · Metabolic acidosis (excessive acidification of blood and tissue fluid) commonly associated with hypoglycemia

[0043] Treatment of malaria according to the present invention may include the combined administration of one or more other drugs. According to a preferred embodiment, the treatment includes the combined administration of artesunate. Combination therapy using the combined administration of artesunate is particularly suitable for the treatment of severe malaria.

[0044] The aqueous pyronaridine preparation used in the medical treatment of the present invention is preferably a sterile liquid aqueous pyronaridine preparation specified below.

[0045] Another aspect of the present invention relates to a sterile liquid aqueous formulation comprising at least 70 weight% water and at least 40 μmol / mL of dissolved pyronaridine, wherein the osmotic pressure is in the range of 0.15 to 0.60 Osm / kg, the pH is in the range of 2.5 to 5.8, and the ratio of the osmotic pressure (Osm / kg) of the formulation to the pyronaridine concentration (mmol / mL) of the formulation is less than 2.0.

[0046] The liquid aqueous formulation of the present invention preferably contains 100 to 400 μmol / mL, more preferably 150 to 330 μmol / mL, and most preferably 180 to 300 μmol / mL of dissolved pyronaridine.

[0047] Pironaridine and water together preferably constitute at least 90 weight%, more preferably at least 93 weight%, and most preferably 95 to 98 weight% of an aqueous pironaridine formulation.

[0048] The liquid aqueous formulation preferably does not contain undissolved pyronaridine.

[0049] The osmotic pressure of the aqueous pyronaridine preparation is preferably in the range of 0.18 to 0.50 Osm / kg, most preferably in the range of 0.20 to 0.40 Osm / kg.

[0050] The ratio of the osmotic pressure (Osm / kg) of the aqueous pyronaridine preparation to the pyronaridine concentration (mmol / mL) of the aqueous pyronaridine preparation is preferably in the range of 1.2 to 1.9, more preferably in the range of 1.3 to 1.8, and most preferably in the range of 1.4 to 1.7.

[0051] The pH of the aqueous pyronaridine formulation is preferably in the range of 3.0 to 5.7, more preferably in the range of 4.0 to 5.6, and most preferably in the range of 4.5 to 5.5.

[0052] Aqueous pyronaridine formulations preferably contain at least 72 weight% of water, more preferably 75 to 95 weight% of water, and most preferably 80 to 92 weight% of water.

[0053] Due to the buffering capacity of pyronaridine, it is advantageous to lower the pH using a strong acid; otherwise, it may be difficult or impossible to achieve an osmotic pressure close to the desired isotonicity. Accordingly, in a preferred embodiment, the aqueous pyronaridine formulation contains at least 1 mmol, more preferably 1.5 to 5 mmol, and most preferably 2 to 4 mmol of one or more strong acids selected from hydrochloric acid, hydrobromide, hydroiodide, nitric acid, and sulfuric acid per 1 mmol of pyronaridine.

[0054] According to a particularly preferred embodiment, the aqueous pyronaridine formulation contains at least 1 mmol, more preferably 1.5 to 5 mmol, and most preferably 2 to 4 mmol of hydrochloric acid per 1 mmol of pyronaridine.

[0055] According to a particularly preferred embodiment, the combination of water, pyronaridine, and a strong acid constitutes at least 92% by weight, more preferably at least 96% by weight, and most preferably at least 99% by weight of an aqueous pyronaridine formulation.

[0056] The aqueous pyronaridine formulation of the present invention preferably does not contain phosphate, or has a phosphate content of less than 2 mmol per 1 mmol of pyronaridine, more preferably 1 mmol per 1 mmol of pyronaridine. Less than, much more preferably less than 0.3 mmol per 1 mmol of pyronaridine.

[0057] The liquid aqueous formulation of the present invention preferably contains 100 to 400 μmol / mL, more preferably 150 to 330 μmol / mL, and most preferably 180 to 300 μmol / mL of dissolved pyronaridine.

[0058] Preferably, the aqueous pyronaridine formulation contains 0 to 200 μmol / mL of phosphate, more preferably 0 to 100 μmol / mL of phosphate, and much more preferably 0 to 50 μmol / mL of phosphate. Most preferably, the aqueous pyronaridine formulation does not contain phosphate.

[0059] The inventors have discovered that the stability of an aqueous pyronaridine formulation can be improved by including L-methionine. Accordingly, in a preferred embodiment, the aqueous pyronaridine formulation contains 0.2 to 10 mg / ml of L-methionine, more preferably 0.4 to 6 mg / ml of L-methionine, and most preferably 0.8 to 4 mg / ml of L-methionine.

[0060] Another aspect of the present invention relates to a method for preparing a liquid aqueous formulation described herein, comprising the step of combining a pyronaridine base, water, and an acid.

[0061] The acid used in the method of the present invention is preferably selected from hydrochloric acid, hydrobromide, hydroiodide, nitric acid, and sulfuric acid. Most preferably, the acid used in the method is hydrochloric acid.

[0062] The present invention is further illustrated by the following non-limiting embodiments.

[0063] Examples

[0064] Comparative Example A

[0065] An aqueous solution of pyronaridine tetraphosphate (molar mass 910.03 g) was prepared, and the osmotic pressure of the solution was measured. The results are shown in Table 1.

[0066] Pyronaridine tetraphosphate concentration (mg / mL) Pyronaridine base concentration (mg / mL) osmotic pressure (Osm / kg) Osmotic pressure (Osm / kg) : Pyronaridine concentration (mmol / L) 100 56.9 0.274 0.274 / 0.110 = 2.49 125 71.2 0.348 0.348 / 0.137 = 2.53 150 85.4 0.450 0.450 / 0.165 = 2.73 175 99.6 0.503 0.503 / 0.192 = 2.62 200 113.8 0.587 0.587 / 0.220 = 2.67

[0067] The pH of the 200 mg / mL pyronaridine tetraphosphate solution was 2.60.

[0068] Comparative Example B

[0069] Experiments were conducted to measure the physical appearance of pyronaridine bases in various solvents at a concentration of 10 mg / mL. The results are summarized in Table 2.

[0070] menstruum appearance Final pH MilliQ water yellow physically unstable dispersion 7.90 50 mM citrate buffer in water pH 3.0 dark orange solution 4.35 Acetate buffer 50 mM pH 4.0 in water A very deep orange solution 5.92 50 mM acetate buffer in water pH 5.0 A deep orange physically unstable dispersion 7.06 Phosphate-buffered saline 1X concentration pH 6.0 A deep orange physically unstable dispersion 7.30 Phosphate-buffered saline 1X concentration pH 7.0 orange physically unstable dispersion 7.40 Phosphate-buffered saline 1X concentration pH 8.0 yellow physically unstable dispersion 7.95 40% w / w hydroxypropyl-β-cyclodextrin in water yellow physically unstable dispersion Not measured 30% v / v Polyethylene Glycol (PEG) in water 400 orange physically unstable dispersion Not measured 30% v / v PEG400 + 10% Kolliphor ELP in water orange physically unstable dispersion Not measured 30% v / v water PEG400 + Kolliphor HS15 10% orange physically unstable dispersion Not measured Glycerol orange physically unstable dispersion Not measured cottonseed oil physically unstable dispersion of yellow to orange color Not measured Miglyol 812 orange physically unstable dispersion Not measured

[0071] Example 1

[0072] An aqueous pyronaridine solution according to the present invention was prepared based on the formulation shown in Table 3.

[0073] mg Pironaridin 1,200 HCl(1 M) 5,650 Injectable water Up to 10 mL

[0074] 1200 mg of pyronaridine free base was weighed into a glass vial, and a solution was prepared by neutralizing the base with the required amount of pre-diluted 1 M HCl. To reach a pH of 5.0, 5650 mg of 1 M HCl was used. Finally, all contents were diluted to 10.0 ml with MilliQ water.

[0075] The pyronaridine solution obtained in this way was very deep orange to black in color, contained no undissolved substances, and had a pH of 5.0. The osmotic pressure of the solution was 0.342 Osm / kg.

[0076] The ratio of osmotic pressure (Osm / kg) to pyronaridine concentration (mmol / mL) was 0.342 / 0.232 = 1.48.

[0077] The pyronaridine solution was sterilized by passing it through a sterile 0.22 μm polyethersulfone filter.

[0078] The sterile solution obtained in this way can be suitably administered intramuscularly (e.g., gluteal muscle) in a volume of 5 mL to deliver 600 mg of pyronaridine.

[0079] Example 2

[0080] An aqueous pyronaridine solution according to the present invention was prepared based on the formulation shown in Table 4.

[0081] mg Solution 1 Solution 2 Pironaridin 1,200 1,200 HCl(1 M) 5,650 5,650 L-methionine 16 Injectable water Up to 10 mL Up to 10 mL

[0082] The solution was prepared by weighing pyronaridine free base and, if applicable, L-methionine into a glass vial. Then, the base was neutralized by adding the required amount of pre-diluted 1 M HCl. 5,650 mg of 1 M HCl was used to reach a pH of 5.0. Finally, all contents were diluted to 10.0 ml with MilliQ water.

[0083] The solution obtained in this way was filled into separate clear glass HPLC vials with crimp cap tops. The stability of the solution was investigated by storing it at 40, 25, and 5°C for up to 6 months. The solution was analyzed after 2, 3, 6, and 14 months, and the pyronaridine concentration was monitored by comparing the pyronaridine concentration to the initial pyronaridine concentration. The results are shown in Table 5.

[0084] 2 months 3 months 6 months 14 months Solution 1 · 40℃ 93.3% 89.2% 81.5% Not measured · 25℃ 98.2% 97.9% 96.0% Not measured · 5℃ 100.1% 99.6% 100.6% 100.2% Solution 2 · 40℃ 94.7% 90.7% 82.7% Not measured · 25℃ 99.8% 98.8% 96.9% Not measured · 5℃ 100.1% 101.2% 101.3% 101.3%

Claims

Claim 1 A liquid aqueous formulation of pyronaridine for use in medical treatment, comprising at least 70 weight% water and at least 40 μmol / mL of dissolved pyronaridine, wherein the pH is in the range of 2.5 to 5.8 and the ratio of the osmotic pressure (Osm / kg) of the formulation to the pyronaridine concentration (mmol / mL) of the formulation is less than 2.

0. Claim 2 A liquid aqueous formulation of pyronaridine for use in medical treatment, wherein, in claim 1, the liquid aqueous formulation has an osmotic pressure in the range of 0.15 to 0.60 Osm / kg. Claim 3 A liquid aqueous formulation of pyronaridine for use in medical treatment, wherein, in claim 1 or 2, the liquid aqueous formulation comprises 100 to 400 μmol / mL of dissolved pyronaridine. Claim 4 A liquid aqueous formulation of pyronaridine for use in medical treatment, wherein, in any one of claims 1 to 3, the liquid aqueous formulation is administered intramuscularly. Claim 5 A liquid aqueous formulation of pyronaridine for use in medical treatment, wherein the liquid aqueous formulation is administered intramuscularly to provide pyronaridine at a dose of at least 1 μmol / kg / day. Claim 6 A liquid aqueous formulation of pyronaridine for use in medical treatment, wherein, in any one of claims 1 to 3, the liquid aqueous formulation is administered intranasally. Claim 7 A liquid aqueous formulation of pyronaridine for use in medical treatment, wherein the liquid aqueous formulation is administered nasally to provide pyronaridine at a dose of at least 0.5 μmol / kg / day. Claim 8 A liquid aqueous formulation of pyronaridine for use in medical treatment, wherein, in any one of claims 1 to 3, the liquid aqueous formulation is administered orally to provide pyronaridine at a dose of at least 2 μmol / kg / day. Claim 9 A liquid aqueous formulation of pyronaridine for use in medical treatment, wherein, in any one of claims 1 to 8, the liquid aqueous formulation comprises at least 1 mmol of hydrochloric acid per 1 mmol of pyronaridine. Claim 10 A liquid aqueous formulation of pyronaridine for use in medical treatment, wherein, in any one of claims 1 to 9, the liquid aqueous formulation is used for the treatment of diseases caused by parasites or viruses. Claim 11 A sterile liquid aqueous formulation comprising at least 70 weight% water and at least 40 μmol / mL of dissolved pyronaridine, characterized in that it has an osmotic pressure in the range of 0.15 to 0.60 Osm / kg and a pH in the range of 2.5 to 5.8, and the ratio of the osmotic pressure (Osm / kg) of the formulation to the pyronaridine concentration (mmol / mL) of the formulation is less than 2.

0. Claim 12 A liquid aqueous formulation according to claim 11, wherein the liquid aqueous formulation comprises 100 to 400 μmol / mL of dissolved pyronaridine. Claim 13 A liquid aqueous formulation according to claim 11 or 12, wherein the liquid aqueous formulation has an osmotic pressure in the range of 0.20 to 0.40 Osm / kg. Claim 14 A liquid aqueous formulation according to any one of claims 11 to 13, wherein the liquid aqueous formulation does not contain phosphate or has a phosphate content of less than 2 mmol per 1 mmol of pyronaridine. Claim 15 A liquid aqueous formulation according to any one of claims 11 to 14, wherein the liquid aqueous formulation comprises at least 1 mmol of hydrochloric acid per 1 mmol of pyronaridine. Claim 16 A method for preparing a liquid aqueous formulation according to any one of claims 11 to 15, comprising the step of combining a pyronaridine base, water, and an acid. Claim 17 In paragraph 16, the above acid is selected from hydrochloric acid, hydrobromide, hydroiodide, nitric acid, and sulfuric acid. Claim 18 In paragraph 17, the above acid is hydrochloric acid.