Bosentan pharmaceutical co-crystals, processes for their preparation and uses thereof

Abstract

The application belongs to the technical field of medicines. A bexarotene pharmaceutical cocrystal, a preparation method and application thereof are provided. Specifically, the application discloses a method for forming a cocrystal of bexarotene and L-arginine in a molar ratio of 1:1 or 1:2 by using a grinding method in combination; the cocrystal reduces the melting point and improves the solubility of bexarotene on the basis of retaining the drug activity of bexarotene; and the application of the bexarotene and L-arginine cocrystal as a pharmaceutically active ingredient in the preparation of a drug for preventing and treating pulmonary arterial hypertension.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology. Specifically, the present invention relates to the field of pharmaceutical cocrystal technology, and more specifically to a cocrystal of bexarotene and L-arginine, its preparation method, and use. The compound can be used to treat and / or prevent pulmonary hypertension caused by various causes. Background Art

[0002] Pulmonary artery hypertension (PH) refers to a hemodynamic and pathophysiological condition in which pulmonary artery pressure rises above a certain threshold, potentially leading to right heart failure. It can be an independent disease, a complication, or a syndrome. The hemodynamic diagnostic criteria are: a mean pulmonary artery pressure ≥ 25 mmHg at rest at sea level, as measured by right cardiac catheterization.

[0003] Previous studies have shown that vasodilators have varying degrees of efficacy in the treatment of pulmonary hypertension. It has been confirmed that nitric oxide (NO), a vasodilator produced and released by vascular endothelial cells, acts on neighboring cells through autocrine and paracrine effects, exerting biological effects including smooth muscle relaxation, platelet aggregation, nerve conduction, and cytotoxicity.

[0004] However, vasodilators do not significantly improve long-term prognosis. The reported 5-year survival rate for PAH patients remains only 57%, posing a significant challenge in further extending patient lifespan and improving their quality of life. This is because vasodilators cannot interrupt the process of pulmonary vascular remodeling. Pulmonary vascular remodeling is the pathological basis for the progressive increase in pulmonary vascular resistance. Pulmonary vascular remodeling is the phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs) in response to changes in the internal environment. This transformation is primarily manifested by impaired smooth muscle cell contractility and loss of phenotype-associated proteins. These cells cross the damaged endothelial barrier, migrate to the subintima, and proliferate, exhibiting a "cancer or tumor-like growth" pattern. This leads to thickening of the vascular intima and media, neointima formation, and progressive obstruction of the vascular lumen, increasing vascular resistance and altering hemodynamics, ultimately leading to right heart failure or even complete heart failure. Due to the complex course of PAH and the low rate of early diagnosis, most patients have already experienced severe and irreversible pulmonary vascular remodeling by the time they are diagnosed with PAH.

[0005] Therefore, it is a very important and urgent task to develop a drug for treating pulmonary hypertension that can effectively dilate pulmonary blood vessels and inhibit pulmonary vascular remodeling.

[0006] This study invented a co-crystal compound of L-arginine (L-arg) and bexarotene (BEX), which synergistically improves the efficacy of treating pulmonary arterial hypertension in terms of pharmacological mechanism of action. The combined use of vasodilators L-arginine and bexarotene can not only dilate blood vessels and improve symptoms, but also fundamentally inhibit or even reverse pulmonary vascular remodeling.

[0007] A pharmaceutical cocrystal is a crystal formed by intermolecular non-covalent interactions between active drug molecules and cocrystal ligands in a specific ratio. The formation of a cocrystal can improve a drug's physical and chemical properties, such as increasing stability, solubility, and bioavailability, while reducing hygroscopicity and dissolution. It can also retain or enhance pharmacological activity. For generic chemical drugs, the study of cocrystals can help overcome patent protection held by originator drug companies, enhancing drug innovation and market competitiveness.

[0008] Bexarotene (CAS number: 153559-49-0), chemically named 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)vinyl]benzoic acid, has a molecular formula of C24H28O2 and a chemical structure shown in Formula 1. Bexarotene is a retinoid X receptor agonist clinically approved for the treatment of cutaneous T-cell lymphoma. Studies have confirmed that bexarotene is also a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist. PPAR-γ is widely expressed in normal lung tissue, whereas PPAR-γ gene and protein expression is absent in the pulmonary vessels of patients with severe pulmonary arterial hypertension, suggesting a role for PPAR-γ in maintaining normal pulmonary vascular function. PPAR-γ participates in pulmonary artery vascular remodeling by regulating endothelin expression, cell proliferation, vascular tone, and thrombus coagulation, exerting anti-proliferative, anti-inflammatory, and antioxidant effects. Some currently marketed drugs or newly discovered non-coding RNAs produce anti-PAH pharmacological effects by stimulating PPARγ or regulating its expression. Studies have also shown that bexarotene has inhibitory effects on other tumors such as lung and breast tumors, but it may cause side effects such as hypertriglyceridemia and hypercholesterolemia. However, bexarotene has poor solubility, with a solubility in water of 9.5×10 -4 mg / L, and is only slightly soluble in vegetable oil and ethanol. Therefore, regulating the solubility and dissolution rate of bexarotene is crucial for different routes of administration.

[0009]

[0010] L-arginine (L(+)-Arginine, CAS No. 74-79-3), chemically known as (2S)-2-amino-5-diaminomethylenepentanoic acid, has a molecular formula of C6H14N4O2 and a chemical structure shown in Formula 2. It is a semi-essential amino acid that, under the action of nitric oxide synthase (NOS), generates NO, which in turn produces pharmacological effects such as vasodilation.

[0011]

[0012] This study invented a co-crystal of L-arginine and bexarotene, which not only improves the solubility of bexarotene, but also synergistically enhances the efficacy of treating pulmonary hypertension, improving or even reversing pulmonary vascular remodeling. Summary of the Invention

[0013] The purpose of the present invention is to provide a co-crystal with bexarotene as the active pharmaceutical molecule and L-arginine as the ligand and a preparation method thereof, which can improve the solubility of bexarotene while retaining its pharmacological activity.

[0014] To achieve the above object, the present invention provides the following technical solutions:

[0015] In one aspect, a bexarotene drug cocrystal is formed by combining bexarotene with L-arginine in a molar ratio of 1:1 or 1:2, and when analyzed by powder X-ray diffraction using CuKα radiation experimental conditions, the diffraction peak position: 2-Theta value (°) or d value The relative intensity of the diffraction peaks: the peak height value (Height %) or the peak area value (Area %) has the following characteristics (Table 1).

[0016] Table 1 Powder X-ray diffraction peaks of bexarotene and L-arginine cocrystal

[0017]

[0018]

[0019] The cocrystal of bexarotene and L-arginine, when analyzed using differential scanning calorimetry, exhibits a characteristic melting peak at 136.0±0.61°C in the DSC spectrum when the heating rate is 10°C per minute.

[0020] The bexarotene-L-arginine cocrystal is prepared by a grinding method, which involves placing bexarotene and L-arginine in a mortar, grinding them with a solvent, and then drying them naturally at room temperature. Specifically, the method comprises the following steps: placing bexarotene and L-arginine in a mortar at an equal molar ratio or a 1:2 ratio, grinding them with a solvent, and drying them naturally at room temperature to obtain the bexarotene-L-arginine cocrystal.

[0021] The above-mentioned bexarotene and L-arginine cocrystal is formed with bexarotene as the active pharmaceutical ingredient, L-arginine as the cocrystal former, and anhydrous ethanol as the solvent in a molar ratio of 1:1, and more preferably in a molar ratio of 1:2.

[0022] In a third aspect, the solvent mentioned in the preparation method of bexarotene cocrystal is ethanol or isopropanol.

[0023] Fourthly, the solubility of the bexarotene drug co-crystal is improved compared to that of bexarotene alone.

[0024] That is, the solubility of the bexarotene and L-arginine cocrystal is improved, with water solubility exceeding that of the bexarotene component alone. The bexarotene and L-arginine cocrystal is used in the preparation of a medicament for treating or preventing diseases, including but not limited to arterial pulmonary hypertension, pulmonary hypertension caused by hypoxia and / or lung disease, pulmonary hypertension associated with left heart disease, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension of various unknown mechanisms. The arterial pulmonary hypertension is idiopathic pulmonary hypertension or hereditary pulmonary hypertension.

[0025] The beneficial effects of the present invention are:

[0026] The bexarotene and L-arginine drug cocrystal prepared by the invention can improve the solubility of bexarotene while maintaining its pharmacological activity.

[0027] The present invention provides a method for preparing bexarotene cocrystal, which is a grinding method. The method is simple to operate, low in production cost, highly operable, and suitable for industrialized production expansion. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 Comparative X-ray powder diffraction (XRD) patterns of the bexarotene-L-arginine cocrystal and single-component bexarotene and L-arginine obtained in Examples 1 and 2;

[0029] Figure 2 This is a comparison chart of the X-ray powder diffraction (XRD) of the bexarotene-L-arginine cocrystal obtained in Example 3 and single-component bexarotene and L-arginine;

[0030] Figure 3 The differential scanning calorimetry (DSC) diagram of the bexarotene-L-arginine cocrystal and the single-component bexarotene and L-arginine obtained in Example 1 is shown;

[0031] Figure 4 The differential scanning calorimetry (DSC) diagram of the bexarotene-L-arginine cocrystal and the single-component bexarotene and L-arginine obtained in Example 3 is shown;

[0032] Figure 5 Differential scanning calorimetry (DSC) of the bexarotene-L-arginine co-crystal and single component bexarotene and L-arginine obtained in Example 3;

[0033] Figure 6 Graph of the effect of the bexarotene-L-arginine co-crystal compound obtained in Example 6 on the survival of pulmonary hypertension rats;

[0034] Figure 7 Graph of the effect of the bexarotene-L-arginine co-crystal compound obtained in Example 7 on improving the pulmonary blood flow velocity and prolonging the blood flow acceleration time of pulmonary hypertension rats, *p<0.05, **p<0.01, ***p<0.001;

[0035] Figure 8 Graph of the effect of the bexarotene-L-arginine co-crystal compound obtained in Example 8 on reducing the pulmonary arterial systolic pressure and right ventricular pressure of pulmonary hypertension rats, *p<0.05, **p<0.01, ***p<0.001;

[0036] Figure 9 Graph of the effect of the bexarotene-L-arginine co-crystal compound obtained in Example 9 on reducing the heart coefficient and right heart index of pulmonary hypertension rats, *p<0.05, **p<0.01, ***p<0.001;

[0037] Figure 10 Graph of the effect of the bexarotene-L-arginine co-crystal compound obtained in Example 10 on inhibiting the intima-media thickening of the pulmonary artery of pulmonary hypertension rats, *p<0.05, **p<0.01, ***p<0.001;

[0038] Figure 11 Graph of the effect of the bexarotene-L-arginine co-crystal compound obtained in Example 10 on inhibiting the lumen stenosis of the pulmonary artery and pulmonary arteriole of pulmonary hypertension rats, *p<0.05, **p<0.01, ***p<0.001. DETAILED DESCRIPTION

[0039] The technical solutions of the present application will be further described in detail below by specific examples in combination with the drawings of the specification:

[0040] Example 1

[0041] A bexarotene pharmaceutical co-crystal is prepared by the following method: 300 mg of bexarotene and 150 mg of L-arginine (molar ratio 1:1) are weighed and mixed uniformly in a mortar, 0.2 mL of anhydrous ethanol is added twice, 0.1 mL each time, and the mortar is ground thoroughly at room temperature to obtain a bexarotene-L-arginine co-crystal.

[0042] Example 2

[0043] A bexarotene drug cocrystal is prepared by the following method: 300 mg of bexarotene and 300 mg of L-arginine (molar ratio of 1:2) are weighed, mixed evenly, and placed in a mortar; 0.2 mL of anhydrous ethanol is added twice, 0.1 mL each time; and the mixture is thoroughly ground at room temperature to obtain a bexarotene-L-arginine cocrystal.

[0044] Example 3

[0045] A bexarotene drug cocrystal is prepared by the following method: 300 mg of bexarotene and 150 mg of L-arginine (molar ratio of 1:1) are weighed and mixed evenly in a mortar, 0.2 mL of isopropanol is added twice, 0.1 mL each time, and the mixture is thoroughly ground at room temperature to obtain a bexarotene-L-arginine cocrystal.

[0046] Example 4

[0047] A bexarotene drug cocrystal is prepared by the following method: 300 mg of bexarotene and 300 mg of arginine (molar ratio of 1:2) are weighed and mixed evenly in a mortar, 0.2 mL of isopropanol is added twice, 0.1 mL each time, and the mixture is thoroughly ground at room temperature to obtain a bexarotene-L-arginine cocrystal.

[0048] Example 5

[0049] Solubility Analysis of Bexarotene-L-Arginine Cocrystal

[0050] Weigh 10 mg of finely powdered bexarotene and its cocrystals and add them to 30 mL of water at room temperature (25 ± 2°C). Stir magnetically and observe the dissolution within 30 minutes. If no solute particles are visible, it is considered completely dissolved. Then add another 10 mg of powder and observe the dissolution within 30 minutes. Repeat the process until visible solute particles are present. The results show that 10 mg of bexarotene is almost insoluble in 30 mL of water (Pubchem found that the solubility of bexarotene in water is 9.5x10 -4 mg / L, which is 2.85x10 -9 mg / 30mL), while 10 mg of the cocrystal can be completely dissolved in 30 mL of water, while 20 mg of the cocrystal is not completely dissolved in 30 mL of water, with a small amount of particles visible. Therefore, the solubility of the cocrystal compound of bexarotene-arginine is approximately 0.33-0.66x10 3 mg / L, and its solubility is much higher than that of bexarotene.

[0051] Comparative Example 1

[0052] The preparation method of bexarotene cocrystal in Example 1 was followed, except that water was selected as the solvent, but no drug cocrystal was obtained.

[0053] Comparative Example 2

[0054] The preparation method of bexarotene cocrystal in Example 1 was followed, except that anhydrous methanol was selected as the solvent, but no drug cocrystal was obtained.

[0055] Comparative Example 3

[0056] The preparation method of bexarotene cocrystal in Example 1 was followed, except that acetone was used as the solvent, but no drug cocrystal was obtained.

[0057] Experimental data

[0058] 1. XRD analysis

[0059] Test Method: The cocrystals of bexarotene and L-arginine obtained in Examples 1-4 were characterized by X-ray powder diffraction. X-ray powder diffraction analysis was performed using a Malvern Panalytical Aeris desktop diffractometer, using CuKα X-rays. The measurements were performed at an operating voltage of 40 kV, a current of 7.5 mA, a scan step size of 0.02°, a scan speed of 10° / min, and a scan range of 5 to 40°. The experimental results were plotted using Origin 2021 software.

[0060] Figure 1 The X-ray powder diffraction patterns of the bexarotene-L-arginine cocrystals obtained in Examples 1 and 2 and the comparative spectra of single-component bexarotene and L-arginine are shown; Figure 2 The X-ray powder diffraction pattern of the bexarotene-L-arginine cocrystal obtained in Example 3 and the comparative spectra of single-component bexarotene and L-arginine are shown.

[0061] 2. DSC analysis

[0062] The cocrystals of bexarotene and L-arginine obtained in Examples 1-4 were analyzed on a Mettler-Toledo DSC 3 using a disposable ordinary aluminum crucible, heating from 25°C to 300°C at a rate of 10°C / min and a nitrogen flow rate of 10 mL / min.

[0063] Figure 3 The differential scanning calorimetry diagram of the bexarotene-L-arginine cocrystal and the single-component bexarotene and L-arginine obtained in Example 1; Figure 4 The differential scanning calorimetry diagram of the bexarotene-L-arginine cocrystal and the single-component bexarotene and L-arginine obtained in Example 3; Figure 5 The following are differential scanning calorimetry (DSC) images of the bexarotene-L-arginine cocrystal obtained in Example 4 and the individual components of bexarotene and L-arginine. The results show that the sample begins to melt at approximately 136°C. Bexarotene and L-arginine begin to melt at 226°C and 220-230°C, respectively. The melting point of the cocrystal is significantly lower than that of the individual components.

[0064] Specific biological examples

[0065] Pulmonary arterial hypertension is caused by a variety of reasons, and pulmonary arterial vascular remodeling is the main pathological cause. A one-time injection of monocrotaline (MCT) causes delayed and progressive endothelial cell damage in the rat pulmonary artery, thrombosis of small pulmonary arteries, abnormal proliferation of smooth muscle cells, and other changes, leading to progressive increase in pulmonary arterial pressure and causing a rat model of pulmonary arterial hypertension. In this example, 210 SD rats weighing about 200 g were randomly divided into 7 groups, 30 rats in each group: a normal control group (Control), a pulmonary arterial hypertension model group (Vehicle+MCT), a positive drug sildenafil (Sid+MCT, 60 mg / kg) group, a bexaronidine group (BEX+MCT, 60 mg / kg), an L-arginine group (L-arg+MCT, 30 mg / kg), a bexaronidine and L-arginine mixture group (MIX+MCT, 90 mg / kg, wherein the molar ratio of BEX and L-arg is 1:1, and the mass ratio is 2:1), and a bexaronidine-L-arginine co-crystal group (Co-crystal+MCT, 90 mg / kg) group. Monocrotaline was prepared into a 1% concentration solution with normal saline, and was mixed uniformly under ultrasonic, and the pH was adjusted to 7.2-7.4; the normal control group was given an equal dose of normal saline, and the other groups of rats were given a single dose of intraperitoneal injection of 60 mg / kg MCT to prepare a rat model of pulmonary arterial hypertension. Drug administration began on the day of modeling, and was continuously given once a day for 4 weeks, with 0.5% sodium carboxymethyl cellulose as a solvent control.

[0066] The survival rate, heart coefficient, right heart index, echocardiography detection of pulmonary arterial blood flow velocity and blood flow acceleration time, right heart catheterization detection of pulmonary arterial and right ventricular systolic pressure, determination of right ventricular thickening degree, serum pulmonary arterial hypertension markers, and histomorphological changes were investigated at the end of the experiment to determine the protective effect of the bexaronidine-L-arginine co-crystal compound on rat pulmonary arterial hypertension and its use in the preparation of prevention and treatment of pulmonary arterial hypertension.

[0067] Example 6 Effect of the bexaronidine-L-arginine co-crystal compound on the survival rate of rats with pulmonary arterial hypertension

[0068] After monocrotaline modeling, the survival rate of rats decreased and the mortality rate increased, while each intervention group could improve the survival rate of rats, among which the bexaronidine-L-arginine co-crystal compound had the most obvious improvement effect, which was better than the mixture of the two and the positive drug sildenafil, as shown in Table 1. Figure 6

[0069] Table 2. Effect of the bexaronidine-L-arginine co-crystal compound on the survival rate of rats with pulmonary arterial hypertension​

[0070]

[0071] Example 7 Bexarotene-L-arginine cocrystal compound improves pulmonary blood flow velocity and prolongs blood flow acceleration time in rats with pulmonary hypertension

[0072] On the 27th day after intraperitoneal injection of MCT, pulmonary artery ultrasound was performed to detect the maximum blood velocity (PVmax, mm / s) and pulmonary artery blood flow acceleration time (PAAT, ms). The results were as follows Figure 7 As shown in the results, the maximum blood flow velocity of the pulmonary artery of rats was significantly reduced, and the acceleration time decreased, showing the classic hemodynamic characteristics of pulmonary hypertension. The maximum blood flow velocity of the pulmonary artery of each intervention group was significantly increased, and the acceleration time was prolonged. Among them, the improvement was most obvious in the bexarotene-L-arginine cocrystal compound group (Table 3), indicating the intervention effect of the drug on hemodynamics.

[0073] Table 3. Effects of Bexarotene-L-arginine Cocrystal Compound on Pulmonary Blood Flow Velocity and Blood Flow Acceleration Time in Rats

[0074]

[0075] PVmax: maximum pulmonary artery blood flow velocity, unit: mm / s; PAAT: pulmonary artery blood flow acceleration time, unit: ms.

[0076] Example 8 Bexarotene-L-arginine cocrystal compound reduces systolic blood pressure and right ventricular systolic pressure in rats with pulmonary hypertension

[0077] The results are as follows Figure 8 As shown, MCT induced a significant increase in right ventricular pressure and pulmonary artery pressure in rats. Each drug group could significantly reduce the right ventricular mean systolic pressure and pulmonary artery mean systolic pressure in rats with pulmonary hypertension. The bexarotene-L-arginine cocrystal compound significantly reduced right ventricular pressure and pulmonary artery systolic pressure, and its effect was better than that of the positive drug sildenafil and the mixture of L-arg and BEX.

[0078] Example 9: Effect of Bexarotene-L-Arginine Cocrystal Compound on the Improvement of Right Ventricular Hypertrophy Index in Rats with Pulmonary Hypertension

[0079] After pressure measurement and blood collection, the rats were perfused with normal saline. The thorax was opened to remove the heart, and the atrial tissue was excised. The right ventricular free wall, left ventricle, and ventricular septum (LV+S) were excised. The free wall was blotted with filter paper and weighed. The right ventricular hypertrophy index (RV / (LV+S)) was calculated to assess the degree of right ventricular hypertrophy.

[0080] The results are as follows Figure 9The results showed that the positive drug sildenafil can significantly improve right ventricular hypertrophy caused by pulmonary hypertension. Bexarotene and L-arginine administered alone or as a mixture significantly reduced right ventricular wall hypertrophy in rats with pulmonary hypertension, but the bexarotene-L-arginine cocrystal compound had the greatest improvement. After administration, the rat cardiac index and right ventricular hypertrophy index were close to the levels of normal rats.

[0081] Example 10 Effect of Bexarotene-L-Arginine Cocrystal Compound on Pulmonary Vascular Remodeling

[0082] After systemic perfusion with normal saline, the pulmonary artery and left lung were fixed in 4% neutral paraformaldehyde, embedded in paraffin, serially sectioned, and stained with hematoxylin and eosin. Five randomly selected fields of view were used for each specimen to measure pulmonary artery wall thickness and assess pulmonary artery stenosis. Five randomly selected pulmonary arterioles with a diameter of 100 ± 50 μm were used to calculate the ratio of wall cross-sectional area to lumen area (WA%) using IPP 6.0 (Image-Pro-Plus 6.0) image processing software to assess pulmonary vascular remodeling.

[0083] The results are as follows Figure 10 and 11 As shown, the positive drug sildenafil (Sid) can improve the remodeling of pulmonary arteries and pulmonary arterioles to a certain extent, which is manifested by inhibiting the thickening of the pulmonary artery intima-media and the stenosis of the pulmonary artery and pulmonary arteriole lumen (decreased percentage of lumen area) induced by MCT. Bexarotene, L-arginine, and a mixture of the two all have different degrees of improvement. The effect of the bexarotene-L-arginine cocrystal compound is significantly better than the positive drug sildenafil, which is manifested by the fact that the thickness of the pulmonary artery intima-media and the ratio of the pulmonary artery lumen area of ​​the rats after administration of the bexarotene-L-arginine cocrystal compound are close to those of the normal group rats.

Claims

1. A bexarotene and L-arginine eutectic, characterized in that: Bexarotene and L-arginine form a eutectic at a molar ratio of 1:1 or 1:

2. When using powder X-ray diffraction analysis using CuK α Under radiation experimental conditions, diffraction peak position: 2-Theta value (°) or d value Diffraction peak relative intensity: peak height value (Height%) or peak area value (Area%) has the following characteristics:

2. The bexarotene and L-arginine cocrystal according to claim 1, wherein: When analyzed using differential scanning calorimetry, the material showed a characteristic melting peak at 136.0±0.61°C when the heating rate was 10°C per minute.

3. The method for preparing the bexarotene and L-arginine cocrystal according to claim 1, wherein: The method is a grinding method, which specifically includes the following steps: putting bexarotene and L-arginine into a mortar in equal moles or a ratio of 1:2, adding a solvent for grinding, and naturally drying at room temperature to obtain a bexarotene-L-arginine eutectic, wherein the solvent is ethanol or isopropanol.

4. The method for preparing the bexarotene and L-arginine cocrystal according to claim 3, wherein: The cocrystal is formed with bexarotene as the active pharmaceutical ingredient, L-arginine as the cocrystal former, and anhydrous ethanol as the solvent in a molar ratio of 1:

1.

5. The method for preparing the bexarotene and L-arginine cocrystal according to claim 3, wherein: The cocrystal is formed with bexarotene as the active pharmaceutical ingredient, L-arginine as the cocrystal former, and anhydrous ethanol as the solvent in a molar ratio of 1:

2.

6. Use of the bexarotene and L-arginine cocrystal according to any one of claims 1 to 2 in the preparation of a medicament for treating or preventing a disease, characterized in that: The disease is selected from arterial pulmonary hypertension, pulmonary hypertension caused by hypoxia and / or lung disease, pulmonary hypertension associated with left heart disease, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension of various unknown mechanisms.

7. The use according to claim 6, characterized in that The arterial pulmonary hypertension is idiopathic pulmonary hypertension or hereditary pulmonary hypertension.

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