Bexarotene pharmaceutical co-crystal as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine. The invention provides Bexarotene pharmaceutical co-crystal as well as a preparation method and application thereof. Specifically, the invention discloses a method for combining Bexarotene and L-arginine according to a molar ratio of 1: 1 or 1: 2 by adopting a grinding method to form a eutectic substance. According to the eutectic substance, the melting point is reduced and the solubility of Bexarotene is improved on the basis of retaining the pharmaceutical activity of Bexarotene; the eutectic substance of Bexarotene and L-arginine is used as an active pharmaceutical ingredient to be applied to preparation of drugs for preventing and treating pulmonary arterial hypertension.

Description

Technical Field

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

[0002] Pulmonary artery hypertension refers to a hemodynamic and pathophysiological state in which the pulmonary artery pressure rises above a certain threshold, which can lead to right heart failure. It can be an independent disease, a complication, or a syndrome. Its hemodynamic diagnostic criteria are: at rest at sea level, the mean pulmonary artery pressure detected by right cardiac catheterization is ≥25 mmHg.

[0003] Previous studies have shown that vasodilators have varying degrees of efficacy in the treatment of pulmonary hypertension. It has been confirmed that the vasodilator-active substance produced and released by vascular endothelial cells, "endothelium-dependent relaxing factor", is nitric oxide (NO), which exerts biological effects on neighboring cells through autocrine / paracrine effects, including smooth muscle relaxation, platelet aggregation, nerve conduction, cytotoxic effects, etc.

[0004] However, vasodilators cannot significantly improve long-term prognosis. It is reported that the 5-year survival rate of PAH patients is still only 57%. How to further extend the life of patients and improve their quality of life is a huge challenge. The reason is that vasodilators cannot block the process of pulmonary vascular remodeling. Pulmonary vascular remodeling is the pathological basis for the progressive increase in pulmonary vascular resistance. The so-called pulmonary vascular remodeling is the cell phenotypic transformation of pulmonary artery smooth muscle cells (PASMCs) in order to adapt to changes in the internal environment. It is mainly manifested as smooth muscle cell contractile dysfunction, loss of phenotype-related proteins, and cells crossing the damaged endothelial cell barrier, migrating and proliferating under the intima, showing "cancer or tumor-like growth", causing thickening of the vascular intima and media, formation of new intima, and progressive obstruction of the vascular lumen, increased vascular resistance and hemodynamic changes, and ultimately causing right heart and even whole heart failure. Due to the complex course of PAH and the low rate of early diagnosis, most patients have already suffered severe and irreversible pulmonary vascular remodeling when 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 while effectively inhibiting pulmonary vascular remodeling.

[0006] In this study, a co-crystal compound of L-arginine (L-arg) and bexarotene (BEX) was invented, which synergistically improves the efficacy of treating pulmonary hypertension in terms of pharmacological mechanism. 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] Drug cocrystals refer to crystals formed by intermolecular non-covalent interactions between active drug molecules and cocrystal ligands in a certain ratio. By forming cocrystals, drugs can improve their physical and chemical properties, such as improving stability, solubility and bioavailability, reducing hygroscopicity and dissolution, and retain or improve pharmacological activity. For chemical generic drugs, the study of cocrystals can break the patent protection of original drug companies and improve the innovation and market competitiveness of drugs.

[0008] Bexarotene (CAS No. 153559-49-0), chemical name 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthyl)vinyl]benzoic acid, molecular formula C24H28O2, chemical structure as shown in Formula 1. Bexarotene is a retinol X receptor agonist, clinically approved for the treatment of cutaneous T-cell lymphoma. Studies have confirmed that bexarotene is also a peroxisome proliferation-activated receptorγ (PPAR-γ) agonist. PPAR-γ is widely expressed in normal lung tissue, while the pulmonary vessels of patients with severe pulmonary hypertension lack PPAR-γ gene and protein expression, suggesting that PPARγ plays a role in maintaining normal pulmonary vascular function. PPAR-γ participates in pulmonary artery vascular remodeling by regulating endothelin expression, cell proliferation, vascular tension and thrombus coagulation, and plays an anti-proliferative, anti-inflammatory and antioxidant role. Some drugs currently on the market or newly discovered non-coding RNA produce anti-PAH pharmacological effects by stimulating PPARγ or regulating its expression. At the same time, studies have shown that bexarotene has an inhibitory effect on other tumors such as lung and breast, but it may produce side effects of hypertriglyceridemia and hypercholesterolemia. However, the solubility of bexarotene is very poor, 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 (English name L(+)-Arginine, CAS number: 74-79-3), chemical name (2S)-2-amino-5-diaminomethylenepentanoic acid, molecular formula C6H14N4O2, chemical structure as shown in formula 2. It is a semi-essential amino acid, under the action of nitric oxide synthase (NOS), it generates NO and then 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 improves the efficacy of treating pulmonary hypertension, improves or even reverses pulmonary vascular remodeling. Summary of the invention

[0013] The object of the present invention is to provide a co-crystal with bexarotene as a pharmaceutically active molecule and L-arginine as a ligand and a preparation method thereof, so as to 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 powder X-ray diffraction analysis is performed using CuKα radiation experimental conditions, the diffraction peak position: 2-Theta value (°) or d value The relative intensity of the diffraction peak: 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] When the cocrystal of bexarotene and L-arginine is analyzed using differential scanning calorimetry, it is shown that when the heating rate is 10°C per minute, the DSC spectrum has a characteristic melting peak at 136.0±0.61°C.

[0020] On the other hand, the preparation method of bexarotene and L-arginine cocrystal is a grinding method, which is to put bexarotene and L-arginine into a mortar, add a solvent to grind, and naturally dry at room temperature to obtain the bexarotene-L-arginine cocrystal. Specifically, it includes the following steps: put bexarotene and L-arginine into a mortar in an equal molar ratio or a ratio of 1:2, add a solvent to grind, and naturally dry at room temperature to obtain the bexarotene-L-arginine cocrystal.

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

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

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

[0024] That is, the solubility of the cocrystal of bexarotene and L-arginine is improved, and the water solubility is higher than that of the single component of bexarotene. The cocrystal of bexarotene and L-arginine is used in the preparation of a drug 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 invention provides a method for preparing bexarotene cocrystal, which is a grinding method. The method is simple to operate, low in production cost, strong in operability, and suitable for industrialized expansion of production. BRIEF DESCRIPTION OF THE DRAWINGS

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

[0029] Figure 2 The X-ray powder diffraction (XRD) comparison diagram of the bexarotene-L-arginine co-crystal obtained in Example 3 and the 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;

[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;

[0032] Figure 5 The differential scanning calorimetry (DSC) diagram of the bexarotene-L-arginine cocrystal and the single-component bexarotene and L-arginine obtained in Example 3;

[0033] Figure 6 This is a graph showing the effect of the bexarotene-L-arginine cocrystal compound obtained in Example 6 on the survival of rats with pulmonary hypertension;

[0034] Figure 7 The bexarotene-L-arginine cocrystal compound obtained in Example 7 improves the pulmonary blood flow velocity and prolongs the blood flow acceleration time in rats with pulmonary hypertension, *p<0.05, **p<0.01, ***p<0.001;

[0035] Figure 8 The bexarotene-L-arginine cocrystal compound obtained in Example 8 reduces the pulmonary artery systolic pressure and right ventricular pressure in rats with pulmonary hypertension, *p<0.05, **p<0.01, ***p<0.001;

[0036] Fig. 9 The bexarotene-L-arginine cocrystal compound obtained in Example 9 reduces the cardiac coefficient and right heart index of rats with pulmonary hypertension, *p<0.05, **p<0.01, ***p<0.001;

[0037] Fig.10 The graph shows the results of the bexarotene-L-arginine cocrystal compound obtained in Example 10 inhibiting the thickening of the pulmonary artery intima-media in rats with pulmonary hypertension, *p<0.05, **p<0.01, ***p<0.001;

[0038] Fig.11 This is a graph showing the results of the bexarotene-L-arginine cocrystal compound obtained in Example 10 inhibiting the stenosis of the pulmonary artery and pulmonary arteriole lumen in rats with pulmonary hypertension, *p<0.05, **p<0.01, ***p<0.001. DETAILED DESCRIPTION

[0039] The technical solution of the present invention is further described in detail below through specific embodiments in conjunction with the accompanying drawings:

[0040] Example 1

[0041] A bexarotene drug cocrystal is prepared by the following method: 300 mg of bexarotene and 150 mg of L-arginine (molar ratio 1:1) are weighed and mixed evenly in a mortar, 0.2 mL of anhydrous ethanol is added twice, 0.1 mL / time, and the bexarotene-L-arginine cocrystal is obtained by grinding at room temperature.

[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 1:2) are weighed and mixed evenly in a mortar, 0.2 mL of anhydrous ethanol is added twice, 0.1 mL / time, and the mixture is fully 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 1:1) are weighed and mixed evenly in a mortar, 0.2 mL of isopropanol is added twice, 0.1 mL / time, and the bexarotene-L-arginine cocrystal is obtained by grinding at room temperature.

[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 1:2) are weighed and mixed evenly in a mortar, 0.2 mL of isopropanol is added twice, 0.1 mL / time, and the bexarotene-L-arginine cocrystal is obtained by grinding at room temperature.

[0048] Example 5

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

[0050] Weigh 10 mg of finely powdered bexarotene and its cocrystal, add them to 30 mL of water at room temperature (25 ± 2 ° C), stir them with a magnetic stirrer, and observe the dissolution within 30 minutes; if no solute particles are visible, it can be considered completely dissolved, then continue to add 10 mg of powder, observe the dissolution within 30 minutes, and repeat the operation until solute particles are visible. 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, and 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 could be 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 the drug cocrystal could not be obtained.

[0055] Comparative Example 3

[0056] The preparation method of bexarotene cocrystal in Example 1 was followed, except that acetone was selected as the solvent, but no drug cocrystal could be 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; the X-ray powder diffraction analysis was performed using a Malvern Panalytical Aeris desktop diffractometer, the X-ray was CuKα, the working voltage was 40 kV, the working current was 7.5 mA, the scanning step was 0.02°, the scanning speed was 10° / min, and the scanning range was 5-40°. The experimental results were plotted using Origin2021 software.

[0060] Figure 1 The X-ray powder diffraction pattern of the bexarotene-L-arginine cocrystal obtained in Examples 1 and 2 and the comparative spectra of single-component bexarotene and L-arginine; 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, with a heating rate of 10°C / min from 25°C to 300°C 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 differential scanning calorimetry (DSC) diagram of the bexarotene-L-arginine cocrystal and the single-component bexarotene and L-arginine obtained in Example 4 shows that the sample begins to melt at about 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 the melting point of the single component.

[0064] Specific biological examples

[0065] Pulmonary hypertension is caused by a variety of reasons, and the reconstruction of pulmonary artery vascular structure is its main pathological cause. A single injection of monocrotaline (MCT) causes a progressive increase in pulmonary arterial pressure through delayed and progressive changes in rat pulmonary artery endothelial cells, platelet thrombosis in small pulmonary arteries, and abnormal proliferation of smooth muscle cells, resulting in a rat pulmonary hypertension model. Examples Animals 210 SD rats weighing about 200 g were randomly divided into 7 groups, 30 rats in each group: normal control group (Control), pulmonary hypertension model group (Vehicle+MCT), positive drug sildenafil (Sid+MCT, 60 mg / kg) group, bexarotene group (BEX+MCT, 60 mg / kg), L-arginine group ((L-arg+MCT, 30 mg / kg), bexarotene and L-arginine mixed group (MIX+MCT, 90 mg / kg, wherein the molar ratio of BEX and L-arginine is 1:1, and the mass ratio is 2:1), bexarotene-L-arginine cocrystal group (Co-crystal+MCT, 90 mg / kg) group. Monocrotaline was prepared into a 1% concentration solution with normal saline, mixed evenly under ultrasound, and the pH was adjusted to 7.2-7.4; the normal control group was given an equal dose of normal saline, and the rats in other groups were given a single intraperitoneal injection of 60 mg / kg MCT was used to establish a rat pulmonary hypertension model. The drug was administered starting from the day of modeling and continued for 4 weeks, once a day, with 0.5% sodium carboxymethyl cellulose as the solvent control.

[0066] The experimental endpoints investigated the survival rate, heart coefficient, right heart index, echocardiography to detect pulmonary artery blood flow velocity and blood flow acceleration time, right cardiac catheterization to detect pulmonary artery and right ventricular systolic pressure, the degree of right ventricular thickening, serum pulmonary hypertension markers and tissue morphological changes, to determine the protective effect of bexarotene-L-arginine cocrystal compound on pulmonary hypertension in rats and its use in the preparation of prevention and treatment of pulmonary hypertension.

[0067] Example 6 Effect of Bexarotene-L-arginine Cocrystal Compound on Survival Rate of Rats with Pulmonary 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 them, the bexarotene-L-arginine cocrystal compound had the most obvious improvement effect, which was better than the mixture of the two and the positive drug sildenafil. Figure 6 As shown; at the end of the experiment, the mortality of each group is shown in Table 2. The number of surviving rats in the cocrystal compound administration group was the largest, close to that of the normal group.

[0069] Table 2. Effect of bexarotene-L-arginine cocrystal compound on the survival rate of rats with pulmonary 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 flow velocity (PVmax, mm / s) and pulmonary artery blood flow acceleration time (PAAT, ms). The results were as follows Figure 7 As shown in the data, 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 was significantly increased in each intervention group, 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 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, and each drug group could significantly reduce the mean right ventricular systolic pressure and pulmonary artery systolic pressure in rats with pulmonary hypertension. The bexarotene-L-arginine cocrystal compound significantly reduced the right ventricular pressure and pulmonary artery systolic pressure, and its effect was better than 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 Heart Hypertrophy Index in Rats with Pulmonary Hypertension

[0079] After measuring the pressure, blood was collected and the rats were perfused with saline. The chest cavity was opened to remove the rat heart and the atrial tissue was cut off. The right ventricular free wall, left ventricle and ventricular septum (Left Ventricular plus Septum, LV+S) were cut out. The water on the surface was absorbed with filter paper and weighed respectively. The right ventricular hypertrophy index [RV / (LV+S)] was calculated to determine the degree of right ventricular hypertrophy.

[0080] The results are as follows Fig. 9The results showed that the positive drug sildenafil could significantly improve right ventricular hypertrophy caused by pulmonary hypertension. Bexarotene and L-arginine alone or as a mixture significantly reduced right ventricular wall hypertrophy in rats with pulmonary hypertension, but the bexarotene-L-arginine cocrystal compound showed the greatest improvement. After administration, the cardiac index and right ventricular hypertrophy index of the rats 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 saline, the pulmonary artery and left lung were fixed in 4% neutral paraformaldehyde solution, embedded in paraffin, serially sectioned and stained with HE. Five fields of view were randomly selected for each sample to detect the thickness of the pulmonary artery wall and observe the pulmonary artery stenosis. Five pulmonary arteriolar vessels with a diameter of 100±50μm were randomly selected, and the ratio of the cross-sectional area of ​​the vessel wall to the lumen area WA%=(TA-IA) / TA was calculated using IPP 6.0 (Image-Pro-Plus6.0) image processing software to evaluate the remodeling of the pulmonary vessels.

[0083] The results are as follows Fig.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 the mixture of the two all have different degrees of improvement. The effect of the bexarotene-L-arginine cocrystal compound is significantly better than that of the positive drug sildenafil, which is manifested by the fact that the thickness of the pulmonary artery intima-media and the lumen area ratio of the pulmonary arteries and pulmonary arterioles in rats after administration of the bexarotene-L-arginine cocrystal compound are close to those of the normal group of rats.

Claims

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

2.

2. The bexarotene and L-arginine eutectic according to claim 1, Features: 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:

3. The bexarotene and L-arginine eutectic according to claim 1, Features: When analyzed using differential scanning calorimetry, it is shown that when the heating rate is 10°C per minute, the DSC spectrum has a characteristic melting peak at 136.0±0.61°C.

4. The method for preparing the bexarotene and L-arginine eutectic according to claim 1, Features: The method is a grinding method, which specifically comprises the following steps: putting bexarotene and L-arginine in an equal mole ratio or a ratio of 1:2 into a mortar, adding a solvent for grinding, and naturally drying at room temperature to obtain a bexarotene-L-arginine eutectic.

5. The method for preparing the bexarotene and L-arginine eutectic according to claim 4, Features: The solvent is ethanol or isopropanol.

6. The bexarotene and L-arginine eutectic according to claim 4, Features: The co-crystal is formed with bexarotene as the active pharmaceutical ingredient, L-arginine as the co-crystal former, and anhydrous ethanol as the solvent in a molar ratio of 1:1, and more preferably in a molar ratio of 1:

2.

7. The bexarotene and L-arginine cocrystal according to claim 1, Features: The solubility is improved and the water solubility is higher than that of the single component of bexarotene.

8. Use of the bexarotene and L-arginine cocrystal according to claims 1-7 in the preparation of a medicament for treating or preventing diseases, wherein the diseases include but are 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.

9. The use according to claim 8, wherein the arterial pulmonary hypertension is idiopathic pulmonary hypertension or hereditary pulmonary hypertension.

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