Oxaprazin and isonicotinamide or pyrazinamide eutectic, pharmaceutical composition and preparation method thereof

Abstract

This invention discloses a eutectic mixture of oxaprozin and isonicotinamide or pyrazinamide, a pharmaceutical composition, and a method for preparing the same. The eutectic mixture is prepared by solvent-assisted milling and comprises oxaprozin and isonicotinamide in a molar ratio of 0.1–0.9, or oxaprozin and pyrazinamide in a molar ratio of 0.1–0.9. The eutectic mixtures of oxaprozin + isonicotinamide and oxaprozin + pyrazinamide are melted at 124±4℃ and 141±4℃, respectively. Compared to oxaprozin and isonicotinamide or pyrazinamide alone, the melting point of the eutectic mixture is significantly lower, and the dissolution rate and solubility of oxaprozin, which previously had extremely poor water solubility, are significantly improved. The pharmaceutical composition provided by this invention is easy to industrially produce and apply, and has good application prospects.

Description

Technical Field

[0001] This invention relates to a eutectic compound, a pharmaceutical composition and a method for preparing the same, and more particularly to a eutectic compound of oxaprazine and isonicotinamide or pyrazinamide, a pharmaceutical composition and a method for preparing the same. Background Technology

[0002] Arthritis is a general term for inflammatory diseases that occur in the joints and surrounding tissues of the human body, caused by inflammation, infection, degeneration, trauma, or other factors. It can be classified into dozens of types. Clinical manifestations include redness, swelling, heat, pain, impaired function, and joint deformities. In severe cases, it can lead to joint disability and affect the patient's quality of life.

[0003] Oxaprozin (OXA), CAS No.: 21256-18-8, chemical name: 4,5-diphenyloxazole-2-propionic acid, its structure is shown below:

[0004]

[0005] Oxaprazin is a widely used nonsteroidal anti-inflammatory drug (NSAID). It has been extensively used to treat rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, cervicobrachial syndrome, frozen shoulder, gout, and for anti-inflammatory and analgesic purposes after trauma and surgery. Oxaprazin inhibits protein tyrosine kinases Syk, ZAP-70, and phosphodiesterase IV, thereby effectively reducing symptoms and inflammation associated with contact dermatitis in humans. Oxaprazin is a Class II drug in the Biopharmaceutical Classification System (BCS), characterized by low water solubility and high permeability (log P = 4.19). Oxaprazin meets the BCS low solubility criteria within a pH range of 1.2 to 7.4. The extremely poor water solubility of oxaprazin significantly limits its clinical application.

[0006] The literature (Cherukuvada, S.; Nanga, A., Eutectics as Improved Pharmaceutical Materials: Design, Properties and Characterization. 2014, 50, (8), 906-923. DOI: 10.1039 / c3cc47521b) redefines eutectic materials based on thermodynamic methods and microstructure, and summarizes and looks forward to the development of eutectic materials. The literature (Bazzo, GC; Pezzini, BR; Stulzer, HK, Eutectic Mixtures as an Approach to Enhance Solubility, Dissolution Rate and Oral Bioavailability of Poorly Water-Soluble Drugs. 2020, 588, 119741, DOI: 10.1016 / j.ijpharm.2020.119741) reviews the application of eutectic mixtures in the pharmaceutical field, pointing out that eutectic mixtures have great potential in improving the solubility and dissolution rate of poorly water-soluble drugs.

[0007] In summary, preparing oxapridine into a eutectic compound is expected to improve its dissolution rate and solubility, thereby enhancing its bioavailability. However, further research is needed on related technologies. Summary of the Invention

[0008] Objectives of the invention: The present invention aims to provide a low melting point and high solubility and dissolution rate of oxaprozin and isonicotinamide or pyrazinamide eutectic; another objective of the present invention is to provide a pharmaceutical composition containing oxaprozin and isonicotinamide or pyrazinamide eutectic; yet another objective of the present invention is to provide a method for preparing the oxaprozin and isonicotinamide or pyrazinamide eutectic.

[0009] Technical solution: The eutectic mixture of oxaprazine and isonicotinamide or pyrazinamide described in this invention contains oxaprazine and isonicotinamide in a molar ratio of 0.1 to 0.9 or oxaprazine and pyrazinamide in a molar ratio of 0.1 to 0.9, with the remainder being unavoidable solvents.

[0010] Preferably, the oxaprazine + isonicotinamide eutectic mixture is melted at 124±4℃.

[0011] Preferably, the oxaprazine + pyrazinamide eutectic mixture is melted at 141±4°C.

[0012] Preferably, the oxaprazine + isonicotinamide eutectic mixture comprises oxaprazine + isonicotinamide in a molar ratio of 0.4:0.6 to 0.5:0.5.

[0013] Preferably, the oxaprazine + pyrazinamide eutectic mixture comprises oxaprazine + pyrazinamide in a molar ratio of 0.5:0.5 to 0.67:0.33.

[0014] This invention also provides a method for preparing eutectic compounds of oxaprazine, isonicotinamide, and pyrazinamide, including but not limited to solvent-assisted grinding or solvent dissolution.

[0015] Preferably, the solvent-assisted grinding method includes the following steps: manually grinding oxaprazine + isonicotinamide and oxaprazine + pyrazinamide in a mortar and pestle or mechanically ball milling under solvent assistance, and then drying to obtain the eutectic mixture.

[0016] Preferably, the solvent dissolution method includes the following steps: dissolving oxaprazine + isonicotinamide and oxaprazine + pyrazinamide in solvents by stirring, then removing the solvent and drying to obtain the eutectic mixture.

[0017] Preferably, in the solvent-assisted grinding method, the solid-liquid ratio of the total mass of oxaprolin + isonicotinamide or oxaprolin + pyrazinamide to the solvent is (0.7-1.1) g:1 mL; in the solvent dissolution method, the solid-liquid ratio of the total mass of oxaprolin + isonicotinamide or oxaprolin + pyrazinamide to the solvent is (4-15) mg:1 mL.

[0018] Preferably, the solvent comprises, but is not limited to, one or a mixture of several of the following: methanol, ethanol, isopropanol, n-propanol, acetone, cyclohexane, acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, and dichloromethane.

[0019] The pharmaceutical composition containing oxaprazin and isonicotinamide or pyrazinamide described in this invention can be further used in powders, tablets, granules, capsules, pills, films, ointments, suppositories or pastes.

[0020] This invention selects isonicotinamide (iNAM) and pyrazinamide (PZA) as ligands to design and synthesize eutectic compounds of oxaprolin + isonicotinamide and oxaprolin + pyrazinamide. Eutectic mixtures of oxaprolin + isonicotinamide and oxaprolin + pyrazinamide with eutectic temperatures of 124±4℃ and 141±4℃, respectively, were prepared by solvent-assisted milling or solvent dissolution methods. Compared with oxaprolin and isonicotinamide or pyrazinamide alone, the eutectic mixtures showed significantly lower melting points, significantly higher dissolution rates, and significantly higher saturated solubility.

[0021] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The melting points of the eutectic mixtures of oxaprozin and isonicotinamide, and oxaprozin and pyrazinamide prepared by solvent-assisted grinding or solvent dissolution are 124±4℃ and 141±4℃, respectively. Compared with oxaprozin, isonicotinamide and pyrazinamide alone, the melting point of the eutectic mixture is significantly reduced, and the dissolution rate and saturated solubility of oxaprozin alone are significantly improved; (2) The preparation method is simple and easy to implement, has good reproducibility, is easy to industrialize and apply, and has good application prospects; (3) The drug composition prepared from the eutectic mixture has a significantly improved dissolution rate compared with oxaprozin alone, thereby improving the solubility and dissolution rate of the drug composition. Attached Figure Description

[0022] Figure 1 DSC heat flow-temperature profiles for eutectic mixtures of oxapoxetine and isonicotinamide with different molar ratios, and for oxapoxetine and isonicotinamide individually;

[0023] Figure 2 According to Figure 1 Heat flow-temperature curves of the samples were plotted, and solid-liquid binary phase diagrams of oxapoxetine and isonicotinamide were constructed.

[0024] Figure 3 DSC heat flow-temperature profiles for eutectic mixtures of oxaprazine and pyrazinamide in different molar ratios, and for oxaprazine and pyrazinamide alone;

[0025] Figure 4 According to Figure 3 Heat flow-temperature curves of the samples were plotted, and solid-liquid binary phase diagrams of oxaprazine and pyrazinamide were drawn.

[0026] Figure 5 The graph shows the relationship between the amount of oxapridine dissolved and time in the in vitro dissolution experiments of oxapridine, oxapridine + isonicotinamide eutectic mixture, and oxapridine + pyrazinamide eutectic mixture obtained according to Example 7. Detailed Implementation

[0027] The technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0028] The differential scanning calorimetry (DSC) analysis chromatogram described in this invention was detected by a TA DSC25 instrument from the United States, with a heating rate of 10 K / min; an aluminum crucible was used; the purge gas was nitrogen (60 mL / min), and the protective gas was nitrogen (40 mL / min).

[0029] The conditions for high-performance liquid chromatography described in this invention are shown in Table 1.

[0030] Table 1 Test conditions for high performance liquid chromatography

[0031]

[0032]

[0033] Example 1

[0034] As shown in the table below, according to the molar ratio of oxaprazine and isonicotinamide = X:(1-X) (X = 0.1~0.9), oxaprazine and isonicotinamide were weighed separately and placed in an agate mortar. Ethanol with a total volume of 1 mL was added dropwise in three portions, and the mixture was ground for 30 minutes. Then, the resulting product was vacuum dried at 40°C for 3 hours to obtain a eutectic mixture of oxaprazine and isonicotinamide.

[0035] Table 2 Composition ratio of oxapezil and isonicotinamide

[0036] Sample number Oxyprozin (mg) Isonicotinamide (mg) Moor ratio 1 42.13 157.87 0.1:0.9 2 75.04 124.96 0.2:0.8 3 101.45 98.55 0.3:0.7 4 123.11 76.89 0.4:0.6 5 141.21 58.79 0.5:0.5 6 156.55 43.45 0.6:0.4 7 254.58 45.42 0.7:0.3 8 271.72 28.28 0.8:0.2 9 382.31 17.69 0.9:0.1

[0037] Differential scanning calorimetry (DSC) analysis was performed on the eutectic mixtures of oxaprazine and isonicotinamide obtained from each group of samples in Table 2. The DSC test results are as follows: Figure 1 As shown, the melting point of the eutectic mixture of oxapoxetine (1:0) and isonicotinamide (0:1) is significantly lower than that of oxapoxetine and isonicotinamide alone. Specifically, characteristic absorption peaks appeared around 124℃ in the molar ratio of oxapoxetine to isonicotinamide within the range of 0.1:0.9 to 0.9:0.1. However, three curves in the range of 0.1:0.9 to 0.3:0.7 and four curves in the range of 0.6:0.4 to 0.9:0.1 all showed a second characteristic absorption peak, indicating that the mixing effect of the eutectic mixture was slightly worse. Based on the heat flow-temperature curves of the eutectic mixtures obtained by grinding oxapoxetine and isonicotinamide at different molar ratios, with temperature as the ordinate and the molar ratio content of oxapoxetine (X) as the abscissa, the first endothermic peak at each ratio was connected to obtain the solid phase line, and the second endothermic peak at each ratio was connected to obtain the liquid phase line, thus plotting a binary phase diagram. Figure 2 As shown in the binary phase diagram, the optimal eutectic ratio for the system is 0.4:0.6 to 0.5:0.5 for oxaprolin and isonicotinamide, with a eutectic temperature of approximately 124°C and only one melting peak. This eutectic temperature is significantly lower than the melting points of oxaprolin (1:0) or isonicotinamide (0:1) alone. This demonstrates that the present invention successfully prepares an eutectic mixture of oxaprolin and isonicotinamide using a solvent-assisted grinding method, which significantly improves the dissolution rate and solubility of oxaprolin.

[0038] Example 2

[0039] As shown in the table below, according to the molar ratio of oxaprazine and pyrazinamide = X:(1-X) (X = 0.1~0.9), oxaprazine and pyrazinamide were weighed separately and placed in an agate mortar. Ethanol with a total volume of 1 mL was added dropwise in three portions, and the mixture was ground for 30 minutes. Then, the resulting product was vacuum dried at 40°C for 3 hours to obtain a eutectic mixture of oxaprazine and pyrazinamide.

[0040] Table 3 Composition ratio of oxapezil and pyrazinamide

[0041] Sample number Oxyprozin (mg) Pyrazinamide (mg) Moor ratio 1 41.86 158.14 0.1:0.9 2 74.66 125.34 0.2:0.8 3 108.73 91.27 0.33:0.67 4 140.87 59.13 0.5:0.5 5 247.96 52.04 0.67:0.33 6 271.51 28.49 0.8:0.2 7 382.18 17.82 0.9:0.1

[0042] Differential scanning calorimetry (DSC) analysis was performed on the eutectic mixtures of oxaprazine and pyrazinamide obtained from each group of samples in Table 2. The DSC test results are as follows: Figure 3 As shown, the melting point of the eutectic mixture of oxaprazine (1:0) and pyrazinamide (0:1) is significantly lower than that of oxaprazine alone. Specifically, characteristic absorption peaks appeared around 141℃ in the molar ratio of oxaprazine to pyrazinamide within the range of 0.1:0.9–0.9:0.1. However, two curves in the range of 0.1:0.9–0.2:0.8 and two curves in the range of 0.8:0.2–0.9:0.1 also showed a second characteristic absorption peak, indicating that the mixing effect of the eutectic mixture was slightly worse. Based on the heat flow-temperature curves of the eutectic mixtures obtained by grinding oxaprazine and pyrazinamide at different molar ratios, with temperature as the ordinate and the molar ratio content of oxaprazine (X) as the abscissa, the first endothermic peak site under each ratio was connected to obtain the solid-state line, and the second endothermic peak site under each ratio was connected to obtain the liquid-state line, thus plotting a binary phase diagram. Figure 4 As shown in the binary phase diagram, the optimal eutectic ratio for the system is 0.5:0.5 to 0.67:0.33 for oxaprolin and pyrazinamide, with a eutectic temperature of approximately 141°C and only one melting peak. This indicates that the eutectic temperature is significantly lower than the melting points of oxaprolin (1:0) or pyrazinamide (0:1) alone. This demonstrates that the present invention successfully prepares a eutectic mixture of oxaprolin and pyrazinamide using a solvent-assisted grinding method, which significantly improves the dissolution rate and solubility of oxaprolin.

[0043] Example 3

[0044] 1468 mg (5 mmol) of oxaprazine and 611 mg (5 mmol) of isonicotinamide were weighed into a 250 mL flask, and 200 mL of ethanol was added. The mixture was magnetically stirred at 40 °C for 20 minutes. After the solution clarified, the solvent was removed by rotary evaporation under reduced pressure. The resulting product was then dried in a vacuum drying oven at 40 °C for 6 hours to obtain a eutectic mixture of oxaprazine and isonicotinamide. The test results showed that the DSC curve of this eutectic mixture was consistent with... Figure 1The results were basically consistent when X = 0.5, indicating that a eutectic mixture of oxaprazine and isonicotinamide with a eutectic temperature of about 124℃ was successfully prepared.

[0045] Example 4

[0046] 1468 mg (5 mmol) of oxaprazine and 616 mg (5 mmol) of pyrazinamide were weighed into a 250 mL flask, and 200 mL of ethanol was added. The mixture was magnetically stirred at 40 °C for 20 minutes. After the solution clarified, the solvent was removed by rotary evaporation under reduced pressure. The resulting product was then dried in a vacuum drying oven at 40 °C for 6 hours to obtain a eutectic mixture of oxaprazine and pyrazinamide. The test results showed that the DSC curve of this eutectic mixture was consistent with... Figure 3 The results were basically consistent when X = 0.5, indicating that a eutectic mixture of oxaprazine and pyrazinamide with a eutectic temperature of about 141℃ was successfully prepared.

[0047] Example 5

[0048] 132 mg (0.45 mmol) of oxaprazine and 67 mg (0.55 mmol) of isonicotinamide were weighed and a eutectic mixture of oxaprazine and isonicotinamide was prepared according to the method described in Example 1. Test results showed that the DSC curve of this eutectic mixture was consistent with... Figure 1 The results were basically consistent when X = 0.5, indicating that a eutectic mixture of oxaprazine and isonicotinamide with a eutectic temperature of about 124℃ was successfully prepared.

[0049] Example 6

[0050] 161 mg (0.55 mmol) of oxaprazine and 55 mg (0.45 mmol) of pyrazinamide were weighed and a eutectic mixture of oxaprazine and pyrazinamide was prepared according to the method described in Example 3. Test results showed that the DSC curve of this eutectic mixture was consistent with... Figure 3 The results were basically consistent when X = 0.5, indicating that a eutectic mixture of oxaprazine and pyrazinamide with a eutectic temperature of about 141℃ was successfully prepared.

[0051] Example 7

[0052] In vitro dissolution experiments of eutectic mixtures of oxaprazine and isonicotinamide, and oxaprazine and pyrazinamide

[0053] Test method: Refer to the 2020 edition of the Chinese Pharmacopoeia.

[0054] Instrument Model: RC806ADK Tianda Tianfa

[0055] Weigh out 50 mg of oxaprozin and 70.81 mg of the oxaprozin + isonicotinamide eutectic (containing 50 mg of oxaprozin).

[0056] Oxaprazine + pyrazinamide eutectic 70.99 mg (containing 50 mg oxaprazine) was passed through an 80-mesh standard sieve. The samples were divided into three groups, with three aliquots per group. Each group was added to a dissolution vessel containing 900 mL of pure water and stirred at 75 rpm at 37℃ ± 0.5℃. At minutes 30, 60, 90, 120, 180, 240, 300, 360, and 480, 2 mL of liquid was collected for analysis, and 2 mL of pure water was added. The collected samples were filtered through a 0.22 μm filter membrane, and the oxaprazine content in each sample was determined by high-performance liquid chromatography (HPLC).

[0057] Test results are as follows Figure 5 As shown, the dissolution rate and saturated solubility of the eutectic mixtures of oxaprozin + isonicotinamide and oxaprozin + pyrazinamide are significantly improved compared to oxaprozin alone. This indicates that eutectic mixtures of oxaprozin + isonicotinamide and oxaprozin + pyrazinamide help improve the dissolution rate and saturated solubility of oxaprozin, thereby significantly enhancing its anti-inflammatory efficacy.

[0058] In summary, the eutectic mixtures of oxaprozin + isonicotinamide and oxaprozin + pyrazinamide provided by this invention, prepared by solvent-assisted grinding or solvent dissolution, yielded eutectic temperatures of 124±4℃ and 141±4℃, respectively. Compared to oxaprozin and isonicotinamide or pyrazinamide alone, the eutectic mixtures exhibit significantly lower melting points, significantly higher dissolution rates, and significantly higher saturated solubility. Therefore, this invention, while inheriting the original anti-inflammatory activity of the drugs, significantly enhances their efficacy, is easy to industrialize and apply, and has promising application prospects.

Claims

1. A eutectic compound of oxaprazine and isonicotinamide or pyrazinamide, characterized in that, The molar ratio of oxaprazine to isonicotinamide is 0.1:0.9 to 0.9:0.1, and the molar ratio of oxaprazine to pyrazinamide is 0.1:0.9 to 0.9:0.

1.

2. The eutectic compound of oxaprazine and isonicotinamide or pyrazinamide according to claim 1, characterized in that, The melting points of the oxaprazine and isonicotinamide and the oxaprazine and pyrazinamide eutectic are 124±4 °C and 141±4 °C, respectively.

3. The eutectic compound of oxaprazine and isonicotinamide or pyrazinamide according to claim 1, characterized in that, The molar ratio of oxaprazine to isonicotinamide is 0.4:0.6 to 0.5:0.5, and the molar ratio of oxaprazine to pyrazinamide is 0.5:0.5 to 0.67:0.

33.

4. A method for preparing the eutectic compound of oxaprazine and isonicotinamide or pyrazinamide as described in any one of claims 1-3, characterized in that, This method is either solvent-assisted grinding or solvent dissolution.

5. The method for preparing the eutectic compound of oxaprazine and isonicotinamide or pyrazinamide according to claim 4, characterized in that, The solvent-assisted grinding method includes the following steps: manually grinding oxaprazine and isonicotinamide or pyrazinamide in a mortar and pestle or mechanically ball milling with solvent assistance, and then drying to obtain the eutectic material.

6. The method for preparing the eutectic compound of oxaprazine and isonicotinamide or pyrazinamide according to claim 4, characterized in that, The solvent dissolution method includes the following steps: dissolving oxaprazine and isonicotinamide or pyrazinamide in a solvent by stirring, then removing the solvent and drying to obtain the eutectic compound.

7. The method for preparing the eutectic compound of oxaprazine and isonicotinamide or pyrazinamide according to claim 5, characterized in that, The total mass of the oxaprazine and isonicotinamide or pyrazinamide has a solid-liquid ratio of (0.7-1.1) g to 1 mL with respect to the solvent.

8. The method for preparing the eutectic compound of oxaprazine and isonicotinamide or pyrazinamide according to claim 6, characterized in that, The total mass of the oxaprazine and isonicotinamide or pyrazinamide has a solid-liquid ratio of (4-15) mg to 1 mL with respect to the solvent.

9. The method for preparing the eutectic compound of oxaprazine and isonicotinamide or pyrazinamide according to claim 4, characterized in that, The solvent is one or more of methanol, ethanol, isopropanol, n-propanol, acetone, cyclohexane, acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, and dichloromethane.

10. A pharmaceutical composition comprising oxapezine according to any one of claims 1-3 and isonicotinamide or pyrazinamide eutectic, characterized in that, The pharmaceutical composition is in the form of powder, tablet, granule, capsule, pill, film, ointment, suppository or paste.

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