Oxaprozin and isoniazid eutectic, pharmaceutical composition and preparation method thereof

Abstract

The present invention discloses a eutectic mixture of oxaprozin and isoniazid, a pharmaceutical composition, and a preparation method thereof. The eutectic mixture is prepared by a solvent-assisted grinding method and comprises oxaprozin and isoniazid in a molar ratio of 0.1 to 0.9. The oxaprozin + isoniazid eutectic melts at 134±4°C. Compared to oxaprozin and isoniazid alone, the eutectic mixture significantly reduces the melting point and significantly improves the dissolution rate and solubility of oxaprozin, which previously had extremely poor water solubility. The pharmaceutical composition provided by the present invention is easy to industrially produce and apply, and has good application prospects.

Description

Technical Field

[0001] The present invention relates to a eutectic, a pharmaceutical composition and a preparation method thereof, and in particular to an oxaprozin and isoniazid eutectic, a pharmaceutical composition and a preparation method thereof. Background Art

[0002] Arthritis generally refers to inflammatory diseases that occur in the joints and surrounding tissues of the human body and are caused by inflammation, infection, degeneration, trauma, or other factors. There are dozens of different types of arthritis. Clinical manifestations include redness, swelling, heat, pain, dysfunction, and deformity of the joints. 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] Oxaprozin is one of the most widely used nonsteroidal anti-inflammatory drugs (NSAIDs). Oxaprozin has been widely used to treat rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, cervical-shoulder-wrist syndrome, frozen shoulder, gout, and anti-inflammatory and analgesic effects after trauma and surgery. Oxaprozin can inhibit protein tyrosine kinase Syk, ZAP-70, and phosphodiesterase IV, thereby effectively reducing the symptoms and inflammation associated with human contact dermatitis. Oxaprozin is a Class II drug in the Biopharmaceutical Classification System (BCS) with low water solubility and high permeability (log P = 4.19). Oxaprozin meets the BCS low solubility criteria within the pH range of 1.2 to 7.4. Oxaprozin's extremely poor water solubility has resulted in considerable limitations in its clinical application.

[0006] The literature (Cherukuvada, S.; Nangia, A., Eutectics as Improved Pharmaceutical Materials: Design, Properties and Characterization. 2014, 50, (8), 906-923. DOI: 10.1039 / c3cc47521b) redefined eutectics based on thermodynamic methods and microstructure, and summarized and prospected the development of eutectics. 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) reviewed the application of eutectics in the pharmaceutical field and pointed out that eutectics have great potential in improving the solubility and dissolution rate of poorly water-soluble drugs.

[0007] In summary, preparing oxaprozin into a eutectic is expected to increase the dissolution rate and solubility of oxaprozin, thereby improving its bioavailability. Relevant technologies need to be studied. Summary of the Invention

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

[0009] Technical solution: The oxaprozin and isoniazid eutectic mixture of the present invention comprises oxaprozin and isoniazid in a molar ratio of 0.1 to 0.9, with the remainder being an inevitable solvent.

[0010] Preferably, the oxaprozin+isoniazid eutectic mixture melts at 134±4°C.

[0011] Preferably, the molar ratio of oxaprozin to isoniazid is 0.4:0.6 to 0.6:0.4.

[0012] The present invention also provides a method for preparing the oxaprozin and isoniazid eutectic, including but not limited to a solvent-assisted grinding method or a solvent dissolution method.

[0013] Preferably, the solvent-assisted grinding method comprises the following steps: grinding oxaprozin and isoniazid manually in a mortar or mechanically in a ball mill with the aid of a solvent, and then drying to obtain the eutectic mixture.

[0014] Preferably, the solvent dissolution method comprises the following steps: dissolving oxaprozin and isoniazid in a solvent by stirring, then removing the solvent and drying to obtain the eutectic mixture.

[0015] Preferably, in the solvent-assisted grinding method, the solid-liquid ratio of the total mass of oxaprozin + isoniazid to the solvent is (0.8-1.2) g:1 mL; in the solvent dissolution method, the solid-liquid ratio of the total mass of oxaprozin + isoniazid to the solvent is (5-20) mg:1 mL.

[0016] Preferably, the solvent includes but is not limited to: one or a mixed solvent of methanol, ethanol, isopropanol, n-propanol, acetone, cyclohexane, acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, and dichloromethane.

[0017] The pharmaceutical composition containing the eutectic mixture of the present invention can be further used in powders, tablets, granules, capsules, pills, films, ointments, suppositories or pastes.

[0018] The present invention uses isoniazid (iNH) as a ligand to design and synthesize an oxaprozin + isoniazid eutectic. The oxaprozin + isoniazid eutectic mixture, with a eutectic temperature of 134±4°C, was prepared by solvent-assisted grinding or solvent dissolution. Compared to oxaprozin and isoniazid alone, the eutectic mixture exhibits a significantly lower melting point, significantly improved dissolution rate, and significantly improved saturation solubility.

[0019] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: (1) The melting point of the eutectic prepared by solvent-assisted grinding or solvent dissolution is 134±4°C. Compared with oxaprozin and isoniazid alone, the melting point of the eutectic mixture is significantly lower, and the dissolution rate and saturated solubility of oxaprozin alone are significantly improved; (2) The preparation method is simple and easy, has good reproducibility, is easy to industrialize and apply, and has good application prospects; (3) The dissolution rate of the pharmaceutical composition prepared from the eutectic is significantly improved compared with oxaprozin alone, thereby improving the solubility and dissolution rate of the pharmaceutical composition. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 The DSC heat flow-temperature curves of oxaprozin and isoniazid eutectic mixtures with different molar ratios, and of oxaprozin and isoniazid alone;

[0021] Figure 2 Based on Figure 1 Heat flow-temperature curve of the sample, solid-liquid binary phase diagram of oxaprozin and isoniazid;

[0022] Figure 3 for Figure 1 When the molar ratio of oxaprozin to isoniazid is 0.5:0.5, the PXRD diffraction pattern of the eutectic;

[0023] Figure 4 Graph showing the relationship between the amount of oxaprozin dissolved and time in the in vitro dissolution experiment of oxaprozin and the oxaprozin+isoniazid eutectic mixture obtained in Example 6. DETAILED DESCRIPTION

[0024] The technical solution of the present invention is described in detail below with reference to specific embodiments.

[0025] The differential scanning calorimetry (DSC) analysis chart of the present invention is detected by TA DSC25 of the United States, with a heating rate of 10K / min; an aluminum crucible is used; the purge gas is nitrogen (60ml / min), and the protective gas is nitrogen (40ml / min).

[0026] The conditions of the high performance liquid chromatography of the present invention are shown in Table 1.

[0027] Table 1 HPLC test conditions

[0028]

[0029] Example 1

[0030] As shown in the table below, according to the molar ratio of oxaprozin to isoniazid = X:(1-X) (X=0.1-0.9), oxaprozin and isoniazid were weighed separately and placed in an agate mortar. Ethanol was added dropwise in three portions with a total volume of 1 mL, and the mixture was ground for 30 minutes. The resulting product was then vacuum dried at 40° C. for 3 hours to obtain a eutectic mixture of oxaprozin and isoniazid.

[0031] Table 2 Composition ratio of oxaprozin and isoniazid

[0032] Sample number Oxaprozin (mg) Isoniazid (mg) molar ratio 1 38.40 161.60 0.1:0.9 2 69.68 130.32 0.2:0.8 3 95.65 104.35 0.3:0.7 4 117.56 82.44 0.4:0.6 5 136.28 63.72 0.5:0.5 6 152.47 47.53 0.6:0.4 7 249.92 50.08 0.7:0.3 8 268.60 31.40 0.8:0.2 9 380.25 19.75 0.9:0.1

[0033] Differential scanning calorimetry (DSC) analysis was performed on the eutectic mixture of oxaprozin and isoniazid obtained from each group of samples in Table 2. The DSC test results are shown in FIG. Figure 1As shown. It can be seen that the melting point of the eutectic mixture of oxaprozin and isoniazid is significantly reduced compared to the individual oxaprozin (1:0) and isoniazid (0:1). Among them, the molar ratio of oxaprozin and isoniazid is in the range of 0.1:0.9 to 0.9:0.1, and a characteristic absorption peak appeared at around 134 ° C, but the three curves in the range of 0.1:0.9 to 0.3:0.7 and the three curves in the range of 0.7:0.3 to 0.9:0.1 also had a second characteristic absorption peak, indicating that the mixing effect of the eutectic mixture is slightly worse. According to the heat flow-temperature curve of the eutectic mixture obtained by grinding oxaprozin and isoniazid with different molar ratios, with temperature as the vertical coordinate and the molar ratio content of oxaprozin (X) as the horizontal coordinate, the first endothermic peak site under each ratio is connected to obtain the solid line, and the second endothermic peak site appearing under each ratio is connected to obtain the liquid line, and a binary phase diagram is drawn. As shown Figure 2 As shown in Figure 2, the binary phase diagram shows that the optimal eutectic ratio of the system is when the molar ratio of oxaprozin and isoniazid is 0.4:0.6 to 0.6:0.4. At this time, the eutectic temperature is about 134°C, and there is only one melting peak. It can be seen that the eutectic temperature is much lower than the melting point of oxaprozin (1:0) or isoniazid (0:1) alone. When the molar ratio of oxaprozin and isoniazid is 0.5:0.5, the PXRD diffraction of the eutectic is as follows: Figure 3 The PXRD diffraction peaks of the oxaprozin and isoniazid eutectic are a superposition of the diffraction peaks of oxaprozin and isoniazid alone. Combined with the DSC results, the prepared sample is indeed a eutectic of oxaprozin and isoniazid. The present invention successfully prepares a eutectic mixture of oxaprozin and isoniazid using a solvent-assisted grinding method.

[0034] Example 2

[0035] Weigh 1466 mg (5 mmol) of oxaprozin and 686 mg (5 mmol) of isoniazid in a 250 mL flask, add 200 mL of ethanol, and stir magnetically at 40°C for 20 minutes. After the solution is clarified, the solvent is removed by rotary evaporation under reduced pressure, and the resulting product is dried in a vacuum drying oven at 40°C for 6 hours to obtain a low-melting eutectic mixture of oxaprozin and isoniazid. The test results show that the DSC curve of the low-melting eutectic mixture is consistent with the Figure 1 The results are basically consistent when X=0.5, indicating that a eutectic mixture of oxaprozin and isoniazid with a eutectic temperature of about 134°C was successfully prepared.

[0036] Example 3

[0037] Weigh 1613 mg (5.5 mmol) of oxaprozin and 617 mg (4.5 mmol) of isoniazid into a 250 mL flask, add 200 mL of ethanol, and stir magnetically at 40°C for 20 minutes. After the solution is clarified, the solvent is removed by rotary evaporation under reduced pressure, and the resulting product is then dried in a vacuum drying oven at 40°C for 6 hours to obtain a low-melting eutectic mixture of oxaprozin and isoniazid. The test results show that the DSC curve of the low-melting eutectic mixture is consistent with the Figure 1 The results are basically consistent when X=0.5, indicating that the eutectic mixture of oxaprozin and isoniazid with a eutectic temperature of about 134°C was successfully prepared.

[0038] Example 4

[0039] Weigh 131.09 mg (0.45 mmol) of oxaprozin and 74.91 mg (0.55 mmol) of isoniazid and prepare a eutectic mixture of oxaprozin and isoniazid according to the method described in Example 1. The test results show that the DSC curve of the eutectic mixture is consistent with Figure 1 The results are basically consistent when X=0.5, indicating that a eutectic mixture of oxaprozin and isoniazid with a eutectic temperature of about 134°C was successfully prepared.

[0040] Example 5

[0041] Weigh 162.74 mg (0.55 mmol) of oxaprozin and 62.26 mg (0.45 mmol) of isoniazid and prepare a eutectic mixture of oxaprozin and isoniazid according to the method described in Example 1. The test results show that the DSC curve of the eutectic mixture is consistent with Figure 1 The results are basically consistent when X=0.5, indicating that a eutectic mixture of oxaprozin and isoniazid with a eutectic temperature of about 134°C was successfully prepared.

[0042] Example 6

[0043] In vitro dissolution experiment of oxaprozin and isoniazid eutectic mixture

[0044] Test method: Refer to Chinese Pharmacopoeia 2020 edition

[0045] Instrument model: RC806ADK Tianda Tianfa

[0046] Weigh 50 mg of oxaprozin and 73.37 mg of oxaprozin + isoniazid eutectic (containing 50 mg of oxaprozin) and pass through an 80-mesh standard sieve. Divide the sample into three groups, each containing three aliquots, and add them to a dissolution vessel containing 900 mL of pure water. Stir at 37°C ± 0.5°C and 75 rpm. At 30, 60, 90, 120, 180, 240, 300, 360, and 480 minutes, remove 2 mL of the solution for analysis and add 2 mL of pure water. Filter the removed samples through a 0.22 μm filter membrane, and determine the oxaprozin content in each sample by high-performance liquid chromatography.

[0047] The test results are as follows Figure 4 As shown in the figures, it can be seen that the dissolution rate and saturated solubility of the oxaprozin + isoniazid eutectic mixture are significantly improved compared to oxaprozin alone. This indicates that the oxaprozin + isoniazid eutectic mixture helps to increase the dissolution rate and saturated solubility of oxaprozin, thereby significantly improving the anti-inflammatory efficacy of oxaprozin.

[0048] In summary, the oxaprozin + isoniazid eutectic mixture provided by the present invention is prepared by solvent-assisted grinding or solvent dissolution method to obtain an oxaprozin + isoniazid eutectic mixture with a eutectic temperature of 134±4°C. Compared with oxaprozin and isoniazid alone, the melting point of the eutectic mixture is significantly lowered, and the dissolution rate and saturation solubility are significantly improved. Therefore, in addition to inheriting the original anti-inflammatory activity of the drug, the present invention significantly enhances the efficacy of the drug, is easy to industrialize and apply, and has good application prospects.

Claims

1. An oxaprozin and isoniazid eutectic, characterized in that: The molar ratio of oxaprozin to isoniazid is 0.4:0.6 to 0.6:0.

4.

2. The oxaprozin and isoniazid eutectic according to claim 1, wherein The melting point of the eutectic is 134±4°C.

3. A method for preparing the oxaprozin and isoniazid eutectic according to any one of claims 1 to 2, characterized in that: The method is a solvent-assisted grinding method, which comprises the following steps: manually grinding oxaprozin and isoniazid in a mortar or mechanically ball-milling with the aid of a solvent, and then drying to obtain the eutectic mixture, wherein the solid-liquid ratio of the total mass of the oxaprozin and isoniazid to the solvent is (0.8-1.2) g:1 mL, and the solvent is ethanol.

4. A method for preparing the oxaprozin and isoniazid eutectic according to any one of claims 1 to 2, characterized in that: The method is a solvent dissolution method, which comprises the following steps: stirring and dissolving oxaprozin and isoniazid in a solvent, then removing the solvent and drying to obtain the eutectic mixture, wherein the solid-liquid ratio of the total mass of the oxaprozin and isoniazid to the solvent is (5-20) mg:1 mL, and the solvent is ethanol.

5. A pharmaceutical composition comprising the oxaprozin and isoniazid eutectic according to any one of claims 1 to 2, 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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