Pirfenidone co-crystals, methods of making, pharmaceutical compositions, and uses thereof

Abstract

The application belongs to the technical field of medicines, and particularly relates to a pirfenidone co-crystal, a preparation method thereof, a pharmaceutical composition and application. The pirfenidone co-crystal is prepared from pirfenidone and a co-crystal ligand, and the co-crystal ligand is selected from one of heptanedioic acid, cinnamic acid and saccharin. The pirfenidone co-crystal can not only improve the effect of pirfenidone in relieving acute pancreatitis, but also improve the safety of pirfenidone.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to pirfenidone cocrystals and their preparation methods, pharmaceutical compositions and uses. Background Technology

[0002] Pirfenidone is a pyridone compound used clinically to treat idiopathic pulmonary fibrosis. Its specific mechanism of action is not yet fully understood, but it has been reported to inhibit the synthesis and secretion of various inflammatory factors and reduce lipid peroxidation, exhibiting anti-inflammatory, antioxidant, and anti-fibrotic effects. In addition to its clinically approved indications, Shi Xiaoxian et al. reported in their article "Therapeutic Effect of Pirfenidone on L-Arginine-Induced Acute Pancreatitis in Mice" that pirfenidone can also alleviate L-arginine-induced acute pancreatitis. For the treatment of acute diseases, the absolute safety of the drug is particularly important. There are reports that pirfenidone has a low LD50 in SW mice. 50 The concentration is 1000 mg / kg, and its safety needs further improvement.

[0003] There are currently no reports on using pirfenidone with cocrystal ligands to prepare cocrystals to improve the efficacy and safety of pirfenidone in relieving acute pancreatitis. Summary of the Invention

[0004] To address the shortcomings of existing technologies, the present invention aims to provide a pirfenidone cocrystal, its preparation method, pharmaceutical composition, and uses. The pirfenidone cocrystal provided by the present invention not only enhances the efficacy of pirfenidone in relieving acute pancreatitis but also improves the safety of pirfenidone.

[0005] The technical solution of this invention is:

[0006] A pirfenidone cocrystal, wherein the cocrystal is prepared from pirfenidone and a cocrystal ligand selected from pimelic acid, cinnamic acid and saccharin.

[0007] Furthermore, the eutectic ligand is selected from saccharin.

[0008] Furthermore, the molar ratio of pirfenidone to the cocrystallized ligand is 1:(0.5-2).

[0009] Furthermore, the molar ratio of pirfenidone to the cocrystallized ligand is 1:1.

[0010] Furthermore, the X-ray powder diffraction pattern of the eutectic, expressed as 2θ±0.02°, has characteristic peaks at 10.75°, 13.66°, 15.47°, 17.64°, 17.82°, 18.73°, 20.88°, 21.7°, 22.34°, and 25.43°.

[0011] Furthermore, pirfenidone eutectic was prepared using a wet grinding method.

[0012] Furthermore, the solvent used in preparing pirfenidone eutectic by wet milling is selected from one of acetone, ethanol, and N,N-dimethylformamide.

[0013] Furthermore, when preparing pirfenidone eutectic using the wet grinding method, the mass-to-volume ratio of pirfenidone to solvent is 3:(1.5~2.5)mg / μL.

[0014] Furthermore, when preparing pirfenidone eutectic using the wet milling method, the mass-to-volume ratio of pirfenidone to solvent was 3:2 mg / μL.

[0015] Furthermore, when preparing pirfenidone eutectic using the wet grinding method, the grinding time is 1.5 to 2.5 hours.

[0016] Furthermore, when preparing pirfenidone eutectic using the wet grinding method, the grinding time is 2 hours.

[0017] Another object of the present invention is to provide a pharmaceutical composition comprising the above-described pirfenidone cocrystal.

[0018] Furthermore, the pharmaceutical composition is an oral solid dosage form, which is prepared using the above-mentioned pirfenidone cocrystal as the active ingredient and pharmaceutically acceptable additives.

[0019] Furthermore, the oral solid dosage form is selected from granules, tablets, and capsules.

[0020] Another object of the present invention is to provide the use of the above-described pirfenidone cocrystal, the pirfenidone cocrystal prepared by the above-described method of preparing the above-described pharmaceutical composition in the preparation of a medicament for treating pancreatitis or pulmonary fibrosis.

[0021] Drug cocrystals refer to the formation of new solid-phase crystals by an API and cocrystal conformers (CCFs) in a fixed stoichiometric ratio through hydrogen bonding, π-π stacking, or other non-covalent bonding. Besides improvements in physicochemical properties such as solubility and stability, drug cocrystals may (but are not always) lead to improvements in pharmacodynamics, pharmacokinetics, and toxicology. However, whether a specific API and CCF can form a cocrystal, and whether the formed cocrystal can achieve the expected improvements, are highly uncertain. Currently, there is no technical inspiration to improve the efficacy and safety of pirfenidone in relieving acute pancreatitis through cocrystal technology. This invention provides a pirfenidone cocrystal prepared from pirfenidone and a cocrystal conformer selected from pimelic acid, cinnamic acid, and saccharin, which not only improves the efficacy of pirfenidone in relieving acute pancreatitis but also enhances its safety.

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] (1) The experimental results on the effect of L-arginine-induced acute pancreatitis in mice showed that the serum amylase level of the cocrystal prepared in this invention was statistically significantly lower than that of the pirfenidone group, which indicates that the pirfenidone cocrystal prepared in this invention can improve the effect of pirfenidone in relieving acute pancreatitis.

[0024] (2) The results of the safety study showed that, under the condition that the gavage dose was higher than that of the pirfenidone group, the number of animals that died within 1 week in the pirfenidone cocrystal group prepared by gavage was still significantly lower than that in the pirfenidone group. This indicates that the pirfenidone cocrystal prepared by the present invention is safer than pirfenidone. Attached Figure Description

[0025] Figure 1 XRPD image of the eutectic 3 prepared in this invention;

[0026] Figure 2 Comparison of XRPD values ​​for eutectic 3, API after grinding, and dextrin after grinding;

[0027] Figure 3 This is a DSC and TGA overlay image of the eutectic 3 prepared in this invention;

[0028] Figure 4 Image of the eutectic 3 prepared for this invention under a polarizing microscope. Detailed Implementation

[0029] The present invention will be further described below through specific embodiments, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not depart from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0030] Example 1 Eutectic Screening Test

[0031] 1.1 Materials

[0032] 1.1.1 Reagents

[0033] The reagents used in this embodiment include:

[0034] Active pharmaceutical ingredient: Pirfenidone

[0035] Eutectic ligands: pimelic acid, sebacic acid, lauric acid, myristic acid, cinnamic acid, palmitic acid, stearic acid, pamoic acid, saccharin and fumaric acid, etc.

[0036] Solvents: acetone, ethanol, N,N-dimethylformamide.

[0037] All of the above reagents are highly commercially available.

[0038] 1.1.2 Equipment and Instruments

[0039] The equipment and instruments used in this embodiment are all commonly used in wet grinding methods, and are also equipment and instruments that ordinary pharmaceutical research and development institutions can be equipped with.

[0040] 1.2 Methods

[0041] a) Weigh 30 mg of pirfenidone sample and equimolar amounts of ligand into a mortar;

[0042] b) Add 20 μL of solvent;

[0043] c) After grinding for 2 hours, the obtained solid sample was collected, dried to constant weight, and then the melting point (melting range) was measured. The results are shown in Table 1.

[0044] 1.3 Results

[0045] The results are shown in Table 1.

[0046] Table 1 Results of Eutectic Screening Test

[0047] raw materials Eutectic ligands solvent Product melting range (°C) Eutectic number Pirfenidone Lauric acid acetone >2 Pirfenidone sebacic acid DMF >2 Pirfenidone pimelic acid ethanol <2 Eutectic 1 Pirfenidone Myristic acid acetone >2 Pirfenidone Cinnamon acid DMF <2 Eutectic 2 Pirfenidone Palmitic acid ethanol >2 Pirfenidone saccharin acetone <2 Eutectic 3 Pirfenidone stearic acid DMF >2 Pirfenidone Pamoic acid ethanol >2 Pirfenidone fumaric acid acetone >2

[0048] Weigh 30 mg of pirfenidone sample, add 20 μL of ethanol, grind for 2 h, collect the obtained solid sample, dry to constant weight, and then measure the melting point A1.

[0049] Weigh 30 mg of pirfenidone sample, add 20 μL of DMF, grind for 2 h, collect the obtained solid sample, dry to constant weight, and then measure the melting point B1.

[0050] Weigh 30 mg of pirfenidone sample, add 20 μL of acetone, grind for 2 h, collect the obtained solid sample, dry to constant weight, and then measure the melting point C1.

[0051] Weigh out equimolar amounts of pimelic acid equal to 30 mg of pirfenidone, add 20 μL of ethanol, grind for 2 h, collect the resulting solid sample, dry to constant weight, and then measure the melting point A2.

[0052] Weigh out cinnamic acid in equimolar amounts to 30 mg pirfenidone, add 20 μL DMF, grind for 2 h, collect the resulting solid sample, dry to constant weight, and then measure the melting point B2.

[0053] Weigh out saccharin in equimolar amounts to 30 mg pirfenidone, add 20 μL of acetone, grind for 2 h, collect the resulting solid sample, dry to constant weight, and then measure the melting point C2.

[0054] Calculations showed that |A1-A2|, |B1-B2|, and |C1-C2| were all >5℃, indicating that the corresponding active pharmaceutical ingredient-co-crystalline ligand-solvent combination formed a single compound.

[0055] Elemental analysis results showed that the molar ratio of the active pharmaceutical ingredient to the cocrystal ligand in cocrystal 1, cocrystal 2, and cocrystal 3 was 1:1, and all were nonsolvents.

[0056] The results in Table 1 further confirm that whether the same active pharmaceutical ingredient can form a cocrystal with a cocrystal ligand is highly unpredictable.

[0057] Example 2: Screening for Advantageous Cocrystals – Effects on L-Arginine-Induced Acute Pancreatitis in Mice

[0058] The study basically adopted the method disclosed by Shi Xiaoxian et al. in the article "Therapeutic effect of pirfenidone on L-arginine-induced acute pancreatitis in mice" to investigate the effects of cocrystal 1, cocrystal 2, cocrystal 3 and pirfenidone raw material on L-arginine-induced acute pancreatitis in mice. The serum amylase level measurement results of each group are shown in Table 2.

[0059] Table 2. Results of serum amylase levels in each group

[0060]

[0061] Note:

[0062] a All values ​​are based on pirfenidone.

[0063] The results of the two-tailed t-test with equal variances (Table 2) show:

[0064] The serum amylase level in the model group was statistically significantly higher than that in the blank control group;

[0065] The serum amylase levels in the pirfenidone group, cocrystal group 1, cocrystal group 2, and cocrystal group 3 were statistically significantly lower than those in the model group.

[0066] The serum amylase levels in cocrystallized group 1 and cocrystallized group 3 were statistically significantly lower than those in the pirfenidone group.

[0067] Example 3: Screening for Preferred Crystal Forms (Part 2) – Safety Study

[0068] C57BL / 6 mice, weighing 20-25g and aged 4-6 weeks, were randomly divided into 3 groups, with 5 males and 5 females in each group. The drugs and dosages shown in Table 3 were administered by gavage once. After that, the animals were allowed to eat, drink and move freely. The number of animals that died within 1 week was calculated. The results are shown in Table 3.

[0069] Table 3. Results of the safety study

[0070] Group N dose Number of dead animals pirfenidone group 10 1500mg / kg 8 Eutectic-1 group 10 3000mg / kg 6 Eutectic Group 3 10 3000mg / kg 3

[0071] As shown in Table 3, the LD of eutectic 3 50 >3000 mg / kg, significantly higher than pirfenidone.

[0072] Further structural confirmation of eutectic 3 in Example 4

[0073] 4.1 X-ray Powder Diffraction (XRPD)

[0074] The relevant parameters of the XRPD instrument are shown in Table 4:

[0075] Table 4. Relevant parameters of the XRPD instrument

[0076] instrument Malvern Panalytical Aeris X-ray wavelength Cu,Kα:1.5419 X-ray tubing setup 40kV, 15mA Scanning mode 1D Scan range (2θ) 3.5°-40° Scan step size (2θ) 0.0027166o Scan rate (2θ) 10o / min

[0077] The XRPD pattern of the eutectic 3 prepared in this invention is shown below. Figure 1 As shown in the figure, the XRPD comparison diagrams of eutectic 3, API after grinding, and dextrin after grinding are as follows. Figure 2 As shown. Figure 1 , Figure 2 In the diagram, R70324044-Sac represents eutectic 3. Figure 2 In Chinese, API stands for pirfenidone. Figure 1 The positions and relative intensities of the Top 10 absorption peaks are shown in Table 5.

[0078] Depend on Figure 1 As shown in Table 5, the X-ray powder diffraction pattern of the eutectic 3 prepared in this invention, expressed as 2θ±0.02°, exhibits characteristic peaks at 10.75°, 13.66°, 15.47°, 17.64°, 17.82°, 18.73°, 20.88°, 21.7°, 22.34°, and 25.43°. (From...) Figure 2 It can be seen that eutectic-3 exhibits good crystallinity.

[0079] Table 5 Figure 1 Positions and relative intensities (%) of the top 10 absorption peaks in

[0080] Position (2θ±0.02°) Relative strength (%) 10.75 100 13.66 35.91 15.47 21.78 17.64 16.96 17.82 15.54 18.73 30.56 20.88 25.57 21.7 29 22.34 18.47 25.43 51.89

[0081] 4.2 Thermogravimetric analysis (TGA)

[0082] The relevant parameters of the TGA instrument are shown in Table 6:

[0083] Table 6 Relevant parameters of the TGA instrument

[0084] Experimental instruments TA,TGA500 How to use linear heating Temperature range RT-300.00℃ heating rate 10℃ / min purge gas <![CDATA[N2(>99.999%)]]> Sample tray type Aluminum sample tray, open with no top cover

[0085] 4.3 Differential scanning calorimeter (DSC)

[0086] The relevant parameters of the DSC instrument are shown in Table 7:

[0087] Table 7 Relevant parameters of the DSC instrument

[0088] Experimental instruments TA, DSC250 How to use linear heating Temperature range RT-300.00℃ heating rate 10℃ / min purge gas <![CDATA[N2(>99.999%)]]> Sample tray type Aluminum sample tray, with a lid, and a hole punched in the lid.

[0089] The superimposed DSC and TGA diagrams of eutectic 3 prepared by the present invention are as Figure 3 shown. Figure 3 In it, R70324044-SAC represents eutectic 3. From Figure 3 the TGA test results, it shows that before melting, the weight percent loss of the material is 0.483%, and the weight loss is 0.013 mg. Figure 3 The DSC test results show that the onset melting temperature (Onset x) of the material is 119.32 °C, the enthalpy (normalized) is 85.178 J / g, and the peak temperature is 120.45 °C.

[0090] 4.3 Polarizing microscope analysis (PLM)

[0091] The tested sample was dispersed on a glass slide with methyl silicone oil and observed through PLM.

[0092] The image of eutectic 3 prepared by the present invention under a polarizing microscope is as Figure 4 shown. From Figure 4 it can be seen that under the test conditions with a magnification of 10 * 2.5 times of the polarizing microscope, eutectic 3 prepared by the present invention is small and irregular crystal particles.

[0093] Example 5 Preparation example of preparation

[0094] (1) Capsules

[0095] The capsule formulations containing eutectic 1 (per 100 capsules) are shown in Table 8.

[0096] Table 8. Capsule formulations containing eutectic 1 (per 100 capsules)

[0097] Eutectic 1 3g microcrystalline cellulose 20g Glyceryl monostearate 0.8g

[0098] Preparation method of capsules: Sequential crystal 1, microcrystalline cellulose, and glyceryl monostearate are passed through an 80-mesh sieve and set aside. The prescribed amounts of sequential crystal 1, microcrystalline cellulose, and glyceryl monostearate are mixed and filled into capsules.

[0099] (2) Tablets

[0100] Tablet formulations containing eutectic 3 (per 100 tablets) are shown in Table 9.

[0101] Table 9 Tablet formulations containing eutectic 3 (per 100 tablets)

[0102] Eutectic 3 3.5g Sorbitol 18g Glyceryl monopalmitate 0.8g

[0103] Tablet preparation method: Pass cocrystal 3, sorbitol, and glyceryl monopalmitate through an 80-mesh sieve and set aside. Mix the prescribed amounts of cocrystal 3, sorbitol, and glyceryl monopalmitate, and compress into tablets.

Claims

1. A pirfenidone eutectic, characterized in that, The cocrystal is prepared from pirfenidone and a cocrystal ligand, wherein the cocrystal ligand is selected from saccharin; the molar ratio of pirfenidone to the cocrystal ligand is 1:1; the X-ray powder diffraction pattern of the cocrystal, expressed as 2θ±0.02°, has characteristic peaks at 10.75°, 13.66°, 15.47°, 17.64°, 17.82°, 18.73°, 20.88°, 21.7°, 22.34°, and 25.43°.

2. The method for preparing pirfenidone eutectic according to claim 1, characterized in that, Pirfenidone eutectic was prepared by wet grinding. The solvent used in the wet grinding method was selected from acetone, ethanol and N,N-dimethylformamide. The mass-to-volume ratio of pirfenidone to solvent was 3:(1.5~2.5) mg / μL. The grinding time was 1.5~2.5 hours.

3. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the pirfenidone cocrystal of claim 1.

4. The pharmaceutical composition according to claim 3, characterized in that, The pharmaceutical composition is an oral solid dosage form, which is prepared using the pirfenidone cocrystal as described in claim 1 as the active ingredient, combined with pharmaceutically acceptable additives.

5. Use of the pirfenidone cocrystal according to claim 1, the pirfenidone cocrystal prepared by the method of preparing the pirfenidone cocrystal according to claim 2, or the pharmaceutical composition according to claim 3 or claim 4 in the preparation of a medicament for treating pancreatitis or pulmonary fibrosis.

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