Etoricoxib from a co-amorphous solid formulation

Abstract

The present application belongs to the technical field of medicine, and particularly relates to a self-amorphous solid preparation of etodolac. Etodolac and small-molecule excipients interact through intermolecular hydrogen bonds and ionic bonds, driving the occurrence of self-amorphization. The self-amorphous composition of etodolac-small-molecule excipients is mixed with a filler, a wetting agent, a disintegrating agent and a lubricant to prepare a self-amorphous solid preparation of etodolac. Experiments show that the composition and the developed solid preparation thereof exhibit good solubility and dissolution advantages, effectively improve the defects of the water solubility of etodolac, and avoid the stability problems of amorphous preparations in the production and storage processes, and are expected to enhance the oral absorption and therapeutic effect of the BCS II drug etodolac.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to an etordosulfuric acid self-co-amorphous solid dosage form. Background Technology

[0002] Etoduolic acid, chemically named 1,8-diethyl-1,3,4,9-tetrahydropyran[3,4-b]indole-1-acetic acid, has the following chemical structure:

[0003]

[0004] Etodoxacin is a nonsteroidal anti-inflammatory drug (NSAID) whose main pharmacological action is to inhibit the biological activity of cyclooxygenase, blocking the prostaglandin synthesis pathway, thereby exerting anti-inflammatory, analgesic, and antipyretic effects. This drug has a much higher selectivity for inhibiting COX-2 than COX-1, thus effectively improving the symptoms of various inflammatory diseases such as osteoarthritis and rheumatoid arthritis. It is also suitable for relieving postoperative wound pain, musculoskeletal pain, and other types of pain, and exhibits good antipyretic effects. According to the Biopharmaceutical Classification (BCS) standards, etodoxacin belongs to BCS Class II drugs. Its main drawback is its poor water solubility, a physicochemical property that limits the drug's dissolution and absorption efficiency in vivo, thus affecting its clinical efficacy to some extent.

[0005] Amorphization by disrupting the drug lattice has become an effective means to improve the dissolution performance of poorly soluble drugs and enhance oral bioavailability. However, amorphous drugs, due to their high-energy state, possess inherent thermodynamic instability during preparation, storage, and dissolution, posing significant challenges to their application. In recent years, self-co-amorphization strategies through formulation design have been introduced to overcome the challenges of physical stability in the production and storage of amorphous formulations. The self-co-amorphization process occurs before or during drug administration, using photothermal induction (such as microwaves or lasers) to spontaneously form a co-amorphous system between the drug and excipients, avoiding the physical stability problems in traditional amorphous drug production and representing an effective strategy for improving drug solubility. However, photothermal induction has limitations such as cumbersome operation, high cost, and high energy consumption. Therefore, providing a simple, low-cost method that allows for spontaneous self-co-amorphization during administration has significant application value. Summary of the Invention

[0006] This invention provides a self-co-amorphous composition of etodoxa acid and a small molecule excipient. This composition, consisting of etodoxa acid and another small molecule excipient, spontaneously undergoes a co-amorphous transformation upon contact with polar media such as water, significantly improving the solubility and in vitro dissolution rate of etodoxa acid and effectively addressing its water solubility limitations. Furthermore, the self-co-amorphous composition of etodoxa acid provided by this invention can be used as a formulation for solid dosage forms, and can be further developed into novel solid dosage forms of etodoxa acid such as tablets, capsules, and granules.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] The etodu acid self-co-amorphous solid formulation provided by the present invention is prepared by mixing etodu acid-small molecule excipient self-co-amorphous composition with filler, wetting agent, disintegrant and lubricant.

[0009] The etodu acid-small molecule excipient self-co-amorphous composition consists of etodu acid and small molecule excipients. This co-amorphous composition can undergo self-co-amorphization after simple physical mixing of etodu acid and small molecule excipients, through contact with a trace amount of polar medium.

[0010] The molar ratio of etoposide to the small molecule excipient is 4:1 to 1:4, preferably 2:1 to 1:2, and most preferably 1:1; the small molecule excipient is selected from one or more of lysine, histidine, arginine, glutamic acid, meglumine, glutamine, and tryptophan. Lysine, arginine, and meglumine are preferred.

[0011] In this invention, the polar induction medium for the eosinophilic acid and the small molecule excipient is selected from: deionized water, buffer solutions with different pH values ​​(pH 1.2~pH 7.4), methanol, ethanol, ethylene glycol, and propylene glycol. Water is preferred.

[0012] The filler is selected from one or more of starch, dextrin, pregelatinized starch, microcrystalline cellulose, etc.; the wetting agent is selected from one or more of deionized water, ethanol, etc.; the disintegrant is selected from one or more of dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, croscarmellose ketone, etc.; the lubricant is selected from one or more of magnesium stearate, micronized silica gel, talc powder, etc.

[0013] The self-co-amorphous solid dosage form comprises 25% etodo acid self-co-amorphous composition, 60% filler, 10% wetting agent, 4%~4.5% disintegrant, and 0.5%~1% lubricant.

[0014] The self-co-amorphized products formed by the eosinophilic acid and small molecule excipients in this invention were analyzed by powder X-ray diffraction, differential scanning calorimetry and Fourier transform infrared spectroscopy. The results showed that the crystal diffraction peaks of the self-co-amorphized products almost disappeared or there were very weak crystal diffraction peaks. Moreover, the products all showed a single glass transition temperature. The infrared results confirmed that hydrogen bonding and ionic bonding interactions occurred between molecules during the self-co-amorphization process.

[0015] This invention, through the determination of apparent solubility and in vitro dissolution curves, confirms that three self-co-amorphous compositions can effectively improve the solubility and dissolution rate of the poorly soluble drug etodoxa acid, and can be used in the formulation of novel solid dosage forms of etodoxa acid. Similarly, novel solid dosage forms of etodoxa acid can transform into an amorphous form upon contact with a polar medium, possessing the advantages of high solubility and dissolution rate of amorphous formulations.

[0016] The beneficial effects of this invention are:

[0017] This invention combines etodoxa acid with small molecule excipients, which can spontaneously undergo co-amorphization upon contact with a polar medium. Experiments show that the composition and the developed solid formulation exhibit good solubility and dissolution advantages, effectively improving the water solubility defect of etodoxa acid, and is expected to enhance the oral absorption and therapeutic effect of the BCS II drug etodoxa acid. Attached Figure Description

[0018] Figure 1 This is a powder X-ray diffraction pattern of the etodulic acid-lysine composition undergoing self-co-amorphization (etodulic acid:lysine 1:2, etodulic acid:lysine 1:1, etodulic acid:lysine 2:1).

[0019] Figure 2 This is a powder X-ray diffraction pattern of the etodo acid-arginine composition undergoing self-co-amorphization (etodo acid:arginine 1:2, etodo acid:arginine 1:1, etodo acid:arginine 2:1).

[0020] Figure 3 These are powder X-ray diffraction patterns of the etodoxa acid-meglumine composition undergoing self-co-amorphization (etodoxa acid:meglumine 1:2, etodoxa acid:meglumine 1:1, etodoxa acid:meglumine 2:1).

[0021] Figure 4 These are powder X-ray diffraction patterns of three etodu acid self-co-amorphous compositions undergoing self-co-amorphization in media with different pH polarities (etodu acid: lysine 1:1, etodu acid: arginine 1:1, etodu acid: meglumine 1:1).

[0022] Figure 5These are differential scanning calorimeters of the self-co-amorphous products of the etodu acid-lysine composition (etodu acid:lysine 1:2, etodu acid:lysine 1:1, etodu acid:lysine 2:1).

[0023] Figure 6 These are differential scanning calorimeters of the self-co-amorphous products of the etodoxa acid-arginine composition (etodoxa acid:arginine 1:2, etodoxa acid:arginine 1:1, etodoxa acid:arginine 2:1).

[0024] Figure 7 Differential scanning calorimetry (DSC) spectra of the self-co-amorphous products of the etodoxa acid-meglumine composition (etodoxa acid:meglumine 1:2, etodoxa acid:meglumine 1:1, etodoxa acid:meglumine 2:1).

[0025] Figure 8 These are the infrared spectra of the self-co-amorphous products of three etodu acid self-co-amorphous compositions (etodu acid: lysine 1:1, etodu acid: arginine 1:1, etodu acid: meglumine 1:1).

[0026] Figure 9 This is a characteristic dissolution rate diagram of three self-co-amorphous compositions of three dependent acids;

[0027] Figure 10 This is a non-drainage condition dissolution diagram of three self-co-amorphous compositions of three dependent acids;

[0028] Figure 11 This is a phase solubility diagram of three self-co-electro-amorphous compositions of three dependent acids;

[0029] Figure 12 The image shows a polarization pattern of three types of self-co-amorphous granules containing three different acids.

[0030] Figure 13 This is a polarization image of a tablet containing a self-co-amorphous composition of three types of etoposide acids;

[0031] Figure 14 This is a polarized light image of a capsule containing three types of self-co-amorphous compositions of etoposide acid. Detailed Implementation

[0032] The present invention will be further described below with reference to the embodiments.

[0033] Example 1

[0034] Weigh out 100 mg of a 1:1 etodoxin-lysine composition (i.e., a physical mixture of the two components) and compress it into tablets using a tablet press. At 25°C, add 50 μL of the same amount of deionized water to the surface of the tablets and observe the degree of self-amorphization at 30, 60, and 120 min.

[0035] If self-amorphization occurs, take 10g of the above-mentioned etodo acid-lysine composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and sizing it through a 12-mesh sieve to obtain granules, which are then divided into 100 equal parts. These granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules. The hard capsule shell is composed of 80.85% gelatin, 16% water, 2.5% glycerin (plasticizer), 0.3% agar (thickener), 0.2% titanium dioxide (opause), 0.1% tartrazine (colorant), and 0.05% paraben (preservative).

[0036] Example 2

[0037] Weigh out 100 mg of a 1:1 etodoxin-arginine composition and compress it into tablets using a tablet press. At 25°C, add 50 μL of the same amount of deionized water to the surface of the tablets and observe the degree of self-amorphization at 30, 60, and 120 min.

[0038] If self-amorphization occurs, take 10g of the above-mentioned etodo acid-arginine composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. These granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0039] Example 3

[0040] Weigh out 100 mg of a 1:1 molar ratio of etodoxacin-glucamine composition and compress it into tablets using a tablet press. At 25°C, add 50 μL of the same amount of deionized water to the surface of the tablets and observe the degree of self-amorphization at 30, 60, and 120 min.

[0041] If self-amorphization occurs, take 10g of the above-mentioned etodoxacin-glucamine composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and sizing it through a 12-mesh sieve to obtain granules, which are then divided into 100 equal parts. These granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0042] Example 4

[0043] Weigh out 100 mg of the etodolac-histidine composition with a molar ratio of 1:1 and compress it into tablets using a tablet compressor. At 25°C, add 50 μL of the same amount of deionized water to the surface of the tablets, and observe the degree of self-amorphization at 30, 60, and 120 min.

[0044] If self-amorphization occurs, take 10g of the above-mentioned etodolac-histidine composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. These granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0045] Example 5

[0046] Weigh out 100 mg of a 1:1 molar ratio of etodoxacin-glutamic acid composition and compress it into tablets using a tablet press. At 25°C, add 50 μL of the same amount of deionized water to the surface of the tablets and observe the degree of self-amorphization at 30, 60, and 120 min.

[0047] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-glutamic acid composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, which are then divided into 100 equal parts. These granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0048] Example 6

[0049] Weigh out 100 mg of a combination of etodoxacin and a small molecule excipient (lysine, arginine, or meglumine) in a molar ratio of 4:1, and compress it into tablets using a tablet compressor. At 25°C, add 50 μL of the same amount of deionized water to the surface of the tablets, and observe the degree of self-amorphization at 30, 60, and 120 min.

[0050] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-small molecule excipient composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. The granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0051] Example 7

[0052] Weigh out 100 mg of a combination of etodoxacin and a small molecule excipient (lysine, arginine, or meglumine) in a molar ratio of 2:1, and compress it into tablets using a tablet compressor. At 25°C, add 50 μL of the same amount of deionized water to the surface of the tablets, and observe the degree of self-amorphization at 30, 60, and 120 min.

[0053] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-small molecule excipient composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. The granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0054] Example 8

[0055] Weigh out 100 mg of each of the etodoxa acid-small molecule excipient (lysine, arginine, or meglumine) composition in a molar ratio of 1:2, and compress them into tablets using a tablet compressor. At 25°C, add 50 μL of the same amount of deionized water to the surface of the tablets, and observe the degree of self-amorphization at 30, 60, and 120 min.

[0056] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-small molecule excipient composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. The granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0057] Example 9

[0058] Weigh out 100 mg of each of the etodoxin-small molecule excipient (lysine, arginine, or meglumine) composition in a molar ratio of 1:4, and compress them into tablets using a tablet compressor. At 25°C, add 50 μL of the same amount of deionized water to the surface of the tablets, and observe the degree of self-amorphization at 30, 60, and 120 min.

[0059] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-small molecule excipient composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. The granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0060] Example 10

[0061] Weigh out 100 mg of a 1:1 molar ratio composition of etodoxacin and a small molecule excipient (lysine, arginine, or meglumine) and compress it into tablets using a tablet press. At 25°C, add 50 μL of the same pH 1.2 hydrochloric acid buffer to the surface of the tablets, and observe the degree of self-amorphization at 30, 60, and 120 min.

[0062] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-small molecule excipient composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. The granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0063] Example 11

[0064] Weigh out 100 mg of a 1:1 molar ratio composition of etodoxacin and a small molecule excipient (lysine, arginine, or meglumine) and compress it into tablets using a tablet press. At 25°C, add 50 μL of the same pH 3.0 citrate buffer to the surface of the tablets and observe the degree of self-amorphization at 30, 60, and 120 min.

[0065] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-small molecule excipient composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. The granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0066] Example 12

[0067] Weigh out 100 mg of a 1:1 molar ratio composition of etodoxacin and a small molecule excipient (lysine, arginine, or meglumine) and compress it into tablets using a tablet press. At 25°C, add 50 μL of the same pH 4.5 acetate-sodium acetate buffer solution to the surface of the tablets, and observe the degree of self-amorphization at 30, 60, and 120 min.

[0068] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-small molecule excipient composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. The granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0069] Example 13

[0070] Weigh out 100 mg of a 1:1 molar ratio composition of etodoxacin and a small molecule excipient (lysine, arginine, or meglumine) and compress it into tablets using a tablet compressor. At 25°C, add 50 μL of the same pH 5.4 citrate-disodium hydrogen phosphate buffer solution to the surface of the tablets, and observe the degree of self-amorphization at 30, 60, and 120 min.

[0071] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-small molecule excipient composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. The granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0072] Example 14

[0073] Weigh out 100 mg of a 1:1 molar ratio composition of etodoxacin and a small molecule excipient (lysine, arginine, or meglumine) and compress it into tablets using a tablet press. At 25°C, add 50 μL of the same pH 6.8 phosphate buffer to the surface of the tablets and observe the degree of self-amorphization at 30, 60, and 120 min.

[0074] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-small molecule excipient composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. The granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0075] Example 15

[0076] Weigh out 100 mg of a 1:1 molar ratio composition of etodoxacin and a small molecule excipient (lysine, arginine, or meglumine) and compress it into tablets using a tablet press. At 25°C, add 50 μL of the same pH 7.4 Tris-hydrochloric acid buffer to the surface of the tablets, and observe the degree of self-amorphization at 30, 60, and 120 min.

[0077] If self-amorphization occurs, take 10g of the above-mentioned etodoxa acid-small molecule excipient composition, mix it with 24g of starch, 1.8g of dry starch, and 0.2g of magnesium stearate, add 4g of deionized water to make a soft mass, extrude it through a 14-mesh sieve to granulate, dry it at 70℃, and granulate it through a 12-mesh sieve to obtain granules, and divide it into 100 equal parts. The granules can be further compressed into tablets or filled into hard capsule shells to obtain tablets and capsules.

[0078] Test Example 1: The self-co-amorphized compositions of etoposide and small molecule excipients in Examples 1-3, 6-8, and 10-15 were tested, as follows:

[0079] 1. Powder X-ray diffraction

[0080] X-ray diffraction analysis of the self-co-amorphous composition was performed using a SmartLab9 X-ray diffractometer (Rigaku Corporation, Japan). Cu-Kα was used as the emission source, with the tube voltage set to 40 kV, the tube current to 40 mA, the scan step size to 0.02°, the scan speed to 4° / min, and the scan range to 2θ: 5–40°.

[0081] Measurement results: Figure 1 B~ Figure 3 B is the X-ray diffraction pattern of the 1:1 molar ratio of etodo acid-small molecule excipient composition of Examples 1 to 3 after contact with an aqueous medium. Figure 1 A~ Figure 3 A is the X-ray diffraction pattern of the 1:2 molar ratio etodo acid-small molecule excipient composition of Example 8 after contact with an aqueous medium. Figure 1 C~ Figure 3 C shows the X-ray diffraction pattern of the 2:1 molar ratio ethodolic acid-small molecule excipient composition from Example 7 after contact with an aqueous medium. As can be seen from the figure, the molar ratio of ethodolic acid to the small molecule excipient significantly affects the degree of self-amorphization. When the molar ratio of ethodolic acid to lysine is 1:2, the crystal diffraction peaks weaken most significantly, exhibiting the highest degree of self-amorphization. In the ethodolic acid-arginine and ethodolic acid-glucamine compositions, the molar ratio of 1:1 results in the highest degree of self-amorphization. With prolonged time, the crystal diffraction peaks of all three combinations weaken until they disappear, indicating that spontaneous self-amorphization can occur. This may be because the molar ratio of ethodolic acid to the small molecule excipient in the composition determines the number of molecules participating in the intermolecular reaction, thus affecting the degree of self-amorphization of the ethodolic acid-small molecule excipient composition.

[0082] Figure 4 The X-ray diffraction patterns of the etoduolic acid-lysine self-amorphized compositions, etoduolic acid-arginine self-amorphized compositions, and etoduolic acid-glucamine self-amorphized compositions from Examples 10-15 after contacting them with polar media of different pH values ​​for 30 min. As shown in the figures, the higher the pH value of the medium, the higher the degree of self-amorphization of the three compositions. This is because etoduolic acid is a weakly acidic drug, and its molecular microenvironment may change with increasing pH value, causing more etoduolic acid to dissolve and promoting molecular interactions between etoduolic acid and small molecule excipients, thereby affecting the degree of self-amorphization of the compositions.

[0083] 2. Differential scanning calorimetry

[0084] Approximately 5 mg of each sample was placed in an aluminum crucible and analyzed using a HITACHI DSC 7020 differential scanning calorimeter (Hitachi Profile, Japan). Under nitrogen protection, the temperature was increased from 25 °C to 250 °C at a rate of 10 °C / min.

[0085] Measurement results: Figure 5 B~ Figure 7 B is a differential scanning calorimeter of the self-amorphized product after the 1:1 molar ratio of the eosinophilic acid-small molecule excipient composition of Examples 1 to 3 was contacted with a polar medium for 120 min. Figure 5 A~ Figure 7 A is a differential scanning calorimeter of the self-amorphized product of the 1:2 molar ratio etodo acid-small molecule excipient composition of Example 8 after contacting a polar medium for 120 min. Figure 5 C~ Figure 7 C is a differential scanning calorimeter of the self-amorphized product of the 2:1 molar ratio ethodolate acid-small molecule excipient composition of Example 7 after contacting a polar medium for 120 min. As shown in the figure, the melting endothermic peaks of the original ethodolate acid crystals and the small molecule excipient are weakened or disappear in the self-amorphized product, indicating that the three compositions underwent self-amorphization after contacting the polar medium.

[0086] 3. Infrared spectroscopy

[0087] The interaction between etoposide and small molecule excipients was analyzed using a Thermo Scientific Nicolet iS50 Fourier transform infrared spectrometer (Thermo Fisher Scientific, America). The image was taken at a 4cm² depth. -1 The resolution was 32 scans, with a scanning range of 4000–500 cm. -1 .

[0088] Measurement results: Figure 8 The images show the Fourier transform infrared (FTIR) spectra of the self-co-amorphized products formed by the etoposide acid and small molecule excipients in Examples 1-3. Figure 8 As shown in A, the infrared absorption spectra of the etoposide-lysine self-co-amorphous product formed in Example 1 are at 3347.74, 2961.03, 1569.44, 1395.32, 1457.71, and 743.06 cm⁻¹. -1 There is an absorption peak at that point.

[0089] Depend on Figure 8As shown in B, the infrared absorption spectra of the eosin-arginine self-co-amorphous product formed in Example 2 are at 3335.41, 2963.21, 2828.25, 1597.74, 1361.21, 1179.83, 1102.92, 987.56, 772.08, and 617.54 cm⁻¹. -1 There is an absorption peak at that point.

[0090] Depend on Figure 8 As shown in C, the infrared absorption spectra of the etodoxa acid-glucamine self-co-amorphous product formed in Example 3 are at 3373.13, 2965.38, 2827.53, 1595.56, 1359.76, 1178.38, 1096.39, 778.61, and 619.71 cm⁻¹. -1 There is an absorption peak at that point.

[0091] Compared with the infrared absorption spectra of etodo acid crystals and small molecule excipients, the hydroxyl and carbonyl groups of the three self-co-amorphous products showed weakening and shifting in the spectra of etodo acid crystals, and the hydroxyl, carbonyl or amino groups in the small molecule excipients showed shifting phenomena. This confirms that the self-co-amorphization of etodo acid-small molecule excipients is driven by intermolecular hydrogen bonds or ionic bonds between components.

[0092] Test Example 2: Apparent solubility tests were performed on etodulic acid crystals, the etodulic acid-small molecule excipient compositions from Examples 1-5, 7, 8, 10, 12, and 14, and the etodulic acid self-co-amorphous solid dosage form, as detailed below:

[0093] Excess etodoxa acid crystals, the etodoxa acid-small molecule excipient self-co-amorphous compositions from Examples 1-5, 7, 8, 10, 12, and 14, and the etodoxa acid self-co-amorphous solid dosage form were placed into centrifuge tubes containing 4 mL of deionized water, with three replicates for each sample. The tubes were placed in a 37°C constant-temperature shaker and shaken at 200 rpm for 24 hours. Then, 1 mL of the supernatant was filtered through a 0.22 μm microporous membrane, and the apparent solubility of different samples was determined by high-performance liquid chromatography (HPLC).

[0094] The high-performance liquid chromatography (HPLC) conditions are as follows:

[0095] Instrument: Agilent 1260 high performance liquid chromatograph

[0096] Column: Ultimate XB-C18 (4.6mm × 250mm, 5μm)

[0097] Mobile phase: Acetonitrile - 0.3% phosphoric acid solution = 70:50 (V / V)

[0098] Flow rate: 1.0 mL / min

[0099] Detection wavelength: 275nm

[0100] Results: The solubility results of etodulic acid crystals, etodulic acid-small molecule excipient self-co-amorphous compositions, and etodulic acid self-co-amorphous solid formulations are shown in Table 1. The apparent solubility of etodulic acid crystals in water is 96.33 μg / mL. The solubilities of etodulic acid-lysine, etodulic acid-arginine, and etodulic acid-glucamine compositions in water in Examples 1, 2, and 3 are 1300.20, 1423.01, and 1656.87 μg / mL, respectively. Compared with etodulic acid crystals, these represent increases of 14.50, 14.77, and 17.20 times, respectively. The solubilities of etodulic acid-histidine and etodulic acid-glutamic acid compositions in water in Examples 4 and 5 are 824.39 ± 86.21 and 725.15 ± 96.92 μg / mL, respectively, representing increases of 8.56 and 7.53 times, respectively, compared with etodulic acid crystals.

[0101] Table 1. Apparent solubility of etodu acid crystals, etodu acid-small molecule excipient compositions, and etodu acid-small molecule excipient composition solid dosage forms.

[0102]

[0103]

[0104] Test Example 3: The characteristic dissolution rate of etodoxa acid crystals and the three etodoxa acid-small molecule excipient compositions in Examples 1, 2, and 3 were tested, as follows:

[0105] 200 mg of etodoxa acid crystals and three etodoxa acid-small molecule excipient compositions were weighed in triplicate and compressed into tablets with a diameter of 13 mm using a tablet press. Using beeswax as a mold, the tablets were placed in the beeswax, ensuring only one circular surface was in contact with the dissolution medium. The experiment was conducted according to Method II (paddle method) of General Chapter 0931 in the 2020 edition of the Chinese Pharmacopoeia. The medium temperature was 37℃, the medium volume was 900 mL, and the rotation speed was 50 rpm. The dissolution curve in water was measured. During the experiment, 2 mL samples were taken at the expected time points of 2, 5, 10, 15, 20, 30, 45, 60, 90, and 120 min, and 2 mL of constant temperature medium was added simultaneously. The extracted liquid was filtered through a 0.22 μm aqueous microporous membrane and analyzed by high-performance liquid chromatography (HPLC).

[0106] Test results: Characteristic dissolution rate results are as follows Figure 9As shown in the figure, the three etodu acid-small molecule excipient compositions all exhibited significantly enhanced dissolution rates after the introduction of small molecule excipients. Compared to etodu acid crystals, the characteristic dissolution rates of the etodu acid-lysine composition, the etodu acid-arginine composition, and the etodu acid-glucamine composition increased by 50.66 times, 48.04 times, and 58.61 times, respectively.

[0107] Test Example 4: Non-leaking dissolution tests were conducted on the etodo acid crystals and the three etodo acid-small molecule excipient compositions from Examples 1, 2, and 3, as detailed below:

[0108] A certain amount of etodoxa acid crystals and three etodoxa acid-small molecule excipient compositions were weighed out in triplicate. According to Method II of General Chapter 0931, Part IV of the 2020 edition of the Chinese Pharmacopoeia, the non-leaking release rate was evaluated using the slurry method. The release medium was water at 37°C, with a volume of 200 mL and a rotation speed of 100 rpm. Samples of 2 mL were taken at 5, 10, 20, 30, 45, 60, 90, 120, 240, 360, 480, and 720 min, and 2 mL of isothermal medium was added simultaneously. The collected liquids were filtered through a 0.22 μm microporous membrane and analyzed by high-performance liquid chromatography (HPLC).

[0109] Test results: The non-leaking dissolution results of etodu acid crystals and three etodu acid-small molecule excipient compositions are as follows: Figure 10 As shown, the three compositions reached dissolution equilibrium within the first 60 minutes, at which point the dissolution concentrations of the etoduolic acid-lysine composition, the etoduolic acid-arginine composition, and the etoduolic acid-glucamine composition were 1418.20, 1323.60, and 1052.08 μg / mL, respectively. Etoduolic acid crystals reached dissolution equilibrium at approximately 90 minutes, with a concentration of 84.28 μg / mL. Compared to etoduolic acid crystals, the dissolution concentrations of the etoduolic acid-lysine composition, the etoduolic acid-arginine composition, and the etoduolic acid-glucamine composition increased by 16.83, 15.70, and 12.48 times, respectively.

[0110] Test Example 5: A phase solubility test was conducted on the etodo acid crystals and the three etodo acid-small molecule excipient compositions from Examples 1, 2, and 3, as detailed below:

[0111] The interaction between ethotoxin and lysine, arginine, and meglumine in aqueous solution was analyzed by phase solubility analysis. Excess crystalline ethotoxin was added to 4 mL of aqueous solutions of excipients at different concentrations (range 0.048–12.5 mM). The mixture was shaken at 37 °C and 200 rpm for 24 h. Subsequently, 1 mL of the supernatant was collected, filtered through a 0.22 μm filter, and the sample concentration was determined by high-performance liquid chromatography (HPLC).

[0112] Excess ethotoxin was dissolved in solutions of small molecule excipients (lysine, arginine, and meglumine) at different concentrations. The change in ethotoxin solubility with the concentration of the small molecule excipients was observed to elucidate the solubilization mechanism of ethotoxin by the excipients through phase solubility analysis. As shown in the figure, the solubility of ethotoxin increases with increasing concentration of the small molecule excipients, which is due to the complexation reaction between the small molecule excipients and ethotoxin. Figure 11 As shown, taking the etodo acid-lysine composition as an example, before the lysine concentration reaches 6.25 mM, 1 mol of excipient will dissolve along with 1 mol of etodo acid, exhibiting a 1:1 linear dissolution trend. However, when the lysine concentration exceeds 6.25 mM, the amount of etodo acid dissolved deviates negatively with increasing excipient concentration, showing a typical 1:1 linear dissolution trend. N Type complexation behavior ( Figure 11 A). Similarly, the etodoxa acid-arginine composition and the etodoxa acid-meglumine composition also underwent a similar 1:1 A reaction during the dissolution process. N Type complexation behavior ( Figure 11 (B&C). Therefore, during the dissolution process, the etodo acid and small molecule excipients in the composition undergo intermolecular complexation, which enhances the dissolution performance of the etodo acid.

[0113] Test Example 6: Using the etodo acid self-amorphous composition of the present invention as the formulation, wetting agents, fillers, disintegrants, and lubricants were added and formulated into granules, tablets, and capsules in specific proportions. The prepared granules, tablets, and capsules were immersed in water and immediately removed, then left to stand for 10 minutes. Powder from the surface of the formulation was taken and observed on a glass slide under a 4×10x magnifying glass. The birefringence phenomenon was recorded to observe whether self-amorphization occurred.

[0114] Granule formulation: 10g of the etodo acid-small molecule excipient composition of the present invention is mixed with 24g of starch (filler), 1.8g of dry starch (disintegrant), and 0.2g of magnesium stearate (lubricant). 4g of deionized water (wetting agent) is added to make a soft mass. The mass is extruded through a 14-mesh sieve, dried at 70°C, and granulated through a 12-mesh sieve to obtain granules.

[0115] Tablet formulation: 10g of the etodo acid-small molecule excipient composition of the present invention is mixed with 24g of starch (filler), 1.8g of dry starch (disintegrant), and 0.2g of magnesium stearate (lubricant). 4g of deionized water (wetting agent) is added to make a soft mass. The mass is extruded and granulated through a 14-mesh sieve, dried at 70°C, granulated through a 12-mesh sieve, and divided into 100 portions. The granules are then placed in a tablet press and prepared into tablets under a pressure of 10MPa.

[0116] Capsule formulation: 10g of the etodoxa acid-small molecule excipient composition of the present invention is mixed with 24g of starch (filler), 1.8g of dry starch (disintegrant), and 0.2g of magnesium stearate (lubricant). 4g of deionized water (wetting agent) is added to make a soft mass. The mass is extruded and granulated through a 14-mesh sieve, dried at 70°C, and granulated through a 12-mesh sieve. The granules are divided into 100 portions, and No. 1 capsules (approximately 6.9mm in outer diameter and 19.4mm in length) are selected according to the 400mg prescription dosage to make capsules.

[0117] Immerse the prepared granules, tablets, and capsules in water and immediately remove them, then let them stand for 10 minutes. Collect the powder from the surface of the preparations and record the birefringence phenomenon. Figure 12 The polarization images of the granules containing three types of etodu acid-small molecule excipient compositions prepared in Examples 1, 2, and 3 show no crystalline birefringence, confirming the occurrence of self-co-amorphization transformation (where a is etodu acid-lysine self-co-amorphous granules, b is etodu acid-arginine self-co-amorphous granules, and c is etodu acid-glucamine self-co-amorphous granules). Figure 13 The images show polarized light images of tablets containing three types of etodu acid-small molecule excipient compositions prepared in Examples 1, 2, and 3. The absence of birefringence on the tablet surface confirms that the tablets have undergone co-amorphization (where a is an etodu acid-lysine self-co-amorphous tablet, b is an etodu acid-arginine self-co-amorphous tablet, and c is an etodu acid-glucamine self-co-amorphous tablet). Figure 14 The images show polarized light images of capsules containing three types of etodu acid-small molecule excipient compositions prepared in Examples 1, 2, and 3. No birefringence is observed, indicating an amorphous morphology (where a is an etodu acid-lysine self-co-amorphous capsule, b is an etodu acid-arginine self-co-amorphous capsule, and c is an etodu acid-glucamine self-co-amorphous capsule).

[0118] As can be seen from the above formulation, the etodoxa acid self-amorphous composition can be used as a component of etodoxa acid solid dosage forms. When the solid dosage form is taken, it undergoes a self-amorphous transformation upon contact with water, which can improve the solubility and dissolution rate of etodoxa acid. The related solid dosage form possesses the advantages of amorphous dosage forms while avoiding the physical stability problems associated with them. Clinically, it can be used to treat symptoms such as osteoarthritis, rheumatoid arthritis, and pain.

Claims

1. A self-co-co-amorphous solid dosage form of etoposide, characterized in that: The etodu acid self-co-amorphous solid dosage form is prepared by mixing an etodu acid-small molecule excipient self-co-amorphous composition with fillers, wetting agents, disintegrants and lubricants.

2. The etoposide self-co-amorphous solid dosage form as described in claim 1, characterized in that, The etodu acid-small molecule excipient self-co-amorphous composition is obtained by uniformly mixing etodu acid and small molecule excipients.

3. The etoposide self-co-amorphous solid dosage form as described in claim 2, characterized in that, The small molecule excipients are selected from one or more of the following: lysine, histidine, arginine, glutamic acid, meglumine, glutamine, and tryptophan.

4. The etoposide self-co-amorphous solid dosage form as described in claim 2, characterized in that, The molar ratio of the etopoic acid to the small molecule excipient is 4:1 to 1:

4.

5. The etoposide self-co-amorphous solid dosage form as described in claim 1, characterized in that, The etodu acid self-co-amorphous solid dosage form is composed of 25% etodu acid self-co-amorphous composition, 60% filler, 10% wetting agent, 4%~4.5% disintegrant, and 0.5%~1% lubricant by mass percentage.

6. The etoposide self-co-amorphous solid dosage form as described in claim 1, characterized in that, The filler is selected from one or a combination of starch, dextrin, pregelatinized starch, and microcrystalline cellulose.

7. The etoposide self-co-amorphous solid dosage form as described in claim 1, characterized in that, The wetting agent is selected from one or a combination of deionized water and ethanol.

8. The etoposide self-co-amorphous solid dosage form as described in claim 1, characterized in that, The disintegrant is selected from one or a combination of several of the following: dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and croscarmellose.

9. The etoposide self-co-amorphous solid dosage form as described in claim 1, characterized in that, The lubricant is selected from one or a combination of magnesium stearate, micronized silica gel, and talc.

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