Sulindac self-gelation composition and application thereof in solid and semi-solid preparations

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a sulindac self-gelation composition and application thereof in solid and semi-solid preparations. The composition is composed of sulindac and a biologically safe micromolecular auxiliary material, and in contact with an aqueous medium or a high-humidity environment, the sulindac and the micromolecular auxiliary material are subjected to intermolecular hydrogen bond interaction, self-assembly and gelation, so that the composition is converted from a solid state to a semi-solid gel state. The gelated sample presents a regular and ordered three-dimensional porous network structure and has good viscoelasticity. The sulindac and the small-molecular auxiliary materials are combined to be gelatinized, so that the solubility (gt; 288 times) and a dissolution rate (gt; 4119 times). A preparation strategy and a chemical modification means are not needed, the problem of water solubility of sulindac is effectively solved only by adding small molecular auxiliary materials, and important guidance is provided for prescription composition and design of sulindac.

Description

Technical Field

[0001] The invention belongs to the technical field of medicine, and particularly relates to a sulindac self-gelling composition and application thereof in solid and semisolid preparations. Background Art

[0002] Sulindac is a nonsteroidal anti-inflammatory drug. Its chemical name is (Z)-5-fluoro-2-methyl-1-[(4-methylsulfinylphenyl)methylene]-1H-indene-3-acetic acid, and its chemical structure is:

[0003] Sulindac is a minimally active prodrug that has no inherent efficacy for rheumatic or rheumatoid arthritis. However, it can be converted by liver enzymes into a sulfide that inhibits prostaglandin synthesis. This inhibits cyclooxygenase, reducing prostaglandin synthesis and thus exerting analgesic, anti-inflammatory, and antipyretic effects. However, sulindac is classified as a BCS Class II drug in the biopharmaceutics classification system and has poor water solubility, which to some extent limits its absorption and clinical therapeutic efficacy.

[0004] Currently, drug self-gelation strategies, through the introduction of polymer or small molecule excipients, extend drug retention time in the gastrointestinal tract or promote drug dissolution, with the potential to improve the oral solubility and bioavailability of poorly soluble drugs. Self-gelation requires no external intervention (such as heating or chemical crosslinking agents) and spontaneously forms a three-dimensional network structure through intermolecular forces (hydrogen bonds, hydrophobic interactions, ionic bonds, etc.). This overcomes the limitation of traditional gels, which rely on external conditions for gelation, and demonstrates unique value in the field of drug formulation development.

[0005] However, existing self-gelation research has shown that many drugs, such as lenvatinib mesylate, clarithromycin, cefpodoxime, and vancomycin, tend to aggregate and form sticky gelled clumps during the formulation process or dissolution. Taking the development of solid formulations of lenvatinib mesylate as an example, gelation occurred during wet granulation and dissolution after mixing with excipients. This gelation not only poses a significant challenge to the formulation and process development of the formulation, but the gel formed during dissolution significantly slows the release of the drug, thereby affecting its absorption in the body and clinical efficacy. Summary of the Invention

[0006] The present invention provides a self-gelling composition of sulindac and a small molecule excipient. By uniformly mixing the drug sulindac and the small molecule excipient in a certain molar ratio and then contacting with a trace amount of water, the composition can self-assemble and gel, effectively enhancing the solubility and dissolution rate of the poorly soluble drug sulindac.

[0007] To achieve the above object, the present invention adopts the following technical solutions:

[0008] The sulindac self-gelling composition consists of sulindac and small molecule excipients, wherein the small molecule excipients are lysine, arginine or meglumine, and the molecular weight of the selected excipients is less than 1000Da.

[0009] The sulindac self-gelling composition is prepared by spontaneously gelling sulindac and a small molecule auxiliary material after contacting a trace amount of aqueous medium.

[0010] The molar ratio of sulindac to the small molecule excipient is 10:1 to 1:10, preferably 5:1 to 1:5, and most preferably 1:1.

[0011] The effect of the amount of water (10 to 500 μL) on the gelation of three sulindac-excipient compositions was investigated, with 200 mg of the sulindac self-gelling composition as the basis. 50 to 200 μL was preferred, and 100 μL was most preferred.

[0012] The sulindac self-gelling composition undergoes self-gelling at different temperatures (0-80°C), preferably 10-40°C, and most preferably 25°C.

[0013] The properties of the self-gelling product were analyzed using scanning electron microscopy and rheological studies. Scanning electron microscopy results showed that the gel product exhibited a typical three-dimensional network structure, while rheological tests showed that the gel product maintained good structural stability within a certain strain range.

[0014] The gelled products formed by sulindac and small molecule excipients in the present invention are analyzed by polarizing microscopy, powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. The results show that the crystal birefringence phenomenon in the gelled products is weakened, the crystal diffraction peaks almost disappear or there are weak crystal diffraction peaks, and the products all show a single glass transition temperature. Infrared results confirm that the gelled products are self-assembled through intermolecular hydrogen bond interactions.

[0015] The present invention verifies that the three sulindac self-gelling compositions can effectively improve the solubility and dissolution rate of the poorly soluble drug sulindac by measuring the apparent solubility and in vitro dissolution curve.

[0016] The sulindac self-gelling composition and preparation excipients of the present invention can be prepared into solid and semisolid preparations.

[0017] The excipients of solid preparations are: polyvinyl pyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose sodium, hypromellose, sucrose, and glucose.

[0018] The excipients of semisolid preparations are: vaseline, liquid paraffin, sodium lauryl sulfate, polyethylene glycol, methyl cellulose, and sodium carboxymethyl cellulose.

[0019] Beneficial effects of the present invention:

[0020] The present invention combines sulindac with three small molecule excipients, which can self-assemble and gel when exposed to aqueous media or high humidity environments. Experiments have shown that the composition exhibits good solubility and dissolution advantages. The three sulindac self-gelling compositions of the present invention can be used as formulation components of sulindac solid preparations, which are expected to overcome the water solubility defects of sulindac and promote its absorption in vivo. At the same time, the combination strategy of the present invention also provides new ideas for the formulation design of other poorly soluble drugs.

[0021] The composition is applied to solid preparations (such as tablets), is suitable for industrial production, has stable product quality, and is convenient to take, carry, store, and transport. The composition is applied to semi-solid preparations (such as ointments and gels), which can provide both local and systemic therapeutic effects. Furthermore, it can avoid the first-pass effect in the liver and drug degradation in the gastrointestinal tract, enhance therapeutic effects, and reduce individual differences in medication use. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 The following are scanning electron micrographs of the gelled products of the composition in Example 1 (A: sulindac-lysine gelled product, B: sulindac-arginine gelled product, C: sulindac-meglumine gelled product);

[0023] Figure 2 1 is a rheological test graph of the gelled product of the composition in Example 1 (A: sulindac-lysine gelled product, B: sulindac-arginine gelled product, C: sulindac-meglumine gelled product);

[0024] Figure 3 Polarized light microscope images of the gelled products of the composition in Example 1 (A: sulindac-lysine gelled product, B: sulindac-arginine gelled product, C: sulindac-meglumine gelled product);

[0025] Figure 4 1 is a powder X-ray diffraction pattern of the gelled product of the composition in Example 1 (A: sulindac-lysine composition, B: sulindac-arginine composition, C: sulindac-meglumine composition);

[0026] Figure 5 is a differential scanning calorimetry graph of the gelled products of the compositions in Example 1 (A: sulindac-lysine composition, B: sulindac-arginine composition, C: sulindac-meglumine composition);

[0027] Figure 6 IR spectra of the gelled products of the compositions in Example 1 (A: sulindac-lysine composition, B: sulindac-arginine composition, C: sulindac-meglumine composition);

[0028] Figure 7 is a characteristic dissolution rate graph of the sulindac-excipient composition in Example 1 (A: sulindac-lysine composition, B: sulindac-arginine composition, C: sulindac-meglumine composition);

[0029] Figure 8 This is the non-sink dissolution profile of the sulindac-excipient composition in Example 1.

[0030] Figure 9 This is a polarizing microscope image of the sulindac-excipient composition in Example 1 after the solid preparation excipient is added.

[0031] Figure 10 This is a physical picture of the sulindac-excipient composition in Example 1 after it is added to the semi-solid preparation matrix (① no matrix, ② vaseline, ③ liquid paraffin, ④ sodium lauryl sulfate, ⑤ polyethylene glycol, ⑥ methylcellulose, ⑦ sodium carboxymethylcellulose). DETAILED DESCRIPTION

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

[0033] Example 1

[0034] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 1:1 molar ratio and compress into tablets using a tablet press. Add 100 μL of deionized water to the tablet surface at 25°C. Place in a sealed sample box for 2 hours and observe gelation.

[0035] Example 2

[0036] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 10:1 molar ratio and compress into tablets using a tablet press. Add 100 μL of deionized water to the tablet surface at 25°C. Place in a sealed sample box for 2 hours and observe gelation.

[0037] Example 3

[0038] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 5:1 molar ratio and compress into tablets using a tablet press. Add 100 μL of deionized water to the tablet surface at 25°C. Place in a sealed sample box for 2 hours and observe gelation.

[0039] Example 4

[0040] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a molar ratio of 1:5 and compress into tablets using a tablet press. Add 100 μL of deionized water to the tablet surface at 25°C and place in a sealed sample box for 2 hours before observing for gelation.

[0041] Example 5

[0042] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a molar ratio of 1:10 and compress them into tablets using a tablet press. Add 100 μL of deionized water to the tablet surface at 25°C and place in a sealed sample box for 2 hours before observing for gelation.

[0043] Example 6

[0044] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 1:1 molar ratio and compress into tablets using a tablet press. Add 10 μL of deionized water to the tablet surface at 25°C. Place in a sealed sample box for 2 hours and observe gelation.

[0045] Example 7

[0046] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 1:1 molar ratio and compress into tablets using a tablet press. Add 50 μL of deionized water to the tablet surface at 25°C. Place in a sealed sample box for 2 hours and observe gelation.

[0047] Example 8

[0048] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 1:1 molar ratio and compress into tablets using a tablet press. Add 200 μL of deionized water to the tablet surface at 25°C. Place in a sealed sample box for 2 hours and observe gelation.

[0049] Example 9

[0050] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 1:1 molar ratio and compress into tablets using a tablet press. Add 500 μL of deionized water at 25°C to the tablet surface. Place in a sealed sample box for 2 hours and observe gelation.

[0051] Example 10

[0052] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 1:1 molar ratio and compress into tablets using a tablet press. Add 100 μL of deionized water to the tablet surface at 0°C and place in a sealed sample box for 2 hours before observing for gelation.

[0053] Example 11

[0054] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 1:1 molar ratio and compress into tablets using a tablet press. Add 100 μL of deionized water at 10°C to the tablet surface and place in a sealed sample box for 2 hours before observing for gelation.

[0055] Example 12

[0056] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 1:1 molar ratio and compress into tablets using a tablet press. Add 100 μL of deionized water to the tablet surface at 40°C and place in a sealed sample box for 2 hours before observing for gelation.

[0057] Example 13

[0058] Weigh 200 mg of sulindac and small molecule excipients (lysine, arginine, and meglumine, respectively) at a 1:1 molar ratio and compress into tablets using a tablet press. Add 100 μL of deionized water to the tablet surface at 80°C and place in a sealed sample box for 2 hours before observing for gelation.

[0059] Comparative Example 1

[0060] Weigh 200 mg of sulindac-glutamic acid at a 1:1 molar ratio and compress into tablets using a tablet press. Add 100 μL of deionized water at 25°C to the surface of the tablets. Place in a sealed sample box for 2 hours and observe gelation.

[0061] Comparative Example 2

[0062] Weigh 200 mg of sulindac-proline at a 1:1 molar ratio and compress into tablets using a tablet press. Add 100 μL of deionized water at 25°C to the tablet surface. Place in a sealed sample box for 2 hours and observe gelation.

[0063] Comparative Example 3

[0064] Weigh 200 mg of sulindac and aspartic acid at a 1:1 molar ratio and compress into tablets using a tablet press. Add 100 μL of deionized water to the tablet surface at 25°C. Place in a sealed sample box for 2 hours and observe gelation.

[0065] Comparative Example 4

[0066] The sulindac self-gelling composition is formed by uniformly mixing sulindac and small molecule excipients through simple physical shaking.

[0067] Test Example 1: Hansen solubility calculations were performed on sulindac and selected small molecule excipients, as follows:

[0068] Hansen solubility parameters (δ) were calculated using Molecular Modeling Pro software. Based on the solubility parameter differences (Δδ), small molecule excipients with good compatibility with sulindac were screened. Table 1 shows that sulindac exhibited good compatibility with the selected small molecule excipients. However, as observed in the above examples, only three small molecule excipients, lysine, arginine, and meglumine, exhibited significant gelation upon contact with water when mixed with sulindac.

[0069] Table 1 Hansen solubility parameters (δ) of sulindac crystals and small molecule excipients

[0070]

[0071] Test Example 2: The self-gelling composition of sulindac and small molecule excipients in Example 1 was tested as follows:

[0072] 1. Scanning electron microscope

[0073] Scanning electron microscopy (SEM) was performed using a TM4000 desktop scanning electron microscope (HITACHI, Japan) with a probe current of 20 μA, an accelerating voltage of 15 kV, and a counting time of 60 s to determine the micromorphology of the gelation product formed by sulindac and the small molecule excipient.

[0074] Test results: Scanning electron micrographs of the gelation products of sulindac-lysine combination, sulindac-arginine combination, and sulindac-meglumine combination are shown in Figure 1 .Depend on Figure 1 It can be seen that the three gelled samples all present a typical three-dimensional network structure of gel with obvious pores inside.

[0075] 2. Rheological test

[0076] The rheological properties of the gelation products of sulindac and small molecule excipients were determined using a Kinexus pro rotational rheometer (Malvern, UK). The temperature was set at 25°C, the parallel plate diameter was 20 mm, the measuring gap was 1 mm, and the strain sweep frequency was 1 Hz, ranging from 0.1% to 1000%.

[0077] Test results: The rheological test results of the gelled product formed by sulindac and small molecule excipients in Example 1 are shown in Figure 2 .Depend on Figure 2A shows that when the strain amplitude is lower than 3%, the storage modulus (G') and loss modulus (G") of the sulindac-lysine gelation product remain stable, indicating that its network structure is in the linear viscoelastic region. When the strain exceeds the 3% threshold, the modulus value decays sharply and the viscoelastic response reverses (G">G'), indicating that the three-dimensional network structure of the gelation product is destroyed. Similarly, the upper limits of the linear viscoelastic region of the sulindac-arginine gelation product and the sulindac-meglumine gelation product are 12% and 4% strain, respectively. Rheological analysis shows that sulindac exhibits certain viscoelasticity after gelation with small molecule excipients.

[0078] 3. Polarizing microscope

[0079] Sulindac crystals, excipient crystals, and the gelation product formed by sulindac and small molecule excipients were observed at 4×10 magnification using an MSD1125BP polarizing microscope from Maishidi Technology Co., Ltd. The degree of disappearance of the crystal birefringence was recorded.

[0080] Test results: Figure 3 As shown, sulindac crystals, lysine crystals, arginine crystals, meglumine crystals and sulindac-excipient physical mixtures all exhibit significant crystal birefringence, while the crystal birefringence of the three gelation products formed by sulindac and small molecule excipients basically disappears, indicating that the formed gelation products are almost amorphous.

[0081] 4. Powder X-ray diffraction

[0082] X-ray diffraction analysis of the self-gelling composition was performed using a Rigaku SmartLab 9 X-ray diffractometer. Cu-Kα palladium was used as the radiation source, with a tube voltage of 40 kV, a tube current of 40 mA, a scan step of 0.02°, a scan rate of 4° / min, and a scanning range of 2θ from 5 to 40°.

[0083] Measurement results: The gelled product formed by sulindac and small molecule excipients in Example 1 was subjected to powder X-ray diffraction analysis. The results are as follows: Figure 4 .Depend on Figure 4 It can be seen that compared with sulindac crystals and excipient crystals, the diffraction peaks of the original crystals in the powder X-ray diffraction patterns of the gelled products of sulindac-lysine, sulindac-arginine and sulindac-meglumine compositions basically disappear, forming a single diffuse amorphous diffraction ring.

[0084] 5. Differential Scanning Calorimetry

[0085] About 5 mg each of sulindac crystals, sulindac-excipient physical mixture, and gelation product formed by sulindac and small molecule excipients were placed in an aluminum crucible and analyzed using a HITACHIDSC 7020 differential scanning calorimeter (Hitachi Profile, Japan). Under nitrogen protection, the temperature was increased from 25°C to 250°C at a heating rate of 10°C / min.

[0086] Test results: Figure 5 As shown, the gelation products of sulindac-lysine composition, sulindac-arginine composition and sulindac-meglumine composition showed single glass transition temperatures at 75.25°C, 80.89°C and 33.46°C, respectively, and the melting endothermic peaks of original sulindac crystals and excipients were significantly weakened or even disappeared.

[0087] 6. Infrared spectroscopy

[0088] The interactions between drugs and excipients were analyzed using a Thermo Scientific Nicolet iS50 Fourier transform infrared spectrometer (Thermo Fisher Scientific, America). -1 The resolution was scanned 32 times, and the scanning range was 4000~500cm -1 .

[0089] Measurement results: The Fourier transform infrared spectrum of the gelation product formed by sulindac and small molecule excipients is as follows Figure 6 As shown by Figure 6 A shows that the infrared absorption spectrum of the formed sulindac-lysine gel product is 3407.7, 2824.4, 1635.3, 1599.3, 1357.1, 1177.6, 1105.8, 782.7, 616.7 cm -1 There is an absorption peak at.

[0090] Depend on Figure 6 B shows that the infrared absorption spectrum of the formed sulindac-arginine gelation product is 3359.3, 2825.4, 1626.8, 1596.3, 1462.8, 1356.1, 1172.6, 1100.1, 777.2, 617.5 cm -1 There is an absorption peak at.

[0091] Depend on Figure 6 C shows that the infrared absorption spectrum of the formed sulindac-meglumine gel product is 3386.2, 2826.8, 1596.3, 1464.9, 1356.9, 1171.8, 1104.4, 774.3, 618.9 cm -1 There is an absorption peak at.

[0092] Compared to the infrared absorption spectra of sulindac crystals and the small molecule excipient, the spectra of the gelled products of the three compositions showed weakened and red-shifted carbonyl and hydroxyl stretching vibration peaks of the sulindac crystals. Simultaneously, the stretching vibration peaks of the hydroxyl, carbonyl, or amino groups in the excipients also weakened or shifted. Infrared spectroscopy confirmed that the gelling phenomenon of sulindac-small molecule excipients is driven by self-assembly through intermolecular hydrogen bonding interactions between the components.

[0093] Test Example 3: Apparent solubility tests were conducted on the sulindac crystals and three sulindac-small molecule excipient self-gelling compositions in Example 1, as follows:

[0094] The excess sulindac crystals and the three sulindac-small molecule excipient self-gelling compositions from Example 1 were placed in centrifuge tubes containing 4 mL of deionized water, with three replicates for each sample. The centrifuge tubes were then placed in a shaker and shaken at 37°C and 200 rpm for 24 hours. After shaking, 1 mL of the supernatant was filtered through a 0.22 μm microporous membrane, and the apparent solubility of the different samples was determined by high performance liquid chromatography.

[0095] The HPLC conditions were as follows:

[0096] Instrument: Agilent 1260 high performance liquid chromatograph

[0097] Chromatographic column: Ultimate XB-C18 (4.6 mm × 250 mm, 5 μm)

[0098] Mobile phase: acetonitrile-0.3% phosphoric acid water = 50:50 (V / V)

[0099] Flow rate: 1.0 mL / min

[0100] Detection wavelength: 320nm

[0101] Measurement results: The solubility results of sulindac crystals and three sulindac-small molecule excipient self-gelling compositions are shown in Table 2. The solubility of sulindac crystals in water is 11.77 μg / mL, and the solubilities of the sulindac-lysine composition, sulindac-arginine composition, and sulindac-meglumine composition in water are 3401.52, 3515.77, and 3640.24 μg / mL, respectively, which are 288.10, 298.71, and 309.28 times higher than that of sulindac crystals, respectively.

[0102] Table 2 Apparent solubility of sulindac crystals and sulindac-small molecule excipient composition

[0103]

[0104]

[0105] Test Example 4: The intrinsic dissolution rate test was performed on the sulindac crystals and three sulindac-small molecule excipient compositions in Example 1, as follows:

[0106] 200 mg of sulindac crystals and three sulindac-small molecule excipient compositions were weighed separately, and 3 parts were paralleled and tableted using a tablet press. Using beeswax as a mold, the tablets were placed in beeswax so that only one circular surface was in contact with the dissolution medium. According to the second method (paddle method) device of the 2020 edition of the Chinese Pharmacopoeia, 0931. The medium temperature was 37 ° C, the medium volume was 900 mL, and the speed was 50 rpm to measure the dissolution curve in water. During the test, 2 mL of samples were taken at 2, 5, 10, 15, 20, 30, 45, 60, 90 and 120 min, and 2 mL of constant temperature medium was added at the same time. The removed liquid was filtered with a 0.22 μm aqueous microporous membrane and analyzed by high performance liquid chromatography.

[0107] Test results: The intrinsic dissolution rate results of sulindac crystals and three sulindac-small molecule excipient compositions are as follows: Figure 7 As shown in the figure, after the introduction of the small molecule excipient, the three sulindac-small molecule excipient self-gelling compositions all showed significantly enhanced dissolution rates. Compared to sulindac crystals, the intrinsic dissolution rates of the sulindac-lysine composition, the sulindac-arginine composition, and the sulindac-meglumine composition increased by 6288.04 times, 4119.57 times, and 5342.39 times, respectively.

[0108] Test Example 5: Non-sink dissolution tests were conducted on the sulindac crystals and three sulindac-small molecule excipient self-gelling compositions in Example 1, as follows:

[0109] A certain amount of sulindac crystals and three sulindac-small molecule excipient self-gelling compositions were weighed separately, in parallel. According to the second method of 0931 of the fourth general rule of the 2020 edition of the Chinese Pharmacopoeia, the non-sink release evaluation was performed by the slurry method. The release medium was water, the medium temperature was 37 ° C, the volume was 200 mL, and the rotation speed was 100 rpm. 2 mL of samples were taken at 5, 10, 20, 30, 45, 60, 90, 120, 240, 360, 480 and 720 min, and 2 mL of constant temperature medium was added at the same time. The removed liquid passed through a 0.22 μm microporous filter membrane and was analyzed by high performance liquid chromatography.

[0110] Test results: The non-sink dissolution results of sulindac crystals and three sulindac-small molecule excipient self-gelling compositions are as follows: Figure 8As shown. The sulindac crystals reached a maximum dissolution concentration of 17.22 μg / mL at around 240 min. The three sulindac-excipient self-gelling compositions all reached dissolution equilibrium at around 240 min. The dissolution concentrations of the sulindac-lysine composition, sulindac-arginine composition and sulindac-meglumine composition at this time were 233.85, 244.62 and 275.76 μg / mL, respectively. Compared with sulindac crystals, the dissolution concentrations of the sulindac-lysine composition, sulindac-arginine composition and sulindac-meglumine composition were increased by 13.58, 14.21 and 16.01 times, respectively, and were able to maintain supersaturation for a long time without a decrease in dissolution concentration, which is expected to enhance the in vivo absorption of sulindac.

[0111] Test Example 6: A study was conducted to investigate whether the three sulindac compositions in Example 1 can be used in solid and semisolid preparations, as follows:

[0112] For use in solid preparations (tablets), commonly used solid preparation pharmaceutical excipients (polyvinyl pyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose, sodium hydroxymethyl cellulose, hypromellose, sucrose, glucose) are added to the sulindac-small molecule excipient composition. The total mass of the sulindac-small molecule excipient composition and the solid preparation pharmaceutical excipient at a molar ratio of 1:1 is 200 mg, wherein the mass ratio of the composition to the solid preparation excipient is 1:9, i.e., 20 mg of the sulindac-small molecule excipient composition and 180 mg of the solid preparation pharmaceutical excipient. After uniform mixing, the tablets are pressed. After adding 100 uL of water, the gelation phenomenon is observed by polarizing microscopy.

[0113] For use in semisolid preparations (gels, ointments), a commonly used semisolid preparation matrix (vaseline, liquid paraffin, sodium lauryl sulfate, polyethylene glycol, methylcellulose, sodium carboxymethylcellulose) is added to the sulindac-small molecule excipient composition. The total mass of the sulindac-small molecule excipient composition and the semisolid preparation matrix at a molar ratio of 1:1 is 200 mg, wherein the mass ratio of the composition to the matrix is 1:9, i.e., the sulindac-small molecule excipient composition is 20 mg and the semisolid preparation matrix is 180 mg. 100 uL of water is added and stirred to mix, and the morphology of the formed semisolid preparation sample is observed.

[0114] Test results: Figure 9 As shown in FIG, when other commonly used pharmaceutical excipients for solid preparations are added to the sulindac-small molecule excipient composition, it can still self-gel and exist in an amorphous state after contacting an aqueous medium. This indicates that the composition can be used in the formulation of solid preparations (such as tablets, granules, powders, etc.). In addition, as Figure 10As shown, when a pharmaceutical matrix of a commonly used semi-solid preparation is added to the sulindac-small molecule excipient composition and a trace amount of water is added and stirred, the composition exhibits certain viscoelasticity and semi-solid characteristics, indicating that the composition can be used in semi-solid preparations of sulindac (such as gels, ointments, suppositories, etc.).

Claims

1. A sulindac self-gelling composition, characterized in that: The sulindac self-gelling composition consists of sulindac and small molecule excipients, wherein the small molecule excipients are lysine, arginine or meglumine.

2. The sulindac self-gelling composition according to claim 1, wherein The molar ratio of sulindac to the small molecule excipient is 10:1 to 1:

10.

3. The sulindac self-gelling composition according to claim 1, wherein The preparation method of the sulindac self-gelling composition comprises the following steps: sulindac and a small molecule auxiliary material are self-assembled and gelled when in contact with an aqueous medium or in a high-humidity environment.

4. The sulindac self-gelling composition according to claim 3, wherein Based on a total mass of 200 mg, the amount of aqueous medium added is: 10 to 500 uL.

5. The sulindac self-gelling composition according to claim 3, wherein The temperature at which self-assembly gelation occurs is 0-80°C.

6. A solid or semisolid preparation, characterized in that: The solid and semisolid preparations are composed of a sulindac self-gelling composition and preparation excipients.

7. The solid and semisolid preparation according to claim 6, characterized in that The excipients of solid preparations are: polyvinyl pyrrolidone, microcrystalline cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose sodium, hypromellose, sucrose, and glucose.

8. The solid and semisolid preparation according to claim 6, wherein The excipients of semisolid preparations are: vaseline, liquid paraffin, sodium lauryl sulfate, polyethylene glycol, methyl cellulose, and sodium carboxymethyl cellulose.

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