A stable indometacin formulation and process for its preparation

Abstract

The application discloses a kind of stable indometacin tablets and its preparation process, belong to pharmaceutical preparation technical field.The tablet is composed of indometacin, hydroxypropyl beta-cyclodextrin, soybean phospholipid, composite stabilizer, binder and lubricant, and the composite stabilizer is compounded by succinylated c14-c18 alkyl sulfonate sodium, N-ethyl-L-glutamine and maltodextrin according to specific mass ratio.Preparation process includes liposome inclusion compound preparation, mixing granulation, drying whole particle, total mixing and tabletting.The application realizes the preparation of high drug loading design, and the composite stabilizer forms a multilayer coating protection system with hydroxypropyl beta-cyclodextrin and soybean phospholipid, which synergistically improves the dissolution performance and stability of the preparation, makes the dissolution rate of the preparation fast, and the content of the main component decreases little during long-term storage, solves the problems of low drug loading, poor stability and dissolution of existing indometacin tablets.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a stable indomethacin formulation and its preparation process. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Indomethacin, a classic nonsteroidal anti-inflammatory drug (NSAID), reduces prostaglandin synthesis by inhibiting cyclooxygenase activity, while simultaneously inhibiting leukocyte chemotaxis and lysosomal enzyme release. It possesses significant anti-inflammatory, antipyretic, and analgesic effects and is widely used clinically to treat rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, and acute gout attacks. Its mechanism of action is clear, and its efficacy is definite, making it an important drug in the treatment of bone and joint diseases. Currently, indomethacin is available in tablet, capsule, and suppository formulations. Tablets are the mainstream clinical form due to their convenience in administration and portability. However, ordinary tablets suffer from rapid release and short duration of action. Furthermore, the stability and dissolution performance of currently available indomethacin tablets still have significant room for improvement, making it difficult to fully meet the clinical requirements for high efficacy and stability.

[0004] To address the aforementioned issues, existing technologies have undertaken targeted research and development. For instance, Chinese patent CN106943365A discloses an indomethacin tablet and its preparation method. This technology involves dissolving indomethacin with β-cyclodextrin and soybean lecithin in anhydrous propanol and drying under reduced pressure to obtain a liposome inclusion complex. This complex is then mixed with excipients such as binders, lubricants, and stabilizers, granulated, and tableted. The β-cyclodextrin used is selected from hydroxyethyl β-cyclodextrin or hydroxypropyl β-cyclodextrin, and the stabilizer is poloxamer or glycerol polyethylene glycol castor oil. By combining cyclodextrin inclusion with soybean lecithin for protection, the stability and dissolution of indomethacin are improved, resulting in tablets with high content and good physical strength.

[0005] However, this existing technology still has significant limitations: First, the drug loading is low. In this technology, indomethacin is only 30-40 parts by weight, while the addition of β-cyclodextrin and soybean lecithin is 90-120 parts by weight. The proportion of pharmaceutical excipients is too high, and the proportion of effective drug components is limited. This not only results in insufficient drug loading per unit dose tablet, making it difficult to meet the clinical demand for high-dose medication, but also increases the raw material cost of the formulation due to the large amount of excipients. At the same time, it is easy to cause the tablet weight to be too large, affecting patient compliance. Second, the stability improvement effect is still insufficient. The indole ring and amide bond in the indomethacin molecule are still easily exposed to light, oxygen and moisture. During long-term storage, slow oxidation and hydrolysis reactions will still occur, leading to a decrease in the content of the main component.

[0006] Therefore, based on existing technologies, there is an urgent need to develop an indomethacin formulation with high drug loading and high stability. By optimizing the formulation ratio and inclusion process, the proportion of active ingredients and the drug loading per unit dose can be increased, while constructing an efficient encapsulation and protection system for indomethacin molecules. This will further enhance the chemical stability and long-term storage stability of the formulation, taking into account the clinical efficacy, medication safety, and production feasibility of the formulation. This will solve the technical pain points of insufficient drug loading and poor long-term stability in existing technologies, so as to better meet the needs of large-scale clinical use. Summary of the Invention

[0007] The purpose of this invention is to overcome the technical defects of existing indomethacin tablets, such as low drug loading, insufficient stability, and poor dissolution, and to provide a stable indomethacin tablet. This formulation has high drug loading, excellent chemical stability and dissolution performance, and the content of the main component decreases little during long-term storage, thereby improving patient compliance.

[0008] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0009] An indomethacin tablet, by weight, comprises the following components: 55-70 parts indomethacin, 50-70 parts hydroxypropyl β-cyclodextrin, 30-50 parts soybean lecithin, 5-8 parts composite stabilizer, 2-4 parts binder, and 2-4 parts lubricant; wherein the composite stabilizer is composed of sodium succinate sulfonate, N-ethyl-L-glutamine, and maltodextrin in a mass ratio of 1:2:1.

[0010] Preferably, the adhesive is selected from one or more of hydroxypropyl methylcellulose, povidone, sodium carboxymethyl cellulose, and starch; more preferably, the adhesive is hydroxypropyl methylcellulose.

[0011] Preferably, the lubricant is selected from one or more of magnesium stearate, micronized silica gel, sodium stearate fumarate, and talc; more preferably, the lubricant is a compound of magnesium stearate and micronized silica gel in a mass ratio of 1:1.

[0012] The present invention also discloses the preparation process of the above-mentioned indomethacin tablets, including the following steps:

[0013] (1) Preparation of liposome inclusion complex: Hydroxypropyl β-cyclodextrin was prepared into a saturated aqueous solution at 55~60℃, and indomethacin micro powder passing through a 100-mesh sieve was added. The mixture was stirred at 500~600r / min for 30~40min to obtain a suspension inclusion solution. Soybean lecithin passing through an 80-mesh sieve and a composite stabilizer were added. After stirring and dispersing at 300r / min, the mixture was sheared and emulsified at 9000~10000r / min for 20~25min. After freeze-drying, the mixture was pulverized and passed through an 80-mesh sieve to obtain the liposome inclusion complex.

[0014] (2) Mixing and granulation: After dry mixing of liposome inclusion complex, purified water and binder are sprayed in, stirred and granulated to obtain soft material, which is then passed through a 20-mesh sieve to obtain wet granules;

[0015] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 55~60℃ and then granulated by passing them through an 18-mesh sieve;

[0016] (4) Mixing and tableting: Add lubricant to dry granules and mix for 8-10 minutes, then compress to obtain the finished product.

[0017] Preferably, in step (1), the preparation of the saturated aqueous solution of hydroxypropyl β-cyclodextrin is as follows: add 10 to 12 times the amount of purified water to the hydroxypropyl β-cyclodextrin, stir at 400 to 450 r / min in a constant temperature water bath at 55 to 60°C until completely dissolved, and keep warm at 55°C for later use.

[0018] Preferably, the freeze-drying parameters for step (1) are: ① Pre-freezing: -45~-40℃ for 3~4h; ② Sublimation drying: vacuum degree ≤15Pa, temperature rise to 25~30℃, dry for 14~16h; ③ Desorption drying: vacuum degree ≤10Pa, 35℃ for 2~3h.

[0019] Preferably, in step (2), the liposome inclusion complex is dry-mixed in a wet mixing granulator at 180~200r / min for 5min, then purified water and binder are sprayed in, and then granulated by stirring at 150r / min for 8~10min.

[0020] Preferably, in step (4), the granulated dry granules are added to a three-dimensional motion mixer and mixed for 8 to 10 minutes at a speed of 90 to 100 r / min. After mixing, the mixture is directly transferred to a rotary tablet press for tableting, and the tableting pressure is controlled at 8 to 12 MPa.

[0021] This invention achieves high drug loading design of formulations by precisely controlling the ratio and compounding relationship of each component. The amount of excipients such as hydroxypropyl β-cyclodextrin and soybean lecithin is reasonable, reducing the proportion of excipients. This not only increases the drug loading per unit dose, but also controls the tablet weight, improves patient compliance, and reduces the cost of raw materials for production.

[0022] The core innovation of this invention lies in the compound stabilizer. Sodium succinate sulfonate, N-ethyl-L-glutamine, and maltodextrin are compounded in a mass ratio of 1:2:1, and the components produce a synergistic effect. The precise compounding of the three components achieves a dual improvement in the dissolution performance and stability of the formulation. Furthermore, the compound stabilizer is added during the preparation stage of the liposome inclusion complex, and can synergistically form a multi-layered coating and protective system for indomethacin molecules with hydroxypropyl β-cyclodextrin and soybean lecithin, preventing the drug from contacting external light, oxygen, and moisture, thereby improving the stability of the formulation from the root.

[0023] Meanwhile, the preparation process of this invention optimizes the stirring and emulsification parameters of liposome inclusion, as well as the process conditions of the entire process such as freeze drying, granulation, and tableting, to achieve efficient combination of drugs and excipients. The resulting liposome inclusion complex has high inclusion efficiency, good particle formability, fast dissolution rate and high dissolution degree of the tablets, and the process parameters are controllable and have good repeatability, making it suitable for large-scale industrial production.

[0024] Compared with the prior art, the indomethacin tablets of the present invention have the following beneficial effects:

[0025] 1. High drug loading: Indomethacin has a high proportion of active ingredients, and the drug loading per unit dose can meet the clinical needs for high-dose medication. The amount of excipients is reasonable, which reduces the cost of raw materials for production. The tablet weight is moderate, which improves patient compliance.

[0026] 2. Excellent stability: Accelerated and long-term tests have verified that the content of the main component in the formulation decreases very little during storage, and the chemical stability and long-term storage stability are excellent, effectively solving the technical problems of easy oxidation and hydrolysis of indomethacin in existing formulations.

[0027] 3. Excellent dissolution performance: The formulation has a fast dissolution rate and high degree of dissolution at all time points, which can ensure the rapid release of drugs in the body and exert their effects, thereby improving the clinical treatment effect. Detailed Implementation

[0028] To make the objectives and technical solutions of this invention clearer, the following embodiments are provided for further explanation. However, the scope of protection of this invention is not limited to these embodiments; the embodiments are merely for illustrative purposes. Those skilled in the art should understand that any changes or equivalent substitutions that do not depart from the concept of this invention are included within the scope of protection of this invention.

[0029] Example 1: Indomethacin Tablets

[0030] formula:

[0031] The ingredients are: indomethacin 62.5g, hydroxypropyl β-cyclodextrin 60g, soybean lecithin 40g, compound stabilizer 6.5g, binder 3g, and lubricant 3g. The compound stabilizer is composed of sodium succinate sulfonate, N-ethyl-L-glutamine, and maltodextrin in a mass ratio of 1:2:1. The binder is hydroxypropyl methylcellulose (HPMC K15M). The lubricant is composed of magnesium stearate and micronized silica gel in a mass ratio of 1:1.

[0032] Preparation process:

[0033] (1) Preparation of liposome inclusion complex: Hydroxypropyl β-cyclodextrin was taken and stirred in a constant temperature water bath at 57℃ until completely dissolved. The solution was kept warm to obtain a saturated aqueous solution at 57℃. Indomethacin powder that had passed through a 100-mesh sieve was added and stirred at 550 r / min for 35 min to obtain a suspension inclusion solution. Soybean lecithin and a composite stabilizer that had passed through an 80-mesh sieve were added and stirred at 300 r / min to disperse evenly. The mixture was then sheared and emulsified at 9500 r / min for 22.5 min. After freeze-drying, the mixture was pulverized and passed through an 80-mesh sieve to obtain the liposome inclusion complex. Freeze-drying parameters: ① Pre-freeze: -42.5℃ for 3.5 h; ② Sublimation drying: vacuum degree ≤15 Pa, temperature raised to 27.5℃, drying for 15 h; ③ Desorption drying: vacuum degree ≤10 Pa, temperature kept at 35℃ for 2.5 h.

[0034] (2) Mixing and granulation: The liposome inclusion complex is placed in a wet mixing granulator and dry-mixed at 190 r / min for 5 min. A suitable amount of purified water and binder are sprayed in and granulated at 150 r / min for 9 min to obtain soft material. The soft material is then passed through a 20-mesh sieve to obtain wet granules.

[0035] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 57.5℃ until the moisture content is ≤3%, and then granulated by passing them through an 18-mesh sieve.

[0036] (4) Total mixing and tableting: Add the granulated dry granules to a three-dimensional motion mixer, control the rotation speed to 95 r / min, add lubricant and mix for 9 min. After mixing, directly transfer to a rotary tablet press for tableting. The tableting pressure is controlled at 10 MPa to obtain indomethacin tablets.

[0037] Example 2 Indomethacin Tablets

[0038] formula:

[0039] The ingredients are: indomethacin 55g, hydroxypropyl β-cyclodextrin 50g, soybean lecithin 30g, compound stabilizer 5g, binder 2g, and lubricant 2g. The compound stabilizer is composed of sodium succinate sulfonate, N-ethyl-L-glutamine, and maltodextrin in a mass ratio of 1:2:1. The binder is polyvinylpyrrolidone. The lubricant is magnesium stearate.

[0040] Preparation process

[0041] (1) Preparation of liposome inclusion complex: Hydroxypropyl β-cyclodextrin was stirred in a constant temperature water bath at 55℃ until completely dissolved, and kept at 55℃ to obtain a saturated aqueous solution at 55℃; Indomethacin micro powder passing through a 100-mesh sieve was added, and stirred at 500r / min for 30min to obtain a suspension inclusion solution; Soybean lecithin passing through an 80-mesh sieve and a composite stabilizer were added, and stirred at 300r / min to disperse evenly, and then sheared and emulsified at 9000r / min for 20min. After freeze-drying, the mixture was pulverized and passed through an 80-mesh sieve to obtain the liposome inclusion complex. Freeze-drying parameters: ① Pre-freeze: -45℃ for 3h; ② Sublimation drying: Vacuum degree ≤15Pa, temperature raised to 25℃, drying for 14h; ③ Desorption drying: Vacuum degree ≤10Pa, 35℃ for 2h.

[0042] (2) Mixing and granulation: The liposome inclusion complex is placed in a wet mixing granulator and dry-mixed at 180 r / min for 5 min. A suitable amount of purified water and binder are sprayed in and granulated at 150 r / min for 8 min to obtain soft material. The soft material is then passed through a 20-mesh sieve to obtain wet granules.

[0043] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 55℃ until the moisture content is ≤3%, and then granulated by passing them through an 18-mesh sieve.

[0044] (4) Total mixing and tableting: Add the granulated dry granules to a three-dimensional motion mixer, control the rotation speed to 90 r / min, add lubricant and mix for 8 min. After mixing, directly transfer to a rotary tablet press for tableting. The tableting pressure is controlled at 8 MPa to obtain indomethacin tablets.

[0045] Example 3 Indomethacin Tablets

[0046] formula:

[0047] The ingredients are: indomethacin 70g, hydroxypropyl β-cyclodextrin 70g, soybean lecithin 50g, compound stabilizer 8g, binder 4g, and lubricant 4g. The compound stabilizer is composed of sodium succinate sulfonate, N-ethyl-L-glutamine, and maltodextrin in a mass ratio of 1:2:1. The binder is composed of sodium carboxymethyl cellulose and starch in a mass ratio of 1:1. The lubricant is composed of sodium stearate fumarate and talc in a mass ratio of 1:1.

[0048] Preparation process:

[0049] (1) Preparation of liposome inclusion complex: Hydroxypropyl β-cyclodextrin was stirred in a constant temperature water bath at 60℃ until completely dissolved, and kept at 55℃ to obtain a saturated aqueous solution at 60℃; indomethacin micro powder passing through a 100-mesh sieve was added, and stirred at 600r / min for 40min to obtain a suspension inclusion solution; soybean lecithin passing through an 80-mesh sieve and a composite stabilizer were added, and stirred at 300r / min to disperse evenly, and then sheared and emulsified at 10000r / min for 25min. After freeze-drying, the mixture was pulverized and passed through an 80-mesh sieve to obtain the liposome inclusion complex. Freeze-drying parameters: ① Pre-freeze: -40℃ for 4h; ② Sublimation drying: vacuum degree ≤15Pa, temperature raised to 30℃, drying for 16h; ③ Desorption drying: vacuum degree ≤10Pa, temperature kept at 35℃ for 3h.

[0050] (2) Mixing and granulation: The liposome inclusion complex is placed in a wet mixing granulator and dry-mixed at 200 r / min for 5 min. A suitable amount of purified water and binder are sprayed in and granulated at 150 r / min for 10 min to obtain soft material. The soft material is then passed through a 20-mesh sieve to obtain wet granules.

[0051] (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 60℃ until the moisture content is ≤3%, and then granulated by passing them through an 18-mesh sieve.

[0052] (4) Total mixing and tableting: Add the granulated dry granules to a three-dimensional motion mixer, control the rotation speed to 100 r / min, add lubricant and mix for 10 min. After mixing, directly transfer to a rotary tablet press for tableting. The tableting pressure is controlled at 12 MPa to obtain indomethacin tablets.

[0053] Comparative Example 1

[0054] Formula adjustment: Remove 6.5g of the composite stabilizer from Example 1, while keeping the other components and their amounts unchanged.

[0055] Process adjustment: No stabilizers were added throughout the preparation process, and the remaining steps and parameters were the same as in Example 1.

[0056] Comparative Example 2

[0057] Formula adjustment: The compound stabilizer is composed of N-ethyl-L-glutamine and maltodextrin in a mass ratio of 2:1, with the total amount remaining at 6.5g. The other components and their amounts remain unchanged.

[0058] Process adjustment: The above-mentioned compound stabilizer was added during the preparation of liposome inclusion complex, and the remaining steps and parameters were the same as in Example 1.

[0059] Comparative Example 3

[0060] Formula adjustment: The compound stabilizer is a mixture of sodium succinate sulfonate and maltodextrin in a mass ratio of 1:1, with the total amount remaining at 6.5g. The other components and their amounts remain unchanged.

[0061] Process adjustment: The above-mentioned compound stabilizer was added during the preparation of liposome inclusion complex, and the remaining steps and parameters were the same as in Example 1.

[0062] Comparative Example 4

[0063] Formula adjustment: The compound stabilizer is composed of sodium succinate sulfonate and N-ethyl-L-glutamine in a mass ratio of 1:2, with the total amount remaining at 6.5g. The other components and their amounts remain unchanged.

[0064] Process adjustment: The above-mentioned compound stabilizer was added during the preparation of liposome inclusion complex, and the remaining steps and parameters were the same as in Example 1.

[0065] Comparative Example 5

[0066] Formula adjustment: The compound stabilizer is composed of sodium dodecyl sulfate, N-ethyl-L-glutamine, and maltodextrin in the original mass ratio of 1:2:1, with the total amount still being 6.5g. The other components and their amounts remain unchanged.

[0067] Process adjustment: The above-mentioned replacement stabilizer was added during the preparation stage of liposome inclusion complex, and the remaining steps and parameters were the same as in Example 1.

[0068] Comparative Example 6

[0069] Formula adjustment: The compound stabilizer is composed of sodium succinate sulfonate, L-glutamine, and maltodextrin in the original mass ratio of 1:2:1, with the total amount still being 6.5g. The other components and their amounts remain unchanged.

[0070] Process adjustment: The above-mentioned replacement stabilizer was added during the preparation stage of liposome inclusion complex, and the remaining steps and parameters were the same as in Example 1.

[0071] Comparative Example 7

[0072] Formula adjustment: The compound stabilizer is composed of sodium succinate sulfonate, N-ethyl-L-glutamine, and dextrin in the original mass ratio of 1:2:1, with the total amount still being 6.5g. The other components and their amounts remain unchanged.

[0073] Process adjustment: The above-mentioned replacement stabilizer was added during the preparation stage of liposome inclusion complex, and the remaining steps and parameters were the same as in Example 1.

[0074] Comparative Example 8

[0075] Formula adjustment: The type, ratio, and total amount of the compound stabilizer remain the same as in Example 1 (1:2:1 compound, 6.5g), and the other components and their amounts remain unchanged.

[0076] Process adjustments: No composite stabilizer is added during the preparation stage of the liposome inclusion complex; in the mixing and granulation step (step 2 of Example 1), the composite stabilizer and the liposome inclusion complex are put into a wet mixing granulator for dry mixing, and the remaining steps (dry mixing speed, granulation time, drying parameters, etc.) are the same as in Example 1.

[0077] Comparative Example 9

[0078] Formula adjustment: The compound stabilizer was removed, and only 6.5g of sodium succinate sulfonate was added. The other components and their amounts remained unchanged.

[0079] Process adjustment: Sodium succinate sulfonate was added during the preparation of the liposome inclusion complex, and the remaining steps and parameters were the same as in Example 1.

[0080] Comparative Example 10

[0081] Formula adjustment: The compound stabilizer was removed, and only 6.5g of N-ethyl-L-glutamine was added. The other components and their amounts remained unchanged.

[0082] Process adjustment: N-ethyl-L-glutamine was added during the preparation of the liposome inclusion complex, and the remaining steps and parameters were the same as in Example 1.

[0083] Comparative Example 11

[0084] Formula adjustment: The compound stabilizer was removed, and only 6.5g of maltodextrin was added. The other components and their amounts remained unchanged.

[0085] Process adjustment: Maltodextrin was added during the preparation of liposome inclusion complexes, and the remaining steps and parameters were the same as in Example 1.

[0086] Comparative Example 12

[0087] Formula adjustment: The compound stabilizer is composed of sodium succinate sulfonate, N-ethyl-L-glutamine and maltodextrin in a mass ratio of 2:1:2 (original ratio 1:2:1), and the total amount remains 6.5g. The other components and their amounts remain unchanged.

[0088] Process adjustment: During the preparation of liposome inclusion complex, the above-mentioned stabilizer with disordered ratio was added, and the remaining steps and parameters were the same as in Example 1.

[0089] Indomethacin tablets dissolution

[0090] Dissolution was determined according to the Dissolution and Release Determination Method (General Chapter 0931, Method 1) of the Chinese Pharmacopoeia. Dissolution conditions: 1000 ml of phosphate buffer (pH 6.8) was used as the dissolution medium, and the rotation speed was 100 rpm. Sampling was performed according to the procedure. Test solution: The dissolution solution was collected, filtered, and the filtrate was collected. Determination method: The test solution was taken, and the absorbance was measured at a wavelength of 320 nm according to the ultraviolet-visible spectrophotometry method (General Chapter 0401), following the procedure described in section C. 19 H 16 The absorption coefficient of ClNO4 is 196. Calculate the dissolution amount per tablet.

[0091] Table 1 Dissolution of Indomethacin Tablets

[0092] Table 1 shows that the indomethacin tablets of Examples 1-3 of the present invention exhibit significantly better dissolution performance than the comparative examples at each time point, with faster dissolution rate and higher dissolution degree. In contrast, the comparative examples without the addition of the composite stabilizer, with different / omitted components of the composite stabilizer, adjusted addition method, ratio, or substitution with a single component all showed varying degrees of decrease in dissolution performance. This indicates that the composite stabilizer formulated according to the present invention and added at the liposome inclusion complex stage can effectively improve the dissolution characteristics of indomethacin tablets.

[0093] Indomethacin content

[0094] Determine the indomethacin solution according to the high performance liquid chromatography method (General Chapter 0512) in the Chinese Pharmacopoeia. Test solution: Take 10 tablets of this product, place them separately in a mortar, grind them finely, and grind them separately with approximately 35 ml of methanol in portions. Quantitatively transfer the powder to 50 ml volumetric flasks, sonicate to dissolve indomethacin, cool, dilute to the mark with methanol, shake well, filter, accurately measure 5 ml of the filtrate, place it in a 25 ml volumetric flask, dilute to the mark with 50% methanol solution, and shake well. Reference solution: Accurately weigh approximately 25 mg of indomethacin reference standard, place it in a 50 ml volumetric flask, add an appropriate amount of methanol, sonicate to dissolve, cool, dilute to the mark with methanol, shake well, accurately measure an appropriate amount, and quantitatively dilute with 50% methanol solution to prepare a solution containing approximately 0.1 mg per ml. Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase; 0.1 mol / L glacial acetic acid solution-acetonitrile (50:50) was used as the mobile phase; the detection wavelength was 228 nm; the injection volume was 20 µL. System suitability requirements: The theoretical plate number, calculated based on the indomethacin peak, should be no less than 2000, and the resolution between the indomethacin peak and adjacent impurity peaks should meet the requirements. Assay: Accurately measure the test solution and the reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the content per tablet based on peak area using the external standard method, and determine the average content.

[0095] Table 2. Indomethacin content in accelerated tests

[0096] Accelerated test conditions: temperature 40℃±2℃, relative humidity 75%±5%, 6 months.

[0097] Table 2 shows that under accelerated testing conditions of 40℃±2℃ and 75%±5% relative humidity for 6 months, the indomethacin tablets of Examples 1-3 of the present invention exhibited high retention rates of the main component content, small decreases in content, and excellent stability. The main component content of each comparative example showed a significant decrease, with the comparative example without the addition of the composite stabilizer showing the largest decrease. Replacing / omitting the composite stabilizer component, adjusting its addition method / ratio, and substituting a single component all led to a significant reduction in the chemical stability of the formulation under accelerated conditions, proving that the composite stabilizer formulation and addition method of the present invention are crucial for improving the accelerated stability of the formulation.

[0098] Table 3. Indomethacin content in long-term tests

[0099] Long-term test conditions: temperature 25℃±2℃, relative humidity 60%±10%, 12 months.

[0100] Table 3 shows that under the long-term test conditions of 25℃±2℃ and 60%±10% relative humidity for 12 months, the content of the main component of the indomethacin tablets in Examples 1-3 of the present invention remained at a high level. The content decreased slowly with the extension of storage time and the decrease was very small, indicating good long-term storage stability. The content of the main component in each comparative example showed a significant decreasing trend with the extension of storage time, which was much higher than the decrease in the examples. The formulation or process adjustment of each comparative example would impair the long-term storage stability of the preparation. This further verifies that the compounding ratio, component selection and addition process of the composite stabilizer of the present invention are the key factors to ensure the long-term stability of indomethacin tablets.

[0101] Indomethacin liposome inclusion complex drug loading and encapsulation efficiency

[0102] Drug loading determination

[0103] Drug loading refers to the percentage of indomethacin actually contained in the liposome inclusion complex relative to the total mass of the liposome inclusion complex.

[0104] Encapsulation efficiency determination

[0105] Free drug and encapsulated drug were separated by ultracentrifugation. Encapsulation efficiency refers to the percentage of encapsulated indomethacin mass relative to the total indomethacin mass in the liposome inclusion complex.

[0106] Table 4. Drug loading and encapsulation efficiency of indomethacin liposome inclusion complex

[0107] Table 4 shows that the indomethacin liposome inclusion complexes prepared in the embodiments of the present invention exhibit excellent performance in terms of drug loading and encapsulation efficiency, far superior to the comparative samples. Various formulation and process adjustments, such as not adding the composite stabilizer, replacing / omitting components of the composite stabilizer, adjusting its addition method, changing the compounding ratio, or using single-component substitution, all significantly reduce the drug loading and encapsulation efficiency of the indomethacin liposome inclusion complexes. This fully demonstrates that the specific compounding composition, ratio, and addition method of the composite stabilizer in the preparation stage of the liposome inclusion complex are key factors in improving the drug loading and encapsulation efficiency of the indomethacin liposome inclusion complex, effectively promoting efficient drug and excipient encapsulation and enhancing the drug loading capacity and encapsulation effect of the inclusion system.

Claims

1. An indomethacin tablet, characterized in that, By weight, it consists of the following components: 55-70 parts indomethacin, 50-70 parts hydroxypropyl β-cyclodextrin, 30-50 parts soybean lecithin, 5-8 parts composite stabilizer, 2-4 parts binder, and 2-4 parts lubricant; the composite stabilizer is a compound of sodium succinate sulfonate, N-ethyl-L-glutamine, and maltodextrin in a mass ratio of 1:2:

1.

2. The indomethacin tablet according to claim 1, characterized in that, The adhesive is selected from one or more of hydroxypropyl methylcellulose, polyvinylpyrrolidone, sodium carboxymethyl cellulose, and starch.

3. The indomethacin tablet according to claim 2, characterized in that, The adhesive is hydroxypropyl methylcellulose.

4. The indomethacin tablet according to claim 1, characterized in that, The lubricant is selected from one or more of magnesium stearate, micronized silica gel, sodium stearate fumarate, and talc.

5. The indomethacin tablet according to claim 4, characterized in that, The lubricant is a compound of magnesium stearate and micronized silica gel in a mass ratio of 1:

1.

6. A process for preparing indomethacin tablets as described in any one of claims 1 to 5, characterized in that, The preparation process includes the following steps: (1) Preparation of liposome inclusion complex: Hydroxypropyl β-cyclodextrin was prepared into a saturated aqueous solution at 55~60℃, and indomethacin micro powder passing through a 100-mesh sieve was added. The mixture was stirred at 500~600r / min for 30~40min to obtain a suspension inclusion solution. Soybean lecithin passing through an 80-mesh sieve and a composite stabilizer were added. After stirring and dispersing at 300r / min, the mixture was sheared and emulsified at 9000~10000r / min for 20~25min. After freeze-drying, the mixture was pulverized and passed through an 80-mesh sieve to obtain the liposome inclusion complex. (2) Mixing and granulation: After dry mixing of liposome inclusion complex, purified water and binder are sprayed in, stirred and granulated to obtain soft material, which is then passed through a 20-mesh sieve to obtain wet granules; (3) Drying and granulation: The wet granules are dried at an air inlet temperature of 55~60℃ and then granulated by passing them through an 18-mesh sieve; (4) Mixing and tableting: Add lubricant to dry granules and mix for 8-10 minutes, then compress to obtain the finished product.

7. The preparation process according to claim 6, characterized in that, In step (1), the preparation of the saturated aqueous solution of hydroxypropyl β-cyclodextrin involves adding 10 to 12 times the amount of purified water to the hydroxypropyl β-cyclodextrin, stirring at 400 to 450 r / min in a constant temperature water bath at 55 to 60°C until completely dissolved, and keeping it at 55°C for later use.

8. The preparation process according to claim 6, characterized in that, The freeze-drying parameters for step (1) are as follows: ① Pre-freezing: -45~-40℃ for 3~4h; ② Sublimation drying: vacuum degree ≤15Pa, temperature rise to 25~30℃, dry for 14~16h; ③ Desorption drying: vacuum degree ≤10Pa, 35℃ for 2~3h.

9. The preparation process according to claim 6, characterized in that, In step (2), the liposome inclusion complex is dry-mixed in a wet mixing granulator at 180-200 r / min for 5 min, then purified water and binder are sprayed in, and then granulated by stirring at 150 r / min for 8-10 min.

10. The preparation process according to claim 6, characterized in that, In step (4), the granulated dry particles are added to a three-dimensional motion mixer and mixed for 8 to 10 minutes at a speed of 90 to 100 r / min. After mixing, the particles are directly transferred to a rotary tablet press for tableting, and the tableting pressure is controlled at 8 to 12 MPa.

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