Sustained-release preparation of indobufen and its preparation method and application

Abstract

The application discloses a sustained-release preparation of indobufen and a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The application relates to a sustained-release preparation of indobufen and a preparation method and application thereof. The preparation has the characteristics of stable sustained-release effect, high bioavailability, good drug-taking compliance and small side effect, and is suitable for the prevention and / or treatment of diseases such as ischemic cardiovascular diseases, ischemic cerebrovascular diseases and venous thrombosis.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to an indobufen sustained-release formulation, its preparation method, and its application. Background Technology

[0002] Indobufen is a novel antiplatelet aggregation drug that inhibits platelet cyclooxygenase and reduces the production of thromboxane A2, thereby inhibiting platelet aggregation. It also reduces platelet adhesion and improves blood rheology. Clinically, it is widely used to treat ischemic cardiovascular disease, ischemic cerebrovascular disease, venous thrombosis, lipid metabolism disorders, diabetes, and to prevent thrombosis during cardiopulmonary bypass surgery.

[0003] Currently, most indobufen preparations on the market are immediate-release formulations such as ordinary tablets and capsules. These preparations release the drug rapidly after administration, causing a rapid increase in blood drug concentration, which can easily lead to excessively high peak values. This may irritate the gastrointestinal tract and cause adverse reactions such as nausea, vomiting, and stomach discomfort. At the same time, the blood drug concentration of immediate-release preparations fluctuates greatly, and the time to maintain an effective blood drug concentration is relatively short, requiring multiple daily doses. This results in poor patient adherence, especially for elderly patients or those who take medication long-term, with a higher risk of missed or incorrect doses, affecting the treatment effect.

[0004] To address these issues, sustained-release formulations have become a research hotspot. Sustained-release formulations enable the slow and stable release of drugs, avoiding drastic fluctuations in blood drug concentration, prolonging the duration of effective blood drug concentration, reducing the frequency of dosing, improving patient adherence, and simultaneously reducing local irritation to the gastrointestinal tract. However, indobufen itself has poor solubility, making it difficult for conventional sustained-release formulations to achieve the desired sustained-release effect. Either the release is too rapid to achieve a long-lasting effect, or the release is too slow, resulting in delayed onset of action, failing to meet clinical needs. Furthermore, some sustained-release formulations are prepared using organic solvents, posing a risk of residue, and their complex processes and high costs hinder large-scale industrial production.

[0005] Therefore, developing a micronized indobufen sustained-release formulation with stable sustained-release effect, rapid onset of action, high bioavailability, simple preparation process, low cost, and high safety has important clinical significance and market value. Summary of the Invention

[0006] The purpose of this invention is to address the shortcomings of existing indobufen formulations, such as large fluctuations in blood drug concentration, significant adverse reactions, poor medication adherence, and the lack of sustained-release formulations. This invention provides an indobufen sustained-release formulation, its preparation method, and its application. This formulation uses micronization technology to improve the solubility of indobufen and, with a specific combination of excipients, achieves slow and stable drug release, balancing onset speed and long-lasting effect. At the same time, the preparation process is simple, leaves no organic solvent residue, and is suitable for large-scale industrial production.

[0007] The present invention discloses an indobufen sustained-release formulation comprising: an active pharmaceutical ingredient, a sustained-release material, a blank pellet core, a surfactant, a binder, and a lubricant, wherein the active pharmaceutical ingredient is indobufen or a pharmaceutically acceptable salt thereof, and the sustained-release material is selected from one or a combination of two of hydroxypropyl methylcellulose and dimethyl silicone oil / simethicone oil.

[0008] The sustained-release formulation of indobufen according to the present invention is characterized in that the average particle size of the indobufen after micronization is 3-8 μm.

[0009] The indobufen sustained-release formulation of the present invention is characterized in that the blank pellet core is selected from one or more of the following: sucrose pellet core, microcrystalline cellulose pellet core, starch pellet core, mannitol pellet core, xylitol pellet core, sodium carboxymethyl cellulose / hydroxypropyl methyl cellulose pellet core, calcium carbonate pellet core, calcium hydrogen phosphate pellet core, and silica pellet core; the blank pellet core is preferably a sucrose pellet core; preferably, the particle size of the sucrose pellet core is 200-600 μm, more preferably 400-500 μm.

[0010] The indobufen sustained-release formulation of the present invention is characterized in that the hydroxypropyl methylcellulose is selected from one or more of HPMC E3 or HPMC K100, and one or more of dimethyl silicone oil / simethicone oil; the content of the sustained-release material in the formulation is 1% to 40%; preferably, the sustained-release material is HPMC E3 and HPMC K100, and the weight ratio of the two is 1 to 20: 1 to 20, preferably 5: 1; or, the sustained-release material is dimethyl silicone oil / simethicone oil; or, the sustained-release material is dimethyl silicone oil / simethicone oil, and the weight ratio of the two is 1 to 30: 1 to 30, preferably 10: 1.

[0011] The indobufen sustained-release formulation of the present invention is characterized in that the binder is selected from one or more of the following: water, ethanol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium microcrystalline cellulose or acrylic resin; the content of the binder in the formulation is 0.1% to 20%, preferably 10% to 15%; more preferably, the binder is HPMC E3.

[0012] The indobufen sustained-release formulation of the present invention is characterized in that the lubricant is selected from one or more of the following: talc, magnesium stearate, colloidal silica, polyethylene glycol, or magnesium lauryl sulfate. The content of the lubricant in the formulation is 0.1% to 3%, preferably 1% to 2%; more preferably, the lubricant is talc.

[0013] The indobufen sustained-release formulation of the present invention is characterized in that the surfactant is selected from one or more of the following: sodium lauryl sulfate, sodium stearate, sodium cholate, sodium deoxycholate, benzalkonium chloride, benzalkonium bromide, chlorhexidine, lecithin, Tween derivatives, Span derivatives, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, sucrose fatty acid esters, and glyceryl monostearate. The surfactant content in the formulation is 0.1% to 10%, preferably 2% to 4%; more preferably, the surfactant is sodium lauryl sulfate.

[0014] The indobufen sustained-release formulation of the present invention is characterized in that the in vitro release curve of the sustained-release formulation conforms to the following characteristics (measured using the second method of General Chapter 0931 of the Chinese Pharmacopoeia, Part IV, with 1000 mL of pH 7.6 phosphate buffer as solvent, a rotation speed of 75 rpm, and a temperature of 37°C): after 1 hour, at least 15% of indobufen is released; after 4 hours, about 40% to 60% of indobufen is released; after 8 hours, about 60% to 80% of indobufen is released; and after 12 hours, at least 85% of indobufen is released.

[0015] The method for preparing the indobufen sustained-release formulation of the present invention is characterized by comprising the following steps:

[0016] (1) Pretreatment: Micronized indobufen, sodium dodecyl sulfate and talc are passed through an 80-mesh sieve, and sucrose pellet cores are passed through a 40-60 mesh sieve for later use;

[0017] (2) Preparation of adhesive solution: Take hydroxypropyl methylcellulose E3, add purified water, stir until completely dissolved, and prepare an 8% (w / w) aqueous solution of hydroxypropyl methylcellulose E3 for later use;

[0018] (3) Preparation of drug-containing solution: Mix micronized indobufen, sodium dodecyl sulfate and some talc powder evenly, add to the binder solution, then add dimethyl silicone oil and / or simethicone oil, mix evenly and set aside;

[0019] (4) Preparation of drug-containing microcapsules: Add sucrose pellet cores to a fluidized bed coating machine, set the inlet air temperature to 45-50℃, the outlet air temperature to 30-35℃, the air velocity to 2.0-2.5m / s, and the atomization pressure to 0.2-0.3MPa; spray the drug-containing solution into the fluidized bed to coat the sucrose pellet cores, control the coating speed to 5g / min, until the solution completely coats the surface of the sucrose pellet cores to obtain drug-containing microcapsules;

[0020] (5) Preparation of sustained-release coating solution: Take hydroxypropyl methylcellulose K100 and some talc powder, add purified water, stir until uniformly dispersed, and set aside;

[0021] (6) Sustained-release coating: Place the drug-containing microcapsules in a fluidized bed coating machine, maintain the above process parameters, spray the sustained-release coating liquid from the bottom, control the coating speed at 3g / min, and dry for 15-20min after coating to obtain sustained-release microcapsules;

[0022] (7) Capsule filling: Calculate the filling amount based on 0.2g of indobufen per capsule, add the indobufen sustained-release microspheres into the capsule filling machine, and fill them into gelatin capsules to obtain indobufen sustained-release capsules.

[0023] The indobufen sustained-release formulation described in this invention can be used to prevent and / or treat ischemic cardiovascular disease, ischemic cerebrovascular disease, venous thrombosis, lipid metabolism disorders, diabetes, and to prevent thrombosis during extracorporeal circulation surgery.

[0024] The indobufen sustained-release formulation of the present invention is characterized in that the sustained-release formulation is administered orally, once daily, 1 to 2 tablets each time.

[0025] Compared with the prior art, the present invention has the following significant advantages:

[0026] 1. Stable sustained-release effect, balancing onset and long-lasting effect: This invention uses micronization technology to improve the solubility of indobufen, and combines it with dimethyl silicone oil / simethicone oil as a sustained-release material. Combined with a specific ratio of excipients, it achieves slow and stable drug release, with rapid onset of action in 1 hour and effective blood drug concentration maintained for 12 hours. It only needs to be administered once a day, which significantly improves patient medication compliance and solves the problems of frequent dosing and large fluctuations in blood drug concentration of conventional immediate-release formulations.

[0027] 2. High bioavailability: Micronization increases the specific surface area of ​​indobufen, and when combined with sodium dodecyl sulfate as a surfactant, it effectively improves the solubility and dissolution rate of the drug. At the same time, the outer coating protects the drug from being destroyed by gastric acid, thus improving the absorption efficiency of the drug in the intestine.

[0028] 3. Fewer adverse reactions: The slow release of the drug avoids the stimulation of the gastrointestinal tract caused by excessively high peak blood drug concentration. At the same time, talcum powder, as a lubricant, reduces the problem of excessively high local drug concentration caused by micro-pellet adhesion. In clinical applications, the incidence of adverse reactions such as nausea and stomach discomfort is reduced by more than 60% compared with conventional preparations.

[0029] 4. Simple, safe and controllable preparation process: The fluidized bed coating technology is adopted, and purified water is used as the solvent throughout the process, with no organic solvent residue, resulting in high safety; the process parameters are clear and controllable, with good reproducibility and low production cost, making it suitable for large-scale industrial production;

[0030] 5. Good formulation stability: Through reasonable excipient combination and coating design, the formulation can be stored for 6 months at a temperature of 40℃±2℃ and a relative humidity of 75%±5%, and the drug content and in vitro release curve do not change significantly, indicating good stability and easy storage and transportation.

[0031] It should be noted that, in order to enable those skilled in the art to more clearly understand the inventive content and technical connotation of this invention, the inventors of this invention provide the following explanations regarding the technical terms, symbols, reagents, consumables, and instruments used:

[0032] "0 days": refers to the time when sample preparation was completed;

[0033] "Long-term conditions" refer to a temperature of 30℃±2℃ and a relative humidity of 65%±5%.

[0034] "Acceleration conditions" refer to a temperature of 40℃±2℃ and a relative humidity of 75%±5%. Detailed Implementation

[0035] The present invention will now be described through specific embodiments. Unless otherwise specified, all technical means used in this invention are methods well known to those skilled in the art. Furthermore, the embodiments should be understood as illustrative, not limiting the scope of the invention; the essence and scope of the invention are defined only by the claims. For those skilled in the art, various changes or modifications to the material composition and dosage in these embodiments without departing from the essence and scope of the invention are also within the scope of protection of this invention. All raw materials and reagents used in this invention are commercially available.

[0036] In this embodiment, the dissolution determination method is as follows: referring to the second method of General Chapter 0931 of the Chinese Pharmacopoeia, 1000 mL of pH 7.6 phosphate buffer solution is used as solvent, the rotation speed is 75 rpm, the temperature is 37°C, samples are taken at the set time points, filtered, and the absorbance is measured at 279 nm using an ultraviolet spectrophotometer to calculate the amount of drug dissolved at different times.

[0037] To facilitate understanding of the present invention by those skilled in the art, the present invention provides the following specific embodiments to further illustrate the convenient medication for patients to take and its preparation method:

[0038] Example 1

[0039]

[0040] Preparation method:

[0041] (1) Pretreatment: Micronized indobufen (average particle size 5μm), sodium dodecyl sulfate and talc are passed through an 80-mesh sieve and set aside; sucrose pellet cores are passed through a 40-60 mesh sieve and pellet cores with a particle size of 400-500μm are selected and set aside.

[0042] (2) Preparation of adhesive solution: Take 400g of hydroxypropyl methylcellulose E3, add 5L of purified water, stir until completely dissolved, and prepare an 8% (w / w) aqueous solution of hydroxypropyl methylcellulose E3 for later use;

[0043] (3) Preparation of drug-containing solution: Mix 2kg of micronized indobufen, 100g of sodium dodecyl sulfate and 20g of talc evenly, add it to the binder solution, then add 10g of dimethyl silicone oil and 1g of simethicone oil, mix evenly and set aside.

[0044] (4) Preparation of drug-containing microcapsules: 500g of sucrose pellet cores were added to a fluidized bed coating machine. The fluidized bed inlet air temperature was set to 48℃, the outlet air temperature to 32℃, the air velocity to 2.2m / s, and the atomization pressure to 0.25MPa. The drug-containing solution was sprayed into the fluidized bed using a bottom spray method to coat the sucrose pellet cores. The coating speed was controlled at 5g / min until the solution completely covered the surface of the sucrose pellet cores to obtain drug-containing microcapsules.

[0045] (5) Preparation of sustained-release coating solution: Take 80g of hydroxypropyl methylcellulose K100 and 30g of talc powder, add 1L of purified water, stir until uniformly dispersed, and prepare an outer coating solution with a solid content of 11% for later use;

[0046] (6) Sustained-release coating: The drug-containing microcapsules are placed in a fluidized bed coating machine. The inlet air temperature is maintained at 48℃, the outlet air temperature at 32℃, the air velocity at 2.2m / s, and the atomization pressure at 0.25MPa. The sustained-release coating liquid is sprayed into the fluidized bed using a bottom spray method. The coating speed is controlled at 3g / min. After coating is completed, the microcapsules are dried for 18min to obtain indobufen sustained-release microcapsules.

[0047] (7) Capsule filling: The filling amount is calculated based on 0.2g of indobufen per capsule. The filling amount per capsule is 314.1mg. The indobufen sustained-release microspheres are added to the capsule filling machine and filled into No. 1 gelatin capsules to obtain indobufen sustained-release capsules.

[0048] Example 2

[0049]

[0050] Preparation method:

[0051] (1) Pretreatment: Micronized indobufen (average particle size 8μm), sodium dodecyl sulfate and talc are passed through an 80-mesh sieve and set aside; sucrose pellet cores are sieved and pellet cores with a particle size of 500μm are selected and set aside.

[0052] (2) Preparation of adhesive solution: Take 500g of hydroxypropyl methylcellulose E3, add 5L of purified water, stir until completely dissolved, and prepare an aqueous solution of hydroxypropyl methylcellulose E3 with a mass concentration of 10% for later use;

[0053] (3) Preparation of drug-containing solution: Mix 2kg of micronized indobufen, 120g of sodium dodecyl sulfate and 20g of talc powder evenly, add to the binder solution, then add 10g of dimethyl silicone oil, mix evenly and set aside.

[0054] (4) Preparation of drug-containing microcapsules: 700g of prepared sucrose pellet cores were added to a fluidized bed coating machine. The fluidized bed inlet air temperature was set to 48℃, the outlet air temperature to 32℃, the air velocity to 2.2m / s, and the atomization pressure to 0.25MPa. The drug-containing solution was sprayed into the fluidized bed using a bottom spray method to coat the sucrose pellet cores. The coating speed was controlled at 5g / min until the solution completely covered the surface of the sucrose pellet cores to obtain drug-containing microcapsules.

[0055] (5) Preparation of sustained-release coating solution: Take 100g of hydroxypropyl methylcellulose K100 and 30g of talc powder, add 1L of purified water, stir until uniformly dispersed, and prepare an outer coating solution with a solid content of 13% for later use;

[0056] (6) Sustained-release coating: The drug-containing microcapsules are placed in a fluidized bed coating machine. The inlet air temperature is maintained at 48℃, the outlet air temperature at 32℃, the air velocity at 2.2m / s, and the atomization pressure at 0.25MPa. The sustained-release coating liquid is sprayed into the fluidized bed using a bottom spray method. The coating speed is controlled at 3g / min. After coating is completed, the microcapsules are dried for 18min to obtain indobufen sustained-release microcapsules.

[0057] (7) Capsule filling: The filling amount is calculated based on 0.2g of indobufen per capsule. The filling amount per capsule is 348.0mg. Indobufen sustained-release microspheres are added to the capsule filling machine and filled into No. 0 gelatin capsules to obtain indobufen sustained-release capsules.

[0058] Example 3

[0059]

[0060] Preparation method:

[0061] (1) Pretreatment: Micronized indobufen (average particle size 5μm), sodium dodecyl sulfate, dimethyl silicone oil and talc are passed through an 80-mesh sieve and set aside; sucrose pellet cores are sieved and pellet cores with a particle size of 400μm are selected and set aside.

[0062] (2) Preparation of adhesive solution: Take 400g of hydroxypropyl methylcellulose E3, add 5L of purified water, stir until completely dissolved, and prepare an 8% (w / w) aqueous solution of hydroxypropyl methylcellulose E3 for later use;

[0063] (3) Preparation of drug-containing solution: Mix 2kg of micronized indobufen, 80g of sodium dodecyl sulfate and 20g of talc powder evenly, add to the adhesive solution, then add 1g of simethicone oil, mix evenly and set aside.

[0064] (4) Preparation of drug-containing microcapsules: 400g of sucrose pellet cores were added to a fluidized bed coating machine. The fluidized bed inlet air temperature was set to 48℃, the outlet air temperature to 32℃, the air velocity to 2.2m / s, and the atomization pressure to 0.25MPa. The drug-containing solution was sprayed into the fluidized bed using a bottom spray method to coat the sucrose pellet cores. The coating speed was controlled at 5g / min until the solution completely covered the surface of the sucrose pellet cores to obtain drug-containing microcapsules.

[0065] (5) Preparation of sustained-release coating solution: Take 60g of hydroxypropyl methylcellulose K100 and 20g of talc powder, add 1L of purified water, stir until uniformly dispersed, and prepare an outer coating solution with a solid content of 8% for later use;

[0066] (6) Sustained-release coating: The drug-containing microcapsules are placed in a fluidized bed coating machine. The inlet air temperature is maintained at 48℃, the outlet air temperature at 32℃, the air velocity at 2.2m / s, and the atomization pressure at 0.25MPa. The sustained-release coating liquid is sprayed into the fluidized bed using a bottom spray method. The coating speed is controlled at 3g / min. After coating is completed, the microcapsules are dried for 18min to obtain indobufen sustained-release microcapsules.

[0067] (7) Capsule filling: The filling amount is calculated based on 0.2g of indobufen per capsule. The filling amount per capsule is 299.0mg. Indobufen sustained-release microspheres are added to the capsule filling machine and filled into No. 1 gelatin capsules to obtain indobufen sustained-release capsules.

[0068] Example 4

[0069]

[0070] Preparation method:

[0071] (1) Pretreatment: Micronized indobufen (average particle size 5μm), sodium dodecyl sulfate and talc are passed through an 80-mesh sieve and set aside; sucrose pellet cores are passed through a 40-60 mesh sieve and pellet cores with a particle size of 400-500μm are selected and set aside.

[0072] (2) Preparation of adhesive solution: Take 400g of hydroxypropyl methylcellulose E5, add 5L of purified water, stir until completely dissolved, and prepare an 8% (w / w) aqueous solution of hydroxypropyl methylcellulose E5 for later use;

[0073] (3) Preparation of drug-containing solution: Mix 2kg of micronized indobufen, 100g of sodium dodecyl sulfate and 20g of talc evenly, add it to the binder solution, then add 10g of dimethyl silicone oil and 1g of simethicone oil, mix evenly and set aside.

[0074] (4) Preparation of drug-containing microcapsules: 500g of sucrose pellet cores were added to a fluidized bed coating machine. The fluidized bed inlet air temperature was set to 48℃, the outlet air temperature to 32℃, the air velocity to 2.2m / s, and the atomization pressure to 0.25MPa. The drug-containing solution was sprayed into the fluidized bed using a bottom spray method to coat the sucrose pellet cores. The coating speed was controlled at 5g / min until the solution completely covered the surface of the sucrose pellet cores to obtain drug-containing microcapsules.

[0075] (5) Preparation of sustained-release coating solution: Take 80g of hydroxypropyl methylcellulose K100 and 30g of talc powder, add 1L of purified water, stir until uniformly dispersed, and prepare an outer coating solution with a solid content of 11% for later use;

[0076] (6) Sustained-release coating: The drug-containing microcapsules are placed in a fluidized bed coating machine. The inlet air temperature is maintained at 48℃, the outlet air temperature at 32℃, the air velocity at 2.2m / s, and the atomization pressure at 0.25MPa. The sustained-release coating liquid is sprayed into the fluidized bed using a bottom spray method. The coating speed is controlled at 3g / min. After coating is completed, the microcapsules are dried for 18min to obtain indobufen sustained-release microcapsules.

[0077] (7) Capsule filling: The filling amount is calculated based on 0.2g of indobufen per capsule. The filling amount per capsule is 314.1mg. The indobufen sustained-release microspheres are added to the capsule filling machine and filled into No. 1 gelatin capsules to obtain indobufen sustained-release capsules.

[0078] Example 5

[0079]

[0080] Preparation method:

[0081] (1) Pretreatment: Micronized indobufen (average particle size 3μm), sodium dodecyl sulfate and talc are passed through an 80-mesh sieve and set aside; sucrose pellet cores are passed through a 40-60 mesh sieve and pellet cores with a particle size of 400-500μm are selected and set aside.

[0082] (2) Preparation of adhesive solution: Take 400g of hydroxypropyl methylcellulose E3, add 5L of purified water, stir until completely dissolved, and prepare an 8% (w / w) aqueous solution of hydroxypropyl methylcellulose E3 for later use;

[0083] (3) Preparation of drug-containing solution: Mix 2kg of micronized indobufen, 100g of sodium dodecyl sulfate and 20g of talc evenly, add it to the binder solution, then add 10g of dimethyl silicone oil and 1g of simethicone oil, mix evenly and set aside.

[0084] (4) Preparation of drug-containing microcapsules: 500g of sucrose pellet cores were added to a fluidized bed coating machine. The fluidized bed inlet air temperature was set to 48℃, the outlet air temperature to 32℃, the air velocity to 2.2m / s, and the atomization pressure to 0.25MPa. The drug-containing solution was sprayed into the fluidized bed using a bottom spray method to coat the sucrose pellet cores. The coating speed was controlled at 5g / min until the solution completely covered the surface of the sucrose pellet cores to obtain drug-containing microcapsules.

[0085] (5) Preparation of sustained-release coating solution: Take 80g of hydroxypropyl methylcellulose K4M and 30g of talc powder, add 1L of purified water, stir until uniformly dispersed, and prepare an outer coating solution with a solid content of 11% for later use;

[0086] (6) Sustained-release coating: The drug-containing microcapsules are placed in a fluidized bed coating machine. The inlet air temperature is maintained at 48℃, the outlet air temperature at 32℃, the air velocity at 2.2m / s, and the atomization pressure at 0.25MPa. The sustained-release coating liquid is sprayed into the fluidized bed using a bottom spray method. The coating speed is controlled at 3g / min. After coating is completed, the microcapsules are dried for 18min to obtain indobufen sustained-release microcapsules.

[0087] (7) Capsule filling: The filling amount is calculated based on 0.2g of indobufen per capsule. The filling amount per capsule is 314.1mg. The indobufen sustained-release microspheres are added to the capsule filling machine and filled into No. 1 gelatin capsules to obtain indobufen sustained-release capsules.

[0088] Test Example 1

[0089] Dissolution test

[0090] The dissolution data of the samples in each example at 1 hour, 4 hours, 8 hours, and 12 hours are as follows:

[0091]

[0092] Test Example 2

[0093] Example 1: Stability data under accelerated conditions

[0094]

[0095] Security test

[0096] Thirty healthy SD rats were randomly divided into three groups of 10 rats each: a blank control group (physiological saline), an experimental group (the formulation of this invention, dose 400 mg / kg), and a control group (commercially available ordinary tablets, dose 400 mg / kg). The rats were administered the drug by gavage once daily for 14 consecutive days. The general condition and weight changes of the rats were observed. After the drug administration was completed, the rats' complete blood count and liver and kidney function were measured. The results are as follows:

[0097] (1) General condition: No rats in the blank control group, experimental group and control group died, their mental state was good, their diet and water intake were normal, and there was no obvious abnormal behavior; no gastrointestinal irritation-related symptoms (such as diarrhea, vomiting, etc.) were observed in the experimental group, while 2 rats in the control group had mild diarrhea.

[0098] (2) Changes in body weight: The body weight of rats in all three groups showed a steady increasing trend, and there was no significant difference between the groups (P>0.05).

[0099] (3) Blood routine and liver and kidney function: The blood routine (white blood cells, red blood cells, platelets, etc.) and liver and kidney function (ALT, AST, BUN, Cr, etc.) indicators of the three groups of rats were all within the normal range, and there was no significant difference between the groups (P>0.05).

[0100] Test results show that the micronized indobufen sustained-release formulation prepared in this embodiment has high safety, no obvious toxicity, and significantly less gastrointestinal irritation than ordinary tablets.

[0101] Comparative Example 1: Indobufen sustained-release formulation without micronization

[0102] Except for replacing the micronized indobufen with ordinary indobufen (average particle size 50 μm), the rest of the formulation and preparation method were the same as in Example 1. A non-micronized indobufen sustained-release formulation was prepared, and in vitro dissolution testing was performed. The results are as follows:

[0103] The cumulative dissolution rate was 5.3±0.8% after 1 hour, 28.6±1.5% after 4 hours, and 65.2±2.1% after 12 hours. The release rate was slow and the onset of action was delayed, which could not meet the needs of clinical drug use.

[0104] These comparative examples demonstrate that micronization significantly improves the solubility and dissolution rate of indobufen, thereby enhancing its bioavailability. This is key to achieving the ideal sustained-release effect and high bioavailability of the formulation of this invention.

[0105] Comparative Example 2: Indobufen sustained-release formulation without sodium lauryl sulfate

[0106] Except for the absence of sodium dodecyl sulfate, the formulation and preparation method were identical to those in Example 1. An indobufen sustained-release formulation without surfactant was prepared, and in vitro dissolution testing was performed. The results are as follows:

[0107] The cumulative dissolution rate was 8.9±1.0% after 1 hour, 35.7±1.7% after 4 hours, and 72.3±2.2% after 12 hours, indicating a slow release rate and delayed onset of action.

[0108] This comparative example demonstrates that sodium dodecyl sulfate, as a surfactant, can further improve the solubility and dissolution rate of micronized indobufen, and work synergistically with micronization technology to ensure the onset of action and high bioavailability of the formulation.

[0109] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. An indobufen sustained-release formulation, comprising: an active pharmaceutical ingredient, a sustained-release material, a blank pellet core, a surfactant, a binder, and a lubricant, wherein, The active pharmaceutical ingredient is indobufen or a pharmaceutically acceptable salt thereof, and the sustained-release material is selected from one or a combination of two of hydroxypropyl methylcellulose and dimethyl silicone oil / simethicone oil.

2. The indobufen sustained-release formulation according to claim 1, characterized in that, The average particle size of the indobufen after micronization is 3-8 μm.

3. The indobufen sustained-release formulation according to claim 1, characterized in that, The blank pellet core is selected from one or more of the following: sucrose pellet core, microcrystalline cellulose pellet core, starch pellet core, mannitol pellet core, xylitol pellet core, sodium carboxymethyl cellulose / hydroxypropyl methyl cellulose pellet core, calcium carbonate pellet core, calcium hydrogen phosphate pellet core, and silica pellet core; the blank pellet core is preferably sucrose pellet core; the particle size of the sucrose pellet core is preferably 200-600 μm, more preferably 400-500 μm.

4. The indobufen sustained-release formulation according to claim 1, characterized in that, The sustained-release material contains hydroxypropyl methylcellulose selected from one or more of HPMC E3 or HPMC K100, and the sustained-release material contains one or more of dimethyl silicone oil / simethicone; the content of the sustained-release material in the formulation is 1% to 40%; preferably, the sustained-release material is HPMC E3 and HPMC K100, with a weight ratio of 1 to 20:1 to 20, more preferably 5:1; the sustained-release material is dimethyl silicone oil / simethicone; the sustained-release material is dimethyl silicone oil / simethicone, with a weight ratio of 1 to 30:1 to 30, more preferably 10:

1.

5. The indobufen sustained-release formulation as described in claim 1, characterized in that, The adhesive is selected from one or more of the following: water, ethanol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, sodium microcrystalline cellulose, or acrylic resin; the content of the adhesive in the formulation is 0.1% to 20%, preferably 10% to 15%; more preferably, the adhesive is HPMC E3.

6. The indobufen sustained-release formulation as described in claim 1, characterized in that, The lubricant is selected from one or more of the following: talc, magnesium stearate, colloidal silica, polyethylene glycol, or magnesium lauryl sulfate. The lubricant content in the formulation is 0.1% to 3%, preferably 1% to 2%; more preferably, the lubricant is talc.

7. The indobufen sustained-release formulation as described in claim 1, characterized in that, The surfactant is selected from one or more of the following: sodium dodecyl sulfate, sodium stearate, sodium cholate, sodium deoxycholate, benzalkonium chloride, benzalkonium bromide, chlorhexidine, lecithin, Tween derivatives, Span derivatives, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, poloxamer, sucrose fatty acid esters, and glyceryl monostearate. The surfactant content in the formulation is 0.1% to 10%, preferably 2% to 4%; more preferably, the surfactant is sodium dodecyl sulfate.

8. The indobufen sustained-release formulation according to claim 1, characterized in that, The in vitro release curve of the sustained-release formulation conforms to the following characteristics (measured using Method II of General Chapter 0931 of the Chinese Pharmacopoeia, Part IV, with 1000 mL of pH 7.6 phosphate buffer as solvent, a rotation speed of 75 rpm, and a temperature of 37°C): after 1 hour, at least 15% of indobufen is released; after 4 hours, approximately 40% to 60% of indobufen is released; after 8 hours, approximately 60% to 80% of indobufen is released; and after 12 hours, at least 85% of indobufen is released.

9. A method for preparing an indobufen sustained-release formulation according to any one of claims 1 to 7, characterized in that, Includes the following steps: (1) Pretreatment: Micronized indobufen, sodium dodecyl sulfate and talc are passed through an 80-mesh sieve, and sucrose pellet cores are passed through a 40-60 mesh sieve for later use; (2) Preparation of adhesive solution: Take hydroxypropyl methylcellulose E3, add purified water, stir until completely dissolved, and prepare an 8% (w / w) aqueous solution of hydroxypropyl methylcellulose E3 for later use; (3) Preparation of drug-containing solution: Mix micronized indobufen, sodium dodecyl sulfate and some talc powder evenly, add to the binder solution, then add dimethyl silicone oil and / or simethicone oil, mix evenly and set aside; (4) Preparation of drug-containing microcapsules: Add sucrose pellet cores to a fluidized bed coating machine, set the inlet air temperature to 45-50℃, the outlet air temperature to 30-35℃, the air velocity to 2.0-2.5m / s, and the atomization pressure to 0.2-0.3MPa; spray the drug-containing solution into the fluidized bed to coat the sucrose pellet cores, control the coating speed to 5g / min, until the solution completely coats the surface of the sucrose pellet cores to obtain drug-containing microcapsules; (5) Preparation of sustained-release coating solution: Take hydroxypropyl methylcellulose K100 and some talc powder, add purified water, stir until uniformly dispersed, and set aside; (6) Sustained-release coating: Place the drug-containing microcapsules in a fluidized bed coating machine, maintain the above process parameters, spray the sustained-release coating liquid from the bottom, control the coating speed at 3g / min, and dry for 15-20min after coating to obtain sustained-release microcapsules; (7) Capsule filling: Calculate the filling amount based on 0.2g of indobufen per capsule, add the indobufen sustained-release microspheres into the capsule filling machine, and fill them into gelatin capsules to obtain indobufen sustained-release capsules.

10. An indobufen sustained-release formulation according to any one of claims 1 to 9, which can be used for the prevention and / or treatment of ischemic cardiovascular disease, ischemic cerebrovascular disease, venous thrombosis, lipid metabolism disorders, diabetes, and prevention of thrombosis during cardiopulmonary bypass surgery.

11. The indobufen sustained-release formulation according to claim 10, characterized in that, The sustained-release formulation is administered orally, once daily, 1-2 tablets each time.

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