Oxapyrazine capsule and preparation method thereof

Abstract

The invention discloses a preparation method of an oxapyrazine capsule, which comprises the following steps: 1) preparing a primary suspension: dissolving a polymer carrier material in an organic solvent, and dissolving oxapyrazine in the solution to obtain an oil phase; adding a surfactant into the purified water to obtain a water phase; dropwise adding the oil phase into the water phase, and stirring by using a stirrer to prepare a primary suspension; 2) preparing a nano suspension: performing emulsification treatment by an ultrasonic processor to prepare the nano suspension; removing the organic solvent in a manner of reduced pressure evaporation or dialysis with a dialysis membrane to leave an oxapyrazine nanoparticle suspension; 3) preparation of the oxapyrazine capsule: drying the nano suspension prepared in the step 2) by a freeze drying method or a spray drying method to obtain oxapyrazine nano particles in a solid powder form, and the final average particle size is 300 + / -60nm; and filling a capsule shell with the prepared oxapyrazine nanoparticle powder to prepare the oxapyrazine capsule. The sustained release time of the oxapyrazine capsule prepared by the method is obviously prolonged.

Description

Technical Field

[0001] This application pertains to pharmaceutical technology, specifically an oxymethopyrazine capsule. Background Technology

[0002] Oxyphenidyl is a medication used to treat hyperlipidemia, belonging to the lipid-lowering drug category. This drug is primarily used to treat different types of hyperlipidemia, such as hypertriglyceridemia, hypercholesterolemia, and hypertriglyceridemia combined with hypercholesterolemia. It can lower levels of total cholesterol, triglycerides, low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) in the blood, and may increase high-density lipoprotein (HDL) levels.

[0003] The main ingredient of oxymetapyrazine capsules is oxymetapyrazine, chemically known as 5-methylpyrazine-2-carboxylic acid-4-oxide, with the molecular formula C6H6N2O3 and a molecular weight of 154.13. It is usually taken orally at a dose of 0.25g, 2-3 times daily, after meals. For critically ill patients, the doctor may adjust the dosage based on plasma triglyceride and cholesterol levels, but the total daily dose should not exceed 1.2g. After oral administration, the blood concentration of oxymetapyrazine capsules typically reaches its peak within a short period (e.g., 1-1.5 hours), and its half-life is relatively short (e.g., 1.5 to 2 hours). Oxymetapyrazine is absorbed after ingestion and excreted unchanged in the urine. This necessitates multiple daily doses to maintain its lipid-lowering effect. However, the metabolism and excretion of the drug in the body mainly depend on the liver and kidneys. Multiple doses, especially in patients with liver dysfunction, pose a risk of liver and kidney damage. Therefore, achieving a slow release of oxymetapyrazine capsules is a problem that needs to be addressed.

[0004] In CN1395927A, the sustained-release time of oxymethopyrazine capsules was extended to 8 hours by adjusting the formulation and preparation process; CN101732285A further extended the sustained-release time of oxymethopyrazine capsules to 12 hours; there is still room for optimization in the sustained-release time of oxymethopyrazine capsules. Summary of the Invention

[0005] This application provides an oxymethiprazine capsule and its preparation method, which significantly prolongs the sustained-release time of the oxymethiprazine capsule.

[0006] A method for preparing oxymethopyrazine capsules, comprising:

[0007] 1) Preparation of initial suspension: Dissolve the polymeric carrier material in an appropriate amount of organic solvent, and dissolve oxymethopyrazine in the above solution to obtain an oil phase; add the surfactant to purified water to obtain an aqueous phase; add the oil phase dropwise to the aqueous phase while stirring with a stirrer to obtain an initial suspension;

[0008] 2) Preparation of nano-suspension: Emulsification is performed using an ultrasonic processor to obtain nano-suspension; organic solvent is removed by vacuum evaporation or dialysis membrane, leaving oxymethipazine nanoparticle suspension;

[0009] 3) Preparation of oxymethopyrazine capsules: The nano-suspension obtained in step 2) is dried by freeze-drying or spray drying to obtain oxymethopyrazine nanoparticles in solid powder form with a final average particle size of 300±60nm; the obtained oxymethopyrazine nanoparticle powder is filled into capsule shells to obtain oxymethopyrazine capsules.

[0010] In one specific embodiment of the present invention, the ratio of oxymethopyrazine to polymeric carrier material is 1:5 to 1:9.

[0011] In one specific embodiment of the present invention, the ratio of oxymethopyrazine to polymeric carrier material is 1:7.

[0012] In one specific embodiment of the present invention, the frequency of the ultrasonic processor performing emulsification in step 2) is 400-600W.

[0013] In one specific embodiment of the present invention, the emulsification process performed by the ultrasonic processor in step 2) takes 25-45 minutes.

[0014] In one specific embodiment of the present invention, the amount of surfactant added is 0.8 to 1.5% based on the mass of the oxymethopyrazine nanoparticles.

[0015] In one specific embodiment of the present invention, the polymer carrier material may be one or more of polylactic acid-glycolic acid copolymer, polylactic acid (PLA), and polyethylene glycol (PEG).

[0016] In one specific embodiment of the present invention, the organic solvent is ethyl acetate.

[0017] In one specific embodiment of the present invention, in step 3), the freeze-drying method uses sorbitol as the freeze-drying protectant.

[0018] The present invention also provides an oxymethopyrazine capsule prepared by the above method.

[0019] Beneficial effects:

[0020] 1) Controlled slow drug release: This invention involves specially treating the active pharmaceutical ingredient oxymethopyrazine to form nanoparticles, encapsulating the active ingredient with a polymeric carrier material, and then preparing oxymethopyrazine nanoparticles using a special process before placing them into capsules. The oxymethopyrazine capsules produced using this technology significantly extend the slow drug release period, thereby maintaining a relatively stable blood drug concentration over a longer period. This helps reduce the instability in efficacy caused by fluctuations in drug concentration and improves the overall efficacy of the drug.

[0021] 2) Improve medication adherence: Extending the drug's sustained-release time can reduce the frequency of dosing and lower the incidence of adverse reactions, both of which help improve patient medication adherence. Patients are more willing to take their medication on time and in the correct dosage, thus better controlling their condition. Detailed Implementation

[0022] The technical solutions in the embodiments of this application are clearly described below. Obviously, the described embodiments are only some, not all, of the embodiments of this application. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0023] The terms "first," "second," etc., used in the specification and claims of this application are used to distinguish similar objects and not to describe a specific order or sequence. It should be understood that such use of data can be interchanged where appropriate so that embodiments of this application can be implemented in orders other than those described herein, and the objects distinguished by "first," "second," etc., are generally of the same class and the number of objects is not limited; for example, a first object can be one or more. Furthermore, in the specification and claims, "and / or" indicates at least one of the connected objects, and the character " / " generally indicates that the preceding and following objects are in an "or" relationship.

[0024] This application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

[0025] A method for preparing oxymethopyrazine capsules, comprising:

[0026] 1) Preparation of initial suspension: Dissolve the polymeric carrier material in an appropriate amount of organic solvent, and dissolve oxymethopyrazine in the above solution to obtain an oil phase; add the surfactant to purified water to obtain an aqueous phase; add the oil phase dropwise to the aqueous phase while stirring with a stirrer to obtain an initial suspension;

[0027] 2) Preparation of nano-suspension: Emulsification is performed using an ultrasonic processor to obtain nano-suspension; organic solvent is removed by vacuum evaporation or dialysis membrane, leaving oxymethipazine nanoparticle suspension;

[0028] 3) Preparation of oxymethopyrazine capsules: The nano-suspension obtained in step 2) is dried by freeze-drying or spray drying to obtain oxymethopyrazine nanoparticles in solid powder form with a final average particle size of 300±60nm; the obtained oxymethopyrazine nanoparticle powder is filled into capsule shells to obtain oxymethopyrazine capsules.

[0029] Preferably, the ratio of oxymethopyrazine to the polymeric carrier material is 1:5 to 1:9, and can be 1:5, 1:7, or 1:9.

[0030] Preferably, the frequency of the ultrasonic processor performing the emulsification process in step 2) is 400-600W, which can be 400W, 500W, or 600W.

[0031] Preferably, the emulsification time of the ultrasonic processor in step 2) is 25-45 minutes, which can be 25 minutes, 35 minutes, or 45 minutes.

[0032] Preferably, the amount of surfactant added is 0.8% to 1.5% based on the mass of the oxymethazine nanoparticles, which can be 0.8%, 1.0%, or 1.5%.

[0033] Preferably, the polymeric carrier material can be one or more of polylactic acid-glycolic acid copolymer, polylactic acid (PLA), and polyethylene glycol (PEG).

[0034] Preferably, the organic solvent is ethyl acetate.

[0035] Preferably, in the freeze-drying method described in step 3), the freeze-drying protectant added is sorbitol.

[0036] The present invention also provides an oxymethiprazine capsule, prepared using any of the methods described above.

[0037] The oxymethopyrazine capsules provided by this invention have a significant sustained-release effect, and the efficacy of the oxymethopyrazine capsules can last for 24 hours.

[0038] The above conclusions will be illustrated below with specific examples.

[0039] Example 1

[0040] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 2.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0041] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0042] (3) Preparation of oxymethopyrazine capsules: 2g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsule 1.

[0043] Example 2

[0044] (1) Preparation of initial suspension: 125g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 1.5g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0045] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0046] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 2.

[0047] Example 3

[0048] (1) Preparation of initial suspension: Dissolve 225g polylactic acid (PLA) in 500ml ethyl acetate, add 25g oxymethylpyrazine to the above solution, heat to 40℃ to dissolve, use high-speed homogenization method, internal cut homogenizer, homogenize at 15000rpm for 5min to obtain oil phase; dissolve 2.5g polyvinyl alcohol (PVA) in 2L purified water, after fully dissolving to form aqueous phase; slowly add the obtained oil phase to aqueous phase, set the stirring speed to 3000rpm, stir for 40min to fully emulsify, and obtain initial suspension.

[0049] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0050] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 3.

[0051] Example 4

[0052] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 2.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0053] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 400W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0054] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 4.

[0055] Example 5

[0056] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 2.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0057] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 600W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0058] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain 5 oxymethopyrazine capsules.

[0059] Example 6

[0060] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 2.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0061] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 25 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0062] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 6.

[0063] Example 7

[0064] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 2.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0065] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 45 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0066] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 7.

[0067] Example 8

[0068] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 1.6g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0069] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0070] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 8.

[0071] Example 9

[0072] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 3.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0073] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0074] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 9.

[0075] Comparative Example 1

[0076] (1) Preparation of initial suspension: Dissolve 100g polylactic acid (PLA) in 500ml ethyl acetate, add 25g oxymethylpyrazine to the above solution, heat to 40℃ to dissolve, use high-speed homogenization method, internal cut homogenizer, homogenize at 15000rpm for 5min to obtain oil phase; dissolve 1.25g polyvinyl alcohol (PVA) in 2L purified water, after fully dissolving to form aqueous phase; slowly add the obtained oil phase to aqueous phase, set the stirring speed to 3000rpm, stir for 40 minutes to fully emulsify, and obtain initial suspension.

[0077] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0078] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain 10 oxymethopyrazine capsules.

[0079] Comparative Example 2

[0080] (1) Preparation of initial suspension: Dissolve 250g polylactic acid (PLA) in 500ml ethyl acetate, add 25g oxypyrazine to the above solution, heat to 40℃ to dissolve, use high-speed homogenization method, internal cut homogenizer, homogenize at 15000rpm for 5min to obtain oil phase; dissolve 2.75g polyvinyl alcohol (PVA) in 2L purified water, after fully dissolving to form aqueous phase; slowly add the obtained oil phase to aqueous phase, set the stirring speed to 3000rpm, stir for 40min to fully emulsify, and obtain initial suspension.

[0081] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0082] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 11.

[0083] Comparative Example 3

[0084] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 2.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0085] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 300W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0086] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 12.

[0087] Comparative Example 4

[0088] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 2.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0089] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 700W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0090] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 13.

[0091] Comparative Example 5

[0092] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 2.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0093] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 20 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0094] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 14.

[0095] Comparative Example 6

[0096] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 2.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0097] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 50 min to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100 Pa to evaporate the organic solvent ethyl acetate.

[0098] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 15.

[0099] Comparative Example 7

[0100] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxypyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 1.0g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0101] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0102] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 16.

[0103] Comparative Example 8

[0104] (1) Preparation of initial suspension: 175g polylactic acid (PLA) was dissolved in 500ml ethyl acetate, and 25g oxymethylpyrazine was added to the above solution. The solution was heated to 40℃ and dissolved. The solution was homogenized at 15000rpm for 5min using a high-speed homogenizer to obtain the oil phase. 3.6g polyvinyl alcohol (PVA) was dissolved in 2L purified water. After complete dissolution, the aqueous phase was formed. The obtained oil phase was slowly added to the aqueous phase. The stirring speed was set to 3000rpm and stirred for 40 minutes to fully emulsify and obtain the initial suspension.

[0105] (2) Preparation of nano-suspension: Under normal temperature and pressure, the initial suspension obtained in step (1) was placed on an ultrasonic cell disruptor at 500W for 35 minutes to obtain nano-suspension. Under normal temperature and pressure, the pressure was reduced to 100Pa to evaporate the organic solvent ethyl acetate.

[0106] (3) Preparation of oxymethopyrazine capsules: 1.5g of sorbitol was added to the nano-suspension obtained in step (2) as a freeze-drying protectant. The mixture was pre-frozen at -60℃ for 2-12h, and then freeze-dried at -80℃ and 78×10^(-3)Mbar for 30h to obtain oxymethopyrazine lyophilized powder. The lyophilized powder was then pulverized in an ultrafine pulverizer, and the final average particle size was 300±60nm. The obtained oxymethopyrazine nanoparticle powder was divided into 100 parts and filled into 100 capsule shells to obtain oxymethopyrazine capsules 17.

[0107] Table 1 shows a summary of the statistical results of each experimental variable in Examples 1-9 and Comparative Examples 1-8.

[0108] Table 1. Summary of experimental variables in Examples 1-9 and Comparative Examples 1-8

[0109]

[0110] The release rate of capsules 1-17 prepared in Examples 1-9 and Comparative Examples 1-8 was determined.

[0111] The release rate of oxymetapyrazine capsules was determined using the following in vitro release test method: Take 10 capsules each of capsules 1-17, and dissolve them according to the release rate determination method (Chinese Pharmacopoeia 2005 Edition, Part II, Appendix XD, Method I), using a dissolution test apparatus (Chinese Pharmacopoeia 2005 Edition, Part II, Appendix XC, Method I), with 100 ml of hydrochloric acid solution (9→1000) as the solvent, at a rotation speed of 50 rpm. At 1, 4, 8, 12, 16, 20, and 24 hours, take 10 ml of the solution (and immediately replenish with an equal volume of solvent), filter, accurately measure 3 ml of the filtrate, place it in a 50 ml volumetric flask, and dilute to the mark with the same solvent to obtain the test solution. Separately, take an appropriate amount of oxymetapyrazine reference standard dried to constant weight at 105℃, accurately weigh it, dissolve it in hydrochloric acid solution (9→1000), and quantitatively dilute it to prepare a solution containing 7.5 μg per ml, as the reference solution. The absorbance of the test solution and the reference solution was determined by spectrophotometry (Appendix IV A, Part II, Chinese Pharmacopoeia 2005 Edition) at a wavelength of 269 nm. The release amount of each capsule at 1, 4, 8, 12, 16, 20 and 24 hours was calculated by external standard method. The release amounts and RSD% values ​​of capsules 1-17 at each time point are shown in Table 2.

[0112] Table 2 shows the release amounts and RSD% values ​​of capsules 1-17 at various time points.

[0113]

[0114] The following conclusions can be drawn from observing Table 2:

[0115] Comparing capsules 1-3 and 10-11, it is evident that the release rate of capsule 1-3 is less than 25% of the drug content in the first 1-4 hours, less than 45% in the first 8 hours, less than 75% in the first 16 hours, and less than 87% in the first 20 hours. Release is essentially complete around 24 hours, achieving the goal of continuous drug release for 24 hours. Capsules 10-11, on the other hand, achieve a release rate of 95% or higher in the first 16 hours, plateaus between 20 and 24 hours, and complete release around 20 hours. Therefore, under the same conditions, when the drug-to-carrier ratio is within the range of 1:5 to 1:9, the resulting oxymepiride capsules exhibit better release stability and a sustained efficacy for 24 hours.

[0116] Comparing capsules 1, 4, and 5 with capsules 12 and 13, it is evident that the release rate of capsules 1, 4, and 5 is less than 25% of the drug content in the first 1-4 hours, less than 45% in the first 8 hours, less than 75% in the first 16 hours, and less than 87% in the first 20 hours. Release is essentially complete around 24 hours, achieving the goal of continuous drug release for 24 hours. Capsules 12 and 13, on the other hand, achieve a release rate of 95% or higher in the first 16 hours, plateauing between 20 and 24 hours, and complete release around 20 hours. Therefore, under the same conditions, when preparing nano-suspensions, ultrasonic emulsification power of 400-600W results in oxymetamethrin capsules with better release stability and a sustained efficacy for 24 hours.

[0117] Comparing capsules 1, 6, and 7 with capsules 14 and 15, it is evident that the release rate of capsules 1, 6, and 7 is less than 25% of the drug content in the first 1-4 hours, less than 45% in the first 8 hours, less than 75% in the first 16 hours, and less than 87% in the first 20 hours. Release is essentially complete around 24 hours, achieving the goal of continuous drug release for 24 hours. Capsules 14 and 15, on the other hand, achieve a release rate of 95% or higher in the first 16 hours, plateauing between 20 and 24 hours, and complete release around 20 hours. Therefore, under the same conditions, when preparing nano-suspensions, ultrasonic emulsification power of 400-600W results in oxymetamethrin capsules with better release stability and a sustained efficacy for 24 hours.

[0118] Comparing capsules 1, 8, and 9 with capsules 16 and 17, it is evident that the release rate of capsules 1, 8, and 9 is less than 25% of the drug content in the first 1-4 hours, less than 45% in the first 8 hours, less than 75% in the first 16 hours, and less than 87% in the first 20 hours. Release is essentially complete around 24 hours, achieving the goal of continuous drug release for 24 hours. Capsules 16 and 17, on the other hand, achieve a release rate of 95% or higher in the first 16 hours, plateauing between 20 and 24 hours, and complete release around 20 hours. Therefore, under the same conditions, when preparing nano-suspensions, ultrasonic emulsification power of 400-600W results in oxymetapyrazine capsules with better release stability and a sustained efficacy for 24 hours.

[0119] It is understood that the above embodiments are merely exemplary implementations used to illustrate the principles of this application, and this application is not limited thereto. For those skilled in the art, various modifications and improvements can be made without departing from the spirit and substance of this application, and these modifications and improvements are also considered to be within the scope of protection of this invention.

Claims

1. A method for preparing oxymethopyrazine capsules, characterized in that, include: 1) Preparation of initial suspension: Dissolve the polymeric carrier material in an appropriate amount of organic solvent, and dissolve oxymethopyrazine in the above solution to obtain an oil phase; add the surfactant to purified water to obtain an aqueous phase; add the oil phase dropwise to the aqueous phase while stirring with a stirrer to obtain an initial suspension; 2) Preparation of nano-suspension: Emulsification is performed using an ultrasonic processor to obtain nano-suspension; organic solvent is removed by vacuum evaporation or dialysis membrane, leaving oxymethipazine nanoparticle suspension; 3) Preparation of oxymethopyrazine capsules: The nano-suspension obtained in step 2) is dried by freeze-drying or spray drying to obtain oxymethopyrazine nanoparticles in solid powder form with a final average particle size of 300±60nm; the obtained oxymethopyrazine nanoparticle powder is filled into capsule shells to obtain oxymethopyrazine capsules.

2. The method for preparing an oxymethopyrazine capsule according to claim 1, characterized in that, The ratio of oxymethopyrazine to polymeric carrier material is 1:5 to 1:

9.

3. The method for preparing an oxymethopyrazine capsule according to claim 1, characterized in that, The ratio of oxymethopyrazine to polymeric carrier material is 1:

7.

4. The method for preparing an oxymethopyrazine capsule according to claim 1, characterized in that, The frequency of the ultrasonic processor performing the emulsification process in step 2) is 400-600W.

5. The method for preparing an oxymethopyrazine capsule according to claim 1, characterized in that, Step 2) The emulsification process by the ultrasonic processor takes 25-45 minutes.

6. The method for preparing an oxymethopyrazine capsule according to claim 1, characterized in that, The amount of surfactant added is 0.8-1.5% based on the mass of the oxymethopyrazine nanoparticles.

7. The method for preparing an oxymethopyrazine capsule according to claim 1, characterized in that, The polymer carrier material can be one or more of polylactic acid-glycolic acid copolymer, polylactic acid (PLA), and polyethylene glycol (PEG).

8. The method for preparing an oxymethopyrazine capsule according to claim 1, characterized in that, The organic solvent is ethyl acetate.

9. The method for preparing an oxymethopyrazine capsule according to claim 1, characterized in that, In step 3), the freeze-drying method uses sorbitol as the freeze-drying protectant.

10. An oxymethopyrazine capsule is prepared by any one of the methods described in claims 1-9.

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