A method for preparing inositol nicotinate tablets

Abstract

The application discloses a preparation method of inositol nicotinate tablets and belongs to the technical field of pharmaceutical preparations. The method comprises the following steps: dispersing inositol nicotinate in mixed oil to prepare an oil phase, mixing and emulsifying the oil phase with a water phase, spray drying the drug emulsion powder, and coating the drug emulsion powder with modified chitosan and then directly compressing the drug emulsion powder with excipients. The inositol nicotinate is uniformly dispersed in the mixed oil, so that the drug content uniformity is maintained in the subsequent process, the solid particles are adsorbed on the surface of the drug-containing oil droplets through the emulsification technology, and the drug components are protected. The coating components are reasonably designed, the drug is released at a fixed point, the anti-pressing capacity is endowed, and the drug can be directly compressed. The drug particles after coating are mixed with excipients and then directly compressed, so that the process is simplified, and the coating structure of the drug particles is protected. The inositol nicotinate tablets prepared by the method have stable drug dissolution, good taste and small stimulation to gastric mucosa.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and more specifically, to a method for preparing inositol nicotinic acid ester tablets. Background Technology

[0002] Inositol nicotinic acid ester is a common lipid-lowering drug, and its oral tablets are widely used in the adjunctive treatment of cardiovascular diseases due to their convenience and controllable dosage. However, the existing manufacturing process of inositol nicotinic acid ester tablets still faces many technical bottlenecks, which restrict product quality and clinical application efficacy.

[0003] Currently, the preparation process for inositol nicotinic acid ester tablets typically employs wet granulation. Chinese patent application CN114681417A discloses an orally disintegrating tablet and its preparation method, which optimizes the traditional tablet form into an orally disintegrating tablet with improved taste and absorption by adding excipients such as penetration enhancers and flavoring agents. While flavoring agents can mask the bitterness of the drug and enhance palatability, the cooling sensation they provide can cause discomfort for some sensitive patients, and the long-term safety of artificially synthesized sweeteners must be considered. Chinese patent application CN107737113A discloses a nicotinic acid inositol ester tablet and its preparation method, which mixes nicotinic acid inositol ester with active substances such as paclitaxel, wet granulates the mixture, and compresses it into a tablet core. The tablet core is then coated with a coating composed of titanium dioxide and other components to extend the drug's shelf life. The proposed solution did not effectively design the coating solution, and long-term use of titanium dioxide may pose a risk of gastrointestinal accumulation, which is detrimental to the patient's health.

[0004] Therefore, it is crucial to develop an inositol nicotinic acid ester tablet that balances drug dissolution stability and long-term safety. To address these issues, this invention provides a method for preparing inositol nicotinic acid ester tablets. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing inositol nicotinic acid ester tablets. The method utilizes emulsification technology to uniformly coat inositol nicotinic acid ester dispersed in oils, improving the uniformity of drug dispersion. A uniform drug emulsion powder is prepared by spray drying, making the dissolution behavior of the drug in the tablets more stable and controllable. Through the rational design of the coating components, the physical properties of the formulation can be optimized while ensuring biosafety, and the drug release behavior can be controlled. The coated drug particles are mixed with excipients and compressed into tablets to obtain inositol nicotinic acid ester tablets that balance drug dissolution stability and long-term safety.

[0006] To achieve the above objectives, the present invention provides a method for preparing inositol nicotinic acid ester tablets, the method comprising the following steps:

[0007] Step S1: Pre-dry inositol nicotinic acid ester, pulverize, pour into a vibrating sieve for sieving, and dry to obtain drug powder;

[0008] Step S2: Mix beeswax with base oil, heat until beeswax melts, stir to obtain mixed oil, add drug powder, homogenize, and obtain oil phase;

[0009] Step S3: Disperse cellulose nanocrystals ultrasonically in deionized water, add mogroside and L-cysteine, stir, and obtain an aqueous phase;

[0010] Step S4: Add the oil phase to the aqueous phase, emulsify, and obtain the drug emulsion;

[0011] Step S5: Spray dry the drug emulsion into drug powder, spray with coating solution, dry, and sieve to obtain drug particles with a coating layer.

[0012] Step S6: Mix the drug particles with filler, gliding agent, disintegrant and lubricant, compress into tablets to obtain inositol nicotinic acid ester tablets.

[0013] Further, in step S1, the pre-drying process parameters include: a pre-drying temperature of 50-70℃, a pre-drying time of 60-90 min, and pre-drying until the powder moisture content is less than 5%; the pulverization method is air jet milling, and the air jet milling process parameters include: a feeding speed of 10-20 kg / h, a pulverizing pressure of 0.7-0.8 MPa, and a classifying wheel speed of 3000-4000 rpm; the sieving screen mesh number is 250-325 mesh, the sieving time is 2-5 min, the vibration amplitude of the vibrating screen is 0.5-1 mm, and the frequency is 50-60 Hz; the drying process parameters include: a drying temperature of 50-70℃, a drying time of 90-150 min, and drying until the moisture content of the drug powder is 1-3%.

[0014] Further, in step S2, the base oil is any one or more of medium-chain triglycerides, propylene glycol dioctyl ester, and polyoxyethylene castor oil; the mass ratio of the base oil to beeswax is (90-95):(5-10); the heating temperature is 60-65 ℃; the stirring speed is 500-800 rpm; the mass ratio of the drug powder to the mixed oil is 1:(2-4); the homogenization process parameters include: homogenization speed of 10000-12000 rpm and homogenization time of 3-5 min.

[0015] Using pharmaceutical polar oil as the base oil, a uniform and stable drug oil dispersion system is formed. Adding beeswax to the pharmaceutical polar oil, upon cooling, forms a dense wax network that blocks external moisture, oxygen, and inositol nicotinic acid esters from contact, forming a physical protective barrier and enhancing the dispersion stability of the drug in the oil mixture. The drug is dispersed in the oil mixture in an oil-encapsulated state, ensuring that the drug is efficiently encapsulated in the oil phase core after emulsification, forming a stable emulsion.

[0016] Further, in step S3, the dispersion concentration of the cellulose nanocrystals is 1.2-1.8%; the process parameters for ultrasonic dispersion include: ultrasonic power of 300-500 W, duty cycle of 40-50%, and ultrasonic duration of 2-5 min; the amount of mogroside added is 0.1-0.3% of the total mass of the aqueous phase; the amount of L-cysteine ​​added is 0.1-0.3% of the total mass of the aqueous phase; and the stirring speed is 600-1000 rpm.

[0017] Using cellulose nanocrystals, mogrosides, and L-cysteine ​​as the aqueous phase system, emulsification technology is used to encapsulate the drug-containing oil phase. Cellulose nanocrystals, as nano-solid particles, are adsorbed at the oil-water interface through emulsification to form a stable oil-in-water Pickering emulsion system. The oil phase droplets are encapsulated inside the solid particles, forming uniformly sized emulsion droplets. Mogrosides, as a natural high-intensity sweetener, not only mask the bitterness of the drug but also assist in the stable dispersion of the emulsion, improving patient compliance. L-cysteine, as a natural antioxidant, protects the drug-encapsulated oil phase from oxidation and degradation. The emulsion is then spray-dried to prepare a drug powder, providing a good foundation for subsequent tableting processes.

[0018] Further, in step S4, the volume ratio of the aqueous phase to the oil phase is (7-8):(2-3); the emulsification process includes: pre-emulsification and homogenization emulsification, wherein the pre-emulsification temperature is 62-68 ℃, the pre-emulsification rotation speed is 8000-10000 rpm, the pre-emulsification time is 45-90 s, the homogenization emulsification temperature is 62-68 ℃, the homogenization emulsification time is 3-5 min, and the homogenization emulsification rotation speed is 12000-16000 rpm.

[0019] Further, in step S5, the process parameters for spray drying include: an inlet air temperature of 150-180℃, an airflow pressure of 0.15-0.2 MPa, a feed rate of 10-20 mL / min, and spray drying until the moisture content of the drug emulsion is 1-3%; the coating solution includes modified chitosan, hydroxypropyl methylcellulose phthalate, a plasticizer, and an ammonia solution with a volume fraction of 0.03%; the modified chitosan, hydroxypropyl methylcellulose phthalate, and the plasticizer account for 3.9-5.2% of the total mass of the coating solution; the mass ratio of modified chitosan to hydroxypropyl methylcellulose phthalate in the coating solution is (3-4):1; the plasticizer is glycerol, and the amount added is 25-35% of the total mass of modified chitosan and hydroxypropyl methylcellulose phthalate; the process parameters for spraying the coating solution include: an inlet air temperature of 40-50℃, and an outlet air temperature of 30-35℃. The spraying speed is 5-15 g / min / kg, the atomization pressure is 1-2 bar, and the dry matter mass ratio of the coating layer to the drug emulsion is (5-10):100; the drying temperature is 50-60 ℃, the drying time is 20-40 min, and the drying is carried out until the moisture content of the drug particles is 1-3%; the sieve mesh size is 80-120 mesh, and the sieving time is 45-90 s.

[0020] Furthermore, the method for preparing the modified chitosan includes:

[0021] Step A1: Disperse chitosan in a 1% (v / v) aqueous solution of acetic acid to obtain a chitosan dispersion;

[0022] Step A2: Disperse succinic anhydride in methanol and add it dropwise to the chitosan dispersion, stirring to react;

[0023] Step A3: Add 1 M sodium hydroxide solution to adjust the pH of the system, wash the precipitate with methanol, dialyze, dry, and sieve to obtain modified chitosan.

[0024] Further, in step A1, the chitosan has a mass-volume fraction of 1%; in step A2, the succinic anhydride has a mass-volume fraction of 1%; the stirring speed is 400-600 rpm, and the reaction time is 6-12 h; in step A3, the pH is 6.5-7.5; the dialysis time is 18-36 h, and the dialysis solution is deionized water; the drying temperature is 35-45℃, and the drying time is 20-30 h; the sieve mesh size is 40-80 mesh.

[0025] Further, in step S6, the filler is any one or more of microcrystalline cellulose, anhydrous lactose, and mannitol; the gliding agent is any one or more of colloidal silica and talc; the disintegrant is any one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl cellulose; the lubricant is any one or more of sodium stearate fumarate, magnesium stearate, talc, and silica; the mass ratio of the drug particles, filler, gliding agent, disintegrant, and lubricant is (53-77):(20-40):(0.8-1.2):(2-5):(0.2-0.8); and the tablet hardness is 50-80 N.

[0026] Compared with the prior art, the beneficial effects achieved by the present invention are as follows:

[0027] 1. This application utilizes the solubility characteristics of inositol nicotinic acid esters, employing pharmaceutically grade polar oil as the primary dispersion medium to ensure uniform dispersion of inositol nicotinic acid esters and form a stable oil phase. Subsequently, emulsification technology is used to blend the oil phase with the aqueous phase, allowing the drug to be highly dispersed in the carrier in a molecular or amorphous form. Spray drying then instantly solidifies the mixture into a drug emulsion powder, locking the drug in a high-energy amorphous state, significantly improving the stability of the dissolution behavior of poorly soluble drugs. Spray drying also avoids the risk of drug degradation due to the humid and hot environment during granulation, maximizing the retention of drug activity and further ensuring the stability of drug dissolution behavior. The drug emulsion powder prepared in this application, after coating, exhibits excellent compressibility and flowability, significantly reducing or eliminating the need for traditional binders, thereby simplifying formulations and reducing potential safety risks associated with excipients.

[0028] 2. This application uses a mixture of succinic anhydride-modified chitosan and hydroxypropyl methylcellulose phthalate as the coating solution. After modification with succinic anhydride, carboxyl groups are successfully introduced into the molecular chain of chitosan, enhancing the intermolecular hydrogen bonding and improving the flexibility of the molecular chain, thus giving the coating a certain mechanical strength. The introduced carboxyl groups also expand the solubility range of chitosan, allowing it to dissolve together with hydroxypropyl methylcellulose phthalate in mild alkaline solvents such as ammonia to prepare a stable and homogeneous coating solution, which facilitates subsequent drying. The synergistic effect of the two makes the coating layer stable in the gastric acid environment, effectively avoiding drug irritation to the gastric mucosa. After entering the intestine, the coating dissolves rapidly due to pH influence, allowing the drug to be released stably in the intestine, further improving the drug's dissolution stability and safety. Attached Figure Description

[0029] Figure 1 This is a process flow diagram of the present invention.

[0030] Figure 2 These are drug dissolution curves for Examples 1-3 and Comparative Examples 1-4 of the present invention. Detailed Implementation

[0031] It should be noted that the technical solution of the present invention will be described in detail below through specific embodiments. It should be understood that the embodiments of the present invention and the specific features in the embodiments are detailed descriptions of the technical solution of the present invention, rather than limitations on the technical solution of the present invention. In the absence of conflict, the embodiments of the present invention and the technical features in the embodiments can be combined with each other.

[0032] The term "and / or" simply describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A alone, A and B simultaneously, or B alone. Additionally, the character " / " generally indicates that the preceding and following related objects have an "or" relationship.

[0033] Example 1

[0034] A method for preparing an inositol nicotinic acid ester tablet includes the following steps:

[0035] Step S1: Pre-dry inositol nicotinic acid ester at 60 ℃ for 80 min until the moisture content of inositol nicotinic acid ester is less than 5%; put the pre-dried inositol nicotinic acid ester into an air jet mill for pulverization, setting the feed rate to 15 kg / h, the pulverization pressure to 0.75 MPa, and the classifier wheel speed to 3500 rpm; pour the pulverized drug into a vibrating screen for sieving, with a screen mesh of 300 mesh, a vibrating amplitude of 0.8 mm, and a frequency of 55 Hz, and sieve for 3 min; dry the sieved drug at 60 ℃ for 120 min until the moisture content of the drug powder is 2%, to obtain the drug powder.

[0036] Step S2: Taking a 100 g oil phase system as an example, take 92.5 g of medium-chain triglycerides, add 7.5 g of beeswax, slowly heat to 63°C at 600 rpm, and continue stirring until the beeswax is completely dissolved in the medium-chain triglycerides. Continue stirring at 600 rpm until the system is homogeneous. Take 75 g of mixed oil, add 25 g of drug powder, and continue homogenizing at 11000 rpm for 4 min to obtain the oil phase.

[0037] Step S3: Taking a 100 g aqueous system as an example, take 98.1 g of deionized water, add 1.5 g of cellulose nanocrystals, and sonicate at 360 W for 3 min with a duty cycle of 45% to obtain a cellulose nanocrystal dispersion; add 0.2 g of mogroside and 0.2 g of L-cysteine, and stir at 800 rpm until the mogroside and L-cysteine ​​are completely dissolved to obtain an aqueous phase.

[0038] Step S4: Taking a 100 mL emulsion system as an example, take 75 mL of the aqueous phase, add 25 mL of the oil phase to the aqueous phase, heat to 65 ℃, pre-emulsify at 9000 rpm for 60 s, maintain the system temperature at 65 ℃, increase the rotation speed to 15000 rpm, homogenize and emulsify for 4 min to obtain the drug emulsion.

[0039] Step S5: The drug emulsion is fed into a spray dryer at a rate of 15 mL / min and dried into drug powder. The inlet air temperature for spray drying is 160 ℃, the air pressure is 0.17 MPa, and the moisture content of the drug powder is 1.2%. The drug powder is placed in a fluidized bed, and a coating liquid is sprayed onto its surface through an atomizing device under fluidized conditions. The atomizing pressure is 1.7 bar, the spraying speed is 10 g / min / kg, the inlet air temperature is 45 ℃, and the outlet air temperature is 32 ℃. The drug powder coated with the coating liquid is dried at 55 ℃ for 30 min until its moisture content is 1.5%. At this point, the mass ratio of dry matter between the coating layer and the drug powder is 7:100. The dried drug powder coated with the coating liquid is passed through a 100-mesh sieve for 60 s to obtain drug particles.

[0040] The coating solution was prepared as follows, taking a 100 mL system as an example. First, the chitosan was modified. Taking 4 g of dry chitosan as an example, 4 g of chitosan was dispersed in 400 mL of 1% (v / v) acetic acid aqueous solution to obtain a chitosan dispersion. 4 g of succinic anhydride was dissolved in 400 mL of methanol and added dropwise to the chitosan dispersion. The mixture was stirred at 500 rpm for 8 h. After the reaction was completed, 1 M sodium hydroxide was added to the system until the pH of the system was 7.0. The precipitate was filtered out and washed several times with methanol. The precipitate was dialyzed in deionized water for 24 h to obtain succinic anhydride chitosan. The succinic anhydride chitosan was dried at 40 ℃ for 24 h and passed through a 60-mesh sieve to obtain modified chitosan. Take 2.25 g of modified chitosan and disperse it in 50 mL of 0.03% ammonia solution. Add 0.75 g of hydroxypropyl methylcellulose phthalate and 0.9 g of glycerol. Add 0.03% ammonia solution to 100 mL to obtain the coating solution.

[0041] Step S6: 65 g of drug particles are mixed with 30 g of microcrystalline cellulose, 1 g of colloidal silica, 3.5 g of low-substituted hydroxypropyl cellulose and 0.5 g of sodium stearate and then compressed into tablets to obtain inositol nicotinic acid ester tablets with a hardness of 70 N.

[0042] Example 2

[0043] A method for preparing an inositol nicotinic acid ester tablet includes the following steps:

[0044] Step S1: Pre-dry inositol nicotinic acid ester at 50 ℃ for 60 min until the moisture content of inositol nicotinic acid ester is less than 5%; put the pre-dried inositol nicotinic acid ester into an air jet mill for pulverization, setting the feed rate to 10 kg / h, the pulverization pressure to 0.7 MPa, and the classifier wheel speed to 3000 rpm; pour the pulverized drug into a vibrating screen for sieving, with a screen mesh of 250 mesh, a vibration amplitude of 0.5 mm, and a frequency of 50 Hz, and sieve for 2 min; dry the sieved drug at 50 ℃ for 150 min until the moisture content of the drug powder is 3%, to obtain the drug powder.

[0045] Step S2: Taking a 100 g oil phase system as an example, take 95 g of propylene glycol dioctyl ester, add 5 g of beeswax, slowly heat to 60 ℃ at 500 rpm, and continue stirring until the beeswax is completely dissolved in the propylene glycol dioctyl ester. Continue stirring at 500 rpm until the system is homogeneous. Take 80 g of mixed oil, add 20 g of drug powder, and continue homogenizing at 10000 rpm for 3 min to obtain the oil phase.

[0046] Step S3: Taking a 100 g aqueous system as an example, take 98.6 g of deionized water, add 1.2 g of cellulose nanocrystals, and sonicate at 300 W for 2 min with a duty cycle of 40% to obtain a cellulose nanocrystal dispersion; add 0.1 g of mogroside and 0.1 g of L-cysteine, and stir at 600 rpm until the mogroside and L-cysteine ​​are completely dissolved to obtain the aqueous phase.

[0047] Step S4: Taking a 100 mL emulsion system as an example, take 80 mL of the aqueous phase, add 20 mL of the oil phase to the aqueous phase, heat to 62 ℃, pre-emulsify at 8000 rpm for 90 s, maintain the system temperature at 62 ℃, increase the rotation speed to 12000 rpm, homogenize and emulsify for 3 min to obtain the drug emulsion.

[0048] Step S5: The drug emulsion is fed into a spray dryer at a rate of 10 mL / min and dried into drug powder. The inlet air temperature for spray drying is 150 ℃, the air pressure is 0.15 MPa, and the moisture content of the drug powder is 3%. The drug powder is placed in a fluidized bed, and a coating liquid is sprayed onto its surface through an atomizing device under fluidized conditions. The atomizing pressure is 1 bar, the spraying speed is 5 g / min / kg, the inlet air temperature is 40 ℃, and the outlet air temperature is 30 ℃. The drug powder coated with the coating liquid is dried at 50 ℃ for 20 min until its moisture content is 3%. At this point, the mass ratio of dry matter between the coating layer and the drug powder is 5:100. The dried drug powder coated with the coating liquid is passed through an 80-mesh sieve for 45 s to obtain drug particles.

[0049] The coating solution was prepared as follows, taking a 100 mL system as an example. First, the chitosan was modified. Taking 4 g dry weight of chitosan as an example, 4 g of chitosan was dispersed in 400 mL of 1% (v / v) acetic acid aqueous solution to obtain a chitosan dispersion; 4 g of succinic anhydride was dissolved in 400 mL of methanol and added dropwise to the chitosan dispersion, and the mixture was stirred at 400 rpm for 12 h; after the reaction was completed, 1 M sodium hydroxide was added to the system until the pH of the system was 6.5, the precipitate was filtered out and washed with methanol several times, and the precipitate was dialyzed in deionized water for 18 h to obtain succinic anhydride chitosan. The succinic anhydride chitosan was dried at 35 ℃ for 20 h and passed through a 40-mesh sieve to obtain modified chitosan. Take 2.8 g of modified chitosan and disperse it in 50 mL of 0.03% ammonia solution. Add 0.8 g of hydroxypropyl methylcellulose phthalate and 0.9 g of glycerol. Add 0.03% ammonia solution to 100 mL to obtain the coating solution.

[0050] Step S6: 77 g of drug granules are mixed with 20 g of anhydrous lactose, 0.8 g of talc, 2 g of crospovidone, 0.1 g of magnesium stearate and 0.1 g of silica and then compressed into tablets to obtain inositol nicotinic acid ester tablets with a hardness of 80 N.

[0051] Example 3

[0052] A method for preparing an inositol nicotinic acid ester tablet includes the following steps:

[0053] Step S1: Pre-dry inositol nicotinic acid ester at 70 ℃ for 90 min until the moisture content of inositol nicotinic acid ester is less than 5%; put the pre-dried inositol nicotinic acid ester into an air jet mill for pulverization, setting the feed rate to 20 kg / h, the pulverization pressure to 0.8 MPa, and the classifier wheel speed to 4000 rpm; pour the pulverized drug into a vibrating screen for sieving, with a screen mesh size of 325 mesh, a vibration amplitude of 1 mm, and a frequency of 60 Hz, and sieve for 5 min; dry the sieved drug at 70 ℃ for 90 min until the moisture content of the drug powder is 1%, obtaining the drug powder.

[0054] Step S2: Taking a 100 g oil phase system as an example, take 90 g of polyoxyethylene castor oil, add 10 g of beeswax, slowly heat to 65 ℃ at 800 rpm, and continuously stir until the beeswax is completely dissolved in the polyoxyethylene castor oil. Continue stirring at 800 rpm until the system is homogeneous. Take 67 g of mixed oil, add 33 g of drug powder, and continuously homogenize at 12000 rpm for 5 min to obtain the oil phase.

[0055] Step S3: Taking a 100 g aqueous system as an example, take 97.6 g of deionized water, add 1.8 g of cellulose nanocrystals, and sonicate at 500 W for 5 min with a duty cycle of 50% to obtain a cellulose nanocrystal dispersion; add 0.3 g of mogroside and 0.3 g of L-cysteine, and stir at 1000 rpm until the mogroside and L-cysteine ​​are completely dissolved to obtain the aqueous phase.

[0056] Step S4: Taking a 100 mL emulsion system as an example, take 70 mL of the aqueous phase, add 30 mL of the oil phase to the aqueous phase, heat to 68 ℃, pre-emulsify at 10000 rpm for 45 s, maintain the system temperature at 68 ℃, increase the rotation speed to 16000 rpm, homogenize and emulsify for 5 min to obtain the drug emulsion.

[0057] Step S5: The drug emulsion is fed into a spray dryer at a rate of 20 mL / min and dried into drug powder. The inlet air temperature for spray drying is 180 ℃, the air pressure is 0.2 MPa, and the moisture content of the drug powder is 1%. The drug powder is placed in a fluidized bed, and a coating liquid is sprayed onto its surface through an atomizing device under fluidized conditions. The atomizing pressure is 2 bar, the spraying speed is 15 g / min / kg, the inlet air temperature is 50 ℃, and the outlet air temperature is 35 ℃. The drug powder coated with the coating liquid is dried at 60 ℃ for 40 min until its moisture content is 1%. At this point, the mass ratio of dry matter between the coating layer and the drug powder is 10:100. The dried drug powder coated with the coating liquid is passed through a 120-mesh sieve for 90 s to obtain drug particles.

[0058] The coating solution was prepared as follows, taking a 100 mL system as an example. First, the chitosan was modified. Taking 4 g dry weight of chitosan as an example, 4 g of chitosan was dispersed in 400 mL of 1% (v / v) acetic acid aqueous solution to obtain a chitosan dispersion; 4 g of succinic anhydride was dissolved in 400 mL of methanol and added dropwise to the chitosan dispersion, and the mixture was stirred at 600 rpm for 6 h; after the reaction was completed, 1 M sodium hydroxide was added to the system until the pH of the system was 7.5, the precipitate was filtered out and washed with methanol several times, and the precipitate was dialyzed in deionized water for 36 h to obtain succinic anhydride chitosan. The succinic anhydride chitosan was dried at 45 ℃ for 30 h and passed through an 80-mesh sieve to obtain modified chitosan. Take 3.08 g of modified chitosan and disperse it in 50 mL of 0.03% ammonia solution. Add 0.77 g of hydroxypropyl methylcellulose phthalate and 1.35 g of glycerol. Then add 0.03% ammonia solution to 100 mL to obtain the coating solution.

[0059] Step S6: 53 g of drug granules are mixed with 40 g of mannitol, 1.2 g of colloidal silica, 3 g of cross-linked sodium carboxymethyl cellulose, 2 g of sodium carboxymethyl cellulose and 0.8 g of talc and then compressed into tablets to obtain inositol nicotinic acid ester tablets with a hardness of 50 N.

[0060] Comparative Example 1

[0061] An inositol nicotinic acid ester tablet, the preparation method of which differs from that of Example 1, is that beeswax in the mixed oil is omitted.

[0062] Comparative Example 2

[0063] An inositol nicotinic acid ester tablet is prepared in a manner that differs from that in Example 1 in that the inositol nicotinic acid ester is not dispersed in oil or emulsified; instead, the drug powder is directly coated.

[0064] Comparative Example 3

[0065] An inositol nicotinic acid ester tablet is prepared in a manner different from that in Example 1, but the drug milk powder is not coated; instead, the drug milk powder and excipients are directly mixed and compressed into tablets.

[0066] Comparative Example 4

[0067] An inositol nicotinic acid ester tablet, the preparation method of which differs from that of Example 1, omits hydroxypropyl methylcellulose phthalate in the coating solution.

[0068] The dissolution test of the tablets in Examples 1-3 and Comparative Examples 1-4 was conducted using the basket method. 700 mL of dilute hydrochloric acid (pH=1.2) was used as the gastric dissolution medium, and the mixture was treated at 37±0.5 °C at 50 rpm for 2 h to simulate the dissolution process of inositol nicotinic acid ester tablets in the stomach. After treatment, the system was adjusted to pH=6.8 to obtain the intestinal dissolution medium, and the mixture was treated at 37±0.5 °C at 75 rpm for 10 h to simulate the drug dissolution process in the intestine. Sampling points were set at 0 h, 0.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 10 h, and 12 h, with 10 mL samples taken each time. After sampling, an equal volume of gastric or intestinal dissolution medium at the same temperature was added. The dissolution data for each sampling point were plotted against time to create a dissolution curve. The results of the dissolution test are shown in Table 1.

[0069] Table 1. Dissolution data (%) for Examples 1-3 and Comparative Examples 1-4

[0070]

[0071] Figure 2 The dissolution curves for Examples 1-3 and Comparative Examples 1-4 are shown. The dissolution curves for Examples 1-3 exhibit a stable linear growth pattern, demonstrating that the drug dissolves stably after administration without sudden drug release. After a 2-hour gastric dissolution test, the drug dissolution rates for Examples 1, 2, and 3 were 6.7±0.3%, 7.2±0.3%, and 5.9±0.6%, respectively. After a 10-hour intestinal dissolution test, the drug dissolution rates for Examples 1, 2, and 3 were 95.3±0.9%, 97.3±1.5%, and 94.7±2.0%, respectively, confirming that the inositol nicotinic acid ester tablets prepared according to this invention can release the drug in the intestine, reducing gastric mucosal irritation and discomfort caused by gastric acid release.

[0072] In Comparative Example 1, the oil phase lacked beeswax, and the drug release behavior was similar to that of the examples, but a burst release of the drug occurred in the intestine. This is because the initial dissolution process in the stomach is controlled by the coating. After the coating dissolves, the drug is released from the oil phase. Without the sustained-release support of beeswax in the oil phase, the drug release rate accelerates. After a 12-hour dissolution test, the cumulative dissolution rate of the drug in Comparative Example 2 was only 83.5 ± 3.2%, far lower than other examples and comparative examples. This is because the emulsification and oil phase dispersion processes promote the in vivo dissolution and absorption of the fat-soluble inositol nicotinic acid ester. Directly coating the drug powder makes it difficult for the drug to dissolve rapidly after the coating layer dissolves, resulting in extremely low bioavailability. In Comparative Example 3, the drug emulsion powder was mixed with excipients and then compressed into tablets. The drug had already completely dissolved in the stomach, causing significant irritation to the gastric mucosa. Comparative Example 4 achieved a dissolution rate of 15.3 ± 0.8% in the 2-hour gastric dissolution test, second only to Comparative Example 3. This is because the coating component lacks hydroxypropyl methylcellulose phthalate, and the coating layer composed only of modified chitosan and glycerol cannot protect the drug in gastric juice.

[0073] In summary, this invention utilizes a three-layer protection system of oil dispersion, emulsification encapsulation, and spray coating to ensure stable drug dissolution, reduce drug irritation to the gastric mucosa, minimize drug degradation during production and storage, and ensure the stability of the drug's chemical composition. The invention features a rationally designed drug coating layer, employing modified chitosan and hydroxypropyl methylcellulose phthalate as the coating. These components remain in a molecular state in the acidic gastric environment, preventing dissolution and protecting the drug as it reaches the intestines, thus reducing the irritation of the gastric mucosa by inositol nicotinic acid ester. Upon entering the intestines, the coating ionizes and swells, rapidly dissolving and releasing the drug, thereby enhancing its efficacy. The drug dispersed in oil is transformed into micron-sized drug emulsions through emulsification and spray drying. After the coating dissolves in the intestines, the drug emulsions are released, and under the action of pancreatic enzymes, the drug dissolves from the oil phase, improving its bioavailability. Encapsulating the drug in a triple structure of oil phase, cellulose nanocrystals, and coating can mask the bitterness of the drug itself. The added mogrosides further provide a pleasant taste, which can improve the patient's medication experience and long-term medication adherence.

[0074] The embodiments of the present invention have been described above. However, the present invention 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 the present invention without departing from the spirit and scope of the claims. All of these forms are within the protection scope of the present invention.

Claims

1. A method for preparing inositol nicotinic acid ester tablets, characterized in that, include: Step S1: Pre-dry inositol nicotinic acid ester, pulverize, pour into a vibrating sieve for sieving, and dry to obtain drug powder; Step S2: Mix beeswax with base oil, heat until the beeswax melts, stir to obtain a mixed oil, add drug powder, homogenize, and obtain the oil phase; the base oil is any one or more of medium-chain triglycerides, propylene glycol dioctyl ester, and polyoxyethylene castor oil; Step S3: Disperse cellulose nanocrystals ultrasonically in deionized water, add mogroside and L-cysteine, stir, and obtain an aqueous phase; Step S4: Add the oil phase to the aqueous phase, emulsify, and obtain the drug emulsion; Step S5: Spray dry the drug emulsion into drug emulsion powder, spray with a coating solution composed of modified chitosan, hydroxypropyl methylcellulose phthalate, plasticizer and ammonia solution with a volume fraction of 0.03%, dry, and sieve to obtain drug particles containing a coating layer. Step S6: Mix the drug particles with filler, gliding agent, disintegrant and lubricant, compress into tablets to obtain inositol nicotinic acid ester tablets; The method for preparing the modified chitosan includes: Step A1: Disperse chitosan in a 1% (v / v) aqueous solution of acetic acid to obtain a chitosan dispersion; Step A2: Disperse succinic anhydride in methanol and add it dropwise to the chitosan dispersion, stirring to react; Step A3: Add 1 M sodium hydroxide solution to adjust the pH of the system, wash the precipitate with methanol, dialyze, dry, and sieve to obtain modified chitosan.

2. The method for preparing an inositol nicotinic acid ester tablet according to claim 1, characterized in that, In step S1, the pre-drying process parameters include: a pre-drying temperature of 50-70 ℃, a pre-drying time of 60-90 min, and pre-drying until the powder moisture content is less than 5%; the pulverization method is air jet milling, and the air jet milling process parameters include: a feeding speed of 10-20 kg / h, a pulverizing pressure of 0.7-0.8 MPa, and a classifying wheel speed of 3000-4000 rpm; the sieving screen mesh number is 250-325 mesh, the sieving time is 2-5 min, the vibration amplitude of the vibrating screen is 0.5-1 mm, and the frequency is 50-60 Hz; the drying process parameters include: a drying temperature of 50-70 ℃, a drying time of 90-150 min, and drying until the moisture content of the drug powder is 1-3%.

3. The method for preparing an inositol nicotinic acid ester tablet according to claim 1, characterized in that, In step S2, the mass ratio of the base oil to beeswax is (90-95):(5-10); the heating temperature is 60-65 ℃; the stirring speed is 500-800 rpm; the mass ratio of the drug powder to the mixed oil is 1:(2-4); the homogenization process parameters include: homogenization speed of 10000-12000 rpm and homogenization time of 3-5 min.

4. The method for preparing an inositol nicotinic acid ester tablet according to claim 1, characterized in that, In step S3, the dispersion concentration of the cellulose nanocrystals is 1.2-1.8%. The ultrasonic dispersion process parameters include: ultrasonic power of 300-500 W, duty cycle of 40-50%, and ultrasonic duration of 2-5 min; the amount of mogroside added is 0.1-0.3% of the total mass of the aqueous phase; the amount of L-cysteine ​​added is 0.1-0.3% of the total mass of the aqueous phase; and the stirring speed is 600-1000 rpm.

5. The method for preparing an inositol nicotinic acid ester tablet according to claim 1, characterized in that, In step S4, the volume ratio of the aqueous phase to the oil phase is (7-8):(2-3); the emulsification process includes: pre-emulsification and homogenization emulsification, wherein the pre-emulsification temperature is 62-68 ℃, the pre-emulsification rotation speed is 8000-10000 rpm, and the pre-emulsification time is 45-90 s; the homogenization emulsification temperature is 62-68 ℃, the homogenization emulsification time is 3-5 min, and the homogenization emulsification rotation speed is 12000-16000 rpm.

6. The method for preparing an inositol nicotinic acid ester tablet according to claim 1, characterized in that, In step S5, the spray drying process parameters include: inlet air temperature of 150-180℃, airflow pressure of 0.15-0.2 MPa, feed rate of 10-20 mL / min, and spray drying until the moisture content of the drug emulsion is 1-3%; the modified chitosan, hydroxypropyl methylcellulose phthalate, and plasticizer account for 3.9-5.2% of the total mass of the coating solution; the mass ratio of modified chitosan to hydroxypropyl methylcellulose phthalate in the coating solution is (3-4):1; the plasticizer is glycerol, and the amount added is 25-35% of the total mass of modified chitosan and hydroxypropyl methylcellulose phthalate; the spray coating solution process parameters include: inlet air temperature of 40-50℃, outlet air temperature of 30-35℃, spraying speed of 5-15 g / min / kg, and atomization pressure of 1-2... The dry matter mass ratio of the coating layer to the drug milk powder is (5-10):100; the drying temperature is 50-60 ℃, the drying time is 20-40 min, and the drying is carried out until the moisture content of the drug particles is 1-3%; the sieve mesh number is 80-120 mesh, and the sieving time is 45-90 s.

7. The method for preparing an inositol nicotinic acid ester tablet according to claim 1, characterized in that, In step S6, the filler is any one or more of microcrystalline cellulose, anhydrous lactose, and mannitol; the gliding agent is any one or more of colloidal silica and talc; the disintegrant is any one or more of crospovidone, crospovidone sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl cellulose; the lubricant is any one or more of sodium stearate fumarate, magnesium stearate, talc, and silica; the mass ratio of the drug particles, filler, gliding agent, disintegrant, and lubricant is (53-77):(20-40):(0.8-1.2):(2-5):(0.2-0.8); and the tablet hardness is 50-80 N.

8. The method for preparing an inositol nicotinic acid ester tablet according to claim 1, characterized in that, In step A1, the chitosan has a mass-volume fraction of 1%; in step A2, the succinic anhydride has a mass-volume fraction of 1%; the stirring speed is 400-600 rpm, and the reaction time is 6-12 h; in step A3, the pH is 6.5-7.5; the dialysis time is 18-36 h, and the dialysis solution is deionized water; the drying temperature is 35-45℃, and the drying time is 20-30 h; the sieve mesh size is 40-80 mesh.

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