Preparation method and application of xantinol nicotinate pharmaceutical composition

Abstract

The invention relates to the technical field of medicine preparation, and particularly discloses a preparation method and application of a xantinol nicotinate pharmaceutical composition, and the preparation method comprises the following steps: step S1, preparing the following raw materials in parts by weight: 6.2-7.6 parts of xantinol nicotinate, 86-98 parts of purified water, 16-22 parts of a filler, 64-76 parts of a coating solution, 14-20 parts of a flavoring agent, 42-54 parts of a modified disintegrating solution and 2-4 parts of a lubricant; step S2, preparing the xantinol nicotinate pharmaceutical composition; the coating liquid and the modified disintegrating liquid are added, active functional groups contained in the coating liquid can form hydrogen-bond interaction with the active ingredients of the medicine, flexible long-chain alkane on the coating liquid can be entangled with alkyl chains on the modified disintegrating agent, the modified disintegrating agent not only contains a cellulose nanocrystal structure, but also contains a carboxymethyl structure, so that the cellulose nanocrystal-modified disintegrating agent has the advantages that the cellulose nanocrystal-modified disintegrating agent can be applied to the preparation of the medicine; through the combined action of the structures, the coating property, the disintegration property and the slow release property of the xantinol nicotinate pharmaceutical composition are improved.

Description

Technical Field

[0001] The present application relates to the technical field of drug preparation, and more specifically, to a preparation method of a nicotinic acid xanthinol pharmaceutical composition and its application. Background Art

[0002] Xanthinol nicotinic acid is a drug with vasodilatory effects, which is mainly used clinically to treat ischemic cerebrovascular disease and its sequelae. In terms of pharmacokinetics, Xanthinol nicotinic acid exhibits rapid solubility and absorption. This property enables the drug to quickly reach peak plasma concentration after entering the blood, thereby quickly exerting its therapeutic effect. However, rapid fluctuations in blood drug concentrations also bring certain risks, especially in terms of heart health, where rapid changes in drug concentrations can increase the burden on the heart.

[0003] Nicotinic acid Xanthinol tablets have the advantages of easy administration, adjustable dosage, good stability and applicability, etc. Therefore, they have received extensive clinical attention. However, the excipients in the existing Nicotinic acid Xanthinol tablets will affect the release characteristics of the drug, resulting in slow disintegration rate, large differences in drug solubility, low bioavailability and other problems. In addition, Nicotinic acid Xanthinol tablets also show rapid dissolution and absorption ability after complete disintegration, short duration of drug effect, and are prone to cause drastic fluctuations in blood drug concentration, affecting the heart. Based on the above statements, the present application provides a method for preparing a Nicotinic acid Xanthinol pharmaceutical composition and its application. Summary of the invention

[0004] In order to solve the problems in the prior art of slow disintegration of nicotinic acid xanthinol tablets, large differences in drug solubility, low bioavailability, rapid dissolution and absorption after disintegration, short duration of drug effect, and easy to cause drastic fluctuations in blood drug concentration and affect the heart, the present application provides a preparation method and application of a nicotinic acid xanthinol pharmaceutical composition.

[0005] The purpose of the present invention can be achieved by the following technical solutions: A method for preparing a nicotinate xanthinol pharmaceutical composition comprises the following steps: Step S1, preparing the following raw materials in parts by weight: 6.2-7.6 parts of Xanthinol Nicotinate, 86-98 parts of purified water, 16-22 parts of filler, 64-76 parts of coating liquid, 14-20 parts of flavoring agent, 42-54 parts of modified disintegrant and 2-4 parts of lubricant; Step S2, preparation of a nicotinic acid xanthinol pharmaceutical composition: adding nicotinic acid xanthinol, a flavoring agent, a filler and a lubricant to purified water, stirring until dissolved, adding a coating solution, continuing stirring for 20-30 minutes, rotary evaporation to obtain a nicotinic acid xanthinol inclusion complex, then adding a modified disintegrant, continuing stirring for 12-16 minutes, drying, adjusting the tablet weight, and tableting to obtain a nicotinic acid xanthinol pharmaceutical composition.

[0006] Preferably, the coating solution is prepared by mixing the functionalized inclusion compound, medicinal ethanol and purified water in a mass ratio of 1-2:70:6-10.

[0007] Preferably, the modified disintegrant is prepared by mixing a modified disintegrant, medicinal ethanol and purified water in a mass ratio of 1-2:60:30-40.

[0008] Preferably, the filler is at least one of sucrose, glucose and starch.

[0009] Preferably, the flavoring agent is at least one of mannitol, sorbitol and aspartame.

[0010] Preferably, the lubricant is at least one of magnesium stearate, talc and polyethylene glycol.

[0011] Preferably, the functionalized inclusion compound is prepared by the following steps: Step A1, adding cellulose acetate to N-methylpyrrolidone, heating to 64-76°C, stirring for 1.2-2.4h, continuing to heat to 82-94°C, and then dripping a mixed solution a of octenyl succinic anhydride, sodium acetate and N-methylpyrrolidone, and controlling the dripping to be completed within 30min. After the dripping is completed, the mixture is kept warm for reaction for 6-8h. After the reaction is completed, the pH is adjusted to neutral, washed, and dried to obtain a carboxyl monomer, wherein the mass ratio of cellulose acetate, N-methylpyrrolidone and mixed solution a is 4-6:90-100:45-55, and the mass ratio of octenyl succinic anhydride, sodium acetate and N-methylpyrrolidone in the mixed solution a is 6-8:2-3:30-40. In the above reaction process, acetic acid is used as a solvent, and the active hydroxyl groups on the cellulose acetate react with the octenyl succinic anhydride to undergo a ring-opening esterification reaction to obtain a carboxyl monomer; Step A2, add the carboxyl monomer to anhydrous ethanol, heat it to 36-40°C, stir evenly, and dropwise add a mixed solution b of aminoethyl chitosan, 4-lutidine and anhydrous ethanol while stirring, and control the dripping to be completed within 30 minutes. After the dripping is completed, heat it to reflux, continue to stir and react for 6-8 hours. After the reaction is completed, cool it to room temperature, and rotary evaporate to obtain an amide monomer, wherein the mass ratio of the carboxyl monomer, anhydrous ethanol and the mixed solution b is 2.6-3.4:50-60:22-26, and in the mixed solution b, aminoethyl chitosan, 4-lutidine and anhydrous ethanol are 2.6-3.4:50-60:22-26. The mass ratio of chitosan, 4-lutidine and anhydrous ethanol is 1.4-1.8:0.02-0.06:20-24. In the above reaction process, anhydrous ethanol is used as a solvent, and the carboxyl group on the carboxyl monomer undergoes an amidation reaction with the amino group on the aminoethyl chitosan to obtain an amide monomer. The introduction of the aminoethyl group into the chitosan increases the amino content in the skeleton. A part of the amino group in the aminoethyl chitosan can be used as a reaction site for amidation with the carboxyl monomer, and the other part is retained, thereby improving the hydrophilicity of the amide monomer. Step A3, adding an amide monomer to anhydrous ethanol, heating to 52-60°C, stirring evenly, then adding azobisisobutyronitrile, heating to reflux, continuing stirring to react for 6-8h, filtering, washing the filter cake, and drying to obtain a functionalized inclusion compound, wherein the mass ratio of the amide monomer, anhydrous ethanol and azobisisobutyronitrile is 2.4-2.8:42-54:0.02-0.04. In the above process, anhydrous ethanol is used as a solvent and azobisisobutyronitrile is used as an initiator, and the unsaturated double bonds on the amide monomer undergo free radical polymerization to obtain a functionalized inclusion compound.

[0012] Preferably, the modified disintegrant is prepared by the following steps: Step B1, mixing microcrystalline cellulose and sulfuric acid solution evenly, heating to 55-65°C, continuing to stir and react for 2-3h, adding deionized water, standing for 4-6h, precipitating, removing the supernatant, centrifuging and dialyzing the remaining suspension to neutrality, and drying to obtain cellulose nanocrystals, wherein the mass ratio of microcrystalline cellulose, sulfuric acid solution and deionized water is 1:20-24:12-16. In the above reaction process, microcrystalline cellulose is used as a raw material and sulfuric acid solution is used as an acidifier. After acidification, cellulose nanocrystals are obtained, and the surface area and dispersibility of the microcrystalline cellulose are increased by acidification; Step B2, cellulose nanocrystals are dissolved in a sodium hydroxide aqueous solution, the temperature is raised to 45-55° C., a mixed solution c of chloroacetic acid and deionized water is added dropwise, and the dripping is controlled to be completed within 30 minutes. After the dripping is completed, the temperature is raised to 60-70° C., and the stirring reaction is continued for 4-6 hours. After the reaction is completed, the pH is adjusted to neutral, methanol is added for precipitation, the mixture is allowed to stand, centrifuged, washed, and dried to obtain a modified disintegrant, wherein the mass ratio of cellulose nanocrystals, sodium hydroxide solution, mixed solution c and methanol is 8-16:180-220:50:36-42, and the mass ratio of chloroacetic acid to deionized water in the mixed solution c is 2-4:50. In the above reaction process, under alkaline conditions, the active hydroxyl groups on the cellulose nanocrystals undergo acylation reaction with chloroacetic acid, and then undergo alcoholysis reaction with methanol to obtain a modified disintegrant.

[0013] Preferably, in step B1, the mass fraction of the sulfuric acid solution is 66-68%.

[0014] Preferably, in step B1, the number of centrifugation is 3-5 times, the centrifugal speed is 8000-10000 rpm, the centrifugal time is 10-12 min, and the centrifugal temperature is 0-10°C. Preferably, in step B1, the molecular weight cutoff of the dialysis bag is 12000-14000Da, and the dialysate is water.

[0015] Preferably, in step B2, the mass fraction of the sodium hydroxide aqueous solution is 24-28%.

[0016] Preferably, the nicotinic acid xanthinol pharmaceutical composition prepared by the preparation method is used in the preparation of products for treating cardiovascular and cerebrovascular diseases. In summary, the present application has the following beneficial effects: In order to solve the problems existing in the existing nicotinic acid xanthinol tablets, the present application starts from two aspects. First, a modified disintegrant is added. The modified disintegrant not only contains a cellulose nanocrystal structure, but also contains a carboxymethyl structure. The presence of the carboxymethyl structure can form a more stable solvation structure with the nicotinic acid xanthinol pharmaceutical composition, thereby improving its dissolution performance. At the same time, the cellulose nanocrystal structure not only has a large specific surface area and is easy to absorb water and swell, but also has good adsorption, which helps the cellulose nanocrystals to be closely combined with the nicotinic acid xanthinol and promote the disintegration and release of the nicotinic acid xanthinol when encountering moisture. Second, a functionalized inclusion compound is added. The functionalized inclusion compound The product is prepared by a cyclic esterification reaction between cellulose acetate and octenyl succinic anhydride, an amidation reaction with aminoethyl chitosan, and a free radical polymerization reaction under the action of an initiator. The prepared functionalized inclusion compound contains amino and hydroxyl functional groups, which can not only form hydrogen bonds with the nicotinic acid xanthinol inclusion compound, but also the flexible long-chain alkanes on the functionalized inclusion compound can be entangled with the alkyl chains on the modified disintegrant, thereby wrapping the nicotinic acid xanthinol inclusion compound inside the functionalized inclusion compound, which improves the coating performance of the nicotinic acid xanthinol pharmaceutical composition and avoids the rapid release of drug components after the nicotinic acid xanthinol tablets disintegrate, resulting in drastic fluctuations in blood drug concentration and affecting the heart. DETAILED DESCRIPTION

[0017] In order to make the implementation methods of the present application easier to understand, the present application will be described in detail below in conjunction with specific examples. These examples are only for illustration and are not limited to the scope of application of the present application.

[0018] Preparation Examples 1-3 and Comparative Preparation Examples 1-2 provide a functionalized inclusion compound.

[0019] Preparation Example 1 This preparation example provides a functionalized inclusion compound, which is prepared by the following steps: Step A1, adding cellulose acetate to N-methylpyrrolidone, heating to 64°C, controlling the rotation speed to 450rpm, stirring for 1.2h, continuing to heat to 82°C, and then dripping a mixed solution a of octenyl succinic anhydride, sodium acetate and N-methylpyrrolidone, controlling the dripping to be completed within 30min, and keeping the temperature to react for 6h. After the reaction, adjusting the pH to neutral with 0.7M hydrochloric acid aqueous solution, washing with anhydrous ethanol and deionized water for 3 times in sequence, and drying at 50°C to constant weight to obtain a carboxyl monomer, wherein the mass ratio of cellulose acetate, N-methylpyrrolidone and mixed solution a is 4:90:45, and the mass ratio of octenyl succinic anhydride, sodium acetate and N-methylpyrrolidone in the mixed solution a is 6:2:30; Step A2, adding a carboxyl monomer to anhydrous ethanol, heating to 36°C, stirring at a speed of 550rpm for 35min until uniform, heating to 40°C, adding a mixed solution b of aminoethyl chitosan, 4-lutidine and anhydrous ethanol dropwise while stirring, and controlling the dripping to be completed within 30min. After the dripping is completed, heating to reflux, maintaining the speed unchanged, and continuing to stir and react for 6h. After the reaction is completed, cooling to room temperature, and rotary evaporating at 55°C to constant weight to obtain a functionalized inclusion compound, wherein the mass ratio of the carboxyl monomer, anhydrous ethanol and the mixed solution b is 2.6:50:22, and the mass ratio of aminoethyl chitosan, 4-lutidine and anhydrous ethanol in the mixed solution b is 1.4:0.02:20; Step A3, add the amide monomer to anhydrous ethanol, heat to 52°C, stir at a speed of 700 rpm for 18 minutes until uniform, then add azobisisobutyronitrile, heat to reflux, maintain the speed unchanged, continue stirring to react for 6 hours, filter, wash the filter cake three times with a mass fraction of 35% ethanol aqueous solution, and dry at 60°C to constant weight to obtain a functionalized inclusion complex, wherein the mass ratio of the amide monomer, anhydrous ethanol and azobisisobutyronitrile is 2.4:42:0.02.

[0020] Preparation Example 2 This preparation example provides a functionalized inclusion compound, which is prepared by the following steps: Step A1, adding cellulose acetate to N-methylpyrrolidone, heating to 70°C, controlling the rotation speed to 500rpm, stirring for 1.8h, continuing to heat to 88°C, and then dripping a mixed solution a of octenylsuccinic anhydride, sodium acetate and N-methylpyrrolidone, controlling the dripping to be completed within 30min, and keeping the temperature for reaction for 7h. After the reaction, adjusting the pH to neutral with 0.7M hydrochloric acid aqueous solution, washing with anhydrous ethanol and deionized water for 4 times in sequence, and drying at 55°C to constant weight to obtain a carboxyl monomer, wherein the mass ratio of cellulose acetate, N-methylpyrrolidone and mixed solution a is 5:95:50, and the mass ratio of octenylsuccinic anhydride, sodium acetate and N-methylpyrrolidone in the mixed solution a is 7:2.5:35; Step A2, adding a carboxyl monomer to anhydrous ethanol, heating to 38°C, stirring at a speed of 600rpm for 30min until uniform, heating to 45°C, and dropping a mixed solution b of aminoethyl chitosan, 4-lutidine and anhydrous ethanol while stirring, and controlling the dripping to be completed within 30min. After the dripping is completed, the temperature is raised to reflux, the speed is maintained unchanged, and the stirring reaction is continued for 7h. After the reaction is completed, the temperature is cooled to room temperature, and the mixture is evaporated at 60°C to a constant weight to obtain a functionalized inclusion compound, wherein the mass ratio of the carboxyl monomer, anhydrous ethanol and the mixed solution b is 3.0:55:24, and the mass ratio of aminoethyl chitosan, 4-lutidine and anhydrous ethanol in the mixed solution b is 1.6:0.04:22; Step A3, add the amide monomer to anhydrous ethanol, heat to 56°C, stir at a speed of 750 rpm for 20 min until uniform, then add azobisisobutyronitrile, heat to reflux, maintain the speed unchanged, continue stirring to react for 7 hours, filter, wash the filter cake with a 40% mass fraction of ethanol aqueous solution 4 times, and dry at 65°C to constant weight to obtain a functionalized inclusion complex, wherein the mass ratio of the amide monomer, anhydrous ethanol and azobisisobutyronitrile is 2.6:48:0.03.

[0021] Preparation Example 3 This preparation example provides a functionalized inclusion compound, which is prepared by the following steps: Step A1, adding cellulose acetate to N-methylpyrrolidone, heating to 76°C, controlling the speed to 500rpm and stirring for 2.4h, continuing to heat to 94°C, and then dripping a mixed solution a of octenyl succinic anhydride, sodium acetate and N-methylpyrrolidone, controlling the dripping to be completed within 30min, and keeping the temperature for reaction for 8h. After the reaction, adjusting the pH to neutral with 0.8M hydrochloric acid aqueous solution, washing with anhydrous ethanol and deionized water for 5 times in sequence, and drying at 60°C to constant weight to obtain a carboxyl monomer, wherein the mass ratio of cellulose acetate, N-methylpyrrolidone and mixed solution a is 6:100:55, and the mass ratio of octenyl succinic anhydride, sodium acetate and N-methylpyrrolidone in the mixed solution a is 8:3:40; Step A2, adding a carboxyl monomer to anhydrous ethanol, heating to 40°C, controlling the speed to 650rpm and stirring for 25min until uniform, heating to 50°C, and dropping a mixed solution b of aminoethyl chitosan, 4-lutidine and anhydrous ethanol while stirring, and controlling the dripping to be completed within 30min. After the dripping is completed, the temperature is raised to reflux, the speed is maintained unchanged, and the stirring reaction is continued for 8h. After the reaction is completed, the temperature is cooled to room temperature, and the mixture is evaporated to constant weight at 65°C to obtain a functionalized inclusion compound, wherein the mass ratio of the carboxyl monomer, anhydrous ethanol and the mixed solution b is 3.4:60:26, and the mass ratio of aminoethyl chitosan, 4-lutidine and anhydrous ethanol in the mixed solution b is 1.8:0.06:24; Step A3, add the amide monomer to anhydrous ethanol, heat to 60°C, stir at a speed of 800 rpm for 22 minutes until uniform, then add azobisisobutyronitrile, heat to reflux, maintain the speed unchanged, continue stirring to react for 8 hours, filter, wash the filter cake with a mass fraction of 45% ethanol aqueous solution 5 times, and dry at 70°C to constant weight to obtain a functionalized inclusion complex, wherein the mass ratio of the amide monomer, anhydrous ethanol and azobisisobutyronitrile is 2.8:54:0.04.

[0022] Comparative Preparation Example 1 This comparative preparation example provides a functionalized inclusion compound, which is prepared by the following steps: Step A1, adding cellulose acetate to N-methylpyrrolidone, heating to 64°C, controlling the rotation speed to 450rpm, stirring for 1.2h, continuing to heat to 82°C, and then dripping a mixed solution a of maleic anhydride, sodium acetate and N-methylpyrrolidone, controlling the dripping to be completed within 30min, and keeping the temperature for reaction for 6h. After the reaction, adjusting the pH to neutral with 0.7M hydrochloric acid aqueous solution, washing with anhydrous ethanol and deionized water for 3 times in sequence, and drying at 50°C to constant weight to obtain a carboxyl monomer, wherein the mass ratio of cellulose acetate, N-methylpyrrolidone and mixed solution a is 4:90:45, and the mass ratio of maleic anhydride, sodium acetate and N-methylpyrrolidone in the mixed solution a is 6:2:30; Step A2, adding a carboxyl monomer to anhydrous ethanol, heating to 36°C, stirring at a speed of 550rpm for 35min until uniform, heating to 40°C, adding a mixed solution b of aminoethyl chitosan, 4-lutidine and anhydrous ethanol dropwise while stirring, and controlling the dripping to be completed within 30min. After the dripping is completed, heating to reflux, maintaining the speed unchanged, and continuing to stir and react for 6h. After the reaction is completed, cooling to room temperature, and rotary evaporating at 55°C to constant weight to obtain a functionalized inclusion compound, wherein the mass ratio of the carboxyl monomer, anhydrous ethanol and the mixed solution b is 2.6:50:22, and the mass ratio of aminoethyl chitosan, 4-lutidine and anhydrous ethanol in the mixed solution b is 1.4:0.02:20; Step A3, add the amide monomer to anhydrous ethanol, heat to 52°C, stir at a speed of 700 rpm for 18 minutes until uniform, then add azobisisobutyronitrile, heat to reflux, maintain the speed unchanged, continue stirring to react for 6 hours, filter, wash the filter cake three times with a mass fraction of 35% ethanol aqueous solution, and dry at 60°C to constant weight to obtain a functionalized inclusion complex, wherein the mass ratio of the amide monomer, anhydrous ethanol and azobisisobutyronitrile is 2.4:42:0.02.

[0023] Comparative Preparation Example 2 This comparative preparation example provides a functionalized inclusion compound, which is prepared by the following steps: Step A1, adding cellulose acetate to N-methylpyrrolidone, heating to 64°C, controlling the rotation speed to 450rpm, stirring for 1.2h, continuing to heat to 82°C, and then dripping a mixed solution a of octenyl succinic anhydride, sodium acetate and N-methylpyrrolidone, controlling the dripping to be completed within 30min, and keeping the temperature to react for 6h. After the reaction, adjusting the pH to neutral with 0.7M hydrochloric acid aqueous solution, washing with anhydrous ethanol and deionized water for 3 times in sequence, and drying at 50°C to constant weight to obtain a carboxyl monomer, wherein the mass ratio of cellulose acetate, N-methylpyrrolidone and mixed solution a is 4:90:45, and the mass ratio of octenyl succinic anhydride, sodium acetate and N-methylpyrrolidone in the mixed solution a is 6:2:30; Step A2, adding a carboxyl monomer to anhydrous ethanol, heating to 36°C, stirring at a speed of 550rpm for 35min until uniform, heating to 40°C, and dropping a mixed solution b of chitosan, 4-lutidine and anhydrous ethanol while stirring, and controlling the dripping to be completed within 30min. After the dripping is completed, the temperature is raised to reflux, the speed is maintained unchanged, and the stirring reaction is continued for 6h. After the reaction is completed, the temperature is cooled to room temperature, and the mixture is evaporated at 55°C to a constant weight to obtain a functionalized inclusion compound, wherein the mass ratio of the carboxyl monomer, anhydrous ethanol and the mixed solution b is 2.6:50:22, and the mass ratio of chitosan, 4-lutidine and anhydrous ethanol in the mixed solution b is 1.4:0.02:20; Step A3, add the amide monomer to anhydrous ethanol, heat to 52°C, stir at a speed of 700 rpm for 18 minutes until uniform, then add azobisisobutyronitrile, heat to reflux, maintain the speed unchanged, continue stirring to react for 6 hours, filter, wash the filter cake three times with a mass fraction of 35% ethanol aqueous solution, and dry at 60°C to constant weight to obtain a functionalized inclusion complex, wherein the mass ratio of the amide monomer, anhydrous ethanol and azobisisobutyronitrile is 2.4:42:0.02.

[0024] Preparation Examples 4-6 and Comparative Preparation Example 3 provide a modified disintegrant.

[0025] Preparation Example 4 This preparation example provides a modified disintegrant, which is prepared by the following steps: Step B1, stirring microcrystalline cellulose and 66% sulfuric acid solution at a speed of 500 rpm for 30 minutes until uniform, heating to 55°C, maintaining the speed unchanged, continuing stirring and reacting for 2 hours, adding deionized water, standing for 4 hours, precipitating, removing the supernatant, and centrifuging the remaining suspension at a speed of 8000 rpm and a temperature of 0°C for 3 times, each time for 10 minutes, and then pouring it into a dialysis bag with a molecular weight of 12000Da, dialyzing with deionized water until the suspension is neutral, and drying at 50°C to constant weight to obtain cellulose nanocrystals, wherein the mass ratio of microcrystalline cellulose, 66% sulfuric acid solution and deionized water is 1:20:12; Step B2, cellulose nanocrystals are dissolved in a sodium hydroxide aqueous solution with a mass fraction of 24%, the temperature is raised to 45°C, and a mixed solution c of chloroacetic acid and deionized water is added dropwise, and the dripping is controlled within 30 minutes. After the dripping is completed, the temperature is raised to 60°C, and the reaction is stirred at a speed of 600rpm for 4 hours. After the reaction is completed, the pH is adjusted to neutral with a 0.8M acetic acid aqueous solution, methanol is added to precipitate, and the mixture is allowed to stand for 1 hour, centrifuged, and then washed 3 times with a 40% ethanol aqueous solution by mass fraction, and dried at 55°C to constant weight to obtain a modified disintegrant, wherein the mass ratio of cellulose nanocrystals, sodium hydroxide solution, mixed solution c and methanol is 8:180:50:36, and the mass ratio of chloroacetic acid and deionized water in the mixed solution c is 2:50.

[0026] Preparation Example 5 This preparation example provides a modified disintegrant, which is prepared by the following steps: Step B1, stirring microcrystalline cellulose and 67% sulfuric acid solution at a speed of 550 rpm for 25 min until uniform, heating to 60°C, maintaining the speed unchanged, continuing stirring and reacting for 2.5 h, adding deionized water, standing for 5 h, precipitating, removing the supernatant, and centrifuging the remaining suspension at a speed of 9000 rpm and a temperature of 5°C for 4 times, each time for 15 min, and then pouring it into a dialysis bag with a molecular weight of 13000 Da, dialyzing with deionized water until the suspension is neutral, and drying at 55°C to constant weight to obtain cellulose nanocrystals, wherein the mass ratio of microcrystalline cellulose, 67% sulfuric acid solution and deionized water is 1:22:14; Step B2, cellulose nanocrystals are dissolved in a sodium hydroxide aqueous solution with a mass fraction of 26%, the temperature is raised to 50°C, and a mixed solution c of chloroacetic acid and deionized water is added dropwise, and the dripping is controlled within 30 minutes. After the dripping is completed, the temperature is raised to 65°C, and the reaction is stirred at a speed of 650rpm for 5 hours. After the reaction is completed, the pH is adjusted to neutral with a 1.0M acetic acid aqueous solution, methanol is added to precipitate, and the mixture is allowed to stand for 1.5 hours. Centrifugation, and then washed 4 times with a 45% ethanol aqueous solution by mass fraction, and dried at 60°C to constant weight to obtain a modified disintegrant, wherein the mass ratio of cellulose nanocrystals, sodium hydroxide solution, mixed solution c and methanol is 12:200:50:39, and the mass ratio of chloroacetic acid and deionized water in the mixed solution c is 3:50.

[0027] Preparation Example 6 This preparation example provides a modified disintegrant, which is prepared by the following steps: Step B1, stirring microcrystalline cellulose and 68% sulfuric acid solution at a speed of 600 rpm for 20 minutes until uniform, heating to 65°C, continuing stirring and reacting for 3 hours, adding deionized water, standing for 6 hours, precipitating, removing the supernatant, and centrifuging the remaining suspension at a speed of 10000 rpm and a temperature of 10°C for 5 times, each time for 20 minutes, and then pouring it into a dialysis bag with a molecular weight of 14000Da, dialyzing with deionized water until the suspension is neutral, and drying at 60°C to constant weight to obtain cellulose nanocrystals, wherein the mass ratio of microcrystalline cellulose, 68% sulfuric acid solution and deionized water is 1:24:16; Step B2, cellulose nanocrystals are dissolved in a sodium hydroxide aqueous solution with a mass fraction of 28%, the temperature is raised to 55°C, and a mixed solution c of chloroacetic acid and deionized water is added dropwise, and the dripping is controlled within 30 minutes. After the dripping is completed, the temperature is raised to 70°C, and the reaction is stirred at a speed of 700rpm for 6 hours. After the reaction is completed, the pH is adjusted to neutral with a 1.2M acetic acid aqueous solution, methanol is added to precipitate, and the mixture is allowed to stand for 2.0 hours. Centrifugation, and then washed 5 times with a 50% ethanol aqueous solution by mass fraction, and dried at 65°C to constant weight to obtain a modified disintegrant, wherein the mass ratio of cellulose nanocrystals, sodium hydroxide solution, mixed solution c and methanol is 16:220:50:42, and the mass ratio of chloroacetic acid and deionized water in the mixed solution c is 4:50.

[0028] Comparative Preparation Example 3 This comparative preparation example provides a modified disintegrant, which is prepared by the following steps: Step B1, stirring microcrystalline cellulose and 66% sulfuric acid solution at a speed of 500 rpm for 30 minutes until uniform, heating to 55°C, maintaining the speed unchanged, continuing stirring and reacting for 2 hours, adding deionized water, standing for 4 hours, precipitating, removing the supernatant, and centrifuging the remaining suspension at a speed of 8000 rpm and a temperature of 0°C for 3 times, each time for 10 minutes, and then pouring it into a dialysis bag with a molecular weight of 12000Da, dialyzing with deionized water until the suspension is neutral, and drying at 50°C to constant weight to obtain cellulose nanocrystals, wherein the mass ratio of microcrystalline cellulose, 66% sulfuric acid solution and deionized water is 1:20:12; Step B2, cellulose nanocrystals are dissolved in a sodium hydroxide aqueous solution with a mass fraction of 24%, the temperature is raised to 45°C, and a mixed solution c of acetic acid and deionized water is added dropwise, and the dripping is controlled within 30 minutes. After the dripping is completed, the temperature is raised to 60°C, and the reaction is stirred at a speed of 600rpm for 4 hours. After the reaction is completed, the pH is adjusted to neutral with a 0.8M acetic acid aqueous solution, methanol is added for precipitation, and the mixture is allowed to stand for 1 hour. Centrifugation, the filter cake is then washed 3 times with a 40% ethanol aqueous solution by mass fraction, and dried at 55°C to constant weight to obtain a modified disintegrant, wherein the mass ratio of cellulose nanocrystals, sodium hydroxide solution, mixed solution c and methanol is 8:180:50:36, and the mass ratio of acetic acid to deionized water in the mixed solution c is 2:50.

[0029] Example 1-3 and Comparative Example 1-3 provide a method for preparing a xanthinol nicotinic acid pharmaceutical composition.

[0030] Example 1 This embodiment provides a method for preparing a nicotinate xanthinol pharmaceutical composition, comprising the following steps: Step S1, preparing the following raw materials in parts by weight: 6.2 parts of nicotinate xanthinol, 86 parts of purified water, 16 parts of sucrose, 64 parts of coating solution, 14 parts of mannitol, 42 parts of modified disintegrant and 2 parts of magnesium stearate, wherein the coating solution is prepared by mixing the functionalized inclusion compound prepared in Preparation Example 1, medicinal ethanol and purified water in a mass ratio of 1:70:6; the modified disintegrant is prepared by mixing the modified disintegrant prepared in Preparation Example 4, medicinal ethanol and purified water in a mass ratio of 1:60:30; Step S2, preparation of a nicotinic acid xanthinol pharmaceutical composition: add nicotinic acid xanthinol, mannitol, sucrose and magnesium stearate to purified water, control the speed to 400 rpm and stir for 25 minutes until dissolved, add the coating solution, maintain the speed unchanged, continue stirring for 20 minutes, control the rotary evaporation temperature to 50°C, rotary evaporation to remove purified water to obtain a nicotinic acid xanthinol inclusion complex, then add the modified disintegrant, continue stirring for 12 minutes, dry at 45°C to constant weight, adjust the tablet weight, and press the tablets to obtain a nicotinic acid xanthinol pharmaceutical composition.

[0031] Example 2 This embodiment provides a method for preparing a nicotinate xanthinol pharmaceutical composition, comprising the following steps: Step S1, preparing the following raw materials in parts by weight: 6.9 parts of nicotinate xanthinol, 92 parts of purified water, 19 parts of glucose, 70 parts of functionalized inclusion compound, 17 parts of sorbitol, 48 parts of modified disintegrant and 3 parts of talc, wherein the coating liquid is prepared by mixing the functionalized inclusion compound prepared in Preparation Example 2, medicinal ethanol and purified water in a mass ratio of 1.5:70:8; the modified disintegrant is prepared by mixing the modified disintegrant prepared in Preparation Example 5, medicinal ethanol and purified water in a mass ratio of 1.5:60:35; Step S2, preparation of a nicotinic acid xanthinol pharmaceutical composition: adding nicotinic acid xanthinol, sorbitol, glucose and talc to purified water, stirring for 20 minutes at a speed controlled to 450 rpm until dissolved, adding a coating solution, maintaining the speed unchanged, continuing to stir for 25 minutes, controlling the rotary evaporation temperature to 55° C., rotary evaporation to remove purified water to obtain a nicotinic acid xanthinol inclusion complex, then adding a modified disintegrant, continuing to stir for 14 minutes, drying at 50° C. to a constant weight, adjusting the tablet weight, and tableting to obtain a nicotinic acid xanthinol pharmaceutical composition.

[0032] Example 3 This embodiment provides a method for preparing a nicotinate xanthinol pharmaceutical composition, comprising the following steps: Step S1, preparing the following raw materials in parts by weight: 7.6 parts of nicotinate xanthinol, 98 parts of purified water, 22 parts of sucrose, 76 parts of coating solution, 20 parts of aspartame, 54 parts of modified disintegrant and 4 parts of polyethylene glycol, wherein the coating solution is prepared by mixing the functionalized inclusion compound prepared in Preparation Example 3, medicinal ethanol and purified water in a mass ratio of 2:70:10; the modified disintegrant is prepared by mixing the modified disintegrant prepared in Preparation Example 6, medicinal ethanol and purified water in a mass ratio of 2:60:40; Step S2, preparation of a nicotinic acid xanthinol pharmaceutical composition: adding nicotinic acid xanthinol, aspartame, sucrose and polyethylene glycol to purified water, stirring for 15 minutes at a speed of 500 rpm until dissolved, adding a coating solution, maintaining the speed unchanged, and continuing to stir for 30 minutes, controlling the rotary evaporation temperature to 60° C., rotary evaporating until purified water is removed to obtain a nicotinic acid xanthinol inclusion complex, then adding a modified disintegrant, continuing to stir for 16 minutes, drying at 55° C. to a constant weight, adjusting the tablet weight, and tableting to obtain a nicotinic acid xanthinol pharmaceutical composition.

[0033] Comparative Example 1 This comparative example provides a method for preparing a nicotinate xanthinol pharmaceutical composition, comprising the following steps: Step S1, preparing the following raw materials in parts by weight: 6.2 parts of nicotinate xanthinol, 86 parts of purified water, 16 parts of sucrose, 64 parts of coating solution, 14 parts of mannitol, 42 parts of modified disintegrant and 2 parts of magnesium stearate, wherein the coating solution is prepared by mixing the functionalized inclusion compound prepared in Comparative Preparation Example 1, medicinal ethanol and purified water in a mass ratio of 1:70:6; the modified disintegrant is prepared by mixing the modified disintegrant prepared in Preparation Example 4, medicinal ethanol and purified water in a mass ratio of 1:60:30; Step S2, preparation of a nicotinic acid xanthinol pharmaceutical composition: add nicotinic acid xanthinol, mannitol, sucrose and magnesium stearate to purified water, control the speed to 400 rpm and stir for 25 minutes until dissolved, add the coating solution, maintain the speed unchanged, continue stirring for 20 minutes, control the rotary evaporation temperature to 50°C, rotary evaporation to remove purified water to obtain a nicotinic acid xanthinol inclusion complex, then add the modified disintegrant, continue stirring for 12 minutes, dry at 45°C to constant weight, adjust the tablet weight, and press the tablets to obtain a nicotinic acid xanthinol pharmaceutical composition.

[0034] Comparative Example 2 This comparative example provides a method for preparing a nicotinate xanthinol pharmaceutical composition, comprising the following steps: Step S1, preparing the following raw materials in parts by weight: 6.2 parts of nicotinate xanthinol, 86 parts of purified water, 16 parts of sucrose, 64 parts of coating solution, 14 parts of mannitol, 42 parts of modified disintegrant and 2 parts of magnesium stearate, wherein the coating solution is prepared by mixing the functionalized inclusion compound prepared in Comparative Preparation Example 2, medicinal ethanol and purified water in a mass ratio of 1:70:6; the modified disintegrant is prepared by mixing the modified disintegrant prepared in Preparation Example 4, medicinal ethanol and purified water in a mass ratio of 1:60:30; Step S2, preparation of a nicotinic acid xanthinol pharmaceutical composition: add nicotinic acid xanthinol, mannitol, sucrose and magnesium stearate to purified water, control the speed to 400 rpm and stir for 25 minutes until dissolved, add the coating solution, maintain the speed unchanged, continue stirring for 20 minutes, control the rotary evaporation temperature to 50°C, rotary evaporation to remove purified water to obtain a nicotinic acid xanthinol inclusion complex, then add the modified disintegrant, continue stirring for 12 minutes, dry at 45°C to constant weight, adjust the tablet weight, and press the tablets to obtain a nicotinic acid xanthinol pharmaceutical composition.

[0035] Comparative Example 3 This comparative example provides a method for preparing a nicotinate xanthinol pharmaceutical composition, comprising the following steps: Step S1, preparing the following raw materials in parts by weight: 6.2 parts of nicotinate xanthinol, 86 parts of purified water, 16 parts of sucrose, 64 parts of coating solution, 14 parts of mannitol, 42 parts of modified disintegrant and 2 parts of magnesium stearate, wherein the coating solution is prepared by mixing the functionalized inclusion compound prepared in Preparation Example 1, medicinal ethanol and purified water in a mass ratio of 1:70:6; the modified disintegrant is prepared by mixing the modified disintegrant prepared in Comparative Preparation Example 3, medicinal ethanol and purified water in a mass ratio of 1:60:30; Step S2, preparation of a nicotinic acid xanthinol pharmaceutical composition: add nicotinic acid xanthinol, mannitol, sucrose and magnesium stearate to purified water, control the speed to 400 rpm and stir for 25 minutes until dissolved, add the coating solution, maintain the speed unchanged, continue stirring for 20 minutes, control the rotary evaporation temperature to 50°C, rotary evaporation to remove purified water to obtain a nicotinic acid xanthinol inclusion complex, then add the modified disintegrant, continue stirring for 12 minutes, dry at 45°C to constant weight, adjust the tablet weight, and press the tablets to obtain a nicotinic acid xanthinol pharmaceutical composition.

[0036] Performance Testing 1. Drug inclusion rate test The inclusion rates of the nicotinic acid xanthinol pharmaceutical compositions prepared in Examples 1-3 of the present application and Comparative Examples 1-3 were tested respectively.

[0037] Accurately weigh 10 mg of the nicotinic acid Xanthinol pharmaceutical composition into a small beaker, add 6 mL of deionized water to dissolve it, then pour it into a 10 mL volumetric flask, add artificial intestinal fluid to the scale, make up to volume, and then place it at the optimal absorption wavelength of 210 nm to measure its absorbance (A) with a UV-visible spectrophotometer. The inclusion rate of the inclusion complex is calculated according to the standard curve method. The specific test results are shown in Table 1 below, wherein the preparation method of artificial intestinal fluid is as follows: Take 6.8g of potassium dihydrogen phosphate, add 500mL of water to dissolve it, adjust the pH value to 6.8 with 0.1M sodium hydroxide solution, take 10g of pancreatic enzyme, add 80mL of water to dissolve it, mix the two liquids, and dilute with water to 1000mL to obtain artificial intestinal fluid. The above test results are shown in Table 1: Table 1 Inclusion rate test of nicotinic acid xanthinol pharmaceutical composition

[0038] It can be seen from the data that in terms of inclusion rate: in the preparation process of the functionalized inclusion compound in Comparative Example 1, octenyl succinic anhydride was replaced with maleic anhydride, and the inclusion rate decreased compared with that in Example 1, indicating that the flexible long-chain alkane on the octenyl succinic anhydride can be entangled with the alkyl chain on the modified disintegrant, thereby improving the coating performance of the nicotinic acid tintinoxate pharmaceutical composition; in Comparative Example 2, in the preparation process of the functionalized inclusion compound, aminoethyl chitosan was replaced with chitosan, and the inclusion rate decreased compared with that in Example 1, indicating that aminoethyl chitosan has more hydrophilic groups that can form hydrogen bonds with the modified disintegrant, thereby improving the coating performance of the nicotinic acid tintinoxate pharmaceutical composition; in Comparative Example 3, in the preparation process of the modified disintegrant, chloroacetic acid was replaced with acetic acid, and the inclusion rate decreased compared with that in Example 1, indicating that the carboxymethyl structure on the modified disintegrant can form hydrogen bonds with the amino and hydroxyl groups on the functionalized inclusion compound, thereby improving the coating performance of the nicotinic acid tintinoxate pharmaceutical composition.

[0039] In summary, it can be seen that the inclusion rate of the nicotinic acid xanthinol pharmaceutical composition prepared in Examples 1-3 of the present application is significantly higher than that of Comparative Examples 1-3.

[0040] 2. Disintegration time test Disintegration time test: According to the 2015 edition of the Pharmacopoeia of the People's Republic of China, Part IV, General Rule 0921, the nicotinic acid tintinoxate pharmaceutical composition prepared in Example 1-3 and Comparative Example 1-3 was tested by the disintegration time limit detection method (basket type). One tablet per tube, add a baffle, start the disintegration instrument for testing, record the disintegration time of each tablet of the nicotinic acid tintinoxate pharmaceutical composition, and take the average value. All nicotinic acid tintinoxate pharmaceutical compositions should be completely disintegrated within 1 hour. The test results are shown in Table 2 below: Table 2 Disintegration time test of nicotinic acid xanthinol pharmaceutical composition

[0041] It can be seen from the data that in terms of disintegration time: in Comparative Example 1, during the preparation of the functionalized inclusion compound, octenyl succinic anhydride was replaced with maleic anhydride, and the disintegration time was longer than that in Example 1, indicating that the flexible long-chain alkane on octenyl succinic anhydride can be entangled with the alkyl chain on the modified disintegrant, which is not conducive to the disintegration of nicotinic acid; in Comparative Example 2, during the preparation of the functionalized inclusion compound, aminoethyl chitosan was replaced with chitosan, and the disintegration time was longer than that in Example 1, indicating that aminoethyl chitosan has more hydrophilic groups that can form hydrogen bonds with the modified disintegrant, which is not conducive to the disintegration of nicotinic acid; in Comparative Example 3, during the preparation of the modified disintegrant, chloroacetic acid was replaced with acetic acid, and the disintegration time was longer than that in Example 1, indicating that the carboxymethyl structure on the modified disintegrant can form hydrogen bonds with the amino and hydroxyl groups on the functionalized inclusion compound, which is not conducive to the disintegration of nicotinic acid.

[0042] 3. Release Test Referring to the Chinese Pharmacopoeia 2020 edition, Part IV, General Rule 0931 Dissolution and Dissolution Determination Method (First Method), the speed was 100 rpm, in a pH 6.8 phosphate buffer dissolution medium, the nicotinic acid xanthinol pharmaceutical composition prepared in Example 1-3 and Comparative Example 1-3 was subjected to release determination, and sampling and detection were performed at 2h, 4h, 8h and 12h, respectively. The test results are shown in Table 3 below; Table 3 Release test of nicotinate xanthinol pharmaceutical composition

[0043] It can be seen from the data that in terms of release: in the preparation process of the functionalized inclusion compound in Comparative Example 1, octenyl succinic anhydride was replaced with maleic anhydride, and the release was higher than that in Example 1, indicating that the flexible long-chain alkane on octenyl succinic anhydride can be entangled with the alkyl chain on the modified disintegrant, thereby slowing down the drug release of the nicotinic acid tintinoxate pharmaceutical composition; in the preparation process of the functionalized inclusion compound in Comparative Example 2, aminoethyl chitosan was replaced with chitosan, and the release was higher than that in Example 1, indicating that aminoethyl chitosan has more hydrophilic groups that can form hydrogen bonds with the modified disintegrant, thereby slowing down the drug release of the nicotinic acid tintinoxate pharmaceutical composition. At the same time, compared with Example 1, The nicotinic acid xanthinol pharmaceutical composition prepared in Comparative Examples 1-2 has a fast drug release rate in the early stage, but its drug release rate gradually slows down with the passage of time, which indicates that the functionalized inclusion compound prepared in the present application has the effect of promoting the smooth release of the drug, avoiding the rapid release of drug components after the disintegration of the nicotinic acid xanthinol tablets, resulting in drastic fluctuations in blood drug concentration and affecting the heart; in the preparation process of the modified disintegrant in Comparative Example 3, chloroacetic acid was replaced by acetic acid, and the release degree was higher than that in Example 1, indicating that the carboxymethyl structure on the modified disintegrant can form hydrogen bonds with the amino and hydroxyl groups on the functionalized inclusion compound, thereby slowing down the drug release of the nicotinic acid xanthinol pharmaceutical composition.

[0044] This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims

1. A method for preparing a nicotinate xanthinol pharmaceutical composition, characterized in that: The following steps are involved: Step S1, preparing the following raw materials in parts by weight: 6.2-7.6 parts of nicotinate xanthinol, 86-98 parts of purified water, 16-22 parts of filler, 64-76 parts of coating solution, 14-20 parts of flavoring agent, 42-54 parts of modified disintegrant and 2-4 parts of lubricant, wherein the coating solution is prepared by mixing the functionalized inclusion compound, medicinal ethanol and purified water in a mass ratio of 1-2:70:6-10, and the modified disintegrant is prepared by mixing the modified disintegrant, medicinal ethanol and purified water in a mass ratio of 1-2:60:30-40; Step S2, preparation of a nicotinic acid xanthinol pharmaceutical composition: adding nicotinic acid xanthinol, a flavoring agent, a filler and a lubricant into purified water, stirring until dissolved, adding a coating solution, continuing stirring for 20-30 minutes, rotary evaporation to obtain a nicotinic acid xanthinol inclusion complex, then adding a modified disintegrant, continuing stirring for 12-16 minutes, drying, adjusting the tablet weight, and tableting to obtain a nicotinic acid xanthinol pharmaceutical composition; The functional inclusion compound is prepared by a ring-opening esterification reaction between cellulose acetate and octenyl succinic anhydride to obtain a carboxyl monomer, which is then subjected to an amidation reaction with aminoethyl chitosan to obtain an amide monomer, and finally subjected to a free radical polymerization reaction under the action of azobisisobutyronitrile. The modified disintegrant is firstly prepared by acidifying microcrystalline cellulose with a sulfuric acid solution to obtain cellulose nanocrystals, which are then further acylated with chloroacetic acid and finally reacted with methanol for alcoholysis.

2. The method for preparing a nicotinate xanthinol pharmaceutical composition according to claim 1, characterized in that: The functionalized inclusion compound is prepared by the following steps: Step A1, adding cellulose acetate to N-methylpyrrolidone, heating to 64-76° C., stirring for 1.2-2.4 hours, continuing to heat to 82-94° C., and then dripping a mixed solution a of octenylsuccinic anhydride, sodium acetate and N-methylpyrrolidone, and controlling the dripping to be completed within 30 minutes. After the dripping is completed, the temperature is kept for reaction for 6-8 hours. After the reaction is completed, the pH is adjusted to neutral, washed, and dried to obtain a carboxyl monomer; Step A2, add the carboxyl monomer to anhydrous ethanol, heat it to 36-40°C, stir evenly, and dropwise add a mixed solution b of aminoethyl chitosan, 4-lutidine and anhydrous ethanol while stirring, and control the dripping to be completed within 30 minutes. After the dripping is completed, heat it to reflux, continue stirring and reacting for 6-8 hours. After the reaction is completed, cool it to room temperature, and rotary evaporate to obtain an amide monomer; Step A3, add the amide monomer to anhydrous ethanol, heat to 52-60°C, stir evenly, then add azobisisobutyronitrile, heat to reflux, continue stirring to react for 6-8h, filter with suction, wash the filter cake, and dry to obtain a functionalized inclusion compound.

3. The method for preparing a nicotinate xanthinol pharmaceutical composition according to claim 2, characterized in that: In the step A1, the mass ratio of cellulose acetate, N-methylpyrrolidone and mixed solution a is 4-6:90-100:45-55, and in the mixed solution a, the mass ratio of octenylsuccinic anhydride, sodium acetate and N-methylpyrrolidone is 6-8:2-3:30-40.

4. The method for preparing a nicotinate xanthinol pharmaceutical composition according to claim 2, characterized in that: In the step A2, the mass ratio of the carboxyl monomer, anhydrous ethanol and the mixed solution b is 2.6-3.4:50-60:22-26, in the mixed solution b, the mass ratio of aminoethyl chitosan, 4-lutidine and anhydrous ethanol is 1.4-1.8:0.02-0.06:20-24, and in the step A3, the mass ratio of the amide monomer, anhydrous ethanol and azobisisobutyronitrile is 2.4-2.8:42-54:0.02-0.

04.

5. The method for preparing a nicotinate xanthinol pharmaceutical composition according to claim 1, characterized in that: The modified disintegrant is prepared by the following steps: Step B1, mix microcrystalline cellulose and sulfuric acid solution evenly, heat to 55-65°C, continue stirring and reacting for 2-3 hours, add deionized water, stand for 4-6 hours, precipitate, remove the supernatant, centrifuge and dialyze the remaining suspension to neutrality, and dry to obtain cellulose nanocrystals; Step B2, cellulose nanocrystals are dissolved in a sodium hydroxide aqueous solution, the temperature is raised to 45-55° C., a mixed solution c of chloroacetic acid and deionized water is added dropwise, and the dripping is controlled to be completed within 30 minutes. After the dripping is completed, the temperature is raised to 60-70° C., and the stirring reaction is continued for 4-6 hours. After the reaction is completed, the pH is adjusted to neutral, methanol is added for precipitation, the mixture is allowed to stand, centrifuged, washed, and dried to obtain a modified disintegrant.

6. The method for preparing a nicotinate xanthinol pharmaceutical composition according to claim 5, characterized in that: In the step B1, the mass ratio of microcrystalline cellulose, sulfuric acid solution and deionized water is 1:20-24:12-16.

7. The method for preparing a nicotinate xanthinol pharmaceutical composition according to claim 5, characterized in that: In step B2, the mass ratio of cellulose nanocrystals, sodium hydroxide solution, mixed solution c and methanol is 8-16:180-220:50:36-42, and in the mixed solution c, the mass ratio of chloroacetic acid and deionized water is 2-4:

50.

8. The method for preparing a nicotinate xanthinol pharmaceutical composition according to claim 1, characterized in that: The filler is at least one of sucrose, glucose and starch, and the flavoring agent is at least one of mannitol, sorbitol and aspartame.

9. The method for preparing a nicotinate xanthinol pharmaceutical composition according to claim 1, characterized in that: The lubricant is at least one of magnesium stearate, talc and polyethylene glycol.

10. Use of the nicotinic acid xanthinol pharmaceutical composition prepared by the preparation method according to any one of claims 1 to 9 in preparing products for treating cardiovascular and cerebrovascular diseases.

Images